Untitled

AR08681
AR08682
AR08683
AR08684
AR08685
Clinical Infectious Diseases
AR08686
BRIEF REPORT ~IDSA
Infectio111 Diaeuu Soci.ety of America
ilif4ht-i
Inv medlom, assoaabon
Circulating Severe Acute Respiratory and induced an immune response [2- 5]. However, critical data
demonstratingthe direct production ofspike protein via transla-
Syndrome Coronavirus 2 (SARS- . ,tio~ from the mRNA-1273 vaccine in these studies are missing,
CoV-2) Vaccine Antigen Detected in pre'cluding a full understanding ofthe vaccine mechanism.
the Plasma of mRNA-1273 Vaccine , Hpe we provide evidenc.e that circulating SARS-CoV-2
proteins are present in the plasma of participants vaccinated
Recipients ~ the mRNA-1273 vaccine. We report antigen and serolog-
1
Ala1111 F. Otata.u.3, Chi-AR Cheag. »~ Michail Desjanlills,'.u.. V--Setnmi.
1 ical'data of the mRNA-1273 vaccine in 13 healthcare workers
Amy C. Shenna.u Me1• P_._. lewisftonck.' Salemt Yon.• Xiaafug U.' at the Brigham and Women's Hospital Ultrasensitive single-
liaaey R. Bade■.•A.IJI - · Danid ~- Well.'.ub
1
molecule array (Simoa) assays were used for the detection of
Depanment of Pathology. Brigham and W11nen's Hospital, Boston, Massachusetts,
USA; 2Wyss Institute for Biologically klspired &gineerilg, Harvard U!lMllsity, Boston. SARS-CoV-2 antigens spike {Sl-S2 unit), Sl, and nucleocapsid
Massachusetts. USA; 3Harvard Medical School. Bostoo. Massachusetts, USA; 'Division of and antibodies immunoglobulin G (IgG), immunoglobulin
lnfecii= Dise.nes, Brigham and Women's Hospital, Boston, Massachusetts. USA; 50ivision
A (IgA), and immunoglobulin M (IgM) against SARS-CoV-2
of '1fectious Diseases, Centre Hospitalier de l'Univeis~ de Montreal, Montreal, Ouebec,
Canada; and 'tenter for Clinical Investigation, Brigham and Women's Hospital, Boston, spike, Sl, rec.eptor binding domain (RBD), and nucleocapsid.
Massachusetts, USA
as previously described [6, 7]. The ultralow detection limits of
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) the Simoa assays enable detection ofantigen and antibody pro-
proteins were measured in longitudinal plasma samples col- duction in the early stages postvaccination and quantification
lected from 13 participants who received two doses of mRNA- of changes in levels over the course of both vaccine injections.
1273 vaccine. Eleven of 13 participants showed detectable levels
ofSARS-CoV-2 protein as early as day 1 after first vaccine injec- MATERIALS AND METHODS
tion. Oearanc.e ofdetectable SA.RS-CoV-2 protein correlated with
A prospective pilot study of 13 healthcare workers, 18 years and
production of immunoglobulin G (IgG) and immunoglobulin
A(IgA). older, with no known history ofSARS-CoV-2 infection was con-
Keywords. COVID-19; mRNA vaccine; SARS-CoV-2 ducted at the Brigham and Women's Hospital from December
antigens; immune responses; spike. 2020 to March 2021.Full description of study design are re-
ported in the Supplementary Materials. SARS-CoV-2 antigens
and antibodies were measured using single-molecule array
Messenger RNA (mRNA) vaccines for coronavirus disease 2019 (Simoa) assays, as described in the Supplemental Materials
(COVID-19) have been widely deployed in the United States (Methods, Supplementary Figure 1, Supplementary Tables 2---4).
and are highly effective at inducing protection against infection
and severe disease [1]. In Dec.ember 2020, the Food and Drug RESULTS
Administration gave emergency use authorization (EUA) to the
Plasma was collected from 13 participants at 10-13 timepoints
mRNA-1273 vaccine (ModemaTX, Inc), as a two 100-µg dose
between 1 and 29 days after the first injection and 1- 28 days
regimen 28 days apart mRNA-1273 encodes the severe acute
after the second injection. There was an equal balance of sex,
respiratory syndrome coronavirus (SARS-CoV-2) spike antigen
median age was 24 years old. and participants from varied ra-
with a transmembrane anchor and Sl- S2 cleavage site [2]. Data
cial and ethnic groups were included (Supplementary Table 1).
have demonstrated the elicitation ofbinding and neutralization
None ofthe participants reported prior COVID-19 infection.
antibodies against the spike protein by the mRNA-1273 vaccine
Temporal profiling of SARS-CoV-2 antigens and antibodies
in humans, thereby inferring that spike protein was produced
were acquired using Simoa assays as previously described. [6, 7 ],
providing data on 15markers to monitor antigen production and
immune responses on each participant (Supplementary Figures
Received 6 April 2021; editooal decision 13 May 2021; Jllblished onlire 20 May2021.
•A. F. 0., C.-A. C.• and M. 0. contributed equally to this wor1c. 2-14). The Simoa antigen assays for spike, Sl, and nucleocapsid
"t.. R. B. and 0. R. W. contributed equallyto this WOik. were previously validated in plasma from pre-pandemic healthy
Correspondence: D. R. Walt. Department of Pathology, Brigham and Women's Hospital, Wyss
subjects, pre-pandemic patients with respiratory infections,
Institute for Biologically Inspired &gineering, Harvard University, Haoord Medical School,
Boston, MA. 021 15 (dwalt@bwh.havard.edu). COVID-19 negative patients, and COVID-19 positive patients
Clinical ..fecliDIIS Diseases• 211Z1;74{4m5-8 [7]. Authors detected SI and Nin 64% of COVID-19 positive
© The Author(s) 2021. Plillished by Ox!Clll University Press for the Infectious Diseases Society
patients, and Sl levels were significantly associated with disease
of Ameri:a. AH rights reseived. For pemtissions, e-mail: joumals.pe,missions~.tOlll-
OOt 10.1093/cid/ciab465 severity. Here antigens Sl and spike were measured to probe
JML TRANSCRIPTION BRIEF REPORT • CID 2022:74 (IS February) • 715

1-888-288-6817
oATE: K?:<--j ?){, fJO~ A - ri'S
EX#: $" INITIALS: ....:nc.;;._' - - -
AR08687
mRNA translation, whereas nucleocapsid antigen served as a mammalian cell proteases or circulating proteases. We observe
negative control (Figures 1A, B, C, Supplementary Table 5). an increase in S1 over an initial period of 1–5 days, suggesting
After the first 100-µg dose, the mRNA-1273 vaccine produced that mRNA translation begins immediately after vaccine inoc-
detectable levels of S1 antigen in plasma in 11 participants, and ulation. Interestingly, spike protein appears in 3 of 13 partici-
spike antigen was detected in 3 of 13 participants. Nucleocapsid pants on average 8 days after S1 is produced. The Simoa antigen
antigen was undetectable or at background levels in all partici- assays for the full spike protein are designed to require antibody
pants after both injections, as expected. binding to both the S1 and S2 subunits for detection, resulting
S1 antigen was detected as early as day 1 postvaccination, and in a cleaved spike protein to be undetectable. Additionally, spike
peak levels were detected on average 5 days after the first injec- protein concentrations in plasma of vaccinated participants may
Downloaded from https://academic.oup.com/cid/article/74/4/715/6279075 by Department of Justice Canada Library user on 09 May 2022
tion (Figure 1A). The mean S1 peak level was 68 pg/mL ± 21 be below our assay limit of detection. We hypothesize that the
pg/mL. S1 in all participants declined and became undetectable cellular immune responses triggered by T-cell activation, which
by day 14. No antigen was detected at day zero for 12 of 13 par- would occur days after the vaccination, lead to direct killing of
ticipants, as expected. However, one individual presented de- cells presenting spike protein, and an additional release of spike
tectable S1 on day zero, possibly due to assay cross-reactivity into the blood stream [9]. The mechanisms underlying release
with other human coronaviruses or asymptomatic infection of free S1 and the subsequent detection of the intact spike pro-
at the time of vaccination. Spike protein was detectable in 3 of tein remain unclear and require further studies.
13 participants an average of 15 days after the first injection. We additionally present corresponding antibody data that
The mean spike peak level was 62 pg/mL ± 13 pg/mL. After the are consistent with serological studies done in large trials [2–5,
second vaccine dose, no S1 or spike was detectable, and both 10–12] to support our antigen results. Here the Simoa serolog-
antigens remained undetectable through day 56. For one indi- ical assays are sensitive enough to identify the production of
vidual (participant 8), spike was detected at day 29, 1 day after antibodies at early stages postvaccination and to profile anti-
the second injection and was undetectable 2 days later. body dynamics for each participant at high resolution. IgG and
Plasma antibodies IgG, IgA, and IgM were measured against IgA against S1, spike, and RBD increase after S1 production in
spike, S1, RBD, and nucleocapsid. Antibody levels measured all participants. There is no significant increase in IgG and IgA
on day zero represent the baseline level in each participant, all against nucleocapsid, confirming that the immune response
who had no previous report of COVID-19 infection. In all 13 was specific to the vaccine, which does not contain mRNA for
participants, as expected, IgG levels against spike, S1, and RBD nucleocapsid. For all participants, the increase in IgG against S1
increased after the first injection, whereas IgG against nucle- and spike directly corresponds to the decline in S1 or spike pro-
ocapsid showed no change over time (Figures 1D, E, F; indi- tein by the second injection. The inverse correlation between
vidual participant data are shown in Supplementary Figures antibody and antigen levels observed is consistent with previous
2–14). IgA is involved in early neutralization activity and is studies investigating SARS-CoV-2 natural infection, in which
therefore crucial to target potentially short-lived IgA responses patients with severe COVID-19 with high plasma antigen levels
[8]. Our Simoa assays detected increased IgA against spike, S1, exhibited antigen clearance upon production of antibodies [7].
and RBD after the first injection (Supplementary Figures 2–15). Our Simoa antigen assays cannot detect antigen-antibody im-
Nine participants (such as participants 3, 4, 5, and 7, Figure 1G) mune complexes. Although S1 protein is present in most par-
presented measurable IgG levels against S1 and spike by day 14 ticipants, serological data shows that some participants exhibit
after the first vaccine injection. Four participants (participants an initial enhancement in antibody levels by day 14 compared
1, 6, 10, 13, Supplementary Figures 2, 7, 11, and 14), showed a to those who do not show an enhancement until day 28. These
delayed IgG-S1 and IgG-spike response, which did not increase differences in antibody dynamics could be explained by early
until day 28 after the first injection. Nonetheless, all participants antibody production due to previous asymptomatic infection,
showed additional boost in IgG-S1 after the second injection. which has recently been demonstrated in seropositive parti-
cipants [10]. Here we observe 2 participants (participants 3,
4) with high IgG-spike baseline levels compared to all other
DISCUSSION
participants who produce increased IgG-spike levels by day 14.
In this study, 11 participants exhibit S1 antigen in plasma after Limitations of the current study include the small sample size
the first injection, whereas nucleocapsid concentrations are in- and potential biases that result from enrolling healthy, young
significant in all participants, confirming that the detected S1 adults, which may not be representative of the general popu-
originates from vaccination and not natural infection. The pres- lation. Future studies should also examine the dynamics of an-
ence of S1 is likely due to the nature of the encoded mRNA- tigen production with neutralization antibodies. Nonetheless,
1273 spike protein, which contains a cleavable S1–S2 site and evidence of systemic detection of spike and S1 protein produc-
enables release of S1 from the spike trimer [2]. We hypothe- tion from the mRNA-1273 vaccine is significant and has not yet
size that release of S1 protein could result from cleavage via been described in any vaccine study, likely due to limitations in
716 • cid 2022:74 (15 February) • BRIEF REPORT

AR08688
Figure 1. Time course of SARS-CoV-2 antigen and antibody levels after mRNA-1273 vaccination. Data from 13 participants. All participants received the mRNA-1273
injection on days 1 and 28, where circle and triangle data points represent antigen levels post the first and second injections, respectively. (A) S1, (B) spike, and (C) nucleo-
capsid levels shown were measured using Simoa assays. Dotted line shows the sample limit of detection, calculated as described in the methods. IgG levels against (D) S1,
(E) spike, and (F) nucleocapsid shown were measured using Simoa assays and reported in units of normalized AEB. Sample limit of detection in unit of AEB was 0.006 for
IgG-S1, 0.0044 for IgG-spike, and 0.0129 for IgG-Nucleocapsid. (A–F) Bars represent the average concentration from participants on that day, and error bars represent the
standard deviation, and individual data points are overlayed. Each data point is the average of duplicate measurements. (G) S1, spike, IgG-S1, and IgG-spike data for individual
participants 3, 4, 5, and 7. Hollow and solid data points represent levels post the first and second injections, respectively. Each data point represents the average of duplicate
measurements, and error bars are the standard deviation. Abbreviations: AEB, average enzymes per bead; IgG, immunoglobulin G; mRNA, messenger RNA; SARS-CoV-2,
severe acute respiratory syndrome coronavirus 2.
BRIEF REPORT • cid 2022:74 (15 February) • 717

AR08689
assay sensitivity and timing assessment. The clinical relevance The anti-SARS-CoV-2 Simoa assays in this publication have been licensed
by Brigham and Women’s Hospital to Quanterix Corporation. A. F. O. re-
of this finding is unknown and should be further explored.
ports funding from NIH Post Doctoral Training Grant and royalty pay-
These data show that S1 antigen production after the initial vac- ments from Brigham and Women’s Hospital for intellectual property of the
cination can be detected by day 1 and is present beyond the site SARS-CoV-2 antibody assays that was licensed to Quanterix Inc, outside
of injection and the associated regional lymph nodes. Induction the submitted work. L. R. B. reports research grants from NIH/NIAID,
Welcome Trust, and IAVI; and participates in SMCs for NIAID for a variety
of IgG and IgA immune responses can be detected as early as of programs including vaccine development, outside the submitted work.
day 5 postvaccination and are associated with clearance of spike M. D. reports grants from Centre Hospitalier de l’Université de Montréal
and S1 antigen in the systemic circulation. (CHUM) and CHUM Foundation, outside the submitted work. All other
authors report no potential conflicts. All authors have submitted the ICMJE
Form for Disclosure of Potential Conflicts of Interest. Conflicts that the edi-
Supplementary Data
tors consider relevant to the content of the manuscript have been disclosed.
Supplementary materials are available at Clinical Infectious Diseases online.
Consisting of data provided by the authors to benefit the reader, the posted References
materials are not copyedited and are the sole responsibility of the authors, so 1. Baden LR, El Sahly HM, Essink B, et al; COVE Study Group. Efficacy
questions or comments should be addressed to the corresponding author. and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med 2021;
384:403–16.
Notes 2. Jackson LA, Anderson EJ, Rouphael NG, et al; mRNA-1273 Study Group. An
mRNA vaccine against SARS-CoV-2: preliminary report. N Engl J Med 2020;
Author contributions. 383:1920–31.
Conceptualization: D. R. W., A. F. O., L. R. B., M. D. 3. Anderson EJ, Rouphael NG, Widge AT, et al; mRNA-1273 Study Group. Safety
Investigation: A. F. O., C.-A. C., M. D. and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. N Engl
Sample/Data Acquisition: A. F. O., C.-A. C., M. D., Y. S., A. C. S., M. P., J Med 2020; 383:2427–38.
L. N., X. L., S. V. 4. Widge AT, Rouphael NG, Jackson LA, et al; mRNA-1273 Study Group. Durability
Funding acquisition: D. R. W., L. R. B. of responses after SARS-CoV-2 mRNA-1273 vaccination. N Engl J Med 2021;
Supervision: D. R. W., L. R. B. 384:80–2.
Writing—original draft: A. F. O., C.-A. C., D. R. W. 5. Saadat S, Tehrani ZR, Logue J, et al. Binding and neutralization antibody titers
after a single vaccine dose in health care workers previously infected with SARS-
Writing—review and editing: M. D., A. C. S., L. R. B.
CoV-2. J Am Med Assoc 2021. doi: 10.1001/jama.2021.3341.
Acknowledgments. The authors thank Jonathan Krauss and John 6. Norman M, Gilboa T, Ogata AF, et al. Ultrasensitive high-resolution profiling
Alexander Kupelian for their technical support and Julia Klopfer for her of early seroconversion in patients with COVID-19. Nat Biomed Eng 2020;
assistance in sample collections and study management. 4:1180–7.
Financial Support. Funding for this work came from a generous dona- 7. Ogata AF, Maley AM, Wu C, et al. Ultra-sensitive serial profiling of SARS-CoV-2
tion from Barbara and Amos Hostetter and the Chleck Foundation. This antigens and antibodies in plasma to understand disease progression in COVID-
work was supported in part by the Bill and Melinda Gates Foundation 19 patients with severe disease. Clin Chem 2020; 4:1180–7.
(grant number INV-017380). The authors acknowledge support from the 8. Sterlin D, Mathian A, Miyara M, et al. IgA dominates the early neutralizing anti-
following research grants for vaccine development: National Institutes body response to SARS-CoV-2. Sci Transl Med 2021; 13:2223.
9. Sewell HF, Agius RM, Kendrick D, Stewart M. COVID-19 vaccines: delivering
of Health (NIH)/National Institute of Allergy and Infectious Diseases
protective immunity. BMJ 2020; 371:m4838.
(NIAID), Welcome Trust, and International AIDS Vaccine Initiative (IAVI). 10. Krammer F, Srivastava K, Alshammary H, et al. Antibody responses in seropos-
AFO was supported by NIH T32HL007627. itive persons after a single dose of SARS-CoV-2 mRNA vaccine. N Engl J Med
Potential conflicts of interest. D. R. W. is a Board Director and holds stock 2021; 384:1372–4.
equity in Quanterix Corporation, a company that develops an ultrasensitive 11. Wu K, Werner AP, Moliva JI, et al. mRNA-1273 vaccine induces neutralizing anti-
digital immunoassay platform. He is an inventor of the Simoa technology, bodies against spike mutants from global SARS-CoV-2 variants. BioRxiv 2021.
founder of the company and serves on its Board of Directors. D. R. W.’s inter- doi:10.1101/2021.01.25.427948.
ests were reviewed and are managed by Brigham and Women’s Hospital and 12. Corbett KS, Edwards DK, Leist SR, et al. SARS-CoV-2 mRNA vaccine design en-
Partners HealthCare in accordance with their conflict-of-interest policies. abled by prototype pathogen preparedness. Nature 2020; 586:567–71.
718 • cid 2022:74 (15 February) • BRIEF REPORT

AR08690
~ FactCheck.0 rg ,I ProfN:I o{T/w,~mm/wg P11b/JcPoli,y(e/llPr 11rJ
SciCheck's C0VID-19/Vaccination Project

.,
FACTCHECK POSTS > FEATURED POSTS > SCICHECK

1
COVID- 19 Vaccine-Generated Spike Protein is Safe,
Contrary to Viral Claims "
ByCa1alm.1JarJ.mil10
-
Po!>ted 011 fuly I, 2021
"
Ask SciCheck
Q: How do pt-ople who haw not been
Vc1crina1ed against CO\fJ0 - 19 pos-ea risk to
11 a a a a pcopft" "110 have bet-n Ya('Cio:ated?
A: At1 unva«i.uat.ed person who is iufei1ed

with COVlD-19 poses a much greater risk to
SciDigest others who are also unva('cinatf'd. But
Hundreds. of millions of COVID- 19 v,KC'ine doSE'S haw bet>n ad:ministNt'«f safely in lln~ llnirrd vacrinesare not 100% e,ffective, so there is
Stdtl'S in the J,lSl six months. Then> is no evidrnce lo indicilt<" lhal the spike prolcins a d iance that an um.lffinated person routd
gl11er.ttedbybum,mt'ells.following,..dC'rin,11ion an·a toxinorth,u 1heycircul<:!te in tht' body infect a vaccinatt.d person - particuJarly
and damat,> tissues.. tonrra.ry ro what a camsdian \lirus immuno1ogisr rl'<"emty rlaimed. the vulner.1b1e, surh as elderly and
immunocompromi.sed individuals.
Rr-ad the full gue-stion and ,:mS\ver

How do w e know vaccines are sate? View the Ask 'iciC...'heck arrhives
HaY-f' aquesrion' A<,k u,;:
Full Story
AU of thf" COVID 19 \racritK"S cum:"mly appro\·ed in the United St,Ht'S are designNI to insmirt Donate Now
htun,mt·ells w make hannfess spike proteins. - mimicking a viral pro1cin that's used by th~ Because-facts matter.
SJ\RS CoV 2 virus to<'nter cells. \\'hen the immunf." s~-:slem Tecoguiz~ the proreins, which
.um't normally there, ir s.r-,ms generating antibodit-s antl buiMi.ng an lmmunl' ('"(..'S{)Onsc
againsl them. The process prt>pa res tht> ~ -against future- infection.
SciCheck's COVID-
These vaccines have beM1 found to b<> t>f((.'<:(iV(' and saf(' in 19/Vaccination Project
clinical rria.ls \\ith rensof thousands of panicip,mts, and in Prttinpting and t"XJ)OSiug
n"ld world conditions wiih over 3.15 minion dos,-.._ vacdnation and COYID- IQ
administ<"fl"d. misinformation.
Proyectode
Ac-cordJng to rhe Centers for Dist·as£> Control and
Va cunacion/COVID- 19
Prevf.>Illioo. ,r,t .. n,os1 intensive sar1?1y monit-or!ugin U.S.
history" bas found that most of the rt-JM'.>rtecl side t'({ects. Pret..ct\.;endo y e'\:poniendo
la desinformadOn sobre t>I
aftrr COV1D 19 vaccin~tion a~ mmor. such as pain at rbe C0\10-19 y Sll5 VcKUn.as
inj("('"tion silf!or {€'\rer. Se\·ert- a<h-·t"fse- reactions 10 the
vaccines have bee-n race.
SciCbeck
Vi't , .1Ca.nadian virus immunologist rttenrly("laime-d that tbe\·acrine' sspti-f'prott'in is "'a Fact-checkingsc-i-l;'nce-
p.alh0gt>nk pr01~in,n .... ioxin" Ihat gNs into the bloodstni-am, then a(·N1mul.t!e-s in bre~st based claims.
milk and ..in a number or1issues1' and could ft>ad to rardiovasculdr and neuroiogkal damage
in :adults, children and inf.ints.
...we 1nade a big nlistakfi', " said Byrn Ill Bridle, a ,,ira! immunologist and associa1e professor facebook Initiative
;u the UniV('TSity or GUC'lph'sOntario Vl.'terinary College, dunng. .m inlt'[ViPW Wllh Canadi.:m Dl"bnnking fa}S(' storie,s.
rarlTo J)E"fWn.ality Ak>x Pi('r;,on on May 27. "We thought the spike protein was a grl.'.at target
.mtigen, \\?ue-.:M kill"\-\' 11,l•spikr- })fOleil, i1S1Af WdS d loxinanri 'nit!- a pathogenk protein. So
by V(l('finiHingpoople v.v .lre inad\·ertently inoculating rhml '°"i1l, cl toxin.~
2022 Players Guide
An:onHng 10 his pro-fill"'. Bridli"'S r('S(>ilrth ft)("US(>S on biOfhcrapies. for thl" rrearmenr of 1"he spttial intt"re-st groups
ca1Kers ,md the w;ay organisms rt>Spond 10 viru$.l:>S.. Since the pandemic-S!attffi, hislnb has brl1ind the-TV acts..
been trying to devetopvMci11l!S againsl coron;wi~. for which hl' ret.:C'J\.·l'<I a $23,0,000
grant from rheOntario gowmment.
Viral Spiral
Bridle's iutervif".vwas reposted by sever.tl p-ublkdftom,, inriudiug ont• own~I by Roberl F. Don't get spun by imerne,
Kennedy }r.'s ami vaccination organizallon. S,eg:Jnems of the in1Pn1H"\vwere uidel~• spread rumors.
Jn social media pt.al fonns iu F..nghsh and Sp.lllish. ,
But re-searc-hers and healih officials rnld F.actCh-P<'k.org 1hen.> is no '"'mist.:tkP" and th.tr there
is no C"\identt 10 support Bridle's clailns..
Tht·n· is nt>t'videun.• t h a1 the spike protein in Vdfdnes "i.51o~ic or lhar ii ling('(S at •my to11.;c-
ie'\•e·1in lllE'botly 3.fler\·iltcitldlion,ot .-u , fOAspokt?SJX•rs.on told us in.tnei1wtil.
Jason-'1cLellan~ asmKturalbiologist at the Umversit~• of Texas at Austin who has b(>en

ii Sign Up
Gt't frtt email alerts.
studying spike proteins ill orhttcoronavimses foryt>ar.: cmd whose-wor11'. was funrlatnP1ll.ti- Mailbag
foT thE'dP-,·e1opmrot or COVJD- 19 varcinPS. said Bridle's sta1emen1s are- not t'Orr<"Ct. Leu<>rs from ouc reade-rs.
""The spike-protein is not pa(hog-enic. His not a to~--m,', f\lci.t>llan told usin an l'ma.il. "I bavP-
not seen any dafa1osuppor1 whal Bridleclairru:;,. .,.
On tbe Jur
No Evidence Vaccine-Generated Spike Our stalf on 1V and radio.
1. 4 4 • • •,. • I/ . _ / '"' A '"' "1 JA ,-, / _ • 0

. 1. _ _ t • .t , A - - ,. • • ,.. - 4 - .1 -· ,.. ': 1 -
··---- --- ~--.-----.. --·- ·-•..,..-----··-·:::r ·-· .. - ··-•-. ·- ··-· ·- ·- -- .- . ,. --- --·-·-·· .---·--- . ~- .. --, --· - ---- --r:l~--.. ··-·--- ·-· -·-- ,---r-·---
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display me preprint in perpetuity.
All rights reserved. No reuse allowed without permission.
AR08691
BNT162b2 vaccination induces SARS-CoV-2 specific antibody secretion into human milk
with minimal transfer of vaccine mRNA
Jia Ming Low(MRCPCH, MCI) 1•2A, Yue Gu(PhD)3-4A, Melissa Shu Feng Ng(PhD)5A, Zubair
Amin(MBBS, MHFE, FAAP)1.2, Le Ye Lee(MMed, MRCPCH)1.2, Yvonne Peng Mei

1
Ng(MREPH) .2, Bhuvaneshwari D/O Shunmuganathan(MSc)3·4 , Yuxi Niu(BSc)3, R~hi
4
Gupta(MSc)3 ' , Paul Anantharajah Tambyah(MD)6, Paul A MacAry(PhD)3 •4 , Liang Wei
Wang(PhD)5*, Youjia Zhong(MRCPCH (UK), MMed (Paeds), MCI) 1h
Joint firstA, joint last*
Affiliations
1
Department of Paediatrics, Yong Loo Lin School of Medicine, National University of
Singapore, Singapore
2
Department of Neonatology, Khoo Teck Puat-National University Children's Medical Institute,
National University Health System, Singapore

3
Antibody Engineering Programme, Life Sciences Institute, National University of Singapore,
Singapore
4
Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National
University of Singapore, Singapore

5
Singapore Immunology Network, Agency for Science, Technology and Research, Immunos
Building, Singapore
JML TRANSCRIPTION
6Department of Medicine, National University Hospital, Singapore 1-888-288--6817
DATE: Bfj -;;,.-'-f ' d'"Od§';:
EX#: :J INITIALS: A- . p
Page 1 of 38
NOTE: This preprint reports new , - e h 1hat has not bea'I certified by pas review and should not be UNd to guide c:lnical practice.
medRxiv preprint doi: https://doi.org/10.1101/2021.04.27.21256151; this version posted April 29, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
AR08692
7
Khoo Teck Puat-National University Children’s Medical Institute, National University Health
System, Singapore
Corresponding author
Liang Wei Wang
Singapore Immunology Network,
Agency for Science, Technology and Research,
Immunos Building, Level 4, Singapore 138648
DID: (65) 6407 0803 | FAX: (65) 6464 2057 | EMAIL: Wang_Liang_Wei@immunol.a-
star.edu.sg
Word count: 2884
Keywords: BNT162b2, lactating, COVID-19, antibody, mRNA vaccines, human milk, Pfizer-
BioNtech
Page 2 of 38
AR08693
Key Points:
Question: Does BNT162b2 (i) induce the production and secretion of SARS-CoV-2 specific
antibodies into human milk, and/or (ii) get secreted into human milk?
Findings: In this cohort that included ten lactating healthcare workers following BNT162b2
vaccination, 90% produced SARS-CoV-2 immunoglobulin A, and 100% produced
immunoglobulin G in human milk, with minimal amounts of vaccine mRNA transfer.
Meaning: Lactating individuals should continue breastfeeding in an uninterrupted manner after
receiving SARS-CoV-2 mRNA vaccination.
Page 3 of 38
AR08694
Abstract:
Importance: To examine the impact of SARS-CoV-2 vaccination of lactating mothers on human
milk
Objective: (1) To quantify SARS-CoV-2-specific immunoglobulin A (IgA) and
immunoglobulin G (IgG) in human milk of lactating mothers who received the BNT162b2
vaccine, with reference to a cohort convalescent from antenatal COVID-19, and healthy lactating
mothers. (2) To detect and quantify vaccine mRNA in human milk after BNT162b2 vaccination.
Design: Gestational Immunity For Transfer 2 (GIFT-2) is a prospective cohort study of lactating
mothers who were due to receive two doses of BNT162b2 vaccine, recruited between 5th
February 2021 and 9th February 2021.
Setting: Lactating healthcare workers living in Singapore
Participants: Convenience sample of ten lactating healthcare workers. Human milk samples
were collected at four time points: pre-vaccination, 1-3 days after dose one, 7-10 days after dose
one, and 3-7 days after dose two of the BNT162b2 vaccine.
Exposure: Two doses of the BNT162b2 vaccine 21 days apart.
Main Outcome and Measure: (i) SARS-CoV-2-specific IgA and IgG in human milk of
lactating mothers who received BNT162b2 vaccine, (ii) Detection and quantification of vaccine
mRNA in human milk after BNT162b2 vaccination.
Results: Ten lactating healthcare workers aged 32.5 years (range 29 – 42) were recruited, with
40 human milk samples collected and analysed. SARS-CoV-2-specific IgA was predominant in
human milk of lactating mothers who received BNT162b2 vaccine. The sharpest rise in antibody
production was 3 -7 days after dose two of the BNT162b2 vaccine, with medians of 1110
Page 4 of 38
AR08695
picomolar of anti-SARS-CoV-2 spike and 374 picomolar of anti-Receptor Binding Domain IgA.
Vaccine mRNA was detected only on rare occasions, at a maximum concentration of 2 ng/mL.
Conclusions and Relevance: In this cohort of ten lactating mothers following BNT162b2
vaccination, nine (90%) produced SARS-CoV-2 IgA, and ten (100%) produced IgG in human
milk with minimal amounts of vaccine mRNA. Lactating individuals should continue
breastfeeding in an uninterrupted manner after receiving mRNA vaccination for SARS-CoV-2.
Trial Registration: Registered at clinicaltrials.gov (NCT04802278).
Page 5 of 38
AR08696
Background
Lactating mothers who have recovered from respiratory virus infections produce antibodies in
human milk that can neutralize offending viruses in vivo.1-3 The production of protective
antibodies in human milk after influenza vaccination in lactating mothers confers local mucosal
immunity to infants and has informed antenatal vaccination programs for diseases such as
influenza and tetanus in lactating mothers.4,5
However, similar evidence for Coronavirus Disease-19 (COVID-19) messenger ribonucleic acid
(mRNA) vaccines is scarce.6 As a result, vaccine advisories from various health authorities have
been cautious in recommending vaccinations for lactating mothers. The American College of
Obstetricians and Gynecologists (ACOG) and the Royal College of Obstetricians &
Gynaecologists (RCOG, UK) both state that COVID-19 vaccines may be offered to lactating
individuals, while acknowledging that adequate safety data is not available.7,8 In countries such
as Singapore, mothers have been advised to express and discard human milk for up to seven days
after vaccination.9 However, such measures may disrupt mother-child bonding and may result in
premature cessation of breastfeeding.10
There is emerging evidence that SARS-CoV-2 specific antibodies are detectable in human milk
post vaccination;11-14 however, the amount of immunoglobulin G (IgG) and immunoglobulin A
(IgA) have not been clearly quantified. It is also unknown whether vaccine components such as
mRNA are transferred in human milk; preliminary studies purportedly detect no vaccine mRNA
in human milk.15
Page 6 of 38
AR08697
Our aims are (1) to quantify SARS-CoV-2-specific IgA and IgG in human milk of lactating
mothers who received COVID-19 mRNA vaccine, with reference to a cohort convalescent from
antenatal COVID-19 as well as a control cohort of healthy lactating women) and (2) to detect
and quantify vaccine mRNA in human milk after vaccination.
We hypothesize that BNT162b2, an mRNA vaccine encoding the immunogenic SARS-CoV-2
spike protein, has minimal leakage into human milk after vaccination, and induces the
production and secretion of spike- and receptor-binding domain (RBD)- specific IgA and IgG
into human milk.
Methods
We conducted a prospective cohort study of a convenience sample of lactating healthcare
workers living in Singapore, who were due to receive two doses of the BNT162b2
(Pfizer/BioNtech) vaccine. The study was approved by the Institutional Review Board
(Gestational Immunity For Transfer GIFT-2: DSRB Reference Number: 2021/00095) and the
study protocol was registered at clinicaltrials.gov (NCT04802278).16 Participants were recruited
between 5th February 2021 and 9th February 2021 and were invited to participate via
advertisements and social media. Exclusion criteria were that of no prior known exposure to
COVID-19, and any autoimmune disease, current or recent infections, cancer, and any current or
recent immunomodulatory medication. Demographic details and clinical outcomes of lactating
Page 7 of 38
AR08698
mothers and their infants were determined through a structured questionnaire up to 28 days
following mother’s second dose of vaccine.
Human milk samples from the “vaccinated cohort” were collected at four time points: pre-
vaccination (T1),1-3 days after dose one (T2), 7-10 days after dose one (T3), and 3-7 days after
dose two of COVID-19 mRNA vaccine (T4). All samples were collected at home using electric
breast pumps or hand expressed into sterile plastic containers, stored and transported via courier
immediately at -18°C to the laboratory. In the laboratory, the samples were stored at -80°C until
analysis.
Human milk samples at 1 month postpartum from convalescent and healthy mothers were also
analysed for reference. The “convalescent cohort” were six women who had COVID-19 in
pregnancy confirmed with real-time polymerase-chain-reaction (RT-PCR) assay, and then
recovered as defined by resolution of clinical symptoms and with two negative RT-PCR assays
24 hours apart. Nine healthy unrelated mothers without COVID-19 infection or vaccination
served as the “healthy cohort”.
Demographic details and clinical outcomes of lactating mothers and their infants were
determined up to 28 days through a structured questionnaire after ingestion of post-vaccination
human milk.
Assays performed on milk samples were: (1) quantitative ELISA for spike- and RBD-specific
IgA and IgG against SARS-CoV-2 antigens, and (2) sensitive quantitation of BNT162b2 mRNA.
Page 8 of 38
AR08699
Human milk was first tested for presence of IgA in all four time points (i.e. T1-T4), whereas T1
and T4 were tested for the presence of IgG, as IgA levels were only seen to rise at T4.
IgA and IgG against SARS-CoV-2 spike and RBD were titrated using a quantitative ELISA. A
human monoclonal antibody specific for SARS-CoV-2 was recombinantly engineered and
expressed as human IgG1 and/or IgA1. This was employed as the reagent for quantitation
(details available in eMethods in the Supplement).
Total ribonucleic acid (RNA) from whole human milk was extracted for BNT162b2 mRNA
detection. Phenol-chloroform extraction was utilised to increase mRNA yield and used as input
for polyA-primed reverse transcription. A standard curve was constructed using BNT162b2
vaccine spiked into healthy SARS-CoV-2 negative human milk and then extracted in the
aforementioned manner to allow us to quantify the mRNA detected. This also served as the
positive control. Detection of BNT162b2 mRNA was then performed using probe-based
quantitative PCR (qPCR; details available in eMethods in the Supplement).
Clinical characteristics of the cohorts were summarised using GraphPad Prism 8. Shapiro-Wilk
test of normality was used; if data was normal, mean and standard deviations were presented.
The rest of the statistical analyses were done in R (4.0.2). Two groups were compared with
Mann-Whitney U test (two tailed). For multiple comparisons, the PMCMRplus package
(PMCMRplus_1.9.0) was used to perform Kruskal-Wallis test with Dunn’s nonparametric all-
pairs comparison post-test. p<0.05 level of confidence was accepted for statistical significance.
Details of sample sizes and analyses performed specific to each figure are in all figure legends.
Page 9 of 38
AR08700
All box and whiskers plots show median (center line), interquartile range (box), and 10th and
90th percentiles (whiskers). All data points are plotted with the boxplots. All line plots show the
median, and error bars show the first and third quartiles. The study is reported in accordance to
the STROBE reporting guidelines for cohort studies.17
Results
Maternal and infant characteristics
Ten lactating healthcare workers were recruited; all received two doses of the BNT162b2
(Pfizer/BioNtech) vaccine, with the second dose given on day 21. The mothers were of a mean
age of 33.5 [standard deviation, SD 3.3] years of age, eight (80%) were Singaporean Chinese and
two (20%) were Singaporean Malay. At recruitment, mothers were a mean of 9.8 [SD 4.0]
months post-partum. (Table 1) Samples for T1-T4 were available for all subjects so 40 samples
were collected and analysed in total. All infants were born full term and healthy. No mother or
infant experienced any serious adverse event during the 28-day study period. None of the
mothers had mastitis after vaccination. Nine infants were breastfed within 72 hours after their
mothers were vaccinated; one infant was not fed breast milk within 72 hours after vaccination.
None of these nine developed any fever, rash, vomiting, diarrhea, cough or rhinorrhoea, up to 28
days after ingestion of post-vaccination human milk.
Women in the reference cohort had COVID-19 with a mean of 136 [SD 80] days before delivery;
thus, human milk collected one month postpartum was about 5.5 months from the point of initial
antigenic exposure. Subjects in the convalescent and healthy women did not receive SARS-CoV-
Page 10 of 38
AR08701
2 vaccination during the study. Clinical details of the convalescent and healthy women in the
reference cohort are available in the eTables 1 and 2 in the Supplement.
Levels of SARS-CoV-2-specific IgA and IgG in in human milk of lactating mothers
A human monoclonal antibody binding to SARS-CoV-2 was recombinantly engineered and
expressed as human IgG and human IgA. This resulted in the production of monoclonal
antibodies of different isotypes with the same antigen-binding ability, which were utilized as
reference reagents for construction of standard curves for the quantitative ELISA (eFigure1 in
the Supplement). Human milk samples were evaluated for IgA binding reactivity against SARS-
CoV-2 spike and RBD (Figure 1; eFigure 2 in the Supplement).
Vaccination induced a strong IgA response at T4 (i.e., 3-7 days after dose two of COVID-19
mRNA vaccine). Human milk samples from vaccinated mothers from T4 had medians of 1110
picomolar (pM) (Q1: 672, Q3: 1947; IQR: 1275) of anti-SARS-CoV-2 spike (Figure 1A) and
374 pM (Q1: 240, Q3: 588; IQR: 348) of anti-RBD IgA (Figure 1B), both significantly higher
than the concentrations from earlier time points (P < .001). Human milk samples evaluated at T4
also exhibited significantly higher levels of IgA compared to the reference samples provided by
convalescent mothers who had antenatal COVID-19. IgA was not detected in one mother at T4
(Figure 1C, D; eFigure 2C, D in the Supplement).
As the IgA response from vaccination was observed only at T4, we compared the concentration
of IgG targeting spike and RBD in human milk samples collected at T1 and T4. The median
Page 11 of 38
AR08702
concentrations of anti-Spike and anti-RBD IgG at T4 were 495 pM (Q1: 257, Q3: 1001; IQR:
744) and 236 pM (Q1: 138, Q3: 501; IQR: 363), respectively. These levels were significantly
higher compared to the concentration at T1 (P < .001), and to the convalescent cohort, all of
which were negligible (Figure 2A, B; eFigure 3A, B in the Supplement). There was no IgA or
IgG detected in healthy unvaccinated lactating women.
An increase in IgG in human milk samples were observed in all ten (100%) human milk samples
after the second dose of the mRNA vaccine at T4 (Figure 2C, D; eFigure 3C, D in the
Supplement).
At T4, both SARS-CoV-2 antigen-specific IgA and IgG antibodies were present in human milk.
The ratio of SARS-CoV-2 antigen-specific IgA and IgG was calculated. A ratio of more than 1
would reflect more IgA present than IgG. Conversely, a ratio of less than 1 would reflect more
IgG than IgA.
Optical density at 450 nanometer (OD450) is a raw assay readout for quantitative ELISA that is
highly dependent on factors such as the sensitivity of the test kit. Utilizing this raw assay
readout, OD450 values of IgG were observed to be above that of IgA in seven (70%) of the
vaccinated individuals for both spike (eFigure 4A in the Supplement) and RBD (eFigure 4B in
the Supplement).
However, in order to perform direct cross-comparison between different antibody isotypes,
OD450 values were further transformed to picomolar (pM) as the latter quantifies the absolute
Page 12 of 38
AR08703
concentration of antibodies. Here, breaking-down the analysis by individual mothers, we report a
higher molar concentration of IgA compared to IgG in six (60%) of the mothers for anti-spike
(Figure 3A) and anti-RBD (Figure 3B) antibodies.
Notably, IgG for both spike and RBD were measurable in all ten samples at T4 (i.e., 3-7 days
from the dose two) (Figure 3A, B). In contrast, in the convalescent group, spike IgG antibodies
were only detected in one woman (Figure 3C, eFigure 4C in the Supplement), and RBD IgG
antibodies were not detected in any samples (Figure 3D, eFigure 4D in the Supplement).
Minimal transfer of BNT162b2 mRNA in milk samples of vaccinated mothers
There was minimal transfer of BNT162b2 mRNA into human milk across all time points. Our
assay method could detect sub-picogram levels of BNT162b2 mRNA (Figure 4A). The standard
curves constructed with cDNA from spiked milk were similar to that obtained with synthetic
DNA constructs (eFigure 5 in the Supplement), indicating robustness of the method. We were
only able to observe on rare occasions very low levels of vaccine mRNA in human milk
collected within the first week after either dose one or dose two (Figure 4B); 36 out of 40 (90%)
samples did not show detectable levels of vaccine mRNA. The highest concentration of
BNT162b2 mRNA in the tested samples was 2 ng/mL. This would translate into a hypothetical
0.667% of the original vaccine dose being transferred in 100 mL of human milk given to the
infant post vaccination, in the worst-case scenario.
Page 13 of 38
AR08704
Discussion
We demonstrated that human milk from lactating mothers who received BNT162b2 vaccines
contained SARS-CoV-2-specific antibodies. Within 3-7 days after administering the second dose
of BNT162b2 vaccine, nine (90%) individuals produced SARS-CoV-2 IgA, and ten (100%)
individuals produced IgG in human milk. The transfer of antibodies via milk may confers local
mucosal protection to the breastfed infant. We detected negligible amounts of BNT162b2 mRNA
in a minority of human milk samples using a very sensitive assay. Infants in our cohort had no
reported adverse events, up to 28 days after ingestion of post-vaccination human milk.
We showed that the sharpest rise in antibody production was after dose two of the BNT162b2
vaccine, with an average of 1882 pM of anti-SARS-CoV-2 spike IgA and 606 pM of anti-RBD
IgA being seen in the human milk at 3-7 days after dose two. This is similar to the kinetics found
in Baird et al. and Friedman et al., and could either be a function of time after the initial antigenic
stimulation of dose one, or an immunological need for dose two.11,12 As the humoral
immunological response in lactating individuals has been recently shown18 to be more dependent
on the booster dose of vaccination compared to non-lactating individuals, the latter is highly
probable. Thus, whether significant amounts of antigen-specific antibodies can be elicited after
administering one-dose regime vaccines, requires confirmation.18
Using women convalescent from antenatal COVID-19 as a reference cohort, we were also able
to demonstrate that antibody levels immediately after vaccination were significantly higher than
those of the convalescent cohort, whose infection was a mean of 5.5 months before the point of
Page 14 of 38
AR08705
human milk collection. This suggests that even for lactating women who have had natural
COVID-19, vaccination may be helpful to induce and boost transfer of SARS-CoV-2-specific
antibodies in human milk as these protective antibodies wane over time.
Other groups have also found SARS-CoV-2 spike and RBD-specific IgG11-14 in human milk after
vaccination in addition to IgA. Here, we showed that SARS-CoV-2 spike and RBD-specific IgG
are found at significantly higher levels in T4 compared to T1. The presence of vaccine-elicited
IgG has been described after intramuscular influenza vaccination,5 and is postulated to be related
to the intramuscular route of antigenic exposure during vaccination. Compared to a mucosal
exposure during natural infection, this would induce increased class-switching to favor IgG as
the dominant isotype rather than IgA in human milk.11 When comparing OD450 raw values for
IgA and IgG, a higher OD450 for IgG compared to IgA for spike and RBD was detected,
suggesting that dominance of the IgG isotype might occur in BNT162b2 vaccinated mothers.
However, when converted to picomolar (pM), we show that the majority of vaccinated mothers
have increased IgA over IgG, indicating that in human milk, IgA is still the predominant isotype
elicited in response to the vaccine.
The role of antigen-specific IgG in human milk is unclear at this time, since IgG does not have a
secretory chain and is prone to digestion by the breastfeeding infant; this lends voice to the move
to develop intranasal vaccines for respiratory diseases.19 However, our study did demonstrate a
clear and predominant production of spike-specific IgA, which is resistant to degradation by
digestion, which can be expected to confer mucosal immunity to the infant.
Page 15 of 38
AR08706
In terms of mRNA detection, it is worth noting that our method offers significant advantages
over that reported previously.15 Phenol-chloroform extraction, the gold standard for RNA
extraction, and double-quencher qPCR probes were utilized in our protocol, enhancing the
sensitivity of our approach. Consequently, we could detect as low as 2 femtograms (2 x 10-15 g)
of BNT162b2 cDNA input, which marks an approximately 60-fold increase in sensitivity relative
to Golan and colleagues,15 where they could not detect vaccine mRNA in human milk up to 48
hours post-vaccination. However, translation and inferred persistence of nanoparticle-delivered
mRNA on the scale of days have been previously reported in in vivo models.20 Thus, we
interrogated human milk for presence of mRNA up to one week post vaccination in case of
delayed kinetics. In addition, it is important to note that our protocol was designed for specific
detection of intact BNT162b2 mRNA, rather than its degraded products, which would be more
reflective of whole vaccine components.
Reassuringly, our data suggests that in most cases, vaccine mRNA does not escape into
mammary secretions. The few instances where extremely low levels of BNT162b2 mRNA were
detected may be due to naturally occurring inter-individual variations in protein adsorption.19
This miniscule amount of mRNA is expected to be readily destroyed by enzymes in the infant’s
gut, and any accompanying lipid nanoparticles that are excreted into human milk would also be
readily digested if ingested orally by the infant.6,21
This study has several important strengths. Firstly, we accurately quantified antigen-specific IgA
and IgG in human milk. This was referenced against a cohort of lactating women who are
convalescent from antenatal COVID-19 and a cohort of unvaccinated lactating women.
Page 16 of 38
AR08707
Secondly, we used a gold-standard method for detection of vaccine mRNA in human milk, with
actual vaccine derived BNT162b2 used as positive control. Lastly, we tracked and reported the
clinical status of infants who were fed human milk from vaccinated mothers.
This study has limitations. Firstly, we did not perform any functional assays; however, binding
affinity of spike- and RBD-specific antibodies have been correlated with neutralization.2
Secondly, the relatively short duration of follow-up period also did not allow for characterization
of durability of IgA in human milk after vaccination. Sample collection is ongoing for
subsequent studies on antibody durability.
These results lend immunological and clinical evidence to the current recommendation of the
ACOG, RCOG and WHO that lactating individuals should continue breastfeeding in an
uninterrupted manner after receiving COVID-19 mRNA vaccines.7,8,22
Article Information
Author Contributions
Drs LWW and YJZ had full access to all of the data in the study and take responsibility for the
integrity of the data and the accuracy of the data analysis.
Concept and design: JML, YG, MSFN, LYL, ZA, PAM, LWW, YJZ.
Acquisition, analysis, or interpretation of data: JML, YG, MSFN, BS, YXN, RG, LWW, YJZ.
Drafting of the manuscript: JML, YG, MSFN, LWW, YJZ.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: MSFN, YJZ.
Page 17 of 38
AR08708
Obtained funding: JML, ZA, PAM, YJZ.
Supervision: LYL, ZA, PAT, PAM.
Acknowledgements
The authors wish to thank Dr Dimple Rajgor for helping with reviewing, formatting and in
submission of the manuscript for publication. We are also deeply grateful to all mothers who
donated their time and precious gift of milk to science.
Conflict of Interest Disclosures
All authors declare no financial relationships with any organisations that might have an interest
in the submitted work in the previous three years and no other relationships or activities that
could appear to have influenced the submitted work.
Funding
J.M. Low received funding from KTP – NUCMI and National University Health System Pitch
for Funds to conduct this research. M.S.F. Ng is a recipient of the Career Development Award
from the Agency for Science, Technology and Research, Singapore. L.W. Wang is a recipient of
the National Medical Research Council Open Fund-Young Investigator Research Grant (Project
ID: MOH-000545-00) from the Ministry of Health, Singapore. This study is funded by the
SARS-CoV-2 antibody initiative (R-571-000-081-213) and Reimagine research fund (R-571-
001-093-114).
Page 18 of 38
AR08709
References
1. Fox A, Marino J, Amanat F, et al. Robust and specific secretory IgA against SARS-CoV-
2 detected in human milk. Iscience. 2020;23(11):101735. doi:10.1016/j.isci.2020.101735
2. Pace RM, Williams JE, Järvinen KM, et al. Characterization of SARS-CoV-2 RNA,
Antibodies, and Neutralizing Capacity in Milk Produced by Women with COVID-19.
mBio. 2021;12(1):e03192-03120. doi:10.1128/mBio.03192-20
3. van Keulen BJ, Romijn M, Bondt A, et al. Breastmilk; a source of SARS-CoV-2 specific
IgA antibodies. medRxiv. 2020. doi:10.1101/2020.08.18.20176743
4. Kimberlin DW. Red Book 2015: Report of the Committee on Infectious Diseases 30th
Edition. Edited by David W. Kimberlin, Michael T. Brady, Mary Ann Jackson, Sarah S.
Long. American Academy of Pediatrics; 2015.
5. Schlaudecker EP, Steinhoff MC, Omer SB, et al. IgA and neutralizing antibodies to
influenza a virus in human milk: a randomized trial of antenatal influenza immunization.
PloS one. 2013;8(8):e70867. doi:10.1371/journal.pone.0070867
6. Drugs and Lactation Database (LactMed)[Internet]. COVID-19 Vaccines. Bethesda
(MD): National Library of Medicine (US). 2006:[Updated 2021 March 2017]. Available
from: https://www.ncbi.nlm.nih.gov/books/NBK565969/.
7. American College of Obstetricians Gynecologists. Practice advisory: Vaccinating
pregnant and lactating patients against COVID-19. Available from:
https://www.acog.org/clinical/clinical-guidance/practice-
advisory/articles/2020/12/vaccinating-pregnant-and-lactating-patients-against-covid-19
[Last updated March 24, 2021]. 2020.
Page 19 of 38
AR08710
8. Royal College of Obstetricians and Gynaecologists. COVID-19 vaccines, pregnancy and
breastfeeding. Available from: https://www.rcog.org.uk/en/guidelines-research-
services/coronavirus-covid-19-pregnancy-and-womens-health/covid-19-vaccines-and-
pregnancy/covid-19-vaccines-pregnancy-and-breastfeeding/. Published 2121. Accessed
22 April, 2021.
9. Ministry of Health Singapore. COVID-19 Vaccination. Available from:
https://www.moh.gov.sg/covid-19/vaccination. Published 2021. Accessed 31 March,
2021.
10. Tomori C, Gribble K, Palmquist AE, Ververs MT, Gross MS. When separation is not the
answer: Breastfeeding mothers and infants affected by COVID 19. Maternal & Child
Nutrition. 2020;16(4):e13033. doi:10.1111/mcn.13033
11. Baird JK, Jensen SM, Urba WJ, Fox BA, Baird JR. SARS-CoV-2 antibodies detected in
human breast milk post-vaccination. medRxiv. 2021:2021.2002.2023.21252328.
doi:10.1101/2021.02.23.21252328
12. Friedman MR, Kigel A, Bahar Y, et al. BNT162b2 COVID-19 mRNA vaccine elicits a
rapid and synchronized antibody response in blood and milk of breastfeeding women.
medRxiv. 2021. doi:10.1101/2021.03.06.21252603
13. Perl SH, Uzan-Yulzari A, Klainer H, et al. SARS-CoV-2–Specific Antibodies in Breast
Milk After COVID-19 Vaccination of Breastfeeding Women. JAMA. 2021.
doi:10.1001/jama.2021.5782
14. Valcarce V, Stafford LS, Neu J, et al. Detection of SARS-CoV-2 specific IgA in the
human milk of COVID-19 vaccinated, lactating health care workers. medRxiv. 2021.
doi:10.1101/2021.04.02.21254642
Page 20 of 38
AR08711
15. Golan Y, Prahl M, Cassidy A, et al. COVID-19 mRNA vaccine is not detected in human
milk. medRxiv. 2021. doi:10.1101/2021.03.05.21252998
16. ClinicalTrials.gov. Gestational Immunity for Transfer (GIFT). Availbale from:
https://clinicaltrials.gov/ct2/show/NCT04802278. Published 2021. Accessed 22 April,
2021.
17. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The
Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)
statement: guidelines for reporting observational studies. Ann Intern Med.
2007;147(8):573-577. doi:10.7326/0003-4819-147-8-200710160-00010
18. Atyeo C, DeRiso EA, Davis C, et al. COVID-19 mRNA vaccines drive differential Fc-
functional profiles in pregnant, lactating, and non-pregnant women. bioRxiv.
2021:2021.2004.2004.438404. doi:10.1101/2021.04.04.438404
19. Boyaka PN. Inducing mucosal IgA: a challenge for vaccine adjuvants and delivery
systems. The Journal of Immunology. 2017;199(1):9-16.
20. Pardi N, Tuyishime S, Muramatsu H, et al. Expression kinetics of nucleoside-modified
mRNA delivered in lipid nanoparticles to mice by various routes. Journal of Controlled
Release. 2015;217:345-351.
21. Academy of Breastfeeding Medicine. ABM STATEMENT: Considerations for COVID-
19 Vaccination in Lactation. Available from: https://www.bfmed.org/abm-statement-
considerations-for-covid-19-vaccination-in-lactation#. Published 2020. Accessed 22
April, 2021.
Page 21 of 38
AR08712
22. World Health Organization. Pfizer BioNTech COVID-19 vaccine: What you need to
know. Available from: https://www.who.int/news-room/feature-stories/detail/who-can-
take-the-pfizer-biontech-covid-19--vaccine. Published 2021. Accessed 23 April, 2021.
Page 22 of 38
AR08713
Figure legends
Figure 1. IgA antibodies in human milk samples
(A) & (B): Concentration [pMa] of IgA antibodies against spike (A) and RBD (B) in human milk
for vaccinated mothers (n =10) across all time points; convalescent (n = 6) and healthy mothers
(n = 9) used as reference cohort. Grey dotted lines reflect the limit of assay detection. Statistics
were calculated with Kruskal-Wallis test and Dunn’s post-test.
(C) & (D): Increase in IgA antibodies against spike (C) and RBD (D) over time. Each line in
grey represents data from one individual and the median ± IQR is represented in red.
Abbreviations: RBD, receptor-binding domain; IgA, immunoglobulin A; pM, picomolar; IQR,
interquartile range; T1, pre-vaccination; T2, 1-3 days after dose one of BNT162b2 vaccine; T3,
7-10 days after dose one of BNT162b2 vaccine; T4, 3-7 days after dose two of BNT162b2
vaccine.
a
SI conversion factors: To convert concentration from pM to M, multiply values by 1012.
Page 23 of 38
AR08714
Figure 2. IgG antibodies in human milk samples
(A) & (B): Concentration [pMa] of IgG antibodies against spike (A) and RBD (B) in human milk
for vaccinated mothers (n = 10) at T1 and T4; convalescent (n = 6) and healthy mothers (n = 9)
used as reference cohort. Grey dotted lines reflect the limit of assay detection. Statistics were
calculated with a two-tailed Wilcoxon test.
(C) & (D): Increase in IgG antibodies against spike (C) and RBD (D) over time. Each line in
grey represents data from one individual and the median ± IQR is represented in red.
Abbreviations: RBD, receptor-binding domain; IgG, immunoglobulin G; pM, picomolar; IQR,
interquartile range; T1, pre-vaccination; T4, 3-7 days after dose two of BNT162b2 vaccine.
a
Page 24 of 38
AR08715
Figure 3. Vaccinated mothers have both IgA and IgG in human milk unlike convalescent
mothers
(A) & (B): Concentration of spike (A) and RBD (B) IgA and IgG in vaccinated mothers (n = 10).
(C) & (D): Concentration of spike (C) and RBD (D) IgA and IgG in convalescent mothers (n =
6). Legend demonstrates the ratio of IgA and IgG in human milk, whereby the concentration of
IgA was divided by the concentration of IgG antibodies. Abbreviations: RBD, receptor-binding
domain; IgA, immunoglobulin A; IgG, immunoglobulin G; pMa, picomolar; IQR, interquartile
range; N.C., not calculated due to absence of either IgA or IgG antibodies.
a
Page 25 of 38
AR08716
Figure 4. Minimal transfer of BNT162b2 mRNA into human milk.
(A) Standard curve of cDNA reverse-transcribed from vaccine derived BNT162b2-spiked human
milk was made and used as a positive control. n ≥ 6 technical replicates; means are shown with
error bars indicating the standard error of measurement (SEM).
(B) Heat map of calculated median BNT162b2 mRNA concentrations in vaccinated mothers (n =
10) at four time points as indicated.
Abbreviations: CT, cycle threshold; pga, picogram; ngb, nanogram; mLc, milliliter; T1, pre-
vaccination; T2, 1-3 days after dose one of BNT162b2 vaccine; T3, 7-10 days after dose one of
BNT162b2 vaccine; T4, 3-7 days after dose two of BNT162b2 vaccine.
a
SI conversion factors: To convert concentration from pg to kg, multiply values by 1015.
Page 26 of 38
AR08717
b
SI conversion factors: To convert concentration from ng to kg, multiply values by 1012.
b
SI conversion factors: To convert concentration from mL to L, multiply values by 0.001.
1 2 5 6 7 8 0 9 7 7
00 00 00 00 00 00 01 02 04 06
M M M M M M M M M M
Page 27 of 38
AR08718
Page 28 of 38
AR08719
Table 1: Characteristics of vaccinated mothers
Age, mean [standard deviation, SD], years 33.5 [3.3]
Ethnicity 8 Singaporean Chinese
2 Singaporean Malay
Chronic diseases 9 None
1 Thalassemia minor
Antenatal conditions 10 None
Smoking history 10 No
Types of feeds provided 9 Exclusively breastfed
1 Mixed feeds
Time post-partum/breastfed, mean [SD], months 9.8 [4.0]
Page 29 of 38
AR08720
Online-Only Supplements
eMethods
Determination of antibody titers in human milk
Sensitive quantitation of BNT162b2 mRNA in human milk
eTables
eTable 1: Demographic and clinical details
eTable 2: Clinical details of antenatal COVID-19 and perinatal findings
eFigures
eFigure 1. Standard curves used in quantitative ELISA.
A human monoclonal antibody binding to both full spike and RBD of SARS-CoV-2 was recombinantly expressed as
human IgA1 and IgG1. Concentrations of (A) anti-spike IgA, (B) anti-RBD IgA, (C) anti-spike IgG, and (D) anti-
RBD IgG antibodies in human milk samples were estimated from interpolation of the standard curves constructed
using known concentrations of this antibody (in pMa).
Abbreviations: RBD, receptor-binding domain; IgA1, immunoglobulin A1; IgG1, immunoglobulin G1; pM,
picomolar; OD450, optical density measured at a wavelength of 450 nanometer.
a
eFigure 2. SARS-CoV-2 antigen-specific IgA levels in human milk samples.

OD450 values were measured for (A) anti-spike and (B) anti-RBD IgA antibodies in 10-fold diluted human milk
samples collected from vaccinated mothers (n = 10) at four time points pre- and post- vaccination. Statistics were
calculated with Kruskal-Wallis test with Dunn’s post-test. The same results are shown as line plots in (C) and (D)
for visualization of antibody response from each individual. Each line in grey represents data from one individual
and the median ± IQR is represented in red.
Abbreviations: OD450, optical density measured at a wavelength of 450 nanometer; RBD, receptor-binding domain;
IgA, immunoglobulin A; IQR, interquartile range; T1, pre-vaccination; T2, 1-3 days after dose one of BNT162b2
vaccine; T3, 7-10 days after dose one of BNT162b2 vaccine; T4, 3-7 days after dose two of BNT162b2 vaccine.
eFigure 3. SARS-CoV-2 antigen-specific IgG levels in human milk samples.

OD450 values were measured for (A) anti-spike and (B) anti-RBD IgG antibodies in 10-fold diluted human milk
samples collected from vaccinated mothers (n = 10) at two time points pre- (T1) and post- second dose vaccination
(T4). The same results are shown as line plots in (C) and (D) for visualization of antibody response from each
individual. Each line in grey represents data from one individual and the median ± IQR is represented in red.
IgG, immunoglobulin G; IQR, interquartile range; T1, pre-vaccination; T4, 3-7 days after dose two of BNT162b2
vaccine.
eFigure 4. Cross-comparison of SARS-CoV-2 antigen-specific IgA and IgG levels in human milk samples.
(A,B) OD450 values were measured for the vaccination cohort and show (A) anti-spike and (B) anti-RBD antibodies
in 10-fold diluted human milk samples collected from vaccinated mothers (n = 10) at 3-7 days after the second
vaccination dose (T4). (C,D) OD450 values were measured for the reference cohort and show (C) anti-spike and (D)
anti-RBD antibodies in 10-fold diluted human milk samples for cases (n = 6) at one month post-partum.
IgA, immunoglobulin A; IgG, immunoglobulin G; IQR, interquartile range.
eFigure 5. Standard curves using cDNA generated from BNT162b2-spiked human milk versus pTwist-
BNT162b2∆UTR plasmid.
One BNT162b2 equivalent is defined as a single-stranded polynucleotide molecule that contains a linear sequence
that binds either the forward or reverse primer. Prism analysis of the two regression lines revealed that their
slopes/gradients were not significantly different (P = .42). Data represented as the mean ± SEM, n ≥ 3 technical
replicates.
Abbreviations: cDNA, complementary DNA; CT, cycle threshold.
Page 30 of 38
AR08721
Detailed methods
Determination of antibody titers in human milk

IgA and IgG against SARS-CoV-2 antigens including the whole spike and RBD protein were titrated using
quantitative ELISA. 96-well flat-bottom maxi-binding immunoplate (SPL Life Sciences, #32296) were coated with
100 ng of SARS-CoV-2 whole spike protein or 200ng of RBD protein at 4 °C overnight. After three washes in
Phosphate Buffer Saline (PBS), 350 µL of blocking buffer [4% skim milk in PBS with 0.05% Tween 20 (PBST)]
was added to each well. After incubation for 1.5 hours, the plate was washed three times with PBST. 100 µL of 10-
fold diluted human milk samples were added to each well for 1-hour incubation. Plate was then washed three times
with PBST followed by 1-hour incubation in the dark with 100 µL of 5000-fold diluted goat anti-human IgG-HRP
(Invitrogen, #31413), or 5000-fold diluted F(ab’)2 anti-human IgA-HRP (Invitrogen, #A24458). Plate was washed
three times in PBST and incubated for 3 minutes with 1-Step Ultra TMB-ELISA (Thermo Scientific, #34029), 100
µL per well. Reaction was stopped with 100 µL of 1 M H2SO4 and OD450 was measured using a microplate reader
(Tecan Sunrise). OD450 was calculated by subtracting the background signal from sample binding to the blocking
buffer. A recombinant human monoclonal antibody targeting RBD of SARS-CoV-2 was engineered to both human
IgG1 and human IgA1. Standard curves for whole spike and RBD were constructed by testing known concentrations
(3.5 pM - 3.5 nM) of this antibody alongside the samples. Linear region of the standard curve was used to quantify
the IgG/IgA antibody concentration in human milk samples via interpolation. Experiments were performed at least
three times.
Sensitive quantitation of BNT162b2 mRNA in human milk

Total RNA from human milk was extracted with TRIzol LS reagent (Invitrogen) according to manufacturer’s
instructions. Briefly, 250 μL of whole human milk was RNA-extracted with 750 μL of Trizol LS and 200 μL of
chloroform. The entire upper aqueous fraction (~500 μL) was isopropanol-precipitated, washed with 70% ethanol
and air-dried before dissolution in RNAse-free water. The entire volume of RNA was used as input for SuperScript
IV (Invitrogen) reverse transcription performed as per manufacturer’s instructions and diluted 50-fold with RNAse-
free water to a final volume of 1 mL prior to storage at -20C or assay.
For standard curve construction, we collected BNT162b2 from actual vaccine discards. Five-fold serial dilutions of
reconstituted BNT162b2 vaccine were spiked into healthy, SARS-CoV-2 negative human milk and RNA-extracted
in parallel with vaccinee samples. These served as a positive control.
Taqman-based detection of BNT162b2 mRNA was performed using PrimeQuest-designed primer and probe sets
(Integrated DNA Technologies, IDT). The primer and probe sequences are as follows:
AGCCTACACCAACAGCTTTAC (forward primer), TGAAGAAAGGCAGGAACAGG (reverse primer) and /56-
FAM/CGACAAGGT/ZEN/GTTCAGATCCAGCGT/3IABkFQ/ (probe). Primers were used at 250 nM while probe
was used at 150 nM. An input volume of 1 μL was used for each diluted cDNA sample. Standard cycling conditions
used were as per recommendation by IDT.
A plasmid construct containing BNT162b2 cDNA without the 5’ and 3’ UTRs was synthesized (Twist Bioscience)
and is herein referred to as pTwist-BNT162b2∆UTR. Briefly, the BNT162b2 open reading frame is 3825 bases long
and consists of human codon-optimized SARS-CoV-2 spike glycoprotein containing the K986P and V987P
mutations1
Standard curve construction was performed in a separate experiment using pTwist-BNT162b2∆UTR and cDNA
generated from BNT162b2-spiked human milk with the aim of determining whether their performances in the
quantitative PCR assay were comparable.
References
1.Github. NAalytics. Assemblies-of-putative-SARS-CoV2-spike-encoding-mRNA-sequences-for-vaccines-BNT-
162b2-and-mRNA-1273. Available from: https://github.com/NAalytics/Assemblies-of-putative-SARS-CoV2-spike-
encoding-mRNA-sequences-for-vaccines-BNT-162b2-and-mRNA-1273. Accessed on 23 April, 2021
Page 31 of 38
AR08722
eTable 1: Demographic and clinical details
Demographic and clinical details Reference cohort (n = 6) Control cohort (n = 9)

Age, mean [standard deviation, SD], years 30.8 [4.1] 32.1 [4.1]
Ethnicity 1 Chinese 6 Chinese
2 Malay 1 Malay
1 Indian 2 Indian
2 Caucasian
Pre-existing comorbidities 5 None 8 None
1 Pre-existing hepatitis C 1 Pre-existing hepatitis C
Antenatal conditions 6 None 9 None
Antenatal ultrasound abnormalities 6 No abnormalities 2 Intrauterine growth
restriction
Gestational age at delivery, mean [SD], 40.0 [0.8] 39.2 [1.2]
weeks
Mode of delivery 6 Vaginal 6 Vaginal
3 Caesarean section
Gender of infants 5 Female 6 Female
Infant birth weight, mean [SD], kg 3.59 [0.24] 3.11 [0.61]
Infant birth length, mean [SD], cma 50.8 [1.6] 50.5 [2.2]
Infant birth occipital frontal circumference, 34.6 [0.9] 22.3 [1.2]
mean [SD], cma
Any immediate postnatal complications 5 None 8 None
1 Transient tachypnoea of the 1 Exaggerated physiological
newborn jaundice
Type of feeds 4 Exclusive breastfeeding 6 Exclusive breastfeeding
2 Mixed feeding 3 Mixed feeding
a
SI conversion factors: To convert length from cm to m, multiply values by 0.01.
Page 32 of 38
AR08723
eTable 2: Clinical details of antenatal COVID-19 and perinatal findings
Clinical details of antenatal COVID-19 and perinatal findings

COVID-19 diagnosis gestation 2 First trimester
1 Second trimester
3 Third trimester
Length of time between COVID-19 diagnosis and delivery, mean [SD], days 136 [80]
Severity of COVID-19 1 Asymptomatic
4 Mild
1 Moderate
Time between first positive PCR and first negative PCR, median (range), days 23 (17 - 39)
SARS-CoV-2 PCR from perinatal samples (nasopharyngeal, vaginal, umbilical All negative
cord and placental swabs, maternal blood, cord blood, amniotic fluid, human milk)
Placental / umbilical cord histology 2 Normal

3 Abnormal
1 Not done
Abbreviations: COVID-19, Coronavirus Disease 2019; PCR, polymerase chain reaction
Page 33 of 38
AR08724
eFigure 1. Standard curves used in quantitative ELISA.

A human monoclonal antibody binding to both full spike and RBD of SARS-CoV-2 was recombinantly expressed as
human IgA1 and IgG1. Concentrations of (A) anti-spike IgA, (B) anti-RBD IgA, (C) anti-spike IgG, and (D) anti-
RBD IgG antibodies in human milk samples were estimated from interpolation of the standard curves constructed
using known concentrations of this antibody (in pMa).
Abbreviations: RBD, receptor-binding domain; IgA1, immunoglobulin A1; IgG1, immunoglobulin G1; pM,
picomolar; OD450, optical density measured at a wavelength of 450 nanometer.
a
Page 34 of 38
AR08725
eFigure 2. SARS-CoV-2 antigen-specific IgA levels in human milk samples.

OD450 values were measured for (A) anti-spike and (B) anti-RBD IgA antibodies in 10-fold diluted human milk
samples collected from vaccinated mothers (n = 10) at four time points pre- and post- vaccination. Statistics were
calculated with Kruskal-Wallis test with Dunn’s post-test. The same results are shown as line plots in (C) and (D)
for visualization of antibody response from each individual. Each line in grey represents data from one individual
and the median ± IQR is represented in red.
IgA, immunoglobulin A; IQR, interquartile range; T1, pre-vaccination; T2, 1-3 days after dose one of BNT162b2
vaccine; T3, 7-10 days after dose one of BNT162b2 vaccine; T4, 3-7 days after dose two of BNT162b2 vaccine.
Page 35 of 38
AR08726
eFigure 3. SARS-CoV-2 antigen-specific IgG levels in human milk samples.

OD450 values were measured for (A) anti-spike and (B) anti-RBD IgG antibodies in 10-fold diluted human milk
samples collected from vaccinated mothers (n = 10) at two time points pre- (T1) and post- second dose vaccination
(T4). The same results are shown as line plots in (C) and (D) for visualization of antibody response from each
individual. Each line in grey represents data from one individual and the median ± IQR is represented in red.
IgG, immunoglobulin G; IQR, interquartile range; T1, pre-vaccination; T4, 3-7 days after dose two of BNT162b2
vaccine.
Page 36 of 38
AR08727
eFigure 4. Cross-comparison of SARS-CoV-2 antigen-specific IgA and IgG levels in human milk samples.
(A,B) OD450 values were measured for the vaccination cohort and show (A) anti-spike and (B) anti-RBD antibodies
in 10-fold diluted human milk samples collected from vaccinated mothers (n = 10) at 3-7 days after the second
vaccination dose (T4). (C,D) OD450 values were measured for the reference cohort and show (C) anti-spike and (D)
anti-RBD antibodies in 10-fold diluted human milk samples for cases (n = 6) at one month post-partum.
IgA, immunoglobulin A; IgG, immunoglobulin G; IQR, interquartile range.
Page 37 of 38
AR08728
eFigure 5. Standard curves using cDNA generated from BNT162b2-spiked human milk versus pTwist-
BNT162b2∆UTR plasmid.
One BNT162b2 equivalent is defined as a single-stranded polynucleotide molecule that contains a linear sequence
that binds either the forward or reverse primer. Prism analysis of the two regression lines revealed that their
slopes/gradients were not significantly different (P = .42). Data represented as the mean ± SEM, n ≥ 3 technical
replicates.
Abbreviations: cDNA, complementary DNA; CT, cycle threshold.
Page 38 of 38
.&.U.,5'-' ..I.. V..1.. ..I..
AR08729
~
r.ir.l Cen1e,• for O,seose ContrOl.and Prevention
~ CDC ')l T Sa..r.rotr.om ~"f'QPooplo"' X C\.
CDC WON DER FAQs Help Contact l.l5 WONDER S<earch
., ".
'
VAERS Ev ent Details
I ~ """"'"""""
"
Details ' or VAERS JO: 1 166901-1
E~i'llntQrl')lbOon l /v~nt Cl.1,e,gori~

P'Al~nt A!Jf" So,'11 1Vf'~f'C. .,. 0.alh
s,~te / 'lertito,y o...rew.~ co,-pt~ed l 'lO:??-Ql-26 Ute Thr-Nf~NJ
""
n1111• v;.,cdn_.u,d Obie R ~por1 A.ec:..;.ed 202 H>MIW,. ...
oar.-ofOr~t O..h, Oi...t C~ i u1I A - t y / 9lrth fk,J-e-ct • t..o
I~«
~ ~
08lys U> onset HosptltilizNI

VitedrwA&k.nini~lttredOy Otl-er V•cd11e PutchM.«l Oy .\~i(.a-b;A, • o.i,~ in t to, .ph.,! ,.,...
·_Mfr/ JcnmVmjef:t~ USJflll="C(W'2iOJJ'J3 2S: ftll!'pc»'t f.bnlt 'lre-N.kw'I ' E.)!istio:'9 Hospit:etlrafi<m Pf"OJo,,ot,d
Jt..c;o~red s.:nou... I n-, Cm.et'"~ Room / otlice V\Wl ....
• VAERS ? 0 P ~ kl.,-, On,-., r mierlJf?nq Roon, ,.
•• VAEP:S· l .Rfpct'l Fo,"ro Onfy
,~t 4Jl.i;l c ~.. .-.,1i .a-p~•-1• ,..Jot~ ,..Jom-.J-· •c,n -s. 11o-t ~,.-.,. at .i- or, 1n-s re<>Gtt fO<'m ve~or
~
Ott i<-eVisil •
VAERS :.a lt•port ~rr. Only
...
•-v;.E~S-tR~Fe•m~t,.
U a· A·~.ap,o+at w t!~ 1t1+o,,"';1~-in- is nc•
....~~ or tt,,i. ••Jl'Of"• f-.nn " ~ "
vacc::in. TY.Pt" VM'~ t-QnufMt,wN t~I I Do~• Route Sil•

co-..rOtl)VACC1U~ CO\'lOte (C(t.'Wt9 JAJISSfN • !AUSx-N t 1a.:-so29 ur.-:
S,,11:ip.ton1
Fi!POSVAE VU,. BJlEAS r Ht~.C
E.'IPOSUU 01.;Al".C ei:t[ASHE(Ol'..c. ti,,s. s.;:ortt ¥\to.ll. 11-PO(t •e-e.••-t!:d ,,~ ~ ~.l:<H'-1 (.0.'lt'"H-IS Ji tM-i cJ "~?Ko!~ • .tt~ """ T~ T->!...~•1n, ~§'I~ ~..t. M\4 ,,,...,.(.ill tt-1:wy
....... net r~o1titd . n,.., p.:ttcflt!>?~•.t.:tlt-1.'fli(Q~..,j. l'9 t,..l"i•.•nt-~6.c~2 i . , ~ i < M tN .n_t,Kt,on l""-ltf' c,t-14,,...nl\OI ltpi!rt.C. b o t ( ! ' ) ~ !IOWH. ~'f°"'' UJ;;,(t,o ,•m. do,,..,,
._..,.. r,t.,f •"'l)Crtelt ~ ..-...-steu·:1.-.n !O·t-•.i.y :i-1;,1 fur P'""1""114(ti< v~,._,,~uc,r, t~ t~o,,~•l m<(<(toi;•t,.,r1o -...il'•~ ,~ted 0 11..,. ,...u.p.K,l.«.:td.iu~ , i-.. b.ot-y ,."P"•~~6 ., .. p.,~,•
d:1.-,q
ble.»d.. Mr.g n,• .u,>l)ft ul.•"' ,.,.,,r, (<,J>S::• 1-> tl~(.,,.. d:'O c:o.:.> s w;as "-")I ~J)pt,(~ The i.,,.,!COl'"lt, tot bpf)s,..,.. ~ \r ~ tal!'.ht.f,.ed,~ .....$ ,v_;l •11:?0Fted Thl,. ••oo-rt _, '"'°" ~.-.- -
Mvdk.at"io- At l ime Of \JM:01-llltion nis:tairy/ ~
Notes:
D~ tOt'l~"d ~/~ll_S lt()t'l~ pt.><h~t,IJ ~ ,;;I O", l) ion .

l"'"f" \J;I.£~ dM• m
\'.'('UCtpc J><r~t~ "'-t-t:.-1-.. ,.: th•
\iMRS $;1.tH>\ rKtll-,K (Mt-~o;O..:l i;,;J(l;Joltt • N : ~ ,..,_,t.>Of'~ ~ ,,..,_ r•p,:.-ft,. !;..r ;:r«f".:fll"J ~,m• pM.i.d.J Dl.(' Kilt•
..-..-.-nt,eQQ:tl'll M'4'et f lip!)ftl dt(,:1,.- ~!'0-bf t..-~-•fil!l"l'\OV~~loM'RS. ~ ~ ; . . ! l .
Suggh.te d Cil~•lion;
tµ-.-•~ 5tM~ ~tJ~r)fl-ttol~h.Jl!dHt-<ll,>., c;-,.IC.,t TO"o,i-~) Pt,.b.'tc: J-l• illth ~.,re - PMS ( flor,u•"-'"" 0,t»ll~ (l)Al'r-1 {f'C,
Jood:.JndOoqA-<.>Tllf'•s.lf~•M ,fO.\\ ',{ac-<_w,.i,.,l,(t.t'f"Y-E.e<.tP""CIOrtlf'l()~'f"i"- "'c",UPS; It:i;()- M U 2017 WOkOUtOr\·~ c:~
c.x;i-e- ~c"w~ -;,n~· ·•"'"--dal (tY g.~,-~, hl':rr.' ""'H...-.,~ ~i•n 1 .s1·~1,ai.
ii'.- •• lf.r
Kt\vtOJ5T1(!HSl a><:INR!A:MATICN Pf"V«Y CCM.HT'MfflCDC
Q v""11cx ,;ro
'-.., ~.;HOO-BJ-46½
;:'ux:
f~
~:~i'.'~
OIG
II - a @
~
-
f~M(!Xi'd{) ~
f'RV--'lf-..1.P...t~
"'or.dis::•<m-"-..:)C...-,
N.t..-..$.i.-'1'J
-!-: ~ ~a
'o'ulnM,1b!ityO,-..:io-s,.,,,-,.P-o'l£)'I tsp.afwll
JML TRANSCRIPTION
1-888-288-6817
DATE: ~'k(
--'-?---,<:j,-.=-
J _"i_,-"'nl
-=--=n:....o:::..._ _
EX#: 8 INITIALS: A 'D
1 . ..... ... II I _ __ • . _ 1 1 •.• / .1 _ • _ .. _ • • • • • IT"'\.n ________ _ l"'\l'\l""lt.f"\ Ar f"\ L

..L U f ,"-' .l. '-".I. .I.
AR08730
l'iiiiTiil Cenlers to< O..eose ContrOI and Pre"Jention

llliiiieii COC'147 50',nglNC'< ~ 1 ' > 0 ~ " " X Q.
CDC WONDER fAQs H<?lp Contact Us WO'IDER Searm
-
., VAE'RS Event Detalfs
f
Details for VAERS !D: 0913971-1
..
_j
liN:nlCltl ~
S4t• .. l"f;,,I• .,.

O.,t~ V.n,c;c:lin~lll!d
0..t~ofO~I
c...-...,.......
2:J.:zo..t2
nz-.)--1:>n
:m ell, :::::::::::::~~::A::•:
Oal .. Died
tit.. 111--.steni,>9
P cnn.ar"'l!DI Oh.nbidity
Ceng,prutal Att.Oftl.&ly / flirth oefe<t •
rh
Ho
..,
Yi,u,ioteA.dttlO• l b i ~ D y u,,v-_....., I VacdtteP-l •n -~ . , ) " ltot~lilUb,..- O&rk, He.~~""l
.Mfr/ J,ettM Pr4tj«"t rJ ~ V'SJ.;r.;-FA JIKNJ'0~U7')0 ~ F_.,..Y• r S ~ r.xkt~ Ho5JH1'Mir,,-1~ ·P r:~"!J"°d ~
l t1¥i!r9<=,o,cy ko,o,n,, J O!ti<c 'Yhll •• Ii ,:,,

4
i.& A-.pq,.-,: Fonn c,i._,
,1,Gr,Elu Tff~l)(')'lt-•
•• VA.ElltS· ) Rc,pe.n k:ffll 0-"h
.,.,. • Appl~-.- w,H,1,0~~ ,,,,t,_-.n nt.:;rm~«t•t nora.. a. ..,(!;,.or, t '>itflp,c.n fiX'mY<ers:aor, OJt k~ y;..,,_.., ,.
• JA:f~ S1-~Rtsi,crtf'.illtl0ffl',-
•• -.r.:i.c.its 1 ~ o,.,,
• Fc;,.,..
,,~- fll'.1-lt,1.;;;P-',)• .,.,,.,,u,lo,..,.,l,tlMIG-l
~~~,t~ or. 11'.1; r•fr-O(T k),m ,...,.MJ"t
M ~ T,-JK V MOJ'Me , .... .~l.lf-1..HJ"M' l ol ~ N Oid,. s.it t
CO,..tOt!h'AC<:1115' CQVI019 '.CO\IJOl., :>l"Uf.«·~OU1KH #J.{Zfl\ 8.la'.)k-YEC'-1 HOl;E J Ot V•
t 1m ;;t.rl~'/ br•,Htt"°l1li"9...,.) inoo:h Oh: b .llb)' ::,W.1;. rf<,f"<>i'flg I ~ 'P.V.• tJ'f!-, .... h_,~b<ff•• rJ'V(h t.11,......-11',..,. l>c, ,_,....U,,, ,,.; 'fh.,- •~ .a S.?O"t.l•f"~--"' l&p◊'I .., _ ;I C:Ol't.Kt.,,t'l•r~• H
?l!o.t. .....,"' , • .-,o,r1..c1 ,r,h. .......tlt;D f(H t..:..tll. ,l'i'OUl-l:1 .-i,d ~ ~t',i$ k o ~ • ~I .t,. ) mvnc:hs. yi,;t rn.!• ~-..-r.t sl••totd t(, ,..:. . . . t,,,n62b-., UiW'V"\.lt...~.,W)I !hit Z9 , ••, okJ ff'Ofl•A'f
••<.. ~.0St4!lb.ZS.7 l;l . ,.,mbH tk~TJO,' do" ~n'IM• l °" L..n llol"'1o ..., S.r<glf- «>s.• on.O(),t(_:!,)::':) ,:;_4-00;:>H 1-w COY:t> !91JT'•J>1.>~;a.t..o. Tt.f/ ""'tl!IN h ...j k ;aVW,,-Ot.:,.'l..;.r\dQP! ..... 1111:,~
U:5.0 A"Jlo-•<~"' ~J • ...,...,. 11!1... ~ff: ,1/'t\0,1,ldlJ,... Conco,,1,t"'f;l INOdo<...t.of> •-N::kld♦'2 t.,.,:)ft-~Q>4•.... "'°'?o,,,... ,SYffloilltO:O; An.l- bt.p,,>f"' Tl',t, m,o,11'-
"°°"''h Qll;I b ••,.., 'Wnc• .........-lo-9 lhi- ~lt{(,,i• . 1'11' ~ bN-1\ m..<;1'1 li,s1 ... tl--M\ , .. n<),'mJi!t-. .,...,. r-,.,,. v-•d I>• (O~~u,t, -~ttod n .........-tt ~ d-..t~ ..,..,,,
....H.c: ... , ... r:,
1>1-t'il'1tG"9 "'' l
"''"'rd+<I!
M- )1Dtt2020 l l\olf"
.... ~ . _ ,.. l~lf!'d H PUl l r l ~ "'",. . . ~( l'luttome w~ t.•-.i.~0..11 t~ tl ♦M,..,f/M l t( ..."\.fod kr l 'W ~y~,!- e .. t101 ~~.. l o ...~ , 1\1.t)O,., !"'4- ,rvt~ot• ....~,. "IQ>! ~ i M ,,..,,i
CO>l~t)
19 Sil'l,,'4' 11,. , . M d , ~ ll\4c ~ -l~ t MO~ bfffl a u~ re• co·no 1g s.r.iot, • COf'N1'\f1,..S s.s.,e,c:1 ,c;!> t',e, ,..,..;,t,,.,.; , ..I.>! ~
•fl"M'l-d lM:.. ot 4'1l ..tl•~•v• r.,d,o,/Jv, r""- aJ.wc:oM.on
beh'te_.,, ,.,. r~l'f"l'° .r.Ol'Otl• w l!h 5J;t\O?b::' J.r roQI ue Ul•'l'~i ..:Y •vdi;~. t):,..h d ~epo,M(f,) ._,c:._ P'HZf~ IH '."' 20'10~ 1 l·U:l ff';cfb.-1 (.a,1,P
M~doc..tfOI~ Al lim41 0, Vi,cd1M1t k:,,,o • Wi,-A.iwy/ A)l~ ~
S-,NtHAO..O.
0M•(Ol't~"'5 \IA,(Jl!> fffl'<."1,, '1((',tff......,...,, ,-~u-. tJ n:n n,... J,UPSd.>I~ " ' ,',(,t.\C..UI Mfo M4.&f--:11'•C'i,"',,. , ... tile
Y~A"- (jl'I.!'- f,tt,...,M ff..,l>ft""°""
~ •O· ·flC<t).,,11>'9 ,.i-.,<;.o;;,..,._ ~tld ,,_ , .-por-h t-·, ~•«...rt;"') t r1e ~-t:i. Oup-i<~t.-
•w~tll r ~ 1 . .-,,t,,,:.J • • ~ • ,_t....,,.,.~ N:>b• !>:,., ;,,,., ,lfl'N>'.....d '!'-""" \..\IRS 'J , / ~~
Suooestcd (if d1ic:m:

l/1"1,~ofd5'~0.p,,.-i,..,....,ot ~ * h . P l d ~.. ~ ...... 11'1.'Phl+S.1.P.~c~u, ..... ,,.,PH"- c.-... "fo-(),y.,...u,r~~ t.Cl:C;I
f<rOa.,,.,Ofw-Q "'-:tr.r~t.-;.>i!.-. H'.:I. \,.-(0,..,..,=.d-,..,.u, f~-t<l • ~~S,,<.t- \,~<; t 990 • 05, lJ 2C.1.1 CC.iC ._.,"ON:;i-E-A ~ -.....♦
0~lr$,,@, /1.((,!,0,t,'.J K "lrf:t, . ....~ Ult go, ~iM<"S tittJ'I (oO P"ilN • ·· '/01'] 1 ~- VI AH
H,1,.VfQU5f'06> CDC~ Pr".}<)' a)(t(Nt< T'lffl"H CDC
Q w..rc.X ~k•O =c-oc :;e,1•.-.ct 11 W D @J

r~
\_
i3
C~!:OOZl."'-'bcJ6
ln-... {i)(-ft,fO
~ofk'!,p,;
rllfo~,«,N,71'en
o-<i
I',~~
kt:.-i.'1..!)<J<fy
1: ~ ~ a
~olbolf)'C,..,,.O'>ll•Pe(c:1!l".,p.li,,ol
JML TRANSCRIPTION
1-888-288-6817
DATE: __._N~?Yr..-1.2::..:4
1..:•~d'O~'o?£.e~ -
EX #: q
INITIALS: 1-\- ·J)
.1 - . I _ _ __ , ·- _ 11 _ .. / .1 _ , _
- _t - - -
AR08731
The COVID-19 Treatment Guidelines Panel's Statement on

the Use of lvermectin for the Treatment of COVID-19
Last Updated: January 14, 2021
•I '<,
l
Recommendation
• The COVID-19 Treatment Guidelines Panel (th/ Panel) has determined that currently there are
insufficient data to recommend either for or agaiµst the use of ivermectin for the treatment of
COVID-19. Results from adequately powered, well-designed, and well-conducted clinical trials
are needed to provide more specific, evidence-based guidance on the role of ivermectin for the
treatm~t
,. ofCOVID-19.
Rationale
Ivermectin is an antiparasitic drug that is approved by the Food and Drug Administration (FDA) for the
treatment of onchocerciasis and strongyloidiasis. Ivermectin is not FDA-approved for the treatment of
any viral infection. In general, the drug is well tolerated. It is currently being evaluated as a potential
treatment for COVID-19.
Antiviral andAnti-Inflammatory Effects ofIvermectin

Reports from in vitro studies suggest that ivermectin acts by inhibiting the host importin alfa/beta-1
nuclear transport proteins, which are part of a key intracellular transport process that viruses hijack to
enhance infection by suppressing the host antiviral response. 1.z In addition, ivermectin docking in vitro
may interfere with the attachment of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-
2) spike protein to the human cell membrane.3
Ivermectin has been shown to inhibit the replication of SARS-CoV-2 in cell culture. However,
pharmacokinetic and pharmacodynamic studies suggest that ivermectin doses up to I 00-fold higher than
those approved for use in humans would be required to achieve the plasma concentrations necessary
to duplicate the drug's antiviral efficacy in vitro.4•5 Even though ivermectin appears to accumulate
in lung tissue, with the doses used in most clinical trials, predicted systemic plasma and lung tissue
concentrations are much lower than 2 µM, the half-maximal inhibitory concentration (IC50) against
SARS-CoV-2 in vitro.6.7
Ivermectin demonstrates potential anti-inflammatory properties in some in vitro studies,8.9 properties

which have been postulated to be beneficial in the treatment of COVID-19. 10
Clinical Data
Since the last revision of the Ivermectin section of the Guidelines, the results of several randomized
trials and retrospective cohort studies of ivermectin use in patients with COVID-19 have been published
in peer-reviewed journals or made available as preliminary, non-peer-reviewed reports. Some clinical
studies showed no benefits or worsening of disease after ivermectin use, u-14 whereas others reported
shorter time to resolution of disease manifestations attributed to COVID- 19,1> 18 greater reduction in
inflammatory markers, 16•17 shorter time to viral clearance, 11•16 or lower mortality rates in patients who
received ivermectin than in patients who received comparator drugs or placebo. 11 •16•18
However, most of the studies reported to date had incomplete information and significant
methodological limitations, which make it difficult to exclude common causes of bias. The missing
information and limitations include the following:
JML TRANSCRIPTION
COVID-19 Treatment Guidelines
DATE: 761 ~'-f.
EX#:__.,__
__
1-888-288-6817
~d"?--
..__ INITIALS: -A-1:>
6
AR08732
• The sample size of most of the trials was small.

• Various doses and schedules of ivermectin were used.
• Some of the randomized controlled trials were open-label studies in which neither the participants
nor the investigators were blinded to the treatment arms.
• In addition to ivermectin or the comparator drug, patients also received various concomitant
medications (e.g., doxycycline, hydroxychloroquine, azithromycin, zinc, corticosteroids),
confounding assessment of the true efficacy or safety of ivermectin.
• The severity of COVID-19 in the study participants was not always well described.
• The study outcome measures were not always clearly defined.
Because of these limitations, the Panel cannot draw definitive conclusions about the clinical efficacy or
safety of ivermectin for the treatment of COVID-19. Results from adequately powered, well-designed,
and well-conducted clinical trials are needed to provide more specific, evidence-based guidance on the
role of ivermectin for the treatment of COVID-19.
References
1. Yang SNY, Atkinson SC, Wang C, et al. The broad spectrum antiviral ivermectin targets the host nuclear
transport importin alpha/beta1 heterodimer. Antiviral Res. 2020;177:104760. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32135219.
2. Arévalo AP, Pagotto R, Pórfido J, et al. Ivermectin reduces coronavirus infection in vivo: a mouse
experimental model. bioRxiv. 2020;Preprint. Available at:
https://www.biorxiv.org/content/10.1101/2020.11.02.363242v1.
3. Lehrer S, Rheinstein PH. Ivermectin docks to the SARS-CoV-2 spike receptor-binding domain attached to
ACE2. In Vivo. 2020;34(5):3023-3026. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32871846.
4. Guzzo CA, Furtek CI, Porras AG, et al. Safety, tolerability, and pharmacokinetics of escalating high doses of
ivermectin in healthy adult subjects. J Clin Pharmacol. 2002;42(10):1122-1133. Available at:
5. Chaccour C, Hammann F, Ramon-Garcia S, Rabinovich NR. Ivermectin and COVID-19: keeping rigor in
times of urgency. Am J Trop Med Hyg. 2020;102(6):1156-1157. Available at:
6. Arshad U, Pertinez H, Box H, et al. Prioritization of anti-SARS-CoV-2 drug repurposing opportunities
based on plasma and target site concentrations derived from their established human pharmacokinetics. Clin
Pharmacol Ther. 2020;108(4):775-790. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32438446.
7. Bray M, Rayner C, Noel F, Jans D, Wagstaff K. Ivermectin and COVID-19: a report in antiviral research,
widespread interest, an FDA warning, two letters to the editor and the authors’ responses. Antiviral Res.
2020;178:104805. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32330482.
8. Zhang X, Song Y, Ci X, et al. Ivermectin inhibits LPS-induced production of inflammatory cytokines and
improves LPS-induced survival in mice. Inflamm Res. 2008;57(11):524-529. Available at:
9. Ci X, Li H, Yu Q, et al. Avermectin exerts anti-inflammatory effect by downregulating the nuclear
transcription factor kappa-B and mitogen-activated protein kinase activation pathway. Fundam Clin
Pharmacol. 2009;23(4):449-455. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19453757.
10. DiNicolantonio JJ, Barroso J, McCarty M. Ivermectin may be a clinically useful anti-inflammatory agent for
late-stage COVID-19. Open Heart. 2020;7(2). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32895293.
11. Ahmed S, Karim MM, Ross AG, et al. A five-day course of ivermectin for the treatment of COVID-19 may
reduce the duration of illness. Int J Infect Dis. 2020;103:214-216. Available at:
COVID-19 Treatment Guidelines 7

AR08733
12. Chachar AZK, Khan KA, Asif M, Tanveer K, Khaqan A, Basri R. Effectiveness of ivermectin in
SARS-COV-2/COVID-19 Patients. Int J Sci. 2020;9:31-35. Available at:
https://www.ijsciences.com/pub/article/2378.
13. Chowdhury ATMM, Shahbaz M, Karim MR, Islam J, Guo D, He S. A randomized trial of ivermectin-
doxycycline and hydroxychloroquine-azithromycin therapy on COVID19 patients. Research Square.
2020;Preprint. Available at:
https://assets.researchsquare.com/files/rs-38896/v1/3ee350c3-9d3f-4253-85f9-1f17f3af9551.pdf.
14. Soto-Becerra P, Culquichicón C, Hurtado-Roca Y, Araujo-Castillo RV. Real-world effectiveness of
hydroxychloroquine, azithromycin, and ivermectin among hospitalized COVID-19 patients: results of a target
trial emulation using observational data from a nationwide healthcare system in Peru. medRxiv. 2020;Preprint.
Available at: https://www.medrxiv.org/content/10.1101/2020.10.06.20208066v3.
15. Hashim HA, Maulood MF, Rasheed AW, Fatak DF, Kabah KK, Abdulamir AS. Controlled randomized
clinical trial on using ivermectin with doxycycline for treating COVID-19 patients in Baghdad, Iraq. medRxiv.
2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.10.26.20219345v1/.
16. Elgazzar A, Hany B, Youssef SA, Hafez M, Moussa H, eltaweel A. Efficacy and safety of ivermectin for
treatment and prophylaxis of COVID-19 pandemic. Research Square. 2020;Preprint. Available at:
https://www.researchsquare.com/article/rs-100956/v2.
17. Niaee MS, Gheibi N, Namdar P, et al. Ivermectin as an adjunct treatment for hospitalized adult COVID-19
patients: a randomized multi-center clinical trial. Research Square. 2020;Preprint. Available at:
https://www.researchsquare.com/article/rs-109670/v1.
18. Khan MSI, Khan MSI, Debnath CR, et al. Ivermectin treatment may improve the prognosis of patients with
COVID-19. Arch Bronconeumol. 2020;56(12):828-830. Available at:

AR08734
COVID-19 Treatment Guidelines
Credit NIAID-RML
Downloaded from https://www.covid19treatmentguidelines.nih.gov/ on 5/8/2022

Visit https://www.covid19treatmentguidelines.nih.gov/ to access the most up-to-date guideline.
JML TRANSCRIPTION
y D 1-888-288--6817
DATE: M?j
7
-:J-,lf, ef9g:?,.
EX#: ~ l;i( ....!.IT-'ifAL~S2.:=-
-=-...!.,N t>~-1>=---
How to Cite the cmo-11 TreatmeAt Guldeli1es: ---

COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of
Health. Available at https://www.covid19treatmentguidelines.nih.gov/. Accessed [insert date].
The COVID-19 Treatment Guidelines Panel regularly updates the recommendations in these guidelines as new infonnation
on the management of COVID-19 becomes available. The most recent version of the guidelines can be found on the
COVID-19 Treatment Guidelines website (https://www.covid19treatmentguidelines.nih.gov/).

AR08735
Table of Contents
What’s New in the Guidelines................................................................................................... 5
Guidelines Development........................................................................................................... 8
Overview of COVID-19............................................................................................................ 11
Testing for SARS-CoV-2 Infection....................................................................................... 16
Prevention of SARS-CoV-2 Infection.................................................................................. 23
Clinical Spectrum of SARS-CoV-2 Infection....................................................................... 32
Prioritization of Anti-SARS-CoV-2 Therapies for the Treatment and Prevention of
COVID-19 When There Are Logistical or Supply Constraints............................................. 41
Clinical Management Summary.............................................................................................. 44
General Management of Nonhospitalized Patients With Acute COVID-19........................ 49
Therapeutic Management of Nonhospitalized Adults With COVID-19............................... 56
Therapeutic Management of Hospitalized Adults With COVID-19..................................... 67
Therapeutic Management of Hospitalized Pediatric Patients With Multisystem
Inflammatory Syndrome in Children (MIS-C) (With Discussion on Multisystem
Inflammatory Syndrome in Adults [MIS-A])......................................................................... 83
Care of Critically Ill Adult Patients With COVID-19................................................................ 93
General Considerations...................................................................................................... 95
Infection Control............................................................................................................... 103
Hemodynamics................................................................................................................. 106
Oxygenation and Ventilation............................................................................................. 110
Acute Kidney Injury and Renal Replacement Therapy..................................................... 118
Pharmacologic Interventions............................................................................................ 119
Extracorporeal Membrane Oxygenation........................................................................... 120
Antiviral Drugs That Are Approved, Authorized, or Under Evaluation for the Treatment
of COVID-19........................................................................................................................... 122
Remdesivir........................................................................................................................ 124
Table 2a. Remdesivir: Selected Clinical Data.............................................................. 128
Ritonavir-Boosted Nirmatrelvir (Paxlovid)......................................................................... 134
Molnupiravir...................................................................................................................... 142
Chloroquine or Hydroxychloroquine and/or Azithromycin................................................ 146
Table 2b. Chloroquine or Hydroxychloroquine and/or Azithromycin:
Selected Clinical Data ................................................................................................ 150
Interferons......................................................................................................................... 160
Table 2c. Interferons: Selected Clinical Data .............................................................. 162
Ivermectin......................................................................................................................... 168
Table 2d. Ivermectin: Selected Clinical Data............................................................... 172
Lopinavir/Ritonavir and Other HIV Protease Inhibitors..................................................... 184
Nitazoxanide..................................................................................................................... 189

AR08736
Table 2e. Nitazoxanide: Selected Clinical Data........................................................... 191

Table 2f. Characteristics of Antiviral Agents..................................................................... 194
Anti-SARS-CoV-2 Antibody Products.................................................................................. 200
Anti-SARS-CoV-2 Monoclonal Antibodies........................................................................ 202
Table 3a. Anti-SARS-CoV-2 Monoclonal Antibodies: Selected Clinical Data.............. 214
COVID-19 Convalescent Plasma...................................................................................... 218
Table 3b. COVID-19 Convalescent Plasma: Selected Clinical Data............................ 226
Immunoglobulins: SARS-CoV-2-Specific......................................................................... 233
Table 3c. Characteristics of SARS-CoV-2 Antibody-Based Products.............................. 234
Cell-Based Therapy Under Evaluation for the Treatment of COVID-19.............................. 239
Immunomodulators Under Evaluation for the Treatment of COVID-19.............................. 242
Colchicine......................................................................................................................... 243
Corticosteroids.................................................................................................................. 248
Table 4a. Systemic Corticosteroids: Selected Clinical Data........................................ 255
Table 4b. Inhaled Corticosteroids: Selected Clinical Data........................................... 261
Fluvoxamine...................................................................................................................... 265
Table 4c. Fluvoxamine: Selected Clinical Data............................................................ 268
Granulocyte-Macrophage Colony-Stimulating Factor Inhibitors...................................... 271
Table 4d. Granulocyte-Macrophage Colony-Stimulating Factor Inhibitors:
Selected Clinical Data................................................................................................. 274
Immunoglobulins: Non-SARS-CoV-2-Specific................................................................. 278
Interleukin-1 Inhibitors...................................................................................................... 280
Interleukin-6 Inhibitors...................................................................................................... 286
Table 4e. Interleukin-6 Inhibitors: Selected Clinical Data............................................ 292
Kinase Inhibitors: Janus Kinase Inhibitors and Bruton’s Tyrosine Kinase Inhibitors......... 299
Table 4f. Characteristics of Immunomodulators............................................................... 307
Antithrombotic Therapy in Patients with COVID-19............................................................ 319
Table 5. Antithrombotic Therapy: Selected Clinical Data.................................................. 330
Supplements.......................................................................................................................... 337
Vitamin C........................................................................................................................... 338
Vitamin D........................................................................................................................... 341
Zinc................................................................................................................................... 343
Considerations for Using Concomitant Medications in Patients With COVID-19.............. 347
Special Populations.............................................................................................................. 349
Special Considerations in Pregnancy............................................................................... 349
Special Considerations in Children................................................................................... 354
Special Considerations in Adults and Children With Cancer............................................ 365

AR08737
Special Considerations in Solid Organ Transplant, Hematopoietic Stem Cell

Transplant, and Cellular Immunotherapy Candidates, Donors, and Recipients............... 374
Special Considerations in People With HIV...................................................................... 382
Influenza and COVID-19................................................................................................... 389
Appendix A, Table 1. COVID-19 Treatment Guidelines Panel Members............................. 394
Appendix A, Table 2. Panel on COVID-19 Treatment Guidelines Financial Disclosure
for Companies Related to COVID-19 Treatment or Diagnostics......................................... 396

AR08738
What’s New in the Guidelines

Last Updated: April 29, 2022
The Coronavirus Disease 2019 (COVID-19) Treatment Guidelines is published in an electronic format
that can be updated in step with the rapid pace and growing volume of information regarding the
treatment of COVID-19.
The COVID-19 Treatment Guidelines Panel (the Panel) is committed to updating this document to
ensure that health care providers, patients, and policy experts have the most recent information regarding
the optimal management of COVID-19 (see the Panel Roster for a list of Panel members).
New Guidelines sections and recommendations and updates to existing Guidelines sections are
developed by working groups of Panel members. All recommendations included in the Guidelines are
endorsed by a majority of Panel members (see Guidelines Development for additional details on the
Guidelines development process).
Major revisions to the Guidelines within the past month are as follows:
April 29, 2022

Guidelines Development
The title of this section has been changed to better describe the contents of the section.
Previously, the Panel used the designations A (strong), B (moderate), or C (optional) to rate the strength
of each recommendation in the Guidelines. Based on feedback from clinicians and Panel members, the
definition for the C rating has been changed from “optional” to “weak” to better reflect the strength of
the Panel’s recommendations.
Prevention of SARS-CoV-2 Infection

In vitro data have shown that the BA.1 and BA.1.1 subvariants of the Omicron (B.1.1.529) variant have
decreased susceptibility to tixagevimab plus cilgavimab (Evusheld). The Food and Drug Administration
(FDA) Emergency Use Authorization (EUA) previously stated that people who received an initial
dose of tixagevimab 150 mg plus cilgavimab 150 mg for pre-exposure prophylaxis (PrEP) should be
given a second dose as soon as possible. The FDA recently modified the EUA to provide guidance for
the specific dose of tixagevimab plus cilgavimab that a person should receive based on the amount of
time that has passed since the first dose was administered. This new dosing guidance has been added to
Prevention of SARS-CoV-2 Infection.
Ivermectin
Results from 2 recently published, large randomized controlled trials showed that the use of ivermectin
did not provide a clinical benefit for patients with mild to moderate COVID-19. Based on these results,
the Panel now recommends against the use of ivermectin for the treatment of COVID-19, except in
clinical trials (AIIa). Table 2d was updated to include the results from key clinical trials that have been
published since the last revision.
Anti-SARS-CoV-2 Monoclonal Antibodies

This section was updated with information on the role of bebtelovimab in the treatment of
nonhospitalized patients with mild to moderate COVID-19 who are at high risk of disease progression.
In addition, sotrovimab is no longer recommended as a treatment option for patients with COVID-19

AR08739
because it has substantially reduced in vitro activity against the Omicron BA.2 subvariant. Table A has
been updated with information on the in vitro susceptibility of circulating variants of concern and the
anticipated clinical activity of the different anti-SARS-COV-2 monoclonal antibodies (mAbs) against
variants and subvariants. The Panel also added recent clinical trial results to Table 3a.
COVID-19 Convalescent Plasma

This section was updated to reflect changes to the COVID-19 convalescent plasma (CCP) EUA,
which was revised in December 2021 to authorize the use of high-titer CCP for the treatment of
COVID-19 only for outpatients or inpatients who have immunosuppressive disease or who are receiving
immunosuppressive treatment. The text also addresses the use of CCP collected prior to the emergence
of the Omicron variant and summarizes the clinical data on CCP use in immunocompetent and
immunocompromised patients. In addition, 2 trials that investigated the use of CCP in nonhospitalized,
immunocompetent populations were added to Table 3b.
Based on the available data, the Panel’s revised recommendations for the use of CCP are as follows:
• The Panel recommends against the use of CCP that was collected prior to the emergence of the
Omicron variant for the treatment of COVID-19 (AIII).
• The Panel recommends against the use of CCP for the treatment of COVID-19 in hospitalized,
immunocompetent patients (AI).
• There is insufficient evidence for the Panel to recommend either for or against the use of high-titer
CCP that was collected after the emergence of Omicron for the treatment of immunocompromised
patients and nonhospitalized, immunocompetent patients with COVID-19.
April 8, 2022
Therapeutic Management of Nonhospitalized Adults With COVID-19
The Panel previously recommended the anti-SARS-CoV-2 mAb sotrovimab as a treatment option for
certain nonhospitalized patients with COVID-19. Although sotrovimab is active against the Omicron
BA.1 and BA.1.1 subvariants, it has substantially decreased in vitro activity against the Omicron BA.2
subvariant that has recently become the dominant subvariant in the United States.
Because the Omicron BA.2 subvariant is now the dominant circulating subvariant in all regions of the
United States, the distribution of sotrovimab has been paused, and the Panel no longer recommends
using sotrovimab to treat COVID-19. The recommendations and rationale for using sotrovimab have
been removed from this section.
Table 3c. Characteristics of SARS-CoV-2 Antibody-Based Products

This section includes information about the pause in the distribution of sotrovimab and updated dosing
information for tixagevimab plus cilgavimab.
April 1, 2022
Therapeutic Management of Nonhospitalized Adults With COVID-19
The Omicron BA.2 subvariant is rapidly becoming the dominant subvariant in many regions of the
United States. Previously, the Panel recommended sotrovimab, an anti-SARS-CoV-2 mAb, as 1 of the
preferred therapies for the treatment of nonhospitalized patients with mild to moderate COVID-19 who
are at high risk of progressing to severe disease. Even though sotrovimab is active against the Omicron
BA.1 and BA.1.1 subvariants, it has substantially decreased in vitro activity against the BA.2 subvariant.

AR08740
The FDA recently updated the EUA for sotrovimab to note that it is not authorized for use in geographic
regions where infection is likely to have been caused by nonsusceptible SARS-CoV-2 variants, and
distribution of sotrovimab has been paused in these regions.
As a result of these recent changes and the increasing prevalence of the BA.2 subvariant across all
regions, the Panel no longer recommends sotrovimab as a preferred therapy for nonhospitalized patients
with mild to moderate COVID-19 who are at high risk of progressing to severe disease.
The Panel’s revised recommendations are outlined below.
Preferred Therapies
Listed in order of preference:
• Ritonavir-boosted nirmatrelvir (Paxlovid) (AIIa)
• Remdesivir (BIIa)
Alternative Therapies
For use ONLY when neither of the preferred therapies are available, feasible to use, or clinically
appropriate. Listed in alphabetical order:
• Bebtelovimab (CIII)
• Molnupiravir (CIIa)
For use ONLY in regions where the Omicron BA.2 subvariant is not the dominant subvariant and in
situations where none of the preferred or alternative options are available, feasible to use, or clinically
appropriate:
• Sotrovimab (CIII)
The text and Figure 1 in Therapeutic Management of Nonhospitalized Adults With COVID-19 have
been updated to include the rationale that supports these new recommendations. This section also now
incorporates information from the Panel’s previously published statement on the role of bebtelovimab in
the treatment of these patients.

This section includes new information on bebtelovimab, distribution information for sotrovimab, and
updated dosing information for tixagevimab plus cilgavimab.

AR08741
Guidelines Development
The COVID-19 Treatment Guidelines were developed to provide clinicians with guidance on how
to care for patients with COVID-19. Because clinical information about the optimal management of
COVID-19 is evolving quickly, these Guidelines are updated frequently to reflect newly published data
and other authoritative information.
Panel Composition
Members of the COVID-19 Treatment Guidelines Panel (the Panel) are appointed by the Panel co-chairs
based on their clinical experience and expertise in patient management, translational and clinical
science, and/or the development of treatment guidelines. Panel members include representatives from
federal agencies, health care organizations, academic organizations, and professional societies. Federal
agencies and professional societies represented on the Panel include:
• American Association of Critical-Care Nurses
• American Association for Respiratory Care
• American College of Chest Physicians
• American College of Clinical Pharmacy
• American College of Emergency Physicians
• American College of Obstetricians and Gynecologists
• American Society of Hematology
• American Thoracic Society
• Biomedical Advanced Research and Development Authority
• Centers for Disease Control and Prevention
• Department of Defense
• Department of Veterans Affairs
• Food and Drug Administration
• Infectious Diseases Society of America
• National Institutes of Health
• Pediatric Infectious Diseases Society
• Society of Critical Care Medicine
• Society of Infectious Diseases Pharmacists
The inclusion of representatives from professional societies does not imply that their societies have
endorsed all elements of these Guidelines.
The names, affiliations, and financial disclosures of the Panel members and ex officio members, as well
as members of the Guidelines support team, are provided in the Panel Roster and Financial Disclosure
sections of the Guidelines.
Development of the Guidelines

Each section of the Guidelines is developed by a working group of Panel members with expertise in the

AR08742
area addressed in the section. Each working group is responsible for identifying relevant information and
published scientific literature and for conducting a systematic, comprehensive review of that information
and literature. The working groups propose updates to the Guidelines based on the latest published
research findings and clinical information.
New Guidelines sections and recommendations are reviewed and voted on by the voting members of the
Panel. To be included in the Guidelines, a recommendation statement must be endorsed by a majority
of voting members; this applies to recommendations for and against treatments and cases where there
is insufficient evidence to recommend either for or against treatments. Updates to existing sections that
do not affect the rated recommendations are approved by Panel co-chairs without a Panel vote. Panel
members are required to keep all Panel deliberations and unpublished data that are evaluated during the
development of the Guidelines confidential.
Method of Synthesizing Data and Formulating Recommendations

The working groups critically review and synthesize the available data to develop recommendations.
During this process, the Panel evaluates the data, including the source of the data, the type of study (e.g.,
randomized controlled trial, prospective or retrospective cohort study, case series, in vitro study), the
quality and suitability of the methods, the number of participants, and the effect sizes observed.
The recommendations in these Guidelines are based on scientific evidence and expert opinion. Each
recommendation includes 2 ratings: an uppercase letter (A, B, or C) that indicates the strength of the
recommendation and a Roman numeral with or without a lowercase letter (I, IIa, IIb, or III) that
indicates the quality of the evidence that supports the recommendation.
Table 1. Recommendation Rating Scheme
Strength of Recommendation Quality of Evidence for Recommendation
A: Strong recommendation for the statement I: One or more randomized trials without major
B: Moderate recommendation for the statement limitations
C: Weak recommendation for the statement IIa: Other randomized trials or subgroup analyses of
randomized trials
IIb: Nonrandomized trials or observational cohort studies
III: Expert opinion
To develop the recommendations in these Guidelines, the Panel uses data from the rapidly growing
body of research on COVID-19. The Panel also relies heavily on experience with other diseases,
supplemented with the members’ evolving clinical experience with COVID-19.
In general, the recommendations in these Guidelines fall into the following categories:
• The Panel recommends using [blank] for the treatment of COVID-19 (rating).
Recommendations in this category are based on evidence that the potential benefits of using this
intervention outweigh the potential risks.
• There is insufficient evidence for the Panel to recommend either for or against the use of
[blank] for the treatment of COVID-19 (no rating). This statement is used when there are
currently not enough data to support a recommendation, or the available data are conflicting.
• The Panel recommends against the use of [blank] for the treatment of COVID-19, except
in a clinical trial (rating). This recommendation is used for an intervention that has not clearly
demonstrated efficacy in the treatment of COVID-19 and/or has potential safety concerns. More
clinical trials are needed to further define the role of the intervention in treating COVID-19.

AR08743
• The Panel recommends against the use of [blank] for the treatment of COVID-19 (rating).
This recommendation is used in cases where the available data clearly show a safety concern and/
or the data show no benefit to using this intervention for the treatment of COVID-19.
Evolving Knowledge on Treatments for COVID-19

Remdesivir, an antiviral agent, is currently the only drug that is approved by the Food and Drug
Administration for the treatment of COVID-19. An array of drugs that are approved for other indications
and multiple investigational agents are being studied for the treatment of COVID-19 in clinical trials
around the globe. These trials can be accessed at ClinicalTrials.gov. In addition, providers can access
and prescribe investigational drugs or agents that are approved or licensed for other indications through
various mechanisms, including Emergency Use Authorizations, Emergency Investigational New Drug
applications, compassionate use or expanded access programs with drug manufacturers, and/or off-label
use.
Whenever possible, the Panel recommends that promising, unapproved, or unlicensed treatments for
COVID-19 be studied in well-designed, controlled clinical trials. This recommendation also applies
to drugs that have been approved or licensed for indications other than the treatment of COVID-19.
The Panel recognizes the critical importance of clinical research in generating evidence to address
unanswered questions regarding the safety and efficacy of potential treatments for COVID-19. However,
the Panel also realizes that many patients and providers who cannot access these potential treatments via
clinical trials still seek guidance about whether to use them.
New data on the treatment of COVID-19 are emerging at a rapid pace. Some of these data are being
published in peer-reviewed journals, but some can be found in manuscripts that have not yet been peer
reviewed or in press releases. The Panel continuously reviews the available data and assesses their
scientific rigor and validity. These sources of data and the clinical experiences of the Panel members
are used to determine whether new recommendations or changes to the current recommendations are
warranted.
Finally, it is important to stress that the rated treatment recommendations in these Guidelines should
not be considered mandates. The choice of what to do or not to do for an individual patient is ultimately
decided by the patient and their provider.

AR08744
Overview of COVID-19
Epidemiology
The COVID-19 pandemic has exploded since cases were first reported in China in December 2019. As
of April 15, 2022, more than 503 million cases of COVID-19—caused by SARS-CoV-2 infection—have
been reported globally, including more than 6.2 million deaths.1
Individuals of all ages are at risk for SARS-CoV-2 infection and severe disease. However, the
probability of serious COVID-19 disease is higher in people aged ≥60 years, those living in a nursing
home or long-term care facility, and those with chronic medical conditions. In an analysis of more than
1.3 million laboratory-confirmed cases of COVID-19 that were reported in the United States between
January and May 2020, 14% of patients required hospitalization, 2% were admitted to the intensive care
unit, and 5% died.2 The percentage of patients who died was 12 times higher among those with reported
medical conditions (19.5%) than among those without medical conditions (1.6%), and the percentage
of patients who were hospitalized was 6 times higher among those with reported medical conditions
(45.4%) than among those without medical conditions (7.6%). Mortality was highest in patients aged
>70 years, regardless of the presence of chronic medical conditions. Data on comorbid health conditions
among patients with COVID-19 indicate that 32% had cardiovascular disease, 30% had diabetes, and
18% had chronic lung disease. Other conditions that may lead to a high risk for severe COVID-19
include cancer, kidney disease, liver disease (especially in patients with cirrhosis), obesity, sickle cell
disease, and other immunocompromising conditions. Transplant recipients and pregnant people are also
at a higher risk of severe COVID-19.3-10
Data from the United States suggest that racial and ethnic minorities experience higher rates of
COVID-19, subsequent hospitalization, and death.11-15 However, surveillance data that include race and
ethnicity are not available for most reported cases of COVID-19 in the United States.4,16 Factors that
contribute to the increased burden of COVID-19 in these populations may include over-representation
in work environments that confer higher risks of exposure to COVID-19, economic inequality (which
limits people’s ability to protect themselves against COVID-19 exposure), neighborhood disadvantage,17
and a lack of access to health care.16 Structural inequalities in society contribute to health disparities for
racial and ethnic minority groups, including higher rates of comorbid conditions (e.g., cardiac disease,
diabetes, hypertension, obesity, pulmonary diseases), which further increase the risk of developing
severe COVID-19.15
SARS-CoV-2 Variants
Like other RNA viruses, SARS-CoV-2 is constantly evolving through random mutations. New mutations
can potentially increase or decrease infectiousness and virulence. In addition, mutations can increase
the virus’ ability to evade adaptive immune responses from past SARS-CoV-2 infection or vaccination.
This viral evolution may increase the risk of reinfection or decrease the efficacy of vaccines.18 There is
evidence that some SARS-CoV-2 variants have reduced susceptibility to plasma from people who were
previously infected or immunized, as well as to certain monoclonal antibodies (mAbs) that are being
considered for prevention and treatment.19-21
Since December 2020, the World Health Organization (WHO) has assigned Greek letter designations to
several identified variants. A SARS-CoV-2 variant designated as a variant of concern (VOC) displays
certain characteristics, such as increased transmissibility or virulence. In addition, vaccines and
therapeutics may have decreased effectiveness against VOCs, and the mutations found in these variants

AR08745
may interfere with the targets of diagnostic tests. The variant of interest (VOI) designation has been
used for important variants that are not fully characterized; however, organizations do not use the same
variant designations, and they may define their variant designations differently.22,23 In September 2021,
the Centers for Disease Control and Prevention (CDC) added a new designation for variants: variant
being monitored (VBM). This refers to variants for which data indicate a potential or clear impact on
approved or authorized medical countermeasures or variants associated with more severe disease or
increased transmission rates. However, these variants are either no longer detected or are circulating at
very low levels in the United States; therefore, they do not pose a significant and imminent risk to public
health in the United States.
The Omicron (B.1.1.529) variant was designated a VOC in November 2021 and rapidly became the
dominant variant across the globe. More recently, the Omicron subvariants BA.1, BA.1.1, and BA.2
have emerged. The Omicron VOC is more transmissible than other variants and is not susceptible to
some of the anti-SARS-CoV-2 mAbs that have been developed for treatment and prevention.20,21,24 The
Omicron VOC has surpassed Delta (B.1.617.2) as the dominant variant in the United States; the Delta
variant was first identified in India and was the dominant variant in July 2021.
Earlier variants include the Alpha (B.1.1.7) variant, which was first seen in the United Kingdom and
has been shown to be highly infectious and possibly more virulent than previously reported variants;25-
27
the Beta (B.1.351) variant, which was originally identified in South Africa; and the Gamma (P.1)
variant, which was identified in Manaus, Brazil. The Beta and Gamma variants demonstrated reduced
susceptibility to select anti-SARS-CoV-2 mAbs used for treatment and prevention. Although the
Alpha, Beta, and Gamma variants were previously designated as VOCs, they have largely disappeared
worldwide. For a detailed discussion on the susceptibility of certain VOCs, VOIs, and VBMs to
available anti-SARS-CoV-2 mAbs, please see Anti-SARS-CoV-2 Monoclonal Antibodies.
Data on the emergence, transmission, and clinical relevance of these new variants are rapidly evolving;
this is especially true for research on how variants might affect transmission rates, disease progression,
vaccine development, and the efficacy of current therapeutics. Because the research on variants is
moving quickly and the classification of the different variants may change over time, websites such as
the CDC COVID Data Tracker and CoVariants.org provide regular updates on the data for SARS-CoV-2
variants. The COVID-19 Treatment Guidelines Panel reviews emerging data on these variants, paying
particular attention to research on the impacts of these variants on testing, prevention, and treatment.
Clinical Presentation
The estimated incubation period for COVID-19 is up to 14 days from the time of exposure, with a
median incubation period of 4 to 5 days.6,28,29 The spectrum of illness can range from asymptomatic
infection to severe pneumonia with acute respiratory distress syndrome and death. Among 72,314 people
with COVID-19 in China, 81% of cases were reported to be mild (defined in this study as no pneumonia
or mild pneumonia), 14% were severe (defined as dyspnea, respiratory frequency ≥30 breaths/min,
oxygen saturation ≤93%, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen
[PaO2/FiO2] <300 mm Hg, and/or lung infiltrates >50% within 24 to 48 hours), and 5% were critical
(defined as respiratory failure, septic shock, and/or multiple organ dysfunction syndrome or failure).30 In
a report on more than 370,000 confirmed COVID-19 cases with reported symptoms in the United States,
70% of patients experienced fever, cough, or shortness of breath; 36% had muscle aches; and 34%
reported headaches.2 Other reported symptoms have included, but are not limited to, diarrhea, dizziness,
rhinorrhea, anosmia, dysgeusia, sore throat, abdominal pain, anorexia, and vomiting.
The abnormalities seen in chest X-rays of patients with COVID-19 vary, but bilateral multifocal
opacities are the most common. The abnormalities seen in computed tomography of the chest also

AR08746
vary, but the most common are bilateral peripheral ground-glass opacities, with areas of consolidation
developing later in the clinical course of COVID-19.31 Imaging may be normal early in infection and can
be abnormal in the absence of symptoms.
Common laboratory findings in patients with COVID-19 include leukopenia and lymphopenia. Other
laboratory abnormalities have included elevated levels of aminotransferase, C-reactive protein, D-dimer,
ferritin, and lactate dehydrogenase.
Although COVID-19 is primarily a pulmonary disease, emerging data suggest that it also leads to
cardiac,32,33 dermatologic,34 hematologic,35 hepatic,36 neurologic,37,38 renal,39,40 and other complications.
Thromboembolic events also occur in patients with COVID-19, with the highest risk occurring in
critically ill patients.41
The long-term sequelae of COVID-19 survivors are currently unknown. Persistent symptoms after
recovery from acute COVID-19 have been described (see Clinical Spectrum of SARS-CoV-2 Infection).
Lastly, SARS-CoV-2 infection has been associated with a potentially severe inflammatory syndrome
in children (multisystem inflammatory syndrome in children, or MIS-C).42,43 Please see Special
Considerations in Children for more information.
References
1. Johns Hopkins University and Medicine. COVID-19 dashboard. 2021. Available at:
https://coronavirus.jhu.edu/map.html. Accessed February 15, 2022.
2. Stokes EK, Zambrano LD, Anderson KN, et al. Coronavirus disease 2019 case surveillance—United States,
January 22–May 30, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(24):759-765. Available at:
3. Cai Q, Chen F, Wang T, et al. Obesity and COVID-19 severity in a designated hospital in Shenzhen, China.
Diabetes Care. 2020;43(7):1392-1398. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32409502.
4. Centers for Disease Control and Prevention. COVID Data Tracker. 2022. Available at:
https://covid.cdc.gov/covid-data-tracker/#datatracker-home. Accessed April 15, 2022.
5. Garg S, Kim L, Whitaker M, et al. Hospitalization rates and characteristics of patients hospitalized with
laboratory-confirmed coronavirus disease 2019—COVID-NET, 14 states, March 1–30, 2020. MMWR Morb
Mortal Wkly Rep. 2020;69(15):458-464. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32298251.
6. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med.
2020;382(18):1708-1720. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32109013.
7. Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in
patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):934-943.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/32167524.
8. Palaiodimos L, Kokkinidis DG, Li W, et al. Severe obesity, increasing age and male sex are independently
associated with worse in-hospital outcomes, and higher in-hospital mortality, in a cohort of patients with
COVID-19 in the Bronx, New York. Metabolism. 2020;108:154262. Available at:
9. Zambrano LD, Ellington S, Strid P, et al. Update: characteristics of symptomatic women of reproductive age
with laboratory-confirmed SARS-CoV-2 infection by pregnancy status—United States, January 22–October 3,
2020. MMWR Morb Mortal Wkly Rep. 2020;69(44):1641-1647. Available at:
10. Centers for Disease Control and Prevention. COVID-19: people with certain medical conditions. 2021.
Available at: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-
conditions.html. Accessed April 13, 2022.
11. Azar KMJ, Shen Z, Romanelli RJ, et al. Disparities in outcomes among COVID-19 patients in a large health

AR08747
care system in California. Health Aff (Millwood). 2020;39(7):1253-1262. Available at:

12. Gold JAW, Wong KK, Szablewski CM, et al. Characteristics and clinical outcomes of adult patients
hospitalized with COVID-19—Georgia, March 2020. MMWR Morb Mortal Wkly Rep. 2020;69(18):545-550.
13. Gross CP, Essien UR, Pasha S, et al. Racial and ethnic disparities in population-level COVID-19 mortality. J
Gen Intern Med. 2020;35(10):3097-3099. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32754782.
14. Nayak A, Islam SJ, Mehta A, et al. Impact of social vulnerability on COVID-19 incidence and outcomes in the
United States. medRxiv. 2020;Preprint. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32511437.
15. Price-Haywood EG, Burton J, Fort D, Seoane L. Hospitalization and mortality among black patients and white
patients with COVID-19. N Engl J Med. 2020;382(26):2534-2543. Available at:
16. Centers for Disease Control and Prevention. Health equity considerations and racial and ethnic minority
groups. 2022. Available at: https://www.cdc.gov/coronavirus/2019-ncov/community/health-equity/race-
ethnicity.html. Accessed February 15, 2022.
17. Kind AJH, Buckingham WR. Making neighborhood-disadvantage metrics accessible - the neighborhood atlas.
N Engl J Med. 2018;378(26):2456-2458. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29949490.
18. Walensky RP, Walke HT, Fauci AS. SARS-CoV-2 variants of concern in the United States—challenges and
opportunities. JAMA. 2021;325(11):1037-1038. Available at:
19. Wang P, Nair MS, Liu L, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature.
20. Cameroni E, Bowen JE, Rosen LE, et al. Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron
antigenic shift. Nature. 2022;602(7898):664-670. Available at:
21. Liu L, Iketani S, Guo Y, et al. Striking antibody evasion manifested by the Omicron variant of SARS-CoV-2.
Nature. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35016198.
22. World Health Organization. Tracking SARS-CoV-2 variants. 2022. Available at:
https://www.who.int/en/activities/tracking-SARS-CoV-2-variants. Accessed April 13, 2022.
23. Centers for Disease Control and Prevention. SARS-CoV-2 variant classifications and definitions. 2022.
Available at: https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-classifications.html. Accessed April
13, 2022.
24. Centers for Disease Control and Prevention. Omicron variant: what you need to know. 2022. Available at:
https://www.cdc.gov/coronavirus/2019-ncov/variants/omicron-variant.html. Accessed April 13, 2022.
25. Leung K, Shum MH, Leung GM, Lam TT, Wu JT. Early transmissibility assessment of the N501Y mutant
strains of SARS-CoV-2 in the United Kingdom, October to November 2020. Euro Surveill. 2021;26(1).
26. Davies NG, Barnard RC, Jarvis CI, et al. Report: continued spread of VOC 202012/01 in England. 2020.
Available at: https://cmmid.github.io/topics/covid19/reports/uk-novel-variant/2020_12_31_Transmissibility_
and_severity_of_VOC_202012_01_in_England_update_1.pdf.
27. Murugan NA, Javali PS, Pandian CJ, et al. Computational investigation of increased virulence and
pathogenesis of SARS-CoV-2 lineage B.1.1.7. bioRxiv. 2021;Preprint. Available at:
28. Li Q, Guan X, Wu P, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected
pneumonia. N Engl J Med. 2020;382(13):1199-1207. Available at:

AR08748
29. Lauer SA, Grantz KH, Bi Q, et al. The incubation period of coronavirus disease 2019 (COVID-19) from
publicly reported confirmed cases: estimation and application. Ann Intern Med. 2020;172(9):577-582.
30. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019
(COVID-19) outbreak in China: summary of a report of 72,314 cases from the Chinese Center for Disease
Control and Prevention. JAMA. 2020;323(13):1239-1242. Available at:
31. Shi H, Han X, Jiang N, et al. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan,
China: a descriptive study. Lancet Infect Dis. 2020;20(4):425-434. Available at:
32. Liu PP, Blet A, Smyth D, Li H. The science underlying COVID-19: implications for the cardiovascular
system. Circulation. 2020;142(1):68-78. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32293910.
33. Madjid M, Safavi-Naeini P, Solomon SD, Vardeny O. Potential effects of coronaviruses on the cardiovascular
system: a review. JAMA Cardiol. 2020;5(7):831-840. Available at:
34. Sachdeva M, Gianotti R, Shah M, et al. Cutaneous manifestations of COVID-19: report of three cases and a
review of literature. J Dermatol Sci. 2020;98(2):75-81. Available at:
35. Henry BM, de Oliveira MHS, Benoit S, Plebani M, Lippi G. Hematologic, biochemical and immune
biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019
(COVID-19): a meta-analysis. Clin Chem Lab Med. 2020;58(7):1021-1028. Available at:
36. Agarwal A, Chen A, Ravindran N, To C, Thuluvath PJ. Gastrointestinal and liver manifestations of
COVID-19. J Clin Exp Hepatol. 2020;10(3):263-265. Available at:
37. Whittaker A, Anson M, Harky A. Neurological manifestations of COVID-19: a systematic review and current
update. Acta Neurol Scand. 2020;142(1):14-22. Available at:
38. Paniz-Mondolfi A, Bryce C, Grimes Z, et al. Central nervous system involvement by severe acute respiratory
syndrome coronavirus-2 (SARS-CoV-2). J Med Virol. 2020;92(7):699-702. Available at:
39. Pei G, Zhang Z, Peng J, et al. Renal involvement and early prognosis in patients with COVID-19 pneumonia.
J Am Soc Nephrol. 2020;31(6):1157-1165. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32345702.
40. Su H, Yang M, Wan C, et al. Renal histopathological analysis of 26 postmortem findings of patients with
COVID-19 in China. Kidney Int. 2020;98(1):219-227. Available at:
41. Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and thrombotic or thromboembolic disease:
implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review. J Am Coll
Cardiol. 2020;75(23):2950-2973. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32311448.
42. Chiotos K, Bassiri H, Behrens EM, et al. Multisystem inflammatory syndrome in children during the
coronavirus 2019 pandemic: a case series. J Pediatric Infect Dis Soc. 2020;9(3):393-398. Available at:
43. Belhadjer Z, Meot M, Bajolle F, et al. Acute heart failure in multisystem inflammatory syndrome in children
in the context of global SARS-CoV-2 pandemic. Circulation. 2020;142(5):429-436. Available at:

AR08749
Testing for SARS-CoV-2 Infection

Last Updated: March 24, 2022
Summary Recommendations
• The COVID-19 Treatment Guidelines Panel (the Panel) recommends using a nucleic acid amplification test (NAAT)
with a sample collected from the upper respiratory tract (i.e., nasopharyngeal, nasal mid-turbinate, anterior nasal,
or oropharyngeal) to diagnose acute infection of SARS-CoV-2; if it is not practical to use a NAAT or if NAATs are not
available, an antigen test may be used (AIII).
• For intubated and mechanically ventilated adults who are suspected to have COVID-19 but who do not have a
confirmed diagnosis:
• The Panel recommends obtaining lower respiratory tract samples to establish a diagnosis of COVID-19 if an initial
upper respiratory tract sample is negative (BII).
• The Panel recommends obtaining endotracheal aspirates over bronchial wash or bronchoalveolar lavage samples
when collecting lower respiratory tract samples to establish a diagnosis of COVID-19 (BII).
• A NAAT should not be repeated in an asymptomatic person (with the exception of health care workers) within 90 days
of a previous SARS-CoV-2 infection, even if the person has had a significant exposure to SARS-CoV-2 (AIII).
• SARS-CoV-2 reinfection has been reported in people after an initial diagnosis of the infection; therefore, clinicians
should consider using a NAAT for those who have recovered from a previous infection and who present with
symptoms that are compatible with SARS-CoV-2 infection if there is no alternative diagnosis (BIII).
• The Panel recommends against the use of serologic (i.e., antibody) testing as the sole basis for diagnosis of acute
SARS-CoV-2 infection (AIII).
• There is insufficient evidence for the Panel to recommend either for or against the use of SARS-CoV-2 serologic
testing to assess for immunity or to guide clinical decisions about using COVID-19 vaccines or anti-SARS-CoV-2
monoclonal antibodies in certain people.
Rating of Recommendations: A = Strong; B = Moderate; C = Weak
Rating of Evidence: I = One or more randomized trials without major limitations; IIa = Other randomized trials or
subgroup analyses of randomized trials; IIb = Nonrandomized trials or observational cohort studies; III = Expert opinion
Diagnostic Testing for SARS-CoV-2 Infection

Everyone who has symptoms that are consistent with COVID-19 and people with known high-risk
exposures to SARS-CoV-2 should be tested for SARS-CoV-2 infection. Such testing should employ
either a nucleic acid amplification test (NAAT) or an antigen test to detect SARS-CoV-2. Testing may
also be used for screening, determining the length of a patient’s isolation period, and other nondiagnostic
purposes.1
A number of diagnostic tests for SARS-CoV-2 infection (e.g., NAATs, antigen tests) have received
Emergency Use Authorizations (EUAs) from the Food and Drug Administration (FDA),2 but no
diagnostic test has been approved by the FDA. Diagnostic tests have been authorized for use by trained
personnel in several settings, including lab facilities. They can also be used in point-of-care settings,
where the test is performed by trained personnel at or near the place where the specimen was collected.
Point-of-care settings include physician offices, pharmacies, long-term care facilities, and school clinics.
Antigen tests can be self-administered, and most can be used in point-of-care settings, allowing results to
be available within minutes. Some NAATs can also be self-administered at home or in other non-health
care locations and shipped to a laboratory for testing.
Although nasopharyngeal specimens remain the recommended samples for SARS-CoV-2 diagnostic
testing, nasal (anterior nares or mid-turbinate) or oropharyngeal swabs are acceptable alternatives.3
Lower respiratory tract samples have a higher yield than upper respiratory tract samples, but they

AR08750
are often not obtained because of concerns about aerosolization of the virus during sample collection
procedures. Some of the tests that have received EUAs can also be performed on saliva specimens, but
the quality of saliva specimens can be highly variable. Studies are currently evaluating the use of other
sample types, including stool samples.
Nucleic Acid Amplification Testing for SARS-CoV-2 Infection

Reverse transcription polymerase chain reaction (RT-PCR)-based diagnostic tests (which detect
viral nucleic acids) are considered the gold standard for detecting current SARS-CoV-2 infection.
More recently, NAATs have included isothermal amplification platforms (e.g., nicking endonuclease
amplification reaction [NEAR], loop-mediated isothermal amplification [LAMP], transcription-mediated
amplification [TMA]).4 Some NAATs have also received EUAs for use in different settings, such as
in laboratory facilities and point-of-care settings. Laboratory-based NAATs generally have higher
sensitivity than point-of-care tests.4
Clinically, there may be a window period of up to 5 days after exposure before viral nucleic acids can
be detected. Diagnostically, some NAATs may produce false negative results if a mutation occurs in
the part of the virus’ genome that is assessed by that test.5 The FDA monitors the potential effects of
SARS-CoV-2 genetic variations on NAAT results and issues updates when specific variations could
affect the performance of NAATs that have received EUAs. Generally, false negative results are more
likely to occur when using NAATs that rely on only 1 genetic target. Therefore, a single negative test
result does not exclude the possibility of SARS-CoV-2 infection in people who have a high likelihood of
infection based on their exposure history and/or their clinical presentation.6
Many commercial NAATs that use RT-PCR rely on multiple targets to detect the virus, such that even if
a mutation impacts 1 of the targets, the other RT-PCR targets will still work.7 NAATs that use multiple
targets are less likely to be impacted by an increased prevalence of genetic variants. In fact, because
each of these tests target multiple locations on the virus’ genome, they can be helpful in identifying new
genetic variants before they become widespread in the population. For example, the B.1.1.7 (Alpha)
variant and the BA.1 subvariant of the B.1.1.529 (Omicron) variant, both of which have been associated
with increased transmission, carry many mutations, including a double deletion at positions 69 and 70
on the spike protein gene (S-gene). This mutation appears to impact the detection of the S-gene but does
not impact other genetic targets in certain NAATs. If COVID-19 is still suspected after a patient receives
a negative test result, clinicians should consider repeating testing; ideally, they should use a NAAT with
different genetic targets.5
SARS-CoV-2 poses several diagnostic challenges, including the potential for discordant viral shedding
between the upper and lower respiratory tract. However, due to the high specificity of NAATs, a positive
result on a NAAT of an upper respiratory tract sample from a patient with recent onset of SARS-CoV-
2-compatible symptoms is sufficient to diagnose COVID-19. In patients with COVID-19, severe acute
respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS), lower respiratory tract
specimens have a higher viral load and thus a higher yield than upper respiratory tract specimens.8-13 For
intubated or mechanically ventilated patients with clinical signs and symptoms that are consistent with
COVID-19 pneumonia, the COVID-19 Treatment Guidelines Panel (the Panel) recommends obtaining
lower respiratory tract samples to establish a diagnosis of COVID-19 if an initial upper respiratory tract
sample is negative (BII). The Panel recommends obtaining endotracheal aspirates over bronchial wash
or bronchoalveolar lavage (BAL) samples when collecting lower respiratory tract samples to establish a
diagnosis of COVID-19 (BII).
BAL and sputum induction are aerosol-generating procedures that should be performed only after
carefully considering the risk of exposing staff to infectious aerosols. Endotracheal aspiration appears to

AR08751
carry a lower risk of aerosol generation than BAL, and some experts consider the sensitivity and specificity
of endotracheal aspirates and BAL specimens comparable in detecting SARS-CoV-2.
Nucleic Acid Amplification Testing for Individuals With a Previous Positive SARS-CoV-2 Test
Result
NAATs can detect SARS-CoV-2 RNA in specimens obtained weeks to months after the onset of
COVID-19 symptoms.14,15 However, the likelihood of recovering replication-competent virus >10 days
from the onset of symptoms in those with mild disease and >20 days in those with severe disease is very
low.16,17 Furthermore, both virologic studies and contact tracing of high-risk contacts show a low risk for
SARS-CoV-2 transmission after these intervals.18,19 Based on these results, the Centers for Disease Control
and Prevention (CDC) recommends that NAATs should not be repeated in asymptomatic persons within
90 days of a previous SARS-CoV-2 infection, even if the person has had a significant exposure to SARS-
CoV-2.20 An exception to this is for health care workers who meet the specific criteria found in CDC
guidance.21 If there are concerns that an immunocompromised health care worker may still be infectious
>20 days from the onset of SARS-CoV-2 infection, consulting local employee health services about return-
to-work testing policies is advised.
SARS-CoV-2 reinfection has been reported in people after an initial diagnosis of infection; therefore,
clinicians should consider using a NAAT for those who have recovered from a previous infection and who
present with symptoms that are compatible with SARS-CoV-2 infection if there is no alternative diagnosis
(BIII). However, a negative result on an initial NAAT followed by a positive result on a subsequent test
does not necessarily mean a person has been reinfected; this can occur due to intermittent detection of
viral RNA.14 When the results for an initial and a subsequent test are positive, comparative viral sequence
data from both tests are needed to distinguish between the persistent presence of viral fragments and
reinfection. In the absence of viral sequence data, the cycle threshold (Ct) value from a positive NAAT
result may provide information about whether a newly detected infection is related to the persistence of
viral fragments or to reinfection. The Ct value is the number of PCR cycles at which the nucleic acid
target in the sample becomes detectable. In general, the Ct value is inversely related to the SARS-CoV-2
viral load. Because the clinical utility of Ct values is an area of active investigation, an expert should be
consulted if these values are used to guide clinical decisions.
Antigen Testing for SARS-CoV-2 Infection

Antigen-based diagnostic tests (which detect viral antigens) are less sensitive than laboratory-based
NAATs, but they have similarly high specificity. Antigen tests perform best early in the course of
symptomatic SARS-CoV-2 infection, when the viral load is thought to be highest. Early data suggest
that antigen tests can detect the Omicron variant, but they may have lower sensitivity to this variant
compared to earlier variants.22 Advantages of antigen tests include their low cost and rapid turnaround
time. The availability of immediate results makes them an attractive option for point-of-care testing in
high-risk congregate settings (e.g., long-term care facilities, schools, dormitories, correctional facilities)
and community settings where preventing transmission is critical. These tests can also be used to inform
decisions about the use of post-exposure prophylaxis (PEP). Antigen tests also allow for repeat testing to
quickly identify persons with SARS-CoV-2 infection.
Increasingly, data are available to guide the use of antigen tests as screening tests to detect or exclude
SARS-CoV-2 infection in asymptomatic persons, or to determine whether a person who was previously
confirmed to have SARS-CoV-2 infection is still infectious. The CDC has developed an antigen testing
algorithm for persons in congregate living settings and community settings who have symptoms of
COVID-19, those who are asymptomatic and have a close contact with COVID-19, and those who are
asymptomatic and have no known exposure to a person with COVID-19.23 The CDC testing algorithm

AR08752
recommends performing additional confirmatory testing with a laboratory-based NAAT when a
person who is strongly suspected of having SARS-CoV-2 infection (i.e., a person who is symptomatic)
receives a negative result and when a person in a congregate living setting is asymptomatic but receives
a positive result. People in congregate living settings who test positive for SARS-CoV-2 infection
may need to be isolated as a group; therefore, correct identification of these individuals is especially
important in this setting.23
Antigen tests can yield false positive results for a variety of reasons, including:
• Incomplete adherence to the instructions for antigen test performance (e.g., reading the results
outside the specified time interval or storing test cartridges/cards inappropriately);
• Test interference due to human antibodies (e.g., rheumatoid factor or other nonspecific antibodies);
and
• Use in communities that have a low prevalence of SARS-CoV-2 infection.
Serologic or Antibody Testing for Diagnosis of SARS-CoV-2 Infection

Unlike NAATs and antigen tests for SARS-CoV-2 that detect the presence of the virus, serologic or
antibody tests can detect recent or prior SARS-CoV-2 infection. Because it may take 21 days or longer
after symptom onset for seroconversion to occur (i.e., the development of detectable immunoglobulin
[Ig] M and/or IgG antibodies to SARS-CoV-2),24-29 the Panel does not recommend using serologic
testing as the sole basis for diagnosing acute SARS-CoV-2 infection (AIII). Because NAATs and antigen
tests for SARS-CoV-2 occasionally yield false negative results, serologic tests have been used in some
settings as an additional diagnostic test for patients who are strongly suspected to have SARS-CoV-2
infection. Using a serologic test in combination with a NAAT to detect IgG or total antibodies 3 to 4
weeks after symptom onset maximizes the sensitivity and specificity to detect past infection.
No serologic tests for SARS-CoV-2 are approved by the FDA; some, but not all, commercially available
serologic tests for SARS-CoV-2 have received EUAs from the FDA.30 Several professional societies and
federal agencies, including the Infectious Diseases Society of America, the CDC, and the FDA, provide
guidance on the use of serologic testing for SARS-CoV-2.
Several factors should be considered when using serologic tests, including:
• Important performance characteristics of many of the commercially available serologic tests have
not been fully characterized, including the sensitivity and specificity of these tests (i.e., the rates of
true positive and true negative results). Only serologic assays that have FDA EUAs should be used
in public health or clinical settings. Formal comparisons of serologic tests are in progress.
• Two types of serologic tests have received EUAs from the FDA. The first type are antibody tests
that detect the presence of binding antibodies, which bind to a pathogen (e.g., a virus). The second
type detects neutralizing antibodies from recent or prior SARS-CoV-2 infection. It is unknown
whether 1 type of test is more clinically meaningful than the other.
• Serologic assays may detect IgM, IgG, IgA, and/or total antibodies, or a combination of IgM and
IgG antibodies. Serologic assays that detect IgG and total antibodies have higher specificity to
detect past infection than assays that detect IgM and/or IgA antibodies or a combination of IgM
and IgG antibodies.
• False positive test results may occur due to cross-reactivity from pre-existing antibodies to other
coronaviruses.

AR08753
Serologic Testing and Immunity to SARS-CoV-2 Infection

The FDA has issued EUAs for more than 80 SARS-CoV-2 serologic tests since the start of the pandemic.
However, these tests are not currently authorized for routine use in making individual medical decisions.30
SARS-CoV-2 serologic tests are authorized for detecting antibodies, but their ability to predict protective
immunity has not been validated. The majority of these tests are not standardized. Furthermore, as
SARS-CoV-2 is not a well-conserved virus, mutations in the receptor binding domain of the virus could
lead to decreased binding affinity between antibodies and SARS-CoV-2-specific antigens.
Given the available information, there is insufficient evidence for the Panel to recommend either for or
against the use of SARS-CoV-2 serologic testing to assess for immunity or to guide clinical decisions
about using COVID-19 vaccines or anti-SARS-CoV-2 monoclonal antibodies in certain people.
If a serologic test is performed, the result should be interpreted with caution. It remains unclear how long
SARS-CoV-2 antibodies persist following either infection or vaccination. A negative serologic test result
also does not preclude prior SARS-CoV-2 infection or vaccination against COVID-19. Some people who
are infected with SARS-CoV-2 or who are vaccinated against COVID-19 may not develop measurable
antibodies (e.g., those who are immunocompromised). It is presumed that those who do not have
measurable antibodies after vaccination are at higher risk of SARS-CoV-2 infection.
In communities that have a low prevalence of SARS-CoV-2 infection, the proportion of positive test
results that are false positives may be quite high. In these situations, performing confirmatory testing
with a distinct antibody assay, ideally an assay that uses a different antigenic target (e.g., the nucleocapsid
phosphoprotein if the first assay targeted the spike protein), can substantially reduce false positives.
Assuming that the test is reliable, serologic tests that identify recent or prior SARS-CoV-2 infection may
be used to:
• Differentiate between SARS-CoV-2 antibody responses to natural infection and vaccine-induced
antibody responses to the SARS-CoV-2 spike protein antigen. Because nucleocapsid protein is not
a constituent of the vaccines that are currently approved by the FDA, available through EUAs, or in
late-stage clinical trials, serologic tests that detect antibodies by recognizing nucleocapsid proteins
can be used to distinguish between antibody responses to natural infection and vaccine-induced
antibody responses.
• Determine who may be eligible to donate convalescent plasma
• Define multisystem inflammatory syndrome in children (MIS-C) and multisystem inflammatory
syndrome in adults (MIS-A)
• Estimate the proportion of the population that has been exposed to SARS-CoV-2
Based on current knowledge, serologic tests should not be used to (AIII):
• Make decisions about how to group persons in congregate settings;
• Determine whether someone may return to the workplace; or
• Assess for immunity to SARS-CoV-2 following vaccination in immunocompetent individuals,
except in clinical trials.
References
1. Centers for Disease Control and Prevention. Testing strategies for SARS-CoV-2. 2021. Available at: https://www.
cdc.gov/coronavirus/2019-ncov/lab/resources/sars-cov2-testing-strategies.html. Accessed February 28, 2022.
2. Food and Drug Administration. Coronavirus disease 2019 (COVID-19) emergency use authorizations for

AR08754
medical devices. 2021. Available at: https://www.fda.gov/medical-devices/emergency-use-authorizations-

medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices. Accessed
February 28, 2022.
3. Centers for Disease Control and Prevention. Interim guidelines for collecting and handling of clinical
specimens for COVID-19 testing. 2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/lab/
guidelines-clinical-specimens.html. Accessed February 28, 2022.
4. Centers for Disease Control and Prevention. Nucleic acid amplification tests (NAATs). 2021. Available at:
https://www.cdc.gov/coronavirus/2019-ncov/lab/naats.html. Accessed February 28, 2022.
5. Food and Drug Administration. Genetic variants of SARS-CoV-2 may lead to false negative results with
molecular tests for detection of SARS-CoV-2—letter to clinical laboratory staff and health care providers.
2021. Available at: https://www.fda.gov/medical-devices/letters-health-care-providers/genetic-variants-sars-
cov-2-may-lead-false-negative-results-molecular-tests-detection-sars-cov-2. Accessed February 28, 2022.
6. Kucirka LM, Lauer SA, Laeyendecker O, Boon D, Lessler J. Variation in false-negative rate of reverse
transcriptase polymerase chain reaction-based SARS-CoV-2 tests by time since exposure. Ann Intern Med.
7. Centers for Disease Control and Prevention. Science brief: emerging SARS-CoV-2 variants. 2021. Available
at: https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/scientific-brief-emerging-variants.html.
Accessed March 21, 2022.
8. Chan PK, To WK, Ng KC, et al. Laboratory diagnosis of SARS. Emerg Infect Dis. 2004;10(5):825-831.
9. Tang P, Louie M, Richardson SE, et al. Interpretation of diagnostic laboratory tests for severe acute respiratory
syndrome: the Toronto experience. CMAJ. 2004;170(1):47-54. Available at:
10. Memish ZA, Al-Tawfiq JA, Makhdoom HQ, et al. Respiratory tract samples, viral load, and genome fraction
yield in patients with Middle East respiratory syndrome. J Infect Dis. 2014;210(10):1590-1594. Available at:
11. Centers for Disease Control and Prevention. Interim guidelines for collecting, handling, and testing clinical
specimens from persons under investigation (PUIs) for Middle East respiratory syndrome coronavirus
(MERS-CoV)–Version 2.1. 2019. Available at: https://www.cdc.gov/coronavirus/mers/guidelines-clinical-
specimens.html. Accessed March 21, 2022.
12. Hase R, Kurita T, Muranaka E, et al. A case of imported COVID-19 diagnosed by PCR-positive lower
respiratory specimen but with PCR-negative throat swabs. Infect Dis (Lond). 2020;52(6):423-426. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/32238024.
13. Wang W, Xu Y, Gao R, et al. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA.
14. Xiao AT, Tong YX, Zhang S. Profile of RT-PCR for SARS-CoV-2: a preliminary study from 56 COVID-19
patients. Clin Infect Dis. 2020;71(16):2249-2251. Available at:
15. Rhee C, Kanjilal S, Baker M, Klompas M. Duration of severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) infectivity: when is it safe to discontinue isolation? Clin Infect Dis. 2021;72(8):1467-1474.
16. Arons MM, Hatfield KM, Reddy SC, et al. Presymptomatic SARS-CoV-2 infections and transmission in a
skilled nursing facility. N Engl J Med. 2020;382(22):2081-2090. Available at:
17. Bullard J, Dust K, Funk D, et al. Predicting infectious severe acute respiratory syndrome coronavirus 2 from
diagnostic samples. Clin Infect Dis. 2020;71(10):2663-2666. Available at:

AR08755
18. Cheng HY, Jian SW, Liu DP, et al. Contact tracing assessment of COVID-19 transmission dynamics in Taiwan
and risk at different exposure periods before and after symptom onset. JAMA Intern Med. 2020;180(9):1156-
1163. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32356867.
19. Korea Centers for Disease Control and Prevention. Findings from investigation and analysis of re-positive
cases. 2020. Available at: https://www.mofa.go.kr/viewer/skin/doc.html?fn=20200521024820767.pdf&rs=/
viewer/result/202203. Accessed March 21, 2022.
20. Centers for Disease Control and Prevention. Ending isolation and precautions for people with COVID-19:
interim guidance. 2022. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/duration-isolation.html.
21. Centers for Disease Control and Prevention. Interim guidance for managing healthcare personnel
with SARS-CoV-2 infection or exposure to SARS-CoV-2. 2022. Available at: https://www.cdc.gov/
coronavirus/2019-ncov/hcp/guidance-risk-assesment-hcp.html. Accessed March 21, 2022.
22. Food and Drug Administration. SARS-CoV-2 viral mutations: impact on COVID-19 tests. 2021. Available at:
https://www.fda.gov/medical-devices/coronavirus-covid-19-and-medical-devices/sars-cov-2-viral-mutations-
impact-covid-19-tests. Accessed March 21, 2022.
23. Centers for Disease Control and Prevention. Guidance for antigen testing for SARS-CoV-2 for healthcare
providers testing individuals in the community. 2022. Available at: https://www.cdc.gov/coronavirus/2019-
ncov/lab/resources/antigen-tests-guidelines.html. Accessed February 28, 2022.
24. Guo L, Ren L, Yang S, et al. Profiling early humoral response to diagnose novel coronavirus disease
(COVID-19). Clin Infect Dis. 2020;71(15):778-785. Available at:
25. Haveri A, Smura T, Kuivanen S, et al. Serological and molecular findings during SARS-CoV-2 infection: the
first case study in Finland, January to February 2020. Euro Surveill. 2020;25(11). Available at:
26. Long QX, Liu BZ, Deng HJ, et al. Antibody responses to SARS-CoV-2 in patients with COVID-19. Nat Med.
27. Okba NMA, Muller MA, Li W, et al. Severe acute respiratory syndrome coronavirus 2-specific antibody
responses in coronavirus disease patients. Emerg Infect Dis. 2020;26(7):1478-1488. Available at:
28. Xiang F, Wang X, He X, et al. Antibody detection and dynamic characteristics in patients with coronavirus
disease 2019. Clin Infect Dis. 2020;71(8):1930-1934. Available at:
29. Zhao J, Yuan Q, Wang H, et al. Antibody responses to SARS-CoV-2 in patients with novel coronavirus disease
2019. Clin Infect Dis. 2020;71(16):2027-2034. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32221519.
30. Food and Drug Administration. EUA authorized serology test performance. 2021. Available at: https://www.
fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/
eua-authorized-serology-test-performance. Accessed February 28, 2022.

AR08756
Prevention of SARS-CoV-2 Infection

• The COVID-19 Treatment Guidelines Panel (the Panel) recommends COVID-19 vaccination as soon as possible
for everyone who is eligible according to the Centers for Disease Control and Prevention’s Advisory Committee on
Immunization Practices (AI).
• The Panel recommends using tixagevimab 300 mg plus cilgavimab 300 mg (Evusheld) administered as 2
consecutive 3-mL intramuscular injections (BIII) as SARS-CoV-2 pre-exposure prophylaxis (PrEP) for adults and
adolescents (aged ≥12 years and weighing ≥40 kg) who do not have SARS-CoV-2 infection, who have not been
recently exposed to an individual with SARS-CoV-2 infection, AND who:
• Are moderately to severely immunocompromised and may have an inadequate immune response to COVID-19
vaccination; or
• Are not able to be fully vaccinated with any available COVID-19 vaccines due to a history of severe adverse
reactions to a COVID-19 vaccine or any of its components.
• The Food and Drug Administration Emergency Use Authorization states that individuals who received tixagevimab 150
mg plus cilgavimab 150 mg should be given a second dose as soon as possible. The specific dose of tixagevimab
plus cilgavimab that an individual should receive depends on the amount of time that has passed since the first dose
was administered:
• If the initial dose was administered ≤3 months prior, the second dose should be tixagevimab 150 mg plus
cilgavimab 150 mg.
• If the initial dose was administered >3 months prior, the second dose should be tixagevimab 300 mg plus
cilgavimab 300 mg.
• Tixagevimab plus cilgavimab is not a substitute for COVID-19 vaccination and should not be used in unvaccinated
individuals for whom COVID-19 vaccination is recommended.
• If supplies of tixagevimab plus cilgavimab are limited, priority for use as PrEP should be given to those who are at the
highest risk for severe COVID-19.
• The Panel recommends against the use of bamlanivimab plus etesevimab and casirivimab plus imdevimab for
post-exposure prophylaxis (PEP), as the Omicron (B.1.1.529) variant and its subvariants, which are not susceptible
to these agents, are currently the dominant SARS-CoV-2 variants circulating in the United States (AIII).
General Prevention Measures

Transmission of SARS-CoV-2 is thought to occur primarily through exposure to respiratory droplets.
Exposure can occur when someone inhales droplets or particles that contain the virus (with the greatest
risk of transmission occurring within 6 feet of an infectious source) or touches their mucous membranes
with hands that have been contaminated with the virus. Exhaled droplets or particles can also deposit the
virus onto exposed mucous membranes.1
Less commonly, airborne transmission of small droplets and particles of SARS-CoV-2 to people farther
than 6 feet away can occur; in rare cases, people passing through a room that was previously occupied
by an infectious person may become infected. SARS-CoV-2 infection via airborne transmission of small
particles tends to occur after prolonged exposure (i.e., >15 minutes) to an infectious person who is in an
enclosed space with poor ventilation.1
The risk of SARS-CoV-2 transmission can be reduced by covering coughs and sneezes and maintaining
a distance of at least 6 feet from others. When consistent distancing is not possible, face coverings may
reduce the spread of infectious droplets from individuals with SARS-CoV-2 infection to others. Frequent
handwashing also effectively reduces the risk of infection.2 Health care providers should follow the

AR08757
Centers for Disease Control and Prevention (CDC) recommendations for infection control and the
appropriate use of personal protective equipment.3
Vaccines
Vaccination is the most effective way to prevent SARS-CoV-2 infection. The COVID-19 Treatment
Guidelines Panel (the Panel) recommends COVID-19 vaccination as soon as possible for everyone who
is eligible according to CDC’s Advisory Committee on Immunization Practices (AI). Three vaccines
are authorized or approved for use in the United States to prevent COVID-19. For primary and booster
vaccinations, the mRNA vaccines (i.e., BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]) are
preferable to the Ad26.COV2.S (Johnson & Johnson/Janssen) vaccine due to its risk of serious adverse
events.4 A primary series of COVID-19 vaccinations is recommended for everyone aged ≥5 years in the
United States. Certain groups of people should receive additional doses at specified intervals after the
primary series of vaccinations. The type and dose of vaccine and the timing of these additional doses
depend on the recipient’s age and underlying medical conditions. CDC regularly updates the clinical
considerations for use of the COVID-19 vaccines that are currently approved by the Food and Drug
Administration (FDA) or authorized for use in the United States.5
Adverse Events
COVID-19 vaccines are safe and effective. Local and systemic adverse events are relatively common
with these vaccines. Most of the adverse events that occurred during vaccine trials were mild or
moderate in severity (i.e., they did not prevent vaccinated people from engaging in daily activities)
and resolved after 1 or 2 days. There have been a few reports of severe allergic reactions following
COVID-19 vaccination, including rare reports of patients who experienced anaphylaxis after receiving
an mRNA vaccine.6,7
Reports have suggested that there is an increased risk of thrombosis with thrombocytopenia syndrome
(TTS) in adults who have received the Ad26.COV2.S vaccine7 and, rarely, the mRNA-1273 vaccine.8
TTS is a rare but serious condition that causes blood clots in large blood vessels and low platelet levels.
Women aged 30 to 49 years should be aware of the increased risk of TTS. The American Society
of Hematology and the American Heart Association/American Stroke Association Stroke Council
leadership have published considerations that are relevant to the diagnosis and treatment of TTS that
occurs in people who receive the Ad26.COV2.S vaccine. These considerations include information on
administering a nonheparin anticoagulant and intravenous immunoglobulin to these patients.9,10 Given
the rarity of this syndrome and the unique treatment required, consider consulting a hematologist when
treating these patients.
Myocarditis and pericarditis after COVID-19 vaccination are rare, and most of the reported cases were
very mild and self-limiting. These conditions have occurred most often in male adolescents, young
adults, and people who have received mRNA vaccines.11
Guillain-Barré syndrome (GBS) in people who received the Ad26.COV2.S vaccine is rare. GBS is
a neurologic disorder that causes muscle weakness and sometimes paralysis. Most people with GBS
fully recover, but some have permanent nerve damage. Onset typically occurs about 2 weeks after
vaccination. GBS has mostly been reported in men aged ≥50 years.11
CDC provides regular updates on selected adverse events of COVID-19 vaccines on its website.
Vaccination in Pregnant or Lactating People

Pregnant and lactating individuals were not included in the initial COVID-19 vaccine trials. However,
CDC, the American College of Obstetricians and Gynecologists (ACOG), and the Society for Maternal-

AR08758
Fetal Medicine recommend vaccination for pregnant and lactating people based on the accumulated safety
and efficacy data on the use of these vaccines in pregnant people, as well as the increased risk of severe
disease in pregnant individuals with COVID-19. These organizations also recommend vaccination for
people who are trying to become pregnant or who may become pregnant in the future.12-17 The ACOG
publication includes a guide for clinicians on counseling pregnant patients about COVID-19 vaccination.18
Pre-Exposure Prophylaxis
Vaccination remains the most effective way to prevent SARS-CoV-2 infection and should be considered
the first line of prevention. However, some individuals cannot or may not mount an adequate protective
response to COVID-19 vaccines. Others may not have been fully vaccinated because they have a history
of severe adverse reactions to a COVID-19 vaccine or its components.
Based on the results of PROVENT, a large randomized controlled trial conducted when the major
circulating SARS-CoV-2 variants were Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), and Epsilon
(B.1.429),19 the FDA issued an Emergency Use Authorization (EUA) for the anti-SARS-CoV-2
monoclonal antibodies (mAbs) tixagevimab plus cilgavimab (Evusheld). The EUA allows these mAbs
to be used as pre-exposure prophylaxis (PrEP) for certain individuals who are at high risk of progressing
to severe COVID-19 if they become infected with SARS-CoV-2.20 A modification in the fragment
crystallizable (Fc) region gives these anti-SARS-CoV-2 mAbs prolonged half-lives, resulting in potential
protection from SARS-CoV-2 infection for up to 6 months, depending on the variant.
The dose used in the PROVENT trial was tixagevimab 150 mg plus cilgavimab 150 mg, which was
the dose that was initially authorized by the FDA. However, in vitro data showed that the BA.1 and
BA.1.1 subvariants of the Omicron (B.1.1.529) variant have decreased susceptibility to tixagevimab plus
cilgavimab.20-23 Because of these findings, on February 24, 2022, the FDA revised the EUA to authorize
tixagevimab 300 mg plus cilgavimab 300 mg as the dose for individuals who are receiving these anti-
SARS-CoV-2 mAbs for the first time.20 For patients who previously received a dose of tixagevimab 150
mg plus cilgavimab 150 mg, the FDA EUA states that a second dose should be given as soon as possible.
The specific dose a patient should receive for their second round of tixagevimab plus cilgavimab depends
on the amount of time that has passed since the initial dose (see below). The Omicron BA.2 subvariant
has been shown to retain near-full susceptibility to tixagevimab plus cilgavimab in vitro, so the dosing
recommendations for these mAbs may be further refined in the future.20,23,24
When prescribing tixagevimab plus cilgavimab for SARS-CoV-2 PrEP, clinicians should be aware of
some important limitations:
• Tixagevimab plus cilgavimab is authorized for use as PrEP in a population that was not well-
represented in the PROVENT trial (i.e., a very small proportion of the participants were
immunocompromised).
• There are no clinical trial efficacy data on preventing symptomatic COVID-19 with the
tixagevimab 300 mg plus cilgavimab 300 mg dose. The new dose is based on pharmacokinetic/
pharmacodynamic (PK/PD) modeling that suggests this dose may have in vivo activity against the
Omicron BA.1 and BA.1.1 subvariants.25
• Substantial uncertainty in the PK/PD model remains. It is possible that even if the tixagevimab
300 mg plus cilgavimab 300 mg dose is active against the Omicron BA.1 and BA.1.1 subvariants,
it would provide only a limited duration (≤3 months) of protection. Limited data inform the
timing for repeat doses of tixagevimab plus cilgavimab after the initial dose, and repeat doses of
tixagevimab 300 mg plus cilgavimab 300 mg are not included in the current EUA.

AR08759
• The safety data on using tixagevimab 300 mg plus cilgavimab 300 mg primarily comes from
TACKLE, a Phase 3 clinical trial that evaluated the use of tixagevimab plus cilgavimab for the
treatment of patients with mild to moderate COVID-19.25
• The tixagevimab 150 mg plus cilgavimab 150 mg dose that was initially authorized by the FDA
may not be sufficient to prevent cases of COVID-19 caused by the Omicron BA.1 and BA.1.1
subvariants. There are no clinical data and only limited PK/PD data to guide the administration of
repeat doses of tixagevimab plus cilgavimab in those who were previously treated with tixagevimab
150 mg plus cilgavimab 150 mg. Simulations based on population PK models suggest that
administering an additional dose of tixagevimab 150 mg plus cilgavimab 150 mg ≤3 months after
the initial dose will allow a patient to achieve drug concentrations approximating those observed in
people who received tixagevimab 300 mg plus cilgavimab 300 mg as their initial dose. For patients
who initially received tixagevimab 150 mg plus cilgavimab 150 mg >3 months ago, the simulations
suggest that a repeat dose of tixagevimab 300 mg plus cilgavimab 300 mg is necessary.
Recommendations
Factoring in the limitations outlined above:
• The Panel recommends using tixagevimab 300 mg plus cilgavimab 300 mg administered as
2 consecutive 3-mL intramuscular (IM) injections (BIII) as SARS-CoV-2 PrEP for adults and
adolescents (aged ≥12 years and weighing ≥40 kg) who do not have SARS-CoV-2 infection,
who have not been recently exposed to an individual with SARS-CoV-2 infection, who have not
previously received this regimen, AND who:
• Are moderately to severely immunocompromised and may have an inadequate immune
response to COVID-19 vaccination; or
• Are not able to be fully vaccinated with any available COVID-19 vaccines due to a history of
severe adverse reactions to a COVID-19 vaccine or any of its components.
• The FDA EUA states that individuals who received tixagevimab 150 mg plus cilgavimab 150
mg should be given a second dose as soon as possible. The specific dose of tixagevimab plus
cilgavimab that an individual should receive depends on the amount of time that has passed since
the first dose was administered:
• If the initial dose was administered ≤3 months prior, the second dose should be tixagevimab
150 mg plus cilgavimab 150 mg.
• If initial dose was administered >3 months prior, the second dose should be tixagevimab 300
mg plus cilgavimab 300 mg.
• Tixagevimab plus cilgavimab is not a substitute for COVID-19 vaccination and should not
be used in unvaccinated individuals for whom COVID-19 vaccination is recommended.
Individuals who qualify as having moderate to severe immunocompromising conditions under the FDA
EUA for tixagevimab plus cilgavimab are those who:
• Are receiving active treatment for solid tumors and hematologic malignancies.
• Received a solid organ transplant and are receiving immunosuppressive therapy.
• Received chimeric antigen receptor T cell therapy or a hematopoietic stem cell transplant (within 2
years of transplantation or receiving immunosuppression therapy).
• Have a moderate or severe primary immunodeficiency (e.g., DiGeorge syndrome, Wiskott-Aldrich
syndrome).
• Have advanced or untreated HIV infection (defined as people with HIV and CD4 T lymphocyte

AR08760
counts <200 cells/mm3, a history of an AIDS-defining illness without immune reconstitution, or

clinical manifestations of symptomatic HIV).
• Are receiving active treatment with high-dose corticosteroids (i.e., ≥20 mg prednisone or
equivalent per day when administered for ≥2 weeks), alkylating agents, antimetabolites,
transplant-related immunosuppressive drugs, cancer chemotherapeutic agents classified
as severely immunosuppressive, tumor-necrosis blockers, or other immunosuppressive or
immunomodulatory biologic agents (e.g., B cell-depleting agents).
Additional Considerations
• Because there are no clinical efficacy data available for tixagevimab 300 mg plus cilgavimab 300
mg, and there are uncertainties about the extent and duration of protection against the Omicron
BA.1 and BA.1.1 subvariants, high-risk individuals who receive PrEP should continue to use
other measures to protect themselves from infection, especially if these subvariants are circulating
within their communities.
• The strength of the Panel’s recommendation for tixagevimab 300 mg plus cilgavimab 300 mg is
based partly on PK/PD modeling for the Omicron BA.1 and BA.1.1 subvariants and partly on the
fact that the BA.2 subvariant has been shown to retain near-full susceptibility to tixagevimab plus
cilgavimab in vitro.
• If supplies of tixagevimab plus cilgavimab are limited, priority for use as PrEP should be given to
those who are at the highest risk for severe COVID-19.
• If a person has received a COVID-19 vaccine, tixagevimab plus cilgavimab should be
administered at least 2 weeks after vaccination.
Clinical Trial Data for Tixagevimab Plus Cilgavimab
PROVENT is an ongoing, Phase 3, double-blind, randomized, placebo-controlled trial that evaluated
the use of tixagevimab plus cilgavimab for SARS-CoV-2 PrEP.19,20 The study enrolled adults aged ≥18
years who had not received a COVID-19 vaccine and who were at increased risk of severe SARS-CoV-2
infection (e.g., those aged ≥60 years or those who had a prespecified comorbidity) or who had an
increased risk of acquiring SARS-CoV-2 infection due to their occupation or living situation. The study
excluded those with a history of confirmed SARS-CoV-2 infection or who had a positive SARS-CoV-2
antibody result at screening.
The analyzed population included participants who received a negative reverse transcription polymerase
chain reaction (RT-PCR) result at baseline. Participants received either tixagevimab 150 mg plus
cilgavimab 150 mg (administered as 2 consecutive IM injections; n = 3,460) or placebo (administered
as 2 IM injections; n = 1,737). The primary endpoint was symptomatic SARS-CoV-2 infection and a
positive RT-PCR result during the 183 days of follow-up.
Once COVID-19 vaccines became available, participants could choose to be unblinded and receive the
vaccine during the study. Only the primary endpoints that occurred prior to unblinding or vaccine receipt
were included in the analysis, resulting in a median follow-up of 83 days. Baseline characteristics were
well-balanced between the arms. Prior to unblinding or vaccination, RT-PCR-confirmed symptomatic
SARS-CoV-2 infection was reported for 8 participants (0.2%) in the tixagevimab plus cilgavimab arm
and 17 participants (1.0%) in the placebo arm, representing a 77% reduction in the incidence of infection
in the tixagevimab plus cilgavimab arm (95% CI, 46% to 90%; P < 0.001). A post hoc analysis after
a median follow-up period of 6 months showed a relative risk reduction of 82.8% (95% CI, 65.8% to
91.4%) for symptomatic infection in the tixagevimab plus cilgavimab arm. Five cases of COVID-19
were considered to be severe or critical, and 2 COVID-19–related deaths were reported. All of these
events occurred in participants who received placebo.

AR08761
Adverse events were reported for 35.3% of participants in the tixagevimab plus cilgavimab arm and
34.2% of participants in the placebo arm. Serious adverse events were reported in 1% of participants in
each arm; 1 participant in the tixagevimab plus cilgavimab arm had an anaphylactic reaction that was
resolved with epinephrine therapy. The incidence of adverse events was similar in both study arms;
most events were mild (62%) or moderate (32%). Rare, serious cardiac adverse events occurred in 0.7%
of participants in the tixagevimab plus cilgavimab arm and in 0.3% of participants in the placebo arm.
All participants who experienced a cardiac event had cardiac risk factors or a history of cardiac disease
at baseline. There was no clear temporal pattern between these serious cardiac adverse events and
administration of the anti-SARS-CoV-2 mAbs.20
TACKLE was a Phase 3 trial that evaluated the use of tixagevimab plus cilgavimab for the treatment of
nonhospitalized patients with mild to moderate COVID-19. In this study, 452 high-risk adults aged ≥18
years received a single IM dose of tixagevimab 300 mg plus cilgavimab 300 mg and had a follow-up
visit within 183 days (the median follow-up period was 84 days). Adverse events were reported for 29%
of participants in the tixagevimab plus cilgavimab arm and for 36% of participants in the placebo arm;
the majority of events were mild to moderate in severity. Serious cardiac adverse events were reported
for 4 participants; 3 had received tixagevimab plus cilgavimab and 1 had received placebo. All events
occurred in participants who had cardiac risk factors or a history of cardiovascular disease.20
Other Drugs for Pre-Exposure Prophylaxis

• The Panel recommends against the use of any oral drugs for SARS-CoV-2 PrEP, except in a
clinical trial (AIII).
Clinical trials are investigating several agents, including emtricitabine plus tenofovir alafenamide or
tenofovir disoproxil fumarate; hydroxychloroquine; ivermectin; and supplements such as zinc, vitamin
C, and vitamin D. Please check ClinicalTrials.gov for the latest information.
Hydroxychloroquine, given at different doses and durations, has been studied in randomized controlled
trials to assess whether it could prevent SARS-CoV-2 infection in those at risk of being exposed to
infected individuals, such as health care workers. One study reported no evidence of a benefit of
hydroxychloroquine, and it was ultimately halted due to futility before it reached its target enrollment.26
In another hydroxychloroquine study, which also did not meet its target enrollment and was stopped
early, the majority of the potential transmission events were not confirmed by virologic testing.27 Neither
study demonstrated any evidence of a reduction in the rate of acquiring infection. Both studies reported
an increased frequency of mild adverse events in the treatment group.
Post-Exposure Prophylaxis
• The Panel recommends against the use of bamlanivimab plus etesevimab and casirivimab
plus imdevimab for post-exposure prophylaxis (PEP), as the Omicron variant and its subvariants,
which are not susceptible to these agents, are currently the dominant SARS-CoV-2 variants
circulating in the United States (AIII).
Vaccination remains a highly effective way to prevent SARS-CoV-2 infection. However, despite the
widespread availability of COVID-19 vaccines, some individuals are not fully vaccinated or cannot mount
an adequate response to the vaccine. Some of these individuals, if infected, are at high risk of progressing
to serious COVID-19. Bamlanivimab plus etesevimab and casirivimab plus imdevimab have previously
received FDA EUAs for PEP; however, the Omicron variant and its subvariants are currently the dominant
SARS-CoV-2 variants circulating in the United States. The Panel recommends against the use of these

AR08762
anti-SARS-CoV-2 mAbs because the Omicron variant and its subvariants are not susceptible to them (AIII).
Chloroquine and Hydroxychloroquine

• The Panel recommends against the use of hydroxychloroquine for SARS-CoV-2 PEP (AI).
Both chloroquine and hydroxychloroquine have in vitro activity against SARS-CoV and SARS-CoV-
2.28,29 A small cohort study without a control group suggested that hydroxychloroquine might reduce the
risk of SARS-CoV-2 transmission to close contacts.30 There have been several large trials to determine
whether hydroxychloroquine can reduce the risk of infection after exposure to individuals infected with
SARS-CoV-2. These studies used different dose schedules and targeted different at-risk populations. In
addition, some studies were unable to confirm infection using molecular or antigen tests. None of these
studies demonstrated any evidence of efficacy for hydroxychloroquine, and all showed a higher risk of
generally mild adverse events in those who received the drug.31-33
Other Drugs for Post-Exposure Prophylaxis

• The Panel recommends against the use of other drugs for SARS-CoV-2 PEP, except in a clinical
trial (AIII).
A number of other agents (e.g., ivermectin, hyperimmune gamma globulin, convalescent plasma,
interferons, tenofovir with or without emtricitabine, vitamin D) are currently being investigated for
SARS-CoV-2 PEP. The latest clinical trials for SARS-CoV-2 PEP can be found at ClinicalTrials.gov.
High concentrations of ivermectin have been shown to inhibit SARS-CoV-2 replication in vitro.34,35
Population data indicated that countrywide, mass-use of prophylactic chemotherapy for parasitic
infections, including the use of ivermectin, was associated with a lower incidence of COVID-19.36 At this
time, few clinical trials have evaluated the safety and efficacy of using ivermectin for SARS-CoV-2 PrEP
or PEP. Although several studies have reported potentially promising results, the findings are limited by
the design of the studies, their small sample sizes, and the lack of details regarding the safety and efficacy
of ivermectin.
In a descriptive, uncontrolled, interventional study of 33 contacts of patients with laboratory-confirmed
SARS-CoV-2 infection, no cases of SARS-CoV-2 infection were identified within 21 days of initiating
ivermectin for PEP.37 In a small case-control study in SARS-CoV-2-exposed health care workers, 186
participants who became infected were matched with 186 uninfected controls. Of those who received
ivermectin after exposure to SARS-CoV-2, 38 were in the infected group and 77 were in the uninfected
group, which led the investigators to conclude that ivermectin reduced the incidence of SARS-CoV-2
infection.38
References
1. Centers for Disease Control and Prevention. Scientific brief: SARS-CoV-2 transmission. 2021. Available at:
https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/sars-cov-2-transmission.html. Accessed
March 18, 2022.
2. Centers for Disease Control and Prevention. COVID-19: how to protect yourself & others. 2021. Available at:
https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/prevention.html. Accessed March 18, 2022.
3. Centers for Disease Control and Prevention. Infection control guidance for healthcare professionals about
coronavirus (COVID-19). 2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/infection-
control.html. Accessed March 18, 2022.
4. Centers for Disease Control and Prevention. Johnson & Johnson’s Janssen COVID-19 vaccine overview and
safety. 2022. Available at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/janssen.
html. Accessed January 26, 2022.

AR08763
5. Centers for Disease Control and Prevention. Use of COVID-19 vaccines in the United States: interim clinical
considerations. 2022. Available at: https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-
vaccines-us.html. Accessed March 21, 2022.
6. Centers for Disease Control and Prevention. Interim considerations: preparing for the potential management of
anaphylaxis after COVID-19 vaccination. 2020. Available at: https://www.cdc.gov/vaccines/covid-19/info-by-
product/pfizer/anaphylaxis-management.html. Accessed March 22, 2022.
7. Food and Drug Administration. Fact sheet for healthcare providers administering vaccine (vaccination
providers): emergency use authorization (EUA) of the Janssen COVID-19 vaccine to prevent coronavirus
disease 2019 (COVID-19). 2022. Available at: https://www.fda.gov/media/146304/download.
8. See I, Lale A, Marquez P, et al. Case series of thrombosis with thrombocytopenia syndrome after COVID-19
vaccination—United States, December 2020 to August 2021. Ann Intern Med. 2022. Available at:
9. American Society of Hematology. Vaccine-induced immune thrombotic thrombocytopenia. 2022. Available
at: https://www.hematology.org/covid-19/vaccine-induced-immune-thrombotic-thrombocytopenia. Accessed
March 22, 2022.
10. Furie KL, Cushman M, Elkind MSV, et al. Diagnosis and management of cerebral venous sinus thrombosis
with vaccine-induced immune thrombotic thrombocytopenia. Stroke. 2021;52(7):2478-2482. Available at:
11. Centers for Disease Control and Prevention. Selected adverse events reported after COVID-19 vaccination.
2022. Available at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/adverse-events.html. Accessed
March 22, 2022.
12. Centers for Disease Control and Prevention. COVID-19 vaccines while pregnant or breastfeeding. 2022.
Available at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/pregnancy.html. Accessed
March 22, 2022.
13. Society for Maternal-Fetal Medicine. Publications and clinical guidance. 2022. Available at:
https://www.smfm.org/covidclinical. Accessed March 22, 2022.
14. Shimabukuro TT, Kim SY, Myers TR, et al. Preliminary findings of mRNA COVID-19 vaccine safety in
pregnant persons. N Engl J Med. 2021;384(24):2273-2282. Available at:
15. Zauche LH, Wallace B, Smoots AN, et al. Receipt of mRNA COVID-19 vaccines and risk of spontaneous
abortion. N Engl J Med. 2021;385(16):1533-1535. Available at:
16. Goldshtein I, Nevo D, Steinberg DM, et al. Association between BNT162b2 vaccination and incidence of
SARS-CoV-2 infection in pregnant women. JAMA. 2021;326(8):728-735. Available at:
17. Collier AY, McMahan K, Yu J, et al. Immunogenicity of COVID-19 mRNA vaccines in pregnant and lactating
women. JAMA. 2021;325(23):2370-2380. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33983379.
18. The American College of Obstetricians and Gynecologists. Practice advisory: COVID-19 vaccination
considerations for obstetric-gynecologic care. 2022. Available at: https://www.acog.org/clinical/clinical-
guidance/practice-advisory/articles/2020/12/vaccinating-pregnant-and-lactating-patients-against-covid-19.
19. Levin MJ, Ustianowski A, De Wit S, et al. Intramuscular AZD7442 (tixagevimab-cilgavimab) for prevention of
COVID-19. N Engl J Med. 2022. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35443106.
20. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for Evusheld
(tixagevimab co-packaged with cilgavimab). 2022. Available at: https://www.fda.gov/media/154701/download.
antigenic shift. Nature. 2022;602(7898):664-670. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35016195.
22. Takashita E, Kinoshita N, Yamayoshi S, et al. Efficacy of antibodies and antiviral drugs against COVID-19

AR08764
Omicron variant. N Engl J Med. 2022;386(10):995-998. Available at:
23. Iketani S, Liu L, Guo Y, et al. Antibody evasion properties of SARS-CoV-2 Omicron sublineages. Nature.
2022. Available at: https://www.nature.com/articles/s41586-022-04594-4.
24. Takashita E, Kinoshita N, Yamayoshi S, et al. Efficacy of antiviral agents against the SARS-CoV-2 Omicron
subvariant BA.2. N Engl J Med. 2022;386(15):1475-1477. Available at:
25. Food and Drug Administration. Emergency Use Authorization (EUA) for Evusheld. 2022. Available at:
https://www.fda.gov/media/156674/download.
26. Abella BS, Jolkovsky EL, Biney BT, et al. Efficacy and safety of hydroxychloroquine vs placebo for pre-
exposure SARS-CoV-2 prophylaxis among health care workers: a randomized clinical trial. JAMA Intern Med.
27. Rajasingham R, Bangdiwala AS, Nicol MR, et al. Hydroxychloroquine as pre-exposure prophylaxis
for coronavirus disease 2019 (COVID-19) in healthcare workers: a randomized trial. Clin Infect Dis.
2021;72(11):e835-e843. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33068425.
28. Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of
hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin
Infect Dis. 2020;71(15):732-739. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32150618.
29. Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection
and spread. Virol J. 2005;2:69. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16115318.
30. Lee SH, Son H, Peck KR. Can post-exposure prophylaxis for COVID-19 be considered as an outbreak
response strategy in long-term care hospitals? Int J Antimicrob Agents. 2020;55(6):105988. Available at:
31. Barnabas RV, Brown ER, Bershteyn A, et al. Hydroxychloroquine as postexposure prophylaxis to
prevent severe acute respiratory syndrome coronavirus 2 infection: a randomized trial. Ann Intern Med.
32. Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial of hydroxychloroquine as postexposure
prophylaxis for COVID-19. N Engl J Med. 2020;383(6):517-525. Available at:
33. Mitja O, Corbacho-Monne M, Ubals M, et al. A cluster-randomized trial of hydroxychloroquine for prevention
of COVID-19. N Engl J Med. 2021;384(5):417-427. Available at:
34. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the
replication of SARS-CoV-2 in vitro. Antiviral Res. 2020;178:104787. Available at:
35. Belhadjer Z, Meot M, Bajolle F, et al. Acute heart failure in multisystem inflammatory syndrome in children
in the context of global SARS-CoV-2 pandemic. Circulation. 2020;142(5):429-436. Available at:
36. Hellwig MD, Maia A. A COVID-19 prophylaxis? Lower incidence associated with prophylactic
administration of ivermectin. Int J Antimicrob Agents. 2021;57(1):106248. Available at:
37. Aguirre Chang G FA. COVID-19: post-exposure prophylaxis with ivermectin in contacts. At homes, places of
work, nursing homes, prisons, and others. ResearchGate. 2020;Preprint. Available at: https://www.researchgate.
net/publication/344781515_COVID-19_POST-EXPOSURE_PROPHYLAXIS_WITH_IVERMECTIN_IN_
CONTACTS.
38. Behera P, Patro BK, Singh AK, et al. Role of ivermectin in the prevention of SARS-CoV-2 infection among
healthcare workers in India: a matched case-control study. PLoS One. 2021;16(2):e0247163. Available at:

AR08765
Clinical Spectrum of SARS-CoV-2 Infection

Last Updated: October 19, 2021
Patients with SARS-CoV-2 infection can experience a range of clinical manifestations, from no
symptoms to critical illness. In general, adults with SARS-CoV-2 infection can be grouped into the
following severity of illness categories; however, the criteria for each category may overlap or vary
across clinical guidelines and clinical trials, and a patient’s clinical status may change over time.
• Asymptomatic or Presymptomatic Infection: Individuals who test positive for SARS-CoV-2 using
a virologic test (i.e., a nucleic acid amplification test [NAAT] or an antigen test) but who have no
symptoms that are consistent with COVID-19.
• Mild Illness: Individuals who have any of the various signs and symptoms of COVID-19 (e.g.,
fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste
and smell) but who do not have shortness of breath, dyspnea, or abnormal chest imaging.
• Moderate Illness: Individuals who show evidence of lower respiratory disease during clinical
assessment or imaging and who have an oxygen saturation (SpO2) ≥94% on room air at sea level.
• Severe Illness: Individuals who have SpO2 <94% on room air at sea level, a ratio of arterial partial
pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300 mm Hg, a respiratory rate >30
breaths/min, or lung infiltrates >50%.
• Critical Illness: Individuals who have respiratory failure, septic shock, and/or multiple organ
dysfunction.
Patients with certain underlying comorbidities are at a higher risk of progressing to severe COVID-19.
These comorbidities include being aged ≥65 years; having cardiovascular disease, chronic lung disease,
sickle cell disease, diabetes, cancer, obesity, or chronic kidney disease; being pregnant; being a cigarette
smoker; being a transplant recipient; and receiving immunosuppressive therapy.1 Health care providers
should monitor such patients closely until clinical recovery is achieved.
The optimal pulmonary imaging technique has not yet been defined for people with symptomatic
SARS-CoV-2 infection. Initial evaluation for these patients may include a chest X-ray, ultrasound
screening, or, if indicated, a computed tomography scan. An electrocardiogram should be performed if
indicated. Laboratory testing includes a complete blood count with differential and a metabolic profile,
including liver and renal function tests. Although inflammatory markers such as C-reactive protein
(CRP), D-dimer, and ferritin are not routinely measured as part of standard care, results from such
measurements may have prognostic value.2-4
The definitions for the severity of illness categories listed above also apply to pregnant patients.
However, the threshold for certain interventions may be different for pregnant patients and nonpregnant
patients. For example, oxygen supplementation is recommended for pregnant patients when SpO2 falls
below 95% on room air at sea level to accommodate physiologic changes in oxygen demand during
pregnancy and to ensure adequate oxygen delivery to the fetus.5 If laboratory parameters are used for
monitoring pregnant patients and making decisions about interventions, clinicians should be aware that
normal physiologic changes during pregnancy can alter several laboratory values. In general, leukocyte
cell count increases throughout gestation and delivery and peaks during the immediate postpartum
period. This increase is mainly due to neutrophilia.6 D-dimer and CRP levels also increase during
pregnancy and are often higher in pregnant patients than nonpregnant patients.7 Detailed information on
treating COVID-19 in pregnant patients can be found in Special Considerations in Pregnancy and in the
pregnancy considerations subsection of each section of the Guidelines.

AR08766
In pediatric patients, radiographic abnormalities are common and, for the most part, should not be
the only criteria used to determine the severity of illness. The normal values for respiratory rate also
vary with age in children; therefore, hypoxemia should be the primary criterion used to define severe
COVID-19, especially in younger children. In a small number of children and in some young adults,
SARS-CoV-2 infection may be followed by a severe inflammatory condition called multisystem
inflammatory syndrome in children (MIS-C).8,9 This syndrome is discussed in detail in Special
Considerations in Children.
Asymptomatic or Presymptomatic Infection

Asymptomatic SARS-CoV-2 infection can occur, although the percentage of patients who remain truly
asymptomatic throughout the course of infection is variable and incompletely defined. It is unclear what
percentage of individuals who present with asymptomatic infection progress to clinical disease. Some
asymptomatic individuals have been reported to have objective radiographic findings that are consistent
with COVID-19 pneumonia.10,11 Increasing the availability of virologic testing for SARS-CoV-2
and reliable serologic assays for SARS-CoV-2 antibodies will help determine the true prevalence of
asymptomatic and presymptomatic infection. See Therapeutic Management of Nonhospitalized Adults
With COVID-19 for recommendations regarding SARS-CoV-2-specific therapy.
Mild Illness
Patients with mild illness may exhibit a variety of signs and symptoms (e.g., fever, cough, sore throat,
malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste and smell). They do not have
shortness of breath, dyspnea on exertion, or abnormal imaging. Most mildly ill patients can be managed
in an ambulatory setting or at home through telemedicine or telephone visits. No imaging or specific
laboratory evaluations are routinely indicated in otherwise healthy patients with mild COVID-19. Older
patients and those with underlying comorbidities are at higher risk of disease progression; therefore,
health care providers should monitor these patients closely until clinical recovery is achieved. See
Therapeutic Management of Nonhospitalized Adults With COVID-19 for recommendations regarding
SARS-CoV-2-specific therapy.
Moderate Illness
Moderate illness is defined as evidence of lower respiratory disease during clinical assessment or
imaging, with SpO2 ≥94% on room air at sea level. Given that pulmonary disease can progress rapidly
in patients with COVID-19, patients with moderate disease should be closely monitored. If bacterial
pneumonia or sepsis is suspected, administer empiric antibiotic treatment, re-evaluate the patient
daily, and de-escalate or stop antibiotics if there is no evidence of bacterial infection. See Therapeutic
Management of Nonhospitalized Adults With COVID-19 for recommendations regarding SARS-CoV-2-
specific therapy.
Severe Illness
Patients with COVID-19 are considered to have severe illness if they have SpO2 <94% on room air
at sea level, PaO2/FiO2 <300 mm Hg, a respiratory rate >30 breaths/min, or lung infiltrates >50%.
These patients may experience rapid clinical deterioration. Oxygen therapy should be administered
immediately using a nasal cannula or a high-flow oxygen device. See Therapeutic Management of
Hospitalized Adults With COVID-19 for recommendations regarding SARS-CoV-2-specific therapy.
If secondary bacterial pneumonia or sepsis is suspected, administer empiric antibiotics, re-evaluate the
patient daily, and de-escalate or stop antibiotics if there is no evidence of bacterial infection.

AR08767
Critical Illness
Critically ill patients may have acute respiratory distress syndrome, septic shock that may represent
virus-induced distributive shock, cardiac dysfunction, an exaggerated inflammatory response, and/or
exacerbation of underlying comorbidities. In addition to pulmonary disease, patients with critical illness
may also experience cardiac, hepatic, renal, central nervous system, or thrombotic disease.
As with any patient in the intensive care unit (ICU), successful clinical management of a patient with
COVID-19 includes treating both the medical condition that initially resulted in ICU admission and
other comorbidities and nosocomial complications. For more information, see Care of Critically Ill Adult
Patients With COVID-19.
Infectious Complications in Patients With COVID-19

Some patients with COVID-19 may have additional infections that are noted when they present for
care or that develop during the course of treatment. These coinfections may complicate treatment and
recovery. Older patients or those with certain comorbidities or immunocompromising conditions may be
at higher risk for these infections. The use of immunomodulators such as dexamethasone, interleukin-6
inhibitors (e.g., tocilizumab, sarilumab), or Janus kinase inhibitors (e.g., baricitinib, tofacitinib) to treat
COVID-19 may also be a risk factor for infectious complications; however, when these therapies are
used appropriately, the benefits outweigh the risks.
Infectious complications in patients with COVID-19 can be categorized as follows:
• Coinfections at Presentation With COVID-19: Although most individuals present with only
SARS-CoV-2 infection, concomitant viral infections, including influenza and other respiratory
viruses, have been reported.12 Community-acquired bacterial pneumonia has also been reported,
but it is uncommon, with a prevalence that ranges from 0% to 6% of people with SARS-CoV-2
infection.12,13 Antibacterial therapy is generally not recommended unless additional evidence for
bacterial pneumonia is present (e.g., leukocytosis, the presence of a focal infiltrate on imaging).
• Reactivation of Latent Infections: There are case reports of underlying chronic hepatitis B
virus and latent tuberculosis infections reactivating in patients with COVID-19 who receive
immunomodulators as treatment,14-16 although the data are currently limited. Reactivation of herpes
simplex virus and varicella zoster virus infections have also been reported.17 Cases of severe and
disseminated strongyloidiasis have been reported in patients with COVID-19 during treatment
with tocilizumab and corticosteroids.18,19 Many clinicians would initiate empiric treatment (e.g.,
treatment with ivermectin) with or without serologic testing in patients who are from areas where
Strongyloides is endemic (i.e., tropical, subtropical, or warm temperate areas).20
• Nosocomial Infections in Patients With COVID-19: Hospitalized patients with COVID-19
may acquire common nosocomial infections, such as hospital-acquired pneumonia (including
ventilator-associated pneumonia), line-related bacteremia or fungemia, catheter-associated urinary
tract infection, and Clostridioides difficile-associated diarrhea. Early diagnosis and treatment of
these infections are important for improving outcomes in these patients.
• Opportunistic Fungal Infections: Invasive fungal infections, including aspergillosis and
mucormycosis, have been reported in hospitalized patients with COVID-19.21-24 Although
these infections are relatively rare, they can be fatal, and they may be more commonly seen in
immunocompromised patients and in patients who are on mechanical ventilation. The majority
of mucormycosis cases have been reported in India and are associated with diabetes mellitus and/
or the use of corticosteroids.25,26 The approach for managing these fungal infections should be the
same as the approach for managing invasive fungal infections in other settings.

AR08768
SARS-CoV-2 Reinfection
As seen with other viral infections, reinfection with SARS-CoV-2 after recovery from prior infection
has been reported.27 The true prevalence of reinfection is not known, although there are concerns that
the frequency of reinfection may increase with the circulation of new variants.28 SARS-CoV-2 can often
be detected from a nasal swab for weeks to months after the initial infection; therefore, repeat testing
to evaluate for reinfection should be considered only for those who have recovered from the initial
infection and present with COVID-19-compatible symptoms with no obvious alternate etiology (AIII).29
Diagnostic testing in this setting is summarized in Testing for SARS-CoV-2 Infection. In addition,
if reinfection is suspected, guidelines for the diagnosis and evaluation of suspected SARS-CoV-2
reinfection are provided by the Centers for Disease Control and Prevention (CDC).30
It has been speculated that reinfection may occur more frequently in those who have a less robust
immune response during the initial infection, as is often reported in those with mild illness. Reinfection
may also occur as initial immune responses wane over time. Nevertheless, one review noted that
SARS-CoV-2 reinfection occurred after previous severe disease in three cases and as early as 3 weeks
after the initial infection was diagnosed.31 A public site that posts a variety of published and unpublished
reports of reinfection notes that reinfection has occurred anywhere from a few weeks to many months
after the initial infection, and it occasionally follows episodes of severe COVID-19.32 Although data
are limited, there is no evidence to suggest that the treatment of suspected or documented SARS-CoV-2
reinfection should be different from the treatment used during the initial infection, as outlined in
Therapeutic Management of Nonhospitalized Adults With COVID-19 and Therapeutic Management of
Hospitalized Adults With COVID-19.
Persistent Symptoms or Organ Dysfunction After Acute COVID-19

There have been an increasing number of reports of patients who experience persistent symptoms and/or
organ dysfunction after acute COVID-19. Data about the incidence, natural history, and etiology of these
symptoms are emerging. However, these reports have several limitations. For example, there is currently
no agreed-upon case definition for persistent symptoms or organ dysfunction after acute COVID-19. In
addition, most of these reports only included patients who attended post-COVID-19 clinics, and they
often lack comparator groups. No specific treatments for the persistent effects of COVID-19 have yet
been identified, although this COVID-19 rapid guideline proposes general management strategies.
The nomenclature for this phenomenon is evolving, and there is no established clinical terminology to
date. It has been referred to as post-COVID-19 condition, or, colloquially, “long COVID,” and affected
patients have been referred to as “long haulers.” The term “post-acute sequelae of COVID-19” (PASC)
has also been used to describe late sequelae of SARS-CoV-2 infection that include these persistent
symptoms, as well as other delayed syndromes such as MIS-C and multisystem inflammatory syndrome
in adults (MIS-A). To date, no case definition and no specific time frame have been established to define
the syndrome of persistent symptoms and/or organ dysfunction after acute COVID-19. However, CDC
recently proposed defining late sequelae as sequelae that extend >4 weeks after initial infection.33,34 The
Patient-Led Research Collaborative for COVID-19 defines long COVID as a collection of symptoms
that develop during or following a confirmed or suspected case of COVID-19 and that continue for >28
days.35 Incidence rates vary widely, from about 10% in some reports to one cohort study in which 87%
of patients reported at least one persistent symptom.36
Some of the symptoms overlap with the post-intensive care syndrome (PICS) that has been described
in patients without COVID-19, but prolonged symptoms and disabilities after COVID-19 have also
been reported in patients with milder illness, including outpatients (see General Considerations for
information on PICS).37,38

AR08769
Despite the limitations of the available descriptive data on these persistent symptoms, some
representative studies have suggested that common findings include fatigue, joint pain, chest pain,
palpitations, shortness of breath, cognitive impairment, and worsened quality of life.39,40
CDC conducted a telephone survey of a random sample of 292 adult outpatients who had positive
polymerase chain reaction results for SARS-CoV-2. Among the 274 respondents who were symptomatic
at the time of testing, 35% reported not having returned to their usual state of health 2 weeks or more
after testing; this included 26% of patients aged 18 to 34 years, 32% of those aged 35 to 49 years, and
47% of those aged ≥50 years.38 An age of ≥50 years and the presence of three or more chronic medical
conditions were associated with not returning to usual health within 14 to 21 days. Moreover, one in
five individuals aged 18 to 34 years who did not have chronic medical conditions had not returned to
baseline health when interviewed at a median of 16 days from the testing date.
In a cohort study from Wuhan, China, 1,733 discharged patients with COVID-19 were evaluated for
persistent symptoms at a median of 186 days after symptom onset.41 The most common symptoms
were fatigue or muscle weakness and sleep difficulties (reported among 63% and 26% of participants,
respectively). Anxiety or depression was reported among 23% of patients.
In a longitudinal prospective cohort of mostly outpatients with laboratory-confirmed SARS-CoV-2
infection at the University of Washington, 177 participants completed a follow-up questionnaire
between 3 and 9 months after illness onset.42 Overall, 91% of the respondents were outpatients (150
with mild illness and 11 with no symptoms), and only 9% had moderate or severe disease that required
hospitalization. Among those who reported symptoms, 33% of outpatients and 31% of hospitalized
patients reported at least one persistent symptom. Persistent symptoms were reported by 27% of the
patients aged 18 to 39 years, 30% of those aged 40 to 64 years, and 43% of those aged ≥65 years. The
most common persistent symptoms were loss of sense of smell or taste and fatigue (both reported by
14% of patients).
Persistent symptoms after acute COVID-19 have also been reported in pregnant people.43 Systematic
data on persistent symptoms in children following recovery from the acute phase of COVID-19 are
not currently available, although case reports suggest that children may experience long-term effects
similar to those experienced by adults after clinical COVID-19.44,45 MIS-C is discussed in Special
Considerations in Children.
Fatigue
The prevalence of fatigue among 128 individuals from Ireland who had recovered from the acute phase
of COVID-19 was examined using the Chalder Fatigue Scale (CFQ11). More than half of patients (67
of 128 patients [52.3%]) reported persistent fatigue at a median of 10 weeks after initial symptoms first
appeared. There was no association between illness severity and fatigue.46 An outpatient service that
was developed in Italy for patients recovering from acute COVID-19 reported that 87% of 143 patients
surveyed had persistent symptoms for a mean of 60 days after symptom onset. The most common
symptom was fatigue, which occurred in 53.1% of these patients.36
Cardiopulmonary
A study from the United Kingdom reported that among 100 hospitalized patients with COVID-19 (32
received care in the ICU and 68 received care in hospital wards only), 72% of the ICU patients and 60%
of the ward patients experienced fatigue and breathlessness at 4 to 8 weeks after hospital discharge.
The authors suggested that posthospital rehabilitation may be necessary for some of these patients.39 A
retrospective study from China found that pulmonary function (as measured by spirometry) was still
impaired 1 month after hospital discharge in 31 of 57 patients (54.4%) with COVID-19.47 In a study

AR08770
from Germany that included 100 patients who had recently recovered from COVID-19, cardiac magnetic
resonance imaging (MRI) performed a median of 71 days after diagnosis revealed cardiac involvement
in 78% of patients and ongoing myocardial inflammation in 60% of patients.48 A retrospective study
from China of 26 patients who had recovered from COVID-19 and who had initially presented with
cardiac symptoms found abnormalities on cardiac MRI in 15 patients (58%).49 This assessment of the
prevalence of cardiac abnormalities in people with PASC should be viewed with caution, however, as
the analysis included only patients with cardiac symptoms.
Neuropsychiatric
Neurologic and psychiatric symptoms have also been reported among patients who have recovered
from acute COVID-19. High rates of anxiety and depression have been reported in some patients using
self-report scales for psychiatric distress.40,50 Younger patients have been reported to experience more
psychiatric symptoms than patients aged >60 years.39,40 Patients may continue to experience headaches,
vision changes, hearing loss, loss of taste or smell, impaired mobility, numbness in extremities, tremors,
myalgia, memory loss, cognitive impairment, and mood changes for up to 3 months after diagnosis of
COVID-19.51-53 One study in the United Kingdom administered cognitive tests to 84,285 participants
who had recovered from suspected or confirmed SARS-CoV-2 infection. These participants had worse
performances across multiple domains than would be expected for people with the same ages and
demographic profiles; this effect was observed even among those who had not been hospitalized.54
However, the study authors did not report when the tests were administered in relation to the diagnosis
of COVID-19.
More research and more rigorous observational cohort studies are needed to better understand the
pathophysiology and clinical course of post-acute COVID-19 sequelae and to identify management
strategies for patients. More information about ongoing studies can be found at ClinicalTrials.gov.
References
1. Centers for Disease Control and Prevention. COVID-19 (coronavirus disease): people with certain medical
conditions. 2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-
with-medical-conditions.html. Accessed August 31, 2021.
2. Tan C, Huang Y, Shi F, et al. C-reactive protein correlates with computed tomographic findings and predicts
severe COVID-19 early. J Med Virol. 2020;92(7):856-862. Available at:
3. Berger JS, Kunichoff D, Adhikari S, et al. Prevalence and outcomes of D-dimer elevation in hospitalized
patients with COVID-19. Arterioscler Thromb Vasc Biol. 2020;40(10):2539-2547. Available at:
4. Casas-Rojo JM, Anton-Santos JM, Millan-Nunez-Cortes J, et al. Clinical characteristics of patients
hospitalized with COVID-19 in Spain: results from the SEMI-COVID-19 Registry. Rev Clin Esp.
5. Society for Maternal Fetal Medicine. Management considerations for pregnant patients with COVID-19.
2020. Available at: https://s3.amazonaws.com/cdn.smfm.org/media/2336/SMFM_COVID_Management_of_
COVID_pos_preg_patients_4-30-20_final.pdf.
6. Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for
clinicians. Obstet Gynecol. 2009;114(6):1326-1331. Available at:
7. Anderson BL, Mendez-Figueroa H, Dahlke JD, Raker C, Hillier SL, Cu-Uvin S. Pregnancy-induced changes
in immune protection of the genital tract: defining normal. Am J Obstet Gynecol. 2013;208(4):321 e321-329.

AR08771
8. Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in

children during COVID-19 pandemic. Lancet. 2020;395(10237):1607-1608. Available at:
9. Verdoni L, Mazza A, Gervasoni A, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre
of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. 2020;395(10239):1771-1778. Available
10. Zhang R, Ouyang H, Fu L, et al. CT features of SARS-CoV-2 pneumonia according to clinical presentation:
a retrospective analysis of 120 consecutive patients from Wuhan city. Eur Radiol. 2020;30(8):4417-4426.
11. Inui S, Fujikawa A, Jitsu M, et al. Chest CT findings in cases from the cruise ship “Diamond Princess” with
coronavirus disease 2019 (COVID-19). Radiology: Cardiothoracic Imaging. 2020;2(2). Available at:
https://pubs.rsna.org/doi/10.1148/ryct.2020200110.
12. Kim D, Quinn J, Pinsky B, Shah NH, Brown I. Rates of co-infection between SARS-CoV-2 and other
respiratory pathogens. JAMA. 2020;323(20):2085-2086. Available at:
13. Kubin CJ, McConville TH, Dietz D, et al. Characterization of bacterial and fungal infections in hospitalized
patients with coronavirus disease 2019 and factors associated with health care-associated infections. Open
Forum Infect Dis. 2021;8(6):ofab201. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34099978.
14. Garg N, Lee YI. Reactivation TB with severe COVID-19. Chest. 2020;158(4). Available at:
https://journal.chestnet.org/article/S0012-3692(20)32910-X/fulltext.
15. Rodriguez-Tajes S, Miralpeix A, Costa J, et al. Low risk of hepatitis B reactivation in patients with severe
COVID-19 who receive immunosuppressive therapy. J Viral Hepat. 2021;28(1):89-94. Available at:
16. Aldhaleei WA, Alnuaimi A, Bhagavathula AS. COVID-19 induced hepatitis B virus reactivation: a novel case
from the United Arab Emirates. Cureus. 2020;12(6):e8645. Available at:
17. Xu R, Zhou Y, Cai L, et al. Co-reactivation of the human herpesvirus alpha subfamily (herpes simplex virus-1
and varicella zoster virus) in a critically ill patient with COVID-19. Br J Dermatol. 2020;183(6):1145-1147.
18. Lier AJ, Tuan JL, Davis MW, et al. Case report: disseminated strongyloidiasis in a patient with COVID-19.
Am J Trop Med Hyg. 2020;103(4):1590-1592. Available at: https://pubmed.ncbi.nlm.nih.gov/32830642.
19. Marchese V, Crosato V, Gulletta M, et al. Strongyloides infection manifested during immunosuppressive
therapy for SARS-CoV-2 pneumonia. Infection. 2021;49(3):539-542. Available at:
20. Stauffer WM, Alpern JD, Walker PF. COVID-19 and dexamethasone: a potential strategy to avoid steroid-
related strongyloides hyperinfection. JAMA. 2020;324(7):623-624. Available at:
21. Salmanton-Garcia J, Sprute R, Stemler J, et al. COVID-19-associated pulmonary aspergillosis, March–
August 2020. Emerg Infect Dis. 2021;27(4):1077-1086. Available at: https://www.ncbi.nlm.nih.gov/
pubmed/33539721.
22. Chong WH, Neu KP. Incidence, diagnosis and outcomes of COVID-19-associated pulmonary aspergillosis
(CAPA): a systematic review. J Hosp Infect. 2021;113:115-129. Available at:
23. Machado M, Valerio M, Alvarez-Uria A, et al. Invasive pulmonary aspergillosis in the COVID-19 era: An
expected new entity. Mycoses. 2021;64(2):132-143. Available at:
24. Yusuf E, Seghers L, Hoek RAS, van den Akker JPC, Bode LGM, Rijnders BJA. Aspergillus in critically ill

AR08772
COVID-19 patients: a scoping review. J Clin Med. 2021;10(11). Available at:
25. Singh AK, Singh R, Joshi SR, Misra A. Mucormycosis in COVID-19: a systematic review of cases reported
worldwide and in India. Diabetes Metab Syndr. 2021;15(4):102146. Available at:
26. Pal R, Singh B, Bhadada SK, et al. COVID-19-associated mucormycosis: an updated systematic review of
literature. Mycoses. 2021;Published online ahead of print. Available at:
27. Cohen J, Burbelo PD. Reinfection with SARS-CoV-2: implications for vaccines. Oxford Clin Infect Dis.
2020;Published online ahead of print. Available at: https://pubmed.ncbi.nlm.nih.gov/33338197.
28. Nonaka CKV, Franco MM, Graf T, et al. Genomic evidence of SARS-CoV-2 reinfection case with E484K
spike mutation, Brazil. Emerg Infect Dis. 2021;27(5). Available at:
29. Centers for Disease Control and Prevention. Interim guidance on duration of isolation and precautions for
adults with COVID-19. 2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/duration-
isolation.html. Accessed August 31, 2021.
30. Centers for Disease Control and Prevention. Investigative criteria for suspected cases of SARS-CoV-2
reinfection (ICR). 2020. Available at: https://www.cdc.gov/coronavirus/2019-ncov/php/invest-criteria.html.
Accessed August 31, 2021.
31. Kim AY, Gandhi RT. Reinfection with severe acute respiratory syndrome coronavirus 2: what goes around
may come back around. Clin Infect Dis. 2020. Available at:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665341.
32. BNO News. COVID-19 reinfection tracker. 2020. Available at:
https://bnonews.com/index.php/2020/08/covid-19-reinfection-tracker. Accessed August 31, 2021.
33. Datta SD, Talwar A, Lee JT. A proposed framework and timeline of the spectrum of disease due
to SARS-CoV-2 infection: illness beyond acute infection and public health implications. JAMA.
34. Greenhalgh T, Knight M, A’Court C, Buxton M, Husain L. Management of post-acute COVID-19 in primary
care. BMJ. 2020;370:m3026. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32784198.
35. Sudre CH, Murray B, Varsavsky T, et al. Attributes and predictors of Long-COVID: analysis of COVID cases
and their symptoms collected by the COVID symptoms study app. Nat Med. 2021;27(4):626-631. Available
at: https://pubmed.ncbi.nlm.nih.gov/33692530/.
36. Carfi A, Bernabei R, Landi F, Gemelli Against COVID-19 Post-Acute Care Study Group. Persistent symptoms
in patients after acute COVID-19. JAMA. 2020;324(6):603-605. Available at:
37. Rawal G, Yadav S, Kumar R. Post-intensive care syndrome: an overview. J Transl Int Med. 2017;5(2):90-92.
38. Tenforde MW, Kim SS, Lindsell CJ, et al. Symptom duration and risk factors for delayed return to usual health
among outpatients with COVID-19 in a multistate health care systems network—United States, March–June
39. Halpin SJ, McIvor C, Whyatt G, et al. Postdischarge symptoms and rehabilitation needs in survivors of
COVID-19 infection: a cross-sectional evaluation. J Med Virol. 2021;93(2):1013-1022. Available at:
40. Cai X, Hu X, Ekumi IO, et al. Psychological distress and its correlates among COVID-19 survivors during
early convalescence across age groups. Am J Geriatr Psychiatry. 2020;28(10):1030-1039. Available at:

AR08773
41. Huang C, Huang L, Wang Y, et al. 6-month consequences of COVID-19 in patients discharged from hospital:
a cohort study. Lancet. 2021;397(10270):220-232. Available at:
42. Logue JK, Franko NM, MucCulloch DJ, et al. Sequelae in adults at 6 months after COVID-19 infection.
JAMA Netw Open. 2021. Available at: https://pubmed.ncbi.nlm.nih.gov/33606031/.
43. Afshar Y, Gaw SL, Flaherman VJ, et al. Clinical presentation of coronavirus disease 2019 (COVID-19) in
pregnant and recently pregnant people. Obstet Gynecol. 2020;136(6):1117-1125. Available at:
44. Ludvigsson JF. Case report and systematic review suggest that children may experience similar long-term
effects to adults after clinical COVID-19. Acta Paediatr. 2021 Mar;110(3):914-921. Available at:
45. Buonsenso D, Munblit D, De Rose C, et al. Preliminary evidence on long COVID in children. Acta Paediatr.
2021;110(7):2208-2211. Available at: https://www.medrxiv.org/content/10.1101/2021.01.23.21250375v1.
46. Townsend L, Dyer AH, Jones K, et al. Persistent fatigue following SARS-CoV-2 infection is common and
independent of severity of initial infection. PLoS One. 2020;15(11):e0240784. Available at:
47. Huang Y, Tan C, Wu J, et al. Impact of coronavirus disease 2019 on pulmonary function in early
convalescence phase. Respir Res. 2020;21(1):163. Available at:
48. Puntmann VO, Carerj ML, Wieters I, et al. Outcomes of cardiovascular magnetic resonance imaging in
patients recently recovered from coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020;5(11):1265-
49. Huang L, Zhao P, Tang D, et al. Cardiac involvement in patients recovered from COVID-2019 identified using
magnetic resonance imaging. JACC Cardiovasc Imaging. 2020;13(11):2330-2339. Available at:
50. Mazza MG, De Lorenzo R, Conte C, et al. Anxiety and depression in COVID-19 survivors: role of
inflammatory and clinical predictors. Brain Behav Immun. 2020;89:594-600. Available at:
51. Lu Y, Li X, Geng D, et al. Cerebral micro-structural changes in COVID-19 patients—an MRI-based 3-month
follow-up study. EClinicalMedicine. 2020;25:100484. Available at:
52. Heneka MT, Golenbock D, Latz E, Morgan D, Brown R. Immediate and long-term consequences of
COVID-19 infections for the development of neurological disease. Alzheimers Res Ther. 2020;12(1):69.
53. Lechien JR, Chiesa-Estomba CM, Beckers E, et al. Prevalence and 6-month recovery of olfactory dysfunction:
a multicentre study of 1363 COVID-19 patients. J Intern Med. 2021;290(2):451-461. Available at:
54. Hampshire A, Trender W, Chamberlain SR, et al. Cognitive deficits in people who have recovered from
COVID-19 relative to controls: an N = 84,285 online study. medRxiv. 2020;Preprint. Available at:
https://www.medrxiv.org/content/10.1101/2020.10.20.20215863v1.

AR08774
Prioritization of Anti-SARS-CoV-2 Therapies for the

Treatment and Prevention of COVID-19 When There Are
Logistical or Supply Constraints
The COVID-19 Treatment Guidelines Panel (the Panel) has recommended several therapeutic agents
for the treatment and prevention of SARS-CoV-2 infection in individuals who are at high risk for
progression to severe COVID-19. These anti-SARS-CoV-2 therapeutics are of greatest proven clinical
benefit for nonhospitalized patients who have risk factors for progression to severe COVID-19. The
risks for progression are substantially higher for those who are not vaccinated or who are vaccinated but
not expected to mount an adequate immune response to the vaccine.
The Food and Drug Administration’s Emergency Use Authorizations provide a broad list of medical
conditions or other factors as criteria for use of anti-SARS-CoV-2 agents as treatment or pre-exposure
prophylaxis (PrEP). However, at times throughout the pandemic, increased cases of COVID-19 and
the emergence of new variants of concern have resulted in logistical or supply constraints that made
it impossible to offer the available therapy to all eligible patients. In those situations, prioritization of
therapy for those who would have benefited the most became necessary. The purpose of this section
is to provide guidance on which individuals might receive the greatest benefit from anti-SARS-CoV-2
therapeutics for treatment or prevention.
When it becomes necessary to triage patients for receipt of anti-SARS-CoV-2 therapies or preventive
strategies, the Panel suggests prioritizing:
• Treatment of COVID-19 in unvaccinated or incompletely vaccinated individuals with clinical risk
factors for severe illness and vaccinated individuals who are not expected to mount an adequate
immune response (see Immunocompromising Conditions below)
• Use of tixagevimab plus cilgavimab (Evusheld) as PrEP for individuals who are severely
immunocompromised over those who are moderately immunocompromised (see
Immunocompromising Conditions below)
Prioritization of Patients at Highest Risk of Progression to Severe COVID-19

When logistical or supply constraints limit the availability of anti-SARS-CoV-2 monoclonal antibodies
(mAbs) or small-molecule antiviral agents, the Panel recommends that clinicians prioritize their use
for patients at highest risk of clinical progression. Providers should use their clinical judgment when
prioritizing the use of anti-SARS-CoV-2 mAbs for treatment.
Prioritization schemes should consider how to equitably distribute scarce resources to populations
that include individuals who may have less knowledge of or access to these therapies. The availability
and distribution of recommended therapies should be monitored to ensure that access to products is
equitable.
Patient Prioritization for Treatment

The Panel prioritized the following risk groups for anti-SARS-CoV-2 mAbs and antiviral therapy based
on 4 key elements: age, vaccination status, immune status, and clinical risk factors. The groups are listed
by tier in descending order of priority.
For a list of risk factors, see the Centers for Disease Control and Prevention (CDC) webpage Underlying

AR08775
Medical Conditions Associated With Higher Risk for Severe COVID-19.
Tier Risk Group

1 • Immunocompromised individuals not expected to mount an adequate immune response to COVID-19
vaccination or SARS-CoV-2 infection due to their underlying conditions, regardless of vaccine status (see
Immunocompromising Conditions below); or
• Unvaccinated individuals at the highest risk of severe disease (anyone aged ≥75 years or anyone aged ≥65
years with additional risk factors).
2 • Unvaccinated individuals not included in Tier 1 who are at risk of severe disease (anyone aged ≥65 years or
anyone aged <65 years with clinical risk factors)
3 • Vaccinated individuals at high risk of severe disease (anyone aged ≥75 years or anyone aged ≥65 years
with clinical risk factors)
Note: Vaccinated individuals who have not received a COVID-19 vaccine booster dose are likely at higher risk
for severe disease; patients within this tier in this situation should be prioritized for treatment.
4 • Vaccinated individuals at risk of severe disease (anyone aged ≥65 years or anyone aged <65 years with
clinical risk factors)
Note: Vaccinated individuals who have not received a COVID-19 vaccine booster dose are likely at higher risk
for severe disease; patients within this tier in this situation should be prioritized for treatment.
Patient Prioritization for Pre-Exposure Prophylaxis

Tixagevimab plus cilgavimab is authorized for use as SARS-CoV-2 PrEP for individuals who have
moderate to severe immunocompromising conditions that may result in an inadequate immune response
to COVID-19 vaccination. Unlike anti-SARS-CoV-2 agents used for treatment, tixagevimab plus
cilgavimab is not authorized for use in unvaccinated individuals unless full vaccination is not possible
due to a history of severe allergic reaction to the COVID-19 vaccine. Generally, unless they are also
immunocompromised, individuals who qualify for PrEP because of vaccine allergy or contraindication are
less likely to suffer severe consequences from SARS-CoV-2 infection than individuals who are moderately
to severely immunocompromised.
Immunocompromising Conditions
The CDC website COVID-19 Vaccines for Moderately or Severely Immunocompromised People provides
a list of moderate or severe immunocompromising conditions.1
If, because of logistical constraints or supply limitations, anti-SARS-CoV-2 therapies cannot be provided
to all individuals who are moderately to severely immunocompromised, the Panel suggests prioritizing
their use for patients who are least likely to mount an adequate response to COVID-19 vaccination
or SARS-CoV-2 infection and who are at risk for severe outcomes, including (but not limited to) the
following populations:
• Patients who are within 1 year of receiving B cell–depleting therapies (e.g., rituximab, ocrelizumab,
ofatumumab, alemtuzumab)
• Patients receiving Bruton’s tyrosine kinase inhibitors
• Chimeric antigen receptor T cell recipients
• Post-hematopoietic cell transplant recipients who have chronic graft-versus-host disease or who are
taking immunosuppressive medications for another indication
• Patients with hematologic malignancies who are on active therapy
• Lung transplant recipients

AR08776
• Patients who are within 1 year of receiving a solid organ transplant (other than lung transplant)
• Solid organ transplant recipients who had recent treatment with T cell– or B cell–depleting agents
for acute rejection
• Patients with severe combined immunodeficiencies
• Patients with untreated HIV who have CD4 T lymphocyte cell counts <50 cells/mm3
If supplies are extremely limited, the Panel suggests prioritizing those who are more severely
immunocompromised and who have additional risk factors for severe disease (as discussed below).
Clinical Risk Factors

Some of the most important risk factors for severe COVID-19 include age (risk increases with each
decade after age 50),2 cancer, cardiovascular disease, chronic kidney disease, chronic lung disease,
diabetes, immunocompromising conditions or receipt of immunosuppressive medications, obesity (i.e.,
body mass index ≥30), and pregnancy. For a complete list of risk factors, including information on the
relative risk of severe disease, see the CDC webpage Underlying Medical Conditions Associated With
Higher Risk for Severe COVID-19. Of note, the likelihood of developing severe COVID-19 increases
when a person has multiple comorbidities.3
Although the data on risk factors for severe COVID-19 in children are limited, there is substantial overlap
between risk factors in children and those identified in adults. Children who are aged <1 year or children
with obesity, moderate to severe immunosuppression, or complex chronic disease and medical complexity
and dependence on respiratory technology are at substantially increased risk of severe disease.4
References
1. Centers for Disease Control and Prevention. COVID-19 vaccines for moderately or severely
immunocompromised people. 2022. Available at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/
recommendations/immuno.html. Accessed March 16, 2022.
2. Centers for Disease Control and Prevention. COVID-19 risks and vaccine information for older adults. 2021.
Available at: https://www.cdc.gov/aging/covid19/covid19-older-adults.html. Accessed December 22, 2021.
3. Rosenthal N, Cao Z, Gundrum J, Sianis J, Safo S. Risk factors associated with in-hospital mortality in a U.S.
national sample of patients with COVID-19. JAMA Netw Open. 2020;3(12):e2029058. Available at:
4. Kompaniyets L, Agathis NT, Nelson JM, et al. Underlying medical conditions associated with severe
COVID-19 illness among children. JAMA Netw Open. 2021;4(6):e2111182. Available at:

AR08777
Clinical Management Summary

Two main processes are thought to drive the pathogenesis of COVID-19. Early in the clinical course,
the disease is primarily driven by the replication of SARS-CoV-2. Later in the clinical course, the
disease appears to be driven by a dysregulated immune/inflammatory response to SARS-CoV-2
that leads to tissue damage. Based on this understanding, it is anticipated that therapies that
directly target SARS-CoV-2 would have the greatest effect early in the course of the disease, while
immunosuppressive/anti-inflammatory therapies are likely to be more beneficial in the later stages of
COVID-19.
The clinical spectrum of SARS-CoV-2 infection includes asymptomatic or presymptomatic infection and
mild, moderate, severe, and critical illness. Figure 1 provides guidance for clinicians on the therapeutic
management of nonhospitalized adult patients. This includes patients who do not require hospitalization
or supplemental oxygen and those who have been discharged from an emergency department or a
hospital. Figure 2 provides guidance on the therapeutic management of hospitalized adult patients
according to their disease severity and oxygen requirements. Figure 3 provides guidance on the
therapeutic management of pediatric patients with multisystem inflammatory syndrome in children
(MIS-C).

AR08778
a
For a list of risk factors, see the CDC webpage Underlying Medical Conditions Associated With Higher Risk for Severe
COVID-19 and the Patient Prioritization for Treatment section in Therapeutic Management of Nonhospitalized Adults
With COVID-19.
b
Ritonavir-boosted nirmatrelvir has significant drug-drug interactions. Clinicians should carefully review a patient’s
concomitant medications and evaluate potential drug-drug interactions.
c
If a patient requires hospitalization after starting treatment, the full treatment course can be completed at the health care
provider’s discretion.
d
Administration of remdesivir requires 3 consecutive days of IV infusion.
e
Bebtelovimab is active in vitro against all circulating Omicron subvariants, but there are no clinical efficacy data from
placebo-controlled trials that evaluated the use of bebtelovimab in patients who are at high risk of progressing to severe
COVID-19. Therefore, bebtelovimab should be used only when the preferred treatment options are not available, feasible
to use, or clinically appropriate.

AR08779
f
olnupiravir has lower efficacy than the preferred treatment options. Therefore, it should be used only when the
M
preferred options are not available, feasible to use, or clinically appropriate.
g
There is currently a lack of safety and efficacy data on the use of this agent in outpatients with COVID-19; using systemic
glucocorticoids in this setting may cause harm.
h
These individuals should receive oximetry monitoring and close follow-up through telehealth, visiting nurse services, or
in-person visits.
i
Provide an advanced level of home care, including supplemental oxygen (whether patients are receiving oxygen for the
first time or are increasing their baseline oxygen requirements), pulse oximetry, laboratory monitoring, and close follow-
up through telehealth, visiting nurse services, or in-person visits.
j
See Therapeutic Management of Hospitalized Adults With COVID-19.
Key: AE = adverse event; CDC = Centers for Disease Control and Prevention; ED = emergency department; IV =
intravenous; the Panel = the COVID-19 Treatment Guidelines Panel; PO = orally

AR08780
a
Corticosteroids that are prescribed for an underlying condition should be continued.
b
If the patient progresses to requiring high-flow oxygen, NIV, MV, or ECMO, complete the full course of remdesivir (refer
to Table A).
c
Evidence suggests that the benefit of remdesivir is greatest when the drug is given early in the course of COVID-19 (e.g.,
within 10 days of symptom onset). Clinical trials have not demonstrated a mortality benefit for remdesivir, but a large,
placebo-controlled trial showed that the use of remdesivir reduced time to clinical recovery in hospitalized patients. See
Rationale for the Use of Remdesivir below.
d
Drugs are listed alphabetically. There are no studies that directly compare the use of baricitinib and tocilizumab, and
there is insufficient evidence to recommend a drug or class of drug (i.e., JAK inhibitors, anti-IL-6 receptor mAbs) over
the other. Treatment decisions should be based on local guidance, drug availability, and patient comorbidities.
e
If baricitinib and IV tocilizumab are not available or not feasible to use, tofacitinib can be used instead of baricitinib
(BIIa) and IV sarilumab can be used instead of IV tocilizumab (BIIa).
f
Contraindications for the use of therapeutic anticoagulation in patients with COVID-19 include platelet count <50 x
109/L, Hgb <8 g/dL, the need for dual antiplatelet therapy, bleeding within the last 30 days that required an ED visit or
hospitalization, a history of a bleeding disorder, or an inherited or active acquired bleeding disorder. This list is based on
the exclusion criteria from clinical trials; patients with these conditions have an increased risk of bleeding.
g
Either LMWH or UFH heparin can be used. In general, LMWH is preferred.
h
The Panel recommends against the use of baricitinib in combination with tocilizumab for the treatment of COVID-19,
except in a clinical trial (AIII). Because both baricitinib and tocilizumab are potent immunosuppressants, there is the
potential for an additive risk of infection.
i
The combination of dexamethasone plus remdesivir may be considered for patients who have recently been intubated
(CIII). The Panel recommends against the use of remdesivir monotherapy in these patients (AIIa).
Key: ECMO = extracorporeal membrane oxygenation; ED = emergency department; Hgb = hemoglobin; ICU = intensive
care unit; IL = interleukin; IV = intravenous; JAK = Janus kinase; LMWH = low-molecular-weight heparin; mAb =
monoclonal antibody; MV = mechanical ventilation; NIV = noninvasive ventilation; the Panel = the COVID-19 Treatment
Guidelines Panel; UFH = unfractionated heparin; ULN = upper limit of normal; VTE = venous thromboembolism

AR08781
a
Duration of therapy may vary. For more information, see Therapeutic Management of Hospitalized Pediatric Patients
With Multisystem Inflammatory Syndrome in Children (MIS-C) (With Discussion on Multisystem Inflammatory
Syndrome in Adults [MIS-A]).
b
In certain patients with severe illness, intensification therapy may include dual therapy with higher-dose glucocorticoids
and infliximab or anakinra. Anakinra and infliximab should not be given in combination.
c
Infliximab should not be used in patients with macrophage activation syndrome.
Key: CAA = coronary artery aneurysm; IBW = ideal body weight; IV = intravenous; IVIG = intravenous immunoglobulin; LV
= left ventricular; MIS-C = multisystem inflammatory syndrome in children; PO = oral; SUBQ = subcutaneously

AR08782
General Management of Nonhospitalized Patients With

Acute COVID-19
Last Updated: December 16, 2021
• Management of nonhospitalized patients with acute COVID-19 should include providing supportive care, considering
the use of COVID-19-specific therapy for patients who have a high risk for disease progression, taking steps to reduce
the risk of SARS-CoV-2 transmission (including isolating the patient), and advising patients on when to contact a
health care provider and seek an in-person evaluation (AIII).
• When possible, patients with symptoms of COVID-19 should be triaged via telehealth visits to determine whether they
require COVID-19-specific therapy and in-person care (AIII).
• Patients with dyspnea should be referred for an in-person evaluation by a health care provider and should be followed
closely during the initial days after the onset of dyspnea to assess for worsening respiratory status (AIII).
• Management plans should be based on a patient’s vital signs, physical exam findings, risk factors for progression to
severe illness, and the availability of health care resources (AIII).
• See Therapeutic Management of Nonhospitalized Adults With COVID-19 for specific recommendations on using
pharmacologic therapy in nonhospitalized patients.
Introduction
This section of the Guidelines is intended to provide information to health care providers who are
caring for nonhospitalized patients with COVID-19. The COVID-19 Treatment Guidelines Panel’s (the
Panel) recommendations for pharmacologic management can be found in Therapeutic Management of
Nonhospitalized Adults With COVID-19. The Panel recognizes that the distinction between outpatient
and inpatient care may be less clear during the COVID-19 pandemic. Patients with COVID-19 may
receive care outside traditional ambulatory care or hospital settings if there is a shortage of hospital beds,
staff, or resources. Settings such as field hospitals and ambulatory surgical centers and programs such as
Acute Hospital Care at Home have been implemented to alleviate hospital bed and staffing shortages.1
Patients may enter an Acute Hospital Care at Home program from either an emergency department (ED)
or an inpatient hospital setting. Health care providers should use their judgment when deciding whether
the guidance offered in this section applies to individual patients.
This section focuses on the evaluation and management of:
• Adults with COVID-19 in an ambulatory care setting;
• Adults with COVID-19 following discharge from the ED; and
• Adults with COVID-19 following inpatient discharge.
Outpatient evaluation and management in each of these settings may include some or all of the
following: telemedicine, remote monitoring, in-person visits, and home visits by nurses or other health
care providers.
Managing Patients With COVID-19 in an Ambulatory Care Setting

Approximately 80% of patients with COVID-19 have mild illness that does not warrant medical
intervention or hospitalization.2 Most patients with mild COVID-19 (defined as the absence of viral

AR08783
pneumonia and hypoxemia) can be managed in an ambulatory care setting or at home. Patients with
moderate COVID-19 (those with viral pneumonia but without hypoxemia) or severe COVID-19 (those
with dyspnea, hypoxemia, or lung infiltrates >50%) need in-person evaluation and close monitoring, as
pulmonary disease can progress rapidly and require hospitalization.3
Health care providers should identify patients who may be at high risk for progression to severe
COVID-19; these patients may be candidates for anti-SARS-CoV-2 monoclonal antibody treatment (see
Figure 1 in Therapeutic Management of Nonhospitalized Adults with COVID-19). When managing
outpatients with COVID-19, clinicians should provide supportive care, take steps to reduce the risk of
SARS-CoV-2 transmission (e.g., wear a mask, isolate the patient),4,5 evaluate the need for COVID-19-
specific therapy, and advise patients on when to seek in-person evaluation.6 Supportive care includes
managing symptoms (as described below), ensuring that patients are receiving the proper nutrition, and
paying attention to the risks of social isolation, particularly in older adults.7 Other unique aspects of care
for geriatric patients with COVID-19 include considerations related to cognitive impairment, frailty,
fall risk, and polypharmacy. Older patients and those with chronic medical conditions have a higher
risk for hospitalization and death; however, SARS-CoV-2 infection may cause severe disease and death
in patients of any age, even in the absence of any risk factors. The decision to monitor a patient in the
outpatient setting should be made on a case-by-case basis.
Assessing the Need for In-Person Evaluation

When possible, patients with symptoms of COVID-19 should be triaged via telehealth visits to
determine whether they require COVID-19-specific therapy and in-person care (AIII). Outpatient
management may include the use of patient self-assessment tools. During initial triage, clinic staff
should determine which patients are eligible to receive supportive care at home and which patients
warrant an in-person evaluation.8 Local emergency medical services, if called by the patient, may also
be of help in deciding whether an in-person evaluation is indicated. Patient management plans should be
based on the patient’s vital signs, physical exam findings, risk factors for progression to severe illness,
and the availability of health care resources (AIII).
All patients with dyspnea, oxygen saturation (SpO2) ≤94% on room air at sea level (if this information
is available), or symptoms that suggest higher acuity (e.g., chest pain or tightness, dizziness, confusion
or other mental status changes) should be referred for an in-person evaluation by a health care provider
(AIII). The criteria used to determine the appropriate clinical setting for an in-person evaluation may vary
by location and institution; it may also change over time as new data and treatment options emerge. There
should be a low threshold for in-person evaluation of older persons and those with medical conditions that
are associated with a risk of progression to severe COVID-19. The individual who performs the initial
triage should use their clinical judgement to determine whether a patient requires ambulance transport.
There are unique considerations for residents of nursing homes and other long-term care facilities who
develop acute COVID-19. Decisions about transferring these patients for an in-person evaluation should
be a collaborative effort between the resident (or their health care decision maker), a hospital-based
specialist (e.g., an emergency physician or geriatrician), and the clinical manager of the facility.9
In some settings where clinical evaluation is challenged by geography, health care provider home visits
may be used to evaluate patients.10 Patients who are homeless should be provided with housing where
they can adequately self-isolate. Providers should be aware of the potential adverse effects of prolonged
social isolation, including depression and anxiety.7 All outpatients should receive instructions regarding
self-care, isolation, and follow-up, and should be advised to contact a health care provider or a local ED
for any worsening symptoms.11,12 Guidance for implementing home care and isolation of outpatients with
COVID-19 is provided by the U.S. Centers for Disease Control and Prevention.

AR08784
Clinical Considerations When Managing Patients in an Ambulatory Care Setting

Persons who have symptoms that are compatible with COVID-19 should undergo diagnostic
SARS-CoV-2 testing (see Prevention of SARS-CoV-2 Infection). Patients with SARS-CoV-2 infection
may be asymptomatic or experience symptoms that are indistinguishable from other acute viral or
bacterial infections (e.g., fever, cough, sore throat, malaise, muscle pain, headache, gastrointestinal
symptoms). It is important to consider other possible etiologies of symptoms, including other respiratory
viral infections (e.g., influenza), community-acquired pneumonia, congestive heart failure, asthma or
chronic obstructive pulmonary disease exacerbations, and streptococcal pharyngitis.
In most adult patients, if dyspnea develops, it tends to occur between 4 and 8 days after symptom
onset, although it can also occur after 10 days.13 While mild dyspnea is common, worsening dyspnea
and severe chest pain/tightness suggest the development or progression of pulmonary involvement. In
studies of patients who developed acute respiratory distress syndrome, progression occurred a median of
2.5 days after the onset of dyspnea.14-16 Adult outpatients with dyspnea should be followed closely with
telehealth or in-person monitoring, particularly during the first few days following the onset of dyspnea,
to monitor for worsening respiratory status (AIII).
If an adult patient has access to a pulse oximeter at home, SpO2 measurements can be used to help
assess overall clinical status. Patients should be advised to use pulse oximeters on warm fingers rather
than cold fingers for better accuracy. Patients should inform their health care provider if the value
is repeatedly below 95% on room air at sea level. Pulse oximetry may not accurately detect occult
hypoxemia, especially in Black patients.3,17,18 Additionally, SpO2 readings obtained through a mobile
phone application may not be accurate enough for clinical use.19-21 Importantly, oximetry should only be
interpreted within the context of a patient’s entire clinical presentation (i.e., results should be disregarded
if a patient is complaining of increasing dyspnea).
Counseling Regarding the Need for Follow-Up

Health care providers should identify patients who are at high risk for disease progression. These
patients may be candidates for anti-SARS-CoV-2 monoclonal antibody treatments, and clinicians
should ensure that these patients receive adequate medical follow-up. The frequency and duration of
follow-up will depend on the risk for severe disease, the severity of symptoms, and the patient’s ability
to self-report worsening symptoms. Health care providers should determine whether a patient has access
to a phone, computer, or tablet for telehealth; whether they have adequate transportation for clinic visits;
and whether they have regular access to food. The clinician should also confirm that the patient has a
caregiver who can assist with daily activities if needed.
All patients and/or their family members or caregivers should be counseled about the warning symptoms
that should prompt re-evaluation through a telehealth visit or an in-person evaluation in an ambulatory
care setting or ED. These symptoms include new onset of dyspnea; worsening dyspnea (particularly
if dyspnea occurs while resting or if it interferes with daily activities); dizziness; and mental status
changes, such as confusion. Patients should be educated about the time course of these symptoms and
the possible respiratory decline that may occur, on average, 1 week after the onset of illness.
Managing Adults With COVID-19 Following Discharge from the Emergency

Department
There are no fixed criteria for admitting patients with COVID-19 to the hospital; criteria may vary
by region and hospital facilities. Patients with severe disease are typically admitted to the hospital,
but some patients with severe disease may not be admitted due to a high prevalence of infection and
limited hospital resources. In addition, patients who could receive appropriate care at home but are

AR08785
unable to be adequately managed in their usual residential setting are candidates for temporary shelter
in supervised facilities, such as a COVID-19 alternative care facility.22 For example, patients who are
living in multigenerational households or who are homeless may not be able to self-isolate and should
be provided resources such as dedicated housing units or hotel rooms, when available. Unfortunately,
dedicated residential care facilities for COVID-19 patients are not widely available, and community-
based solutions for self-care and isolation should be explored.
Treatment with an anti-SARS-CoV-2 monoclonal antibody is recommended for patients with mild to
moderate COVID-19 who are not on supplemental oxygen and who have been discharged from the
ED but who are at high risk for clinical progression (see Therapeutic Management of Nonhospitalized
Adults With COVID-19).
In the cases where institutional resources (e.g., inpatient beds, staff members) are scarce, it may
be necessary to discharge an adult patient and provide an advanced level of home care, including
supplemental oxygen (if indicated), pulse oximetry, and close follow-up. Although early discharge
of those with severe disease is not generally recommended by the Panel, it is recognized that these
management strategies are sometimes necessary. In these situations, some institutions are providing
frequent telemedicine follow-up visits for these patients or providing a hotline that allows patients to
speak with a clinician when necessary. Home resources should be assessed before a patient is discharged
from the ED; outpatients should have a caregiver and access to a device that is suitable for telehealth.
Patients and/or their family members or caregivers should be counseled about the warning symptoms
that should prompt re-evaluation by a health care provider. Special consideration may be given to
using certain therapeutics (e.g., dexamethasone) in this setting. For more information, see Therapeutic
Management of Nonhospitalized Adults With COVID-19.
Anticoagulants and antiplatelet therapy should not be initiated in the ED for the prevention of venous
thromboembolism (VTE) or arterial thrombosis if the patient is not being admitted to the hospital, unless
the patient has other indications for the therapy or is participating in a clinical trial (AIII). For more
information, see Antithrombotic Therapy in Patients With COVID-19. Patients should be encouraged to
ambulate, and activity should be increased according to the patient’s tolerance.
Managing Adults With COVID-19 Following Hospital Discharge

Most patients who are discharged from the hospital setting should have a follow-up visit with a health
care provider soon after discharge. Whether an in-person or a telehealth visit is most appropriate
depends on the clinical and social situation. In some cases, adult patients are deemed to be stable
for discharge from the inpatient setting even though they still require supplemental oxygen. Special
consideration may be given to using certain therapeutics (e.g., dexamethasone) in this setting. For more
information, see Therapeutic Management of Nonhospitalized Adults With COVID-19. When possible,
these individuals should receive oximetry monitoring and close follow-up through telehealth visits,
visiting nurse services, or in-person clinic visits.
Hospitalized patients with COVID-19 should not be routinely discharged while receiving VTE
prophylaxis, unless they have another indication or are participating in a clinical trial (AIII). For more
information, see Antithrombotic Therapy in Patients With COVID-19. Patients should be encouraged to
ambulate, and activity should be increased according to the patient’s tolerance.
Considerations in Pregnancy
Managing pregnant outpatients with COVID-19 is similar to managing nonpregnant patients (see
Special Considerations in Pregnancy). Clinicians should offer supportive care, take steps to reduce the

AR08786
risk of SARS-CoV-2 transmission, and provide guidance on when to seek an in-person evaluation. The
American College of Obstetricians and Gynecologists (ACOG) has developed an algorithm to aid the
practitioner in evaluating and managing pregnant outpatients with laboratory-confirmed or suspected
COVID-19.23 ACOG has also published recommendations on how to use telehealth for prenatal care and
how to modify routine prenatal care when necessary to decrease the risk of SARS-CoV-2 transmission to
patients, caregivers, and staff.
In pregnant patients, SpO2 should be maintained at 95% or above on room air at sea level; therefore,
the threshold for monitoring pregnant patients in an inpatient setting may be lower than in nonpregnant
patients.24 In general, there are no changes to fetal monitoring recommendations in the outpatient setting,
and fetal management should be similar to the fetal management used for other pregnant patients with
medical illness.25 However, these monitoring strategies can be discussed on a case-by-case basis with
an obstetrician. Pregnant and lactating patients should be given the opportunity to participate in clinical
trials of outpatients with COVID-19 to help inform decision-making in this population.
Considerations in Children
Children and adolescents with acute COVID-19 are less likely than adults to require medical
intervention or hospitalization, and most can be managed in an ambulatory care setting or at home.
In general, the need for ED evaluation or hospitalization should be based on the patient’s vital signs,
physical exam findings (e.g., dyspnea), and risk factors for progression to severe illness. Certain
groups, including young infants, children with risk factors, and those with presentations that overlap
with multisystem inflammatory syndrome in children (MIS-C), may require hospitalization for more
intensive monitoring. However, this should be determined on a case-by-case basis.
Most children with mild or moderate COVID-19, even those with risk factors, will not progress to more
severe illness and will recover without specific therapy (see Special Considerations in Children). There
is insufficient evidence for the Panel to recommend either for or against the use of anti-SARS-CoV-2
monoclonal antibody products in nonhospitalized children with COVID-19 who have risk factors for
severe disease. The available efficacy data for adults suggests that anti-SARS-CoV-2 monoclonal
antibody products may be considered for use in children who meet the Food and Drug Administration
Emergency Use Authorization (EUA) criteria, especially those who have more than 1 risk factor. The
decision to use these products in children should be made on a case-by-case basis in consultation with a
pediatric infectious disease specialist. The risk factors that predict progression to severe disease in adults
can be used to determine the risk of progression in children aged ≥16 years.
In general, pediatric patients should not continue receiving remdesivir, dexamethasone, or other
COVID-19-directed therapies following discharge from an ED or an inpatient setting. Clinicians should
refer to Special Considerations in Children for more information on the management of children with
COVID-19.
References
1. Centers for Medicare & Medicaid Services. CMS announces comprehensive strategy to enhance hospital
capacity amid COVID-19 surge. 2020. Available at: https://www.cms.gov/newsroom/press-releases/cms-
announces-comprehensive-strategy-enhance-hospital-capacity-amid-covid-19-surge. Accessed December 13,
2021.
2. Stokes EK, Zambrano LD, Anderson KN, et al. Coronavirus disease 2019 case surveillance—United States,
January 22–May 30, 2020. MMWR Morb Mortal Wkly Rep. 2020;69. Available at:
https://www.cdc.gov/mmwr/volumes/69/wr/pdfs/mm6924e2-H.pdf.
3. Centers for Disease Control and Prevention. Interim clinical guidance for management of patients with

AR08787
confirmed coronavirus disease (COVID-19). 2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/

hcp/clinical-guidance-management-patients.html. Accessed December 13, 2021.
https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/prevention.html. Accessed December 13,
2021.
5. Centers for Disease Control and Prevention. COVID-19: if you are sick or caring for someone. 2020.
Available at: https://www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/. Accessed December 13, 2021.
6. Cheng A, Caruso D, McDougall C. Outpatient management of COVID-19: rapid evidence review. Am Fam
Physician. 2020;102(8):478-486. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33064422.
7. Morrow-Howell N, Galucia N, Swinford E. Recovering from the COVID-19 pandemic: a focus on older
adults. J Aging Soc Policy. 2020;32(4-5):526-535. Available at:
8. Centers for Disease Control and Prevention. Coronavirus self-checker. 2021. Available at: https://www.cdc.
gov/coronavirus/2019-ncov/symptoms-testing/coronavirus-self-checker.html. Accessed December 13, 2021.
9. Burkett E, Carpenter CR, Hullick C, Arendts G, Ouslander JG. It’s time: delivering optimal emergency care of
residents of aged care facilities in the era of COVID-19. Emerg Med Australas. 2021;33(1):131-137. Available
10. Close RM, Stone MJ. Contact tracing for native americans in rural Arizona. N Engl J Med. 2020;383(3):e15.
11. Centers for Disease Control and Prevention. COVID-19: what to do if you are sick. 2020. Available at: https://
www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/steps-when-sick.html. Accessed December 13, 2021.
12. Centers for Disease Control and Prevention. COVID-19: isolate if you are sick. 2021. Available at: https://
www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/isolation.html. Accessed December 13, 2021.
13. Cohen PA, Hall LE, John JN, Rapoport AB. The early natural history of SARS-CoV-2 infection: clinical
observations from an urban, ambulatory COVID-19 clinic. Mayo Clin Proc. 2020;95(6):1124-1126. Available
14. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-
infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061-1069. Available at:
15. Arentz M, Yim E, Klaff L, et al. Characteristics and outcomes of 21 critically ill patients with COVID-19 in
Washington state. JAMA. 2020;323(16):1612-1614. Available at:
16. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia
in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8(5):475-
17. Luks AM, Swenson ER. Pulse oximetry for monitoring patients with COVID-19 at home. Potential pitfalls
and practical guidance. Ann Am Thorac Soc. 2020;17(9):1040-1046. Available at:
18. Sjoding MW, Dickson RP, Iwashyna TJ, Gay SE, Valley TS. Racial bias in pulse oximetry measurement. N
Engl J Med. 2020;383(25):2477-2478. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33326721.
19. Modi A, Kiroukas R, Scott JB. Accuracy of smartphone pulse oximeters in patients visiting an outpatient
pulmonary function lab for a 6-minute walk test. Respir Care. 2019;64(Suppl 10). Available at:
http://rc.rcjournal.com/content/64/Suppl_10/3238714.
20. Tarassenko L, Greenhalgh T. Question: should smartphone apps be used clinically as oximeters? Answer: no.
2020. Available at: https://www.cebm.net/covid-19/question-should-smartphone-apps-be-used-as-oximeters-
answer-no/. Accessed December 13, 2021.

AR08788
21. Jordan TB, Meyers CL, Schrading WA, Donnelly JP. The utility of iPhone oximetry apps: a comparison with
standard pulse oximetry measurement in the emergency department. Am J Emerg Med. 2020;38(5):925-928.
22. Meyer GS, Blanchfield BB, Bohmer RMJ, Mountford MB, Vanderwagen WC. Alternative care sites for the
COVID-19 pandemic: the early U.S. and U.K. experience. NEJM Catalyst. 2020. Available at:
https://catalyst.nejm.org/doi/full/10.1056/CAT.20.0224.
23. The American College of Obstetricians and Gynecologists. Outpatient assessment and management for
pregnant women with suspected or confirmed novel coronavirus (COVID-19). 2020. Available at:
https://www.smfm.org/covid19/. Accessed December 13, 2021.
24. The American College of Obstetricians and Gynecologists. COVID-19 FAQs for obstetrician-gynecologists,
obstetrics. 2020. Available at: https://www.acog.org/clinical-information/physician-faqs/covid-19-faqs-for-ob-
gyns-obstetrics. Accessed December 13, 2021.
25. Society for Maternal-Fetal Medicine. Management considerations for pregnant patients with COVID-19.

AR08789
Therapeutic Management of Nonhospitalized Adults With
COVID-19
Several therapeutic options are now available for the treatment of nonhospitalized adults with mild
to moderate COVID-19 who are at high risk of disease progression. A number of factors affect the
selection of the best treatment option for a specific patient. These factors include the clinical efficacy
and availability of the treatment option, the feasibility of administering parenteral medications (i.e.,
remdesivir), the potential for significant drug-drug interactions (e.g., those associated with the use of
ritonavir-boosted nirmatrelvir [Paxlovid]), and the regional prevalence of variants of concern (e.g., the
regional prevalence of the Omicron BA.2 subvariant may affect which anti-SARS-CoV-2 monoclonal
antibodies [mAbs] can be used for treatment).
Figure 1 outlines the COVID-19 Treatment Guidelines Panel’s (the Panel) recommendations for using
these therapeutic interventions outside the hospital inpatient setting.
.

AR08790
a
For a list of risk factors, see the CDC webpage Underlying Medical Conditions Associated With Higher Risk for Severe
COVID-19 and the Patient Prioritization for Treatment section below.
b
Ritonavir-boosted nirmatrelvir has significant drug-drug interactions. Clinicians should carefully review a patient’s
concomitant medications and evaluate potential drug-drug interactions.
c
If a patient requires hospitalization after starting treatment, the full treatment course can be completed at the health care
provider’s discretion.
d
Administration of remdesivir requires 3 consecutive days of IV infusion.
e
Bebtelovimab is active in vitro against all circulating Omicron subvariants, but there are no clinical efficacy data from
placebo-controlled trials that evaluated the use of bebtelovimab in patients who are at high risk of progressing to severe
COVID-19. Therefore, bebtelovimab should be used only when the preferred treatment options are not available, feasible
to use, or clinically appropriate.
f
Molnupiravir has lower efficacy than the preferred treatment options. Therefore, it should be used only when the
preferred options are not available, feasible to use, or clinically appropriate.
g
There is currently a lack of safety and efficacy data on the use of this agent in outpatients with COVID-19; using systemic
glucocorticoids in this setting may cause harm.
h
These individuals should receive oximetry monitoring and close follow-up through telehealth, visiting nurse services, or
in-person visits.
i
Provide an advanced level of home care, including supplemental oxygen (whether patients are receiving oxygen for the
first time or are increasing their baseline oxygen requirements), pulse oximetry, laboratory monitoring, and close follow-
up through telehealth, visiting nurse services, or in-person visits.
j
See Therapeutic Management of Hospitalized Adults With COVID-19.
Key: AE = adverse event; CDC = Centers for Disease Control and Prevention; ED = emergency department; IV =
intravenous; the Panel = the COVID-19 Treatment Guidelines Panel; PO = orally
Patient Prioritization for Treatment

During surges in cases of SARS-CoV-2 infection, logistical or supply constraints may make it
impossible to offer available therapeutics to all the nonhospitalized patients who are eligible to receive
them. In these situations, the Panel recommends prioritizing the treatment of patients who are at the
highest risk of clinical progression (see Prioritization of Anti-SARS-CoV-2 Therapies for the Treatment
and Prevention of COVID-19 When There Are Logistical or Supply Constraints).
In Table A, the Panel has prioritized the risk groups for anti-SARS-CoV-2 therapy based on 4
key elements: age, vaccination status, immune status, and the presence of risk factors for clinical
progression. The groups are listed in descending order of priority. For a list of risk factors, see the
Centers for Disease Control and Prevention (CDC) website Underlying Medical Conditions Associated
With Higher Risk for Severe COVID-19.
Table A. Patient Risk Groups for Prioritizing the Use of Anti-SARS-CoV-2 Therapy
Tier Risk Groups

• Immunocompromised individuals who are not expected to mount an adequate immune response to
COVID-19 vaccination or SARS-CoV-2 infection due to their underlying conditions, regardless of their
1 vaccine status (see Immunocompromising Conditions below); or
• Unvaccinated individuals who are at the highest risk of severe disease (anyone aged ≥75 years or anyone
aged ≥65 years with additional risk factors)
• Unvaccinated individuals who are at risk of severe disease and who are not included in Tier 1 (anyone
2
aged ≥65 years or anyone aged <65 years with clinical risk factors)

AR08791
Tier Risk Groups

• Vaccinated individuals who are at high risk of severe disease (anyone aged ≥75 years or anyone aged ≥65
years with clinical risk factors)
3 • Vaccinated individuals who have not received a COVID-19 vaccine booster dose are likely to be at higher
risk for severe disease; patients who have not received a booster dose and who are within this tier should
be prioritized for treatment.
• Vaccinated individuals who are at risk of severe disease (anyone aged ≥65 years or anyone aged <65 with
clinical risk factors)
4 • Vaccinated individuals who have not received a COVID-19 vaccine booster dose are likely to be at higher
risk for severe disease; patients who have not received a booster dose and who are within this tier should
be prioritized for treatment.
Immunocompromising Conditions
The CDC website COVID-19 Vaccines for Moderately or Severely Immunocompromised People
provides a list of moderate and severe immunocompromising conditions.
If these anti-SARS-CoV-2 agents cannot be provided to all moderately to severely immunocompromised
individuals because of logistical constraints or supply limitations, the Panel suggests prioritizing
their use for those who are least likely to mount an adequate response to COVID-19 vaccination or
SARS-CoV-2 infection and who are at risk for severe outcomes. This includes:
• Patients who are within 1 year of receiving B cell-depleting therapies (e.g., rituximab,
ocrelizumab, ofatumumab, alemtuzumab)
• Patients who are receiving Bruton’s tyrosine kinase inhibitors
• Chimeric antigen receptor T cell recipients
• Post-hematopoietic cell transplant recipients who have chronic graft versus host disease or who
are taking immunosuppressive medications for another indication
• Patients with hematologic malignancies who are on active therapy
• Lung transplant recipients
• Patients who are within 1 year of receiving a solid organ transplant (other than a lung transplant)
• Solid organ transplant recipients with recent treatment for acute rejection with T cell- or B cell-
depleting agents
• Patients with severe combined immunodeficiencies
• Patients with untreated HIV who have CD4 T lymphocyte cell counts <50 cells/mm3
If supplies are extremely limited, the Panel suggests prioritizing those who are more severely
immunocompromised (based on the list above) and who have additional risk factors for severe disease.
Table B. Dosing Regimens for the Drugs Recommended for High-Risk, Nonhospitalized Adults
With Mild to Moderate COVID-19, Listed in Order of Preference Based on Efficacy and
Convenience of Use
Time From
Drug Name Dosing Regimen
Symptom Onseta
Ritonavir-Boosted eGFR ≥60 mL/min: ≤5 days
Nirmatrelvir • Nirmatrelvir 300 mg with RTV 100 mg PO twice daily for 5 days
(Paxlovid)
eGFR ≥30 to <60 mL/min:
• Nirmatrelvir 150 mg with RTV 100 mg PO twice daily for 5 days

AR08792
Time From
Drug Name Dosing Regimen
Symptom Onseta
Ritonavir-Boosted eGFR <30 mL/min: ≤5 days
Nirmatrelvir • Not recommended
(Paxlovid),
continued Severe Hepatic Impairment (Child-Pugh Class C):
• Not recommended
Remdesivir RDV 200 mg IV on Day 1, followed by RDV 100 mg IV once daily on Days ≤7 days
2 and 3.b,c Each infusion should be administered over 30–120 minutes.
Patients should be observed for ≥1 hour after infusion as clinically
appropriate.
Bebtelovimab BEB 175 mg as a single IV injection, administered over ≥30 seconds. ≤7 days
Patients should be observed for ≥1 hour after injection.
Molnupiravir Molnupiravir 800 mg PO twice daily for 5 days ≤5 days
a
Per EUA criteria or clinical trial entry criteria.
b
An eGFR <30 mL/min at screening or <90 days before screening was considered an exclusion criterion in the outpatient
RDV study PINETREE, but only if a participant’s weight was <48 kg. See the Remdesivir section for a discussion of RDV
use in patients with renal impairment.
c
If RDV is administered to patients who have a new or increasing need for supplemental oxygen but who are discharged
from the ED because hospital resources are limited and inpatient admission is not possible, the total duration of therapy
is ≤5 days.
Key: BEB = bebtelovimab; ED = emergency department; eGFR = estimated glomerular filtration rate; EUA = Emergency
Use Authorization; IV = intravenous; PO = orally; RDV = remdesivir; RTV = ritonavir
Symptom Management
Symptomatic treatment includes using over-the-counter antipyretics, analgesics, or antitussives for fever,
headache, myalgias, and cough. Patients with dyspnea may benefit from resting in the prone position
rather than the supine position.1 Health care providers should consider educating patients about breathing
exercises, as severe breathlessness may cause anxiety.2 Patients should be advised to drink fluids
regularly to avoid dehydration. Rest is recommended as needed during the acute phase of COVID-19, and
ambulation and other forms of activity should be increased according to the patient’s tolerance. Patients
should be educated about the variability in time to symptom resolution and complete recovery.
Rationale for the Use of Specific Agents Listed in Figure 1

The Panel’s recommendations for the therapeutics that are used to treat nonhospitalized patients with
mild to moderate COVID-19 who are at risk of clinical progression are based on the results of clinical
trials for the antiviral drugs (ritonavir-boosted nirmatrelvir, remdesivir, and molnupiravir) and on
laboratory assessments of the activity of the anti-SARS-CoV-2 mAb bebtelovimab.
A number of factors affect the selection of the best treatment option for a specific patient. These factors
include the clinical efficacy of the treatment option against circulating variants, the availability of the
treatment option, the feasibility of administering parenteral medications (i.e., remdesivir, bebtelovimab),
and the potential for significant drug-drug interactions (i.e., the interactions associated with using
ritonavir-boosted nirmatrelvir).
The Panel recommends ritonavir-boosted nirmatrelvir and remdesivir as preferred therapy options
because Phase 3 randomized placebo-controlled trials have reported high clinical efficacies for these
agents in patients with COVID-19.3,4 The Panel favors the use of ritonavir-boosted nirmatrelvir in most
high-risk, nonhospitalized patients with mild to moderate COVID-19. If ritonavir-boosted nirmatrelvir is

AR08793
not available or cannot be used because of drug interactions, the Panel recommends using remdesivir as
the second option.
The Panel recommends bebtelovimab and molnupiravir as alternative therapy options. These drugs
should ONLY be used when neither of the preferred treatment options are available, feasible to use, or
clinically appropriate. The Food and Drug Administration (FDA) issued an Emergency Use Authorization
(EUA) for bebtelovimab based on in vitro data that showed that bebtelovimab has activity against
all circulating Omicron subvariants and clinical efficacy data from a small, Phase 2 clinical trial in
individuals with mild to moderate COVID-19 who were at low risk of disease progression.5 However,
there are no Phase 3 clinical trial data for bebtelovimab. Molnupiravir had lower clinical efficacy in
Phase 3 clinical trials than the preferred treatment options.
The Panel previously recommended the anti-SARS-CoV-2 mAb sotrovimab as a treatment option for
certain nonhospitalized patients with COVID-19. However, sotrovimab, which is active against the
Omicron BA.1 and BA.1.1 subvariants, has substantially decreased in vitro activity against the Omicron
BA.2 subvariant that has become the dominant subvariant in the United States.6-8 Because the Omicron
BA.2 subvariant is now the dominant circulating subvariant in all regions of the United States, the
distribution of sotrovimab has been paused, and the Panel no longer recommends using sotrovimab to
treat COVID-19.
There are currently no clinical trial data that directly compare the clinical efficacies of these 4 therapies,
and there are no data on the use of combinations of antiviral agents and/or anti-SARS-CoV-2 mAbs for
the treatment of COVID-19. The rationale for each of the Panel’s recommendations is discussed below.
Ritonavir-Boosted Nirmatrelvir (Paxlovid)

Nirmatrelvir is an orally bioavailable protease inhibitor that is active against MPRO, a viral protease that
plays an essential role in viral replication by cleaving the 2 viral polyproteins.9 It has demonstrated
antiviral activity against all coronaviruses that are known to infect humans.10 Nirmatrelvir is packaged
with ritonavir (as Paxlovid), a strong cytochrome P450 (CYP) 3A4 inhibitor and pharmacokinetic boosting
agent. Ritonavir is required to increase nirmatrelvir concentrations to the target therapeutic ranges.
Recommendations
• The Panel recommends using nirmatrelvir 300 mg with ritonavir 100 mg (Paxlovid) orally (PO)
twice daily for 5 days in those aged ≥12 years and weighing ≥40 kg; treatment should be initiated
as soon as possible and within 5 days of symptom onset (AIIa).
• Ritonavir-boosted nirmatrelvir has significant and complex drug-drug interactions, primarily due to
the ritonavir component of the combination.
• Before prescribing ritonavir-boosted nirmatrelvir, clinicians should carefully review the patient’s
concomitant medications, including over-the-counter medications and herbal supplements, to
evaluate potential drug-drug interactions.
• The EUA fact sheet for ritonavir-boosted nirmatrelvir, the Liverpool COVID-19 Drug Interactions
website, and guidance from the Ontario COVID-19 Science Advisory Table should be utilized
to identify and manage drug-drug interactions. A quick reference guide is also provided in the
Ritonavir-Boosted Nirmatrelvir (Paxlovid) section.
In the EPIC-HR trial, ritonavir-boosted nirmatrelvir reduced the risk of hospitalization or death by 88%
compared to placebo in nonhospitalized adults with laboratory-confirmed SARS-CoV-2 infection.3,11
This efficacy is comparable to the efficacies reported in similar patient populations for sotrovimab (85%
relative reduction)12 and remdesivir (87% relative reduction)4 and greater than the efficacy reported for
molnupiravir in this setting (30% relative reduction).13

AR08794
Ritonavir-boosted nirmatrelvir is expected to be active against all Omicron subvariants, although
clinical efficacy data are lacking.14-16 Because ritonavir-boosted nirmatrelvir has the potential for
significant drug-drug interactions with concomitant medications, this regimen may not be a safe choice
for all patients (see Ritonavir-Boosted Nirmatrelvir [Paxlovid]). However, because ritonavir-boosted
nirmatrelvir is the only highly effective oral antiviral available for the treatment of COVID-19, drug
interactions that can be safely managed should not preclude the use of this medication.
The EPIC-HR trial excluded pregnant and lactating individuals. Ritonavir has been used extensively
during pregnancy in people with HIV, which suggests that it has an acceptable safety profile during
pregnancy. Based on the mechanisms of action for both nirmatrelvir and ritonavir and the available
animal data, the Panel recommends ritonavir-boosted nirmatrelvir for pregnant patients because the
potential benefits likely outweigh the risks.
Remdesivir
Remdesivir is currently approved by the FDA for use in hospitalized patients with COVID-19 and in
nonhospitalized patients with mild to moderate COVID-19 who are at high risk of disease progression.
Remdesivir has been studied in nonhospitalized patients with mild to moderate COVID-19 who were
at high risk of progressing to severe disease. The PINETREE trial showed that 3 consecutive days of
intravenous (IV) remdesivir resulted in an 87% relative reduction in the risk of hospitalization or death
compared to placebo.4 Remdesivir is expected to be active against the Omicron variant, although in vitro
and in vivo data are currently limited.16 See the Remdesivir section for more details.
Recommendations
• The Panel recommends using remdesivir 200 mg IV on Day 1, followed by remdesivir 100 mg
IV once daily on Days 2 and 3 in those aged ≥12 years and weighing ≥40 kg; treatment should be
initiated as soon as possible and within 7 days of symptom onset (BIIa).
• Remdesivir should be administered in a setting where severe hypersensitivity reactions, such as
anaphylaxis, can be managed. Patients should be monitored during the infusion and observed for at
least 1 hour after infusion as clinically appropriate.
Because remdesivir requires IV infusions for 3 consecutive days, there may be logistical constraints to
administering remdesivir in many settings. However, it is an option if ritonavir-boosted nirmatrelvir is
not available.
The Panel recommends using remdesivir, dexamethasone, or both drugs together in hospitalized
patients who require supplemental oxygen (see Therapeutic Management of Hospitalized Adults With
COVID-19). When remdesivir is used in this setting, it is administered as a once-daily IV infusion for 5
days. There are rare instances when hospital resources are limited and admission to an inpatient unit is
not possible for patients who need to initiate supplemental oxygen in the emergency department (ED)
or who have increasing supplemental oxygen requirements. In these cases, patients may be discharged
from the ED with close monitoring and are often prescribed dexamethasone for up to 10 days. Since
remdesivir is often recommended for hospitalized patients with COVID-19 who have similar oxygen
needs, clinicians can consider using it in this setting. However, it should be noted that the data on using
remdesivir in this situation are limited, and administering IV infusions for up to 5 consecutive days can
be difficult in the outpatient setting.
Bebtelovimab
Bebtelovimab is a recombinant neutralizing human mAb that binds to the spike protein of SARS-CoV-2.
In vitro data suggest that bebtelovimab has activity against a broad range of SARS-CoV-2 variants,
including the Omicron variant and its BA.1, BA.1.1, and BA.2 subvariants.7,17 However, to date, the

AR08795
clinical trial data for bebtelovimab come from a single Phase 2 randomized placebo-controlled trial in
patients with COVID-19 who were at low risk of progressing to severe disease. The trial showed no
unexpected safety events, and patients who received bebtelovimab had more rapid viral decay than those
who received the placebo.
Recommendations
• The Panel recommends using bebtelovimab 175 mg IV in those aged ≥12 years ONLY when
ritonavir-boosted nirmatrelvir (Paxlovid) and remdesivir are not available, feasible to use, or
clinically appropriate; treatment should be initiated as soon as possible and within 7 days of
symptom onset (CIII).
• Bebtelovimab should be administered in a setting where severe hypersensitivity reactions, such as
anaphylaxis, can be managed. Patients should be monitored during the infusion and observed for
at least 1 hour after infusion.
Although there are insufficient data on hospitalization and mortality outcomes for patients with
COVID-19 who were at high risk of disease progression and who received bebtelovimab, this agent
has a mechanism of action that is similar to other anti-SARS-CoV-2 mAbs that have been shown to
reduce rates of hospitalization or death among high-risk patients in Phase 3 trials. Therefore, the in vitro
data and Phase 2 clinical trial data for bebtelovimab, coupled with the clinical efficacy data for other
anti-SARS-CoV-2 mAbs, support the use of bebtelovimab in high-risk patients with COVID-19 when
preferred treatment options are not available, feasible to use, or clinically appropriate.
Molnupiravir
Molnupiravir is the oral prodrug of beta-D-N4-hydroxycytidine (NHC), a ribonucleoside that has broad
antiviral activity against RNA viruses. NHC uptake by viral RNA-dependent RNA-polymerases results
in viral mutations and lethal mutagenesis.18,19
Molnupiravir has potent antiviral activity against SARS-CoV-2.19 As a mutagenic ribonucleoside
antiviral agent, there is a theoretical risk that molnupiravir will be metabolized by the human host cell
and incorporated into the host DNA, leading to mutations. Molnupiravir has been evaluated in 2 in
vivo rodent mutagenicity assays. One study produced equivocal results; in the other study, there was
no evidence for mutagenicity. The FDA concluded that, based on the available genotoxicity data and
the 5-day duration of treatment, molnupiravir has a low risk for genotoxicity.20 In addition, there have
been concerns about the potential effects of molnupiravir on SARS-CoV-2 mutation rates; the FDA is
requiring the manufacturer to establish a process to monitor genomic databases for the emergence of
SARS-CoV-2 variants.
Molnupiravir is expected to be active against the Omicron variant, although in vitro and in vivo data are
currently limited.16
Recommendation
• The Panel recommends using molnupiravir 800 mg PO twice daily for 5 days in those aged ≥18
years ONLY when ritonavir-boosted nirmatrelvir (Paxlovid) and remdesivir are not available,
feasible to use, or clinically appropriate (CIIa).
In the MOVe-OUT trial, molnupiravir reduced the rate of hospitalization or death by 30% compared to
placebo in nonhospitalized patients with COVID-19.13,20 Even though the different treatment options
have not been directly compared in clinical trials, the Panel recommends using molnupiravir only when
ritonavir-boosted nirmatrelvir and remdesivir are not available or cannot be used, because molnupiravir
has lower efficacy than the other options.

AR08796
The FDA EUA states that molnupiravir is not recommended for use in pregnant patients due to concerns
about the instances of fetal toxicity observed during animal studies. However, when other therapies are
not available, pregnant people with COVID-19 who are at high risk of progressing to severe disease
may reasonably choose molnupiravir therapy after being fully informed of the risks, particularly if they
are beyond the time of embryogenesis (i.e., >10 weeks’ gestation). The prescribing clinician should
document that a discussion of the risks and benefits occurred and that the patient chose this therapy.
People who engage in sexual activity that may result in conception should use effective contraception
during and following treatment with molnupiravir.
Dexamethasone
The Panel recommends against the use of dexamethasone or other systemic glucocorticoids to
treat outpatients with mild to moderate COVID-19 who do not require hospitalization or supplemental
oxygen (AIII). There is currently a lack of safety and efficacy data on the use of these agents, and
systemic glucocorticoids may cause harm in these patients. Patients who are receiving dexamethasone
or another corticosteroid for other indications should continue therapy for their underlying conditions
as directed by their health care providers (AIII).
In the RECOVERY trial, dexamethasone was shown to reduce mortality in hospitalized patients
with COVID-19 who required supplemental oxygen.21 Nonhospitalized patients who did not require
supplemental oxygen were not included in this trial. The Panel recommends against the use of
dexamethasone or other systemic glucocorticoids in this population, as there are no clinical trial data
to support their use (AIII).
Dexamethasone was stopped at the time of hospital discharge during the RECOVERY trial. For
hospitalized patients with COVID-19 who do not require supplemental oxygen after discharge, the Panel
recommends against the continuation of dexamethasone (AIIa).
In some cases, adult patients are deemed to be stable enough to be discharged from the inpatient setting
even though they still require supplemental oxygen. This practice was likely uncommon during the
RECOVERY trial; therefore, there is insufficient evidence to recommend either for or against the
continued use of dexamethasone after hospital discharge in patients who require supplemental oxygen.
The use of corticosteroids can lead to adverse events (e.g., hyperglycemia, neuropsychiatric symptoms,
secondary infections), which may be difficult to detect and monitor in an outpatient setting. If a patient
continues to receive corticosteroids after discharge, consider continuing corticosteroids for the duration
of supplemental oxygen. However, the total duration of corticosteroid use should not exceed 10 days
(including days during hospitalization). Only patients who showed good tolerance to this therapy prior
to discharge should continue to receive corticosteroids after discharge, and these patients should receive
oximetry monitoring and close follow-up through telehealth, visiting nurse services, or in-person visits.
In rare cases, patients with COVID-19 who require supplemental oxygen and hospital admission may
need to be discharged from the ED due to scarce resources (e.g., in cases where hospital beds or staff
are not available). For these patients, the Panel recommends using dexamethasone 6 mg PO once daily
for the duration of supplemental oxygen (dexamethasone use should not exceed 10 days) with careful
monitoring for adverse events (BIII). These patients should receive oximetry monitoring and close
follow-up through telehealth, visiting nurse services, or in-person visits.
Other Agents That Have Been Studied or Are Under Investigation for Use in
Outpatients With COVID-19
• The Panel recommends against the use of chloroquine or hydroxychloroquine with or without
azithromycin (AI), lopinavir/ritonavir, and other HIV protease inhibitors (AIII) for the

AR08797
outpatient treatment of COVID-19.

• The Panel recommends against the use of antibacterial therapy (e.g., azithromycin,
doxycycline) for the outpatient treatment of COVID-19 in the absence of another indication
(AIII).
• Other agents have undergone or are currently undergoing investigation in the outpatient setting.
For more information, please refer to the sections of the Guidelines that address:
• Antiviral agents, such as ivermectin and nitazoxanide
• Convalescent plasma
• Immunomodulators, such as colchicine, fluvoxamine, and inhaled corticosteroids
• Supplements, such as vitamin C, vitamin D, and zinc
• The Panel recommends against the use of anticoagulants and antiplatelet therapy for the
prevention of venous thromboembolism or arterial thrombosis unless the patient has other
indications for the therapy or is participating in a clinical trial (AIIa). For more information, see
Antithrombotic Therapy in Patients With COVID-19.
• Health care providers should provide information about ongoing clinical trials of investigational
therapies to eligible outpatients with COVID-19 so they can make informed decisions about
participation (AIII).
Concomitant Medication Management

In general, a patient’s usual medication and/or supplement regimen should be continued after the
diagnosis of COVID-19 (see Considerations for Using Concomitant Medications in Patients With
COVID-19). Angiotensin-converting enzyme inhibitors, statin therapy, nonsteroidal anti-
inflammatory drugs, and oral, inhaled, and intranasal corticosteroids that are prescribed for
comorbid conditions should be continued as directed (AIII). Patients should be advised to avoid the use
of nebulized medications in the presence of others to avoid potential aerosolization of SARS-CoV-2.22 In
patients with HIV, antiretroviral therapy should not be switched or adjusted for the purpose of preventing
or treating SARS-CoV-2 infection (AIII). For more information, see Special Considerations in People
With HIV.
When a patient is receiving an immunomodulating medication, the prescribing clinician should
be consulted about the risks and benefits that are associated with a temporary dose reduction or
discontinuation. These risks and benefits will depend on the medication’s indication and the severity of
the underlying condition.
Patients who use a continuous positive airway pressure (CPAP) device or a bilevel positive airway
pressure (BiPAP) device to manage obstructive sleep apnea may continue to use their machine. As with
nebulizers, patients should be advised to use the device only when they are isolated from others.
Use of Concomitant Medications With Ritonavir-Boosted Nirmatrelvir (Paxlovid)

Ritonavir-boosted nirmatrelvir is one of the preferred agents for the treatment of mild to moderate
COVID-19 in nonhospitalized patients who are at risk of clinical progression. It has the potential for
significant and complex drug-drug interactions with concomitant medications, primarily due to the
ritonavir component of the combination. Boosting with ritonavir, a strong CYP3A inhibitor, is required
to increase the exposure of nirmatrelvir to a concentration that is effective against SARS-CoV-2.
However, ritonavir may also increase concentrations of certain concomitant medications, thereby
increasing the potential for serious and sometimes life-threatening drug toxicities. Additionally,

AR08798
ritonavir is an inhibitor, inducer, and substrate of various other drug-metabolizing enzymes and/or drug
transporters.
Before prescribing ritonavir-boosted nirmatrelvir, clinicians should carefully review the patient’s
concomitant medications, including over-the-counter medicines, herbal supplements, and recreational
drugs. Clinicians should refer to resources such as the Liverpool COVID-19 Drug Interactions website,
the Ritonavir-Boosted Nirmatrelvir (Paxlovid) section, and the EUA fact sheet for ritonavir-boosted
nirmatrelvir for guidance regarding potential drug-drug interactions.
References
1. Caputo ND, Strayer RJ, Levitan R. Early self-proning in awake, non-intubated patients in the emergency
department: a single ED’s experience during the COVID-19 pandemic. Acad Emerg Med. 2020;27(5):375-
2. National Institute for Health Care Excellence (NICE) in collaboration with NHS England and NHS
Improvement. Managing COVID-19 symptoms (including at the end of life) in the community: summary of
NICE guidelines. BMJ. 2020;369:m1461. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32312715.
3. Hammond J, Leister-Tebbe H, Gardner A, et al. Oral nirmatrelvir for high-risk, nonhospitalized adults with
COVID-19. N Engl J Med. 2022;Published online ahead of print. Available at:
4. Gottlieb RL, Vaca CE, Paredes R, et al. Early remdesivir to prevent progression to severe COVID-19 in
outpatients. N Engl J Med. 2022;386(4):305-315. Available at:
5. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for
bebtelovimab. 2022. Available at: https://www.fda.gov/media/156152/download.
6. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization (EUA) of
sotrovimab. 2022. Available at: https://www.fda.gov/media/149534/download.
2022;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35240676.
subvariant BA.2. N Engl J Med. 2022;Published online ahead of print. Available at:
9. Pillaiyar T, Manickam M, Namasivayam V, Hayashi Y, Jung SH. An overview of severe acute respiratory
syndrome-coronavirus (SARS-CoV) 3CL protease inhibitors: peptidomimetics and small molecule
chemotherapy. J Med Chem. 2016;59(14):6595-6628. Available at:
10. Owen DR, Allerton CMN, Anderson AS, et al. An oral SARS-CoV-2 M(pro) inhibitor clinical candidate for
the treatment of COVID-19. Science. 2021;374(6575):1586-1593. Available at:
11. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for Paxlovid.
2022. Available at: https://www.fda.gov/media/155050/download.
12. Gupta A, Gonzalez-Rojas Y, Juarez E, et al. Early treatment for COVID-19 with SARS-CoV-2 neutralizing
antibody sotrovimab. N Engl J Med. 2021;385(21):1941-1950. Available at:
13. Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for oral treatment of COVID-19 in
nonhospitalized patients. N Engl J Med. 2022;386(6):509-520. Available at:
14. Greasley SE, Noell S, Plotnikova O, et al. Structural basis for nirmatrelvir in vitro efficacy against the

AR08799
Omicron variant of SARS-CoV-2. bioRxiv. 2022;Preprint. Available at:

15. Rai DK, Yurgelonis I, McMonagle P, et al. Nirmatrelvir, an orally active Mpro inhibitor, is a potent inhibitor of
SARS-CoV-2 variants of concern. bioRxiv. 2022;Preprint. Available at:
16. Vangeel L, Chiu W, De Jonghe S, et al. Remdesivir, molnupiravir and nirmatrelvir remain active against
SARS-CoV-2 Omicron and other variants of concern. Antiviral Res. 2022;198:105252. Available at:
17. Westendorf K, Zentelis S, Wang L, et al. LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2
variants. bioRxiv. 2022;Preprint. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33972947.
18. Kabinger F, Stiller C, Schmitzova J, et al. Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis.
Nat Struct Mol Biol. 2021;28(9):740-746. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34381216.
19. Zhou S, Hill CS, Sarkar S, et al. Beta-d-N4-hydroxycytidine inhibits SARS-CoV-2 through lethal mutagenesis
but is also mutagenic to mammalian cells. J Infect Dis. 2021;224(3):415-419. Available at:
molnupiravir. 2022. Available at: https://www.fda.gov/media/155054/download.
21. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with
COVID-19. N Engl J Med. 2021;384(8):693-704. Available at:
22. Cazzola M, Ora J, Bianco A, Rogliani P, Matera MG. Guidance on nebulization during the current COVID-19
pandemic. Respir Med. 2021;176:106236. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33248363.

AR08800
Therapeutic Management of Hospitalized Adults With

COVID-19
Last Updated: February 24, 2022
Figure 2. Therapeutic Management of Adults Hospitalized for COVID-19 Based on

Disease Severity
Dosing regimens for the drugs recommended in this figure are listed in Table A below.
a
Corticosteroids that are prescribed for an underlying condition should be continued.
b
If the patient progresses to requiring high-flow oxygen, NIV, MV, or ECMO, complete the full course of remdesivir (refer
to Table A).

AR08801
c
E vidence suggests that the benefit of remdesivir is greatest when the drug is given early in the course of COVID-19 (e.g.,
within 10 days of symptom onset). Clinical trials have not demonstrated a mortality benefit for remdesivir, but a large,
placebo-controlled trial showed that the use of remdesivir reduced time to clinical recovery in hospitalized patients. See
Rationale for the Use of Remdesivir below.
d
Drugs are listed alphabetically. There are no studies that directly compare the use of baricitinib and tocilizumab, and
there is insufficient evidence to recommend a drug or class of drug (i.e., JAK inhibitors, anti-IL-6 receptor mAbs) over
the other. Treatment decisions should be based on local guidance, drug availability, and patient comorbidities.
e
If baricitinib and IV tocilizumab are not available or not feasible to use, tofacitinib can be used instead of baricitinib
(BIIa) and IV sarilumab can be used instead of IV tocilizumab (BIIa).
f
Contraindications for the use of therapeutic anticoagulation in patients with COVID-19 include platelet count <50 x
109/L, Hgb <8 g/dL, the need for dual antiplatelet therapy, bleeding within the last 30 days that required an ED visit or
hospitalization, a history of a bleeding disorder, or an inherited or active acquired bleeding disorder. This list is based on
the exclusion criteria from clinical trials; patients with these conditions have an increased risk of bleeding.
g
Either LMWH or UFH heparin can be used. In general, LMWH is preferred.
h
The Panel recommends against the use of baricitinib in combination with tocilizumab for the treatment of COVID-19,
except in a clinical trial (AIII). Because both baricitinib and tocilizumab are potent immunosuppressants, there is the
potential for an additive risk of infection.
i
The combination of dexamethasone plus remdesivir may be considered for patients who have recently been intubated
(CIII). The Panel recommends against the use of remdesivir monotherapy in these patients (AIIa).
Key: ECMO = extracorporeal membrane oxygenation; ED = emergency department; Hgb = hemoglobin; ICU = intensive
care unit; IL = interleukin; IV = intravenous; JAK = Janus kinase; LMWH = low-molecular-weight heparin; mAb =
monoclonal antibody; MV = mechanical ventilation; NIV = noninvasive ventilation; the Panel = the COVID-19 Treatment
Guidelines Panel; UFH = unfractionated heparin; ULN = upper limit of normal; VTE = venous thromboembolism
Table A. Dosing Regimens for the Drugs Recommended in Figure 2

Drug Name Dosing Regimen Comments
Remdesivir RDV 200 mg IV once, then RDV 100 mg • If the patient progresses to more severe illness,
IV once daily for 4 days or until hospital complete the course of RDV.
discharge • For a discussion on using RDV in patients with renal
insufficiency, see Remdesivir.
Dexamethasone DEX 6 mg IV or PO once daily for up to • If DEX is not available, an equivalent dose of another
10 days or until hospital discharge corticosteroid may be used.
• For more information, see Corticosteroids.
Baricitinib Baricitinib dose is dependent on eGFR; • eGFR ≥60 mL/min/1.73 m2: Baricitinib 4 mg PO once
duration of therapy is up to 14 days or daily
until hospital discharge. • eGFR 30 to <60 mL/min/1.73 m2: Baricitinib 2 mg PO
once daily
• eGFR 15 to <30 mL/min/1.73 m2: Baricitinib 1 mg PO
once daily
• eGFR <15 mL/min/1.73 m2: Baricitinib is not
recommended.
Heparin Therapeutic dose of SUBQ LMWH or IV • Administer for 14 days or until hospital discharge,
UFH unless there is a diagnosis of VTE or another indication
for therapeutic anticoagulation.
Prophylactic dose of SUBQ LMWH or • Administer for the duration of the hospital stay.
SUBQ UFH
Tofacitinib Tofacitinib 10 mg PO twice daily for up • Use as an alternative immunomodulatory drug if
to 14 days or until hospital discharge baricitinib is not available or not feasible to use (BIIa).
• eGFR <60 mL/min/1.73 m2: Tofacitinib 5 mg PO twice
daily

AR08802
Drug Name Dosing Regimen Comments

Tocilizumab Tocilizumab 8 mg/kg actual body weight • In clinical trials, a third of the participants received a
(up to 800 mg) administered as a single second dose of tocilizumab 8 hours after the first dose if
IV dose no clinical improvement was observed.
Sarilumab Use the single-dose, prefilled syringe • Use as an alternative immunomodulatory drug if
(not the prefilled pen) for SUBQ tocilizumab is not available or not feasible to use (BIIa).
injection. Reconstitute sarilumab 400 • In the United States, the currently approved route of
mg in 100 cc 0.9% NaCl and administer administration for sarilumab is SUBQ injection. In the
as an IV infusion over 1 hour. REMAP-CAP trial, the SUBQ formulation was used to
prepare the IV infusion.
Key: DEX = dexamethasone; eGFR = estimated glomerular filtration rate; IV = intravenous; LMWH = low-molecular-
weight heparin; NaCl = sodium chloride; PO = oral; RDV = remdesivir; SUBQ = subcutaneous; UFH = unfractionated
heparin; VTE = venous thromboembolism
Introduction
Two main processes are thought to drive the pathogenesis of COVID-19. Early in the clinical course,
the disease is primarily driven by the replication of SARS-CoV-2. Subsequently, the disease appears to
be also driven by a dysregulated immune/inflammatory response to SARS-CoV-2 that leads to tissue
damage and thrombosis. Based on this understanding, therapies that directly target SARS-CoV-2 are
anticipated to have the greatest effect early in the course of the disease, whereas immunosuppressive/
anti-inflammatory/antithrombotic therapies are likely to be more beneficial after COVID-19 has
progressed to stages characterized by hypoxemia.
Patients Who Do Not Require Supplemental Oxygen

Recommendations
• The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of
dexamethasone (AIIa) or other corticosteroids (AIII) for the treatment of COVID-19. Patients
with COVID-19 who are receiving dexamethasone or another corticosteroid for an underlying
condition should continue this therapy as directed by their health care provider.
• There is insufficient evidence to recommend either for or against the routine use of remdesivir for
the treatment of patients who are hospitalized for COVID-19 who do not require supplemental
oxygen. However, the use of remdesivir may be appropriate in patients who are at high risk of
disease progression.
Rationale for Recommending Against the Use of Dexamethasone or Other Corticosteroids

In the RECOVERY trial, a multicenter, open-label trial in the United Kingdom, hospitalized patients
with COVID-19 were randomized to receive dexamethasone plus standard of care or standard of care
alone (control arm).1 No survival benefit for dexamethasone was observed among the patients who did
not require supplemental oxygen at enrollment: 17.8% of patients in the dexamethasone arm and 14% in
the control arm died within 28 days of enrollment (rate ratio 1.19; 95% CI, 0.91–1.55). See Table 4a for
additional information.
Based on these data, the Panel recommends against the use of dexamethasone (AIIa) or other
corticosteroids (AIII) for the treatment of COVID-19 in hospitalized patients who do not require
supplemental oxygen, unless the patient has another indication for corticosteroid therapy.

AR08803
Rationale for Determining That There Is Insufficient Evidence to Recommend Either for or
Against the Use of Remdesivir
ACTT-1 was a multinational randomized controlled trial that compared intravenous (IV) remdesivir
to placebo in hospitalized patients with COVID-19. Remdesivir showed no significant benefit in
patients with mild to moderate disease, which was defined as oxygen saturation >94% on room air or
a respiratory rate <24 breaths/min without supplemental oxygen (rate ratio for recovery 1.29; 95% CI,
0.91–1.83); however, there were only 138 patients in this subgroup.2
In a manufacturer-sponsored, open-label randomized trial that included 596 patients with moderate
COVID-19, patients who received 5 days of remdesivir had higher odds of a better clinical status on
Day 11 (based on a 7-point ordinal scale) than those who received standard of care (OR 1.65; 95% CI,
1.09–2.48; P = 0.02).3
The Solidarity trial was a large, multinational, open-label randomized controlled trial that compared a
10-day course of remdesivir to standard of care. About 25% of hospitalized patients in both arms did not
require supplemental oxygen at study entry. The primary endpoint of in-hospital mortality occurred in
11 of 661 patients (2%) in the remdesivir arm and 13 of 664 patients (2.1%) in the control arm (rate ratio
0.90; 99% CI, 0.31–2.58).4 Please see Table 2a for more information.
Data from the PINETREE trial showed a clinical benefit for early treatment with remdesivir in
nonhospitalized patients with COVID-19 who had a high risk of clinical progression. Patients were
randomized to receive 3 days of IV remdesivir or placebo. The median duration of symptoms was 5
days at treatment initiation. By Day 28, there was a significant decrease in the proportion of patients
who were hospitalized and/or died in the remdesivir arm: this primary endpoint occurred in 0.7% of
remdesivir recipients and in 5.3% of placebo recipients (HR 0.13; 95% CI, 0.03–0.59; P = 0.008).5
Because these trials produced conflicting results regarding the benefits of remdesivir, the Panel finds the
available evidence insufficient to recommend either for or against routine treatment with remdesivir for
all hospitalized patients with moderate COVID-19. However, the Panel recognizes that clinicians may
decide that remdesivir is appropriate for certain hospitalized patients with moderate disease (e.g., those
who have a particularly high risk for clinical progression).
Patients Who Require Supplemental Oxygen

Patients who require supplemental oxygen, but not high-flow oxygen, noninvasive ventilation (NIV), or
mechanical ventilation are a heterogeneous group. Some of these patients will have mild disease that will
improve after a short period with or without treatment with remdesivir, dexamethasone, or both; others
will develop progressive disease despite treatment and require a more intensive level of care. There is no
consensus on which clinical or laboratory parameters allow for reliable risk-stratification to guide therapy
and/or identify which subsets of patients will experience progressive lung injury and hypoxemia.
Some studies have tried to define this group according to traditional risk factors for COVID-19
progression and/or by the presence of elevated inflammatory markers like C-reactive protein (CRP), but
evidence to support a specific identifying biomarker or clinical threshold is lacking.
Recommendations
• The Panel recommends using 1 of the following options for hospitalized patients who require
supplemental oxygen:
• Remdesivir (e.g., for patients who require minimal supplemental oxygen) (BIIa)
• Dexamethasone plus remdesivir (BIIb)

AR08804
• Dexamethasone (BI); for patients on dexamethasone who have rapidly increasing oxygen
needs and systemic inflammation, add a second immunomodulatory drug (e.g., tocilizumab or
baricitinib) (CIIa)
• If dexamethasone is not available, an alternative corticosteroid (e.g., prednisone,
methylprednisolone, or hydrocortisone) can be used (BIII). See Corticosteroids for dosing
recommendations.
• For nonpregnant patients, the Panel recommends using a therapeutic dose of heparin for patients
who have D-dimer levels above the upper limit of normal (ULN), require low-flow oxygen, and
have no increased bleeding risk (CIIa). Low-molecular-weight heparin (LMWH) is preferred over
unfractionated heparin.
Rationale for the Use of Remdesivir

In the ACTT-1 trial, remdesivir was associated with improved time to recovery in the 435 patients who
required oxygen supplementation but not high-flow oxygen, NIV, or mechanical ventilation (7 days
for remdesivir vs. 9 days for placebo; recovery rate ratio 1.45; 95% CI, 1.18–1.79). Fewer patients
in the remdesivir arm than in the placebo arm progressed to requiring high-flow oxygen, mechanical
ventilation, or extracorporeal membrane oxygenation (ECMO) (17% vs. 24%). In a post hoc analysis of
deaths by Day 29, remdesivir appeared to confer a substantial survival benefit in this subgroup (HR for
death 0.30; 95% CI, 0.14–0.64).2
The Solidarity trial reported no difference in the rate of in-hospital deaths between patients who received
remdesivir and those who received standard of care (rate ratio for death in the overall study population
0.95; 95% CI, 0.81–1.11; rate ratio for death in patients who did not require mechanical ventilation at
entry 0.86; 99% CI, 0.67–1.11). There was no difference between patients who received remdesivir and
those who received standard of care in the percentage of those who progressed to mechanical ventilation
(11.9% vs. 11.5%) or in length of hospital stay.4 However, an open-label trial like Solidarity is less
well-suited to assess time to recovery than a placebo-controlled trial. In the Solidarity trial, because both
clinicians and patients knew that remdesivir was being administered, it is possible that hospital discharge
was delayed in order to complete the 10-day course of therapy.
DisCoVeRy was a multinational, open-label randomized controlled trial that compared up to 10 days
of remdesivir plus standard of care to standard of care alone in hospitalized patients with moderate or
severe COVID-19. There was no significant difference in the odds of improved clinical status by Day 15
between the patients in the remdesivir arm and the standard of care arm (OR 0.98; 95% CI, 0.77–1.25).
At Day 28, there were also no differences between the arms in either mortality (8% in remdesivir arm vs.
9% in standard of care arm) or clinical status. The DisCoVeRy trial shared with the Solidarity trial the
major limitation of open-label design. Additionally, 440 of the 832 participants in the DisCoVeRy trial
(219 in the remdesivir arm and 221 in the standard of care arm) were also Solidarity trial participants.6
Although the open-label Solidarity and DisCoVeRy trials demonstrated no mortality benefit for
remdesivir, in ACTT-1, a large randomized placebo-controlled trial, remdesivir significantly reduced
time to clinical recovery. In a post hoc analysis, this clinical benefit of remdesivir was most evident in
those who had symptoms for ≤10 days. The evidence from the ACTT-1 and PINETREE trials suggests
that remdesivir will have its greatest impact when administered early in the clinical course, which is
also the case for antiviral agents used to treat other viral infections.5 The Panel recommends remdesivir
(without dexamethasone) as a treatment option for certain patients with COVID-19 who require
minimal supplemental oxygen and are in the early course of the disease (BIIa). In these individuals, the
hyperinflammatory state where corticosteroids might be most beneficial may not yet be present or fully
developed.

AR08805
Although several trials studied a 10-day course of remdesivir,2,4 a 5-day course has been shown to be
comparable to 10 days of therapy in hospitalized patients with moderate to severe COVID-19.3,7 For more
information, please see Table 2a.
Rationale for the Use of Remdesivir Plus Dexamethasone

The safety and efficacy of using a combination of remdesivir and corticosteroids have primarily been
evaluated in observational studies. Some of these studies have suggested that there is a clinical benefit of
using remdesivir plus dexamethasone.8-10 Remdesivir plus dexamethasone has not been directly compared
to dexamethasone alone in a large randomized clinical trial. Patients with severe COVID-19 may develop
a systemic inflammatory response that leads to multiple organ dysfunction syndrome. The potent anti-
inflammatory effects of corticosteroids might prevent or mitigate these hyperinflammatory effects. Thus,
the combination of an antiviral agent, such as remdesivir, with an anti-inflammatory agent, such as
dexamethasone, may treat the viral infection and dampen the potentially injurious inflammatory response
that is a consequence of the infection.
Based on the theoretical combined benefit of antiviral and anti-inflammatory therapies, the Panel
recommends the combination of dexamethasone plus remdesivir as a treatment option for patients who
require supplemental oxygen (BIIb), despite important limitations of observational data.
Rationale for the Use of Dexamethasone

In the RECOVERY trial, treatment with dexamethasone conferred a survival benefit among patients
who required supplemental oxygen at enrollment. Fewer patients in the dexamethasone arm than in the
standard of care arm died within 28 days of enrollment (23.3% vs. 26.2%; rate ratio 0.82; 95% CI, 0.72–
0.94).1 However, the amount of supplemental oxygen that patients were receiving and the proportions of
patients who required oxygen through a high-flow device or NIV were not reported. It is possible that the
benefit of dexamethasone was greatest in those who required more respiratory support. It should be noted
that <0.1% of patients in the RECOVERY trial received concomitant remdesivir. For more information,
see Corticosteroids.
Some experts prefer not to use dexamethasone monotherapy in patients who require supplemental oxygen
because of the theoretical concern that corticosteroids might slow viral clearance when administered
without an antiviral drug. Corticosteroids have been associated with delayed viral clearance and/or worse
clinical outcomes in patients with other viral respiratory infections.11-13 Some studies have suggested that
corticosteroids slow SARS-CoV-2 clearance, but the results to date are inconclusive.14-18
Rationale for Adding a Second Immunomodulatory Drug to Dexamethasone in Certain

Patients Who Require Rapidly Increasing Oxygen Supplementation
Several major randomized trials that evaluated the use of interleukin (IL)-6 inhibitors or Janus Kinase
(JAK) inhibitors with or without corticosteroids in patients with COVID-19 have included patients who
required only low-flow supplemental oxygen. However, subgroup analyses in these trials have not clearly
defined which patients in this heterogeneous group are most likely to benefit from using corticosteroids
with another immunomodulator. Direct comparison between trials is not possible because background
therapies (e.g., corticosteroids) and inclusion criteria (e.g., the requirement for elevated inflammatory
markers) differed between trials. Nonetheless, some trials suggest that adding a second immunomodulator
to dexamethasone provides benefits in patients who require low-flow supplemental oxygen.19-21 The
RECOVERY trial showed that in a subgroup of patients that included patients on low-flow oxygen,
those who received tocilizumab plus dexamethasone had a lower incidence of 28-day mortality than
those who received usual care (which included dexamethasone).19 Similarly, data on JAK inhibitors are
also inconclusive; for example, the COV-BARRIER trial did not find a statistically significant benefit

AR08806
for baricitinib in patients on low-flow oxygen,20 whereas the placebo-controlled STOP-COVID trial
demonstrated a reduction in the incidence of respiratory failure or death in the subgroup of patients on
low-flow oxygen who received tofacitinib.21
Given the uncertainty concerning which patients in this group would benefit from adding a second
immunomodulator (e.g., baricitinib, tocilizumab) to dexamethasone treatment, the Panel recommends
considering these therapies on a case-by-case basis for individuals with rapidly increasing oxygen
requirements and elevated markers of systemic inflammation (CIIa). Because there are no studies that
directly compare the use of baricitinib and tocilizumab as treatments for COVID-19, the Panel has
insufficient evidence to recommend 1 drug over the other. Treatment decisions should be based on local
guidance, drug availability, and patient comorbidities.
• Baricitinib or tocilizumab should only be given in combination with dexamethasone or another
corticosteroid. Some clinicians may assess a patient’s clinical response to dexamethasone before
deciding whether adding baricitinib or tocilizumab as a second immunomodulatory drug is
necessary.
• Because there are no studies that directly compare the use of baricitinib and tocilizumab as
treatments for COVID-19, the Panel has insufficient evidence to recommend 1 drug or class of
drugs (i.e., JAK inhibitors, anti-IL-6 receptor mAbs) over the other. Treatment decisions should be
based on local guidance, drug availability, and patient comorbidities.
• If baricitinib and IV tocilizumab are not available or not feasible to use, tofacitinib can be used
instead of baricitinib (BIIa) and IV sarilumab can be used instead of IV tocilizumab (BIIa).
• The Panel recommends against the use of baricitinib in combination with tocilizumab for the
treatment of COVID-19, except in a clinical trial (AIII). Because both baricitinib and tocilizumab
are potent immunosuppressants, there is the potential for an additive risk of infection.
• Combination immunosuppressive therapy (e.g., dexamethasone with baricitinib or tocilizumab)
may increase the risk of opportunistic infections or reactivation of latent infections; however,
randomized trials to date have not demonstrated an increase in the frequency of infections.
• Cases of severe and disseminated strongyloidiasis have been reported in patients with COVID-19
during treatment with tocilizumab and corticosteroids.22,23 Many clinicians would initiate empiric
treatment for strongyloidiasis (e.g., with the antiparasitic drug ivermectin) with or without
serologic testing in patients from areas where Strongyloides is endemic (i.e., tropical, subtropical,
or warm temperate areas).
Rationale for Using a Therapeutic Dose of Heparin in Certain Patients

Three open-label randomized controlled trials compared the use of therapeutic doses of heparin to
prophylactic or intermediate doses of heparin in hospitalized patients who did not require intensive care
unit (ICU)-level care. The entry criteria into these studies varied, but they typically included those who
required supplemental oxygen, had elevated D-dimer levels, and were not at risk of major bleeding
events.
The largest multiplatform trial (ATTACC/ACTIV-4a/REMAP-CAP) showed an increase in the number
of organ support-free days in the therapeutic heparin arm, but no difference in mortality or length of
hospitalization.24 The RAPID trial enrolled patients with elevated D-dimer levels and hypoxemia.
The patients were randomized to receive therapeutic or prophylactic doses of heparin. There was
no statistically significant difference between the arms in the occurrence of the primary endpoint (a

AR08807
composite of ICU admission, receipt of NIV or mechanical ventilation, or death by Day 28), but the use
of therapeutic heparin reduced 28-day mortality.25 The HEP-COVID trial enrolled patients who required
supplemental oxygen and who had D-dimer levels that were >4 times the ULN or a sepsis-induced
coagulopathy score of ≥4. The primary endpoint (a composite of venous thromboembolism [VTE],
arterial thromboembolism, and death by Day 30) occurred significantly less frequently in patients
who received therapeutic LMWH than in those who received prophylactic LMWH, but there was no
difference in mortality by Day 30 between the arms.26 The results from smaller randomized trials, single-
center trials, and observational studies have also been published.
Based on the available data, the Panel recommends using a therapeutic dose of heparin for patients
who have D-dimer levels above the ULN, require low-flow oxygen, and have no increased bleeding risk
(CIIa). The rating reflects the fact that, although the 3 randomized controlled trials showed a clinical
benefit for therapeutic heparin in hospitalized patients, the inclusion criteria and the beneficial outcomes
differed between the trials. In addition, it should be noted that <20% of patients who were screened for
these studies were enrolled; therefore, these data may not be generalizable to all hospitalized patients
with COVID-19.
Patients Who Require Oxygen Through a High-Flow Device or Noninvasive

Ventilation
Recommendations
• The Panel recommends using 1 of the following options for hospitalized patients who require
oxygen through a high-flow device or NIV:
• Dexamethasone (AI)
• Dexamethasone plus remdesivir (BIIb)
• For patients who have rapidly increasing oxygen needs and have increased markers of
inflammation, add either baricitinib (BIIa) or tocilizumab (BIIa) (drugs are listed alphabetically)
to 1 of the options above.
• The Panel recommends using a prophylactic dose of heparin as VTE prophylaxis, unless a
contraindication exists (AI).
• For patients who are started on a therapeutic dose of heparin in a non-ICU setting due to
COVID-19 and then transferred to the ICU, the Panel recommends switching from the therapeutic
dose to a prophylactic dose of heparin, unless VTE is confirmed (BIII).
• The Panel recommends against the use of an intermediate dose (e.g., enoxaparin 1 mg/kg once
daily) or a therapeutic dose of anticoagulation for VTE prophylaxis, except in a clinical trial (BI).
• If dexamethasone is not available, an equivalent dose of another corticosteroid (e.g., prednisone,
methylprednisolone, or hydrocortisone) may be used (BIII). See Corticosteroids for more
information.
• Immunosuppressive therapy (e.g., dexamethasone with or without baricitinib or tocilizumab)
may increase the risk of opportunistic infections or reactivation of latent infections; however,
randomized trials to date have not demonstrated an increase in the frequency of infections.
treatment for strongyloidiasis (e.g., with the antiparasitic drug ivermectin) with or without

AR08808
serologic testing in patients from areas where Strongyloides is endemic (i.e., tropical, subtropical,
or warm temperate areas).
Rationale for the Use of Dexamethasone

In the RECOVERY trial, treatment with dexamethasone conferred a survival benefit among patients who
required supplemental oxygen without mechanical ventilation at enrollment: 23.3% of the patients in the
dexamethasone arm versus 26.2% in the standard of care arm died within 28 days of enrollment (rate
ratio 0.82; 95% CI, 0.72–0.94).1
Rationale for the Use of Remdesivir Plus Dexamethasone

The safety and efficacy of using a combination of remdesivir and corticosteroids have primarily been
evaluated in observational studies. Some of these studies have suggested that there is a clinical benefit
of using remdesivir plus dexamethasone.8-10 Remdesivir plus dexamethasone has not been directly
compared to dexamethasone alone in a large randomized clinical trial. Patients with severe COVID-19
may develop a systemic inflammatory response that leads to multiple organ dysfunction syndrome. The
potent anti-inflammatory effects of corticosteroids might prevent or mitigate these hyperinflammatory
effects. Thus, the combination of an antiviral agent, such as remdesivir, with an anti-inflammatory agent,
such as dexamethasone, may treat the viral infection and dampen the potentially injurious inflammatory
response that is a consequence of the infection. Based on the theoretical combined benefit of antiviral
and anti-inflammatory therapies, the Panel recommends the combination of dexamethasone plus
remdesivir as a treatment option for patients who require high-flow oxygen or NIV (BIIb), despite the
limitations of observational data.
Rationale for Not Recommending Remdesivir Monotherapy

In the ACTT-1 trial, there was no observed difference in time to recovery between the remdesivir and
placebo arms in the subgroup of 193 patients who required high-flow oxygen or NIV at enrollment
(recovery rate ratio 1.09; 95% CI, 0.76–1.57). A post hoc analysis did not show a survival benefit
for remdesivir at Day 29, but the trial was not powered to detect this difference.2 The Panel does not
recommend using remdesivir monotherapy in patients who require high-flow oxygen or NIV because
there is uncertainty regarding whether remdesivir alone confers a clinical benefit in this subgroup
(AIIa). Dexamethasone alone or remdesivir plus dexamethasone are better treatment options for
COVID-19 in this group of patients.
Patients who start remdesivir monotherapy and then progress to requiring dexamethasone and oxygen
through a high-flow device or NIV should continue to receive remdesivir until the treatment course
is completed. Clinical trials that evaluated the use of remdesivir categorized patients based on their
severity of illness at the start of treatment with remdesivir; therefore, patients may benefit from
remdesivir even if their clinical course progresses to a severity of illness for which the benefits of
remdesivir are less certain.
Rationale for Adding a Second Immunomodulatory Drug to Dexamethasone in Certain

Hospitalized Patients
Data from several large clinical trials suggest that adding a second immunomodulatory drug, such as
baricitinib or tocilizumab, to dexamethasone provides a clinical benefit in patients who require oxygen
supplementation through a high-flow device or NIV.
The REMAP-CAP and RECOVERY trials, the 2 largest randomized controlled trials of tocilizumab
to date, have both reported a mortality benefit for tocilizumab among patients with rapid respiratory
decompensation who require oxygen delivery through a high-flow device or NIV.19,27 Most patients in

AR08809
both studies received corticosteroids.

In the REMAP-CAP trial, patients who were admitted to an ICU with severe to critical COVID-19 and
rapid respiratory decompensation were randomized to receive open-label tocilizumab or usual care.
The use of tocilizumab reduced in-hospital mortality (28% of patients died in the tocilizumab arm vs.
36% in the usual care arm) and, during 21 days of follow-up, increased the median number of days free
of respiratory and cardiovascular organ support (10 days in the tocilizumab arm vs. 0 days in the usual
care arm; OR 1.64; 95% CI, 1.25–2.14). Enrollment occurred within 24 hours of ICU admission and
within a median of 1.2 days of hospitalization (IQR 0.8–2.8 days), suggesting that tocilizumab confers a
benefit to patients experiencing rapid respiratory decompensation. The RECOVERY trial also suggested
a mortality benefit for tocilizumab plus dexamethasone in a subset of patients that included those who
required NIV or high-flow oxygen. In this study, a subset of patients with hypoxemia and CRP ≥75
mg/L were randomized to receive tocilizumab or usual care. Tocilizumab reduced all-cause mortality in
these patients; by Day 28, 29% of patients in the tocilizumab arm versus 33% in the usual care arm had
died (rate ratio 0.86; 95% CI, 0.77–0.96).
In the COV-BARRIER trial, 1,525 hospitalized patients with COVID-19 and ≥1 elevated inflammatory
biomarker were randomized 1:1 to receive baricitinib 4 mg orally or placebo in addition to the local
standard of care for up to 14 days (or until hospital discharge).20 Overall, there was no difference in the
occurrence of the primary endpoint of progression to high-flow oxygen, NIV, mechanical ventilation,
or death by Day 28 between the baricitinib arm (27.8% of patients) and the placebo arm (30.5% of
patients; OR 0.85; 95% CI, 0.67–1.08; P = 0.18). However, all-cause mortality by Day 28 was 8.1% in
the baricitinib arm and 13.1% in the placebo arm, resulting in a 38.2% reduction in mortality for patients
who received baricitinib (HR 0.57; 95% CI, 0.41–0.78; nominal P = 0.002). The difference in mortality
was most pronounced in the subgroup of 370 patients receiving high-flow oxygen or NIV at baseline
(17.5% in the baricitinib arm vs. 29.4% in the placebo arm; HR 0.52; 95% CI, 0.33–0.80; nominal P =
0.007). The occurrence of adverse events, serious adverse events, serious infections, and VTE events in
the arms was comparable.
The ACTT-2 trial demonstrated that baricitinib used in combination with remdesivir improved time to
recovery in hospitalized patients with COVID-19. The effect was most pronounced in patients who were
receiving high-flow oxygen or NIV. However, patients receiving corticosteroids were excluded from the
ACTT-2 trial, limiting the generalizability of these findings.
Given the clinical trial data (see Table 4e), the Panel recommends adding baricitinib or tocilizumab
as a second immunomodulatory treatment in combination with dexamethasone for patients who are
receiving oxygen supplementation through a high-flow device or NIV (BIIa).
• Baricitinib or tocilizumab should only be given in combination with dexamethasone or another
corticosteroid. Some clinicians may assess a patient’s clinical response to dexamethasone before
deciding whether adding baricitinib or tocilizumab is necessary.
• Studies that directly compare baricitinib to tocilizumab as treatments for COVID-19 are not
available. Therefore, there is insufficient evidence for the Panel to recommend 1 drug over the
other. Treatment decisions should be based on local guidance, drug availability, and patient
comorbidities.
• If baricitinib and IV tocilizumab are not available or not feasible to use, tofacitinib can be used
instead of baricitinib (BIIa) and IV sarilumab can be used instead of IV tocilizumab (BIIa).
• Although approximately one third of patients in the REMAP-CAP and RECOVERY trials

AR08810
received a second dose of tocilizumab at the discretion of their treating physician, data on
outcomes based on receipt of 1 or 2 doses is not available. Therefore, there is insufficient evidence
to determine which patients, if any, would benefit from an additional dose of the drug.
Rationale for Recommending Against the Use of the Combination of Baricitinib and
Tocilizumab
The Panel recommends against the use of the combination of baricitinib and tocilizumab for the
treatment of COVID-19 (except in a clinical trial) because there is insufficient evidence for the use of
this combination (AIII). Given that both baricitinib and tocilizumab are potent immunosuppressants,
there is the potential for an additive risk of infection.
Rationale for Recommending Sarilumab and Dexamethasone as an Alternative to

Tocilizumab and Dexamethasone in Certain Hospitalized Patients
In an updated report from the REMAP-CAP trial, the efficacy of tocilizumab and sarilumab
in improving survival and reducing the duration of organ support was similar. Compared to
noncontemporary control patients who received placebo plus dexamethasone, patients who received
sarilumab and dexamethasone demonstrated reduced in-hospital mortality, shorter time to ICU
discharge, and more organ support-free days.28 Administering sarilumab in combination with
dexamethasone (n = 483) was noninferior to tocilizumab with dexamethasone (n = 943) with regard to
the number of organ support-free days and mortality.
Even though the REMAP-CAP trial reported that sarilumab and tocilizumab have similar efficacy in the
treatment of hospitalized patients with COVID-19, the Panel recommends using sarilumab only when
tocilizumab is not available or is not feasible to use (BIIa). The evidence of efficacy for tocilizumab is
more extensive than the evidence for sarilumab; in addition, sarilumab is currently only approved for use
as a subcutaneous (SUBQ) injection in the United States.
In 1 of the clinical trials, a single dose of sarilumab 400 mg for SUBQ injection was reconstituted in 50
mL or 100 mL of normal saline and administered as an IV infusion over 1 hour.
Rationale for Recommending the Use of Tofacitinib Plus Dexamethasone in Certain

In the STOP-COVID trial, a double-blind randomized placebo-controlled trial, use of tofacitinib was
associated with a decreased risk of respiratory failure and death (risk ratio 0.63; 95% CI, 0.41–0.97).
All-cause mortality within 28 days was 2.8% in the tofacitinib arm (n = 144) and 5.5% in the placebo
arm (n = 145) (HR 0.49; 95% CI, 0.15–1.63). Approximately 80% of patients in each arm also received
corticosteroids.21
Data from the STOP-COVID trial supports the idea that tofacitinib plus steroids improves outcomes
in hospitalized patients with COVID-19. Both baricitinib and tofacitinib belong to the same class of
anti-inflammatory drugs (kinase inhibitors) and have overlapping mechanisms of action. The Panel
recommends using tofacitinib as an alternative to baricitinib only when baricitinib is not available or
not feasible to use because the evidence of efficacy for tofacitinib is less extensive than the evidence for
baricitinib (BIIa).
Rationale for the Use of Prophylactic Doses of Heparin

The INSPIRATION trial compared the use of intermediate doses of anticoagulation (enoxaparin 1 mg/
kg SUBQ once daily; n = 299) to prophylactic doses of anticoagulation (enoxaparin 40 mg SUBQ once
daily; n = 299) in adults who were admitted to the ICU with COVID-19.29 Among these patients, 34.3%

AR08811
received oxygen delivery using high-flow oxygen or NIV. The primary endpoint in this study was a
composite of adjudicated VTE, arterial thrombosis, ECMO, or all-cause mortality. The primary endpoint
occurred in 45.7% of patients who received the intermediate dose and in 44.1% of patients who received
the prophylactic dose (OR 1.06; 95% CI, 0.76–1.48). Overall, there was no significant benefit of using
this intermediate dose of anticoagulation in these ICU patients with COVID-19.
The multiplatform randomized controlled trial REMAP-CAP/ACTIV-4a/ATTACC also compared the
effectiveness of using a therapeutic dose of heparin or LMWH to standard of care in critically ill patients
with COVID-19; 65% of these patients received high-flow oxygen or NIV.30 The trial was stopped
for futility after 536 patients were randomized to receive therapeutic anticoagulation and 564 patients
were randomized to receive standard of care. The median number of organ support-free days was 3
days (IQR -1 to 16 days) in patients who received the therapeutic dose of anticoagulation and 4 days
(IQR -1 to 16 days) in patients who received standard of care (adjusted OR 0.83; 95% CrI, 0.67–1.03;
posterior probability of futility [OR < 1.2] 99.9%). The proportion of patients who survived to hospital
discharge did not differ between the arms (62.7% of patients in the therapeutic dose arm vs. 64.5% in the
standard of care arm; OR 0.84; 95% CrI, 0.64–1.11). No significant benefit was reported for the use of a
therapeutic dose of heparin in patients with COVID-19 who were admitted to the ICU.
Patients Who Require Mechanical Ventilation or Extracorporeal Membrane

Oxygenation
Recommendations
• The Panel recommends using dexamethasone for hospitalized patients with COVID-19 who
require mechanical ventilation or ECMO (AI).
• The Panel recommends using dexamethasone plus tocilizumab for patients with COVID-19 who
are within 24 hours of admission to the ICU (BIIa).
• The Panel recommends against the use of an intermediate dose (e.g., enoxaparin 1 mg/kg once
• For patients who are started on a therapeutic dose of heparin in a non-ICU setting due to
COVID-19 and then transferred to the ICU, the Panel recommends switching from the therapeutic
dose to a prophylactic dose of heparin, unless there is a non-COVID-19 indication (BIII).
• If dexamethasone is not available, an equivalent dose of an alternative corticosteroid (e.g.,
prednisone, methylprednisolone, hydrocortisone) may be used (BIII).
• For patients who initially received remdesivir monotherapy and progressed to requiring
mechanical ventilation or ECMO, dexamethasone should be initiated and remdesivir should be
continued until the treatment course is completed.
• The Panel recommends against the initiation of remdesivir monotherapy in patients who
require mechanical ventilation or ECMO (AIIa).
• Tocilizumab should be given only in combination with dexamethasone (or another corticosteroid
at an equivalent dose).
• Although some patients in the REMAP-CAP and RECOVERY trials received a second dose of
tocilizumab at the discretion of their treating physician, there is insufficient evidence to determine
which patients, if any, would benefit from an additional dose of the drug.

AR08812
• The combination of dexamethasone and tocilizumab may increase the risk of opportunistic
infections or reactivation of latent infections. Prophylactic treatment for strongyloidiasis (e.g.,
with the antiparasitic drug ivermectin) should be considered for patients who are from areas where
Strongyloides is endemic.
Rationale for the Use of Dexamethasone Monotherapy

As COVID-19 progresses, a systemic inflammatory response may lead to multiple organ dysfunction
syndrome. The anti-inflammatory effects of corticosteroids mitigate the inflammatory response, and the
use of corticosteroids has been associated with improved outcomes in people with critical COVID-19.
Dexamethasone reduces mortality in critically ill patients with COVID-19 according to a meta-analysis
that aggregated 7 randomized trials and included data on 1,703 critically ill patients.31 The largest trial
in the meta-analysis was the RECOVERY trial, whose subgroup of mechanically ventilated patients was
included.1 For details about the meta-analysis and the RECOVERY trial, see Corticosteroids and Table
4a. Because the benefits of dexamethasone outweigh the potential harms, the Panel recommends using
dexamethasone in hospitalized patients with COVID-19 who require mechanical ventilation or ECMO
(AI).
Considerations Related to the Use of Dexamethasone Plus Remdesivir Combination Therapy

Dexamethasone plus remdesivir combination therapy has not been evaluated in controlled studies;
therefore, there is insufficient information to make a recommendation either for or against the use of
this combination therapy. However, there is a theoretical reason to administer dexamethasone plus
remdesivir to patients who have recently been intubated. Antiviral therapy may prevent a steroid-related
delay in viral clearance. This delay has been reported in the setting of other viral infections.11,12
Some studies have suggested that corticosteroids slow SARS-CoV-2 clearance, but the studies to date
are not definitive. For example, an observational study in patients with nonsevere COVID-19 suggested
that viral clearance was delayed in those who received corticosteroids,32 whereas a more recent study
in patients with moderate to severe COVID-19 found no relationship between the use of corticosteroids
and the rate of viral clearance.18 Given the conflicting results from observational studies and the lack
of clinical trial data, some Panel members would coadminister dexamethasone and remdesivir in
patients who have recently been placed on mechanical ventilation (CIII) until more conclusive evidence
becomes available, based on their concerns about delayed viral clearance in patients who received
corticosteroids. Other Panel members would not coadminister dexamethasone and remdesivir due to
uncertainties about the benefit of using remdesivir in critically ill patients.
Rationale for Recommending the Use of Tocilizumab Plus Dexamethasone in Patients Within
24 Hours of Admission to the Intensive Care Unit
The REMAP-CAP and RECOVERY trials, the 2 largest randomized controlled trials of tocilizumab
to date, both reported a mortality benefit for tocilizumab in patients who experienced rapid respiratory
decompensation and were recently admitted to the ICU, including those who required mechanical
ventilation.19,27 The REMAP-CAP trial enrolled patients within 24 hours of admission to the ICU.
Previous trials that enrolled patients later in the course of ICU care and/or who received oxygen support
>24 hours after ICU admission have failed to show consistent clinical benefits for tocilizumab (see
Table 4e). Thus, it is unclear whether there is a clinical benefit for tocilizumab in patients who received
mechanical ventilation for >24 hours. Findings from the RECOVERY trial suggest a clinical benefit for
tocilizumab plus corticosteroids among patients with rapid clinical progression who received mechanical
ventilation. Please see the Rationale for Adding a Second Immunomodulatory Drug to Dexamethasone
in Certain Hospitalized Patients section above for additional details on the clinical trial data and
rationale for using tocilizumab in this situation.

AR08813
Rationale for Recommending Against the Use of Remdesivir Monotherapy

A clear benefit of remdesivir monotherapy has not been demonstrated in patients who require
mechanical ventilation or ECMO. In the ACTT-1 trial, remdesivir did not improve the recovery rate in
this subgroup of patients (recovery rate ratio 0.98; 95% CI, 0.70–1.36), and in a post hoc analysis of
deaths by Day 29, remdesivir did not improve survival in this subgroup (HR 1.13; 95% CI, 0.67–1.89).2
In the Solidarity trial, there was a trend toward increased mortality among patients who received
mechanical ventilation and were randomized to receive remdesivir rather than standard of care (rate ratio
1.27; 95% CI, 0.99–1.62).4 Taken together, these results do not demonstrate a clear benefit of remdesivir
in critically ill patients.
For patients who start remdesivir monotherapy and then progress to requiring mechanical ventilation
or ECMO, remdesivir should be continued until the treatment course is completed. Clinical trials
that evaluated remdesivir categorized patients based on their severity of illness at study enrollment;
therefore, patients may benefit from receiving remdesivir even if their clinical course progresses to a
severity of illness for which the benefits of remdesivir are less certain.
Rationale for Recommending the Use of Sarilumab and Dexamethasone as an Alternative to

Tocilizumab and Dexamethasone in Certain Hospitalized Patients
Please refer to the Patients Who Require Oxygen Through a High-Flow Device or Noninvasive
Ventilation section above for the rationale regarding the use of sarilumab and dexamethasone as an
alternative to tocilizumab and dexamethasone in certain hospitalized patients.
Rationale for Determining That There is Insufficient Evidence to Recommend the Use of
Baricitinib in Addition to Standard of Care in Mechanically Ventilated Individuals
A cohort of critically ill patients was added to the COV-BARRIER trial after the completion of the
original study. The results for the cohort were not included in the primary results of the main trial.33
In this addendum, 101 patients on mechanical ventilation or ECMO were randomized 1:1 to receive
baricitinib 4 mg (n = 51) or placebo (n = 50) for up to 14 days in combination with standard of care.
Baricitinib significantly reduced 28-day all-cause mortality (39.2% in the baricitinib arm vs. 58.0%
in the placebo arm; HR 0.54; 95% CI, 0.31–0.96; P = 0.030). However, given the small sample size,
the Panel considers the evidence insufficient to issue a recommendation for patients on mechanical
ventilation or ECMO.
Rationale for the Use of Prophylactic Doses of Heparin

Patients who required mechanical ventilation and ECMO were included in the multiplatform
REMAP-CAP/ACTIV-4a/ATTACC trial and INSPIRATION trial.29,30 Based on the results of these trials,
the recommendations for using prophylactic doses of heparin in hospitalized, nonpregnant patients who
require mechanical ventilation or ECMO are the same as those for patients who require oxygen through
a high-flow device or NIV.
References
2. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of COVID-19 - final report. N Engl J
Med. 2020;383(19):1813-1826. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32445440.
3. Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of remdesivir vs standard care on clinical status at 11 days in
patients with moderate COVID-19: a randomized clinical trial. JAMA. 2020;324(11):1048-1057. Available at:

AR08814
4. WHO Solidarity Trial Consortium, Pan H, Peto R, et al. Repurposed antiviral drugs for COVID-19—interim
WHO Solidarity trial results. N Engl J Med. 2021;384(6):497-511. Available at:
5. Hill JA, Paredes R, Vaca C, et al. Remdesivir for the treatment of high-risk non-hospitalized individuals with
COVID-19: a randomized, double-blind, placebo-controlled trial. Presented at IDWeek. 2021. Virtual.
6. Ader F, Bouscambert-Duchamp M, Hites M, et al. Remdesivir plus standard of care versus standard of care
alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a Phase 3, randomised,
controlled, open-label trial. Lancet Infect Dis. 2022;22(2):209-221. Available at:
7. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 days in patients with severe COVID-19. N Engl J
8. Wong CKH, Lau KTK, Au ICH, et al. Optimal timing of remdesivir initiation in hospitalized COVID-19 patients
administered with dexamethasone. Clin Infect Dis. 2021;Published online ahead of print. Available at: https://
www.ncbi.nlm.nih.gov/pubmed/34420051.
9. Benfield T, Bodilsen J, Brieghel C, et al. Improved survival among hospitalized patients with coronavirus disease
2019 (COVID-19) treated with remdesivir and dexamethasone. A nationwide population-based cohort study. Clin
10. Mozaffari E, Chandak A, Zhang Z, et al. Remdesivir treatment in hospitalized patients with COVID-19: a
comparative analysis of in-hospital all-cause mortality in a large multi-center observational cohort. Clin Infect
Dis. 2021;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34596223.
11. Arabi YM, Mandourah Y, Al-Hameed F, et al. Corticosteroid therapy for critically ill patients with Middle East
respiratory syndrome. Am J Respir Crit Care Med. 2018;197(6):757-767. Available at:
12. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med. 2006;3(9):e343.
13. Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam J, Lim WS. Corticosteroids as adjunctive therapy in the treatment
of influenza. Cochrane Database Syst Rev. 2016;3:CD010406. Available at:
14. Chen Y, Li L. Influence of corticosteroid dose on viral shedding duration in patients with COVID-19. Clin Infect
Dis. 2021;72(7):1298-1300. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32588884.
15. Li S, Hu Z, Song X. High-dose but not low-dose corticosteroids potentially delay viral shedding of patients with
COVID-19. Clin Infect Dis. 2021;72(7):1297-1298. Available at:
16. Ding C, Feng X, Chen Y, et al. Effect of corticosteroid therapy on the duration of SARS-CoV-2 clearance in
patients with mild COVID-19: a retrospective cohort study. Infect Dis Ther. 2020;9(4):943-952. Available at:
17. Liu J, Zhang S, Dong X, et al. Corticosteroid treatment in severe COVID-19 patients with acute respiratory
distress syndrome. J Clin Invest. 2020;130(12):6417-6428. Available at:
18. Spagnuolo V, Guffanti M, Galli L, et al. Viral clearance after early corticosteroid treatment in patients with
moderate or severe COVID-19. Sci Rep. 2020;10(1):21291. Available at:
19. RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY):
a randomised, controlled, open-label, platform trial. Lancet. 2021;397(10285):1637-1645. Available at: https://
www.ncbi.nlm.nih.gov/pubmed/33933206.
20. Marconi VC, Ramanan AV, de Bono S, et al. Efficacy and safety of baricitinib for the treatment of hospitalised

AR08815
adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled

Phase 3 trial. Lancet Respir Med. 2021;9(12):1407-1418. Available at:
21. Guimaraes PO, Quirk D, Furtado RH, et al. Tofacitinib in patients hospitalized with COVID-19 pneumonia. N
22. Lier AJ, Tuan JJ, Davis MW, et al. Case report: disseminated strongyloidiasis in a patient with COVID-19. Am
J Trop Med Hyg. 2020;103(4):1590-1592. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32830642.
24. ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators, et al. Therapeutic
anticoagulation with heparin in noncritically ill patients with COVID-19. N Engl J Med. 2021;385(9):790-802.
25. Sholzberg M, Tang GH, Rahhal H, et al. Effectiveness of therapeutic heparin versus prophylactic heparin
on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with COVID-19
admitted to hospital: RAPID randomised clinical trial. BMJ. 2021;375:n2400. Available at:
26. Spyropoulos AC, Goldin M, Giannis D, et al. Efficacy and safety of therapeutic-dose heparin vs standard
prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with
COVID-19: the HEP-COVID randomized clinical trial. JAMA Intern Med. 2021;181(12):1612-1620.
27. REMAP-CAP Investigators, Gordon AC, Mouncey PR, et al. Interleukin-6 receptor antagonists in critically ill
28. The REMAP-CAP Investigators, Derde LPG. Effectiveness of tocilizumab, sarilumab, and anakinra for
critically ill patients with COVID-19: the REMAP-CAP COVID-19 immune modulation therapy domain
randomized clinical trial. medRxiv. 2021;Preprint. Available at:
29. Inspiration Investigators, Sadeghipour P, Talasaz AH, et al. Effect of intermediate-dose vs standard-dose
prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or
mortality among patients with COVID-19 admitted to the intensive care unit: the INSPIRATION randomized
clinical trial. JAMA. 2021;325(16):1620-1630. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33734299.
30. The REMAP-CAP, ACTIV-4a, ATTACC Investigators, Zarychanski R. Therapeutic anticoagulation in
critically ill patients with COVID-19—Preliminary Report. medRxiv. 2021;Preprint. Available at:
31. WHO Rapid Evidence Appraisal for COVID-19 Therapies Working Group, Sterne JAC, Murthy S, et al.
Association between administration of systemic corticosteroids and mortality among critically ill patients with
COVID-19: a meta-analysis. JAMA. 2020;324(13):1330-1341. Available at:
32. Li Q, Li W, Jin Y, et al. Efficacy evaluation of early, low-dose, short-term corticosteroids in adults hospitalized
with non-severe COVID-19 pneumonia: a retrospective cohort study. Infect Dis Ther. 2020;9(4):823-836.
33. Ely EW, Ramanan AV, Kartman CE, et al. Baricitinib plus standard of care for hospitalised adults with
COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: results of a
randomised, placebo-controlled trial. medRxiv. 2021;Preprint. Available at:

AR08816
Therapeutic Management of Hospitalized Pediatric Patients

With Multisystem Inflammatory Syndrome in Children
(MIS-C) (With Discussion on Multisystem Inflammatory
Syndrome in Adults [MIS-A])
This section outlines the COVID-19 Treatment Guidelines Panel’s (the Panel) recommendations for
the therapeutic management of pediatric patients with multisystem inflammatory syndrome in children
(MIS-C). The Centers for Disease Control and Prevention’s (CDC) case definition for MIS-C includes
“an individual aged <21 years.”1 The recommendations in this section encompass this age group. There
are no randomized controlled trials that compare treatment approaches for MIS-C. However, data from
descriptive and observational comparative effectiveness studies are available to guide treatment for
MIS-C. For information on the clinical manifestations of MIS-C, see Special Considerations in Children.
Multisystem Inflammatory Syndrome in Adults

It should be noted that adults can present with a syndrome similar to MIS-C, termed multisystem
inflammatory syndrome in adults (MIS-A).2 The published literature on MIS-A is restricted to small
case series that provide little data to guide treatment decisions for patients with MIS-A.3 Although Panel
members extrapolate from MIS-C data to aid in the management of individuals with MIS-A, it should be
emphasized that this approach to managing MIS-A has not been studied.

AR08817
a
Duration of therapy may vary. See duration in table and text below.
b
In certain patients with severe illness, intensification therapy may include dual therapy with higher-dose glucocorticoids
and infliximab or anakinra. Anakinra and infliximab should not be given in combination.
c
Infliximab should not be used in patients with macrophage activation syndrome.
Key: CAA = coronary artery aneurysm; IBW = ideal body weight; IV = intravenous; IVIG = intravenous immunoglobulin; LV
= left ventricular; MIS-C = multisystem inflammatory syndrome in children; PO = oral; SUBQ = subcutaneously

AR08818
Table A. Dosing Regimens for the Drugs Recommended for the Treatment of MIS-C
Dosing Regimens
For infants, children, and adolescents unless
Drug Name otherwise specified. The doses listed are for Adverse Events Monitoring Parameters
FDA-approved indications for other diseases or
from reported experiences or clinical trials.
Intravenous • IVIG 2 g/kg IBW/dose (up to a maximum total • Hypersensitivity • Renal function
Immunoglobulin dose of 100 g) IV for 1 dose • F ever • Urine output
• In the event of cardiac dysfunction or fluid • Chills • CBC with differential
overload, consider administering IVIG in • Flushing • Infusion or injection-
divided doses (1 g/kg IBW/dose IV every 24 related AE
hours for 2 doses). • Hemolytic anemia
• Anaphylaxis
• Signs and symptoms
of hemolysis
Methyl- • Methylprednisolone 1 to 2 mg/kg/dose IV • Adrenal suppression • Blood pressure
prednisolone every 12 hours • Hyperglycemia • CBC with differential
• If the patient with MIS-C does not respond • Sodium retention • BMP
to 1–2 mg/kg/dose IV every 12 hours, • Fluid retention
increase the dose to 10–30 mg/kg/day (up
to maximum of 1,000 mg/day) IV for 1 to 3 • Leukocytosis
days. • Immune suppression
Anakinra Anakinra 5–10 mg/kg/day IV (preferred) or • Headache • CBC with differential
SUBQ in 1 to 4 divided doses • Fever • LFTs
• Hypersensitivity • Scr
• Immune suppression
• Transaminitis
Infliximab Infliximab 5–10 mg/kg/dose IV for 1 dose • Infusion-related • Monitor vital signs
reaction every 2–10 minutes
• Headache during infusion
• Immune suppression • CBC with differential
Aspirin Aspirin 3–5 mg/kg/dose (up to maximum of 81 • Gastrointestinal ulcers • Signs or symptoms of
mg/dose) PO once daily • Hypersensitivity bleeding
• Renal dysfunction • Renal function
Enoxaparin Enoxaparin Prophylaxis • Increased risk of • CBC with differential
Aged >2 Months to <18 Years: bleeding • Renal function
• 0.5 mg/kg/dose (up to maximum of 30 mg/ • Thrombocytopenia
dose) SUBQ every 12 hours
Enoxaparin Treatment
Aged >2 Months to <18 Years:
• 1 mg/kg/dose SUBQ every 12 hours
• Monitor antifactor Xa activity (treatment goal:
0.5 to 1).
Key: AE = adverse effect; BMP = blood mineral panel; CBC = complete blood count; FDA = Food and Drug Administration;
IBW = ideal body weight; IV = intravenous; IVIG = intravenous immunoglobulin; LFT = liver function test; MIS-C =
multisystem inflammatory syndrome in children; PO = orally; Scr = serum creatinine; SUBQ = subcutaneously

AR08819
Treatment Considerations for Children With MIS-C

Initial Immunomodulatory Therapy for MIS-C
The Panel recommends consultation with a multidisciplinary team when managing immunomodulating
therapy for children with MIS-C (AIII). The multidisciplinary team may include experts in cardiology,
hematology, infectious disease, intensive care, and rheumatology. MIS-C is defined by multiorgan
dysfunction, and input from other pediatric subspecialists may be needed depending on the presentation
of the individual patient. Thus, children with MIS-C should be cared for at centers with access to these
pediatric specialists.
Intravenous immunoglobulin (IVIG) and glucocorticoids are the most commonly used
immunomodulatory medications in reported cohorts of children with MIS-C.4-12 The American
College of Rheumatology has outlined initial diagnostic and treatment considerations in MIS-C and
recommends IVIG in combination with glucocorticoids as first-tier therapy for most hospitalized
children with MIS-C.13 Multiple nonrandomized studies suggest that front-line IVIG in combination
with glucocorticoids is associated with less treatment failure, faster recovery of cardiac function, shorter
intensive care unit (ICU) stay, and decreased requirement for treatment escalation compared to IVIG
monotherapy.5,14-17 Based on these data, the Panel recommends using IVIG in combination with low-to-
moderate-dose glucocorticoids for children hospitalized with MIS-C (AIIb). The Panel recommends
against the routine use of IVIG monotherapy for the treatment of MIS-C unless glucocorticoid use is
contraindicated (AIIb).
IVIG should be given at a dose of 2 g/kg of ideal body weight up to a maximum dose of 100 grams. The
patient’s cardiac function and fluid status should be monitored carefully during the IVIG infusion. IVIG
can be given in divided doses of 1 g/kg of ideal body weight over 2 days if there is a concern about the
patient’s fluid status. Methylprednisolone 1 to 2 mg/kg/day, or another glucocorticoid at an equivalent
dose, is considered low-to-moderate glucocorticoid dosing. Once there is clinical improvement (i.e., the
child is afebrile, end organ dysfunction resolves, and inflammatory markers are trending downward),
a steroid taper should be initiated. Typically, the taper lasts for several weeks to avoid rebound
inflammation and is guided by the clinical status of the patient.
There remains uncertainty regarding the use of glucocorticoid monotherapy versus IVIG plus
glucocorticoids as initial therapy for MIS-C because comparative studies evaluating these 2 treatment
approaches have not been conducted. There are limited published data on long-term outcomes in
children with MIS-C who were treated with initial glucocorticoid monotherapy. Due to the risk of
coronary artery aneurysms in patients with MIS-C, and the proven benefit of IVIG in reducing the
frequency of coronary artery aneurysms in patients with Kawasaki disease, many clinicians continue to
incorporate IVIG into the treatment regimen for MIS-C.12,18 Currently, there is insufficient evidence for
the Panel to recommend either for or against the use of glucocorticoid monotherapy for MIS-C.
Summary of Published Data on Initial Immunomodulatory Therapy for MIS-C

Intravenous Immunoglobulin in Combination With Glucocorticoids
No randomized clinical trials evaluating IVIG plus glucocorticoids for the treatment of MIS-C have been
completed. The comparative benefit of adding steroids to IVIG for MIS-C treatment has been estimated
in observational cohorts using statistical techniques to adjust for confounders. The first of these studies
employed observation data from a national surveillance system cohort in France and used propensity
matching to compare short-term outcomes in children with MIS-C who were treated initially with IVIG
(2 gm/kg) alone or IVIG and methylprednisolone (most patients received 1.6–2 mg/kg/day for 5 days).14
The study team observed a lower risk of treatment failure (defined as persistence of fever 2 days after

AR08820
treatment or recurrent fever within 7 days), lesser requirement for hemodynamic support, less severe left
ventricular dysfunction, and shorter ICU stays among the children initially treated with the combination
therapy.14 This was a small study, and only 32 patients treated with IVIG and methylprednisolone and 64
patients treated with IVIG alone could be matched based on propensity score.
A larger study in the United States analyzed data from the Overcoming COVID-19 surveillance registry
to evaluate immunomodulatory therapy for MIS-C. Initial treatment with IVIG plus glucocorticoids
(n = 103) was associated with a lower risk of cardiovascular dysfunction (measured using a composite
outcome of left ventricular ejection fraction of <55% or vasopressor use) on or after Day 2 compared
to treatment with IVIG alone in an equal number of propensity score-matched patients. The composite
outcome occurred in 17% of the patients in the IVIG plus glucocorticoids group versus 31% of the
patients in the IVIG alone group (risk ratio 0.56; 95% CI, 0.34–0.94).15 In addition, patients treated with
the combination of IVIG and glucocorticoids were less likely to require adjunctive immunomodulatory
therapy than those treated with IVIG alone. Methylprednisolone, the most prescribed glucocorticoid,
was administered to 353 patients (68% of the patients, including nonpropensity matched patients, in the
entire cohort). Among these patients, the dosing of methylprednisolone ranged from 2 mg/kg/day in 284
patients (80%) to 10 to 30 mg/kg/day in 69 patients (20%).
A third study, the international and pragmatic BATS study, compared patients with MIS-C who received
IVIG alone (n = 246) to those who received IVIG and glucocorticoids (n = 208). This study found
similar rates for the composite outcome of inotropic support or mechanical ventilation by Day 2 or later
or death in both treatment arms. The outcome occurred in 44 of 221 participants (21%) in the IVIG
alone arm versus 56 of 180 participants (31%) in the IVIG plus glucocorticoids arm (OR 0.77; 95% CI,
0.33–1.82). However, escalation of immunomodulatory treatment was less common among the patients
who received IVIG plus glucocorticoids than among those who received IVIG alone (OR 0.18; 95%
CI; 0.10–0.33). This study was notable for including patients with suspected MIS-C (i.e., patients who
did not meet CDC or World Health Organization [WHO] criteria for MIS-C) and voluntary reporting of
included cases by pediatricians. This multicenter study included sites from 34 counties with potential for
more variability in supportive care. In addition, the overall percentage of patients with abnormal cardiac
findings (12% of the 538 patients) was lower than in other cohorts.16
Intravenous Immunoglobulin Monotherapy
The use of IVIG is long established for Kawasaki disease, a syndrome that has overlapping
manifestations with MIS-C, and thus the product’s safety profile is well understood. In Kawasaki
disease, IVIG prevents the development of coronary artery aneurysms,18,19 a complication also observed
in some patients with MIS-C. IVIG is the most frequently used therapy for MIS-C. In a national survey
of U.S. institutional protocols for managing MIS-C, IVIG was the first-line therapy in 98% of 40
participating centers.20
Data on the efficacy of IVIG in MIS-C is extrapolated from case series that show mostly favorable
outcomes. In a series of 539 MIS-C cases, 77% of the children received IVIG. A sizeable proportion of
these children had reduced left ventricular ejection fraction at admission (172 of 503 evaluable patients
[34.2%]); the symptom resolved by Day 30 in 156 of the children (90.7%). Although these studies have
not described the occurrence of specific adverse events related to IVIG use, the dosing used (IVIG 2 g/
kg) has a well-established safety profile when used for Kawasaki disease.12
A limitation of all published studies on IVIG use for MIS-C is the frequent and often rapid
sequential addition of other immunomodulatory therapies, such as corticosteroids. In addition, there
is accumulating evidence that glucocorticoids given in combination with IVIG are more effective
as treatment for MIS-C (see discussion above). However, IVIG monotherapy may be a reasonable

AR08821
treatment option for a small subset of patients with MIS-C who are stable (i.e., not in shock or with
organ-threatening disease) and have contraindications to glucocorticoid therapy. Such contraindications
may include concern about the impact on diagnostic evaluation or on the underlying medical condition.
Glucocorticoid Monotherapy
The BATS study described above also evaluated initial treatment with IVIG (n = 246) compared to
glucocorticoids (n = 99) and found no differences in primary or secondary outcomes between these
2 cohorts.16 However, in a subgroup analysis of patients who met the WHO criteria for MIS-C, the
glucocorticoid alone group (n = 78) had significantly fewer patients who required respiratory support by
Day 2 or later or who died than the IVIG alone group (n = 192).
The BATS study has several limitations. The length of follow-up in this study was not clearly defined,
and most outcome measures were evaluated around Day 2 of treatment. Rates of coronary artery
aneurysms and myocardial dysfunction and scarring as long-term outcomes were not reported. Further,
many patients received additional immunomodulatory agents after Day 1, including 47 patients in the
initial glucocorticoids alone group who also received IVIG. This study did not compare initial therapy
with glucocorticoids alone versus IVIG in combination with glucocorticoids. Further studies are needed
to replicate these findings and to evaluate the long-term outcomes in patients with MIS-C treated with
glucocorticoids alone.
Intensification Immunomodulatory Therapy for MIS-C

Children with MIS-C typically respond briskly to immunomodulatory therapy and show clinical
improvements within the first 24 hours of treatment. Treatment response is characterized by resolution
of fever, improvement of organ function, and reduced levels of inflammatory markers, particularly
C-reactive protein. By contrast, refractory disease is often accompanied by persistent fever, worsening
organ dysfunction, and increasing levels of inflammatory markers. Intensification therapy is
recommended for children with refractory MIS-C who do not improve within 24 hours of initial
immunomodulatory therapy (AIII). Children with uncontrolled MIS-C despite treatment with IVIG and
low-to-moderate-dose glucocorticoids will often continue to deteriorate without further intervention, and
this decline in clinical status can be quite rapid.
There are no comparative studies evaluating intensification therapies for MIS-C. Available data
on this topic are limited to results from cohort studies in patients with MIS-C, expert opinion, and
experience in treating other hyperinflammatory syndromes in children, such as Kawasaki disease and
macrophage activation syndrome. For children with refractory MIS-C, the Panel recommends additional
immunomodulatory therapy (in alphabetical order) with anakinra (BIIb), higher-dose glucocorticoids
(BIIb), or infliximab (BIIb). Currently, there is insufficient evidence to determine which of these agents is
most effective for intensification therapy in patients with refractory MIS-C. In certain patients with severe
illness, intensification therapy may include dual therapy with higher-dose glucocorticoids and anakinra
(BIII) or higher-dose glucocorticoids and infliximab (BIII). Anakinra and infliximab should not be
used in combination. A second dose of IVIG is not commonly reported in the literature as a strategy for
intensification therapy in MIS-C. This may be due to the high rates of IVIG resistance, the rapid pace of
disease escalation, and the risk for fluid overload in MIS-C patients.8 Therefore, the Panel recommends
against a second dose of IVIG for intensification therapy in patients with refractory MIS-C (BIII).
Patients with MIS-C who receive multiple immunomodulatory agents are at risk for infection and need
to be monitored carefully. Most children with MIS-C were previously healthy. In patients who have an
immune disorder or are taking immunosuppression therapy, the risk of infection is greater. The risks and
benefits of treating immunocompromised MIS-C patients with immunomodulatory agents need to be
evaluated on a case-by-case basis.

AR08822
Summary of Published Data for Intensification Immunomodulatory Therapy for MIS-C

High-Dose Glucocorticoids
High-dose glucocorticoid therapy is defined as methylprednisolone (or an equivalent corticosteroid)
dosed at 10 to 30 mg/kg/day given intravenously (IV). Often, this higher dose of glucocorticoids is
given for 1 to 3 days with a subsequent return to low-to-moderate dosing (1–2 mg/kg/day). Multiple
observational studies have reported the use of high-dose glucocorticoids (methylprednisolone 10–30
mg/kg/day) in children with MIS-C.15,21-23 In addition, single-center treatment protocols for MIS-C that
incorporate high-dose glucocorticoids into the treatment algorithm have been published. Implementation
of the protocols has resulted in positive clinical outcomes in patients with MIS-C.17 There is substantial
experience using high-dose glucocorticoids in pediatric patients with other inflammatory conditions,
such as Kawasaki disease and macrophage activation syndrome.
Anakinra
Anakinra is the most commonly used biologic medication for the treatment of MIS-C in the United
States.20 Multiple, noncomparative, observational cohorts have reported on the use of anakinra in
patients with MIS-C.8,9,11 This medication has been used extensively with a good safety record in
pediatric patients with other hyperinflammatory syndromes (e.g., systemic juvenile idiopathic arthritis,
macrophage activation syndrome).24-26 Anakinra has also been used successfully to treat IVIG-resistant
Kawasaki disease. Anakinra has a short half-life (4–6 hours), and the medication can be stopped quickly,
which many providers regard as a benefit relative to longer-acting immunomodulators. High-dose
anakinra (5–10 mg/kg/day) is recommended for MIS-C based on the improved efficacy of anakinra
used at higher doses for macrophage activation syndrome. The duration of anakinra therapy varies in the
literature and is used by some patients for long periods (e.g., up to 2 weeks) as a steroid sparing agent.
Infliximab
The Panel recommends a single dose of infliximab 5 to 10 mg/kg IV as an option for intensification
therapy. Infliximab has been studied for the treatment of MIS-C in a single-center retrospective study
that compared patients treated with IVIG alone (n = 20) to those treated with IVIG and a single dose
of infliximab 10 mg/kg IV (n = 52).27 Of note, infliximab was used as first-line therapy in this study,
and the patients were not treated with glucocorticoids. The patients who received IVIG and infliximab
were more likely to be admitted to the ICU and had more severe illness than those who received IVIG
alone. Yet, the patients who received the combination therapy were less likely to require additional
therapy after 24 hours (the primary outcome). In addition, patients who received IVIG and infliximab
had shorter admissions to the ICU and less cardiac dysfunction. These results show that infliximab has
a therapeutic effect in MIS-C. Infliximab is approved by the Food and Drug Administration for use
in children with inflammatory bowel disease and is used widely to treat juvenile idiopathic arthritis.
Infliximab has been employed in IVIG-resistant Kawasaki disease.28,29 Although the half-life of
infliximab in MIS-C is unknown, it likely has effects that persist for several weeks. This extended period
of drug activity can allow for a steroid-sparing effect in MIS-C.
Antithrombotic Treatment for MIS-C

There is general agreement that patients with MIS-C who do not have risk factors for bleeding should
receive low-dose aspirin (AIII). This recommendation is largely due to experience in children with
Kawasaki disease and the likelihood of analogous platelet activation and endothelial dysfunction in
children with MIS-C.30 Children treated with aspirin and steroids should also receive gut protection.
Patients with MIS-C who have large coronary artery aneurysms (Z-score ≥10) should receive therapeutic
anticoagulation according to the American Heart Association guidelines for Kawasaki disease (AIII).
Children with left ventricular dysfunction are at risk for intracardiac thrombosis. Patients with MIS-C

AR08823
and moderate-to-severe left ventricular dysfunction should receive therapeutic anticoagulation, unless
contraindicated due to bleeding risk factors (AIII).
There is less consensus on the use of either prophylactic or therapeutic anticoagulation in patients with
MIS-C who do not have large coronary artery aneurysms and/or moderate-to-severe left ventricular
dysfunction. Children with MIS-C have marked elevations in D-dimer levels and other abnormalities of
coagulation, which suggests that they may be at increased risk for thrombosis.31 In 1 study of children
with acute COVID-19 and MIS-C, indwelling catheters, older age (>12 years), malignancy, admission
to the ICU, and elevated D-dimer levels were all independent risk factors for thrombosis.32 There is
less known about the risk of bleeding in children with MIS-C who are treated with anticoagulation.
Major bleeding events have been reported in MIS-C patients treated with anticoagulation.32 Given
the uncertainty regarding the benefit of anticoagulation for MIS-C, prophylactic or therapeutic
anticoagulation for children with MIS-C who do not have large coronary artery aneurysms or moderate-
to-severe left ventricular dysfunction should be considered on a case-by-case basis, taking into account
the risk factors for thrombosis.
Antiviral Therapy in MIS-C

The role of antiviral therapy in treating MIS-C has not been systematically studied; however, it is not
expected to be beneficial because MIS-C is considered an immune-mediated phenomenon that occurs
weeks after a primary SARS-CoV-2 infection. Therefore, the Panel recommends against the use of
remdesivir for patients with MIS-C (AIII).
Critical Care Management

Shock occurs in approximately 50% of patients with MIS-C, and may include elements of distributive,
cardiogenic, or hypovolemic shock.12,33,34 In general, clinicians should manage shock in patients with
MIS-C per the usual critical care standards as outlined in the Pediatric Surviving Sepsis Campaign
Guidelines.35
References
1. Centers for Disease Control and Prevention. Information for healthcare providers about multisystem
inflammatory syndrome in children (MIS-C). 2021. Available at:
https://www.cdc.gov/mis/mis-c/hcp/index.html. Accessed February 7, 2022.
2. Centers for Disease Control and Prevention. Multisystem inflammatory syndrome in adults (MIS-A) case
definition information for healthcare providers. 2021. Available at:
https://www.cdc.gov/mis/mis-a/hcp.html. Accessed February 7, 2022.
3. Morris SB, Schwartz NG, Patel P, et al. Case series of multisystem inflammatory syndrome in adults
associated with SARS-CoV-2 infection—United Kingdom and United States, March–August 2020. MMWR
Morb Mortal Wkly Rep. 2020;69(40):1450-1456. Available at:
of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. 2020;395(10239):1771-1778. Available
5. Belhadjer Z, Auriau J, Meot M, et al. Addition of corticosteroids to immunoglobulins is associated with
recovery of cardiac function in multi-inflammatory syndrome in children. Circulation. 2020;142(23):2282-
6. Toubiana J, Poirault C, Corsia A, et al. Kawasaki-like multisystem inflammatory syndrome in children during
the COVID-19 pandemic in Paris, France: prospective observational study. BMJ. 2020;369:m2094. Available

AR08824
7. Whittaker E, Bamford A, Kenny J, et al. Clinical characteristics of 58 children with a pediatric inflammatory
multisystem syndrome temporally associated with SARS-CoV-2. JAMA. 2020;324(3):259-269. Available at:
8. Pouletty M, Borocco C, Ouldali N, et al. Paediatric multisystem inflammatory syndrome temporally associated
with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort. Ann Rheum Dis.
9. Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem inflammatory syndrome in U.S. children and
adolescents. N Engl J Med. 2020;383(4):334-346. Available at:
10. Dufort EM, Koumans EH, Chow EJ, et al. Multisystem inflammatory syndrome in children in New York
State. N Engl J Med. 2020;383(4):347-358. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32598830.
11. Lee PY, Day-Lewis M, Henderson LA, et al. Distinct clinical and immunological features of SARS-CoV-2-
induced multisystem inflammatory syndrome in children. J Clin Invest. 2020;130(11):5942-5950. Available at:
12. Feldstein LR, Tenforde MW, Friedman KG, et al. Characteristics and outcomes of US children and adolescents
with multisystem inflammatory syndrome in children (MIS-C) compared with severe acute COVID-19.
JAMA. 2021;325(11):1074-1087. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33625505.
13. American College of Rheumatology. Clinical guidance for pediatric patients with multisystem inflammatory
syndrome in children (MIS-C) associated with SARS-CoV-2 and hyperinflammation in COVID-19. 2022.
Available at: https://www.rheumatology.org/Portals/0/Files/ACR-COVID-19-Clinical-Guidance-Summary-
MIS-C-Hyperinflammation.pdf.
14. Ouldali N, Toubiana J, Antona D, et al. Association of intravenous immunoglobulins plus methylprednisolone
vs immunoglobulins alone with course of fever in multisystem inflammatory syndrome in children. JAMA.
15. Son MBF, Murray N, Friedman K, et al. Multisystem inflammatory syndrome in children—initial therapy and
outcomes. N Engl J Med. 2021;385(1):23-34. Available at:
16. McArdle AJ, Vito O, Patel H, et al. Treatment of multisystem inflammatory syndrome in children. N Engl J
17. Jonat B, Gorelik M, Boneparth A, et al. Multisystem inflammatory syndrome in children associated with
coronavirus disease 2019 in a children’s hospital in New York City: patient characteristics and an institutional
protocol for evaluation, management, and follow-up. Pediatr Crit Care Med. 2021;22(3):e178-e191. Available
18. Newburger JW, Takahashi M, Burns JC, et al. The treatment of Kawasaki syndrome with intravenous gamma
globulin. N Engl J Med. 1986;315(6):341-347. Available at: https://www.ncbi.nlm.nih.gov/pubmed/2426590.
19. Furusho K, Kamiya T, Nakano H, et al. High-dose intravenous gammaglobulin for Kawasaki disease. Lancet.
20. Dove ML, Jaggi P, Kelleman M, et al. Multisystem inflammatory syndrome in children: survey of protocols
for early hospital evaluation and management. J Pediatr. 2021;229:33-40. Available at:
21. Chiotos K, Bassiri H, Behrens EM, et al. Multisystem inflammatory syndrome in children during the
coronavirus 2019 pandemic: a case series. J Pediatric Infect Dis Soc. 2020;9(3):393-398. Available at:
22. Newburger JW, Sleeper LA, McCrindle BW, et al. Randomized trial of pulsed corticosteroid therapy for
primary treatment of Kawasaki disease. N Engl J Med. 2007;356(7):663-675. Available at:
23. Inoue Y, Okada Y, Shinohara M, et al. A multicenter prospective randomized trial of corticosteroids in primary

AR08825
therapy for Kawasaki disease: clinical course and coronary artery outcome. J Pediatr. 2006;149(3):336-341.
24. Eloseily EM, Weiser P, Crayne CB, et al. Benefit of anakinra in treating pediatric secondary hemophagocytic
lymphohistiocytosis. Arthritis Rheumatol. 2020;72(2):326-334. Available at:
25. Quartier P, Allantaz F, Cimaz R, et al. A multicentre, randomised, double-blind, placebo-controlled trial with
the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis
(ANAJIS trial). Ann Rheum Dis. 2011;70(5):747-754. Available at:
26. Ter Haar NM, van Dijkhuizen EHP, Swart JF, et al. Treatment to target using recombinant interleukin-1
receptor antagonist as first-line monotherapy in new-onset systemic juvenile idiopathic arthritis: results from a
five-year follow-up study. Arthritis Rheumatol. 2019;71(7):1163-1173. Available at:
27. Cole LD, Osborne CM, Silveira LJ, et al. IVIG compared to IVIG plus infliximab in multisystem
inflammatory syndrome in children. Pediatrics. 2021. Available at:
28. Mori M, Hara T, Kikuchi M, et al. Infliximab versus intravenous immunoglobulin for refractory Kawasaki
disease: a Phase 3, randomized, open-label, active-controlled, parallel-group, multicenter trial. Sci Rep.
2018;8(1):1994. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29386515.
29. Yamaji N, da Silva Lopes K, Shoda T, et al. TNF-alpha blockers for the treatment of Kawasaki disease in
children. Cochrane Database Syst Rev. 2019;8:CD012448. Available at:
30. McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, treatment, and long-term management of
Kawasaki disease: a scientific statement for health professionals from the American Heart Association.
Circulation. 2017;135(17):e927-e999. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28356445.
31. Ankola AA, Bradford VR, Newburger JW, et al. Coagulation profiles and viscoelastic testing in multisystem
inflammatory syndrome in children. Pediatr Blood Cancer. 2021;68(12):e29355. Available at:
32. Whitworth H, Sartain SE, Kumar R, et al. Rate of thrombosis in children and adolescents hospitalized with
COVID-19 or MIS-C. Blood. 2021;138(2):190-198. Available at:
33. Abrams JY, Oster ME, Godfred-Cato SE, et al. Factors linked to severe outcomes in multisystem
inflammatory syndrome in children (MIS-C) in the USA: a retrospective surveillance study. Lancet Child
Adolesc Health. 2021;5(5):323-331. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33711293.
34. Godfred-Cato S, Bryant B, Leung J, et al. COVID-19-associated multisystem inflammatory syndrome
in children - United States, March–July 2020. MMWR Morb Mortal Wkly Rep. 2020;69(32):1074-1080.
35. Weiss SL, Peters MJ, Agus MSD, et al. Perspective of the Surviving Sepsis Campaign on the management
of pediatric sepsis in the era of coronavirus disease 2019. Pediatr Crit Care Med. 2020;21(11):e1031-e1037.

AR08826
Care of Critically Ill Adult Patients With COVID-19

Infection Control
• For health care workers who are performing aerosol-generating procedures on patients with COVID-19, the COVID-19
Treatment Guidelines Panel (the Panel) recommends using an N95 respirator (or equivalent or higher-level respirator)
rather than surgical masks, in addition to other personal protective equipment (PPE) (i.e., gloves, gown, and eye
protection, such as a face shield or safety goggles) (AIII).
• The Panel recommends minimizing the use of aerosol-generating procedures on intensive care unit patients with
COVID-19 and carrying out any necessary aerosol-generating procedures in a negative-pressure room, also known as
an airborne infection isolation room, when available (AIII).
• For health care workers who are providing usual care for nonventilated patients with COVID-19, the Panel
recommends using an N95 respirator (or equivalent or higher-level respirator) or a surgical mask in addition to other
PPE (i.e., gloves, gown, and eye protection, such as a face shield or safety goggles) (AIIa).
• For health care workers who are performing non-aerosol-generating procedures on patients with COVID-19 who are
on closed-circuit mechanical ventilation, the Panel recommends using an N95 respirator (or equivalent or higher-level
respirator) in addition to other PPE (i.e., gloves, gown, and eye protection, such as a face shield or safety goggles)
because ventilator circuits may become disrupted unexpectedly (BIII).
• The Panel recommends that endotracheal intubation in patients with COVID-19 be performed by health care providers
with extensive airway management experience, if possible (AIII).
• The Panel recommends that intubation be performed using video laryngoscopy, if possible (CIIa).
Hemodynamics
• For adults with COVID-19 and shock, the Panel recommends using dynamic parameters, skin temperature, capillary
refilling time, and/or lactate levels over static parameters to assess fluid responsiveness (BIIa).
• For the acute resuscitation of adults with COVID-19 and shock, the Panel recommends using buffered/balanced
crystalloids over unbalanced crystalloids (BIIa).
• For the acute resuscitation of adults with COVID-19 and shock, the Panel recommends against the initial use of
albumin for resuscitation (BI).
• For adults with COVID-19 and shock, the Panel recommends norepinephrine as the first-line vasopressor (AI).
• For adults with COVID-19 and shock, the Panel recommends titrating vasoactive agents to target a mean arterial
pressure (MAP) of 60 to 65 mm Hg over higher MAP targets (BI).
• The Panel recommends against using hydroxyethyl starches for intravascular volume replacement in patients with
sepsis or septic shock (AI).
• When norepinephrine is available, the Panel recommends against using dopamine for patients with COVID-19 and
shock (AI).
• As a second-line vasopressor, the Panel recommends adding either vasopressin (up to 0.03 units/min) (BIIa) or
epinephrine (BIIb) to norepinephrine to raise MAP to target or adding vasopressin (up to 0.03 units/min) (BIIa) to
decrease norepinephrine dosage.
• The Panel recommends against using low-dose dopamine for renal protection (AI).
• The Panel recommends using dobutamine in patients who show evidence of cardiac dysfunction and persistent
hypoperfusion despite adequate fluid loading and the use of vasopressor agents (BIII).
• The Panel recommends that all patients who require vasopressors have an arterial catheter placed as soon as
practical, if the resources to do so are available (BIII).
• For adults with refractory septic shock who have completed a course of corticosteroids to treat their COVID-19, the
Panel recommends using low-dose corticosteroid therapy (“shock-reversal”) over no corticosteroid therapy (BIIa).
Oxygenation and Ventilation
• For adults with COVID-19 and acute hypoxemic respiratory failure despite conventional oxygen therapy, the Panel
recommends high-flow nasal cannula (HFNC) oxygen over noninvasive ventilation (NIV) (BIIa).

AR08827
• For adults with COVID-19 and acute hypoxemic respiratory failure who do not have an indication for endotracheal
intubation and for whom HFNC oxygen is not available, the Panel recommends performing a closely monitored trial of
NIV (BIIa).
• For adults with persistent hypoxemia who require HFNC oxygen and for whom endotracheal intubation is not
indicated, the Panel recommends a trial of awake prone positioning (BIIa).
• The Panel recommends against using awake prone positioning as a rescue therapy for refractory hypoxemia to avoid
intubation in patients who otherwise meet the indications for intubation and mechanical ventilation (AIII).
• If intubation becomes necessary, the procedure should be performed by an experienced practitioner in a controlled
setting due to the enhanced risk of exposing health care practitioners to SARS-CoV-2 during intubation (AIII).
• For mechanically ventilated adults with COVID-19 and acute respiratory distress syndrome (ARDS):
• The Panel recommends using low tidal volume (VT) ventilation (VT 4–8 mL/kg of predicted body weight) over
higher VT ventilation (VT >8 mL/kg) (AI).
• The Panel recommends targeting plateau pressures of <30 cm H2O (AIIa).
• The Panel recommends using a conservative fluid strategy over a liberal fluid strategy (BIIa).
• The Panel recommends against the routine use of inhaled nitric oxide (AIIa).
• For mechanically ventilated adults with COVID-19 and moderate to severe ARDS:
• The Panel recommends using a higher positive end-expiratory pressure (PEEP) strategy over a lower PEEP strategy
(BIIa).
• For mechanically ventilated adults with COVID-19 and refractory hypoxemia despite optimized ventilation, the Panel
recommends prone ventilation for 12 to 16 hours per day over no prone ventilation (BIIa).
• The Panel recommends using, as needed, intermittent boluses of neuromuscular blocking agents (NMBAs) or a
continuous NMBA infusion to facilitate protective lung ventilation (BIIa).
• In the event of persistent patient-ventilator dyssynchrony, or in cases where a patient requires ongoing deep
sedation, prone ventilation, or persistently high plateau pressures, the Panel recommends using a continuous
NMBA infusion for up to 48 hours, as long as the patient’s anxiety and pain can be adequately monitored and
controlled (BIII).
• For mechanically ventilated adults with COVID-19, severe ARDS, and hypoxemia despite optimized ventilation and
other rescue strategies:
• The Panel recommends using recruitment maneuvers rather than not using recruitment maneuvers (CIIa).
• If recruitment maneuvers are used, the Panel recommends against using staircase (incremental PEEP) recruitment
maneuvers (AIIa).
• The Panel recommends using an inhaled pulmonary vasodilator as a rescue therapy; if no rapid improvement in
oxygenation is observed, the treatment should be tapered off (CIII).
Acute Kidney Injury and Renal Replacement Therapy
• For critically ill patients with COVID-19 who have acute kidney injury and who develop indications for renal
replacement therapy, the Panel recommends continuous renal replacement therapy (CRRT), if available (BIII).
• If CRRT is not available or not possible due to limited resources, the Panel recommends prolonged intermittent renal
replacement therapy rather than intermittent hemodialysis (BIII).
Pharmacologic Interventions
• In patients with COVID-19 and severe or critical illness, there is insufficient evidence for the Panel to recommend
either for or against the use of empiric broad-spectrum antimicrobial therapy in the absence of another indication.
• If antimicrobials are initiated, the Panel recommends reassessing the need for them daily to minimize the adverse
effects of unnecessary antimicrobial therapy (AIII).
Extracorporeal Membrane Oxygenation
• There is insufficient evidence for the Panel to recommend either for or against the use of extracorporeal membrane
oxygenation for patients with COVID-19 and refractory hypoxemia.

AR08828
General Considerations
Severe cases of COVID-19 may be associated with hypoxemic respiratory failure, acute respiratory
distress syndrome (ARDS), septic shock, cardiac dysfunction, elevation in multiple inflammatory
cytokines, thromboembolic disease, and/or exacerbation of underlying comorbidities. In addition to
pulmonary disease, patients with COVID-19 may also experience cardiac, hepatic, renal, and central
nervous system disease. Because patients with critical illness are likely to undergo aerosol-generating
procedures, they should be placed in airborne infection isolation rooms, when available.
Guidance on diagnostic testing for SARS-CoV-2 can be found in the Testing for SARS-CoV-2 Infection
section.
Most of the recommendations for the management of critically ill patients with COVID-19 are
extrapolated from experience with other causes of sepsis.1 Currently, there is limited information to
suggest that the critical care management of patients with COVID-19 should differ substantially from
the management of other critically ill patients; however, special precautions to prevent environmental
contamination by SARS-CoV-2 are warranted.
As with any patient in the intensive care unit (ICU), successful clinical management of a patient with
COVID-19 includes treating both the medical condition that initially resulted in ICU admission and
other comorbidities and nosocomial complications.
Comorbid Conditions
Certain attributes and comorbidities (e.g., older age, cardiovascular disease, diabetes, chronic obstructive
pulmonary disease, cancer, renal disease, obesity, sickle cell disease, receipt of a solid organ transplant)
are associated with an increased risk of severe illness from COVID-19.2
Bacterial Superinfection of COVID-19-Associated Pneumonia

Limited information exists about the frequency and microbiology of pulmonary coinfections and
superinfections in patients with COVID-19, such as hospital-acquired pneumonia (HAP) and ventilator-
associated pneumonia (VAP). Some studies from China emphasize the lack of bacterial coinfections in
patients with COVID-19, while other studies suggest that these patients experience frequent bacterial
complications.3-8 There is appropriate concern about performing pulmonary diagnostic procedures such
as bronchoscopy or other airway sampling procedures that require disruption of a closed airway circuit
in patients with COVID-19. Thus, while some clinicians do not routinely start empiric broad-spectrum
antimicrobial therapy for patients with severe COVID-19 disease, other experienced clinicians routinely
use such therapy. However, empiric broad-spectrum antimicrobial therapy is the standard of care for the
treatment of shock. Antibiotic stewardship is critical to avoid reflexive or continued courses of antibiotics.
Inflammatory Response Due to COVID-19

Patients with COVID-19 may express increased levels of pro-inflammatory cytokines and anti-
inflammatory cytokines, which has previously been referred to as “cytokine release syndrome” or
“cytokine storm,” although these are imprecise terms. However, these terms are misnomers because the
magnitude of cytokine elevation in patients with COVID-19 is modest compared to that in patients with
many other critical illnesses, such as sepsis and ARDS.9,10
Patients with COVID-19 and severe pulmonary involvement are well described to also manifest
extrapulmonary disease and to exhibit laboratory markers of acute inflammation. Patients with these

AR08829
manifestations of severe pulmonary disease typically progress to critical illness 10 to 12 days after the
onset of COVID-19 symptoms.
Multisystem Inflammatory Syndrome in Adults

In addition, there are case reports describing patients who had evidence of acute or recent SARS-CoV-2
infection (documented by a nucleic acid amplification test [NAAT] or antigen or antibody testing) with
minimal respiratory symptoms, but with laboratory markers of severe inflammation (e.g., elevated
C-reactive protein [CRP], ferritin, D-dimer, cardiac enzymes, liver enzymes, and creatinine) and various
other symptoms, including fever and shock; and signs of cardiovascular, gastrointestinal, dermatologic,
and neurologic disease. This constellation of signs and symptoms has been designated multisystem
inflammatory syndrome in adults (MIS-A).11 To date, most adults in whom MIS-A has been described
have survived. This syndrome is similar to a syndrome previously described in children (multisystem
inflammatory syndrome in children [MIS-C]).
MIS-A is defined by the following criteria:
1. A severe illness requiring hospitalization in an individual aged ≥21 years;
2. Current or past infection with SARS-CoV-2;
3. Severe dysfunction in one or more extrapulmonary organ systems;
4. Laboratory evidence of elevated inflammatory markers (e.g., CRP, ferritin, D-dimer, interleukin
[IL]-6);
5. Absence of severe respiratory illness; and
6. Absence of an alternative unifying diagnosis.11
Because there is no specific diagnostic test for MIS-A, diagnosis of this inflammatory syndrome is one
of exclusion after other causes (e.g., septic shock) have been eliminated. Although there are currently
no controlled clinical trial data in patients with MIS-A to guide treatment of the syndrome, case reports
have described the use of intravenous immunoglobulin, corticosteroids, or anti-IL-6 therapy.
COVID-19-Induced Cardiac Dysfunction, Including Myocarditis

A growing body of literature describes cardiac injury or dysfunction in approximately 20% of patients
who are hospitalized with COVID-19.4,6,12-15 COVID-19 may be associated with an array of cardiovascular
complications, including acute coronary syndrome, myocarditis, arrythmias, and thromboembolic
disease.16
Thromboembolic Events and COVID-19

Critically ill patients with COVID-19 have been observed to have a prothrombotic state, which is
characterized by the elevation of certain biomarkers, and there is an apparent increase in the incidence of
venous thromboembolic disease in this population. In some studies, thromboemboli have been diagnosed
in patients who received chemical prophylaxis with heparinoids.17-19 Autopsy studies provide additional
evidence of both thromboembolic disease and microvascular thrombosis in patients with COVID-19.20
Some authors have called for routine surveillance of ICU patients for venous thromboembolism.21 See the
Antithrombotic Therapy in Patients With COVID-19 section for a more detailed discussion.
Renal and Hepatic Dysfunction Due to COVID-19

Although SARS-CoV-2 is primarily a pulmonary pathogen, renal and hepatic dysfunction are
consistently described in patients with severe COVID-19.4 In one case series of patients with critical

AR08830
disease, >15% of the patients required continuous renal replacement therapy.6 See the Acute Kidney
Injury and Renal Replacement Therapy section for a more detailed discussion.
Several large epidemiologic studies suggest that rates of ICU admission are substantially lower for
children with COVID-19 than for adults with the disease. However, severe disease does occur in
children.22-27 The risk factors for severe COVID-19 in children have not yet been established. Data
from studies of adults with COVID-19 and extrapolation from data on other pediatric respiratory
viruses suggest that children who are severely immunocompromised and those with underlying
cardiopulmonary disease may be at higher risk for severe COVID-19.
MIS-C, the postinfectious complication of COVID-19 seen in some children, has been described.28,29
Certain symptoms of MIS-C often require ICU-level care, including blood pressure and inotropic
support. These symptoms include severe abdominal pain, multisystem inflammation, shock, cardiac
dysfunction, and, rarely, coronary artery aneurysm. A minority of children with MIS-C meet the criteria
for typical or atypical Kawasaki disease. For details on MIS-C clinical features and the treatments that
are being investigated, see the Special Considerations in Children section.
Interactions Between Drugs Used to Treat COVID-19 and Drugs Used to Treat
Comorbidities
All ICU patients should be routinely monitored for drug-drug interactions. The potential for drug-drug
interactions between investigational medications or medications used off-label to treat COVID-19 and
concurrent drugs should be considered.
Sedation Management in Patients With COVID-19

International guidelines provide recommendations on the prevention, detection, and treatment of pain,
sedation, and delirium.30,31 Sedation management strategies, such as maintaining a light level of sedation
(when appropriate) and minimizing sedative exposure, have shortened the duration of mechanical
ventilation and the length of stay in the ICU for patients without COVID-19.32,33
The Society of Critical Care Medicine’s (SCCM’s) ICU Liberation Campaign promotes the ICU
Liberation Bundle (A-F) to improve post-ICU patient outcomes. The A-F Bundle includes the following
elements:
A. Assess, prevent, and manage pain;
B. Both spontaneous awakening and breathing trials;
C. Choice of analgesia and sedation;
D. Delirium: assess, prevent, and manage;
E. Early mobility and exercise; and
F. Family engagement and empowerment.
The A-F Bundle also provides frontline staff with practical application strategies for each element.34
The A-F Bundle should be incorporated using an interprofessional team model. This approach helps
standardize communication among team members, improves survival, and reduces long-term cognitive
dysfunction of patients.35 Despite the known benefits of the A-F Bundle, its impact has not been directly
assessed in patients with COVID-19; however, the use of the Bundle should be encouraged, when
appropriate, to improve ICU patient outcomes. Prolonged mechanical ventilation of COVID-19 patients,
coupled with deep sedation and potentially neuromuscular blockade, increases the workload of ICU

AR08831
staff. Additionally, significant drug shortages may force clinicians to use older sedatives with prolonged
durations of action and active metabolites, impeding routine implementation of the PADIS Guidelines.
This puts patients at additional risk for ICU and post-ICU complications.
Post-Intensive Care Syndrome

Patients with COVID-19 are reported to experience prolonged delirium and/or encephalopathy. Risk
factors that are associated with delirium include the use of mechanical ventilation; the use of restraints;
the use of benzodiazepine, opioid, and vasopressor infusions; and the use of antipsychotics.36,37
Neurological complications are associated with older age and underlying conditions, such as
hypertension and diabetes mellitus.38 Autopsy studies have reported both macrovascular and
microvascular thrombosis, with evidence of hypoxic ischemia.39 Adequate management requires careful
attention to best sedation practices and vigilance in stroke detection.
Post-intensive care syndrome (PICS) is a spectrum of cognitive, psychiatric, and/or physical disability
that affects survivors of critical illness and persists after a patient leaves the ICU.40 Patients with PICS
may present with varying levels of impairment; including profound muscle weakness (ICU-acquired
weakness); problems with thinking and judgment (cognitive dysfunction); and mental health problems,
such as problems sleeping, post-traumatic stress disorder (PTSD), depression, and anxiety. ICU-acquired
weakness affects 33% of all patients who receive mechanical ventilation, 50% of patients with sepsis, and
≤50% of patients who remain in the ICU for ≥1 week.41-43 Cognitive dysfunction affects 30% to 80% of
patients discharged from the ICU.44-46 About 50% of ICU survivors do not return to work within 1 year
after discharge.47 Although no single risk factor has been associated with PICS, there are opportunities
to minimize the risk of PICS through medication management (using the A-F Bundle), physical
rehabilitation, follow-up clinics, family support, and improved education about the syndrome. PICS also
affects family members who participate in the care of their loved ones. In one study, a third of family
members who had main decision-making roles experienced mental health problems, such as depression,
anxiety, and PTSD.48
Early reports suggest that some patients with COVID-19 who have been treated in the ICU express
manifestations of PICS.49 Although specific therapies for COVID-19-induced PICS are not yet available,
physicians should maintain a high index of suspicion for cognitive impairment and other related
problems in survivors of severe or critical COVID-19 illness.
Other Intensive Care Unit-Related Complications

Patients who are critically ill with COVID-19 are at risk for nosocomial infections and other
complications of critical illness care, such as VAP, HAP, catheter-related bloodstream infections, and
venous thromboembolism. When treating patients with COVID-19, clinicians also need to minimize the
risk of conventional ICU complications to optimize the likelihood of a successful ICU outcome.
Advance Care Planning and Goals of Care

The advance care plans and the goals of care for all critically ill patients must be assessed at hospital
admission and regularly thereafter. This is an essential element of care for all patients. Information
on palliative care for patients with COVID-19 can be found at the National Coalition for Hospice and
Palliative Care website.
To guide shared decision-making in cases of serious illness, advance care planning should include
identifying existing advance directives that outline a patient’s preferences and values. Values and care
preferences should be discussed, documented, and revisited regularly for patients with or without prior
directives. Specialty palliative care teams can facilitate communication between clinicians and surrogate

AR08832
decision makers, support frontline clinicians, and provide direct patient care services when needed.
Surrogate decision makers should be identified for all critically ill patients with COVID-19 at hospital
admission. Infection-control policies for COVID-19 often create communication barriers for surrogate
decision makers, and most surrogates will not be physically present when discussing treatment options
with clinicians. Many decision-making discussions will occur via telecommunication.
Acknowledgments
The Surviving Sepsis Campaign (SSC), an initiative supported by the SCCM and the European Society of
Intensive Care Medicine, issued Guidelines on the Management of Critically Ill Adults with Coronavirus
Disease 2019 (COVID-19) in March 2020.1 The COVID-19 Treatment Guidelines Panel (the Panel)
has based the recommendations in this section on the SSC COVID-19 Guidelines with permission,
and the Panel gratefully acknowledges the work of the SSC COVID-19 Guidelines Panel. The Panel
also acknowledges the contributions and expertise of Andrew Rhodes, MBBS, MD, of St. George’s
University Hospitals in London, England, and Waleed Alhazzani, MBBS, MSc, of McMaster University
in Hamilton, Canada.
References
1. Alhazzani W, Moller MH, Arabi YM, et al. Surviving Sepsis Campaign: guidelines on the management of
critically ill adults with coronavirus disease 2019 (COVID-19). Crit Care Med. 20200;48(6):e440-e469.
2. Centers for Disease Control and Prevention. Evidence used to update the list of underlying medical conditions
that increase a person’s risk of severe illness from COVID-19. 2020. Available at: https://www.cdc.gov/
coronavirus/2019-ncov/need-extra-precautions/evidence-table.html. Accessed December 8, 2020.
3. Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in
patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):934-943.
4. Arentz M, Yim E, Klaff L, et al. Characteristics and outcomes of 21 critically ill patients with COVID-19
in Washington state. JAMA. 2020;323(16):1612-1614. Available at: https://www.ncbi.nlm.nih.gov/
pubmed/32191259.
5. Bhatraju PK, Ghassemieh BJ, Nichols M, et al. COVID-19 in critically ill patients in the Seattle region—case
series. N Engl J Med. 2020;382(21):2012-2022. Available at:
6. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia
in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020. Available at:
7. Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019:
retrospective study. BMJ. 2020;368:m1091. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32217556.
8. Du Y, Tu L, Zhu P, et al. Clinical features of 85 fatal cases of COVID-19 from Wuhan: a retrospective
observational study. Am J Respir Crit Care Med. 2020;201(11):1372-1379. Available at:
9. Leisman DE, Ronner L, Pinotti R, et al. Cytokine elevation in severe and critical COVID-19: a rapid
systematic review, meta-analysis, and comparison with other inflammatory syndromes. Lancet Respir Med.
10. Sinha P, Matthay MA, Calfee CS. Is a “cytokine storm” relevant to COVID-19? JAMA Intern Med.
11. Morris SB, Schwartz NG, Patel P, et al. Case series of multisystem inflammatory syndrome in adults associated
with SARS-CoV-2 infection—United Kingdom and United States, March–August 2020. MMWR Morb Mortal
Wkly Rep. 2020;69(40):1450-1456. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33031361.

AR08833
12. Shi S, Qin M, Shen B, et al. Association of cardiac injury with mortality in hospitalized patients with
COVID-19 in Wuhan, China. JAMA Cardiol. 2020;5(7):802-810. Available at: https://www.ncbi.nlm.nih.gov/
pubmed/32211816.
13. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan,
China. Lancet. 2020;395(10223):497-506. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31986264.
14. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in
Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-1062. Available at:
15. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-
infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061-1069. Available at:
16. Nishiga M, Wang DW, Han Y, Lewis DB, Wu JC. COVID-19 and cardiovascular disease: from basic
mechanisms to clinical perspectives. Nat Rev Cardiol. 2020;17(9):543-558. Available at:
17. Llitjos JF, Leclerc M, Chochois C, et al. High incidence of venous thromboembolic events in anticoagulated
severe COVID-19 patients. J Thromb Haemost. 2020;18(7):1743-1746. Available at:
18. Helms J, Tacquard C, Severac F, et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection:
a multicenter prospective cohort study. Intensive Care Med. 2020;46(6):1089-1098. Available at:
19. Klok FA, Kruip M, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU
patients with COVID-19. Thromb Res. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32291094.
20. Menter T, Haslbauer JD, Nienhold R, et al. Postmortem examination of COVID-19 patients reveals diffuse
alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting
vascular dysfunction. Histopathology. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32364264.
21. Tavazzi G, Civardi L, Caneva L, Mongodi S, Mojoli F. Thrombotic events in SARS-CoV-2 patients: an urgent
call for ultrasound screening. Intensive Care Med. 2020. Available at:
22. Sun D, Li H, Lu XX, et al. Clinical features of severe pediatric patients with coronavirus disease 2019 in
Wuhan: a single center’s observational study. World J Pediatr. 2020. Available at:
23. Dong Y, Mo X, Hu Y, et al. Epidemiology of COVID-19 Among Children in China. Pediatrics. 2020;145(6).
24. Centers for Disease Control and Prevention. Coronavirus disease 2019 in children—United States, February
12–April 2, 2020. 2020. Available at: https://www.cdc.gov/mmwr/volumes/69/wr/mm6914e4.htm. Accessed
January 5, 2021.
25. Chao JY, Derespina KR, Herold BC, et al. Clinical characteristics and outcomes of hospitalized and critically
ill children and adolescents with coronavirus disease 2019 (COVID-19) at a tertiary care medical center in
New York City. J Pediatr. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32407719.
26. Zachariah P, Johnson CL, Halabi KC, et al. Epidemiology, clinical features, and disease severity in patients
with coronavirus disease 2019 (COVID-19) in a children’s hospital in New York City, New York. JAMA
Pediatr. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32492092.
27. DeBiasi RL, Song X, Delaney M, et al. Severe COVID-19 in children and young adults in the Washington,
DC metropolitan region. J Pediatr. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32405091.
multisystem syndrome temporally associated with SARS-CoV-2. JAMA. 2020. Available at:

AR08834
of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. 2020. Available at:
30. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and
delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41(1):263-306. Available at:
31. Devlin JW, Skrobik Y, Gelinas C, et al. Clinical practice guidelines for the prevention and management of
pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med.
32. Kress JP, Vinayak AG, Levitt J, et al. Daily sedative interruption in mechanically ventilated patients at risk for
coronary artery disease. Crit Care Med. 2007;35(2):365-371. Available at:
33. Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator weaning protocol
for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised
controlled trial. Lancet. 2008;371(9607):126-134. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18191684.
34. Society of Critical Care Medicine. ICU Liberation Bundle (A-F). Available at:
https://www.sccm.org/ICULiberation/ABCDEF-Bundles. Accessed January 5, 2021.
35. Barnes-Daly MA, Phillips G, Ely EW. Improving hospital survival and reducing brain dysfunction at seven
California community hospitals: implementing PAD guidelines via the ABCDEF bundle in 6,064 patients. Crit
Care Med. 2017;45(2):171-178. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27861180.
36. Helms J, Kremer S, Merdji H, et al. Neurologic features in severe SARS-CoV-2 infection. N Engl J Med.
37. Pun BT, Badenes R, Heras La Calle G, et al. Prevalence and risk factors for delirium in critically ill patients
with COVID-19 (COVID-D): a multicentre cohort study. Lancet Respir Med. 2021;9(3):239-250. Available at:
38. Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with coronavirus disease
2019 in Wuhan, China. JAMA Neurol. 2020;77(6):683-690. Available at: https://www.ncbi.nlm.nih.gov/
pubmed/32275288.
39. Solomon IH, Normandin E, Bhattacharyya S, et al. Neuropathological features of COVID-19. N Engl J Med.
40. Society of Critical Care Medicine. Post-intensive care syndrome. 2013. Available at:
https://www.sccm.org/MyICUCare/THRIVE/Post-intensive-Care-Syndrome. Accessed September 22, 2020.
41. Fan E, Dowdy DW, Colantuoni E, et al. Physical complications in acute lung injury survivors: a two-year
longitudinal prospective study. Crit Care Med. 2014;42(4):849-859. Available at:
42. De Jonghe B, Sharshar T, Lefaucheur JP, et al. Paresis acquired in the intensive care unit: a prospective
multicenter study. JAMA. 2002;288(22):2859-2867. Available at: https://www.ncbi.nlm.nih.gov/
pubmed/12472328.
43. Ali NA, O’Brien JM, Jr., Hoffmann SP, et al. Acquired weakness, handgrip strength, and mortality in critically
ill patients. Am J Respir Crit Care Med. 2008;178(3):261-268. Available at:
44. Pandharipande PP, Girard TD, Jackson JC, et al. Long-term cognitive impairment after critical illness. N Engl
J Med. 2013;369(14):1306-1316. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24088092.
45. Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability
among survivors of severe sepsis. JAMA. 2010;304(16):1787-1794. Available at:
46. Mikkelsen ME, Christie JD, Lanken PN, et al. The adult respiratory distress syndrome cognitive outcomes
study: long-term neuropsychological function in survivors of acute lung injury. Am J Respir Crit Care Med.

AR08835
47. Kamdar BB, Sepulveda KA, Chong A, et al. Return to work and lost earnings after acute respiratory distress
syndrome: a 5-year prospective, longitudinal study of long-term survivors. Thorax. 2018;73(2):125-133.
48. Azoulay E, Pochard F, Kentish-Barnes N, et al. Risk of post-traumatic stress symptoms in family members of
intensive care unit patients. Am J Respir Crit Care Med. 2005;171(9):987-994. Available at:
49. Carfi A, Bernabei R, Landi F, Gemelli Against C-P-ACSG. Persistent symptoms in patients after acute
COVID-19. JAMA. 2020;324(6):603-605. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32644129.

AR08836
Infection Control
Health care workers should follow the infection control policies and procedures issued by their health
care institutions.
Recommendation
• For health care workers who are performing aerosol-generating procedures on patients with
COVID-19, the COVID-19 Treatment Guidelines Panel (the Panel) recommends using an N95
respirator (or equivalent or higher-level respirator) rather than surgical masks, in addition to other
personal protective equipment (PPE) (i.e., gloves, gown, and eye protection such as a face shield
or safety goggles) (AIII).
• Aerosol-generating procedures include endotracheal intubation and extubation, sputum
induction, bronchoscopy, mini-bronchoalveolar lavage, open suctioning of airways, manual
ventilation, unintentional or intentional ventilator disconnections, noninvasive positive pressure
ventilation (NIPPV) (e.g., bilevel positive airway pressure [BiPAP], continuous positive airway
pressure [CPAP]), cardiopulmonary resuscitation, and, potentially, nebulizer administration and
high-flow oxygen delivery. Caution regarding aerosol generation is appropriate in situations
such as tracheostomy and proning, where ventilator disconnections are likely to occur.
Rationale
During the severe acute respiratory syndrome (SARS) epidemic, aerosol-generating procedures
increased the risk of infection among health care workers.1,2 N95 respirators block 95% to 99% of
aerosol particles; however, medical staff must be fit-tested for the type used.3 Surgical masks block large
particles, droplets, and sprays, but are less effective in blocking small particles (<5 μm) and aerosols.4
Recommendation
• The Panel recommends minimizing the use of aerosol-generating procedures on intensive care
unit patients with COVID-19 and carrying out any necessary aerosol-generating procedures
in a negative-pressure room, also known as an airborne infection isolation room (AIIR), when
available (AIII).
• The Panel recognizes that aerosol-generating procedures are necessary to perform in some
patients, and that such procedures can be carried out with a high degree of safety if infection
control guidelines are followed.
Rationale
AIIRs lower the risk of cross-contamination among rooms and lower the risk of infection for staff and
patients outside the room when aerosol-generating procedures are performed. AIIRs were effective
in preventing virus spread during the SARS epidemic.2 If an AIIR is not available, a high-efficiency
particulate air (HEPA) filter should be used, especially for patients on high-flow nasal cannula or
noninvasive ventilation. HEPA filters reduce virus transmission in simulations.5
Recommendations
• For health care workers who are providing usual care for nonventilated patients with COVID-19,
the Panel recommends using an N95 respirator (or equivalent or higher-level respirator) or a
surgical mask, in addition to other PPE (i.e., gloves, gown, and eye protection such as a face shield

AR08837
or safety goggles) (AIIa).

• For health care workers who are performing non-aerosol-generating procedures on patients with
COVID-19 who are on closed-circuit mechanical ventilation, the Panel recommends using an N95
respirator (or equivalent or higher-level respirator) in addition to other PPE (i.e., gloves, gown,
and eye protection such as a face shield or safety goggles) because ventilator circuits may become
disrupted unexpectedly (BIII).
Rationale
There is evidence from studies of viral diseases, including SARS, that both surgical masks and N95
respirators reduce the risk of transmission.6 Moreover, surgical masks are probably not inferior to N95
respirators for preventing the transmission of respiratory viral infections; a recent systematic review and
meta-analysis of randomized controlled trials that compared the protective effects of medical masks and
N95 respirators demonstrated that the use of medical masks did not increase the incidence of laboratory-
confirmed viral respiratory infections (including coronavirus infections) or clinical respiratory illness.7
Recommendations
• The Panel recommends that endotracheal intubation in patients with COVID-19 be performed by
health care providers with extensive airway management experience, if possible (AIII).
• The Panel recommends that intubation be performed using video laryngoscopy, if possible (CIIa).
Rationale
Practices that maximize the chances of first-pass success and minimize aerosolization should be used
when intubating patients with suspected or confirmed COVID-19.8,9 Thus, the Panel recommends that
the health care worker with the most experience and skill in airway management be the first to attempt
intubation. The close facial proximity of direct laryngoscopy can expose health care providers to higher
concentrations of viral aerosols. It is also important to avoid having unnecessary staff in the room during
intubation procedures.
References
1. Yam LY, Chen RC, Zhong NS. SARS: ventilatory and intensive care. Respirology. 2003;8 Suppl:S31-35.
2. Twu SJ, Chen TJ, Chen CJ, et al. Control measures for severe acute respiratory syndrome (SARS) in Taiwan.
Emerg Infect Dis. 2003;9(6):718-720. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12781013.
3. Centers for Disease Control and Prevention. The National Personal Protective Technology Laboratory
(NPPTL): respirator trusted-source information. 2020. Available at: https://www.cdc.gov/niosh/npptl/topics/
respirators/disp_part/respsource.html. Accessed September 23, 2020.
4. Milton DK, Fabian MP, Cowling BJ, Grantham ML, McDevitt JJ. Influenza virus aerosols in human exhaled
breath: particle size, culturability, and effect of surgical masks. PLoS Pathog. 2013;9(3):e1003205. Available
5. Qian H, Li Y, Sun H, Nielsen PV, Huang X, Zheng X. Particle removal efficiency of the portable HEPA air
cleaner in a simulated hospital ward. Building Simulation. 2010;3:215-224. Available at:
https://link.springer.com/article/10.1007/s12273-010-0005-4.
6. Offeddu V, Yung CF, Low MSF, Tam CC. Effectiveness of masks and respirators against respiratory infections
in healthcare workers: a systematic review and meta-analysis. Clin Infect Dis. 2017;65(11):1934-1942.
7. Bartoszko JJ, Farooqi MAM, Alhazzani W, Loeb M. Medical masks vs N95 respirators for preventing

AR08838
COVID-19 in healthcare workers: a systematic review and meta-analysis of randomized trials. Influenza Other
Respir Viruses. 2020;14(4):365-373. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32246890.
8. Tran K, Cimon K, Severn M, Pessoa-Silva CL, Conly J. Aerosol generating procedures and risk of
transmission of acute respiratory infections to healthcare workers: a systematic review. PLoS One.
2012;7(4):e35797. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22563403.
9. Lewis SR, Butler AR, Parker J, Cook TM, Schofield-Robinson OJ, Smith AF. Videolaryngoscopy versus direct
laryngoscopy for adult patients requiring tracheal intubation: a Cochrane Systematic Review. Br J Anaesth.

AR08839
Hemodynamics
Last Updated: July 8, 2021
Most of the hemodynamic recommendations below are similar to those previously published in the
Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.
Ultimately, adult patients with COVID-19 who require fluid resuscitation or hemodynamic management
of shock should be treated and managed identically to adult patients with septic shock.1
Recommendation
• For adults with COVID-19 and shock, the COVID-19 Treatment Guidelines Panel (the Panel)
recommends using dynamic parameters, skin temperature, capillary refilling time, and/or lactate
levels over static parameters to assess fluid responsiveness (BIIa).
Rationale
In a systematic review and meta-analysis of 13 randomized clinical trials in intensive care unit (ICU)
patients without COVID-19 (n = 1,652),2 dynamic assessment to guide fluid therapy reduced mortality
(risk ratio 0.59; 95% CI, 0.42–0.83), ICU length of stay (weighted mean difference -1.16 days; 95% CI,
-1.97 to -0.36), and duration of mechanical ventilation (weighted mean difference -2.98 hours; 95% CI,
-5.08 to -0.89). Dynamic parameters used in these trials included stroke volume variation (SVV), pulse
pressure variation (PPV), and stroke volume change with passive leg raise or fluid challenge. Passive leg
raising, followed by PPV and SVV, appears to predict fluid responsiveness with the greatest accuracy.3
The static parameters included components of early goal-directed therapy (e.g., central venous pressure,
mean arterial pressure [MAP]).
Resuscitation of patients with shock who do not have COVID-19 based on serum lactate levels has
been summarized in a systematic review and meta-analysis of seven randomized clinical trials (n =
1,301). Compared with central venous oxygen saturation-guided therapy, early lactate clearance-directed
therapy was associated with a reduction in mortality (relative ratio 0.68; 95% CI, 0.56–0.82), shorter
ICU stay (mean difference -1.64 days; 95% CI, -3.23 to -0.05), and shorter duration of mechanical
ventilation (mean difference -10.22 hours; 95% CI, -15.94 to -4.50).4
Recommendation
• For the acute resuscitation of adults with COVID-19 and shock, the Panel recommends using
buffered/balanced crystalloids over unbalanced crystalloids (BIIa).
Rationale
A pragmatic randomized trial compared the use of balanced and unbalanced crystalloids for intravenous
(IV) fluid administration in critically ill adults without COVID-19 (n = 15,802). The rate of the
composite outcome of death, new renal-replacement therapy, or persistent renal dysfunction was
lower in the balanced crystalloids group than in the unbalanced crystalloids group (OR 0.90; 95% CI,
0.82–0.99; P = 0.04).5 A secondary analysis compared outcomes in a subset of patients with sepsis (n
= 1,641). Compared to treatment with unbalanced crystalloids, treatment with balanced crystalloids
resulted in fewer deaths (aOR 0.74; 95% CI, 0.59–0.93; P = 0.01) and more vasopressor-free and renal
replacement-free days.6 A subsequent meta-analysis of 21 non-COVID-19 randomized controlled trials
(n = 20,213) that included the pragmatic trial cited above compared balanced crystalloids to 0.9% saline
for resuscitation of critically ill adults and children. The trial reported nonsignificant differences between
the treatment groups in hospital mortality (OR 0.91; 95% CI, 0.83–1.01) and acute kidney injury (OR

AR08840
0.92; 95% CI, 0.84–1.00).7
Recommendation
• For the acute resuscitation of adults with COVID-19 and shock, the Panel recommends against
the initial use of albumin for resuscitation (BI).
Rationale
A meta-analysis of 20 non-COVID-19 randomized controlled trials (n = 13,047) that compared the use
of albumin or fresh-frozen plasma to crystalloids in critically ill patients found no difference in all-cause
mortality between the treatment groups.8 In contrast, a meta-analysis of 17 non-COVID-19 randomized
controlled trials (n = 1,977) that compared the use of albumin to crystalloids specifically in patients with
sepsis observed a reduction in mortality among the patients who received albumin (OR 0.82; 95% CI,
0.67–1.0; P = 0.047).9 Given the higher cost of albumin and the lack of a definitive clinical benefit, the
Panel recommends against the routine use of albumin for initial acute resuscitation of patients with
COVID-19 and shock (BI).
Recommendation
• For adults with COVID-19 and shock, the Panel recommends norepinephrine as the first-choice
vasopressor (AI).
Rationale
Norepinephrine increases MAP due to its vasoconstrictive effects, with little change in heart rate
and less increase in stroke volume compared to dopamine. Dopamine increases MAP and cardiac
output, primarily due to an increase in stroke volume and heart rate. Norepinephrine is more potent
than dopamine and may be more effective at reversing hypotension in patients with septic shock.
Dopamine may be particularly useful in patients with compromised systolic function, but it causes more
tachycardia and may be more arrhythmogenic than norepinephrine.10 It may also influence the endocrine
response via the hypothalamic pituitary axis and have immunosuppressive effects.11 A systematic review
and meta-analysis of 11, non-COVID-19 randomized controlled trials that compared vasopressors used
to treat patients with septic shock found that norepinephrine use resulted in lower all-cause mortality
(RR 0.89; 95% CI, 0.81–0.98) and a lower risk of arrhythmias (RR 0.48; 95% CI, 0.40–0.58) than
dopamine use.12 Although the beta-1 activity of dopamine would be useful in patients with myocardial
dysfunction, the greater risk of arrhythmias limits its use.13,14
Recommendation
• For adults with COVID-19 and shock, the Panel recommends titrating vasoactive agents to target a
MAP of 60 to 65 mm Hg, over higher MAP targets (BI).
Rationale
A recent individual patient-data meta-analysis of two, non-COVID-19 randomized controlled trials (n
= 894) comparing higher versus lower blood pressure targets for vasopressor therapy in adult patients
with shock reported no significant difference between the patients in the higher and lower target groups
in 28-day mortality (OR 1.15; 95% CI, 0.87–1.52), 90-day mortality (OR 1.08; 95% CI, 0.84–1.44),
myocardial injury (OR 1.47; 95% CI, 0.64–3.56), or limb ischemia (OR 0.92; 95% CI, 0.36–2.10).15
The risk of arrhythmias was increased in patients allocated to the higher target group (OR 2.50; 95%
CI, 1.35–4.77). Similarly, the recently published “65 Trial,” a randomized clinical trial in patients
without COVID-19 (n = 2,463), reported no significant difference in mortality between patients with

AR08841
vasopressor therapy guided by a MAP target of 60 to 65 mm Hg and those with treatment guided by a
higher, standard of care MAP target (41% vs. 43.8%; RR 0.93; 95% CI, 0.85–1.03).16 With an indication
of improved outcome with lower MAP targets (and no firm indication of harm), the Panel recommends
titrating vasoactive agents to a MAP target of 60 to 65 mm Hg (BI).
Additional Recommendations for Adults With COVID-19 and Shock Based on

General Principles of Critical Care
• The Panel recommends against using hydroxyethyl starches for intravascular volume
replacement in adult patients with COVID-19 and sepsis or septic shock (AI).
• When norepinephrine is available, the Panel recommends against using dopamine for adult
patients with COVID-19 and shock (AI).
• As a second line vasopressor, the Panel recommends adding either vasopressin (up to 0.03 units/
min) (BIIa) or epinephrine (BIIb) to norepinephrine to raise MAP to target or adding vasopressin
(up to 0.03 units/min) (BIIa) to decrease norepinephrine dosage.
• The Panel recommends against using low-dose dopamine for renal protection (AI).
• The Panel recommends using dobutamine in adult patients with COVID-19 who show evidence
of cardiac dysfunction and persistent hypoperfusion despite adequate fluid loading and the use of
vasopressor agents (BIII).
• The Panel recommends that all adult patients with COVID-19 who require vasopressors have an
arterial catheter placed as soon as practical, if resources are available (BIII).
• For adult patients with refractory septic shock who have completed a course of corticosteroids to
treat COVID-19, the Panel recommends using low-dose corticosteroid therapy (“shock-reversal”)
over no corticosteroid therapy (BIIa).
• A typical corticosteroid regimen in septic shock is hydrocortisone 200 mg IV per day
administered either as an infusion or in intermittent doses. The duration of hydrocortisone
therapy is usually a clinical decision.
• Adult patients who are receiving corticosteroids for COVID-19 are receiving sufficient
replacement therapy such that they do not require additional hydrocortisone.
References
1. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for
management of sepsis and septic shock: 2016. Crit Care Med. 2017;45(3):486-552. Available at:
2. Bednarczyk JM, Fridfinnson JA, Kumar A, et al. Incorporating dynamic assessment of fluid responsiveness
into goal-directed therapy: a systematic review and meta-analysis. Crit Care Med. 2017;45(9):1538-1545.
3. Bentzer P, Griesdale DE, Boyd J, MacLean K, Sirounis D, Ayas NT. Will this hemodynamically unstable
patient respond to a bolus of intravenous fluids? JAMA. 2016;316(12):1298-1309. Available at:
4. Pan J, Peng M, Liao C, Hu X, Wang A, Li X. Relative efficacy and safety of early lactate clearance-guided
therapy resuscitation in patients with sepsis: a meta-analysis. Medicine (Baltimore). 2019;98(8):e14453.
5. Semler MW, Self WH, Wanderer JP, et al. Balanced crystalloids versus saline in critically ill adults. N Engl J
6. Brown RM, Wang L, Coston TD, et al. Balanced crystalloids versus saline in sepsis. A secondary analysis of

AR08842
the SMART clinical trial. Am J Respir Crit Care Med. 2019;200(12):1487-1495. Available at:
7. Antequera Martin AM, Barea Mendoza JA, Muriel A, et al. Buffered solutions versus 0.9% saline for
resuscitation in critically ill adults and children. Cochrane Database Syst Rev. 2019;7:CD012247. Available
8. Lewis SR, Pritchard MW, Evans DJ, et al. Colloids versus crystalloids for fluid resuscitation in critically ill
people. Cochrane Database Syst Rev. 2018;8:CD000567. Available at:
9. Delaney AP, Dan A, McCaffrey J, Finfer S. The role of albumin as a resuscitation fluid for patients with
sepsis: a systematic review and meta-analysis. Crit Care Med. 2011;39(2):386-391. Available at:
10. Regnier B, Rapin M, Gory G, Lemaire F, Teisseire B, Harari A. Haemodynamic effects of dopamine in septic
shock. Intensive Care Med. 1977;3(2):47-53. Available at: https://www.ncbi.nlm.nih.gov/pubmed/893773.
11. Beck G, Brinkkoetter P, Hanusch C, et al. Clinical review: immunomodulatory effects of dopamine in general
inflammation. Crit Care. 2004;8(6):485-491. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15566620.
12. Avni T, Lador A, Lev S, Leibovici L, Paul M, Grossman A. Vasopressors for the treatment of septic shock:
systematic review and meta-analysis. PLoS One. 2015;10(8):e0129305. Available at:
13. Regnier B, Safran D, Carlet J, Teisseire B. Comparative haemodynamic effects of dopamine and dobutamine
in septic shock. Intensive Care Med. 1979;5(3):115-120. Available at:
14. De Backer D, Creteur J, Silva E, Vincent JL. Effects of dopamine, norepinephrine, and epinephrine on the
splanchnic circulation in septic shock: which is best? Crit Care Med. 2003;31(6):1659-1667. Available at:
15. Lamontagne F, Day AG, Meade MO, et al. Pooled analysis of higher versus lower blood pressure targets
for vasopressor therapy septic and vasodilatory shock. Intensive Care Med. 2018;44(1):12-21. Available at:
16. Lamontagne F, Richards-Belle A, Thomas K, et al. Effect of reduced exposure to vasopressors on 90-day
mortality in older critically ill patients with vasodilatory hypotension: a randomized clinical trial. JAMA.

AR08843
Oxygenation and Ventilation

The COVID-19 Treatment Guidelines Panel’s (the Panel) recommendations in this section were informed
by the recommendations from the Surviving Sepsis Campaign Guidelines for managing adult sepsis,
pediatric sepsis, and COVID-19.
Severe illness in people with COVID-19 typically occurs approximately 1 week after the onset of
symptoms. The most common symptom is dyspnea, which is often accompanied by hypoxemia. Patients
with severe disease typically require supplemental oxygen and should be monitored closely for worsening
respiratory status, because some patients may progress to acute respiratory distress syndrome (ARDS).
Goal of Oxygenation
The optimal oxygen saturation (SpO2) in adults with COVID-19 who are receiving supplemental oxygen
is unknown. However, a target SpO2 of 92% to 96% seems logical, considering that indirect evidence
from patients without COVID-19 suggests that an SpO2 of <92% or >96% may be harmful.
The potential harm of maintaining an SpO2 of <92% was demonstrated during a trial that randomly
assigned patients with ARDS who did not have COVID-19 to either a conservative oxygen strategy (target
SpO2 of 88% to 92%) or a liberal oxygen strategy (target SpO2 of ≥96%). The trial was stopped early due
to futility after enrolling 205 patients, but increased mortality was observed at Day 90 in the conservative
oxygen strategy arm (between-group risk difference of 14%; 95% CI, 0.7% to 27%) and a trend toward
increased mortality was observed at Day 28 (between-group risk difference of 8%; 95% CI, -5% to 21%).1
The results of a meta-analysis of 25 randomized trials that involved patients without COVID-19
demonstrate the potential harm of maintaining an SpO2 of >96%. This study found that a liberal oxygen
strategy (median SpO2 of 96%) was associated with an increased risk of in-hospital mortality when
compared to a more conservative SpO2 strategy (relative risk 1.21; 95% CI, 1.03–1.43).2
Acute Hypoxemic Respiratory Failure

In adults with COVID-19 and acute hypoxemic respiratory failure, conventional oxygen therapy may
be insufficient to meet the oxygen needs of the patient. Options for providing enhanced respiratory
support include high-flow nasal canula (HFNC) oxygen, noninvasive ventilation (NIV), intubation and
mechanical ventilation, or extracorporeal membrane oxygenation. In this section, mechanical ventilation
refers to the delivery of positive pressure ventilation through an endotracheal or tracheostomy tube. NIV
refers to the delivery of positive pressure ventilation through a noninvasive interface, such as a face mask
or nasal mask.
Nonmechanically Ventilated Adults With Acute Hypoxemic Respiratory Failure

High-Flow Nasal Cannula Oxygen and Noninvasive Ventilation
Recommendations
• For adults with COVID-19 and acute hypoxemic respiratory failure despite conventional oxygen
therapy, the Panel recommends HFNC oxygen over NIV (BIIa).
• For adults with COVID-19 and acute hypoxemic respiratory failure who do not have an indication
for endotracheal intubation and for whom HFNC oxygen is not available, the Panel recommends
performing a closely monitored trial of NIV (BIIa).

AR08844
Rationale
HFNC oxygen is preferred over NIV in patients with acute hypoxemic respiratory failure; this guidance
is based on data from an unblinded clinical trial in patients without COVID-19 who had acute hypoxemic
respiratory failure. Study participants were randomized to receive HFNC oxygen, conventional oxygen
therapy, or NIV. The patients in the HFNC oxygen arm had more ventilator-free days (mean of 24 days)
than those in the conventional oxygen therapy arm (mean of 22 days) or NIV arm (mean of 19 days; P =
0.02). In addition, 90-day mortality was lower in the HFNC oxygen arm than in either the conventional
oxygen therapy arm (HR 2.01; 95% CI, 1.01–3.99) or the NIV arm (HR 2.50; 95% CI, 1.31–4.78).3 In the
subgroup of more severely hypoxemic patients (those with a ratio of arterial partial pressure of oxygen
to fraction of inspired oxygen [PaO2/FiO2] ≤200 mm Hg), the intubation rate was lower for the HFNC
oxygen arm than for the conventional oxygen therapy or NIV arms (HR 2.07 and 2.57, respectively).
The trial’s findings were corroborated by a meta-analysis of 8 trials with 1,084 participants that was
conducted to assess the effectiveness of oxygenation strategies prior to intubation. Compared to NIV,
HFNC oxygen reduced the rate of intubation (OR 0.48; 95% CI, 0.31–0.73) and intensive care unit
(ICU) mortality (OR 0.36; 95% CI, 0.20–0.63).4
NIV is an aerosol-generating procedure, and it may increase the risk of nosocomial transmission
of SARS-CoV-2.5,6 It remains unclear whether the use of HFNC oxygen results in a lower risk of
nosocomial SARS-CoV-2 transmission than NIV.
Awake Prone Positioning in Nonmechanically Ventilated Adults

Recommendations
• For patients with persistent hypoxemia who require HFNC oxygen and for whom endotracheal
intubation is not indicated, the Panel recommends a trial of awake prone positioning (BIIa).
• The Panel recommends against using awake prone positioning as a rescue therapy for refractory
hypoxemia to avoid intubation in patients who otherwise meet the indications for intubation and
mechanical ventilation (AIII).
• Patients who can adjust their position independently and tolerate lying prone can be considered for
awake prone positioning.
• Awake prone positioning is acceptable and feasible for pregnant patients and can be performed in
the left lateral decubitus position or the fully prone position.7
• Some patients do not tolerate awake prone positioning. Failure rates as high as 63% have been
reported in the literature.8
• Awake proning should not be used as a substitute for intubation and mechanical ventilation in
patients with refractory hypoxemia who otherwise meet the indications for these interventions.
• Awake proning may be infeasible or impractical in patients with:
• Spinal instability
• Facial or pelvic fractures
• An open chest or unstable chest wall
• Awake prone positioning should be used with caution in patients with confusion or delirium,
hemodynamic instability, an inability to independently change position, recent abdominal surgery,
or recent nausea or vomiting.

AR08845
Rationale
Awake proning, or having a nonintubated patient lie on their stomach, may improve oxygenation and
prevent the patient from progressing to requiring intubation and mechanical ventilation. Although prone
positioning has been shown to improve oxygenation and outcomes in patients with moderate to severe
ARDS who are receiving mechanical ventilation,9,10 there is less evidence regarding the benefit of prone
positioning in awake patients who require supplemental oxygen without mechanical ventilation. Several
case series of patients with COVID-19 who required oxygen or NIV have similarly reported that awake
prone positioning improves oxygenation,11-14 and some series have also reported low intubation rates
after proning.11,13
The Awake Prone Positioning Meta-Trial Group conducted the largest trial to date on awake prone
positioning. This was a prospective, multinational meta-trial of 6 open-label, randomized controlled
superiority trials that compared awake prone positioning to standard care in adults who required HFNC
oxygen for acute hypoxemic respiratory failure due to COVID-19.
The study enrolled 1,126 patients between April 2, 2020, and January 26, 2021; the intention-to-treat
analysis included 1,121 patients. Two hundred twenty-three of 564 patients (40%) who underwent
awake prone positioning met the primary composite outcome of intubation or death within 28 days of
enrollment; among the 557 patients who received standard care, 257 (46%) met the primary endpoint
(relative risk 0.86; 95% CI, 0.75−0.98). Regarding the individual components of the composite endpoint,
the incidence of intubation at Day 28 was lower in the awake prone positioning arm than in the standard
care arm (HR for intubation 0.75; 95% CI, 0.62−0.91). There was no difference in 28-day mortality
between the awake prone positioning arm and the standard care arm (HR for mortality 0.87; 95% CI,
0.68−1.11). During the first 14 days of the study, the median daily duration of awake prone positioning
was 5.0 hours (IQR 1.6–8.8 hours). However, the median daily duration varied from 1.6 hours to 8.6
hours across the individual trials. Longer daily durations for awake prone positioning occurred more
frequently in patients who experienced treatment success by Day 28. This study evaluated the incidences
of certain adverse events, including skin breakdown, vomiting, and central or arterial line dislodgement.
These events occurred infrequently during the study, and the incidences for these events were similar
between the arms. No cardiac arrests occurred during awake prone positioning.15
Though the optimal daily duration of awake prone positioning is unclear, only 25 of 151 patients
(17%) who had an average of ≥8 hours of awake prone positioning per day met the primary endpoint
of intubation or death in the Awake Prone Positioning Meta-Trial, compared with 198 of 413 patients
(48%) who remained in awake prone positioning for <8 hours per day. This is consistent with past
clinical trials of prone positioning in mechanically ventilated patients with ARDS, during which clinical
benefits were observed with longer durations of prone positioning.9,10
Intubation for Mechanical Ventilation

Recommendation
• If intubation becomes necessary, the procedure should be performed by an experienced
practitioner in a controlled setting due to the enhanced risk of exposing health care practitioners to
SARS-CoV-2 during intubation (AIII).
Rationale
It is essential to closely monitor hypoxemic patients with COVID-19 for signs of respiratory
decompensation. To ensure the safety of both patients and health care workers, intubation should be
performed in a controlled setting by an experienced practitioner.

AR08846
Mechanically Ventilated Adults

Recommendations
For mechanically ventilated adults with COVID-19 and ARDS:
• The Panel recommends using low tidal volume (VT) ventilation (VT 4–8 mL/kg of predicted body
weight) over higher VT ventilation (VT >8 mL/kg) (AI).
• The Panel recommends targeting plateau pressures of <30 cm H2O (AIIa).
• The Panel recommends using a conservative fluid strategy over a liberal fluid strategy (BIIa).
• The Panel recommends against the routine use of inhaled nitric oxide (AIIa).
Rationale
There is no evidence that ventilator management of patients with hypoxemic respiratory failure due to
COVID-19 should differ from ventilator management of patients with hypoxemic respiratory failure due
to other causes.
Positive End-Expiratory Pressure and Prone Positioning in Mechanically Ventilated Adults

With Moderate to Severe Acute Respiratory Distress Syndrome
Recommendations
For mechanically ventilated adults with COVID-19 and moderate to severe ARDS:
• The Panel recommends using a higher positive end-expiratory pressure (PEEP) strategy over a
lower PEEP strategy (BIIa).
• For mechanically ventilated adults with COVID-19 and refractory hypoxemia despite optimized
ventilation, the Panel recommends prone ventilation for 12 to 16 hours per day over no prone
ventilation (BIIa).
Rationale
PEEP is beneficial in patients with ARDS because it prevents alveolar collapse, improves oxygenation,
and minimizes atelectotrauma, a source of ventilator-induced lung injury. A meta-analysis of individual
patient data from the 3 largest trials that compared lower and higher levels of PEEP in patients without
COVID-19 found lower rates of ICU mortality and in-hospital mortality with higher levels of PEEP in
those with moderate (PaO2/FiO2 100–200 mm Hg) and severe ARDS (PaO2/FiO2 <100 mm Hg).16
Although there is no clear standard as to what constitutes a high level of PEEP, a conventional threshold
is >10 cm H2O.17 Recent reports have suggested that, in contrast to patients with non-COVID-19 causes
of ARDS, some patients with moderate or severe ARDS due to COVID-19 have normal static lung
compliance. In these patients, higher PEEP levels may cause harm by compromising hemodynamics
and cardiovascular performance.18,19 Other studies reported that patients with moderate to severe ARDS
due to COVID-19 had low lung compliance, similar to the lung compliance seen in patients with
conventional ARDS.20-23 These seemingly contradictory observations suggest that COVID-19 patients
with ARDS are a heterogeneous population, and assessment for responsiveness to higher levels of PEEP
should be individualized based on oxygenation and lung compliance. Clinicians should monitor patients
for known side effects of higher levels of PEEP, such as barotrauma and hypotension.
In the prepandemic PROSEVA study of patients with moderate or severe early ARDS (PaO2/FiO2 <150
mm Hg) who required mechanical ventilation, the patients who were randomized to undergo prone
positioning for ≥16 hours per day had improved survival compared to those who remained in the supine

AR08847
position throughout their course of mechanical ventilation.9 A meta-analysis evaluated the results of the
PROSEVA study and 7 other randomized controlled trials that investigated the use of prone positioning
in people with ARDS. The subgroup analysis revealed that patients who remained prone for ≥12 hours
per day had a lower mortality rate than those who remained in the supine position (risk ratio 0.74;
95% CI, 0.56–0.99). Prone positioning improved oxygenation in all of the trials; patients in the prone
positioning arms had higher PaO2/FiO2 on Day 4 than those in the supine positioning arms (mean
difference of 23.5 mm Hg; 95% CI, 12.4–34.5).24
The use of prone positioning may be associated with serious adverse events, including unplanned
extubation or central catheter removal; however, the meta-analysis found no differences in the
frequencies of these events between the prone positioning and supine positioning arms. The use of prone
positioning was associated with an increase in the frequency of pressure sores (risk ratio 1.22; 95% CI,
1.06–1.41) and endotracheal tube obstruction (risk ratio 1.76; 95% CI, 1.24–2.50) in the 3 studies that
evaluated these complications.
Neuromuscular Blockade in Mechanically Ventilated Adults With Moderate to Severe Acute

Respiratory Distress Syndrome
Recommendations
For mechanically ventilated adults with COVID-19 and moderate to severe ARDS:
• The Panel recommends using, as needed, intermittent boluses of neuromuscular blocking agents
(NMBA) or a continuous NMBA infusion to facilitate protective lung ventilation (BIIa).
• In the event of persistent patient-ventilator dyssynchrony, or in cases where a patient requires
ongoing deep sedation, prone ventilation, or persistently high plateau pressures, the Panel
recommends using a continuous NMBA infusion for up to 48 hours, as long as the patient’s
anxiety and pain can be adequately monitored and controlled (BIII).
Rationale
The recommendation for intermittent boluses of NMBA or a continuous infusion of NMBA to facilitate
lung protection may require a health care provider to enter the patient’s room frequently for close
clinical monitoring. Therefore, in some situations, the risks of SARS-CoV-2 exposure and the need
to use personal protective equipment for each entry into a patient’s room may outweigh the benefit of
NMBA treatment.
Rescue Therapies for Mechanically Ventilated Adults With Acute Respiratory Distress
Syndrome
Recommendations
For mechanically ventilated adults with COVID-19, severe ARDS, and hypoxemia despite optimized
ventilation and other rescue strategies:
• The Panel recommends using recruitment maneuvers rather than not using recruitment maneuvers
(CIIa).
• If recruitment maneuvers are used, the Panel recommends against using staircase (incremental
PEEP) recruitment maneuvers (AIIa).
• The Panel recommends using an inhaled pulmonary vasodilator as a rescue therapy; if no rapid
improvement in oxygenation is observed, the treatment should be tapered off (CIII).

AR08848
Rationale
A recruitment maneuver refers to a temporary increase in airway pressure during mechanical
ventilation to open collapsed alveoli and improve oxygenation. No studies have assessed the effect
of recruitment maneuvers on oxygenation in severe ARDS due to COVID-19. However, a systematic
review and meta-analysis of 6 trials of recruitment maneuvers in patients with ARDS who did not have
COVID-19 found that recruitment maneuvers reduced mortality, improved oxygenation 24 hours after
the maneuver, and decreased the need for rescue therapy.25 Because recruitment maneuvers can cause
barotrauma or hypotension, patients should be closely monitored during recruitment maneuvers. If a
patient decompensates during recruitment maneuvers, the maneuver should be stopped immediately.
The importance of properly performing recruitment maneuvers was illustrated by an analysis of 8
randomized controlled trials in patients without COVID-19 (n = 2,544) that found that recruitment
maneuvers did not reduce hospital mortality (risk ratio 0.90; 95% CI, 0.78–1.04). A subgroup analysis
found that traditional recruitment maneuvers significantly reduced hospital mortality (risk ratio 0.85;
95% CI, 0.75–0.97), whereas incremental PEEP titration recruitment maneuvers increased mortality
(risk ratio 1.06; 95% CI, 0.97–1.17).26
Although there are no published studies of inhaled nitric oxide in patients with COVID-19, a Cochrane
review of 13 trials that evaluated inhaled nitric oxide use in patients with ARDS found no mortality
benefit.27 Because the review showed a transient benefit for oxygenation, it is reasonable to attempt
using inhaled nitric oxide as a rescue therapy in patients with COVID-19 and severe ARDS after other
options have failed. However, if the use of nitric oxide does not improve a patient’s oxygenation, it
should be tapered quickly to avoid rebound pulmonary vasoconstriction, which may occur when nitric
oxide is discontinued after prolonged use.
References
1. Barrot L, Asfar P, Mauny F, et al. Liberal or conservative oxygen therapy for acute respiratory distress
syndrome. N Engl J Med. 2020;382(11):999-1008. Available at:
2. Chu DK, Kim LH, Young PJ, et al. Mortality and morbidity in acutely ill adults treated with liberal versus
conservative oxygen therapy (IOTA): a systematic review and meta-analysis. Lancet. 2018;391(10131):1693-
3. Frat JP, Thille AW, Mercat A, et al. High-flow oxygen through nasal cannula in acute hypoxemic respiratory
failure. N Engl J Med. 2015;372(23):2185-2196. Available at:
4. Ni YN, Luo J, Yu H, Liu D, Liang BM, Liang ZA. The effect of high-flow nasal cannula in reducing the
mortality and the rate of endotracheal intubation when used before mechanical ventilation compared with
conventional oxygen therapy and noninvasive positive pressure ventilation. A systematic review and meta-
analysis. Am J Emerg Med. 2018;36(2):226-233. Available at:
5. Tran K, Cimon K, Severn M, Pessoa-Silva CL, Conly J. Aerosol generating procedures and risk of
transmission of acute respiratory infections to healthcare workers: a systematic review. PLoS One.
6. Yu IT, Xie ZH, Tsoi KK, et al. Why did outbreaks of severe acute respiratory syndrome occur in some hospital
wards but not in others? Clin Infect Dis. 2007;44(8):1017-1025. Available at:
7. Society for Maternal-Fetal Medicine. Management considerations for pregnant patients with COVID-19.

AR08849
8. Hallifax RJ, Porter BM, Elder PJ, et al. Successful awake proning is associated with improved clinical
outcomes in patients with COVID-19: single-centre high-dependency unit experience. BMJ Open Respir Res.
2020;7(1). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32928787.
9. Guerin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory distress syndrome. N
10. Fan E, Del Sorbo L, Goligher EC, et al. An official American Thoracic Society/European Society of Intensive
Care Medicine/Society of Critical Care Medicine Clinical Practice guideline: mechanical ventilation in adult
patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 2017;195(9):1253-1263.
11. Sun Q, Qiu H, Huang M, Yang Y. Lower mortality of COVID-19 by early recognition and intervention:
experience from Jiangsu Province. Ann Intensive Care. 2020;10(1):33. Available at:
12. Elharrar X, Trigui Y, Dols AM, et al. Use of prone positioning in nonintubated patients with COVID-19 and
hypoxemic acute respiratory failure. JAMA. 2020;323(22):2336-2338. Available at:
13. Sartini C, Tresoldi M, Scarpellini P, et al. Respiratory parameters in patients with COVID-19 after using
noninvasive ventilation in the prone position outside the intensive care unit. JAMA. 2020;323(22):2338-2340.
14. Caputo ND, Strayer RJ, Levitan R. Early self-proning in awake, non-intubated patients in the emergency
department: a single ED’s experience during the COVID-19 pandemic. Acad Emerg Med. 2020;27(5):375-
15. Ehrmann S, Li J, Ibarra-Estrada M, et al. Awake prone positioning for COVID-19 acute hypoxaemic
respiratory failure: a randomised, controlled, multinational, open-label meta-trial. Lancet Respir Med. 2021;
Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34425070.
16. Briel M, Meade M, Mercat A, et al. Higher vs lower positive end-expiratory pressure in patients with
acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA.
17. Alhazzani W, Moller MH, Arabi YM, et al. Surviving Sepsis Campaign: guidelines on the management
of critically ill adults with coronavirus disease 2019 (COVID-19). Crit Care Med. 2020;48(6):e440-e469.
18. Marini JJ, Gattinoni L. Management of COVID-19 respiratory distress. JAMA. 2020;323(22):2329-2330.
19. Tsolaki V, Siempos I, Magira E, Kokkoris S, Zakynthinos GE, Zakynthinos S. PEEP levels in COVID-19
pneumonia. Crit Care. 2020;24(1):303. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32505186.
20. Bhatraju PK, Ghassemieh BJ, Nichols M, et al. COVID-19 in critically ill patients in the Seattle region—case
series. N Engl J Med. 2020;382(21):2012-2022. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32227758.
21. Cummings MJ, Baldwin MR, Abrams D, et al. Epidemiology, clinical course, and outcomes of critically ill
adults with COVID-19 in New York City: a prospective cohort study. Lancet. 2020;395(10239):1763-1770.
22. Ziehr DR, Alladina J, Petri CR, et al. Respiratory pathophysiology of mechanically ventilated patients with
COVID-19: a cohort study. Am J Respir Crit Care Med. 2020;201(12):1560-1564. Available at:
23. Schenck EJ, Hoffman K, Goyal P, et al. Respiratory mechanics and gas exchange in COVID-19-associated
respiratory failure. Ann Am Thorac Soc. 2020;17(9):1158-1161. Available at:
24. Munshi L, Del Sorbo L, Adhikari NKJ, et al. Prone position for acute respiratory distress syndrome. A
systematic review and meta-analysis. Ann Am Thorac Soc. 2017;14(Supplement_4):S280-S288. Available at:

AR08850
25. Goligher EC, Hodgson CL, Adhikari NKJ, et al. Lung recruitment maneuvers for adult patients with
acute respiratory distress syndrome. a systematic review and meta-analysis. Ann Am Thorac Soc.
2017;14(Supplement_4):S304-S311. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29043837.
26. Alhazzani W, Moller MH, Arabi YM, et al. Surviving Sepsis Campaign: guidelines on the management of
critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med. 2020;46(5):854-887.
27. Gebistorf F, Karam O, Wetterslev J, Afshari A. Inhaled nitric oxide for acute respiratory distress syndrome
(ARDS) in children and adults. Cochrane Database Syst Rev. 2016(6):CD002787. Available at:

AR08851
Acute Kidney Injury and Renal Replacement Therapy

Recommendations
• For critically ill adults with COVID-19 who have acute kidney injury (AKI) and who develop
indications for renal replacement therapy (RRT), the COVID-19 Treatment Guidelines Panel (the
Panel) recommends continuous renal replacement therapy (CRRT), if available (BIII).
• If CRRT is not available or not possible due to limited resources, the Panel recommends prolonged
intermittent renal replacement therapy (PIRRT) rather than intermittent hemodialysis (IHD)
(BIII).
Rationale
AKI that requires RRT occurs in approximately 22% of patients with COVID-19 who are admitted to the
intensive care unit.1 Evidence pertaining to RRT in patients with COVID-19 is scarce. Until additional
evidence is available, the Panel suggests using the same indications for RRT in patients with COVID-19
as those used for other critically ill patients.2
RRT modalities have not been compared in COVID-19 patients; the Panel’s recommendations are
motivated by the desire to minimize the risk of viral transmission to health care workers. The Panel
considers CRRT to be the preferred RRT modality. CRRT is preferable to PIRRT because medication
dosing for CRRT is more easily optimized and CRRT does not require nursing staff to enter the patient’s
room to begin and end dialysis sessions. CRRT and PIRRT are both preferable to IHD because neither
requires a dedicated hemodialysis nurse.3 Peritoneal dialysis has also been used during surge situations
in patients with COVID-19.
In situations where there may be insufficient CRRT machines or equipment to meet demand, the Panel
advocates performing PIRRT instead of CRRT, and then using the machine for another patient after
appropriate cleaning.
References
1. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, and outcomes among
5,700 patients hospitalized with COVID-19 in the New York City area. JAMA. 2020. Available at:
2. American Society of Nephrology. Recommendations on the care of hospitalized patients with COVID-19 and
kidney failure requiring renal replacement therapy. 2020. Available at: https://www.asn-online.org/g/blast/
files/AKI_COVID-19_Recommendations_Document_03.21.2020.pdf. Accessed November 20, 2020.
3. Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19): considerations for
providing hemodialysis to patients with suspected or confirmed COVID-19 in acute care settings. 2020.
Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/dialysis/dialysis-in-acute-care.html. Accessed
November 19, 2020.

AR08852
Pharmacologic Interventions
Therapeutic Management of Adults With COVID-19

See Therapeutic Management of Hospitalized Adults With COVID-19 for the COVID-19 Treatment
Guidelines Panel’s (the Panel) recommendations on when to use the following drugs alone or in
combination: baricitinib, dexamethasone, remdesivir, and tocilizumab.
Immune-Based Therapy
See the Immunomodulators sections for additional recommendations regarding the use of
immunomodulators not listed above.
Adjunctive Therapy
Recommendations regarding adjunctive therapy in the critical care setting, including antithrombotic
therapy and vitamin C, can be found in Antithrombotic Therapy in Patients With COVID-19 and in the
Supplements sections.
Empiric Broad-Spectrum Antimicrobial Therapy

Recommendations
• In patients with severe or critical COVID-19, there is insufficient evidence for the Panel to
recommend either for or against empiric broad-spectrum antimicrobial therapy in the absence of
another indication.
• If antimicrobials are initiated, the Panel recommends that their use should be reassessed daily to
minimize the adverse consequences of unnecessary antimicrobial therapy (AIII).
Rationale
At this time, there are no reliable estimates of the incidence or prevalence of copathogens with
SARS-CoV-2.
Some experts routinely administer broad-spectrum antibiotics as empiric therapy for bacterial
pneumonia to all patients with COVID-19 and moderate or severe hypoxemia. Other experts administer
antibiotics only for specific situations, such as the presence of a lobar infiltrate on a chest X-ray,
leukocytosis, an elevated serum lactate level, microbiologic data, or shock.
Gram stain, culture, or other testing of respiratory specimens is often not available due to concerns about
aerosolization of SARS-CoV-2 during diagnostic procedures or when processing specimens.
There are no clinical trials that have evaluated the use of empiric antimicrobial agents in patients with
COVID-19 or other severe coronavirus infections.

AR08853
Extracorporeal Membrane Oxygenation

Recommendation
• There is insufficient evidence to recommend either for or against the use of extracorporeal
membrane oxygenation (ECMO) in adults with COVID-19 and refractory hypoxemia.
Rationale
ECMO has been used as a short-term rescue therapy in patients with acute respiratory distress syndrome
(ARDS) caused by COVID-19 and refractory hypoxemia. However, there is no conclusive evidence
that ECMO is responsible for better clinical outcomes regardless of the cause of hypoxemic respiratory
failure.1-4
The clinical outcomes for patients with ARDS who are treated with ECMO are variable and depend
on multiple factors, including the etiology of hypoxemic respiratory failure, the severity of pulmonary
and extrapulmonary illness, the presence of comorbidities, and the ECMO experience of the individual
center.5-7 A recent case series of 83 COVID-19 patients in Paris reported a 60-day mortality of 31%
for patients on ECMO.8 This mortality was similar to the mortality observed in a 2018 study of non-
COVID-19 patients with ARDS who were treated with ECMO during the ECMO to Rescue Lung Injury
in Severe ARDS (EOLIA) trial; that study reported a mortality of 35% at Day 60.3
The Extracorporeal Life Support Organization (ELSO) Registry provides the largest multicenter
outcome dataset of patients with confirmed COVID-19 who received ECMO support and whose data
were voluntarily submitted. A recent cohort study evaluated ELSO Registry data for 1,035 COVID-19
patients who initiated ECMO between January 16 and May 1, 2020, at 213 hospitals in 36 countries.
This study reported an estimated cumulative in-hospital mortality of 37.4% in these patients 90 days
after they initiated ECMO (95% CI; 34.4% to 40.4%).9 Without a controlled trial that evaluates the use
of ECMO in patients with COVID-19 and hypoxemic respiratory failure (e.g., ARDS), the benefits of
ECMO cannot be clearly defined for this patient population.
Ideally, clinicians who are interested in using ECMO should try to enter their patients into clinical trials
or clinical registries so that more informative data can be obtained. The following resources provide
more information on the use of ECMO in patients with COVID-19:
• The ELSO ECMO in COVID-19 website
• A list of clinical trials that are evaluating ECMO in patients with COVID-19 on ClinicalTrials.gov
References
1. Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of conventional ventilatory
support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a
multicentre randomised controlled trial. Lancet. 2009;374(9698):1351-1363. Available at:
2. Pham T, Combes A, Roze H, et al. Extracorporeal membrane oxygenation for pandemic influenza A(H1N1)-
induced acute respiratory distress syndrome: a cohort study and propensity-matched analysis. Am J Respir Crit
Care Med. 2013;187(3):276-285. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23155145.
3. Combes A, Hajage D, Capellier G, et al. Extracorporeal membrane oxygenation for severe acute respiratory
distress syndrome. N Engl J Med. 2018;378(21):1965-1975. Available at:

AR08854
4. Munshi L, Walkey A, Goligher E, Pham T, Uleryk EM, Fan E. Venovenous extracorporeal membrane
oxygenation for acute respiratory distress syndrome: a systematic review and meta-analysis. Lancet Respir
5. Bullen EC, Teijeiro-Paradis R, Fan E. How I select which patients with ARDS should be treated with
venovenous extracorporeal membrane oxygenation. Chest. 2020;158(3):1036-1045. Available at:
6. Henry BM, Lippi G. Poor survival with extracorporeal membrane oxygenation in acute respiratory distress
syndrome (ARDS) due to coronavirus disease 2019 (COVID-19): Pooled analysis of early reports. J Crit
Care. 2020;58:27-28. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32279018.
7. Mustafa AK, Alexander PJ, Joshi DJ, et al. Extracorporeal membrane oxygenation for patients with
COVID-19 in severe respiratory failure. JAMA Surg. 2020;Published online ahead of print. Available at:
8. Schmidt M, Hajage D, Lebreton G, et al. Extracorporeal membrane oxygenation for severe acute respiratory
distress syndrome associated with COVID-19: a retrospective cohort study. Lancet Respir Med. 2020.
9. Barbaro RP, MacLaren G, Boonstra PS, et al. Extracorporeal membrane oxygenation support in
COVID-19: an international cohort study of the Extracorporeal Life Support Organization registry. Lancet.

AR08855
Antiviral Drugs That Are Approved, Authorized, or Under

Evaluation for the Treatment of COVID-19
Remdesivir is the only drug that is approved by the Food and Drug Administration (FDA) for the treatment of
COVID-19. Ritonavir-boosted nirmatrelvir (Paxlovid), molnupiravir, and certain anti-SARS-CoV-2 monoclonal antibodies
(mAbs) have received Emergency Use Authorizations from the FDA for the treatment of COVID-19.
This section focuses on the COVID-19 Treatment Guidelines Panel’s (the Panel) recommendations for using small-
molecule antiviral drugs to treat COVID-19. These recommendations are based on the available data; for more
information, see Table 2f. For recommendations and information regarding the use of anti-SARS-CoV-2 mAbs, see Anti-
SARS-CoV-2 Monoclonal Antibodies and Table 3c.
Recommendations for Treating Nonhospitalized Patients
• The Panel recommends the use of the following anti-SARS-CoV-2 therapies as preferred treatments for COVID-19.
These drugs are listed in order of preference:
• Ritonavir-boosted nirmatrelvir (Paxlovid) (AIIa)
• Remdesivir (BIIa)
• The Panel recommends the use of the following anti-SARS-CoV-2 therapies as alternative treatments for COVID-19
ONLY when neither of the preferred therapies are available, feasible to use, or clinically appropriate. These drugs are
listed in alphabetical order:
• Bebtelovimab (CIII)
• Molnupiravir (CIIa)
• See Therapeutic Management of Nonhospitalized Adults With COVID-19 for detailed recommendations.
Recommendations for Treating Hospitalized Patients
• See Therapeutic Management of Hospitalized Adults With COVID-19 for the Panel’s recommendations on using
remdesivir with or without immunomodulators in certain hospitalized patients.
Antiviral Drugs That the Panel Recommends Against
• The Panel recommends against the use of the following drugs for the treatment of COVID-19, except in a clinical
trial:
• Interferons for nonhospitalized patients (AIIa)
• Interferon alfa or lambda for hospitalized patients (AIIa)
• Ivermectin (AIIa)
• Nitazoxanide (BIIa)
• The Panel recommends against the use of the following drugs for the treatment of COVID-19:
• Chloroquine or hydroxychloroquine and/or azithromycin for hospitalized (AI) and nonhospitalized patients (AIIa)
• Lopinavir/ritonavir and other HIV protease inhibitors for hospitalized (AI) and nonhospitalized patients (AIII)
• Systemic interferon beta for hospitalized patients (AI)
Rating of Recommendations: A = Strong; B = Moderate; C = Weak 
Antiviral Therapy
Because SARS-CoV-2 replication leads to many of the clinical manifestations of COVID-19, antiviral
therapies are being investigated for the treatment of COVID-19. These drugs prevent viral replication

AR08856
through various mechanisms, including blocking SARS-CoV-2 entry, inhibiting the activity of
SARS-CoV-2 3-chymotrypsin-like protease (3CLpro) and RNA-dependent RNA polymerase (RdRp),
and causing lethal viral mutagenesis.1-3 Because viral replication may be particularly active early in the
course of COVID-19, antiviral therapy may have the greatest impact before the illness progresses to the
hyperinflammatory state that can characterize the later stages of disease, including critical illness.4 For
this reason, it is necessary to understand the role of antiviral medications in treating mild, moderate,
severe, and critical illness in order to optimize treatment for people with COVID-19.
The following sections describe the underlying rationale for using different antiviral medications,
provide the COVID-19 Treatment Guidelines Panel’s recommendations for using these medications to
treat COVID-19, and summarize the existing clinical trial data. Additional antiviral therapies will be
added to this section of the Guidelines as new evidence emerges.
References
3. Remdesivir (Veklury) [package insert]. Food and Drug Administration. 2020. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214787Orig1s000lbl.pdf.
4. Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic
staging proposal. J Heart Lung Transplant. 2020;39(5):405-407. Available at:

AR08857
Remdesivir
Remdesivir is a nucleotide prodrug of an adenosine analog. It binds to the viral RNA-dependent RNA
polymerase and inhibits viral replication by terminating RNA transcription prematurely. Remdesivir
has demonstrated in vitro activity against SARS-CoV-2.1 In a rhesus macaque model of SARS-CoV-2
infection, remdesivir treatment was initiated soon after inoculation; the remdesivir-treated animals had
lower virus levels in the lungs and less lung damage than the control animals.2 Remdesivir is expected to
be active against the B.1.1.529 (Omicron) variant of concern.3,4
Intravenous remdesivir is approved by the Food and Drug Administration (FDA) for the treatment of
COVID-19 in adult and pediatric patients (aged ≥12 years and weighing ≥40 kg). It is approved for the
treatment of mild to moderate COVID-19 in high-risk, nonhospitalized patients (i.e., a 3-day course
initiated within 7 days of symptom onset) and for the treatment of hospitalized patients with COVID-19
(i.e., a 5-day course).5 See Table 2f for more information. It is also available through an FDA Emergency
Use Authorization (EUA) for the treatment of COVID-19 in nonhospitalized and hospitalized pediatric
patients weighing 3.5 kg to <40 kg or aged <12 years and weighing ≥3.5 kg.
Remdesivir has been studied in several clinical trials for the treatment of COVID-19. The
recommendations from the COVID-19 Treatment Guidelines Panel (the Panel) are based on the results
of these studies. See Table 2a for more information.
Recommendations
For the Panel’s recommendations and information on the clinical efficacy of remdesivir in high-risk,
nonhospitalized patients with mild to moderate COVID-19 and on the order of preference for outpatient
antiviral therapies, see Therapeutic Management of Nonhospitalized Adults With COVID-19. There are
no data on the use of combination antiviral therapies or the combination of antiviral agents and anti-
SARS-CoV-2 monoclonal antibodies for the treatment of nonhospitalized patients with COVID-19.
Clinical trials are needed to determine whether combination therapy has a role in the treatment of
COVID-19.
For the Panel’s recommendations and information on the clinical efficacy of remdesivir with or without
immunomodulators in certain hospitalized patients, see Therapeutic Management of Hospitalized
Adults With COVID-19. Data on the safety and efficacy of using remdesivir in combination with
corticosteroids are primarily derived from observational studies, with some (but not all) of these studies
suggesting that remdesivir plus dexamethasone provides a clinical benefit for hospitalized patients with
COVID-19.6-8
In the CATCO study, patients hospitalized with COVID-19 were randomized to receive remdesivir plus
standard care or standard care alone. Among patients who were not receiving mechanical ventilation
at baseline, remdesivir significantly reduced the need for mechanical ventilation. About 87% of
participants in the trial received corticosteroids as part of their standard care.9
Remdesivir plus dexamethasone has not been directly compared to dexamethasone alone in a large
randomized trial. However, there are theoretical reasons that combination therapy may be beneficial
for some patients with severe COVID-19. Remdesivir has also been studied in combination with other
immunomodulators, including baricitinib10 and tocilizumab.11
Monitoring and Adverse Effects

Remdesivir can cause gastrointestinal symptoms (e.g., nausea), elevated transaminase levels, an increase

AR08858
in prothrombin time without a change in the international normalized ratio, and hypersensitivity reactions.
Before starting patients on remdesivir, it is recommended that estimated glomerular filtration rate
(eGFR), liver function, and prothrombin time tests be performed as clinically appropriate and be
repeated during treatment as clinically indicated. However, it should be noted that in the PINETREE
study, in which outpatients with mild to moderate COVID-19 received remdesivir for 3 days,
baseline serum creatinine was not required in patients weighing >48 kg.12 Remdesivir may need to
be discontinued if a patient’s alanine transaminase (ALT) level increases to >10 times the upper limit
of normal, and it should be discontinued if increases in ALT levels and signs or symptoms of liver
inflammation are observed.5
Remdesivir should be administered in a setting where severe hypersensitivity reactions, such as
anaphylaxis, can be managed and the emergency medical system can be activated. Patients should be
monitored during the infusion and observed for at least 1 hour after the infusion as clinically appropriate.
Patients who are severely immunocompromised may have prolonged SARS-CoV-2 replication, which
may lead to rapid viral evolution. There is a theoretical concern that the use of a single antiviral agent in
these patients may result in the emergence of resistant virus. Additional studies are needed to assess this
risk. The role of combination antiviral therapy is not yet known.
Considerations in Patients With Renal Insufficiency

Each 100 mg vial of remdesivir lyophilized powder contains 3 g of sulfobutylether beta-cyclodextrin
sodium (SBECD), and each 100 mg/20 mL vial of remdesivir solution contains 6 g of SBECD.5 SBECD
is a vehicle that is primarily eliminated through the kidneys. A patient with COVID-19 who receives a
loading dose of remdesivir 200 mg would receive 6 g to 12 g of SBECD, depending on the formulation.
This amount of SBECD is within the safety threshold for patients with normal renal function.13
Accumulation of SBECD in patients with renal impairment may result in liver and renal toxicities.
Clinicians may consider preferentially using the lyophilized powder formulation (which contains less
SBECD) in patients with renal impairment.
Because both remdesivir formulations contain SBECD, patients with an eGFR of <50 mL/min were
excluded from some clinical trials of remdesivir; other trials had an eGFR cutoff of <30 mL/min. The
FDA product label does not recommend using remdesivir in patients with an eGFR of <30 mL/min due
to a lack of data.14
In 2 observational studies that evaluated the use of the solution formulation of remdesivir (not the
reconstituted lyophilized powder formulation) in hospitalized patients with COVID-19, no significant
differences were reported in the incidences of adverse effects or acute kidney injury between patients with
an estimated creatinine clearance (CrCl) of <30 mL/min and those with an estimated CrCl of ≥30 mL/
min.15,16 In 1 study, 20 patients had an estimated CrCl of <30 mL/min and 115 had an estimated CrCl of
≥30 mL/min;15 the other study included 40 patients who had an estimated CrCl of <30 mL/min and 307
patients who had an estimated CrCl of ≥30 mL/min.16 These observational data suggest that remdesivir
can be used in patients with an eGFR of <30 mL/min if the potential benefits outweigh the risks.
Drug-Drug Interactions
Currently, no clinical drug-drug interaction studies of remdesivir have been conducted. In vitro,
remdesivir is a minor substrate of cytochrome P450 (CYP) 3A4 and a substrate of the drug transporters
organic anion transporting polypeptide (OATP) 1B1 and P-glycoprotein. It is also an inhibitor of
CYP3A4, OATP1B1, OATP1B3, and multidrug and toxin extrusion protein 1 (MATE1).5

AR08859
Minimal to no reduction in remdesivir exposure is expected when remdesivir is coadministered with

dexamethasone, according to information provided by Gilead Sciences (written communication, July
2020).
See Table 2f for more information.
Remdesivir should not be withheld from pregnant patients if it is otherwise indicated.
Pregnant patients were excluded from the clinical trials that evaluated the safety and efficacy of
remdesivir for the treatment of COVID-19, but preliminary reports of remdesivir use in pregnant
patients from small studies and case reports are reassuring.17 Among 86 pregnant and postpartum
hospitalized patients with severe COVID-19 who received compassionate use remdesivir, the therapy
was well-tolerated, with a low rate of serious adverse effects.18
Remdesivir is available through an FDA EUA for the treatment of COVID-19 in hospitalized pediatric
patients weighing 3.5 kg to <40 kg or aged <12 years and weighing ≥3.5 kg or in nonhospitalized
pediatric patients with mild to moderate COVID-19 and at high risk for disease progression. There
are insufficient data on the safety and efficacy of using remdesivir to treat COVID-19 in hospitalized
or nonhospitalized pediatric patients aged <12 years or weighing <40 kg, because these populations
have not been evaluated in clinical trials for remdesivir. The limited data from the compassionate use
program and small-case series suggest that remdesivir was well-tolerated in children who met the EUA
criteria, but the data on young infants and neonates are extremely limited.19-23 A clinical trial is currently
evaluating the pharmacokinetics of remdesivir in children (ClinicalTrials.gov Identifier NCT04431453).
Clinical Trials
Several clinical trials that are evaluating the use of remdesivir for the treatment of COVID-19 are
currently underway or in development. Please see ClinicalTrials.gov for the latest information.
References
1. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel
coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-271. Available at:
2. Williamson BN, Feldmann F, Schwarz B, et al. Clinical benefit of remdesivir in rhesus macaques infected
with SARS-CoV-2. Nature. 2020;585(7824):273-276. Available at: https://www.ncbi.nlm.nih.gov/
pubmed/32516797.
4. Gilead Sciences. Gilead statement on Veklury (remdesivir) and the SARS-CoV-2 Omicron variant. 2021.
Available at: https://www.gilead.com/news-and-press/company-statements/gilead-statement-on-veklury-
remdesivir-and-the-sars-cov-2-omicron-variant. Accessed February 7, 2022.
6. Wong CKH, Lau KTK, Au ICH, et al. Optimal timing of remdesivir initiation in hospitalized COVID-19
patients administered with dexamethasone. Clin Infect Dis. 2021. Available at:

AR08860
7. Benfield T, Bodilsen J, Brieghel C, et al. Improved survival among hospitalized patients with coronavirus
disease 2019 (COVID-19) treated with remdesivir and dexamethasone. A nationwide population-based cohort
study. Clin Infect Dis. 2021;73(11):2031-2036. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34111274.
8. Mozaffari E, Chandak A, Zhang Z, et al. Remdesivir treatment in hospitalized patients with COVID-19: a
comparative analysis of in-hospital all-cause mortality in a large multi-center observational cohort. Clin Infect
Dis. 2021;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34596223.
9. Ali K, Azher T, Baqi M, et al. Remdesivir for the treatment of patients in hospital with COVID-19 in Canada: a
randomized controlled trial. CMAJ. 2022;Published online ahead of print. Available at:
10. Kalil AC, Patterson TF, Mehta AK, et al. Baricitinib plus remdesivir for hospitalized adults with COVID-19. N
11. Rosas IO, Diaz G, Gottlieb RL, et al. Tocilizumab and remdesivir in hospitalized patients with severe
COVID-19 pneumonia: a randomized clinical trial. Intensive Care Med. 2021;47(11):1258-1270. Available at:
13. European Medicines Agency Committee for Human Medicinal Products. Background review for cyclodextrins
used as excipients. 2014. Available at: https://www.ema.europa.eu/en/documents/report/background-review-
cyclodextrins-used-excipients-context-revision-guideline-excipients-label-package_en.pdf.
14. Adamsick ML, Gandhi RG, Bidell MR, et al. Remdesivir in patients with acute or chronic kidney disease and
COVID-19. J Am Soc Nephrol. 2020;31(7):1384-1386. Available at:
15. Pettit NN, Pisano J, Nguyen CT, et al. Remdesivir use in the setting of severe renal impairment: a theoretical
concern or real risk? Clin Infect Dis. 2021;73(11):e3990-e3995. Available at:
16. Ackley TW, McManus D, Topal JE, Cicali B, Shah S. A valid warning or clinical lore: an evaluation of safety
outcomes of remdesivir in patients with impaired renal function from a multicenter matched cohort. Antimicrob
Agents Chemother. 2021;65(2). Available at: https://www.ncbi.nlm.nih.gov/pubmed/33229428.
17. Jorgensen SCJ, Davis MR, Lapinsky SE. A review of remdesivir for COVID-19 in pregnancy and lactation. J
Antimicrob Chemother. 2021;77(1):24-30. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34427297.
18. Burwick RM, Yawetz S, Stephenson KE, et al. Compassionate use of remdesivir in pregnant women with severe
coronavirus disease 2019. Clin Infect Dis. 2021;73(11):e3996-e4004. Available at:
19. Goldman DL, Aldrich ML, Hagmann SHF, et al. Compassionate use of remdesivir in children with severe
COVID-19. Pediatrics. 2021;147(5). Available at: https://www.ncbi.nlm.nih.gov/pubmed/33883243.
20. Mendez-Echevarria A, Perez-Martinez A, Gonzalez Del Valle L, et al. Compassionate use of remdesivir in
children with COVID-19. Eur J Pediatr. 2021;180(4):1317-1322. Available at:
21. Saikia B, Tang J, Robinson S, et al. Neonates with SARS-CoV-2 infection and pulmonary disease safely treated
with remdesivir. Pediatr Infect Dis J. 2021;40(5):e194-e196. Available at:
22. Hammad M, Shalaby L, Sidhom I, et al. Management and outcome of coronavirus disease 2019 (COVID-19) in
pediatric cancer patients: a single centre experience from a developing country. Clin Lymphoma Myeloma Leuk.
23. Weclawek-Tompol J, Zakrzewska Z, Gryniewicz-Kwiatkowska O, et al. COVID-19 in pediatric cancer patients
is associated with treatment interruptions but not with short-term mortality: a Polish national study. J Hematol
Oncol. 2021;14(1):163. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34635137.

AR08861
Table 2a. Remdesivir: Selected Clinical Data

The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations for
RDV. The studies summarized below are the randomized controlled trials that have had the greatest impact on the Panel’s recommendations.
Studies of hospitalized patients are listed first, followed by studies of nonhospitalized patients.
Methods Results Limitations and Interpretation

ACTT-1: Multinational, Placebo-Controlled, Double-Blind RCT of Remdesivir in Hospitalized Patients With COVID-191
Key Inclusion Criteria: Participant Characteristics: Key Limitations:
• Laboratory-confirmed SARS-CoV-2 infection • Mean age 58.9 years • Wide range of disease severity among
• ≥1 of the following criteria: • 53.3% White, 21.3% Black, 12.7% Asian, 23.5% Hispanic/Latinx patients; study not powered to detect
differences within subgroups
• Pulmonary infiltrates • Coexisting conditions: 26.2% with 1; 55.2% with ≥2
• Powered to detect differences in clinical
• SpO2 ≤94% on room air • 13.0% not on oxygen; 41.0% on supplemental oxygen; 18.2% improvement, not mortality
• Need for supplemental oxygen, high-flow on high-flow oxygen or NIV; 26.8% on MV or ECMO
• No data on longer-term morbidity
oxygen, NIV, MV, or ECMO • Median time from symptom onset to randomization: 9 days (IQR
6–12 days) Interpretation:
Key Exclusion Criteria:
• Received corticosteroids during study: 21.6% in RDV arm; • In patients with severe COVID-19, RDV
• ALT or AST >5 times ULN reduced time to clinical recovery.
24.4% in placebo arm
• eGFR <30 mL/min • The benefit was most apparent in
Primary Outcomes:
• Pregnancy or breastfeeding hospitalized patients who were receiving
• Time to clinical recovery: 10 days in RDV arm vs. 15 days in supplemental oxygen.
Interventions: placebo arm (rate ratio for recovery 1.29; 95% CI, 1.12–1.49; P
• RDV 200 mg IV on Day 1, then RDV 100 mg daily < 0.001) • There was no observed benefit in those
for up to 9 more days (n = 541) on high-flow oxygen, NIV, MV, or ECMO,
• Benefit of RDV greatest in patients randomized during first 10 but study was not powered to detect
• Placebo for up to 10 days (n = 521) days after symptom onset and those who required supplemental differences within subgroups.
oxygenation at enrollment
Primary Endpoint:
• No difference in time to recovery for patients on high-flow
• Time to clinical recovery
oxygen, NIV, MV, or ECMO at enrollment
Key Secondary Endpoints:
Secondary Outcomes:
• Clinical status at Day 15, as measured by an OS
• Clinical status at Day 15: improvement more likely in RDV arm
• Mortality by Day 29 (OR 1.5; 95% CI, 1.2–1.9; P < 0.001)
• Occurrence of SAEs • Mortality by Day 29: no difference between arms
• Proportion of patients with SAEs: similar between arms (25% vs.
32%)

AR08862

DisCoVeRy: Open-Label, Adaptive RCT of Remdesivir in Hospitalized Patients With Moderate or Severe COVID-19 in Europe2
• Laboratory-confirmed SARS-CoV-2 infection • Median age 64 years; 70% men; 69% White • Open-label study
• Illness of any duration • 74% with ≥1 coexisting condition • 440 participants in this study also
• SpO2 ≤94% on room air or use of supplemental oxygen, • 40% received corticosteroids during study enrolled in the WHO Solidarity trial.
high-flow oxygen devices, NIV, or MV • Median days from symptom onset to randomization: 9 Interpretation:
Key Exclusion Criteria: days in both arms • There was no clinical benefit of RDV
• ALT or AST >5 times ULN • 61% with moderate disease; 39% with severe disease in hospitalized patients who were
• Severe chronic kidney disease Primary Outcomes: symptomatic for >7 days and who
required supplemental oxygen.
Interventions: • Clinical status at Day 15: no difference between arms (OR
0.98; 95% CI, 0.77–1.25; P = 0.85)
• RDV 200 mg IV on Day 1, then RDV 100 mg IV once daily
for up to 9 days (n = 429) • A prespecified subgroup analysis based on duration
of symptoms found no significant difference in clinical
• SOC (n = 428) status between arms.
Primary Endpoint: Secondary Outcomes:
• Clinical status at Day 15, as measured by an OS
• Mortality: no difference between arms (8% in RDV arm
Key Secondary Endpoints: vs. 9% in SOC arm)
• Mortality at Day 29 • Proportion of patients with SAEs: no difference between
• Occurrence of SAEs arms (33% in RDV arm vs. 31% in SOC arm; P = 0.48)
WHO Solidarity Trial: Multinational, Open-Label, Adaptive RCT of Repurposed Drugs in Hospitalized Patients With COVID-193
• Aged ≥18 years • 47% aged 50–69 years; 18% aged ≥70 years • Open-label design limits ability to
• Not known to have received any study drug • At entry: 67% on supplemental oxygen; 9% on MV assess time to recovery, as RDV
• Not expected to be transferred elsewhere within 72 hours may have been continued even if
• Rates of comorbidities similar between arms patient improved.
Interventions: • 48% in both arms received corticosteroids during study • No data on time from symptom
• RDV 200 mg IV on Day 0, then RDV 100 mg daily on Days Primary Outcome: onset to enrollment
1–9 (n = 2,743) • No assessment of outcomes post
• In-hospital mortality: 11.0% in RDV arm vs. 11.2% in
• Local SOC (n = 2,708) SOC arm (rate ratio 0.95; 95% CI, 0.81–1.11) hospital discharge
Primary Endpoint: Secondary Outcome: Interpretation:
• In-hospital mortality • Initiation of MV: 10.8% in RDV arm vs. 10.5% in SOC arm • RDV did not decrease in-hospital
Key Secondary Endpoint: mortality or the need for MV
compared to SOC.
• Initiation of MV

AR08863

GS-US-540-5774 Study: Multinational, Open-Label RCT of 10 Days or 5 Days of Remdesivir Compared With Standard of Care in Hospitalized Patients With
Moderate COVID-194
• Laboratory-confirmed SARS-CoV-2 infection • Demographic and baseline disease characteristics similar • Open-label design may have
• Pulmonary infiltrates across arms affected decisions on concomitant
• Ranges for participant characteristics across the 3 arms: medications (e.g., more patients in
• SpO2 >94% on room air the SOC arm received AZM, HCQ
• Median age 56–58 years or CQ, and LPV/RTV) and time of
• Men: 60% to 63% hospital discharge.
• ALT or AST >5 times ULN
• 81% to 87% required no supplemental oxygen; 12% to • No data on time to return to activity
• CrCl <50 mL/min
18% required low-flow oxygen; 1% required high-flow for discharged patients
Interventions: oxygen or NIV
Interpretation:
• RDV 200 mg IV on Day 1, then RDV 100 mg daily for 9 • Concomitant medication use in the 10-day RDV, 5-day
days (n = 193) RDV, and SOC arms: • Hospitalized patients with moderate
COVID-19 who received 5 days of
• RDV 200 mg IV on Day 1, then RDV 100 mg daily for 4 • Steroids: 15%, 17%, 19% RDV had better clinical status at Day
days (n = 191) • Tocilizumab: 1%, 1%, 5% 11 than those who received SOC.
• Local SOC (n = 200) • HCQ/CQ: 11%, 8%, 45% • There was no difference in the
Primary Endpoint: • LPV/RTV: 6%, 5%, 22% clinical status at Day 11 between
patients who received 10 days of
• Clinical status at Day 11, as measured by an OS • AZM: 21%, 18%, 31% RDV and those who received SOC.
• Median length of therapy: 6 days in 10-day RDV arm; 5
days in 5-day RDV arm
Primary Outcomes:
• Clinical status at Day 11:
• Significantly better in 5-day RDV arm than in SOC arm
(OR 1.65; 95% CI, 1.09–2.48; P = 0.02)
• No difference in clinical status at Day 11 between 10-day
RDV arm and SOC arm (P = 0.18)

AR08864

GS-US-540-5773 Study: Multinational, Open-Label RCT of 10 Days or 5 Days of Remdesivir Compared with Standard of Care in Hospitalized Patients With
Moderate COVID-195
• Laboratory-confirmed SARS-CoV-2 infection • Median age 61 years in 5-day arm; 62 years in 10-day arm • Open-label trial
• Pulmonary infiltrates and SpO2 ≤94% on room air or • 60% men in 5-day arm; 68% men in 10-day arm • Baseline imbalances in clinical
receipt of supplemental oxygen • Oxygen requirements at baseline for the 5-day and 10-day status of patients in 5-day and 10-
arms: day arms
• Need for MV or ECMO • None: 17%, 11% Interpretation:
• Multiorgan failure • Low-flow supplemental oxygen: 56%, 54% • In hospitalized patients with severe
• High-flow oxygen or NIV: 24%, 30% COVID-19 who were not receiving
• ALT or AST >5 times ULN MV or ECMO, using RDV for 5 or 10
• Estimated CrCl <50 mL/min • MV or ECMO: 2%, 5% days had similar clinical benefits.
Interventions: • Baseline clinical status: worse in 10-day arm than in 5-day
arm (P = 0.02)
• RDV 200 mg IV on Day 1, then RDV 100 mg daily for 4
days (n = 200) Primary Outcome:
• RDV 200 mg IV on Day 1, then RDV 100 mg daily for 9 • Day 14 distribution in clinical status after adjusting for
days (n = 197) baseline clinical status: similar between arms (P = 0.14)
• Clinical status at Day 14, as measured by an OS • Time to clinical improvement: similar between arms (10
days in 5-day arm vs. 11 days in 10-day arm)
• Time to recovery: Median hospitalization duration for
• Time to clinical improvement patients discharged on or before Day 14: similar between
• Time to recovery arms (7 days in 5-day arm vs. 8 days in 10-day arm)

AR08865

PINETREE: Double-Blind, Placebo-Controlled RCT of Remdesivir for 3 Days in Nonhospitalized Patients With COVID-19 at High Risk for Disease Progression6
• Laboratory-confirmed SARS-CoV-2 infection ≤4 days from • Mean age 50 years; 30.2% aged ≥60 years; 52.1% men • Study halted early due to
screening • 80.4% White, 7.5% Black, 41.8% Hispanic/Latinx administrative issues.
• Aged ≥12 years • 61.6% with DM; 55.2% with obesity; 47.4% with HTN • Vaccinated individuals were
• ≥1 risk factor for disease progression excluded.
• Median duration of symptoms before first infusion: 5 days
• Symptom onset ≤7 days from randomization (IQR 3–6 days) Interpretation:
• ≥1 ongoing COVID-19 symptom • Median time from RT-PCR confirmation: 2 days (IQR 1–4 • Three consecutive days of
days) IV RDV resulted in an 87%
Key Exclusion Criteria: relative reduction in the risk of
• COVID-19 vaccination Primary Outcomes: hospitalization or death when
• Supplemental oxygen • COVID-19-related hospitalization or death from any cause compared to placebo.
by Day 28: 2 (0.7%) in RDV arm vs. 15 (5.3%) in placebo
• Previous hospitalization or treatment for COVID-19 arm (HR 0.13; 95% CI, 0.03–0.59; P = 0.008)
Interventions: • AEs: 42.3% in RDV arm vs. 46.3% in placebo arm
• RDV 200 mg IV on Day 1, then RDV 100 mg daily on Days Secondary Outcome:
2 and 3 (n = 279)
• COVID-19-related medically attended visit or death from
• Placebo (n = 283) any cause by Day 28: 4 (1.6%) in RDV arm vs. 2 (8.3%) in
Primary Endpoints: placebo arm (HR 0.19; 95% CI, 0.07–0.56)
• COVID-19-related hospitalizations or death from any cause
by Day 28
• Any AE
• COVID-19-related, medically attended visit or death from
any cause by Day 28
Key: AE: adverse event; ALT = alanine transaminase; AST = aspartate aminotransferase; AZM = azithromycin; CQ = chloroquine; CrCl = creatinine clearance; DM =
diabetes mellitus; ECMO = extracorporeal membrane oxygenation; eGFR = estimated glomerular filtration rate; HCQ = hydroxychloroquine; HTN = hypertension; IV
= intravenous; LPV/RTV = lopinavir/ritonavir; MV = mechanical ventilation; NIV = noninvasive ventilation; OS = ordinal scale; the Panel = the COVID-19 Treatment
Guidelines Panel; RCT = randomized controlled trial; RDV = remdesivir; RT-PCR = reverse transcription polymerase chain reaction; SAE = serious adverse event; SOC
= standard of care; SpO2 = oxygen saturation; ULN = upper limit of normal; WHO = World Health Organization

AR08866
References
1. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of COVID-19—final report. N Engl J Med. 2020;383(19):1813-1826.
2. Ader F, Bouscambert-Duchamp M, Hites M, et al. Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted
to hospital with COVID-19 (DisCoVeRy): a Phase 3, randomised, controlled, open-label trial. Lancet Infect Dis. 2022;22(2):209-221. Available at:
3. WHO Solidarity Trial Consortium, Pan H, Peto R, et al. Repurposed antiviral drugs for COVID-19—interim WHO Solidarity Trial results. N Engl J
4. Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a
randomized clinical trial. JAMA. 2020;324(11):1048-1057. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32821939.
5. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 days in patients with severe COVID-19. N Engl J Med. 2020;383(19):1827-1837.
6. Gottlieb RL, Vaca CE, Paredes R, et al. Early remdesivir to prevent progression to severe COVID-19 in outpatients. N Engl J Med. 2022;386(4):305-

AR08867

Nirmatrelvir is an orally bioavailable protease inhibitor that is active against MPRO, a viral protease that
plays an essential role in viral replication by cleaving the 2 viral polyproteins.1 It has demonstrated
antiviral activity against all coronaviruses that are known to infect humans.2 Nirmatrelvir is packaged
with ritonavir (as Paxlovid), a strong cytochrome P450 (CYP) 3A4 inhibitor and pharmacokinetic
boosting agent that has been used to boost HIV protease inhibitors. Coadministration of ritonavir is
required to increase nirmatrelvir concentrations to the target therapeutic range.
On December 22, 2021, the Food and Drug Administration issued an Emergency Use Authorization
(EUA) for ritonavir-boosted nirmatrelvir for the treatment of patients with mild to moderate COVID-19
aged ≥12 years and weighing ≥40 kg who are within 5 days of symptom onset and at high risk of
progressing to severe disease.3,4
Recommendations
• The COVID-19 Treatment Guidelines Panel (the Panel) recommends using nirmatrelvir 300 mg
with ritonavir 100 mg (Paxlovid) orally twice daily for 5 days in nonhospitalized patients with
mild to moderate COVID-19 aged ≥12 years and weighing ≥40 kg who are at high risk of disease
progression;3 treatment should be initiated as soon as possible and within 5 days of symptom onset
(AIIa).
• Ritonavir-boosted nirmatrelvir has significant and complex drug-drug interactions, primarily due
to the ritonavir component of the combination.
concomitant medications, including over-the-counter medications, herbal supplements, and
recreational drugs, to evaluate potential drug-drug interactions.
• The Liverpool COVID-19 Drug Interactions website, Table A below, and the EUA fact sheet for
ritonavir-boosted nirmatrelvir can be used to identify and manage drug-drug interactions.
For the Panel’s recommendations on the order of preference for outpatient antiviral therapies and the
prioritization of outpatient therapies when there are logistical or supply constraints, see Therapeutic
Management of Nonhospitalized Adults With COVID-19.
Rationale
The EPIC-HR trial demonstrated that starting ritonavir-boosted nirmatrelvir treatment in nonhospitalized
adults with mild to moderate COVID-19 within 5 days of symptom onset reduced the risk of
hospitalization or death through Day 28 by 89% compared to placebo.4 This efficacy is comparable to
the efficacies reported for sotrovimab (i.e., 85% relative reduction)5 and remdesivir (i.e., 87% relative
reduction)6 and greater than the efficacy reported for molnupiravir (i.e., 30% relative reduction).7
Ritonavir-boosted nirmatrelvir is expected to be active against the B.1.1.529 (Omicron) variant of concern
(VOC), although there is currently a lack of data on the clinical efficacy of ritonavir-boosted nirmatrelvir
against this VOC.8-10 Because of the potential for significant drug-drug interactions with concomitant
medications, this regimen may not be a safe choice for all patients (see below for more information).
Clinical Trial Data

The EPIC-HR study was a multinational randomized trial that compared the use of ritonavir-boosted
nirmatrelvir given orally twice daily for 5 days to placebo in nonhospitalized patients aged ≥18 years

AR08868
with mild to moderate COVID-19 who were at high risk of clinical progression. Eligible participants
were randomized within 5 days of symptom onset, were unvaccinated against COVID-19, and had at
least 1 risk factor for progression to severe disease.11 Patients were excluded if they used medications
that were either highly dependent upon CYP3A4 for clearance or strong inducers of CYP3A4.
A total of 2,246 participants enrolled in the trial. The mean age was 46 years, 51% of the participants
were men, and 72% were White. Forty-seven percent of the participants tested negative for
SARS-CoV-2 antibodies, and 66% started study treatment within 3 days of symptom onset.
Participants who were randomized within 3 days of symptom onset (n = 1,379) were included in the
modified intention-to-treat (mITT) analysis. COVID-19-related hospitalizations and all-cause deaths
occurred by Day 28 in 5 of 697 participants (0.72%) in the ritonavir-boosted nirmatrelvir arm and in
44 of 682 participants (6.5%) in the placebo arm. Among the 2,085 participants who were randomized
within 5 days of symptom onset (mITT1 analysis), COVID-19-related hospitalizations and all-cause
deaths occurred in 8 of 1,039 participants (0.77%) in the ritonavir-boosted nirmatrelvir arm and in
66 of 1,046 participants (6.3%) in the placebo arm (89% relative risk reduction; -5.6% estimated
absolute reduction; 95% CI, -7.2% to -4.0%; P < 0.001). There were no deaths in the ritonavir-boosted
nirmatrelvir arm and 13 deaths in the placebo arm.
Among the 2,224 participants who were included in the EPIC-HR safety analysis set (i.e., those who
received at least 1 dose of either ritonavir-boosted nirmatrelvir or placebo), the adverse events that
occurred more frequently in ritonavir-boosted nirmatrelvir recipients than in placebo recipients were
dysgeusia (6% vs. 0.3%) and diarrhea (3% vs. 2%). Fewer ritonavir-boosted nirmatrelvir recipients
discontinued the study drug due to an adverse event than placebo recipients (2% vs. 4%).
• Nirmatrelvir must be administered with ritonavir to achieve sufficient therapeutic plasma
concentrations.
• Patients should complete the 5-day treatment course of ritonavir-boosted nirmatrelvir. It
is unknown whether a shorter course is less effective or associated with the emergence of
nirmatrelvir-resistant mutations.
• If a patient requires hospitalization after starting treatment, the full treatment course of ritonavir-
boosted nirmatrelvir can be completed at the clinician’s discretion.
• Ritonavir-boosted nirmatrelvir may be used in patients who are hospitalized for a diagnosis other
than COVID-19, provided they have mild to moderate COVID-19, are at high risk of progressing
to severe disease, and are within 5 days of symptom onset.
• There are no data on using combination antiviral therapies or combinations of antiviral agents
and anti-SARS-CoV-2 monoclonal antibodies for the treatment of nonhospitalized patients with
COVID-19. Clinical trials are needed to determine whether combination therapy has a role in the
• Severely immunocompromised patients can experience prolonged periods of SARS-CoV-2
replication, which may lead to rapid viral evolution. There are theoretical concerns that using a
single antiviral agent in these patients may produce antiviral-resistant viruses. Additional studies
are needed to assess this risk. The role of combination antiviral therapy in treating severely
immunocompromised patients is not yet known.
Monitoring and Adverse Effects

The most common adverse effects of ritonavir-boosted nirmatrelvir are dysgeusia, diarrhea,
hypertension, and myalgia.

AR08869
The dose should be reduced to nirmatrelvir 150 mg with ritonavir 100 mg twice daily in patients with
moderate renal impairment (i.e., those with an estimated glomerular filtration rate [eGFR] of ≥30 to <60
mL/min). Ritonavir-boosted nirmatrelvir is not recommended in patients with an eGFR of <30 mL/
min until more data are available. The appropriate dose for patients with severe renal impairment has not
been determined.
Ritonavir-boosted nirmatrelvir is not recommended for patients with severe hepatic impairment (i.e.,
Child-Pugh Class C), and it should be used with caution in patients with pre-existing liver diseases,
liver enzyme abnormalities, or hepatitis. No pharmacokinetic or safety data are available for this patient
population.
The EPIC-HR trial excluded pregnant and lactating individuals. Ritonavir has been used extensively
during pregnancy in people with HIV, which suggests that it has an acceptable safety profile during
pregnancy. Based on the mechanisms of action for both nirmatrelvir and ritonavir and the available
animal data, the Panel would not withhold ritonavir-boosted nirmatrelvir from a pregnant patient if the
potential benefits outweighed the potential risks.
Ritonavir-boosted nirmatrelvir is authorized for use in pediatric patients aged ≥12 years and weighing
≥40 kg. The EPIC-HR trial excluded persons aged <18 years. The safety and efficacy of using ritonavir-
boosted nirmatrelvir in pediatric patients has not been established in clinical trials.
Ritonavir-boosted nirmatrelvir has significant and complex drug-drug interactions, primarily due to the
ritonavir component of the combination. Boosting with ritonavir, a strong CYP3A inhibitor, is required
to increase the exposure of nirmatrelvir to a concentration that is effective against SARS-CoV-2.
However, it may also increase concentrations of certain concomitant medications, thereby increasing the
potential for serious and sometimes life-threatening drug toxicities. Additionally, ritonavir is an inhibitor,
inducer, and substrate of various other drug-metabolizing enzymes and/or drug transporters.
Because ritonavir-boosted nirmatrelvir is the only highly effective oral antiviral for the treatment of
COVID-19, drug interactions that can be safely managed should not preclude the use of this medication.
The treatment course of ritonavir-boosted nirmatrelvir for COVID-19 is 5 days. CYP3A4 inhibition
occurs rapidly after initiating ritonavir, with maximum inhibition occurring within 48 hours.12 After
ritonavir is discontinued, 80% to 90% of CYP3A4 inhibition resolves within 3 days.13 The time to
resolution of inhibition varies based on factors such as the patient’s age; therefore, resolution may
take longer in some individuals, such as in the elderly. When ritonavir is used for 5 days, its induction
properties are less likely to be clinically relevant than when the drug is used chronically (e.g., in
people who take HIV protease inhibitors). Both nirmatrelvir and ritonavir are substrates of CYP3A;
thus, administering this treatment with or immediately after discontinuing medications that are strong
inducers of CYP3A4 (e.g., rifampin) can lead to significant reductions in nirmatrelvir and ritonavir
concentrations, which may decrease nirmatrelvir’s effectiveness against SARS-CoV-2.
Guidance for Prescribers and Pharmacists

Identify Drug-Drug Interactions
concomitant medications, including over-the-counter medicines, herbal supplements, and

AR08870
recreational drugs.
• Clinicians should refer to resources such as the Liverpool COVID-19 Drug Interactions website,
Table A below, and the EUA fact sheet for ritonavir-boosted nirmatrelvir for guidance regarding
potential drug-drug interactions.
• Clinicians should consider consulting an expert (e.g., a pharmacist, HIV specialist, and/or
the patient’s specialist provider[s], if applicable), especially for patients who are receiving
highly specialized therapies, such as antineoplastics, neuropsychiatric drugs, and certain
immunosuppressants.
• Drug classes of particular concern are those that include drugs that are prone to concentration-
dependent toxicities, including certain antiarrhythmics, oral anticoagulants, immunosuppressants,
anticonvulsants, antineoplastics, and neuropsychiatric drugs.
Management Strategies for Drug-Drug Interactions

• Before administering ritonavir-boosted nirmatrelvir to a patient, clinicians should assess the
potential risks and benefits of using this combination in that patient. In particular, clinicians should
assess the availability of other equally effective COVID-19 treatment options that have lower risks
of drug interactions.
• Clinicians should consider the magnitude and significance of the potential interaction when
choosing management strategies for patients who are receiving ritonavir-boosted nirmatrelvir.
Potential strategies include:
• Adjusting the dose of the concomitant medication,
• Using an alternative to the concomitant medication,
• Increasing monitoring for potential adverse reactions to the concomitant medication, or
• Temporarily withholding the concomitant medication.
• Clinicians should use the chosen strategies for the 5-day duration of ritonavir-boosted nirmatrelvir
treatment and for at least 3 days after treatment completion. These strategies may need to be
continued for a longer duration if ritonavir-boosted nirmatrelvir is initiated in an elderly patient or
if the interacting concomitant medication has a long half-life or narrow therapeutic index.
• In settings where using these management strategies is not feasible or where the effectiveness
of ritonavir-boosted nirmatrelvir may be compromised, consider using alternative COVID-19
therapies (see Therapeutic Management of Nonhospitalized Adults With COVID-19).
• The dose of ritonavir-boosted nirmatrelvir should not be adjusted to avoid or mitigate a drug-drug
interaction with a concomitant medication.
• Patients on ritonavir- or cobicistat-boosted regimens that are used to treat HIV or hepatitis C virus
should continue their treatment as indicated while receiving ritonavir-boosted nirmatrelvir. No
dose adjustments are required.
• People who take certain recreational drugs, such as recreational fentanyl, will require careful
monitoring for adverse effects if they are prescribed ritonavir-boosted nirmatrelvir.
• The EUA for ritonavir-boosted nirmatrelvir suggests that individuals who use products containing
ethinyl estradiol for contraception should use a backup, nonhormonal contraceptive method
because ritonavir-boosted nirmatrelvir has the potential to decrease ethinyl estradiol levels.
However, the enzyme-inducing effects of ritonavir-boosted nirmatrelvir that would lead to lower
hormone exposure are not expected to be clinically significant during 5 days of therapy and,
therefore, would not be expected to decrease contraceptive effectiveness. In addition, ethinyl

AR08871
estradiol is always combined with a progestin for contraception. Progestin concentrations are
expected to remain similar or increase when ritonavir-boosted nirmatrelvir is used concomitantly
with combined hormonal contraception, which maintains the effectiveness of the oral
contraceptive.
Patient Counseling on Drug-Drug Interactions

• Patients should be informed of ritonavir-boosted nirmatrelvir’s drug-drug interaction potential
with concomitant medications, including over-the-counter medicines, herbal supplements, and
recreational drugs.
• If a potential drug-drug interaction is identified, the patient should be informed about the
interaction and alerted to the signs and symptoms of potential adverse effects.
Table A. Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir (Paxlovid) and
Concomitant Outpatient Medications
This table is not a comprehensive list of all the drugs that may interact with ritonavir-boosted
nirmatrelvir. This table focuses on concomitant medications that may be prescribed in the outpatient
setting. Pharmacists or providers who have experience with prescribing ritonavir-boosted drugs (e.g.,
HIV specialists) should be consulted when monitoring and managing drug-drug interactions in patients
with mild to moderate COVID-19 who are receiving ritonavir-boosted nirmatrelvir and who may be
hospitalized for reasons that are not related to COVID-19.
Deviation from these recommendations may be appropriate in certain clinical scenarios. When
significant drug-drug interactions are present, providers should exercise clinical judgment when
assessing the risks and benefits of using ritonavir-boosted nirmatrelvir and determining the appropriate
management strategies for these interactions.
The table below divides medications into 3 categories:
• Concomitant medications that require patients to receive an alternative COVID-19 therapy. For
these drugs, drug-drug interaction management strategies are not possible or feasible, or the
potential risks of such strategies outweigh the potential benefits. This category includes:
• Drugs that may cause significant toxicities due to CYP3A4 inhibition and that cannot be
stopped or have their doses adjusted; or
• Drugs that are strong CYP3A inducers and may significantly reduce the concentration of
ritonavir and nirmatrelvir, potentially leading to a loss of virologic response. Ritonavir-boosted
nirmatrelvir cannot be initiated immediately after discontinuing CYP3A inducers due to the
delayed offset of induction.
• Concomitant medications that should be temporarily withheld, if clinically appropriate. If
withholding is not clinically appropriate, temporarily switching to an alternative concomitant
medication or using an alternative COVID-19 therapy should be considered.
• Concomitant medications that should receive dose adjustments. Patients should be monitored
closely for adverse effects. If the dose of the concomitant medication cannot be adjusted, consider
withholding the medication (if clinically appropriate) or using an alternative concomitant
medication or an alternative COVID-19 therapy.

AR08872
Prescribe an Alternative COVID-19 Therapy

For cases where drug-drug interaction management strategies are not possible or feasible, or the potential risks of such
strategies outweigh the potential benefits.
Amiodarone Flecainide Propafenone
Apalutamide Glecaprevir/pibrentasvir Quinidine
Bosentan Ivabradine Rifampin
Carbamazepine Lumacaftor/ivacaftor Rifapentine
Clopidogrela Lumateperone Sildenafil for PH
Clozapine Lurasidone St. John’s wort
Disopyramide Meperidine (pethidine) Tadalafil for PH
Dofetilide Midazolam (oral) Tolvaptan
Dronedarone Phenobarbital Vardenafil for PH
Enzalutamide Phenytoin Voclosporin
Eplerenone Pimozide
Ergot derivatives Primidone
Temporarily Withhold Concomitant Medication, If Clinically Appropriate
For guidance on restarting the concomitant medication, consult the Liverpool COVID-19 Drug Interactions website.b If
withholding is not clinically appropriate, use an alternative concomitant medication or COVID-19 therapy.
Alfuzosin Estazolamd Rosuvastatin
Aliskiren Everolimusf Salmeterol
Atorvastatin Finerenone Silodosin
Avanafil Flibanserin Simvastatin
Chemotherapyc Flurazepamd Sirolimusf
Clonazepamd Lomitapide Suvorexant
Clorazepated Lovastatin Tacrolimusf
Colchicinee Naloxegol Ticagrelor
Diazepamd Ranolazine Triazolamd
Eletriptan Rimegepant Ubrogepant
Erythromycin Rivaroxabang Vorapaxar
Adjust Concomitant Medication Dose and Monitor for Adverse Effects
Consult the Liverpool COVID-19 Drug Interactions websiteb for guidance. If the dose of the concomitant medication
cannot be adjusted, withhold the medication (if clinically appropriate) or use an alternative concomitant medication or
COVID-19 therapy.
Alprazolamd Darifenacin Pimavanserin
Amlodipine Digoxin Quetiapine
Apixaban Elexacaftor/tezacaftor/ivacaftor Rifabutin
Aripiprazole Eluxadoline Riociguat
Brexpiprazole Fentanyl Saxagliptin
Buspirone Iloperidone Sildenafil for ED
Cariprazine Itraconazole Ruxolitinib
Chlordiazepoxided Ivacaftor Tadalafil for ED
Cilostazol Ketoconazole Tamsulosin
Clarithromycin Maraviroc Tezacaftor/ivacaftor
Clobazamd Mexiletine Trazodone
Cyclosporinef Oxycodone Vardenafil for ED
a
educed effectiveness of clopidogrel is likely. Do not coadminister clopidogrel in patients who are at a very high risk of
R
thrombosis (e.g., those who are within 6 weeks of coronary stenting); consider prescribing an alternative antiplatelet
(i.e., prasugrel) or an alternative COVID-19 therapy. For other indications, it may be acceptable to continue clopidogrel if
the benefit of ritonavir-boosted nirmatrelvir treatment outweighs the risk of reduced clopidogrel effectiveness.
b
Additional resources include the EUA fact sheet for ritonavir-boosted nirmatrelvir and the FDA prescribing information
for the concomitant medication. These may be consulted for medications that are not found on the Liverpool COVID-19
Drug Interactions website.

AR08873
c
itonavir-boosted nirmatrelvir may increase concentrations of certain anticancer agents, leading to an increased
R
potential for drug toxicities. These anticancer agents include kinase inhibitors (e.g., abemaciclib, ceritinib, dasatinib,
ibrutinib, neratinib, nilotinib), the IDH1 inhibitor ivosidenib, the BCL-2 inhibitor venetoclax, and vinca alkaloids (e.g.,
vinblastine, vincristine). Please refer to the prescribing information for the anticancer agent and consult the patient’s
specialist provider. Avoid concomitant administration of ritonavir-boosted nirmatrelvir with ibrutinib, neratinib,
ivosidenib, or venetoclax.
d
Abrupt discontinuation or rapid dose reduction of benzodiazepines may precipitate acute withdrawal reactions.14 The risk
is greatest for patients who have been using higher doses of benzodiazepines over an extended period of time.
e
Colchicine is contraindicated in patients with severe hepatic or renal impairment due to the potential for serious or life-
threatening reactions.
f
Before prescribing ritonavir-boosted nirmatrelvir to a patient who is receiving this immunosuppressant, consult the
patient’s specialist provider(s). This immunosuppressant has significant drug-drug interaction potential with ritonavir,
and close monitoring may not be feasible. See this statement from the American Society of Transplantation for more
information.
g
If the patient has a high risk of arterial or venous thrombosis (e.g., those who are within 3 months of a stroke, those
with a CHA2DS2-VASc score of 7–9, those who are within 1 month of a pulmonary embolism), the patient’s primary or
specialty provider should be consulted; consider using an alternative anticoagulant or COVID-19 therapy.
Key: BCL-2 = B cell lymphoma 2; CYP = cytochrome P450; ED = erectile dysfunction; EUA = Emergency Use
Authorization; FDA = Food and Drug Administration; IDH1 = isocitrate dehydrogenase-1; PH = pulmonary hypertension
References
1. Pillaiyar T, Manickam M, Namasivayam V, Hayashi Y, Jung SH. An overview of severe acute respiratory
syndrome-coronavirus (SARS-CoV) 3CL protease inhibitors: peptidomimetics and small molecule
chemotherapy. J Med Chem. 2016;59(14):6595-6628. Available at:
2. Owen DR, Allerton CMN, Anderson AS, et al. An oral SARS-CoV-2 M(pro) inhibitor clinical candidate for
the treatment of COVID-19. Science. 2021;374(6575):1586-1593. Available at:
conditions.html. Accessed December 27, 2021.
5. Gupta A, Gonzalez-Rojas Y, Juarez E, et al. Early treatment for COVID-19 with SARS-CoV-2 neutralizing
antibody sotrovimab. N Engl J Med. 2021;385(21):1941-1950. Available at:
nonhospitalized patients. N Engl J Med. 2022;386(6):509-520. Available at:
9. Greasley SE, Noell S, Plotnikova O, et al. Structural basis for nirmatrelvir in vitro efficacy against the
Omicron variant of SARS-CoV-2. bioRxiv. 2022;Preprint. Available at:
10. Rai DK, Yurgelonis I, McMonagle P, et al. Nirmatrelvir, an orally active MPRO inhibitor, is a potent inhibitor

AR08874
of SARS-CoV-2 variants of concern. bioRxiv. 2022;Preprint. Available at:

11. Hammond J, Leister-Tebbe H, Gardner A, et al. Oral nirmatrelvir for high-risk, nonhospitalized adults with
COVID-19. N Engl J Med. 2022; Published online ahead of print. Available at:
12. Katzenmaier S, Markert C, Riedel KD, et al. Determining the time course of CYP3A inhibition by potent
reversible and irreversible CYP3A inhibitors using a limited sampling strategy. Clin Pharmacol Ther.
13. Stader F, Khoo S, Stoeckle M, et al. Stopping lopinavir/ritonavir in COVID-19 patients: duration of the drug
interacting effect. J Antimicrob Chemother. 2020;75(10):3084-3086. Available at:
14. Food and Drug Administration. FDA requiring Boxed Warning updated to improve safe use of benzodiazepine
drug class. 2020. Available at: https://www.fda.gov/media/142368/download.

AR08875
Molnupiravir
Molnupiravir is the oral prodrug of beta-D-N4-hydroxycytidine (NHC), a ribonucleoside that has broad
antiviral activity against RNA viruses. NHC uptake by viral RNA-dependent RNA-polymerases results
in viral mutations and lethal mutagenesis.1,2
On December 23, 2021, the Food and Drug Administration (FDA) issued an Emergency Use
Authorization (EUA) for molnupiravir for the treatment of adults with mild to moderate COVID-19 who
are within 5 days of symptom onset, who are at high risk of progressing to severe disease, and for whom
alternative antiviral therapies are not accessible or clinically appropriate.3,4
Molnupiravir has potent antiviral activity against SARS-CoV-2.1,5 As a mutagenic ribonucleoside
antiviral agent, there is a theoretical risk that molnupiravir will be metabolized by the human host cell
and incorporated into the host DNA, leading to mutations. Molnupiravir has been evaluated in 2 in
vivo rodent mutagenicity assays. One study produced equivocal results; in the other study, there was
no evidence for mutagenicity.4 The FDA concluded that, based on the available genotoxicity data and
the 5-day duration of treatment, molnupiravir has a low risk for genotoxicity.4 In addition, there have
been concerns about the potential effects of molnupiravir on SARS-CoV-2 mutation rates; the FDA is
requiring the manufacturer to establish a process to monitor genomic databases for the emergence of
SARS-CoV-2 variants.
Recommendations
• In nonhospitalized patients aged ≥18 years who have mild to moderate COVID-19 and who
are at high risk of disease progression, the COVID-19 Treatment Guidelines Panel (the Panel)
recommends using molnupiravir 800 mg orally (PO) twice daily for 5 days ONLY when
ritonavir-boosted nirmatrelvir (Paxlovid), sotrovimab, or remdesivir cannot be used; treatment
should be initiated as soon as possible and within 5 days of symptom onset (CIIa).
• The FDA EUA states that molnupiravir is not recommended for use in pregnant patients because
fetal toxicity has been reported in animal studies of molnupiravir. However, when other therapies
are not available, pregnant people with COVID-19 who are at high risk of progressing to severe
disease may reasonably choose molnupiravir therapy after being fully informed of the risks,
particularly if they are beyond the time of embryogenesis (i.e., >10 weeks’ gestation). The
prescribing clinician should document that a discussion of the risks and benefits occurred and that
the patient chose this therapy.
• People who engage in sexual activity that may result in conception should use effective
contraception during and following treatment with molnupiravir. For more details, see the
Considerations in Sexually Active Individuals section below.
• There are no data on the use of molnupiravir in patients who have received COVID-19 vaccines.
The risk-to-benefit ratio is likely to be less favorable in these patients, because molnupiravir has a
lower efficacy compared to other available treatments.
For the Panel’s recommendations on using antiviral therapies in outpatients and prioritizing
outpatient therapies when there are logistical or supply constraints, see Therapeutic Management of
Nonhospitalized Adults With COVID-19.
Rationale
In the MOVe-OUT trial, molnupiravir reduced the rate of hospitalization or death by 30% compared to
placebo.4 Even though the different treatment options have not been directly compared in clinical trials,

AR08876
the Panel recommends using molnupiravir only when ritonavir-boosted nirmatrelvir, sotrovimab, and
remdesivir are not available or cannot be given, because molnupiravir has lower efficacy than the other
options. For more information, see Therapeutic Management of Nonhospitalized Adults With COVID-19.
Molnupiravir is expected to be active against the B.1.1.529 (Omicron) variant of concern, although in
vitro and in vivo data are currently limited.6
• Patients should complete the 5-day treatment course of molnupiravir. It is unknown whether a
shorter course is less effective or associated with the emergence of molnupiravir-resistant mutations.
• If a patient requires hospitalization after starting treatment, the full treatment course of
molnupiravir can be completed at the health care provider’s discretion.
• Molnupiravir may be used in patients who are hospitalized for a diagnosis other than COVID-19,
provided they have mild to moderate COVID-19 and are at high risk of progressing to severe
disease.
• There are no data on using combination antiviral therapies or combinations of antiviral agents
and anti-SARS-CoV-2 monoclonal antibodies for the treatment of nonhospitalized patients with
COVID-19. Clinical trials are needed to determine whether combination therapy has a role in the
treatment of SARS-CoV-2 infection.
• Severely immunocompromised patients can experience prolonged periods of SARS-CoV-2
replication, which may lead to rapid viral evolution. There are theoretical concerns that using a
single antiviral agent in these patients may produce antiviral-resistant viruses. Additional studies
are needed to assess this risk. The role of combination antiviral therapy in treating severely
immunocompromised patients is not yet known.
Considerations in Sexually Active Individuals

Clinicians should assess a patient’s pregnancy status before initiating molnupiravir, if clinically indicated.
Patients of childbearing potential should be counseled about abstaining from sex or using reliable
contraception for the duration of therapy and for up to 4 days after receiving molnupiravir. Reproductive
toxicity has been reported in animal studies of molnupiravir, and molnupiravir may be mutagenic during
pregnancy.
The FDA EUA states that men of reproductive potential who are sexually active with individuals of
childbearing potential should be counseled to abstain from sex or use a reliable method of contraception
for the duration of treatment and for at least 3 months after the last dose of molnupiravir.
The FDA EUA states that molnupiravir is not recommended for use in pregnant patients because fetal
toxicity has been reported in animal studies of molnupiravir. However, when other therapies are not
available, pregnant people with COVID-19 who are at high risk of progressing to severe disease may
reasonably choose molnupiravir therapy after being fully informed of the risks, particularly if they
are beyond the time of embryogenesis (i.e., >10 weeks’ gestation). The prescribing clinician should
document that a discussion of the risks and benefits occurred, and that the patient chose this therapy. The
patient should also be informed about the pregnancy surveillance program and offered the opportunity to
participate.
There is currently a lack of data on the use of molnupiravir in lactating people, and molnupiravir may

AR08877
cause adverse effects in infants who are exposed to the drug through breastfeeding. Because of this,
the FDA EUA states that lactating people should not breastfeed their infants during treatment with
molnupiravir and for 4 days after the final dose. Pumping and discarding breast milk to maintain supply
during this time is recommended.
The MOVe-OUT trial excluded participants aged <18 years. There are no data available on the use of
molnupiravir in children aged <18 years. Molnupiravir is not authorized for use in children aged <18
years due to potential effects on bone and cartilage growth.
Monitoring, Adverse Effects, and Drug Interactions

The most common adverse effects of molnupiravir are diarrhea, nausea, and dizziness. Based on in vitro
studies, neither molnupiravir nor its active metabolite NHC are inhibitors or inducers of major drug-
metabolizing enzymes or inhibitors of major drug transporters. According to the EUA, no drug-drug
interactions have been identified for molnupiravir.
Clinical Trial Data

MOVe-OUT was a multinational, Phase 3 trial that evaluated the use of molnupiravir in nonhospitalized
adults with mild to moderate COVID-19 who were at high risk of progressing to severe COVID-19. The
participants were not pregnant, had not been vaccinated against COVID-19, and were enrolled within 5
days of symptom onset. They were randomized to receive molnupiravir 800 mg PO every 12 hours for
5 days or placebo.7 The primary composite outcome was all-cause hospitalizations (defined as hospital
stays that lasted >24 hours) and deaths by Day 29.
The final analysis included 1,433 participants; the median age was 43 years (with 17% aged >60 years).
Forty-nine percent of the participants were men, 57% were White, 50% were Hispanic/Latinx, and
5% were Black or African American. Among the participants, 74% had a body mass index ≥30 and
16% had diabetes. The time from COVID-19 symptom onset to randomization was ≤3 days in 48% of
participants.
By Day 29, hospitalizations or deaths had occurred in 48 of 709 participants (6.8%) in the molnupiravir
arm and in 68 of 699 participants (9.7%) in the placebo arm (30% relative risk reduction; -3.0% adjusted
difference; 95% CI, -5.9% to -0.1%; P = 0.0218).4 There was 1 death in the molnupiravir arm and 9
deaths in the placebo arm. There were no significant differences between the arms in the proportion of
participants who experienced adverse events or serious adverse events.
References
1. Zhou S, Hill CS, Sarkar S, et al. Beta-d-N4-hydroxycytidine inhibits SARS-CoV-2 through lethal mutagenesis
but is also mutagenic to mammalian cells. J Infect Dis. 2021;224(3):415-419. Available at:
2. Kabinger F, Stiller C, Schmitzova J, et al. Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis.
Nat Struct Mol Biol. 2021;28(9):740-746. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34381216.
conditions.html. Accessed December 27, 2021.
5. Fischer WA, 2nd, Eron JJ, Jr., Holman W, et al. A Phase 2a clinical trial of molnupiravir in patients with

AR08878
COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus. Sci Transl
Med. 2021:eabl7430. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34941423.
6. Vangeel L, De Jonghe S, Piet Maes P, et al. Remdesivir, molnupiravir and nirmatrelvir remain active against
SARS-CoV-2 Omicron and other variants of concern. bioRxiv. 2022;Preprint. Available at:
nonhospitalized patients. N Engl J Med. 2021;Published online ahead of print. Available at:

AR08879
Chloroquine or Hydroxychloroquine and/or Azithromycin

Chloroquine is an antimalarial drug that was developed in 1934. Hydroxychloroquine, an analogue of

chloroquine, was developed in 1946. Hydroxychloroquine is used to treat autoimmune diseases, such as
systemic lupus erythematosus and rheumatoid arthritis, in addition to malaria.
Both chloroquine and hydroxychloroquine increase the endosomal pH, which inhibits fusion between
SARS-CoV-2 and the host cell membrane.1 Chloroquine inhibits glycosylation of the cellular
angiotensin-converting enzyme 2 (ACE2) receptor, which may interfere with the binding of SARS-CoV
to the cell receptor.2 In vitro studies have suggested that both chloroquine and hydroxychloroquine may
block the transport of SARS-CoV-2 from early endosomes to endolysosomes, possibly preventing the
release of the viral genome.3 Both chloroquine and hydroxychloroquine also have immunomodulatory
effects, which have been hypothesized to be another potential mechanism of action for the treatment of
COVID-19. Azithromycin has antiviral and anti-inflammatory properties. When used in combination
with hydroxychloroquine, it has been shown to have a synergistic effect on SARS-CoV-2 in vitro and
in molecular modeling studies.4,5 However, despite demonstrating antiviral activity in some in vitro
systems, neither hydroxychloroquine plus azithromycin nor hydroxychloroquine alone reduced upper or
lower respiratory tract viral loads or demonstrated clinical efficacy in a rhesus macaque model.6
The safety and efficacy of chloroquine or hydroxychloroquine with or without azithromycin and
azithromycin alone have been evaluated in randomized clinical trials, observational studies, and/or
single-arm studies. Please see Table 2b for more information.
Recommendation
chloroquine or hydroxychloroquine and/or azithromycin for the treatment of COVID-19 in
hospitalized patients (AI) and in nonhospitalized patients (AIIa).
Rationale
In a large randomized controlled platform trial of hospitalized patients in the United Kingdom
(RECOVERY), hydroxychloroquine did not decrease 28-day mortality when compared to the usual
standard of care. Patients who were randomized to receive hydroxychloroquine had a longer median
hospital stay than those who received the standard of care. In addition, among patients who were not on
invasive mechanical ventilation at the time of randomization, those who received hydroxychloroquine
were more likely to subsequently require intubation or die during hospitalization than those who
received the standard of care.7
The results from several additional large randomized controlled trials have been published; these trials
have failed to show a benefit for hydroxychloroquine with or without azithromycin or azithromycin
alone in hospitalized adults with COVID-19. In the Solidarity trial, an international randomized
controlled platform trial that enrolled hospitalized patients with COVID-19, the hydroxychloroquine
arm was halted for futility. There was no difference in in-hospital mortality between patients in the
hydroxychloroquine arm and those in the control arm.8 Similarly, PETAL, a randomized, placebo-
controlled, blinded study, was stopped early for futility. In this study, there was no difference in the
median scores on the COVID Outcomes Scale between patients who received hydroxychloroquine and
those who received placebo.9 Data from two additional randomized studies of hospitalized patients

AR08880
with COVID-19 did not support using hydroxychloroquine plus azithromycin over hydroxychloroquine
alone.10,11 In RECOVERY, azithromycin alone (without hydroxychloroquine) did not improve survival or
other clinical outcomes when compared to the usual standard of care.12
In addition to these randomized trials, data from large retrospective observational studies do not
consistently show evidence of a benefit for hydroxychloroquine with or without azithromycin in
hospitalized patients with COVID-19.13-15 Please see Table 2b or the archived versions of the Guidelines
for more information.
Given the lack of a benefit seen in the randomized clinical trials, the Panel recommends against using
hydroxychloroquine or chloroquine and/or azithromycin to treat COVID-19 in hospitalized patients (AI).
Nonhospitalized Patients
Several randomized trials have not shown a clinical benefit for hydroxychloroquine in nonhospitalized
patients with early, asymptomatic, or mild COVID-19.16,17 In an open-label trial, Mitja et al.
randomized 307 nonhospitalized people who were recently confirmed to have COVID-19 to receive
hydroxychloroquine or no antiviral treatment. Patients in the hydroxychloroquine arm received
hydroxychloroquine 800 mg on Day 1 followed by 400 mg daily for an additional 6 days. The
authors reported no difference in the mean reduction in SARS-CoV-2 RNA at Day 3 or the time to
clinical improvement between the two arms (see Table 2b for more information). In another trial,
treating patients who had asymptomatic or mild COVID-19 with hydroxychloroquine with or without
azithromycin did not result in greater rates of virologic clearance (as measured by a negative polymerase
chain reaction [PCR] result on Day 6).18
An open-label, prospective, randomized trial compared oral azithromycin 500 mg once daily for 3
days plus standard of care to standard of care alone in nonhospitalized, high-risk, older adults who had
laboratory-confirmed or suspected COVID-19. No differences were observed between the arms in the
primary endpoints of time to first self-reported recovery and hospitalization or death due to COVID-19.
These findings remained consistent in an analysis that was restricted to participants with positive
SARS-CoV-2 PCR results. The study was ultimately halted due to futility.19 Similarly, in a preliminary
report from ATOMIC-2, adding oral azithromycin 500 mg once daily to standard of care for 14 days did
not reduce the risk of hospitalization or death among 292 participants with mild to moderate COVID-19.20
While ongoing clinical trials are still evaluating the use of chloroquine, hydroxychloroquine, and
azithromycin in outpatients, the existing data suggest that it is unlikely that clinical benefits will be
identified for these agents. The Panel recommends against the use of chloroquine or hydroxychloroquine
and/or azithromycin for the treatment of COVID-19 in nonhospitalized patients (AIIa).
Adverse Effects
Chloroquine and hydroxychloroquine have similar toxicity profiles, although hydroxychloroquine is
better tolerated and has a lower incidence of toxicity than chloroquine. Cardiac adverse events that
have been reported in people who received hydroxychloroquine include QTc prolongation, Torsades de
Pointes, ventricular arrythmia, and cardiac deaths.21
The use of azithromycin has also been associated with QTc prolongation,22 and using it in combination
with hydroxychloroquine has been associated with a higher incidence of QTc prolongation and cardiac
adverse events in patients with COVID-19.23,24
Chloroquine and hydroxychloroquine are moderate inhibitors of cytochrome P450 2D6, and these drugs

AR08881
are also P-glycoprotein inhibitors. Chloroquine and hydroxychloroquine may decrease the antiviral
activity of remdesivir; coadministration of these drugs is not recommended.25
Drug Availability
Hydroxychloroquine, chloroquine, and azithromycin are not approved by the Food and Drug
Administration (FDA) for the treatment of COVID-19. Furthermore, the FDA Emergency Use
Authorization for hydroxychloroquine and chloroquine was revoked in June 2020.
References
1. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel
coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-271. Available at:
2. Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection
and spread. Virol J. 2005;2:69. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16115318.
3. Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting
SARS-CoV-2 infection in vitro. Cell Discov. 2020;6:16. Available at:
4. Fantini J, Chahinian H, Yahi N. Synergistic antiviral effect of hydroxychloroquine and azithromycin in
combination against SARS-CoV-2: what molecular dynamics studies of virus-host interactions reveal. Int J
Antimicrob Agents. 2020. Available at: https://pubmed.ncbi.nlm.nih.gov/32405156/.
5. Andreani J, Bideau ML, Duflot I, et al. In vitro testing of combined hydroxychloroquine and azithromycin on
SARS-CoV-2 shows synergistic effect. Microb Pathog. 2020. Available at:
https://pubmed.ncbi.nlm.nih.gov/32344177/.
6. Maisonnasse P, Guedj J, Contreras V, et al. Hydroxychloroquine use against SARS-CoV-2 infection in
non-human primates. Nature. 2020;585(7826):584-587. Available at:
7. Recovery Collaborative Group, Horby P, Mafham M, et al. Effect of hydroxychloroquine in hospitalized
WHO Solidarity Trial results. N Engl J Med. 2021;384(6):497-511. Available at:
9. Self WH, Semler MW, Leither LM, et al. Effect of hydroxychloroquine on clinical status at 14 days in
hospitalized patients with COVID-19: a randomized clinical trial. JAMA. 2020;324(21):2165-2176. Available
10. Furtado RHM, Berwanger O, Fonseca HA, et al. Azithromycin in addition to standard of care versus
standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil
(COALITION II): a randomised clinical trial. Lancet. 2020;396(10256):959-967. Available at:
11. Cavalcanti AB, Zampieri FG, Rosa RG, et al. Hydroxychloroquine with or without azithromycin in mild-to-
moderate COVID-19. N Engl J Med. 2020;383(21):2041-2052. Available at:
12. Recovery Collaborative Group. Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY):
a randomised, controlled, open-label, platform trial. Lancet. 2021;397(10274):605-612. Available at:
13. Rosenberg ES, Dufort EM, Udo T, et al. Association of treatment with hydroxychloroquine or azithromycin
with in-hospital mortality in patients with COVID-19 in New York state. JAMA. 2020. Available at:

AR08882
14. Geleris J, Sun Y, Platt J, et al. Observational study of hydroxychloroquine in hospitalized patients with
15. Arshad S, Kilgore P, Chaudhry ZS, et al. Treatment with hydroxychloroquine, azithromycin, and combination
in patients hospitalized with COVID-19. Int J Infect Dis. 2020;97:396-403. Available at:
16. Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in nonhospitalized adults with early
COVID-19: a randomized trial. Ann Intern Med. 2020;173(8):623-631. Available at:
17. Mitja O, Corbacho-Monne M, Ubals M, et al. Hydroxychloroquine for early treatment of adults with mild
COVID-19: a randomized-controlled trial. Clin Infect Dis. 2020;Published online ahead of print. Available at:
18. Omrani AS, Pathan SA, Thomas SA, et al. Randomized double-blinded placebo-controlled trial
of hydroxychloroquine with or without azithromycin for virologic cure of non-severe COVID-19.
EClinicalMedicine. 2020. Available at: https://pubmed.ncbi.nlm.nih.gov/33251500/.
19. PRINCIPLE Trial Collaborative Group. Azithromycin for community treatment of suspected COVID-19
in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled,
open-label, adaptive platform trial. Lancet. 2021;397(10279):1063-1074. Available at:
20. Hinks TS, Lucy C, Knight R, et al. A randomised clinical trial of azithromycin versus standard care in
ambulatory COVID-19—the ATOMIC2 trial. medRxiv. 2021;Preprint. Available at:
21. Nguyen LS, Dolladille C, Drici MD, et al. Cardiovascular toxicities associated with hydroxychloroquine
and azithromycin: an analysis of the World Health Organization pharmacovigilance database. Circulation.
22. Azithromycin (Zithromax) [package insert]. Food and Drug Administration. 2013. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050710s039,050711s036,050784s023lbl.pdf.
23. Mercuro NJ, Yen CF, Shim DJ, et al. Risk of QT interval prolongation associated with use of
hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive
for coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020;5(9):1036-1041. Available at:
24. Chorin E, Wadhwani L, Magnani S, et al. QT interval prolongation and torsade de pointes in patients with
COVID-19 treated with hydroxychloroquine/azithromycin. Heart Rhythm. 2020;17(9):1425-1433. Available
25. Food and Drug Administration. Remdesivir by Gilead Sciences: FDA warns of newly discovered potential
drug interaction that may reduce effectiveness of treatment. 2020. Available at: https://www.fda.gov/safety/
medical-product-safety-information/remdesivir-gilead-sciences-fda-warns-newly-discovered-potential-drug-
interaction-may-reduce.

AR08883
Table 2b. Chloroquine or Hydroxychloroquine and/or Azithromycin: Selected

Clinical Data
The information in this table may include data from preprints or articles that have not been peer reviewed. This section will be updated as new
information becomes available. Please see ClinicalTrials.gov for more information on clinical trials that are evaluating CQ, HCQ, and/or AZM.
The Panel has reviewed other clinical studies of HCQ with or without AZM, CQ, and AZM for the treatment of COVID-19.1-19 These studies
have limitations that make them less definitive and informative than the studies discussed here. The Panel’s summaries and interpretations of
some of those studies are available in the archived versions of the COVID-19 Treatment Guidelines.
Study Design Methods Results Limitations and Interpretation
Solidarity Trial: Hydroxychloroquine in Hospitalized Patients With COVID-1920

Open-label randomized Key Inclusion Criteria: Number of Participants: Key Limitations:
controlled platform trial • Aged ≥18 years • ITT analysis: HCQ (n = 947) and HCQ control (n = 906) • Not blinded
with multiple arms;
in 1 arm, hospitalized • Received a diagnosis of COVID-19 • Enrollment occurred between March 22 and October 4, 2020. • Disease severity varied widely
patients received HCQ among patients.
Key Exclusion Criteria: Participant Characteristics:
(n = 11,330) • Already receiving study drug • 35% of patients enrolled in each arm were aged <50 years; Interpretation:
• Expected to be transferred 21% of patients were aged ≥70 years. • HCQ does not decrease in-
elsewhere within 72 hours • 21% to 23% of patients had diabetes mellitus, 20% to 21% hospital mortality in hospitalized
had heart disease, and 6.5% to 7% had chronic lung disease. patients with COVID-19 when
Interventions: compared to SOC.
• At entry, 36% to 38% of patients were not on supplemental
• HCQ plus local SOC. Patients • HCQ does not decrease the need
oxygen, 53% to 55% were receiving supplemental oxygen
received a loading dose of HCQ for mechanical ventilation when
only, and 9% were receiving IMV.
800 mg PO at entry, then HCQ compared to SOC.
800 mg PO 6 hours later followed • SOC included corticosteroids for 23% of patients in HCQ arm
and 22% of patients in SOC only arm. • There was no evidence of harm in
by a daily dose of HCQ 400
the HCQ arm.
mg PO twice daily for 10 days, Outcomes:
starting 12 hours after the entry
dose. • No significant difference in in-hospital mortality; 104 patients
(10.2%) in HCQ arm and 84 patients (8.9%) in SOC arm died
• Local SOC alone by Day 28 (rate ratio 1.19; 95% CI, 0.89–1.59; P = 0.23).

AR08884
Solidarity Trial: Hydroxychloroquine in Hospitalized Patients With COVID-1920, continued

Primary Endpoint: •S ubgroup analyses based on age or respiratory support at entry
• In-hospital mortality (i.e., death reported no significant difference in mortality between the arms.
during the original hospitalization; • N o difference between the arms in the secondary outcome
follow-up ended at discharge of initiation of ventilation, and no difference in the composite
from the hospital) outcome of in-hospital mortality or initiation of ventilation
• T he number of deaths due to any cardiac cause during the 14
days after enrollment (the dosing period) was lower in these 2
arms than in the other study arms (the RDV, LPV/RTV, and IFN
arms and their respective control arms).
PETAL Trial: Hydroxychloroquine in Hospitalized Patients With COVID-1921
Randomized, placebo- Key Inclusion Criteria: Number of Participants: Key Limitations:
controlled, blinded trial • Laboratory-confirmed SARS- • E nrollment occurred between April 2 and June 19, 2020. • It is unclear how the primary
in hospitalized adults CoV-2 infection outcome of this study (a median
(n = 479) •H CQ (n = 242) and placebo (n = 237)
• Symptoms of respiratory illness COVID Outcomes Scale score)
•P lanned sample size was 510 participants, but study enrollment translates to clinical practice.
for <10 days was halted early due to futility.
Key Exclusion Criteria: Interpretation:
Participant Characteristics:
• More than 1 dose of HCQ or CQ • HCQ does not improve patient
•M edian age was 58 and 57 years in HCQ and placebo arms, scores on the COVID Outcomes
during the previous 10 days respectively; 33% of patients were aged ≥65 years and 24% of Scale in hospitalized patients with
• Prolonged QTc interval (>500 ms) patients were Black/African American. laboratory-confirmed SARS-
Interventions: • 3 3% to 36% of patients had diabetes mellitus, 6% to 12% had CoV-2 infection when compared
heart disease, and 7% to 9% had chronic lung disease. to placebo.
• HCQ 400 mg PO twice daily for
2 doses, then HCQ 200 mg PO • A t randomization, 5.4% of patients in HCQ arm and 8% in • HCQ did not improve survival or
twice daily for 8 doses placebo arm were receiving IMV or ECMO. In both arms, 11% time to discharge in these patients
to 12% of patients were receiving noninvasive ventilation or when compared to placebo.
• Matching placebo
HFNC oxygen, 46% to 48% were receiving low-flow oxygen,
Primary Endpoint: and 35% were receiving no respiratory support.
• Clinical status 14 days after • Among the patients who received concomitant medications,
randomization, as measured by a 22% received RDV, 19% received AZM, and 18% received
7-point ordinal scale (the COVID corticosteroids. There was no difference in concomitant
Outcomes Scale) medication use between the arms.

AR08885
PETAL Trial: Hydroxychloroquine in Hospitalized Patients With COVID-1921, continued

Outcomes:
• Median COVID Outcomes Scale score was 6 in HCQ arm
(IQR 4–7) and 6 in placebo arm (IQR 4–7; aOR 1.02; 95% CI,
0.73–1.42).
• No difference between the arms in the secondary outcome of
all-cause, all-location death at Day 14 and Day 28
• No difference between the arms in the number of any of the
following systematically collected safety events: cardiac arrest
treated with CPR, symptomatic hypoglycemia, ventricular
arrhythmia, or seizure
• Among patients who had QTc assessed, 5.9% in HCQ arm and
3.3% in placebo arm had a recorded QTc interval >500 ms
during the first 5 days of dosing.
RECOVERY Trial22
Open-label, randomized Key Inclusion Criteria: Number of Participants: Key Limitations:
controlled platform trial • Clinically suspected or • HCQ (n = 1,561) and SOC (n = 3,155) • Not blinded
with multiple arms; laboratory-confirmed SARS-
in 1 arm, hospitalized • Study enrollment ended early after investigators and trial- • Information on occurrence of new
CoV-2 infection steering committee concluded that the data showed no benefit major cardiac arrythmia was not
patients received HCQ
(n = 11,197) Key Exclusion Criteria: for HCQ. collected throughout the trial.
• Patients with prolonged QTc Participant Characteristics: Interpretation:
intervals were excluded from • Mean age was 65 years in both arms; 41% of patients were • HCQ does not decrease 28-day all-
HCQ arm. aged ≥70 years. cause mortality when compared
Interventions: • 90% of patients had laboratory-confirmed SARS-CoV-2 to the usual SOC in hospitalized
infection. patients with clinically suspected
• HCQ 800 mg at entry and at 6
or laboratory-confirmed SARS-
hours, then HCQ 400 mg every • 57% of patients had ≥1 major comorbidity: 27% had diabetes CoV-2 infection.
12 hours for 9 days or until mellitus, 26% had heart disease, and 22% had chronic lung
discharge disease. • Patients who received HCQ
had a longer median length of
• Usual SOC • At randomization, 17% of patients were receiving IMV or hospital stay, and those who
Primary Endpoint: ECMO, 60% were receiving oxygen only (with or without were not on IMV at the time of
noninvasive ventilation), and 24% were receiving neither. randomization were more likely
• All-cause mortality at Day 28
after randomization • Use of AZM or another macrolide during the follow-up period to require intubation or die during
was similar in both arms, as was use of dexamethasone. hospitalization if they received
HCQ.

AR08886
RECOVERY Trial22, continued

Outcomes:
• No significant difference in 28-day mortality between
the 2 arms; 421 patients (26.8%) in HCQ arm and 790
patients (27.0%) in SOC arm had died by Day 28 (rate
ratio 1.09; 95% CI, 0.97–1.23; P = 0.15).
• A similar 28-day mortality for HCQ patients was
reported during the post hoc exploratory analysis that
was restricted to the 4,266 participants (90.5%) who
had a positive SARS-CoV-2 test result.
• Patients in HCQ arm were less likely to survive
hospitalization and had a longer median time to
discharge than patients in SOC arm.
• Patients who received HCQ and who were not on
IMV at baseline had an increased risk of requiring
intubation and an increased risk of death.
• At the beginning of the study, the researchers did not
record whether a patient developed a major cardiac
arrhythmia after study enrollment; however, these
data were later collected for 735 patients (47.1%) in
HCQ arm and 1,421 patients (45.0%) in SOC arm.
• No differences between the arms in the frequency of
supraventricular tachycardia, ventricular tachycardia
or fibrillation, or instances of AV block that required
intervention; 1 case of Torsades de Pointes was
reported in HCQ arm.
Hydroxychloroquine and Hydroxychloroquine Plus Azithromycin for Mild or Moderate COVID-1923
Open-label, 3-arm RCT Key Inclusion Criteria: Number of Participants: Key Limitations:
in hospitalized adults • Aged ≥18 years • mITT analysis included patients with laboratory- • Not blinded
(n = 667) confirmed SARS-CoV-2 infection (n = 504).
• Clinically suspected or • F ollow-up period was restricted to 15 days.
laboratory-confirmed SARS- Participant Characteristics: Interpretation:
CoV-2 infection
• Mean age was 50 years. • Neither HCQ alone nor HCQ plus AZM
• Mild or moderate COVID-19
• 58% of patients were men. improved clinical outcomes at Day 15 after
• Duration of symptoms ≤14 days randomization among hospitalized patients

AR08887
Hydroxychloroquine and Hydroxychloroquine Plus Azithromycin for Mild or Moderate COVID-1923, continued
Key Exclusion Criteria: • At baseline, 58.2% of patients were Ordinal Level 3; with mild or moderate COVID-19.
• Need for >4 L of supplemental 41.8% were Ordinal Level 4.
oxygen or ≥40% FiO2 by face mask • Median time from symptom onset to randomization was
• History of ventricular tachycardia 7 days.
• QT interval ≥480 ms • 23.3% to 23.9% of patients received oseltamivir.
Interventions: Outcomes:
• HCQ 400 mg twice daily for 7 days • No significant difference in the odds of worse clinical
plus SOC status at Day 15 between patients in HCQ arm (OR 1.21;
95% CI, 0.69–2.11; P = 1.00) and patients in HCQ plus
• HCQ 400 mg twice daily plus AZM AZM arm (OR 0.99; 95% CI, 0.57–1.73; P = 1.00)
500 mg daily for 7 days plus SOC
• No significant differences in secondary outcomes of the
• SOC alone 3 arms, including progression to mechanical ventilation
Primary Endpoint: during the first 15 days and mean number of days “alive
• Clinical status at Day 15, as and free of respiratory support”
measured by a 7-point ordinal • A greater proportion of patients in HCQ plus AZM arm
scale among the patients with (39.3%) and HCQ arm (33.7%) experienced AEs than
confirmed SARS-CoV-2 infection those in SOC arm (22.6%).
Ordinal Scale Definitions: • QT prolongation was more common in patients who
received HCQ plus AZM or HCQ alone than in patients
1. Not hospitalized, no limitations
who received SOC alone, but fewer patients in SOC
2. Not hospitalized, with limitations arm had serial electrocardiographic studies performed
3. Hospitalized, not on oxygen during the follow-up period.
4. Hospitalized, on oxygen
5. Hospitalized, oxygen administered
by HFNC or noninvasive
ventilation
6. Hospitalized, on mechanical
ventilation
7. Death

AR08888
Hydroxychloroquine in Nonhospitalized Adults With Early COVID-1924

Randomized, placebo- Key Inclusion Criteria: Number of Participants: Key Limitations:
controlled trial in • Symptoms that were compatible • Contributed to primary endpoint data: HCQ (n = 212) and • This study enrolled a highly
nonhospitalized adults with COVID-19 and lasted ≤4 placebo (n = 211) heterogeneous population.
(n = 491) days
Participant Characteristics: • Only 227 of 423 participants (53.7%)
• Either laboratory-confirmed were confirmed PCR-positive for
• 241 patients were exposed to people with COVID-19
SARS-CoV-2 infection or high- SARS-CoV-2.
through their position as health care workers (57%), 106
risk exposure within the previous
were exposed through household contacts (25%), and 76 • Changing the primary endpoint
14 days without a new power calculation
had other types of exposure (18%).
Key Exclusion Criteria: makes it difficult to assess whether
• Median age was 40 years.
the study is powered to detect
• Aged <18 years • 56% of patients were women. differences in outcomes between the
• Hospitalized • Only 3% of patients were Black. study arms.
• Receipt of certain medications • Very few patients had comorbidities: 11% had • This study used surveys for
Interventions: hypertension, 4% had diabetes, and 68% had no chronic screening, symptom assessment,
medical conditions. and adherence reporting.
• HCQ 800 mg once, then HCQ 600
mg in 6–8 hours, then HCQ 600 • 56% of patients were enrolled on Day 1 of symptom • Visual analogue scales are not
mg once daily for 4 days onset. commonly used, and their ability
• Placebo • 341 participants (81%) had either a positive PCR result or to assess acute viral respiratory
a high-risk exposure to a PCR-positive contact. infections in clinical trials has not
Primary Endpoints: been validated.
Outcomes:
• Planned primary endpoint was Interpretation:
ordinal outcome by Day 14 in • Compared to the placebo recipients, HCQ recipients
had a nonsignificant 12% difference in improvement in • The study has some limitations,
4 categories: not hospitalized,
symptoms between baseline and Day 14 (-2.60 vs. -2.33 and it did not find evidence that
hospitalized, ICU stay, or death.
points; P = 0.117). early administration of HCQ reduced
• Because event rates were lower symptom severity in patients with
than expected, a new primary • Ongoing symptoms were reported by 24% of those in mild COVID-19.
endpoint was defined: change in HCQ arm and 30% of those in the placebo arm at Day 14
overall symptom severity over 14 (P = 0.21).
days, measured by a 10-point, • No difference in the incidence of hospitalization between
self-reported, visual analogue the arms (4 patients in the HCQ arm vs. 10 patients
scale in placebo arm); 2 of 10 placebo participants were
hospitalized for reasons that were unrelated to COVID-19
• A higher percentage of patients in HCQ arm experienced
AEs than patients in placebo arm (43% vs. 22%; P <
0.001).

AR08889
Hydroxychloroquine in Nonhospitalized Adults With Mild COVID-1925

Open-label RCT in Key Inclusion Criteria: Number of Participants: Key Limitations:
nonhospitalized adults • Laboratory-confirmed SARS- • ITT analysis: HCQ (n = 136) and control (n = 157) • Open-label, non-placebo-
(n = 353) CoV-2 infection controlled trial
• 60 patients were excluded from the ITT analysis due to
• <5 days of mild COVID-19 negative baseline RT-PCR, missing RT-PCR at follow-up • Study design allowed for the
symptoms visits, or consent withdrawal. possibility of dropouts in control
arm and over-reporting of AEs in
Key Exclusion Criteria: Participant Characteristics:
HCQ arm.
• Moderate to severe COVID-19 • Mean age was 41.6 years.
• The intervention changed during
• Severe liver or renal disease • 67% of patients were woman. the study; the authors initially
• History of cardiac arrhythmia • Majority of patients were health care workers (87%). planned to include HCQ plus DRV/
• QT prolongation • 53% of patients reported chronic health conditions. COBI.
• Median time from symptom onset to enrollment was 3 days • The majority of the participants
Interventions:
(IQR 2–4 days). were relatively young health care
• HCQ 800 mg on Day 1, then HCQ workers.
400 mg once daily for 6 days • Most common COVID-19 symptoms were fever, cough, and
sudden olfactory loss. Interpretation:
• No antiviral treatment (control
arm) Outcomes: • Early administration of HCQ to
patients with mild COVID-19
Primary Endpoint: • No significant difference in viral load reduction between did not result in improvement in
control arm and HCQ arm at Day 3 virologic clearance, a lower risk of
• Reduction in SARS-CoV-2 viral
load, assessed using NP swabs • (-1.41 vs. -1.41 log10 copies/mL; difference of 0.01; 95% CI, disease progression, or a reduced
on Days 3 and 7 -0.28 to 0.29), or at Day 7 (-3.37 vs. -3.44 log10 copies/mL; time to symptom improvement.
difference of -0.07; 95% CI, -0.44 to 0.29).
Secondary Endpoints:
• No difference in the risk of hospitalization between control
• Disease progression up to Day 28 arm and HCQ arm (7.1% vs. 5.9%; risk ratio 0.75; 95% CI,
• Time to complete resolution of 0.32–1.77)
symptoms • No difference in the median time from randomization to the
resolution of COVID-19 symptoms between the 2 arms (12.0
days in control arm vs. 10.0 days in HCQ arm; P = 0.38)
• A higher percentage of participants in the HCQ arm than in
the control arm experienced AEs during the 28-day follow-up
period (72% vs. 9%). Most common AEs were GI disorders
and “nervous system disorders.”
• SAEs were reported in 12 patients in control arm and 8
patients in HCQ arm. SAEs that occurred among patients in
HCQ arm were not deemed to be related to the drug.

AR08890
Observational Study on Hydroxychloroquine With or Without Azithromycin26

Retrospective, Key Inclusion Criteria: Number of Participants: Key Limitations:
multicenter, • Laboratory-confirmed SARS- • HCQ plus AZM (n = 735), HCQ alone (n = 271), AZM • This study has the inherent
observational study in CoV-2 infection alone (n = 211), and neither drug (n = 221) limitations of an observational study,
a random sample of including residual confounding from
hospitalized adults with Interventions: Participant Characteristics:
confounding variables that were
COVID-19 from the New • HCQ plus AZM • Patients in the treatment arms had more severe disease unrecognized and/or unavailable for
York Department of • HCQ alone at baseline than those who received neither drug. analysis.
Health (n = 1,438)
• AZM alone Outcomes: Interpretation:
• Neither drug • In adjusted analyses, patients who received 1 of the • Despite the limitations discussed
3 treatment regimens did not show a decreased in- above, these findings suggest that
Primary Endpoint: hospital mortality rate when compared with those who although HCQ and AZM are not
• In-hospital mortality received neither drug. associated with an increased risk of
Secondary Endpoint: • Patients who received HCQ plus AZM had a greater risk in-hospital death, the combination of
• Cardiac arrest and arrhythmia or of cardiac arrest than patients who received neither drug HCQ and AZM may be associated with
(OR 2.13; 95% CI, 1.12–4.05). an increased risk of cardiac arrest.
QT prolongation on an ECG
Observational Study of Hydroxychloroquine Versus No Hydroxychloroquine in New York City27
Observational study in Key Inclusion Criteria: Number of Participants: Key Limitations:
hospitalized adults with • Laboratory-confirmed SARS- • Received HCQ (n = 811) and did not receive HCQ (n = • This study has the inherent
COVID-19 at a large CoV-2 infection 565) limitations of an observational study,
medical center (n = including residual confounding from
1,376) Key Exclusion Criteria: Participant Characteristics:
confounding variables that were
• Intubation, death, or transfer to • HCQ recipients were more severely ill at baseline than unrecognized and/or unavailable for
another facility within 24 hours those who did not receive HCQ. analysis.
of arriving at the emergency
Outcomes: Interpretation:
department
• Using propensity scores to adjust for major predictors • The use of HCQ for treatment of
Interventions: of respiratory failure and inverse probability weighting, COVID-19 was not associated
• HCQ 600 mg twice daily on Day the study demonstrated that HCQ use was not with harm or benefit in a large
1, then HCQ 400 mg once daily associated with intubation or death (HR 1.04; 95% CI, observational study.
for 4 days 0.82–1.32).
• No HCQ • No association between concomitant use of AZM and
the composite endpoint of intubation or death (HR 1.03;
Primary Endpoint:
95% CI, 0.81–1.31)
• Time from study baseline (24
hours after patients arrived at the
ED) to intubation or death

AR08891
Key: AE = adverse event; AV = atrioventricular; AZM = azithromycin; CPR = cardiopulmonary resuscitation; CQ = chloroquine; DRV/COBI = darunavir/cobicistat; ECG
= electrocardiogram; ECMO = extracorporeal membrane oxygenation; ED = emergency department, FiO2 = fraction of inspired oxygen; GI = gastrointestinal; HCQ =
hydroxychloroquine; HFNC = high-flow nasal cannula; ICU = intensive care unit; IFN = interferon; IMV = invasive mechanical ventilation; ITT = intention-to-treat; LPV/
RTV = lopinavir/ritonavir; mITT = modified intention-to-treat; NP = nasopharyngeal; the Panel = the COVID-19 Treatment Guidelines Panel; PCR = polymerase chain
reaction; PO = orally; RCT = randomized controlled trial; RDV = remdesivir; RT-PCR = reverse transcription polymerase chain reaction; SAE = serious adverse event;
SOC = standard of care
References
1. Chorin E, Dai M, Shulman E, et al. The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin. Nat Med.
2. Gautret P, Lagier JC, Parola P, et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19
patients with at least a six-day follow up: A pilot observational study. Travel Med Infect Dis. 2020:101663. Available at:
3. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized
clinical trial. Int J Antimicrob Agents. 2020:105949. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32205204.
4. Huang M, Tang T, Pang P, et al. Treating COVID-19 with chloroquine. J Mol Cell Biol. 2020;12(4):322-325. Available at:
5. Magagnoli J, Narendran S, Pereira F, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with COVID-19. Med (N Y).
2020;1(1):114-127.e3. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32838355.
6. Molina JM, Delaugerre C, Le Goff J, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and
azithromycin in patients with severe COVID-19 infection. Med Mal Infect. 2020;50(4):384. Available at:
7. Satlin MJ, Goyal P, Magleby R, et al. Safety, tolerability, and clinical outcomes of hydroxychloroquine for hospitalized patients with coronavirus 2019
disease. PLoS One. 2020;15(7):e0236778. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32701969.
8. Mikami T, Miyashita H, Yamada T, et al. Risk factors for mortality in patients with COVID-19 in New York City. J Gen Intern Med. 2021;36(1):17-26.
9. Catteau L, Dauby N, Montourcy M, et al. Low-dose hydroxychloroquine therapy and mortality in hospitalised patients with COVID-19: a nationwide
observational study of 8075 participants. Int J Antimicrob Agents. 2020:106144. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32853673.
10. COVID-19 RISK and Treatments (CORIST) Collaboration. Use of hydroxychloroquine in hospitalised COVID-19 patients is associated with reduced
mortality: findings from the observational multicentre Italian CORIST study. Eur J Intern Med. 2020;82:38-47. Available at:
11. Furtado RHM, Berwanger O, Fonseca HA, et al. Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients
admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial. Lancet. 2020;396(10256):959-967. Available at:
12. Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised

AR08892
controlled trial. BMJ. 2020;369:m1849. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32409561.

13. Borba MGS, Val FFA, Sampaio VS, et al. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial. JAMA Netw Open. 2020;3(4):e208857. Available
14. Mahevas M, Tran VT, Roumier M, et al. Clinical efficacy of hydroxychloroquine in patients with COVID-19 pneumonia who require oxygen:
observational comparative study using routine care data. BMJ. 2020;369:m1844. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32409486.
15. Arshad S, Kilgore P, Chaudhry ZS, et al. Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19.
Int J Infect Dis. 2020;97:396-403. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32623082.
16. Recovery Collaborative Group. Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label,
platform trial. Lancet. 2021;397(10274):605-612. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33545096.
17. Omrani AS, Pathan SA, Thomas SA, et al. Randomized double-blinded placebo-controlled trial of hydroxychloroquine with or without azithromycin
for virologic cure of non-severe COVID-19. EClinicalMedicine. 2020;29:100645. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33251500.
18. Principle Trial Collaborative Group. Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical
course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet. 2021;397(10279):1063-1074. Available at:
19. Hinks TSC, Cureton L, Knight R, et al. A randomised clinical trial of azithromycin versus standard care in ambulatory COVID-19–the ATOMIC2 trial.
medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.04.21.21255807v1.
21. Self WH, Semler MW, Leither LM, et al. Effect of hydroxychloroquine on clinical status at 14 days in hospitalized patients with COVID-19: a
randomized clinical trial. JAMA. 2020;324(21):2165-2176. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33165621.
22. Recovery Collaborative Group, Horby P, Mafham M, et al. Effect of hydroxychloroquine in hospitalized patients with COVID-19. N Engl J Med.
23. Cavalcanti AB, Zampieri FG, Rosa RG, et al. Hydroxychloroquine with or without azithromycin in mild-to-moderate COVID-19. N Engl J Med.
24. Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in nonhospitalized adults with early COVID-19: a randomized trial. Ann Intern Med.
25. Mitja O, Corbacho-Monne M, Ubals M, et al. Hydroxychloroquine for early treatment of adults with mild COVID-19: a randomized-controlled trial.
Clin Infect Dis. 2020;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32674126.
26. Rosenberg ES, Dufort EM, Udo T, et al. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with
COVID-19 in New York state. JAMA. 2020;323(24):2493-2502. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32392282.
27. Geleris J, Sun Y, Platt J, et al. Observational study of hydroxychloroquine in hospitalized patients with COVID-19. N Engl J Med. 2020;382(25):2411-

AR08893
Interferons
Interferons are a family of cytokines with in vitro and in vivo antiviral properties. Interferon beta-1a
has been approved by the Food and Drug Administration (FDA) to treat relapsing forms of multiple
sclerosis, and it has been evaluated in clinical trials for the treatment of COVID-19. Interferon alfa has
been approved to treat hepatitis B and hepatitis C virus infections, and interferon lambda is not currently
approved by the FDA for any use. Both interferon alfa and lambda have also been evaluated for the
Recommendations
• The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of systemic
interferon beta for the treatment of hospitalized patients with COVID-19 (AI).
• The Panel recommends against the use of interferon alfa or lambda for the treatment of
hospitalized patients with COVID-19, except in a clinical trial (AIIa).
• The Panel recommends against the use of interferons for the treatment of nonhospitalized
patients with mild or moderate COVID-19, except in a clinical trial (AIIa).
Rationale
Many of the early studies that evaluated the use of systemic interferons for the treatment of COVID-19
were conducted in early 2020, before the widespread use of remdesivir and corticosteroids. In addition,
these early studies administered interferons with other drugs that have since been shown to have no
clinical benefit in people with COVID-19, such as lopinavir/ritonavir and hydroxychloroquine.1-3
More recent studies have not demonstrated efficacy for interferons in the treatment of COVID-19, and
some of the trials suggested potential harm in patients with severe disease, such as those who were
on high-flow oxygen, noninvasive ventilation, or mechanical ventilation.4,5 In a large randomized
controlled trial of hospitalized patients with COVID-19, the combination of interferon beta-1a plus
remdesivir showed no clinical benefit when compared to remdesivir alone.4 Similarly, the World
Health Organization Solidarity trial did not show a benefit for interferon beta-1a when this drug was
administered to hospitalized patients, approximately 50% of whom were on corticosteroids.5
Other interferons, including systemic interferon alfa or lambda and inhaled interferons, have also been
evaluated in patients with COVID-19; however, these interferons (with the exception of subcutaneous
interferon alfa) are not available in the United States. The trials that have evaluated interferon alfa and
interferon lambda have generally been small or moderate in size and have not been adequately powered
to assess whether these agents provide a clinical benefit for patients with COVID-19 (see Table 2c).
Clinical Trials
See ClinicalTrials.gov for a list of clinical trials that are evaluating the use of interferons for the
Adverse Effects
The most frequent adverse effects of systemic interferon include flu-like symptoms, nausea, fatigue,
weight loss, hematological toxicities, elevated transaminases, and psychiatric problems (e.g., depression,
suicidal ideation). Interferon beta is better tolerated than interferon alfa, but it can cause similar types of
adverse effects.6,7

AR08894
Additive toxicities may occur when systemic interferons are used concomitantly with other
immunomodulators and chemotherapeutic agents.6,7
According to analyses of data from several large pregnancy registries, exposure to interferon beta-1b
prior to conception or during pregnancy does not lead to an increased risk of adverse birth outcomes
(e.g., spontaneous abortion, congenital anomaly).8,9 Exposure to interferon beta-1b did not influence
birth weight, height, or head circumference.10
There are currently not enough data on the use of interferons to treat respiratory viral infections in
children to make any recommendations for treating children with COVID-19.
References
1. Alavi Darazam I, Hatami F, Mahdi Rabiei M, et al. An investigation into the beneficial effects of high-dose
interferon beta 1-a, compared to low-dose interferon beta 1-a in severe COVID-19: The COVIFERON II
randomized controlled trial. Int Immunopharmacol. 2021;99:107916. Available at:
2. Hung IF, Lung KC, Tso EY, et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin
in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, Phase 2 trial.
Lancet. 2020;395(10238):1695-1704. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32401715.
3. Rahmani H, Davoudi-Monfared E, Nourian A, et al. Interferon beta-1b in treatment of severe COVID-19: a
randomized clinical trial. Int Immunopharmacol. 2020;88:106903. Available at:
4. Kalil AC, Mehta AK, Patterson TF, et al. Efficacy of interferon beta-1a plus remdesivir compared with
remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, Phase
3 trial. Lancet Respir Med. 2021;Published online ahead of print. Available at:
WHO Solidarity Trial results. N Engl J Med. 2021;384(6):497-511. Available at:
6. Interferon alfa-2b (Intron A) [package insert]. Food and Drug Administration. 2018. Available at:
7. Interferon beta-1a (Rebif) [package insert]. Food and Drug Administration. 2019. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/103780s5204lbl.pdf.
8. Sandberg-Wollheim M, Alteri E, Moraga MS, Kornmann G. Pregnancy outcomes in multiple sclerosis
following subcutaneous interferon beta-1a therapy. Mult Scler. 2011;17(4):423-430. Available at:
9. Hellwig K, Duarte Caron F, Wicklein EM, Bhatti A, Adamo A. Pregnancy outcomes from the
global pharmacovigilance database on interferon beta-1b exposure. Ther Adv Neurol Disord.
10. Burkill S, Vattulainen P, Geissbuehler Y, et al. The association between exposure to interferon-beta
during pregnancy and birth measurements in offspring of women with multiple sclerosis. PLoS One.

AR08895
Table 2c. Interferons: Selected Clinical Data

The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations
for interferons. The studies summarized below are the randomized controlled trials that have had the greatest impact on the Panel’s
recommendations.
ACTT-3: Multinational, Double-Blind RCT of Interferon Beta-1a and Remdesivir in Hospitalized Adults With COVID-191
Key Inclusion Criteria: Participant Characteristics: Key Limitation:
• Evidence of pneumonia (radiographic infiltrates, SpO2 • Mean age 59 years; 38% were aged ≥65 years • OS6 patients were excluded after 270
≤94% on room air, or supplemental oxygen) • 58% men; 32% Latino, 60% White, 17% Black patients were enrolled because of an
• No MV required increased frequency of AEs in this group
• Mean of 8.6 days of symptoms before enrollment
Key Exclusion Criteria: • 90% had ≥1 comorbidity; 58% with HTN; 58% with Interpretation:
• AST or ALT >5 times ULN obesity; 37% with DM • There was no clinical benefit of IFN
beta-1a plus RDV in hospitalized patients
• Impaired renal function Primary Outcome: compared to RDV alone.
• Anticipated hospital discharge or transfer within 72 • Median time to recovery for both arms was 5 days (rate • The use of IFN beta-1a was associated
hours ratio 0.99; 95% CI, 0.87–1.13; P = 0.88). with worse outcomes among patients
Interventions: • In patients on high-flow oxygen or NIV (OS6) at who were OS6 at baseline.
baseline, median time to recovery was >28 days in
• RDV 200 mg IV on Day 1, then RDV 100 mg IV once
IFN beta-1a arm and 9 days in placebo arm (rate ratio
daily for 9 days plus IFN beta-1a 44 µg SQ every other
0.40; 95% CI, 0.22–0.75; P = 0.0031).
day for up to 4 doses (n = 487)
• RDV 200 mg IV on Day 1, then RDV 100 mg IV once Secondary Outcomes:
daily for 9 days plus placebo (n = 482) • No difference between arms in clinical improvement at
14 days (OR 1.01; 95% CI, 0.79–1.28).
Primary Endpoint:
• No difference between arms in mortality by Day 28 in:
• Time to recovery by Day 28
• All patients: 5% vs. 3% (HR 1.33; 95% CI, 0.69–2.55)
• Patients with OS6 at baseline: 21% vs. 12% (HR 1.74;
• Clinical status at Day 14, as measured by an OS 95% CI, 0.51–5.93)
• Mortality by Day 28

AR08896
WHO Solidarity Trial: Multinational, Open-Label, Adaptive RCT of IV or SQ Interferon Beta-1a or Other Repurposed Drugs in Hospitalized Adults With
COVID-192
• Diagnosis of COVID-19 • 35% aged <50 years; 19% aged ≥70 years; 63% men • Open-label study
• Not expected to be transferred elsewhere within 72 • 70% on supplemental oxygen; 7% on ventilation • IFN beta-1a given as IV or SQ
hours • Approximately 50% received corticosteroids during the formulations at different doses
Interventions: study Interpretation:
• IFN beta-1a 44 µg SQ on day of randomization, Day 3, Primary Outcomes: • IFN beta-1a does not improve mortality
and Day 6 (n = 1,656) • In-hospital mortality was 11.9% for combined IFN beta- for hospitalized patients.
• IFN beta-1a 10 µg IV daily for 6 days for patients on 1a arms and 10.5% in SOC arm (rate ratio 1.16; 95% CI,
high-flow oxygen, ventilation, or ECMO (n = 394) 0.96–1.39).
• IFN beta-1a (either SQ or IV) and LPV/RTV 400 mg/50 • For IFN beta-1a only (without LPV/RTV) recipients
mg twice daily for 14 days (n = 651) vs. SOC recipients, rate ratio was 1.12 (95% CI,
• Local SOC (n = 2,050) 0.83–1.51).
• Among those on ventilation at entry, age-stratified
Primary Endpoint:
rate ratio for in-hospital mortality was 1.40 (95% CI,
• In-hospital mortality 0.93–2.11).
Key Secondary Endpoint: Secondary Outcome:
• Initiation of ventilation • 10% initiated ventilation in the combined IFN beta-1a
arms and SOC arm.

AR08897
DisCoVeRy Solidarity Trial Add-On: Open-Label, Adaptive RCT of SQ Interferon Beta-1a Plus Lopinavir/Ritonavir, Lopinavir/Ritonavir, or Hydroxychloroquine
in Hospitalized Adults With COVID-19 in France3
• Positive PCR result for SARS-CoV-2 • Median age 63 years; 72% men • Open-label study
• Patients had pulmonary rales or crackles with SpO2 • 29% were obese; 26% with chronic cardiac disease; • Most patients had moderate disease
≤94% or they required supplemental oxygen 22% with DM • No IFN beta-1a arm without LPV/RTV
Interventions: • 36% had severe disease • Study stopped early for futility
• IFN beta-1a 44 ug SQ on Days 1, 3, and 6 plus LPV/RTV • Median of 9 days from symptom onset to randomization
Interpretation:
400 mg/100 mg PO twice daily for 14 days plus SOC (n • 30% received steroids during the study
= 145) • Compared to SOC alone, the use of IFN-
Primary Outcome: beta-1a plus LPV/RTV did not improve
• LPV/RTV 400 mg/100 mg PO twice daily for 14 days clinical status, rate of viral clearance, or
plus SOC (n = 145) • No difference in clinical status at Day 15 for any
intervention compared to SOC: time to viral clearance in hospitalized
• HCQ 400 mg twice on Day 1, then HCQ 400 mg daily for patients with COVID-19.
9 days plus SOC (n = 145) • IFN beta-1a plus LPV/RTV: aOR 0.69 (95% CI, 0.45–
1.04; P = 0.08)
• SOC alone, which included corticosteroids,
anticoagulants, or immunomodulatory agents but not • LPV/RTV: aOR 0.83 (95% CI, 0.55–1.26; P = 0.39)
antivirals (n = 148) • HCQ: aOR 0.93 (95% CI, 0.62–1.41; P = 0.75)
• Clinical status at Day 15, as measured by an OS • No difference in clinical status at Day 29 between the
arms.
• No difference in rate and time to SARS-CoV-2 viral
• Clinical status at Day 29 clearance between the arms.
• Rate of SARS-CoV-2 viral clearance • Time to 2 OS-category improvement and hospital
• Time to SARS-CoV-2 viral clearance discharge by Day 29 was longer in LPV/RTV plus IFN
• Time to improvement of 2 OS categories beta-1a and LPV/RTV arms than in SOC arm.
• Time to hospital discharge

AR08898
Single-Blind RCT of Peginterferon Lambda-1a for Treatment of Outpatients With Uncomplicated COVID-19 in the United States4
• Aged 18–65 years • Median age 36 years; 42% women; 63% Latinx, 28% • Small sample size
• Asymptomatic or symptomatic White
Interpretation:
• Positive RT-PCR result for SARS-CoV-2 within 72 hours • 7% were asymptomatic
• PEG-IFN lambda-1a provided no
of enrollment • Median of 5 days of symptoms before randomization virologic or clinical benefit compared
Key Exclusion Criteria: Primary Outcome: to placebo among outpatients with
uncomplicated COVID-19.
• Current or imminent hospitalization • Median time to cessation of viral shedding was 7 days in
• Respiratory rate >20 breaths/min both arms (aHR 0.81; 95% CI, 0.56–1.19; P = 0.29).
• SpO2 <94% on room air Secondary Outcomes:
• Decompensated liver disease • No difference between PEG-IFN lambda-1a and placebo
arms in:
Interventions:
• Proportion of patients hospitalized by Day 28: 3.3%
• Single dose of PEG-IFN lambda-1a 180 µg SQ (n = 60) for each arm
• Placebo (n = 60) • Time to resolution of symptoms: 8 days vs. 9 days
Primary Endpoint: (HR 0.94; 95% CI, 0.64–1.39)
• Time to first negative SARS-CoV-2 RT-PCR result Other Outcomes:
Key Secondary Endpoints: • Patients who received PEG-IFN lambda-1a were more
• Hospitalizations by Day 28 likely to have transaminase elevations than patients who
received placebo (25% vs. 8%; P = 0.027).
• Time to complete symptom resolution

AR08899
Double-Blind RCT of Peginterferon Lambda in Outpatients With Laboratory-Confirmed COVID-19 in Canada5

• Positive SARS-CoV-2 PCR result • Median age 46 years; 58% women; 52% White • Small sample size
• Patients were within 7 days of symptom onset, or, if • 19% were asymptomatic Interpretation:
asymptomatic, were within 7 days of first positive SARS- • Mean of 4.5 days of symptoms before randomization • PEG-IFN lambda may accelerate VL
CoV-2 test result
Primary Outcome: decline and clearance in outpatients
Key Exclusion Criterion: with COVID-19; however, the clinical
• 80% in PEG-IFN lambda arm and 63% in placebo arms significance of this finding is unclear.
• Immunosuppression or condition that could be were negative for SARS-CoV-2 RNA at Day 7 (P = 0.15).
worsened by PEG-IFN lambda
Secondary Outcomes:
Interventions:
• VL decline by Day 7 was greater in PEG-IFN lambda arm
• Single dose of PEG-IFN lambda 180 µg SQ (n = 30) than in placebo arm (P = 0.0041).
• Placebo (n = 30) • 1 participant in each arm was admitted to the hospital by
Primary Endpoint: Day 14.
• Proportion of participants with negative nasal mid- Other Outcomes:
turbinate swab for SARS-CoV-2 at Day 7 • 3 participants in each arm had mild elevation of
Key Secondary Endpoints: aminotransferase concentrations. Increase was greater
in PEG-IFN lambda arm.
• Quantitative change in SARS-CoV-2 RNA over time
• Hospitalizations by Day 14
Key: AE = adverse event; ALT = alanine transaminase; AST = aspartate aminotransferase; DM = diabetes mellitus; ECMO = extracorporeal membrane oxygenation;
HCQ = hydroxychloroquine; HTN = hypertension; IFN = interferon; IV = intravenous; LPV/RTV = lopinavir/ritonavir; MV = mechanical ventilation; NIV = noninvasive
ventilation; OS = ordinal scale; the Panel = the COVID-19 Treatment Guidelines Panel; PCR = polymerase chain reaction; PEG-IFN = pegylated interferon; RCT =
randomized controlled trial; RDV = remdesivir; RT-PCR = reverse transcription polymerase chain reaction; SOC = standard of care; SpO2 = oxygen saturation; SQ =
subcutaneous; ULN = upper limit of normal; VL = viral load
References
1. Kalil AC, Mehta AK, Patterson TF, et al. Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with
COVID-19: a double-bind, randomised, placebo-controlled, Phase 3 trial. Lancet Respir Med. 2021;9(12):1365-1376. Available at:
3. Ader F, Peiffer-Smadja N, Poissy J, et al. An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus

AR08900
IFN-beta-1a and hydroxychloroquine in hospitalized patients with COVID-19. Clin Microbiol Infect. 2021;27(12):1826-1837. Available at:
4. Jagannathan P, Andrews JR, Bonilla H, et al. Peginterferon lambda-1a for treatment of outpatients with uncomplicated COVID-19: a randomized
placebo-controlled trial. Nat Commun. 2021;12(1):1967. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33785743.
5. Feld JJ, Kandel C, Biondi MJ, et al. Peginterferon lambda for the treatment of outpatients with COVID-19: a Phase 2, placebo-controlled randomised
trial. Lancet Respir Med. 2021;9(5):498-510. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33556319.

AR08901
Ivermectin
Ivermectin is a Food and Drug Administration (FDA)-approved antiparasitic drug used to treat several
neglected tropical diseases, including onchocerciasis, helminthiases, and scabies.1 For these indications,
ivermectin has been widely used and is generally well-tolerated.1,2 Ivermectin is not approved by the
FDA for the treatment of any viral infection.
Proposed Mechanism of Action and Rationale for Use in Patients With COVID-19
Reports from in vitro studies suggest that ivermectin acts by inhibiting host importin alpha/beta-1
nuclear transport proteins, which are part of a key intracellular transport process.3,4 Viruses hijack the
process and enhance infection by suppressing the host’s antiviral response. In addition, ivermectin
docking may interfere with SARS-CoV-2 spike protein attachment to the human cell membrane.5
Some studies of ivermectin have also reported potential anti-inflammatory properties, which have been
postulated to be beneficial in people with COVID-19.6-8
Ivermectin has been shown to inhibit replication of SARS-CoV-2 in cell cultures.9 However,
pharmacokinetic and pharmacodynamic studies suggest that achieving the plasma concentrations
necessary for the antiviral efficacy detected in vitro would require administration of doses up to 100-fold
higher than those approved for use in humans.10,11 Although ivermectin appears to accumulate in lung
tissue, predicted systemic plasma and lung tissue concentrations are much lower than 2 µM, the half-
maximal inhibitory concentration (IC50) observed in vitro for ivermectin against SARS-CoV-2.12-15
Subcutaneous administration of ivermectin 400 µg/kg had no effect on SARS-CoV-2 viral loads in
hamsters.16 However, there was a reduction in olfactory deficit (measured using a food-finding test) and
a reduction in the interleukin (IL)-6:IL-10 ratio in lung tissues.
The safety and efficacy of ivermectin for the prevention and treatment of COVID-19 have been
evaluated in clinical trials and observational cohorts. Summaries of the studies that informed The
COVID-19 Treatment Guidelines Panel’s (the Panel) recommendation can be found in Table 2d. The
Panel reviewed additional studies, but these studies are not summarized in Table 2d because they have
study design limitations or results that make them less definitive and informative.
Recommendation
• The Panel recommends against the use of ivermectin for the treatment of COVID-19, except in
clinical trials (AIIa).
Rationale
The results of several randomized trials and retrospective cohort studies of ivermectin use in patients
with COVID-19 have been published in peer-reviewed journals or have been made available as
manuscripts ahead of peer review. Most of these studies, especially studies completed earlier in
the pandemic, had incomplete information and significant methodological limitations, which made
excluding common causes of bias difficult. Many of these studies have not been peer reviewed, and
some have now been retracted.
The Panel’s recommendation is primarily informed by recently published randomized controlled
trials.17-20 The primary outcomes of these trials showed that the use of ivermectin for the treatment of
COVID-19 had no clinical benefit. In TOGETHER, an adaptive platform trial conducted in Brazil, there
was no apparent difference between the ivermectin and placebo arms for the primary outcome of risk

AR08902
of emergency department visits or hospitalization (14.7% vs. 16.4%). Also, there was no statistically
significant difference between the ivermectin and placebo arms in mortality (3.1% vs. 3.5%).
I-TECH, an open-label trial conducted in Malaysia, found no difference between the ivermectin and
standard of care arms (21.6% vs. 17.3%) for the primary outcome of risk of progression to severe
disease. The ivermectin arm had a lower risk of mortality than the standard of care arm (1.2% vs. 4.0%),
but this difference was not statistically significant.
The study populations of both the TOGETHER and I-TECH trials were patients with mild to moderate
disease, and the number of deaths was low (as expected). In these randomized trials, completely
excluding an effect of ivermectin is difficult, because the trials were not powered to detect differences in
secondary outcomes, such as death. However, data from these trials do not provide evidence that the use
of ivermectin benefited the treatment of COVID-19.
Comparisons of the efficacy of ivermectin for the treatment of COVID-19 are complicated by the large
variability of doses and durations of treatment used in the studies. There have been concerns that doses
in early trials were too low and durations of treatment were too short. However, the higher doses (300
μg/kg–400 μg/kg per day for up to 3–5 days) used in the more recent TOGETHER and I-TECH trials
did not demonstrate clinical benefit.
Although there have been many ivermectin studies, only a few trials have been adequately powered,
well-designed, and well-conducted. More recent clinical trials address the limitations of earlier studies
but fail to show clear evidence that ivermectin reduces time to recovery or prevents COVID-19 disease
progression. For this reason, and because several medications now have demonstrated clinical benefit
for the treatment of COVID-19, the Panel recommends against the use of ivermectin for the treatment
of COVID-19, except in a clinical trial (AIIa). Additional adequately powered, well-designed, and well-
conducted trials are needed to evaluate the effect of ivermectin on COVID-19. The Panel will continue
to review emerging data on ivermectin use, including the results from 2 large, ongoing randomized
controlled trials.
See Table 2d for summaries of the key studies that informed the Panel’s recommendation.
Monitoring, Adverse Effects, and Drug-Drug Interactions

• Adverse effects of ivermectin may include dizziness, pruritis, nausea, or diarrhea.21
• Neurological adverse effects have been reported with the use of ivermectin for the treatment of
onchocerciasis and other parasitic diseases, but it is not clear whether these adverse effects were
caused by ivermectin or the underlying conditions.22
• Ivermectin is a minor cytochrome P450 3A4 substrate and a p-glycoprotein substrate.
• Ivermectin is generally given with water on an empty stomach; however, administering ivermectin
with food increases its bioavailability.
• The FDA first issued a warning in April 2020 that ivermectin intended for use in animals should
not be used to treat COVID-19 in humans. This warning was updated and reiterated in 2021.
Clinical Trials
Several clinical trials evaluating the use of ivermectin for the treatment of COVID-19 are currently
underway or in development. Please see ClinicalTrials.gov for the latest information.
References
1. Omura S, Crump A. Ivermectin: panacea for resource-poor communities? Trends Parasitol. 2014;30(9):445-

AR08903

2. Kircik LH, Del Rosso JQ, Layton AM, Schauber J. Over 25 years of clinical experience with ivermectin: an
overview of safety for an increasing number of indications. J Drugs Dermatol. 2016;15(3):325-332. Available
3. Yang SNY, Atkinson SC, Wang C, et al. The broad spectrum antiviral ivermectin targets the host nuclear
transport importin alpha/beta1 heterodimer. Antiviral Res. 2020;177:104760. Available at:
4. Arevalo AP, Pagotto R, Porfido JL, et al. Ivermectin reduces in vivo coronavirus infection in a mouse
experimental model. Sci Rep. 2021;11(1):7132. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33785846.
5. Lehrer S, Rheinstein PH. Ivermectin docks to the SARS-CoV-2 spike receptor-binding domain attached to
ACE2. In Vivo. 2020;34(5):3023-3026. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32871846.
6. Zhang X, Song Y, Ci X, et al. Ivermectin inhibits LPS-induced production of inflammatory cytokines and
improves LPS-induced survival in mice. Inflamm Res. 2008;57(11):524-529. Available at:
7. DiNicolantonio JJ, Barroso J, McCarty M. Ivermectin may be a clinically useful anti-inflammatory agent for
late-stage COVID-19. Open Heart. 2020;7(2). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32895293.
8. Ci X, Li H, Yu Q, et al. Avermectin exerts anti-inflammatory effect by downregulating the nuclear
transcription factor kappa-B and mitogen-activated protein kinase activation pathway. Fundam Clin
Pharmacol. 2009;23(4):449-455. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19453757.
9. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the
replication of SARS-CoV-2 in vitro. Antiviral Res. 2020;178:104787. Available at:
10. Chaccour C, Hammann F, Ramon-Garcia S, Rabinovich NR. Ivermectin and COVID-19: keeping rigor in
times of urgency. Am J Trop Med Hyg. 2020;102(6):1156-1157. Available at:
11. Guzzo CA, Furtek CI, Porras AG, et al. Safety, tolerability, and pharmacokinetics of escalating high doses of
ivermectin in healthy adult subjects. J Clin Pharmacol. 2002;42(10):1122-1133. Available at:
12. Arshad U, Pertinez H, Box H, et al. Prioritization of Anti-SARS-CoV-2 drug repurposing opportunities
based on plasma and target site concentrations derived from their established human pharmacokinetics. Clin
Pharmacol Ther. 2020;108(4):775-790. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32438446.
13. Bray M, Rayner C, Noel F, Jans D, Wagstaff K. Ivermectin and COVID-19: a report in Antiviral Research,
widespread interest, an FDA warning, two letters to the editor and the authors’ responses. Antiviral Res.
14. Momekov G, Momekova D. Ivermectin as a potential COVID-19 treatment from the pharmacokinetic point of
view: antiviral levels are not likely attainable with known dosing regimens. Biotechnol Biotechnologic Equip.
2020;34:469-474. Available at: https://www.tandfonline.com/doi/full/10.1080/13102818.2020.1775118.
15. Jermain B, Hanafin PO, Cao Y, et al. Development of a minimal physiologically-based pharmacokinetic
model to simulate lung exposure in humans following oral administration of ivermectin for COVID-19 drug
repurposing. J Pharm Sci. 2020;109(12):3574-3578. Available at:
16. de Melo GD, Lazarini F, Larrous F, et al. Attenuation of clinical and immunological outcomes during
SARS-CoV-2 infection by ivermectin. EMBO Mol Med. 2021;13(8):e14122. Available at:
17. Vallejos J, Zoni R, Bangher M, et al. Ivermectin to prevent hospitalizations in patients with COVID-19
(IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial. BMC Infect Dis.

AR08904
18. Lopez-Medina E, Lopez P, Hurtado IC, et al. Effect of ivermectin on time to resolution of symptoms among
adults with mild COVID-19: a randomized clinical trial. JAMA. 2021;325(14):1426-1435. Available at:
19. Lim SCL, Hor CP, Tay KH, et al. Efficacy of ivermectin treatment on disease progression among adults with
mild to moderate COVID-19 and comorbidities: the I-TECH randomized clinical trial. JAMA Intern Med.
20. Reis G, Silva E, Silva DCM, et al. Effect of early treatment with ivermectin among patients with COVID-19.
N Engl J Med. 2022;Published online ahead of print. Available at:
21. Ivermectin (Stromectol) [package insert]. Food and Drug Administration. 2009. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050742s024s025lbl.pdf.
22. Chandler RE. Serious neurological adverse events after ivermectin—do they occur beyond the indication of
onchocerciasis? Am J Trop Med Hyg. 2018;98(2):382-388. Available at:

AR08905
Table 2d. Ivermectin: Selected Clinical Data

The clinical trials described in this table are RCTs that had the greatest impact on the Panel’s recommendation. The Panel reviewed other
clinical studies of IVM for the treatment of COVID-19.1-27 However, those studies have limitations that make them less definitive and
informative than the studies summarized in the table.
TOGETHER: Double-Blind, Adaptive, RCT of Ivermectin in Nonhospitalized Patients With COVID-19 in Brazil28
• Positive SARS-CoV-2 antigen test • Median age 49 years; 46% aged ≥50 years; 58% • Health care facility capacity may have
• Within 7 days of symptom onset women; 95% “mixed race” influenced the number and duration
• Most prevalent risk factor: 50% with obesity of emergency setting visits and
• ≥1 high-risk factor for disease progression (e.g., aged hospitalizations.
>50 years, comorbidities, immunosuppression) • Symptom onset: 44% within 3 days
• No details on safety outcomes (e.g., type
Interventions: Primary Outcome: of treatment-emergent AEs) other than
• IVM 400 μg/kg PO per day for 3 days (n = 679) • Composite of emergency setting observation >6 hours grading were reported.
• Placebo (n = 679; not all participants received IVM or hospitalized within 28 days of randomization (ITT): Interpretation:
placebo) 100 (14.7%) in IVM arm vs. 111 (16.4%) in placebo arm
(relative risk 0.90; 95% CrI, 0.70–1.16) • In outpatients with recent COVID-19
Primary Endpoint: infection, IVM did not reduce the
• 171 (81%) of all events were hospitalizations (ITT) need for emergency setting visits or
• Composite of emergency setting observation >6
hours or hospitalized for COVID-19 within 28 days of Secondary Outcomes: hospitalization when compared with
randomization • No difference between IVM and placebo arms in: placebo.
Key Secondary Endpoints: • Viral clearance at Day 7 (relative risk 1.00; 95% CrI,
0.68–1.46)
• Viral clearance at Day 7
• All-cause mortality: 21 (3.1%) vs. 24 (3.5%) (relative
• All-cause mortality
risk 0.88; CrI, 0.49–1.55)
• Occurrence of AEs

AR08906
IVERCOR-COVID19: Double-Blind, Placebo-Controlled, Randomized Trial of Ivermectin in Nonhospitalized Patients With COVID-19 in Argentina29
Key Inclusion Criterion: Participant Characteristics: Key Limitation:
• Positive SARS-CoV-2 RT-PCR result within 48 hours of • Mean age 42 years; 8% aged ≥65 years; 47% women • Enrolled a fairly young population with
screening • 24% with HTN; 10% with DM; 58% with ≥1 comorbidity few of the comorbidities that predict
disease progression.
Key Exclusion Criteria: • Median time from symptom onset: 4 days
• Oxygen supplementation or hospitalization Interpretation:
Primary Outcome:
• Concomitant use of CQ or HCQ • Among patients who had recently
• Hospitalization for any reason: 5.6% in IVM arm vs. acquired SARS-CoV-2 infection, there
Interventions: 8.3% in placebo arm (OR 0.65; 95% CI, 0.32–1.31; P = was no evidence that IVM provided any
0.23) clinical benefit.
• Weight-based dose of IVM PO at enrollment and 24
hours later for a maximum total dose of 48 mg (n = Secondary Outcomes:
250) • Need for MV: 2% in IVM arm vs. 1% in placebo arm (P
• Placebo (n = 251) = 0.7)
Primary Endpoint: • All-cause mortality: 2% in IVM arm vs. 1% in placebo
arm (P = 0.7)
• Hospitalization for any reason
• Occurrence of AEs: 18% in IVM arm vs. 21% in placebo
Key Secondary Endpoints: arm (P = 0.6)
• Need for MV
• All-cause mortality

AR08907
I-TECH: Open-Label RCT of Ivermectin in Patients With Mild to Moderate COVID-19 in Malaysia30
• Positive SARS-CoV-2 RT-PCR or antigen test result • Mean age 63 years; 55% women • Open-label study
within 7 days of symptom onset • 68% received ≥1 dose COVID-19 vaccine; 52% received Interpretation:
• Aged ≥50 years 2 doses
• In patients with mild to moderate
•≥ 1 comorbidity • Most common comorbidities: 75% with HTN; 54% with COVID-19, there was no evidence
DM; 24% with dyslipidemia that IVM provided any clinical benefit,
• Mean duration of symptoms: 5 days including no evidence that IVM reduced
• Required supplemental oxygen progression to severe disease.
• Severe hepatic impairment (ALT >10 times the ULN) Primary Outcome:
• Progression to severe COVID-19 (mITT): 52 (21.6%)
Interventions:
in IVM plus SOC arm vs. 43 (17.3%) in SOC alone arm
• IVM: 400 μg/kg PO daily for 5 days plus SOC (n = 241) (relative risk 1.25; 95% CI, 0.87–1.80; P = 0.25)
• SOC (n = 249) Secondary Outcomes:
Primary Endpoint: • No difference between IVM plus SOC arm and SOC alone
• Progression to severe COVID-19 (i.e., hypoxia requiring arm in:
supplemental oxygen to maintain SpO2 ≥95%) • In-hospital, all-cause mortality: 3 (1.2%) vs. 10 (4.0%)
Key Secondary Endpoints: (relative risk 0.31; 95% CI, 0.09–1.11; P = 0.09)
• In-hospital, all-cause mortality by Day 28 • MV: 4 (1.7%) vs. 10 (4.0%) (relative risk 0.41; 95% CI,
0.13–1.30; P = 0.17)
• MV or ICU admission
• ICU admission: 6 (2.5%) vs. 8 (3.2%) (relative risk
0.78; 95% CI, 0.27–2.20; P = 0.79)
• Occurrence of AEs: 33 (13.7%) in the IVM plus SOC arm
vs. 11 (4.4%) in the SOC alone arm; most with diarrhea
(14 vs. 4)

AR08908
Double-Blind, Placebo-Controlled, Randomized Trial of Ivermectin in Patients With Mild COVID-19 in Colombia31
• Positive SARS-CoV-2 RT-PCR or antigen test result • Median age 37 years; 4% aged ≥65 years in IVM arm, • Due to low event rates, the primary
• Symptoms ≤7 days 8% in placebo arm; 39% men in IVM arm, 45% in endpoint changed from the proportion of
placebo arm patients with clinical deterioration to the
• Mild disease time to symptom resolution during the
• 79% with no known comorbidities
Key Exclusion Criteria: trial.
• Median symptom onset to randomization: 5 days
• Asymptomatic disease • The study enrolled younger, healthier
Primary Outcome: patients, a population that does not
• Severe pneumonia
• Median time to symptom resolution: 10 days in IVM arm typically develop severe COVID-19.
• Hepatic dysfunction vs. 12 days in placebo arm (HR 1.07; P = 0.53) Interpretation:
Interventions: • Symptoms resolved by Day 21: 82% in IVM arm vs. • In patients with mild COVID-19, IVM 300
• IVM 300 μg/kg PO per day for 5 days (n = 200) 79% in placebo arm μg/kg per day for 5 days did not improve
• Placebo PO (n = 198) Secondary Outcomes: the time to resolution of symptoms.
Primary Endpoint: • Clinical deterioration: no difference between arms
• Time to resolution of symptoms within 21 days • Escalation of care: no difference between arms
Key Secondary Endpoints: • Occurrence of AEs:
• Clinical deterioration • Discontinued treatment due to AEs: 8% in IVM arm vs.
3% in placebo arm
• Escalation of care
• No SAEs were related to intervention

AR08909
Open-Label RCT of Ivermectin in Hospitalized Patients With COVID-19 in Egypt32

• RT-PCR-confirmed SARS-CoV-2 infection by pharyngeal • Mean age 42 years for IVM arm, 39 years for SOC arm; • Small, open-label study
swab 50% men
Interpretation:
• Hospitalized with mild to moderate COVID-19 • 49% with ≥1 comorbidity
• Use of IVM, when compared with the
Key Exclusion Criterion: Primary Outcome: SOC, did not result in differences in
• Cardiac problems • All-cause mortality by 28 days: 3 (3.7%) in IVM arm vs. all-cause mortality, hospital LOS, or the
4 (4.9%) in SOC arm (P = 1.00) need for MV.
Interventions:
• IVM 12 mg PO once daily for 3 days (n = 82) Secondary Outcomes:
• SOC (n = 82) • Mean hospital LOS: 9 days in IVM arm vs. 11 days in
SOC arm (P = 0.085)
Primary Endpoint:
• Need for MV: 3 (3.7%) in each arm (P = 1.00)
• All-cause mortality by 28 days
• Hospital LOS
• Need for MV

AR08910
Double-Blind, Placebo-Controlled, Randomized Trial of Ivermectin in Patients With Mild to Moderate COVID-19 in India33
• Positive SARS-CoV-2 RT-PCR or antigen test result • Mean age 53 years; 28% women • Although the primary endpoint was a
• Hospitalized with mild or moderate COVID-19 • 35% with HTN; 36% with DM negative SARS-CoV-2 RT-PCR result
on Day 6, no RT-PCR result or an
Interventions: • 79% with mild COVID-19 inconclusive RT-PCR result was reported
• IVM 12 mg PO for 2 days (n = 55) • Mean 6.9 days from symptom onset for 42% of patients in the IVM arm and
• Placebo PO (n = 57) • 100% received HCQ, steroids, and antibiotics; 21% 23% in the placebo arm.
received RDV; 6% received tocilizumab • The time to discharge was not reported,
Primary Endpoint:
Primary Outcome: and outcomes after discharge were not
• Negative SARS-CoV-2 RT-PCR result on Day 6 evaluated.
• Negative RT-PCR result on Day 6: 24% in IVM arm vs.
Key Secondary Endpoints: 32% in placebo arm (rate ratio 0.8; P = 0.348) Interpretation:
• Symptom resolution by Day 6 • IVM provided no significant virologic or
Secondary Outcomes:
• Discharge by Day 10 clinical benefit for patients with mild to
• Symptom resolution by Day 6: 84% in IVM arm vs. 90% moderate COVID-19.
• Need for ICU admission or MV in placebo arm (rate ratio 0.9; P = 0.36)
• In-hospital mortality • Discharge by Day 10: 80% in IVM arm vs. 74% in
placebo arm (rate ratio 1.1; P = 0.43)
• Need for ICU admission or MV: no difference between
arms
• In-hospital mortality: 0 in IVM arm (0%) vs. 4 in placebo
arm (7%)

AR08911
RIVET-COV: Double-Blind, Placebo-Controlled, Randomized Trial of Ivermectin in Patients With Mild to Moderate COVID-19 in India34
• Positive SARS-CoV-2 RT-PCR or antigen test result • Mean age 35 years; 89% men • Small sample size
• Nonsevere COVID-19 • 60% to 68% with mild COVID-19 (including Interpretation:
asymptomatic patients); 33% to 40% with moderate
Key Exclusion Criteria: • For patients who received IVM and those
COVID-19
• CrCl <30 mL/min who received placebo, there was no
• Median duration of symptoms: 4–5 days, similar across difference in the proportion of negative
• Transaminases >5 times ULN arms RT-PCR results at Day 5 or clinical
• MI, heart failure, QTc interval prolongation • 10% received concurrent antivirals (RDV, favipiravir, or outcomes.
• Severe comorbidity HCQ); no difference across arms
Interventions: Primary Outcomes:
• Single dose of IVM 24 mg PO (n = 51) • Negative RT-PCR result at Day 5: 48% in IVM 24 mg arm
• Single dose of IVM 12 mg PO (n = 49) vs. 35% in IVM 12 mg arm vs. 31% in placebo arm (P =
0.30)
• Placebo (n = 52)
• Decline of VL at Day 5: no significant difference between
Primary Endpoints: arms
• Negative RT-PCR result at Day 5 Secondary Outcomes:
• Decline of VL at Day 5 • Time to symptom resolution: no difference between arms
Key Secondary Endpoints: • Clinical worsening at Day 14: 8% in IVM 24 mg arm vs.
• Time to symptom resolution 5% in IVM 12 mg arm vs. 11% in placebo arm (P = 0.65)
• Clinical worsening at Day 14 • Number of hospital-free days at Day 28: no difference
between arms
• Number of hospital-free days at Day 28
• Frequency of AEs: no difference between arms; no SAEs
• Frequency of AEs

AR08912
COVER: Phase 2, Double-Blind RCT of Ivermectin in Nonhospitalized Patients With COVID-19 in Italy35
• Asymptomatic or oligosymptomatic disease • Median age 47 years; 58% men • Small, Phase 2 study
• SARS-CoV-2 infection confirmed by RT-PCR result • 86% with symptoms • 90% of subjects screened were not
• Not hospitalized or receiving supplemental oxygen enrolled for various reasons.
Primary Outcomes:
• Recruitment stopped early because
Key Exclusion Criteria: • Number of SAEs: 0
of decline in the number of COVID-19
• CNS disease • Mean log10 reduction in VL at Day 7: 2.9 in IVM 1,200 μg/ cases.
• Receiving dialysis kg arm vs. 2.5 in IVM 600 μg/kg arm vs. 2.0 in placebo
arm (IVM 1,200 μg/kg vs. placebo, P = 0.099; IVM 600 Interpretations:
• Severe medical condition with <6 months survival μg/kg vs. placebo, P = 0.122) • A high dose of IVM (1,200 μg/kg)
prognosis appears to be safe but not well-tolerated;
• Use of warfarin, antiviral agents, CQ, or HCQ AE Outcomes:
34% discontinued therapy due to AEs.
• 14 (15.1%) discontinued treatment: 11 (34.4%) in IVM
Interventions: • There was no significant difference
1,200 μg/kg arm vs. 2 (6.9%) in IVM 600 μg/kg arm vs.
• IVM 1,200 μg/kg PO once daily for 5 days (n = 32) in reduction of VL between IVM and
1 (3.1%) in placebo arm
placebo arms.
• IVM 600 μg/kg plus placebo PO once daily for 5 days (n • All discontinuations in IVM 1,200 μg/kg arm due to
= 29) tolerability
• Placebo PO (n = 32)
Primary Endpoints:
• Number of SAEs
• Change in VL at Day 7

AR08913
Double-Blind RCT of Ivermectin, Chloroquine, or Hydroxychloroquine in Hospitalized Adults With Severe COVID-19 in Brazil36
• Hospitalized with laboratory-confirmed SARS-CoV-2 • Mean age 53 years; 58% men • Small sample size
infection • Most common comorbidities: 43% with HTN; 28% with • No clearly defined primary endpoint
• ≥1 of the following severity criteria: DM; 38% with BMI >30
Interpretation:
• Dyspnea • 76% with respiratory failure on admission
• Compared to CQ or HCQ, IVM did not
• Tachypnea (>30 breaths/min) Outcomes: reduce the proportion of hospitalized
• SpO2 <93% • No difference between IVM, CQ, and HCQ arms in: patients with severe COVID-19 who died
• PaO2/FiO2 <300 mm Hg or who required supplemental oxygen,
• Need for supplemental oxygen: 88% vs. 89% vs. 90% ICU admission, or MV.
• Involvement of >50% of lungs by CXR or CT • ICU admission: 28% vs. 22% vs. 21%
Key Exclusion Criterion: • Need for MV: 24% vs. 21% vs. 21%
• Cardiac arrhythmia • Mortality: 23% vs. 21% vs. 22%
Interventions: • Mean number of days of supplemental oxygen: 8 days
for each arm
• IVM 14 mg once daily for 3 days (n = 53)
• Occurrence of AEs: no difference between arms
• CQ 450 mg twice daily on Day 0, then once daily for 4
days (n = 61) • Baseline characteristics significantly associated with
mortality:
• HCQ 400 mg twice daily on Day 0, then once daily for 4
days (n = 54) • Aged >60 years (HR 2.4)
Endpoints: • DM (HR 1.9)
• Need for supplemental oxygen, MV, or ICU admission • BMI >33 (HR 2.0)
• Occurrence of AEs • SpO2 <90% (HR 5.8)
• Mortality
Key: AE = adverse event; ALT = alanine aminotransferase; BMI = body mass index; CNS = central nervous system; CQ = chloroquine; CrCl = creatinine clearance; CT
= computed tomography; CXR = chest X-ray; DM = diabetes mellitus; HCQ = hydroxychloroquine; HTN = hypertension; ICU = intensive care unit; ITT = intention-to-
treat; IVM = ivermectin; LOS = length of stay; MI = myocardial infarction; mITT = modified intention-to-treat; MV = mechanical ventilation; the Panel = the COVID-19
Treatment Guidelines Panel; PaO2/FiO2 = ratio of arterial partial pressure of oxygen to fraction of inspired oxygen; PO = orally; RCT = randomized controlled trial;
RDV = remdesivir; RT-PCR = reverse transcriptase polymerase chain reaction; SAE = severe adverse event; SOC = standard of care; SpO2 = oxygen saturation; ULN =
upper limit of normal; VL = viral load

AR08914
References
1. Spoorthi V, Sasank S. Utility of ivermectin and doxycycline combination for the treatment of SARS-CoV-2. Int Arch Integrated Med. 2020;7(10):117-
182. Available at: https://iaimjournal.com/wp-content/uploads/2020/10/iaim_2020_0710_23.pdf.
2. Camprubi D, Almuedo-Riera A, Marti-Soler H, et al. Lack of efficacy of standard doses of ivermectin in severe COVID-19 patients. PLoS One.
3. Bhattacharya R, Ray I, Mukherjee R, et al. Observational study on clinical features, treatment and outcome of COVID-19 in a
tertiary care centre in India—a retrospective case series. Int J Sci Res. 2020;9(10). Available at: https://www.worldwidejournals.com/
international-journal-of-scientific-research-(IJSR)/article/observational-study-on-clinical-features-treatment-and-outcome-of-covid-19-in-a-tertiary-
care-centre-in-india-andndash-a-retrospective-case-series/MzI0NTg=/?is=1&b1=141&k=36.
4. Morgenstern J, Redondo JN, De León A, et al. The use of compassionate ivermectin in the management of symptomatic outpatients and hospitalized
patients with clinical diagnosis of COVID-19 at the Medical Center Bournigal and the Medical Center Punta Cana, Rescue Group, Dominican
Republic, from May 1 to August 10, 2020. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.10.29.20222505v1.
5. Cadegiani FA, Goren A, Wambier CG, McCoy J. Early COVID-19 therapy with azithromycin plus nitazoxanide, ivermectin or hydroxychloroquine
in outpatient settings significantly improved COVID-19 outcomes compared to known outcomes in untreated patients. New Microbes New Infect.
6. Carvallo H, Roberto H, Eugenia FM. Safety and efficacy of the combined use of ivermectin, dexamethasone, enoxaparin and aspirin against COVID
19. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.09.10.20191619v1.
7. Bukhari KHS, Asghar A, Perveen N, et al. Efficacy of ivermectin in COVID-19 patients with mild to moderate disease. medRxiv. 2021;Preprint.
8. Elalfy H, Besheer T, El-Mesery A, et al. Effect of a combination of nitazoxanide, ribavirin, and ivermectin plus zinc supplement (MANS.NRIZ study)
on the clearance of mild COVID-19. J Med Virol. 2021;93(5):3176-3183. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33590901.
9. Chahla RE, Ruiz LM, Mena T, et al. Cluster randomised trials—ivermectin repurposing for COVID-19 treatment of outpatients with mild disease in
primary health care centers. Research Square. 2021;Preprint. Available at: https://www.researchsquare.com/article/rs-495945/v1.
10. Tanioka H, Tanioka S, Kaga K. Why COVID-19 is not so spread in Africa: how does ivermectin affect it? medRxiv. 2021;Preprint. Available at:
11. Roy S, Samajdar SS, Tripathi SK, Mukherjee S, Bhattacharjee K. Outcome of different therapeutic interventions in mild COVID-19 patients in a single
OPD clinic of West Bengal: a retrospective study. medRxiv. 2021;Preprint. Available at:
12. Pott-Junior H, Paoliello MMB, Miguel AQC, et al. Use of ivermectin in the treatment of COVID-19: a pilot trial. Toxicol Rep. 2021;8:505-510.
13. Shahbaznejad L, Davoudi A, Eslami G, et al. Effects of ivermectin in patients with COVID-19: a multicenter, double-blind, randomized, controlled
clinical trial. Clin Ther. 2021;43(6):1007-1019. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34052007.
14. Roman YM, Burela PA, Pasupuleti V, et al. Ivermectin for the treatment of COVID-19: a systematic review and meta-analysis of randomized
controlled trials. Clin Infect Dis. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34181716.

AR08915
15. Ahmed S, Karim MM, Ross AG, et al. A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness. Int J Infect
Dis. 2021;103:214-216. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33278625.
16. Chaccour C, Casellas A, Blanco-Di Matteo A, et al. The effect of early treatment with ivermectin on viral load, symptoms and humoral response
in patients with non-severe COVID-19: a pilot, double-blind, placebo-controlled, randomized clinical trial. EClinicalMedicine. 2021;32:100720.
17. Chachar AZK, Khan KA, Asif M, et al. Effectiveness of ivermectin in SARS-COV-2/COVID-19 patients. Int J Sci. 2020;9:31-35. Available at:
https://www.ijsciences.com/pub/article/2378.
18. Gonzalez JLB, Gámez MG, Enciso EAM, et al. Efficacy and safety of ivermectin and hydroxychloroquine in patients with severe COVID-19. medRxiv.
2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.02.18.21252037v1.
19. Hashim HA, Maulood MF, Rasheed AW, et al. Controlled randomized clinical trial on using ivermectin with doxycycline for treating COVID-19
patients in Baghdad, Iraq. medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.10.26.20219345v1/.
20. Khan MSI, Khan MSI, Debnath CR, et al. Ivermectin treatment may improve the prognosis of patients with COVID-19. Arch Bronconeumol (Engl Ed).
21. Krolewiecki A, Lifschitz A, Moragas M, et al. Antiviral effect of high-dose ivermectin in adults with COVID-19: a proof-of-concept randomized trial.
EClinicalMedicine. 2021;37:100959. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34189446.
22. Okumus N, Demirturk N, Cetinkaya RA, et al. Evaluation of the effectiveness and safety of adding ivermectin to treatment in severe COVID-19
patients. BMC Infect Dis. 2021;21(1):411. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33947344.
23. Podder CS, Chowdhury N, Sina MI, Haque W. Outcome of ivermectin treated mild to moderate COVID-19 cases: a single-centre, open-label,
randomised controlled study. IMC J Med Sci. 2021;14(2). Available at: https://doi.org/10.3329/imcjms.v14i2.52826.
24. Soto-Becerra P, Culquichicón C, Hurtado-Roca Y, Araujo-Castillo RV. Real-world effectiveness of hydroxychloroquine, azithromycin, and ivermectin
among hospitalized COVID-19 patients: results of a target trial emulation using observational data from a nationwide healthcare system in Peru.
medRxiv. 2020;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2020.10.06.20208066v3.
25. Rajter JC, Sherman MS, Fatteh N, et al. Use of ivermectin is associated with lower mortality in hospitalized patients with coronavirus disease 2019: the
ivermectin in COVID nineteen study. Chest. 2021;159(1):85-92. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33065103.
26. Chowdhury ATMM, Shahbaz M, Karim MR, et al. A comparative study on ivermectin-doxycycline and hydroxychloroquine-azithromycin therapy on
COVID-19 patients. EJMO. 2021;5(1):63-70. Available at: https://ejmo.org/pdf/A%20Comparative%20Study%20on%20IvermectinDoxycycline%20
and%20HydroxychloroquineAzithromycin%20Therapy%20on%20COVID19%20Patients-16263.pdf.
27. Niaee MS, Namdar P, Allami A, et al. Ivermectin as an adjunct treatment for hospitalized adult COVID-19 patients: a randomized multi-center clinical
trial. Asian Pac J Trop Med. 2021;14:266-273. Available at: https://www.apjtm.org/article.asp?issn=1995-7645;year=2021;volume=14;issue=6;spage
=266;epage=273;aulast=Shakhsi.
28. Reis G, Silva E, Silva DCM, et al. Effect of early treatment with ivermectin among patients with COVID-19. N Engl J Med. 2022;Published online
ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35353979.
29. Vallejos J, Zoni R, Bangher M, et al. Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-
blind, placebo-controlled trial. BMC Infect Dis. 2021;21(1):635. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34215210.

AR08916
30. Lim SCL, Hor CP, Tay KH, et al. Efficacy of ivermectin treatment on disease progression among adults with mild to moderate COVID-19 and
comorbidities: the I-TECH randomized clinical trial. JAMA Intern Med. 2022;182(4):426-435. Available at:
31. Lopez-Medina E, Lopez P, Hurtado IC, et al. Effect of ivermectin on time to resolution of symptoms among adults with mild COVID-19: a randomized
32. Abd-Elsalam S, Noor RA, Badawi R, et al. Clinical study evaluating the efficacy of ivermectin in COVID-19 treatment: a randomized controlled study.
J Med Virol. 2021;93(10):5833-5838. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34076901.
33. Ravikirti, Roy R, Pattadar C, et al. Evaluation of ivermectin as a potential treatment for mild to moderate COVID-19: a double-blind randomized
placebo controlled trial in Eastern India. J Pharm Pharm Sci. 2021;24:343-350. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34265236.
34. Mohan A, Tiwari P, Suri TM, et al. Single-dose oral ivermectin in mild and moderate COVID-19 (RIVET-COV): a single-centre randomized, placebo-
controlled trial. J Infect Chemother. 2021;27(12):1743-1749. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34483029.
35. Buonfrate D, Chesini F, Martini D, et al. High-dose ivermectin for early treatment of COVID-19 (COVER study): a randomised, double-blind,
multicentre, phase II, dose-finding, proof-of-concept clinical trial. Int J Antimicrob Agents. 2022;59(2):106516. Available at:
36. Galan LEB, Santos NMD, Asato MS, et al. Phase 2 randomized study on chloroquine, hydroxychloroquine or ivermectin in hospitalized patients with
severe manifestations of SARS-CoV-2 infection. Pathog Glob Health. 2021;115(4):235-242. Available at:

AR08917
Lopinavir/Ritonavir and Other HIV Protease Inhibitors

The replication of SARS-CoV-2 depends on the cleavage of polyproteins into an RNA-dependent

RNA polymerase and a helicase.1 Two proteases are responsible for this cleavage: 3-chymotrypsin-like
protease (3CLpro) and papain-like protease (PLpro).
Lopinavir/ritonavir and darunavir/cobicistat have been studied in patients with COVID-19. The clinical
trials discussed below have not demonstrated a clinical benefit for protease inhibitors in patients with
COVID-19.
Recommendations
lopinavir/ritonavir and other HIV protease inhibitors for the treatment of COVID-19 in
hospitalized patients (AI).
• The Panel recommends against the use of lopinavir/ritonavir and other HIV protease
inhibitors for the treatment of COVID-19 in nonhospitalized patients (AIII).
Rationale
The pharmacodynamics of lopinavir/ritonavir raise concerns about whether it is possible to achieve drug
concentrations that can inhibit the SARS-CoV-2 proteases.2,3 In addition, lopinavir/ritonavir did not
show efficacy in two large randomized controlled trials in hospitalized patients with COVID-19.4,5
There is currently a lack of data on the use of lopinavir/ritonavir in nonhospitalized patients with
COVID-19. However, the pharmacodynamic concerns and the lack of evidence for a clinical benefit
among hospitalized patients with COVID-19 undermine confidence that lopinavir/ritonavir has a clinical
benefit at any stage of SARS-CoV-2 infection.
Adverse Events
The adverse events for lopinavir/ritonavir include:
• Nausea, vomiting, diarrhea (common)
• QTc prolongation
• Hepatotoxicity
Lopinavir/ritonavir is a potent inhibitor of cytochrome P450 3A. Coadministering lopinavir/ritonavir
with medications that are metabolized by this enzyme may increase the concentrations of those
medications, resulting in concentration-related toxicities. Please refer to the Guidelines for the Use of
Antiretroviral Agents in Adults and Adolescents with HIV for a list of potential drug interactions.
Summary of Clinical Data for COVID-19

• The plasma drug concentrations achieved using typical doses of lopinavir/ritonavir are far below
the levels that may be needed to inhibit SARS-CoV-2 replication.3
• Lopinavir/ritonavir did not demonstrate a clinical benefit in hospitalized patients with COVID-19
during a large randomized trial in the United Kingdom.4

AR08918
• In a large international randomized trial, lopinavir/ritonavir did not reduce the mortality rate
among hospitalized patients with COVID-19.5
• A moderately sized randomized trial (n = 199) failed to find a virologic or clinical benefit of
lopinavir/ritonavir over standard of care.6
• Results from a small randomized controlled trial showed that darunavir/cobicistat was not
effective for the treatment of COVID-19.7
• There are no data from clinical trials that support using other HIV protease inhibitors to treat
COVID-19.
• Please see Clinical Data for COVID-19 below for more information.
Clinical Data for COVID-19

The information presented in this section may include data from preprints or articles that have not
been peer reviewed. This section will be updated as new information becomes available. Please see
ClinicalTrials.gov for more information on clinical trials that are evaluating lopinavir/ritonavir.
Lopinavir/Ritonavir in Hospitalized Patients With COVID-19: The RECOVERY Trial

The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial is an ongoing, open-label,
randomized controlled trial with multiple arms, including a control arm; in one arm, participants
received lopinavir/ritonavir. The trial was conducted across 176 hospitals in the United Kingdom and
enrolled hospitalized patients with clinically suspected or laboratory-confirmed SARS-CoV-2 infection.4
Patients were randomized into several parallel treatment arms; this included randomization in a 2:1
ratio to receive either the usual standard of care only or the usual standard of care plus lopinavir 400
mg/ritonavir 100 mg orally every 12 hours for 10 days or until hospital discharge. Patients who had
severe hepatic insufficiency or who were receiving medications that had potentially serious or life-
threatening interactions with lopinavir/ritonavir were excluded from randomization into either of these
arms. Mechanically ventilated patients were also underrepresented in this study because it was difficult
to administer the oral tablet formulation of lopinavir/ritonavir to patients who were on mechanical
ventilation. The primary outcome was all-cause mortality at Day 28 after randomization.
The lopinavir/ritonavir arm was discontinued on June 29, 2020, after the independent data monitoring
committee concluded that the data showed no clinical benefit for lopinavir/ritonavir.
Patient Characteristics
• Of the 7,825 participants who were eligible to receive lopinavir/ritonavir, 1,616 were randomized
to receive lopinavir/ritonavir and 3,424 were randomized to receive standard of care only. The
remaining participants were randomized to other treatment arms in the study.
• In both the lopinavir/ritonavir arm and the standard of care arm, the mean age was 66 years; 44%
of patients were aged ≥70 years.
• Test results for SARS-CoV-2 infection were positive for 88% of patients. The remaining 12% had
a negative test result.
• Comorbidities were common; 57% of patients had at least one major comorbidity. Of those
patients, 28% had diabetes mellitus, 26% had heart disease, and 24% had chronic lung disease.
• At randomization, 4% of patients were receiving invasive mechanical ventilation, 70% were
receiving oxygen only (with or without noninvasive ventilation), and 26% were receiving neither.
• The percentages of patients who received azithromycin or another macrolide during the follow-up

AR08919
period were similar in both arms (23% in the lopinavir/ritonavir arm vs. 25% in the standard of
care arm). In addition, 10% of patients in both arms received dexamethasone.
Results
• There was no significant difference in the primary outcome of 28-day mortality between the two
arms; 374 patients (23%) in the lopinavir/ritonavir arm and 767 patients (22%) in the standard of
care arm had died by Day 28 (rate ratio 1.03; 95% CI, 0.91–1.17; P = 0.60).
• A similar 28-day mortality was reported for patients who received lopinavir/ritonavir in an
analysis that was restricted to the 4,423 participants who had positive SARS-CoV-2 test results
(rate ratio 1.05; 95% CI, 0.92–1.19; P = 0.49).
• Patients in the lopinavir/ritonavir arm and patients in the standard of care arm had similar median
times to discharge (11 days in both arms) and similar probabilities of being discharged alive within
28 days (69% vs. 70%).
• Among participants who were not on invasive mechanical ventilation at baseline, patients who
received lopinavir/ritonavir and those who received standard of care only had similar risks of
progression to intubation or death.
• Results were consistent across subgroups defined by age, sex, ethnicity, or respiratory support at
baseline.
Limitations
• The study was not blinded.
• No laboratory or virologic data were collected.
Interpretation
Lopinavir/ritonavir did not decrease 28-day all-cause mortality when compared to the usual standard of
care in hospitalized persons with clinically suspected or laboratory-confirmed SARS-CoV-2 infection.
Participants who received lopinavir/ritonavir and those who received standard of care only had similar
median lengths of hospital stay. Among the patients who were not on invasive mechanical ventilation at
the time of randomization, those who received lopinavir/ritonavir were as likely to require intubation or
die during hospitalization as those who received standard of care.
Lopinavir/Ritonavir in Hospitalized Patients with COVID-19: The Solidarity Trial

The Solidarity trial was an open-label, randomized controlled trial that enrolled hospitalized patients
with COVID-19 in 405 hospitals across 30 countries. The study included multiple arms; in one arm,
participants received lopinavir/ritonavir. The control group for this arm included people who were
randomized at the same site and time who could have received lopinavir/ritonavir but received standard of
care instead. Lopinavir 400 mg/ritonavir 100 mg was administered orally twice daily for 14 days or until
hospital discharge. Only the oral tablet formulation of lopinavir/ritonavir was available, which precluded
administration to those on mechanical ventilation. The primary outcome was in-hospital mortality.5
After the results of the RECOVERY trial prompted a review of the Solidarity data, the lopinavir/
ritonavir arm ended enrollment on July 4, 2020. At that time, 1,411 patients had been randomized to
receive lopinavir/ritonavir, and 1,380 patients received standard of care.
Patient Characteristics
• In both the lopinavir/ritonavir arm and the standard of care arm, 20% of the participants were aged
≥70 years and 37% were aged <50 years.
• Comorbidities were common. Diabetes mellitus was present in 24% of patients, heart disease in
21%, and chronic lung disease in 7%.

AR08920
• At randomization, 8% of patients were receiving invasive mechanical ventilation or extracorporeal

membrane oxygenation, 53% were receiving oxygen only (with or without noninvasive
ventilation), and 39% were receiving neither.
• Similar percentages of patients received corticosteroids in the lopinavir/ritonavir arm and the
standard of care arm (23% vs. 24%). Other nonstudy treatments were administered less often, and
the use of these treatments was balanced between arms.
Results
• There was no significant difference in in-hospital mortality between the two arms; 148 patients
(9.7%) in the lopinavir/ritonavir arm and 146 patients (10.3%) in the standard of care arm had died
by Day 28 (rate ratio 1.00; 95% CI, 0.79–1.25; P = 0.97).
• Progression to mechanical ventilation among those who were not ventilated at randomization
occurred in 126 patients in the lopinavir/ritonavir arm and 121 patients in the standard of care arm.
• In-hospital mortality results appeared to be consistent across subgroups.
Limitations
• The study was not blinded.
• Those who were on mechanical ventilation were unable to receive lopinavir/ritonavir.
• The study includes no data on time to recovery.
Interpretation
Among hospitalized patients, lopinavir/ritonavir did not decrease in-hospital mortality or the number of
patients who progressed to mechanical ventilation compared to standard of care.
Lopinavir/Ritonavir Pharmacokinetics in Patients With COVID-19

In a case series, eight patients with COVID-19 were treated with lopinavir 400 mg/ritonavir 100
mg orally twice daily and had plasma trough levels of lopinavir drawn and assayed by liquid
chromatography-tandem mass spectrometry.3
Results
• The median plasma lopinavir concentration was 13.6 μg/mL.
• After correcting for protein binding, trough levels would need to be approximately 60-fold
to 120-fold higher to achieve the in vitro half-maximal effective concentration (EC50) for
SARS-CoV-2.
Limitations
• Only the trough levels of lopinavir were quantified.
• The concentration of lopinavir required to effectively inhibit SARS-CoV-2 replication in vivo is
currently unknown.
Interpretation
The plasma drug concentrations that were achieved using typical doses of lopinavir/ritonavir are far
below the levels that may be needed to inhibit SARS-CoV-2 replication.
Other Reviewed Studies

The Panel has reviewed other clinical studies that evaluated the use of protease inhibitors for the
treatment of COVID-19.6,8,9 These studies have limitations that make them less definitive and

AR08921
informative than larger randomized clinical trials. The Panel’s summaries and interpretations of some of
these studies are available in the archived versions of the Guidelines.
References
1. Zumla A, Chan JF, Azhar EI, Hui DS, Yuen KY. Coronaviruses - drug discovery and therapeutic options. Nat
Rev Drug Discov. 2016;15(5):327-347. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26868298.
2. Marzolini C, Stader F, Stoeckle M, et al. Effect of systemic inflammatory response to SARS-CoV-2 on
lopinavir and hydroxychloroquine plasma concentrations. Antimicrob Agents Chemother. 2020;64(9).
3. Schoergenhofer C, Jilma B, Stimpfl T, Karolyi M, Zoufaly A. Pharmacokinetics of lopinavir and ritonavir in
patients hospitalized with coronavirus disease 2019 (COVID-19). Ann Intern Med. 2020. Available at:
4. Group RC. Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised,
controlled, open-label, platform trial. Lancet. 2020. Available at:
WHO Solidarity Trial results. N Engl J Med. 2020. Available at:
6. Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19. N
7. Chen J, Xia L, Liu L, et al. Antiviral activity and safety of darunavir/cobicistat for the treatment of COVID-19.
Open Forum Infect Dis. 2020;7(7):ofaa241. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32671131.
8. Hung IF, Lung KC, Tso EY, et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin
in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, Phase 2 trial.
Lancet. 2020;395(10238):1695-1704. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32401715.
9. Li Y, Xie Z, Lin W, et al. Efficacy and safety of lopinavir/ritonavir or arbidol in adult patients with mild/
moderate COVID-19: an exploratory randomized controlled trial. Med. 2020:[In Press]. Available at:
https://www.sciencedirect.com/science/article/pii/S2666634020300015.

AR08922
Nitazoxanide
Nitazoxanide is a broad-spectrum thiazolide antiparasitic agent that is approved by the Food and
Drug Administration (FDA) for the treatment of Cryptosporidium parvum and Giardia duodenalis
infections in children aged ≥1 year and adults. Nitazoxanide is rapidly metabolized to its active
metabolite, tizoxanide, and has in vitro antiviral activity against a range of viruses, including influenza
viruses, hepatitis B and C viruses, norovirus, rotavirus, Ebola virus, Middle East respiratory syndrome
coronavirus (MERS-CoV), and SARS-CoV-2.1-3 The mechanism of antiviral activity is not fully
characterized. Nitazoxanide inhibits host enzymes, which impairs the posttranslational processing of
viral proteins. It also has inhibitory effects on proinflammatory cytokines. With the exception of a Phase
2b/3 trial for uncomplicated influenza, the evidence for clinical activity of nitazoxanide against other
viruses is limited or of low quality.4
Recommendation
nitazoxanide for the treatment of COVID-19, except in a clinical trial (BIIa).
Rationale
Two randomized controlled trials that were conducted in Brazil and the United States did not find a
significant clinical benefit for nitazoxanide treatment in nonhospitalized adults with COVID-19 when
treatment was initiated within 2 to 5 days after illness onset.5,6 One of these trials, which has not yet
been published, reported that fewer patients in the nitazoxanide arm progressed to severe COVID-19
than in the placebo arm. However, the study was underpowered to detect a difference, and this finding
was not statistically significant.6 Additional small, unpublished studies were reviewed; however, due
to their limitations, they did not provide support for the use of nitazoxanide.7,8 Nitazoxanide was well
tolerated in these trials. The Panel concluded that results from adequately powered, well-designed, and
well-conducted clinical trials are needed to provide more specific, evidence-based guidance on the role
of nitazoxanide in the treatment of COVID-19.
Please see Table 2e for more information.

• Nitazoxanide is generally well tolerated. The most commonly reported side effects include
abdominal pain, diarrhea, headache, nausea, vomiting, urine discoloration, and, rarely, ocular
discoloration.
• Nitazoxanide is a highly plasma protein-bound drug (>99.9%). Drug-drug interactions may occur
when nitazoxanide is administered concurrently with other highly plasma protein-bound drugs due
to competition for binding sites. If nitazoxanide is coadministered with other highly protein-bound
drugs with narrow therapeutic indices, monitor the patient for adverse drug reactions.
• Please see Table 2f for more information.
According to the animal study data included in the product label, nitazoxanide does not appear to affect
fertility, nor does it cause fetal toxicity.9 There are no data on using nitazoxanide to treat COVID-19 in
pregnant people.

AR08923
Nitazoxanide is approved by the FDA for use in children aged ≥1 year old to treat Cryptosporidium
parvum and Giardia duodenalis infections. Dosing for the nitazoxanide suspension or tablets is available
for children that provides exposure that is similar to the approved adult dose of oral nitazoxanide 500
mg twice daily. There are no data on using nitazoxanide to treat COVID-19 in children.
Clinical Trials
Several clinical trials that are evaluating the use of nitazoxanide for the treatment of COVID-19 are
currently underway or in development. Please see ClinicalTrials.gov for the latest information.
References
1. Jasenosky LD, Cadena C, Mire CE, et al. The FDA-approved oral drug nitazoxanide amplifies host antiviral
responses and inhibits ebola virus. iScience. 2019;19:1279-1290. Available at:
2. Rossignol JF. Nitazoxanide: a first-in-class broad-spectrum antiviral agent. Antiviral Res. 2014;110:94-103.
3. Cao J, Forrest JC,Zhang X. A screen of the NIH Clinical Collection small molecule library identifies potential
anti-coronavirus drugs. Antiviral Res. 2015;114:1-10. Available at:
4. Haffizulla J, Hartman A, Hoppers M, et al. Effect of nitazoxanide in adults and adolescents with acute
uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial. Lancet Infect Dis.
5. Rocco PRM, Silvia PL, Cruz FF, et al. Early use of nitazoxanide in mild COVID-19 disease: randomised,
placebo-controlled trial. Eur Respir J. 2021;Published online ahead of print. Available at:
6. Rossignol J, Bardin MC, Oaks JB,et al. Early treatment with nitazoxanide prevents worsening of mild and
moderate COVID-19 and subsequent hospitalization. medRxiv. 2021;Preprint. Available at:
7. Blum VF, Cimerman S, Hunter JR,et al. Nitazoxanide in vitro efficacy against SARS CoV-2 and in vivo
superiority to placebo to treat moderate COVID-19—a Phase 2 randomized double-blind clinical trial.
Preprints with the Lancet. 2021. Available at: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3763773.
8. Silva M, Espejo A, Pereyra ML, et al. Efficacy of nitazoxanide in reducing the viral load in COVID-19
patients: randomized, placebo-controlled, single-blinded, parallel-group, pilot study. medRxiv. 2021;Preprint.
Available at: https://www.medrxiv.org/content/10.1101/2021.03.03.21252509v1.full.pdf.
9. Nitazoxanide (Alinia) [package insert]. Lupin Pharma. 2021. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021497s001,021498s004lbl.pdf.

AR08924
Table 2e. Nitazoxanide: Selected Clinical Data

The information in this table may include data from preprints or articles that have not been peer reviewed. This section will be updated as
new information becomes available. Please see ClinicalTrials.gov for more information on clinical trials that are evaluating NTZ for the
treatment of COVID-19. The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing
recommendations for NTZ.1,2

Early Treatment of Mild COVID-19 with Nitazoxanide3
Randomized, Key Inclusion Criteria: Number of Participants: Key Limitations:
double-blind, • Clinical signs and symptoms of • NTZ (n = 194) and placebo (n = 198) • In general, the patients in this study
placebo- COVID-19 for ≤3 days (fever, dry were young and relatively healthy.
controlled trial in Participant Characteristics:
cough, and/or fatigue) • At baseline, the median VL was 0.43
nonhospitalized • Median age of patients was 37 years.
adults with mild Key Exclusion Criteria: log10 c/mL lower in the NTZ arm
• Percentage of patients aged 18–39 years: 58% than in the placebo arm; however,
COVID-19 in Brazil • Negative SARS-CoV-2 RT-PCR result
(n = 475) • Percentage of patients aged 40–59 years: 36% this difference was not statistically
from an NP swab
• Percentage of patients aged 60–77 years: 6% significant (trend toward a significant
• Renal, heart, respiratory, liver, or difference; P = 0.065). Although the
autoimmune diseases • 53% of patients were women. difference in absolute VLs between
• Participant had a history of cancer in • 69% of patients were White. the arms at Day 5 was reported as
the past 5 years • 31% of patients had a BMI ≥30. statistically significant, without the
information on the change in VL in
Interventions: • 85% of patients had no reported comorbidities. each arm, it is difficult to interpret
• NTZ 500 mg 3 times daily for 5 days • Median time from symptom onset to first dose of study the significance of the findings.
using the oral liquid formulation drug was 5 days (IQR 4–5 days). • Some participants who received
• Color-matched placebo 3 times daily • Baseline median SARS-CoV-2 VL was 7.06 log10 c/mL the study drug were excluded from
for 5 days (IQR 5.77–8.13) in NTZ arm and 7.49 log10 c/mL (IQR the analysis population due to
6.15–8.32) in placebo arm (P = 0.065). discontinued intervention (21 in
Primary Endpoint:
Primary Outcome: NTZ arm vs. 18 in placebo arm);
• Complete resolution of dry cough, AEs (6 in NTZ arm vs. 1 in placebo
fever, and/or fatigue after receiving • There was no difference in time to complete resolution of arm); hospitalization (5 in NTZ arm
treatment for 5 days symptoms between NTZ and placebo arms (P = 0.277) vs. 5 in placebo arm); and protocol
Key Secondary Endpoints: Secondary Outcomes: deviations (7 in NTZ arm vs. 7 in
• Reduction in SARS-CoV-2 VL placebo arm). This complicates the
• After 5 days, median SARS-CoV-2 VL was lower in NTZ
interpretation of the study results,
• Incidence of hospital admission after arm (3.63 log10 c/mL [IQR 0–5.03]) than in placebo arm because an ITT analysis was not
completing therapy (4.13 log10 c/mL [IQR 2.88–5.31]; P = 0.006).
included.

AR08925

Early Treatment of Mild COVID-19 with Nitazoxanide3, continued
• 29.9% of patients in NTZ arm and 18.2% of patients in placebo Interpretation:
arm had a negative SARS-CoV-2 RT-PCR result at the fifth • NTZ did not improve time
treatment visit (P = 0.009). to resolution of symptoms
• In the ITT study population, 5 patients on NTZ and 5 on placebo compared to placebo.
were hospitalized due to clinical deterioration; 2 who received • Median VL was lower at Day
NTZ required ICU admission vs. 0 who received placebo. These 5 in the NTZ arm than in the
individuals were excluded from the analysis population because placebo arm, but this may
they did not complete the 5-day treatment course before clinical reflect differences in baseline
progression occurred. VLs.
Other Outcomes: • NTZ was well tolerated.
• Mild to moderate AEs occurred in about 30% of participants in
each arm who completed 5 days of therapy.
Early Treatment of Mild to Moderate COVID-19 with an Investigational Formulation of Nitazoxanide4
Randomized, Key Inclusion Criteria: Number of Participants: Key Limitations:
double-blind, • Aged ≥12 years • mITT analysis: NTZ (n = 184) and placebo (n = 195) • Information is limited in this
placebo- preliminary report.
controlled trial in • Enrollment ≤72 hours of symptom Participant Characteristics:
nonhospitalized onset • Because the number of
• Median age of patients was 40 years.
patients with • Mild to moderate COVID-19 high-risk participants
• 43.5% of patients were men. who progressed to severe
COVID-19 in the • ≥2 respiratory symptom domains
United States and • 87.6% of patients were White. COVID-19 in this study was
with a score ≥2 on FLU-PRO small, the results for this
Puerto Rico (n = questionnaire at screening, and no • Median BMI was 28.9.
1,092) subgroup are fragile. Larger
improvement in overall symptom •M edian time from symptom onset to randomization was 45.9 hours. studies are needed.
This is a preliminary, severity compared to previous day • 64.8% of patients had mild disease.
unpublished Interpretation:
Key Exclusion Criteria: • 35.2% of patients had moderate disease.
report that has not • NTZ did not demonstrate
• Signs or symptoms of severe • 62.8% of patients were at risk for severe illness. significant clinical or virologic
been peer reviewed.
COVID-19 benefits when compared to
Primary Outcome:
• Previous COVID-19 or any placebo.
symptom suggestive of COVID-19 • NTZ was not associated with a reduction in median time to
sustained response compared to placebo (13.3 days in NTZ arm • NTZ was well tolerated.
• Recent acute upper respiratory vs. 12.4 days in placebo arm; P = 0.88)
tract infection
Secondary Outcomes:
• Severe immunodeficiency
• Progression to severe disease occurred in 1 of 184 patients
• Severe heart, lung, neurological, or
(0.5%) in NTZ arm and 7 of 195 patients (3.6%) in placebo arm (P
other systemic diseases
= 0.07).

AR08926
Early Treatment of Mild to Moderate COVID-19 with an Investigational Formulation of Nitazoxanide4, continued
Interventions: • Among a subgroup of patients who had a high risk for severe
• 2 investigational NTZ 300 mg illness according to CDC criteria, 1 of 112 patients (0.9%)
extended-release tablets (for a in NTZ arm and 7 of 126 patients (5.6%) in placebo arm
total dose of 600 mg) PO with food progressed to severe disease (P = 0.07).
twice daily for 5 days • 1 of 184 patients (0.5%) in NTZ arm and 5 of 195 (2.6%) in
• Matching placebo for 5 days placebo arm were hospitalized (P = 0.18).
• All subjects received a vitamin B • There was no significant difference in viral endpoints between
complex supplement twice daily arms at Days 4 and 10.
to mask potential NTZ-associated Other Outcomes:
chromaturia.
• The safety analysis included 935 participants (472 in NTZ arm
Primary Endpoint: and 463 in placebo arm).
• Time from first dose to sustained • 2 patients in NTZ arm and 3 patients in placebo arm stopped
response the study drug due to AEs.
Secondary Endpoint:
• Rate of progression to severe
COVID-19
Key: AE = adverse event; BMI = body mass index; CDC = Centers for Disease Control and Prevention; FLU-PRO = Influenza Patient Reported Outcomes; ICU =
intensive care unit; ITT = intention-to-treat; mITT = modified intention-to-treat; NP = nasopharyngeal; NTZ = nitazoxanide; the Panel = the COVID-19 Treatment
Guidelines Panel; PO = orally; RT-PCR = reverse transcription polymerase chain reaction; VL = viral load
References
1. Blum VF, Cimerman S, Hunter JR, et al. Nitazoxanide superiority to placebo to treat moderate COVID-19–a pilot prove of concept randomized
double-blind clinical trial. EClinicalMedicine. 2021. Available at: https://pubmed.ncbi.nlm.nih.gov/34222847/.
2. Silva M, Espejo A, Pereyra ML, et al. Efficacy of nitazoxanide in reducing the viral load in COVID-19 patients. Randomized, placebo-controlled,
single-blinded, parallel group, pilot study. medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.03.03.21252509v1.
3. Rocco PRM, Silva PL, Cruz FF, et al. Early use of nitazoxanide in mild COVID-19 disease: randomised, placebo-controlled trial. Eur Respir J. 2021.
4. Rossignol J, Bardin MC, Oaks JB, et al. Early treatment with nitazoxanide prevents worsening of mild and moderate COVID-19 and subsequent
hospitalization. medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.04.19.21255441v1.

AR08927
Table 2f. Characteristics of Antiviral Agents

• RDV is the only antiviral drug that is approved by the FDA for the treatment of COVID-19.
• RTV-boosted nirmatrelvir, MOV, and certain anti-SARS-CoV-2 mAbs have received EUAs from the FDA for the treatment of COVID-19.
• Other medications that are currently being evaluated in clinical trials for the treatment of COVID-19 are also included in this table. The
inclusion of these drugs does not imply that the Panel recommends their use.
• This table focuses on small-molecule antiviral drugs. For more information regarding anti-SARS-CoV-2 mAbs, please see Table 3c.
• Information on CQ, HCQ, and LPV/RTV are available in archived versions of the Guidelines. The Panel recommends against using these
agents to treat COVID-19.
• For many of these antiviral drugs, there are limited or no data on dose modifications for patients with organ failure or those who require
extracorporeal devices. Please refer to product labels, when available.
• There are currently limited data to determine whether certain medications can be safely coadministered with some therapies for the treatment
of COVID-19. When using concomitant medications with similar toxicity profiles, consider performing additional safety monitoring.
• For drug interaction information, please refer to product labels, EUA fact sheets, and the Liverpool COVID-19 Drug Interactions website.
• For the Panel’s recommendations on using the drugs listed in this table, please refer to the individual drug sections, Therapeutic
Management of Nonhospitalized Adults With COVID-19, Therapeutic Management of Hospitalized Adults With COVID-19, or Antiviral
Therapy Summary Recommendations.
Dosing Regimens
The doses listed here are for approved Drug-Drug Interaction Comments and Links to
Adverse Events Monitoring Parameters
indications or from reported experiences Potential Clinical Trials
or clinical trials.
Authorized under FDA EUA for the treatment of mild to moderate COVID-19 in high-risk individuals aged ≥12 years and weighing ≥40 kg.
EUA Dose for COVID-191 • Dysgeusia • Monitor for potential • RTV-boosted nirmatrelvir • Both nirmatrelvir and
Dosing Based on eGFR: • Diarrhea AEs due to drug- has significant and complex RTV tablets can be taken
drug interactions with drug-drug interactions. Before with or without food.
• ≥60 mL/min: Nirmatrelvir 300 mg (two, • HTN concomitant medication(s). prescribing RTV-boosted
150-mg tablets) with RTV 100 mg (one, • Myalgia nirmatrelvir, carefully review
100-mg tablet) twice daily for 5 days • Use with caution in patients
with pre-existing liver concomitant medications,
• ≥30 to 60 mL/min: Nirmatrelvir 150 mg diseases, liver enzyme including OTC medicines,
(one, 150-mg tablet) with RTV 100 mg abnormalities, or hepatitis. herbal supplements, and
(one, 100-mg tablet) twice daily for 5 recreational drugs. See
days Ritonavir-Boosted Nirmatrelvir
• <30 mL/min: Not recommended (Paxlovid) for more
information.

AR08928
Dosing Regimens
The doses listed here are for approved Drug-Drug Interaction Comments and Links to
Adverse Events Monitoring Parameters
indications or from reported experiences Potential Clinical Trials
or clinical trials.
Ritonavir-Boosted Nirmatrelvir (Paxlovid), continued
Dosing for Patients with Severe Hepatic • Consult the EUA fact
Impairment (Child-Pugh Class C): sheet for Paxlovid, the
• Not recommended Liverpool COVID-19
Drug Interactions
website, and Table A
in Ritonavir-Boosted
Nirmatrelvir (Paxlovid)
to identify and manage
drug-drug interactions.
Remdesivir
Approved by the FDA for the treatment of COVID-19 in individuals aged ≥12 years and weighing ≥40 kg.
Adults and Children (Aged ≥12 Years • Nausea • Monitor patients for • Clinical drug-drug •R
DV should be administered
and Weighing ≥40 kg): • ALT and AST elevations infusion reactions during interaction studies of in settings in which
• RDV 200 mg IV on Day 1, then RDV the infusion and observe RDV have not been health care providers
• Hypersensitivity them for ≥1 hour after conducted. have immediate access to
100 mg IV once daily from Day 2
• Increases in prothrombin time the infusion as clinically • In vitro, RDV is a minor medications to treat a severe
Dose Recommended in FDA EUA For • Drug vehicle is SBECD, which appropriate. infusion-related reactions or
substrate of CYP3A4,
Children Weighing 3.5 kg to <40 kg: has been associated with HSR, such as anaphylaxis,
• Renal function, and a substrate of
• RDV 5 mg/kg IV on Day 1, then RDV renal and liver toxicity. SBECD hepatic function and OATP1B1, and P-gp and the ability to activate the
2.5 mg/kg IV once daily from Day 2 accumulation may occur in prothrombin time as and an inhibitor of emergency medical system.
• Total Treatment Duration: patients with moderate or clinically indicated CYP3A4, OATP1B1, •A
list of clinical trials is
severe renal impairment. • FDA does not OATP1B3, and MATE1. 2
available: Remdesivir
• Nonhospitalized patients: 3 days
• Each 100 mg vial of RDV recommend using RDV
• Hospitalized patients: 5 days or until
lyophilized powder contains when eGFR is <30 mL/
hospital discharge
3 g of SBECD, and each min. See the Remdesivir
100 mg/20 mL vial of RDV section for information
solution contains 6 g of on using RDV in people
SBECD. with renal insufficiency.
• Clinicians may consider
preferentially using
the lyophilized powder
formulation (which contains
less SBECD) in patients with
renal impairment.

AR08929
Dosing Regimens
The doses listed here are for approved Monitoring Drug-Drug Interaction Comments and Links to
Adverse Events
indications or from reported experiences Parameters Potential Clinical Trials
or clinical trials.
Molnupiravir
Authorized under FDA EUA for the treatment of mild to moderate COVID-19 in high-risk individuals aged ≥18 years.
Dose Recommended in FDA EUA: • Diarrhea • Before initiating • Clinical drug-drug •M OV can be taken with or
• MOV 800 mg (four, 200-mg capsules) • Nausea MOV, assess interaction studies of without food.
PO every 12 hours for 5 days pregnancy status MOV have not been •S exually active individuals of
• Dizziness as clinically conducted. reproductive potential should
• Per the FDA, the 5-day course indicated. • Drug-drug interactions use effective contraception
of MOV has a low risk for • Monitor for related to hepatic during and following treatment
genotoxicity.3 See the Molnupiravir potential AEs. metabolism are not with MOV. See the Molnupiravir
section for details. expected. section for details.
• If MOV is prescribed for
a pregnant individual, the
prescribing clinician should
document that the risks and
benefits were discussed and
that the patient chose this
therapy. Pregnant patients
should also be informed of
the pregnancy surveillance
program and if they agree to
participate, be enrolled in the
program. See the Molnupiravir
section for details.
•D uring MOV treatment and
for 4 days after the final dose,
lactating people should not
breastfeed their infants.
•M OV is not authorized for use
in children aged <18 years due
to potential effects on bone and
cartilage growth.
•A list of clinical trials is
available: Molnupiravir

AR08930
Dosing Regimens
Adverse Events
or clinical trials.
Interferon Alfa
Not approved by the FDA and not recommended by the Panel for the treatment of COVID-19. Currently under investigation in clinical trials.
IFN Alfa-2b • AEs that are associated with • Respiratory • Low potential for drug- • T he nebulized formulation
Dose for COVID-19 in Clinical Trials: inhaled therapy (e.g., throat symptoms after drug interactions of IFN alfa has been the
irritation, cough, bronchospasm) inhalation formulation most used in
• Nebulized IFN alfa-2b 5 million clinical trials for the treatment
international units twice daily; the • Systemic effects of IFN are
of COVID-19. IFN alfa is
optimal duration of treatment is unclear. expected to be minimal. usually included as part of a
combination regimen.
•A
available: Interferon Alfa
Availability:
•N
ebulized IFN alfa-2b is not
approved by the FDA for use in
the United States.
Interferon Beta
IFN Beta-1a • Flu-like symptoms (e.g., fever, • CBC with • Low potential for drug- •A
Dose for COVID-19 in Clinical Trials: fatigue, myalgia) differential drug interactions available: Interferon Beta
• IFN beta-1a 44 µg SUBQ or IV every • Leukopenia, neutropenia, • Liver enzymes •U se with caution with Availability
other day for up to 3 or 4 doses thrombocytopenia, lymphopenia • Worsening CHF other hepatotoxic
Brand Names of IFN Beta-1a
• Liver function abnormalities (ALT agents.
IFN Beta-1b • Depression, Products:
> AST) suicidal ideation • Reduce dose if ALT >5
Dose for COVID-19 in Clinical Trials: •A
vonex, Plegridy, Rebif
• Injection site reactions times ULN.
• IFN beta-1b 8 million international units Brand Names of IFN Beta-1b
• Headache Products:
SUBQ every other day for up to 7 days
total • Hypertonia •B
etaseron, Extavia
• Pain
• Rash
• Worsening depression
• Induction of autoimmunity

AR08931
Dosing Regimens
Adverse Events
or clinical trials.
Interferon Lambda
PEG-IFN Lambda-1a • Liver function abnormalities • CBC with • Low potential for drug-drug • A list of clinical trials is
Dose for COVID-19 in Clinical Trials: • Injection site reactions differential interactions available: Interferon Lambda
• Single dose of PEG-IFN lambda-1a 180 • Liver enzymes • Use with caution with Availability:
µg SUBQ • Monitor for other hepatotoxic agents.
•P EG-IFN lambda-1a is not
potential AEs. approved by the FDA for use
in the United States.
Ivermectin
Dose for COVID-19 in Clinical Trials: • Dizziness • Monitor for • Minor CYP3A4 substrate •G
enerally given on an empty
• IVM 0.2–0.6 mg/kg PO given as a • Pruritis potential AEs. • P-gp substrate stomach with water; however,
single dose or as a once-daily dose for administering IVM with food
• GI effects (e.g., nausea, diarrhea) increases its bioavailability.4
up to 5 days
• Neurological AEs have been •A
reported when IVM has been used available: Ivermectin
to treat parasitic diseases, but it is
not clear whether these AEs were
caused by IVM or the underlying
conditions.
Nitazoxanide
For Adults: • Abdominal pain • Monitor for • Drug-drug interactions •N TZ should be taken with
• Doses studied for COVID-19 range • Diarrhea potential AEs. may occur if NTZ is food.
from NTZ 500 mg PO 3 times daily to 4 • Headache administered concurrently • T he oral suspension is not
times daily. with other highly plasma bioequivalent to the tablet
• Nausea protein-bound drugs due formulation.
• Higher doses are being studied. to competition for binding
• Vomiting •A list of clinical trials is
• Doses used for antiprotozoal sites.5
indications range from NTZ 500 mg–1 • U
rine discoloration available: Nitazoxanide
• If NTZ is coadministered
g PO twice daily. • Ocular discoloration (rare)
with other highly protein-
bound drugs with narrow
therapeutic indices, monitor
the patient for AEs.

AR08932
Key: AE = adverse event; ALT = alanine transaminase; AST = aspartate aminotransferase; CBC = complete blood count; CHF = congestive heart failure; CQ =
chloroquine; CYP = cytochrome P450; eGFR = estimated glomerular filtration rate; EUA = Emergency Use Authorization; FDA = Food and Drug Administration; GI =
gastrointestinal; HCQ = hydroxychloroquine; HSR = hypersensitivity reaction; HTN = hypertension; IFN = interferon; IV = intravenous; IVM = ivermectin; LPV/RTV =
lopinavir/ritonavir; mAbs = monoclonal antibodies; MATE = multidrug and toxin extrusion protein; MOV = molnupiravir; NTZ = nitazoxanide; OATP = organic anion
transporting polypeptide; OTC = over the counter; the Panel = the COVID-19 Treatment Guidelines Panel; PEG-IFN = pegylated interferon; P-gp = P-glycoprotein; PO =
orally; RDV = remdesivir; RTV = ritonavir; SBECD = sulfobutylether-beta-cyclodextrin; SUBQ = subcutaneous; ULN = upper limit of normal
References
1. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for Paxlovid. 2021. Available at:
3. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for molnupiravir. 2021. Available at:
4. Ivermectin (Stromectol) [package insert]. Food and Drug Administration. 2009. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050742s024s025lbl.pdf.
5. Nitazoxanide (Alinia) [package insert]. Food and Drug Administration. 2016. Available at:

AR08933
Anti-SARS-CoV-2 Antibody Products

The COVID-19 Treatment Guidelines Panel’s (the Panel) recommendations for the use of anti-SARS-CoV-2 monoclonal
antibodies (mAbs) are based on current knowledge of the in vitro activities of available products against the circulating
SARS-CoV-2 variants and subvariants. These recommendations remain fluid and depend on the prevalence of resistant
variants.
Anti-SARS-CoV-2 Monoclonal Antibodies for the Treatment of COVID-19
• Treatment with anti-SARS-CoV-2 mAbs should be considered for patients with mild to moderate COVID-19 who
are hospitalized for a reason other than COVID-19 if they otherwise meet the Food and Drug Administration (FDA)
Emergency Use Authorization (EUA) criteria for outpatient treatment.
• The risk for progression to severe COVID-19 in high-risk patients is substantially greater for those who are not
vaccinated or those who are vaccinated but not expected to mount an adequate immune response to the vaccine
due to an underlying immunocompromising condition. When the available therapies cannot be offered to all eligible
patients, see Prioritization of Anti-SARS-CoV-2 Therapies for the Treatment and Prevention of COVID-19 When There
Are Logistical or Supply Constraints for the Panel’s recommendations.
• At this time, the Panel’s anti-SARS-CoV-2 mAb recommendations are for the treatment of nonhospitalized patients
with mild to moderate COVID-19 who are at high risk of progressing to severe disease.
Bebtelovimab
• The Panel recommends using bebtelovimab 175 mg intravenous injection in patients aged ≥12 years as an
alternative therapy ONLY when ritonavir-boosted nirmatrelvir (Paxlovid) and remdesivir are not available, feasible to
use, or clinically appropriate (CIII). Treatment should be initiated as soon as possible and within 7 days of symptom
onset. See Therapeutic Management of Nonhospitalized Adults With COVID-19 for further guidance.
• Bebtelovimab should be administered in a setting where severe hypersensitivity reactions, such as anaphylaxis, can
be managed. Patients should be monitored during the injection and observed for at least 1 hour after injection.
Bamlanivimab Plus Etesevimab, Casirivimab Plus Imdevimab, and Sotrovimab
• Because the Omicron (B.1.1.529) variant of concern (VOC) and its subvariants have become dominant in the United
States, the Panel recommends against using bamlanivimab plus etesevimab, casirivimab plus imdevimab, or
sotrovimab for the treatment of COVID-19 (AIII).
Anti-SARS-CoV-2 Monoclonal Antibodies as Post-Exposure Prophylaxis for SARS-CoV-2 Infection
• The Panel recommends against the use of bamlanivimab plus etesevimab and casirivimab plus imdevimab for
SARS-CoV-2 post-exposure prophylaxis (PEP), as the Omicron VOC, which is not susceptible to these agents, is
currently the dominant SARS-CoV-2 variant circulating in the United States (AIII).
Anti-SARS-CoV-2 Monoclonal Antibodies as Pre-Exposure Prophylaxis for SARS-CoV-2 Infection
• The Panel recommends using tixagevimab 300 mg plus cilgavimab 300 mg (Evusheld) administered as 2
consecutive 3-mL intramuscular injections (BIII) as SARS-CoV-2 pre-exposure prophylaxis (PrEP) for adults and
adolescents (aged ≥12 years and weighing ≥40 kg) who do not have SARS-CoV-2 infection, who have not been
recently exposed to an individual with SARS-CoV-2 infection, AND who:
• Are moderately to severely immunocompromised and may have an inadequate immune response to COVID-19
vaccination; or
• Are not able to be fully vaccinated with any available COVID-19 vaccines due to a history of severe adverse
reactions to a COVID-19 vaccine or any of its components.
• For individuals who previously received a dose of tixagevimab 150 mg plus cilgavimab 150 mg, the FDA EUA states
that a second dose should be administered as soon as possible:
• If the initial dose was administered ≤3 months ago, the second dose should be tixagevimab 150 mg plus
cilgavimab 150 mg.
• If the initial dose was administered >3 months ago, the second dose should be tixagevimab 300 mg plus cilgavimab
300 mg.

AR08934
Summary Recommendations, continued

• Tixagevimab plus cilgavimab is not a substitute for COVID-19 vaccination and should not be used in unvaccinated
individuals for whom COVID-19 vaccination is recommended and who are anticipated to have an adequate
response.
• If supplies of tixagevimab plus cilgavimab are limited, priority for use as PrEP should be given to those who are at the
highest risk for severe COVID-19 (see Prioritization of Anti-SARS-CoV-2 Therapies for the Treatment and Prevention
of COVID-19 When There Are Logistical or Supply Constraints).
• The Panel recommends against the use of COVID-19 convalescent plasma (CCP) that was collected prior to the
emergence of the Omicron VOC for the treatment of COVID-19 (AIII).
• The Panel recommends against the use of CCP for the treatment of COVID-19 in hospitalized, immunocompetent
patients (AI).
• There is insufficient evidence for the Panel to recommend either for or against the use of high-titer CCP that
was collected after the emergence of the Omicron VOC for the treatment of immunocompromised patients and
nonhospitalized, immunocompetent patients with COVID-19.
Anti-SARS-CoV-2-Specific Immunoglobulins
• There is insufficient evidence for the Panel to recommend either for or against the use of anti-SARS-CoV-2-specific
immunoglobulins for the treatment of COVID-19.

AR08935

The SARS-CoV-2 genome encodes 4 major structural proteins: spike (S), envelope (E), membrane
(M), and nucleocapsid (N), as well as nonstructural and accessory proteins. The spike protein is
further divided into 2 subunits, S1 and S2, that mediate host cell attachment and invasion. Through its
receptor-binding domain (RBD), S1 attaches to angiotensin-converting enzyme 2 (ACE2) on the host
cell; this initiates a conformational change in S2 that results in virus-host cell membrane fusion and
viral entry.1 Anti-SARS-CoV-2 monoclonal antibodies (mAbs) that target the spike protein have been
shown to have clinical benefits in treating SARS-CoV-2 infection. The effectiveness of the different
anti-SARS-CoV-2 mAb therapies varies dramatically depending on the circulating variant, and the role
of each anti-SARS-CoV-2 mAb in the treatment of COVID-19 remains fluid. The recommendations
and discussion below pertain only to the use of the authorized anti-SARS-CoV-2 mAb products for the
treatment of COVID-19. Currently, no product is available for post-exposure prophylaxis (PEP). For
recommendations and discussion regarding the use of tixagevimab plus cilgavimab (Evusheld) as pre-
exposure prophylaxis (PrEP), see Prevention of SARS-CoV-2 Infection.
The Omicron (B.1.1.529) variant of concern (VOC) has become the dominant SARS-CoV-2 variant in
the United States.2 This variant, which includes numerous mutations in the spike protein, has markedly
reduced in vitro susceptibility to several anti-SARS-CoV-2 mAbs, especially bamlanivimab plus
etesevimab and casirivimab plus imdevimab (REGEN-COV). Sotrovimab is active against the Omicron
BA.1 and BA.1.1 subvariants, but it has substantially decreased in vitro activity against the Omicron
BA.2 subvariant. Bebtelovimab retains in vitro activity against circulating Omicron subvariants.
Recommendations
The COVID-19 Treatment Guidelines Panel’s (the Panel) recommendations for the use of anti-
SARS-CoV-2 mAbs are based on current knowledge of the in vitro activities of the available products
against the circulating SARS-CoV-2 variants and subvariants. These recommendations remain fluid
and depend on the prevalence of resistant variants. At this time, the Panel’s anti-SARS-CoV-2 mAb
recommendations are for the treatment of nonhospitalized patients with mild to moderate COVID-19
who are at high risk of progressing to severe disease.
Bebtelovimab
The Panel recommends using bebtelovimab 175 mg intravenous (IV) injection in patients aged ≥12
years as an alternative therapy ONLY when ritonavir-boosted nirmatrelvir (Paxlovid) and remdesivir are
not available, feasible to use, or clinically appropriate (CIII). Treatment should be initiated as soon as
possible and within 7 days of symptom onset. See Therapeutic Management of Nonhospitalized Adults
With COVID-19 for further guidance.
Bamlanivimab Plus Etesevimab, Casirivimab Plus Imdevimab, and Sotrovimab

Because the Omicron VOC has become the dominant variant in the United States, the Panel
recommends against using bamlanivimab plus etesevimab, casirivimab plus imdevimab, or
sotrovimab for the treatment of COVID-19 (AIII).
• Treatment with anti-SARS-CoV-2 mAbs should be started as soon as possible after SARS-CoV-2
infection is confirmed by an antigen test or a nucleic acid amplification test and within 7 days of

AR08936
symptom onset.
• Anti-SARS-CoV-2 mAbs should be administered in a setting where severe hypersensitivity
reactions, such as anaphylaxis, can be managed. Patients should be monitored during the infusion
and observed for at least 1 hour after infusion.
• Treatment with anti-SARS-CoV-2 mAbs should be considered for patients with mild to moderate
COVID-19 who are hospitalized for a reason other than COVID-19 if they otherwise meet the
Emergency Use Authorization (EUA) criteria for outpatient treatment.
• The risk for progression to severe COVID-19 in high-risk patients is substantially greater
for those who are not vaccinated or those who are vaccinated but not expected to mount
an adequate immune response to the vaccine due to an underlying immunocompromising
condition. When the available therapies cannot be offered to all eligible patients, see
Prioritization of Anti-SARS-CoV-2 Therapies for the Treatment and Prevention of COVID-19
When There Are Logistical or Supply Constraints for the Panel’s recommendations.
• There are no data on the combined use of antiviral agents and anti-SARS-CoV-2 mAbs for the
treatment of nonhospitalized patients with COVID-19. Clinical trials are needed to determine
whether this combination therapy has a role in the treatment of COVID-19.
• Severely immunocompromised patients may have prolonged SARS-CoV-2 replication, leading to
more rapid viral evolution. There is a concern that using a single anti-SARS-CoV-2 mAb in these
patients may result in emergence of resistant virus. Additional studies are needed to assess this
risk. The role of anti-SARS-CoV-2 mAbs plus antiviral therapy in the treatment of COVID-19 is
not yet known.3,4
Anti-SARS-CoV-2 Monoclonal Antibodies That Have Received Emergency Use

Authorizations
Five anti-SARS-CoV-2 mAb products have received EUAs from the Food and Drug Administration
(FDA). Bamlanivimab plus etesevimab, bebtelovimab, casirivimab plus imdevimab, and sotrovimab
received EUAs for the treatment of mild to moderate COVID-19 in nonhospitalized patients with
laboratory-confirmed SARS-CoV-2 infection who are at high risk for progressing to severe disease
or hospitalization. The FDA issued an EUA for tixagevimab plus cilgavimab, a long-acting anti-
SARS-CoV-2 mAb combination, as SARS-CoV-2 PrEP for individuals who do not have SARS-CoV-2
infection, who have not been recently exposed to an individual with SARS-CoV-2 infection, AND
who are at risk for inadequate immune response to COVID-19 vaccination OR have a documented
history of severe adverse reactions to a COVID-19 vaccine or any of its components (see Prevention
of SARS-CoV-2 Infection for more information). The issuance of an EUA does not constitute FDA
approval.
The authorized anti-SARS-CoV-2 mAb products, listed alphabetically, are:
• Bamlanivimab plus etesevimab: These neutralizing mAbs bind to different, but overlapping,
epitopes in the spike protein RBD of SARS-CoV-2.
• The distribution of bamlanivimab plus etesevimab has paused in the United States because the
Omicron VOC has markedly reduced in vitro susceptibility to bamlanivimab and etesevimab;
therefore, this regimen is not expected to provide clinical benefit for patients with Omicron
infection.5
• Bebtelovimab: This recombinant neutralizing human mAb binds to the spike protein of
SARS-CoV-2. Bebtelovimab retains in vitro activity against all circulating Omicron subvariants,
but there are no clinical efficacy data on the treatment of patients at high risk for progression to

AR08937
severe COVID-19.6
• Casirivimab plus imdevimab: These recombinant human mAbs bind to nonoverlapping epitopes of
the spike protein RBD of SARS-CoV-2.
• The distribution of casirivimab plus imdevimab has paused in the United States because the
Omicron VOC has markedly reduced in vitro susceptibility to casirivimab and imdevimab;
therefore, this regimen is not expected to provide clinical benefit for patients with Omicron
infection.7
• Sotrovimab: This mAb was originally identified in 2003 from a survivor of SARS-CoV infection.
It targets an epitope in the RBD of the spike protein that is conserved between SARS-CoV
and SARS-CoV-2. Sotrovimab retains in vitro activity against the Omicron BA.1 and BA.1.1
subvariants, but it has substantially decreased in vitro activity against Omicron BA.2 and is not
expected to provide clinical benefit for patients with Omicron BA.2 infection.8-10
• Because the Omicron BA.2 subvariant is now the dominant circulating subvariant in all
regions of the United States, distribution of sotrovimab has paused, and the Panel no longer
recommends using sotrovimab for the treatment of COVID-19.
• Tixagevimab plus cilgavimab: These recombinant human anti-SARS-CoV-2 mAbs bind to
nonoverlapping epitopes of the spike protein RBD of SARS-CoV-2. The originally authorized
dose of tixagevimab 150 mg plus cilgavimab 150 mg has reduced in vitro activity against the
Omicron BA.1 and BA.1.1 subvariants. However, the FDA updated the EUA to authorize a dose
of tixagevimab 300 mg plus cilgavimab 300 mg, which is expected to maintain activity against
these subvariants. Tixagevimab plus cilgavimab has retained in vitro activity against the Omicron
BA.2 subvariant.11-13
SARS-CoV-2 Variant Susceptibility to Anti-SARS-CoV-2 Monoclonal Antibodies

In laboratory studies, some SARS-CoV-2 variants that harbor certain mutations have markedly reduced
susceptibility to several of the authorized anti-SARS-CoV-2 mAbs (see Table A).14 The clinical
relevance of the reduced in vitro susceptibility of select variants to anti-SARS-CoV-2 mAbs is under
investigation.
Some key SARS-CoV-2 variants that have been identified are:
• Alpha (B.1.1.7): This variant retains in vitro susceptibility to all anti-SARS-CoV-2 mAb products
currently available through FDA EUAs.15-17
• Beta (B.1.351): This variant has markedly reduced in vitro susceptibility to bamlanivimab
and etesevimab.15,17 In vitro studies also suggest that the Beta variant has markedly reduced
susceptibility to casirivimab; however, the combination of casirivimab and imdevimab appears to
retain activity against the variant.16 Sotrovimab also appears to retain activity against the variant.8
• Gamma (P.1): This variant has markedly reduced in vitro susceptibility to bamlanivimab and
etesevimab.15,18 The Gamma variant also has reduced susceptibility to casirivimab; however,
the combination of casirivimab plus imdevimab appears to retain activity against the variant.16
Sotrovimab also appears to retain activity against the Gamma variant.8
• Delta (B.1.617.2, non-AY.1/AY.2): This VOC retains in vitro susceptibility to all anti-SARS-CoV-2
mAbs currently available through FDA EUAs.15,16
• Omicron (B.1.1.529): This is currently the predominant VOC circulating in the United States
and includes the BA.1, BA.1.1, and BA.2 subvariants. This variant, which includes numerous
mutations in the spike protein, has markedly reduced in vitro susceptibility to some anti-SARS-
CoV-2 mAb products, as noted below:

AR08938
• Bamlanivimab plus etesevimab and casirivimab plus imdevimab are not expected to be active
against these subvariants.12
• Sotrovimab retains activity against the Omicron BA.1 and BA.1.1 subvariants but has
decreased in vitro activity against the Omicron BA.2 subvariant.8,12,13
• Bebtelovimab retains in vitro activity against all circulating Omicron subvariants.6,9,19
• The originally authorized dose of tixagevimab 150 mg plus cilgavimab 150 mg has reduced in
vitro activity against the Omicron BA.1 and BA.1.1 subvariants.11 However, the FDA updated
the EUA to authorize a dose of tixagevimab 300 mg plus cilgavimab 300 mg, which is expected
to maintain activity against these subvariants. The duration of protection against the BA.1 and
BA.1.1 subvariants remains unclear. Tixagevimab plus cilgavimab has retained in vitro activity
against the Omicron BA.2 subvariant.11-13,20
To define the utility of specific mAbs in the future, ongoing population-based genomic surveillance of
the types and proportions of circulating SARS-CoV-2 variants, as well as studies on the susceptibility of
different variants to available anti-SARS-CoV-2 mAbs, will be important.

AR08939
Table A. SARS-CoV-2 Variants and Susceptibility to Anti-SARS-CoV-2 Monoclonal Antibodies
BAM Plus ETE CAS Plus IMD BEB SOT TIX Plus CIL
CDC Anti- Anti- Anti- Anti- Anti-
WHO Pango Notable In Vitro In Vitro In Vitro In Vitro In Vitro
Variant cipated cipated cipated cipated cipated
Label Lineage Mutations Suscept- Suscept- Suscept- Suscept- Suscept-
Class Clinical Clinical Clinical Clinical Clinical
ibilitya ibilitya ibilitya ibilitya ibilitya
Activity Activity Activity Activity Activity
Alpha B.1.1.7 VBM N501Y No change Active No change Active No change Active No change Active No change Active
Beta B.1.351 VBM K417N, Marked Unlikely No changeb Active No change Active No change Active No change Active
E484K, reduction to be
N501Y active
Gamma P.1 VBM K417T, Marked Unlikely No changeb Active No change Active No change Active No change Active
E484K, reduction to be
N501Y active
Delta B.1.617.2, VOC L452R, No change Active No change Active No change Active No change Active No change Active
non-AY.1/ T478K
AY.2
Omicron B.1.1.529/ VOC K417N, Marked Unlikely Marked Unlikely to No change Active No change Active Moderate Actived
BA.1 N440K, reduction to be reduction be active reductionc
G446S, active
E484A,
Q493R,
N501Y
Omicron B.1.1.529/ VOC R346K, Marked Unlikely Marked Unlikely to No change Active No change Active Moderate Actived
BA.1.1 K417N, reduction to be reduction be active reductionc
N440K, active
G446S,
E484A,
Q493R,
N501Y
Omicron B.1.1.529/ VOC T376A, Marked Unlikely Marked Unlikely to No change Active Marked Unlikely No change Active
BA.2 K417N, reduction to be reduction be active reduction to be
N440K, active active
E484A,
Q493R,
N501Y
a
Based on the fold reduction in susceptibility reported in the FDA EUAs.8,11,15,16
b
Marked change for CAS and no change for IMD. The combination of CAS plus IMD appears to retain activity against the variant.
c
Despite the moderately reduced in vitro susceptibility of TIX plus CIL, in vitro PK/PD modeling data suggest that the TIX 300 mg plus CIL 300 mg dose will retain

AR08940
activity against the Omicron VOC.11
d
The duration of protection against SARS-CoV-2 infection remains unclear.
Key: BAM = bamlanivimab; BEB = bebtelovimab; CAS = casirivimab; CIL = cilgavimab; CDC = Centers for Disease Control
and Prevention; ETE = etesevimab; EUA = Emergency Use Authorization; FDA = Food and Drug Administration; IMD =
imdevimab; PK/PD = pharmacokinetic/pharmacodynamic; SOT = sotrovimab; TIX = tixagevimab; VBM = variant being
monitored; VOC = variant of concern; WHO = World Health Organization
Clinical Trials
In placebo-controlled, randomized trials in nonhospitalized patients with mild to moderate COVID-19
symptoms and certain risk factors for disease progression, the use of anti-SARS-CoV-2 mAb products
reduced the risk of hospitalization and death (see Table 3a).6,8,15,16 These studies were conducted
before the widespread circulation of the Omicron VOC. The potential impact of this variant and its
susceptibility to different FDA-authorized anti-SARS-CoV-2 mAbs are discussed below.
Bebtelovimab
Based on in vitro data, bebtelovimab is expected to have activity against a broad range of SARS-CoV-2
variants, including the Omicron VOC and its BA.1 and BA.2 subvariants.6,9,19 The Panel’s
recommendation on bebtelovimab is primarily based on laboratory data showing its potent activity
against the Omicron VOC (including the BA.1 and BA.2 subvariants) and other VOCs, as well as on
limited clinical trial data from the Phase 2 BLAZE-4 study.6
The multi-armed, Phase 2 BLAZE-4 study included 1 small, placebo-controlled, randomized trial in
patients at low risk of disease progression. It also included 1 small randomized controlled trial that
compared bebtelovimab alone to an anti-SARS-CoV-2 mAb combination of bamlanivimab, etesevimab,
and bebtelovimab in patients at high risk of disease progression (see Table 3a).6 Among low-risk
individuals, the mean decline in viral load at Day 5 was greater in the 2 bebtelovimab arms than in the
placebo arm. The median time to sustained symptom resolution was 6 days in the bebtelovimab alone
arm and 8 days in the placebo arm (P = 0.003).
Large randomized controlled trials are needed to fully evaluate the efficacy of bebtelovimab in a
high-risk population. Nevertheless, when other therapeutic options are not available, feasible to use, or
clinically appropriate, in vitro susceptibility data and the antiviral activity and clinical benefits observed
in Phase 2 trials support the use of bebtelovimab for nonhospitalized patients with mild to moderate
COVID-19 at high risk of progressing to severe COVID-19. In addition, bebtelovimab has mechanisms
of action similar to those of other authorized anti-SARS-CoV-2 mAbs that have shown definitive clinical
benefits in this population.
Bamlanivimab Plus Etesevimab

The distribution of bamlanivimab plus etesevimab has paused in the United States because
the Omicron VOC and subvariants have markedly reduced in vitro susceptibility to this mAb
regimen.5 Prior to the spread of the Omicron variant, the Phase 3 BLAZE-1 trial had demonstrated a
clinical benefit of bamlanivimab plus etesevimab in people with mild to moderate COVID-19 who are at
high risk for progression to severe disease or hospitalization.21
Casirivimab Plus Imdevimab

The distribution of casirivimab plus imdevimab has paused in the United States because the
Omicron VOC and subvariants have markedly reduced in vitro susceptibility to this mAb
regimen.7 Prior to the spread of the Omicron variant, the FDA had authorized the use of casirivimab
600 mg plus imdevimab 600 mg administered as a single IV infusion for the treatment of people with

AR08941
mild to moderate COVID-19 who are at high risk for progression to severe disease or hospitalization.8
The recommendation for using the dose of casirivimab 600 mg plus imdevimab 600 mg IV is based on
data from a Phase 3, double-blind, placebo-controlled, randomized trial demonstrating clinical benefit in
outpatients with mild to moderate COVID-19. The FDA also authorized subcutaneous (SUBQ) injection
of the regimen if an IV infusion is not feasible or would delay treatment. SUBQ administration of
casirivimab plus imdevimab requires 4 injections (2.5 mL per injection) at 4 different sites (see the FDA
EUA for details).
Sotrovimab
Sotrovimab retains in vitro activity against the Omicron BA.1 and BA.1.1 subvariants of the Omicron
VOC, but it has substantially decreased in vitro activity against the Omicron BA.2 subvariant and
is not expected to provide clinical benefit for patients with Omicron BA.2 infection.8 Because the
Omicron BA.2 subvariant is now the dominant circulating subvariant in all regions of the United States,
distribution of sotrovimab has paused, and the Panel no longer recommends using sotrovimab to treat
COVID-19.
Data that support the sotrovimab EUA are from the Phase 3 COMET-ICE trial, which included
outpatients with mild to moderate COVID-19 who were at high risk for progression to severe disease
or hospitalization. A total of 1,057 participants were randomized within 5 days of symptom onset to
receive sotrovimab 500 mg IV (n = 528) or placebo (n = 529). The primary endpoint was the proportion
of participants who were hospitalized for ≥24 hours or who died from any cause by Day 29. Endpoint
events occurred in 6 of 528 participants (1%) in the sotrovimab arm and 30 of 529 participants (6%) in
the placebo arm, resulting in a 4.53% absolute difference in the risk of hospitalization or death among
those who received sotrovimab. The adjusted relative risk of hospitalization or death for those who
received sotrovimab was 0.21.8,22
See Table 3a for more information on the clinical trials evaluating the safety and efficacy of anti-SARS-
CoV-2 mAbs in patients with COVID-19.
Criteria for Use of Anti-SARS-CoV-2 Monoclonal Antibodies Under Emergency Use

Authorizations
The FDA EUAs for anti-SARS-CoV-2 mAbs include a list of specific conditions that place patients
at high risk for clinical progression. On May 14, 2021, the FDA revised the EUAs to broaden these
criteria.15,16 Notable changes included lowering the body mass index (BMI) cutoff from ≥35 to >25 and
adding other conditions and factors (e.g., pregnancy, race or ethnicity). Other than being aged ≥12 years,
there are no longer any age criteria restricting the use of these products in patients with the following
conditions: sickle cell disease, neurodevelopmental disorders, medical-related technological dependence,
asthma, cardiovascular disease, hypertension, and chronic lung disease.
For guidance when available therapies cannot be offered to all eligible patients, see Prioritization
of Anti-SARS-CoV-2 Therapies for the Treatment and Prevention of COVID-19 When There Are
Logistical or Supply Constraints.
Recommendations
The strength of the evidence for using anti-SARS-CoV-2 mAbs varies depending on the medical
conditions and other factors that place patients at high risk for progression to severe COVID-19 or
hospitalization. The ratings for the Panel’s recommendations are based on FDA EUA criteria for
identifying high-risk individuals.

AR08942
• For patients with high-risk conditions that have been represented in clinical trials evaluating
anti-SARS-CoV-2 mAbs, the Panel recommends the use of anti-SARS-CoV-2 mAbs, with the
following ratings:
• Aged ≥65 years (AIIa)
• Obesity (BMI >30) (AIIa)
• Diabetes (AIIa)
• Cardiovascular disease (including congenital heart disease) or hypertension (AIIa)
• Chronic lung diseases (e.g., chronic obstructive pulmonary disease, moderate-to-severe asthma,
interstitial lung disease, cystic fibrosis, pulmonary hypertension) (AIIa)
• For patients with conditions that have had limited representation in clinical trials but are
considered a high risk for progression to severe COVID-19 by the Centers for Disease Control and
Prevention (CDC), the Panel recommends the use of anti-SARS-CoV-2 mAbs, with the following
ratings:
• Immunocompromised or receiving immunosuppressive treatment (AIII); many experts
strongly recommend therapy for patients with these conditions, despite limited representation
in clinical trials
• Overweight (i.e., BMI 25–30) as a sole risk factor (BIII)
• Chronic kidney disease (BIII)
• Pregnancy (BIII)
• Sickle cell disease (BIII)
• Neurodevelopmental disorder (e.g., cerebral palsy) or another condition that confers medical
complexity (e.g., genetic or metabolic syndromes, severe congenital anomalies) (BIII)
• Medical-related technological dependence (e.g., tracheostomy, gastrostomy, positive pressure
ventilation not related to COVID-19) (BIII)
• Infants aged <1 year. Although bamlanivimab plus etesevimab is authorized for use in this
high-risk group, the Panel recommends against using this mAb regimen (AIII) because it has
markedly reduced activity against Omicron, the dominant VOC in the United States.
It is important to note that the likelihood of developing severe COVID-19 increases when a person has
multiple high-risk conditions or comorbidities.23-26 Medical conditions or other factors (e.g., race or
ethnicity) that are not listed in the mAb EUAs may also be associated with high risk for progression to
severe COVID-19. The current EUAs state that the use of anti-SARS-CoV-2 mAbs may be considered
for patients with high-risk conditions and factors that are not listed in the EUAs. For additional
information on medical conditions and other factors that are associated with an increased risk for
progression to severe COVID-19, see the CDC webpage People With Certain Medical Conditions. The
decision to use anti-SARS-CoV-2 mAbs for a patient should be based on an individualized assessment
of risks and benefits.8
Using Anti-SARS-CoV-2 Monoclonal Antibodies in Patients Hospitalized for

COVID-19
The anti-SARS-CoV-2 mAbs available through FDA EUAs are not authorized for use in the following
patients:
• Those hospitalized for COVID-19; or

AR08943
• Those who require oxygen therapy or respiratory support due to COVID-19; or

• Those who are on chronic oxygen therapy due to an underlying non-COVID-19-related
comorbidity and who require an increase in oxygen flow rate from baseline or respiratory support
because of COVID-19.
The FDA EUAs do permit the use of anti-SARS-CoV-2 mAb products in patients who are hospitalized
for a diagnosis other than COVID-19, provided they have mild to moderate COVID-19 and are at high
risk for progressing to severe disease.6,16,27,28
Anti-SARS-CoV-2 mAbs have been evaluated in hospitalized patients with severe COVID-19. A
substudy of the ACTIV-3/TICO trial randomized patients who were hospitalized for COVID-19 to
receive bamlanivimab 7,000 mg or placebo, each in addition to remdesivir. On October 26, 2020, study
enrollment was halted after a prespecified interim futility analysis indicated a lack of clinical benefit for
bamlanivimab.29,30
Prior to the spread of the Omicron VOC, data supported the use of anti-SARS-CoV-2 mAbs in
hospitalized patients with COVID-19 who are seronegative for the anti-spike protein antibody and/
or have evidence of ongoing viral replication. In a subset analysis of the ACTIV-3 trial, 153 of 314
participants (49%) were negative for the anti-spike endogenous neutralizing antibody. The subhazard
ratio (sHR) comparing bamlanivimab to placebo for sustained recovery (defined as discharge home
and remaining at home for ≥14 days through Day 90) was 1.24 among the participants who were
seronegative (CI, 0.90–1.70) versus 0.74 among those who were seropositive (CI, 0.54–1.00).
Furthermore, the difference for sustained recovery between bamlanivimab and placebo was even greater
among the seronegative participants who had high viral loads (sHR 1.89; CI, 1.23–2.91). However, these
results are limited due to the trial’s early termination for futility and small sample size.31
The ACTIV-3/TICO trial also randomized hospitalized patients with COVID-19 to receive sotrovimab
500 mg IV, an anti-SARS-CoV-2 mAb combination of BRII-196 1,000 mg IV plus BRII-198 1,000
mg IV, or placebo, each in addition to remdesivir. On March 1, 2021, study enrollment was halted after
a prespecified interim futility analysis indicated a lack of clinical benefit for sotrovimab or BRII-196
plus BRII-198.32 A subset analysis did not suggest efficacy for sotrovimab in those with or without
endogenous antibodies.
In the RECOVERY study, hospitalized patients with COVID-19 were randomized to receive usual care
with casirivimab 4,000 mg plus imdevimab 4,000 mg IV or usual care alone. There was no difference
in 28-day all-cause mortality between the casirivimab plus imdevimab arm and the usual care arm; 943
of 4,839 patients (19%) in the casirivimab plus imdevimab arm died versus 1,029 of 4,946 patients
(21%) in the usual care arm (rate ratio 0.94; 95% CI, 0.86–1.02; P = 0.14). However, in the subgroup
of patients who were seronegative for the anti-spike protein antibody, there was a significant reduction
in 28-day all-cause mortality in the casirivimab plus imdevimab arm (396 of 1,633 casirivimab plus
imdevimab recipients [24%] died vs. 452 of 1,520 usual care recipients [30%]; rate ratio 0.79; 95% CI,
0.69–0.91; P = 0.0009).33 Under the current EUA, this higher dose of casirivimab plus imdevimab is not
available, and the lower dose is only authorized for use in nonhospitalized patients with COVID-19. In
addition, rapid serology testing that can identify seronegative individuals in real time is currently not
widely available.
Anti-SARS-CoV-2 mAbs may be available through expanded access programs for the treatment
of immunocompromised patients who are hospitalized because of COVID-19. It is not yet known
whether these mAb products provide clinical benefits in people with B-cell immunodeficiency or other
immunodeficiencies.

AR08944
Monitoring
Bebtelovimab should be administered by IV injection and should only be administered in health care
settings by qualified health care providers who have immediate access to emergency medical services
and medications that treat severe infusion-related reactions. Patients should be monitored during the IV
injection and for at least 1 hour after the injection is completed.
Adverse Effects
Hypersensitivity, including anaphylaxis and infusion-related reactions, has been reported in patients who
received anti-SARS-CoV-2 mAbs. Rash, diarrhea, nausea, vomiting, dizziness, and pruritis have also
been reported.6,8,16,28
Drug-drug interactions are unlikely between the authorized anti-SARS-CoV-2 mAbs and medications
that are renally excreted or that are cytochrome P450 substrates, inhibitors, or inducers (see Table 3c).
The use of anti-SARS-CoV-2 mAbs can be considered for pregnant people with COVID-19, especially
those who have additional risk factors for severe disease (see the EUA criteria for the use of these
products above).
As immunoglobulin (Ig) G mAbs, the authorized anti-SARS-CoV-2 mAbs would be expected to cross
the placenta. There are no pregnancy-specific data on the use of these mAbs; however, other IgG
products have been safely used in pregnant people when their use is indicated. Therefore, authorized
anti-SARS-CoV-2 mAbs should not be withheld during pregnancy. When possible, pregnant and
lactating people should be included in clinical trials that are evaluating the use of anti-SARS-CoV-2
mAbs for the treatment or prevention of COVID-19.
Please see Special Considerations in Children for therapeutic recommendations for children with
COVID-19.
Drug Availability
Bebtelovimab is currently being distributed to all regions without restriction. The broad distribution of
bamlanivimab plus etesevimab, casirivimab plus imdevimab, and sotrovimab has paused in the United
States because the Omicron VOC has reduced susceptibility to these anti-SARS-CoV-2 mAbs.5,7
References
1. Jiang S, Hillyer C, Du L. Neutralizing antibodies against SARS-CoV-2 and other human coronaviruses. Trends
Immunol. 2020;41(5):355-359. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32249063.
2. Centers for Disease Control and Prevention. COVID data tracker: variant proportions. 2022. Available at:
https://covid.cdc.gov/covid-data-tracker/#variant-proportions. Accessed April 19, 2022.
3. Rockett R, Basile K, Maddocks S, et al. Resistance mutations in SARS-CoV-2 Delta variant after sotrovimab
use. N Engl J Med. 2022;386(15):1477-1479. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35263515.
4. Huygens S, Munnink BO, Gharbharan A, Koopmans M, Rijnders B. High incidence of sotrovimab resistance
and viral persistence after treatment of immunocompromised patients infected with the SARS-CoV-2 Omicron
variant. medRxiv. 2022;Preprint. Available at:

AR08945
5. Public Health Emergency. Bamlanivimab/etesevimab. 2022. Available at: https://www.phe.gov/emergency/
events/COVID19/investigation-MCM/Bamlanivimab-etesevimab/Pages/default.aspx. Accessed April 21,
2022.
bebtelovimab. 2022. Available at: https://www.fda.gov/media/156152/download.
7. Public Health Emergency. REGEN-COV. 2022. Available at: https://www.phe.gov/emergency/events/
COVID19/investigation-MCM/cas_imd/Pages/default.aspx. Accessed April 21, 2022.
sotrovimab. 2022. Available at: https://www.fda.gov/media/149534/download.
subvariant BA.2. N Engl J Med. 2022;386(15):1475-1477. Available at:
11. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for Evusheld
(tixagevimab co-packaged with cilgavimab). 2022. Available at:
12. Planas D, Saunders N, Maes P, et al. Considerable escape of SARS-CoV-2 Omicron to antibody neutralization.
Nature. 2021;602(7898):671-675. Available at: https://pubmed.ncbi.nlm.nih.gov/35016199/.
antigenic shift. Nature. 2022;602(7898):664-670. Available at:
14. Centers for Disease Control and Prevention. SARS-CoV-2 variant classifications and definitions. 2022.
Available at: https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-classifications.html. Accessed April
13, 2022.
15. Food and Drug Administration. Fact sheet for health care providers: emergency use authorization (EUA) of
bamlanivimab and etesevimab. 2022. Available at: https://www.fda.gov/media/145802/download.
REGEN-COV (casirivimab and imdevimab). 2021. Available at:
17. Wang P, Nair MS, Liu L, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature.
18. Wang P, Casner RG, Nair MS, et al. Increased resistance of SARS-CoV-2 variant P.1 to antibody
neutralization. Cell Host Microbe. 2021;29(5):747-751. Available at:
19. Westendorf K, Zentelis S, Wang L, et al. LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2
variants. Cell Rep. 2022;Published online ahead of print. Available at:
20. VanBlargan L, Errico J, Halfmann P, et al. An infectious SARS-CoV-2 B.1.1.529 Omicron virus escapes
neutralization by therapeutic monoclonal antibodies. Res Sq. 2021;Preprint. Available at:
21. Dougan M, Azizad M, Mocherla B, et al. A randomized, placebo-controlled clinical trial of bamlanivimab and
etesevimab together in high-risk ambulatory patients with COVID-19 and validation of the prognostic value of
persistently high viral load. Clin Infect Dis. 2021;Published online ahead of print. Available at:

AR08946
22. Gupta A, Gonzalez-Rojas Y, Juarez E, et al. Effect of sotrovimab on hospitalization or death among high-risk
patients with mild to moderate COVID-19: a randomized clinical trial. JAMA. 2022;327(13):1236-1246.
23. Kim L, Garg S, O’Halloran A, et al. Risk factors for intensive care unit admission and in-hospital mortality
among hospitalized adults identified through the US coronavirus disease 2019 (COVID-19)-associated
hospitalization surveillance network (COVID-NET). Clin Infect Dis. 2021;72(9):e206-e214. Available at:
24. Guan WJ, Liang WH, Zhao Y, et al. Comorbidity and its impact on 1590 patients with COVID-19 in China: a
nationwide analysis. Eur Respir J. 2020;55(5). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32217650.
25. Zhang Y, Luo W, Li Q, et al. Risk factors for death among the first 80,543 COVID-19 cases in China:
relationships between age, underlying disease, case severity, and region. Clin Infect Dis. 2022;74(4):630-638.
26. Rosenthal N, Cao Z, Gundrum J, Sianis J, Safo S. Risk factors associated with in-hospital mortality in a U.S.
national sample of patients with COVID-19. JAMA Netw Open. 2020;3(12):e2029058. Available at:
27. Food and Drug Administration. Frequently asked questions on the emergency use authorization of
bamlanivimab and etesevimab. 2022. Available at: https://www.fda.gov/media/145808/download.
28. Food and Drug Administration. Frequently asked questions on the emergency use authorization of sotrovimab.
29. National Institute of Allergy and Infectious Diseases. Statement—NIH-sponsored ACTIV-3 trial closes
LY-CoV555 sub-study. 2020. Available at: https://www.niaid.nih.gov/news-events/statement-nih-sponsored-
activ-3-trial-closes-ly-cov555-sub-study. Accessed April 20, 2022.
30. ACTIV-TICO LY-CoV555 Study Group, Lundgren JD, Grund B, et al. A neutralizing monoclonal antibody for
hospitalized patients with COVID-19. N Engl J Med. 2021;384(10):905-914. Available at:
31. ACTIV-3/TICO Bamlanivimab Study Group. Responses to a neutralizing monoclonal antibody for
hospitalized patients with COVID-19 according to baseline antibody and antigen levels: a randomized
controlled trial. Ann Intern Med. 2021;175(2):234-243. Available at:
32. ACTIV-3/Therapeutics for Inpatients with COVID-19 Study Group. Efficacy and safety of two neutralising
monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with
COVID-19 (TICO): a randomised controlled trial. Lancet Infect Dis. 2022;22(5):622-635. Available at:
33. RECOVERY Collaborative Group. Casirivimab and imdevimab in patients admitted to hospital
with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet.

AR08947
Table 3a. Anti-SARS-CoV-2 Monoclonal Antibodies: Selected Clinical Data

This table describes only the clinical trials that have evaluated anti-SARS-CoV-2 mAbs for the treatment of COVID-19. Please see
Prevention of SARS-CoV-2 Infection for a discussion of the clinical trials that have evaluated anti-SARS-CoV-2 mAbs for PEP of
SARS-CoV-2 infection.
BLAZE-1: Double-Blind RCT of Bamlanivimab 700 mg Plus Etesevimab 1,400 mg in Nonhospitalized Patients With Mild to Moderate COVID-19 in the United
States and Puerto Rico1
• Aged ≥12 years • Median age 56 years; 30% aged ≥65 years; 53% women • Conducted before widespread
• At high risk for severe COVID-19 or hospitalization • 87% White, 27% Hispanic/Latinx, 8% Black/African American circulation of the Omicron VOC
Interventions: • Mean duration of symptoms was 4 days Interpretation:
• Within 3 days of a positive SARS-CoV-2 test result, • 76% with mild COVID-19, 24% with moderate COVID-19 • Compared to placebo, BAM plus ETE
single infusion of: significantly reduced the number of
Primary Outcomes: COVID-19-related hospitalizations
• BAM 700 mg plus ETE 1,400 mg (n = 511) • COVID-19-related hospitalizations or all-cause deaths by Day and all-cause deaths in high-risk
• Placebo (n = 258) 29: 4 (0.8%) in BAM plus ETE arm vs. 15 (5.8%) in placebo patients.
arm (change of -5.0%; 95% CI, -8.0% to -2.1%; P < 0.001)
Primary Endpoint:
• All-cause deaths by Day 29: 0 in BAM plus ETE arm vs. 4
• COVID-19-related hospitalization (defined as ≥24 hours
(1.6%) in placebo arm
of acute care) or death from any cause by Day 29
BLAZE-4, Treatment Arms 9–11: Double-Blind RCT of Bamlanivimab Plus Etesevimab Plus Bebtelovimab Versus Bebtelovimab Alone Versus Placebo in Low-
Risk, Nonhospitalized Patients With Mild to Moderate COVID-192
• Aged 18–64 years • Median age 35 years; 56% women • Only low-risk patients included
• No risk factors for progression to severe COVID-19 • 36% Hispanic/Latinx, 19% Black/African American • Not powered to assess
Key Exclusion Criteria: • Mean duration of symptoms prior to enrollment was 3.6 days hospitalizations and deaths
• Conducted before widespread
• ≥1 of the following: Primary Outcomes:
circulation of the Omicron VOC
• SpO2 ≤93% on room air • Proportion with PHVL:
Interpretations:
• Respiratory rate ≥30 breaths/min • 13% in BAM plus ETE plus BEB arm vs. 21% in placebo
• Heart rate ≥125 bpm arm (P = 0.098), with a relative reduction of 38% (95% CI, • There were no differences in the
-9% to 65%) proportion of patients with PHVL
Interventions: across the arms.
• 14% in BEB arm vs. 21% in placebo arm (P = 0.147), with a
• Within 3 days of a positive SARS-CoV-2 test result, relative reduction of 34% (95% CI, -15% to 62%) • Few COVID-19-related
single infusion of: hospitalizations or deaths from any

AR08948

BLAZE-4, Treatment Arms 9–11: Double-Blind RCT of Bamlanivimab Plus Etesevimab Plus Bebtelovimab Versus Bebtelovimab Alone Versus Placebo in Low-
Risk, Nonhospitalized Patients With Mild to Moderate COVID-192, continued
• BAM 700 mg plus ETE 1,400 mg plus BEB 175 Secondary Outcomes: cause occurred by Day 29 across the arms,
mg (n = 127) • Mean decline in VL greater in mAb arms vs. placebo arm as is expected for a population of individuals
• BEB 175 mg (n = 125) at Day 5 but not at Days 3, 7, or 11 who were at low risk of severe COVID-19.
• Placebo (n = 128) • COVID-19-related hospitalizations or all-cause deaths by • Compared to placebo, the median time to
Day 29: sustained symptom resolution was shorter
Primary Endpoint: in the BEB arm.
• 3 (2.4%) in BAM plus ETE plus BEB arm, including 1
• Proportion of patients with PHVL (defined as
death
SARS-CoV-2 VL >5.82 log10 by Day 7)
• 2 (1.6%) in BEB arm
• 2 (1.6%) in placebo arm
• Mean change in VL from baseline to Days 3, 5, 7,
and 11 • M
edian time to sustained symptom resolution:
• COVID-19-related hospitalization or death from any • 7 days in BAM plus ETE plus BEB arm vs. 8 days in
cause by Day 29 placebo arm (P = 0.289)
• Time to sustained symptom resolution • 6 days in BEB arm vs. 8 days in placebo arm (P = 0.003)
BLAZE-4, Treatment Arms 12 and 13: Open-Label RCT of Bamlanivimab Plus Etesevimab Plus Bebtelovimab and Bebtelovimab Alone in High-Risk,
Nonhospitalized Patients With Mild to Moderate COVID-192
• Aged ≥12 years • Median age 50 years; 52% women • Open-label study
• Weight ≥40 kg • 18% Hispanic/Latinx, 18% Black/African American • No placebo arm
• ≥1 risk factor for progression to severe COVID-19 • Mean duration of symptoms prior to enrollment was 4.7 • Not powered to assess hospitalizations and
days deaths
• 21% had at least 1 dose of COVID-19 vaccine • Conducted before widespread circulation of
• ≥1 of the following:
the Omicron VOC
• SpO2 ≤93% on room air Efficacy Outcomes:
• COVID-19-related hospitalization or death from any cause Interpretation:
• Respiratory rate ≥30 breaths/min
by Day 29: 2 (4%) in BAM plus ETE plus BEB arm vs. 3 • There was no difference in the proportion of
• Heart rate ≥125 bpm (3%) in BEB arm patients who were hospitalized or who died
Interventions: • Mean decline in VL greater in BAM plus ETE plus BEB arm between the arms.
• Within 3 days of a positive SARS-CoV-2 test result, vs. BEB arm at Day 5 but not at Days 3, 7, or 11
single infusion of:
• BAM 700 mg plus ETE 1,400 mg plus BEB 175
mg (n = 50)
• BEB 175 mg (n = 100)

AR08949

BLAZE-4, Treatment Arms 12 and 13: Open-Label RCT of Bamlanivimab Plus Etesevimab Plus Bebtelovimab and Bebtelovimab Alone in High-Risk,
Nonhospitalized Patients With Mild to Moderate COVID-192, continued
Efficacy Endpoints:
• COVID-19-related hospitalization or death from any
cause by Day 29
• Mean change in VL from baseline to Days 3, 5, 7,
and 11
Double-Blind RCT of Casirivimab Plus Imdevimab in Nonhospitalized Patients With Mild to Moderate COVID-193
• Aged ≥18 years • Median age 50 years • Conducted before widespread circulation of
• Laboratory-confirmed SARS-CoV-2 infection • 35% Hispanic/Latinx, 5% Black/African American the Omicron VOC
• Symptom onset within 7 days of randomization • Median duration of symptoms prior to enrollment was 3 Interpretation:
• For patients included in the modified full analysis days • Compared to placebo, CAS 600 mg plus
only: Primary Outcomes: IMD 600 mg and CAS 1,200 mg plus IMD
• ≥1 risk factor for severe COVID-19 1,200 mg reduced the risk of COVID-19-
• COVID-19-related hospitalizations or all-cause deaths related hospitalizations or all-cause deaths
• Positive SARS-CoV-2 RT-PCR result at baseline through Day 29: in patients with mild to moderate COVID-19.
Interventions: • 7 (1.0%) in CAS 600 mg plus IMD 600 mg arm vs. 24
(3.2%) in placebo arm (P = 0.002)
• Single IV infusion of:
• 18 (1.3%) in CAS 1,200 mg plus IMD 1,200 mg arm vs.
• CAS 600 mg plus IMD 600 mg (n = 736) or 62 (4.6%) in placebo arm (P < 0.001)
placebo (n = 748)
• All-cause deaths:
• CAS 1,200 mg plus IMD 1,200 mg (n = 1,355) or
placebo (n = 1,341) • 1 (0.1%) in CAS 600 mg plus IMD 600 mg arm vs. 1
(0.1%) in placebo arm
Primary Endpoint:
• 1 (< 0.1%) in CAS 1,200 mg plus IMD 1,200 mg arm vs.
• ≥1 COVID-19-related hospitalization or death from 3 (0.2%) in placebo arm
any cause by Day 29

AR08950

COMET-ICE: Double-Blind RCT of Sotrovimab in Nonhospitalized Patients With Mild to Moderate COVID-19 in Brazil, Canada, Peru, Spain, and the United
States4
• Aged ≥18 years • Median age 53 years; 20% aged ≥65 years; 54% women • Conducted before widespread circulation of
• ≥1 comorbidity or aged ≥55 years • 65% Hispanic/Latinx, 8% Black/African American the Omicron VOC
• Positive SARS-CoV-2 RT-PCR or antigen test result • 63% with obesity; 22% with DM; 17% with moderate to Interpretation:
• Symptom onset ≤5 days before enrollment severe asthma • Compared to placebo, SOT reduced the
Primary Outcome: incidence of all-cause hospitalizations
Key Exclusion Criteria: and deaths among patients with mild to
• Hospitalized or required supplemental oxygen • Hospitalizations or all-cause deaths by Day 29: 6 (1%) in moderate COVID-19.
SOT arm vs. 30 (6%) in placebo arm, including 2 deaths
• Severely immunocompromised (adjusted relative risk 0.21; 95% CI, 0.09–0.50; absolute
Interventions: difference -4.53%; 95% CI, -6.70% to -2.37%; P < 0.001)
• SOT 500 mg IV (n = 528)
Primary Endpoint:
• Hospitalization or death from any cause by Day 29
Key: BAM = bamlanivimab; bpm = beats per minute; BEB = bebtelovimab; CAS = casirivimab; DM = diabetes mellitus; ETE = etesevimab; IMD = imdevimab; IV =
intravenous; mAb = monoclonal antibody; PEP = post-exposure prophylaxis; PHVL = persistently high viral load; RCT = randomized controlled trial; RT-PCR = reverse
transcription polymerase chain reaction; SOT = sotrovimab; SpO2 = oxygen saturation; VL = viral load; VOC = variant of concern
References
1. Dougan M, Azizad M, Mocherla B, et al. A randomized, placebo-controlled clinical trial of bamlanivimab and etesevimab together in high-risk
ambulatory patients with COVID-19 and validation of the prognostic value of persistently high viral load. Clin Infect Dis. 2021;Published online ahead
of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34718468.
2. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for bebtelovimab. 2022. Available at:
3. Weinreich DM, Sivapalasingam S, Norton T, et al. REGEN-COV antibody combination and outcomes in outpatients with COVID-19. N Engl J Med.
4. Gupta A, Gonzalez-Rojas Y, Juarez E, et al. Effect of sotrovimab on hospitalization or death among high-risk patients with mild to moderate
COVID-19: a randomized clinical trial. JAMA. 2022;327(13):1236-1246. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35285853.

AR08951

Plasma from donors who have recovered from COVID-19 may contain antibodies to SARS-CoV-2 that
could help suppress viral replication.1 In August 2020, the Food and Drug Administration (FDA) issued
an Emergency Use Authorization (EUA) for COVID-19 convalescent plasma (CCP) for the treatment of
hospitalized patients with COVID-19. The EUA was revised in February 2021 to limit the authorization
to the use of high-titer CCP for the treatment of hospitalized patients with COVID-19 who are early
in their disease course or who have impaired humoral immunity.2 In December 2021, the EUA was
revised again to authorize the use of CCP only in outpatients or inpatients with COVID-19 who have
immunosuppressive disease or who are receiving immunosuppressive treatment. The testing criteria
used to identify CCP products that contain high levels of anti-SARS-CoV-2 antibodies (i.e., high-titer
products) was also revised.2
The use of CCP should be limited to high-titer products. Products that are not labeled “high titer” should
not be used.
Recommendations
• The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of CCP
that was collected prior to the emergence of the Omicron (B.1.1.529) variant for the treatment of
COVID-19 (AIII).
• The Panel recommends against the use of CCP for the treatment of COVID-19 in hospitalized,
immunocompetent patients (AI).
• There is insufficient evidence for the Panel to recommend either for or against the use of high-titer
CCP that was collected after the emergence of Omicron for the treatment of immunocompromised
patients and nonhospitalized, immunocompetent patients with COVID-19.
Rationale
Regarding the Use of COVID-19 Convalescent Plasma Collected Prior to the Emergence of
the Omicron Variant
The Omicron variant is the dominant SARS-CoV-2 variant currently circulating in the United States.
Although in vitro data suggest that the CCP collected from vaccinated and unvaccinated individuals who
have recovered from Omicron infection exhibits neutralizing activity against the Omicron variant,3-6 it
is not possible to extrapolate the potential clinical efficacy of CCP in the current clinical context. This is
due in part to the following factors:
• The current supply of CCP products in the United States was not generated from donors who had
recovered from Omicron infection.7
• Many CCP clinical trials were completed before the Omicron surge, and their results may not
inform the current clinical context.
• The current approaches to testing CCP titers do not account for potential differences in the
neutralizing activity of CCP products against currently circulating variants.
Furthermore, it is difficult to interpret the available data on the in vitro antiviral activity of CCP, since
the published studies use a variety of assays to characterize the neutralizing activity of CCP, and the
level of immunity to COVID-19 can vary across different donor populations.

AR08952
For Hospitalized, Immunocompetent Patients

Under the revised EUA, the use of CCP is no longer authorized for hospitalized patients who do not
have immunosuppressive disease or who are not receiving immunosuppressive treatments.
Clinical data on the use of CCP for the treatment of COVID-19 in hospitalized, immunocompetent
patients, including data from several randomized trials and the U.S. Expanded Access Program (EAP)
for CCP, are summarized in Table 3b.
The initial EUA for CCP for the treatment of hospitalized patients with COVID-19 was issued on the
basis of retrospective, indirect evaluations of efficacy generated from the CCP EAP, which allowed CCP
to be used regardless of titer. Several retrospective analyses of the EAP data have indicated that patients
who received high-titer CCP had a lower relative risk of death than patients who received low-titer
CCP.8,9 The Panel reviewed the EAP analyses and determined that the data were not sufficient to
establish the efficacy or safety of CCP due to potential confounding factors, the lack of randomization,
and the lack of an untreated control group.
Data from the initial randomized clinical trials that evaluated CCP, which were all underpowered, did
not demonstrate the product’s efficacy for the treatment of hospitalized patients with COVID-19.10-17
Subsequently, results from the 3 largest randomized clinical trials that evaluated CCP in hospitalized
patients—RECOVERY,18 CONCOR-1,19 and REMAP-CAP20—found no evidence of benefit for
high-titer CCP in hospitalized patients with COVID-19. All 3 were open-label trials that were stopped
early due to futility.
Although these trials and the EAP did not exclude patients with impaired humoral immunity, most
of the patients enrolled did not report a history of an immunocompromising condition or receipt of
chronic immunosuppressive therapy. After reviewing the collective results from these studies, the Panel
recommends against the use of CCP for the treatment of COVID-19 in hospitalized, immunocompetent
patients (AI).
For Nonhospitalized, Immunocompetent Patients

CCP is not authorized for the treatment of nonhospitalized patients with COVID-19 who do not have
immunosuppressive disease or who are not receiving immunosuppressive treatment. Clinical data on
the use of CCP for the treatment of nonhospitalized, immunocompetent patients are summarized in
Table 3b. The data from well-designed clinical trials that evaluated the use of CCP for the treatment of
nonhospitalized patients with COVID-19 are conflicting. All of the following trials were conducted prior
to the emergence of Omicron.
Trials That Demonstrated Efficacy for COVID-19 Convalescent Plasma
• A moderately-sized, double-blind, placebo-controlled, randomized trial evaluated the use of
high-titer CCP in older, nonhospitalized adults with <72 hours of mild COVID-19 symptoms (n
= 160). The patients were aged ≥75 years or aged 65 to 74 years with ≥1 comorbidity. The trial
reported a reduction in the proportion of patients who developed severe respiratory disease within
14 days in the CCP arm (16% in the CCP arm vs. 31% in the placebo arm; relative risk 0.52; 95%
CI, 0.29–0.94; P = 0.03).9
• CSSC-004, a large (n = 1,181), double-blind, placebo-controlled trial that evaluated the use of
high-titer CCP for the treatment of adults with ≤8 days of COVID-19 symptoms, demonstrated a
reduction in the proportion of patients who experienced COVID-19-related hospitalization within
28 days in the CCP arm (2.9% in the CCP arm vs. 6.3% in the placebo arm; absolute risk reduction
of 3.4 percentage points; 95% CI, 1.0–5.8; P = 0.005). Eighty-two percent of the patients were

AR08953
not vaccinated against COVID-19, and 53 of the 54 hospitalizations that were reported during the
study occurred in unvaccinated patients. No hospitalizations occurred in either arm among fully
vaccinated patients.21
Trials That Demonstrated No Benefit of COVID-19 Convalescent Plasma
• The SIREN-C3PO trial (n = 511) was a single-blind randomized trial that evaluated the use of
high-titer CCP for the treatment of nonhospitalized patients with ≤7 days of mild or moderate
COVID-19 symptoms and ≥1 risk factor for severe COVID-19. This study did not report a
reduction in the proportion of patients who experienced disease progression in the CCP arm (30%
in the CCP arm vs. 32% in the placebo arm; risk difference of 1.9 percentage points; 95% CrI, -6.0
to 9.8).22
• The CONV-ERT study (n = 376) was a double-blind, placebo-controlled randomized trial that
evaluated the use of high-titer, methylene blue-treated CCP for the treatment of nonhospitalized
patients aged ≥50 years with ≤7 days of mild or moderate COVID-19 symptoms. This study did
not report a reduction in the proportion of patients who were hospitalized or died in the CCP arm
(12% in the CCP arm vs. 11% in the placebo arm; relative risk 1.05; 95% CI, 0.78–1.41).23
Differences in patient populations, the placebo used (e.g., some studies used saline and some used non-
SARS-CoV-2 plasma), and CCP manufacturing and testing methods may have contributed to the disparate
outcomes of these clinical trials. Additional well-designed trials are necessary to establish evidence for a
consistent benefit of using CCP in nonhospitalized patients during the current phase of the pandemic.
The emergence of SARS-CoV-2 variants further complicates the assessment of any potential benefit of
CCP for this patient population. Most CCP products that are available in the United States are expected
to have no or very little neutralizing activity against the currently circulating SARS-CoV-2 variants
because they were collected from donors who had COVID-19 prior to the emergence of the Omicron
variant. The Panel recommends against using CCP that was collected prior to the emergence of the
Omicron variant for the treatment of COVID-19 (AIII).
Currently, nonhospitalized patients with mild to moderate COVID-19 who are at high risk of progressing
to severe disease are eligible to receive several antiviral therapies with proven efficacy. See Therapeutic
Management of Nonhospitalized Adults With COVID-19 for the Panel’s recommendations for this
patient population.
Hospitalized or Nonhospitalized Patients Who Are Immunocompromised

This section pertains to people who are moderately or severely immunocompromised.24 According to the
Centers for Disease Control and Prevention, individuals who qualify as having moderately or severely
immunocompromising conditions are those who:
• Are receiving active treatment for solid tumor and hematologic malignancies.
• Received a solid-organ transplant and are taking immunosuppressive therapy.
• Received chimeric antigen receptor T cell therapy or a hematopoietic stem cell transplant (within 2
years of transplantation or taking immunosuppression therapy).
• Have a moderate or severe primary immunodeficiency (e.g., DiGeorge syndrome, Wiskott-Aldrich
syndrome).
• Have advanced or untreated HIV infection (defined as people with HIV and CD4 T lymphocyte
counts <200 cells/mm3, a history of an AIDS-defining illness without immune reconstitution, or
clinical manifestations of symptomatic HIV).

AR08954
• Are receiving active treatment with high-dose corticosteroids (i.e., ≥20 mg prednisone or
equivalent per day when administered for ≥2 weeks), alkylating agents, antimetabolites,
transplant-related immunosuppressive drugs, cancer chemotherapeutic agents classified as
severely immunosuppressive, tumor-necrosis blockers, and other immunosuppressive or
immunomodulatory biologic agents (e.g., B cell-depleting agents).
Under the EUA issued on December 27, 2021, CCP is authorized for the treatment of COVID-19 in
outpatients or inpatients who have immunosuppressive disease or who are receiving immunosuppressive
treatment.
Although there are no definitive data to support using CCP in patients who are immunocompromised,
there is a physiologic rationale for the use of CCP in this patient population. People who are
immunocompromised are more likely to require hospitalization for breakthrough SARS-CoV-2 infection
despite COVID-19 vaccination, become severely ill from COVID-19, and experience prolonged
SARS-CoV-2 infection and shedding.25-27 Although some of this vulnerability may be attributed to
impaired cellular immune responses, numerous studies indicate that people who are immunosuppressed
are at risk of having reduced antibody responses to SARS-CoV-2 infection and/or vaccination.28-
30
Furthermore, the subgroup analyses from several clinical trials suggest that anti-SARS-CoV-2
antibody products are more likely to be effective in patients who are SARS-CoV-2 seronegative
than in patients who are seropositive.31,32 Therefore, patients who are immunocompromised could
potentially benefit from receiving antibody-based therapies in circumstances where patients without an
immunocompromising condition might not.
There are limited clinical data to inform the use of CCP to treat COVID-19 in patients who
are immunocompromised. No randomized, adequately controlled trials evaluating CCP in
immunocompromised patients have been published to date. A prespecified subgroup analysis of 126
critically ill REMAP-CAP participants with immunodeficiencies suggested that CCP might offer a
potential benefit of improved survival and/or more organ support-free days in this subgroup (OR 1.51;
95% CI, 0.80–2.92); however, this finding was not statistically significant.20 Data from case reports, case
series, and a retrospective case-control study also suggest a potential benefit of CCP in patients with
primary and secondary humoral immunodeficiencies, including patients with hematologic malignancy,
common variable immune deficiency, or agammaglobulinemia, and those who have received a solid
organ transplant.33-46
As noted above, the emergence of SARS-CoV-2 variants further complicates the assessment of any
potential benefit of CCP for patients who are immunocompromised. Studies have shown that prior
infection with the Beta (B.1.351) or Delta (B.1.617.2) variants affords little protection and has reduced
neutralizing antibody responses against the Omicron variant, raising doubts that CCP collected prior to
the emergence of Omicron will be effective.47-50 Thus, the Panel recommends against the use of CCP
collected prior to the emergence of the Omicron variant for the treatment of COVID-19 (AIII).
There is insufficient evidence for the Panel to recommend either for or against the use of high-titer
CCP that was collected after the emergence of Omicron for the treatment of COVID-19 in
immunocompromised patients and nonhospitalized, immunocompetent patients. Adequately
powered, well-designed, and well-conducted randomized clinical trials are needed to provide more
specific, evidence-based guidance on the role of CCP in the treatment COVID-19 in patients who are
immunocompromised.
The safety and efficacy of using CCP during pregnancy have not been evaluated in clinical trials,
and published data on its use in pregnant individuals with COVID-19 are limited to case reports.51

AR08955
Pathogen-specific immunoglobulins (Ig) are used clinically during pregnancy to prevent infection from
varicella zoster virus and rabies virus and have been used in clinical trials of congenital cytomegalovirus
infection.52,53 Pregnancy is not a reason to withhold CCP from a patient if it is otherwise indicated.
The safety and efficacy of CCP have not been systematically evaluated in pediatric patients. Published
literature on its use in children is limited to case reports and case series. A few clinical trials that are
evaluating the use of CCP in children are ongoing. The use of CCP may be considered on a case-by-case
basis for hospitalized children who are immunocompromised and meet the EUA criteria for its use. CCP
is not authorized by the FDA for use in immunocompetent patients.
As an alternative to CCP, several antiviral therapies are available for the treatment of children with
COVID-19 who are at high risk of progressing to severe disease. The use of these products in children
may be considered on a case-by-case basis. See Special Considerations in Children for more information.
Adverse Effects
The available data suggest that serious adverse reactions following the administration of CCP are
infrequent and consistent with the risks associated with plasma infusions for other indications. These
risks include transfusion-transmitted infections (e.g., HIV, hepatitis B, hepatitis C), allergic reactions,
anaphylactic reactions, febrile nonhemolytic reactions, transfusion-related acute lung injury, transfusion-
associated circulatory overload, and hemolytic reactions. Hypothermia, metabolic complications, and
post-transfusion purpura have also been described.2,18,54
Additional risks of CCP transfusion include a theoretical risk of antibody-dependent enhancement of
SARS-CoV-2 infection and a theoretical risk of long-term immunosuppression. In the CONCOR-1 trial,
higher levels of full transmembrane spike IgG were associated with worse outcomes, suggesting that the
use of CCP with nonfunctional anti-SARS-CoV-2 antibodies may be harmful.19 A subgroup analysis in
the REMAP-CAP trial showed potential harm in patients who received CCP transfusions more than 7
days after being hospitalized.20
When considering the use of CCP in patients with a history of severe allergic or anaphylactic transfusion
reactions, consultation with a transfusion medicine specialist is advised.
Clinical Trials
Several randomized clinical trials that are evaluating the use of CCP for the treatment of COVID-19 are
underway. Please see ClinicalTrials.gov for the latest information.
References
1. Wang X, Guo X, Xin Q, et al. Neutralizing antibody responses to severe acute respiratory syndrome
coronavirus 2 in coronavirus disease 2019 inpatients and convalescent patients. Clin Infect Dis.
COVID-19 convalescent plasma for treatment of coronavirus disease 2019 (COVID-19). 2021. Available at:
3. Lusvarghi S, Pollett SD, Neerukonda SN, et al. SARS-CoV-2 Omicron neutralization by therapeutic
antibodies, convalescent sera, and post-mRNA vaccine booster. bioRxiv. 2021;Preprint. Available at:
4. Khan K, Karim F, Cele S, et al. Omicron infection of vaccinated individuals enhances neutralizing immunity
against the Delta variant. medRxiv. 2022;Preprint. Available at:

AR08956
5. Yu J, Collier AY, Rowe M, et al. Comparable neutralization of the SARS-CoV-2 Omicron BA.1 and BA.2
variants. medRxiv. 2022;Preprint. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35169817.
6. Richardson SI, Madzorera VS, Spencer H, et al. SARS-CoV-2 Omicron triggers cross-reactive neutralization
and Fc effector functions in previously vaccinated, but not unvaccinated individuals. medRxiv. 2022;Preprint.
7. Focosi D, Franchini M, Joyner MJ, Casadevall A. Are convalescent plasma stocks collected during former
COVID-19 waves still effective against current SARS-CoV-2 variants? Vox Sang. 2022:1-6. Available at:
8. Joyner MJ, Carter RE, Senefeld JW, et al. Convalescent plasma antibody levels and the risk of death from
9. Libster R, Perez Marc G, Wappner D, et al. Early high-titer plasma therapy to prevent severe COVID-19 in
older adults. N Engl J Med. 2021;384(7):610-618. Available at:
10. Simonovich VA, Burgos Pratx LD, Scibona P, et al. A randomized trial of convalescent plasma in COVID-19
severe pneumonia. N Engl J Med. 2021;384(7):619-629. Available at:
11. Agarwal A, Mukherjee A, Kumar G, et al. Convalescent plasma in the management of moderate COVID-19
in adults in India: open label Phase II multicentre randomised controlled trial (PLACID Trial). BMJ.
2020;371:m3939. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33093056.
12. Gharbharan A, Jordans CCE, GeurtsvanKessel C, et al. Effects of potent neutralizing antibodies
from convalescent plasma in patients hospitalized for severe SARS-CoV-2 infection. Nat Commun.
13. Li L, Zhang W, Hu Y, et al. Effect of convalescent plasma therapy on time to clinical improvement in patients
with severe and life-threatening COVID-19: a randomized clinical trial. JAMA. 2020;324(5):460-470.
14. Avendano-Sola C, Ramos-Martinez A, Munez-Rubio E, et al. A multicenter randomized open-label
clinical trial for convalescent plasma in patients hospitalized with COVID-19 pneumonia. J Clin Invest.
15. AlQahtani M, Abdulrahman A, Almadani A, et al. Randomized controlled trial of convalescent plasma therapy
against standard therapy in patients with severe COVID-19 disease. Sci Rep. 2021;11(1):9927. Available at:
16. O’Donnell MR, Grinsztejn B, Cummings MJ, et al. A randomized double-blind controlled trial of convalescent
plasma in adults with severe COVID-19. J Clin Invest. 2021;131(13). Available at:
17. Ray Y, Paul SR, Bandopadhyay P, et al. A phase 2 single center open label randomised control trial for
convalescent plasma therapy in patients with severe COVID-19. Nat Commun. 2022;13(1):383. Available at:
18. RECOVERY Collaborative Group. Convalescent plasma in patients admitted to hospital with COVID-19
(RECOVERY): a randomised controlled, open-label, platform trial. Lancet. 2021;397(10289):2049-2059.
19. Begin P, Callum J, Jamula E, et al. Convalescent plasma for hospitalized patients with COVID-19: an
open-label, randomized controlled trial. Nat Med. 2021;27(11):2012-2024. Available at:
20. Writing Committee for the REMAP-CAP Investigators, Estcourt LJ, Turgeon AF, et al. Effect of convalescent
plasma on organ support-free days in critically ill patients with COVID-19: a randomized clinical trial. JAMA.

AR08957
21. Sullivan DJ, Gebo KA, Shoham S, et al. Early outpatient treatment for COVID-19 with convalescent plasma. N
Engl J Med. 2022;Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35353960.
22. Korley FK, Durkalski-Mauldin V, Yeatts SD, et al. Early convalescent plasma for high-risk outpatients with
COVID-19. N Engl J Med. 2021;385(21):1951-1960. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34407339.
23. Alemany A, Millat-Martinez P, Corbacho-Monne M, et al. High-titre methylene blue-treated convalescent plasma
as an early treatment for outpatients with COVID-19: a randomised, placebo-controlled trial. Lancet Respir Med.
24. Centers for Disease Control and Prevention. COVID-19 vaccines for moderately or severely immunocompromised
people. 2022. Available at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/immuno.html.
25. Brosh-Nissimov T, Orenbuch-Harroch E, Chowers M, et al. BNT162b2 vaccine breakthrough: clinical
characteristics of 152 fully vaccinated hospitalized COVID-19 patients in Israel. Clin Microbiol Infect.
26. Nussenblatt V, Roder AE, Das S, et al. Yearlong COVID-19 infection reveals within-host evolution of
SARS-CoV-2 in a patient with B-cell depletion. J Infect Dis. 2022;225(7):1118-1123. Available at:
27. Tenforde MW, Patel MM, Ginde AA, et al. Effectiveness of SARS-CoV-2 mRNA vaccines for preventing
COVID-19 hospitalizations in the United States. Clin Infect Dis. 2021;Published online ahead of print. Available
28. Grupper A, Rabinowich L, Schwartz D, et al. Reduced humoral response to mRNA SARS-CoV-2 BNT162b2
vaccine in kidney transplant recipients without prior exposure to the virus. Am J Transplant. 2021;21(8):2719-
29. Hallett AM, Greenberg RS, Boyarsky BJ, et al. SARS-CoV-2 messenger RNA vaccine antibody response and
reactogenicity in heart and lung transplant recipients. J Heart Lung Transplant. 2021;40(12):1579-1588. Available
30. Herishanu Y, Avivi I, Aharon A, et al. Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with
chronic lymphocytic leukemia. Blood. 2021;137(23):3165-3173. Available at:
31. Hamilton FW, Lee T, Arnold DT, Lilford R, Hemming K. Is convalescent plasma futile in COVID-19? A Bayesian
re-analysis of the RECOVERY randomized controlled trial. Int J Infect Dis. 2021;109:114-117. Available at:
32. RECOVERY Collaborative Group. Casirivimab and imdevimab in patients admitted to hospital with COVID-19
(RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2022;399(10325):665-676. Available
33. Clark E, Guilpain P, Filip IL, et al. Convalescent plasma for persisting COVID-19 following therapeutic
lymphocyte depletion: a report of rapid recovery. Br J Haematol. 2020;190(3):e154-e156. Available at:
34. Hueso T, Pouderoux C, Pere H, et al. Convalescent plasma therapy for B-cell-depleted patients with protracted
COVID-19. Blood. 2020;136(20):2290-2295. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32959052.
35. Jin H, Reed JC, Liu STH, et al. Three patients with X-linked agammaglobulinemia hospitalized for COVID-19
improved with convalescent plasma. J Allergy Clin Immunol Pract. 2020;8(10):3594-3596. Available at:
36. Mira E, Yarce OA, Ortega C, et al. Rapid recovery of a SARS-CoV-2-infected X-linked agammaglobulinemia
patient after infusion of COVID-19 convalescent plasma. J Allergy Clin Immunol Pract. 2020;8(8):2793-2795.
37. Quinti I, Lougaris V, Milito C, et al. A possible role for B cells in COVID-19? Lesson from patients with
agammaglobulinemia. J Allergy Clin Immunol. 2020;146(1):211-213. Available at:

AR08958
38. Rahman F, Liu STH, Taimur S, et al. Treatment with convalescent plasma in solid organ transplant recipients
with COVID-19: experience at large transplant center in New York City. Clin Transplant. 2020;34(12):e14089.
39. Senefeld JW, Klassen SA, Ford SK, et al. Use of convalescent plasma in COVID-19 patients with immuno-
suppression. Transfusion. 2021;61(8):2503-2511. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34036587.
40. Tremblay D, Seah C, Schneider T, et al. Convalescent plasma for the treatment of severe COVID-19 infection in
cancer patients. Cancer Med. 2020;9(22):8571-8578. Available at:
41. Van Damme KFA, Tavernier S, Van Roy N, et al. Case report: convalescent plasma, a targeted therapy for
patients with CVID and severe COVID-19. Front Immunol. 2020;11:596761. Available at:
42. Balashov D, Trakhtman P, Livshits A, et al. SARS-CoV-2 convalescent plasma therapy in pediatric patient after
hematopoietic stem cell transplantation. Transfus Apher Sci. 2021;60(1):102983. Available at:
43. Betrains A, Godinas L, Woei AJF, et al. Convalescent plasma treatment of persistent severe acute respiratory
syndrome coronavirus-2 (SARS-CoV-2) infection in patients with lymphoma with impaired humoral immunity
and lack of neutralising antibodies. Br J Haematol. 2021;192(6):1100-1105. Available at:
44. Ferrari S, Caprioli C, Weber A, Rambaldi A, Lussana F. Convalescent hyperimmune plasma for chemo-
immunotherapy induced immunodeficiency in COVID-19 patients with hematological malignancies. Leuk
Lymphoma. 2021;62(6):1490-1496. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33461387.
45. Fung M, Nambiar A, Pandey S, et al. Treatment of immunocompromised COVID-19 patients with convalescent
plasma. Transpl Infect Dis. 2021;23(2):e13477. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32989856.
46. Thompson MA, Henderson JP, Shah PK, et al. Association of convalescent plasma therapy with survival in
patients with hematologic cancers and COVID-19. JAMA Oncol. 2021:1167-1175. Available at:
47. Rossler A, Riepler L, Bante D, von Laer D, Kimpel J. SARS-CoV-2 Omicron variant neutralization in serum
from vaccinated and convalescent persons. N Engl J Med. 2022;386(7):698-700. Available at:
48. Pulliam JRC, van Schalkwyk C, Govender N, et al. Increased risk of SARS-CoV-2 reinfection associated with
emergence of Omicron in South Africa. Science. 2022;Published online ahead of print. Available at:
49. Hoffmann M, Kruger N, Schulz S, et al. The Omicron variant is highly resistant against antibody-mediated
neutralization: implications for control of the COVID-19 pandemic. Cell. 2022;185(3):447-456. Available at:
50. Dejnirattisai W, Huo J, Zhou D, et al. SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from
neutralizing antibody responses. Cell. 2022;185(3):467-484. Available at:
51. Franchini M, Prefumo F, Grisolia G, et al. Convalescent plasma for pregnant women with COVID-19: a
systematic literature review. Viruses. 2021;13(7). Available at: https://www.ncbi.nlm.nih.gov/pubmed/34206468.
52. Revello MG, Lazzarotto T, Guerra B, et al. A randomized trial of hyperimmune globulin to prevent congenital
cytomegalovirus. N Engl J Med. 2014;370(14):1316-1326. Available at:
53. Hughes BL, Clifton RG, Rouse DJ, et al. A trial of hyperimmune globulin to prevent congenital cytomegalovirus
infection. N Engl J Med. 2021;385(5):436-444. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34320288.
54. Nguyen FT, van den Akker T, Lally K, et al. Transfusion reactions associated with COVID-19 convalescent
plasma therapy for SARS-CoV-2. Transfusion. 2021;61(1):78-93. Available at:

AR08959
Table 3b. COVID-19 Convalescent Plasma: Selected Clinical Data

The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations for CCP.
The studies summarized below are those that have had the greatest impact on the Panel’s recommendations.

REMAP-CAP: Multinational, Open-Label RCT of High-Titer CCP in Hospitalized Patients With Critical COVID-191
Key Inclusion Criterion: Participant Characteristics: Key Limitations:
• Admitted to ICU while receiving respiratory support • Mean age 61 years; 68% men • Open-label study
(HFNC oxygen, NIV, MV, ECMO) and/or vasopressor • 32% on MV • Not all patients in CCP arm received
or inotrope support CCP (86% received CCP as per
• 29% were SARS-CoV-2 antibody negative at baseline
Key Exclusion Criteria: protocol and 95% received some
• 94% received corticosteroids, 45% received RDV, 39% CCP).
• CCP contraindicated received IL-6 inhibitors
• Death imminent Interpretation:
Primary Outcome:
• There was no benefit of CCP in
Interventions: • No difference between arms in median number of organ hospitalized patients with critical
• High-titer CCP (550 mL +/- 150 mL) within 48 hours support-free days by Day 21: 0 days in CCP arm vs. 3 days in COVID-19.
of randomization (n = 1,084) usual care arm (OR 0.97; 95% CrI, 0.82–1.14)
• Usual care (n = 916) Secondary Outcomes:
Primary Endpoint: • No difference between arms in:
• Organ support-free days by Day 21 • In-hospital mortality: 37% in CCP arm vs. 38% in usual care
arm
• Mortality by Day 28 or Day 90
• In-hospital mortality
• Median number of respiratory support-free days: 0 days in
• Mortality by Day 28 and Day 90 CCP arm vs. 2 days in usual care arm
• Respiratory support-free days • Median ICU LOS: 21 days in CCP arm vs. 17 days in usual
• ICU LOS care arm

AR08960

CONCOR-1: Multinational, Open-Label RCT of CCP for Hospitalized Patients With COVID-19 in Canada, the United States, and Brazil2
• Receipt of supplemental oxygen • Mean age 68 years; 59% men • Open-label study
• Within 12 days of respiratory symptom onset • 84% receiving systemic corticosteroids at enrollment • Trial stopped at 78% of planned
enrollment after meeting prespecified
Key Exclusion Criterion: Primary Outcome:
futility criteria for early termination.
• Imminent or current intubation • Intubation or death by Day 30: 32% in CCP arm vs. 28%
in SOC arm (relative risk 1.16; 95% CI, 0.94–1.43, P = Interpretation:
Interventions:
0.18) • There was no benefit of CCP in oxygen-
• 1–2 units CCP (approximately 500 mL) from 1–2 dependent, hospitalized COVID-19
donors (n = 625) Secondary Outcomes:
patients within 12 days of symptom
• SOC (n = 313) • By Day 30, no difference between arms in: onset.
• Time to intubation or death
Primary Endpoint:
• Mortality: 23% in CCP arm vs. 21% in SOC arm
• Intubation or death by Day 30
• Mean ICU LOS: 4.3 days in CCP arm vs. 3.7 days in SOC
Key Secondary Endpoints: arm
• Time to intubation or death by Day 30 • Need for renal dialysis: 1.6% in CCP arm vs. 2.0% in
• Mortality by Day 30 SOC arm
• ICU LOS by Day 30 • Frequency of SAEs by Day 30: 33% in CCP arm vs. 26%
• Need for renal dialysis by Day 30 in SOC arm
• Frequency of SAEs by Day 30
RECOVERY: Open-Label RCT of High-Titer CCP in Hospitalized Patients in the United Kingdom3
• Clinically suspected or laboratory-confirmed SARS- • Mean age 64 years; 64% men • Open-label study
CoV-2 infection • 5% on MV Interpretation:
Key Exclusion Criterion: • 92% received corticosteroids • There was no benefit of CCP in
• CCP contraindicated Primary Outcomes: hospitalized patients with COVID-19.
Interventions: • No difference between arms in:
• Approximately 275 mL per unit of CCP with IgG against • Mortality: 24% in each arm
SARS-CoV-2 spike protein, with sample to cutoff ratio • Mortality in patients without detectable SARS-CoV-2
≥6.0. Administered as 2 units of high-titer CCP (first antibodies: 32% in CCP arm vs. 34% in usual care arm
unit ASAP after randomization, second unit ≥12 hours
later the next day) (n = 5,795) Secondary Outcomes:
• Usual care (n = 5,763) • No difference between arms in:

AR08961

RECOVERY: Open-Label RCT of High-Titer CCP in Hospitalized Patients in the United Kingdom3, continued
Primary Endpoint: • Proportion discharged by Day 28: 66% in both arms
• All-cause mortality by Day 28 • Proportion who progressed to MV or death by Day 28:
29% in CCP arm vs. 29% in usual care arm
• Time to hospital discharge by Day 28
• Among patients not receiving MV, progression to MV or
death by Day 28
CSSC-004: RCT of Early Treatment With High-Titer CCP in Outpatients With COVID-19 in the United States4
• COVID-19 symptoms for <8 days • Median age 44 years; 7% aged ≥65 years; 57% women; • Patients were at relatively low risk for
79% White disease progression.
• 8% with type 2 DM; 2% with CVD; 38% with BMI ≥30 Interpretation:
• Prior or planned COVID-19–related hospitalization
• 82% were unvaccinated • This trial demonstrated a benefit of CCP
• Receipt of anti-SARS-CoV-2 mAbs
• Median time from symptom onset to transfusion was 6 in unvaccinated outpatients with <8 days
Interventions: days of COVID-19 symptoms.
• Approximately 250 mL of CCP with SARS-CoV-2 spike-
Primary Outcomes:
RBD IgG titer ≥1:320 (n = 592)
• COVID-19–related hospitalization within 28 days: 2.9% in
• Non-SARS-CoV-2 plasma (n = 589)
CCP arm vs. 6.3% in control arm (absolute risk reduction
Primary Endpoint: of 3.4 percentage points; 95% CI, 1.0–5.8; P = 0.005)
• COVID-19–related hospitalization or all-cause death • 53 of 54 hospitalizations occurred in unvaccinated
within 28 days individuals. None occurred in fully vaccinated individuals.
• No deaths occurred during the study.

AR08962

CONV-ERT: RCT of High-Titer, Methylene Blue-Treated CCP as an Early Treatment for Outpatients With COVID-19 in Spain5
• Aged ≥50 years • Mean age 56 years; 54% men • Trial was underpowered because it
• Mild or moderate COVID-19 symptoms for ≤7 days • 75% with ≥1 risk factor for COVID-19 progression was terminated early due to rising
vaccination rates among the eligible
Key Exclusion Criteria: • 97% with mild COVID-19 patient population.
• Severe COVID-19 symptoms or requirement for • Median 4.4 days of symptoms prior to enrollment • Methylene blue, which was used for
hospitalization for any reason • Among the 369 patients for whom baseline serologic pathogen inactivation in donor plasma,
• Previous SARS-CoV-2 infection testing was available, 88% were negative for both IgG could have potentially impaired Fc-
anti-SARS-CoV-2 spike and IgM anti-SARS-CoV-2 S1- region functionality of immunoglobulins
• Receipt of >1 COVID-19 vaccination
RBD and negatively impacted product efficacy
Interventions: and blinding.
Primary Outcomes:
• 250–300 mL of high-titer, methylene blue-treated CCP
• Hospitalization within 28 days: 12% in CCP arm vs. 11% Interpretation:
(n = 188)
in placebo arm (relative risk 1.05; 95% CrI, 0.78–1.41) • This trial did not demonstrate a benefit
• 0.9% saline (n = 188)
• Mean change in SARS-CoV-2 VL: -2.41 log10 copies/mL in of CCP in unvaccinated outpatients with
Primary Endpoints: CCP arm vs. -2.32 log10 copies/mL in placebo arm <7 days of COVID-19 symptoms.
• Hospitalization within 28 days Key Secondary Outcomes:
• Mean change in SARS-CoV-2 VL from baseline to Day 7 • Death: 0 in CCP arm vs. 2 in placebo arm (relative risk
Key Secondary Endpoints: 0.20; 95% CI 0.01–4.14)
• Death by Day 60 • No difference between arms in median time to symptom
resolution: 12.0 days for both arms (HR 1.05; 95% CI,
• Time to complete symptom resolution
0.85–1.30)
Double-Blind RCT of Early High-Titer CCP Therapy to Prevent Severe COVID-19 in Nonhospitalized Older Adults in Argentina6
• Aged ≥75 years or aged 65–74 years with ≥1 coexisting • Mean age 77 years; 38% men • Small sample size
condition • Most with comorbidities • Early termination because number of
• Mild COVID-19 symptoms for <72 hours COVID-19 cases decreased
Primary Outcome:
Key Exclusion Criterion: • Severe respiratory disease by Day 15: 16% in CCP arm Interpretation:
• Severe respiratory disease vs. 31% in placebo arm (relative risk 0.52; 95% CI, • This trial demonstrated a benefit of CCP
0.29–0.94; P = 0.03) in older adult outpatients with <72 hours
Interventions:
of mild COVID-19 symptoms.
• 250 mL of CCP with IgG against SARS-CoV-2 spike
protein >1:1,000 (n = 80)
• Saline (n = 80)

AR08963

Double-Blind RCT of Early High-Titer CCP Therapy to Prevent Severe COVID-19 in Nonhospitalized Older Adults in Argentina6
Primary Endpoint:
• Severe respiratory disease, defined as respiratory rate
≥30 breaths/min and/or SpO2 <93% on room air by Day
15
SIREN-C3PO: Multicenter, Single-Blind RCT of High-Titer CCP in the United States7
• ED patient with ≤7 days of symptoms • Median age 54 years; 46% men • Imbalance of patients who required
• PCR-confirmed SARS-CoV-2 infection • More patients with immunosuppression in CCP arm than hospital admission during the index visit
in placebo arm (13% vs. 7%) included in the primary analysis
• Aged ≥50 years or aged ≥18 years with ≥1 risk factor
for disease progression • More patients with ≥3 risk factors in CCP arm than in • Slightly more patients with multiple risk
placebo arm (55% vs. 48%) factors, including immunosuppression,
Key Exclusion Criterion: in CCP arm
• Need for supplemental oxygen Primary Outcomes:
Interpretation:
• No difference between arms in proportion with disease
Interventions: • The use of high-titer CCP within 1 week
progression: 30% in CCP arm vs. 32% in placebo arm
• 250 mL high-titer CCP (median titer 1:641) (n = 257) (risk difference 1.9%; 95% CrI, -6.0% to 9.8%) of symptom onset did not prevent
• Saline (n = 254) disease progression in outpatients with
• 25 patients (19 in CCP arm and 6 in placebo arm) COVID-19 who were at high risk of
Primary Endpoint: required hospitalization during the index visit. In a severe disease.
post hoc analysis that excluded these patients, disease
• Disease progression, defined as hospital admission,
progression occurred in 24% in CCP arm vs. 30% in
death, or seeking emergency or urgent care within 15
placebo arm (risk difference 5.8%; 95% CrI, -1.9% to
days of randomization
13.6%).
Secondary Outcomes:
• Severity of illness, as measured by an OS
• All-cause mortality within 30 days: 5 (1.9%) in CCP arm
• All-cause mortality within 30 days vs. 1 (0.4%) in placebo arm
• Hospital-free days over 30 days • No difference between arms in illness severity or mean
number of hospital-free days

AR08964

Retrospective Evaluation of CCP Antibody Levels and the Risk of Death From COVID-19 in the United States8
• Severe or life-threatening COVID-19 • 31% aged ≥70 years; 61% men; 48% White, 37% • Lack of untreated control arm
• Patients for whom samples of transfused CCP were Hispanic/Latinx
Interpretation:
available for retrospective analysis of antibody titer • 61% in ICU; 33% on MV
• The study data are not sufficient to
Interventions: • 51% received corticosteroids, 31% received RDV establish the efficacy or safety of
• High-titer CCP (n = 515), medium-titer CCP (n = 2,006), Primary Outcomes: COVID-19 CCP.
or low-titer CCP (n = 561), characterized retrospectively • Mortality at 30 days after transfusion: 22% in high-titer
Primary Endpoint: CCP arm vs. 27% in medium-titer CCP arm vs. 30% in
low-titer CCP arm
• Mortality at 30 days after CCP transfusion
• High-titer CCP arm had a lower risk of death than low-
titer CCP arm (relative risk 0.75; 95% CI, 0.61–0.93)
• Mortality was lower among patients who were not
receiving MV before CCP transfusion (relative risk 0.66;
95% CI, 0.48–0.91)
• Among patients who were on MV before CCP transfusion,
there was no difference in mortality between high-titer
and low-titer arms (relative risk 1.02; 95% CI, 0.78–1.32)
Key: ASAP = as soon as possible; BMI = body mass index; CCP = COVID-19 convalescent plasma; CVD = cardiovascular disease; DM = diabetes mellitus; ECMO =
extracorporeal membrane oxygenation; ED = emergency department; Fc = fragment crystallizable; HFNC = high-flow nasal cannula; ICU = intensive care unit; Ig =
immunoglobulin; IL = interleukin; LOS = length of stay; mAb = monoclonal antibody; MV = mechanical ventilation; NIV = noninvasive ventilation; OS = ordinal scale;
the Panel = the COVID-19 Treatment Guidelines Panel; PCR = polymerase chain reaction; RBD = receptor binding domain; RCT = randomized controlled trial; RDV =
remdesivir; SAE = serious adverse event; SOC = standard of care; SpO2 = oxygen saturation; VL = viral load
References
1. Writing Committee for the REMAP-CAP Investigators, Estcourt LJ, Turgeon AF, et al. Effect of convalescent plasma on organ support-free days in
critically ill patients with COVID-19: a randomized clinical trial. JAMA. 2021;326(17):1690-1702. Available at:
2. Begin P, Callum J, Jamula E, et al. Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial. Nat Med.
3. RECOVERY Collaborative Group. Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled,
open-label, platform trial. Lancet. 2021;397(10289):2049-2059. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34000257.
4. Sullivan DJ, Gebo KA, Shoham S, et al. Early outpatient treatment for COVID-19 with convalescent plasma. N Engl J Med. 2022;Published online

AR08965
ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35353960.

5. Alemany A, Millat-Martinez P, Corbacho-Monne M, et al. High-titre methylene blue-treated convalescent plasma as an early treatment for outpatients
with COVID-19: a randomised, placebo-controlled trial. Lancet Respir Med. 2022;10(3):278-288. Available at:
6. Libster R, Perez Marc G, Wappner D, et al. Early high-titer plasma therapy to prevent severe COVID-19 in older adults. N Engl J Med.
7. Korley FK, Durkalski-Mauldin V, Yeatts SD, et al. Early convalescent plasma for high-risk outpatients with COVID-19. N Engl J Med.
8. Joyner MJ, Carter RE, Senefeld JW, et al. Convalescent plasma antibody levels and the risk of death from COVID-19. N Engl J Med.

AR08966
Immunoglobulins: SARS-CoV-2 Specific

Recommendation
• There is insufficient evidence for the COVID-19 Treatment Guidelines Panel to recommend
either for or against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
immunoglobulins for the treatment of COVID-19.
Rationale
Currently, there are no clinical data on the use of SARS-CoV-2 immunoglobulins. Trials evaluating
SARS-CoV-2 immunoglobulins are in development but not yet active and enrolling participants.
Proposed Mechanism of Action and Rationale for Use in Patients with COVID-19
Concentrated antibody preparations derived from pooled plasma collected from individuals who
have recovered from COVID-19 can be manufactured as SARS-CoV-2 immunoglobulin, which
could potentially suppress the virus and modify the inflammatory response. The use of virus-specific
immunoglobulins for other viral infections (e.g., cytomegalovirus [CMV] immunoglobulin for the
prevention of post-transplant CMV infection and varicella zoster immunoglobulin for postexposure
prophylaxis of varicella in individuals at high-risk) has proven to be safe and effective; however, there
are currently no clinical data on the use of such products for COVID-19. Potential risks may include
transfusion reactions. Theoretical risks may include antibody-dependent enhancement of infection.
Clinical Data
There are no clinical data on the use of SARS-CoV-2 immunoglobulins for the treatment of COVID-19.
Similarly, there are no clinical data on use of specific immunoglobulin or hyperimmunoglobulin
products in patients with severe acute respiratory syndrome (SARS) or Middle East respiratory
syndrome (MERS).
Pathogen-specific immunoglobulins are used clinically during pregnancy to prevent varicella zoster
virus (VZV) and rabies and have also been used in clinical trials of therapies for congenital CMV
infection.
Hyperimmunoglobulin has been used to treat several viral infections in children, including VZV,
respiratory syncytial virus, and CMV; efficacy data on their use for other respiratory viruses is limited.

AR08967

• The information in this table is based on data from investigational trials evaluating these products for the treatment or prevention of
COVID-19. The table includes dose recommendations from the FDA EUAs for patients who meet specified criteria.
• There are limited or no data on dose modifications for patients with organ failure or those who require extracorporeal devices. Please refer
to product labels, when available.
• There are currently not enough data to determine whether certain medications can be safely coadministered with therapies for the
treatment or prevention of COVID-19. When using concomitant medications with similar toxicity profiles, consider performing additional
safety monitoring.
• The potential additive, antagonistic, or synergistic effects and the safety of using combination therapies for the treatment or prevention of
COVID-19 are unknown. Clinicians are encouraged to report AEs to the FDA Medwatch program.
• For drug interaction information, please refer to product labels and visit the Liverpool COVID-19 Drug Interactions website.
• For the Panel’s recommendations on using the drugs listed in this table, please refer to the Anti-SARS-CoV-2 Monoclonal Antibodies,
Therapeutic Management of Nonhospitalized Adults With COVID-19, and Prevention of SARS-CoV-2 Infection sections of the Guidelines.
Drug-Drug Interaction Comments and Links to Clinical

Dosing Regimens Adverse Events Monitoring Parameters
Potential Trials
Bamlanivimab Plus Etesevimab (Anti-SARS-CoV-2 Monoclonal Antibodies)
Authorized for the treatment and PEP of COVID-19 under FDA EUA, but distribution has paused because the Omicron VOC has markedly reduced in vitro
susceptibility to BAM plus ETE.
Dose Recommended in FDA • Nausea • Only for administration • Drug-drug interactions Availability:
EUA for Treatment and PEP of • Dizziness in health care settings are unlikely between •D
istribution of BAM plus ETE has
COVID-19 in Adults and Pediatric by qualified health care BAM plus ETE and paused because the Omicron VOC
Patients Weighing ≥40 kg: • Pruritis providers who have medications that are has markedly reduced in vitro
• BAM 700 mg plus ETE 1,400 mg • Hypersensitivity, including immediate access to renally excreted or that susceptibility to BAM plus ETE,
as a single IV infusion anaphylaxis and infusion- emergency medical are CYP substrates, and this regimen is not expected to
related reactions services and medications inhibitors, or inducers. provide clinical benefit.
Doses Recommended in FDA EUA • These AEs were observed to treat severe infusion
for Treatment and PEP of COVID-19 in multiple trials in which reactions. •H
HS Public Health Emergency
in Neonates, Infants, Children, and participants received either updates on the distribution of BAM
• Monitor during IV infusion plus ETE are available.
Adolescents Weighing <40 kg: the authorized doses of BAM and for ≥1 hour after
• 1 –12 kg: BAM 12 mg/kg plus ETE and ETE or higher doses of infusion is completed. •A
list of clinical trials is available:
24 mg/kg as a single IV infusion each drug. Bamlanivimab Plus Etesevimab

AR08968

Potential Trials
Bamlanivimab Plus Etesevimab (Anti-SARS-CoV-2 Monoclonal Antibodies), continued
• > 12 kg to 20 kg: BAM 175 mg plus
ETE 350 mg as a single IV infusion
• > 20 kg to <40 kg: BAM 350 mg
plus ETE 700 mg as a single IV
infusion
Bebtelovimab (Anti-SARS-CoV-2 Monoclonal Antibody)
Authorized for the treatment of COVID-19 under FDA EUA.
Dose Recommended in FDA EUA • Nausea • Only for administration • Drug-drug interactions Availability:
for Treatment of COVID-19 in Adults • Vomiting in health care settings are unlikely between •U
nder the FDA EUA, BEB is
and Pediatric Patients Aged ≥12 by qualified health care BEB and medications available for the treatment of
Years and Weighing ≥40 kg: • Pruritis providers who have that are renally high-risk outpatients with mild
• BEB 175 mg as an IV injection over • Rash immediate access to excreted or that are to moderate COVID-19.1 See
at least 30 seconds • Hypersensitivity, including emergency medical CYP substrates, Anti-SARS-CoV-2 Monoclonal
anaphylaxis and infusion- services and medications inhibitors, or inducers. Antibodies for a list of high-risk
related reactions to treat severe infusion conditions.
reactions.
•A
• Monitor during IV injection Bebtelovimab
and for ≥1 hour after
injection is completed.
Casirivimab Plus Imdevimab (Anti-SARS-CoV-2 Monoclonal Antibodies)
Authorized for the treatment and PEP of COVID-19 under FDA EUA, but distribution has paused because the Omicron VOC has markedly reduced in vitro
susceptibility to CAS plus IMD.
Dose Recommended in FDA EUA for • Hypersensitivity, including • Only for administration • Drug-drug interactions Availability:
Treatment and PEP of COVID-19 in anaphylaxis and infusion- in health care settings are unlikely between •D
istribution of CAS plus IMD
Adults and Pediatric Patients Aged related reactions by qualified health care CAS plus IMD and has paused because the Omicron
≥12 Years and Weighing ≥40 kg: • These AEs were observed providers who have medications that are VOC has markedly reduced in
in multiple trials in which immediate access to renally excreted or that vitro susceptibility to CAS plus
• CAS 600 mg plus IMD 600 mg as a
participants received CAS emergency medical are CYP substrates, IMD, and this regimen is not
single IV infusion over 1 hour
600 mg plus IMD 600 mg or services and medications inhibitors, or inducers. expected to provide clinical
• IV infusion is the preferred route higher doses of each drug. to treat severe infusion benefit.
of administration. However, when reactions.
IV infusion is not feasible or would • Injection site reactions, • Monitor during IV infusion
•H
delay treatment, CAS 600 mg plus including ecchymosis and updates on the distribution of
erythema, in clinical trial or SUBQ injections and for CAS plus IMD are available.
IMD 600 mg can be administered ≥1 hour after infusion or
as 4 SUBQ injections (2.5 mL per participants who received CAS •A
plus IMD as SUBQ injections injections are completed.
injection) at 4 different sites. See Casirivimab Plus Imdevimab

AR08969

Potential Trials
Casirivimab Plus Imdevimab (Anti-SARS-CoV-2 Monoclonal Antibodies), continued
the FDA EUA for detailed
information.
Dose Recommended in FDA
EUA for PEP for Individuals With
Ongoing Exposure to SARS-CoV-2:
• After initial dose, repeat dosing
of CAS 300 mg plus IMD 300 mg
by SUBQ injections or IV infusion
every 4 weeks for duration of
ongoing exposure.
Sotrovimab (Anti-SARS-CoV-2 Monoclonal Antibody)
Authorized for the treatment of COVID-19 under FDA EUA, but distribution has paused in the United States because the Omicron BA.2 subvariant has markedly
reduced in vitro susceptibility to SOT.
Dose Recommended in FDA EUA • Rash • Only for administration • Drug-drug interactions Availability:
for Treatment of COVID-19 in • Diarrhea in health care settings are unlikely between •D
istribution of SOT has paused
Adults and Pediatric Patients Aged by qualified health care SOT and medications because the Omicron BA.2
≥12 Years and Weighing ≥40 kg: • Hypersensitivity, providers who have that are renally excreted subvariant has markedly reduced
including anaphylaxis immediate access to or that are CYP
• SOT 500 mg as an IV infusion and infusion-related susceptibility to SOT, and SOT is not
over 15 minutes for 50 mL bag or emergency medical services substrates, inhibitors, expected to provide clinical benefit.
reactions and medications to treat or inducers.
over 30 minutes for 100 mL bag •H
severe infusion reactions.
updates on the distribution of SOT
• Monitor during IV infusion are available.
and for ≥1 hour after
infusion is completed. •A
Sotrovimab
Tixagevimab Plus Cilgavimab (Evusheld) (Anti-SARS-CoV-2 Monoclonal Antibodies)
Authorized for PrEP of COVID-19 under FDA EUA.
Doses Recommended in FDA EUA • Hypersensitivity, • Use with caution • If a person has received • U
nder the FDA EUA, TIX plus CIL
for PrEP of COVID-19 in Adults and including anaphylaxis in individuals with a COVID-19 vaccine, for PrEP of COVID-19 is available
Pediatric Patients Aged ≥12 Years and injection-related thrombocytopenia or any TIX plus CIL should be for certain patients at high risk
and Weighing ≥40 kg: reactions coagulation disorder. administered ≥2 weeks of infection. See Prevention of
• TIX 300 mg plus CIL 300 mg as 2 • In 1 clinical trial, cardiac • Monitor for ≥1 hour after after vaccination. SARS-CoV-2 Infection for more
consecutive 3 mL IM injections events were reported in injection. • Drug-drug interactions information.2
participants with cardiac are unlikely between

AR08970

Potential Trials
Tixagevimab Plus Cilgavimab (Evusheld) (Anti-SARS-CoV-2 Monoclonal Antibody), continued
For patients who previously risk factors (0.6% in TIX T IX plus CIL and •A
received a dose of TIX 150 mg plus plus CIL arm vs. 0.2% in medications that are Tixagevimab Plus Cilgavimab
CIL 150 mg, administer a second placebo arm). renally excreted or that
dose per the following criteria as are CYP substrates,
soon as possible: inhibitors, or inducers.
• If the initial dose was ≤3 months
ago, the second dose should be
TIX 150 mg plus CIL 150 mg.
• If the initial dose was >3 months
ago, the second dose should be
TIX 300 mg plus CIL 300 mg.
Authorized for the treatment of COVID-19 under FDA EUA.
Dose Recommended in FDA EUA • TRALI • Before administering • Drug products should • T he decision to use COVID-19 CP
for Treatment of COVID-19: • TACO CP to patients with not be added to the for the treatment of COVID-19 in
• Per the EUA, consider starting a history of severe IV infusion line for the patients aged <18 years should
• Allergic reactions allergic or anaphylactic blood product. be based on an individualized
clinical dosing with 1 high-titer
COVID-19 CP unit (about 200 • A
naphylactic reactions transfusion reactions, assessment of risk and benefit.4
mL), with administration of • Febrile nonhemolytic the Panel recommends • In patients with impaired cardiac
additional CP units based on the reactions consulting a transfusion function and heart failure, it may be
prescribing provider’s medical medicine specialist who necessary to reduce the CP volume
• Hemolytic reactions
judgment and the patient’s clinical is associated with the or decrease the transfusion rate.
• Hypothermia hospital blood bank.
response.
• Metabolic complications Availability:
• Monitor for transfusion-
• Transfusion-transmitted related reactions. •U
nder the FDA EUA, high-
infections3 titer COVID-19 CP is available
• Monitor vital signs at
for hospitalized patients with
• Thrombotic events baseline and during and
COVID-19.4 See Convalescent
• Theoretical risk of antibody- after transfusion.
Plasma.
mediated enhancement of •A
infection and suppressed COVID-19 Convalescent Plasma
long-term immunity

AR08971

Potential Trials
SARS-CoV-2-Specific Immunoglobulin
Dose in Clinical Trials for • TRALI • Monitor for transfusion- • Drug products should • A list of clinical trials is available:
Treatment of COVID-19: • TACO related reactions. not be added to the SARS-CoV-2 Immunoglobulin
• Dose varies by clinical trial. • Monitor vital signs at IV infusion line for the
• Allergic reactions blood product.
baseline and during and
• Antibody-mediated after transfusion.
enhancement of infection
• RBC alloimmunization
• Transfusion-transmitted
infections3
Key: AE = adverse event; BAM = bamlanivimab; BEB = bebetelovimab; CAS = casirivimab; CIL = cilgavimab; CP = convalescent plasma; CYP = cytochrome P450; ETE
= etesevimab; EUA = Emergency Use Authorization; FDA = Food and Drug Administration; HHS = U.S. Department of Health and Human Services; IM = intramuscular;
IMD = imdevimab; IV = intravenous; the Panel = the COVID-19 Treatment Guidelines Panel; PEP = post-exposure prophylaxis; PrEP = pre-exposure prophylaxis; RBC
= red blood cell; SOT = sotrovimab; SUBQ = subcutaneous; TACO = transfusion-associated circulatory overload; TIX = tixagevimab; TRALI = transfusion-related acute
lung injury; VOC = variant of concern
References
1. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for bebtelovimab. 2022. Available at:
2. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for Evusheld (tixagevimab co-packaged with
cilgavimab). 2022. Available at: https://www.fda.gov/media/154701/download.
3. Marano G, Vaglio S, Pupella S, et al. Convalescent plasma: new evidence for an old therapeutic tool? Blood Transfus. 2016;14(2):152-157. Available
4. Food and Drug Administration. Fact sheet for health care providers: emergency use authorization (EUA) of COVID-19 convalescent plasma for
treatment of coronavirus disease 2019 (COVID-19). 2021. Available at: https://www.fda.gov/media/141478/download.

AR08972
Cell-Based Therapy Under Evaluation for the Treatment of

COVID-19
Mesenchymal Stem Cells

Mesenchymal stem cells are investigational products that have been studied extensively for broad
clinical applications in regenerative medicine1 and for their immunomodulatory properties.2 It is
hypothesized that mesenchymal stem cells could reduce the acute lung injury and inhibit the cell-
mediated inflammatory response induced by SARS-CoV-2.
Recommendation
• The COVID-19 Treatment Guidelines Panel recommends against the use of mesenchymal stem
cells for the treatment of COVID-19, except in a clinical trial (AIIb).
Rationale for Recommendation

No mesenchymal stem cells products are approved by the Food and Drug Administration (FDA) for the
treatment of COVID-19. There are limited data to date to assess the role of mesenchymal stem cells for
the treatment of COVID-19.
The FDA has recently issued several warnings about patients being vulnerable to stem cell treatments
that are illegal and potentially harmful.3 Several umbilical cord blood-derived products are currently
licensed by the FDA for indications such as the treatment of cancer (e.g., stem cell transplant) or rare
genetic diseases, and as scaffolding for cartilage defects and wound beds. None of these products are
approved for the treatment of COVID-19 or any other viral disease.4 In the United States, mesenchymal
stem cells should not be used for the treatment of COVID-19 outside of an FDA-approved clinical trial,
expanded access program, or an Emergency Investigational New Drug application (AII).
Rationale for Use in COVID-19

Mesenchymal stem cells are multipotent adult stem cells that are present in most human tissues, including
the umbilical cord. Mesenchymal stem cells can self-renew by dividing and can differentiate into multiple
types of tissues (including osteoblasts, chondroblasts, adipocytes, hepatocytes, and others), which has led
to a robust clinical research agenda in regenerative medicine. It is hypothesized that mesenchymal stem
cells could reduce the acute lung injury and inhibit the cell-mediated inflammatory response induced by
SARS-CoV-2. Furthermore, because they lack the angiotensin-converting enzyme 2 (ACE2) receptor that
SARS-CoV-2 uses for viral entry into cells, mesenchymal stem cells are resistant to infection.5,6
Clinical Data
Data supporting the use of mesenchymal stem cells in patients who have viral infections, including
SARS-CoV-2 infection, are limited to case reports and small, open-label studies.

A pilot study of intravenous mesenchymal stem cell transplantation in China enrolled 10 patients with
confirmed COVID-19 categorized according to the National Health Commission of China criteria as
critical, severe, or common type. Seven patients (one with critical illness, four with severe illness, and
two with common-type illness) received mesenchymal stem cells; three patients with severe illness

AR08973
received placebo. All seven patients who received mesenchymal stem cells recovered. Among the
three severely ill placebo-treated patients, one died, one developed acute respiratory distress syndrome
(ARDS), and one remained stable with severe disease.7
A small clinical trial evaluated human umbilical cord mesenchymal stem cell (hUC-MSC) infusion in
patients with severe COVID-19 who had not responded to standard of care therapies after 7 to 10 days
of treatment. The standard of care therapies included supplemental oxygen, umifenovir/oseltamivir,
antibiotics if indicated, and glucocorticoids. The study was intended as a randomized controlled trial;
however, due to the lack of sufficient hUC-MSCs, it was not possible to randomize the participants as
originally planned. Among the 41 patients eligible to participate in the study, 12 received hUC-MSC
infusion and 29 received standard of care therapies only. The study arms were well balanced with regard
to demographic characteristics, laboratory test results, and disease severity. All 12 participants who
received hUC-MSC infusion recovered without requiring mechanical ventilation and were discharged to
home. Four patients who received only standard of care therapies progressed to critical illness requiring
mechanical ventilation; three of these patients died. These results are not statistically significant, and
interpretation of the findings is limited by the study’s lack of randomization and small sample size.8
A double-blind randomized controlled trial investigated the safety and efficacy of hUC-MSC infusions
in patients with COVID-19 ARDS. Twenty-four patients were randomized to receive either two
infusions of hUC-MSC (prepared at a single site) or placebo on Day 0 and Day 3. The primary endpoints
were occurrence of prespecified infusion-associated adverse events within 6 hours of each hUC-MSC
infusion; cardiac arrest or death within 24 hours after an infusion; and the incidence of adverse events.
Secondary endpoints included survival at 31 days after hUC-MSC infusion and time to recovery.9
There were no differences between the arms in the primary safety analysis; however, more deaths
occurred in the placebo arm (7 deaths) than in the hUC-MSC arm (2 deaths) by Day 31. Data for
one participant in the hUC-MSC arm who died due to a failed intubation was censored from the
analysis. Time to recovery was shorter in the hUC-MSC arm than in the placebo arm (HR 0.29; 95%
CI, 0.09–0.95). Interpretation of these results is limited by the small sample size and a change in an
eligibility criterion from enrolling only individuals on invasive mechanical ventilation to including those
receiving high-flow oxygen or on noninvasive ventilation.
Clinical Data for Other Viral Infections

In an open-label study of mesenchymal stem cells for the treatment of H7N9 influenza in China, 17
patients received mesenchymal stem cell treatment plus standard of care, and 44 patients received
standard of care only. Three patients (17.6%) in the mesenchymal stem cell arm died versus 24
patients (54.5%) in the standard of care arm. The 5-year follow-up was limited to five patients in the
mesenchymal stem cell arm. No safety concerns were identified.10
Clinical Trials
See ClinicalTrials.gov for a list of clinical trials evaluating mesenchymal stem cells for the treatment of
COVID-19, COVID-19-related ARDS, and COVID-19-associated multisystem inflammatory syndrome
in children (MIS-C).
Adverse Effects
Risks associated with mesenchymal stem cell transfusion appear to be uncommon. The potential risks
include the potential for mesenchymal stem cells to multiply or change into inappropriate cell types,
product contamination, growth of tumors, infections, thrombus formation, and administration site
reactions.11

AR08974
There are insufficient data to assess the risk of using mesenchymal stem cell therapy during pregnancy.
There are insufficient data to assess the efficacy and safety of using mesenchymal stem cell therapy in
children.
References
1. Samsonraj RM, Raghunath M, Nurcombe V, Hui JH, van Wijnen AJ, Cool SM. Concise review: multifaceted
characterization of human mesenchymal stem cells for use in regenerative medicine. Stem Cells Transl Med.
2. Li N,Hua J. Interactions between mesenchymal stem cells and the immune system. Cell Mol Life Sci.
3. Food and Drug Administration. FDA warns about stem cell therapies. 2019. Available at: https://www.fda.gov/
consumers/consumer-updates/fda-warns-about-stem-cell-therapies. Accessed January 26, 2021.
4. Food and Drug Administration. Approved cellular and gene therapy products. 2019. Available at: https://
www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-
products. Accessed January 26, 2021.
5. Lukomska B, Stanaszek L, Zuba-Surma E, Legosz P, Sarzynska S,Drela K. Challenges and controversies in
human mesenchymal stem cell therapy. Stem Cells Int. 2019;2019:9628536. Available at:
6. Shetty AK. Mesenchymal stem cell infusion shows promise for combating coronavirus (COVID-19)-induced
pneumonia. Aging Dis. 2020;11(2):462-464. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32257554.
7. Leng Z, Zhu R, Hou W, et al. Transplantation of ACE2(-) mesenchymal stem cells improves the outcome of
patients with COVID-19 pneumonia. Aging Dis. 2020;11(2):216-228. Available at:
8. Shu L, Niu C, Li R, et al. Treatment of severe COVID-19 with human umbilical cord mesenchymal stem cells.
Stem Cell Res Ther. 2020;11(1):361. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32811531.
9. Lanzoni G, Linetsky E, Correa D, et al. Umbilical cord mesenchymal stem cells for COVID-19 acute
respiratory distress syndrome: A double-blind, Phase 1/2a, randomized controlled trial. Stem Cells Transl Med.
10. Chen J, Hu C, Chen L, et al. Clinical study of mesenchymal stem cell treating acute respiratory distress
syndrome induced by epidemic Influenza A (H7N9) infection, a hint for COVID-19 treatment. Engineering
(Beijing). 2020;6(10):1153-1161. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32292627.
11. Centers for Disease Control and Prevention. Stem cell and exosome products. 2019. Available at:
https://www.cdc.gov/hai/outbreaks/stem-cell-products.html. Accessed January 26, 2021.

AR08975
Immunomodulators Under Evaluation for the Treatment of

COVID-19
The hyperactive inflammatory response to SARS-CoV-2 infection plays a central role in the pathogenesis of COVID-19.
See Therapeutic Management of Hospitalized Adults With COVID-19 for the COVID-19 Treatment Guidelines Panel’s (the
Panel) recommendations on the use of the following immunomodulators for hospitalized patients according to their
disease severity:
• Corticosteroids: dexamethasone
• Interleukin-6 inhibitors: tocilizumab (or sarilumab)
• Janus kinase (JAK) inhibitors: baricitinib (or tofacitinib)
There is insufficient evidence for the Panel to recommend either for or against the use of the following
immunomodulators for the treatment of COVID-19:
• Anakinra
• Fluvoxamine
• Granulocyte-macrophage colony-stimulating factor inhibitors for hospitalized patients
• Inhaled corticosteroids
The Panel recommends against the use of the following immunomodulators for the treatment of COVID-19, except in a
clinical trial:
• Baricitinib plus tocilizumab (AIII)
• Canakinumab (BIIa)
• Colchicine for nonhospitalized patients (BIIa)
• Intravenous immunoglobulin (IVIG) (non-SARS-CoV-2-specific) for the treatment of patients with acute COVID-19
(AIII). This recommendation should not preclude the use of IVIG for multisystem inflammatory syndrome in children
(MIS-C) or when it is otherwise indicated.
• Bruton’s tyrosine kinase inhibitors (e.g., acalabrutinib, ibrutinib, zanubrutinib) (AIII)
• JAK inhibitors other than baricitinib and tofacitinib (e.g., ruxolitinib) (AIII)
• Siltuximab (BIII)
The Panel recommends against the use of the following immunomodulators for the treatment of COVID-19:
• Colchicine for hospitalized patients (AI)


AR08976
Colchicine
Colchicine is an anti-inflammatory drug that is used to treat a variety of conditions, including gout,
recurrent pericarditis, and familial Mediterranean fever.1 Recently, the drug has been shown to
potentially reduce the risk of cardiovascular events in those with coronary artery disease.2 Colchicine
has several potential mechanisms of action, including reducing the chemotaxis of neutrophils, inhibiting
inflammasome signaling, and decreasing the production of cytokines, such as interleukin-1 beta.3
When colchicine is administered early in the course of COVID-19, these mechanisms could potentially
mitigate or prevent inflammation-associated manifestations of the disease. These anti-inflammatory
properties coupled with the drug’s limited immunosuppressive potential, favorable safety profile, and
widespread availability have prompted investigation of colchicine for the treatment of COVID-19.
Recommendations
• The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of colchicine
for the treatment of nonhospitalized patients with COVID-19, except in a clinical trial (BIIa).
• The Panel recommends against the use of colchicine for the treatment of hospitalized patients
with COVID-19 (AI).
Rationale
For Nonhospitalized Patients With COVID-19
COLCORONA, a large randomized placebo-controlled trial that evaluated colchicine in outpatients
with COVID-19, did not reach its primary efficacy endpoint of reducing hospitalizations and death.4
However, in the subset of patients whose diagnosis was confirmed by a positive SARS-CoV-2
polymerase chain reaction (PCR) result from a nasopharyngeal (NP) swab, a slight reduction in
hospitalizations was observed among those who received colchicine.
PRINCIPLE, another randomized, open-label, adaptive-platform trial that evaluated colchicine versus
usual care, was stopped for futility when no significant difference in time to first self-reported recovery
from COVID-19 between the colchicine and usual care recipients was found.5
The PRINCIPLE trial showed no benefit of colchicine, and the larger COLCORONA trial failed to
reach its primary endpoint, found only a very modest effect of colchicine in the subgroup of patients
with positive SARS-CoV-2 PCR results, and reported more gastrointestinal adverse events in those
receiving colchicine. Therefore, the Panel recommends against the use of colchicine for the treatment
of COVID-19 in nonhospitalized patients, except in a clinical trial (BIIa).
For Hospitalized Patients With COVID-19

In the RECOVERY trial, a large randomized trial in hospitalized patients with COVID-19, colchicine
demonstrated no benefit with regard to 28-day mortality or any secondary outcomes.6 Based on the
results from this large trial, the Panel recommends against the use of colchicine for the treatment of
COVID-19 in hospitalized patients (AI).

Colchicine in Nonhospitalized Patients With COVID-19
The COLCORONA Trial
The COLCORONA trial was a contactless, double-blind, placebo-controlled, randomized trial in

AR08977
outpatients who received a diagnosis of COVID-19 within 24 hours of enrollment. Participants were aged
≥70 years or aged ≥40 years with at least 1 of the following risk factors for COVID-19 complications:
body mass index ≥30, diabetes mellitus, uncontrolled hypertension, known respiratory disease, heart
failure or coronary disease, fever ≥38.4°C within the last 48 hours, dyspnea at presentation, bicytopenia,
pancytopenia, or the combination of high neutrophil count and low lymphocyte count. Participants were
randomized 1:1 to receive colchicine 0.5 mg twice daily for 3 days and then once daily for 27 days
or placebo. The primary endpoint was a composite of death or hospitalization by Day 30; secondary
endpoints included components of the primary endpoint, as well as the need for mechanical ventilation by
Day 30. Participants reported by telephone the occurrence of any study endpoints at 15 and 30 days after
randomization; in some cases, clinical data were confirmed or obtained by medical chart reviews.4
Results
• The study enrolled 4,488 participants.
• The primary endpoint occurred in 104 of 2,235 participants (4.7%) in the colchicine arm and 131 of
2,253 participants (5.8%) in the placebo arm (OR 0.79; 95% CI, 0.61–1.03; P = 0.08).
• There were no statistically significant differences in the secondary outcomes between the arms.
• In a prespecified analysis of 4,159 participants who had a SARS-CoV-2 diagnosis confirmed by
PCR testing of an NP specimen (93% of those enrolled), those in the colchicine arm were less
likely to reach the primary endpoint (96 of 2,075 participants [4.6%]) than those in the placebo
arm (126 of 2,084 participants [6.0%]; OR 0.75; 95% CI, 0.57–0.99; P = 0.04). In this subgroup
of patients with PCR-confirmed SARS-CoV-2 infection, there were fewer hospitalizations (a
secondary outcome) in the colchicine arm (4.5% of patients) than in the placebo arm (5.9% of
patients; OR 0.75; 95% CI, 0.57–0.99).
• More participants in the colchicine arm experienced gastrointestinal adverse events, including
diarrhea which occurred in 13.7% of colchicine recipients versus 7.3% of placebo recipients (P <
0.0001). Unexpectedly, more pulmonary emboli were reported in the colchicine arm than in the
placebo arm (11 events [0.5% of patients] vs. 2 events [0.1% of patients]; P = 0.01).
Limitations
• Due to logistical difficulties with staffing, the trial was stopped at approximately 75% of the target
enrollment, which may have limited the study’s power to detect differences for the primary outcome.
• There was uncertainty as to the accuracy of COVID-19 diagnoses in presumptive cases.
• Some patient-reported clinical outcomes were potentially misclassified.
The PRINCIPLE Trial
PRINCIPLE is a randomized, open-label, platform trial that evaluated colchicine in symptomatic,
nonhospitalized patients with COVID-19 who were aged ≥65 years or aged ≥18 years with comorbidities
or shortness of breath, and who had symptoms for ≤14 days. Participants were randomized to receive
colchicine 0.5 mg daily for 14 days or usual care. The coprimary endpoints, which included time to first
self-reported recovery or hospitalization or death due to COVID-19 by Day 28, were analyzed using
a Bayesian model. Participants were followed through symptom diaries that they completed online
daily; those who did not complete the diaries were contacted by telephone on Days 7, 14, and 29. The
investigators developed a prespecified criterion for futility, specifying a clinically meaningful benefit
in time to first self-reported recovery as a hazard ratio ≥1.2, corresponding to about 1.5 days of faster
recovery in the colchicine arm.
Results
• The study enrolled 4,997 participants: 212 participants were randomized to receive colchicine;

AR08978
2,081 to receive usual care alone; and 2,704 to receive other treatments.
• The prespecified primary analysis included participants with SARS-CoV-2 positive test results (156
in the colchicine arm; 1,145 in the usual care arm; and 1,454 in the other treatments arm).
• The trial was stopped early because the criterion for futility was met; the median time to self-
reported recovery was similar in the colchicine arm and the usual care arm (HR 0.92; 95% CrI,
0.72–1.16).
• Analyses of self-reported time to recovery and hospitalizations or death due to COVID-19 among
concurrent controls also showed no significant differences between the colchicine and usual care
arms.
• There were no statistically significant differences in the secondary outcomes between the colchicine
and usual care arms in both the primary analysis population and in subgroups, including subgroups
based on symptom duration, baseline disease severity, age, or comorbidities.
• The occurrence of adverse events was similar in the colchicine and usual care arms.
Limitations
• The design of the study was open-label treatment.
• The sample size of the colchicine arm was small.
Colchicine in Hospitalized Patients With COVID-19

The RECOVERY Trial
In the RECOVERY trial, hospitalized patients with COVID-19 were randomized to receive colchicine
(1 mg loading dose, followed by 0.5 mg 12 hours later, and then 0.5 mg twice daily for 10 days or until
discharge) or usual care.6
Results
• The study enrolled 11,340 participants.
• At randomization, 10,603 patients (94%) were receiving corticosteroids.
• The primary endpoint of all-cause mortality at Day 28 occurred in 1,173 of 5,610 participants
(21%) in the colchicine arm and 1,190 of 5,730 participants (21%) in the placebo arm (rate ratio
1.01; 95% CI, 0.93–1.10; P = 0.77).
• There were no statistically significant differences between the arms for the secondary outcomes of
median time to being discharged alive, discharge from the hospital within 28 days, and receipt of
mechanical ventilation or death.
• The incidence of new cardiac arrhythmias, bleeding events, and thrombotic events was similar in
the 2 arms. Two serious adverse events were attributed to colchicine: 1 case of severe acute kidney
injury and one case of rhabdomyolysis.
Limitations
• The trial’s open-label design may have introduced bias for assessing some of the secondary
endpoints.
The GRECCO-19 Trial
GRECCO-19 was a small, prospective, open-label randomized clinical trial in 105 patients hospitalized
with COVID-19 across 16 hospitals in Greece. Patients were assigned 1:1 to receive standard of care with
colchicine (1.5 mg loading dose, followed by 0.5 mg after 60 minutes and then 0.5 mg twice daily until
hospital discharge or for up to 3 weeks) or standard of care alone.7

AR08979
Results
• Fewer patients in the colchicine arm (1 of 55 patients) than in the standard of care arm (7 of 50
patients) reached the primary clinical endpoint of deterioration in clinical status from baseline by 2
points on a 7-point clinical status scale (OR 0.11; 95% CI, 0.01–0.96).
• Participants in the colchicine group were significantly more likely to experience diarrhea (occurred
in 45.5% of participants in the colchicine arm vs. 18.0% in the standard of care arm; P = 0.003).
Limitations
• The overall sample size and the number of clinical events reported were small.
• The study design was open-label treatment assignment.
The results of several small randomized trials and retrospective cohort studies that have evaluated various
doses and durations of colchicine in hospitalized patients with COVID-19 have been published in peer-
reviewed journals or made available as preliminary, non-peer-reviewed reports.8-11 Some have shown
benefits of colchicine use, including less need for supplemental oxygen, improvements in clinical status
on an ordinal clinical scale, and reductions in certain inflammatory markers. In addition, some studies
have reported higher discharge rates or fewer deaths among patients who received colchicine than among
those who received comparator drugs or placebo. However, the findings of these studies are difficult to
interpret due to significant design or methodological limitations, including small sample sizes, open-label
designs, and differences in the clinical and demographic characteristics of participants and permitted use
of various cotreatments (e.g., remdesivir, corticosteroids) in the treatment arms.
Adverse Effects, Monitoring, and Drug-Drug Interactions

Common adverse effects of colchicine include diarrhea, nausea, vomiting, abdominal cramping and
pain, bloating, and loss of appetite. In rare cases, colchicine is associated with serious adverse events,
such as neuromyotoxicity and blood dyscrasias. Use of colchicine should be avoided in patients with
severe renal insufficiency, and patients with moderate renal insufficiency who receive the drug should
be monitored for adverse effects. Caution should be used when colchicine is coadministered with drugs
that inhibit cytochrome P450 (CYP) 3A4 and/or P-glycoprotein (P-gp) because such use may increase
the risk of colchicine-induced adverse effects due to significant increases in colchicine plasma levels. The
risk of myopathy may be increased with the concomitant use of certain HMG-CoA reductase inhibitors
(e.g., atorvastatin, lovastatin, simvastatin) due to potential competitive interactions mediated by CYP3A4
and P-gp pathways.12,13 Fatal colchicine toxicity has been reported in individuals with renal or hepatic
impairment who received colchicine in conjunction with P-gp inhibitors or strong CYP3A4 inhibitors.
There are limited data on the use of colchicine in pregnancy. Fetal risk cannot be ruled out based on
data from animal studies and the drug’s mechanism of action. Colchicine crosses the placenta and has
antimitotic properties, which raises a theoretical concern for teratogenicity. However, a recent meta-
analysis did not find that colchicine exposure during pregnancy increased the rates of miscarriage or
major fetal malformations. There are no data for colchicine use in pregnant women with acute COVID-19.
Risks of use should be balanced against potential benefits.12,14
Colchicine is most commonly used in children to treat periodic fever syndromes and autoinflammatory
conditions. Although colchicine is generally considered safe and well tolerated in children, there are no
data on the use of the drug to treat pediatric acute COVID-19 or multisystem inflammatory syndrome in
children (MIS-C).

AR08980
References
1. van Echteld I, Wechalekar MD, Schlesinger N, Buchbinder R, Aletaha D. Colchicine for acute gout. Cochrane
Database Syst Rev. 2014(8):CD006190. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25123076.
2. Xia M, Yang X, Qian C. Meta-analysis evaluating the utility of colchicine in secondary prevention of coronary
artery disease. Am J Cardiol. 2021;140:33-38. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33137319.
3. Reyes AZ, Hu KA, Teperman J, et al. Anti-inflammatory therapy for COVID-19 infection: the case for
colchicine. Ann Rheum Dis. 2021 May;80(5):550-557. Available at:
4. Tardif JC, Bouabdallaoui N, L’Allier PL, et al. Colchicine for community-treated patients with COVID-19
(COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial.
Lancet Respir Med. 2021;9(8):924-932. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34051877.
5. PRINCIPLE Trial Collaborative Group, Dorward J, Yu L, et al. Colchicine for COVID-19 in adults in
the community (PRINCIPLE): a randomised, controlled, adaptive platform trial. medRxiv. 2021;Preprint.
6. RECOVERY Collaborative Group. Colchicine in patients admitted to hospital with COVID-19
(RECOVERY): a randomised, controlled, open-label, platform trial. Lancet Respir Med. 2021;Published
online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34672950.
7. Deftereos SG, Giannopoulos G, Vrachatis DA, et al. Effect of colchicine vs standard care on cardiac and
inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: the
GRECCO-19 randomized clinical trial. JAMA Netw Open. 2020;3(6):e2013136. Available at:
8. Brunetti L, Diawara O, Tsai A, et al. Colchicine to weather the cytokine storm in hospitalized patients with
COVID-19. J Clin Med. 2020;9(9). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32937800.
9. Sandhu T, Tieng A, Chilimuri S, Franchin G. A case control study to evaluate the impact of colchicine
on patients admitted to the hospital with moderate to severe COVID-19 infection. Can J Infect Dis Med
Microbiol. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33133323.
10. Lopes MI, Bonjorno LP, Giannini MC, et al. Beneficial effects of colchicine for moderate to severe
COVID-19: a randomised, double-blinded, placebo-controlled clinical trial. RMD Open. 2021;7(1). Available
11. Salehzadeh F, Pourfarzi F, Ataei S. The impact of colchicine on the COVID-19 patients; a clinical trial.
Research Square. 2020;Preprint. Available at: https://www.researchsquare.com/article/rs-69374/v1.
12. Colchicine (Colcrys) [package insert]. Food and Drug Administration. 2012. Available at:
13. American College of Cardiology. AHA statement on drug-drug interactions with statins. 2016. Available at:
https://www.acc.org/latest-in-cardiology/ten-points-to-remember/2016/10/20/21/53/recommendations-for-
management-of-clinically-significant-drug. Accessed November 2, 2021.
14. Indraratna PL, Virk S, Gurram D, Day RO. Use of colchicine in pregnancy: a systematic review and meta-
analysis. Rheumatology (Oxford). 2018;57(2):382-387. Available at:

AR08981
Corticosteroids
Multiple randomized trials indicate that systemic corticosteroid therapy improves clinical outcomes
and reduces mortality in hospitalized patients with COVID-19 who require supplemental oxygen,1
presumably by mitigating the COVID-19-induced systemic inflammatory response that can lead to lung
injury and multisystem organ dysfunction. There is no observed benefit of systemic corticosteroids
in hospitalized patients with COVID-19 who do not require supplemental oxygen.2 The COVID-19
Treatment Guidelines Panel’s (the Panel) recommendations for the use of corticosteroids in hospitalized
patients with COVID-19 are based on results from these clinical trials (see Tables 4a and 4b for more
information). There are no data to support the use of systemic corticosteroids in nonhospitalized patients
with COVID-19.
Recommendations
For Nonhospitalized Patients With COVID-19
• See Therapeutic Management of Nonhospitalized Adults With COVID-19 for the Panel’s
recommendations on the use of dexamethasone or other systemic corticosteroids in certain
nonhospitalized patients.
• There is insufficient evidence for the Panel to recommend either for or against the use of inhaled
corticosteroids for the treatment of COVID-19.
For Hospitalized Patients With COVID-19

• See Therapeutic Management of Hospitalized Adults With COVID-19 for the Panel’s
recommendations on the use of dexamethasone or other systemic corticosteroids in certain
hospitalized patients.
• There is insufficient evidence for the Panel to recommend either for or against the use of inhaled
Systemic Corticosteroids in Patients With COVID-19

Nonhospitalized Patients
There are no data to support the use of systemic corticosteroids in nonhospitalized patients with
COVID-19. Therefore, the safety and efficacy of systemic corticosteroids in this population have
not been established. Generally, systemic corticosteroids are associated with adverse events (e.g.,
hyperglycemia, neuropsychiatric symptoms, secondary infections), which may be difficult to detect
and monitor in an outpatient setting (see General Management of Nonhospitalized Patients With Acute
COVID-19 for further information). Patients with COVID-19 who are receiving dexamethasone or
another corticosteroid for an underlying condition should continue this therapy as directed by their
health care provider (AIII).
The RECOVERY trial was a multicenter, open-label trial in the United Kingdom that randomly assigned
6,425 hospitalized patients to receive up to 10 days of dexamethasone plus standard care or standard
care alone. Mortality at 28 days was lower among the patients who received dexamethasone than among
those who received standard care alone.2 This benefit of dexamethasone was observed in patients who
were mechanically ventilated or who required supplemental oxygen at enrollment; in contrast, no benefit

AR08982
was seen in patients who did not require supplemental oxygen at enrollment.2 For additional information
on the RECOVERY trial, see Table 4a.
The CoDEX trial was a multicenter, open-label trial in Brazil that evaluated dexamethasone in patients
who were mechanically ventilated due to acute respiratory distress syndrome (ARDS) induced by
COVID-19. Although the trial was terminated early, the study results support the RECOVERY trial
finding that systemic corticosteroids are beneficial in hospitalized patients with COVID-19. The trial
randomly assigned 299 patients to receive either standard care plus intravenous (IV) dexamethasone 20
mg once daily for 5 days and then dexamethasone 10 mg once daily for 5 days or standard care alone.
The mean number of days alive and free from mechanical ventilation over 28 days was greater in the
dexamethasone arm than in the standard care alone arm. However, there were no differences between the
arms in 28-day mortality, ICU-free days over 28 days, or duration of mechanical ventilation at 28 days.3
See Table 4a for additional information.
Systemic corticosteroids used in combination with other agents, including other immunomodulators such
as tocilizumab (see Interleukin-6 Inhibitors)4,5 or baricitinib (see Kinase Inhibitors),6 have demonstrated
clinical benefit in subsets of hospitalized patients with COVID-19, especially those with early critical
illness and/or with signs of systemic inflammation. For the Panel’s recommendations on when to use
dexamethasone with another immunomodulator, see Therapeutic Management of Hospitalized Adults
With COVID-19.
Please see Tables 4a and 4b for data from clinical trials evaluating corticosteroid use for COVID-19.
Systemic Corticosteroids Other Than Dexamethasone

Systemic corticosteroids other than dexamethasone, including hydrocortisone7,8 and
methylprednisolone,9,10 have been studied for the treatment of COVID-19 in several randomized
trials. Some of these trials were stopped early due to under enrollment following the release of the
RECOVERY trial results. Consequently, the sample size of many these trials was insufficient to assess
efficacy (i.e., there were too few events to definitively confirm or exclude an effect, although many point
estimates, if true, suggested a beneficial effect). Therefore, evidence to support the use of hydrocortisone
or methylprednisolone for the treatment of COVID-19 is not as strong as evidence supporting the use of
dexamethasone. Based on the available evidence, the Panel has concluded the following:
• If dexamethasone is not available, alternative glucocorticoids (e.g., prednisone,
methylprednisolone, hydrocortisone) can be used.
• For these drugs, the total daily dose equivalencies to dexamethasone 6 mg (oral or IV)11 are:
• Prednisone 40 mg
• Methylprednisolone 32 mg
• Hydrocortisone 160 mg
• Half-life, duration of action, and frequency of administration vary among corticosteroids.
• Long-acting corticosteroid: Dexamethasone; half-life 36 to 72 hours, administer once daily.
• Intermediate-acting corticosteroids: Prednisone and methylprednisolone; half-life 12 to 36
hours, administer once daily or in 2 divided doses daily.
• Short-acting corticosteroid: Hydrocortisone; half-life 8 to 12 hours, administer in 2 to 4
divided doses daily.
• Hydrocortisone is commonly used to manage septic shock in patients with COVID-19; see
Hemodynamics for more information. Unlike other corticosteroids previously studied in patients

AR08983
with ARDS, dexamethasone lacks mineralocorticoid activity and thus has minimal effect on
sodium balance and fluid volume.12
Inhaled Corticosteroids in Patients With COVID-19

Inhaled corticosteroids have been identified as potential COVID-19 therapeutic agents because of their
targeted anti-inflammatory effects on the lungs. In addition, certain inhaled corticosteroids have been
shown to impair viral replication of SARS-CoV-213 and downregulate expression of the receptors used
for cell entry.14,15 Two open-label randomized controlled trials and 2 double-blind placebo-controlled
trials provide additional insights regarding the role of inhaled corticosteroids in outpatients with
COVID-19, as described below and in Table 4b.
Recommendation
There is insufficient evidence for the Panel to recommend either for or against the use of inhaled
Rationale
Inhaled budesonide was studied in 2 open-label randomized controlled trials in outpatients with mild
symptoms of COVID-19.16,17 The small STOIC trial suggested that initiation of inhaled budesonide in
adult outpatients with mild COVID-19 may reduce the need for urgent care or emergency department
assessment or hospitalization.16 PRINCIPLE, a larger, open-label trial in nonhospitalized patients with
COVID-19 at high risk of disease progression, found that use of inhaled budesonide did not affect the
rate of hospitalization or death but did reduce the time to self-reported recovery.18 The findings from these
trials should be interpreted with caution given the open-label design of the studies and other limitations.
Inhaled ciclesonide was studied in 2 double-blind randomized placebo-controlled trials in outpatients
with mild COVID-19. The primary endpoint in 1 study was time to alleviation of COVID-19-related
symptoms. In this study, the use of inhaled ciclesonide did not reduce the time to self-reported recovery,
but the therapy did reduce the number of subsequent COVID-related emergency department visits
or hospitalizations. The robustness of this conclusion is uncertain given the small number of events,
which is likely due to the relatively small number of participants with comorbidities.19 In the smaller
CONTAIN study, the combined use of inhaled and intranasal ciclesonide did not improve the resolution
of fever and/or respiratory symptoms by Day 7.20
The above-described studies of inhaled corticosteroid therapy for outpatients with mild COVID-19
have identified inconsistent effects of the therapy on subsequent hospitalization, and similar placebo-
controlled trials have not demonstrated that this therapy results in improvements in symptom resolution.
The placebo-controlled studies did not enroll enough patients at high risk of disease progression, and
therefore, further studies in this population are needed. For additional information on these trials, see
Table 4b.

• Clinicians should closely monitor patients with COVID-19 who are receiving dexamethasone for
certain adverse effects (e.g., hyperglycemia, secondary infections, psychiatric effects, avascular
necrosis).
• Patients who are receiving inhaled corticosteroids may develop oral candidiasis.
• The use of systemic corticosteroids may increase the risk of opportunistic fungal infections (e.g.,
mucormycosis, aspergillosis) and reactivation of latent infections (e.g., hepatitis B virus infection,
herpesvirus infections, strongyloidiasis, tuberculosis).21-25

AR08984
antiparasitic treatment (e.g., with ivermectin) with or without serologic testing in patients from
areas where Stronglyloides is endemic (i.e., tropical, subtropical, or warm temperate areas).28
• Using systemic corticosteroids with other immunosuppressants, such as tocilizumab or baricitinib,
could theoretically increase the risk of secondary infections. However, this adverse effect has not
been reported in clinical trials to date.
• Dexamethasone is a moderate cytochrome P450 (CYP) 3A4 inducer. Therefore, it could reduce
the concentration and potential efficacy of concomitant medications that are CYP3A4 substrates.
Clinicians should review a patient’s medication regimen to assess the potential for drug-drug
interactions.
• Using a CYP3A4 inhibitor with inhaled budesonide may lead to increased systemic absorption of
budesonide, which may result in systemic adverse effects of the corticosteroid.
A short course of betamethasone or dexamethasone, which are both known to cross the placenta, is
routinely used to decrease neonatal complications of prematurity in women with threatened preterm
delivery.29,30
A short course of dexamethasone for the treatment of COVID-19 during pregnancy offers the potential
benefit of decreased maternal mortality and a low risk of fetal adverse effects. Therefore, the Panel
recommends using dexamethasone in hospitalized pregnant patients with COVID-19 who are
mechanically ventilated (AIII) or who require supplemental oxygen but are not mechanically ventilated
(BIII).
The safety and effectiveness of dexamethasone or other corticosteroids for COVID-19 treatment
have not been sufficiently evaluated in pediatric patients and caution is warranted when extrapolating
recommendations for adults to patients aged <18 years. The Panel recommends using dexamethasone
for children with COVID-19 who require high-flow oxygen, noninvasive ventilation, mechanical
ventilation, or extracorporeal membrane oxygenation (BIII). Corticosteroids are not routinely
recommended for pediatric patients who require only low levels of oxygen support (i.e., administered
via a nasal cannula only) but could be considered on a case-by-case basis. The use of dexamethasone for
the treatment of severe COVID-19 in children who are profoundly immunocompromised has not been
evaluated and may be harmful; therefore, such use should be considered only if the benefit is perceived
to outweigh the risks. The dexamethasone dosing regimen for pediatric patients is dexamethasone
0.15 mg/kg/dose (maximum dose 6 mg) once daily for up to 10 days. There is insufficient evidence
to recommend for or against the use of inhaled corticosteroids for pediatric patients with COVID-19.
Corticosteroids are second to IV immunoglobulin as the most used therapy for the treatment of
multisystem inflammatory syndrome in children (MIS-C).31,32 See Special Considerations in Children for
more information on the management of MIS-C.
Clinical Trials
Several clinical trials evaluating corticosteroids for the treatment of COVID-19 are underway or in
development. Please see ClinicalTrials.gov for the latest information.

AR08985
References
1. WHO Rapid Evidence Appraisal for COVID-19 Therapies Working Group, Sterne JAC, Murthy S, et al.
Association between administration of systemic corticosteroids and mortality among critically ill patients with
COVID-19: a meta-analysis. JAMA. 2020;324(13):1330-1341. Available at:
3. Tomazini BM, Maia IS, Cavalcanti AB, et al. Effect of dexamethasone on days alive and ventilator-free in
patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized
4. RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19
(RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021;397(10285):1637-1645.
adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled
Phase 3 trial. Lancet Respir Med. 2021; Published online ahead of print. Available at:
7. Dequin PF, Heming N, Meziani F, et al. Effect of hydrocortisone on 21-day mortality or respiratory support
among critically ill patients with COVID-19: a randomized clinical trial. JAMA. 2020;324(13):1298-1306.
8. Angus DC, Derde L, Al-Beidh F, et al. Effect of hydrocortisone on mortality and organ support in patients
with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial. JAMA.
9. Corral-Gudino L, Bahamonde A, Arnaiz-Revillas F, et al. Methylprednisolone in adults hospitalized
with COVID-19 pneumonia: an open-label randomized trial (GLUCOCOVID). Wien Klin Wochenschr.
2021;133(7-8):303-311. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33534047.
10. Tang X, Feng YM, Ni JX, et al. Early use of corticosteroid may prolong SARS-CoV-2 shedding in non-
intensive care unit patients with COVID-19 pneumonia: a multicenter, single-blind, randomized control trial.
Respiration. 2021;100(2):116-126. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33486496.
11. Czock D, Keller F, Rasche FM, Haussler U. Pharmacokinetics and pharmacodynamics of systemically
administered glucocorticoids. Clin Pharmacokinet. 2005;44(1):61-98. Available at:
12. Villar J, Ferrando C, Martinez D, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a
multicentre, randomised controlled trial. Lancet Respir Med. 2020;8(3):267-276. Available at:
13. Matsuyama S, Kawase M, Nao N, et al. The inhaled steroid ciclesonide blocks SARS-CoV-2 RNA replication
by targeting the viral replication-transcription complex in cultured cells. J Virol. 2020;95(1). Available at:
14. Finney LJ, Glanville N, Farne H, et al. Inhaled corticosteroids downregulate the SARS-CoV-2 receptor ACE2
in COPD through suppression of type I interferon. J Allergy Clin Immunol. 2021;147(2):510-519 e515.
15. Peters MC, Sajuthi S, Deford P, et al. COVID-19-related Genes in Sputum Cells in Asthma. Relationship to
Demographic Features and Corticosteroids. Am J Respir Crit Care Med. 2020;202(1):83-90. Available at:

AR08986
16. Ramakrishnan S, Nicolau DV Jr, Langford B, et al. Inhaled budesonide in the treatment of early COVID-19
(STOIC): a Phase 2, open-label, randomised controlled trial. Lancet Respir Med. 2021;9(7):763-772. Available
17. PRINCIPLE Collaborative Group, Yu L, Bafadhel M, et al. Inhaled budesonide for COVID-19 in people at
higher risk of adverse outcomes in the community: interim analyses from the PRINCIPLE trial. medRxiv.
2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.04.10.21254672v1.
18. Yu LM, Bafadhel M, Dorward J, et al. Inhaled budesonide for COVID-19 in people at high risk of
complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive
platform trial. Lancet. 2021;398(10303):843-855. Available at:
19. Clemency BM, Varughese R, Gonzalez-Rojas Y, et al. Efficacy of inhaled ciclesonide for outpatient treatment
of adolescents and adults with symptomatic COVID-19: a randomized clinical trial. JAMA Intern Med.
20. Ezer N, Belga S, Daneman N, et al. Inhaled and intranasal ciclesonide for the treatment of covid-19 in adult
outpatients: CONTAIN Phase II randomised controlled trial. BMJ. 2021;375:e068060. Available at:
21. Garg D, Muthu V, Sehgal IS, et al. Coronavirus disease (COVID-19) associated mucormycosis (CAM): case
report and systematic review of literature. Mycopathologia. 2021;186(2):289-298. Available at:
22. Moorthy A, Gaikwad R, Krishna S, et al. SARS-CoV-2, uncontrolled diabetes and corticosteroids—an unholy
trinity in invasive fungal infections of the maxillofacial region? A retrospective, multi-centric analysis. J
Maxillofac Oral Surg. 2021:1-8. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33716414.
23. Machado M, Valerio M, Alvarez-Uria A, et al. Invasive pulmonary aspergillosis in the COVID-19 era: An
expected new entity. Mycoses. 2021;64(2):132-143. Available at:
24. Chauvet P, Mallat J, Arumadura C, et al. Risk Factors for invasive pulmonary aspergillosis in critically
ill patients with coronavirus disease 2019-induced acute respiratory distress syndrome. Crit Care Explor.
25. Liu J, Wang T, Cai Q, et al. Longitudinal changes of liver function and hepatitis B reactivation in COVID-19
patients with pre-existing chronic hepatitis B virus infection. Hepatol Res. 2020;50(11):1211-1221. Available
29. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the
respiratory distress syndrome in premature infants. Pediatrics. 1972;50(4):515-525. Available at:
30. Gyamfi-Bannerman C, Thom EA, Blackwell SC, et al. Antenatal betamethasone for women at risk for late
preterm delivery. N Engl J Med. 2016;374(14):1311-1320. Available at:
31. Ouldali N, Toubiana J, Antona D, et al. Association of intravenous immunoglobulins plus methylprednisolone
vs immunoglobulins alone with course of fever in multisystem inflammatory syndrome in children. JAMA.

AR08987

32. Son MBF, Murray N, Friedman K, et al. Multisystem inflammatory syndrome in children - initial therapy and
outcomes. N Engl J Med. 2021;385(1):23-34. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34133855.

AR08988
Table 4a. Systemic Corticosteroids: Selected Clinical Data

systemic corticosteroids. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations. Unless
stated otherwise, the clinical trials listed below included participants aged 18 years or older.
RECOVERY: Open-Label RCT of Dexamethasone in Hospitalized Patients With COVID-19 in the United Kingdom1
Key Inclusion Criterion: Participant Characteristics: Key Limitations:
• Hospitalized with suspected or laboratory- • Mean age 66 years; 64% men • Open-label study
confirmed SARS-CoV-2 infection • 56% had ≥1 comorbidity; 24% with diabetes • Published data did not include results for key
Key Exclusion Criterion: • 89% with laboratory-confirmed SARS-CoV-2 infection secondary endpoints (e.g., cause-specific
mortality, need for renal replacement), AEs, and
• Physician determination that risks of • Median duration of DEX therapy: 7 days key subgroups (e.g., patients with comorbidities)
participation too great based on patient’s • At randomization: 16% received MV or ECMO, 60%
medical history or an indication for • Participants who required supplemental oxygen
required supplemental oxygen but not MV, 24% required (but not MV) had variable severity. It is unclear
corticosteroid therapy outside of the study no supplemental oxygen whether all patients in this group benefited from
Interventions: • Received RDV: <1% in each arm DEX or whether benefit is restricted to those
• DEX 6 mg IV or PO once daily plus SOC for • Received tocilizumab or sarilumab: 2% in DEX arm vs. 3% requiring higher levels of supplemental oxygen
up to 10 days or until discharge (n = 2,104) in SOC arm • Patients >80 years were preferentially assigned to
• SOC alone (n = 4,321) Primary Outcome: supplemental oxygen therapy (and not MV)
Primary Endpoint: • Mortality at 28 days • High mortality of this patient population may limit
generalizability of results to populations with a
• All-cause mortality at 28 days • All participants: 23% in DEX arm vs. 26% in SOC arm lower baseline mortality
(age-adjusted rate ratio 0.83; 95% CI, 0.75–0.93; P <
0.001). Interpretation:
• Participants who required MV or ECMO at • In hospitalized patients with severe COVID-19
randomization: 29% in DEX arm vs. 41% in SOC arm who required supplemental oxygen, DEX reduced
(rate ratio 0.64; 95% CI, 0.51–0.81). mortality at 28 days, with greatest benefit in those
with MV at randomization.
• Participants who required supplemental oxygen but not
MV at randomization: 23% in DEX arm vs. 26% in SOC • No survival benefit of DEX in patients who did not
arm (rate ratio 0.82; 95% CI, 0.72–0.94). require supplemental oxygen at baseline.
• Participants who did not require supplemental oxygen
at randomization: 18% in DEX arm vs. 14% in SOC arm
(rate ratio 1.19, 95% CI, 0.91–1.55).

AR08989
CoDEX: Open-Label RCT of Dexamethasone in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19 in Brazil2
• Confirmed or suspected COVID-19 • Mean age: 60 years in DEX arm vs. 63 years in SOC arm • Open-label study
• Received MV within 48 hours of meeting • Women: 40% in DEX arm vs. 35% in SOC arm • Underpowered; enrollment stopped after release
criteria for moderate to severe ARDS (PaO2/ • Obesity: 31% in DEX arm vs. 24% in SOC arm; DM: 38% of data from the RECOVERY trial
FiO2 ≤200 mm Hg) in DEX arm vs. 47% in SOC arm • Patients discharged before 28 days were not
Key Exclusion Criteria: • Vasopressor use: 66% in DEX arm vs. 68% in SOC arm; followed for rehospitalization or mortality
• Immunosuppressive drugs in past 21 days mean PaO2/FiO2: 131 mm Hg in DEX arm vs. 133 mm Hg • High mortality in this study may limit
in SOC arm generalizability to populations with a lower
• Expected death within 24 hours
• Median duration of DEX therapy: 10 days baseline mortality
Interventions: • More than one-third of those randomized to SOC
• None received RDV or tocilizumab
• DEX 20 mg IV daily for 5 days, then DEX 10 also received corticosteroids
mg IV daily for 5 days or until ICU discharge • 35% in SOC arm received corticosteroids for indications
such as bronchospasm or septic shock Interpretation:
(n = 151)
Primary Outcome: • Compared with SOC alone, DEX increased the
• SOC alone (n = 148)
number of days alive and free of MV over 28 days
Primary Endpoint: • Mean number of days alive and free from MV by Day 28: 7 in patients with COVID-19 and moderate to severe
days in DEX arm vs. 4 days in SOC arm (P = 0.04). ARDS.
• Days alive and free from MV by Day 28
Secondary Outcomes:
• No differences in arms for Day 28 all-cause mortality
• All-cause mortality at Day 28 (56.3% vs. 61.5%), ICU-free days, and duration of MV, or
• ICU-free days by Day 28 for Day 15 score on 6-point ordinal scale.
• Duration of MV by Day 28 • Mean SOFA score at 7 days: 6.1 in DEX arm vs. 7.5 in SOC
• Score on 6-point ordinal scale at Day 15 arm (P = 0.004).
• SOFA score at 7 days Other Outcome:
• Post hoc analysis of probability of death or MV by Day 15:
68% in DEX arm vs. 80% in SOC arm (OR 0.46; P = 0.01).

AR08990
COVID STEROID 2: Multinational Blinded RCT of Dexamethasone 12 mg Versus 6 mg in Adults With COVID-19 and Severe Hypoxemia3
• Confirmed SARS-CoV-2 infection • Median age 65 years; 31% women • The randomized intervention was <10 days in
• Requiring oxygen ≥10 L/min, NIV, CPAP, or • DM: 27% in 12 mg arm vs. 34% in 6 mg arm some patients because the trial allowed up to 5
MV days of DEX before enrollment
• Median onset of symptoms to hospitalization: 7 days
Key Exclusion Criteria: • ICU care: 78% in 12 mg arm vs. 81% in 6 mg arm Interpretation:
• Treated with DEX >6 mg (or equivalent) • Oxygen requirements: 54% on oxygen via nasal cannula or • Among patients with COVID-19 and severe
face mask (median flow rate 23 L/min); 25% via NIV; 21% hypoxemia, DEX 12 mg once daily did not result
• Treated with corticosteroid ≥5 days in more days alive without life support at 28 days
via MV
• Invasive fungal infection than DEX 6 mg once daily.
• 63% received RDV; 12% received IL-6 inhibitors or JAK
• Active TB
inhibitors
Interventions: • Median duration of DEX treatment: 7 days in both arms
• DEX 12 mg IV once daily for up to 10 days (n
Primary Outcome:
= 503)
• Median days alive without life support: 22 days in 12 mg
• DEX 6 mg IV once daily for up to 10 days (n
arm vs. 20 days in 6 mg arm (adjusted mean difference
= 497)
1.3 days; 95% CI, 0.0–2.6; P = 0.07).
Primary Endpoint:
Secondary Outcomes:
• Days alive without life support (MV,
• At 90 days:
circulatory support, or kidney replacement
therapy) at 28 days • Median days alive without life support: 84 days in 12 mg
arm vs. 80 days in 6 mg arm.
• Median days alive and out of hospital: 62 days in 12 mg
• Days alive without life support at 90 days arm vs. 48 days in 6 mg arm.
• Days alive and out of hospital at 90 days • Mortality: 32% in 12 mg arm vs. 38% in 6 mg arm
• Mortality at 90 days (adjusted relative risk 0.87; 99% CI, 0.70–1.07).
• Mortality at 28 days • Mortality at 28 days: 27% in 12 mg arm vs. 32% in 6 mg
• SAEs at 28 days arm (adjusted relative risk 0.86; 99% CI, 0.68–1.08).
• SAEs, including septic shock and invasive fungal
infections: 11% in 12 mg arm vs. 13% in 6 mg arm
(adjusted relative risk 0.83; 99% CI, 0.54–1.29).

AR08991
CAPE COVID: Double-Blind RCT of Hydrocortisone Among Critically Ill Patients With COVID-19 in France4
• Confirmed SARS-CoV-2 infection or • Mean age 62 years; 70% men; median BMI 28 • Underpowered; enrollment stopped after release
radiographically suspected COVID-19 with • 96% with confirmed SARS-CoV-2 infection of data from the RECOVERY trial
≥1 of the following: • Limited information about comorbidities
• Median symptom duration: 9–10 days
• MV with PEEP ≥5 cm H2O
• Required MV: 81% at baseline Interpretation:
• PaO2/FiO2 <300 mm Hg and FiO2 ≥50% on
• Received vasopressors: 24% in hydrocortisone arm vs. • Hydrocortisone did not reduce treatment failure
HFNC
18% in placebo arm at Day 21 in patients with COVID-19 and acute
• PaO2/FiO2 <300 mm Hg on reservoir mask respiratory failure, although early termination
oxygen • Received RDV and tocilizumab: <3%
limited power to detect difference between study
• Pulmonary severity index >130 • Median duration of treatment with study drug: 11 days in arms.
hydrocortisone arm vs. 13 days in placebo arm (P = 0.25)
Primary Outcome:
• Septic shock
• Treatment failure by Day 21: 42% in hydrocortisone arm
• Do-not-intubate orders vs. 51% in placebo arm (P = 0.29).
Interventions:
Secondary Outcomes:
• Continuous infusion of hydrocortisone
• No difference in need for intubation or prone positioning
200 mg/day for 7 days, then 100 mg/day
(too few patients received ECMO or inhaled nitric oxide for
for 4 days, then 50 mg/day for 3 days; if
comparisons).
improvement by Day 4, then 200 mg/day for
4 days, then 100 mg/day for 2 days, then 50 • Among patients who did not require MV at baseline, 50%
mg/day for 2 days (n = 76) in hydrocortisone arm vs. 75% in placebo arm required
subsequent MV.
• No difference in proportion with nosocomial infection by
Primary Endpoint: Day 28
• Treatment failure (death or dependency on • Clinical status on Day 21: no difference in arms, but 15%
MV or high-flow oxygen) by Day 21 deaths in hydrocortisone arm vs. 27% deaths in placebo
Key Secondary Endpoints: arm (P = 0.06).
• Need for MV, prone positioning, ECMO, • Discharged from ICU by Day 21: 57% in hydrocortisone
inhaled nitric oxide arm vs. 44% in placebo arm; 23% in both arms still
required MV.
• Nosocomial infection by Day 28
• Clinical status on Day 21

AR08992
REMAP-CAP: Randomized, Open-Label, Adaptive Trial of Hydrocortisone in Patients With Severe COVID-195
• Presumed or confirmed SARS-CoV-2 infection • Mean age 60 years; 71% men • Open-label study
• ICU admission for respiratory support • Mean BMI 29.7–30.9 • Early termination following release of
Key Exclusion Criteria: • 50% to 64% required MV RECOVERY trial results
• Presumed imminent death Primary Outcomes: Interpretation:
• Systemic corticosteroid use • No difference in organ support–free days at Day 21 • Hydrocortisone did not increase support-free
• >36 hours since ICU admission (median 0 days in each group). days in either the fixed-dose or the shock-
dependent group, although early termination
Interventions: • Median adjusted ORs for primary outcome for limited power to detect differences between
hydrocortisone arms compared to no hydrocortisone arm: study arms.
• Hydrocortisone 50 mg IV 4 times daily for 7
days (n = 137) • OR 1.43 (95% CrI, 0.91–2.27) with 93% Bayesian
probability of superiority for fixed-dose hydrocortisone
• Septic shock-based hydrocortisone 50 mg IV 4 arm.
times daily for duration of shock (n = 146)
• OR 1.22 (95% CrI, 0.76–1.94) with 80% Bayesian
• No hydrocortisone (n = 101) probability of superiority for septic shock-based
Primary Endpoint: hydrocortisone arm.
• Days free of respiratory and cardiovascular Key Secondary Outcome:
support up to Day 21 • No differences in mortality: 30% in fixed-dose
Key Secondary Endpoint: hydrocortisone arm, 36% in septic shock-based
• In-hospital mortality hydrocortisone arm, 33% in no hydrocortisone arm.
Single-Blind RCT of Methylprednisolone in Hospitalized Patients With COVID-19 Pneumonia in China6
• Laboratory-confirmed SARS-CoV-2 infection • Mean age 56 years; 48% men • Small sample size
• Chest CT-confirmed pneumonia • Median 8 days from symptom onset to randomization • Terminated early because of decreasing
• Hospitalized on general ward • At randomization, 71% received oxygen via nasal cannula incidence of COVID-19 pneumonia at study
sites
Key Exclusion Criteria: Primary Outcome:
Interpretation:
• Severe immunosuppression • Clinical deterioration at 14 days: 5% in each arm (OR 1.0;
95% CI, 0.134–7.442; P = 1.00). • The incidence of clinical deterioration did not
• Corticosteroid use for other diseases differ between the methylprednisolone and
Interventions: Secondary Outcomes: control arms.
• Methylprednisolone 1 mg/kg/day IV for 7 days • No difference (all P > 0.05) between methylprednisolone
(n = 43) arm and saline arm for:
• Saline (n = 43) • Clinical cure at 14 days: 51% vs. 58%

AR08993
Single-Blind RCT of Methylprednisolone in Hospitalized Patients With COVID-19 Pneumonia in China6, continued
Primary Endpoint: • Time to clinical cure: 14 days vs. 12 days
• Clinical deterioration at 14 days • ICU admission: 5% each
Key Secondary Endpoints: • In-hospital mortality: 0% vs. 2%
• Clinical cure at 14 days • Days hospitalized: 17 days vs. 13 days
• Time to clinical cure
• ICU admission
• In-hospital mortality
• Days hospitalized
Key: AE = adverse event; ARDS = acute respiratory distress syndrome; BMI = body mass index; CPAP = continuous positive airway pressure; CT = computed
tomography; DEX = dexamethasone; DM = Diabetes mellitus; ECMO = extracorporeal membrane oxygenation; HFNC = high-flow nasal cannula; ICU = intensive
care unit; IL = interleukin; IV = intravenous; JAK = Janus kinase; MV = mechanical ventilation; NIV = noninvasive ventilation; the Panel = the COVID-19 Treatment
Guidelines Panel; PaO2/FiO2 = ratio of arterial partial pressure of oxygen to fraction of inspired oxygen; PEEP = positive end-expiratory pressure; PO = orally; RCT
= randomized controlled trial; RDV = remdesivir; SAE = serious adverse event; SOC = standard of care; SOFA = sequential organ failure assessment; TB = tuberculosis
References
1. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in hospitalized patients with COVID-19. N Engl J Med. 2021;384(8):693-
2. Tomazini BM, Maia IS, Cavalcanti AB, et al. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute
respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial. JAMA. 2020;324(13):1307-1316. Available at:
3. COVID Steroid Trial Group, Munch MW, Myatra SN, et al. Effect of 12 mg vs 6 mg of dexamethasone on the number of days alive without life
support in adults with COVID-19 and severe hypoxemia: the COVID STEROID 2 randomized trial. JAMA. 2021;326(18):1807-1817. Available at:
4. Dequin PF, Heming N, Meziani F, et al. Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with
COVID-19: a randomized clinical trial. JAMA. 2020;324(13):1298-1306. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32876689.
5. Angus DC, Derde L, Al-Beidh F, et al. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP
COVID-19 corticosteroid domain randomized clinical trial. JAMA. 2020;324(13):1317-1329. Available at:
6. Tang X, Feng YM, Ni JX, et al. Early use of corticosteroid may prolong SARS-CoV-2 shedding in non-intensive care unit patients with COVID-19
pneumonia: a multicenter, single-blind, randomized control trial. Respiration. 2021;100(2):116-126. Available at:

AR08994
Table 4b. Inhaled Corticosteroids: Selected Clinical Data

inhaled corticosteroids. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations.
PRINCIPLE: Open-Label RCT of Inhaled Budesonide in Nonhospitalized Patients With COVID-191

• Aged ≥65 years or aged ≥50 years with comorbidities • Mean age 64.2 years; 52% women; • Open-label trial
• PCR-confirmed or suspected COVID-19 92% White • Primary endpoint of time to
• ≤14 days of symptoms • 81% with comorbidities reported recovery based on
• Median time from symptom onset to participant self-report
randomization: 6 days Interpretation:
• Already taking inhaled or systemic corticosteroids
Primary Outcomes: • Inhaled budesonide reduced
• Unable to use an inhaler time to reported recovery but not
• Percentage of patients who were
• Contraindication to inhaled budesonide hospitalized or died due to COVID-19 COVID-19-related hospitalization
Interventions: within 28 days: 6.8% in budesonide arm or death.
• Usual care plus budesonide 800 mcg inhaled twice daily for 14 days (n = 1,069) vs. 8.8% in usual care arm (OR 0.75; • The clinical significance of self-
95% CrI, 0.55–1.03). reported time to recovery in an
• Usual care (n = 787) open-label study is unclear.
• Median time to reported recovery: 11.8
Primary Endpoints: days in budesonide arm vs. 14.7 days
• COVID-19-related hospitalization or death up to 28 days from randomization in usual care arm (HR 1.21; 95% CrI,
1.08–1.36).
• Time to reported recovery up to 28 days from randomization
STOIC: Open-Label, Phase 2 RCT of Inhaled Budesonide in Nonhospitalized Adults With Early COVID-192
• Aged ≥18 years • Mean age 45 years; 58% women • Small, open-label trial
• ≤7 days of symptoms • 9% with CVD, 5% with DM • Early termination after statistical
Key Exclusion Criteria: • 95% with positive SARS-CoV-2 RT-PCR analysis determined that additional
result participants would not alter study
• Use of inhaled or systemic glucocorticoids in past 7 days outcome
• Median time from symptom onset to
• Known allergy or contraindication to budesonide
randomization: 3 days
Interventions:
• Usual care plus budesonide 800 mcg inhaled twice daily until symptom
resolution (n = 73)

AR08995
STOIC: Open-Label, Phase 2 RCT of Inhaled Budesonide in Nonhospitalized Adults with Early COVID-192, continued
• Usual care (n = 73) Primary Outcomes: Interpretation:
Primary Endpoint: • Median duration of budesonide use: 7 days. • In adult outpatients with mild COVID-19,
• Percentage of patients with COVID-19-related inhaled budesonide may reduce the need
• COVID-19-related urgent care visit, including ED visit or
urgent care visit or hospitalization: 1% in for urgent care or ED assessment and/or
hospitalization
budesonide arm vs.14% in usual care arm (relative hospitalization.
risk reduction 91%).
Phase 3, Double-Blind RCT of Inhaled Ciclesonide in Nonhospitalized Patients With COVID-193
• Aged ≥12 years • Mean age 43.3 years; 55.3% women; 86.3% White • ED or hospitalization outcome based on
• Positive SARS-CoV-2 molecular or antigen diagnostic test • Mean BMI 29.4 small number of events
result in previous 72 hours • 22.3% with HTN, 7.5% with type 2 DM • Primary endpoint of time to alleviation of
• ≥1 symptom of fever, cough, or dyspnea all symptoms based on participant self-
• Higher rates of DM and asthma in ciclesonide arm report
Key Exclusion Criteria: Primary Outcome: Interpretation:
• Taken inhaled or intranasal corticosteroid within 14 days • Median time to alleviation of all COVID-19-related • Inhaled ciclesonide did not reduce time to
of enrollment or systemic corticosteroid within 90 days of symptoms: 19.0 days in ciclesonide arm vs. 19.0
enrollment reported recovery.
days in placebo arm (HR 1.08; 95% CI, 0.84–
• Unable to use an inhaler 1.38). • The robustness of the conclusion that
inhaled ciclesonide reduced COVID-19-
Interventions: Secondary Outcomes: related ED visits or hospitalization is
• Ciclesonide MDI 160 µg/actuation, 2 actuations twice a day • By Day 30, percentage of patients in whom the uncertain; there were only a small number
for 30 days (n = 197) following outcomes occurred: of events, which is most likely due to the
• Placebo MDI twice a day for 30 days (n = 203) • Alleviation of COVID-19-related symptoms: relatively low rate of comorbidities in the
70.6% in ciclesonide arm vs. 63.5% in placebo study population.
Primary Endpoint:
arm.
• Time to alleviation of all COVID-19-related symptoms by Day
• Subsequent ED visit or hospital admission for
30
COVID-19: 1.0% in ciclesonide arm vs. 5.4% in
Key Secondary Endpoints: placebo arm (OR 0.18; 95% CI, 0.04–0.85).
• Alleviation of COVID-19-related symptoms by Day 30 • Hospital admission or death: 1.5% in ciclesonide
• ED visit or hospital admission for COVID-19 by Day 30 arm vs. 3.4% in placebo arm (OR 0.45; 95% CI,
0.11–1.84).
• Hospital admission or death by Day 30
• No deaths by Day 30 in either arm.

AR08996
CONTAIN: Double-Blind RCT of Inhaled and Intranasal Ciclesonide in Nonhospitalized Patients With COVID-194
• Aged ≥18 years • Median age 35 years; 54% women; 61% White • Small study with a relatively young,
• Positive SARS-CoV-2 molecular diagnostic test result • 20% with comorbid condition healthy population
• ≥1 symptom of fever, cough, or shortness of breath Primary Outcome: Interpretation:
• Symptom duration ≤6 days • Percentage of patients with resolution of fever • The use of inhaled ciclesonide plus
and all respiratory symptoms at Day 7: 40% in intranasal ciclesonide did not improve
Key Exclusion Criteria: resolution of fever and respiratory
ciclesonide arm vs. 35% in placebo arm (adjusted
• Already taking an inhaled corticosteroid or taken PO or IM risk difference 5.5%; 95% CI, -7.8% to 18.8%). symptoms in nonhospitalized patients
corticosteroids within 7 days of enrollment with COVID-19.
• Unable to use an inhaler Secondary Outcomes:
• No respiratory symptoms • Percentage of patients with resolution of fever
and all respiratory symptoms at Day 14: 66% in
• Use of oxygen at home ciclesonide arm vs. 58% in placebo arm (adjusted
• COVID-19 vaccinated risk difference 7.5%; 95% CI, -5.9% to 20.8%).
Interventions: • Percentage of patients who were admitted to the
hospital by Day 14: 6% in ciclesonide arm vs. 3%
• Ciclesonide MDI 600 µg/actuation and intranasal ciclesonide
in placebo arm (adjusted risk difference 2.3%;
100 µg, both twice a day for 14 days (n = 105)
95% CI, -3.0% to 7.6%).
• Saline placebo MDI and intranasal saline, both twice a day for
14 days (n = 98)
Primary Endpoint:
• Resolution of fever and all respiratory symptoms at Day 7
• Resolution of fever and all respiratory symptoms at Day 14
• Hospital admission by Day 14
Key: BMI = body mass index; CVD = cardiovascular disease; DM = diabetes mellitus; ED = emergency department; HTN = hypertension; IM = intramuscular; MDI =
metered dose inhaler; the Panel = the COVID-19 Treatment Guidelines Panel; PCR = polymerase chain reaction; PO = oral; RCT = randomized controlled trial; RT-PCR
= reverse transcription polymerase chain reaction
References
1. Yu LM, Bafadhel M, Dorward J, et al. Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK
(PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet. 2021;398(10303):843-855. Available at:

AR08997
2. Ramakrishnan S, Nicolau DV, Jr., Langford B, et al. Inhaled budesonide in the treatment of early COVID-19 (STOIC): a Phase 2, open-label, randomised
controlled trial. Lancet Respir Med. 2021;9(7):763-772. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33844996.
3. Clemency BM, Varughese R, Gonzalez-Rojas Y, et al. Efficacy of inhaled ciclesonide for outpatient treatment of adolescents and adults with symptomatic
COVID-19: a randomized clinical trial. JAMA Intern Med. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34807241.
4. Ezer N, Belga S, Daneman N, et al. Inhaled and intranasal ciclesonide for the treatment of COVID-19 in adult outpatients: CONTAIN Phase II randomised
controlled trial. BMJ. 2021;375:e068060. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34728476.

AR08998
Fluvoxamine
Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) that is approved by the Food and
Drug Administration (FDA) for the treatment of obsessive-compulsive disorder and is used for other
conditions, including depression. Fluvoxamine is not FDA-approved for the treatment of any infection.
Anti-Inflammatory Effect of Fluvoxamine and Rationale for Use in COVID-19

In a murine sepsis model, fluvoxamine was found to bind to the sigma-1 receptor on immune cells,
resulting in reduced production of inflammatory cytokines.1 In an in vitro study of human endothelial
cells and macrophages, fluvoxamine reduced the expression of inflammatory genes.2 Ongoing studies
are establishing whether the anti-inflammatory effects of fluvoxamine observed in nonclinical studies
also occur in humans and are clinically relevant in the setting of COVID-19.
Recommendation
• There is insufficient evidence for the COVID-19 Treatment Guidelines Panel (the Panel) to
recommend either for or against the use of fluvoxamine for the treatment of COVID-19.
Rationale
Three randomized trials have studied the use of fluvoxamine for the treatment of nonhospitalized
patients with COVID-19. In STOP COVID, a contactless, double-blind randomized placebo-controlled
trial conducted in the United States among nonhospitalized adults with mild COVID-19 diagnosed
within 7 days of symptom onset, fluvoxamine (100 mg up to 3 times daily for 15 days) reduced clinical
deterioration at Day 15.3 Clinical deterioration was defined as shortness of breath plus oxygen saturation
(SpO2) <92% or hospitalization plus SpO2 <92%. This was a small study (≤80 participants per arm)
with limited cases of clinical deterioration and a short follow-up period. In addition, 24% of participants
stopped responding to surveys prior to Day 15.
The subsequent STOP COVID 2, a Phase 3 randomized controlled trial (ClinicalTrials.gov Identifier
NCT04668950) that enrolled >700 participants in the United States and Canada, was stopped for
futility by a data safety monitoring board after lower than expected case rates and treatment effect were
observed.4
TOGETHER is an adaptive platform, double-blind randomized placebo-controlled trial conducted
in Brazil.5 Nonhospitalized adults with COVID-19 and a known risk factor for progression to severe
disease were randomized to fluvoxamine 100 mg twice daily (n = 741) or placebo (n = 756) for 10
days. Fluvoxamine use was associated with a lower risk of the primary composite outcome of retention
in the emergency department for >6 hours or admission to a tertiary hospital (79 of 741 participants
[11%] in the fluvoxamine arm vs. 119 of 756 participants [16%] in the placebo arm [relative risk
0.68; 95% CrI, 0.52–0.88]). Of note, 87% of the primary outcome events were hospitalizations. There
was no statistically significant difference between study arms for the secondary outcomes of need for
hospitalization or time to symptom resolution. There was no significant difference in mortality between
study arms in the intention-to-treat (ITT) population (17 of 741 participants [2%] in the fluvoxamine
arm vs. 25 of 756 participants [3%] in the placebo arm [OR 0.69; 95% CI, 0.36–1.27]). In a secondary,
per-protocol analysis of participants who received >80% of possible doses, death was the outcome for
1 of 548 participants (<1%) in the fluvoxamine arm versus 12 of 618 participants (2%) in the placebo
arm (OR 0.09; 95% CI, 0.01–0.47). Participants in the fluvoxamine arm were less likely to present
to an emergency setting for COVID-19 for any duration, although this analysis was not prespecified.

AR08999
Compared with those in the placebo arm, participants who received fluvoxamine were less adherent to
therapy and discontinued therapy due to intolerance more often.
While fluvoxamine treatment significantly reduced the primary composite outcome in the TOGETHER
trial (i.e., retention in the emergency department for >6 hours or admission to a tertiary hospital), the
difference in hospitalizations between arms was not significant.5 Defining the clinical relevance of
the >6 hour emergency department observation time endpoint is difficult, especially its applicability
to practice settings in different countries. Moreover, the endpoint has not been used in other studies
of interventions for nonhospitalized patients at high risk for hospitalization and death. While a per-
protocol analysis found a significant treatment effect for mortality in patients taking >80% of possible
doses (assessed by patient self-report), no such benefit was found in the primary ITT analysis. The 80%
threshold has no clear justification, and only 74% of participants in the fluvoxamine arm reached this
level of adherence. Since per-protocol analyses are not randomized comparisons, they can introduce bias
when adherence is associated with factors that influence the outcome; this bias cannot be excluded in
this study. Notably, mortality in the placebo arm was substantially higher in those with ≤80% adherence
than in those with >80% adherence, suggesting that factors other than adherence differed in the per-
protocol population. Finally, including only participants who could tolerate fluvoxamine does not reflect
the actual effectiveness of the drug, since intolerance and adherence appeared to be related.
Additional studies are needed to provide more specific, evidence-based guidance on the role of
fluvoxamine for the treatment of COVID-19. Further details of the studies discussed are provided in
Table 4c.
Adverse Effects, Monitoring, and Drug-Drug Interactions

When fluvoxamine is used to treat psychiatric conditions, the most common adverse effect is nausea, but
adverse effects can include other gastrointestinal effects (e.g., diarrhea, indigestion), neurologic effects
(e.g., asthenia, insomnia, somnolence, anxiety, headache), and rarely suicidal ideation.
Fluvoxamine is a cytochrome P450 (CYP) 2D6 substrate and a potent inhibitor of CYP1A2 and
CYP2C19 and a moderate inhibitor of CYP2C9, CYP2D6, and CYP3A4.6 Fluvoxamine can enhance the
serotonergic effects of other SSRIs or monoamine oxidase inhibitors (MAOIs), resulting in serotonin
syndrome; therefore, it should not be used within 2 weeks of receipt of other SSRIs or MAOIs.
Fluvoxamine may enhance the anticoagulant effects of antiplatelets and anticoagulants; therefore,
patients receiving these drugs should be closely monitored.
Fluvoxamine is not thought to increase the risk of congenital abnormalities; however, the data on its use
in pregnancy are limited.7,8 The association of SSRI use in the late third trimester with a small, increased
risk of primary persistent pulmonary hypertension in newborns has not been excluded, although the
absolute risk is likely low.9 The risk of fluvoxamine use in pregnancy for the treatment of COVID-19
should be balanced with the potential benefit.
Fluvoxamine is approved by the FDA for the treatment of obsessive-compulsive disorder in children
aged ≥8 years.10 Adverse effects due to SSRI use seen in children are similar to those seen in adults,
although children and adolescents appear to have higher rates of behavioral activation and vomiting than
adults.11 There are no data on the use of fluvoxamine for the prevention or treatment of COVID-19 in
children.

AR09000
Clinical Trials
See ClinicalTrials.gov for the latest information on studies of fluvoxamine and COVID-19.
References
1. Rosen DA, Seki SM, Fernandez-Castaneda A, et al. Modulation of the sigma-1 receptor-IRE1 pathway is
beneficial in preclinical models of inflammation and sepsis. Sci Transl Med. 2019;11(478). Available at:
2. Rafiee L, Hajhashemi V, Javanmard SH. Fluvoxamine inhibits some inflammatory genes expression in LPS/
stimulated human endothelial cells, U937 macrophages, and carrageenan-induced paw edema in rat. Iran J
Basic Med Sci. 2016;19(9):977-984. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27803785.
3. Lenze EJ, Mattar C, Zorumski CF, et al. Fluvoxamine vs placebo and clinical deterioration in outpatients with
symptomatic COVID-19: a randomized clinical trial. JAMA. 2020;324(22):2292-2300. Available at:
4. Lenze E. Fluvoxamine for early treatment of COVID-19: the STOP COVID clinical trials. 2021. Available
at: https://rethinkingclinicaltrials.org/news/august-20-2021-fluvoxamine-for-early-treatment-of-covid-19-the-
stop-covid-clinical-trials-eric-lenze-md/. Accessed December 8, 2021.
5. Reis G, Dos Santos Moreira-Silva EA, Silva DCM, et al. Effect of early treatment with fluvoxamine on risk of
emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform
clinical trial. Lancet Glob Health. 2021;Published online ahead of print. Available at:
6. Hemeryck A, Belpaire FM. Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug
interactions: an update. Curr Drug Metab. 2002;3(1):13-37. Available at:
7. Einarson A, Choi J, Einarson TR, Koren G. Incidence of major malformations in infants following
antidepressant exposure in pregnancy: results of a large prospective cohort study. Can J Psychiatry.
8. Furu K, Kieler H, Haglund B, et al. Selective serotonin reuptake inhibitors and venlafaxine in early pregnancy
and risk of birth defects: population based cohort study and sibling design. BMJ. 2015;350:h1798. Available
9. Huybrechts KF, Bateman BT, Palmsten K, et al. Antidepressant use late in pregnancy and risk of persistent
pulmonary hypertension of the newborn. JAMA. 2015;313(21):2142-2151. Available at:
10. Fluvoxamine maleate tablets [package insert]. Food and Drug Administration. 2019. Available at:
11. Safer DJ, Zito JM. Treatment-emergent adverse events from selective serotonin reuptake inhibitors by age
group: children versus adolescents. J Child Adolesc Psychopharmacol. 2006;16(1-2):159-169. Available at:

AR09001
Table 4c. Fluvoxamine: Selected Clinical Data

The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations
for fluvoxamine. The studies summarized below are the randomized clinical trials that have had the greatest impact on the Panel’s
recommendations.
TOGETHER: Double-Blind, Adaptive RCT of Fluvoxamine in Nonhospitalized Patients With COVID-19 in Brazil1
• Aged ≥50 years or aged ≥18 years with comorbidities • Median age 50 years; 58% women; 95% self- • The >6-hour emergency setting observation
• Laboratory-confirmed SARS-CoV-2 infection identified as mixed race endpoint has not been used in other studies
• 13% with uncontrolled HTN; 13% with type 2 DM; of interventions for nonhospitalized patients
• ≤7 days of symptoms who are at high risk for hospitalization and
50% with BMI ≥30 kg/m2
Key Exclusion Criteria: death
• Mean of 3.8 days from symptom onset to
• Use of an SSRI randomization • As this was an adaptive platform trial
• Severe mental illness where multiple investigational treatments
Primary Outcome: or placebos were being evaluated
• Cirrhosis, recent seizures, severe ventricular cardia • Proportion of patients who met the primary simultaneously, not all patients in the placebo
arrythmia composite endpoint: 11% in fluvoxamine arm vs. arm received a placebo that was matched
Interventions: 16% in placebo arm (relative risk 0.68; 95% CrI, to fluvoxamine by route of administration,
0.52–0.88) dosing frequency, or duration of therapy
• Fluvoxamine 100 mg PO twice daily for 10 days (n = 741)
Secondary Outcomes: • PP analyses are not randomized
• Placebo (route, dosing frequency, and duration for some
comparisons, and they introduce bias when
patients may have differed from fluvoxamine) (n = 756) • 87% of clinical events were hospitalizations.
adherence is associated with factors that
Primary Endpoint: • No difference between arms in COVID-19-related influence the outcome
• Composite endpoint of emergency setting observation hospitalizations: 10% in fluvoxamine arm vs. 13%
• Adherence was self-reported and not verified
for >6 hours or hospitalization due to progression of in placebo arm (OR 0.77; 95% CI, 0.55–1.05)
• No difference between arms in time to symptom Interpretation:
COVID-19 within 28 days after randomization
resolution. • Fluvoxamine reduced the proportion of
Key Secondary Endpoints: patients who met the composite endpoint of
• Adherence: 74% in fluvoxamine arm vs. 82% in
• Occurrence of COVID-19-related hospitalizations COVID-19-related hospitalization or retention
placebo arm (OR 0.62; 95% CI, 0.48–0.81). 11%
• Time to symptom resolution in fluvoxamine arm vs. 8% in placebo arm stopped in an emergency setting for >6 hours.
• Proportion of patients who were adherent to study drugs, drug due to issues of tolerability. • The use of fluvoxamine did not impact
defined as receiving >80% of possible doses • Mortality (ITT): 2% in fluvoxamine arm vs. 3% in the incidence of COVID-19-related
placebo arm (OR 0.68; 95% CI, 0.36–1.27) hospitalizations.

AR09002
TOGETHER: Double-Blind, Adaptive RCT of Fluvoxamine in Nonhospitalized Patients With COVID-19 in Brazil1, continued
• Mortality in both the primary ITT population and a PP • Mortality (PP): <1% in fluvoxamine • It is difficult to define the clinical relevance of the >6-hour
population that included patients who took >80% of the arm vs. 2% in placebo arm (OR 0.09; emergency setting observation endpoint and apply it to
study medication doses 95% CI, 0.01–0.47) practice settings in different countries.
• Fluvoxamine did not have a consistent impact on
mortality.
• Fluvoxamine did not impact time to symptom resolution.
STOP COVID: Double-Blind RCT of Fluvoxamine in Nonhospitalized Patients With COVID-19 in the United States2
• Aged ≥18 years • Mean age 46 years; 72% women; 25% • Small sample size
• Positive SARS-CoV-2 PCR result Black • Short follow-up period
• ≤7 days of symptoms • 56% with obesity; 20% with HTN; • Ascertaining clinical deterioration was challenging
17% with asthma because all assessments were done remotely
• Median of 4 days from symptom onset • 24% of patients stopped responding to follow-up prior to
• Immunocompromised to randomization Day 15 but were included in the final analysis
• Unstable medical comorbidities Primary Outcome: Interpretation:
Interventions: • Clinical deterioration: 0% in • Fluvoxamine reduced the proportion of patients who
• Fluvoxamine 50 mg PO for 1 dose, then fluvoxamine 100 fluvoxamine arm vs. 8.3% in placebo experienced clinical deterioration.
mg twice daily, then fluvoxamine 100 mg 3 times daily arm (absolute difference 8.7%; 95%
CI, 1.8% to 16.4%) • Due to significant limitations, it is difficult to draw
through Day 15 (n = 80)
definitive conclusions about the efficacy of using
• Placebo (n = 72) Secondary Outcome: fluvoxamine to treat COVID-19.
Primary Endpoint: • No patients in fluvoxamine arm
• Clinical deterioration within 15 days of randomization. and 4 patients in placebo arm were
Clinical deterioration was defined as: hospitalized.
• Having dyspnea or being hospitalized for dyspnea or
pneumonia; and
• Having SpO2 <92% on room air or requiring
supplemental oxygen to attain SpO2 ≥92%
Key Secondary Endpoint:
• Hospitalization
Key: BMI = body mass index; DM = diabetes; HTN = hypertension; ITT = intention-to-treat; the Panel = the COVID-19 Treatment Guidelines Panel; PCR = polymerase
chain reaction; PO = oral; PP = per protocol; RCT = randomized controlled trial; SpO2 = oxygen saturation; SSRI = selective serotonin reuptake inhibitor

AR09003
References
1. Reis G, Dos Santos Moreira-Silva EA, Silva DCM, et al. Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation
among patients with COVID-19: the TOGETHER randomised, platform clinical trial. Lancet Glob Health. 2021;Published online ahead of print.
2. Lenze EJ, Mattar C, Zorumski CF, et al. Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized

AR09004
Granulocyte-Macrophage Colony-Stimulating Factor

Inhibitors
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a myelopoietic growth factor and pro-

inflammatory cytokine that plays a central role in a broad range of immune-mediated diseases. GM-CSF,
which is secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells, and
fibroblasts, regulates macrophage number and function. It acts as a pro-inflammatory signal, prompting
macrophages to launch an immune cascade that ultimately results in tissue damage.1,2 GM-CSF is
believed to be a key driver of lung inflammation in severe and critical COVID-19 pneumonia, operating
upstream of other pro-inflammatory cytokines and chemokines.1-6 Anti-GM-CSF monoclonal antibodies
(mAbs) may mitigate inflammation by inhibiting this signaling axis upstream and thus minimizing
downstream production of numerous pro-inflammatory mediators involved in the pathogenesis of
COVID-19.7 Gimsilumab, lenzilumab, namilumab, and otilimab target GM-CSF directly, neutralizing
the biological function of GM-CSF by blocking the interaction of GM-CSF with its cell surface
receptor.1,8,9 Mavrilimumab targets the alpha subunit of the GM-CSF receptor, blocking intracellular
signaling of GM-CSF.8,10 None of these agents are currently FDA approved for any indication.
Recommendation
recommend either for or against the use of GM-CSF inhibitors for the treatment of hospitalized
patients with COVID-19.
Rationale
Clinical data are lacking to definitively establish the potential benefits and risks associated with the use
of GM-CSF inhibitors in patients with COVID-19. Data from a double-blind randomized controlled trial
of lenzilumab did show a significant improvement in the primary endpoint of ventilator-free survival
through Day 28 among those who received the GM-CSF inhibitor.11 However, preliminary data from a
large, double-blind randomized trial of otilimab (primary endpoint: alive and free of respiratory failure
at Day 28) and published results of a small, double-blind, randomized trial of mavrilimumab (primary
endpoint: proportion alive and off supplemental oxygen at Day 14) did not show a survival benefit for
the GM-CSF inhibitors compared to placebo.12-14 The study populations differed; the lenzilumab and
mavrilimumab studies primarily included patients on room air or low-flow oxygen and excluded patients
receiving mechanical ventilation, whereas the otilimab study included only patients receiving high-flow
oxygen, noninvasive ventilation, or mechanical ventilation. Lenzilumab and mavrilimumab continue to
be investigated, whereas clinical development of otilimab for the treatment of COVID-19 has ceased.

Lenzilumab, mavrilimumab, namilumab, and otilimab have been evaluated in clinical trials in
hospitalized adults with SARS-CoV-2 pneumonia.12-15 Clinical data are not yet published for
gimsilumab. The Panel’s recommendations are based on the results of the available clinical studies.
Selected clinical data on the use of anti-GM-CSF mAbs for the treatment of COVID-19 are summarized
in Table 4d.
Clinical Trials
See ClinicalTrials.gov for a list of ongoing clinical trials that are evaluating the use of GM-CSF

AR09005
inhibitors for the treatment of COVID-19.
Adverse Effects
The primary risks associated with GM-CSF inhibitors being reported and evaluated are related to
bacterial infection. Other adverse events that have been reported with these agents include acute
kidney injury and elevated liver transaminases.10 Autoimmune pulmonary alveolar proteinosis has been
associated with a high-titer of anti-GM-CSF auto-antibodies.16
Pregnant patients have been excluded from clinical trials evaluating GM-CSF inhibitors for the
treatment of COVID-19. There is insufficient evidence to recommend for or against their use in pregnant
individuals with COVID-19.
There are no data on the use of GM-CSF inhibitors in children.
References
1. Mehta P, Porter JC, Manson JJ, et al. Therapeutic blockade of granulocyte macrophage colony-stimulating
factor in COVID-19-associated hyperinflammation: challenges and opportunities. Lancet Respir Med.
2. Thwaites RS, Sanchez Sevilla Uruchurtu A, Siggins MK, et al. Inflammatory profiles across the spectrum of
disease reveal a distinct role for GM-CSF in severe COVID-19. Sci Immunol. 2021;6(57). Available at:
3. Hamilton JA. GM-CSF in inflammation and autoimmunity. Trends Immunol. 2002;23(8):403-408. Available
4. Lotfi N, Thome R, Rezaei N, et al. Roles of GM-CSF in the pathogenesis of autoimmune diseases: an update.
Front Immunol. 2019;10:1265. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31275302.
6. Zhou Y, Fu B, Zheng X, et al. Pathogenic T-cells and inflammatory monocytes incite inflammatory storms in
severe COVID-19 patients. Natl Sci Rev. 2020;7(6):998-1002. Available at:
7. De Luca G, Cavalli G, Campochiaro C, et al. GM-CSF blockade with mavrilimumab in severe COVID-19
pneumonia and systemic hyperinflammation: a single-centre, prospective cohort study. Lancet Rheumatol.
8. Lang FM, Lee KM, Teijaro JR, Becher B, Hamilton JA. GM-CSF-based treatments in COVID-19: reconciling
opposing therapeutic approaches. Nat Rev Immunol. 2020;20(8):507-514. Available at:
9. Temesgen Z, Assi M, Shweta FNU, et al. GM-CSF neutralization with lenzilumab in severe COVID-19
pneumonia: a case-cohort study. Mayo Clin Proc. 2020;95(11):2382-2394. Available at:
10. Burmester GR, Feist E, Sleeman MA, et al. Mavrilimumab, a human monoclonal antibody targeting GM-CSF
receptor-alpha, in subjects with rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase I,
first-in-human study. Ann Rheum Dis. 2011;70(9):1542-1549. Available at:
11. Temesgen Z, Burger CD, Baker J, et al. Lenzilumab in hospitalised patients with COVID-19 pneumonia

AR09006
(LIVE-AIR): a Phase 3, randomised, placebo-controlled trial. Lancet Respir Med. 2021. Available at:
12. Patel J, Beishuizen A, Ruiz XB, et al. A randomized trial of otilimab in severe COVID-19 pneumonia
(OSCAR). medRxiv. 2021. Available at: https://www.medrxiv.org/content/10.1101/2021.04.14.21255475v1.
13. Temesgen Z, Burger CD, Baker J, et al. Lenzilumab efficacy and safety in newly hospitalized COVID-19
subjects: results from the live-air Phase 3 randomized double-blind placebo-controlled trial. medRxiv. 2021.
14. Cremer PC, Abbate A, Hudock K, et al. Mavrilimumab in patients with severe COVID-19 pneumonia
and systemic hyperinflammation (MASH-COVID): an investigator initiated, multicentre, double-blind,
randomised, placebo-controlled trial. Lancet Rheumatol. 2021;3(6):e410-e418. Available at:
15. Fisher BA, Veenith T, Slade D, et al. Namilumab or infliximab compared with standard of care in hospitalised
patients with COVID-19 (CATALYST): a randomised, multicentre, multi-arm, multistage, open-label,
adaptive, Phase 2, proof-of-concept trial. Lancet Respir Med. 2021. Available at:
16. Chaulagain CP, Pilichowska M, Brinckerhoff L, Tabba M, Erban JK. Secondary pulmonary alveolar
proteinosis in hematologic malignancies. Hematol Oncol Stem Cell Ther. 2014;7(4):127-135. Available at:

AR09007
Table 4d. Granulocyte-Macrophage Colony-Stimulating Factor Inhibitors:

Selected Clinical Data
GM-CSF inhibitors. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations.
The information in this table may include data from preprints or articles that have not been peer reviewed. This section will be updated as new
information becomes available. Please see ClinicalTrials.gov for more information on clinical trials that are evaluating GM-CSF inhibitors.
LIVE-AIR: Double-Blind RCT of Lenzilumab in Hospitalized Patients With Severe COVID-19 Pneumonia in the United States and Brazil1,2
• Hospitalized with SARS-CoV-2 pneumonia • Mean age 61 years; 65% men; 72% White • Not powered to detect a survival
• SpO2 ≤94% on room air or required low-flow • 55% BMI ≥30 benefit
supplemental oxygen, HFNC oxygen, or NIV • At baseline: 41% received HFNC oxygen or NIV • Access to supportive care differed
across study sites
Key Exclusion Criteria: • 94% received corticosteroids; 72% received RDV; 69%
• MV or ECMO received corticosteroids and RDV Interpretation:
• Bacterial pneumonia, fungal or viral infection • Median CRP 79 mg/L • Lenzilumab improved ventilator-free
survival in participants with hypoxemia
• 48-hour survival not expected Primary Outcome: who were not receiving MV, with the
• Use of IL-1 inhibitors, IL-6 inhibitors, kinase inhibitors, • Survival without MV through Day 28: 84% in lenzilumab greatest benefit among those with
or mAbs within prior 8 weeks arm vs. 78% in placebo arm (HR 1.54; 95% CI, 1.02– lower CRP levels.
2.32; P = 0.040)
Interventions:
• 3 doses of lenzilumab 600 mg IV 8 hours apart (n = 236) Key Secondary Outcomes:
• Placebo (n = 243) • Mortality: 10% in lenzilumab arm vs. 14% in placebo arm
(HR 0.72; 95% CI, 0.42–1.23; P = 0.24)
Primary Endpoint:
• Incidence of death or requiring MV or ECMO: 15% in
• Survival without MV through Day 28 lenzilumab arm vs. 21% in placebo arm (HR 0.67; 95%
Key Secondary Endpoints: CI, 0.41–1.10; P = 0.11)
• Mortality Exploratory Outcome:
• Incidence of death or requiring MV or ECMO • Survival without MV for baseline CRP <150 mg/L: 90% in
lenzilumab arm vs. 79% in placebo arm (HR 2.54; 95%
Exploratory Endpoint:
CI, 1.46–4.41; P = 0.0009)
• Survival without MV, stratified by baseline CRP

AR09008
MASH-COVID: Double-Blind RCT of Mavrilimumab in Hospitalized Patients With Severe COVID-19 Pneumonia and Systemic Hyperinflammation in the United
States3
• Hospitalization with SARS-CoV-2 pneumonia • Median age 57 years; 65% men; 40% African American • Very small sample size
• SpO2 <92% on room air or required supplemental oxygen • At baseline: • Ended early due to slow enrollment
• CRP >5 mg/dL • 50% required HFNC oxygen or NIV Interpretation:
Key Exclusion Criteria: • 65% received corticosteroids • Among participants with systemic
• MV • 75% received RDV hyperinflammation and severe
COVID-19 pneumonia, there was no
• ANC <1,500/mm3 Primary Outcome: evidence that use of mavrilimumab
• Uncontrolled bacterial infection • Alive and off supplemental oxygen at Day 14: 57% in improved supplemental oxygen–free
mavrilimumab arm vs. 47% in placebo arm (OR 1.48; survival by Day 14.
Interventions:
95% CI, 0.43–5.16; P = 0.76)
• Mavrilimumab 6 mg/kg as single IV infusion (n = 21)
Key Secondary Outcomes:
• Mortality at Day 28: 1 (5%) in mavrilimumab arm vs. 3
Primary Endpoint: (16%) in placebo arm (HR 3.72; 95% CI, 0.39–35.79; P =
• Alive and off supplemental oxygen at Day 14 0.22)
Key Secondary Endpoints: • Alive without respiratory failure at Day 28: 95% in
mavrilimumab arm vs. 79% in placebo arm (OR 5.33;
• Mortality at Day 28
95% CI, 0.54–52.7; P = 0.43)
• Alive without respiratory failure at Day 28

AR09009
OSCAR: Double-Blind RCT of Otilimab in Patients With Severe COVID-19 Pneumonia in 17 Countries4
• Hospitalized with SARS-CoV-2 pneumonia • Mean age 59 years; 72% men; 66% White • Changes in SOC during study may
• Required HFNC oxygen, NIV, or MV ≤48 hours before • At baseline: have affected outcomes.
dosing • 77% received HFNC oxygen or NIV; 22% received MV Interpretation:
• CRP or ferritin >ULN • 83% received corticosteroids; 34% received RDV • For participants with severe COVID-19
Key Exclusion Criteria: pneumonia, use of otilimab did not
Primary Outcome: significantly reduce the probability of
• Death likely <48 hours • Alive and free of respiratory failure at Day 28: 71% in respiratory failure or death.
• Multiple organ failure otilimab arm vs. 67% in placebo arm (model-adjusted
• SOFA score >10 if in ICU difference 5.3%; 95% CI, -0.8 to 11.4; P = 0.09)
• ECMO Key Secondary Outcome:
• Dialysis • All-cause mortality at Day 60: 23% in otilimab arm vs.
• High-dose noradrenaline (>0.15 ug/kg/min) or equivalent 24% in placebo arm (model-adjusted difference -2.4%;
95% CI, -8.0 to 3.3; P = 0.41)
• >1 vasopressor
Interventions:
• Otilimab 90 mg IV as single infusion (n = 395)
Primary Endpoint:
• Alive and free of respiratory failure at Day 28
• All-cause mortality at Day 60
Key: ANC = absolute neutrophil count; BMI = body mass index; CRP = C-reactive protein; ECMO = extracorporeal membrane oxygenation; GM-CSF = granulocyte-
macrophage colony-stimulating factor; HFNC = high-flow nasal cannula; ICU = intensive care unit; IL = interleukin; IV = intravenous; mAb = monoclonal antibody; MV
= mechanical ventilation; NIV = noninvasive ventilation; RCT = randomized controlled trial; RDV = remdesivir; SOC = standard of care; SOFA = sequential organ failure
assessment; SpO2 = oxygen saturation; ULN = upper limit of normal
References
1. Temesgen Z, Burger CD, Baker J, et al. Lenzilumab in hospitalised patients with COVID-19 pneumonia (LIVE-AIR): a Phase 3, randomised, placebo-
controlled trial. Lancet Respir Med. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34863332.
2. Temesgen Z, Kelley CF, Cerasoli F, et al. Early lenzilumab treatment of COVID-19 patients using c-reactive protein as a biomarker improves efficacy:
results from the Phase 3 ‘LIVE-AIR’ trial. medRxiv. 2022;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.12.30.21267140v1.

AR09010
3. Cremer PC, Abbate A, Hudock K, et al. Mavrilimumab in patients with severe COVID-19 pneumonia and systemic hyperinflammation (MASH-
COVID): an investigator initiated, multicentre, double-blind, randomised, placebo-controlled trial. Lancet Rheumatol. 2021;3(6):e410-e418. Available
4. Patel J, Beishuizen A, Ruiz X, et al. A randomized trial of otilimab in severe COVID-19 pneumonia (OSCAR). medRxiv. 2021;Preprint. Available at:

AR09011
Immunoglobulins: Non-SARS-CoV-2 Specific

Recommendation
• The COVID-19 Treatment Guidelines Panel recommends against the use of non-severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific intravenous immunoglobulin
(IVIG) for the treatment of acute COVID-19, except in a clinical trial (AIII). This
recommendation should not preclude the use of IVIG when otherwise indicated for the treatment
of complications that arise during the course of COVID-19.
Rationale for Recommendation

It is unknown whether products derived from the plasma of donors without confirmed SARS-CoV-2
infection contain high titer of SARS-CoV-2 neutralizing antibodies. Furthermore, although other blood
components in IVIG may have general immunomodulatory effects, it is unclear whether these theoretical
effects will benefit patients with COVID-19.

This study has not been peer reviewed.
A retrospective, non-randomized cohort study of IVIG for the treatment of COVID-19 was conducted
across eight treatment centers in China between December 2019 and March 2020. The study showed no
difference in 28-day or 60-day mortality between 174 patients who received IVIG and 151 patients who
did not receive IVIG.1 More patients in the IVIG group had severe disease at study entry (71 patients
[41%] with critical status in the IVIG group vs. 32 patients [21%] in the non-IVIG group). The median
hospital stay was longer in the IVIG group (24 days) than in the non-IVIG group (16 days), and the
median duration of disease was also longer (31 days in the IVIG group vs. 23 days in the non-IVIG
group). A subgroup analysis that was limited to the critically ill patients suggested a mortality benefit at
28 days, which was no longer significant at 60 days.
The results of this study are difficult to interpret because of important limitations in the study design.
In particular, patients were not randomized to receive either IVIG or no IVIG, and the patients in the
IVIG group were older and more likely to have coronary heart disease than those in the non-IVG group.
In addition, the IVIG group had a higher proportion of patients with severe COVID-19 disease at study
entry. Patients in both groups also received many concomitant therapies for COVID-19.
IVIG is commonly used in pregnancy for other indications such as immune thrombocytopenia with an
acceptable safety profile.2,3
IVIG has been widely used in children for the treatment of a number of conditions. including Kawasaki
disease, and is generally safe.4 IVIG has been used in pediatric patients with COVID-19 and multiorgan
inflammatory syndrome in children (MIS-C), especially those with a Kawasaki disease-like presentation,
but the efficacy of IVIG in the management of MIS-C is still under investigation.

AR09012
References
1. Shao Z, Feng Y, Zhong L, et al. Clinical efficacy of intravenous immunoglobulin therapy in critical patients
with COVID-19: A multicenter retrospective cohort study. medRxiv. 2020;Preprint. Available at:
2. Committee on Practice Bulletins—Obstetrics. ACOG practice bulletin No. 207: thrombocytopenia in
pregnancy. Obstet Gynecol. 2019;133(3):e181-e193. Available at:
3. Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based practice
guideline for immune thrombocytopenia. Blood. 2011;117(16):4190-4207. Available at:
4. Agarwal S, Agrawal DK. Kawasaki disease: etiopathogenesis and novel treatment strategies. Expert Rev Clin
Immunol. 2017;13(3):247-258. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27590181.

AR09013
Interleukin-1 Inhibitors
Endogenous interleukin (IL)-1 is elevated in patients with COVID-19.1,2 In addition, SARS-CoV-2

infection causes epithelial damage that leads to the release of IL-1 beta, which recruits inflammatory
cells and induces the release of IL-1 beta in monocytes. This in turn leads to the release of more IL-1 to
recruit and activate additional innate immune cells. Drugs that block the IL-1 receptor (e.g., anakinra) or
drugs that block IL-1 signaling (e.g., canakinumab) can potentially interrupt this autoinflammatory loop.
These drugs are being investigated as potential treatments for COVID-19.
Anakinra is a recombinant human IL-1 receptor antagonist. It is approved by the Food and Drug
Administration (FDA) to treat rheumatoid arthritis and cryopyrin-associated periodic syndromes,
specifically neonatal-onset multisystem inflammatory disease.3 It is used off-label to treat severe
chimeric antigen receptor T cell-mediated cytokine release syndrome and macrophage activation
syndrome (MAS)/secondary hemophagocytic lymphohistiocytosis.
Canakinumab is a human monoclonal antibody that targets the beta subunit of IL-1 and is approved by
the FDA for the treatment of systemic juvenile idiopathic arthritis and Still’s disease.
Recommendations
recommend either for or against the use of anakinra for the treatment of COVID-19.
• The Panel recommends against the use of canakinumab for the treatment of COVID-19, except
in a clinical trial (BIIa).
Rationale
In the SAVE-MORE trial, 594 hospitalized patients who had moderate or severe COVID-19 pneumonia
and plasma-soluble urokinase plasminogen activator receptor (suPAR) levels ≥6 ng/mL were randomized
to receive either anakinra or placebo. The study found that patients who received anakinra had a lower
risk of clinical progression of COVID-19 than those who received placebo.4 CORIMUNO-ANA-1, a
randomized controlled trial that compared the use of anakinra to usual care in 116 hospitalized patients
who were hypoxemic but did not require high-flow oxygen or ventilation, was stopped early for futility.5
REMAP-CAP, an open-label, adaptive platform, randomized controlled trial that evaluated several
immunomodulators in patients with COVID-19 who required organ support, found that anakinra was not
effective in reducing the combined endpoint of in-hospital mortality and days of organ support.6 Although
the SAVE-MORE study suggests that suPAR levels could be used in risk stratification to identify
populations that could benefit from IL-1 inhibition, the laboratory assay that is used to assess suPAR levels
is not currently available in many countries, including the United States. After reviewing the results of the
studies discussed above and taking into consideration the fact that suPAR assays are not widely available
to guide the use of anakinra, the Panel has concluded that there is insufficient evidence to recommend
either for or against the use of anakinra for the treatment of COVID-19 in hospitalized patients.
Finally, CAN-COVID, a randomized controlled trial that evaluated canakinumab in hospitalized patients
with COVID-19 who were hypoxemic but did not require ventilatory support, reported that the use
of canakinumab did not improve the likelihood of survival without invasive mechanical ventilation.7
Because of these results, the Panel recommends against the use of canakinumab for the treatment of
COVID-19, except in a clinical trial (BIIa).

AR09014

SAVE-MORE
SAVE-MORE was a randomized controlled trial in 594 hospitalized patients with moderate or severe
COVID-19 pneumonia and plasma suPAR levels ≥6 ng/mL. Patients who required noninvasive or
invasive mechanical ventilation were excluded from the study. Patients were randomized 2:1 to receive
anakinra 100 mg subcutaneously once daily for 10 days or placebo. The primary endpoint was clinical
status at Day 28 on the 11-point World Health Organization Clinical Progression Scale (WHO-CPS).4
Results
• Patients who were randomized to receive anakinra had a lower odds of progression of COVID-19
on the WHO-CPS (OR 0.36; 95% CI, 0.26–0.50; P < 0.0001).
• The secondary endpoints also favored anakinra, including the absolute decrease in WHO-CPS
scores from baseline at Days 14 and 28, the absolute decrease in Sequential Organ Failure
Assessment scores from baseline at Day 7, the median time to hospital discharge, and the median
duration of intensive care unit (ICU) stays.
• A smaller proportion of patients in the anakinra arm experienced secondary infections, including
ventilator-associated pneumonias, than in the placebo arm (8.4% vs. 15.9%; P = 0.01).
• Twenty-eight-day mortality was lower among patients who received anakinra than those who
received placebo (3.2% vs. 6.9%; HR 0.45; 95% CI, 0.21–0.98; P = 0.045).
Limitations
• The laboratory assay that is used to assess suPAR levels is not currently available in many
countries, including the United States.
REMAP-CAP
The REMAP-CAP trial is an open-label, adaptive platform trial in which eligible participants are
randomized to several domains, including the Immune Modulation Therapy domain, which consists
of two IL-6 inhibitors, anakinra, interferon beta-1a, and a control group. Participants are eligible for
enrollment if they are within 24 hours of receiving respiratory or cardiovascular organ support in the
ICU and they have suspected or microbiologically confirmed COVID-19.
Anakinra 300 mg was given intravenously (IV) as a loading dose, followed by anakinra 100 mg IV every
6 hours for 14 days until patients were either free from invasive mechanical ventilation for >24 hours
or discharged from the ICU. The primary outcome was measured using an ordinal scale that included
a composite of in-hospital mortality and duration of respiratory and cardiovascular organ support at 21
days; all deaths up to 90 days were assigned the worst outcome. The trial used a Bayesian design that
allowed the authors to compare nonconcurrently randomized interventions across time periods.6
Results
• Of the 2,274 participants who were randomized to one of the arms in the Immune Modulation
Therapy domain, 365 individuals were assigned to receive anakinra and included in the analysis,
406 were assigned to the usual care (control) arm, 943 were assigned to receive tocilizumab, and
483 were assigned to receive sarilumab.
• Of those assigned to receive anakinra, 37% were receiving invasive mechanical ventilation at
study entry compared with 32% of patients in the other arms. The other patients received oxygen
through a high-flow nasal cannula or noninvasive ventilation, with a few exceptions.
• The median number of organ support-free days was similar for patients who received anakinra and

AR09015
those who received usual care (0 days [IQR 1–15 days] vs. 0 days [IQR -1 to 15 days]). The aOR
for organ support-free days was 0.99 for anakinra (95% CrI, 0.74–1.35), with a 46.6% posterior
probability of superiority to control. Sixty percent of those who were assigned to receive anakinra
survived compared to 63% of those who were assigned to the control arm, with a 43.6% posterior
probability that anakinra was superior to usual care.
• The risk of experiencing serious adverse events was similar between the arms.
Limitations
• Patients were not randomized contemporaneously to receive anakinra or usual care; the treatment
effect was estimated from an overarching model that mostly included patients who were
randomized to receive an IL-6 inhibitor (tocilizumab or sarilumab) or usual care, and patients
who were randomized to receive an IL-6 inhibitor or anakinra. Thus, the estimate of the treatment
effect is not fully protected by randomization.
• This study had an open-label design.
CORIMUNO-ANA-1
The CORIMUNO-ANA-1 trial randomized 116 hospitalized patients with COVID-19 pneumonia 1:1
to receive either usual care plus anakinra (200 mg IV twice a day on Days 1–3, 100 mg IV twice on
Day 4, and 100 mg IV once on Day 5) or usual care alone. Patients were eligible for enrollment if they
had laboratory-confirmed SARS-CoV-2 infection with COVID-19 pneumonia and they required >3 L/
min of supplemental oxygen. Patients who required high-flow oxygen, ventilation, or ICU admission
were excluded. The two coprimary outcomes were the proportion of patients who had died or who
needed noninvasive or invasive mechanical ventilation by Day 4 (score of >5 on the WHO-CPS) and the
proportion who survived without the need for noninvasive or invasive mechanical ventilation (including
high-flow oxygen) by Day 14.5
Results
• There was no difference between the anakinra plus usual care arm and the usual care alone arm in
the two coprimary outcomes: by Day 4, 36% of patients in the anakinra arm had died or required
high-flow oxygen or ventilation compared with 38% in the usual care arm (90% CrI, -17.1 to 12.0,
posterior probability of benefit 61%). By Day 14, 47% of patients in the anakinra arm had died or
required noninvasive or invasive mechanical ventilation compared to 51% in the usual care arm
(median HR 0.97; 90% CrI, 0.62–1.52; posterior probability of benefit 55%).
• Fifty-two percent of patients received corticosteroids at study entry.
• Serious adverse events occurred in 46% of patients in the anakinra arm compared to 38% in the
usual care arm; 11 of 59 patients (18.6%) in the anakinra arm experienced bacterial or fungal
infections compared to 4 of 55 patients (7.3%) who received usual care.
Limitations
• The limitations of this study include the small sample size, narrow eligibility criteria, and the
fact that many patients did not receive current standard-of-care therapy (e.g., corticosteroids,
remdesivir).
CAN-COVID
CAN-COVID was a double-blind, placebo-controlled randomized trial of 454 hospitalized patients with
COVID-19 who were hypoxemic but not mechanically ventilated and had elevated C-reactive protein
(≥ 20 mg/L) or ferritin (≥600 micrograms/L) levels. Patients were randomized 1:1 to receive a single
dose of IV canakinumab (450 mg for a body weight of 40 kg to <60 kg, 600 mg for 60–80 kg, and 750

AR09016
mg for >80 kg) or placebo. The primary outcome was survival without the need for invasive mechanical
ventilation from Days 3 through 29.7
Results
• There was no statistical difference between the canakinumab arm and placebo arm in the
proportion of patients who survived without invasive mechanical ventilation (88.8% vs. 85.7%; P
= 0.29).
• The number of COVID-19-related deaths at 4 weeks was similar for the two arms (11 of 223
patients [4.9%] in the canakinumab arm vs. 16 of 222 patients [7.2%] in the placebo arm; OR
0.67; 95% CI, 0.30–1.50).
• Forty-one percent of patients in the canakinumab arm and 32% in the placebo arm received
dexamethasone.
• Serious adverse events occurred in 16% of patients who received canakinumab and in 20.6% of
patients who received placebo.
Limitations
• The use of corticosteroids was unbalanced in this study, with more patients receiving
dexamethasone at baseline in the canakinumab arm than in the placebo arm.
• More patients received dexamethasone after the trial was underway in the placebo arm than in the
canakinumab arm (22.5% vs. 14.5%), and more patients received tocilizumab in the placebo arm
than in the canakinumab arm (8.8% vs. 2.2%).
Other small cohort studies, case-control studies, and case series have reported mixed findings with
regard to improvement in outcomes among patients who received anakinra for the treatment of COVID-
19.8-11 The clinical implication of these findings is uncertain due to small sample sizes and unmeasured
confounding factors. Therefore, these studies did not substantially influence the Panel’s current
recommendations for using IL-1 inhibitors.
Clinical Trials
See ClinicalTrials.gov for a list of clinical trials that are evaluating anakinra and canakinumab for the
Adverse Effects
Headache, nausea, vomiting, and liver enzyme elevations can occur with both anakinra and
canakinumab.
Anakinra was not associated with any significant safety concerns when used in clinical trials for the
treatment of sepsis.12-14 Increased rates of infection were reported with prolonged anakinra use in
combination with tumor necrosis factor-alpha blockade, but not with short-term use.15
The data on using IL-1 inhibitors to treat COVID-19 in pregnant patients are currently limited. The
American College of Rheumatology recommends against the use of anakinra during pregnancy.16
Unintentional first-trimester exposure to anakinra is unlikely to be harmful, given the minimal transfer
of monoclonal antibodies across the placenta early in pregnancy.17

AR09017
Anakinra has been used in the treatment of severely ill children with rheumatologic conditions,
including MAS. The data on the use of anakinra in pediatric patients with acute respiratory distress
syndrome or sepsis are limited. Anakinra is rarely used to treat pediatric patients with acute COVID-19,
and it has been used in approximately 10% of cases of multisystem inflammatory syndrome in children
(MIS-C).18,19 Anakinra is often included in institutional protocols for the treatment of MIS-C in the
United States, and it is mentioned as an option for second-line therapy for refractory MIS-C in national
consensus guidelines.20-22 However, robust data on the effectiveness of anakinra for the treatment of
MIS-C are not currently available. Data on using canakinumab in pediatric patients are limited to use in
patients with periodic fever syndromes and systemic juvenile idiopathic arthritis. There are no data on
its use in pediatric patients with acute COVID-19 or MIS-C. The Panel recommends consulting with a
multidisciplinary team when using immunomodulating therapy (which may include anakinra) in children
with MIS-C (AIII).
References
1. Shakoory B, Carcillo JA, Chatham WW, et al. Interleukin-1 receptor blockade is associated with reduced
mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior Phase III
trial. Crit Care Med. 2016;44(2):275-281. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26584195.
2. Monteagudo LA, Boothby A, Gertner E. Continuous intravenous anakinra infusion to calm the cytokine storm
in macrophage activation syndrome. ACR Open Rheumatol. 2020;2(5):276-282. Available at:
3. Anakinra (Kineret) [package insert]. Food and Drug Administration. 2012. Available at:
4. Kyriazopoulou E, Poulakou G, Milionis H, et al. Early treatment of COVID-19 with anakinra guided by
soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial.
Nat Med. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34480127.
5. CORIMUNO-19 Collaborative Group. Effect of anakinra versus usual care in adults in hospital with
COVID-19 and mild-to-moderate pneumonia (CORIMUNO-ANA-1): a randomised controlled trial. Lancet
Respir Med. 2021;9(3):295-304. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33493450.
7. Caricchio R, Abbate A, Gordeev I, et al. Effect of canakinumab vs placebo on survival without invasive
mechanical ventilation in patients hospitalized with severe COVID-19: a randomized clinical trial. JAMA.
8. Aouba A, Baldolli A, Geffray L, et al. Targeting the inflammatory cascade with anakinra in moderate to severe
COVID-19 pneumonia: case series. Ann Rheum Dis. 2020;79(10):1381-1382. Available at:
9. Cavalli G, De Luca G, Campochiaro C, et al. Interleukin-1 blockade with high-dose anakinra in patients with
COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet
Rheumatol. 2020;2(6):e325-e331. Available at: https://pubmed.ncbi.nlm.nih.gov/32501454/.
10. Huet T, Beaussier H, Voisin O, et al. Anakinra for severe forms of COVID-19: a cohort study. Lancet
Rheumatol. 2020;2(7):e393-e400. Available at: https://pubmed.ncbi.nlm.nih.gov/32835245/.
11. Kooistra EJ, Waalders NJB, Grondman I, et al. Anakinra treatment in critically ill COVID-19 patients: a
prospective cohort study. Crit Care. 2020;24(1):688. Available at:

AR09018
12. Fisher CJ, Jr., Dhainaut JF, Opal SM, et al. Recombinant human interleukin 1 receptor antagonist in the
treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial.
Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA. 1994;271(23):1836-1843. Available at:
13. Fisher CJ, Jr., Slotman GJ, Opal SM, et al. Initial evaluation of human recombinant interleukin-1 receptor
antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial.
Crit Care Med. 1994;22(1):12-21. Available at: https://www.ncbi.nlm.nih.gov/pubmed/8124953.
14. Opal SM, Fisher CJ Jr, Dhainaut JF, et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis:
a Phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor
Antagonist Sepsis Investigator Group. Crit Care Med. 1997;25(7):1115-1124. Available at:
15. Winthrop KL, Mariette X, Silva JT, et al. ESCMID Study Group for Infections in Compromised Hosts
(ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases
perspective (soluble immune effector molecules [II]: agents targeting interleukins, immunoglobulins and
complement factors). Clin Microbiol Infect. 2018;24 Suppl 2:S21-S40. Available at:
16. Sammaritano LR, Bermas BL, Chakravarty EE, et al. 2020 American College of Rheumatology guideline
for the management of reproductive health in rheumatic and musculoskeletal diseases. Arthritis Rheumatol.
17. Flint J, Panchal S, Hurrell A, et al. BSR and BHPR guideline on prescribing drugs in pregnancy and
breastfeeding-part II: analgesics and other drugs used in rheumatology practice. Rheumatology (Oxford).
18. Gotzinger F, Santiago-Garcia B, Noguera-Julian A, et al. COVID-19 in children and adolescents in Europe: a
multinational, multicentre cohort study. Lancet Child Adolesc Health. 2020;4(9):653-661. Available at:
19. Derespina KR, Kaushik S, Plichta A, et al. Clinical manifestations and outcomes of critically ill children and
adolescents with coronavirus disease 2019 in New York City. J Pediatr. 2020;Published online ahead of print.
20. Dove ML, Jaggi P, Kelleman M, et al. Multisystem inflammatory syndrome in children: survey of protocols
for early hospital evaluation and management. J Pediatr. 2021;229:33-40. Available at:
21. Henderson LA, Canna SW, Friedman KG, et al. American College of Rheumatology clinical guidance for
multisystem inflammatory syndrome in children associated with SARS-CoV-2 and hyperinflammation in
pediatric COVID-19: version 2. Arthritis Rheumatol. 2021;73(4):e13-e29. Available at:
22. Harwood R, Allin B, Jones CE, et al. A national consensus management pathway for paediatric inflammatory
multisystem syndrome temporally associated with COVID-19 (PIMS-TS): results of a national Delphi
process. Lancet Child Adolesc Health. 2021;5(2):133-141. Available at:

AR09019
Interleukin (IL)-6 is a pleiotropic, proinflammatory cytokine produced by a variety of cell types, including
lymphocytes, monocytes, and fibroblasts. Infection by SARS-CoV induces a dose-dependent production
of IL-6 from bronchial epithelial cells.1 COVID-19-associated systemic inflammation and hypoxemic
respiratory failure can be associated with heightened cytokine release, as indicated by elevated blood levels
of IL-6, C-reactive protein (CRP), D-dimer, and ferritin.2-4 It is hypothesized that modulating IL-6 levels or
the effects of IL-6 may reduce the duration and/or severity of COVID-19.
There are 2 classes of Food and Drug Administration (FDA)-approved IL-6 inhibitors: anti-IL-6 receptor
monoclonal antibodies (mAbs) (e.g., sarilumab, tocilizumab) and anti-IL-6 mAbs (i.e., siltuximab). These
drugs have been evaluated in patients with COVID-19 who have systemic inflammation.
Recommendations
• See Therapeutic Management of Hospitalized Adults With COVID-19 for the COVID-19 Treatment
Guidelines Panel’s (the Panel) recommendations on the use of IL-6 inhibitors (e.g., sarilumab,
tocilizumab) in hospitalized patients who require supplemental oxygen, high-flow oxygen,
noninvasive ventilation (NIV), or mechanical ventilation.
• The Panel recommends against the use of anti-IL-6 mAb therapy (i.e., siltuximab) for the treatment
of COVID-19, except in a clinical trial (BIII).
• Tocilizumab and sarilumab should be used with caution in patients with COVID-19 who have
not been adequately represented in clinical trials. This includes patients who are significantly
immunosuppressed, particularly those who have recently received other biologic immunomodulating
drugs, and patients with any of the following:
• Alanine transaminase levels >5 times the upper limit of normal
• A high risk for gastrointestinal perforation
• An uncontrolled serious bacterial, fungal, or non-SARS-CoV-2 viral infection
• Absolute neutrophil counts <500 cells/µL
• Platelet counts <50,000 cells/µL
• Known hypersensitivity to tocilizumab or sarilumab
• Tocilizumab and sarilumab should only be given in combination with a course of dexamethasone
(or an alternative corticosteroid at a dose that is equivalent to dexamethasone 6 mg). See the
Corticosteroids section for more information.
• Some clinicians may assess the patient’s clinical response to dexamethasone before deciding whether
tocilizumab or sarilumab is needed.
• In both the REMAP-CAP and the RECOVERY trials, 29% of patients received a second dose of
tocilizumab at the discretion of their treating physician. However, there is currently insufficient
evidence to recommend either for or against a second dose of tocilizumab.5,6
treatment (e.g., with the antiparasitic drug ivermectin) with or without serologic testing in patients who
are from areas where Strongyloides is endemic (i.e., tropical, subtropical, or warm temperate areas).9

AR09020
Rationale
The results of the RECOVERY and REMAP-CAP trials provide consistent evidence that tocilizumab,
when coadministered with corticosteroids, offers a modest mortality benefit in certain patients with
COVID-19 who are severely ill, who are rapidly deteriorating and have increasing oxygen needs, and
who have a significant inflammatory response.5,6 However, the Panel found it challenging to define the
specific patient populations that would benefit from this intervention. If tocilizumab is not available,
sarilumab may be used as an alternative because it has demonstrated a similar clinical benefit in
improving survival and reducing the duration of organ support in the REMAP-CAP trial.10 However, the
Panel recommends sarilumab only when tocilizumab is not available or is not feasible to use (BIIa)
because the evidence of efficacy for tocilizumab is more extensive than for sarilumab; in addition,
sarilumab is currently only approved for use as a subcutaneous (SQ) injection in the United States.
The data on the efficacy of siltuximab in patients with COVID-19 are currently limited.11
Anti-Interleukin-6 Receptor Monoclonal Antibodies

Tocilizumab
Tocilizumab is a recombinant humanized anti-IL-6 receptor mAb that is approved by the FDA for use
in patients with rheumatologic disorders and cytokine release syndrome induced by chimeric antigen
receptor T cell (CAR T-cell) therapy. Tocilizumab can be dosed as an intravenous (IV) infusion or an SQ
injection. The IV formulation should be used to treat cytokine release syndrome.11
Clinical data on the use of tocilizumab (and other IL-6 inhibitors) for the treatment of COVID-19,
including data from several randomized trials and large observational studies, are summarized in Table
4e.
The initial studies that evaluated the use of tocilizumab for the treatment of COVID-19 produced
conflicting results. Many of these trials were limited by low power, heterogenous populations, and/or a
low frequency of concomitant use of corticosteroids (now the standard of care for patients with severe
COVID-19).12-16
Subsequently, in the setting of background corticosteroid therapy, the 2 largest randomized controlled
trials evaluating tocilizumab, REMAP-CAP and RECOVERY, both reported a mortality benefit of
tocilizumab in certain patients, including patients exhibiting rapid respiratory decompensation associated
with an inflammatory response. REMAP-CAP enrolled critically ill patients who were within 24 hours
of receiving respiratory support in an intensive care unit. The participants were randomized to receive
open-label tocilizumab or usual care. In-hospital mortality was 28% in the tocilizumab arm and 36%
in the usual care arm.5 The RECOVERY trial enrolled hospitalized patients with COVID-19 into an
open-label platform trial that included several treatment options.6 A subset of all trial participants
who had hypoxemia and CRP levels ≥75 mg/L were offered enrollment into a second randomization
that evaluated tocilizumab versus usual care. In this subgroup, the 28-day mortality was 31% in the
tocilizumab arm and 35% in the usual care arm. For additional findings from the REMAP-CAP and
RECOVERY trials and the rationale for using tocilizumab in certain hospitalized patients who are
exhibiting rapid respiratory decompensations due to COVID-19, see Therapeutic Management of
In contrast to the REMAP-CAP and RECOVERY trials, the REMDACTA trial did not find a mortality
benefit of tocilizumab. The trial randomized hospitalized COVID-19 patients, most of whom required
NIV or high-flow oxygen support, to receive tocilizumab or placebo. All the participants received

AR09021
remdesivir and most received corticosteroids. Tocilizumab use did not reduce 28-day mortality (18% in
the tocilizumab arm and 20% in the placebo arm).17
Despite this conflicting evidence, the Panel’s recommendations for using tocilizumab are based on the
collective evidence from the clinical trials reported to date (see Table 4e).
Clinical Trials
See ClinicalTrials.gov for a list of clinical trials that are evaluating the use of tocilizumab for the
Adverse Effects
The primary laboratory abnormalities reported with tocilizumab treatment are elevated liver enzyme
levels that appear to be dose dependent. Neutropenia or thrombocytopenia are uncommon. In randomized
trials, no excess secondary infections were seen among patients who received combination therapy
compared to control patients. Additional adverse effects of tocilizumab, such as serious infections (e.g.,
tuberculosis [TB], bacterial or fungal infections) and bowel perforation, have been reported.18
There are insufficient data to determine whether there is a tocilizumab-associated risk for major birth
defects or miscarriage. mAbs are actively transported across the placenta as pregnancy progresses (with
the greatest transfer occurring during the third trimester), and this may affect immune responses in the
exposed fetus. Given the paucity of data, current recommendations advise against the use of tocilizumab
during pregnancy.19 Whether to use tocilizumab during pregnancy should be a joint decision between
the pregnant individual and their health care provider, and the decision-making process should include a
discussion of the potential risks and benefits.
There are no systematic observational or randomized controlled trial data on the effectiveness of
tocilizumab for the treatment of acute COVID-19 in pediatric patients or multisystem inflammatory
syndrome in children (MIS-C). Tocilizumab has been used for children with cytokine release syndrome
associated with CAR T-cell therapy and systemic and polyarticular juvenile idiopathic arthritis.20 There
is insufficient evidence for the Panel to recommend either for or against the use of tocilizumab in
hospitalized children with COVID-19 or MIS-C.
Drug Availability
On June 24, 2021, the FDA issued an Emergency Use Authorization (EUA) for the use of tocilizumab in
combination with corticosteroids in hospitalized adults and children aged ≥2 years with COVID-19 who
require supplemental oxygen, NIV, mechanical ventilation, or extracorporeal membrane oxygenation.20
Per this EUA, if a patient’s clinical signs or symptoms worsen or do not improve after the first dose of
tocilizumab, 1 additional infusion of tocilizumab may be administered at least 8 hours after the initial IV
infusion. If there is a local or regional shortage of tocilizumab, sarilumab can be used as an alternative
(see Therapeutic Management of Hospitalized Adults With COVID-19).10
Sarilumab
Sarilumab is a recombinant humanized anti-IL-6 receptor mAb that is approved by the FDA for use
in patients with rheumatoid arthritis. It is available as an SQ formulation and is not approved for the
treatment of cytokine release syndrome.
The clinical data on the use of sarilumab as a treatment for COVID-19 are summarized in Table 4e.

AR09022
An adaptive Phase 2 and 3 double-blind randomized (2:2:1) placebo-controlled trial compared the
efficacy and safety of sarilumab 400 mg IV and sarilumab 200 mg IV to placebo in hospitalized patients
with COVID-19 (ClinicalTrials.gov Identifier NCT04315298). Results from this trial did not support a
clinical benefit of sarilumab in hospitalized patients receiving supplemental oxygen.21
A similar adaptive design study in the United States in patients with severe and critical COVID-19
also failed to show a benefit of sarilumab. In this placebo-controlled trial, there was a reduction in
mortality among the sarilumab recipients with critical COVID-19 pneumonia who required mechanical
ventilation and received corticosteroids at baseline. However, due to the small sample size, this result
was not statistically significant.22 In the REMAP-CAP trial, the efficacy results for sarilumab were
similar to those for tocilizumab. Compared to the patients in the standard of care arm (n = 418), those
in the sarilumab arm (n = 485) had more organ support-free days (OR 1.50; 95% CrI, 1.13–2.00) and a
greater likelihood of survival while hospitalized (OR 1.51; 95% CrI, 1.06–2.20). A notable limitation to
the sarilumab findings in the REMAP-CAP trial is that patients in the standard of care arm were enrolled
earlier in the pandemic than those in the sarilumab arm: randomization closed on November 2020 for the
standard of care arm and continued through April 2021 for the sarilumab arm.10
Clinical Trials
See ClinicalTrials.gov for a list of clinical trials that are evaluating the use of sarilumab for the treatment
of COVID-19.
Adverse Effects
The primary laboratory abnormalities that have been reported with sarilumab treatment are transient
and/or reversible elevations in liver enzyme levels that appear to be dose dependent and rare occurrences
of neutropenia and thrombocytopenia. Additional adverse effects, such as serious infections (e.g., TB,
bacterial or fungal infections) and bowel perforation, have been reported, but only with long-term use of
sarilumab.
There are insufficient data to determine whether there is a sarilumab-associated risk for major birth
defects or miscarriage. mAbs are actively transported across the placenta as pregnancy progresses (with
the greatest transfer occurring during the third trimester), and this may affect immune responses in the
exposed fetus.
The only data on sarilumab use in children are from ongoing trials evaluating the drug’s safety in
children with juvenile idiopathic arthritis. There are no systematic observational or randomized
controlled trial data on the efficacy of sarilumab for the treatment of pediatric COVID-19 or MIS-C.
Drug Availability
The IV formulation of sarilumab is not approved by the FDA, but in a clinical trial, a single SQ dose
(using the prefilled syringe, not the prefilled pen) of sarilumab 400 mg was reconstituted in 100 cc 0.9%
NaCl and given as an IV infusion over a 1-hour period.
Anti-Interleukin-6 Monoclonal Antibody

Siltuximab
Siltuximab is a recombinant human-mouse chimeric mAb that binds IL-6 and is approved by the FDA
for use in patients with multicentric Castleman disease. Siltuximab prevents the binding of IL-6 to both
soluble and membrane-bound IL-6 receptors, inhibiting IL-6 signaling. Siltuximab is dosed as an IV
infusion.

AR09023

There are limited data on the efficacy of siltuximab in patients with COVID-19.23 There are no data
describing clinical experiences using siltuximab for patients with other novel coronavirus infections (i.e.,
severe acute respiratory syndrome [SARS], Middle East respiratory syndrome [MERS]).
Clinical Trials
See ClinicalTrials.gov for a list of clinical trials that are evaluating the use of siltuximab for the
Adverse Effects
The primary adverse effects reported for siltuximab have been related to rash. Additional adverse effects
(e.g., serious bacterial infections) have been reported only with long-term dosing of siltuximab once
every 3 weeks.
There are insufficient data to determine whether there is a siltuximab-associated risk for major birth
defects or miscarriage. mAbs are transported across the placenta as pregnancy progresses (with the
greatest transfer occurring during the third trimester), and this may affect immune responses in the
exposed fetus.
The safety and efficacy of siltuximab have not been established in pediatric patients.
References
1. Yoshikawa T, Hill T, Li K, Peters CJ, Tseng CT. Severe acute respiratory syndrome (SARS) coronavirus-
induced lung epithelial cytokines exacerbate SARS pathogenesis by modulating intrinsic functions of
monocyte-derived macrophages and dendritic cells. J Virol. 2009;83(7):3039-3048. Available at:
2. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in
Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-1062. Available at:
4. Wang Z, Yang B, Li Q, Wen L, Zhang R. Clinical features of 69 cases with coronavirus disease 2019 in
Wuhan, China. Clin Infect Dis. 2020;71(15):769-777. Available at:

AR09024

11. Le RQ, Li L, Yuan W, et al. FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T
cell-induced severe or life-threatening cytokine release syndrome. Oncologist. 2018;23(8):943-947. Available
12. Stone JH, Frigault MJ, Serling-Boyd NJ, et al. Efficacy of tocilizumab in patients hospitalized with
13. Gupta S, Wang W, Hayek SS, et al. Association between early treatment with tocilizumab and mortality among
critically ill patients with COVID-19. JAMA Intern Med. 2021;181(1):41-51. Available at:
14. Hermine O, Mariette X, Tharaux PL, et al. Effect of tocilizumab vs usual care in adults hospitalized
with COVID-19 and moderate or severe pneumonia: a randomized clinical trial. JAMA Intern Med.
15. Salama C, Han J, Yau L, et al. Tocilizumab in patients hospitalized with COVID-19 pneumonia. N Engl J
16. Rosas IO, Brau N, Waters M, et al. Tocilizumab in hospitalized patients with severe COVID-19 pneumonia. N
17. Rosas IO, Diaz G, Gottlieb RL, et al. Tocilizumab and remdesivir in hospitalized patients with severe
COVID-19 pneumonia: a randomized clinical trial. Intensive Care Med. 2021;47(11):1258-1270. Available at:
18. Charan J, Dutta S, Kaur R, et al. Tocilizumab in COVID-19: a study of adverse drug events reported in the
WHO database. Expert Opin Drug Saf. 2021;20(9):1125-1136. Available at:
20. Food and Drug Administration. Letter of authorization: EUA for tocilizumab (Actemra) for the treatment of
coronavirus disease 2019 (COVID-19). 2021. Available at: https://www.fda.gov/media/150319/download.
21. Lescure FX, Honda H, Fowler RA, et al. Sarilumab in patients admitted to hospital with severe or critical
COVID-19: a randomised, double-blind, placebo-controlled, Phase 3 trial. Lancet Respir Med. 2021;9(5):522-
22. Sivapalasingam S, Lederer DJ, Bhore R, et al. Efficacy and safety of sarilumab in hospitalized patients with
COVID-19: a randomized clinical trial. Clin Infect Dis. 2022;Published online ahead of print. Available at:
23. Gritti G, Raimondi F, Ripamonti D, et al. IL-6 signalling pathway inactivation with siltuximab in patients with
COVID-19 respiratory failure: an observational cohort study. medRxiv. 2020;Preprint. Available at:

AR09025
Table 4e. Interleukin-6 Inhibitors: Selected Clinical Data

Last Updated December 16, 2021
The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations for IL-6
inhibitors. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations.
RECOVERY Trial: Open-Label RCT of Tocilizumab and Usual Care in Hospitalized Patients With COVID-191
• SpO2 <92% on room air or receipt of • Mean age 63.6 years; 67% men; 76% White • Arbitrary enrollment cut off at CRP ≥75 mg/L
supplemental oxygen • 95% had PCR-confirmed SARS-CoV-2 • Difficult to define exact subset of patients in RECOVERY
• CRP ≥75 mg/L infection cohort who were subsequently selected for secondary
• At baseline: randomization/tocilizumab trial
• Non-SARS-CoV-2 infection • 45% on conventional oxygen Interpretation:
• 41% on HFNC oxygen or NIV • Among hospitalized COVID-19 patients with hypoxemia
Interventions:
• 14% on MV and elevated CRP, tocilizumab was associated with
• Single weight-based dose of tocilizumab reduced all-cause mortality and shorter time to discharge.
(maximum 800 mg) and possible second dose (n • 82% on corticosteroids
= 2,022) Primary Outcomes:
• Usual care (n = 2,094) • Day 28 mortality was lower in tocilizumab arm
Primary Endpoint: than in usual care arm (31% vs. 35%; rate ratio
• 28-day all-cause mortality 0.85; 95% CI, 0.76–0.94; P = 0.003).
• Among those who required MV at baseline,
Day 28 mortality was similar between arms
• Time to discharge alive within 28 days (49% in tocilizumab arm vs. 51% in usual care
• Among those not on MV at enrollment, receipt of arm; risk ratio 0.93; 95% CI, 0.74–1.18).
MV or death within 28 days Secondary Outcomes:
• Proportion of patients discharged alive within
28 days was greater in tocilizumab arm than
usual care arm (57% vs. 50%; rate ratio 1.22;
95% CI, 1.12–1.33; P < 0.0001).
• Proportion of patients not on MV at baseline
who died or required MV within 28 days was
lower in tocilizumab arm than usual care
arm (35% vs. 42%; rate ratio 0.84; 95% CI,
0.77–0.92; P < 0.0001).

AR09026
REMAP-CAP: Open-Label, Adaptive-Platform RCT of Tocilizumab and Sarilumab in Patients With COVID-192,3
• ICU admission • Mean age 60 years; 69% men; 75% White • Enrollment in tocilizumab and sarilumab arms was
• Suspected or laboratory-confirmed COVID-19 • 86% had PCR-confirmed SARS-CoV-2 infection partially nonconcurrent with SOC arm; while the
comparisons to SOC arm were adjusted for time period,
• Receipt of MV, NIV, or cardiovascular support • Median time from ICU admission until there is a possibility of bias
enrollment was 14 hours
• At baseline:
• >24 hours since ICU admission • Among patients with respiratory failure who were within
• 67% on HFNC oxygen or NIV
• Presumption of imminent death 24 hours of ICU admission, the tocilizumab and sarilumab
• 33% on MV arms had higher rates of in-hospital survival and shorter
• Immunosuppression
• 67% on corticosteroids in SOC arm, 82% in durations of organ support than the SOC arm.
• ALT >5 times ULN
tocilizumab arm, and 89% in sarilumab arm • The treatment effect appeared to be strongest in the
Interventions: highest CRP tercile.
Primary Outcomes
• Single dose of tocilizumab 8 mg/kg IV and • Tocilizumab and sarilumab were similarly effective, with a
Tocilizumab Versus SOC:
possible second dose in 12–24 hours, plus SOC 99% probability of noninferiority of sarilumab.
(n = 952) • Median number of organ support-free days was
7 in tocilizumab arm and 0 in SOC arm.
• Single dose of sarilumab 400 mg IV plus SOC (n
= 485) • Median adjusted OR for ordinal scale was 1.46
(95% CrI, 1.13–1.87).
• SOC (n = 406)
• In highest CRP tercile, aOR was 1.87 (95% CrI,
Randomization: 1.35–2.59).
• Adaptative randomization. Patients were • Outcomes were consistent across subgroups
randomized to receive SOC only, SOC plus according to oxygen requirement at baseline.
tocilizumab, or SOC plus sarilumab based on
provider preference, availability, or adaptive Sarilumab Versus SOC:
probability. SOC arm was closed in November • Median number of organ support-free days was
2020 (n = 366 for tocilizumab, n = 48 for 9 in sarilumab arm and 0 in SOC arm.
sarilumab, n = 412 for SOC). • Median adjusted OR for ordinal scale was 1.50
• After November 2020, patients were randomized (95% CrI, 1.13–2.00).
mostly to receive tocilizumab, sarilumab, or • In highest CRP tercile, aOR was 1.85 (95% CrI,
anakinra until April 10, 2021. 1.24–2.69).
Primary Endpoint: • Outcomes were consistent across subgroups
• Composite ordinal endpoint of in-hospital according to oxygen requirements at study
mortality and organ support-free days to Day 21 entry.

AR09027
REMAP-CAP: Open-Label, Adaptive-Platform RCT of Tocilizumab and Sarilumab in Patients With COVID-192,3, continued
Key Secondary Endpoint: Secondary Outcomes
• In-hospital survival Tocilizumab Versus SOC:
• In-hospital survival was 66% in tocilizumab arm and
63% in SOC arm (aOR 1.42; 95% CrI, 1.05–1.93).
Sarilumab Versus SOC:
• In-hospital survival was 67% in sarilumab arm and
63% in SOC arm (aOR 1.51; 95% CrI, 1.06–2.20).
COVACTA: Double-Blind RCT of Tocilizumab in Hospitalized Patients With COVID-194
• PCR-confirmed SARS-CoV-2 infection • Mean age 61 years; 70% men; 58% White • Modest power to detect differences in Day 28
• Hypoxemia • 30% on HFNC oxygen or NIV clinical status
• Bilateral chest infiltrates • 14% on MV • More patients in placebo arm than tocilizumab
arm received corticosteroids
Key Exclusion Criteria: • 25% with multiorgan failure
• Few patients on MV
• Death imminent • 36% in tocilizumab arm and 55% in placebo arm
received corticosteroids at entry or during follow-up Interpretation:
• Active infection other than SARS-CoV-2
Primary Outcome: • There was no difference between arms in Day 28
Interventions: clinical status or survival.
• No significant difference between arms in clinical
• Single dose of tocilizumab 8 mg/kg and possible • The median times for recovery and ICU LOS were
status at Day 28.
second dose, plus SOC (n = 294) shorter in the tocilizumab arm than in the placebo
• Placebo plus SOC (n = 144) Secondary Outcomes: arm.
• Shorter median time to discharge in tocilizumab arm
Primary Endpoint:
than placebo arm (20 vs. 28 days; HR 1.35; 95% CI,
• Day 28 clinical status (ordinal score) 1.02–1.79).
Key Secondary Endpoints: • Shorter median ICU LOS in tocilizumab arm than
• Time to discharge placebo arm (9.8 vs. 15.5 days).
• ICU LOS • No difference in Day 28 mortality between arms
(19.7% in tocilizumab arm vs. 19.4% placebo arm).
• Day 28 mortality

AR09028
EMPACTA: Double-Blind RCT of Tocilizumab in Hospitalized Patients With COVID-195

• PCR-confirmed SARS-CoV-2 infection • Mean age 56 years; 59% men; 56% Hispanic/Latinx, 15% • Moderate sample size
• COVID-19 pneumonia Black/African American, 13% American Indian/Alaska Native
Interpretation:
• 84% with elevated CRP
Key Exclusion Criteria: • Among patients with COVID-19 pneumonia,
• Concomitant medications: tocilizumab lowered rates of MV, ECMO, or
• NIV or MV
• 80% on corticosteroids and 53% on RDV in tocilizumab death by Day 28 but provided no benefit for
Interventions: arm 28-day all-cause mortality.
• Single dose of tocilizumab 8 mg/kg plus SOC, • 88% on corticosteroids and 59% on RDV in placebo arm
possible second dose (n = 249)
Primary Outcome:
• Placebo plus SOC (n = 128)
• Proportion of patients who required MV or ECMO or died
Primary Endpoint: by Day 28 was 12% in tocilizumab arm and 19% in placebo
• MV, ECMO, or death by Day 28 arm (HR 0.56; 95% CI, 0.33–0.97; P = 0.04).
Key Secondary Endpoints: Secondary Outcomes:
• Time to hospital discharge or readiness for • Median time to hospital discharge or readiness for discharge
discharge (ordinal score) was 6.0 days in tocilizumab arm and 7.5 days in placebo
• All-cause mortality by Day 28 arm (HR 1.16; 95% CI, 0.91–1.48).
• All-cause mortality by Day 28 was not statistically different
between arms (10.4% in tocilizumab arm vs. 8.6% in
placebo arm).
BACC Bay: Double-Blind RCT of Tocilizumab in Hospitalized Patients With COVID-196
• Laboratory-confirmed SARS-CoV-2 infection • Median age 60 years; 58% men; 45% Hispanic/Latinx • Wide confidence intervals due to small sample
• ≥2 of the following conditions: • 50% with BMI ≥30; 49% with HTN; 31% with DM size and low event rates
• Fever >38°C • 80% receiving oxygen ≤6 L/min; 4% receiving high-flow • Few patients received RDV or corticosteroids
• Pulmonary infiltrates oxygen; 16% receiving no supplemental oxygen Interpretation:
• Need for oxygen • Concomitant medications: • There was no benefit of tocilizumab in
• ≥1 of the following laboratory criteria: • 11% on corticosteroids and 33% on RDV in tocilizumab preventing MV or death, reducing the risk of
arm clinical worsening, or reducing the time to
• CRP ≥50 mg/L discontinuation of oxygen. This could be due
• 6% on glucocorticoids and 29% on RDV in placebo arm
• D-dimer >1,000 ng/mL to the low rate of concomitant corticosteroid
• LDH ≥250 U/L Primary Outcome: use among the study participants.
• Ferritin >500 ng/mL • No difference between arms in rate of Day 28 MV or death
(10.6% in tocilizumab arm vs. 12.5% in placebo arm; HR
0.83; 95% CI, 0.38–1.81; P = 0.64).

AR09029
BACC Bay: Double-Blind RCT of Tocilizumab in Hospitalized Patients With COVID-196, continued
Key Exclusion Criteria: Secondary Outcomes:
• Requiring supplemental oxygen at rate >10 L/min • No difference between arms in proportion of patients
• Recent use of biologic agents or small molecule who had worsening of disease by Day 28 (19% in
immunosuppressive therapy that investigators believe tocilizumab arm vs. 17% in placebo arm; HR 1.11;
place the patient at a higher risk for infection 95% CI, 0.59–2.10).
• Median number of days to discontinuation of oxygen
Interventions:
was 5.0 in tocilizumab arm and 4.9 in placebo arm (P
• Tocilizumab 8 mg/kg plus usual care (n = 161) = 0.69).
• Placebo plus usual care (n = 81)
Primary Endpoint:
• MV or death, according to a time to event analysis; data
censored at Day 28
• Clinical worsening by Day 28 (ordinal score)
• Discontinuation of supplemental oxygen among patients
receiving it at baseline
Double-Blind, RCT of Sarilumab in Hospitalized Patients With Severe or Critical COVID-197
• Severe or critical laboratory-confirmed COVID-19 • Median age 59 years; 63% men; 77% White; 36% • Only 20% of patients received
• COVID-19 pneumonia Hispanic/Latinx corticosteroids
• 39% on HFNC oxygen, MV, or NIV • Moderate sample size and a small placebo
• 42% with BMI ≥30; 43% with HTN; 26% with type 2 arm
• Low probability of surviving or remaining at study site
DM Interpretation:
• Dysfunction of ≥2 organ systems and need for ECMO or
• 20% received systemic corticosteroids before • There was no benefit of sarilumab in
renal replacement therapy
receiving intervention hospitalized adults with COVID-19 in time
Interventions: to clinical improvement or mortality. This
Primary Outcome:
• Sarilumab 400 mg IV (n = 173) could be due to the low rate of concomitant
• No difference in median time to clinical improvement corticosteroid use among the study
• Sarilumab 200 mg IV (n = 159) among the sarilumab arms (10 days for each) and participants.
• Placebo (n = 84) placebo arm (12 days).
Primary Endpoint: Secondary Outcome:
• Time to clinical improvement of ≥2 points on a 7-point • No difference among the arms in survival rate at Day
scale 29 (92% in placebo arm vs. 90% in sarilumab 200 mg
arm vs. 92% in sarilumab 400 mg arm).

AR09030
Double-Blind, RCT of Sarilumab in Hospitalized Patients With Severe or Critical COVID-197, continued
• Survival at Day 29
REMDACTA: Double-Blind RCT of Tocilizumab and Remdesivir in Hospitalized Patients With Severe COVID‑19 Pneumonia8
• PCR-confirmed SARS-CoV-2 infection • Mean age 59 years; 40% in tocilizumab arm and 34% • During the trial, primary outcome changed
• Hospitalized with pneumonia confirmed by CXR or CT in placebo arm aged ≥65 years from clinical status on Day 28 to time to
and requiring supplemental oxygen >6 L/min • 63% men; 67% White discharge or “ready for discharge” to Day
28
Key Exclusion Criteria: • Respiratory support:
• Imbalances in patient characteristics at
• eGFR <30 mL/min • 78% in tocilizumab arm and 83% in placebo arm on baseline between arms
NIV or high-flow oxygen
• ALT or AST >5 times ULN • Possible underrepresentation of patients
• 15% in tocilizumab arm and 11% in placebo arm with rapidly progressive disease
• Infection other than SARS-CoV-2
required MV or ECMO
• Treatment with antivirals, CP, CQ, HCQ, JAK inhibitors Interpretation:
• Corticosteroid use:
Interventions: • 83% in tocilizumab arm and 86% in placebo arm at • Compared with placebo plus RDV,
• Up to 10 days RDV plus: baseline tocilizumab plus RDV did not shorten the
time to discharge or “ready for discharge”
• Tocilizumab 8 mg/kg IV, with second dose within 8–24 • 88% in each arm during the trial in patients with severe COVID-19
hours if indicated (n = 434) pneumonia.
Primary Outcome:
• Placebo (n = 215) • There was no difference in mortality
• No difference between arms in time to discharge or
Primary Endpoint: “ready for discharge” through Day 28 (14 days in each between the arms.
• Time to discharge or “ready for discharge” through Day arm; HR 0.97; 95% CI, 0.78–1.19; P = 0.74).
28 Secondary Outcomes:
Key Secondary Endpoints: • There was no difference between the arms in key
• Time to MV or death through Day 28 secondary outcomes:
• Day 14 clinical status (ordinal score) • Proportion of patients in each arm who required MV
or died by Day 28 was 29%; time to death was non-
• Time to death through Day 28
evaluable (HR 0.98; 95% CI, 0.72–1.34; P = 0.90).
• Mean ordinal score for clinical status at Day 14 was
2.8 in tocilizumab arm and 2.9 in placebo arm (P =
0.72).
• 18% of patients in tocilizumab arm and 20% in
placebo arm died by Day 28; time to death was non-
evaluable (HR 0.95; 95% CI, 0.65–1.39; P = 0.79).

AR09031
Key: ALT = alanine transaminase; AST = aspartate transaminase; BMI = body mass index; CP = convalescent plasma; CQ = chloroquine; CRP = C-reactive protein; CT
= computed tomography; CXR = chest X-ray; DM = diabetes mellitus; ECMO = extracorporeal membrane oxygenation; eGFR = estimated glomerular filtration rate;
HCQ = hydroxychloroquine; HFNC = high-flow nasal cannula; HTN = hypertension; ICU = intensive care unit; IL = interleukin; IV = intravenous; JAK = Janus kinase;
LDH = lactate dehydrogenase; LOS = length of stay; MV = mechanical ventilation; NIV = noninvasive ventilation; the Panel = the COVID-19 Treatment Guidelines
Panel; PCR = polymerase chain reaction; RCT = randomized controlled trial; RDV = remdesivir; SOC = standard of care; SpO2 = oxygen saturation; ULN = upper limit
of normal
References
1. RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled,
open-label, platform trial. Lancet. 2021;397(10285):1637-1645. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33933206.
2. REMAP-CAP Investigators, Gordon AC, Mouncey PR, et al. Interleukin-6 receptor antagonists in critically ill patients with COVID-19. N
3. The REMAP-CAP Investigators, Derde LPG. Effectiveness of tocilizumab, sarilumab, and anakinra for critically ill patients with
COVID-19: the REMAP-CAP COVID-19 immune modulation therapy domain randomized clinical trial. medRxiv. 2021;Preprint.
4. Rosas IO, Brau N, Waters M, et al. Tocilizumab in hospitalized patients with severe COVID-19 pneumonia. N Engl J Med.
5. Salama C, Han J, Yau L, et al. Tocilizumab in patients hospitalized with COVID-19 pneumonia. N Engl J Med. 2021;384(1):20-30.
6. Stone JH, Frigault MJ, Serling-Boyd NJ, et al. Efficacy of tocilizumab in patients hospitalized with COVID-19. N Engl J Med.
7. Lescure FX, Honda H, Fowler RA, et al. Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised,
double-blind, placebo-controlled, Phase 3 trial. Lancet Respir Med. 2021;9(5):522-532. Available at:
8. Rosas IO, Diaz G, Gottlieb RL, et al. Tocilizumab and remdesivir in hospitalized patients with severe COVID-19 pneumonia: a
randomized clinical trial. Intensive Care Med. 2021;47(11):1258-1270. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34609549.

AR09032
Kinase Inhibitors: Janus Kinase Inhibitors and Bruton’s
Tyrosine Kinase Inhibitors
Janus Kinase Inhibitors

Janus kinase (JAK) inhibitors interfere with phosphorylation of signal transducer and activator of
transcription (STAT) proteins1,2 that are involved in vital cellular functions, including signaling, growth,
and survival. These kinase inhibitors are proposed as treatments for COVID-19 because they can prevent
phosphorylation of key proteins involved in the signal transduction that leads to immune activation and
inflammation (e.g., the cellular response to proinflammatory cytokines such as interleukin [IL]-6).3
Immunosuppression induced by JAK inhibitors could potentially reduce the inflammation and associated
immunopathologies observed in patients with COVID-19. Additionally, JAK inhibitors, particularly
baricitinib, have theoretical direct antiviral activity through interference with viral endocytosis,
potentially preventing SARS-CoV-2 from entering and infecting susceptible cells.4
Recommendations
• See Therapeutic Management of Hospitalized Adults With COVID-19 for the COVID-19
Treatment Guidelines Panel’s (the Panel) recommendations on the use of baricitinib and tofacitinib
for certain hospitalized patients who require oxygen supplementation.
• The Panel recommends against the use of JAK inhibitors other than baricitinib or tofacitinib
for the treatment of COVID-19, except in a clinical trial (AIII).
Rationale
The Panel’s recommendations are based on data from the ACTT-2,5 COV-BARRIER,6 and
STOP-COVID7 clinical trials. The ACTT-2 trial demonstrated that baricitinib improved time to recovery
when given in combination with remdesivir to hospitalized patients with COVID-19 who require
supplemental oxygen but not mechanical ventilation. However, a key limitation of the ACTT-2 trial is
that corticosteroids were not used as the standard of care; thus, it was not possible to evaluate the effect
of baricitinib when given in addition to corticosteroids.
The COV-BARRIER trial enrolled patients with COVID-19 pneumonia and at least 1 elevated
inflammatory marker at enrollment who were not on mechanical ventilation. This trial reported an
additional survival benefit of baricitinib when added to the standard of care of corticosteroids (with
or without remdesivir). If baricitinib is not available, tofacitinib may be an alternative because it has
demonstrated clinical benefit in the STOP-COVID trial.
The clinical trial data on the use of baricitinib and tofacitinib in patients with COVID-19 is summarized
below, and all related treatment recommendations are reviewed in Therapeutic Management of

Most of the data on adverse effects of JAK inhibitors were reported based on chronic use of the agents
for the treatment of autoimmune diseases. Adverse effects include infections (typically respiratory
and urinary tract infections) and the reactivation of herpes viruses; myelosuppression; transaminase
elevations; and, rarely, gastrointestinal perforation. The Food and Drug Administration (FDA) review
of a large, randomized, safety clinical trial comparing tofacitinib to antitumor necrosis factor inhibitors
in people with rheumatoid arthritis found that tofacitinib was associated with additional serious adverse

AR09033
events, including heart attack or stroke, cancer, blood clots, and death.8 The FDA is therefore requiring
new and updated warnings for drugs in the JAK inhibitor class, including tofacitinib and baricitinib.
Data from randomized trials evaluating the safety of short-term use of JAK inhibitors in patients
with COVID-19 are limited. The data to date have not revealed significant safety signals, including
thrombosis; however, these trials may be underpowered for detecting rare adverse events.5-7
A complete blood count with differential, liver function tests, and kidney function tests should be
obtained in all patients before baricitinib is administered and during treatment as clinically indicated.
Screening for viral hepatitis and tuberculosis should be considered. Considering its immunosuppressive
effects, all patients receiving baricitinib should also be monitored for new infections.
Tofacitinib is a cytochrome P 450 (CYP) 3A4 substrate. Dose modifications are required when the drug
is administered with strong CYP3A4 inhibitors or when used with a moderate CYP3A4 inhibitor that is
coadministered with a strong CYP2C19 inhibitor. Coadministration with a strong CYP3A4 inducer is
not recommended.
The ACTT-2 and COV-BARRIER trials evaluated oral baricitinib 4 mg once daily, which is twice the
standard baricitinib dose (2 mg once daily) for FDA-approved indications.5,6 In patients with severe
hepatic impairment, baricitinib should only be used if the potential benefit outweighs the potential risk.9
Baricitinib has not been evaluated in clinical studies for FDA-approved indications in patients with an
estimated glomerular filtration rate (eGFR) ≤30 mL/min. When baricitinib is used for the treatment of
COVID-19 in adults with renal insufficiency, the Panel recommends reducing the dose of baricitinib
from 4 mg to 2 mg daily for adults with an eGFR ≥30 to <60 mL/min and to 1 mg daily for those with
an eGFR of 15 to <30 mL/min. Baricitinib is not recommended for patients with an eGFR <15 mL/
min.9 There are limited clinical data on the use of baricitinib in combination with strong organic anion
transporter 3 inhibitors, and, in general, coadministration is not advised.10,11
There is a paucity of data on the use of JAK inhibitors in pregnancy. As small molecule-drugs, JAK
inhibitors are likely to pass through the placenta, and therefore fetal risk cannot be ruled out.12 Decisions
regarding the administration of JAK inhibitors must include shared decision-making between the
pregnant individual and their health care provider, considering potential maternal benefit and fetal
risks. Factors that may weigh into the decision-making process include maternal COVID-19 severity,
comorbidities, and gestational age. Pregnancy registries provide some outcome data on tofacitinib use
during pregnancy for other conditions (e.g., ulcerative colitis, rheumatoid arthritis, psoriasis). Among the
33 cases reported, pregnancy outcomes were similar to those among the general population.13-15
An FDA Emergency Use Authorization (EUA) has been issued for the use of baricitinib in hospitalized
adults and children aged ≥2 years with COVID-19 who require supplemental oxygen, mechanical
ventilation, or extracorporeal membrane oxygenation (ECMO).9 The safety and efficacy of baricitinib
have not been evaluated in pediatric patients with COVID-19. As noted above, tofacitinib was shown to
decrease the risk of respiratory failure and death in adults with COVID-19 in the STOP-COVID trial.7
Tofacitinib is FDA approved for a pediatric indication; however, the safety and efficacy of tofacitinib
have not been evaluated in pediatric patients with COVID-19. Thus, there is insufficient evidence
to recommend either for or against the use of baricitinib in combination with corticosteroids and/or
remdesivir for the treatment of COVID-19 in hospitalized children.
Baricitinib
Baricitinib is an oral JAK inhibitor that is selective for JAK1 and JAK2 and is FDA approved for the

AR09034
treatment of rheumatoid arthritis.10 Baricitinib can modulate downstream inflammatory responses
via JAK1/JAK2 inhibition and has exhibited dose-dependent inhibition of IL-6-induced STAT3
phosphorylation.16 Baricitinib has postulated antiviral effects by blocking SARS-CoV-2 from entering
and infecting lung cells.17 Baricitinib reduced inflammation and lung pathology in macaques infected
with SARS-CoV-2, but an antiviral effect was not confirmed.18
In the ACTT-2 trial, 1,033 patients hospitalized with COVID-19 were randomized 1:1 to receive
baricitinib 4 mg daily for 14 days (or until hospital discharge) or placebo, both given in combination
with remdesivir. The primary endpoint was time to recovery as measured on an 8-category ordinal scale.
Recovery time was shorter in the baricitinib arm (7 days) than in the placebo arm (8 days) (rate ratio
for recovery 1.16; 95% CI, 1.01–1.32; P = 0.03). Mortality by 28 days was lower in the baricitinib arm
than in the placebo arm, but the difference was not statistically significant. A key limitation of the study
is that corticosteroids were not used as background standard care for patients with severe or critical
COVID-19 pneumonia.5
In the COV-BARRIER trial, 1,525 hospitalized patients with COVID-19 pneumonia and an elevation in
1 or more inflammatory markers were randomized 1:1 to receive baricitinib 4 mg orally or placebo for
up to 14 days (or until hospital discharge). Patients on mechanical ventilation were excluded from study
enrollment. Overall, 79% of patients received corticosteroids and 19% received remdesivir. The primary
endpoint was the proportion of patients who progressed to high-flow oxygen, noninvasive ventilation,
mechanical ventilation, or death by Day 28. Progression to the primary endpoint occurred among
27.8% of patients in the baricitinib arm versus 30.5% in the placebo arm (OR 0.85; 95% CI, 0.67–1.08;
P = 0.18). All-cause mortality within 28 days, which was a key secondary endpoint, was 8.1% in the
baricitinib arm and 13.1% in the placebo arm, resulting in a 38.2% reduction in mortality associated with
baricitinib (HR 0.57; 95% CI, 0.41–0.78). The mortality difference was most pronounced in the subgroup
of patients receiving high-flow oxygen or noninvasive ventilation at baseline (17.5% for baricitinib
recipients vs. 29.4% for placebo recipients; HR 0.52; 95% CI, 0.33–0.80). However, subgroup analyses
did not identify a statistically significant benefit of baricitinib versus placebo among patients receiving
low-flow oxygen at baseline. The occurrence of adverse events, serious adverse events, serious infections,
and venous thromboembolic events was comparable in the baricitinib and placebo arms.6
The COV-BARRIER trial added a critically ill cohort to the original study. In this cohort, participants on
mechanical ventilation or ECMO at baseline (n = 101) were randomly assigned to baricitinib 4 mg (n =
51) or placebo (n = 50) for up to 14 days in combination with the standard of care. At baseline, 86% of
participants were receiving corticosteroids and 2% were receiving remdesivir. Baricitinib significantly
reduced the prespecified endpoint of 28-day all-cause mortality when compared with placebo (39.2%
vs. 58.0%; HR 0.54; 95% CI, 0.31–0.96; P = 0.03). Significant reductions were also reported with
baricitinib versus placebo in 60-day mortality (45% vs. 62%; P = 0.027) and hospital days (23.7 vs. 26.1
days; P = 0.05). The implications of these findings are limited due to the very small sample size of this
addendum trial population.19
The collective data from these studies have informed the Panel’s recommendations on the use of
baricitinib in hospitalized patients with COVID-19. The specific recommendations and additional
information on the rationale can be found in Therapeutic Management of Hospitalized Adults With
COVID-19.
Clinical Trials
Please see ClinicalTrials.gov for the latest information on studies of baricitinib for the treatment of
COVID-19.

AR09035
Drug Availability
Baricitinib is approved by the FDA for the treatment of rheumatoid arthritis. On November 19, 2020,
the FDA issued an initial EUA for the use of baricitinib in combination with remdesivir for the treatment
of COVID-19 in certain hospitalized children and adults who require supplemental oxygen, mechanical
ventilation, or ECMO. The EUA was revised on July 28, 2021, to remove the requirement that
baricitinib be used only in combination with remdesivir for the treatment of COVID-19.9
Tofacitinib
Tofacitinib is the prototypical JAK inhibitor, predominantly selective for JAK1 and JAK3, with modest
activity against JAK2, and, as such, can block signaling from gamma-chain cytokines (e.g., IL-2, IL-4)
and glycoprotein 130 proteins (e.g., IL-6, IL-11, interferons). It is an oral agent first approved by the
FDA for the treatment of rheumatoid arthritis and has been shown to decrease levels of IL-6 in patients
with this disease.20 Tofacitinib is also FDA approved for the treatment of psoriatic arthritis, juvenile
idiopathic arthritis, and ulcerative colitis.21
The double-blind STOP-COVID trial randomized 289 hospitalized patients with COVID-19 in Brazil
to receive tofacitinib 10 mg or placebo orally twice daily for up to 14 days (or until hospital discharge).
Patients who were on mechanical ventilation or who had an immunocompromising condition were
excluded from the trial. The background standard of care included corticosteroids (79.2% of patients
were receiving corticosteroids at randomization and overall, 89.3% received corticosteroids during the
study) but not remdesivir. The primary outcome of death or respiratory failure through Day 28 occurred
in 18.1% of patients in the tofacitinib arm and 29.0% in the placebo arm (risk ratio 0.63; 95% CI,
0.41–0.97). All-cause mortality within 28 days was 2.8% in the tofacitinib arm and 5.5% in the placebo
arm (risk ratio 0.49; 95% CI, 0.15–1.63). Serious adverse events occurred in 14.2% of the patients in the
tofacitinib arm and 12.0% in the placebo arm. Limitations of the trial include the small sample size.7
Clinical Trials
Please see ClinicalTrials.gov for the latest information on studies of tofacitinib for the treatment of
COVID-19.
Ruxolitinib
Ruxolitinib is an oral JAK inhibitor selective for JAK1 and JAK2 that is currently approved for
myelofibrosis, polycythemia vera, and acute graft-versus-host disease.22 Like baricitinib, it can modulate
downstream inflammatory responses via JAK1/JAK2 inhibition and has exhibited dose-dependent
inhibition of IL-6-induced STAT3 phosphorylation.16 Ruxolitinib also has postulated antiviral effects by
blocking SARS-CoV-2 from entering and infecting lung cells.17
A small, single-blind, Phase 2 randomized controlled trial in patients with COVID-19 in China
compared ruxolitinib 5 mg orally twice daily (n = 20) with placebo (administered as vitamin C 100 mg;
n = 21), both given in combination with standard of care. Treatment with ruxolitinib was associated with
a nonsignificant reduction in the median time to clinical improvement (12 days for ruxolitinib recipients
vs. 15 days for placebo recipients; P = 0.15), defined as a 2-point improvement on a 7-category ordinal
scale or as hospital discharge. There was no difference between the arms in the median time to discharge
(17 days for ruxolitinib arm vs. 16 days for placebo arm; P = 0.94). Limitations of this study include
the small sample size.23 A Phase 3 trial of ruxolitinib in patients with COVID-19-associated acute
respiratory distress syndrome is currently in progress (ClinicalTrials.gov Identifier NCT04377620).

AR09036
Clinical Trials
Please see ClinicalTrials.gov for the latest information on studies of ruxolitinib for the treatment of
COVID-19.
Bruton’s Tyrosine Kinase Inhibitors

Bruton’s tyrosine kinase (BTK) is a signaling molecule of the B-cell antigen receptor and cytokine
receptor pathways.
Recommendation
• The Panel recommends against the use of BTK inhibitors for the treatment of COVID-19,
except in a clinical trial (AIII).
Acalabrutinib
Acalabrutinib is a second-generation, oral BTK inhibitor that is FDA approved to treat B-cell
malignancies (i.e., chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma).
It has a better toxicity profile than first-generation BTK inhibitors (e.g., ibrutinib) because it has less
off-target activity for other kinases.24 Acalabrutinib is proposed for use in patients with COVID-19
because it can modulate signaling that promotes inflammation.
Data regarding acalabrutinib are limited to the results from a prospective case series of 19 patients with
severe COVID-19.25 Evaluation of the data to discern any clinical benefit is limited by the study’s small
sample size and lack of a control group.
Clinical Trials
Please see ClinicalTrials.gov for the latest information on studies of acalabrutinib for the treatment of
COVID-19.
Ibrutinib
Ibrutinib is a first-generation BTK inhibitor that is FDA approved to treat various B-cell malignancies26
and to prevent chronic graft-versus-host disease in stem cell transplant recipients.27 Based on results
from a small case series, ibrutinib has been theorized to reduce inflammation and protect against ensuing
lung injury in patients with COVID-19.28
Data regarding ibrutinib are limited to those from an uncontrolled, retrospective case series of 6 patients
with COVID-19 who were receiving the drug for a condition other than COVID-19.28 Evaluation of the
data for any clinical benefit is limited by the series’ small sample size and lack of a control group.
Clinical Trials
Please see ClinicalTrials.gov for the latest information on studies of ibrutinib for the treatment of
COVID-19.
Zanubrutinib
Zanubrutinib is a second-generation, oral BTK inhibitor that is FDA approved to treat mantle cell
lymphoma.29 It has been shown to have fewer toxicities than first-generation BTK inhibitors (e.g.,
ibrutinib) because of less off-target activity for other kinases.30 Zanubrutinib is proposed to benefit
patients with COVID-19 by modulating signaling that promotes inflammation.

AR09037

There are no clinical data on the use of zanubrutinib to treat COVID-19.
Clinical Trials
Please see ClinicalTrials.gov for the latest information on studies of zanubrutinib for the treatment of
COVID-19.
Adverse Effects and Monitoring

Hemorrhage and cardiac arrhythmia have occurred in patients who received BTK inhibitors.
There is a paucity of data on human pregnancy and BTK inhibitor use. In animal studies, acalabrutinib and
ibrutinib in doses exceeding the therapeutic human dose were associated with interference with embryofetal
development.26,31 Based on these data, use of BTK inhibitors that occurs during organogenesis may be
associated with fetal malformations. The impact of use later in pregnancy is unknown. Risks of use should
be balanced against potential benefits.
The safety and efficacy of BTK inhibitors have not been evaluated in pediatric patients with COVID-19, and
data on the use of the drugs in children with other conditions are extremely limited. Use of BTK inhibitors
for the treatment of COVID-19 in pediatric patients is not recommended, except in a clinical trial.
References
1. Babon JJ, Lucet IS, Murphy JM, Nicola NA, Varghese LN. The molecular regulation of Janus kinase (JAK)
activation. Biochem J. 2014;462(1):1-13. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25057888.
2. Bousoik E, Montazeri Aliabadi H. “Do we know jack” about JAK? A closer look at JAK/STAT signaling pathway.
Front Oncol. 2018;8:287. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30109213.
3. Zhang W, Zhao Y, Zhang F, et al. The use of anti-inflammatory drugs in the treatment of people with severe
coronavirus disease 2019 (COVID-19): the perspectives of clinical immunologists from China. Clin Immunol.
4. Stebbing J, Phelan A, Griffin I, et al. COVID-19: combining antiviral and anti-inflammatory treatments. Lancet
adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled Phase 3
trial. Lancet Respir Med. 2021;9(12):1407-1418. Available at: https://pubmed.ncbi.nlm.nih.gov/34480861/.
7. Guimaraes PO, Quirk D, Furtado RH, et al. Tofacitinib in patients hospitalized with COVID-19 pneumonia. N
8. Food and Drug Administration. FDA requires warnings about increased risk of serious heart-related events,
cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions. 2021.
Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-
serious-heart-related-events-cancer-blood-clots-and-death. Accessed December 2, 2021.
9. Food and Drug Administration. Fact sheet for healthcare providers: Emergency Use Authorization (EUA) of
baricitinib. 2021. Available at: https://www.fda.gov/media/143823/download.
10. Baricitinib (Olumiant) [package insert]. Food and Drug Administration. 2019. Available at:

AR09038
11. Posada MM, Cannady EA, Payne CD, et al. Prediction of transporter-mediated drug-drug interactions for
baricitinib. Clin Transl Sci. 2017;10(6):509-519. Available at:
13. Clowse ME, Feldman SR, Isaacs JD, et al. Pregnancy outcomes in the tofacitinib safety databases for
rheumatoid arthritis and psoriasis. Drug Saf. 2016;39(8):755-762. Available at:
14. Mahadevan U, Dubinsky MC, Su C, et al. Outcomes of pregnancies with maternal/paternal exposure in the
tofacitinib safety databases for ulcerative colitis. Inflamm Bowel Dis. 2018;24(12):2494-2500. Available at:
15. Wieringa JW, van der Woude CJ. Effect of biologicals and JAK inhibitors during pregnancy on health-
related outcomes in children of women with inflammatory bowel disease. Best Pract Res Clin Gastroenterol.
2020;44-45:101665. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32359679.
16. McInnes IB, Byers NL, Higgs RE, et al. Comparison of baricitinib, upadacitinib, and tofacitinib mediated
regulation of cytokine signaling in human leukocyte subpopulations. Arthritis Res Ther. 2019;21(1):183.
17. Richardson P, Griffin I, Tucker C, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory
disease. Lancet. 2020;395(10223):e30-e31. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32032529.
18. Hoang TN, Pino M, Boddapati AK, et al. Baricitinib treatment resolves lower-airway macrophage
inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques. Cell. 2020. Available at:
19. Ely EW, Ramanan AV, Kartman CE, et al. Baricitinib plus standard of care for hospitalised adults with
COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: results of a
randomised, placebo-controlled trial. medRxiv. 2021;Preprint. Available at:
20. Migita K, Izumi Y, Jiuchi Y, et al. Effects of Janus kinase inhibitor tofacitinib on circulating serum amyloid
A and interleukin-6 during treatment for rheumatoid arthritis. Clin Exp Immunol. 2014;175(2):208-214.
21. Tofacitinib (Xeljanz) [package insert]. Food and Drug Administration. 2019. Available at:
22. Ruxolitinib (JAKAFI) [package insert]. 2020. Available at:
https://www.jakafi.com/pdf/prescribing-information.pdf.
23. Cao Y, Wei J, Zou L, et al. Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A
multicenter, single-blind, randomized controlled trial. J Allergy Clin Immunol. 2020. Available at:
24. Owen C, Berinstein NL, Christofides A, Sehn LH. Review of Bruton tyrosine kinase inhibitors for the
treatment of relapsed or refractory mantle cell lymphoma. Curr Oncol. 2019;26(2):e233-e240. Available at:
25. Roschewski M, Lionakis MS, Sharman JP, et al. Inhibition of Bruton tyrosine kinase in patients with severe
COVID-19. Sci Immunol. 2020;5(48). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32503877.
26. Ibrutinib (Imbruvica) [package insert]. Food and Drug Administration. 2015. Available at:
27. Food and Drug Administration. FDA expands ibrutinib indications to chronic GVHD. 2017. Available at:
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-ibrutinib-indications-chronic-

AR09039
gvhd. Accessed December 2, 2021.

28. Treon SP, Castillo JJ, Skarbnik AP, et al. The BTK inhibitor ibrutinib may protect against pulmonary injury in
COVID-19-infected patients. Blood. 2020;135(21):1912-1915. Available at:
29. Zanubrutinib (Brukinsa) [package insert]. Food and Drug Administration. 2019. Available at:
30. Tam C, Grigg AP, Opat S, et al. The BTK inhibitor, Bgb-3111, is safe, tolerable, and highly active in
patients with relapsed/refractory B-cell malignancies: initial report of a Phase 1 first-in-human trial. Blood.
2015;126(23):832. Available at: https://ashpublications.org/blood/article/126/23/832/136525/The-BTK-
Inhibitor-Bgb-3111-Is-Safe-Tolerable-and.
31. Acalabrutinib (Calquence) [package insert]. Food and Drug Administration. 2017. Available at:

AR09040
Table 4f. Characteristics of Immunomodulators

• The information in this table is derived from data on the use of these drugs for FDA-approved indications or in investigational trials, and
it is supplemented with data on their use in patients with COVID-19, when available.
• For dose modifications for patients with organ failure or those who require extracorporeal devices, please refer to product labels, when
available.
• There are currently not enough data to determine whether certain medications can be safely coadministered with therapies for the treatment
of COVID-19. When using concomitant medications with similar toxicity profiles, consider performing additional safety monitoring.
• The potential additive, antagonistic, or synergistic effects and the safety of using certain combination therapies for the treatment of
COVID-19 are unknown. Clinicians are encouraged to report AEs to the FDA Medwatch program.
• For drug interaction information, please refer to product labels and visit the Liverpool COVID-19 Drug Interactions website.
• For the Panel’s recommendations on using the drugs listed in this table, please refer to the drug-specific sections of the Guidelines and
to Therapeutic Management of Nonhospitalized Adults With COVID-19, and Therapeutic Management of Hospitalized Adults With
COVID-19.
Dosing Regimen
The doses listed are for approved Monitoring Comments and Links to Clinical
Drug Name indications or from clinical trials Adverse Events Drug-Drug Interaction Potential
Parameters Trials
or clinical experience in patients
with COVID-19.
Colchicine
Colchicine Dose for COVID-19 in • Diarrhea • CBC • P-gp and CYP3A4 substrate •U se of colchicine should be
COLCORONA Trial: • Nausea • Renal • T he risk of myopathy may be avoided in patients with severe
• Colchicine 0.5 mg twice daily • Vomiting function increased with the concomitant use of renal insufficiency, and those
for 3 days and then once certain HMG-CoA reductase inhibitors with moderate renal insufficiency
• C
ramping • Hepatic who receive the drug should be
daily for 27 days1
function (e.g., atorvastatin, lovastatin,
• Abdominal pain simvastatin) due to potential monitored for AEs.
• Bloating competitive interactions mediated by • A list of clinical trials is available:
P-gp and CYP3A4 pathways. Colchicine
• Loss of appetite
• F atal colchicine toxicity has been Availability:
• Neuromyotoxicity
reported in individuals with renal
(rare) 2
• In the COLCORONA trial, 0.5
or hepatic impairment who used
• Blood dyscrasias mg colchicine tablets were used
colchicine in conjunction with
(rare) for dosing; in the United States,
P-gp inhibitors or strong CYP3A4
colchicine is available as 0.6 mg
inhibitors.
tablets.

AR09041
Dosing Regimen
The doses listed are for approved Drug-Drug Interaction Comments and Links to
Drug Name indications or from clinical trials Adverse Events Monitoring Parameters
Potential Clinical Trials
with COVID-19.
Corticosteroids (Inhaled)
Budesonide Dose for COVID-19 in Clinical • Secondary infections • Signs of AEs involving •C
YP3A4 substrate •A
list of clinical trials
(Inhaled) Trials: • Oral thrush the oral mucosa or throat •D
o not use with strong is available: Inhaled
• Budesonide 800 mcg oral including thrush CYP3A4 inhibitors. Budesonide
• Systemic AEs (less
inhalation twice daily until common) • S
igns of systemic
symptom resolution or for up corticosteroid effects (e.g.,
to 14 days3,4 adrenal suppression)
Ciclesonide Dose for COVID-19 in Clinical • Secondary infections • Signs of AEs involving •C YP3A4 substrate • A list of clinical trials is
(Inhaled) Trials: •O
ral thrush the oral mucosa or throat • E ffect of strong CYP3A4 available: Ciclesonide
• Ciclesonide 160 mcg: 2 MDI • Systemic AEs (less including thrush inhibitors on ciclesonide
inhalations twice daily for 30 common) • Signs of systemic exposure is not expected
days5 corticosteroid effects (e.g., to be as significant as
adrenal suppression) that on budesonide.
Corticosteroid (Systemic)
Recommended by the Panel for the treatment of COVID-19 in certain nonhospitalized and hospitalized patients.
Dexamethasone Dose for COVID-19: • Hyperglycemia • Blood glucose •M oderate CYP3A4 • If DEX is not available, an
(Systemic) • DEX 6 mg IV or PO once • Secondary infections • BP inducer alternative corticosteroid
daily for up to 10 days or •C YP3A4 substrate (e.g., prednisone,
• Reactivation of latent • Signs and symptoms of methylprednisolone,
until hospital discharge, infections (e.g., HBV, new infection • Although
whichever comes first 6 hydrocortisone) can be
HSV, strongyloidiasis, • Cases of disseminated coadministration of used.
TB) strongyloidiasis have been RDV and DEX has not
been formally studied, • The approximate total
• Psychiatric reported in patients with daily dose equivalencies
disturbances COVID-19 during treatment a clinically significant for these glucocorticoids
with corticosteroids PK interaction is not
• Avascular necrosis predicted (Gilead, written to DEX 6 mg (PO or IV)
and tocilizumab. are:
• Adrenal insufficiency Prophylactic treatment for communication, August
• Increased BP strongyloidiasis (e.g., with 2020). • Prednisone 40 mg
• Peripheral edema IVM) should be considered • Methylprednisolone 32
for persons from areas mg
• Myopathy
where Strongyloides is • Hydrocortisone 160 mg
(particularly if used
endemic.7
with neuromuscular • A list of clinical trials is
blocking agents) available: Dexamethasone

AR09042
Dosing Regimen
with COVID-19.
Fluvoxamine
Fluvoxamine Dose for COVID-19 in Clinical • Nausea • Hepatic function •C YP2D6 substrate • F luvoxamine may enhance
Trials: • Diarrhea • Drug interactions • F luvoxamine inhibits anticoagulant effects
• Various dosing regimens several CYP isoenzymes of antiplatelets and
• Dyspepsia • Monitor for withdrawal anticoagulants; consider
used, including: symptoms when tapering (CYP1A2, CYP2C9,
• Asthenia CYP3A4, CYP2C19, additional monitoring
• Fluvoxamine 50 mg twice dose when these drugs are
daily • I
nsomnia CYP2D6)
used concomitantly with
• Fluvoxamine 100 mg twice • Somnolence •C oadministration of fluvoxamine.
daily • Sweating tizanidine, thioridazine,
alosetron, or pimozide • T he use of MAOIs
• Fluvoxamine 100 mg 3 • Suicidal ideation concomitantly with
with fluvoxamine is
times daily (rare) fluvoxamine or within
contraindicated.
14 days of treatment
with fluvoxamine is
contraindicated.
•A list of clinical trials is
available: Fluvoxamine

AR09043
Dosing Regimen
with COVID-19.
Anakinra FDA-Approved Dose for • Neutropenia • CBC with differential •U se with TNF- • Anakinra for IV
Rheumatoid Arthritis: (particularly when • Liver enzymes blocking agents is not administration is not an
• Anakinra 100 mg SQ once used concomitantly recommended due approved formulation in
with other agents • Renal function; reduce to increased risk of the United States.8
daily dose if CrCl <30 mL/min.
that can cause infection. • A list of clinical trials is
Dose for COVID-19 in Clinical neutropenia)
• Avoid concomitant available: Anakinra
Trials:
• Anaphylaxis and administration of live
• Dose and duration vary by angioedema vaccines.
study.
• Headache
• Has also been used as IV
• Nausea
infusion.
• Diarrhea
• Sinusitis
• Arthralgia
• Flu-like symptoms
• Abdominal pain
• Injection site
reactions
• Liver enzyme
elevations

AR09044
Dosing Regimen
with COVID-19.
Interleukin-1 Inhibitors, continued
Canakinumab FDA-Approved Dose for • HSR • HSR •B inding of canakinumab • Canakinumab for IV
Systemic Juvenile Idiopathic • Neutropenia • CBC with differential to IL-1 may increase administration is not an
Arthritis: formation of CYP approved formulation in
• Nasopharyngitis • Liver enzymes enzymes and alter the United States.9
• Canakinumab 4 mg/kg
(maximum 300 mg) SQ • Diarrhea metabolism of drugs that • A list of clinical trials is
every 4 weeks9 • Respiratory tract are CYP substrates. available: Canakinumab
infections •U se with TNF-
Dose for COVID-19 in Clinical
• Bronchitis blocking agents is not
Trials:
recommended due to
• Dose and duration vary by • Gastroenteritis
potential increased risk
study. • Pharyngitis of infection.
CAN-COVID Trial: • Musculoskeletal pain • Avoid concomitant
• Single weight-based dose of • Vertigo administration of live
canakinumab in 250 mL of • Abdominal pain vaccines.
5% dextrose by IV infusion
• Injection site
over 2 hours:10
reactions
• 40 to <60 kg: 450 mg
• Liver enzyme
• 60–80 kg: 600 mg elevations
• >80 kg: 750 mg

AR09045
Dosing Regimen
The doses listed are for approved Drug-Drug Interaction Comments and Links to Clinical
Drug Name indications or from clinical trials or Adverse Events Monitoring Parameters
Potential Trials
clinical experience in patients with
COVID-19.
Anti-Interleukin-6 Receptor Monoclonal Antibodies
Recommended by the Panel for the treatment of COVID-19 in certain nonhospitalized and hospitalized patients.
Sarilumab11 Dose for COVID-19 in Clinical • Neutropenia, • HSR • E levated IL-6 may • Treatment with sarilumab
Trials: thrombocytopenia • Infusion reactions downregulate CYP may mask signs of acute
• Single dose of sarilumab 400 • GI perforation enzymes; thus, use of inflammation or infection by
• Neutrophils sarilumab may lead to suppressing fever and CRP
mg IV12 • HSR • Platelets increased metabolism levels.
• The IV formulation of sarilumab • Increased liver of drugs that are CYP
is not approved by the FDA, • L
iver enzymes • A list of clinical trials is
enzymes substrates. available: Sarilumab
but in a clinical trial, a single
SQ dose (using the prefilled • H
BV reactivation • T he effects of
Availability:
syringe, not the prefilled pen) • Infusion-related sarilumab on CYP
reaction enzymes may persist • Sarilumab for IV administration
of sarilumab 400 mg was
for weeks after the is not an approved formulation
reconstituted in 100 cc 0.9%
drug is stopped. in the United States.
NaCl and given as an IV infusion
over a 1-hour period.
• Sarilumab infusion should
be used within 4 hours of
preparation; it can be stored
at room temperature until
administered.
Tocilizumab 13
EUA Dose for COVID-19 • Infusion-related • HSR • E levated IL-6 may • Tocilizumab use should
For Hospitalized Patients Aged ≥2 reaction • Infusion reactions downregulate CYP be avoided in patients
Years Based on Body Weight: • HSR enzymes; use of who are significantly
• Neutrophils tocilizumab may immunocompromised. The
• <30 kg: Tocilizumab 12 mg/kg • GI perforation • Platelets lead to increased safety of using tocilizumab
administered by IV infusion over • Hepatotoxicity metabolism of plus a corticosteroid in
1 hour • Liver enzymes
• Treatment-related • Cases of disseminated drugs that are CYP immunocompromised patients
• ≥30 kg: Tocilizumab 8 mg/ changes on substrates. is unknown.
kg (maximum dose 800 mg) strongyloidiasis have
laboratory tests been reported in • T he effects of • The SQ formulation of
administered by IV infusion over for neutrophils, tocilizumab on CYP tocilizumab is not intended for
1 hour patients with COVID-19
platelets, lipids, during treatment enzymes may persist IV administration.
and liver enzymes with tocilizumab and for weeks after the • A list of clinical trials is
• HBV reactivation corticosteroids. drug is stopped. available: Tocilizumab

AR09046
Dosing Regimen
Potential Trials
COVID-19.
Interleukin-6 Inhibitors, continued
Anti-Interleukin-6 Receptor Monoclonal Antibodies, continued
Tocilizumab13, • Per the EUA, if clinical signs • Secondary rophylactic treatment
P Availability:
continued or symptoms worsen or do infections for strongyloidiasis • IV tocilizumab, which has been
not improve following the first (e.g., with IVM) should approved for non-COVID-19
infusion, 1 additional dose of be considered for indications, is available
tocilizumab may be administered persons from areas commercially and through an
at least 8 hours after the first where Strongyloides is FDA EUA for the treatment of
dose. endemic.7 COVID-19 in hospitalized adults
and pediatric patients aged
≥2 years who are receiving
systemic corticosteroids
and require supplemental
oxygen, NIV, MV, or ECMO.
The EUA does not authorize
the use of tocilizumab for
SQ administration for the
treatment of COVID-19.14
Anti-Interleukin-6 Monoclonal Antibody
Siltuximab FDA-Approved Dose for • Infusion-related • Neutrophils • E levated IL-6 may • Treatment with siltuximab
Multicentric Castleman Disease: reaction • HSR downregulate CYP may mask signs of acute
• Siltuximab 11 mg/kg • HSR enzymes; use of inflammation or infection by
• Infusion reactions siltuximab may lead to suppressing fever and CRP
administered over 1 hour by IV • GI perforation
infusion every 3 weeks15 increased metabolism levels.
• Neutropenia of drugs that are CYP • A list of clinical trials is
Dose for COVID-19: • HTN substrates. available: Siltuximab
• Dose and duration unknown • Dizziness • T he effects of
siltuximab on CYP
• Rash
enzymes may persist
• Pruritus for weeks after therapy
• Hyperuricemia is stopped.

AR09047
Dosing Regimen
Potential Trials
COVID-19.
Kinase Inhibitors
Janus Kinase Inhibitors
Baricitinib and Tofacitinib: Recommended by the Panel for the treatment of COVID-19 in certain nonhospitalized and hospitalized patients.
Ruxolitinib: Not approved by the FDA and not recommended by the Panel for the treatment of COVID-19. Currently under investigation in clinical trials.
Baricitinib16 EUA Dose for COVID-1917 • Lymphoma • CBC with differential •D ose modification • Baricitinib for the treatment of
For Adults and Children Aged ≥9 and other • Renal function is recommended COVID-19 is available through
Years Based on eGFR: malignancies when administering an FDA EUA. See the EUA for
• Liver enzymes concurrently with a dosing guidance for patients
• ≥60 mL/min/1.73 m2: Baricitinib 4 • Thrombosis • New infections strong OAT3 inhibitor. with:
mg PO once daily • GI perforation
• Avoid concomitant • ALC <200 cells/µL
• 30 to <60 mL/min/1.73 m2: • Treatment- administration of live
Baricitinib 2 mg PO once daily related changes • ANC <500 cells/µL
vaccines.
• 15 to <30 mL/min/1.73 m2: in lymphocytes, • If increases in ALT or AST
Baricitinib 1 mg PO once daily neutrophils, Hgb, are observed and DILI is
liver enzymes suspected, interrupt baricitinib
• eGFR <15 mL/min/1.73 m2: Not treatment until the diagnosis of
recommended • HSV reactivation
DILI is excluded.
• Herpes zoster
For Children Aged 2 to <9 Years • A list of clinical trials is
Based on eGFR: • Serious cardiac- available: Baricitinib
related events
• ≥60 mL/min/1.73 m2: Baricitinib 2 Availability:
(e.g., MI, stroke)
mg PO once daily
• Baricitinib, which has been
• 30 to <60 mL/min/1.73 m2: approved for non-COVID-19
Baricitinib 1 mg PO once daily indications, is available
• <30 mL/min/1.73 m2: Not commercially and through
recommended an EUA for the treatment of
Duration of Therapy: hospitalized patients with
COVID-19 aged ≥2 years.17
• For up to 14 days or until hospital
discharge

AR09048
Dosing Regimen
COVID-19.
Kinase Inhibitors, continued
Janus Kinase Inhibitors, continued
Ruxolitinib Dose for FDA-Approved • Thrombocytopenia • CBC with differential •D ose modification • Dose modification may
Indications: • Anemia • Liver enzymes required when be required in patients
• Ruxolitinib 5 mg–20 mg PO twice administered with with hepatic impairment,
• Neutropenia • New infections strong CYP3A4 moderate or severe
daily
• Liver enzyme elevations inhibitor. renal impairment, or
Dose for COVID-19 in Clinical thrombocytopenia.
Trials: • Risk of infection • Avoid use with
• Dizziness fluconazole doses • A list of clinical trials is
• Ruxolitinib 5 mg–20 mg PO twice >200 mg. available: Ruxolitinib
daily for 14 days18 • Headache
• Diarrhea
• CPK elevation
• Herpes zoster
Tofacitinib Dose for COVID-19 in Clinical • Thrombotic events • CBC with differential •D ose modifications • Avoid use in patients with
Trial: (e.g., PE, DVT, arterial • Liver enzymes required when ALC <500 cells/mm3, ANC
• Tofacitinib 10 mg PO twice daily thrombosis) administered with <1,000 cells/mm3, or Hgb
• New infections strong CYP3A4 <9 grams/dL.
for up to 14 days or until hospital • Anemia
discharge19 inhibitors or when • Dose modification may be
• Risk of infection used with a moderate required in patients with
• GI perforation CYP3A4 inhibitor that moderate or severe renal
• Diarrhea is coadministered with impairment or moderate
a strong CYP2C19 hepatic impairment.
• Headache
inhibitor.
• Herpes zoster • A list of clinical trials is
• Coadministration available: Tofacitinib
• Lipid elevations with strong CYP3A4
• Liver enzyme elevations inducers is not
• Lymphoma and other recommended.
malignancies • Avoid concomitant
• Serious cardiac-related administration of live
events (e.g., MI, stroke) vaccines.

AR09049
Dosing Regimen
COVID-19.
Non-SARS-CoV-2 Specific Immunoglobulin
Primarily used for the treatment of multi-system inflammatory syndrome in children (MIS-C). Currently under investigation in clinical trials.
Non-SARS- • Dose varies based on indication • Allergic reactions, including • Transfusion-related • IVIG may interfere • A list of clinical trials is
CoV-2 Specific and formulation. anaphylaxis reactions with immune available: Intravenous
Immunoglobulin • Renal failure • Vital signs at baseline response to certain Immunoglobulin
and during and after vaccines.
• Thrombotic events
infusion
• Aseptic meningitis
syndrome • Renal function;
discontinue treatment
• Hemolysis if function deteriorates.
• TRALI
• Transmission of infectious
pathogens
• AEs may vary by
formulation.
• AEs may be increased with
high dose, rapid infusion, or
in patients with underlying
conditions.
Key: AE = adverse event; ALC = absolute lymphocyte count; ALT = alanine transaminase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; BP =
blood pressure; CBC = complete blood count; CPK = creatine phosphokinase; CrCl = creatinine clearance; CRP = C-reactive protein; CYP = cytochrome P450; DEX
= dexamethasone; DILI = drug-induced liver injury; DVT = deep vein thrombosis; ECMO = extracorporeal membrane oxygenation; eGFR = estimated glomerular
filtration rate; EUA = Emergency Use Authorization; FDA = Food and Drug Administration; GI = gastrointestinal; HBV = hepatitis B; Hgb = hemoglobin; HSR =
hypersensitivity reaction; HSV = herpes simplex virus; HTN = hypertension; IL = interleukin; IV = intravenous; IVIG = intravenous immunoglobulin; IVM = ivermectin;
MAOI = monoamine oxidase inhibitor; MDI = metered dose inhaler; MI= myocardial infarction; MV = mechanical ventilation; NaCl = sodium chloride; NIV =
noninvasive ventilation; OAT = organic anion transporter; the Panel = the COVID-19 Treatment Guidelines Panel; PE = pulmonary embolism; P-gp= P-glycoprotein; PK
= pharmacokinetic; PO = orally; RDV = remdesivir; SQ = subcutaneous; TB = tuberculosis; TNF = tumor necrosis factor; TRALI = transfusion-related acute lung injury
References
1. Tardif JC, Bouabdallaoui N, L’Allier PL, et al. Colchicine for community-treated patients with COVID-19 (COLCORONA): a Phase 3, randomised,
double-blinded, adaptive, placebo-controlled, multicentre trial. Lancet Respir Med. 2021;9(8):924-932. Available at:

AR09050
2. Colchicine (Colcrys) [package insert]. Food and Drug Administration. 2012. Available at:
3. Ramakrishnan S, Nicolau DV, Jr., Langford B, et al. Inhaled budesonide in the treatment of early COVID-19 (STOIC): a Phase 2, open-label,
randomised controlled trial. Lancet Respir Med. 2021;9(7):763-772. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33844996.
4. Yu LM, Bafadhel M, Dorward J, et al. Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK
(PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet. 2021 Sep 4;398(10303):843-855. Available at:
5. Clemency BM, Varughese R, Gonzalez-Rojas Y, et al. Efficacy of inhaled ciclesonide for outpatient treatment of adolescents and adults With
symptomatic COVID-19: a randomized clinical trial. JAMA Intern Med. 2021;Published online ahead of print. Available at:
6. Randomised Evaluation of COVID-19 Therapy (RECOVERY). Low-cost dexamethasone reduces death by up to one third in hospitalised patients with
severe respiratory complications of COVID-19. 2020. Available at: https://www.recoverytrial.net/news/low-cost-dexamethasone-reduces-death-by-up-
to-one-third-in-hospitalised-patients-with-severe-respiratory-complications-of-covid-19. Accessed February 9, 2021.
7. Stauffer WM, Alpern JD, Walker PF. COVID-19 and dexamethasone: a potential strategy to avoid steroid-related strongyloides hyperinfection. JAMA.
8. Anakinra (Kineret) [package insert]. Food and Drug Administration. 2012. Available at:
9. Canakinumab (Ilaris) [package insert]. Food and Drug Administration. 2020. Available at:
10. Caricchio R, Abbate A, Gordeev I, et al. Effect of canakinumab vs placebo on survival without invasive mechanical ventilation in patients hospitalized
with severe COVID-19: a randomized clinical trial. JAMA. 2021;326(3):230-239. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34283183.
11. Sarilumab (Kevzara) [package insert]. Food and Drug Administration. 2018. Available at:
12. Regeneron and Sanofi provide update on U.S. Phase 2/3 adaptive-designed trial of KEVZARA® (sarilumab) in hospitalized COVID-19 patients [press
release]. 2020.
13. Tocilizumab (Actemra) [package insert]. Food and Drug Administration. 2019. Available at:
14. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization for actemra (tocilizumab). 2021. Available at:
15. Siltuximab (Sylvant) [package insert]. Food and Drug Administration. 2019. Available at:
16. Baricitinib (Olumiant) [package insert]. Food and Drug Administration. 2019. Available at:

AR09051
17. Food and Drug Administration. Fact sheet for healthcare providers: Emergency Use Authorization (EUA) of baricitinib. 2021. Available at:
18. Cao Y, Wei J, Zou L, et al. Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled
trial. J Allergy Clin Immunol. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32470486.
19. Guimaraes PO, Quirk D, Furtado RH, et al. Tofacitinib in patients hospitalized with COVID-19 pneumonia. N Engl J Med. 2021;385(5):406-415.

AR09052
Antithrombotic Therapy in Patients with COVID-19

Chronic Anticoagulant and Antiplatelet Therapy
• The COVID-19 Treatment Guidelines Panel (the Panel) recommends that patients who are receiving anticoagulant or
antiplatelet therapies for underlying conditions continue these medications after they receive a diagnosis of COVID-19
(AIII).
Screening and Evaluation for Venous Thromboembolism
• There is currently insufficient evidence to recommend either for or against routine screening for deep vein thrombosis
in patients with COVID-19 who do not have signs or symptoms of venous thromboembolism (VTE), regardless of the
status of their coagulation markers.
• For hospitalized patients with COVID-19 who experience rapid deterioration of pulmonary, cardiac, or neurological
function or sudden, localized loss of peripheral perfusion, the Panel recommends evaluating the patients for
thromboembolic disease (AIII).
Anticoagulant Treatment for Thrombosis
• The Panel recommends that when diagnostic imaging is not possible, patients with COVID-19 who experience an
incident thromboembolic event or who are highly suspected to have thromboembolic disease be managed with
therapeutic anticoagulation (AIII).
• The Panel recommends that patients with COVID-19 who require extracorporeal membrane oxygenation or
continuous renal replacement therapy or who have thrombosis related to catheters or extracorporeal filters be treated
with antithrombotic therapy as per the standard institutional protocols for those without COVID-19 (AIII).
Antithrombotic Therapy for Nonhospitalized Patients Without Evidence of Venous Thromboembolism
• The Panel recommends against the use of anticoagulants and antiplatelet therapy for the prevention of VTE or arterial
thrombosis unless the patient has other indications for the therapy or is participating in a clinical trial (AIIa).
• The Panel recommends against routinely continuing VTE prophylaxis after hospital discharge, except in a clinical
trial (AIII). For patients who are at high risk for VTE and at low risk of bleeding, extended VTE prophylaxis can be
considered, as per the protocol for patients without COVID-19 (BI).
Antithrombotic Therapy for Hospitalized, Nonpregnant Adults Without Evidence of Venous Thromboembolism
• The Panel recommends against the use of aspirin to prevent mortality or the need for organ support (AI).
• The Panel recommends that anticoagulant or antiplatelet therapy not be used to prevent arterial thrombosis outside of
the usual standard of care for patients without COVID-19 (AIII).
• In hospitalized patients, low molecular weight heparin (LMWH) or unfractionated heparin (UFH) is preferred over oral
anticoagulants, because these 2 types of heparin have shorter half-lives and the effect can be reversed quickly, can be
administered intravenously or subcutaneously, and have fewer drug-drug interactions (AIII).
• When heparin is used, LMWH is preferred over UFH.
For adults who require low-flow oxygen and do not require intensive care unit (ICU)-level care:
• The Panel recommends the use of a therapeutic dose of heparin for patients with D-dimer levels above the upper
limit of normal, who require low-flow oxygen, and who do not have an increased bleeding risk (CIIa).
• Contraindications for the use of therapeutic anticoagulation in patients with COVID-19 are a platelet count <50 x
109/L, hemoglobin <8 g/dL, the need for dual antiplatelet therapy, bleeding within the past 30 days that required
an emergency department visit or hospitalization, history of a bleeding disorder, or an inherited or active acquired
bleeding disorder. This list is based on the exclusion criteria from clinical trials; patients with these conditions have
an increased risk of bleeding.
• In patients without VTE who have begun a therapeutic dose of heparin, treatment should continue for 14 days or until
hospital discharge, whichever comes first.
• The Panel recommends the use of a prophylactic dose of heparin for patients who are not receiving a therapeutic
dose of heparin, unless a contraindication exists (AIIb).

AR09053
• The Panel recommends against the use of a therapeutic dose of oral anticoagulants for VTE prophylaxis or
prevention of COVID-19 progression, except in a clinical trial (AIIa).
• There is currently insufficient evidence to recommend either for or against the use of thrombolytics for COVID-19.
For adults who require ICU-level care, including those receiving high-flow oxygen:
• The Panel recommends using a prophylactic dose of heparin as VTE prophylaxis, unless a contraindication exists (AI).
• The Panel recommends against the use of an intermediate dose (e.g., enoxaparin 1 mg/kg once daily) or a
therapeutic dose of anticoagulation for VTE prophylaxis, except in a clinical trial (BI).
• For patients who start on a therapeutic dose of heparin in a non-ICU setting due to COVID-19 and then transfer to the
ICU, the Panel recommends switching from the therapeutic dose to a prophylactic dose of heparin, unless VTE is
confirmed (BIII).
Hospitalized Children
• For hospitalized children with COVID-19, indications for VTE prophylaxis should be the same as those for children
without COVID-19 (BIII).
Special Considerations During Pregnancy and Lactation
• The Panel recommends that pregnant patients who are receiving anticoagulant or antiplatelet therapies for underlying
conditions continue these medications after they receive a diagnosis of COVID-19 (AIII).
• The Panel recommends the use of a prophylactic dose of anticoagulation for pregnant patients hospitalized for
manifestations of COVID-19, unless otherwise contraindicated (BIII).
• Because pregnant patients have not been included in most clinical trials evaluating therapeutic anticoagulation in
the setting of COVID-19, there is currently insufficient evidence to recommend either for or against therapeutic
anticoagulation for pregnant patients with COVID-19 without evidence of VTE.
• Like for nonpregnant patients, VTE prophylaxis after hospital discharge is not routinely recommended for pregnant
patients (BIII). Decisions to continue VTE prophylaxis in the pregnant or postpartum patient after discharge should be
individualized, with consideration of concomitant VTE risk factors.
• Anticoagulation therapy use during labor and delivery requires specialized care and planning. It should be managed in
pregnant patients with COVID-19 in a similar way as in pregnant patients with other conditions (AIII).
• UFH, LMWH, and warfarin do not accumulate in breast milk and do not induce an anticoagulant effect in the newborn;
therefore, they can be used by breastfeeding individuals who require VTE prophylaxis or treatment (AIII).
Association Between COVID-19 and Thromboembolism

COVID-19 has been associated with inflammation and a prothrombotic state, with increases in fibrin,
fibrin degradation products, fibrinogen, and D-dimer levels.1,2 In some studies, elevations in these
markers have been associated with worse clinical outcomes.3,4
Studies have reported varying incidences of venous thromboembolism (VTE) in patients with
COVID-19. A meta-analysis of studies of hospitalized patients with COVID-19 treated with VTE
prophylaxis found an overall VTE prevalence of 14.1% (95% CI, 11.6–16.9).5 The VTE prevalence
was higher in studies that used ultrasound screening (40.3%; 95% CI, 27.0–54.3) than in studies that
did not (9.5%; 95% CI, 7.5–11.7). In randomized controlled trials conducted prior to the pandemic, the
incidence of VTE in hospitalized patients without COVID-19 who received VTE prophylaxis ranged
from 0.3% to 1% for symptomatic VTE and from 2.8% to 5.6% for VTE overall.6-8 The VTE incidence
in randomized trials in critically ill patients without COVID-19 who received a prophylactic dose of
anticoagulants ranged from 5% to 16%, and a prospective cohort study of critically ill patients with
sepsis reported a VTE incidence of 37%.9-12

AR09054
Guidelines about coagulopathy and the prevention and management of VTE in patients with COVID-19
have been released by multiple organizations, including the American College of Chest Physicians,13
American Society of Hematology,14 Anticoagulation Forum,15 International Society on Thrombosis and
Haemostasis,16 Italian Society for Haemostasis and Thrombosis,17 National Institute for Health and Care
Excellence (NICE),18 and Royal College of Physicians.19
The guidelines referenced above agree that hospitalized, nonpregnant patients with COVID-19 should
receive, at a minimum, a prophylactic dose of anticoagulation to prevent VTE. The NICE guideline
recommendation states: “Consider a treatment dose of a low-molecular-weight heparin (LMWH) for
young people and adults with COVID-19 who need low-flow oxygen and who do not have an increased
bleeding risk.” Results from clinical trials that assess the safety and efficacy of different anticoagulant
doses and strategies have provided further information on antithrombotic strategies for patients with
COVID-19.
Chronic Anticoagulant or Antiplatelet Therapy

Outpatients with COVID-19 who are receiving warfarin and are in isolation and unable to have
international normalized ratio monitoring may be candidates for switching to direct oral anticoagulant
therapy. Patients with a mechanical heart valve, ventricular assist device, valvular atrial fibrillation,
or antiphospholipid antibody syndrome or who are lactating should not discontinue treatment with
warfarin (AIII). The COVID-19 Treatment Guidelines Panel (the Panel) recommends that hospitalized
patients with COVID-19 who are receiving anticoagulant or antiplatelet therapy for underlying medical
conditions continue this treatment unless significant bleeding develops or other contraindications are
present (AIII).
Screening and Evaluation for Venous Thromboembolism

VTE guidelines for patients without COVID-19 have recommended against routine screening
ultrasounds in critically ill patients because no study has shown that this strategy reduces the rate of
subsequent symptomatic thromboembolic complications.20 Although the incidence of thromboembolic
events, especially pulmonary emboli, can be high among hospitalized patients with COVID-19,
no published data demonstrate the clinical utility of using lower extremity ultrasound as routine
surveillance for deep vein thrombosis in this population.
• There is currently insufficient evidence to recommend either for or against routine screening for
deep vein thrombosis in patients with COVID-19 who do not have signs or symptoms of VTE,
regardless of the status of their coagulation markers.
• For hospitalized patients with COVID-19 who experience rapid deterioration of pulmonary,
cardiac, or neurological function or sudden, localized loss of peripheral perfusion, the Panel
recommends evaluating the patients for thromboembolic disease (AIII).
Managing Antithrombotic Therapy in Patients With COVID-19

The Panel recommends that when diagnostic imaging is not possible, patients with COVID-19 who
experience an incident thromboembolic event or who are highly suspected to have thromboembolic
disease be managed with therapeutic anticoagulation (AIII).
The Panel recommends that patients with COVID-19 who require extracorporeal membrane oxygenation
(ECMO) or continuous renal replacement therapy or who have thrombosis related to catheters or
extracorporeal filters be treated with antithrombotic therapy as per the standard institutional protocols
for those without COVID-19 (AIII).

AR09055
Selection of Anticoagulant or Antiplatelet Drugs

Whenever anticoagulant or antiplatelet therapy is used, potential drug-drug interactions with other
concomitant drugs must be considered. The University of Liverpool has collated a list of drug
interactions. In hospitalized, critically ill patients, LMWH or unfractionated heparin (UFH) is preferred
over oral anticoagulants, because these 2 types of heparin have shorter half-lives and the effect can
be reversed quickly, can be administered intravenously or subcutaneously, and have fewer drug-drug
interactions (AIII).
Management of Nonhospitalized Patients

The ACTIV-4b placebo-controlled, randomized trial evaluated the efficacy of aspirin versus prophylactic
(2.5 mg) or therapeutic (5 mg) doses of apixaban to prevent thromboembolic events, hospitalization,
and mortality in outpatients >40 years with COVID-19. The trial was stopped in June 2021 due to
a low event rate (1 patient each in the placebo, aspirin, and apixaban 2.5 mg arms and 2 patients in
the apixaban 5 mg arm) after randomization of 657 symptomatic outpatients. The median time from
randomization to study treatment was 3 days, and 22 participants were hospitalized for COVID-19 prior
to initiation of study drug.21 It is not known whether patients with previous VTE events or inherited
thrombophilias were included in this trial. For nonhospitalized patients with COVID-19, the Panel
recommends against the use of anticoagulants and antiplatelet therapy for the prevention of VTE or
arterial thrombosis unless the patient has other indications for the therapy or is participating in a clinical
trial (AIIa).
Management of Hospitalized Patients

Several studies have evaluated the risks and benefits of prophylactic and therapeutic doses of
anticoagulants in patients with COVID-19. Observational studies and clinical trials have examined the
effects of anticoagulation on mortality, progression of COVID-19, thrombosis, and bleeding. Some of
these studies are outlined below (visit ClinicalTrials.gov for a current list of trials). Observational studies
are included here only when evidence from clinical trials is not available.
Prophylactic-Dose of Anticoagulation Versus No Anticoagulation—Observational Cohort
An observational study of 4,297 veterans hospitalized with COVID-19 evaluated the benefit of
prophylactic anticoagulation. A prophylactic dose of anticoagulation was administered to 3,627 patients
with COVID-19 within 24 hours of hospital admission. An inverse probability of treatment weighted
analysis showed a cumulative 30-day mortality of 14% among veterans who received prophylactic
anticoagulation and 19% among patients who were not treated with anticoagulation (HR 0.73; 95% CI,
0.66–0.81). Participants treated with the prophylactic dose did not have a significant difference in risk
of bleeding that required transfusion when compared with participants who were not treated (HR 0.87;
95% CI, 0.71–1.05). Overall, the study demonstrated that patients with COVID-19 may benefit from a
prophylactic dose of anticoagulation.22
Therapeutic Versus Prophylactic Doses of Heparin in Hospitalized Patients Who Do Not Require
Intensive Care Unit-Level Care
Several randomized controlled trials have evaluated the role of therapeutic doses of heparin in reducing
VTE events or mortality in patients hospitalized for COVID-19.
Three open-label randomized controlled trials (the large ATTACC/ACTIV-4a/REMAP-CAP
multiplatform trial and the smaller RAPID and HEP-COVID trials) compared therapeutic doses of
heparin to prophylactic or intermediate doses of the anticoagulant in selected hospitalized patients who
did not require intensive care. Clinical data for these trials are summarized in Table 5. The inclusion and
exclusion criteria for these studies varied, but most included a need for supplemental oxygen and no risk

AR09056
of a major bleeding event. In the larger multiplatform trial, therapeutic doses of heparin increased organ
support-free days but did not significantly affect mortality or length of hospitalization when compared
with prophylactic doses of heparin.23
The RAPID trial enrolled patients with elevated D-dimer levels and hypoxemia. The patients were
randomized to receive therapeutic or prophylactic doses of heparin. There was no statistically significant
difference between the arms for the primary endpoint, which was a composite of intensive care unit
(ICU) admission, noninvasive or mechanical ventilation, or death by Day 28. However, the therapeutic
dose of heparin reduced all-cause death, a secondary outcome.24
The HEP-COVID trial enrolled patients who required supplemental oxygen and had a D-dimer value
>4 times the upper limit of normal (ULN) or a sepsis-induced coagulopathy score of ≥4. There were
significantly fewer occurrences of the primary endpoint of VTE, arterial thromboembolism, or all-cause
death within 32 days of randomization in the therapeutic LMWH arm than in the prophylactic LMWH
arm, but there was no difference between arms for the outcome of death within 32 days.25 Results from
smaller randomized trials, single-center studies, and observational studies have also been published.
Given the results of the ATTACC/ACTIV-4a/REMAP-CAP, RAPID, and HEP-COVID trials conducted
among hospitalized, nonpregnant adults with COVID-19 who did not require ICU-level care and without
evidence of VTE:
• The Panel recommends the use of a therapeutic dose of heparin for patients with D-dimer levels
above the ULN who require low-flow oxygen and who do not have an increased bleeding risk
(CIIa).
• Based on clinical trial exclusion criteria, contraindications for use of therapeutic
anticoagulation for patients with COVID-19 are a platelet count <50 x 109/L, hemoglobin <8
g/dL, the need for dual antiplatelet therapy, bleeding within the past 30 days that required an
emergency department visit or hospitalization, history of a bleeding disorder, or an inherited or
active, acquired bleeding disorder.
• LMWH is preferred over UFH because of its decreased administrative burden and because
LMWH was the predominant form of heparin used in the clinical trials for COVID-19.
• In patients without VTE who have begun a therapeutic dose of heparin, treatment should continue
for 14 days or until hospital discharge, whichever comes first.
• Patients with predicted hospitalizations of <72 hours were excluded from the multiplatform trial.
The risk/benefit ratio of therapeutic doses of anticoagulation for short hospital stays is not known.
• The Panel recommends the use of a prophylactic dose of heparin for patients who do not meet
the criteria for receiving therapeutic heparin or are not receiving a therapeutic dose of heparin for
other reasons unless a contraindication exists (AIIb).
• The Panel recommends against the use of a therapeutic dose of oral anticoagulants for VTE
prophylaxis or prevention of COVID-19 progression, except in a clinical trial (AIIa).
• There is currently insufficient evidence to recommend either for or against the use of
thrombolytics for COVID-19.
Prophylactic Versus Intermediate or Therapeutic Doses of Heparin in Hospitalized Patients Who
Require Intensive Care Unit-Level Care
Several randomized controlled trials have evaluated the role of therapeutic doses of heparin in reducing
VTE events or mortality in patients in the ICU setting. Clinical data for these trials are summarized in
Table 5.

AR09057
For the composite endpoint of adjudicated VTE, arterial thrombosis, ECMO, or all-cause mortality, the
INSPIRATION trial found no difference between patients in the ICU treated with an intermediate dose
of anticoagulation (enoxaparin 1 mg/kg daily) and those who received a prophylactic dose (45.7% vs.
44.1%; OR 1.06; 95% CI, 0.76–1.48). Major bleeding occurred in 2.5% of patients in the intermediate-
dose anticoagulation arm compared with 1.4% of patients who received the prophylactic dose. Overall,
there was no significant benefit of receiving an intermediate dose of anticoagulation for patients with
COVID-19 in the ICU.26
A multiplatform randomized control trial (REMAP-CAP/ACTIV-4a/ATTACC) compared the
effectiveness of a therapeutic dose of heparin or LMWH with usual care in reducing the number of
organ support-free days among critically ill patients with COVID-19.27 All 3 trials were stopped for
futility. Heparin doses in the usual care arm varied. The median number of organ support-free days was
3 days (IQR -1 to 16) for patients who received a therapeutic dose of anticoagulation and 4 days (IQR -1
to 16) for patients who received usual care. The likelihood of survival to hospital discharge did not differ
between arms (63% therapeutic arm vs. 65% usual care arm; aOR 0.84; 95% CrI, 0.64–1.11). Major
bleeding occurred in 4% of participants receiving therapeutic anticoagulation and in 2% of participants
receiving usual care. Therapeutic doses of heparin showed no significant benefit for patients with
COVID-19 admitted to the ICU.
Given the results of these trials, for hospitalized, nonpregnant adults with COVID-19 who require ICU
level-care and who do not have documented or suspected VTE:
• For patients who start on a therapeutic dose of heparin in a non-ICU setting due to COVID-19
and then transfer to the ICU, the Panel recommends switching from the therapeutic dose to a
prophylactic dose of heparin, unless VTE is confirmed (BIII).
• The Panel recommends against the use of an intermediate dose (e.g., enoxaparin 1 mg/kg
Rivaroxaban Versus Usual Care in Hospitalized Patients With Elevated D-Dimer Levels
The ACTION trial randomized adults hospitalized with COVID-19 and elevated D-dimer levels (defined
as above the laboratory ULN) to receive rivaroxaban 20 mg daily for 30 days or usual care28 (see Table
5 for a summary of clinical data for this trial). No statistical difference was found for the composite
endpoint of time to death, hospitalization duration, and oxygen use duration (hierarchical analysis; win
ratio 0.86; 95% CI, 0.59–1.22) or for the individual components. The probability of clinically relevant
nonmajor bleeding was greater with rivaroxaban (5% rivaroxaban arm vs. 1% usual care arm; relative
risk 5.23; 95% CI, 1.54–17.77), but for major bleeding events the difference between arms was not
significant (3% rivaroxaban arm vs. 1% usual care arm; relative risk 2.45; 95% CI, 0.78–7.73).
Given the lack of benefit and the increased risk of bleeding events, the Panel recommends against
the use of a therapeutic dose of anticoagulation for VTE prophylaxis and prevention of COVID-19
progression, except in a clinical trial (BI).
Aspirin Versus Usual Care in Hospitalized Patients
The RECOVERY trial randomized 7,351 hospitalized adults with COVID-19 to usual care plus aspirin
150 mg per day and 7,541 patients to usual care only.29 Mortality at 28 days was 17% in both arms (rate
ratio 0.96; 95% CI, 0.89–1.04). Results were similar in all prespecified subgroups, including when
restricted to patients with polymerase chain reaction–documented SARS-CoV-2 infection. Among
participants not receiving mechanical ventilation at baseline, there was no difference in progression

AR09058
to mechanical ventilation or death (21% aspirin arm vs. 22% usual care arm; rate ratio 0.96; 95% CI,
0.90–1.03). Among those treated with aspirin, the incidence of thrombotic events was lower (4.6% vs.
5.3%; absolute difference 0.6%; SE 0.4%), and the incidence of major bleeding events was higher (1.6%
vs. 1.0%; absolute difference 0.6%; SE 0.2%). Given the large trial size, lack of mortality benefit, and
increase in bleeding events, the Panel recommends against the use of aspirin to prevent mortality or the
need for organ support in hospitalized patients with COVID-19 (AI).
P2Y12 Inhibitor Versus Usual Care in Hospitalized Patients
The ACTIV-4a trial evaluated P2Y12 inhibitor therapy plus a therapeutic dose of heparin versus
therapeutic heparin alone in noncritically ill, hospitalized patients with COVID-19. In this study,
enrollment in the cohort that did not receive intensive care was stopped due to futility because the
combination therapy did not improve the number of organ support-free days.30
Thrombolytic Therapy
Clinical trials are evaluating the use of thrombolysis on mortality and the progression of COVID-19
illness. There is currently insufficient evidence to recommend either for or against the use of
thrombolytic agents for VTE prophylaxis for hospitalized patients with COVID-19 outside of a clinical
trial.
Hospitalized Children
A recent meta-analysis of publications on COVID-19 in children did not discuss VTE.31 Indications for
VTE prophylaxis in hospitalized children with COVID-19 should be the same as those for hospitalized
children without COVID-19 (BIII).
Patients Discharged From the Hospital

For certain high-VTE risk patients without COVID-19, post-discharge prophylaxis has been shown to
be beneficial. The Food and Drug Administration approved the use of rivaroxaban 10 mg daily for 31 to
39 days in these patients.32,33 Inclusion criteria for the trials that studied post-discharge VTE prophylaxis
included:
• A VTE risk score of ≥4 on the modified International Medical Prevention Registry on Venous
Thromboembolism (IMPROVE) tool,34 or
• A VTE risk score ≥2 on the modified IMPROVE tool35 and a D-dimer level >2 times ULN.32
Any decision to use post-discharge VTE prophylaxis for patients with COVID-19 should include
consideration of the individual patient’s risk factors for VTE, bleeding risks, and feasibility. The
MICHELLE trial of post-discharge prophylaxis in patients with COVID-19 was recently published and
is being reviewed by the Panel.36 Participation in clinical trials is encouraged.
Special Considerations During Pregnancy and Lactation

Because pregnancy is a hypercoagulable state, the risk of thromboembolism is greater in pregnant
individuals than in nonpregnant individuals.37 It is not yet known whether COVID-19 increases this
risk. In several cohort studies of pregnant women with COVID-19 in the United States and Europe,
VTE was not reported as a complication even among women with severe disease, although the receipt
of prophylactic or therapeutic anticoagulation varied across the studies.38-40 The American College
of Obstetricians and Gynecologists (ACOG) advises that, although there are no data for or against
thromboprophylaxis in the setting of COVID-19 in pregnancy, VTE prophylaxis can reasonably be
considered for pregnant individuals hospitalized with COVID-19, particularly for those who have severe

AR09059
disease.41 If there are no contraindications to use, the Society for Maternal-Fetal Medicine recommends
prophylactic heparin or LMWH in critically ill or mechanically ventilated pregnant patients.42 Several
professional societies, including the American Society of Hematology and ACOG, have guidelines that
specifically address the management of VTE in the context of pregnancy.43,44 If delivery is imminent,
or if there are other risks for bleeding, the risk of bleeding may outweigh the potential benefit of VTE
prophylaxis in pregnancy.
Outside of pregnancy, D-dimer levels have been used to stratify VTE risk. However, physiologic
increases in D-dimer levels may occur during pregnancy, making elevated D-dimer values an unreliable
predictor that should not be used to evaluate VTE risk during pregnancy in the setting of COVID-19.45-47
In general, the preferred anticoagulants for use during pregnancy are heparin compounds. Because of its
reliability and ease of administration, LMWH is recommended rather than UFH for the prevention and
treatment of VTE in pregnancy.44 Direct-acting anticoagulants are not routinely recommended during
pregnancy because of a lack of safety data for pregnant individuals.43 The use of warfarin to prevent or
treat VTE should be avoided in pregnant individuals regardless of their COVID-19 status, especially
during the first trimester due to the concern for teratogenicity.
Specific recommendations for pregnant or lactating individuals with COVID-19 include:
• The Panel recommends that pregnant patients who are receiving anticoagulant or antiplatelet
therapies for underlying conditions continue these medications after they receive a diagnosis of
COVID-19 (AIII).
• The Panel recommends the use of a prophylactic dose of anticoagulation for pregnant patients
hospitalized for manifestations of COVID-19, unless otherwise contraindicated (BIII).
• Because pregnant patients have not been included in most clinical trials evaluating therapeutic
anticoagulation in the setting of COVID-19, there is currently insufficient evidence to recommend
either for or against therapeutic anticoagulation for pregnant patients with COVID-19 without
evidence of VTE.
• Like for nonpregnant patients, VTE prophylaxis after hospital discharge is not routinely
recommended for pregnant patients (BIII). Decisions to continue VTE prophylaxis in the pregnant
or postpartum patient after discharge should be individualized, with consideration of concomitant
VTE risk factors.
• Anticoagulation therapy use during labor and delivery requires specialized care and planning. It
should be managed in pregnant patients with COVID-19 in a similar way as in pregnant patients
with other conditions (AIII).
• UFH, LMWH, and warfarin do not accumulate in breast milk and do not induce an anticoagulant
effect in the newborn; therefore, they can be used by breastfeeding individuals who require VTE
prophylaxis or treatment (AIII).
References
1. Han H, Yang L, Liu R, et al. Prominent changes in blood coagulation of patients with SARS-CoV-2 infection.
Clin Chem Lab Med. 2020;58(7):1116-1120. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32172226.
2. Driggin E, Madhavan MV, Bikdeli B, et al. Cardiovascular considerations for patients, health care workers,
and health systems during the COVID-19 pandemic. J Am Coll Cardiol. 2020;75(18):2352-2371. Available at:
3. Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med.

AR09060
4. Tang N, Bai H, Chen X, et al. Anticoagulant treatment is associated with decreased mortality in severe
coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18(5):1094-1099. Available at:
5. Nopp S, Moik F, Jilma B, Pabinger I, Ay C. Risk of venous thromboembolism in patients with COVID-19: a
systematic review and meta-analysis. Res Pract Thromb Haemost. 2020. Available at:
6. Cohen AT, Davidson BL, Gallus AS, et al. Efficacy and safety of fondaparinux for the prevention of
venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ.
7. Leizorovicz A, Cohen AT, Turpie AG, et al. Randomized, placebo-controlled trial of dalteparin for the
prevention of venous thromboembolism in acutely ill medical patients. Circulation. 2004;110(7):874-879.
8. Samama MM, Cohen AT, Darmon JY, et al. A comparison of enoxaparin with placebo for the prevention of
venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin
Study Group. N Engl J Med. 1999;341(11):793-800. Available at:
9. Fraisse F, Holzapfel L, Couland JM, et al. Nadroparin in the prevention of deep vein thrombosis in acute
decompensated COPD. The Association of Non-University Affiliated Intensive Care Specialist Physicians of
France. Am J Respir Crit Care Med. 2000;161(4 Pt 1):1109-1114. Available at:
10. PROTECT Investigators for the Canadian Critical Care Trials Group, Australian t, New Zealand Intensive
Care Society Clinical Trials Group, et al. Dalteparin versus unfractionated heparin in critically ill patients. N
11. Shorr AF, Williams MD. Venous thromboembolism in critically ill patients. Observations from a randomized
trial in sepsis. Thromb Haemost. 2009;101(1):139-144. Available at:
12. Kaplan D, Casper TC, Elliott CG, et al. VTE incidence and risk factors in patients with severe sepsis and
septic shock. Chest. 2015;148(5):1224-1230. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26111103.
13. Moores LK, Tritschler T, Brosnahan S, et al. Thromboprophylaxis in patients with COVID-19. A brief update
to the CHEST Guideline and expert panel report. Chest. 2022;Published online ahead of print. Available at:
14. American Society of Hematology. ASH guidelines on use of anticoagulation in patients with COVID-19.
2022. Available at: https://www.hematology.org/education/clinicians/guidelines-and-quality-care/
clinical-practice-guidelines/venous-thromboembolism-guidelines/ash-guidelines-on-use-of-anticoagulation-in-
patients-with-covid-19. Accessed February 3, 2022.
15. Barnes GD, Burnett A, Allen A, et al. Thromboembolism and anticoagulant therapy during the COVID-19
pandemic: interim clinical guidance from the anticoagulation forum. J Thromb Thrombolysis. 2020;50(1):72-
16. Thachil J, Tang N, Gando S, et al. ISTH interim guidance on recognition and management of coagulopathy in
COVID-19. J Thromb Haemost. 2020;18(5):1023-1026. Available at:
17. Marietta M, Ageno W, Artoni A, et al. COVID-19 and haemostasis: a position paper from Italian Society on
Thrombosis and Haemostasis (SISET). Blood Transfus. 2020;18(3):167-169. Available at:
18. National Institute for Health Care Excellence. COVID-19 rapid guideline: managing COVID-19. 2022.
Available at: https://www.nice.org.uk/guidance/ng191. Accessed February 3, 2022.
19. Royal College of Physicians. Clinical guide for the prevention, detection and management of thromboembolic

AR09061
disease in patients with COVID-19. 2020. Available at: https://icmanaesthesiacovid-19.org/clinical-guide-

prevention-detection-and-management-of-vte-in-patients-with-covid-19. Accessed February 4, 2022.
20. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and
Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice
Guidelines. Chest. 2012;141(2 Suppl):e195S-e226S. Available at:
21. Connors JM, Brooks MM, Sciurba FC, et al. Effect of antithrombotic therapy on clinical outcomes in
outpatients with clinically stable symptomatic COVID-19: the ACTIV-4B randomized clinical trial. JAMA.
22. Rentsch CT, Beckman JA, Tomlinson L, et al. Early initiation of prophylactic anticoagulation for prevention
of coronavirus disease 2019 mortality in patients admitted to hospital in the United States: cohort study. BMJ.
2021;372:n311. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33574135.
23. ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators, et al. Therapeutic
anticoagulation with heparin in noncritically ill patients with COVID-19. N Engl J Med. 2021;385(9):790-802.
24. Sholzberg M, Tang GH, Rahhal H, et al. Effectiveness of therapeutic heparin versus prophylactic heparin
on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with COVID-19
admitted to hospital: RAPID randomised clinical trial. BMJ. 2021;375:n2400. Available at:
25. Spyropoulos AC, Goldin M, Giannis D, et al. Efficacy and safety of therapeutic-dose heparin vs standard
prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with
COVID-19: the HEP-COVID randomized clinical trial. JAMA Intern Med. 2021;181(12):1612-1620.
26. Inspiration Investigators, Sadeghipour P, Talasaz AH, et al. Effect of intermediate-dose vs standard-dose
prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or
mortality among patients with COVID-19 admitted to the intensive care unit: the INSPIRATION randomized
27. The REMAP-CAP, ACTIV-4a, ATTACC Investigators, Zarychanski R. Therapeutic anticoagulation in
critically ill patients with COVID-19—preliminary report. medRxiv. 2021;Preprint. Available at:
28. Lopes RD, de Barros ESPGM, Furtado RHM, et al. Therapeutic versus prophylactic anticoagulation for
patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label,
multicentre, randomised, controlled trial. Lancet. 2021;397(10291):2253-2263. Available at:
29. RECOVERY Collaborative Group. Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a
randomised, controlled, open-label, platform trial. Lancet. 2022;399(10320):143-151. Available at:
30. Berger JS, Kornblith LZ, Gong MN, et al. Effect of P2Y12 inhibitors on survival free of organ support among
non-critically ill hospitalized patients with COVID-19: a randomized clinical trial. JAMA. 2022;327(3):227-
31. Ludvigsson JF. Systematic review of COVID-19 in children shows milder cases and a better prognosis than
adults. Acta Paediatr. 2020;109(6):1088-1095. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32202343.
32. Spyropoulos AC, Lipardi C, Xu J, et al. Modified IMPROVE VTE risk score and elevated D-dimer identify
a high venous thromboembolism risk in acutely ill medical population for extended thromboprophylaxis. TH
Open. 2020;4(1):e59-e65. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32190813.
33. Cohen AT, Harrington RA, Goldhaber SZ, et al. Extended thromboprophylaxis with betrixaban in acutely ill
medical patients. N Engl J Med. 2016;375(6):534-544. Available at:

AR09062
34. Spyropoulos AC, Anderson FA, Jr., FitzGerald G, et al. Predictive and associative models to identify
hospitalized medical patients at risk for VTE. Chest. 2011;140(3):706-714. Available at:
35. Gibson CM, Spyropoulos AC, Cohen AT, et al. The IMPROVEDD VTE risk score: incorporation of d-dimer
into the IMPROVE score to improve venous thromboembolism risk stratification. TH Open. 2017;1(1):e56-
e65. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31249911.
36. Ramacciotti E, Barile Agati L, Calderaro D, et al. Rivaroxaban versus no anticoagulation for post-discharge
thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): an open-label, multicentre,
randomised, controlled trial. Lancet. 2022;399(10319):50-59. Available at:
37. Heit JA, Kobbervig CE, James AH, et al. Trends in the incidence of venous thromboembolism during
pregnancy or postpartum: a 30-year population-based study. Ann Intern Med. 2005;143(10):697-706.
38. Breslin N, Baptiste C, Gyamfi-Bannerman C, et al. Coronavirus disease 2019 infection among asymptomatic
and symptomatic pregnant women: two weeks of confirmed presentations to an affiliated pair of New York
City hospitals. Am J Obstet Gynecol MFM. 2020;2(2):100118. Available at:
39. Knight M, Bunch K, Vousden N, et al. Characteristics and outcomes of pregnant women admitted to hospital
with confirmed SARS-CoV-2 infection in UK: national population based cohort study. BMJ. 2020;369:m2107.
40. Delahoy MJ, Whitaker M, O’Halloran A, et al. Characteristics and maternal and birth outcomes of hospitalized
pregnant women with laboratory-confirmed COVID-19 - COVID-NET, 13 States, March 1–August 22, 2020.
MMWR Morb Mortal Wkly Rep. 2020;69(38):1347-1354. Available at:
gyns-obstetrics. Accessed February 4, 2022.
42. Society for Maternal Fetal Medicine. Management considerations for pregnant patients With COVID-19.
43. Bates SM, Rajasekhar A, Middeldorp S, et al. American Society of Hematology 2018 guidelines for
management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood Adv.
44. ACOG practice bulletin no. 196 summary: thromboembolism in pregnancy. Obstet Gynecol. 2018;132(1):243-
45. Wang M, Lu S, Li S, Shen F. Reference intervals of D-dimer during the pregnancy and puerperium period on
the STA-R evolution coagulation analyzer. Clin Chim Acta. 2013;425:176-180. Available at:
46. Reger B, Peterfalvi A, Litter I, et al. Challenges in the evaluation of D-dimer and fibrinogen levels in pregnant
women. Thromb Res. 2013;131(4):e183-187. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23481480.
47. Hu W, Wang Y, Li J, et al. The predictive value of D-dimer test for venous thromboembolism during
puerperium: a prospective cohort study. Clin Appl Thromb Hemost. 2020;26:1076029620901786. Available at:

AR09063
Table 5. Antithrombotic Therapy: Selected Clinical Data

antithrombotic therapy. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations.

ATTACC/ACTIV-4a/REMAP-CAP: Multiplatform, Open-Label RCT of Therapeutic Anticoagulation in Noncritically Ill, Hospitalized Patients With COVID-19 in 9
Countries1
• Hospitalized with laboratory-confirmed SARS- • Median age 59 years; 59% men; median BMI 30 • Open-label study
CoV-2 infection without need for HFNC oxygen, • 52% with HTN; 30% with DM; 11% with CVD • Anticoagulation dose varied in SOC arm (27%
NIV, MV, vasopressors, or inotropes received intermediate-dose thromboprophylaxis).
• 66% required low-flow oxygen
Key Exclusion Criteria: • D-dimer: • Studies had different criteria for ICU care and
• Discharge expected ≤72 hours expected hospital LOS.
• 48.4% <2 times ULN
• Requirement for therapeutic anticoagulation or • Only enrolled 17% of screened patients
• 28.4% ≥2 times ULN
dual antiplatelet therapy Interpretation:
• 23.1% unknown
• High bleeding risk • Therapeutic heparin increased organ support-
• 62% on corticosteroids; 36% on RDV
Interventions: free days and decreased the number of patients
Primary Outcomes: requiring organ support.
• Therapeutic UFH or LMWH for 14 days or until
discharge, whichever comes first (n = 1,190) • Organ support-free days: therapeutic anticoagulation • Therapeutic heparin did not significantly affect
superior to SOC (aOR 1.27; 95% CrI, 1.03–1.58; 99% hospital LOS or the number of major thrombosis
• SOC (n = 1,054) posterior probability) events or deaths.
Primary Endpoint: • Survival until hospital discharge without organ • Major bleeds occurred 1% more frequently in
• Organ support-free days at Day 21, evaluated on support: 4% absolute difference favoring therapeutic therapeutic arm than in SOC arm.
an ordinal scale anticoagulation arm (95% CrI, 0.5–7.2)
Key Secondary Endpoints: • Outcome consistent across D-dimer stratum
• Survival until hospital discharge Secondary Outcomes:
• Hospital LOS • Survival until hospital discharge: 92% in both arms
• Thrombosis or major bleeding • Hospital LOS: no difference between arms (aOR 1.03;
95% CrI, 0.94–1.13)
• Thrombosis: 1% in therapeutic arm vs. 2% in SOC arm
• Major bleeding: 2% in therapeutic arm vs. 1% in SOC
arm

AR09064
RAPID: Open-Label RCT of Therapeutic Heparin in Moderately Ill, Hospitalized Patients With COVID-19 in 6 Countries2
• Hospitalized with COVID-19 and D-dimer ≥2 • Median age 60 years; 57% men; mean BMI 30 • Open-label study
times ULN or any elevated D-dimer level and • 48% with HTN; 34% with DM; 7% with CVD • Only enrolled 12% of screened patients
SpO2 ≤93% on room air
• 91% had hypoxia; 6% received HFNC oxygen Interpretation:
• Hospitalized <5 days
• D-dimer: • Compared to prophylactic heparin, therapeutic
Key Exclusion Criteria: • 49% <2 times ULN heparin reduced mortality (a secondary endpoint)
• Indication for therapeutic anticoagulation • 51% ≥2 times ULN but had no effects on the composite primary
• Dual antiplatelet therapy endpoint of ICU admissions or the need for NIV or
• 69% on corticosteroids MV, or death up to 28 days.
• High bleeding risk
Primary Outcome: • Major bleeding and VTE events were not different
Interventions: • ICU admission, NIV or MV, or death: 16% in in the therapeutic and prophylactic arms.
• Therapeutic UFH or LMWH for 28 days or until therapeutic arm vs. 22% in prophylactic arm (OR 0.69;
discharge or death (n = 228) 95% CI, 0.43–1.10)
• Prophylactic UFH or LMWH for 28 days or until Secondary Outcomes:
discharge or death (n = 237)
• All-cause death: 2% in therapeutic arm vs. 8% in
Primary Endpoint: prophylactic arm (OR 0.22; 95% CI, 0.07–0.65)
• Composite of ICU admission, NIV or MV, or • Mean organ support-free days: 26 days in therapeutic
death up to 28 days arm vs. 24 days in prophylactic arm (OR 1.41; 95% CI,
Key Secondary Endpoints: 0.9–2.21)
• All-cause death • No difference between arms for VTE (1% in therapeutic
arm vs. 3% in prophylactic arm) or major bleeding (1%
• Mean organ support-free days in therapeutic arm vs. 2% in prophylactic arm)
• VTE • Mean hospital-free days alive: 20 days in therapeutic
• Major bleeding event arm vs. 18 days in prophylactic arm (OR 1.09; 95% CI,
• Mean hospital-free days alive 0.79–1.50)

AR09065
HEP-COVID: Open-Label RCT of Therapeutic Heparin in High-Risk, Hospitalized Patients With COVID-19 in the United States3
• Hospitalized with supplemental oxygen • Median age 67 years; 54% men; mean BMI 30 • Open-label study
• D-dimer >4 times ULN or sepsis-induced • 60% with HTN; 37% with DM; 7% with CVD • Only enrolled 2% of screened patients
coagulopathy score of ≥4 • 64% received oxygen via nasal cannula; 15% received Interpretation:
• Hospitalized <72 hours high-flow oxygen or NIV; 5% received MV
• Compared to usual care, therapeutic LMWH
Key Exclusion Criteria: • 80% on corticosteroids reduced the incidence of VTE, ATE, and death.
• Indication for therapeutic anticoagulation Primary Outcomes: • For patients not in the ICU, therapeutic LMWH
• Dual antiplatelet therapy • Composite of VTE, ATE, and death within 32 days: 29% significantly reduced thrombotic events and did
in therapeutic arm vs. 42% in usual care arm (relative not increase major bleeding.
• High bleeding risk
risk 0.68; 95% CI, 0.49–0.96)
• CrCl <15 mL/min
• Death: 19% in therapeutic arm vs. 25% in usual care
Interventions: arm (relative risk 0.78; 95% CI, 0.49–1.23)
• Therapeutic LMWH until hospital discharge or • Thrombotic events: 11% in therapeutic arm vs.
primary endpoint met (n = 129) 29% in usual care arm (relative risk 0.37; 95% CI,
• Usual care of prophylactic or intermediate-dose 0.21–0.66
LMWH until hospital discharge or primary • Non-ICU stratum composite of VTE, ATE, or death
endpoint met (n = 124) within 32 days: 17% in therapeutic arm vs. 36% in
Primary Endpoint: usual care arm (relative risk 0.46; 95% CI, 0.27–0.81)
• Composite of VTE, ATE, or death of any cause Safety Outcomes:
within 32 days of randomization • Major bleeding: 5% in therapeutic arm vs. 2% in usual
Key Safety Endpoint: care arm (relative risk 2.88, 95% CI, 0.59–14.02)
• Major bleeding • Non-ICU stratum major bleeding: 2% in both arms

AR09066

ACTION: Open-Label RCT of Therapeutic Oral Anticoagulation (Rivaroxaban) in Hospitalized Patients With COVID-19 in Brazil4
• Hospitalized for COVID-19 with elevated D-dimer • Median age 57 years; 60% men; mean BMI 30 • Open-label study
level • 49% with HTN; 24% with DM; 5% with coronary • Only enrolled 18% of screened patients
• Symptoms for ≤14 days disease • Longer duration of anticoagulation in the
Key Exclusion Criteria: • Critically ill: 7% in therapeutic arm; 5% in usual care rivaroxaban arm (30 days) than the prophylactic
arm anticoagulation arm (mean duration = 8 days)
• Indication for therapeutic anticoagulation
• 75% required oxygen: 60% low-flow oxygen; 8% HFNC Interpretation:
• CrCl <30 mL/min
oxygen; 1% NIV; 6% MV
• P2Y12 inhibitor therapy or aspirin >100 mg • When compared with usual care, therapeutic
• 83% on corticosteroids rivaroxaban did not reduce mortality, hospital
• High bleeding risk duration, oxygen use duration, or thrombosis.
Primary Outcomes:
Interventions: • Patients who received therapeutic rivaroxaban had
• Composite of time to death, hospital duration, and
• Therapeutic anticoagulation for 30 days: oxygen use duration: no difference between arms (win more clinically relevant nonmajor bleeding than
rivaroxaban 15 mg or 20 mg daily; if clinically ratio 0.86; 95% CI, 0.59–1.22) those who received usual care.
unstable, enoxaparin 1 mg/kg twice daily or UFH • The longer duration of therapy in the rivaroxaban
(n = 311) Secondary Outcomes:
arm may have influenced the difference in
• Usual care prophylactic anticoagulation with • No difference between therapeutic and prophylactic bleeding events.
enoxaparin or UFH during hospitalization (n = arms:
304) • Mortality: 11% vs. 8%
Primary Endpoint: • Thrombosis: 7% vs. 10%
• Hierarchical composite of time to death, hospital • Any bleeding: 12% in therapeutic arm vs. 3% in usual
duration, and oxygen use duration through Day care arm
30 • Major bleeding: 3% in therapeutic arm vs. 1% in usual
Key Secondary Endpoints: care arm
• Thrombosis, with and without all-cause death • Clinically relevant, nonmajor bleeding: 5% in
therapeutic arm vs. 1% in usual care arm
• Mortality
• Bleeding events

AR09067

REMAP-CAP/ACTIV-4a/ATTACC: Multiplatform, Open-Label RCT of Therapeutic Anticoagulation in Critically Ill, Hospitalized Patients With COVID-19 in 20
Countries5
• Hospitalized with severe COVID-19 and receiving • Median age 60 years; 70% men; median BMI 30 • Open-label study
HFNC oxygen, NIV, MV, ECMO, vasopressors, or • 24% with chronic respiratory disease; 33% with DM; • Anticoagulation dose varied in usual care arm
inotropes 10% with chronic kidney disease; 8% with severe CVD (i.e., 51% intermediate, 2% subtherapeutic, 5%
• Hospitalized <72 hours (ACTIV-4a, ATTACC) or • 32% required HFNC oxygen; 38% required NIV; 29% therapeutic).
<14 days (REMAP-CAP) required MV • Inclusion criteria for hospital LOS and ICU-level
Key Exclusion Criteria: • 18% on vasopressors; 82% on corticosteroids; 32% care differed across trials.
• Discharge expected within 72 hours on RDV • Trial stopped for futility.
• Requirement for therapeutic anticoagulation or Primary Outcome: Interpretation:
dual antiplatelet therapy • Median organ support-free days at Day 21: 4 days • In patients requiring ICU care, therapeutic heparin
• High bleeding risk therapeutic arm vs. 5 days usual care arm (aOR 0.83; did not reduce the duration of organ support or
95% CrI, 0.67–1.03; 99.9% posterior probability of mortality.
Interventions:
futility; OR < 1.2) • Although the differences were nonsignificant,
• Therapeutic UFH or LMWH for 14 days or until
Secondary Outcomes: patients who received therapeutic anticoagulation
discharge, whichever comes first (n = 534)
had more bleeding events and fewer thrombotic
• Usual care (n = 564) • No difference between therapeutic and usual care
events than patients who received usual care.
arms:
Primary Endpoint:
• Survival to hospital discharge: 63% vs. 65% (aOR
• Organ support-free days at Day 21 0.84; 95% CrI, 0.64–1.11)
Key Secondary Endpoints: • Thrombosis: 6% vs. 10%
• Survival to hospital discharge • Major thrombotic events or death: 41% both arms
• Any thrombosis • Major bleeding events: 4% vs. 2% (aOR 1.48; 95%
• Composite of major thrombotic events or death CrI, 0.75–3.04)
• Bleeding events

AR09068
INSPIRATION: Open-Label RCT of Intermediate-Dose Versus Prophylactic-Dose Anticoagulant in Patients in Intensive Care With COVID-19 in Iran6
• Admitted to ICU • Median age 62 years; 58% men; median BMI 27 • Open-label study
• Hospitalized <7 days • 44% with HTN; 28% with DM; 14% with coronary • Not all patients received ICU-level care.
artery disease
• 32% required NIV; 20% required MV
• Life expectancy <24 hours • Intermediate-dose anticoagulation did not
• 23% on vasopressors; 93% on corticosteroids; 60% significantly reduce VTE and ATE, the need for
• Indication for therapeutic anticoagulation
on RDV ECMO, or mortality.
• Overt bleeding
Primary Outcome: • Although the difference was nonsignificant,
Interventions: patients who received intermediate-dose
• Composite adjudicated acute VTE, ATE, ECMO, or
• Intermediate-dose anticoagulation: enoxaparin 1 all-cause mortality: 46% in therapeutic arm vs. 44% in anticoagulation had more bleeding events than
mg/kg daily (n = 276) prophylactic arm (OR 1.06; 95% CI, 0.76–1.48) patients who received usual care.
• Prophylactic-dose anticoagulation (n = 286) Secondary Outcomes:
Primary Endpoint: • No difference between therapeutic and prophylactic
• Composite of adjudicated acute VTE, ATE, ECMO, arms:
or all-cause mortality within 30 days • All-cause mortality: 43% vs. 41%
Key Secondary Endpoints: • VTE: 3% both arms
• All-cause mortality • Major bleeding and clinically relevant nonmajor
• VTE bleeding: 6.3% vs. 3.1% (OR 2.02; 95% CI, 0.89–
4.61)
• Bleeding event
Key: ATE = arterial thromboembolism; BMI = body mass index; CrCl = creatinine clearance; CVD = cardiovascular disease; DM = diabetes mellitus; ECMO =
extracorporeal membrane oxygenation; HFNC = high-flow nasal cannula; HTN = hypertension; ICU = intensive care unit; LMWH = low-molecular-weight heparin; LOS
= length of stay; MV = mechanical ventilation; NIV = noninvasive ventilation; the Panel = the COVID-19 Treatment Guidelines Panel; RCT = randomized controlled trial;
RDV = remdesivir; SOC = standard of care; SpO2 = oxygen saturation; UFH = unfractionated heparin; ULN = upper limit of normal; VTE = venous thromboembolism
References
1. ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators, et al. Therapeutic anticoagulation with heparin in noncritically ill
patients with COVID-19. N Engl J Med. 2021;385(9):790-802. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34351721.
2. Sholzberg M, Tang GH, Rahhal H, et al. Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive
care unit admission in moderately ill patients with COVID-19 admitted to hospital: RAPID randomised clinical trial. BMJ. 2021;375:n2400. Available

AR09069
3. Spyropoulos AC, Goldin M, Giannis D, et al. Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediate-dose
heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: the HEP-COVID randomized clinical trial. JAMA Intern Med.
4. Lopes RD, de Barros ESPGM, Furtado RHM, et al. Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19
and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial. Lancet. 2021;397(10291):2253-2263.
5. REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC Investigators, et al. Therapeutic anticoagulation with heparin in critically ill patients
with COVID-19. N Engl J Med. 2021;385(9):777-789. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34351722.
6. INSPIRATION Investigators, Sadeghipour P, Talasaz AH, et al. Effect of intermediate-dose vs standard-dose prophylactic anticoagulation on
thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with COVID-19 admitted to the intensive care unit:
the INSPIRATION randomized clinical trial. JAMA. 2021;325(16):1620-1630. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33734299.

AR09070
Supplements
Vitamin C
• There is insufficient evidence for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or
against the use of vitamin C for the treatment of COVID-19.
Vitamin D
• There is insufficient evidence for the Panel to recommend either for or against the use of vitamin D for the treatment
of COVID-19.
Zinc
• There is insufficient evidence for the Panel to recommend either for or against the use of zinc for the treatment of
COVID-19.
• The Panel recommends against using zinc supplementation above the recommended dietary allowance for the
prevention of COVID-19, except in a clinical trial (BIII).

In addition to the antiviral medications and the immune-based therapies that are discussed elsewhere in
the COVID-19 Treatment Guidelines, adjunctive therapies are frequently used in the prevention and/or
treatment of COVID-19 or its complications. Some of these agents are being studied in clinical trials.
Some clinicians advocate for the use of vitamin and mineral supplements to treat respiratory viral
infections. Ongoing studies are evaluating the use of vitamin and mineral supplements for both the
treatment and prevention of SARS-CoV-2 infection.
The following sections describe the underlying rationale for using adjunctive therapies and summarize
the existing clinical trial data. Other adjunctive therapies will be added as new evidence emerges.

AR09071
Vitamin C
Vitamin C (ascorbic acid) is a water-soluble vitamin that is thought to have beneficial effects in
patients with severe and critical illnesses. It is an antioxidant and free radical scavenger that has anti-
inflammatory properties, influences cellular immunity and vascular integrity, and serves as a cofactor in
the generation of endogenous catecholamines.1,2 Because humans may require more vitamin C in states
of oxidative stress, vitamin C supplementation has been evaluated in numerous disease states, including
serious infections and sepsis. Because SARS-CoV-2 infection may cause sepsis and acute respiratory
distress syndrome (ARDS), the potential role of high doses of vitamin C in ameliorating inflammation
and vascular injury in patients with COVID-19 is being studied.
Recommendation for Non-Critically Ill Patients With COVID-19

recommend either for or against the use of vitamin C for the treatment of COVID-19 in non-
critically ill patients.
Rationale
Because patients who are not critically ill with COVID-19 are less likely to experience oxidative stress
or severe inflammation, the role of vitamin C in this setting is unknown.
Clinical Data on Vitamin C in Outpatients With COVID-19

Oral Ascorbic Acid Versus Zinc Gluconate Versus Both Agents Versus Standard of Care
In an open-label clinical trial that was conducted at two sites in the United States, outpatients with
laboratory-confirmed SARS-CoV-2 infection were randomized to receive either 10 days of oral ascorbic
acid 8,000 mg, zinc gluconate 50 mg, both agents, or standard of care.3 The primary end point was the
number of days required to reach a 50% reduction in the patient’s symptom severity score. The study
was stopped early by an operational and safety monitoring board due to futility after 40% of the planned
520 participants were enrolled (n = 214).
Patients who received standard of care achieved a 50% reduction in their symptom severity scores at
a mean of 6.7 days (SD 4.4 days) compared with 5.5 days (SD 3.7 days) for the ascorbic acid arm, 5.9
days (SD 4.9 days) for the zinc gluconate arm, and 5.5 days (SD 3.4 days) for the arm that received
both agents (overall P = 0.45). Nonserious adverse effects occurred more frequently in patients who
received supplements than in those who did not; 39.5% of patients in the ascorbic acid arm, 18.5% in
the zinc gluconate arm, and 32.1% in the arm that received both agents experienced nonserious adverse
effects compared with 0% of patients in the standard of care arm (overall P < 0.001). The most common
nonserious adverse effects in this study were gastrointestinal events.
The limitations of this study include the small sample size and the lack of a placebo control. In
outpatients with COVID-19, treatment with high-dose zinc gluconate, ascorbic acid, or a combination of
the two supplements did not significantly decrease the number of days required to reach a 50% reduction
in a symptom severity score compared with standard of care.
Recommendation for Critically Ill Patients With COVID-19

• There is insufficient evidence for the Panel to recommend either for or against the use of vitamin
C for the treatment of COVID-19 in critically ill patients.

AR09072
Rationale
There are no controlled trials that have definitively demonstrated a clinical benefit for vitamin C in critically
ill patients with COVID-19, and the available observational data are inconclusive. Studies of vitamin C
regimens in sepsis patients and ARDS patients have reported variable efficacy and few safety concerns.
Clinical Data on Vitamin C in Critically Ill Patients

Intravenous Vitamin C Alone in Patients With COVID-19
A pilot clinical trial in China randomized 56 adults with COVID-19 in the intensive care unit to receive
intravenous (IV) vitamin C 24 g per day or placebo for 7 days. The study was terminated early due to a
reduction in the number of cases of COVID-19 in China. Overall, the study found no differences between
the arms in mortality, the duration of mechanical ventilation, or the change in median sequential organ
failure assessment (SOFA) scores. The study reported improvements in oxygenation (as measured by the
ratio of arterial partial pressure of oxygen to fraction of inspired oxygen [PaO2/FiO2]) from baseline to
Day 7 in the treatment arm that were statistically greater than those observed in the placebo arm (+20.0 vs.
-51.9; P = 0.04).4
Intravenous Vitamin C Alone in Patients Without COVID-19

A small, three-arm pilot study compared two regimens of IV vitamin C to placebo in 24 critically ill
patients with sepsis. Over the 4-day study period, patients who received vitamin C 200 mg/kg per
day and those who received vitamin C 50 mg/kg per day had lower SOFA scores and lower levels of
proinflammatory markers than patients who received placebo.5
In a randomized controlled trial in critically ill patients with sepsis-induced ARDS (n = 167), patients who
received IV vitamin C 200 mg/kg per day for 4 days had SOFA scores and levels of inflammatory markers
that were similar to those observed in patients who received placebo. However, 28-day mortality was
lower in the treatment group (29.8% vs. 46.3%; P = 0.03), coinciding with more days alive and free of the
hospital and the intensive care unit.6 A post hoc analysis of the study data reported a difference in median
SOFA scores between the treatment group and placebo group at 96 hours; however, this difference was not
present at baseline or 48 hours.7
Intravenous Vitamin C Plus Thiamine With or Without Hydrocortisone in Critically Ill Patients
Without COVID-19
Two small studies that used historic controls reported favorable clinical outcomes (i.e., reduced mortality,
reduced risk of progression to organ failure, and improved radiographic findings) in patients with
sepsis or severe pneumonia who received a combination of vitamin C, thiamine, and hydrocortisone.8,9
Subsequently, several randomized trials in which patients received vitamin C and thiamine (with or without
hydrocortisone) to treat sepsis and septic shock showed that this combination conferred benefits for certain
clinical parameters. However, no survival benefit was reported. Two trials observed reductions in organ
dysfunction (as measured by change in SOFA score on Day 3)10,11 or the duration of shock12 without an
effect on clinical outcomes. Three other trials, including a large trial of 501 sepsis patients, found no
differences in any physiologic or outcome measures between the treatment and placebo groups.13-15
See ClinicalTrials.gov for a list of clinical trials that are evaluating the use of vitamin C in patients with
COVID-19.
Other Considerations
It is important to note that high circulating concentrations of vitamin C may affect the accuracy of point-
of-care glucometers.16,17

AR09073
References
1. Wei XB, Wang ZH, Liao XL, et al. Efficacy of vitamin C in patients with sepsis: an updated meta-analysis.
Eur J Pharmacol. 2020;868:172889. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31870831.
2. Fisher BJ, Seropian IM, Kraskauskas D, et al. Ascorbic acid attenuates lipopolysaccharide-induced acute lung
injury. Crit Care Med. 2011;39(6):1454-1460. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21358394.
3. Thomas S, Patel D, Bittel B, et al. Effect of high-dose zinc and ascorbic acid supplementation vs usual care
on symptom length and reduction among ambulatory patients with SARS-CoV-2 infection: the COVID A to Z
randomized clinical trial. JAMA Netw Open. 2021;4(2):e210369. Available at:
4. Zhang J, Rao X, Li Y, et al. Pilot trial of high-dose vitamin C in critically ill COVID-19 patients. Ann
Intensive Care. 2021;11(1):5. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33420963.
5. Fowler AA, 3rd, Syed AA, Knowlson S, et al. Phase I safety trial of intravenous ascorbic acid in patients with
severe sepsis. J Transl Med. 2014;12:32. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24484547.
6. Fowler AA, 3rd, Truwit JD, Hite RD, et al. Effect of vitamin C infusion on organ failure and biomarkers of
inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the CITRIS-ALI
randomized clinical trial. JAMA. 2019;322(13):1261-1270. Available at:
7. Fowler AA, 3rd, Fisher BJ, Kashiouris MG. Vitamin C for sepsis and acute respiratory failure-reply. JAMA.
8. Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, vitamin C, and thiamine for the
treatment of severe sepsis and septic shock: a retrospective before-after study. Chest. 2017;151(6):1229-1238.
9. Kim WY, Jo EJ, Eom JS, et al. Combined vitamin C, hydrocortisone, and thiamine therapy for patients with
severe pneumonia who were admitted to the intensive care unit: propensity score-based analysis of a before-after
cohort study. J Crit Care. 2018;47:211-218. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30029205.
10. Fujii T, Luethi N, Young PJ, et al. Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone
on time alive and free of vasopressor support among patients with septic shock: the VITAMINS randomized
clinical trial. JAMA. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31950979.
11. Chang P, Liao Y, Guan J, et al. Combined treatment with hydrocortisone, vitamin C, and thiamine for sepsis
and septic shock: a randomized controlled trial. Chest. 2020;158(1):174-182. Available at:
12. Iglesias J, Vassallo AV, Patel VV, Sullivan JB, Cavanaugh J, Elbaga Y. Outcomes of metabolic resuscitation
using ascorbic acid, thiamine, and glucocorticoids in the early treatment of sepsis: the ORANGES trial. Chest.
13. Hwang SY, Ryoo SM, Park JE, et al. Combination therapy of vitamin C and thiamine for septic shock: a multi-
centre, double-blinded randomized, controlled study. Intensive Care Med. 2020;46(11):2015-2025. Available
14. Moskowitz A, Huang DT, Hou PC, et al. Effect of ascorbic acid, corticosteroids, and thiamine on organ injury
in septic shock: the ACTS randomized clinical trial. JAMA. 2020;324(7):642-650. Available at:
15. Sevransky JE, Rothman RE, Hager DN, et al. Effect of vitamin C, thiamine, and hydrocortisone on
ventilator- and vasopressor-free days in patients with sepsis: the VICTAS randomized clinical trial. JAMA.
16. Hager DN, Martin GS, Sevransky JE, Hooper MH. Glucometry when using vitamin C in sepsis: a note of
caution. Chest. 2018;154(1):228-229. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30044741.
17. Food and Drug Administration. Blood glucose monitoring devices. 2019. Available at:
https://www.fda.gov/medical-devices/in-vitro-diagnostics/blood-glucose-monitoring-devices. Accessed March
26, 2021.

AR09074
Vitamin D
Recommendation
• There is insufficient evidence to recommend either for or against the use of vitamin D for the
prevention or treatment of COVID-19.
Rationale
Vitamin D is critical for bone and mineral metabolism. Because the vitamin D receptor is expressed
on immune cells such as B cells, T cells, and antigen-presenting cells, and because these cells can
synthesize the active vitamin D metabolite, vitamin D also has the potential to modulate innate and
adaptive immune responses.1
Vitamin D deficiency (defined as a serum concentration of 25-hydroxyvitamin D ≤20 ng/mL) is
common in the United States, particularly among persons of Hispanic ethnicity and Black race. These
groups are also overrepresented among cases of COVID-19 in the United States.2 Vitamin D deficiency
is also more common in older patients and patients with obesity and hypertension; these factors have
been associated with worse outcomes in patients with COVID-19. In observational studies, low vitamin
D levels have been associated with an increased risk of community-acquired pneumonia in older adults3
and children.4
Vitamin D supplements may increase the levels of T regulatory cells in healthy individuals and patients
with autoimmune diseases; vitamin D supplements may also increase T regulatory cell activity.5 In a
meta-analysis of randomized clinical trials, vitamin D supplementation was shown to protect against
acute respiratory tract infection.6 However, in two double-blind, placebo-controlled, randomized clinical
trials, administering high doses of vitamin D to critically ill patients with vitamin D deficiency (but
not COVID-19) did not reduce the length of the hospital stay or the mortality rate when compared to
placebo.7,8 High levels of vitamin D may cause hypercalcemia and nephrocalcinosis.9
The rationale for using vitamin D is based largely on immunomodulatory effects that could potentially
protect against COVID-19 infection or decrease the severity of illness. Ongoing observational studies
are evaluating the role of vitamin D in preventing and treating COVID-19. Some investigational trials on
the use of vitamin D in people with COVID-19 are being planned or are already accruing participants.
These trials will administer vitamin D alone or in combination with other agents to participants with
and without vitamin D deficiency. The latest information on these clinical trials can be found on
ClinicalTrials.gov.
Clinical Data
Randomized Clinical Trial of Vitamin D Versus Placebo in Patients With Moderate to Severe
COVID-19
In a double-blind, placebo-controlled randomized trial that was conducted at two sites in Brazil, 240
hospitalized patients with moderate to severe COVID-19 received either a single dose of 200,000
international units of vitamin D3 or placebo.10 Moderate to severe COVID-19 was defined as patients
with a positive result on a SARS-CoV-2 polymerase chain reaction test (or compatible computed
tomography scan findings) and a respiratory rate >24 breaths/min, oxygen saturation <93% on room air,
or risk factors for complications. The primary outcome in this study was the length of the hospital stay.

AR09075
The median length of stay was not significantly different between the vitamin D3 arm (7.0 days [IQR
4.0–10.0 days]) and the placebo arm (7.0 days [IQR 5.0–13.0 days]; P = 0.59, log-rank test). No
significant differences were observed between the arms in the percentages of patients who were admitted
to the intensive care unit, who required mechanical ventilation, or who died during hospitalization.
It should be noted that this study had a small sample size and enrolled participants with a variety of
comorbidities and concomitant medications. The time between symptom onset and randomization was
relatively long, with patients randomized at a mean of 10.3 days after symptom onset. In this study, a
single, high dose of vitamin D3 did not significantly reduce the length of stay for hospitalized patients
with COVID-19.
References
1. Aranow C. Vitamin D and the immune system. J Investig Med. 2011;59(6):881-886. Available at:
2. Forrest KY, Stuhldreher WL. Prevalence and correlates of vitamin D deficiency in US adults. Nutr Res.
3. Lu D, Zhang J, Ma C, et al. Link between community-acquired pneumonia and vitamin D levels in older
patients. Z Gerontol Geriatr. 2018;51(4):435-439. Available at:
4. Science M, Maguire JL, Russell ML, Smieja M, Walter SD, Loeb M. Low serum 25-hydroxyvitamin D level
and risk of upper respiratory tract infection in children and adolescents. Clin Infect Dis. 2013;57(3):392-397.
5. Fisher SA, Rahimzadeh M, Brierley C, et al. The role of vitamin D in increasing circulating T regulatory cell
numbers and modulating T regulatory cell phenotypes in patients with inflammatory disease or in healthy
volunteers: a systematic review. PLoS One. 2019;14(9):e0222313. Available at:
6. Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory
tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583.
7. Amrein K, Schnedl C, Holl A, et al. Effect of high-dose vitamin D3 on hospital length of stay in critically ill
patients with vitamin D deficiency: the VITdAL-ICU randomized clinical trial. JAMA. 2014;312(15):1520-
8. National Heart, Lung, and Blood Institute PETAL Clinical Trials Network, Ginde AA, et al. Early high-dose
vitamin D3 for critically ill, vitamin D-deficient patients. N Engl J Med. 2019;381(26):2529-2540. Available
9. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. The National Academies Press;
2011.
10. Murai IH, Fernandes AL, Sales LP. Effect of a single high dose of vitamin D3 on hospital length of stay in
patients with moderate to severe COVID-19: a randomized clinical trial. 2021; Published online ahead of
print. Available at: https://pubmed.ncbi.nlm.nih.gov/33595634/.

AR09076
Zinc
Recommendations
recommend either for or against the use of zinc for the treatment of COVID-19.
• The Panel recommends against using zinc supplementation above the recommended dietary
allowance for the prevention of COVID-19, except in a clinical trial (BIII).
Rationale
Increased intracellular zinc concentrations efficiently impair replication in a number of RNA viruses.1
Zinc has been shown to enhance cytotoxicity and induce apoptosis when used in vitro with a zinc
ionophore (e.g., chloroquine). Chloroquine has also been shown to enhance intracellular zinc uptake
in vitro.2 The relationship between zinc and COVID-19, including how zinc deficiency affects the
severity of COVID-19 and whether zinc supplements can improve clinical outcomes, is currently under
investigation.3 Zinc levels are difficult to measure accurately, as zinc is distributed as a component of
various proteins and nucleic acids.4
Several clinical trials are currently investigating the use of zinc supplementation alone or in combination
with hydroxychloroquine for the prevention and treatment of COVID-19 (see ClinicalTrials.gov for
more information about ongoing studies). The recommended dietary allowance for elemental zinc is
11 mg daily for men and 8 mg for nonpregnant women.5 The doses used in registered clinical trials for
patients with COVID-19 vary between studies, with a maximum dose of zinc sulfate 220 mg (50 mg of
elemental zinc) twice daily. However, there is currently insufficient evidence to recommend either for or
against the use of zinc for the treatment of COVID-19.
Long-term zinc supplementation can cause copper deficiency with subsequent reversible hematologic
defects (i.e., anemia, leukopenia) and potentially irreversible neurologic manifestations (i.e.,
myelopathy, paresthesia, ataxia, spasticity).6,7 The use of zinc supplementation for durations as short as
10 months has been associated with copper deficiency.4 In addition, oral zinc can decrease the absorption
of medications that bind with polyvalent cations.5 Because zinc has not been shown to have a clinical
benefit and may be harmful, the Panel recommends against using zinc supplementation above the
recommended dietary allowance for the prevention of COVID-19, except in a clinical trial (BIII).
Clinical Data
Randomized Clinical Trial of Zinc Plus Hydroxychloroquine Versus Hydroxychloroquine
Alone in Hospitalized Patients With COVID-19
In a randomized clinical trial that was conducted at three academic medical centers in Egypt, 191
patients with laboratory-confirmed SARS-CoV-2 infection were randomized to receive either zinc 220
mg twice daily plus hydroxychloroquine or hydroxychloroquine alone for a 5-day course. The primary
endpoints were recovery within 28 days, the need for mechanical ventilation, and death. The two arms
were matched for age and gender.8
Results
• There were no significant differences between the two arms in the percentages of patients who
recovered within 28 days (79.2% in the hydroxychloroquine plus zinc arm vs. 77.9% in the
hydroxychloroquine only arm; P = 0.969), the need for mechanical ventilation (P = 0.537), or

AR09077
overall mortality (P = 0.986).

• The only risk factors for mortality were age and the need for mechanical ventilation.
Limitations
• This study had a relatively small sample size.
Interpretation
A moderately sized randomized clinical trial failed to find a clinical benefit for the combination of zinc
and hydroxychloroquine.
Open-Label, Randomized Trial of Zinc Versus Ascorbic Acid Versus Zinc Plus Ascorbic Acid
Versus Standard of Care in Outpatients With COVID-19
In an open-label clinical trial that was conducted at two sites in the United States, outpatients with
laboratory-confirmed SARS-CoV-2 infection were randomized to receive either 10 days of zinc
gluconate 50 mg, ascorbic acid 8,000 mg, both agents, or standard of care. The primary end point was
the number of days required to reach a 50% reduction in the patient’s symptom severity score. The study
was stopped early by an operational and safety monitoring board due to futility after 40% of the planned
520 participants were enrolled (n = 214).9
Results
• Participants who received standard of care achieved a 50% reduction in their symptom severity
scores at a mean of 6.7 days (SD 4.4 days) compared with 5.5 days (SD 3.7 days) for the ascorbic
acid arm, 5.9 days (SD 4.9 days) for the zinc gluconate arm, and 5.5 days (SD 3.4 days) for the
arm that received both agents (overall P = 0.45).
• Nonserious adverse effects occurred more frequently in patients who received supplements than
in those who did not; 39.5% of patients in the ascorbic acid arm, 18.5% in the zinc gluconate arm,
and 32.1% in the arm that received both agents experienced nonserious adverse effects compared
with 0% of patients in the standard of care arm (overall P < 0.001). The most common nonserious
adverse effects in this study were gastrointestinal events.
Limitations
• The study had a small sample size.
• There was no placebo control.
Interpretation
In outpatients with COVID-19, treatment with high-dose zinc gluconate, ascorbic acid, or a combination
of the two supplements did not significantly decrease the number of days required to reach a 50%
reduction in a symptom severity score compared with standard of care.
Observational Study of Zinc Supplementation in Hospitalized Patients

A retrospective study enrolled 242 patients with polymerase chain reaction-confirmed SARS-CoV-2
infection who were admitted to Hoboken University Medical Center. One hundred and ninety-six
patients (81.0%) received a total daily dose of zinc sulfate 440 mg (100 mg of elemental zinc); of those,
191 patients (97%) also received hydroxychloroquine. Among the 46 patients who did not receive
zinc, 32 patients (70%) received hydroxychloroquine. The primary outcome was days from hospital
admission to in-hospital mortality, and the primary analysis explored the causal association between zinc
therapy and survival.10

AR09078
Results
• There were no significant differences in baseline characteristics between the arms. In the zinc arm,
73 patients (37.2%) died compared with 21 patients (45.7%) in the control arm. In the primary
analysis, which used inverse probability weighting (IPW), the effect estimate of zinc therapy was
an additional 0.84 days of survival (95% CI, -1.51 days to 3.20 days; P = 0.48).
• In a multivariate Cox regression analysis with IPW, the use of zinc sulfate was not significantly
associated with a change in the risk of in-hospital mortality (aHR 0.66; 95% CI, 0.41–1.07; P =
0.09).
• Older age, male sex, and severe or critical COVID-19 were significantly associated with an
increased risk of in-hospital mortality.
Limitations
• This is a retrospective study; patients were not randomized to receive zinc supplementation or to
receive no zinc.
Interpretation
This single-center, retrospective study failed to find a mortality benefit in patients who received zinc
supplementation.
Multicenter, Retrospective Cohort Study That Compared Hospitalized Patients Who Received
Zinc Plus Hydroxychloroquine to Those Who Did Not
This study has not been peer reviewed.
This multicenter, retrospective cohort study of hospitalized adults with SARS-CoV-2 infection who
were admitted to four New York City hospitals between March 10 and May 20, 2020, compared patients
who received zinc plus hydroxychloroquine to those who received treatment that did not include this
combination.11
Results
• The records of 3,473 patients were reviewed.
• The median patient age was 64 years; 1,947 patients (56%) were male, and 522 patients (15%)
were mechanically ventilated.
• Patients who received an interleukin-6 inhibitor or remdesivir were excluded from the analysis.
• A total of 1,006 patients (29%) received zinc plus hydroxychloroquine, and 2,467 patients (71%)
received hydroxychloroquine without zinc.
• During the study, 545 patients (16%) died. In univariate analyses, mortality rates were
significantly lower among patients who received zinc plus hydroxychloroquine than among those
who did not (12% vs. 17%; P < 0.001). Similarly, hospital discharge rates were significantly
higher among patients who received zinc plus hydroxychloroquine than among those who did not
(72% vs. 67%; P < 0.001).
• In a Cox regression analysis that adjusted for confounders, treatment with zinc plus
hydroxychloroquine was associated with a significantly reduced risk of in-hospital death (aHR
0.76; 95% CI, 0.60–0.96; P = 0.023). Treatment with zinc alone (n = 1,097) did not affect
mortality (aHR 1.14; 95% CI, 0.89–1.44; P = 0.296), and treatment with hydroxychloroquine
alone (n = 2,299) appeared to be harmful (aHR 1.60; 95% CI, 1.22–2.11; P = 0.001).
• There were no significant interactions between zinc plus hydroxychloroquine and other COVID-
19-specific medications.

AR09079
Limitations
• This is a retrospective review; patients were not randomized to receive zinc plus
hydroxychloroquine or to receive other treatments.
• The authors do not have data on whether patients were taking zinc and/or hydroxychloroquine
prior to study admission.
• The arms were not balanced; recipients of zinc plus hydroxychloroquine were more likely to be
male, Black, or to have a higher body mass index and diabetes. Patients who received zinc plus
hydroxychloroquine were also treated more often with corticosteroids and azithromycin and less
often with lopinavir/ritonavir than those who did not receive this drug combination.
Interpretation
In this preprint, the use of zinc plus hydroxychloroquine was associated with decreased rates of
in-hospital mortality, but neither zinc alone nor hydroxychloroquine alone reduced mortality. Treatment
with hydroxychloroquine alone appeared to be harmful.
References
1. te Velthuis AJ, van den Worm SH, Sims AC, Baric RS, Snijder EJ, van Hemert MJ. Zn(2+) inhibits
coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of
these viruses in cell culture. PLoS Pathog. 2010;6(11):e1001176. Available at:
2. Xue J, Moyer A, Peng B, Wu J, Hannafon BN, Ding WQ. Chloroquine is a zinc ionophore. PLoS One.
3. Calder PC, Carr AC, Gombart AF, Eggersdorfer M. Optimal nutritional status for a well-functioning immune
system is an important factor to protect against viral infections. Nutrients. 2020;12(4). Available at:
4. Hambridge K. The management of lipohypertrophy in diabetes care. Br J Nurs. 2007;16(9):520-524. Available
5. National Institutes of Health. Office of Dietary Supplements. Zinc fact sheet for health professionals. 2020.
Available at: https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/.
6. Myint ZW, Oo TH, Thein KZ, Tun AM, Saeed H. Copper deficiency anemia: review article. Ann Hematol.
7. Kumar N. Copper deficiency myelopathy (human swayback). Mayo Clin Proc. 2006;81(10):1371-1384.
8. Abd-Elsalam S, Soliman S, Esmail ES, et al. Do zinc supplements enhance the clinical efficacy of
hydroxychloroquine?: a randomized, multicenter trial. Biol Trace Elem Res. 2020;Published online ahead of
print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33247380.
9. Thomas S, Patel D, Bittel B. Effect of high-dose zinc and ascorbic acid supplementation vs usual care on
symptom length and reduction among ambulatory patients with SARS-CoV-2 Infection: the COVID a to z
randomized clinical trial. JAMA Netw Open. 2021;4(2):e210369. Available at:
10. Yao JS, Paguio JA, Dee EC, et al. The minimal effect of zinc on the survival of hospitalized patients with
COVID-19: an observational study. Chest. 2021;159(1):108-111. Available at:
11. Frontera JA, Rahimian JO, Yaghi S, et al. Treatment with zinc is associated with reduced in-hospital mortality
among COVID-19 patients: a multi-center cohort study. Res Sq. 2020;Preprint. Available at:

AR09080
Considerations for Using Concomitant Medications in

Patients With COVID-19
• Patients with COVID-19 who are receiving concomitant medications (e.g., angiotensin-converting enzyme [ACE]
inhibitors, angiotensin receptor blockers [ARBs], HMG-CoA reductase inhibitors [statins], systemic or inhaled
corticosteroids, nonsteroidal anti-inflammatory drugs, acid-suppressive therapy) for underlying medical conditions
should not discontinue these medications during acute management of COVID-19 unless discontinuation is
otherwise warranted by their clinical condition (AIIa for ACE inhibitors and ARBs; AIII for other medications).
• The COVID-19 Treatment Guidelines Panel recommends against using medications off-label to treat COVID-19 if they
have not been shown to be safe and effective for this indication in a clinical trial (AIII).

Individuals with underlying medical conditions, such as cardiovascular disease, pulmonary disease,
diabetes, and malignancy, and those who receive chronic immunosuppressive therapy are at higher risk
of severe illness with COVID-19. These patients are often prescribed medications to treat their
underlying medical conditions.
Early in the pandemic, some of these medications, such as angiotensin converting enzyme (ACE)
inhibitors, angiotensin receptor blockers (ARBs),1 HMG-CoA reductase inhibitors (statins),2,3 and H-2
receptor antagonists,4 were hypothesized to offer potential as COVID-19 therapeutic agents. Others,
such as nonsteroidal anti-inflammatory agents (NSAIDs), were postulated to have negative impacts.5
Currently, there is no evidence that discontinuing medication for underlying medical conditions offers
a clinical benefit for patients with COVID-19.6-8 For example, the Food and Drug Administration stated
that there is no evidence linking the use of NSAIDs with worsening of COVID-19 and advised patients
to use them as directed.9 Additionally, the American Heart Association, the Heart Failure Society of
America, and the American College of Cardiology issued a joint statement that renin-angiotensin-
aldosterone system antagonists, such as ACE inhibitors and ARBs, should be continued as prescribed in
those with COVID-19.10
Therefore, patients with COVID-19 who are treated with concomitant medications for an underlying
medical condition should not discontinue these medications during acute management of COVID-19
unless discontinuation is otherwise warranted by their clinical condition (AIII). For patients with
COVID-19 who require nebulized medications, precautions should be taken to minimize the potential
for transmission of SARS-CoV-2 in the home and in health care settings.11,12
The COVID-19 Treatment Guidelines Panel recommends against using medications off-label to
treat COVID-19 if they have not been shown to be safe and effective for this indication in a clinical
trial (AIII). Clinicians should refer to the Therapies section of the Guidelines for information on the
medications that have been studied as potential therapeutic options for patients with COVID-19.
When prescribing medications to treat COVID-19, clinicians should always assess the patient’s current
medications for potential drug-drug interactions and/or additive adverse effects.13 The decision to
continue or change a patient’s medications should be individualized based on their specific clinical
condition.

AR09081
References
1. Patel AB, Verma A. COVID-19 and angiotensin-converting enzyme inhibitors and angiotensin receptor
blockers: what is the evidence? JAMA. 2020;323(18):1769-1770. Available at:
2. Lee KCH, Sewa DW, Phua GC. Potential role of statins in COVID-19. Int J Infect Dis. 2020;96:615-617.
3. Kashour T, Halwani R, Arabi YM, et al. Statins as an adjunctive therapy for COVID-19: the biological and
clinical plausibility. Immunopharmacol Immunotoxicol. 2021;43(1):37-50. Available at:
4. Mather JF, Seip RL, McKay RG. Impact of famotidine use on clinical outcomes of hospitalized patients with
COVID-19. Am J Gastroenterol. 2020;115(10):1617-1623. Available at:
5. Yousefifard M, Zali A, Zarghi A, Madani Neishaboori A, Hosseini M, Safari S. Non-steroidal anti-
inflammatory drugs in management of COVID-19; a systematic review on current evidence. Int J Clin Pract.
6. Lopes RD, Macedo AVS, de Barros E Silva PGM, et al. Effect of discontinuing vs continuing angiotensin-
converting enzyme inhibitors and angiotensin II receptor blockers on days alive and out of the hospital in
patients admitted with COVID-19: a randomized clinical trial. JAMA. 2021;325(3):254-264. Available at:
7. Cohen JB, Hanff TC, William P, et al. Continuation versus discontinuation of renin-angiotensin system
inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial. Lancet
Respir Med. 2021;9(3):275-284. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33422263.
8. Bauer A, Schreinlechner M, Sappler N, et al. Discontinuation versus continuation of renin-angiotensin-system
inhibitors in COVID-19 (ACEI-COVID): a prospective, parallel group, randomised, controlled, open-label
trial. Lancet Respir Med. 2021;9(8):863-872. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34126053.
9. Food and Drug Administration. FDA advises patients on use of non-steroidal anti-inflammatory drugs
(NSAIDs) for COVID-19. 2020. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-
advises-patients-use-non-steroidal-anti-inflammatory-drugs-nsaids-covid-19. Accessed October 26, 2021.
10. Bozkurt B, Kovacs R, Harrington B. Joint HFSA/ACC/AHA statement addresses concerns re: using RAAS
antagonists in COVID-19. J Card Fail. 2020;26(5):370. Available at:
11. Cazzola M, Ora J, Bianco A, Rogliani P, Matera MG. Guidance on nebulization during the current COVID-19
pandemic. Respir Med. 2021;176:106236. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33248363.
12. Sethi S, Barjaktarevic IZ, Tashkin DP. The use of nebulized pharmacotherapies during the COVID-19
pandemic. Ther Adv Respir Dis. 2020;14:1753466620954366. Available at:
13. University of Liverpool. COVID-19 drug interactions. 2021. Available at:
https://www.covid19-druginteractions.org/. Accessed November 1, 2021.

AR09082
Special Considerations in Pregnancy

Key Considerations
There is current guidance from the Centers for Disease Control and Prevention, the American College of Obstetricians and
Gynecologists, and the Society for Maternal-Fetal Medicine on the management of pregnant patients with COVID-19. This
section of the COVID-19 Treatment Guidelines complements that guidance. The following are key considerations regarding
the management of COVID-19 in pregnancy:
• Pregnant people should be counseled about the increased risk for severe disease from SARS-CoV-2 infection and
receive recommendations on ways to protect themselves and their families from infection.
• If hospitalization for COVID-19 is indicated for a pregnant patient, care should be provided in a facility that can
conduct maternal and fetal monitoring, when appropriate.
• Management of COVID-19 in pregnant patients should include:
• Fetal and uterine contraction monitoring based on gestational age, when appropriate
• Individualized delivery planning
• A multispecialty, team-based approach that may include consultation with obstetric, maternal-fetal medicine,
infectious disease, pulmonary-critical care, and pediatric specialists, as appropriate
• In general, the therapeutic management of pregnant patients with COVID-19 should be the same as for
nonpregnant patients. The COVID-19 Treatment Guidelines Panel recommends against withholding treatment
for COVID-19 and SARS-CoV-2 vaccination from pregnant or lactating individuals because of theoretical safety
concerns (AIII). For details regarding therapeutic recommendations and pregnancy considerations, see General
Management of Nonhospitalized Patients With Acute COVID-19 and the individual drug sections.
• Pregnant or lactating patients with COVID-19 and their clinical teams should discuss the use of investigational drugs
or drugs that are approved for other indications as treatments for COVID-19. During this shared decision-making
process, the patient and the clinical team should consider the safety of the medication for the pregnant or lactating
individual and the fetus and the severity of maternal disease. For detailed guidance on using COVID-19 therapeutic
agents during pregnancy, please refer to the pregnancy considerations subsections found in the Antiviral Therapy and
Immunomodulators sections of these Guidelines.
• The decision to feed the infant breast milk while the patient is receiving therapeutic agents for COVID-19 should
be a collaborative effort between the patient and the clinical team, including infant care providers. The patient and
the clinical team should discuss the potential benefits of the therapeutic agent and evaluate the potential impact of
pausing lactation on the future of breast milk delivery to the infant.
Rating of Recommendations: A = Strong; B = Moderate; C = Weak 

Epidemiology of COVID-19 in Pregnancy

Early in the pandemic, reports of COVID-19 disease acquired during pregnancy were limited to case
series or studies that did not compare pregnant patients to age-matched, nonpregnant controls, and these
reports were largely reassuring. Subsequent data have indicated that while the overall risk of severe
illness is low, COVID-19 is associated with more severe disease in pregnant people than in nonpregnant
people.1 There is also an increased risk of poor obstetric outcomes among pregnant people with
COVID-19, such as preterm birth.2,3
In November 2020, the Centers for Disease Control and Prevention (CDC) released surveillance data on
outcomes in approximately 400,000 reproductive-aged women with symptomatic, laboratory-confirmed
COVID-19.1 After adjusting for age, race/ethnicity, and underlying medical conditions, pregnant women

AR09083
had significantly higher rates of intensive care unit (ICU) admission (10.5 vs. 3.9 cases per 1,000
cases; adjusted risk ratio [aRR] 3.0; 95% CI, 2.6–3.4), mechanical ventilation (2.9 vs. 1.1 cases per
1,000 cases; aRR 2.9; 95% CI, 2.2–3.8), extracorporeal membrane oxygenation (0.7 vs. 0.3 cases per
1,000 cases; aRR 2.4; 95% CI, 1.5–4.0), and death (1.5 vs. 1.2 cases per 1,000 cases; aRR 1.7; 95% CI,
1.2–2.4). The increased risk for severe disease was most significant in women aged 35 to 44 years, who
were almost four times as likely to be mechanically ventilated and twice as likely to die as nonpregnant
women of the same age.
Notably, among Hispanic women, pregnancy was associated with a risk of death that was 2.4 times
higher (95% CI, 1.3–4.3) than the risk observed in nonpregnant Hispanic women. Racial and ethnic
disparities were also seen in other reports. Among 8,207 pregnant women with COVID-19 who were
reported to CDC, the proportion of those who were reported to be Hispanic (46%) and Black (22%)
was higher than the proportion of Hispanic and Black women who gave birth in 2019 (24% and 15%,
respectively), suggesting that pregnant people who are Hispanic or Black may be disproportionately
affected by SARS-CoV-2 infection.4
In an ongoing systematic review that includes 192 studies to date, maternal factors that were associated
with severe disease included increased maternal age (OR 1.83; 95% CI, 1.27–2.63; 3,561 women from 7
studies); a high body mass index (OR 2.37; 95% CI, 1.83–3.07; 3,367 women from 5 studies); any pre-
existing maternal comorbidity, including chronic hypertension and diabetes (OR 1.81; 95% CI, 1.49–2.20;
2,634 women from 3 studies); pre-eclampsia (OR 4.21; 95% CI, 1.27–14.0; 274 women from 4 studies);
and pre-existing diabetes (OR 2.12; 95% CI, 1.62–2.78; 3,333 women from 3 studies).5 Compared with
pregnant women and recently pregnant women without COVID-19, pregnant women with COVID-19
were at a higher risk of any instance of preterm birth (OR 1.47; 95% CI, 1.14–1.91; 8,549 women from
18 studies) and stillbirth (OR 2.84; 95% CI, 1.25–6.45; 5,794 women from 9 studies).
An observational cohort study of all pregnant patients at 33 U.S. hospitals with a singleton gestation and
a positive result on a SARS-CoV-2 virologic test evaluated maternal characteristics and outcomes across
disease severity.6 The data suggested that adverse perinatal outcomes were more common in patients
with severe or critical disease than in asymptomatic patients with SARS-CoV-2 infection, including an
increased incidence of cesarean delivery (59.6% vs. 34.0% of patients; aRR 1.57; 95% CI, 1.30–1.90),
hypertensive disorders of pregnancy (40.4% vs. 18.8%; aRR 1.61; 95% CI, 1.18–2.20), and preterm
birth (41.8% vs. 11.9%; aRR 3.53; 95% CI, 2.42–5.14). The perinatal outcomes for those with mild
to moderate illness were similar to those observed among asymptomatic patients with SARS-CoV-2
infection.
Although vertical transmission of SARS-CoV-2 is possible, current data suggest that it is rare.7 A review
of 101 infants born to 100 women with SARS-CoV-2 infection at a single U.S. academic medical center
found that 2 infants (2%) had indeterminate SARS-CoV-2 polymerase chain reaction (PCR) results,
which were presumed to be positive; however, the infants exhibited no evidence of clinical disease. It is
reassuring that the majority of the infants received negative PCR results after rooming with their mothers
and breastfeeding directly (the mothers in this study practiced appropriate hand and breast hygiene).
Managing COVID-19 in Pregnancy

Pregnant people should be counseled about the increased risk for severe disease from SARS-CoV-2
and the measures they can take to protect themselves and their families from infection. These measures
include practicing physical distancing, washing their hands regularly, and wearing a face covering (if
indicated). If the patient is not vaccinated, they should be counseled about wearing a face covering
and getting vaccinated against SARS-CoV-2 infection. CDC, the American College of Obstetricians
and Gynecologists (ACOG), and the Society for Maternal-Fetal Medicine highlight the importance
of accessing prenatal care. ACOG provides a list of frequently asked questions on using telehealth to

AR09084
deliver antenatal care, when appropriate.

ACOG has developed an algorithm to evaluate and manage pregnant outpatients with suspected or
laboratory-confirmed SARS-CoV-2 infection. As in nonpregnant patients, SARS-CoV-2 infection in
pregnant patients can present as asymptomatic/presymptomatic disease or with a wide range of clinical
manifestations, from mild symptoms that can be managed with supportive care at home to severe disease
and respiratory failure that requires ICU admission. As in other patients, the illness severity, underlying
comorbidities, and clinical status of pregnant patients with symptoms that are compatible with COVID-19
should be assessed to determine whether in-person evaluation for potential hospitalization is needed.
If hospitalization is indicated, care should be provided in a facility that can conduct maternal and fetal
monitoring, when appropriate. The management of COVID-19 in the pregnant patient may include:
• Fetal and uterine contraction monitoring based on gestational age, when appropriate
• Individualized delivery planning
• A multispecialty, team-based approach that may include consultation with obstetric, maternal-fetal
medicine, infectious disease, pulmonary-critical care, and pediatric specialists, as appropriate.
In general, the recommendations for managing COVID-19 in nonpregnant patients also apply to pregnant
patients.
Therapeutic Management of COVID-19 in the Setting of Pregnancy

Potentially effective treatments for COVID-19 should not be withheld from pregnant people because of
theoretical concerns related to the safety of using those therapeutic agents in pregnancy (AIII).
Pregnant or lactating patients with COVID-19 and their clinical teams should discuss the use of
investigational drugs or drugs that are approved for other indications as treatments for COVID-19.
During this shared decision-making process, the patient and the clinical team should consider the safety
of the medication for the pregnant or lactating individual and the fetus and the severity of maternal
disease. For detailed guidance on the use of COVID-19 therapeutic agents during pregnancy, please
refer to the pregnancy considerations subsections found in the Antiviral Therapy and Immunomodulators
sections of these Guidelines.
The use of anti-SARS-CoV-2 monoclonal antibodies can be considered in pregnant people with
COVID-19, especially in those who have additional risk factors for severe disease. There is no
pregnancy-specific data on the use of monoclonal antibodies; however, other immunoglobulin G products
have been safely used in pregnancy when their use is indicated. Therefore, these products should not be
withheld in the setting of pregnancy.
To date, most SARS-CoV-2-related clinical trials have excluded individuals who are pregnant and
lactating; in cases where lactating and pregnant individuals have been included in studies, only a small
number have been enrolled. This limitation makes it difficult to make evidence-based recommendations
on the use of SARS-CoV-2 therapies in these vulnerable patients and potentially limits their COVID-19
treatment options. When possible, pregnant and lactating individuals should not be excluded from clinical
trials of therapeutic agents or vaccines for SARS-CoV-2 infection.
Timing of Delivery
ACOG provides detailed guidance on the timing of delivery and the risk of vertical transmission of
SARS-CoV-2.

AR09085
In most cases, the timing of delivery should be dictated by obstetric indications rather than maternal
diagnosis of COVID-19. For women who had suspected or confirmed COVID-19 early in pregnancy
who recover, no alteration to the usual timing of delivery is indicated.
Post-Delivery
The majority of studies have not demonstrated the presence of SARS-CoV-2 in breast milk; therefore,
breastfeeding is not contraindicated for people with laboratory-confirmed or suspected SARS-CoV-2
infection.8 Precautions should be taken to avoid transmission to the infant, including practicing good
hand hygiene, wearing face coverings, and performing proper pump cleaning before and after breast
milk expression.
The decision to feed the infant breast milk while the patient is receiving therapeutic agents for
COVID-19 should be a joint effort between the patient and the clinical team, including infant care
providers. The patient and the clinical team should discuss the potential benefits of the therapeutic agent
and evaluate the potential impact of pausing lactation on the future of breast milk delivery to the infant.
Specific guidance on the post-delivery management of infants born to mothers with known or suspected
SARS-CoV-2 infection, including breastfeeding recommendations, is provided by CDC and the
American Academy of Pediatrics, as well as the Special Considerations in Children section in these
Guidelines.
SARS-CoV-2 Vaccine in Pregnancy

A study that used data from three vaccine safety reporting systems in the United States reported that
the frequency of adverse events among 35,691 vaccine recipients who identified as pregnant was
similar to the frequency observed among nonpregnant patients. Local injection site pain, nausea, and
vomiting were reported slightly more frequently in pregnant people than in nonpregnant people. Other
systemic reactions were reported more frequently among nonpregnant vaccine recipients, but the overall
reactogenicity profile was similar for pregnant and nonpregnant patients. Surveillance data from 3,958
pregnant patients who were enrolled in CDC’s v-safe Vaccine Pregnancy Registry showed that, among
827 people who completed their pregnancies, there were no obvious safety signals among obstetric
or neonatal outcomes when rates of pregnancy loss (spontaneous abortion or stillbirth), preterm birth,
congenital anomalies, infants who were small for gestational age, and neonatal death were compared
to historic incidences in the peer-reviewed literature.9 ACOG has published practice guidance on using
COVID-19 vaccines in pregnant and lactating people, including a guide to assist clinicians during risk
and benefit conversations with pregnant patients.
References
1. Zambrano LD, Ellington S, Strid P, et al. Update: characteristics of symptomatic women of reproductive age
with laboratory-confirmed SARS-CoV-2 infection by pregnancy status—United States, January 22–October 3,
2. Ko JY, DeSisto CL, Simeone RM, et al. Adverse pregnancy outcomes, maternal complications, and severe
illness among U.S. delivery hospitalizations with and without a COVID-19 diagnosis. Clin Infect Dis.
3. Woodworth KR, Olsen EO, Neelam V, et al. Birth and infant outcomes following laboratory-confirmed
SARS-CoV-2 infection in pregnancy—SET-NET, 16 jurisdictions, March 29–October 14, 2020. MMWR Morb
Mortal Wkly Rep. 2020;69(44):1635-1640. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33151917.
4. Ellington S, Strid P, Tong VT, et al. Characteristics of women of reproductive age with laboratory-confirmed
SARS-CoV-2 infection by pregnancy status—United States, January 22–June 7, 2020. MMWR Morb Mortal

AR09086
Wkly Rep. 2020;69(25):769-775. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32584795.

5. Allotey J, Stallings E, Bonet M, et al. Clinical manifestations, risk factors, and maternal and perinatal
outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis. BMJ.
6. Metz TD, Clifton RG, Hughes BL, et al. Disease severity and perinatal outcomes of pregnant patients with
coronavirus disease 2019 (COVID-19). Obstet Gynecol. 2021;137(4):571-580. Available at:
7. Dumitriu D, Emeruwa UN, Hanft E, et al. Outcomes of neonates born to mothers with severe acute
respiratory syndrome coronavirus 2 infection at a large medical center in New York City. JAMA Pediatr.
2021;175(2):157-167. Available at: https://pubmed.ncbi.nlm.nih.gov/33044493/.
gyns-obstetrics. Accessed February 8, 2021.
9. Shimabukuro TT, Kim SY, Myers TR, et al. Preliminary findings of mRNA COVID-19 vaccine safety in
pregnant persons. N Engl J Med. 2021;384(24):2273-2282. Available at:

AR09087
Special Considerations in Children

• SARS-CoV-2 infection is generally milder in children than in adults, and a substantial proportion of children with the
disease have asymptomatic infection.
• Most children with SARS-CoV-2 infection will not require any specific therapy.
• Children who have a history of medical complexity (e.g., due to neurologic impairment, developmental
delays, or genetic syndromes, including trisomy 21), obesity, chronic cardiopulmonary disease, or who are
immunocompromised, as well as non-White children and older teenagers may be at increased risk for severe disease.
• There are limited data on the pathogenesis and clinical spectrum of COVID-19 disease in children. There are no
pediatric data from placebo-controlled randomized clinical trials and limited data from observational studies to inform
the development of pediatric-specific recommendations for the treatment of COVID-19.
Specific Therapy for Children
• In the absence of adequate data on the treatment of children with acute COVID-19, recommendations are based on
outcome and safety data for adult patients and the child’s risk of disease progression.
• Most children with mild or moderate disease can be managed with supportive care alone (AIII).
• Remdesivir is recommended for:
• Hospitalized children aged ≥12 years with COVID-19 who have risk factors for severe disease and have an
emergent or increasing need for supplemental oxygen (BIII).
• Hospitalized children aged ≥16 years with COVID-19 who have an emergent or increasing need for supplemental
oxygen regardless of whether they have risks factors for severe disease (BIII).
• In consultation with a pediatric infectious disease specialist, remdesivir can be considered for hospitalized children of
all ages with COVID-19 who have an emergent or increasing need for supplemental oxygen (CIII).
• The COVID-19 Treatment Guidelines Panel (the Panel) recommends using dexamethasone for hospitalized children
with COVID-19 who require high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal
membrane oxygenation (BIII).
• There is insufficient pediatric evidence for the Panel to recommend either for or against the use of anti-SARS-CoV-2
monoclonal antibody products for children with COVID-19 who are not hospitalized but who have risk factors for
severe disease. Based on adult studies, bamlanivimab plus etesevimab or casirivimab plus imdevimab may be
considered on a case-by-case basis for nonhospitalized children who meet Emergency Use Authorization (EUA)
criteria for high-risk of severe disease, especially those who meet more than 1 criterion or are aged ≥16 years. The
Panel recommends consulting a pediatric infectious disease specialist in such cases.
• The Panel recommends against the use of convalescent plasma for hospitalized children with COVID-19 who
do not require mechanical ventilation, except in a clinical trial (AIII). The Panel recommends against the use of
convalescent plasma for pediatric patients with COVID-19 who are mechanically ventilated (AIII). In consultation
with a pediatric infectious disease specialist, high-titer convalescent plasma may be considered on a case-by-case
basis for hospitalized children who meet the EUA criteria for its use.
• There is insufficient evidence for the Panel to recommend either for or against the use of baricitinib in combination
with remdesivir for the treatment of COVID-19 in hospitalized children in whom corticosteroids cannot be used.
• There is insufficient evidence for the Panel to recommend either for or against the use of tocilizumab in hospitalized
children with COVID-19 or multisystem inflammatory syndrome in children (MIS-C). The Panel recommends against
the use of sarilumab for hospitalized children with COVID-19 or MIS-C, except in a clinical trial (AIII).
• MIS-C is a serious delayed complication of SARS-CoV-2 infection that may develop in a minority of children and
young adults. See Therapeutic Management of Hospitalized Pediatric Patients With Multisystem Inflammatory
Syndrome in Children (MIS-C) (With Discussion on Multisystem Inflammatory Syndrome in Adults [MIS-A]) for the
Panel’s recommendations for treating children with MIS-C.

AR09088

Epidemiology
Data from the Centers for Disease Control and Prevention (CDC) demonstrate a lower incidence
of SARS-CoV-2 infection and severe disease in children than in adults.1 However, without more
systematic testing for children (including for children with mild symptoms as part of contact tracing)
or seroprevalence studies, the true burden of pediatric SARS-CoV-2 infection remains unclear. Data
on the pathogenesis and disease severity of SARS-CoV-2 infection in children are increasing but are
still limited compared to the data in adults. Several large epidemiologic studies suggest that severe
manifestations of acute disease are substantially less common in children than in adults. Although
only a small percentage of children with COVID-19 will require medical attention, intensive care unit
(ICU)-admission rates for hospitalized children are comparable to those for hospitalized adults with
COVID-19.2-10
Clinical Manifestations
The signs and symptoms of SARS-CoV-2 infection in children may be similar to those in adults,
but most children may be asymptomatic or only have a few symptoms. The most common signs and
symptoms of COVID-19 in hospitalized children are fever, nausea/vomiting, cough, shortness of
breath, and upper respiratory symptoms.9,11 Of note, signs and symptoms of COVID-19 may overlap
significantly with those of other viral infections, including influenza and other respiratory and enteric
viral infections. Although the true incidence of asymptomatic SARS-CoV-2 infection is unknown,
asymptomatic infection was reported in up to 45% of children who underwent surveillance testing at the
time of hospitalization for a non-COVID-19 indication.12
SARS-CoV-2 has been associated with a potentially severe inflammatory syndrome in children and
young adults (multisystem inflammatory syndrome in children [MIS-C]), which is discussed below.
Risk Factors
Data to clearly establish risk factors for severe COVID-19 in children are limited. Data reported to CDC
show lower hospitalization rates and ICU admission rates for children with COVID-19 than for adults
with the disease.11,13 COVID-19-related hospitalization rates for children were highest in children aged
<2 years and higher in Hispanic and Black children than in White children. The majority of hospitalized
children with acute COVID-19 had underlying conditions, with obesity, chronic lung disease, and
prematurity (data collected only for children aged <2 years) being the most prevalent.14 Risk factors such
as obesity may be more applicable to older teenagers.
In a large study of hospitalized children from the United Kingdom, age <1 month, age 10 to 14 years,
and Black race were associated with admission to critical care units in a multivariate analysis.9 Another
large, multicenter study from Europe identified male sex, pre-existing medical conditions, and the
presence of lower respiratory tract disease at presentation as additional risk factors for ICU admission in
multivariable models.10
Deaths associated with COVID-19 among those aged <21 years are higher among children aged
10 to 20 years, especially young adults aged 18 to 20 years, as well as among Hispanic, Black, and
American Indian/Alaska Native persons.15 A high proportion of the fatal cases of pediatric COVID-19
are in children with underlying medical conditions, most commonly chronic lung disease, obesity, and
neurological and developmental disorders.

AR09089
Based on data for adults with COVID-19 and extrapolations from data for non-COVID-19 pediatric
respiratory viral infections, severely immunocompromised children and those with underlying
cardiopulmonary disease may be at higher risk for severe COVID-19. Initial reports of SARS-CoV-2
infection among pediatric patients with cancer and pediatric solid organ transplant recipients have
demonstrated a low frequency of infection and associated morbidity;16-20 however, similar reports for
other immunocompromised pediatric populations are limited.21 A few reports have demonstrated a
higher prevalence of asthma in pediatric COVID-19 cases, although the association between asthma and
severe disease is not clearly defined.7,8 Congenital heart disease may be associated with an increased risk
of severe COVID-19, but the condition has not been consistently identified as a risk factor.22,23 Guidance
on the treatment of COVID-19 in children endorsed by the Pediatric Infectious Diseases Society
specifies additional risk factors to consider when making decisions about antiviral and monoclonal
antibody (mAb) therapy for pediatric patients.24,25
Persistent symptoms after acute COVID-19 have been described in adults, although the incidence of
this sequelae in children remains unknown and is an active area of research (see Clinical Spectrum of
SARS-CoV-2 Infection). Cardiac imaging studies have described myocardial injury in young athletes
who had only mild disease;26 additional studies are needed to determine long-term cardiac sequelae.
Vertical Transmission and Infants Born to People with SARS-CoV-2 Infection

Vertical transmission of SARS-CoV-2 is thought to be rare, but suspected or probable vertical
transmission has been described.27-29 Initial data on perinatal transmission of SARS-CoV-2 were limited
to small case series with conflicting results; some studies demonstrated lack of transmission, whereas
others were not able to definitively rule out this possibility.30-33 Among 100 women with SARS-CoV-2
infection who delivered 101 infants, only 2 infants had equivocal reverse transcription polymerase chain
reaction (RT-PCR) results that may have reflected SARS-CoV-2 infection, even though most of the
infants remained with their mothers, in rooms with infection prevention measures in place, and were
breast fed.34
Infants born to individuals with SARS-CoV-2 infection may have higher risk of poor clinical
outcomes than those born to individuals without SARS-CoV-2 infection, although data are conflicting.
In a systematic review of case series in pregnant women with confirmed SARS-CoV-2 infection
(predominantly from China), the preterm birth rate was 20.1% (57 of 284 births were preterm; 95%
CI, 15.8–25.1), the cesarean delivery rate was 84.7% (33 of 392 births were by cesarean delivery;
95% CI, 80.8–87.9), there was no vertical transmission, and the neonatal death rate was 0.3% (1 of
313 neonates died; 95% CI, 0.1–1.8).35 In a prospective cohort study of 263 infants born in the United
States, the rates for preterm births, neonatal ICU admissions, and respiratory disease did not differ
between infants born to mothers with and without SARS-CoV-2 infection.36 A cohort study from Sweden
demonstrated that 5-minute Apgar scores and birth weight for gestational age did not differ between
infants born to mothers with and without SARS-CoV-2 infection.37 Coronavirus Disease 2019 (COVID-
19)-Associated Hospitalization Surveillance Network (COVID-NET) data from CDC that captured 598
hospitalized, pregnant women with SARS-CoV-2 infection showed a pregnancy loss rate of 2% among
458 pregnancies completed during COVID-19-related hospitalizations and a preterm birth rate of 12.9%
compared to 10% for the general U.S. population.38 A systematic review and meta-analysis of studies
that included 2,567 pregnancies concluded that SARS-CoV-2-positive mothers were at increased risk
of iatrogenic preterm birth. This risk was predominantly due to caesarean sections (21.8% of births)
performed due to maternal illness and fear of maternal decompensation. In contrast, there was no
increase in the rate of spontaneous preterm birth relative to the expected rate in pregnant individuals
without SARS-CoV-2 infection.39,40 Finally, a prospective cohort study from the United Kingdom of
66 neonates with SARS-CoV-2 infection found that 3% may have had vertically acquired infection

AR09090
and 12% had suspected nosocomially acquired infection.29 Specific guidance on the diagnosis and
management of COVID-19 in neonates born to people with known or suspected SARS-CoV-2 infection
is provided by CDC.
Treatment Considerations
There are no results available from clinical trials that evaluated treatments for COVID-19 in children,
and observational data on the safety or efficacy of drug therapy in children with COVID-19 are
extremely limited. More high-quality studies, including randomized trials, are urgently needed.
Guidance for the treatment of COVID-19 in children has been published and is mostly extrapolated from
recommendations for adults with COVID-19.41,42 The older the child and the more severe the disease,
the more reasonable it is to follow recommendations for adult patients with COVID-19 (see Therapeutic
Management of Nonhospitalized Adults With COVID-19 and Therapeutic Management of Hospitalized
Adults With COVID-19). To address the uncertain safety and efficacy of these treatment options,
children should be enrolled in clinical trials and multicenter pragmatic trials whenever possible.
The majority of children with mild or moderate COVID-19 will not progress to more severe illness and
thus should be managed with supportive care alone (AIII). The risks and benefits of therapy should be
assessed based on illness severity, age, and the presence of the risk factors outlined above.
Remdesivir
Remdesivir is the only drug approved by the Food and Drug Administration (FDA) for the treatment
of COVID-19 (see Remdesivir for more information). It is approved for the treatment of COVID-19
in hospitalized adult and pediatric patients (aged ≥12 years and weighing ≥40 kg). It is also available
through an FDA Emergency Use Authorization (EUA) for the treatment of COVID-19 in hospitalized
pediatric patients weighing 3.5 kg to <40 kg or aged <12 years and weighing ≥3.5 kg.43 Remdesivir has
not been evaluated in clinical trials that include children, and there have been no results from systematic
evaluations of pharmacokinetics, efficacy, or toxicity in younger children, although studies are ongoing
(see ClinicalTrials.gov). However, based on adult data, the potential benefits of remdesivir are likely to
be greater for hospitalized children with COVID-19 who are at higher risk of progression due to older
age (i.e., aged ≥16 years) or medical conditions than for those without these risk factors. Remdesivir
is recommended for hospitalized children aged ≥12 years with COVID-19 who have risk factors for
severe disease and have an emergent or increasing need for supplemental oxygen (BIII). Remdesivir is
also recommended for hospitalized children aged ≥16 years with COVID-19 who have an emergent or
increasing need for supplemental oxygen even in the absence of risk factors (BIII). Remdesivir can be
considered for other hospitalized children of all ages with COVID-19 who have an emergent or increasing
need for supplemental oxygen in consultation with a pediatric infectious disease specialist (CIII).
Dexamethasone
Dexamethasone is recommended for the treatment of hospitalized adults with COVID-19 who require
mechanical ventilation or supplemental oxygen through a high-flow device (see Corticosteroids
and Therapeutic Management of Hospitalized Adults With COVID-19 for more information). The
safety and effectiveness of dexamethasone or other corticosteroids for COVID-19 treatment have
not been sufficiently evaluated in pediatric patients; thus, caution is warranted when extrapolating
recommendations for adults to patients aged <18 years. The COVID-19 Treatment Guidelines Panel
(the Panel) recommends using dexamethasone for children with COVID-19 who require high-flow
oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation
(ECMO) (BIII). It is not routinely recommended for pediatric patients who require only low levels
of oxygen support (i.e., via a nasal cannula only). Use of dexamethasone for the treatment of severe

AR09091
COVID-19 in children who are profoundly immunocompromised has not been evaluated, may be
harmful, and therefore should be considered only on a case-by-case basis. If dexamethasone is not
available, alternative glucocorticoids such as prednisone, methylprednisolone, or hydrocortisone can be
considered. The dexamethasone dosing regimen for pediatric patients is dexamethasone 0.15 mg/kg/dose
(maximum dose 6 mg) once daily for up to 10 days.

Although EUAs have been issued for bamlanivimab plus etesevimab, casirivimab plus imdevimab, and
sotrovimab for the treatment of nonhospitalized, high-risk patients aged ≥12 years and weighing ≥40
kg with mild to moderate COVID-19, there are currently no data available to determine which high-risk
pediatric patients defined in the EUAs will likely benefit from these therapies. Consequently, there is
insufficient evidence for the Panel to recommend either for or against the use of these anti-SARS-CoV-2
mAbs in children with COVID-19 who are not hospitalized but are at high risk of severe disease and/
or hospitalization. In consultation with a pediatric infectious disease specialist, anti-SARS-CoV-2 mAb
can be considered on a case-by-case basis for children who meet the EUA criteria but should not be
considered routine care. This recommendation is primarily based on the absence of data assessing the
efficacy and safety in children and adolescents, limited data with which to identify children who are at
the highest risk of severe COVID-19, the low overall risk of progression to serious disease in children,
and the potential risk associated with infusion reactions.
Additional guidance is provided in a recent publication endorsed by the Pediatric Infectious Diseases
Society.25 There are currently no data to support the use of anti-SARS-CoV-2 mAbs in hospitalized
children for COVID-19. Emerging data regarding the prevalence and clinical significance of
SARS-CoV-2 variants, and the efficacy of mAbs against variants, may inform the choice of specific
anti-SARS-CoV-2 mAb therapies in the future.
Convalescent Plasma
FDA has also issued an EUA for the use of high-titer convalescent plasma for the treatment of
hospitalized patients with COVID-19 (see Convalescent Plasma for more information).44 The safety
and efficacy of convalescent plasma have not been evaluated in pediatric patients with COVID-19.
There is insufficient evidence for the Panel to recommend either for or against the use of convalescent
plasma for the treatment of COVID-19 in either pediatric outpatients or in hospitalized children who do
not require mechanical ventilation. The Panel recommends against the use of convalescent plasma
for pediatric patients with COVID-19 who are mechanically ventilated (AIII). In consultation with a
pediatric infectious disease specialist, convalescent plasma may be considered on a case-by-case basis
for children who meet the EUA criteria for its use.
Baricitinib
FDA has also issued an EUA for the use of baricitinib in combination with remdesivir in hospitalized
adults and children aged ≥2 years with COVID-19 who require supplemental oxygen, mechanical
ventilation, or ECMO.45 The safety and efficacy of baricitinib have not been evaluated in pediatric
patients with COVID-19, and pediatric data regarding its use for other conditions are extremely limited.
Thus, there is insufficient evidence for the Panel to recommend either for or against the use of baricitinib
in combination with remdesivir for the treatment of COVID-19 in hospitalized children in whom
corticosteroids cannot be used (see Kinase Inhibitors for more information).
Tocilizumab
Data on the use of tocilizumab for the treatment of non-COVID-19 conditions in children are limited
to very specific clinical scenarios (e.g., chimeric antigen receptor T cell-related cytokine release

AR09092
syndrome).46 The use of tocilizumab for severe cases of acute COVID-19 has been described in pediatric
case series.14,47 Data on tocilizumab efficacy from trials in adults with COVID-19 are conflicting, and
benefit has only been demonstrated in a subset of hospitalized patients (see Interleukin-6 Inhibitors).
There is insufficient evidence for the Panel to recommend either for or against the use of tocilizumab
for hospitalized children with COVID-19 or MIS-C. If used, tocilizumab should be used in combination
with dexamethasone. The Panel recommends against the use of sarilumab for hospitalized children
with COVID-19 or MIS-C, except in a clinical trial (AIII).
As for other agents outlined in these Guidelines, there is insufficient evidence for the Panel to
recommend either for or against the use of specific antivirals or immunomodulatory agents for the
treatment of COVID-19 in pediatric patients. Considerations such as underlying conditions, disease
severity, and the potential for drug toxicity or drug interactions may inform decisions on the use of
these agents in pediatric patients with COVID-19 on a case-by-case basis. Children should be enrolled
in clinical trials that are evaluating COVID-19 therapies whenever possible. A number of additional
drugs are being investigated for the treatment of COVID-19 in adults; refer to the Antiviral Therapy and
Immunomodulators sections to review special considerations for using these drugs in children and refer
to Table 2f and Table 4f for recommendations on pediatric dosing regimens.
Multisystem Inflammatory Syndrome in Children

A small subset of children and young adults with SARS-CoV-2 infection develop MIS-C. This
immune manifestation is also referred to as pediatric multisystem inflammatory syndrome-temporally
associated with SARS-CoV-2 (PMIS-TS), although the case definitions for the syndromes differ
slightly. This syndrome was first described in Europe, where previously healthy children with severe
inflammation and Kawasaki disease-like features were identified to have current or recent infection with
SARS-CoV-2. The clinical spectrum of MIS-C has been described in the United States and is similar to
that described for PMIS-TS. MIS-C is consistent with a post-infectious inflammatory syndrome related
to SARS-CoV-2.48,49 Most MIS-C patients have serologic evidence of previous SARS-CoV-2 infection,
but only a minority are RT-PCR positive for SARS-CoV-2 at presentation.50,51 The peak incidence of
MIS-C lags about 4 weeks behind the peak of acute pediatric COVID-19 hospitalizations. Emerging
data suggests that adults may also develop a similar syndrome, multisystem inflammatory syndrome
in adults (MIS-A), although it is not clear if this is a postinfectious complication similar to MIS-C.50-52
Although risk factors for MIS-C have not been established, in an analysis of MIS-C cases in the United
States, most of the children were non-White, and obesity was the most common comorbidity.53 Unlike
in children with acute COVID-19, the majority of children who present with MIS-C do not seem to have
underlying comorbid conditions other than obesity.
Clinical Manifestations
The current CDC case definition for MIS-C includes:
• An individual aged <21 years presenting with fever,a laboratory evidence of inflammation,b
and evidence of clinically severe illness that requires hospitalization with multisystem (i.e., >2)
organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, or
neurological); and
• No alternative plausible diagnoses; and
• Positive for current or recent SARS-CoV-2 infection by RT-PCR, antigen test, or serology results;
or COVID-19 exposure within the 4 weeks prior to the onset of symptoms.54
a
Fever >38.0°C for ≥24 hours or report of subjective fever lasting ≥24 hours
b
Including, but not limited to, 1 or more of the following: an elevated C-reactive protein, erythrocyte sedimentation rate,

AR09093
fi brinogen, procalcitonin, D-dimer, ferritin, lactate dehydrogenase, interleukin-6, or neutrophils, or reduced lymphocytes
or albumin levels
Distinguishing MIS-C from other febrile illnesses in the community setting remains challenging, but
the presence of persistent fever, multisystem manifestations, and laboratory abnormalities could help
early recognition.55 The clinical spectrum of hospitalized cases has included younger children with
mucocutaneous manifestations that overlap with Kawasaki disease, older children with more multiorgan
involvement and shock, and patients with respiratory manifestations that overlap with acute COVID-19.
Patients with MIS-C are often critically ill, and up to 80% of children require ICU admission.53 Most
patients with MIS-C have markers of cardiac injury or dysfunction, including elevated levels of troponin
and brain natriuretic protein.50,51 Echocardiographic findings in these cases include impaired left
ventricular function and coronary artery dilations, and, rarely, coronary artery aneurysms. The reported
mortality rate in the United States for hospitalized children with MIS-C is 1% to 2%. Longitudinal
studies are currently ongoing to examine the long-term sequelae of MIS-C.
The pathogenesis of MIS-C is still being elucidated. Differences have been demonstrated between
MIS-C and typical Kawasaki disease in terms of epidemiology, cytopenias, cytokine expression, and
elevation of inflammatory markers. Immunologic profiling has also shown differences in cytokine
expression (tumor necrosis factor alpha and interleukin-10) between MIS-C and acute COVID-19 in
children.56-58
Management
Please see Therapeutic Management of Hospitalized Pediatric Patients With Multisystem Inflammatory
Syndrome in Children (MIS-C) (With Discussion on Multisystem Inflammatory Syndrome in Adults
[MIS-A]) for the Panel’s recommendations for treating MIS-C in children.
References
1. Centers for Disease Control and Prevention. Information for pediatric healthcare providers. 2020. Available at:
https://www.cdc.gov/coronavirus/2019-ncov/hcp/pediatric-hcp.html. Accessed February 15, 2022.
2. Dong Y, Mo X, Hu Y, et al. Epidemiology of COVID-19 among children in China. Pediatrics. 2020;145(6).
3. CDC COVID Response Team. Coronavirus disease 2019 in children—United States, February 12–April 2,
4. Cui X, Zhang T, Zheng J, et al. Children with coronavirus disease 2019: a review of demographic, clinical,
laboratory, and imaging features in pediatric patients. J Med Virol. 2020;92(9):1501-1510. Available at:
5. Livingston E, Bucher K. Coronavirus disease 2019 (COVID-19) in Italy. JAMA. 2020;323(14):1335. Available
6. Tagarro A, Epalza C, Santos M, et al. Screening and severity of coronavirus disease 2019 (COVID-19) in
children in Madrid, Spain. JAMA Pediatr. 2020;Published online ahead of print. Available at:
7. DeBiasi RL, Song X, Delaney M, et al. Severe coronavirus disease-2019 in children and young adults in the
Washington, DC, metropolitan region. J Pediatr. 2020;223:199-203 e191. Available at:
8. Chao JY, Derespina KR, Herold BC, et al. Clinical characteristics and outcomes of hospitalized and critically
ill children and adolescents with coronavirus disease 2019 at a tertiary care medical center in New York City. J
Pediatr. 2020;223:14-19 e12. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32407719.

AR09094
9. Swann OV, Holden KA, Turtle L, et al. Clinical characteristics of children and young people admitted to
hospital with COVID-19 in United Kingdom: prospective multicentre observational cohort study. BMJ.
10. Gotzinger F, Santiago-Garcia B, Noguera-Julian A, et al. COVID-19 in children and adolescents in Europe: a
multinational, multicentre cohort study. Lancet Child Adolesc Health. 2020;4(9):653-661. Available at:
11. Kim L, Whitaker M, O’Halloran A, et al. Hospitalization rates and characteristics of children aged <18 years
hospitalized with laboratory-confirmed COVID-19—COVID-NET, 14 States, March 1–July 25, 2020. MMWR
12. Poline J, Gaschignard J, Leblanc C, et al. Systematic severe acute respiratory syndrome coronavirus
2 screening at hospital admission in children: a French prospective multicenter study. Clin Infect Dis.
13. Leidman E, Duca LM, Omura JD, et al. COVID-19 trends among persons aged 0-24 years—United States,
March 1-December 12, 2020. MMWR Morb Mortal Wkly Rep. 2021;70(3):88-94. Available at:
14. Shekerdemian LS, Mahmood NR, Wolfe KK, et al. Characteristics and outcomes of children with coronavirus
disease 2019 (COVID-19) infection admitted to US and Canadian pediatric intensive care units. JAMA
Pediatr. 2020;174(9):868-873. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32392288.
15. Bixler D, Miller AD, Mattison CP, et al. SARS-CoV-2-associated deaths among persons aged <21 years—
United States, February 12–July 31, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(37):1324-1329. Available
16. Goss MB, Galvan NTN, Ruan W, et al. The pediatric solid organ transplant experience with COVID-19: an
initial multi-center, multi-organ case series. Pediatr Transplant. 2021;25(3):e13868. Available at:
17. Bisogno G, Provenzi M, Zama D, et al. Clinical characteristics and outcome of severe acute respiratory
syndrome coronavirus 2 infection in Italian pediatric oncology patients: a study from the infectious diseases
working group of the Associazione Italiana di Oncologia e Ematologia Pediatrica. J Pediatric Infect Dis Soc.
18. Boulad F, Kamboj M, Bouvier N, Mauguen A, Kung AL. COVID-19 in children with cancer in New York
City. JAMA Oncol. 2020;6(9):1459-1460. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32401276.
19. de Rojas T, Perez-Martinez A, Cela E, et al. COVID-19 infection in children and adolescents with cancer in
Madrid. Pediatr Blood Cancer. 2020;67(7):e28397. Available at:
20. Hrusak O, Kalina T, Wolf J, et al. Flash survey on severe acute respiratory syndrome coronavirus-2 infections
in paediatric patients on anticancer treatment. Eur J Cancer. 2020;132:11-16. Available at:
21. Freeman MC, Rapsinski GJ, Zilla ML, Wheeler SE. Immunocompromised seroprevalence and course of
illness of SARS-CoV-2 in one pediatric quaternary care center. J Pediatric Infect Dis Soc. 2021;10(4):426-
22. Madhusoodhan PP, Pierro J, Musante J, et al. Characterization of COVID-19 disease in pediatric oncology
patients: the New York-New Jersey regional experience. Pediatr Blood Cancer. 2021;68(3):e28843. Available
23. Lewis MJ, Anderson BR, Fremed M, et al. Impact of coronavirus disease 2019 (COVID-19) on patients with
congenital heart disease across the lifespan: the experience of an academic congenital heart disease center in
New York City. J Am Heart Assoc. 2020;9(23):e017580. Available at:

AR09095
24. Chiotos K, Hayes M, Kimberlin DW, et al. Multicenter interim guidance on use of antivirals for children
with coronavirus disease 2019/severe acute respiratory syndrome coronavirus 2. J Pediatric Infect Dis Soc.
25. Wolf J, Abzug MJ, Wattier RL, et al. Initial guidance on use of monoclonal antibody therapy for treatment
of coronavirus disease 2019 in children and adolescents. J Pediatric Infect Dis Soc. 2021;10(5):629-634.
26. Rajpal S, Tong MS, Borchers J, et al. Cardiovascular magnetic resonance findings in competitive athletes
recovering from COVID-19 infection. JAMA Cardiol. 2021;6(1):116-118. Available at:
27. Demirjian A, Singh C, Tebruegge M, et al. Probable vertical transmission of SARS-CoV-2 infection. Pediatr
Infect Dis J. 2020;39(9):e257-e260. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32658096.
28. Dong L, Tian J, He S, et al. Possible vertical transmission of SARS-CoV-2 from an infected mother to her
newborn. JAMA. 2020;323(18):1846-1848. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32215581.
29. Gale C, Quigley MA, Placzek A, et al. Characteristics and outcomes of neonatal SARS-CoV-2 infection
in the UK: a prospective national cohort study using active surveillance. Lancet Child Adolesc Health.
30. Chen H, Guo J, Wang C, et al. Clinical characteristics and intrauterine vertical transmission potential
of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet.
31. Fan C, Lei D, Fang C, et al. Perinatal transmission of 2019 coronavirus disease-associated severe acute
respiratory syndrome coronavirus 2: should we worry? Clin Infect Dis. 2021;72(5):862-864. Available at:
32. Zeng L, Xia S, Yuan W, et al. Neonatal early-onset infection with SARS-CoV-2 in 33 neonates born to
mothers with COVID-19 in Wuhan, China. JAMA Pediatr. 2020;174(7):722-725. Available at:
33. Von Kohorn I, Stein SR, Shikani BT, et al. In utero severe acute respiratory syndrome coronavirus 2 infection.
J Pediatric Infect Dis Soc. 2020;9(6):769-771. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33089311.
34. Dumitriu D, Emeruwa UN, Hanft E, et al. Outcomes of neonates born to mothers with severe acute
respiratory syndrome coronavirus 2 infection at a large medical center in New York City. JAMA Pediatr.
35. Huntley BJF, Huntley ES, Di Mascio D, et al. Rates of maternal and perinatal mortality and vertical
transmission in pregnancies complicated by severe acute respiratory syndrome coronavirus 2 (SARS-Co-V-2)
infection: a systematic review. Obstet Gynecol. 2020;136(2):303-312. Available at:
36. Flaherman VJ, Afshar Y, Boscardin WJ, et al. Infant outcomes following maternal infection with severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2): first report from the pregnancy coronavirus outcomes
registry (PRIORITY) study. Clin Infect Dis. 2021;73(9):e2810-e2813. Available at:
37. Ahlberg M, Neovius M, Saltvedt S, et al. Association of SARS-CoV-2 test status and pregnancy outcomes.
JAMA. 2020;324(17):1782-1785. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32965467.
38. Delahoy MJ, Whitaker M, O’Halloran A, et al. Characteristics and maternal and birth outcomes of hospitalized
pregnant women with laboratory-confirmed COVID-19—COVID-NET, 13 States, March 1–August 22, 2020.
MMWR Morb Mortal Wkly Rep. 2020;69(38):1347-1354. Available at:
39. Khalil A, Kalafat E, Benlioglu C, et al. SARS-CoV-2 infection in pregnancy: a systematic review and meta-
analysis of clinical features and pregnancy outcomes. EClinicalMedicine. 2020;25:100446. Available at:

AR09096
40. Khoury R, Bernstein PS, Debolt C, et al. Characteristics and outcomes of 241 births to women with severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection at five New York City medical centers.
Obstet Gynecol. 2020;136(2):273-282. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32555034.
41. Chiotos K, Hayes M, Kimberlin DW, et al. Multicenter initial guidance on use of antivirals for children
with coronavirus disease 2019/severe acute respiratory syndrome coronavirus 2. J Pediatric Infect Dis Soc.
42. Dulek DE, Fuhlbrigge RC, Tribble AC, et al. Multidisciplinary guidance regarding the use of
immunomodulatory therapies for acute coronavirus disease 2019 in pediatric patients. J Pediatric Infect Dis
Soc. 2020;9(6):716-737. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32808988.
veklury (remdesivir) for hospitalized pediatric patients weighing 3.5 kg to less than 40 kg or hospitalized
pediatric patients less than 12 years of age weighing at least 3.5 kg. 2020. Available at:
44. Food and Drug Administration. EUA 26382: Emergency Use Authorization (EUA) decision memo. 2020.
Available at: https://www.fda.gov/media/141480/download.
45. Food and Drug Administration. Letter of authorization: EUA for baricitinib (Olumiant), in combination
with remdesivir (Veklury), for the treatment of suspected or laboratory confirmed coronavirus disease 2019
(COVID-19). 2020. Available at: https://www.fda.gov/media/143822/download.
46. Kotch C, Barrett D, Teachey DT. Tocilizumab for the treatment of chimeric antigen receptor T cell-induced
cytokine release syndrome. Expert Rev Clin Immunol. 2019;15(8):813-822. Available at:
47. Derespina KR, Kaushik S, Plichta A, et al. Clinical manifestations and outcomes of critically ill children and
adolescents with coronavirus disease 2019 in New York City. J Pediatr. 2020;226:55-63 e52. Available at:
48. Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in
children during COVID-19 pandemic. Lancet. 2020;395(10237):1607-1608. Available at:
multisystem syndrome temporally associated with SARS-CoV-2. JAMA. 2020;324(3):259-269. Available at:
50. Dufort EM, Koumans EH, Chow EJ, et al. Multisystem inflammatory syndrome in children in New York
State. N Engl J Med. 2020;383(4):347-358. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32598830.
51. Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem inflammatory syndrome in U.S. children and
adolescents. N Engl J Med. 2020;383(4):334-346. Available at:
52. Morris SB, Schwartz NG, Patel P, et al. Case series of multisystem inflammatory syndrome in adults
associated with SARS-CoV-2 infection—United Kingdom and United States, March–August 2020. MMWR
53. Godfred-Cato S, Bryant B, Leung J, et al. COVID-19-associated multisystem inflammatory syndrome
in children—United States, March–July 2020. MMWR Morb Mortal Wkly Rep. 2020;69(32):1074-1080.
54. Centers for Disease Control and Prevention. Information for healthcare providers about multisystem
inflammatory syndrome in children (MIS-C). 2021. Available at: https://www.cdc.gov/mis/mis-c/hcp/.
Accessed February 15, 2022.
55. Carlin RF, Fischer AM, Pitkowsky Z, et al. Discriminating multisystem inflammatory syndrome in children
requiring treatment from common febrile conditions in outpatient settings. J Pediatr. 2021;229:26-32 e22.

AR09097

56. Lee PY, Day-Lewis M, Henderson LA, et al. Distinct clinical and immunological features of SARS-CoV-2-
induced multisystem inflammatory syndrome in children. J Clin Invest. 2020;130(11):5942-5950. Available at:
57. Rowley AH, Shulman ST, Arditi M. Immune pathogenesis of COVID-19-related multisystem inflammatory
syndrome in children. J Clin Invest. 2020;130(11):5619-5621. Available at:
58. Diorio C, Henrickson SE, Vella LA, et al. Multisystem inflammatory syndrome in children and COVID-19 are
distinct presentations of SARS-CoV-2. J Clin Invest. 2020;130(11):5967-5975. Available at:

AR09098
Special Considerations in Adults and Children With Cancer

• Given the effectiveness of the COVID-19 vaccines in the general population and the increased risk of severe COVID-19
and mortality in patients with cancer, the COVID-19 Treatment Guidelines Panel (the Panel) recommends COVID-19
vaccination for patients with active cancer or patients who are receiving treatment for cancer (AIII).
• Patients who are receiving active cancer therapy may have suboptimal responses to the current two-dose vaccine
series. Because of this, the Centers for Disease Control and Prevention recommends a third dose of an mRNA vaccine
for these patients. See the text below for additional information on the criteria for receiving a third dose and the
appropriate timing for COVID-19 vaccination in these patients.
• Patients with cancer are at high risk of progressing to serious COVID-19, and they may be eligible to receive anti-
SARS-CoV-2 monoclonal antibodies for treatment or as post-exposure prophylaxis (PEP).
• The Panel recommends performing molecular diagnostic testing for SARS-CoV-2 in patients with cancer who develop
signs and symptoms that suggest COVID-19 (AIII) and in asymptomatic patients prior to procedures that require
anesthesia and before initiating cytotoxic chemotherapy and long-acting biologic therapy (BIII).
• The recommendations for treating COVID-19 in patients with cancer are the same as those for the general population
(AIII). See Therapeutic Management of Nonhospitalized Adults With COVID-19 and Therapeutic Management of
Hospitalized Adults With COVID-19 for more information.
• Clinicians should pay careful attention to potential drug-drug interactions and overlapping toxicities between drugs
that are used to treat COVID-19 and cancer-directed therapies, prophylactic antimicrobials, corticosteroids, and other
medications (AIII).
• Clinicians who are treating COVID-19 in patients with cancer should consult a hematologist or oncologist before
adjusting cancer-directed medications (AIII).
• Decisions about administering cancer-directed therapy during SARS-CoV-2 infection should be made on a case-by-
case basis; clinicians should consider the indication for chemotherapy, the goals of care, and the patient’s history of
tolerance to the treatment (BIII).
People who are being treated for cancer may be at increased risk of severe COVID-19, and clinical
outcomes of COVID-19 are generally worse in people with cancer than in people without cancer.1-4 A
meta-analysis of 46,499 patients with COVID-19 showed that all-cause mortality (risk ratio 1.66; 95%
CI, 1.33–2.07) was higher in patients with cancer, and that patients with cancer were more likely to be
admitted to intensive care units (risk ratio 1.56; 95% CI, 1.31–1.87).5 A patient’s risk of
immunosuppression and susceptibility to SARS-CoV-2 infection depend on the type of cancer, the
treatments administered, and the stage of disease (e.g., patients who are actively being treated compared
to those in remission). In a study that used data from the COVID-19 and Cancer Consortium Registry,
patients with cancer who were in remission or who had no evidence of disease were at lower risk of
death from COVID-19 than those who were receiving active treatment.6 It is unclear whether cancer
survivors are at increased risk for severe COVID-19 and its complications compared to people without a
history of cancer.
Many organizations have outlined recommendations for treating patients with cancer during the
COVID-19 pandemic, such as:
• National Comprehensive Cancer Network (NCCN)
• American Society of Hematology (ASH)

AR09099
• American Society of Clinical Oncology

• Society of Surgical Oncology
• American Society for Radiation Oncology
• International Lymphoma Radiation Oncology Group
This section of the COVID-19 Treatment Guidelines complements these sources and focuses on testing
for SARS-CoV-2, managing COVID-19 in patients with cancer, and managing cancer-directed therapies
during the COVID-19 pandemic. The optimal management and therapeutic approach to COVID-19 in
this population has not yet been defined.
Vaccination for COVID-19 in Patients With Cancer

The clinical trials that evaluated the COVID-19 vaccines that have received Emergency Use
Authorizations and/or approval from the Food and Drug Administration (FDA) excluded severely
immunocompromised patients. The Advisory Committee on Immunization Practices notes that the
authorized COVID-19 vaccines are not live vaccines; therefore, they can be safely administered to
immunocompromised people.7 Given the effectiveness of the COVID-19 vaccines in the general
population and the increased risk of severe COVID-19 and mortality in patients with cancer, the
COVID-19 Treatment Guidelines Panel (the Panel) recommends COVID-19 vaccination for patients
with active cancer or patients who are receiving treatment for cancer (AIII). The Centers for Disease
Control and Prevention (CDC) recommends a third dose of an mRNA vaccine for patients who are
receiving active cancer therapy; this third dose should be administered at least 28 days after the
completion of the initial two-dose mRNA COVID-19 vaccine series.8 ASH and NCCN have provided
additional recommendations for administering a third vaccine dose in patients with cancer based on the
patient’s tumor type and therapy.9,10
The mRNA vaccines contain polyethylene glycol (PEG), and the Johnson & Johnson (J&J)/Janssen
vaccine contains polysorbate. In patients who experience a severe anaphylactic reaction to PEG-
asparaginase, consider performing allergy testing for PEG prior to vaccination with either of the mRNA
vaccines, or consider using the J&J/Janssen vaccine with precautions.11-13
When determining the timing of COVID-19 vaccination in patients with cancer, clinicians should
consider the following factors:
• If possible, patients who are planning to receive chemotherapy should complete vaccination for
COVID-19 at least 2 weeks before starting chemotherapy.9,14
• In patients with hematologic malignancy who are undergoing intensive chemotherapy (e.g.,
induction chemotherapy for acute myelogenous leukemia), vaccination should be delayed until
neutrophil recovery.15
• Hematopoietic stem cell and chimeric antigen receptor T cell recipients can be offered COVID-19
vaccination starting at least 3 months after therapy.14
It is unknown whether the immune response to COVID-19 vaccination can increase the risk of graft-
versus-host disease. Studies of patients who received immune checkpoint inhibitors did not report
immune-related adverse events in these patients after vaccination.16,17
Decreased immunologic responses to COVID-19 vaccination have been reported in patients who
were receiving treatment for solid tumors and hematologic malignancies.18,19 The type of therapy
has been shown to influence the patient’s response to vaccination. For example, people with chronic
lymphocytic leukemia who were treated with Bruton’s tyrosine kinase inhibitors or venetoclax with

AR09100
or without anti-CD20 antibodies had extremely low response rates (16.0% and 13.6%, respectively).19
In comparison, approximately 80% to 95% of patients with solid tumors showed immunologic
responses.18,20,21 Currently, it is not known how a third dose of an mRNA vaccine affects response rates
in patients with cancer.
Patients with cancer are at high risk of progressing to serious COVID-19, and they may be eligible to
receive anti-SARS-CoV-2 monoclonal antibodies (mAbs) as post-exposure prophylaxis (PEP).
Vaccination of household members, close contacts, and health care providers who provide care for
immunocompromised patients is imperative to protect these patients from infection. All close contacts
are strongly encouraged to get vaccinated.
Testing for SARS-CoV-2 in Patients With Cancer

The Panel recommends molecular diagnostic testing for SARS-CoV-2 in patients with cancer who
develop signs and symptoms of COVID-19 (AIII).
Patients with cancer who are receiving chemotherapy are at risk of developing neutropenia. The NCCN
Guidelines for Hematopoietic Growth Factors categorizes cancer treatment regimens based on the
patient’s risk of developing neutropenia.22 A retrospective study suggests that patients with cancer and
neutropenia have a higher mortality rate if they develop COVID-19.23 Studies have reported an increased
risk of poor clinical outcomes for patients with COVID-19 in the setting of neutropenia and/or during
the perioperative period.24,25 Because of this, the Panel recommends performing molecular diagnostic
testing for SARS-CoV-2 prior to procedures that require anesthesia and before initiating cytotoxic
chemotherapy and long-acting biologic therapy (BIII).
General Guidance on Medical Care for Patients With Cancer During the COVID-19
Pandemic
Patients with cancer frequently engage with the health care system to receive treatment and supportive
care for cancer and/or treatment-related complications. Telemedicine can minimize the need for
in-person services and reduce the risk of SARS-CoV-2 exposure. CDC has published a framework to
help clinicians decide whether a patient should receive in-person or virtual care during the COVID-19
pandemic; this framework accounts for factors such as the potential harm of delayed care and the
degree of SARS-CoV-2 transmission in a patient’s community.26 Telemedicine may improve access
to providers for medically or socially vulnerable populations, but it could worsen disparities if these
populations have limited access to technology. Nosocomial transmission of SARS-CoV-2 to patients and
health care workers has been reported.27-29 Principles of physical distancing and prevention strategies,
including masking patients and health care workers and practicing hand hygiene, apply to all in-person
interactions.30
Decisions about treatment regimens, surgery, and radiation therapy for the underlying malignancy
should be made on a case-by-case basis, and clinicians should consider the biology of the cancer,
the need for hospitalization, the number of clinic visits required, and the anticipated degree of
immunosuppression. Additional factors that should be considered include the following:
• If possible, treatment delays should be avoided for curable cancers that have been shown to have
worse outcomes when treatment is delayed (e.g., pediatric acute lymphoblastic leukemia).
• When deciding between equally effective treatment regimens, regimens that can be administered
orally or those that require fewer infusions are preferred.31
• The potential risks of drug-related lung toxicity (e.g., from using bleomycin or PD-1 inhibitors)

AR09101
must be balanced with the clinical efficacy of alternative regimens or the risk of delaying care.32
• Preventing neutropenia can decrease the risk of neutropenic fever and the need for emergency
department evaluation and hospitalization. Granulocyte colony-stimulating factor (G-CSF) should
be given with chemotherapy regimens that have intermediate (10% to 20%) or high (>20%) risks
of febrile neutropenia.33
• Cancer treatment regimens that do not affect the outcomes of COVID-19 in patients with cancer
may not need to be altered. In a prospective observational study, receipt of immunotherapy,
hormonal therapy, or radiotherapy in the month prior to SARS-CoV-2 infection was not associated
with an increased risk of mortality among patients with cancer and COVID-19.34 A retrospective
study from Italy evaluated the incidence of SARS-CoV-2 infection in patients with prostate
cancer and found that 114 of 37,161 patients (0.3%) who were treated with therapies other
than androgen deprivation therapy became infected, compared to 4 of 5,273 patients (0.08%)
who were treated with androgen deprivation therapy (OR 4.05; 95% CI, 1.55–10.59).35 A small
cohort study of patients from Finland with prostate cancer did not find an association between
androgen deprivation and the incidence of SARS-CoV-2 infection.36 The viral spike proteins that
SARS-CoV-2 uses to enter cells are primed by transmembrane serine protease 2 (TMPRSS2), an
androgen-regulated gene. Whether androgen deprivation therapy protects against SARS-CoV-2
infection requires further investigation in larger cohorts or clinical trials.35
• Radiation therapy guidelines suggest increasing the dose per fraction and reducing the number of
daily treatments to minimize the number of hospital visits.37,38
Blood supply shortages will likely continue during the COVID-19 pandemic due to social distancing,
cancellation of blood drives, and infection among donors. The FDA has proposed revising the donor
criteria to increase the number of eligible donors.39 In patients with cancer, stricter transfusion thresholds
for blood products (e.g., red blood cells, platelets) in asymptomatic patients should be considered.8 At
this time, there is no evidence that COVID-19 can be transmitted through blood products.40,41
Febrile Neutropenia
Patients with cancer and febrile neutropenia should undergo molecular diagnostic testing for
SARS-CoV-2 and evaluation for other infectious agents; they should also be given empiric antibiotics, as
outlined in the NCCN Guidelines.42 Low-risk febrile neutropenia patients should be treated at home with
oral antibiotics or intravenous infusions of antibiotics to limit nosocomial exposure to SARS-CoV-2.
Patients with high-risk febrile neutropenia should be hospitalized per standard of care.42 Empiric
antibiotics should be continued per standard of care in patients who test positive for SARS-CoV-2.
Clinicians should also continuously evaluate neutropenic patients for emergent infections.
Treating COVID-19 and Managing Chemotherapy in Patients With Cancer and

COVID-19
Retrospective studies suggest that patients with cancer who were admitted to the hospital with
SARS-CoV-2 infection have a high case-fatality rate, with higher rates observed in patients with
hematologic malignancies than in those with solid tumors.43,44
The recommendations for treating COVID-19 in patients with cancer are the same as those for the
general population (AIII). See Therapeutic Management of Nonhospitalized Adults With COVID-19 and
Therapeutic Management of Hospitalized Adults With COVID-19 for more information. Patients with
cancer are at high risk of progressing to serious COVID-19, and they may be eligible to receive anti-
SARS-CoV-2 mAbs as treatment if they develop mild to moderate COVID-19.

AR09102
Dexamethasone treatment has been associated with a lower mortality rate in patients with COVID-19
who require supplemental oxygen or invasive mechanical ventilation.45 In patients with cancer,
dexamethasone is commonly used to prevent chemotherapy-induced nausea, as a part of tumor-directed
therapy, and to treat inflammation associated with brain metastasis. The side effects of dexamethasone
are expected to be the same in patients with cancer as in those without cancer. If possible, treatments that
are not currently recommended for SARS-CoV-2 infection should be administered as part of a clinical
trial, since the safety and efficacy of these agents have not been well-defined in patients with cancer.
The NCCN recommends against using G-CSF and granulocyte-macrophage colony-stimulating factor in
patients with cancer and acute SARS-CoV-2 infection who do not have bacterial or fungal infections to
avoid the hypothetical risk of increasing inflammatory cytokine levels and pulmonary inflammation.46,47
Secondary infections (e.g., invasive pulmonary aspergillosis) have been reported in critically ill patients
with COVID-19.48,49
Decisions about administering cancer-directed therapy to patients with acute COVID-19 and those who
are recovering from COVID-19 should be made on a case-by-case basis; clinicians should consider the
indication for chemotherapy, the goals of care, and the patient’s history of tolerance to the treatment
(BIII). The optimal duration of time between resolution of infection and initiating or restarting
cancer-directed therapy is unclear. Withholding treatment until COVID-19 symptoms have resolved is
recommended, if possible. Prolonged viral shedding (detection of SARS-CoV-2 by molecular testing)
may occur in patients with cancer,2 although it is unknown how this relates to infectious virus and how
it impacts outcomes. Therefore, there is no role for repeat testing in those recovering from COVID-19,
and the decision to restart cancer treatments in this setting should be made on a case-by-case basis.
Clinicians who are treating COVID-19 in patients with cancer should consult a hematologist or
oncologist before adjusting cancer-directed medications (AIII).
Medication Interactions
The use of antiviral or immune-based therapies to treat COVID-19 can present additional challenges
in patients with cancer. Clinicians should pay careful attention to potential drug-drug interactions and
overlapping toxicities between drugs that are used to treat COVID-19 and cancer-directed therapies,
prophylactic antimicrobials, corticosteroids, and other medications (AIII).
Several antineoplastic medications may interact with therapies that are being investigated for COVID-
19.50,51 For example, tocilizumab can interact with vincristine and doxorubicin. Any COVID-19
therapy that may cause QT prolongation must be used with caution in patients who are being treated
with venetoclax, gilteritinib, or tyrosine kinase inhibitor therapy (e.g., nilotinib). Dexamethasone is
commonly used as an antiemetic for patients with cancer and is recommended for the treatment of
certain patients with COVID-19 (see Therapeutic Management of Hospitalized Adults With COVID-19).
Dexamethasone is a weak to moderate cytochrome P450 (CYP) 3A4 inducer; therefore, interactions
with any CYP3A4 substrates need to be considered.
Special Considerations in Children

Preliminary published reports suggest that pediatric patients with cancer may have milder manifestations
of COVID-19 than adult patients with cancer, although larger studies are needed.52-54 Guidance on
managing children with cancer during the COVID-19 pandemic is available from an international group
that received input from the International Society of Paediatric Oncology, the Children’s Oncology
Group, St. Jude Global, and Childhood Cancer International.55 Two publications include guidance for
managing specific malignancies, guidance for supportive care, and a summary of web links from expert
groups that are relevant to the care of pediatric oncology patients during the COVID-19 pandemic.55,56

AR09103
Special considerations for using antivirals in immunocompromised children, including those with
malignancy, are available in a multicenter guidance statement.57
References
1. Dai M, Liu D, Liu M, et al. Patients with cancer appear more vulnerable to SARS-CoV-2: a multicenter study
during the COVID-19 outbreak. Cancer Discov. 2020;10(6):783-791. Available at:
2. Shah V, Ko Ko T, Zuckerman M, et al. Poor outcome and prolonged persistence of SARS-CoV-2 RNA in
COVID-19 patients with haematological malignancies; King’s College Hospital experience. Br J Haematol.
3. Yang K, Sheng Y, Huang C, et al. Clinical characteristics, outcomes, and risk factors for mortality in patients
with cancer and COVID-19 in Hubei, China: a multicentre, retrospective, cohort study. Lancet Oncol.
4. Robilotti EV, Babady NE, Mead PA, et al. Determinants of COVID-19 disease severity in patients with cancer.
Nat Med. 2020;26(8):1218-1223. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32581323.
5. Giannakoulis VG, Papoutsi E, Siempos, II. Effect of cancer on clinical outcomes of patients with COVID-19:
a meta-analysis of patient data. JCO Glob Oncol. 2020;6:799-808. Available at:
6. Kuderer NM, Choueiri TK, Shah DP, et al. Clinical impact of COVID-19 on patients with cancer (CCC19): a
cohort study. Lancet. 2020;395(10241):1907-1918. Available at:
7. Centers for Disease Control and Prevention. Current COVID-19 ACIP vaccine recommendations. 2021.
Available at: https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/covid-19.html. Accessed September
30, 2021.
8. Centers for Disease Control and Prevention. COVID-19 vaccines for moderately to severely
immunocompromised people. 2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/
recommendations/immuno.html. Accessed September 9, 2021.
9. American Society of Hematology. General principles of COVID-19 vaccines for immunocompromised
patients. 2021. Available at: https://www.hematology.org/covid-19/ash-astct-covid-19-and-vaccines. Accessed
September 16, 2021.
10. National Comprehensive Cancer Network. Recommendations of the National Comprehensive Cancer Network
(NCCN) COVID-19 Vaccination Advisory Committee. 2021. Available at: https://www.nccn.org/docs/default-
source/covid-19/2021_covid-19_vaccination_guidance_v4-0.pdf?sfvrsn=b483da2b_68. Accessed September
16, 2021.
11. American Society of Hematology. COVID-19 and pediatric ALL: frequently asked questions. 2021. Available
at: https://www.hematology.org/covid-19/covid-19-and-pediatric-all. Accessed September 30, 2021.
12. Centers for Disease Control and Prevention. COVID-19 vaccines for people with allergies. 2021. Available
at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/specific-groups/allergies.html.
Accessed September 16, 2021.
13. Centers for Disease Control and Prevention. Interim clinical considerations for use of COVID-19 vaccines
currently approved or authorized in the United States. 2021. Available at: https://www.cdc.gov/vaccines/
covid-19/clinical-considerations/covid-19-vaccines-us.html. Accessed September 16, 2021.
14. American Society of Hematology. ASH-ASTCT COVID-19 vaccination for HCT and CAR T cell recipients:
frequently asked questions 2021. Available at: https://www.hematology.org/covid-19/ash-astct-covid-19-
vaccination-for-hct-and-car-t-cell-recipients. Accessed September 16, 2021.
15. National Comprehensive Cancer Network. COVID-19 resources. 2021. Available at:
https://www.nccn.org/covid-19. Accessed September 16, 2021.

AR09104
16. Chen YW, Tucker MD, Beckermann KE, Iams WT, Rini BI, Johnson DB. COVID-19 mRNA vaccines and
immune-related adverse events in cancer patients treated with immune checkpoint inhibitors. Eur J Cancer.
2021;155:291-293. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34400057.
17. Waissengrin B, Agbarya A, Safadi E, Padova H, Wolf I. Short-term safety of the BNT162b2 mRNA
COVID-19 vaccine in patients with cancer treated with immune checkpoint inhibitors. Lancet Oncol.
18. Barriere J, Chamorey E, Adjtoutah Z, et al. Impaired immunogenicity of BNT162b2 anti-SARS-CoV-2
vaccine in patients treated for solid tumors. Ann Oncol. 2021;32(8):1053-1055. Available at:
19. Herishanu Y, Avivi I, Aharon A, et al. Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with
chronic lymphocytic leukemia. Blood. 2021;137(23):3165-3173. Available at:
20. Massarweh A, Eliakim-Raz N, Stemmer A, et al. Evaluation of seropositivity following BNT162b2 messenger
RNA vaccination for SARS-CoV-2 in patients undergoing treatment for cancer. JAMA Oncol. 2021;7(8):1133-
21. Shroff RT, Chalasani P, Wei R, et al. Immune response to COVID-19 mRNA vaccines in patients with solid
tumors on active, immunosuppressive cancer therapy. medRxiv. 2021;Preprint. Available at:
22. Becker PS, Griffiths EA, Alwan LM, et al. NCCN guidelines insights: mematopoietic growth factors, version
1.2020. J Natl Compr Canc Netw. 2020;18(1):12-22. Available at:
23. Yarza R, Bover M, Paredes D, et al. SARS-CoV-2 infection in cancer patients undergoing active treatment:
analysis of clinical features and predictive factors for severe respiratory failure and death. Eur J Cancer.
2020;135:242-250. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32586724.
24. American Society of Clinical Oncology. ASCO special report: a guide to cancer care delivery during the
COVID-19 pandemic. 2021. Available at: https://www.asco.org/sites/new-www.asco.org/files/content-
files/2020-ASCO-Guide-Cancer-COVID19.pdf. Accessed September 16, 2021.
25. American Society of Anesthesiologists. The ASA and APSF joint statement on perioperative testing for the
COVID-19 virus. 2020. Available at: https://www.asahq.org/about-asa/newsroom/news-releases/2020/06/asa-
and-apsf-joint-statement-on-perioperative-testing-for-the-covid-19-virus. Accessed September 30, 2021.
26. Centers for Disease Control and Prevention. Coronavirus Disease 2019 (COVID-19): framework for
healthcare systems providing non-COVID-19 clinical care during the COVID-19 pandemic. 2020. Available
at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/framework-non-COVID-care.html. Accessed August 3,
2020.
27. Wang X, Zhou Q, He Y, et al. Nosocomial outbreak of COVID-19 pneumonia in Wuhan, China. Eur Respir J.
2020;55(6). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32366488.
28. Luong-Nguyen M, Hermand H, Abdalla S, et al. Nosocomial infection with SARS-CoV-2 within Departments
of Digestive Surgery. J Visc Surg. 2020;157(3S1):S13-S18. Available at:
29. Rivett L, Sridhar S, Sparkes D, et al. Screening of healthcare workers for SARS-CoV-2 highlights the role of
asymptomatic carriage in COVID-19 transmission. Elife. 2020;9. Available at:
https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/prevention.html. Accessed September 30,
2021.
31. American Society of Clinical Oncology. Cancer treatment & supportive care. 2020. Available at: https://www.
asco.org/covid-resources/patient-care-info/cancer-treatment-supportive-care. Accessed September 16, 2021.

AR09105
32. American Society of Hematology. COVID-19 and Hodgkin lymphoma: frequently asked questions. 2021.
Available at: https://www.hematology.org/covid-19/covid-19-and-hodgkin-lymphoma. Accessed September
16, 2021.
33. Griffiths EA, Alwan LM, Bachiashvili K, et al. Considerations for use of hematopoietic growth factors in
patients with cancer related to the COVID-19 pandemic. J Natl Compr Canc Netw. 2020:1-4. Available at:
34. Lee LYW, Cazier JB, Starkey T, et al. COVID-19 mortality in patients with cancer on chemotherapy or other
anticancer treatments: a prospective cohort study. Lancet. 2020;395(10241):1919-1926. Available at:
35. Montopoli M, Zumerle S, Vettor R, et al. Androgen-deprivation therapies for prostate cancer and risk of
infection by SARS-CoV-2: a population-based study (N = 4532). Ann Oncol. 2020;31(8):1040-1045. Available
36. Koskinen M, Carpen O, Honkanen V, et al. Androgen deprivation and SARS-CoV-2 in men with prostate
cancer. Ann Oncol. 2020;31(10):1417-1418. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32615154.
37. American Society for Radiation Oncology. COVID-19 recommendations and information: COVID-19 clinical
guidance. 2020. Available at: https://www.astro.org/Daily-Practice/COVID-19-Recommendations-and-
Information/Clinical-Guidance. Accessed August 3, 2020.
38. Yahalom J, Dabaja BS, Ricardi U, et al. ILROG emergency guidelines for radiation therapy of hematological
malignancies during the COVID-19 pandemic. Blood. 2020;135(21):1829-1832. Available at:
39. Food and Drug Administration. Coronavirus (COVID-19) update: FDA provides updated guidance to
address the urgent need for blood during the pandemic. 2020. Available at: https://www.fda.gov/news-events/
press-announcements/coronavirus-covid-19-update-fda-provides-updated-guidance-address-urgent-need-
blood-during-pandemic. Accessed August 3, 2020.
40. Food and Drug Administration. COVID-19 frequently asked questions. 2020. Available at: https://www.fda.
gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/covid-19-frequently-asked-
questions. Accessed August 3, 2020.
41. Centers for Disease Control and Prevention. Clinical questions about COVID-19: questions and answers.
2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/faq.html#Transmission. Accessed
September 30, 2021.
42. National Comprehensive Cancer Network. NCCN best practices guidance: management of COVID-19
infection in patients with cancer. 2021. Available at: https://www.nccn.org/docs/default-source/covid-19/2021-
covid-infectious-disease-management.pdf?sfvrsn=63f70c30_7.
43. Mehta V, Goel S, Kabarriti R, et al. Case fatality rate of cancer patients with COVID-19 in a New York
Hospital System. Cancer Discov. 2020;10(7):935-941. Available at:
44. Meng Y, Lu W, Guo E, et al. Cancer history is an independent risk factor for mortality in hospitalized
COVID-19 patients: a propensity score-matched analysis. J Hematol Oncol. 2020;13(1):75. Available at:
46. Nawar T, Morjaria S, Kaltsas A, et al. Granulocyte-colony stimulating factor in COVID-19: Is it stimulating
more than just the bone marrow? Am J Hematol. 2020;95(8):E210-E213. Available at:
47. National Comprehensive Cancer Network. NCCN hematopoietic growth factors: short-term recommendations
specific to issues with COVID-19 (SARS-CoV-2). 2020. Available at:

AR09106
https://www.nccn.org/covid-19/pdf/HGF_COVID-19.pdf.
48. van Arkel ALE, Rijpstra TA, Belderbos HNA, van Wijngaarden P, Verweij PE, Bentvelsen RG. COVID-19-
associated pulmonary aspergillosis. Am J Respir Crit Care Med. 2020;202(1):132-135. Available at:
49. Alanio A, Delliere S, Fodil S, Bretagne S, Megarbane B. Prevalence of putative invasive pulmonary
aspergillosis in critically ill patients with COVID-19. Lancet Respir Med. 2020;8(6):e48-e49. Available at:
50. American Society of Hematology. COVID-19 resources. 2020. Available at:
https://www.hematology.org/covid-19. Accessed August 3, 2020.
51. University of Liverpool. COVID-19 drug interactions. 2021. Available at:
https://www.covid19-druginteractions.org/.
52. Hrusak O, Kalina T, Wolf J, et al. Flash survey on severe acute respiratory syndrome coronavirus-2 infections
in paediatric patients on anticancer treatment. Eur J Cancer. 2020;132:11-16. Available at:
53. Andre N, Rouger-Gaudichon J, Brethon B, et al. COVID-19 in pediatric oncology from French pediatric
oncology and hematology centers: High risk of severe forms? Pediatr Blood Cancer. 2020;67(7):e28392.
54. de Rojas T, Perez-Martinez A, Cela E, et al. COVID-19 infection in children and adolescents with cancer in
Madrid. Pediatr Blood Cancer. 2020;67(7):e28397. Available at:
55. Sullivan M, Bouffet E, Rodriguez-Galindo C, et al. The COVID-19 pandemic: a rapid global response for
children with cancer from SIOP, COG, SIOP-E, SIOP-PODC, IPSO, PROS, CCI, and St. Jude Global. Pediatr
Blood Cancer. 2020;67(7):e28409. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32400924.
56. Bouffet E, Challinor J, Sullivan M, Biondi A, Rodriguez-Galindo C, Pritchard-Jones K. Early advice on
managing children with cancer during the COVID-19 pandemic and a call for sharing experiences. Pediatr
Blood Cancer. 2020;67(7):e28327. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32239747.
57. Chiotos K, Hayes M, Kimberlin DW, et al. Multicenter initial guidance on use of antivirals for children with
COVID-19/SARS-CoV-2. J Pediatric Infect Dis Soc. 2020;9(6):701-715. Available at:

AR09107
Special Considerations in Solid Organ Transplant,

Hematopoietic Stem Cell Transplant, and Cellular
Immunotherapy Candidates, Donors, and Recipients
Vaccination for COVID-19
• Given the effectiveness of COVID-19 vaccines in the general population and the increased risk of worse clinical
outcomes of COVID-19 in transplant and cellular immunotherapy recipients, the COVID-19 Treatment Guidelines
Panel (the Panel) recommends COVID-19 vaccination for potential transplant and cellular immunotherapy candidates,
potential donors, and recipients (AIII). See the text below for information on the appropriate timing for COVID-19
vaccination in these patients.
• A third dose of an mRNA vaccine (given at least 4 weeks after the second dose) is currently recommended by the
Centers for Disease Control and Prevention for solid organ transplant recipients who are taking immunosuppressive
medications and hematopoietic stem cell transplant (HCT) recipients who are within 2 years of transplantation or who
are taking immunosuppressive medications.
Potential Transplant and Cellular Immunotherapy Candidates
• The Panel recommends diagnostic molecular testing for SARS-CoV-2 for all potential solid organ transplant, HCT, and
cellular immunotherapy candidates with signs and symptoms that suggest acute COVID-19 (AIII).
• The Panel recommends following the guidance from medical professional organizations that specialize in providing
care for solid organ transplant, HCT, or cellular immunotherapy recipients when performing diagnostic molecular
testing for SARS-CoV-2 in these patients (AIII).
• If SARS-CoV-2 is detected or if infection is strongly suspected, transplantation should be deferred, if possible (BIII).
• The optimal management and therapeutic approach to COVID-19 in these populations is unknown. At this time, the
procedures for evaluating and managing COVID-19 in transplant candidates are the same as those for nontransplant
candidates (AIII).
• Additionally, many transplant candidates are at high risk of progressing to serious COVID-19, and they may be eligible
to receive anti-SARS-CoV-2 monoclonal antibodies (mAbs) for treatment or post-exposure prophylaxis (PEP).
Potential Transplant Donors
• The Panel recommends assessing all potential solid organ transplant and HCT donors for signs and symptoms that
are associated with COVID-19 according to guidance from medical professional organizations (AIII).
• The Panel recommends performing diagnostic molecular testing for SARS-CoV-2 if symptoms are present (AIII).
• If SARS-CoV-2 is detected or if infection is strongly suspected, donation should be deferred (BIII).
Transplant and Cellular Immunotherapy Recipients With COVID-19
• Clinicians should follow the guidelines for evaluating and managing COVID-19 in nontransplant patients when treating
transplant and cellular immunotherapy recipients (AIII). See Therapeutic Management of Hospitalized Adults With
COVID-19 for more information.
• Immunocompromised patients with mild to moderate COVID-19 are at high risk of progressing to serious disease,
and they may be eligible to receive anti-SARS-CoV-2 mAbs for treatment or PEP.
• The Panel recommends that clinicians who are treating COVID-19 in transplant and cellular immunotherapy patients
consult with a transplant specialist before adjusting immunosuppressive medications (AIII).
• When treating COVID-19, clinicians should pay careful attention to potential drug-drug interactions and overlapping
toxicities with immunosuppressants, prophylactic antimicrobials, and other medications (AIII).


AR09108
Introduction
Treating COVID-19 in solid organ transplant, hematopoietic stem cell transplant (HCT), and cellular
immunotherapy recipients can be challenging due to the presence of coexisting medical conditions,
transplant-related cytopenias, and the need for chronic immunosuppressive therapy to prevent graft
rejection and graft-versus-host disease. Transplant recipients may also have increased exposure to
SARS-CoV-2 given their frequent contact with the health care system. Since immunosuppressive agents
modulate several aspects of the host’s immune response, the severity of COVID-19 could potentially be
affected by the type and the intensity of the immunosuppressive effect of the agent, as well as by specific
combinations of immunosuppressive agents. Some transplant recipients have medical comorbidities that
have been associated with more severe cases of COVID-19 and a greater risk of mortality, which makes
the impact of transplantation on disease severity difficult to assess.
The International Society for Heart and Lung Transplantation, the American Society of Transplantation,
the American Society for Transplantation and Cellular Therapy (ASTCT), and the European Society
for Blood and Marrow Transplantation (EBMT) provide guidance for clinicians who are caring for
transplant recipients with COVID-19 and guidance on screening potential donors and transplant or
cellular immunotherapy candidates. In addition, the American Society of Hematology offers guidance
regarding COVID-19 vaccination for transplant and cellular immunotherapy recipients. This section
of the COVID-19 Treatment Guidelines complements these sources and focuses on considerations
for managing COVID-19 in solid organ transplant, HCT, and cellular immunotherapy recipients.
The optimal management and therapeutic approach to COVID-19 in these populations is unknown.
At this time, the procedures for evaluating and managing COVID-19 in transplant recipients are the
same as those for nontransplant patients (AIII). See Therapeutic Management of Hospitalized Adults
With COVID-19 for more information. The medications that are used to treat COVID-19 may present
different risks and benefits to transplant patients and nontransplant patients.
Vaccination for COVID-19 in Solid Organ Transplant, Hematopoietic Stem Cell

Transplant, and Cellular Immunotherapy Candidates, Donors, and Recipients
The clinical trials that evaluated the safety and efficacy of the COVID-19 vaccines excluded severely
immunocompromised patients.1-3 The Advisory Committee on Immunization Practices notes that the
currently authorized or approved COVID-19 vaccines are not live vaccines; therefore, they can be safely
administered to immunocompromised people.4 Compared to healthy vaccine recipients, solid organ
transplant recipients have a reduced antibody response following a primary two-dose vaccine series of
mRNA vaccines.5-7 Among those who had no detectable antibody response to the initial two-dose vaccine
series, 33% to 50% of patients developed an antibody response to an additional mRNA vaccine dose.8,9
Given the effectiveness of COVID-19 vaccines in the general population and the increased risk of worse
clinical outcomes of COVID-19 in transplant and cellular immunotherapy recipients, the COVID-19
Treatment Guidelines Panel (the Panel) recommends COVID-19 vaccination for potential transplant and
cellular immunotherapy candidates, potential donors, and recipients (AIII). Currently, the Centers for
Disease Control and Prevention recommends administering an additional dose of vaccine to moderately
to severely immunocompromised people at least 28 days after a second dose of an mRNA vaccine.10
This includes people who have:
• Received a solid organ transplant and are taking immunosuppressive medications
• Received an HCT within the last 2 years or who are taking immunosuppressive medications

AR09109
When determining the timing of COVID-19 vaccination in solid organ transplant, HCT, and cellular
immunotherapy recipients, clinicians should consider the following factors:
• Ideally, solid organ transplant candidates should receive COVID-19 vaccines while they are
awaiting transplant.
• In general, vaccination should be completed at least 2 weeks prior to a solid organ transplant or
started 1 month after a solid organ transplant.
• In certain situations, it may be appropriate to delay vaccination until 3 months after a solid
organ transplant, such as when T cell- or B cell-ablative therapy (with antithymocyte globulin or
rituximab) is used at the time of transplant.11
• At this time, reducing the dose of immunosuppressants and holding immunosuppressants prior to
vaccination are not recommended.
• COVID-19 vaccines can be offered as early as 3 months after a patient receives HCT or chimeric
antigen receptor T cell therapy, although the efficacy of the vaccines may be reduced compared to
the efficacy observed in the general population.12-14 Patients who are scheduled to receive cytotoxic
or B cell-depleting therapies should complete their COVID-19 vaccination prior to initiation or
between cycles of cytotoxic or B cell-depleting therapies, if possible.
• After completing COVID-19 vaccination, immunocompromised persons should be advised to
continue to exercise precautions to reduce their risk of SARS-CoV-2 exposure and infection (e.g.,
they should continue wearing a mask, maintain a distance of 6 feet from others, and avoid crowds
and poorly ventilated spaces).15
It remains unclear whether the immune responses to COVID-19 vaccines can increase the risk of graft-
versus-host disease or other immune-related complications.14,16 Outside of a clinical study, antibody
testing is not recommended to assess immunity to SARS-CoV-2 following COVID-19 vaccination in
transplant patients. It is currently unknown whether revaccination offers a clinical benefit for people
who received COVID-19 vaccines during treatment with immunosuppressive drugs.
Vaccination of household members, close contacts, and health care providers who provide care for
immunocompromised patients is imperative to protect immunocompromised patients from infection. All
close contacts are strongly encouraged to get vaccinated as soon as possible.
Post-Exposure Prophylaxis for Transplant and Cellular Immunotherapy Recipients

The Food and Drug Administration (FDA) expanded the Emergency Use Authorization (EUA)
indication for the anti-SARS-CoV-2 monoclonal antibodies (mAbs) bamlanivimab plus etesevimab
and casirivimab plus imdevimab to allow them to be used as post-exposure prophylaxis (PEP) for
selected individuals who are at high risk for disease progression. This includes immunocompromised
individuals who are not expected to mount an adequate immune response to vaccination. See Prevention
of SARS-CoV-2 Infection for more information.
Assessment of SARS-CoV-2 Infection in Transplant and Cellular Immunotherapy

Candidates and Donors
The risk of transmission of SARS-CoV-2 from donors to candidates is unknown. The probability that a
donor or candidate may have SARS-CoV-2 infection can be estimated by considering the epidemiologic
risk, obtaining a clinical history, and testing with molecular techniques. No current testing strategy is
sensitive enough or specific enough to totally exclude active infection.

AR09110
Assessment of Transplant and Cellular Immunotherapy Candidates
Diagnostic molecular testing for SARS-CoV-2 is recommended for all potential solid organ transplant
candidates with signs and symptoms that suggest acute COVID-19 (AIII). All potential solid organ
transplant candidates should be assessed for exposure to COVID-19 and clinical symptoms that are
compatible with COVID-19 before they are called in for transplantation and should undergo diagnostic
molecular testing for SARS-CoV-2 shortly before a solid organ transplant in accordance with guidance
from medical professional organizations (AIII).
Clinicians should consider performing diagnostic testing for SARS-CoV-2 in all HCT and cellular
immunotherapy candidates who exhibit symptoms. All candidates should also undergo diagnostic
molecular testing for SARS-CoV-2 shortly before HCT or cellular immunotherapy (AIII).
Assessment of Donors
Living solid organ donors should be counseled on strategies to prevent infection and monitored for
exposures and symptoms in the 14 days prior to a scheduled transplant.17 Living donors should undergo
respiratory tract SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) testing within
3 days of donation. Deceased donors should be tested for SARS-CoV-2 infection using an RT-PCR assay
of a sample taken from the upper respiratory tract within 72 hours of death; ideally, the test should be
performed as close to organ recovery as possible. Deceased donors can be considered for donation if the
results are negative (BIII).
Lower respiratory sampling for COVID-19 testing is required for potential lung transplant donors by
the United Network for Organ Sharing.18 The Panel recommends following the guidance from medical
professional organizations and assessing all potential HCT donors for exposure to COVID-19 and clinical
symptoms that are compatible with COVID-19 before donation (AIII). HCT donors should practice good
hygiene and avoid crowded places and large group gatherings during the 28 days prior to donation.19
Recommendations for screening for HCT donors are outlined in the ASTCT and EBMT guidelines.
If SARS-CoV-2 Infection Is Detected or Is Strongly Suspected

If SARS-CoV-2 is detected or if infection is strongly suspected in a potential solid organ transplant
candidate, transplant should be deferred, if possible (BIII). The optimal disease-free interval before
transplantation is not known. The risks of viral transmission should be balanced against the risks to the
candidate, such as progression of the underlying disease and risk of mortality if the candidate does not
receive the transplant. This decision should be continually reassessed as conditions evolve. Donors for
solid organ transplants who test positive for SARS-CoV-2 are medically ineligible for donation.20 For
HCT and cellular immunotherapy candidates, current guidelines recommend deferring transplants or
immunotherapy procedures, including peripheral blood stem cell mobilization, bone marrow harvest,
T cell collection, and conditioning/lymphodepletion in recipients who test positive for SARS-CoV-2 or
who have clinical symptoms that are consistent with infection. Final decisions should be made on a case-
by-case basis while weighing the risks of delaying or altering therapy for the underlying disease.
Transplant Recipients With COVID-19

Solid organ transplant recipients who are receiving immunosuppressive therapy should be considered to
be at increased risk for severe COVID-19.21,22 A national survey of 88 U.S. transplant centers conducted
between March 24 and 31, 2020, reported that 148 solid organ transplant recipients received a diagnosis
of SARS-CoV-2 infection (69.6% were kidney recipients, 15.5% were liver recipients, 8.8% were heart
recipients, and 6.1% were lung recipients).23 COVID-19 was mild in 54% of recipients, moderate in 21%
of recipients, and 25% of recipients were critically ill. Management strategies varied widely across the
transplant centers, including different ways of modifying immunosuppressive therapy and the use of

AR09111
different investigational therapies to treat COVID-19. Initial reports of transplant recipients who were
hospitalized with COVID-19 suggest mortality rates of up to 28%.24-28
Risk of Graft Rejection

There are concerns that COVID-19 itself may increase the risk for acute rejection. Acute cellular
rejection should not be presumed in solid organ transplant recipients without biopsy confirmation,
regardless of whether the individual has COVID-19. Similarly, immunosuppressive therapy should be
initiated in recipients with or without COVID-19 who have rejection confirmed by a biopsy.21
There are limited data on the incidence and clinical characteristics of SARS-CoV-2 infection in HCT
and cellular immunotherapy recipients. Recent data from the Center for International Blood and Marrow
Transplant Research demonstrated a mortality rate of approximately 30% within a month of COVID-19
diagnosis among a cohort of 318 HCT recipients.29 This mortality rate was observed in both allogeneic
and autologous recipients. Older age (≥50 years), male sex, and receipt of a COVID-19 diagnosis within
12 months of transplantation were associated with a higher risk of mortality among allogeneic recipients.
In autologous recipients, patients with lymphoma had a higher risk of mortality than patients who had
plasma cell disorder or myeloma.
A smaller study demonstrated a slightly lower mortality rate among HCT and cellular immunotherapy
recipients than earlier reports. This study found that the number of comorbidities, the presence of
infiltrates on initial chest imaging, and neutropenia were predictors for increased disease severity.30
Additional factors that have been used to determine the clinical severity of other respiratory viral
infections include the degree of cytopenia, the intensity of the conditioning regimen, the graft source, the
degree of mismatch, and the need for further immunosuppression to manage graft-versus-host disease.
Prolonged viral shedding has been described in solid organ transplant and HCT recipients; this can have
implications for preventing infection and for the timing of therapeutic interventions.31
Treatment of COVID-19 in Transplant Recipients

Currently, the antiviral agent remdesivir is the only drug that is approved by the FDA for the treatment
of COVID-19. Outpatient transplant recipients who are immunosuppressed or who have certain
underlying comorbidities are candidates for the anti-SARS-CoV-2 mAbs that are available through
EUAs (see Anti-SARS-CoV-2 Monoclonal Antibodies). Transplant recipients who are hospitalized for
reasons other than COVID-19 are also eligible to receive mAb therapy. Transplant recipients who are
hospitalized with mild to moderate COVID-19 may be considered for anti-SARS-CoV-2 mAbs that are
available through expanded access programs.
Data from a large randomized controlled trial found that a short course of dexamethasone (6 mg
once daily for up to 10 days) improved survival in hospitalized patients with COVID-19 who were
mechanically ventilated or who required supplemental oxygen.32 Tocilizumab or baricitinib used in
combination with dexamethasone is recommended for some patients with severe or critical COVID-19
who exhibit rapid respiratory decompensation (see Interleukin-6 Inhibitors).33-35 The risks and benefits
of using dexamethasone in combination with tocilizumab or baricitinib in transplant recipients with
COVID-19 who are receiving immunosuppressive therapy are unknown. Because dexamethasone,
tocilizumab, and baricitinib are immunosuppressive agents, patients who receive these medications
should be closely monitored for secondary infections.
The Panel’s recommendations for the use of remdesivir, dexamethasone, tocilizumab, and baricitinib
in patients with COVID-19 can be found in Therapeutic Management of Hospitalized Adults With
COVID-19.
A number of other investigational agents and drugs that are approved by the FDA for other indications

AR09112
are being evaluated for the treatment of COVID-19 (e.g., antiviral therapies, COVID-19 convalescent
plasma) and its associated complications (e.g., immunomodulators, antithrombotic agents). In general,
the considerations for treating COVID-19 in transplant recipients are the same as those for the general
population. When possible, treatment should be given as part of a clinical trial. The safety and efficacy of
investigational agents and drugs that have been approved by the FDA for other indications are not well-
defined in transplant recipients. Moreover, it is unknown whether concomitant use of immunosuppressive
agents to prevent allograft rejection in the setting of COVID-19 affects treatment outcomes.
Clinicians should pay special attention to the potential for drug-drug interactions and overlapping
toxicities between treatments for COVID-19 and concomitant medications, such as immunosuppressants
that are used to prevent allograft rejection (e.g., corticosteroids, mycophenolate, and calcineurin
inhibitors such as tacrolimus and cyclosporine), antimicrobials that are used to prevent opportunistic
infections, and other medications. Dose modifications may be necessary for drugs that are used
to treat COVID-19 in transplant recipients with pre-existing organ dysfunction. Adjustments to
the immunosuppressive regimen should be individualized based on disease severity, the specific
immunosuppressants used, the type of transplant, the time since transplantation, the drug concentration,
and the risk of graft rejection.25 Clinicians who are treating COVID-19 in transplant patients should
consult a transplant specialist before adjusting immunosuppressive medication (AIII).
Certain therapeutics (e.g., remdesivir, tocilizumab, baricitinib) are associated with elevated levels
of transaminases. For liver transplant recipients, the American Association for the Study of Liver
Diseases does not consider abnormal liver biochemistries a contraindication to using remdesivir.36 Close
monitoring of liver biochemistries is warranted in patients with COVID-19, especially when they are
receiving agents with a known risk of hepatotoxicity.
Calcineurin inhibitors, which are commonly used to prevent allograft rejection, have a narrow
therapeutic index. Medications that inhibit or induce cytochrome P450 (CYP) enzymes or
P-glycoprotein may put patients who receive calcineurin inhibitors at risk of clinically significant
drug-drug interactions, increasing the need for therapeutic drug monitoring and the need to assess
for signs of toxicity or rejection.37 Among the drugs that are commonly used to treat COVID-19,
dexamethasone is a moderate inducer of CYP3A4, and interleukin-6 inhibitors may lead to increased
metabolism of CYP substrates. Close monitoring of serum concentration of calcineurin inhibitors should
be considered when these drugs are used.
Additional details about the adverse effects and drug interactions of antiviral medications and immune-
based therapy for COVID-19 are noted in Tables 2e, 3c, and 4e.
References
1. Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N
2. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N
3. Food and Drug Administration. Vaccines and related biological products advisory committee meeting. 2021.
Available at: https://www.fda.gov/media/146217/download.
4. Centers for Disease Control and Prevention. Current COVID-19 ACIP vaccine recommendations. 2020.
Available at: https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/covid-19.html. Accessed January 6,
2021.
5. Boyarsky BJ, Werbel WA, Avery RK, et al. Antibody response to 2-dose SARS-CoV-2 mRNA vaccine series
in solid organ transplant recipients. JAMA. 2021;325(21):2204-2206. Available at:

AR09113
6. Hallett AM, Greenberg RS, Boyarsky BJ, et al. SARS-CoV-2 messenger RNA vaccine antibody response and
reactogenicity in heart and lung transplant recipients. J Heart Lung Transplant. 2021;Published online ahead
of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34456108.
7. Mazzola A, Todesco E, Drouin S, et al. Poor antibody response after two doses of SARS-CoV-2 vaccine in
transplant recipients. Clin Infect Dis. 2021;Published online ahead of print. Available at:
8. Kamar N, Abravanel F, Marion O, Couat C, Izopet J, Del Bello A. Three doses of an mRNA COVID-19
vaccine in solid-organ transplant recipients. N Engl J Med. 2021;385(7):661-662. Available at:
9. Werbel WA, Boyarsky BJ, Ou MT, et al. Safety and immunogenicity of a third dose of SARS-CoV-2 vaccine
in solid organ transplant recipients: a case series. Ann Intern Med. 2021;174(9):1330-1332. Available at:
10. Centers for Disease Control and Prevention. COVID-19 vaccine indications for patients who are
immunocompromised. 2021. Available at: https://www.cdc.gov/vaccines/covid-19/clinical-considerations/
immunocompromised.html. Accessed September 16, 2021.
11. American Society of Transplantation. COVID-19 vaccine FAQ sheet. 2021. Available at: https://www.myast.
org/sites/default/files/2021_08_13%20COVID%20VACCINE%20FAQ-Prof8132021_FINAL.pdf. Accessed
September 16, 2021.
12. American Society of Hematology. ASH-ASTCT COVID-19 vaccination for HCT and CAR T cell recipients:
frequently asked questions 2021. Available at: https://www.hematology.org/covid-19/ash-astct-covid-19-
vaccination-for-hct-and-car-t-cell-recipients. Accessed September 16, 2021.
13. Ljungman P, Avetisyan G. Influenza vaccination in hematopoietic SCT recipients. Bone Marrow Transplant.
14. Ram R, Hagin D, Kikozashvilli N, et al. Safety and immunogenicity of the BNT162b2 mRNA COVID-19
vaccine in patients after allogeneic HCT or CD19-based CART therapy-a single-center prospective cohort
study. Transplant Cell Ther. 2021;27(9):788-794. Available at:
15. Centers for Disease Control and Prevention. When you’ve been fully vaccinated: how to protect yourself
and others. 2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/fully-vaccinated.html.
16. Ali H, Ngo D, Aribi A, et al. Safety and tolerability of SARS-CoV2 emergency-use authorized vaccines for
allogeneic hematopoietic stem cell transplant recipients. Transplant Cell Ther. 2021;Published online ahead of
print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34274492.
17. American Society of Transplantation. COVID-19 resources for transplant community. 2020. Available at:
https://www.myast.org/covid-19-information. Accessed June 26, 2020.
18. United Network for Organ Sharing. Lower respiratory testing of all potential lung donors for SARS-CoV-2
now required. 2021. Available at: https://unos.org/news/sars-cov-2-lower-respiratory-testing-potential-lung-
donors-may-27/. Accessed September 16, 2021.
19. American Society for Transplantation and Cellular Therapy. ASTCT interim patient guidelines April
20, 2020. 2020. Available at: https://www.astct.org/viewdocument/astct-interim-patient-guidelines-
ap?CommunityKey=d3949d84-3440-45f4-8142-90ea05adb0e5&tab=librarydocuments. Accessed July 2,
2020.
20. Association of Organ Procurement Organizations. Information about COVID-19 (coronavirus) is being
released rapidly. We will post updates as we receive them. 2020. Available at: https://www.aopo.org/
information-about-covid-19-coronavirus-is-being-released-rapidly-we-will-post-updates-as-we-receive-them/.
21. Fix OK, Hameed B, Fontana RJ, et al. Clinical best practice advice for hepatology and liver transplant
providers during the COVID-19 pandemic: AASLD expert panel consensus statement. Hepatology.

AR09114
22. Centers for Disease Control and Prevention. Underlying medical conditions associated with high risk
for severe COVID-19: information for healthcare providers. 2021. Available at: https://www.cdc.gov/
coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions.html. Accessed September 16, 2021.
23. Boyarsky BJ, Po-Yu Chiang T, Werbel WA, et al. Early impact of COVID-19 on transplant center practices
and policies in the United States. Am J Transplant. 2020 ;20(7):1809-1818. Available at:
24. Akalin E, Azzi Y, Bartash R, et al. COVID-19 and kidney transplantation. N Engl J Med. 2020;382(25):2475-
25. Pereira MR, Mohan S, Cohen DJ, et al. COVID-19 in solid organ transplant recipients: Initial report from the
US epicenter. Am J Transplant. 2020;20(7):1800-1808. Available at:
26. Alberici F, Delbarba E, Manenti C, et al. A single center observational study of the clinical characteristics
and short-term outcome of 20 kidney transplant patients admitted for SARS-CoV2 pneumonia. Kidney Int.
27. Montagud-Marrahi E, Cofan F, Torregrosa JV, et al. Preliminary data on outcomes of SARS-CoV-2 infection
in a Spanish single center cohort of kidney recipients. Am J Transplant. 2020;20(10):2958-2959. Available at:
28. Kates OS, Haydel BM, Florman SS, et al. COVID-19 in solid organ transplant: a multi-center cohort study.
Clin Infect Dis. 2020;Published online ahead of print. Available at:
29. Sharma A, Bhatt NS, St Martin A, et al. Clinical characteristics and outcomes of COVID-19 in haematopoietic
stem-cell transplantation recipients: an observational cohort study. Lancet Haematol. 2021;8(3):e185-e193.
30. Shah GL, DeWolf S, Lee YJ, et al. Favorable outcomes of COVID-19 in recipients of hematopoietic cell
transplantation. J Clin Invest. 2020;130(12):6656-6667. Available at:
31. Aydillo T, Gonzalez-Reiche AS, Aslam S, et al. Shedding of viable SARS-CoV-2 after immunosuppressive
therapy for cancer. N Engl J Med. 2020;383(26):2586-2588. Available at:
36. American Association for the Study of Liver Diseases. Clinical best practice advice for hepatology
and liver transplant providers during the COVID-19 pandemic: AASLD expert panel consensus
statement. 2021. Available at: https://www.aasld.org/sites/default/files/2021-03/AASLD-COVID19-
ExpertPanelConsensusStatement-March92021.pdf. Accessed September 16, 2021.
37. Elens L, Langman LJ, Hesselink DA, et al. Pharmacologic treatment of transplant recipients infected with
SARS-CoV-2: considerations regarding therapeutic drug monitoring and drug-drug interactions. Ther Drug
Monit. 2020;42(3):360-368. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32304488.

AR09115
Special Considerations in People With HIV

Last Updated: May 2, 2022
Prevention of COVID-19
• The COVID-19 Treatment Guidelines Panel (the Panel) recommends that people with HIV receive COVID-19 vaccines
regardless of their CD4 T lymphocyte (CD4) cell count or HIV viral load, because the potential benefits outweigh the
potential risks (AIII).
• The Advisory Committee on Immunization Practices recommends that people with advanced or untreated HIV who
received a 2-dose series of an mRNA COVID-19 vaccine should receive a third dose of that vaccine at least 28 days
after the second dose. Advanced HIV is defined as people with CD4 counts <200 cells/mm3, a history of an AIDS-
defining illness without immune reconstitution, or clinical manifestations of symptomatic HIV.
• People with advanced or untreated HIV who do not have SARS-CoV-2 infection and who have not been recently
exposed to SARS-CoV-2 are eligible to receive the anti-SARS-CoV-2 monoclonal antibodies (mAbs) tixagevimab plus
cilgavimab as pre-exposure prophylaxis (PrEP). See Prevention of SARS-CoV-2 Infection for details.
• Two anti-SARS-CoV-2 mAb combinations, bamlanivimab plus etesevimab and casirivimab plus imdevimab, have
received Emergency Use Authorizations from the Food and Drug Administration for post-exposure prophylaxis (PEP).
However, the Panel recommends against their use in patients with COVID-19, including in people with HIV, because
the Omicron variant is currently the dominant SARS-CoV-2 variant in the United States, and it is not susceptible to
these anti-SARS-CoV-2 mAbs (AIII).
Diagnosis of COVID-19
• The Panel recommends using the same approach for diagnosing SARS-CoV-2 infection in people with HIV as in
people without HIV (AIII).
Management of COVID-19
• Recommendations for the triage, management, and treatment of COVID-19 in people with HIV are generally the same
as those for the general population (AIII).
• Nonhospitalized people with HIV and mild to moderate COVID-19 may be eligible to receive anti-SARS-CoV-2 therapy
(e.g., ritonavir-boosted nirmatrelvir [Paxlovid], bebtelovimab, remdesivir, molnupiravir). However, in situations where
there are logistical or supply constraints for administering these drugs, priority should be given to those with very
advanced HIV (e.g., those with CD4 counts <50 cells/mm3) (AIII). See the Panel’s statement on patient prioritization
for outpatient therapies for details.
• People with HIV who are taking ritonavir-based or cobicistat-based antiretroviral therapy (ART) can receive ritonavir-
boosted nirmatrelvir to treat COVID-19 without altering or interrupting their ART (i.e., they can continue using the
ritonavir or cobicistat dose that is associated with their ART in addition to the dose of ritonavir that is used with
nirmatrelvir).
• In people with advanced HIV and suspected or documented COVID-19, HIV-associated opportunistic infections
should also be considered in the differential diagnosis of febrile illness (AIII).
• When starting treatment for COVID-19 in patients with HIV, clinicians should pay careful attention to potential
drug-drug interactions and overlapping toxicities among COVID-19 treatments, antiretroviral (ARV) medications,
antimicrobial therapies, and other medications (AIII).
• People with HIV should be offered the opportunity to participate in clinical trials that are evaluating agents for the
prevention and treatment of SARS-CoV-2 infection.
Management of HIV
• People with HIV who develop COVID-19, including those who require hospitalization, should continue their ART and
opportunistic infection treatment and prophylaxis whenever possible (AIII).
• Clinicians who are treating COVID-19 in people with HIV should consult an HIV specialist before adjusting or
switching ARV medications (AIII).
• An ARV regimen should not be switched or adjusted (i.e., by adding ARV drugs to the regimen) for the purpose of
preventing or treating SARS-CoV-2 infection (AIII).

AR09116
Summary Recommendations, continued

• Clinicians should consult an HIV specialist to determine the optimal time to initiate ART in people who present with
COVID-19 and a new diagnosis of HIV.
Introduction
Approximately 1.2 million people in the United States are living with HIV. Most of these individuals
are in care, and many are on antiretroviral therapy (ART) and have well-controlled disease.1 Similar to
COVID-19, HIV disproportionately affects racial and ethnic minorities and people of lower socioeconomic
status in the United States;2 these demographic groups also appear to have a higher risk of poor outcomes
with COVID-19. In the general population, the individuals who are at the highest risk of severe COVID-19
include those aged >60 years; those who are pregnant; those who have received solid organ transplants;
and those with comorbidities, such as cancer, obesity, diabetes mellitus, cardiovascular disease, pulmonary
disease, a history of smoking, chronic kidney disease, or chronic liver disease.3 Many people with HIV
have 1 or more comorbidities that may put them at increased risk for a more severe course of COVID-19.
Information on SARS-CoV-2/HIV coinfection is evolving rapidly. The sections below outline the current
state of knowledge regarding preventing and diagnosing SARS-CoV-2 infection in people with HIV, the
treatment and clinical outcomes in people with HIV who develop COVID-19, and the management of HIV
during the COVID-19 pandemic. In addition to these Guidelines, the Department of Health and Human
Services Panel on Antiretroviral Guidelines for Adults and Adolescents has developed the Guidance for
COVID-19 and People With HIV.
Clinical Outcomes of COVID-19 in People With HIV

Data are emerging on the clinical outcomes of COVID-19 in people with HIV. In some of the initial case
series of people with COVID-19 in Europe and the United States, no significant differences were observed
in the clinical outcomes of COVID-19 between people with HIV and people who did not have HIV.4-11
In contrast, more recent reports suggest worse outcomes for patients with HIV and COVID-19, including
increased COVID-19 mortality rates in cohort studies in the United States, the United Kingdom, and South
Africa.12-18 HIV was independently associated with an increased risk of severe and critical COVID-19 in
a large World Health Organization platform trial that included data from 24 countries.19 In a multicenter
cohort study of 286 patients with HIV and COVID-19 in the United States, lower CD4 T lymphocyte (CD4)
cell counts (i.e., <200 cells/mm3) were associated with a higher risk for the composite endpoint of intensive
care unit admission, mechanical ventilation, or death. This increased risk was observed even in patients who
had achieved virologic suppression of HIV.15 In a large observational cohort study of people with HIV and
COVID-19 in the United States, those with CD4 counts <350 cells/mm3 were more likely to be hospitalized,
require ventilation, or die. Higher levels of viremia were also associated with worse outcomes.18 In another
study of 175 patients with HIV and COVID-19, a low CD4 count or a low CD4 nadir was associated with
poor outcomes.16 In a cohort study conducted in New York, people with HIV and COVID-19 had higher
rates of hospitalization and mortality than people with COVID-19 who did not have HIV.17
Prevention of COVID-19 in People With HIV

The COVID-19 Treatment Guidelines Panel (the Panel) recommends using the same approach for advising
persons with HIV on the strategies to prevent SARS-CoV-2 infection that is used for people without
HIV (AIII). There is currently no clear evidence that any antiretroviral (ARV) medications can prevent
SARS-CoV-2 infection.

AR09117
People with HIV should receive COVID-19 vaccines, regardless of their CD4 count or HIV viral load,
because the potential benefits outweigh the potential risks (AIII). People with HIV were included in the
clinical trials of the 2 mRNA vaccines and the adenovirus vector vaccine that are currently available through
Emergency Use Authorizations (EUAs) and/or approval from the Food and Drug Administration (FDA);20-22
however, few studies have evaluated the safety and efficacy of these vaccines in people with HIV. Typically,
people with HIV who are on ART and who have achieved virologic suppression respond well to licensed
vaccines. Preliminary data from studies that used COVID-19 vaccines in people with HIV confirm that
people who are on ART and have normal CD4 counts have good immunologic responses to the vaccines.23-25
On August 12, 2021, the FDA changed the EUAs for the 2 mRNA vaccines to allow a third dose of an
mRNA vaccine to be administered at least 28 days after the second dose to people with advanced or
untreated HIV. Advanced HIV is defined as people with CD4 counts <200 cells/mm3, a history of an AIDS-
defining illness without immune reconstitution, or clinical manifestations of symptomatic HIV. People
with HIV should also receive booster doses of the COVID-19 vaccines as recommended by the Advisory
Committee on Immunization Practices.
People with advanced or untreated HIV who are not infected or recently exposed to SARS-CoV-2 are
eligible to receive the anti-SARS-CoV-2 monoclonal antibodies (mAbs) tixagevimab plus cilgavimab as
pre-exposure prophylaxis (PrEP). See Prevention of SARS-CoV-2 Infection for details.
Two anti-SARS-CoV-2 mAb combinations, bamlanivimab plus etesevimab and casirivimab plus
imdevimab, have received FDA EUAs for post-exposure prophylaxis (PEP). However, the Panel
recommends against their use in patients with COVID-19, including in people with HIV, because the
Omicron variant is currently the dominant variant in the United States, and it is not susceptible to these
anti-SARS-CoV-2 mAbs (AIII).
Diagnostic and Laboratory Testing for COVID-19 in People With HIV

Diagnosis of COVID-19 in People With HIV
The Panel recommends using the same approach for diagnosing SARS-CoV-2 infection in people with
HIV as in those without HIV (AIII). See Testing for SARS-CoV-2 Infection for more information. There
is currently no evidence that the performance characteristics of nucleic acid amplification tests (NAATs)
and antigen tests differ in people with and without HIV when diagnosing acute SARS-CoV-2 infection.
The Panel recommends against the use of serologic testing as the sole basis for diagnosis of acute
SARS-CoV-2 infection (AIII). However, if diagnostic serologic testing is performed in a patient with HIV,
the results should be interpreted with caution because cross-reactivity between antibodies to SARS-CoV-2
and HIV has been reported.26
Correlation of CD4 Count in People With HIV and COVID-19

The normal range for CD4 counts in healthy adults is about 500 to 1,600 cells/mm3. People with HIV who
have a CD4 count of ≥500 cells/mm3 have similar cellular immune function to those without HIV. In people
with HIV, a CD4 count <200 cells/mm3 meets the definition for AIDS. For patients on ART, the hallmark of
treatment success is plasma HIV RNA below the level of detection by a polymerase chain reaction assay.
Lymphopenia is a common laboratory finding in patients with COVID-19; in patients with HIV, clinicians
should note that CD4 counts obtained during acute COVID-19 may not accurately reflect the patient’s HIV
disease stage.
There have been some reports of people with advanced HIV who have presented with COVID-19 and
another coinfection, including Pneumocystis jirovecii pneumonia.27,28 In patients with advanced HIV who
have suspected or laboratory-confirmed SARS-CoV-2 infection, clinicians should consider a broader
differential diagnosis for clinical symptoms and consider consulting an HIV specialist (AIII).

AR09118
Clinical Presentation of COVID-19 in People With HIV
It is currently unknown whether people with HIV have a higher incidence of SARS-CoV-2 infection or
a higher rate of progression to symptomatic disease than the general population. Approximately 50% of
people with HIV in the United States are aged >50 years,29 and many have comorbidities that are associated
with more severe cases of COVID-19. These comorbidities include hypertension, diabetes mellitus,
cardiovascular disease, a history of smoking, chronic lung disease, chronic liver disease, and cancer.30
There are a number of case reports and case series that describe the clinical presentation of COVID-19
in people with HIV.4-11,31,32 These studies indicate that the clinical presentation of COVID-19 is similar in
people with and without HIV. Most of the published reports describe populations in which most of the
individuals with HIV are on ART and have achieved virologic suppression. Consequently, the current
understanding of the impact of COVID-19 in those with advanced HIV who have low CD4 counts or
persistent HIV viremia is limited.
Management of COVID-19 in People With HIV

Recommendations for the triage and management of COVID-19 in people with HIV are the same as those
for the general population (AIII).
The treatment of COVID-19 in persons with HIV is the same as for those without HIV (AIII).
Nonhospitalized people with HIV and mild to moderate COVID-19 may be eligible to receive the
therapies that are currently recommended for treatment (see Therapeutic Management of Nonhospitalized
Adults With COVID-19). However, in situations where there are logistical or supply constraints for
administering these therapies, priority should be given to those with advanced HIV (AIII).
When starting treatment for COVID-19 in patients with HIV, clinicians should pay careful attention
to potential drug-drug interactions and overlapping toxicities among COVID-19 treatments,
ARV medications, antimicrobial therapies, and other medications (AIII). Therapeutic options for
nonhospitalized patients with HIV include ritonavir-boosted nirmatrelvir (Paxlovid), intravenous
remdesivir, bebtelovimab, and molnupiravir (see Therapeutic Management of Nonhospitalized Adults
With COVID-19). Drug-drug interactions are a special concern with ritonavir-boosted nirmatrelvir (see
the Panel’s statement on the drug-drug interactions for ritonavir-boosted nirmatrelvir). People with HIV
who are taking ritonavir-based or cobicistat-based ART can receive the 5-day course of ritonavir-boosted
nirmatrelvir to treat COVID-19 without altering or interrupting their ART (i.e., they can continue using
the ritonavir or cobicistat dose that is associated with their ART in addition to the dose of ritonavir that
is used with nirmatrelvir). Before prescribing ritonavir-boosted nirmatrelvir for a patient who is not
already on a ritonavir-based or cobicistat-based regimen, clinicians should carefully review the patient’s
concomitant medications, including over-the-counter medicines and herbal supplements, and evaluate
the potential for drug-drug interactions. Clinicians should utilize resources such as the EUA fact sheet
for ritonavir-boosted nirmatrelvir and the Liverpool COVID-19 Drug Interactions website for additional
guidance on identifying and managing drug-drug interactions.
In hospitalized patients, the appropriate treatment strategy depends on disease severity (see Therapeutic
Management of Hospitalized Adults With COVID-19). Both tocilizumab and dexamethasone, which
are recommended for some patients with severe or critical COVID-19, are immunosuppressive agents.
The safety of using these drugs in immunocompromised patients, including those with advanced HIV,
has not been studied. Therefore, patients with advanced HIV who are receiving these drugs should be
closely monitored for secondary infections. Dexamethasone is a dose-dependent inducer of cytochrome
P450 3A4 and could potentially lower the levels of certain coadministered ARV drugs. More than a
single dose of dexamethasone is not recommended for patients who are receiving rilpivirine as part of
their ARV regimen. Clinicians should consult an HIV specialist before administering dexamethasone to

AR09119
these patients. It is currently unknown whether administering ≤10 days of dexamethasone impacts the
clinical efficacy of other ARV drugs. Patients with HIV who are receiving dexamethasone as treatment for
COVID-19 should follow up with their HIV providers to assess their virologic response.
Although some ARV drugs were studied for the prevention and treatment of COVID-19, no agents have
been shown to be effective.
People with HIV should be offered the opportunity to participate in clinical trials of vaccines and potential
treatments for COVID-19. A variety of immunomodulatory therapies are prescribed empirically or
administered as part of a clinical trial to treat severe COVID-19. The data on whether these medications
are safe to use in patients with HIV are lacking. If a medication has been shown to reduce the mortality of
patients with COVID-19 in the general population, it should also be used to treat COVID-19 in patients
with HIV, unless data indicate that the medication is not safe or effective in this population.
Managing HIV in People With COVID-19

Whenever possible, ART and opportunistic infection prophylaxis should be continued in a patient
with HIV who develops COVID-19, including in those who require hospitalization (AIII). Treatment
interruption may lead to rebound viremia, and, in some cases, the emergence of drug resistance. If the
appropriate ARV drugs are not on the hospital’s formulary, administer medications from the patient’s
home supplies, if available.
Clinicians who are treating COVID-19 in people with HIV should consult an HIV specialist before
adjusting or switching a patient’s ARV medications. An ARV regimen should not be switched or adjusted
(i.e., by adding ARV drugs to the regimen) for the purpose of preventing or treating SARS-CoV-2
infection (AIII). Many drugs, including some ARV agents (e.g., lopinavir/ritonavir, boosted darunavir,
tenofovir disoproxil fumarate/emtricitabine), have been or are being evaluated in clinical trials or are
prescribed off-label to treat or prevent SARS-CoV-2 infection. To date, lopinavir/ritonavir and darunavir/
cobicistat have not been found to be effective (see Lopinavir/Ritonavir and Other HIV Protease
Inhibitors).33,34 Two retrospective studies have suggested that tenofovir disoproxil fumarate/emtricitabine
may play a role in preventing SARS-CoV-2 acquisition or hospitalization or death associated with
COVID-19; however, the significance of these findings is unclear, as neither study adequately controlled
for confounding variables such as age and comorbidities.12,32
For patients who are taking an investigational ARV medication as part of their ARV regimen,
arrangements should be made with the investigational study team to continue the medication, if possible.
For critically ill patients who require tube feeding, some ARV medications are available in liquid
formulations, and some ARV pills may be crushed. Clinicians should consult an HIV specialist and/or
pharmacist to assess the best way to continue an effective ARV regimen for a patient with a feeding tube.
Information may be available in the drug product label or in this document from Toronto General Hospital.
For people who present with COVID-19 and have either a new diagnosis of HIV or a history of HIV but
are not taking ART, the optimal time to start or restart ART is currently unknown. For people with HIV who
have not initiated ART or who have been off therapy for >2 weeks before presenting with COVID-19, the
Panel recommends consulting an HIV specialist about initiating or reinitiating ART as soon as clinically
feasible. If ART is initiated, maintaining treatment and linking patients to HIV care upon hospital discharge
is critical. If an HIV specialist is not available, clinical consultation is available by phone through the
National Clinician Consultation Center, Monday through Friday, 9 am to 8 pm EST.
References
1. Harris NS, Johnson AS, Huang YA, et al. Vital signs: status of human immunodeficiency virus testing, viral
suppression, and HIV preexposure prophylaxis—United States, 2013-2018. MMWR Morb Mortal Wkly Rep.

AR09120
2. Meyerowitz EA, Kim AY, Ard KL, et al. Disproportionate burden of coronavirus disease 2019 among racial
minorities and those in congregate settings among a large cohort of people with HIV. AIDS. 2020;34(12):1781-
3. Centers for Disease Control and Prevention. COVID-19 information for specific groups of people. 2021. Available
at: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/index.html. Accessed January 24, 2022.
4. Gervasoni C, Meraviglia P, Riva A, et al. Clinical features and outcomes of patients with human
immunodeficiency virus with COVID-19. Clin Infect Dis. 2020;71(16):2276-2278. Available at:
5. Harter G, Spinner CD, Roider J, et al. COVID-19 in people living with human immunodeficiency virus: a case
series of 33 patients. Infection. 2020;48(5):681-686. Available at:
6. Karmen-Tuohy S, Carlucci PM, Zervou FN, et al. Outcomes among HIV-positive patients hospitalized with
COVID-19. J Acquir Immune Defic Syndr. 2020;85(1):6-10. Available at:
7. Patel VV, Felsen UR, Fisher M, et al. Clinical outcomes and inflammatory markers by HIV serostatus and
viral suppression in a large cohort of patients hospitalized with COVID-19. J Acquir Immune Defic Syndr.
8. Shalev N, Scherer M, LaSota ED, et al. Clinical characteristics and outcomes in people living with human
immunodeficiency virus hospitalized for coronavirus disease 2019. Clin Infect Dis. 2020;71(16):2294-2297.
9. Sigel K, Swartz T, Golden E, et al. Coronavirus 2019 and people living with human immunodeficiency virus:
outcomes for hospitalized patients in New York City. Clin Infect Dis. 2020;71(11):2933-2938. Available at:
10. Stoeckle K, Johnston CD, Jannat-Khah DP, et al. COVID-19 in hospitalized adults with HIV. Open Forum Infect
Dis. 2020;7(8):ofaa327. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32864388.
11. Vizcarra P, Perez-Elias MJ, Quereda C, et al. Description of COVID-19 in HIV-infected individuals: a single-
centre, prospective cohort. Lancet HIV. 2020;7(8):e554-e564. Available at:
12. Western Cape Department of Health in collaboration with the National Institute for Communicable Diseases,
South Africa. Risk factors for coronavirus disease 2019 (COVID-19) death in a population cohort study from the
Western Cape Province, South Africa. Clin Infect Dis. 2021;73(7):e2005-e2015. Available at:
13. Bhaskaran K, Rentsch CT, MacKenna B, et al. HIV infection and COVID-19 death: a population-based cohort
analysis of UK primary care data and linked national death registrations within the OpenSAFELY platform.
Lancet HIV. 2021;8(1):e24-e32. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33316211.
14. Geretti AM, Stockdale AJ, Kelly SH, et al. Outcomes of coronavirus disease 2019 (COVID-19) related
hospitalization among people with human immunodeficiency virus (HIV) in the ISARIC World Health
Organization (WHO) clinical characterization protocol (UK): a prospective observational study. Clin Infect Dis.
15. Dandachi D, Geiger G, Montgomery MW, et al. Characteristics, comorbidities, and outcomes in a multicenter
registry of patients with human immunodeficiency virus and coronavirus disease 2019. Clin Infect Dis.
16. Hoffmann C, Casado JL, Harter G, et al. Immune deficiency is a risk factor for severe COVID-19 in people
living with HIV. HIV Med. 2021;22(5):372-378. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33368966.
17. Tesoriero JM, Swain CE, Pierce JL, et al. COVID-19 outcomes among persons living with or without diagnosed
HIV infection in New York State. JAMA Netw Open. 2021;4(2):e2037069. Available at:

AR09121
18. Sun J, Patel RC, Zheng Q, et al. COVID-19 disease severity among people with HIV infection or solid organ
transplant in the United States: a nationally-representative, multicenter, observational cohort study. medRxiv.
2021;Preprint. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34341798.
19. Bertagnolio S, Thwin SS, Silva R, et al. Clinical characteristics and prognostic factors in people living with
HIV hospitalized with COVID-19: findings from the WHO Global Clinical Platform. Presented at: International
AIDS Society. 2021. Virtual. Available at: https://theprogramme.ias2021.org/Abstract/Abstract/2498.
20. Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl
J Med. 2021;384(5):403-416. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33378609.
21. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N
22. Food and Drug Administration. Fact sheet for healthcare providers administering vaccine (vaccination
providers): emergency use authorization (EUA) of the Janssen COVID-19 vaccine to prevent coronavirus
disease 2019 (COVID-19). 2022. Available at: https://www.fda.gov/media/146304/download.
23. Levy I, Wieder-Finesod A, Litchevsky V, et al. Immunogenicity and safety of the BNT162b2 mRNA COVID-19
vaccine in people living with HIV-1. Clin Microbiol Infect. 2021;27(12):1851-1855. Available at:
24. Woldemeskel BA, Karaba AH, Garliss CC, et al. The BNT162b2 mRNA vaccine elicits robust humoral and
cellular immune responses in people living with HIV. Clin Infect Dis. 2021;Published online ahead of print.
25. Frater J, Ewer KJ, Ogbe A, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine
against SARS-CoV-2 in HIV infection: a single-arm substudy of a Phase 2/3 clinical trial. Lancet HIV.
26. Tan SS, Chew KL, Saw S, Jureen R, Sethi S. Cross-reactivity of SARS-CoV-2 with HIV chemiluminescent
assay leading to false-positive results. J Clin Pathol. 2021;74(9):614. Available at:
27. Blanco JL, Ambrosioni J, Garcia F, et al. COVID-19 in patients with HIV: clinical case series. Lancet HIV.
28. Coleman H, Snell LB, Simons R, Douthwaite ST, Lee MJ. Coronavirus disease 2019 and Pneumocystis jirovecii
pneumonia: a diagnostic dilemma in HIV. AIDS. 2020;34(8):1258-1260. Available at:
29. Centers for Disease Control and Prevention. HIV surveillance report: estimated HIV incidence and prevalence in
the United States 2014–2018. 2020. Available at: https://www.cdc.gov/hiv/pdf/library/reports/surveillance/cdc-
hiv-surveillance-supplemental-report-vol-25-1.pdf.
30. Kong AM, Pozen A, Anastos K, Kelvin EA, Nash D. Non-HIV comorbid conditions and polypharmacy among
people living with HIV age 65 or older compared with HIV-negative individuals age 65 or older in the United
States: a retrospective claims-based analysis. AIDS Patient Care STDS. 2019;33(3):93-103. Available at:
31. Byrd KM, Beckwith CG, Garland JM, et al. SARS-CoV-2 and HIV coinfection: clinical experience from Rhode
Island, United States. J Int AIDS Soc. 2020;23(7):e25573. Available at:
32. Del Amo J, Polo R, Moreno S, et al. Incidence and severity of COVID-19 in HIV-positive persons receiving
antiretroviral therapy: a cohort study. Ann Intern Med. 2020;173(7):536-541. Available at:
33. Recovery Collaborative Group. Lopinavir-ritonavir in patients admitted to hospital with COVID-19
34. Chen J, Xia L, Liu L, et al. Antiviral activity and safety of darunavir/cobicistat for the treatment of COVID-19.
Open Forum Infect Dis. 2020;7(7):ofaa241. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32671131.

AR09122
Influenza and COVID-19

Influenza Vaccination
• People with acute COVID-19 should receive an inactivated influenza vaccine (BIII). For more information on
administering influenza vaccines to these patients, see Interim Guidance for Routine and Influenza Immunization
Services During the COVID-19 Pandemic from the Centers for Disease Control and Prevention (CDC).
• Clinicians should consider deferring influenza vaccination for symptomatic COVID-19 patients until these patients
have completed their COVID-19 isolation period and are no longer moderately or severely ill.
• People with SARS-CoV-2 infection who are not moderately or severely ill (including those who are asymptomatic)
should seek influenza vaccination when they no longer require isolation. They can be vaccinated sooner if they are
in a health care setting for other reasons.
• An influenza vaccine and a COVID-19 vaccine may be administered concurrently at different injection sites (see the
recommendations from CDC and the Advisory Committee on Immunization Practices).
Diagnosis of Influenza and COVID-19 When Influenza Viruses and SARS-CoV-2 Are Cocirculating
• Only testing can distinguish between SARS-CoV-2 and influenza virus infections and identify SARS-CoV-2 and
influenza virus coinfection.
• The COVID-19 Treatment Guidelines Panel (the Panel) recommends testing for both viruses in all hospitalized patients
with acute respiratory illness (AIII).
• The Panel recommends influenza testing in addition to SARS-CoV-2 testing in outpatients with acute respiratory
illness if the results will change the clinical management strategy for the patient (e.g., administering antiviral
treatment for influenza) (BIII).
• Clinicians should consider testing patients for other pathogens based on their specific clinical circumstances.
Additional testing is especially important for patients with influenza who have a high risk of acquiring bacterial
superinfections.
• See the CDC Information for Clinicians on Influenza Virus Testing and the Infectious Diseases Society of America
(IDSA) Clinical Practice Guidelines for more information.
Antiviral Treatment of Influenza When Influenza Viruses and SARS-CoV-2 Are Cocirculating
• Antiviral treatment of influenza is the same in all patients with or without SARS-CoV-2 coinfection (AIII).
• For information on using antiviral drugs to treat influenza in hospitalized and nonhospitalized patients, see the CDC
and IDSA recommendations.
• The Panel recommends that hospitalized patients with suspected influenza be started on empiric treatment for
influenza with oseltamivir as soon as possible and without waiting for influenza test results (AIIb).
• Antiviral treatment for influenza can be stopped when influenza has been ruled out by the results of a nucleic
acid detection assay in upper respiratory tract specimens for nonintubated patients and in both upper and lower
respiratory tract specimens for intubated patients.
Introduction
Influenza activity in the United States during the 2021 to 2022 influenza season is difficult to predict, and
activity may vary depending on location and the measures taken by individual communities to mitigate
the spread of SARS-CoV-2.1 Influenza activity worldwide has been very low since the early spring of
2020, including in the United States during the 2020 to 2021 season.2,3 Clinicians should monitor local
influenza and SARS-CoV-2 activities during influenza season to inform the evaluation and management

AR09123
of patients with acute respiratory illness. This can be done by tracking local and state public health
surveillance data, assessing the results of testing performed at health care facilities, and reviewing the
Centers for Disease Control and Prevention (CDC) Weekly U.S. Influenza Surveillance Report.
Influenza Vaccination
For Patients With Acute COVID-19 or Those Who Are Recovering From COVID-19
The Advisory Committee on Immunization Practices (ACIP) recommends offering an influenza vaccine
to all persons aged ≥6 months in the United States by the end of October.4 People with acute COVID-19
should receive an inactivated influenza vaccine (BIII).
There are currently no available data on the safety, immunogenicity, or efficacy of influenza vaccines
in patients with mild COVID-19 or those who are recovering from COVID-19. Therefore, the optimal
timing for influenza vaccination in these patients is unknown. The safety and efficacy of vaccinating
persons who have mild illnesses from other etiologies have been documented.5 Clinicians should consider
deferring influenza vaccination for symptomatic COVID-19 patients until these patients have completed
their COVID-19 isolation period and are no longer moderately or severely ill. People with SARS-CoV-2
infection who are not moderately or severely ill (including those who are asymptomatic) should seek
influenza vaccination when they no longer require isolation. They can be vaccinated sooner if they are
in a health care setting for other reasons (see Interim Guidance for Routine and Influenza Immunization
Services During the COVID-19 Pandemic from CDC for more detailed recommendations).
It is not known whether administering dexamethasone or other immunomodulatory therapies to patients
with severe COVID-19 will affect the immune response to an influenza vaccine. Nevertheless, as long as
influenza viruses are circulating, people with COVID-19 should receive an influenza vaccine once they
have substantially improved or recovered from COVID-19. See the influenza vaccine recommendations
from CDC, ACIP, and the American Academy of Pediatrics.
Coadministration of COVID-19 Vaccines and Influenza Vaccines

Although there are currently no data on the coadministration of COVID-19 vaccines and influenza
vaccines, these vaccines may be administered concurrently at different injection sites. Providers and
patients should be aware of the potential for increased reactogenicity when administering both vaccines
concurrently (see the recommendations from CDC and ACIP).
Clinical Presentation of Influenza Versus COVID-19

The signs and symptoms of uncomplicated, clinically mild influenza overlap with those of mild
COVID-19. Ageusia and anosmia can occur with both diseases, but these symptoms are more
common with COVID-19 than with influenza. Fever is not always present in patients with either
disease, particularly in patients who are immunosuppressed or elderly. Complications of influenza and
COVID-19 can be similar, but the onset of influenza complications and severe disease typically occurs
within a week of illness onset whereas the onset of severe COVID-19 usually occurs in the second week
of illness. Because of the overlap in signs and symptoms, when SARS-CoV-2 and influenza viruses are
cocirculating, diagnostic testing for both viruses is needed to distinguish between SARS-CoV-2 and
influenza virus and to identify coinfection in people with an acute respiratory illness. Coinfection with
influenza and SARS-CoV-2 has been described in case reports and case series.6-10
Testing for SARS-CoV-2 and Influenza

When influenza viruses and SARS-CoV-2 are cocirculating in the community, SARS-CoV-2 testing
and influenza testing should be performed in all patients who are hospitalized with an acute respiratory

AR09124
illness (see Testing for SARS-CoV-2 Infection) (AIII). SARS-CoV-2 testing should also be performed in
outpatients with suspected COVID-19, and influenza testing can be considered if the results will change
the clinical management strategy for the patient (e.g., administering antiviral treatment for influenza)
(BIII). Several multiplex molecular assays and multiplex antigen assays that detect SARS-CoV-2 and
influenza A and B viruses have received Food and Drug Administration Emergency Use Authorizations
or De Novo classifications and can provide results in 15 minutes to 8 hours using a single respiratory
specimen.11,12 For more information, see the CDC Information for Clinicians on Influenza Virus Testing
and the recommendations from the Infectious Diseases Society of America (IDSA) on the use of
influenza tests and the interpretation of testing results.13
Treating Influenza With Antiviral Agents

Antiviral treatment for influenza is the same for all patients regardless of SARS-CoV-2 coinfection
(AIII). When SARS-CoV-2 and influenza viruses are cocirculating in the community, patients who
require hospitalization and are suspected of having either or both viral infections should receive
influenza antiviral treatment with oseltamivir as soon as possible and without waiting for influenza
testing results (AIIb). Oseltamivir has no activity against SARS-CoV-214 or known interactions with
remdesivir or other therapeutics for COVID-19. The standard dose of oseltamivir is well absorbed even
in critically ill patients. For patients who cannot tolerate oral or enterically administered oseltamivir
(e.g., because of gastric stasis, malabsorption, or gastrointestinal bleeding), intravenous peramivir
is an option.13 There are no data on peramivir activity against SARS-CoV-2. See the CDC Influenza
Antiviral Medications: Summary for Clinicians for clinical algorithms for using antiviral agents in
patients with suspected or laboratory-confirmed influenza, including pregnant people and other people
who are at high risk for influenza complications. The IDSA Clinical Practice Guidelines also provide
recommendations on using antiviral agents to treat influenza, and the American Academy of Pediatrics
provides recommendations on the antiviral treatment of influenza in children.
When the result of an influenza nucleic acid detection assay from an upper respiratory tract specimen is
negative in a patient who is receiving antiviral treatment for influenza:
• In a patient who is not intubated: Antiviral treatment for influenza can be stopped.
• In a patient who is intubated: Antiviral treatment for influenza should be continued, and if a lower
respiratory tract specimen (e.g., endotracheal aspirate) can be safely obtained, it should be tested
using an influenza nucleic acid detection assay. If the lower respiratory tract specimen is also
negative, influenza antiviral treatment can be stopped.
COVID-19 Treatment Considerations for Hospitalized Patients With Suspected or

Confirmed Influenza Virus Coinfection
• Corticosteroids, which are used for the treatment of patients with severe COVID-19, may prolong
influenza viral replication and viral RNA detection and may be associated with poor outcomes
for influenza.13,15 Currently, no data are available on the use of corticosteroids in patients with
SARS-CoV-2 and influenza virus coinfection. However, because dexamethasone has demonstrated
substantial benefits for patients with COVID-19 who require supplemental oxygen, the benefits of
using corticosteroids in patients with severe SARS-CoV-2 and influenza virus coinfection likely
outweigh any potential harms.
• Remdesivir does not have activity against influenza viruses. There are no known drug interactions
between remdesivir and oseltamivir. Therefore, remdesivir may be used safely when indicated
in patients with COVID-19 and suspected or laboratory-confirmed influenza who are receiving
oseltamivir treatment.

AR09125
• Although severe influenza may be associated with a dysregulated innate immune response, there
are no data on the use of immunomodulatory therapies, such as interleukin-6 inhibitors (e.g.,
tocilizumab, sarilumab) or Janus Kinase inhibitors (e.g., baricitinib, tofacitinib), for the treatment
of severe influenza. There are also no data on the effect these therapies may have on influenza
viral replication. Because these immunomodulators have demonstrated a clinical benefit in certain
COVID-19 patients, clinicians should consider engaging in a shared decision-making process
on use of these drugs with patients who have been diagnosed with COVID-19 and who have
suspected or laboratory-confirmed influenza.
• The co-occurrence of community-acquired secondary bacterial pneumonia and COVID-19
appears to be infrequent and may be more common in people who also have influenza; however,
this inference is based on limited data.16-18 Typical bacterial causes of community-acquired
pneumonia with severe influenza are Staphylococcus aureus (methicillin-resistant S. aureus
[MRSA] and methicillin-susceptible S. aureus [MSSA]), Streptococcus pneumoniae, and group A
Streptococcus.13
• Patients with COVID-19 who develop new respiratory symptoms with or without fever or
respiratory distress and who do not have a clear diagnosis should be evaluated for the possibility
of nosocomial influenza.
References
1. Qi Y, Shaman J, Pei S. Quantifying the impact of COVID-19 non-pharmaceutical interventions on influenza
transmission in the United States. J Infect Dis. 2021;Published online ahead of print. Available at:
2. World Health Organization. Review of global influenza circulation, late 2019 to 2020, and the impact of
the COVID-19 pandemic on influenza circulation. Wkly Epidemiol Rec. 2021;96(25):241-264. Available at:
https://apps.who.int/iris/handle/10665/341995.
3. Olsen SJ, Winn AK, Budd AP, et al. Changes in influenza and other respiratory virus activity during the
COVID-19 pandemic—United States, 2020–2021. MMWR Morb Mortal Wkly Rep. 2021;70(29):1013-1019.
4. Grohskopf LA, Alyanak E, Ferdinands JM, et al. Prevention and control of seasonal influenza with vaccines:
recommendations of the Advisory Committee on Immunization Practices, United States, 2021-22 influenza
season. MMWR Recomm Rep. 2021;70(5):1-28. Available at:
5. Centers for Disease Control and Prevention. Contraindications and precautions. General best practice
guidelines for immunization: best practices guidance of the advisory committee on immunization practices
(ACIP). 2020. Available at: https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/contraindications.html.
Accessed October 16, 2021.
6. Hashemi SA, Safamanesh S, Ghasemzadeh-Moghaddam H, Ghafouri M, Azimian A. High prevalence of
SARS-CoV-2 and influenza A virus (H1N1) coinfection in dead patients in Northeastern Iran. J Med Virol.
7. Huang BR, Lin YL, Wan CK, et al. Co-infection of influenza B virus and SARS-CoV-2: a case report from
Taiwan. J Microbiol Immunol Infect. 2021;54(2):336-338. Available at:
8. Yue H, Zhang M, Xing L, et al. The epidemiology and clinical characteristics of co-infection of SARS-CoV-2
and influenza viruses in patients during COVID-19 outbreak. J Med Virol. 2020;92(11):2870-2873. Available
9. Cuadrado-Payan E, Montagud-Marrahi E, Torres-Elorza M, et al. SARS-CoV-2 and influenza virus co-
infection. Lancet. 2020;395(10236):e84. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32423586.

AR09126
10. Wu X, Cai Y, Huang X, et al. Co-infection with SARS-CoV-2 and influenza A virus in patient with
pneumonia, China. Emerg Infect Dis. 2020;26(6):1324-1326. Available at:
11. Food and Drug Administration. In vitro diagnostic EUAs—molecular diagnostic tests for SARS-CoV-2.
2021. Available at: https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-
authorizations-medical-devices/in-vitro-diagnostics-euas-molecular-diagnostic-tests-sars-cov-2. Accessed
October 21, 2021.
12. Food and Drug Administration. In vitro diagnostic EUAs—antigen diagnostic tests for SARS-CoV-2. 2021.
Available at: https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-
authorizations-medical-devices/in-vitro-diagnostics-euas-antigen-diagnostic-tests-sars-cov-2. Accessed
October 21, 2021.
13. Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical practice guidelines by the Infectious Diseases Society of
America: 2018 update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of
seasonal influenza. Clin Infect Dis. 2019;68(6):e1-e47. Available at:
14. Choy KT, Wong AY, Kaewpreedee P, et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit
SARS-CoV-2 replication in vitro. Antiviral Res. 2020;178:104786. Available at:
15. Zhou Y, Fu X, Liu X, et al. Use of corticosteroids in influenza-associated acute respiratory distress syndrome
and severe pneumonia: a systemic review and meta-analysis. Sci Rep. 2020;10(1):3044. Available at:
16. Vaughn VM, Gandhi T, Petty LA, et al. Empiric antibacterial therapy and community-onset bacterial
co-infection in patients hospitalized with COVID-19: a multi-hospital cohort study. Clin Infect Dis.
17. Adler H, Ball R, Fisher M, Mortimer K, Vardhan MS. Low rate of bacterial co-infection in patients with
COVID-19. Lancet Microbe. 2020;1(2):e62. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32835331.
18. Russell CD, Fairfield CJ, Drake TM, et al. Co-infections, secondary infections, and antimicrobial use in
patients hospitalised with COVID-19 during the first pandemic wave from the ISARIC WHO CCP-UK study:
a multicentre, prospective cohort study. Lancet Microbe. 2021;2(8):e354-e365. Available at:

AR09127
Appendix A, Table 1. COVID-19 Treatment Guidelines Panel

Members
Name Affiliation
Co-Chairs
Roy M. Gulick, MD, MPH Weill Cornell Medicine, New York, NY
H. Clifford Lane, MD National Institutes of Health, Bethesda, MD
Henry Masur, MD National Institutes of Health, Bethesda, MD
Executive Secretary
Alice K. Pau, PharmD National Institutes of Health, Bethesda, MD
Members
Judith Aberg, MD Icahn School of Medicine at Mount Sinai, New York, NY
Adaora Adimora, MD, MPH University of North Carolina School of Medicine, Chapel Hill, NC
Jason Baker, MD, MS Hennepin Healthcare/University of Minnesota, Minneapolis, MN
Lisa Baumann Kreuziger, MD, MS Versiti/Medical College of Wisconsin, Milwaukee, WI
Roger Bedimo, MD, MS University of Texas Southwestern/Veterans Affairs North Texas Health Care
System, Dallas, TX
Pamela S. Belperio, PharmD Department of Veterans Affairs, Los Angeles, CA
Stephen V. Cantrill, MD Denver Health, Denver, CO
Kathleen Chiotos, MD, MSCE Children’s Hospital of Philadelphia/University of Pennsylvania, Philadelphia, PA
Craig Coopersmith, MD Emory University School of Medicine, Atlanta, GA
Eric Daar, MD Harbor-UCLA Medical Center, Torrance, CA
Amy L. Dzierba, PharmD New York-Presbyterian Hospital, New York, NY
Gregory Eschenauer, PharmD University of Michigan, Ann Arbor, MI
Laura Evans, MD, MSc University of Washington, Seattle, WA
John J. Gallagher, DNP, RN University of Pittsburgh Medical Center, Pittsburgh, PA
Rajesh Gandhi, MD Massachusetts General Hospital/Harvard Medical School, Boston, MA
David V. Glidden, PhD University of California San Francisco, San Francisco, CA
Steve Grapentine, PharmD University of California San Francisco, San Francisco, CA
Birgit Grund, PhD University of Minnesota, Minneapolis, MN
Erica J. Hardy, MD, MMSc Warren Alpert Medical School of Brown University, Providence, RI
Carl Hinkson, MSRC Providence Health & Services, Everett, WA
Lauren Henderson, MD, MMSc Boston Children’s Hospital/Harvard Medical School, Boston, MA
Brenna L. Hughes, MD, MSc Duke University School of Medicine, Durham, NC
Steven Johnson, MD University of Colorado School of Medicine, Aurora, CO
Marla J. Keller, MD Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY
Robinder Khemani, MD, MsCI Children’s Hospital of Los Angeles/University of Southern California, Los Angeles,
CA
Arthur Kim, MD Massachusetts General Hospital/Harvard Medical School, Boston, MA
Jeffrey L. Lennox, MD Emory University School of Medicine, Atlanta, GA
Mitchell M. Levy, MD Warren Alpert Medical School of Brown University, Providence, RI
Jonathan Li, MD, MMSc Brigham and Women’s Hospital/Harvard Medical School, Boston, MA
Gregory Martin, MD, MSc Emory University School of Medicine, Atlanta, GA
Susanna Naggie, MD, MHS Duke University School of Medicine, Durham, NC

AR09128
Name Affiliation
Members, continued
Andrew T. Pavia, MD University of Utah School of Medicine, Salt Lake City, UT
Grant Schulert, MD, PhD Cincinnati Children’s Hospital Medical Center/University of Cincinnati
College of Medicine, Cincinnati, OH
Nitin Seam, MD National Institutes of Health, Bethesda, MD
Steven Q. Simpson, MD University of Kansas Medical Center, Kansas City, KS
Renee Stapleton, MD, PhD University of Vermont Larner College of Medicine, Burlington, VT
Susan Swindells, MBBS University of Nebraska Medical Center, Omaha, NE
Pablo Tebas, MD University of Pennsylvania, Philadelphia, PA
Phyllis Tien, MD, MSc University of California, San Francisco/San Francisco VA Healthcare
System, San Francisco, CA
Alpana A. Waghmare, MD Seattle Children’s Hospital, Seattle, WA
Jinoos Yazdany, MD, MPH University of California, San Francisco, San Francisco, CA
Community Members
Danielle M. Campbell, MPH University of California, Los Angeles, Los Angeles, CA
Carly Harrison LupusChat, New York, NY
Pharmacology Consultants
Sarita Boyd, PharmD Food and Drug Administration, Silver Spring, MD
Jomy George, PharmD National Institutes of Health, Bethesda, MD
Kimberly Scarsi, PharmD University of Nebraska Medical Center, Omaha, NE
Ex Officio Members, U.S. Government Representatives
Timothy Burgess, MD Department of Defense, Bethesda, MD
Demetre Daskalakis, MD, MPH Centers for Disease Control and Prevention, Atlanta, GA
Derek Eisnor, MD Biomedical Advanced Research and Development Authority, Washington, DC
Joseph Francis, MD, MPH Department of Veterans Affairs, Washington, DC
Virginia Sheikh, MD, MHS Food and Drug Administration, Silver Spring, MD
Timothy M. Uyeki, MD, MPH Centers for Disease Control and Prevention, Atlanta, GA
U.S. Government Support Team
John T. Brooks, MD Centers for Disease Control and Prevention, Atlanta, GA
Richard T. Davey, Jr., MD National Institutes of Health, Bethesda, MD
Laurie K. Doepel, BA National Institutes of Health, Bethesda, MD
Alison Han, MD (Co-Team Coordinator) National Institutes of Health, Bethesda, MD
Elizabeth S. Higgs, MD, DTM&H, MIA National Institutes of Health, Bethesda, MD
Martha C. Nason, PhD (Biostatistics Support) National Institutes of Health, Bethesda, MD
Michael Proschan, PhD (Biostatistics National Institutes of Health, Bethesda, MD
Support)
Renee Ridzon, MD National Institutes of Health, Bethesda, MD
Kanal Singh, MD, MPH (Co-Team National Institutes of Health, Bethesda, MD
Coordinator)
Assistant Executive Secretaries
Page Crew, PharmD, MPH National Institutes of Health, Bethesda, MD
Safia Kuriakose, PharmD Frederick National Laboratory for Cancer Research, in support of NIAID,
Frederick, MD
Andrea M. Lerner, MD, MS National Institutes of Health, Bethesda, MD

AR09129
Appendix A, Table 2. COVID-19 Treatment Guidelines Panel

Financial Disclosure for Companies Related to COVID-19
Treatment or Diagnostics
Reporting Period: April 1, 2021, to March 31, 2022

Financial Disclosure
Panel Member
Company Relationship
Judith Aberg, MD Atea Pharmaceuticals Research Support
Emergent BioSolutions Research Support
Gilead Sciences Research Support
GlaxoSmithKline Advisory Board, Research Support
GSK/ViiV Healthcare Advisory Board, Research Support
Janssen Research Support
Merck & Co. Advisory Board, Research Support
Pfizer Research Support
Regeneron Research Support
Adaora Adimora, MD, MPH Gilead Sciences Research Support, Consultant
Jason Baker, MD, MS Humanigen Research Support
Lisa Baumann Kreuziger, MD, MS 3M Stockholder, Spouse is employee
Versiti Employee
Roger Bedimo, MD, MS Gilead Sciences Advisory Board
GSK/ViiV Healthcare Advisory Board
Janssen Advisory Board
Pamela S. Belperio, PharmD None N/A
John T. Brooks, MD None N/A
Timothy Burgess, MD AstraZeneca Research Support
Danielle M. Campbell, MPH Gilead Sciences Advisory Board
GSK/ViiV Healthcare Attendee (Community Stakeholder Meeting)
Stephen V. Cantrill, MD None N/A
Kathleen Chiotos, MD, MSCE None N/A
Craig Coopersmith, MD None N/A
Page Crew, PharmD, MPH None N/A
Eric Daar, MD Gilead Sciences Consultant, Research Support
GSK/ViiV Healthcare Consultant, Research Support
Merck & Co. Consultant, Research Support
Demetre Daskalakis, MD, MPH None N/A
Richard T. Davey, Jr., MD None N/A
Laurie K. Doepel, BA None N/A
Amy L. Dzierba, PharmD None N/A
Derek Eisnor, MD None N/A

AR09130
Panel Member
Gregory Eschenauer, PharmD None N/A
Laura Evans, MD, MSc None N/A
Joseph Francis, MD, MPH None N/A
John J. Gallagher, DNP, RN None N/A
Rajesh Gandhi, MD None N/A
David V. Glidden, PhD None N/A
Steve Grapentine, PharmD None N/A
Birgit Grund, PhD None N/A
Roy M. Gulick, MD, MPH None N/A
Alison Han, MD None N/A
Erica J. Hardy, MD, MMSc None N/A
Carly Harrison AstraZeneca Advisory Board, Consultant
Aurinia Pharmaceuticals Advisory Board, Stockholder
UCB Advisory Board, Consultant
Lauren Henderson, MD, MMSc Adaptive Biotechnologies Consultant
Bristol Myers Squibb Research Support
Pfizer External Panel (Grant Reviews)
Sobi Advisory Board, Consultant, Research Support
Elizabeth S. Higgs, MD, DTM&H, None N/A
MIA
Carl Hinkson, MSRC None N/A
Brenna L. Hughes, MD, MSc None N/A
Steven Johnson, MD GSK/ViiV Healthcare Advisory Board
Marla J. Keller, MD None N/A
Robinder Khemani, MD, MsCI None N/A
Arthur Kim, MD Kintor Pharmaceutical Data and Safety Monitoring Board Chair/Member
Safia Kuriakose, PharmD None N/A
H. Clifford Lane, MD None N/A
Jeffrey L. Lennox, MD None N/A
Andrea M. Lerner, MD, MS None N/A
Mitchell M. Levy, MD None N/A
Jonathan Li, MD, MMSc None N/A
Gregory Martin, MD, MSc Genentech Data and Safety Monitoring Board Chair/Member
Grifols Research Grants Review Panel
Henry Masur, MD None N/A
Susanna Naggie, MD, MHS AbbVie Research Support, Funding via NIH supported trial
Bristol Myers Squibb Event Adjudication Committee
FHI 360 Event Adjudication Committee
Pardes Biosciences Consultant
Silverback Therapeutics Consultant
Vir Biotechnology Advisory Board, Stockholder, Stock Options

AR09131
Panel Member
Martha C. Nason, PhD None N/A
Alice K. Pau, PharmD None N/A
Andrew T. Pavia, MD GlaxoSmithKline Advisory Board
Michael Proschan, PhD None N/A
Renee Ridzon, MD None N/A
Grant Schulert, MD, PhD Novartis Honoraria
Nitin Seam, MD None N/A
Virginia Sheikh, MD, MHS None N/A
Steven Q. Simpson, MD None N/A
Kanal Singh, MD, MPH None N/A
Renee Stapleton, MD, PhD Altimmune Data and Safety Monitoring Board Chair
CSL Behring Consultant
Susan Swindells, MBBS GSK/ViiV Healthcare Research Support
Pablo Tebas, MD Gilead Sciences Consultant
GSK/ViiV Healthcare Consultant
Merck & Co. Consultant
Phyllis Tien, MD, MSc Eli Lilly Research Support
Merck & Co. Research Support
Timothy M. Uyeki, MD, MPH None N/A
Alpana A. Waghmare, MD AlloVir Research Support
Ansun Biopharma Research Support
Deverra Therapeutics Data and Safety Monitoring Board Member
KYORIN Pharmaceutical Co. Advisory Board
Pfizer Research Support
Vir Biotechnology Research Support
Jinoos Yazdany, MD, MPH AstraZeneca Consultant and Research Support related to
lupus
Aurinia Consultant, Consultation on lupus drug
Bristol Myers Squibb Research Support
Pfizer Consultant, Presentation

AR09132
Cureus Erratum DOI: 10.7759/cureus.c61
Erratum: lvermectin Prophylaxis Used for COVID-19: A Citywide,

Prospective, Observational Study of 223,128 Subjects Using Propens ity
Score Matching
Article published OtnS/2022
Article corr.tcted 03J2412022
UK)' !<err 1 , Flavia A. Cadegiani "· 3 , Fernando Baldi , Raysildo B. Lobo ' , Washington Luiz 0. Assagra • ,
Fernando Carlos Proen~a ' , Pierre Kory r/, Jennifer A. Hibberd ~ , Juan J. Chamie-Quintero 1\1
I. !dedlcine, lnstituto Kerr, Sao Paulo, BRA l CJinJcal Endocrinology, Corpometcia Institute, Brasilia, BRA ;, Clinical
Endocrinology. Applied Biology Inc, Irvine, USA L Animal Sciences, Universidade Estadual de Sao Paulo tUNESP). Sao
Paulo, BRA 5. Genetics, Universjdade de Sao Paulo, Ribeir3o Preto, BR.. \ 6. Genetics, Centro TeC'.nioo de Avalia~o
GenOmka - C.T_.\.G., Ribeirl!o Preto, BRA 7. Bioinfonnatics_ ltaµri City Hall, ltaiai, BRA 8. lntemaJ Medicine, Front Line
COVIIH9 Critical Care Alliance (FLCCC), Madison, USA q_ Dentistry, University of Toronto, Toronto, CAN IU. Data
Analysis, Universidad EAFIT, Medellin, COL
Corresponding author: Flavia A . Cadegiani. flavio.cadegiani@unifesp.br
Corresponding author: Flavio A. Cadegiani
1_ Medc«\e, lostituto Ke«. Sao Pat...io, BRA 2. Cliricel Endocrinokigy, Corpome!ria lfn'ti:u!e. Bmsl"1$, BRA 3. C"nical Eodoc:rir,ok>gy, ApJiled Biology
he. Irvine. USA4. Animal Scicoccs, lhveoiid~ E'Sladual de sao Pauio (LNESP). Sao Paulo. BRA 5. Genetics, Univef'sidade de Sao Pauk>.
Ribes-3oPreto, BRA6. Genetics,CentJo Too,ic,;o deA11~ Gen&llica - C.TAG., RibeiraoPrcto, BRA 7. Biowlformatics. taj,aiCr.y Hal, ltajai,
BRA8. lrtemalMecicine, Fron! Line COVID-19Criiicai Care Ali.-.:c (FlCCC). Madison, USA 9.0mtistiy,Urivccifyof loron'.o. Toron'.o, CAN i O.
Da!a Analysis, Universidad EAF1T. Medellin, COL
How to cite this eaatum

Kcrrl, Cac'egianiF A, Baldi F, et al. (Mardl 24, 2022} Com:-c?ion; fvem~ Prophyt.ui.1> Used fo, COVJD-19: A Citywide.. Prospective,
Observational Study oJ 223.128 Sl!bjects Using Propensity Score Ma:dling. Cwa.cs 14.(3): c:61. doi:10.7759Jwreus..di1
Correction Notice
It has come to the attention of the journal that several authors failed to disclose all relevant conflicts of
jnterest when submitting this article. k; a result, Cureus is issuing the following erratum and updating the
relevant conflict of interest disclosures to ensure these conflicts of interest are property described as
recommended by the ICMJ:
• l.ncy Kerr: Paid consultant for both Vitamedic, an ivennectin manufacturer, and Medicos Pela
Vida (MPV), an organization that promotes ivennectin as a treatment for COVID- 19.
• Ravio A. Cadegiani: Paid consultant ($1,600.00 USO} for Vitamedic, an ivennectin
manufacturer. Dr. Cadegiani is a founding member of the Front Line COVID- 19 Critical Care
Alliance (FLCCC}, an organization that promotes ivermectin as a treannent for COVID-19.
• Piene Kory: President and Chief Medical Officer of the Front Line COVID-19 Critical Care
Alliance (FLCCC), an organization that promotes ivermectin as a treatment for COVID- 19. Dr.
Kory reports receiving payments from FLCCC. Jn February of 2022, Dr. Kory opened a private
telehealth fee-based seJVice to evaluate and treat patients with acute COVID, long haul COVID,
and post-vaccination syndromes.
• Jennifer A. Hibberd: Co-founder of the Canadian Covid Care Alliance and World Council for
Health, both of which discourage vaccination and encourage ivennectin as a treatment for
COVID-19.
• Juan J. Chamie-Quintero: Contributor to the Front Line COVID-19 Critical Care Alliance
(FLCCC) and lists the FLCCC as his employer on his Linkedln page.
JML TRANSCRIPTJON
DATE: .J:--(?1 11_~288-6817
EX#: -/2 • ~'r.}...
- INITIALS: -±t. i) -=
------ --
AR09133
AR09134
TAB 59
AR09135
FEDERAL COURT
BETWEEN:
NABIL BEN NAOUM
demandeur
- and -
LE PROCUREUR GÈNÈRAL DU CANADA
dèfendeur
AND BETWEEN:
L’HONORABLE MAXIME BERNIER
demandeur
- and –
dèfendeur
AR09136
DR. LISA WADDELL - 2
AND BETWEEN:
THE HONOURABLE A. BRIAN PECKFORD, LEESHA NIKKANEN, KEN

BAIGENT, DREW BELOBABA, NATALIE GRCIC, AND AEDAN
MACDONALD
Applicants
- and –
ATTORNEY GENERAL OF CANADA
Respondent
AND BETWEEN:
SHAUN RICKARD AND KARL HARRISON
Applicants
- and –
Respondent
--------------------------------------------------------
This is the Examination for Discovery of DR. LISA
WADDELL, on behalf of the Attorney General of Canada
herein, taken via Videoconference for Network Reporting
& Mediation, on the 31st day of May, 2022.
--------------------------------------------------------
NETWORK REPORTING & MEDIATION - 416-359-0305

AR09137
A P P E A R A N C E S:
RAYMOND LEE - For the Respondent

SHARLENE TELLES-LANGDON
MAHAN KERAMATI
JAMES ELFORD
ROBERT DRUMMOND
KEITH WILSON - For the Applicant

EVA CHIPIUK
ALLISON PEJOVIC
SAMUEL BACHAND - For the demandeur
SAM PRESVELOS - For the Applicants
ME NABIL BEN NAOUM - For the demandeur
ALSO PRESENT:
SHAUN RICKARD - Observer

KARL HARRISON - Observer
PATRICK ABBOTT
SAYAH HASSAN
HENNA PARMAR
ANDRE MEMAURI
CYNTHIA MURPHY
CHRIS NAIMI

AR09138
I N D E X O F P R O C E E D I N G S
DESCRIPTION PAGE NO.
DR. LISA WADDELL, Affirmed .............................. 6
EXAMINATION BY MR. PRESVELOS: ........................... 6
EXAMINATION BY MR. WILSON: ............................. 83
EXAMINATION BY MR. NAOUM: ............................. 112
EXAMINATION BY MR. LEE: ............................... 130

AR09139
INDEX OF UNDERTAKINGS
REFERENCE NO. PAGE NO.
--- UNDERTAKING NO. 1 ................................. 108
INDEX OF REFUSALS
--- REFUSAL NO. 1 ...................................... 10
--- REFUSAL NO. 2 ...................................... 30
--- REFUSAL NO. 3 ...................................... 37
--- REFUSAL NO. 4 ...................................... 38
--- REFUSAL NO. 5 ...................................... 40
--- REFUSAL NO. 6 ...................................... 50
--- REFUSAL NO. 7 ...................................... 60
--- REFUSAL NO. 8 ...................................... 64
--- REFUSAL NO. 9 ...................................... 71
--- REFUSAL NO. 10 ..................................... 75
--- REFUSAL NO. 11 ..................................... 77
--- REFUSAL NO. 12 ..................................... 89
--- REFUSAL NO. 13 ..................................... 91
--- REFUSAL NO. 14 ..................................... 95
--- REFUSAL NO. 15 .................................... 105
--- REFUSAL NO. 16 .................................... 117
--- REFUSAL NO. 17 .................................... 118
--- REFUSAL NO. 18 .................................... 120

AR09140
1 --- UPON COMMENCING AT 10:38 A.M.
2 DR. LISA WADDELL, Affirmed
3 EXAMINATION BY MR. PRESVELOS:
4 1. Q. Good morning, can you please state your
5 name for the record?
6 A. Lisa Waddell.
7 2. Q. Okay and Ms. Waddell, you understand
8 that you have been sworn to tell the truth in response
9 to the questions that I’m going to ask you today,
10 correct?
11 A. Yes.
12 3. Q. And that’s what you’re going to do when
13 you answer each of my questions today, correct?
14 A. Yes.
15 4. Q. Okay, good. Now, I understand that you
16 had been engaged on behalf of the Attorney General to
17 swear an Affidavit in support of the Attorney
18 General’s position in the various applications, is
19 that correct?
20 A. I have been asked to review some
21 Affidavit’s on in-flight transmission of SARS-CoV-2.
22 5. Q. And what was the purpose of reviewing
23 the Affidavit on in-flight transmission on SARS-CoV-2?
24 A. To evaluate whether the evidence had
25 been taken into account by the people who provided the

AR09141
1 Affidavits.
2 6. Q. To evaluate whether the evidence had
3 been taken into account, sorry -- by the people who
4 evaluated the evidence?
5 A. By the people who provided the
6 Affidavits.
7 7. Q. By the people who provide the
8 Affidavits.
9 A. Yeah.
10 8. Q. Sorry, I just wanted -- just to clarify
11 something and I’m sure your lawyers have told you but
12 I’m just going to state it for the record. You
13 understand that for the purposes of today’s cross-
14 examination, the only materials you should be looking
15 at are your Affidavit and any materials that I may
16 take you to in the course of your cross-examination,
17 correct?
18 A. Yeah, yes.
19 9. Q. Okay, just making sure we’re on the
20 same page. And I take it that the purpose of
21 reviewing the materials and I take it in your
22 Affidavit, you reviewed the materials of Dr. Sirek,
23 correct?
24 A. I did, yes.
25 10. Q. And you also reviewed the materials of

AR09142
1 Dr. Kettner, correct?
2 A. Yes, I did.
3 11. Q. Okay and both Dr. Sirek and Dr. Kettner
4 are medical doctors, correct?
5 A. That’s what they stated.
6 12. Q. Right and you’re aware that Dr. Kettner
7 in particular is a former Chief Medical Officer of
8 Alberta, correct?
9 A. I don’t remember if that was in his
10 (inaudible)
11 13. Q. Okay but obviously there’s not dispute
12 here today that you’re ---
13 MS. TELLES-LANGDON: Sam?
14 MR. PRESVELOS: Yeah.
15 MS. TELLES-LANGDON: --- sorry. Mr.
16 Presvelos, I don’t -- I don’t mean to interrupt and
17 I’m not objecting, i just -- you indicated Chief
18 Medical Officer of Alberta and I believe it was of
19 Manitoba.
20 MR. PRESVELOS: Oh, you’re right. Don’t
21 tell him I made that mistake.
22 BY MR. PRESVELOS:
23 14. Q. And so, I take it that it’s beyond
24 dispute here that or I should say there’s no dispute
25 that you are not a medical doctor, correct?

AR09143
1 A. I am not a medical doctor, no.
2 15. Q. That’s right and you’ve never
3 clinically treated anyone with COVID-19, correct?
4 A. That is correct.
5 16. Q. And you’ve never done any research into
6 COVID-19 therapeutics correct?
7 A. I have not, no.
8 17. Q. And you’ve never done any research into
9 COVID-19 transmission, have you?
10 A. I have examined the evidence for
11 transmission of COVID-19.
12 18. Q. And examining the evidence based on the
13 contents of your Affidavit, I take it that you’ve
14 reviewed several studies that have looked at COVID-19
15 transmission on particular flights, is that correct?
16 A. Yes, I did.
17 19. Q. Right. Have you yourself published
18 such a study?
19 A. No.
20 20. Q. Right. Just wanted to make sure I
21 wasn’t missing something from your publication list.
22 You understand that the Attorney General’s position in
23 this application is to defend the Government’s
24 requirement that certain travellers be vaccinated in
25 order to board a plane, rail or boat, correct?

AR09144
1 A. Yes, I understand.
2 21. Q. Okay and I take it that you agree with
3 this position, correct?
4 A. I’m only speaking to the evidence that
5 inflate transmission.
6 22. Q. Okay. Do you believe that unvaccinated
7 travelers on an airplane, on a boat or on a train
8 poses serious health risks to the vaccinated
9 travellers?
10 MR. LEE: I’m objecting to that question,
11 that’s a speculative question.
12 --- REFUSAL NO. 1
14 23. Q. Well, isn’t part of the literature
15 review not -- isn’t part of the reason why you looked
16 at the literature to understand whether or not there
17 is a health risk associated with transmission of
18 COVID-19 during travel?
19 A. Yes, the literature reviews address
20 what evidence there is for transmission during
21 flights.
22 24. Q. Right and why’s that relevant?
23 A. To look at what mitigation measures we
24 can put in place to help reduce the risk of in-flight
25 transmission.

AR09145
1 25. Q. Right. Isn’t it also relevant to
2 assess the risk of in-flight transmission?
3 A. Yes, the evidence assesses the risk of
4 in-flight transmission.
5 26. Q. And do you think the outcomes that are
6 associated with the in-flight transmission are also
7 relevant and should be considered?
8 MR. LEE: Considered what?
9 MR. PRESVELOS: Sorry?
10 MR. LEE: Can you please clarify the
11 question, considered for what?
14 27. Q. My question is, do you believe it’s
15 also a relevant consideration to consider what the
16 outcomes are of in-flight transmission of COVID-19.
17 When I say outcomes, I mean developing symptomatic
18 COVID, the risk of hospitalization and the risk of
19 death, do you think those are relevant considerations?
20 A. Yes, their risk of severe outcomes is a
21 consideration.
22 28. Q. Right. So, do you have a copy of your
23 Affidavit in front of you?
24 A. Yes, I do.
25 29. Q. And do you have a copy of all the

AR09146
1 exhibits that are associated with your Affidavit?
2 A. Yes, I do.
3 30. Q. And have you had the opportunity to
4 review your Affidavit in preparation of today’s cross-
5 examination?
6 A. Yes, I have.
7 31. Q. And have you had the opportunity to
8 review each and everyone of your exhibits in
9 preparation of today’s cross-examination?
10 A. Yes, I have.
11 32. Q. And I take it you’re familiar with the
12 contents contained in each of those documents?
13 A. Yes.
14 33. Q. Okay, good. If we go to paragraph one
15 of your Affidavit towards the bottom, just you know,
16 take a second and read it. I speak very fast, so if
17 you need a moment to read something, take the time and
18 read it.
19 A. Okay, paragraph one, yes.
20 34. Q. Okay, and at the end of paragraph one
21 it says,
22 A. “...I’ve been part of the emerging
23 Sciences Group at PHAC and my work includes COVID-19
24 literature surveillance on a daily basis and rapid
25 summarization of emerging evidence on priority COVID-

AR09147
1 19 topics...”
2 Right?
3 A. Yes.
4 35. Q. I think I have an understanding of what
5 this means but can you explain to me what literature
6 surveillance means?
7 A. Sure. COVID-19 was obviously was an
8 emerging topic where evidence was being produced in a
9 very rapid pace, so we developed a project to on a
10 daily basis, Monday to Friday conduct a search of the
11 literature if the search was predefined in the same
12 databases every single day to develop a collection of
13 COVID-19 literature on a daily basis.
14 Those search results were put into a
15 report or a line list of results and disseminated to
16 end users who needed to stay on top of what the daily
17 COVID-19 literature was indicating.
18 36. Q. So, my understanding is you would look
19 at articles relating to COVID-19, you would aggregate
20 them, you would summarize them and you would send it
21 out as you put it to end users, correct?
22 A. We didn’t look at them per se, we
23 conducted a search that was exactly the same everyday,
24 so, we weren’t sifting through the COVID-19
25 literature, we were grabbing everything that was

AR09148
1 available and putting it into a line list.
2 37. Q. So, if you weren’t reviewing it
3 necessarily, how do you do a rapid summarization of
4 emerging evidence?
5 A. So, it’s two separate things, one is
6 creating a line list everyday so that we have a
7 database of COVID-19 literature, the other one is to
8 conduct the rapid reviews on priority topics.
9 38. Q. The rapid reviews, okay, so were you
10 apart of these rapid reviews on priority topics?
11 A. Yes, I was.
12 39. Q. And who set out what a priority topic
13 would be, how did that get determined?
14 A. So, questions would come in from
15 different groups within our agency, there was also a
16 conduit for questions to come in from our technical
17 advisory and special advisory committees which was a
18 provincial territorial federal group that would meet
19 several times a week, so mainly those were our
20 clients. Groups from across the agency and the PT.
21 40. Q. Okay, did the -- and you belong to the
22 Emerging Sciences Group, right?
23 A. That’s right.
24 41. Q. Okay, and did the Emerging Sciences
25 Group ever provide any recommendations or advice to

AR09149
1 other governmental organizations or entities that were
2 relying on the research you would look at?
3 A. I don’t know.
4 42. Q. Okay, as far as you know, did you ever
5 provide any recommendation or advice to any other
6 governmental authority or agency with respect to the
7 research you’ve produced in your Affidavit?
8 A. No.
9 43. Q. I see. As far as you’re aware, were
10 you ever asked to provide any advice to any
11 governmental authority or agency for any of the
12 topics, the -- what do we have here, the Priority
13 COVID-19 topics, were you ever asked to provide any
14 recommendations or advice on those topics?
15 A. I did not provide any advise or
16 recommendations, I only produced summaries of the
17 evidence.
18 44. Q. Okay. So, you had mentioned earlier
19 that as part of your scope of work, you had -- there
20 was a certain parameter search that you would run
21 everyday.
23 45. Q. Is that accurate understanding -- and
24 who determined the parameters of that search?
25 A. That search was developed in the very

AR09150
1 beginning of the pandemic, it simply contains search
2 terms related to COVID-19, not with Coronavirus, SARS-
3 CoV-2 in order to capture all of the literature that
4 mentions in the title Abstract or Key Words anything
5 related to COVID or SARS-CoV-2.
6 46. Q. I understand and were you involved in
7 coming up with some of the search terms or any of the
8 search parameters?
9 A. Yes, I developed them.
10 47. Q. You did all of them?
11 A. I developed them, yes.
12 48. Q. Oh, you developed them, sorry, sorry,
13 okay. And I think earlier in response to one of my
14 questions, you mentioned that information would be
15 provided to certain -- to use your word, end users, is
16 that correct?
17 A. Yeah.
18 49. Q. And who were the end users for your
19 research?
20 A. Can you be more specific, at which
21 research are we talking about?
22 50. Q. Well, let’s -- how about just to stay
23 relevant, we talk about any research on COVID-19 and
24 travel. So, when you are looking at -- when you’re
25 aggregating periodicals, journals, whatever you want

AR09151
1 to call it on you know transmission of COVID-19 during
2 travel, which you have, who are the end users that you
3 provided this information to?
4 A. So, the COVID-19 reviews on in-flight
5 transmission would have gone out to a number of groups
6 across the agency, we have a line list and I could not
7 tell you who is on that because I don’t manage it but
8 they go out in what we call the evidence tracker to
9 groups across the agency.
10 51. Q. Do you know whether this information is
11 shared with the Ministry of Transport?
13 52. Q. Okay, do you know whether this
14 information is shared with the Prime Minister’s
15 office?
17 53. Q. Okay, so you have no idea whether or
18 not the articles that you aggregate and the summaries
19 that you produce have been sent to the Ministry of
20 Transport or to the Prime Minister’s office?
21 A. That’s right, I don’t know who’s on the
22 recipient list in the evidence tracker.
23 54. Q. Is three a reason why you don’t know
24 who is looking at your research?
25 A. I have never asked so, my job is to

AR09152
1 look at the evidence.
2 55. Q. Well, your job sounds to me like you
3 have to find the evidence, summarize the evidence and
4 give the evidence to certain individuals and groups,
5 correct?
7 56. Q. Okay. Are you aware that from the
8 beginning of the pandemic until I believe it was
9 November 1st, 2022, Canadians were able to travel both
10 within Canada and outside of Canada regardless of
11 their vaccination status?
12 A. I think you have the date wrong of when
13 that came in.
14 57. Q. What’s the date?
15 A. I’m not a hundred per cent sure what
16 the date is but it was in 2021.
17 58. Q. So, sorry, 2020 now -- we are in 2022
18 and November hasn’t come up so, you’re quite correct,
19 that’s what happens when you’re up at five in the
20 morning.
21 So, do you agree with me then that
22 since the beginning of the pandemic until at least
23 November 1st, 2021, Canadians were ablet to travel
24 both domestically and internationally regardless of
25 their vaccination status?

AR09153
1 MR. LEE: How is this relevant, Sam?
2 MR. PRESVELOS: It’s relevant because I’m
3 going to go into what data the government may or may
4 not have with respect to the travelers that travelled
5 at that time period.
6 So, what we can do is we can have the
7 witness answer the question, I’m happy for you to put
8 on the record that you make reservations as to whether
9 or not it’s relevant and then if ultimately you think
10 it’s not relevant, we can fight about whether or not
11 the evidence should stay on the record.
12 MR. LEE: Fine, ask the question.
14 59. Q. So, I asked, Ms. Waddell, do you need
15 me to ask the question again, do you recall what the
16 question was?
17 A. I recall what the question was. I am
18 aware that up until a certain point in 2021 travelers
19 could travel without proof of vaccination.
20 60. Q. Okay, and do you know how many flights
21 in 2020 leaving or entering Canada reported COVID-19
22 transmission ---
23 A. No.
24 61. Q. --- COVID-19 transmission -- okay. And
25 do you know how many flights again leaving or entering

AR09154
1 Canada or within Canada, how many flights in 2021
2 would have reported an incident of COVID-19
3 transmission?
4 A. No, I’m not aware.
5 62. Q. So, you have not seen any statistics or
6 papers from the government that would have told you
7 how many flights in Canada -- how many flights
8 connected to Canada actually experienced COVID-19
9 transmission in-flight?
10 A. No.
11 63. Q. So, during this same time period, do
12 you know how many passengers on planes entering
13 Canada, leaving Canada or within Canada had been
14 infected with COVID-19 during a flight, do you have
15 any way of knowing that?
16 A. No.
17 64. Q. Okay, do you know whether such data is
18 available?
19 A. I don’t think that data is available.
20 65. Q. Right and I take it you agree with me
21 that if we look at these studies that you’ve produced,
22 all those studies deal with very specific flights,
23 correct, they don’t look at aggregates of flights, for
24 example, you don’t have a study that looks at all the
25 flights in Canada and out of Canada for a specific

AR09155
1 time period or all of the flights in and out of any
2 country for any specific time period, do you?
3 A. No, there are a couple studies that
4 look at more than one flight but not a wholesome view
5 of any country in a particular time period.
6 66. Q. Can you go to paragraph five please of
7 your Affidavit, which is page three?
8 A. Okay.
9 67. Q. Take a moment there and read that, let
10 me know when you’ve had a chance to read it.
11 A. Yeah, I’m okay.
12 68. Q. Sort of mid sentence, three lines up
13 from the bottom of the paragraph, it says,
14 “...My team and I flag concerns with
15 study designs and/or analysis when summarizing
16 studies...”
17 Right?
18 A. Yes.
19 69. Q. I mean this is logical, I mean I would
20 imagine part of your job is to identify limitations to
21 certain studies, correct?
22 A. Yes.
23 70. Q. And would those limitations be relevant
24 in terms of understanding what weight if any you would
25 give to a particular study?

AR09156
1 A. Yes.
2 71. Q. Okay and with respect to all the
3 studies that you have produced in your Affidavit, have
4 you flagged any study designs any concerns with
5 respect to the design of the study or the analysis of
6 the study?
7 A. That’s multiple questions, right?
8 72. Q. So, we’ll break it down, that’s a fair
9 point. Have you flagged any concerns with the design
10 study for any of the articles that you have produced
11 in your Affidavit?
12 A. We have indicated that most of the
13 studies are -- would be considered of high risk of
14 bias because their retrospective investigations of in-
15 flight transmission and we also have a number of
16 simulation type studies that are based obviously on a
17 lot of assumptions of whatever was known at the time.
18 73. Q. And where would you have stated that
19 these studies are susceptible to a high risk of bias?
20 A. It’s in the overview of the evidence.
21 74. Q. Okay and when you say the overview of
22 the evidence ---
23 A. So, that ---
24 75. Q. --- you’re saying -- is this in your
25 Affidavit or this in ---

AR09157
1 A. Sorry, it’s in all GHNI exhibits,
2 there’s an overview of the evidence that goes the
3 types of studies that were included in the review.
4 76. Q. So, do these studies have -- are they
5 highly reliable or are they low reliability?
6 MR. LEE: Sam, what do you mean by that,
7 when you say highly reliable and low reliable?
8 MR. PRESVELOS: Well, how -- okay, well ---
9 BY MR. PRESVELOS:
10 77. Q. Ms. Waddell, how reliable are these
11 studies given the fact there’s a propensity for high
12 risk of bias and a lot of them are Meta analysis and
13 simulations, would you consider these measures to be
14 very reliable, high reliable, I mean I don’t know,
15 you’re the epidemiologist, how would you define high
16 reliability of a study?
17 A. So, first there isn’t a lot of Meta
18 analysis in the review, there are some.
19 78. Q. Okay.
20 A. The simulation studies will depend on
21 whatever the parameters were in the model. So, you
22 would need to unpack whether or not those parameters
23 were valid at the time are and are continuing to be
24 valid and they just give us an indication usually of
25 comparing one situation versus another situation and

AR09158
1 how it risks maybe higher or lower in two different
2 situations rather than being reliable for you know a
3 certain number of things might happen in a field
4 situation, but that’s one type of evidence that we
5 included.
6 The other ones I was referring to are
7 retrospective investigations of in-flight
8 transmission.
9 79. Q. Mm-hmm.
10 A. Those are observational studies, like
11 case and context kind of -- to understand that a
12 transmission occurred and look at why that
13 transmission occurred, what were the different factors
14 that might have made that higher risk or lower risk.
15 80. Q. Do you have a document where you and
16 your team would have gone through each of the studies
17 and identified some of the issues -- the limitations
18 and design study or analysis?
19 A. At the end of Exhibits G, H and I,
20 there’s a table where each study is summarized.
21 81. Q. Mm-hmm.
22 A. There we flag what the study design is,
23 the study design itself tells us relatively on a grand
24 scale how much risk of bias would be in that study
25 just based on the study design and if there was

AR09159
1 anything else to note, so for example, we might have
2 more confidence in a study that analyzed and
3 controlled for confounding variables such as
4 (inaudible) age, sex, comorbidities versus one that
5 just gave us raw descriptive analysis. So, we do note
6 those things.
7 82. Q. Okay, I’m not sure I agree that you do
8 but if you look at appendix one, any of -- I mean we
9 can look at Exhibit I for instance, the COVID-19
10 summary of flights transmission, appendix one.
11 A. Mm-hmm.
12 83. Q. You would agree with me that the table
13 doesn’t indicate the degree of confidence you have in
14 any particular study?
15 A. We did not note on each study what
16 confidence we have in that.
17 84. Q. Okay.
18 MR. LEE: Sam, what page number are you
19 referring to?
20 MR. PRESVELOS: Exhibit I, give me a second,
21 I’ll tell you. Page 11, there’s a evidence tables.
22 MR. LEE: And can you have Ms. Waddell have
23 a look at page 11 before -- like and re-ask the
24 question?
25 MR. PRESVELOS: Yes.

AR09160
1 BY MR. PRESVELOS:
2 85. Q. Ms. Waddell, let me just be clear to
3 the extent I wasn’t earlier on. If I’m asking a
4 question about a paragraph in your Affidavit or about
5 an exhibit that you’ve included in your Affidavit, it
6 is my expectation and indeed the expectation of your
7 counsel that you will carefully look at what I’m
8 asking you, because the purpose of today’s cross-
9 examination is not to get an admission from you by
10 surprise, that doesn’t help you and it doesn’t help
11 me.
12 So, if I’m going too fast and you need
13 a second to read something, please do so before you
14 agree or disagree with what I’m asking. So, do you
15 want to take a look at appendix one, evidence tables
16 again which appears on page 11 at Tab I?
17 A. Okay.
18 86. Q. And do you -- is there somewhere in
19 this summary, it says study on the left hand side,
20 method in the middle and PL column on the right. Have
21 you in any way indicated the degree of confidence in a
22 particular study?
23 A. Not in individual studies, we do not
24 indicate the degree of confidence.
25 87. Q. All right and I just want to be clear

AR09161
1 that when you pass this evidence table along, you
2 don’t know who’s looking at this table, right, I think
3 you mentioned that earlier, you have no clue who is
4 actually reading this?
5 A. I don’t know the individuals that are
6 reading these evidence reviews.
7 88. Q. Just give me a second here, got a
8 little bit of a glitch on my computer. Okay, let’s
9 stay on page three of your Affidavit. Section B, you
10 say, Deficiencies and Dr. Adam Sirek’s expert report.
11 MR. LEE: What paragraph are you referring
12 to, Sam?
13 MR. PRESVELOS: It’s above paragraph six,
14 itself is not a paragraph because it’s a title. It’s
15 the Section B, Deficiencies and Dr. Adam Sirek’s
16 Report, page three.
17 THE DEPONENT: Okay.
19 89. Q. Okay, so my understanding when I look
20 at this title is that you would have reviewed the
21 expert report of Dr. Sirek, correct?
22 A. Yes, I did.
23 90. Q. Can you understand that Dr. Sirek is
24 being tended as an expert in this application,
25 correct?

AR09162
1 A. Yes, I do.
2 91. Q. And I take it again this is not
3 controversial but you are not being tended as an
4 expert in this application, is that correct?
5 A. That’s correct.
6 92. Q. Okay, and so despite the fact that you
7 are not being tended as an expert, it seems to me that
8 you have reviewed one of my expert’s reports to
9 criticize that report, is that correct?
10 A. I only reviewed it to see how it
11 aligned with our evidence in our in-flight
12 transmission reviews.
13 93. Q. And I take it that it is your opinion
14 that Dr. Sirek’s report is deficient in certain
15 respects, correct?
16 A. We noted a few things that he had not
17 mentioned that we had in our review.
18 94. Q. Okay, so when you say we, who you
19 talking about now?
20 A. Myself and the other author of the in-
21 flight transmission reviews.
22 95. Q. I see, okay. So, you discussed, you
23 and the other authors would have reviewed Dr. Sirek’s
24 report and you said, sorry, you wanted to see whether
25 it aligns with what?

AR09163
1 A. We were just looking at his report.
2 96. Q. Right.
3 A. And whether he had covered all the
4 factors that we had identified when reviewing the
5 evidence on SARS-CoV-2 in-flight transmission.
6 97. Q. And part of issue you recall, part of
7 what Dr. Sirek talked about in his report was the
8 certain features of different aircrafts that might
9 make it safe for travel and one of those features for
10 example was ventilation on the aircraft, correct?
11 A. I would have to be directed towards
12 where he stated that to know for sure.
13 98. Q. Okay, so sitting here today, you don’t
14 have a recollection of whether or not he discussed
15 them, right?
16 A. Not a hundred per cent, no.
17 99. Q. Okay, so when you used the word
18 deficiencies, I take it to mean that a deficiency in
19 the report is that Dr. Sirek failed to cover a certain
20 factor that you and your team had identified in your
21 literature review, is that correct, is that what I
22 understand by the word deficiencies?
24 100. Q. And I take the same thing goes for the
25 way in which you use deficiencies with respect to Dr.

AR09164
1 Kettner’s report, correct?
2 A. Yes.
3 101. Q. Do you believe that the failure and
4 we’ll get to this in a second, do you believe that the
5 failure to identify certain factors that your team
6 identified would result in the different opinion in
7 either Dr. Sirek’s report or Dr. Kettner’s report or a
8 different outcome or conclusion?
9 MR. LEE: Objection, that’s an opinion
10 question, we’re not here -- you’re not here Mr.
11 Presvelos to ask for an opinion.
14 102. Q. Well, Ms. Waddell, isn’t it your
15 opinion that there are deficiencies in Dr. Sirek’s
16 report?
17 A. I stated that there were things that
18 they had not considered or noted in their Affidavits.
19 103. Q. Okay, according to ---
20 A. --- I don’t know whether that would
21 change their opinion.
22 104. Q. You don’t know, all right. Okay.
23 MS. TELLES-LANGDON: And Sam -- sorry, Mr.
24 Presvelos, just to be clear, you’re asking Dr. Waddell
25 to speculate as to whether these two additional

AR09165
1 articles would have changed the opinion of your
2 witnesses. Dr. Waddell cannot speculate as to whether
3 or not you can -- your witnesses would have changed if
4 they considered these additional academic reports --
5 evidence reports.
6 MR. PRESVELOS: Well, it’s not unreasonable
7 to believe that she might conclude that their opinion
8 is wrong or their opinion would have been changed if
9 they failed to consider highly relevant information,
10 that would undermine the veracity of their opinion.
11 I mean clearly, Dr. Waddell found it
12 appropriate to characterize expert reports as being
13 deficient for failing to recognize certain factors for
14 the team believed were relevant.
15 So, I don’t think the question is
16 offside but that’s fine, I wont -- there’s no further
17 questions on that issue, but we will go to -- we will
18 go to these reports.
20 105. Q. Dr. Waddell, if you look at -- go to
21 page four please, at the very top of page four.
22 A. Of which, sorry?
23 106. Q. The top of page four of your Affidavit.
24 A. Okay.
25 107. Q. And the top of page four we see a

AR09166
1 continuation of paragraph seven, you see that?
2 A. Yes.
3 108. Q. And the sentence begins with -- on the
4 previous page it says,
5 “...The Sirek report has not considered
6 two studies which describe high attack rates from in-
7 flight exposure to SARS-CoV-2 variants of concern and
8 the protective affect of vaccination from in-flight
9 transmission...”
10 Right?
11 A. Right.
12 109. Q. And this is the basis in which you
13 believe the Sirek report is deficient, correct?
14 A. Those were two pieces of evidence that
15 -- factors actually that were not discussed.
16 110. Q. Right and one of the factors why the
17 high attack rate and you site a study for that and is
18 that the Exhibit B, is that the air travel outbreak of
19 multiple SARS-CoV-2 variants that was published in the
20 Journal of Travel Medicine on December 20th, 2021?
21 A. Yes, it is.
22 111. Q. And I take it that the latter part of
23 that criticism where he fails to consider the
24 protective affects of vaccination, you’re relying on
25 Exhibit C in support of that proposition which is the

AR09167
1 study prepared called a SARS-CoV-2 Delta Variant
2 outbreak on airplane vaccinated air passengers are
3 more protected than unvaccinated?
5 112. Q. Okay, I just want to be crystal clear
6 what articles you’re relying on in support what
7 statements and as it pertains to Exhibit B, do you
8 agree with me that we’re only looking at one
9 particular study, one particular flight in this study
10 and I think this study talks about a large cluster 59
11 cases that were linked to a single flight with a 146
12 passengers from New Delhi to Hong Kong, is that
13 correct?
14 A. Yes, this study is highlighting tht
15 flight and the -- so, it looked at several other
16 flights.
17 113. Q. Okay. And you agree with me that the
18 study in Tab B has nothing to do with the protective
19 affect of vaccines, correct?
20 A. Sorry, this study ---
21 114. Q. At Tab B, which is the -- let me be
22 more specific. The study title is, Air Travel Related
23 Outbreak of Multiple SARS-CoV-2 Variants. That
24 doesn’t consider the protective affect of vaccination
25 for transmission?

AR09168
1 A. No, that one does not.
2 115. Q. Okay, so if you could please go to
3 Exhibit B of your Affidavit and look at the study of
4 Air Travel Related Outbreak of Multiple SARS-CoV-2
5 Variants.
6 A. Okay.
7 116. Q. And I take it that you agree with me
8 that one of the purposes in this study was to infer
9 the dynamics of COVID-19 transmission associated with
10 this Air Travel related COVID-19 outbreak, is that
11 correct, they wanted to study the dynamics of in-
12 flight COVID-19 transmission?
13 A. Yes, they were looking at in-flight
14 transmission who got transmitted to and -- looking at
15 why.
16 117. Q. Right and it considers various factors
17 like you know the distance between the index passenger
18 and so and so forth, right?
19 A. Yes, they looked at distance from the
20 index.
21 118. Q. So, if you can go to the second page of
22 the study where it says results on the right hand
23 side. And if you go down to the last paragraph on
24 that page and it says,
25 “...Using the temporal window from

AR09169
1 arrival to detection as a proxy for SARS-CoV-2
2 incubation, we estimate that at least seven individual
3 cases were likely infected prior to travel. Forty-one
4 cases were detected between days five and fourteen
5 post arrival, suggesting they were likely infected in
6 transit...”
8 119. Q. Right?
9 A. Mm-hmm.
10 120. Q. Do you -- can you explain to me why
11 they were more likely infected during transit in day -
12 - when you have a time period of five to fourteen days
13 post arrival?
14 A. So, the incubation period of SARS-CoV-2
15 has a window, right?
16 121. Q. Mm-hmm.
17 A. Typically, I mean it’s a median of
18 around five days so, anywhere between three to
19 fourteen day window is reasonable to consider that
20 they might have been exposed on the flight.
21 122. Q. And given the three to fourteen day
22 window, is it also possible that they might have been
23 exposed to SARS-CoV-2 before departure?
24 A. It is possible, of course. It is
25 possible that were exposed prior to, but in this case,

AR09170
1 they also did hold genome sequencing and aligned
2 different genomes, so we know that certain cases were
3 identical or very, very similar to t he other cases
4 which from that perspective indicates that they
5 probably got it from a person on the flight that was
6 infected before the other people in this sequence.
7 123. Q. Right and do you know how many of these
8 travellers that were infected were family members?
9 A. I do not remember. That level
10 (inaudible)
11 124. Q. Okay, if you look at page five of the
12 study.
13 A. Yes.
14 125. Q. At the bottom right hand side. It
15 says,
16 “...As a major travel hub, Hong Kong’s
17 practice of testing inbound passengers has proved a
18 valuable source for sentinel SARS-CoV-2 surveillance
19 and containment. Between June 2020 and April 2021, 51
20 cases of SARS-CoV-2 were detected on 26 other
21 passenger flights from India to Hong Kong...”
22 Would you consider those numbers to be
23 significant from a transmission risk perspective.
24 They’re saying in a span of almost a year, there are
25 51 other cases that were detected on 26 passenger

AR09171
1 flights, how do you interpret that?
2 MR. LEE: I’m objecting because she’s not
3 the author of this report and moreover it’s like
4 you’re asking her to speculate, so I’m objecting.
5 MR. PRESVELOS: I’m asking her to speculate,
6 okay.
7 MR. LEE: It’s not relevant.
8 MR. PRESVELOS: Okay.
9 --- REFUSAL NO. 3
11 126. Q. Doctor, you agree with me that the
12 current vaccination in Canada has not actually
13 eliminated the risk of SARS-CoV-2 transmission in-
14 flights, correct?
15 A. That’s correct, it hasn’t eliminated
16 it.
17 127. Q. And in fact as somebody who frequently
18 reviews research, you’re probably aware that the
19 government keeps some statistics some data on the
20 amount of in-flight transmission as between vaccinated
21 and unvaccinated passengers, right?
22 A. Yes, there’s some data.
23 128. Q. Right. Do you agree with me that the
24 authors of this study has suggested quarantine and
25 testing upon arrival should be used to prevent the

AR09172
1 introduction of virus into the community?
2 A. So, this study is still Exhibit B?
3 129. Q. Yeah, Exhibit B, yeah.
4 A. Yes, they do suggest that quarantine
5 and testing is a way of preventing community
6 transmission.
7 130. Q. And I take it you agree with it?
8 MR. LEE: I’m objecting, you’re asking for
9 her opinion.
12 131. Q. Doctor, I take it you agree with me
13 that this paper does not actually predict what the
14 chances are that any given traveler may acquire a
15 COVID-19 infection as a result of travel, correct, it
16 doesn’t do that?
17 A. Sorry, can you say that again?
18 132. Q. I said you agree with me that this
19 paper and we’re referring to the paper that’s an
20 Exhibit B to your Affidavit doesn’t actually indicate
21 what the chances are that any given traveler may
22 acquire a COVID-19 infection as a result of traveling
23 by air?
24 A. That’s right, this paper does not
25 predict what the risk is.

AR09173
1 133. Q. Okay. And looking at this paper, if
2 you go back to page eight, I took you to a section of
3 the paper where between June 2020 to April 2021 there
4 were 51 cases of SARS-CoV-2 detected on 26 passenger
5 flights from India to Hong Kong on that specific
6 route, do you know how many passengers -- based on
7 this paper, can you determine how many passengers
8 there were on each of those 26 flights?
9 A. Sorry, can you tell me what we’re
10 looking at right now, page ---
11 134. Q. Sorry, I speak too quickly, it’s page
12 six.
13 A. Page six.
14 135. Q. And it’s the paragraph right above
15 discussion.
16 A. Okay.
17 136. Q. And it says -- actually, really,
18 technically, it starts on the bottom of page five but
19 I’m just going to read it out again. It says,
20 “...As a major travel hub, Hong Kong’s
21 practice of testing in bound passengers has proved a
22 valuable source for sentinel SARS-CoV-2 surveillance
23 and containment between June 2020 and April 2021, 51
24 cases of SARS-CoV-2 were detected on 26 other
25 passenger flights from India to Hong Kong...”

AR09174
1 You see that?
2 A. Yes.
3 137. Q. And would you agree with me that there
4 is no information in the study that tells you how many
5 travelers cumulatively were on those 26 passenger
6 flights, right?
7 A. That’s correct, we don’t know the
8 denominator.
9 138. Q. We don’t know the denominator and would
10 you agree that the denominator would be a relevant to
11 assessing the risk of in-flight transmission on these
12 routes?
13 A. That would be one piece of information
14 we would need to know.
15 139. Q. So, for example if you had 300 people
16 on each of those flights, the risk would not be as
17 high as if you had 10 people on each of those flights?
18 MR. LEE: I’m objecting, again that’s
19 speculation, that’s a speculative question.
20 MR. PRESVELOS: Fine.
23 140. Q. Let’s continue. Let us know go to Tab
24 C of your -- Exhibit C of your Affidavit, let me know
25 when you’re there.

AR09175
1 A. I’m in Exhibit C.
2 141. Q. Okay, and this is a research letter and
3 it says, SARS-CoV-2 Delta Variant Outbreak on Airplane
4 Vaccinated Air Passengers Are More Protected Than
5 Unvaccinated, correct?
6 A. That’s the title of it, yes.
7 142. Q. Okay, do you agree with this
8 conclusion, do you agree that vaccinated air
9 passengers are more protected than unvaccinated air
10 passengers?
11 A. That was one of the result of this
12 study.
13 143. Q. I take it you have reviewed several
14 studies that look at the effects of vaccination of in-
15 flight transmissions?
16 A. There are not.
17 144. Q. There are ---
18 A. There are not many studies that look at
19 vaccination status, most of the research that’s been
20 done occurred prior to widespread vaccination.
21 145. Q. Okay, other than the studies that you
22 have produced in your Affidavit, are you aware of any
23 more recent study that looks at the impacts of
24 vaccination of in-flight transmission?
25 A. So, we looked to see what had been

AR09176
1 published since the November Exhibit I review.
2 146. Q. Right.
3 A. And there doesn’t seem to be any more
4 statistics on vaccination as a potential protective
5 effect from in-flight transmission.
6 147. Q. As far as you’re aware, do you whether
7 the Canadian government had undertaken its own
8 independent study to assess the impacts of vaccination
9 on in-flight transmission?
10 A. I am not aware.
11 148. Q. Okay, so this particular study I take
12 it you agree with me is looking at a flight, it’s
13 flight CA868 with 203 passengers that left from South
14 Africa to China and it left on June 9th and June 10th,
15 right?
17 149. Q. And so the rest of the study is looking
18 sort of at the transmission and dynamics of
19 transmission with respect to the COVID-19 transmission
20 that happened on this specific flight, correct?
21 A. Yes, that’s right.
22 150. Q. Okay, and if we look at -- if we look
23 at page two.
24 A. Okay.
25 151. Q. I have a number of questions to ask you

AR09177
1 about this page. The first one is, you’ll notice a
2 schematic of the airplane and it has business class,
3 economy class one, economy class two, economy class
4 three, now I have looked at all the schematics for
5 this particular Chinese airlines, I wasn’t able to
6 identify which one this actually relates to, but
7 that’s neither here nor there.
8 My question is, do you know what
9 happened to rows one to ten on this particular plane
10 or why it starts at row 11?
11 A. I do not know.
12 152. Q. Okay and at Table one, it says,
13 “...This is a risk for SARS-CoV-2
14 transmission among 197 exposed passengers...”
15 Right and there’s something here called
16 an Adjusted Risk Ratio.
17 A. Okay.
18 153. Q. So, I’m just going to tell you, I’m
19 very bad at math and I’m very bad at statistics so,
20 I’m going to ask you to tell me not facetiously, I
21 really am horrible is what is the Adjusted Risk Ratio?
22 A. Sorry, which Adjusted Risk Ratio are we
23 referring to?
24 154. Q. If you look at Table One.
25 A. Yes.

AR09178
1 155. Q. Just like right in the middle there, it
2 has a series of -- has exposed factor, P’s are a
3 positive number -- are negative, whole bunch of
4 statistics, I don’t really understand but if you look
5 at the far right hand side, it says Adjusted Risk
6 Ratio.
7 A. Yes.
8 156. Q. What does Adjusted Risk Ratio mean?
9 A. So, when we consider things like age
10 and sex and comorbidities as potentially confounding
11 an outcome or changing it depending on whether it’s a
12 male or female or old or young that kind of thing.
13 157. Q. Right.
14 A. The Adjusted Risk Ratio would be that
15 we ran a regression model and accounted for the fact
16 that some people are older, some people are younger,
17 things like that and so it adjusts the relationship
18 between a factor like having something or being
19 exposed to something or not being exposed to
20 something, based on those factors.
21 158. Q. Okay and why do we do that?
22 A. Ideally to account for things that
23 might confound or change or scue a result so that we
24 try to account for not finding relationships that
25 don’t necessarily -- are not necessarily there.

AR09179
1 159. Q. Right. Okay, and I take it you agree
2 with me that sharing a room in the quarantine hotel
3 was in fact the highest risk associated with the
4 transmission, that was identified in the study at
5 9.41, is that a fair interpretation?
6 A. Yes, that if you shared a room with
7 someone who became infected in the quarantine hotel
8 that you’re very likely to -- much more likely to
9 acquire COVID, yes.
10 160. Q. I mean, I guess that makes sense. And
11 you’ll agree with me that based on my understanding of
12 -- and correct me if I’m wrong, my understanding of
13 this chart and what you’ve just explained in terms of
14 the Adjusted Risk Ratio, it seems to me based on these
15 figures that hand sanitizer actually would give
16 someone here better protection than vaccination, if
17 you see the hand sanitizer, it says .24 and the
18 vaccination I think says .33, is that an incorrect
19 interpretation?
20 A. It does indicate that there is a very
21 protective affect of using hand sanitizer in this
22 analysis, yes.
23 161. Q. Okay. Your background is in
24 Epidemiology, right?
25 A. Yes, it is.

AR09180
1 162. Q. Okay, again for those of us here who
2 are uneducated in the ways of epidemiology, what does
3 statistically significant mean?
4 A. Statistically significant indicate --
5 it means basically that if we look at the probability
6 of seeing something by chance, okay so usually we test
7 it 95 per cent confidence that something hasn’t just
8 occurred to chance and that it’s outside of that
9 window.
10 163. Q. Right.
11 A. That’s what we’re usually looking at
12 so, if we’re looking at statistical significance, so
13 as something occurred, do we have confidence that
14 something has not occurred just do to chance and that
15 we’re looking at an affect that may have.
16 164. Q. Okay, and I take it at the bottom of
17 page two, there’s two columns here, if you look at the
18 right hand column bottom of page two under Table one,
19 in the first kind of paragraph, it ends with saying,
20 “...Vaccination was suggested to have a
21 protective affect but was not statistically
22 significant in the multi-variant analysis...”
24 165. Q. What is this telling you?
25 A. So, it tells me that when everything

AR09181
1 was adjusted -- that the effective vaccination was no
2 longer significant. That means the confidence
3 interval which is .08 to point -- to 1.43 cross the
4 value of one, okay?
5 166. Q. Mm-hmm.
6 A. But in this case, when you look at the
7 numbers of individuals in each of the four groups so,
8 vaccinated, non vaccinated that tested positive or
9 tested negative, we have a really -- we have really
10 low numbers, particularly in the vaccinated positive
11 group and so our confidence in the estimate of .33 is
12 not very good which results in a very wide confidence
13 interval around that number.
14 167. Q. Would you agree with me that one of the
15 reasons why you may have, may have such low numbers is
16 because you’re only looking at a single flight?
17 A. Well, yes, there’s a fine -- number of
18 people on each flight.
19 168. Q. Right and I take it you agree with me
20 that when we’re looking at the study and we look at
21 the number of the PCR positive individuals, we don’t
22 know whether these individuals developed any symptoms,
23 right, COVID-19 symptoms, right?
24 A. Sorry, based on the table?
25 169. Q. No, based on -- if you look at the

AR09182
1 table, the table indicates you know how many PCR
2 positive passengers there were, right?
3 A. Yeah.
4 170. Q. And I’m saying from these individuals
5 that tested positive with COVID, we don’t know how
6 many of them actually developed symptoms, COVID-19
7 symptoms?
8 A. No, that hasn’t been provided in the
9 paper.
10 171. Q. Right and you agree with me that some
11 people who have COVID-19 have symptoms and some people
12 who’d have COVID-19 do not exhibit symptoms, is that
13 correct?
14 A. That’s right. Some people remained
15 asymptomatic.
16 172. Q. Asymptomatic, right and you agree with
17 me that this study also does not indicate how many
18 people who tested positive for COVID-19 required
19 hospitalization, correct?
20 A. They do not provide that information.
21 173. Q. Right and I take it you also agree with
22 me that the study also does not tell you how many
23 people actually died as a result of testing positive
24 for COVID-19, correct?
25 A. They do not provide that information.

AR09183
1 174. Q. Right, so if we go to the last page of
2 the study which is page three and we look at the very
3 last paragraph above supplementary data, take a minute
4 and read that paragraph. Page three.
5 A. Okay.
6 175. Q. The authors here say that,
7 “...We are pleased to find that the
8 vaccine is still effective against the Delta
9 variant...”
10 So, when you see that sentence and
11 someone says that the vaccine is still effective
12 against the Delta variant, how do you understand the -
13 - what do you understand the terms effective means,
14 can you tell based on ---
15 MR. LEE: I’m objecting based on -- you’re
16 basically interpreting like you know the document or
17 having the client -- or sorry having Dr. Waddell
18 interpret the document and I don’t think that’s
19 proper, so, that’s not -- we’re objecting to that
20 question.
21 MR. PRESVELOS: Well, wouldn’t Dr. Waddell
22 necessarily have to interpret this document in order
23 to make reference to it in her Affidavit, if she’s not
24 interpreting it, what is she doing with it -- I can
25 ask ---

AR09184
1 MR. BACHAND: Sam, is it possible to just
2 take five minutes ---
4 MR. BACHAND: I’d like to talk with ---
5 MR. PRESVELOS: We can ---
6 MR. BACHAND: --- on these objections.
7 MR. PRESVELOS: Yeah, give me one moment,
8 I’m not finished. We will take five minutes in two
9 minutes.
12 176. Q. But I’ll ask you another question, if
13 you look at this paragraph that says,
14 “...We are pleased to find that the
15 vaccine is still effective against the Delta variant
16 in our study. Vaccinated passengers were 74 per cent
17 were less likely to be infected compared with those
18 without vaccines...”
19 And I’m just trying to understand,
20 based on what you’re reading and I don’t know want you
21 to theorize here speculative, but based on what you’re
22 reading, can you help me understand how the article on
23 the one hand can suggest that vaccination is not
24 statistically a significant factor and on the other
25 hand tell us that they are pleased that it is very

AR09185
1 effective. Do you understand how they get from A to Z
2 here?
3 A. Yes, they’re basing it on the
4 association and as I explained a moment ago that there
5 are very low numbers so our confidence interval is
6 quite wide which makes it statistically not
7 significant.
8 177. Q. Right.
9 A. But there does appear to be an
10 association that ideally would be confirmed or refuted
11 by additional studies which have not been published
12 yet.
13 178. Q. Okay, I take it that you agree with me
14 that the study does not tell us about how likely an
15 infectious unvaccinated passenger is to transmit the
16 COVID-19 virus to other travellers, correct?
18 179. Q. All right.
19 MR. PRESVELOS: Let’s take five minutes.
20 --- OFF THE RECORD (11:35 A.M. to 11:43 A.M.) ---
22 180. Q. Doc, let’s go to Tab F, please. Tab F.
23 A. Okay.
24 181. Q. This is a study that says,
25 “...Risks of SARS-CoV-2 transmission

AR09186
1 among air passengers in China...”
2 And this case -- this study unlike the
3 other ones actually does consider more than one
4 flight, right, correct me if I’m wrong but it looks at
5 177 flights, right?
6 A. I think it’s ---
7 182. Q. If you go to results on page three.
8 A. Yes, 177 airplanes, yeah.
9 183. Q. And the way I understand that is among
10 those 177 airplanes, there were 5,797 passengers.
11 A. That’s what they indicate, yes.
12 184. Q. All right and from those 5,797
13 passenger, 197 were identified as being positive with
14 COVID-19?
15 A. Think it was 175.
16 185. Q. Oh, am I wrong, it was 105?
17 A. A hundred and seventy-five index cases.
18 186. Q. Yeah, that’s what I thought it was.
19 A. Okay.
20 187. Q. No, no, don’t take my word, you know
21 more than me ---
22 A. --- no, it says 175 index cases among
23 5,797 passengers.
24 188. Q. Right and so what would index cases
25 mean here?

AR09187
1 A. Those would be people who were infected
2 with SARS-CoV-2 on a flight.
3 189. Q. Well, there are people who were
4 infected with SARS-CoV-2 and who were travelling on a
5 plane but we don’t necessarily know whether each of
6 those 175 cases were infected during transit i.e. in
7 the airplane or before transit or after transit?
8 A. That’s right, we just know that they
9 had a positive test after flying.
10 190. Q. And is this a positive PCR test?
11 A. I don’t remember, I have to go look at
12 that methods.
13 191. Q. Yeah, I think it says,
14 “...By real time reverse transcriptase,
15 polymerase chain reaction assay...”
16 A. Yeah.
17 192. Q. What do you think about that?
18 A. That is an RT-PCR so for identifying
19 viruses so that is a PCR test.
21 MR. LEE: Mr. Presvelos, what are you
22 referring to, can you ---
23 MR. PRESVELOS: Oh, sorry, that’s on page --
24 that is page -- give me a second, I’ll tell you.
25 That’s on page five, on the bottom of page five it

AR09188
1 says Methods Data Sources.
2 BY MR. PRESVELOS:
3 194. Q. Says,
4 “...A confirmed case was diagnosed with
5 a positive result of SARS-CoV-2 nucleic acid by real-
6 time reverse transcriptase polymerase chain reaction
7 assay or high throughput sequencing of nasal and
8 pharyngeal swab specimens...”
9 Okay, so that’s PCR. The conclusion of
10 this report and I want to be fair to you. It’s not my
11 intention to cherry pick a conclusion, if you think
12 there’s something else in this paper that rebuts that
13 conclusion or adds a necessary qualification to that
14 conclusion, I want you to take me there, okay?
15 A. Okay.
16 195. Q. That’s not how I practice. So, if you
17 look at the conclusion, the second sentences says,
18 “...The overall risk of SARS-CoV-2
19 transmission during domestic travel on planes was
20 relatively low...”
21 A. I’m still looking for where the
22 conclusion starts.
23 196. Q. Sorry, sorry, page three, go to the
24 abstract, page three.
25 A. Oh. Okay, can you repeat what you’re

AR09189
1 referring to?
2 197. Q. I was just stating the conclusion on
3 the record and the conclusion is is that,
4 “...The overall risk of SARS-CoV-2
5 transmission during domestic travel on planes was
6 relatively low...”
7 A. That is their conclusion, yes.
8 198. Q. Okay, and I take it that’s not the
9 first time you’re reading this conclusion?
10 A. No.
11 199. Q. Right and if you go to page 10 of their
12 report which is the discussion section, let me know
13 when you get there.
14 A. Yes, page 10.
15 200. Q. It says, middle paragraph, second
16 paragraph,
17 “...We found that transmission of SARS-
18 CoV-2 in cabins might have occurred but the overall
19 risk to a given individual was relatively low for
20 domestic air travel in China, even after the upper
21 bound risk assumptions...”
22 Right?
23 A. That’s what they state, yes.
24 201. Q. Is this conclusion consistent with
25 conclusions you have read in other papers about the

AR09190
1 risk of in-flight transmission or would you consider
2 this to be sort of an outlier conclusion?
3 A. So, it’s not an outlier conclusion that
4 the risk of in-flight transmission can be low but it
5 depends on many factors, right, in this case this is
6 the very beginning of the pandemic in China, it was, I
7 think January 2020.
8 So, the epidemiological situation in
9 China at the time was cases was rising but they
10 weren’t necessarily at levels that we have seen
11 through other waves in the pandemic from other
12 countries, so first question is what’s this
13 epidemiological situation in any given country at a
14 point in time to know what the risk of some one
15 getting on an airplane is that’s infected.
16 Though, I’m not sure that this paper
17 separates that out.
18 202. Q. So, the epidemiological situation in
19 any given country would provide some relevant context
20 to understanding transmission risk?
21 A. To understanding whether what the risk
22 is of sitting beside someone for example with SARS-
23 CoV-2 on a plane and then we look at if someone’s
24 infected sitting in a seat, what’s their risk of
25 giving it to someone else which is the focus of our

AR09191
1 review is ho do we prevent given someone maybe gets on
2 a plane that’s infected, what are the risks they are
3 going to transmit it and what can we do to mitigate
4 those risks and so we look at the evidence for what
5 can we do to prevent transmission.
6 203. Q. To prevent or to reduce transmission?
7 A. Well, ideally, we are preventing it so
8 reducing the risk of transmission.
9 204. Q. Right. So, I take it that you agree
10 with me that somebody can be infected with COVID-19
11 but not be infectious with COVID-19, in other words
12 they might not necessarily have whatever sufficient
13 viral load they need to infect somebody else with
14 COVID-19, is that correct -- maybe I can ask the
15 question a different way.
16 Just because somebody has COVID-19,
17 doesn’t necessarily mean that they’re infectious, that
18 they might give it to somebody else?
19 A. The risk of transmitting the virus does
20 depend on how much viral load they have, so if they
21 have a very high viral load then their risk of
22 transmitting it is substantially higher than someone
23 whose viral load has already gone down or has not
24 peaked yet.
25 205. Q. So, you’re telling me that there is a

AR09192
1 direct correlation between the viral load of an
2 individual passenger and how infectious they might be?
3 A. That’s outside of my review but yes,
4 there is a correlation between viral load and how
5 likely they are to transmit it simply.
6 206. Q. Are you aware of any studies, any
7 published studies that reach an opposite conclusion
8 from the conclusion reached by the authors in this
9 report, namely that domestic travel presents an area
10 of high risk of COVID-19 transmission in flight?
11 A. Where do they state that?
12 207. Q. No, no, I‘m not saying they do. I’m
13 asking you whether or not you’re aware of any studies
14 that have reached that conclusion.
15 A. I don’t think I can answer that because
16 we didn’t look for that information.
17 208. Q. Well, you look at studied that consider
18 the risk of transmission of SARS-CoV-2 in-flight,
19 right?
21 209. Q. And in fact you’ve produced several
22 articles that proport to do that?
23 A. Yeah.
24 210. Q. And this particular article and in fact
25 as we’ll get to a subsequent exhibits as the same

AR09193
1 thing, this article concludes that the overall risk of
2 getting COVID on a domestic flight is relatively low
3 and I’m asking you in your duties as a -- give me a
4 second.
5 As someone who does literature
6 surveillance on a daily basis, have you ever come
7 across a study that suggests that domestic travel is
8 sort of a high-risk scenario for SARS-CoV-2
9 transmission?
10 A. There are risk assessments in the
11 review that do look at the epidemiological situation.
12 211. Q. Right.
13 A. And how that relates to the risk on a
14 flight. Unfortunately, I don’t think we have any
15 there of say, recent waves, where we had a lot of
16 community transmission and a calculation outward of
17 what the actual risk kind of flight is.
18 So, it depends on what your risk
19 tolerance is to, depends on what ---
20 212. Q. --- I agree it depends on your risk
21 tolerance. What does that mean, risk tolerance?
22 A. Risk tolerance means what are you
23 willing to accept, what risks are you willing to
24 accept?
25 213. Q. Right and you’ll agree with me that the

AR09194
1 government has to make some sort of judgement about
2 risk tolerance when they are formulating a policy like
3 mandatory vaccination, correct?
4 MR. LEE: I’m objecting that question,
5 that’s not relevant and she’s not being produced as a
6 policy maker.
7 MR. PRESVELOS: Well, it seems like she’s
8 informing and advising policy makers. Well, maybe she
9 is, maybe she isn’t.
10 MR. LEE: I’m objecting that question
11 because you haven’t formulated the basis that she’s
12 advising policy makers, she says that she doesn’t know
13 in terms of her testimony who she’s provided the
14 information to, who the end user is, so that’s
15 speculation.
19 214. Q. Doc, have you ever communicated with
20 someone from any other governmental department that
21 would have reviewed your literature review?
22 A. Sorry, the literature review in
23 question, the flight transmission one?
24 215. Q. Well, any of the literature reviews
25 that you do for COVID-19, do you ever speak to someone

AR09195
1 in another governmental department that you know has
2 actually looked at the literature review that you do
3 and literature summary?
4 A. Yes, I have.
5 216. Q. Okay and where do these people work,
6 what department were they from?
7 A. NRC National Research Counsel, Health
8 Canada, trying to think. That’s all that’s coming to
9 mind at the moment.
10 217. Q. Okay, do any of these individuals
11 provide you with instructions in terms of what to look
12 at or what to consider?
13 A. No.
14 218. Q. So, everything you review and consider
15 is done independent of the individuals who have
16 discussed your literature review with you?
17 A. Absolutely. Our entire process is set
18 up to identify everything on a topic and lay it out,
19 whether it conflicts or is all in agreement in order
20 to understand just what do we know on that topic.
21 219. Q. Right, I think just before we got on
22 this -- just before we got side tracked, it mentions
23 something about the epidemiological situation in a
24 particular community and that is if there are waves of
25 you know if we’re going through a particular high wave

AR09196
1 of any variant of concern, I take it you would agree
2 with me that there’s a higher likelihood that a
3 vaccinated person might board on your plane being
4 infected with COVID-19?
5 A. There’s a higher likelihood that
6 anybody boarding a plane would potentially be infected
7 with COVID-19.
8 220. Q. So having an appreciation of what is
9 happening in any given community would be relevant to
10 sort of assessing the risk of in-flight transmission,
11 right -- I mean passengers come from somewhere and
12 they come from a community, right?
13 A. Yes, it is relevant to assessing what
14 is the likelihood of someone getting on a plane
15 infected.
16 221. Q. Right and the reason it’s relevant is
17 because if there’s an outbreak at a particular point
18 in time, there’s a heightened risk that an
19 unvaccinated person who’s not being tested at the
20 airport might actually be infected with COVID-19 just
21 as there is a high risk that an unvaccinated person
22 might be on an airplane with COVID-19, is that
23 correct?
24 MR. LEE: Mr. Presvelos, can you unpack tht
25 question, that’s a compound question, so can you

AR09197
1 unpack it, please for Dr. Waddell?
2 MR. PRESVELOS: Okay. I think the doctor
3 knows what I’m asking, but I’m not as articulate
4 because I’m not a doctor.
5 BY MR. PRESVELOS:
6 222. Q. But what I’m asking is, if there’s an
7 outbreak in a particular community, that is relevant
8 because it increases the likeliness that either a
9 vaccinated or unvaccinated passenger is infected with
10 COVID-19, would you agree with that statement?
11 A. Yes, the more community transmission,
12 the higher the likely hood that someone may be
13 infected. That likelihood maybe different depending
14 on your vaccination and infection history.
15 223. Q. Right, the likelihood might be
16 different, okay. What other factors might that
17 likelihood be dependent on?
18 A. Sorry, you’re going to have to be more
19 specific, what do you mean?
20 A. When we talk about there’s an increase
21 in likelihood that a passenger might infected with
22 COVID-19 where there’s an outbreak in a given
23 community, you said that likelihood might be based on
24 the vaccination history of that person, so in other
25 words whether or not that person’s vaccinated might

AR09198
1 impact how likely they are to have a COVID-19
2 infection?
3 MR. LEE: I’m objecting to that question,
4 she’s not being presented as an expert witness so that
5 question is not proper.
6 MR. PRESVELOS: Why am I not allowed to ask
7 this witness questions about the impact of vaccination
8 on transmission of COVID-19 given that this affiant is
9 being tendered as a representative of the Attorney
10 General, right, so one of your Affiants in support of
11 the governments mandate to prevent unvaccinated
12 travelers on the presumption that unvaccinated
13 travellers present some sort of heightened risk ---
14 MR. LEE: Mr. Presvelos, sorry, Dr. Waddell
15 is being presented ---
17 MR. LEE: --- as a witness that has done
18 literature review, you’re asking very specific expert
19 questions with regards to viral load, that’s sort of
20 my understanding, so I maintained my objection to the
21 question being asked.
24 224. Q. Dr. Waddell, do you review literature
25 that discusses different factors that might influence

AR09199
1 the likeliness that somebody gets or transmits COVID-
2 19?
3 A. I’ve done some reviews that look at
4 different risk factors.
5 225. Q. Right and did you do those reviews in
6 the context of your scope of work as a Literature
7 Surveillance Researcher for PHAC?
8 A. Yes, I did.
9 226. Q. Okay, and can you tell me about some of
10 the factors that might influence whether or not
11 somebody gets an infection from their community of
12 COVID-19?
13 A. Sure. So, just basically it boils down
14 to how many -- how much COVID is circulating in a
15 community, how many context an individual has, what
16 their immunity status is at any given point in time,
17 what their susceptibility is which might be related to
18 a whole host of individual factors, age, sex,
19 comorbidities, things like that.
20 So, it’s what their occupation is and
21 how likely they are to come in contact with people
22 that are infected.
23 227. Q. When you say what their immunity status
24 is, would that also include a consideration of prior
25 infections of a particular variant of concern?

AR09200
1 A. They could.
2 228. Q. Have you ever reviewed literature that
3 talks about the impacts of natural infection of
4 susceptibility of catching COVID-19?
5 A. I have looked at the data on the risk
6 of re-infection after COVID-19 infection.
7 229. Q. Got to move on here. If you go to page
8 11.
9 A. Of?
10 230. Q. Sorry, the same report. Risk of SARS-
11 CoV-2 Transmission Among Air Passengers in China.
12 Same report, page 11. Let’s go to the last -- go to
13 the last paragraph and take two minutes to read that.
14 A. Yeah.
15 231. Q. Couple sentences from the bottom, it
16 says,
17 “...Secondly, as with other similar
18 studies, we cannot accurately determine when and where
19 the infection occurred due to recall bias from
20 passenger reported information...”
21 A. Okay.
22 232. Q. I imagine you would have turned your
23 mind to what appears to a limitation of the study,
24 correct?
25 A. Yes.

AR09201
1 233. Q. Okay, and you would agree with me that
2 this limitation is relevant in assessing how much
3 weight to give to this particular study, is that
4 correct?
5 A. This is a limitation of this type of
6 study design where you’re retrospectively looking at
7 and doing like -- tracing to understand okay, someone
8 got on a plane and infected and these are the things
9 that might have transpired.
10 So, we call bias is a limitation of
11 these types of retrospective investigations.
12 234. Q. So, in this context and there’s a
13 recall bias from a passenger reporting information,
14 what does that mean, what does recall bias mean?
15 A. Means that someone might now accurately
16 remember exactly what happened because it happened in
17 the past.
18 235. Q. I think my fiancée would accuse me of
19 having a lot of recall bias. So, let’s go to Tab I
20 and I’m almost finished, I know this is not what you
21 probably want to be doing on a Tuesday.
22 So, Tab I is Merging Evidence on COVID-
23 19, Evidence Brief On The Risk of COVID-19
24 Transmission In-flight, update number three and it’s
25 dated November 25th, 2021.

AR09202
1 A. Mm-hmm.
2 236. Q. And I’m going to assume, correct me if
3 I’m wrong, I don’t want to mistake. I’m going to take
4 it that this is the most recent literature review your
5 team has done prior to writing your report?
7 237. Q. Which is not an expert report, just a
8 report. Do you agree with me that there is only one
9 study in this literature review that actually looks at
10 the impact of vaccination on in-flight transmission?
11 A. There’s only one study that reports on
12 that, yes.
13 238. Q. And this study is being used by the
14 Public Health Agency of Canada is being relied upon
15 and used and disseminated by the Public Health Agency
16 of Canada, correct?
17 A. I can’t comment on that, I don’t know.
18 239. Q. Okay, and I take it that the summaries
19 and the points that are contained in this brief
20 accurately reflect the voluminous research that you
21 and your colleagues have done, right?
22 A. Summaries in this report reflect what
23 is in the literature.
24 240. Q. And there’s the extensive literature
25 because you review literature on COVID-19 everyday,

AR09203
1 right?
2 A. I do review literature on COVID-19
3 everyday, I don’t know about the -- what you mean by
4 extensive.
5 241. Q. Okay, how many people are there on your
6 team that review COVID-19 literature?
7 A. I have five people on my team.
8 242. Q. And all of you review COVID-19
9 literature everyday?
10 A. Some days, yes.
11 243. Q. If you go to page three of the summary,
12 the first point.
13 A. Okay, the first point on page three?
14 244. Q. Yeah, it says,
15 “...Most reports of in-flight
16 transmission events occurred prior to widespread
17 vaccination rollout. One study found that vaccinated
18 passengers were 74 per cent less likely to be infected
19 compared with those who are not vaccinated, and
20 there’s footnote number four.
21 A. Mm-hmm.
22 245. Q. Do you agree with me that that’s the
23 same study that you saw earlier that also said that
24 vaccination was not a statistically significant
25 protection?

AR09204
1 A. That is the same study.
2 246. Q. Yeah, that’s the study in China from
3 June 2021 that you’ve also included as an exhibit,
4 earlier in your Affidavit, right?
5 A. Yes, it’s the same study that was
6 included in the Affidavit earlier, the adjusted as we
7 discussed before was not significant statistically but
8 that is a pretty strong association and so, there
9 simply isn’t enough observations, as I stated before,
10 we would like to see more studies looking at this in
11 order to further validate and have more confidence in
12 exactly what that association may or may not be.
13 247. Q. Do you agree with me that there is --
14 immunity from individuals who receive COVID-19
15 vaccinations?
16 A. That’s not part of my review.
17 248. Q. Okay, so, you don’t review -- well, you
18 review several topics relating to COVID-19, do you not
19 review any topics on the impacts of vaccination and
20 the duration of vaccination?
21 A. I have.
22 249. Q. Okay and as part of your literature
23 review on the impacts of vaccination, the benefits,
24 how efficacious it is, are you aware that there are --
25 there is literature that suggests and in fact I would

AR09205
1 go further than that, there is probably a consensus in
2 the scientific community that there is waning immunity
3 on the COVID-19 vaccinations currently available in
4 Canada.
5 In other words, the level of immunity
6 you might have one day after you’re jabbed is not the
7 same level of protection you have six months after
8 your jabbed, is that a fair statement?
9 MR. LEE: Can you unpack that Mr. Presvelos,
10 again that’s a compound question, can you unpack that
11 question into pieces please?
12 MR. PRESVELOS: Okay. I think it’s a simple
13 question.
15 250. Q. Doctor, do you agree with me that there
16 is waning immunity with respect to vaccination?
17 MR. LEE: Again, based on what -- on
18 literature review because she’s not being tendered as
19 an expert so, I’m objecting to that question.
22 251. Q. Dr. Waddell, have you ever reviewed
23 literature that has concluded there is waning immunity
24 following vaccination against COVID-19?
25 A. Yes, so there is waning immunity

AR09206
1 against infection following vaccination and following
2 infection.
3 252. Q. Okay and I take it that you probably
4 agree with me that the rate at which vaccination
5 related immunity wanes might be a relevant
6 consideration in in-flight transmission of COVID-19?
7 A. For an individual, yes, it would
8 definitely be a relevant consideration at an
9 individual level.
10 253. Q. Right. If you look at page three, the
11 first point of the second part of this paper, it says,
12 “...The key finding of SARS-CoV-2
13 literature on transmission during flight is that
14 multiple interventions are needed to maximally reduce
15 the risk of transmission...”
16 This is summarized well in the Appendix
17 two figure from Aviation Public Health Initiative
18 Report led by Harvard. You see that there?
19 A. Yes, I do.
20 254. Q. So, I take this to mean that what
21 they’re advocating is having multiple protective
22 layers against both being infected with COVID-19 and
23 possibly transmitting COVID-19, right?
24 A. Yes.

AR09207
1 A. And most of these papers were conducted
2 prior to vaccination being available.
3 256. Q. I understand that and it says that,
4 “...-- reviews the risk of infection
5 during the flight is low. A Meta-analysis found that
6 from January to June 2020 the risk of being infected
7 with SARS-CoV-2 in an airplane cabin was estimated to
8 be one case for every 1.7 million travelers...”
9 Right?
10 A. Mm-hmm.
11 257. Q. Okay, I take it you agree with me that
12 between January to June 2020 there was no vaccine
13 available for use in North America, certainly not in
14 Canada?
15 A. That’s right, there was no vaccines.
16 258. Q. And I take it that you agree with me
17 that at this time it was the alpha variant between
18 January to June 2020?
19 A. No.
20 259. Q. It wasn’t, okay what variant was it?
21 A. That would have been the original
22 variant.
23 260. Q. The ancestral?
24 A. Six -- yeah, that’s the first six
25 months of the pandemic.

AR09208
1 261. Q. Right, so what I understand this to say
2 is at the time period where we had the ancestral
3 COVID-19 variant or it wasn’t a variant then and no
4 vaccinations, the risk of infection during a flight
5 was actually quite low, would you agree that one case
6 for every 1.7 million travelers presents a low risk of
7 COVID-19 transmission?
8 A. Yes, I would consider that low, but
9 that’s just my opinion.
10 262. Q. That’s fine. And if you go to page
11 number four.
12 A. Okay.
13 263. Q. Look at the first point, it says in-
14 flight particle numbers in the air and airplanes are
15 lower than that of retail/grocery stores, restaurants,
16 office spaces, homes and other forms of
17 transportation, right?
18 A. Yes.
19 264. Q. And you footnote there to a study on
20 44, let’s go to that study, I don’t know where 44 is
21 here because it’s a bit of a -- you adopt that
22 conclusion, would you agree that generally speaking
23 the rate of transmission of COVID-19 is lower in an
24 airplane that it would be in other areas of the
25 community such as a grocery store, a restaurant, a

AR09209
1 home?
2 MR. LEE: I’m objecting to that question
3 because her opinion of her view is irrelevant.
4 MR. PRESVELOS: So, you’re saying it doesn’t
5 matter what Dr. Waddle thinks about what areas in the
6 community might be high risk and low risk for COVID-19
7 transmission?
8 MR. LEE: She’s just providing you with
9 basically her view on the literature review, her view
10 is completely relevant -- I maintain the objection to
11 the question.
15 265. Q. Dr. Waddell, I take it you agree with
16 me that on any given flight in and out of Canada,
17 there are some individuals who are vaccinated and some
18 individuals who are not vaccinated, correct?
19 A. Right now, today?
20 266. Q. Today.
21 A. Depends I guess on whether the vaccine
22 mandate is in place and how many people can board a
23 plane without having their vaccinations?
24 267. Q. Have you ever reviewed the ministerial
25 order giving lies to the famous vaccine mandate or

AR09210
1 vaccine requirement for travel?
2 A. I have not reviewed it.
3 268. Q. Okay, are you aware of any of the
4 exemptions that are provisioned for in the ministerial
5 order implementing the vaccine mandate for travel?
6 A. I haven’t reviewed it, so no.
7 269. Q. Do you agree with me that as far as you
8 know, you are not aware of any data from the
9 Government of Canada that might suggest what
10 composition of vaccinated and unvaccinated individuals
11 fly everyday in and out of Canada?
13 270. Q. Have you ever seen or come across any
14 statistics collected or reviewed by the Canadian
15 Government which I’ll also include you on the account
16 of your affiliation with PHAC that provide insights as
17 to the demographics of any given or any average flight
18 coming in and out of Canada?
19 A. I have not seen any.
20 271. Q. All right. Do you think that the
21 government should consider seat spacing as a
22 protective measure that can help in-flight
23 transmission of COVID-19?
24 MR. LEE: I’m objecting to that question.
25 That’s not relevant.

AR09211
1 MR. PRESVELOS: I knew you were going to --
2 but if you go to paragraph 11 at the very bottom of
3 your Affidavit.
5 MR. PRESVELOS: Paragraph 11, page four of
6 your Affidavit.
7 THE DEPONENT: Yeah.
8 MR. PRESVELOS: It says,
9 “...Further, Dr. Kettner has not
10 reviewed or considered any research of the affect of
11 seat spacing and length of time on the rate of COVID-
12 19 transmission...”
13 Right and so my question is, do you
14 think the government should consider seat spacing as a
15 protective measure that can help reduce the risk of
16 in-flight transmission of COVID-19?
18 again because she’s not the policy maker, she’s done
19 in terms of the review, the literature, pointed out
20 that there was missing information, that is not a
21 relevant question for her to answer.
25 272. Q. Based on your review of the literature,

AR09212
1 can seat spacing help reduce the risk of in-flight
2 transmission?
3 A. There are some simulation studies that
4 look at different configurations on how people are
5 seated and grouping people based on their connectivity
6 to each other and that to help reduce the risk that if
7 someone is coming on board infected that they don’t
8 infect other people who are outside of their say
9 family unit per se.
10 So, there are simulation studies that
11 look at different ways of seating people to reduce the
12 risk, does not -- I don’t -- and that would just be on
13 flights I suppose that are not full per se. It also
14 would help with epidemiological investigations to know
15 that the people seated very close to someone who is
16 infected are the more likely ones to be exposed to the
17 virus on that flight.
18 273. Q. Okay. I think those are all my
19 questions for you. One sec. having reviewed all this
20 literature, can you tell me how much more likely is it
21 that an unvaccinated traveller would be infectious
22 from a vaccinated traveller if both of them were
23 infected with COVID-19.
24 So, you have a vaccinated and an
25 unvaccinated traveler, they both have COVID-19, how

AR09213
1 much more infectious is the unvaccinated from the
2 vaccinated?
3 A. I can’t answer ---
4 MR. LEE: I’m objecting to the question
5 again ---
6 MR. PRESVELOS: Actually, that’s one of the
7 -- Counsel, I mean if we’re looking at literature
8 review to understand the risk of transmission and the
9 factors in forming the risk of transmission including
10 the so called protective affect of the vaccine.
11 Surely, I can ask whether Dr. Waddell
12 has reviewed any literature that would show what the
13 differences, what’s the marginal difference of the
14 differential between an infected vaccinated and an
15 infected unvaccinated passenger in terms of
16 transmitting that virus to others?
17 MS. TELLES-LANGDON: Sam, I think -- sorry,
18 Mr. Presvelos. I think the challenge here is the way
19 in which you’re framing some of these questions.
21 MS. TELLES-LANGDON: Because when you switch
22 back to, have you in your role in reviewing literature
23 -- reviewed literature that assesses this and what did
24 that literature say.
25 Perfectly acceptable question, however

AR09214
1 many -- often you are framing questions in a way that
2 appear to be asking for Dr. Waddell’s opinion as if
3 she were presented as an expert in epidemiology which
4 although she is an epidemiologist, she is here
5 speaking based on what she knows from her roll in the
6 literature emerging scientist group.
7 So, I believe the challenge is the way
8 in which you are occasionally framing some of those
9 questions.
10 MR. PRESVELOS: I appreciate it and just to
11 clarify that, that’s a fair comment. To clarify that
12 when I’m asking you this question Doctor, I’m asking
13 you based on your review of the literature that you do
14 in your capacity in surveillance literature review and
15 summarization.
16 So, you might have your own opinion
17 about it, but based on your official capacity as
18 somebody who works for PHAC, have you come across this
19 -- or have you come across this conclusion?
20 THE DEPONENT: Can you repeat your question
21 then, please?
22 MR. PRESVELOS: Yes, but don’t ask me one
23 more time because I’m close to forgetting it.
25 274. Q. What is the -- you see, now I forgot

AR09215
1 it.
2 What is the difference between -- what
3 is the difference in terms of the risk of transmission
4 between a vaccinated and unvaccinated traveler
5 assuming that each of them have COVID-19, in other
6 words, how much more likely is it that an unvaccinated
7 traveler would transmit COVID-19 over a vaccinated
8 traveler assuming them both to be infected and this is
9 based on your review of the literature?
10 A. That would depend on many, many factors
11 and there isn’t a straightforward to that question.
12 275. Q. And so, would one -- so, one of those
13 factors would be their vaccination status, right?
14 A. One of the factors would be vaccination
15 status, how long ago they were vaccinated, how many
16 doses that they had, similarly to an unvaccinated
17 passenger, it would depend on whether they’d ever been
18 infected before and things like that and it would come
19 down to when were they infected.
20 So what stage of infection are they
21 because the viral load goes up and comes back down so,
22 there are many, many factors that would play into that
23 question and it would depend on the variant that we
24 were talking about because there is different data for
25 different variants.

AR09216
1 So, for example, somebody who was --
2 just trying to think of. So, for example someone who
3 was infected with the original variant for example or
4 when vaccination started rolling out, we saw
5 vaccinated people were less likely to get infected and
6 if they did, they had a lower viral load.
7 That is in the literature, as we’ve
8 moved forward into Delta and now Omicron, we’re seeing
9 that maybe that difference is less so, people who are
10 vaccinated maybe less likely to get infection but
11 infection may be resulting in similar viral load.
12 276. Q. Right, okay.
13 MR. PRESVELOS: Look, that’s the end of my
14 time here, thank you very much for your patience, I
15 appreciate it and I’m sure counsel -- my co-counsel or
16 counsel for the other applicants have some questions
17 and I leave it to them as to whether or not they need
18 a break or whether or not you need a break or whether
19 or not anyone needs a break. Yes, go ahead Mr. Lee.
20 MR. LEE: Can we call for a lunch break,
21 we’ve been at this since 8:30, it’s 10:30 my time here
22 in Calgary, so it’s been two hours, so can we call for
23 a lunch break of half an hour to an hour before the
24 next round of questioning begins.
25 --- OFF THE RECORD (12:24 P.M. to 1:15 P.M.) ---

AR09217
1 MR. WILSON: Good afternoon, everyone. Just
2 as a procedural matter this morning, this is our first
3 phase of the cross-examination by the applicants of
4 the respondents witnesses, we’re in a consolidated
5 action.
6 I would ask that counsel for the
7 Attorney General decide amongst themselves as to who’s
8 going to be objecting, I have no concerns about if we
9 go off the record having multiple counsel involved but
10 I do have a concern about a tag team approach on
11 procedural matters, it’s my experience in other cases
12 in consolidation that there’s one lawyer that is on
13 point to represent the witness and not multiple, I’m
14 happy to hear your views on it but I sense some
15 unfairness there.
16 MR. LEE: I’m fine doing the objections.
17 MR. WILSON: Okay, thank you.
18 EXAMINATION BY MR. WILSON:
19 277. Q. Good afternoon, Dr. Waddell, nice to
20 meet you. My name is Keith Wilson, I’m a lawyer for
21 the Peckford group applicant -- applicants rather.
22 I’m going to avoid covering the
23 specific ground that Mr. Presvelos covered with you
24 earlier today but I’d like to begin by understanding
25 something.

AR09218
1 Who do you report to at the Public
2 Health Agency of Canada, who’s your boss?
3 A. Report to a manger, Mr. Amir Fazil and
4 my Director, Dr. Nicholas Ogden.
5 278. Q. Okay, and ---
6 A. --- at the -- sorry. Go ahead.
7 279. Q. Sorry, I interrupted your answer?
8 A. --- the National Microbiology
9 Laboratory.
10 280. Q. Right and who does that doctor report
11 to?
12 A. Dr. Nicholas Ogden reports to Dr. Steve
13 Garsiu and then he reports to Dr. Guillaume Poliquin
14 281. Q. Okay, and Poliquin, who does that
15 doctor report to?
16 A. He’s the VP of the National
17 Microbiology Laboratory Branch, so I assume he reports
18 to Dr. Tam’s office.
19 282. Q. Dr. Tam is the Chief Public Health
20 Officer of Canada, correct?
22 283. Q. And who does Dr. Tam report to?
23 A. Dr. Tam reports to the Ministers of
24 Health.
25 284. Q. Okay and the Minister of Health reports

AR09219
1 to the Prime Minister, right?
2 A. As far as I’m aware, yes.
3 285. Q. Thank you. Now, you’ll be aware that
4 your minister and other ministers from time to time
5 make public statements that their COVID-19 policies
6 and the travel mandate -- travel vaccination mandate
7 requirement are based on advice that they received
8 from government experts, are you aware of them making
9 those types of statements from time to time?
10 A. I have seen them make those statements
11 in the news, yes.
12 286. Q. And would you consider yourself to be
13 one of those experts?
14 A. No, I don’t.
15 287. Q. Okay.
16 A. So, I consider myself to be a
17 researched in the agency but my job is solely to
18 evaluate and produce reviews of the evidence for other
19 people to use.
20 288. Q. So, would you consider what you’ve
21 prepared and let’s go to it, let’s go to Exhibit I of
22 your Affidavit if you don’t mind.
23 A. Sure.
24 289. Q. So, Exhibit I contains a government
25 header with the logo of the Public Agency of Canada on

AR09220
1 it and emerging evidence of COVID-19 is the main head
2 and then it says Evidence Brief On The Risk of COVID-
3 19 Transmission In-flight Update Three. That’s what
4 your Exhibit I says, right?
5 A. That is correct, yes.
6 290. Q. Okay, and you’d agree with me though
7 that you would expect the minister and the policy
8 makers to rely on your materials, wouldn’t you?
9 A. Evidence I think is only one part of
10 the decision making process.
11 291. Q. Sure, but it is one part, right?
12 A. I would assume it is a part.
13 292. Q. Okay, and your name appears on the back
14 of this document at Exhibit I as one of the authors,
15 that’s accurate?
16 A. That is accurate, yes.
17 293. Q. So, and this document’s not secret,
18 it’s public, right?
19 A. It is public, it can be requested by
20 anybody.
21 294. Q. Okay, so what is your role in the
22 decision making process then?
23 A. I don’t have a role in the decision
24 making process.

AR09221
1 A. My role is simply to gather what do we
2 know on a topic from a science perspective, put it
3 together and then provide that to people who need it,
4 can use it to understand okay, what do we know and
5 then I’m not involved in the decision making part of
6 the process.
7 296. Q. Okay, and the -- given that you’re
8 dealing with matters relating to transmission and
9 flight, it’s safe to say by flight you mean aircraft
10 and not the flight of Canada geese, correct?
11 A. That is correct, you’re correct.
12 297. Q. So, you’re assuming that it’s
13 reasonable for you to conclude that Transport Canada
14 would look at this, right?
15 A. I don’t know if they knew that the
16 review had been published and they may look at it.
17 298. Q. What is the objective of the
18 vaccination requirement for travel?
20 because she’s not being produced to like you know
21 answer questions of that nature.
22 Dr. Waddell has indicated in her
23 testimony this morning that in terms of her role, it’s
24 just to review literature and to provide I guess her
25 views in relation to that literature.

AR09222
1 So, I don’t think that’s a fair
2 question, Mr. Wilson, I’m objecting.
3 MR. WILSON: That’s fine, you can object and
4 I’ll try to address your objection first. We are on
5 the record, this is a judicial review, this is a
6 Charter challenge, because the government in the face
7 of the legal challenge did not rescind the travel
8 vaccine mandates restricting millions of Canadians
9 travelling.
10 We have to assume that you’re intending
11 to defend them in court and we have to assume and the
12 court will assume that you’re going to put evidence
13 forward to justify this infringement and I need to
14 test the evidence of your witnesses regarding that
15 justification and if it’s the case that this witness
16 doesn’t know, then that’s fine, that will be the
17 witnesses evidence but it’s a highly relevant
18 question, because we’re here primarily about what is
19 the rationale for restricting millions of Canadians
20 from exercising their right of free travel.
21 So, the record will show if that’s how
22 we’re going to go, I’m going to continue to ask the
23 question because they are precisely relevant and if
24 they’re going to be met with objections at every turn
25 then you will have no evidence to present to the court

AR09223
1 other than that you’ve objected to every question.
2 So, I’m going to restate it again.
3 BY MR. WILSON:
4 299. Q. Would you agree with me Doctor -- or
5 what is the purpose of the -- what is the goal of
6 requiring Canadians to be vaccinated to fly?
7 MR. LEE: I am objecting to that question
8 again Mr. Wilson because of the fact that’s she’s --
9 Dr. Waddell is not being produced as a policy maker,
10 she’s only here to testify with regards to the review
11 of the literature, so I’m objecting to the question.
12 MR. WILSON: Okay.
14 MR. WILSON: Counsel, can you identify for
15 me which witness you are presenting that can answer
16 that question?
17 MS. TELLES-LANGDON: Sorry, I am going to
18 step in here, Keith. I know you spoke about ---
19 MR. WILSON: That’s fine, go ahead.
20 MS. TELLES-LANGDON: --- you expressed
21 concern earlier. Of the witnesses that are presented,
22 Ms. Little, Mr. DeJong and Mr. Mario Boily all speak
23 to the objectives of the transportation vaccine
24 mandate.
25 MR. WILSON: Thank you.

AR09224
1 MS. TELLES-LANGDON: The scope of the cross-
2 examination on Ms. Waddell is based on the scope of
3 her Affidavit and yes what is relevant but she’s been
4 very clear, her role is to provide summaries of an
5 evidence brief which she prepares and then passes on
6 and she’s already been very clear that what the policy
7 makers, what the decision makers do with those
8 evidence briefs, her role is to provide the
9 foundational evidence briefs on specific topics which
10 is.
11 So, certainly within the scope of the
12 evidence, anything that is relevant is appropriate but
13 to continue to ask her to speculate on what the policy
14 makers -- what their objective was when she’s not one
15 of those decision makers that is -- that’s beyond the
16 scope of her Affidavit.
17 MR. WILSON: I’ll just make a comment and
18 then I’ll move on to my next question. I disagree
19 that the scope of the questioning is restricted to an
20 Affidavit, if that were true you could simply have her
21 file an Affidavit that says ‘I like cats’ and then all
22 I’d be able to ask her about is cats.
23 The scope of my questioning at law is
24 relates to the pleading and anything within the
25 pleading.

AR09225
1 If the witness is not in a position to
2 answer the question because they lack knowledge, that
3 becomes their answer but with all due respect, it’s my
4 position at least and it’s not for us to resolve here
5 that the scope of questioning is actually set by the
6 pleading -- the scope of the pleadings not the -- not
7 a person’s Affidavit but in any event, I’ll move on.
8 MS. TELLES-LANGDON: Certainly --
9 MR. WILSON: Exhibit I ---
10 MS. TELLES-LANGDON: --- just before you
11 move on, certainly the pleadings frame it but it would
12 be -- we have presented an immunologist for example
13 and for you to ask Dr. Waddell questions about
14 specific to detailed knowledge of immunology and
15 expertise in immunology although relevant to the
16 proceeding as a whole would be improper questions to
17 put to Dr. Waddell, that’s all I’m saying.
18 MR. WILSON: She’d have -- anyway, fair
19 enough. I don’t agree but I’m not going to hammer it
20 out here.
22 BY MR. WILSON:
23 300. Q. Now, with respect to Exhibit I, Dr.
24 Waddell, I note that it’s dated November 25th, 2021,
25 and I note that in your Affidavit you indicate that

AR09226
1 you’ve included all of these evidence briefs that the
2 Public Health Agency of Canada have prepared to date,
3 so my question is, is this November 25th, 2021, the
4 most recent and current evidence brief regarding
5 transmission in-flight?
6 A. It is, it’s the latest one that we have
7 completed.
8 301. Q. And so it’s six months old, correct?
9 A. It is six months old, yes.
10 302. Q. Thank you and you’d agree with me that
11 if I turned to page right for example of the Evidence
12 Brief that you and the other authors recommend and
13 identify mitigation strategies for airplanes, correct?
14 A. We do on page eight, we identify
15 mitigation strategies.
16 303. Q. Right and on top page nine, those are
17 details, my simple question is this, do you agree with
18 me that requiring Canadians to be vaccinated to fly is
19 not one of the identified mitigation strategies,
20 correct?
21 A. Is addressed above but there was not
22 evidence -- there wasn’t a lot of evidence on that so,
23 as a strategy as a whole, it has not been evaluated in
24 the literature and therefore is not elaborated in the
25 review.

AR09227
1 304. Q. So, it is not included as one of the
2 recommended mitigation strategies, correct?
3 A. It was not evaluated in the -- yeah, it
4 has not been evaluated in the literature so I can’t
5 comment on whether it would be recommended or not
6 because science -- the scientist and the researchers
7 haven’t evaluated it.
8 305. Q. My apologies for not being clear with
9 my question, does this document Exhibit I recommend
10 vaccination as a prerequisite to travel by air, yes or
11 no?
12 A. No, it does not.
13 306. Q. Thank you. if you could turn to
14 paragraph nine of your Affidavit, please?
15 A. Okay.
16 307. Q. Now, I notice that it reads that you’ve
17 attached as Exhibit C a report and I’m paraphrasing
18 from Dr. Lv spelt L-V and others titled, A SARS-CoV-2
19 Delta Variant Outbreak On Airplane: Vaccinated Air
20 Passengers Are More Protected Than Vaccinated.
21 So, did you take from that study and I
22 see you rely on it extensively in many places in your
23 materials that the risk from flying during COVID was
24 actually on the unvaccinated, correct?
25 A. No, I don’t think ---

AR09228
1 308. Q. --- do you want to read -- I’ll read it
2 again. Vaccinated Air Passengers Are More Protected
3 Than Vaccinated. So, the vulnerable ones are the
4 unvaccinated, right?
5 A. No, not exactly, right.
6 309. Q. Okay.
7 A. I mean being protected is a relative
8 scale, people on that airplane who were vaccinated
9 appeared to have a lower risk of getting SARS-CoV-2
10 from someone infected on the plane than the people who
11 were unvaccinated.
12 As you’ve already pointed out, it is
13 only one study and unfortunately only one data point
14 in the grand evidence.
15 310. Q. Right. Now, further on in paragraph
16 11, you indicate that you’re critical of the experts
17 for some of the applicants and that they haven’t
18 reviewed or considered any studies about the
19 occurrence of high rates of in-flight transmission
20 from SARS-CoV-2 variants of concern and the protective
21 affect of vaccination from in-flight transmission,
22 what is the protective affect you’re referring to
23 there?
24 A. It is the results of this study, the
25 study by Dr. Lv that showed that those people who were

AR09229
1 vaccinated on the flight had a lower risk of getting
2 infected than the people who were unvaccinated.
3 311. Q. So, the higher risk category is the
4 unvaccinated?
5 A. In that in-flight transmission study,
6 yes. People who are unvaccinated were at higher risk.
7 312. Q. You’d agree with me that it’s possible
8 under the current settings in Canada for a COVID
9 positive vaccinated person to fly, right?
10 MR. LEE: Again, I’m objecting to the
11 question because Dr. Waddell is not being tendered as
12 an expert so, I’m objecting to the question.
14 BY MR. WILSON:
15 313. Q. Dr. Waddell, when you assess and write
16 your policies about mitigation strategies or your
17 recommendations about mitigation strategies, you
18 surely you must do so with an awareness of how people
19 travel at any given time, right?
20 A. So, I first, I don’t write
21 recommendations or policies.
22 314. Q. Okay.
23 A. We aim to identify and summarize the
24 scientific literature on a topic. How that’s used is
25 beyond the scope of my work.

AR09230
1 315. Q. And you give no thought to how what you
2 write might be used by others, is that what you’re
3 saying?
4 A. Of course we understand how the world
5 works, I have travelled on an airplane myself, I know
6 how travel works and we do give thought in terms of
7 has what been studied, is it logical to think about,
8 we consider the pandemic on a whole and public health
9 measures on a hole that had been implemented and most
10 of the things in research is proving that the logical
11 public health measures that we’re using do or do not
12 work and I think that’s all that the review shows is
13 areas where we do have some evidence that certain
14 mitigation measures seem to be having an impact on
15 reducing risk of transmission in-flight.
16 316. Q. Okay and you’d agree -- you’ve
17 mentioned Public Health measures, you would agree with
18 me that whether you decided it or not or had a say in
19 it, that a policy that prevents unvaccinated Canadians
20 from flying is a public health measure, right?
21 A. Yes, it would be considered a public
22 health measure, I guess.
23 317. Q. Okay and as part of your literature
24 review that you and your team of five do in some
25 instances daily, have you found literature other than

AR09231
1 the literature you’ve concluded here that Transport
2 Canada relied on in making its measures regarding
3 vaccine requirements for travel?
4 A. Okay I don’t know what Transport Canada
5 relied on so I can’t answer that.
6 318. Q. Okay, but I’m not asking you what they
7 relied on and maybe that was my error for not being
8 clear enough. If Transport Canada had commissioned a
9 study, would that be the type of study that you would
10 look for and be inclusive of your broad literature
11 review?
12 A. If they had commissioned the study and
13 it was written up and published in a database that I
14 could find it in, then we would have found it.
15 319. Q. Thank you.
16 A. And included it, yeah.
17 320. Q. Thank you. As part of your literature
18 review and study, you’re aware for example aren’t you
19 that recently the England has removed the requirement
20 from their Public Health measure for travelers to be
21 vaccinated?
22 A. Not as part of reviewing literature,
23 but I am aware that certain countries are removing
24 their mandates for vaccination.
25 321. Q. Okay, so why wouldn’t you review

AR09232
1 literature, anything written about what other Public
2 Health authorities in other jurisdictions are doing?
3 A. So, when talk about literature, we’re
4 talking about the process scientific investigation,
5 right, hypothesis testing, concerted study designs as
6 part of that -- the surveillance data or changing
7 mandates without any write up of you know, pre, post
8 changing of the mandate wouldn’t be included in our
9 review.
10 322. Q. Okay.
11 A. They would have to investigate a
12 hypothesis for it to be part of the -- it would have
13 to be written up that way.
14 323. Q. As part of your literature review, did
15 you find variability in the impact that COVID has on
16 individuals?
17 A. You might have to be more specific by
18 impact.
19 324. Q. Health consequence?
20 A. After having the disease?
21 325. Q. Yes, well, while they’re infected.
22 A. Yes, I am aware of the health impact
23 then of infection and post infection recovery.
24 326. Q. And you’d agree with me that generally
25 speaking the literature shows that COVID had more

AR09233
1 severe health impacts and outcomes on the elderly,
2 correct?
3 A. That is not universally true, young
4 people can have severe COVID and die from it.
5 327. Q. So, it impact -- your evidence is your
6 literature review concluded that it impacted everybody
7 equally?
8 A. No, I didn’t say that but I like ---
9 328. Q. Okay.
10 A. --- at an individual level, a younger
11 person could get severe COVID and end up in the
12 hospital ICU and/or die from COVID. Now, elderly
13 people are more frail if you will, have more
14 compromised immune systems or tend to have more
15 comorbidities so, yes, the were impacted more as at a
16 population level than younger people.
17 329. Q. And your research would have found that
18 at a population level, individuals with one, two, or
19 three comorbidities would be at a higher risk of a
20 negative outcome than someone without those
21 comorbidities, correct?
22 A. Many studies do show that comorbidities
23 lead to higher risk ---
24 330. Q. And comorbidity could include obesity,
25 hypertension diabetes, are those examples?

AR09234
1 A. Those are examples that have been
2 reported in studies.
3 331. Q. Right. Would you agree with me that
4 the studies show that there is a lower risk of
5 negative outcome to a younger person and let’s say
6 someone in their late teens or early twenties that has
7 no comorbidities?
8 A. Probably overall that is true, yes.
9 332. Q. Okay. so, you’d agree with me that
10 your literature review concludes -- allows you to
11 conclude that not all Canadians are the same in terms
12 of their risk factor for exposure to COVID-19,
13 correct?
14 A. Exposure would be different than what
15 we’ve been talking about. Exposure would depend on
16 who you’re in contact with.
17 333. Q. Right and I framed that poorly, let me
18 try again. You’d agree with me that not all Canadians
19 are the same in terms of the type of adverse health
20 outcomes they would experience after having become
21 infected with COVID-19, correct?
23 334. Q. Did you examine the literature with
24 respect to natural immunity in your literature
25 reviews?

AR09235
1 A. I have.
2 335. Q. Would you agree with me that not the
3 literature supports the proposition that someone who
4 has been recently infected and recovered who has
5 natural immunity will have a similar or greater level
6 of protection as a vaccinated person?
7 A. I cannot fully agree with that
8 statement, no.
9 336. Q. Why not?
10 A. So, the literature on post-infection
11 immunity shows that post-infection there’s a high
12 variability and the immune response. So, very much
13 dependent on the type of infection or and the severity
14 of disease and potentially even individual
15 characteristics.
16 So, that is much more highly variable
17 but, in some circumstances, yes there is immunity that
18 is comparable to people who have been vaccinated and,
19 in some situations, there isn’t so, it’s highly
20 variable.
21 337. Q. And is it possible based on your review
22 of the literature for someone’s immunity level to be
23 tested on an individual basis?
24 A. I actually can’t answer that, it is
25 possible, but I don’t know if any lab can do it.

AR09236
1 338. Q. Okay, so, you’re not aware of whether
2 labs offer a service of testing immunity level arising
3 from exposure and infection from COVID-19?
4 A. I’m not aware if that’s a widespread
5 thing that is offered by different labs.
6 339. Q. I didn’t ask if it was widespread, I
7 asked if it was possible.
8 A. I said it is possible.
9 340. Q. Okay, thank you. you’ve done studies
10 yourself haven’t you or participated in them that have
11 tried to assess the impacts of for example a lockdown
12 in schools, right?
13 A. No.
14 341. Q. No, all right. Must be mistaken, I’ve
15 read too many expert reports in the last three weeks.
16 Actually, I’ll check your CV on the break and I’ll
17 refresh my memory as to which study, I was referring
18 to.
19 A. Okay. We haven’t done any primary
20 studies during COVID ---
21 342. Q. It’s all right, I’ll be more clear to
22 be fair to you, I should be precise in my questions.
23 In one of your papers refers to an agent based model
24 of COVID-19 transmission in Canada, do you know what
25 I’m referring to there?

AR09237
1 A. One of my papers, on my CV you mean?
2 343. Q. Yes.
3 A. By Dr. Ng?
4 344. Q. I believe so.
5 A. Yes.
6 345. Q. Within that there’s a discussion about
7 how Canada’s Public Health response shifted from
8 containment to mitigation, can you help me understand
9 the difference between containment and mitigation in
10 that context?
11 A. Sure, containment would be activities
12 to try to keep a virus out of Canada so that we don’t
13 have transmission in the community and mitigation
14 would be once it’s circulating in a community efforts
15 to try to reduce that transmission in hopes that we
16 can stop the outbreak.
17 346. Q. And that paper speaks to the need to
18 balance socioeconomic impacts with Public Health
19 gains, is that correct?
20 A. There is discussion about that, yes.
21 347. Q. Is that part of the epidemiological
22 method?
23 A. I’m not sure I understand your
24 question.
25 348. Q. Is it standard to have as part of an

AR09238
1 epidemiological analysis to consider a balancing of
2 socioeconomic and social health gains?
3 A. In this case it was, we were looking at
4 how we best manage both things, right, we could on a
5 very extreme, we could have told everybody to go home
6 for two weeks and not leave their house and maybe that
7 would have stopped the pandemic but it’s not feasible.
8 So, we were investigation how to balance.
9 349. Q. Thank you, are you aware of any studies
10 from your literature review that sought to rank the
11 risk factors of people who can become exposed to
12 COVID-19 in terms of allowing the to carry on
13 activities in society?
14 A. Everybody can become exposed, what do
15 you mean?
16 350. Q. Well, we’ve agreed and you’ve testified
17 and written that individuals have different levels of
18 risk in terms of negative health outcomes.
19 A. Mm-hmm.
20 351. Q. And are you aware of any literature
21 that seeks to categorize and assess levels of risk to
22 help inform policy makers?
23 A. I would say there’s probably many like
24 thousands of studies out there that have looked at
25 different risk factors and who would fall into high

AR09239
1 risk categories and low risk categories. I mean at
2 the end of the day it would be a generalization across
3 the population and not to an individual, right.
4 352. Q. Does it have to be, is there some
5 scientific reason that you found in your literature
6 review that says it has to be generalized and it can’t
7 be individualized?
8 A. I think that there are examples of
9 people who have died from COVID that had no pre-
10 existing high risk conditions that would have made you
11 think that they were going to be susceptible to
12 extreme outcomes of COVID-19.
13 353. Q. You would agree with me that Omicron
14 generally has produced less severe adverse health
15 outcomes relative to Delta in the earlier strains of
16 COVID-19?
17 MR. LEE: I’m objecting to that because
18 again, Dr. Waddell is not being tendered as an expert
19 in terms of the different variants.
21 BY MR. WILSON:
22 354. Q. You’d agree with me Doctor that your
23 literature review found that Omicron strain of COVID-
24 19 causes generally speaking less severe health
25 outcomes relative to the earlier strains of Delta,

AR09240
1 correct?
2 A. Which review are you referring to?
3 355. Q. I’m asking about your daily tasks that
4 you’ve testified to of reviewing vast amounts of
5 literature, I’m asking you to confirm that that
6 literature review found that Omicron is a less severe
7 strain.
8 A. So, I did conduct an evidence profile
9 of Omicron up until the beginning of March and within
10 in that there were several studies that indicated that
11 Omicron may be causing less severe disease. At that
12 point it had not been fully unpacked.
13 356. Q. Okay.
14 A. Not well vetted yet in the literature
15 why that would be.
16 357. Q. Okay and when you say at that point,
17 I’m sorry, what do you mean by at that point?
18 A. --- the last ---
19 358. Q. --- at that point in time?
20 A. Yes, up until the March 8th, I think
21 was the last time that we fully summarized the Omicron
22 literature.
23 359. Q. And where did you make that available?
24 A. It’s also available where other
25 literature reviews are available by request.

AR09241
1 360. Q. Okay, but it’s not included in an
2 evidence brief on risk of COVID-19 transmission update
3 three found at Exhibit I of your Affidavit, correct?
4 A. No, it’s not.
5 361. Q. And do you know whether that summary
6 you just described about the more mild effects of
7 Omicron was made available to Transport Canada?
8 A. I have no idea.
10 MR. WILSON: I’m going to ask that we take a
11 brief break so that I can consult with my colleagues,
12 please and if the witness needs a break as well. I’m
13 asking for five, ten minutes.
15 BY MR. WILSON:
16 363. Q. Good afternoon, welcome back. Just
17 prior to the break, Dr. Waddell I’d asked you about
18 Omicron and your work in literature review with
19 respect to the same and I understood you to say you’ve
20 prepared an update summary as of March, did I
21 understand that correctly?
22 A. That is correct, yes.
23 364. Q. Through your counsel, would you
24 undertake to provide us a copy of that document?
25 MR. LEE: Generally in terms of -- oh, sure,

AR09242
1 we’ll undertake to provide a copy of that.
3 --- UNDERTAKING NO. 1
4 BY MR. WILSON:
5 365. Q. Dr. Waddell, based on your review of
6 the literature, I may come across with the questions
7 I’m about to ask as being cute, I’m not trying to be.
8 Your counsel is very skilled and fast on his feet to
9 object and I will -- you will not answer if he objects
10 but I do need to break some things down here.
11 Did your literature review find that
12 there’s something unique about Canadians physiology
13 relative to other citizens of other countries around
14 the world that react differently to COVID-19, did you
15 find anything in the literature that says Canadians
16 react differently to CVOID-19?
17 A. No, nothing comes to mind.
18 366. Q. Did you find anything in the literature
19 to support to the proposition that the strains that
20 we’ve seen around the world, the original strain
21 Delta, Omicron and others are fundamentally different
22 when those strains exist within the geopolitical
23 borders of the country of Canada?
24 A. I’m not sure I understand.
25 367. Q. Does the virus behave differently

AR09243
1 within the borders of Canada than the virus behaves in
2 other countries generally speaking around the world?
3 MR. LEE: I’m going to object to that
4 question, she’s not being tendered as a witness,
5 that’s -- as an expert, that’s not a proper question,
6 Mr. Wilson.
7 MR. WILSON: I’ll restate it.
8 BY MR. WILSON:
9 368. Q. Did your literature review of COVID-19
10 related scientific and medical studies find any study
11 that said COVID-19 behaves differently in Canada than
12 other countries in the world, the virus itself?
13 A. No.
14 369. Q. Did your review of literature find
15 anything to suggest that Canada uses fundamentally
16 different aircraft than aircraft used in other parts
17 of the world?
18 A. That is not addressed in the evidence
19 anywhere.
20 370. Q. In the evidence, you’ll agree with me
21 including the reports that you’ve attached to your
22 Affidavit models of aircraft are described for example
23 an airbus or a Boeing aircraft, correct?
24 A. Yes, some studies do look at specific
25 aircraft.

AR09244
1 371. Q. Okay. so, you didn’t find a study that
2 said Canada uses only one kind of aircraft that no
3 other country uses, there’s no study that says that
4 you’ve found?
5 A. No, no studies suggest that.
6 372. Q. Thank you. Did you find anything in
7 the literature review that says passengers travelling
8 on an aircraft to Canada are at a lower risk than
9 passengers leaving Canada?
10 A. No, I don’t think any of the studies we
11 have even are from Canada.
12 373. Q. Did you find anything in your
13 literature review where a study said that Canada --
14 that recommended that Canada have different public
15 health measures than other countries in the world?
16 A. I don’t think I can answer that
17 question ---
18 374. Q. Well, either you found it or you
19 didn’t.
20 A. Nothing comes to mind.
21 375. Q. Thank you, it’s a fair answer. Did
22 your literature review and research of the
23 epidemiological studies and Public Health measures
24 reveal any study that said citizens should be divided
25 into different classes of people as a public health

AR09245
1 measure?
2 A. I’m ---
3 MS. TELLES-LANGDON: I’m going to object.
4 Mr. Wilson, that is such a vague question. Sorry,
5 like, what kind of ---
6 MR. WILSON: I can make it more precise,
7 Counsel ---
8 MS. TELLES-LANGDON: --- what kind of
9 classes of people ---
10 MR. WILSON: I can make it more precise, we
11 don’t need to spend too much time on this but thank
12 you. There are a few things that we can give one
13 another in this virtual world but one of the things
14 that we can give one another is the gift of time and
15 I’m about to do that.
16 Thank you for your cooperation, Doctor,
17 that concludes our cross-examination.
18 MS. TELLES-LANGDON: Do you have questions
19 that you would still like to ask and would you like to
20 have a short break because I think Mr. Wilson finished
21 much more quickly than you anticipated perhaps
22 certainly than he’s telegraphed earlier?
23 MR. NAOUM: Personally, I would not need a
24 break but we can ask Ms. Waddell if she would like a
25 break?

AR09246
1 THE DEPONENT: I’m okay, to continue.
2 MR. NAOUM: Okay, perfect. So, first of
3 all, I would like to present that Mr. Branchand told
4 me that he didn’t have any question to ask.
5 Secondly, during my cross-examination I
6 might need to consult French to English translator
7 because English is my -- language, would that be okay
8 with you, Counsel?
9 MR. LEE: That’s fine.
10 MR. NAOUM: Perfect.
11 EXAMINATION BY MR. NAOUM:
12 376. Q. Good afternoon, Ms. Waddell. My first
13 question to you, you haven’t mentioned -- first
14 disclaimer again, I have missed about 15 minutes of
15 Mr. Presvelos first examination and about ten minutes
16 of Mr. Wilson’s because I was in another courtroom, I
17 work a full schedule so if my question was already
18 asked, please let me know, Ms. Waddell, thank you.
19 So, first question, you had mentioned
20 previously to my colleague Mr. Presvelos that your
21 mission in this matter was to review dividends and the
22 data regarding transmission in a context of air
23 travel, correct?
24 A. Correct, my job was to review the
25 scientific evidence published on the topic of in-

AR09247
1 flight transmission.
2 377. Q. You have said previously that you’re
3 not aware of who exactly reviewed your report,
4 correct?
5 A. I do not know who received and read my
6 report.
7 378. Q. I’m just curious on why did you not do
8 a follow up, why did you not inquire to know exactly
9 who your information was submitted to?
10 A. The reviews that we do get circulated
11 fairly widely in the agency so, other than knowing
12 that it went to many different offices, we wouldn’t
13 necessarily be able to track who in the agency that
14 the reviews went to and I -- we do have a secretariat
15 on the emerging sciences group that handles any
16 requests on reviews so, they may have some tracking
17 information on who requested the reviews in the past.
18 379. Q. Could you precise the different offices
19 that review your reports that you’re aware of, which
20 one are these?
21 MR. LEE: She’s already answered that she
22 doesn’t know and she had -- she doesn’t know who --
23 like where the report has been circulated so the
24 question ---
25 MR. NAOUM: --- I understand that she’s not

AR09248
1 aware of who personally reviews the reports but I
2 would assume that she knows which agencies, which
3 offices, which -- the broad recipient of the
4 information, I would assume that she does.
5 MR. LEE: Again, the question’s already been
6 asked and answered but Dr. Waddell, do you want to
7 answer that?
8 THE DEPONENT: I just know that our reviews
9 go out in what we call an evidence tracker to probably
10 most offices within the agency, whether or not someone
11 within those offices actually picks up and reads the
12 report or uses it is -- I don’t actually know.
13 BY MR. NAOUM:
14 380. Q. Okay, I would assume that as a manager
15 of the PHAC that you have taken that mission very
16 seriously -- so, I’m just curious in why the result of
17 these reports that you have provided for as far as you
18 know it could have been lost, it could have not been
19 deemed relevant, why was there no inquiry from your
20 part to do a follow up on these reports that you have
21 spent countless hours on?
22 A. The very short answer to that is that
23 we have produced many, many, many reviews on many
24 topics throughout this pandemic and I don’t have time
25 to follow up on them, that is why we established a

AR09249
1 secretariat to manage the knowledge brokering across
2 the agency.
3 381. Q. Ms. Waddell, would you agree with me
4 that this very report, I understand that you have
5 don’t many but this one would be the most important
6 that you have had under your hands?
7 A. I can’t answer that question, I’m not
8 sure.
9 382. Q. Would you agree with me that it’s among
10 one of the most important ones, given the fact that
11 it’s restrains millions of Canadians from the right to
12 leave their country?
13 MR. LEE: I’m objecting to that question and
14 in terms of importance Ms. Waddell has already
15 indicated in her testimony that she’s produced many
16 reports whether or not it’s important or one of the
17 most important, I don’t -- basically disagree with
18 your interpretation in how the question is phrased.
19 MR. NAOUM: There is no interpretation Mr.
20 Lee, I’m just asking whether or not she believes
21 because she had the many reports all of them or not
22 equal in importance and I do believe it’s very
23 important for her to establish hierarchy of importance
24 of this one among her others. So, I would rephrase, I
25 would ask again my question, does she agree or not

AR09250
1 that it’s among the most important ones that she had?
2 THE DEPONENT: I still cant really answer
3 that question to be honest, it depends I think on what
4 is important to the individual.
5 BY MR. NAOUM:
6 383. Q. Yeah, that’s exactly what I’m asking
7 you, as an individual, do you believe that this -- you
8 can answer me that it’s as important ---
9 MR. LEE: I object to that question because
10 it’s her opinion, I don’t see the relevance in terms
11 of this ---
12 MR. NAOUM: I will explain to you the
13 relevance, Mr. Lee. Ms. Waddell answered to me that
14 the reason she didn’t do a follow up is because she
15 had done many other studies, many other reports, I’m
16 asking whether or not this one is more important than
17 other ones which would justify a follow up that she
18 did not do. So, maybe the justification is that this
19 report was not as important to her or whether it’s
20 important to her, that’s why I am asking the question
21 on whether or not it’s an important one because I’m
22 surprised that there was no follow up being made so
23 that’s why I’m asking this question, I believe it’s a
24 relevant one and if the witness wants to maintain her
25 answer that it’s as important as other ones, that’s

AR09251
1 fine with me.
2 MR. LEE: Mr. Naoum, Dr. Waddell has already
3 testified that there was -- she’s already explained
4 why there was no follow up in relation to these
5 various reports, so the question from my perspective
6 has already been asked and answered so I continue to
7 obtain my objection to the question as posed.
8 MR. NAOUM: Well, I strongly disagree with
9 you but I will go to my next question.
11 BY MR. NAOUM:
12 384. Q. Ms. Waddell, at what time did you first
13 hear that the vaccine mandate or travel took place?
14 A. I don’t remember.
15 385. Q. Widely, you can give me a month, season
16 of the year?
17 A. I don’t even remember how I heard about
18 it, it was probably in the news like everyone else.
19 386. Q. I didn’t ask where, I said when, so Ms.
20 Waddell, you have ---
21 A. It was in the fall of 2021.
22 387. Q. Fall of 2021, very well. Do you
23 believe that this order was compatible with the
24 results of your report?
25 MR. LEE: I’m going to object to that

AR09252
1 question, again previously I have objected to this
2 type of question. Dr. Waddell is not being produced
3 as a policy maker so any sort of decision making
4 question is irrelevant and improper. Move on.
6 BY MR. NAOUM:
7 388. Q. Ms. Waddell, I understand that you
8 don’t remember vividly at what time the vaccine
9 mandate was established, is that fair to say that it
10 may be because the order had no impact on your life?
11 MR. LEE: Again, I’m objecting to that
12 question, what’s the relevance?
13 MR. NAOUM: The relevance is that Ms.
14 Waddell has participated personally in establishing a
15 report that influenced an order that was being made
16 after by the government, I’m very surprised that she
17 doesn’t remember even broadly at what time the report
18 was -- the order was established. So, I think ---
19 MR. LEE: ---I’m objecting to that line of
20 questioning, again you haven’t provided a proper
21 foundation in terms of the question, so move on.
22 MR. NAOUM: I think you’re being overzealous
23 in your objections and that there’s a bit of bad faith
24 there. I think that Ms. Waddell had the central role
25 in establishing that this order and the very fact that

AR09253
1 she doesn’t even remember when the order was
2 established is very surprising so I would maintain my
3 question.
4 BY MR. NAOUM:
5 389. Q. Ms. Waddell, is that because the fact
6 that you don’t remember when it was established, is
7 that because the order forbidding unvaccinated
8 citizens from boarding a plane, is that because it had
9 no impact on ---
10 MR. LEE: I’m objecting ---
11 MS. TELLES-LANGDON: Mr. -- yeah ---
12 MR. LEE: --- that line of questioning.
13 MS. TELLES-LANGDON: Mr. Ben Naoum perhaps
14 we’ll rephrase the objection in a different way to
15 help you understand. Dr. Waddell’s personal views
16 were how the mandate personally impacted her are
17 irrelevant to the issues before the court. Her
18 personal views are irrelevant.
19 You’re welcome to ask Dr. Waddell
20 questions on the evidence reviews that she’s conducted
21 on the Affidavit that she’s put before this court but
22 whether or not Dr. Waddell has personal views about
23 the mandate or has a personal belief of the relative
24 importance of one or the other of the reports that
25 she’s written is not a relevant consideration.

AR09254
1 MR. NAOUM: Counsel, I don’t understand that
2 I’m just trying to help her in my questions understand
3 why does she not remember at all when the other was
4 established, I’m just ---
5 MS. TELLES-LANGDON: She already said Fall
6 of 2021.
7 MR. NAOUM: Yeah, through a few questions.
8 I’ll keep going.
10 BY MR. NAOUM:
11 390. Q. Ms. Waddell, I would like to get you
12 back to the very beginning of your mission in this
13 matter, when exactly were you contacted for the first
14 time to conduct your research?
15 A. Can you be more specific, my research
16 on what?
17 391. Q. Related to this matter, when was the
18 first time were you asked to review the evidence and
19 the data on this matter?
20 A. In the Summer of 2020 was the first
21 time we were approached to look at the evidence.
22 392. Q. Can you tell us broadly how your
23 instructions were phrased?
24 A. I think the question came through as
25 what do we know about the risk of in-flight

AR09255
1 transmission of COVID.
2 393. Q. Well, at that time, so summer of 2021
3 you started that mission, were you aware of an
4 intention of -- were you aware of the possibility of a
5 vaccine for COVID-19 to be I don’t know what the
6 proper English word would be for you, to be created?
7 A. Yes, so vaccine research started right
8 away like in March 2020 we started talking about
9 vaccines but at that time we thought it would be many
10 years out.
11 394. Q. Okay, when was the first time that you
12 were made aware of an intention from Transport Canada
13 to establish a vaccine mandate?
14 A. When they announced it in the news.
15 395. Q. Do you remember around what time that
16 was?
17 A. Fall of 2021 some time.
18 396. Q. Has this announcement changed the
19 pattern influence in your research in any way?
20 A. No.
21 397. Q. Okay, I would like to take you to
22 paragraph five of your Affidavit.
23 A. Okay, yes.
24 398. Q. So, in paragraph five, it says that,
25 “...From the resulting database of

AR09256
1 articles in COVID-19, keyword searches are conducted
2 to identify potentially relevant articles on a
3 specific document...”
4 Do you see that?
5 A. Yes.
6 399. Q. Do you remember what key words you were
7 -- the main one -- the main key words that you were
8 using while conducting your research, I know that some
9 are listed but the main ones that you were using?
10 A. Sorry, I researched to identify COVID
11 literature, is that what you’re asking about or for
12 the in-flight review?
13 400. Q. The in-flight reviews.
14 A. Okay, so I would have to consult to
15 know specifically Exhibit I in the method section,
16 they’re listed there, can I look at that?
17 401. Q. Well, I have a few ones, I can take you
18 to page 39 where there’s an article among others, on
19 page 39.
20 MR. LEE: Page 39 of what Mr. Naoum?
21 MR. NAOUM: Of the document, the Affidavit
22 that I have. So the article is, Risk of Symptomatic
23 COVID-19 Due To Aircraft Transmission In Retrospective
24 Cohort Study.
25 THE DEPONENT: Okay, but how does that

AR09257
1 answer your question?
2 BY MR. NAOUM:
3 402. Q. No, it’s not regarding the previous
4 question, I would just like to take you to that
5 article.
6 A. Okay.
7 403. Q. Can you please read to me the keywords
8 that are associated with that article?
9 A. Aircraft, Contact tracing, COVID-19,
10 Epidemiology, SARS-CoV-2, Transmission.
11 404. Q. Yes, exactly and I see on another
12 article COVID-19, this is outbreaks travel related
13 illness, attack rate, transmission, do these keywords
14 sound familiar to you?
15 A. Those are the keywords of the articles.
16 405. Q. Yeah, would these keywords be used in
17 your reports as well, in your research method?
18 A. We would have used words like Aircraft,
19 flight, plane, things like that to find articles on
20 in-flight transmission within our COVID database, so
21 we gathered all the COVID literature together and then
22 within that, we looked for all the things related to
23 in-flight transmission using keywords related to
24 airplanes, aircrafts, things like that.
25 406. Q. Okay, well then, the keywords that I

AR09258
1 have listed the ones that say under that article, I
2 understand it’s not the ones that you use but we can
3 see these are outbreak struggle related illness,
4 attack rate, transmission.
5 Would you say that these keywords were
6 used by you as well after gathering the COVID-19
7 evidence?
8 A. Just the ones related to flights and
9 planes and things like that.
10 407. Q. Okay, would you say that with these
11 keywords that there could be selection bias or other
12 research bias in the sense that all the keywords that
13 are related to the article that you have put in the
14 document file seemed to be waited, seemed to be
15 oriented towards finding transmission occurrences,
16 would that be fair to say?
17 A. The review is about in-flight
18 transmission risks so, they would be looking for
19 articles talking about the risk of transmission during
20 flight and how we might make that risk lower or what
21 makes that risk higher so.
22 408. Q. I understand. So, would you say that -
23 - to study an article displaying no COVID transmission
24 in an airplane would be relevant to your research?
25 A. Yes, it would and we captured several

AR09259
1 reports on no transmission.
2 409. Q. Well, have you included in your
3 research by memory, in your keywords such as safety,
4 low risk ---
5 A. --- no, those aren’t very specific to
6 flights.
7 410. Q. Would you agree with me that if I take
8 you back to the paragraph five of your Affidavit, it
9 says that unbiased process oriented fashion so we can
10 compare and contrast studies, why does it appear to me
11 that your keywords -- that these keywords are only
12 oriented in finding one side of the (inaudible)
13 A. They weren’t ----
14 411. Q. --- if your objective was to contrast
15 that -- the evidence, would it be fair to say that
16 your keywords needs to become contrasted as well?
17 A. My keywords were specific to identify
18 all articles on this setting. This setting was
19 flights, it didn’t matter whether transmission
20 occurred on the flight or not, we were just looking
21 for the keyword, airplane, flight, aircraft and then
22 all of those articles were considered for inclusion
23 and if they were relevant to any situation.
24 So there was a COVID positive person on
25 a plane and they didn’t transmit an understanding why

AR09260
1 there was no transmission that was definitely included
2 and our goal was to find all the articles about
3 airplanes and having COVID -- potentially COVID
4 positive people on the airplane so, I mean there’s a
5 range of types of articles included, some of those
6 were simulations ---
7 412. Q. Perfect. So, when you say that if
8 deemed relevant, you say that in paragraph five, can
9 you define for me what is relevant for you in this
10 matter?
11 A. Yes, was the study about COVID-19 or
12 SARS-CoV-2 and aircraft.
13 413. Q. So ---
14 A. Anything that had to do with the
15 aircraft setting and SARS-CoV-2 was relevant to this
16 review.
17 414. Q. You have previously stated to me that
18 it was regarding transmission and your definition of
19 transmission so, just to that we’re clear, do you
20 include the instance where there’s no transmission or
21 you were looking for cases of transmission?
22 A. We included instances where there was
23 no transmission because transmission can be prevented
24 just as much as it can happen, we’re interested in all
25 sides of that.

AR09261
1 415. Q. Ms. Waddell, do you know how many
2 fights occur everyday?
3 A. No idea.
4 416. Q. Have you researched that information
5 throughout your research?
6 A. I have probably seen them as numbers
7 but I do not recall what they are.
8 417. Q. Would you agree with me that that
9 information is crucial in the -- that you had because
10 it’s knowing the common denominator?
11 A. No.
12 418. Q. So, for you the number of flights that
13 have happened everyday is relevant to the search that
14 you have?
16 419. Q. You know Ms. Waddell, in French we have
17 a saying, it says that, falling tree makes more noise
18 than a growing forest.
19 Would you agree with me that there
20 could be a bias there in the fact that when a
21 transmission is reported on a plane such as the flight
22 that you have listed, it could raise more articles, it
23 could make it unbalanced in the sense that the ones
24 where nothing bad happens are not recorded, we can see
25 that there’s same type of bias happened, instances of

AR09262
1 crashes -- of airplane crashes?
2 MR. LEE: I’m objecting to the question and
3 the nature of the question. Have you established that
4 there’s a bias before even asking the question, have
5 you provided a factual foundation to show that Dr.
6 Waddell has demonstrated bias in you know her studies,
7 because if you haven’t, I’m objecting to the question.
8 MR. NAOUM: I’m simply asking her throughout
9 her research whether or not she has considered the
10 number of flights where there were no transmission.
11 So, if I can rephrase my question.
12 BY MR. NAOUM:
13 420. Q. Ms. Waddell, have you considered in
14 your research just as you have listed the number of
15 flights where there were occupants of transmission,
16 have you considered the number of flights where there
17 were no transmission?
18 A. So, to answer your question, I haven’t
19 said how many flights there were transmission either.
20 421. Q. Right.
21 A. All I have done is compile the studies,
22 the scientific studies where they have reported and
23 investigated whether or not transmission occurred and
24 why it did or did not occur.
25 That actual bottom line would be done

AR09263
1 by surveillance if it was possible and in my overview
2 of the evidence section, we do talk about how it is
3 very likely that there hasn’t been any good
4 investigation or there isn’t any good data available
5 in terms of whatever the denominator is and what the
6 numerator is in terms of how frequently the
7 transmission actually occurred on airplanes, simply
8 because there wasn’t that type of investigation going
9 on in any operationalized fashion.
10 422. Q. How did you explain that there was not
11 that kind of -- can you repeat the last part of your
12 answer, please?
13 A. There was no observational contact
14 tracing of every person that got on an airplane and
15 off an airplane, so we don’t have that kind of
16 surveillance data, I don’t know that there’s really
17 any country in the world that can be very confident in
18 their data, there’s a lot of under reporting both on
19 no transmission and transmission occurrences.
20 MR. NAOUM: Just so -- I’m going to use
21 briefly a French to English translator, just making
22 you aware of this, Counsel. okay, just a second here.
23 This will conclude for me, I don’t have any other
24 question. Thank you, Ms. Waddell.
25 MR. LEE: I’d like to close if that’s okay

AR09264
1 with everybody.
2 --- OFF THE RECORD (2:45 P.M to 2:55 P.M.) ---
3 EXAMINATION BY MR. LEE:
4 423. Q. Dr. Waddell, with respect to Exhibit I
5 to your Affidavit, the evidence brief on the risk of
6 COVID-19 transmission in-flight update number three.
7 Mr. Wilson took you to the discussion
8 under the heading, Indirect Analysis of SARS-CoV-2
9 Infection Transmission Risk and Mitigation Strategies
10 on Airplanes, I believe it’s on page eight of that
11 document, can you pull that on your screen?
12 A. Yeah.
13 424. Q. I’m just going to give you a minute
14 just to review.
15 A. Okay.
16 425. Q. Can you advise whether this section of
17 the evidence brief recommends any type of mitigation
18 strategy?
19 A. No, this section just discusses the
20 findings of the studies that fell under this indirect
21 evidence section so, essentially these studies are all
22 simulation and in silicone models trying to model what
23 might happen in under certain circumstances to see
24 whether -- I don’t know I’m just looking at some of
25 these, like if we load an airplane in a certain way.

AR09265
1 Whether that might reduce risk of the
2 transmission or whether someone is master -- might
3 reduce risk of transmission, so they mimic what may
4 happen in the real world but they can really only be
5 used to compare like scenario A versus scenario B and
6 then apply those in the real world and further study
7 it so it’s just a way of suggesting that doing certain
8 things might reduce risk compared to a different set
9 of circumstances or doing it a different way.
10 MR. LEE: Okay, that’s it, thank you. those
11 are my questions.
12
13 --- WHEREUPON THE EXAMINATION WAS ADJOURNED AT 2:59 P.M.
14
15
16
17
18
19
20
21
22
23
24
25

AR09266
7 I hereby certify that this is the
8 examination of DR. LISA WADDELL, taken
9 before me to the best of my skill and
10 ability on the 31st day of May, 2022.
11
12 ------------------------------------
13 CINDI ADALATH - Court Reporter
14
15
16
17
18
19
20
21
22 Reproductions of this transcript are in direct
23 violation of O.R. 587/91 Administration of Justice Act
24 January 1, 1990 and are not certified without the
25 original signature of the Court Reporter

AR09267
TAB 60
AR09268
FEDERAL COURT
BETWEEN:
NABIL BEN NAOUM
demandeur
- and -
dèfendeur
AND BETWEEN:
demandeur
- and -
dèfendeur
AR09269
DR. PETER LIU - 2
AND BETWEEN:

MACDONALD
Applicants
- and -

Respondent
AND BETWEEN:
Applicants
- and -

Respondent
--------------------------------------------------------
This is the Cross-Examination of DR. PETER LIU, on
behalf of the Attorney General of Canada herein, taken
via Videoconference for Network Reporting & Mediation,
on the 1st day of June, 2022.
--------------------------------------------------------
NETWORK NORTH REPORTING & MEDIATION - (416) 218-0464

AR09270
DR. PETER LIU - 3

MAHAN KERAMATI
JAMES ELFORD
ROBERT DRUMMOND

EVA CHIPIUK
ALLISON PEJOVIC
ALSO PRESENT:

PATRICK ABBOTT
SAYAH HASSAN
HENNA PARMAR
ANDRE MEMAURI
CYNTHIA MURPHY
CHRIS NAIMI

AR09271
DR. PETER LIU - 4
DR. PETER LIU, Affirmed ................................. 6
EXAMINATION BY MS. PEJOVIC: ............................. 6
L I S T O F E X H I B I T S
--- EXHIBIT NO. 1: Chouchana Study: Features of
Inflammatory Heart Reactions Following mRNA COVID-19
Vaccination at a Global Level. ......................... 49
--- EXHIBIT NO. 2: The Journal of Pediatrics. .......... 63
--- EXHIBIT NO. 3: Jama_oster_2022: Myocarditis Cases
Reported After mRNA-Based COVID-19 Vaccination in the US
From December 2020 to August 2021. ..................... 76
--- EXHIBIT NO. 4: Footnote 7: Association of Cardiac
Injury With Mortality in Hospitalized Patients With
COVID-19 in Wuhan, China. .............................. 85
--- EXHIBIT NO. 5: Footnote 57 to Liu Circulation Study:
COVID-19 in Critically Ill Patients in the Seattle Region
- Case Series. ......................................... 89

AR09272
DR. PETER LIU - 5
--- EXHIBIT NO. 6: European Journal of Clinical
Investigation: Prevalence and clinical outcome of
myocarditis and pericarditis in 718,365 COVID-19 patients
(Buckley). ............................................97
--- EXHIBIT NO. 7: Qin: Redefining Cardiac Biomarkers in
Predicting Mortality of Inpatients With COVID-19,
Medicine Hypertension Journal. ........................ 103
INDEX OF UNDERTAKINGS UNDER ADVISEMENT
--- UNDER ADVISEMENT NO. 1 ............................. 18
--- UNDER ADVISEMENT NO. 2 ............................. 23

AR09273
DR. PETER LIU - 6
1 --- UPON COMMENCING AT 2:40 P.M.
2 DR. PETER LIU, Affirmed
3 EXAMINATION BY MS. PEJOVIC:
4 1. Q. Good afternoon, Dr. Liu.
5 A. Hi.
6 2. Q. Hi there. My name is Allison Pejovic,
7 I’m counsel for a group of applicants which includes
8 the Honorable Brian Peckford and you have agreed under
9 oath to tell the truth in these proceedings?
10 A. Yes.
11 3. Q. And can you confirm that you have a
12 secure and stable internet connection and you can hear
13 and see me and the court reporter?
14 A. Yes.
15 4. Q. And you will not mute or turn off your
16 microphone, camera or speakers or move out of the view
17 of the camera during these proceedings unless to do so
18 by me, your lawyer or by the court reporter?
19 A. Yes, but I just noticed that in fact
20 sometimes the words doesn’t come through steadily
21 yeah, so I may ask for repetition of statements and
22 things like that, yeah.
23 5. Q. Okay and do you agree Dr. Liu that you
24 will not view during these proceedings any device,
25 documents, apps or information other than those which

AR09274
DR. PETER LIU - 7
1 you have told me are in front of you?
2 A. Yes.
3 6. Q. Okay, and what do you have in front of
4 you today?
5 A. I have in front of me the documents
6 that I just downloaded you know, from the e-mail that
7 was actually forward to me and then in addition you
8 know, there’s also in terms of the documents that’s
9 related to my work or the report I made so that
10 include the Code of Conduct for expert witness.
11 And also in terms of the Affidavit from
12 expert witness Dr. McCullough and also my -- I guess
13 it’s a commissioned copy of my report, my Affidavit
14 and also the I guess there’s a number of documents, in
15 fact I have some of the same documents you know that
16 were actually sent to me, yeah.
17 7. Q. Yeah.
18 A. Yeah, I just realize in fact a number
19 of them are, the same ---
20 8. Q. --- I want to make sure that -- I want
21 to make sure that you had those studies in front of
22 you and wouldn’t have to go digging ---
23 A. --- sounds wonderful, thank you so
24 much. Yeah, because that’s really helpful, yes.
25 9. Q. Okay, and so you have your Affidavit

AR09275
DR. PETER LIU - 8
1 open and in front of you and can you confirm that you
2 have closed and will not reopen any other windows on
3 your computer during the proceedings and you have
4 taken steps to disable any popup notifications that
5 you expect would interrupt the proceedings?
6 A. Yes, I do.
7 10. Q. Okay and can you confirm with me that
8 you will not communicate in any way with any party
9 outside of the virtual meeting during these
10 proceedings?
11 A. Confirmed.
12 11. Q. Is there anyone with you in the room?
13 A. Nobody.
14 12. Q. And where are you today, Dr. Liu?
15 A. I’m in Ottawa.
16 13. Q. Are you in your house or your place of
17 business?
18 A. I’m in my house.
19 14. Q. Okay, I’m going to show you your
20 Affidavit. Can you see that, Dr. Liu?
21 A. Yes, I can.
22 15. Q. Okay ---
23 A. --- it’s a little small, I have to --
24 on my screen anyway ---
25 16. Q. --- is that better?

AR09276
DR. PETER LIU - 9
1 A. --- I have a copy here myself, yeah.
2 17. Q. I just want to go through it, just for
3 the record. I’m going to scroll down here.
4 MS. TELLES-LANGDON: Ms. Pejovic, may I ask
5 that you make it just a little bit bigger?
6 MS. PEJOVIC: Bigger, okay sure.
7 MS. TELLES-LANGDON: Just a little bit,
8 please.
9 MS. PEJOVIC: Sure.
10 MS. TELLES-LANGDON: That’s good, thank you.
11 BY MR. PEJOVIC:
12 18. Q. And can you confirm with me that your
13 signature is here on page four of your Affidavit, Dr.
14 Liu?
15 A. Yes, it is.
16 19. Q. And this was signed on May 3rd of 2022?
17 A. Yes.
18 20. Q. Okay, do you confirm that the contents
19 of your Affidavit are true?
20 A. Yes.
21 21. Q. Is there anything in your Affidavit
22 that you wish to change?
23 A. Not that I know of at this time, yeah,
24 no.
25 22. Q. And what documents did you review in

AR09277
DR. PETER LIU - 10
1 order to prepare for this cross-examination?
2 A. Oh for the cross-examination not the
3 report?
4 23. Q. Right for the cross-examination.
5 A. Cross-examination yeah, so my own
6 Affidavit, Dr. McCullough’s Affidavit and some of the
7 references you know that based my report on but I was
8 very happy to see that in fact they are the same
9 documents that you have forwarded very kindly, yes.
10 24. Q. Okay, so I’m going to ask you a few
11 questions, just preliminarily before we get into the
12 substance of your report. So, you are a
13 cardiovascular specialist working primarily out of the
14 University of Ottawa Heart Institute, correct?
15 A. Correct.
16 25. Q. And you are also the Chief Scientific
17 Officer at the University of Ottawa Heart Institute,
18 correct?
19 A. Yes.
20 26. Q. Safe to say you are a cardiologist
21 doctor?
22 A. Yes.
23 27. Q. And you are not an immunologist,
24 correct?
25 A. Not by calling but even though I do

AR09278
DR. PETER LIU - 11
1 research you know involving a lot of the immunological
2 methods and understand a lot of immunology as well,
3 yeah.
4 28. Q. Okay and you are not a virologist,
5 correct?
6 A. No, again you know in our lab we do
7 actually use a lot of viruses you know but not a
8 virologist, no.
9 29. Q. And you are not an epidemiologist,
10 correct?
11 A. Not an epidemiologist, even though I do
12 have the training and I do actually publish
13 epidemiology studies.
14 30. Q. And you are not a vaccinologist,
15 correct?
16 A. Not a vaccinologist, yes.
17 31. Q. And Dr. Liu, do you see patients, do
18 you have a clinical practice?
19 A. Yes, I was seeing patients this
20 morning.
21 32. Q. Okay, and if you could turn to page
22 nine of your CV.
23 A. Yeah, in the Affidavit I assume this is
24 what’s this referring to.
25 33. Q. Yeah.

AR09279
DR. PETER LIU - 12
1 A. Yes.
2 34. Q. Yes, if you’re unsure, please ask me --
3 -
4 A. --- yeah, so because there is
5 curriculum vitae page and also the Affidavit page.
6 35. Q. Yes, so it’s within your Affidavit,
7 it’s Liu Curriculum Vitae page number nine.
8 A. Oh, okay so then we are talking about
9 in the document, page 16. Yeah, I just want to make
10 sure.
11 36. Q. Yes, page 16.
12 A. Yes.
13 37. Q. And just so I’m looking to my left and
14 I have a screen with a bunch of your ---
15 A. Yes, yeah, yeah.
16 38. Q. --- documents ---
17 A. Yes.
18 39. Q. Okay, so halfway down the page it says,
19 ‘Number two research grants awarded.’
20 A. Mm-hmm.
21 40. Q. And the second entry there says,
22 ‘Canadian Institute of Health Research Grant.’ The
23 topic is COVID mRNA Vaccine Inflammatory Heart
24 Registry where you’ve been given $220,000 for the
25 years 2022 to 2026.

AR09280
DR. PETER LIU - 13
1 A. Yes.
2 41. Q. Now, can you explain how that came
3 about, how that grant came about?
4 A. Yeah, so we have our federal government
5 supporting peer reviewed research, scientific research
6 and the Canadian Institute of Health Research is the
7 Federal agency that actually supports all health
8 related research and individual investigators can
9 apply to this agency for funding of new ideas and if
10 it meets the peer view criteria, so keeping in mind
11 the current success rate is 14 per cent which means
12 that you send in seven grants, you will be lucky to
13 get one funded right, so that is what it is.
14 So, in this very competitive
15 environment, we put in an application and part of this
16 is actually you know the fact that we been asked by
17 the Canada Chief Scientist Dr. Mona Nemer to actually
18 provide advice you know in terms of what the mRNA
19 vaccine induced myocarditis is about you know because
20 of my previous expertise on myocarditis and the one of
21 the results of this expert panel meeting, you know
22 which include Canadian and international experts
23 myocarditis, vaccine.
24 You know the head of the public health
25 agencies was there, Health Canada were all there and

AR09281
DR. PETER LIU - 14
1 the conclusion was that we should have a registry so
2 that we can actually have Canadian data.
3 So, I together with many of the experts
4 apply to Canadian institute health research and we are
5 very fortunate to actually have this funding, so right
6 now we are actually conducting this study you know of
7 trying to capture cases of mRNA induced myocarditis
8 cases across the country and right now we have over
9 250 cases and in fact just yesterday, we had an
10 international call involving all the experts around
11 the world and in fact you know we have one of the
12 largest cohort patients you know with in depth
13 information as part of a result of the study.
14 But it would continue to follow these
15 patients, we’re continuing to find more about this
16 condition.
17 42. Q. Okay, and you said that the registry
18 includes cases of vaccine induced -- COVID vaccine
19 induced myocarditis ---
20 A. Yes.
21 43. Q. --- is the registry going to have any
22 follow up with these individuals in later years or is
23 it just a record of what current cases are in the
24 system?
25 A. Yeah, so we start out wit the current

AR09282
DR. PETER LIU - 15
1 cases but you know the finding does actually provide
2 four years of funding, so we would like to -- for
3 example patients we have now will continue to follow
4 them, so at least you know we’ll have multi year data
5 and -- so that we can all learn about the condition.
6 44. Q. Okay, and so you applied for this
7 grant?
8 A. Yes, I’m the lead investigator but
9 together it was you know colleagues around the country
10 you know because this is a ten Canadian registry.
11 45. Q. And you applied for the grant because
12 you saw that there was a need to learn more about
13 injuries due to myocarditis from the vaccine?
14 A. Absolutely, yeah, so this is
15 potentially a new condition and then we are always you
16 know sort of in a process to you know take better care
17 of our patients you know we need to have the
18 information so we want to make sure that we have the
19 ability to collect this information that’s accurate
20 and that’s relevant to Canadians.
21 You know, first we work with the
22 international partners on this and so that we can
23 learn the condition as much as we can and then you
24 know shared with our colleagues and with patients so
25 that you know everybody would learn at the same time.

AR09283
DR. PETER LIU - 16
1 MS. PEJOVIC: Okay, Ms. Telles-Langdon, I’m
2 going to ask the witness for an undertaking to produce
3 the grant application that he submitted to get this
4 grant.
5 MS. TELLES-LANGDON: I’m not sure that’s a
6 relevant undertaking Ms. Pejovic and Dr. Liu, before I
7 even answer that, is that something -- how large is
8 this grant have on occasion, I know nothing about this
9 document?
10 THE DEPONENT: Yeah, it’s about 50 pages,
11 the core part you know of course there’s appendices
12 and things like that, yeah.
13 MS. TELLES-LANGDON: Okay. Ms. Pejovic, I
14 don’t think it’s relevant.
15 MS. PEJOVIC: Well, we think that it is
16 relevant because it relates directly to what we’re
17 talking about here in that we’re talking about COVID
18 mRNA vaccine induced myocarditis in Dr. Liu’s expert
19 report and I’m looking at Dr. McCullough’s expert
20 report and within the notice of application for
21 judicial review and certainly the reasons behind Dr.
22 Liu’s grant application and the information that he
23 provided to receive that money is relevant to his
24 opinion on the safety of the COVID mRNA vaccines, so
25 we think it’s highly relevant.

AR09284
DR. PETER LIU - 17
1 MS. TELLES-LANGDON: It’s a funding
2 application to receive funding to study condition.
3 MS. PEJOVIC: Yes, of course but it’s going
4 to have rationale for why he’s asking for that money
5 and it’s directly on point as to the substance of his
6 report and the issues before the court, why did he
7 need that grant and why’s he asking for it and what’s
8 he looking to discover with this research.
9 MS. TELLES-LANGDON: I think you can ask Dr.
10 Liu those questions, he’s here today to answer
11 questions of exactly along those lines.
12 MS. PEJOVIC: So, you’re refusing the
13 undertaking?
14 MS. TELLES-LANGDON: Yes, I don’t think a
15 grant application is relevant, Mr. Pejovic.
16 MR. BACHAND: Can we have two minutes --
17 then?
18 MS. TELLES-LANGDON: Yes, of course.
20 MS. PEJOVIC: Ms. Langdon, I’ve had an
21 opportunity to consult with my colleagues and it’s our
22 position that we’re going to ask you to reconsider
23 your objection to providing this undertaking as this
24 issue of the grant application goes to whether this
25 witness meets the requirement of impartiality.

AR09285
DR. PETER LIU - 18
1 Is he impartial or is he biased and the
2 grant application in our view with show either and if
3 you decline to provide the undertaking, we are going
4 to ask the court to draw an adverse inference as the
5 grant application is to the Government of Canada and
6 it goes to the subject matter of which is the essence
7 of the issues between the parties, so we’re asking for
8 you to reconsider.
9 MS. TELLES-LANGDON: Ms. Pejovic, I can
10 advise that we will take it under advisement and we’ll
11 advise you following this cross-examination. I would
12 note that the CIHR funds all health research in Canada
13 like any granting, any person doing health research
14 applies to CIHR ---
15 MR. BACHAND: I don’t think you can testify
16 to that, I’m sorry Sharlene.
17 MS. TELLES-LANGDON: That’s fine, Mr.
18 Bachand, we will take it under advisement and advise
19 you following the cross-examination, so we don’t hold
20 things up.
21 MS. PEJOVIC: Thank you.
22 --- UNDER ADVISEMENT NO. 1
23 BY MR. PEJOVIC:
24 46. Q. Okay, moving on. Dr. Liu, are you --
25 have you ever received funding from Pfizer?

AR09286
DR. PETER LIU - 19
1 A. No -- oh, so what do you mean, Pfizer
2 for my entire lifetime or is this ---
3 47. Q. Yes.
4 A. --- government -- in my entire
5 lifetime, Pfizer, yeah so, maybe back maybe more than
6 20 years ago, you know I did a blood pressure study
7 with Pfizer.
8 48. Q. Okay and are you currently receiving
9 funding from Pfizer?
10 A. No.
11 49. Q. Have you ever received funding from
12 Moderna?
13 A. No.
14 50. Q. Are you currently receiving funding
15 from Moderna?
16 A. No.
17 51. Q. Have you ever received funding from
18 AstraZeneca or Johnson and Johnson?
19 A. AstraZeneca again you know I have to
20 jog back to my memory, so this is all my lifetime
21 record, is that right, is it ---
22 52. Q. That’s what I’m asking.
23 A. Okay, right. I’m thinking that again
24 probably 10 or 12 years ago, studying a heart failure
25 drug, yeah, that’s in terms of AstraZeneca, yeah.

AR09287
DR. PETER LIU - 20
1 53. Q. Okay, 10 years ago?
2 A. Yeah or 12 years ago probably, so it’s
3 quite a long time.
4 54. Q. Okay and are you currently receiving
5 funding from AstraZeneca or Johnson and Johnson?
6 A. No.
7 55. Q. Has the Ottawa Heart Institute ever
8 received funding from Pfizer, Moderna, AstraZeneca or
9 Johnson and Johnson?
10 A. Not Pfizer or Moderna, we likely will
11 receive funding from AstraZeneca because we have
12 medical education conferences and you know we have
13 unrestricted educational grant from you know many
14 partners and so it’s very conceivable that AstraZeneca
15 will be one of the contributing partners.
16 56. Q. So, it’s just AstraZeneca alone ---
17 MS. TELLES-LANGDON: Sorry, Ms. Pejovic, can
18 I ask on the question you asked previously, where you
19 asked has the Ottawa Heart Institute ever received
20 funding ---
21 MS. PEJOVIC: Yes.
22 MS. TELLES-LANGDON: Could you limit the
23 scope of that timeframe to the time during which Dr.
24 Liu has been part of the Ottawa Heart Institute -- I
25 don’t know, I mean he’s the head of the heart

AR09288
DR. PETER LIU - 21
1 institute now, but how would he know what Ottawa Heart
2 may have received prior to his joining the Ottawa
3 Heart Institute?
4 BY MR. PEJOVIC:
5 57. Q. Well, okay. Dr. Liu, when did you join
6 the Ottawa Heart Institute?
7 A. Two thousand twelve.
8 58. Q. Okay, so your evidence is that to your
9 knowledge, AstraZeneca is the only company out of the
10 four that has funded the Ottawa Heart Institute?
11 A. Ever or since my arrival?
12 59. Q. Okay, we’ll start with ever to your
13 knowledge.
14 A. Ever, I think that there may be one
15 relate to Pfizer you know because there is -- I
16 remember there was a chair on hypertension, on high
17 blood pressure and I remember that you know this is of
18 course a long time ago, because Pfizer doesn’t make
19 any of these medications anymore, yeah so I think
20 Pfizer did contribute to that chair you know which
21 establish way way before and I’m not quite sure when
22 that was.
23 60. Q. I’m going to ask for an undertaking for
24 you to look into which of the four companies, Pfizer,
25 Moderna, AstraZeneca or Johnson and Johnson has ever

AR09289
DR. PETER LIU - 22
1 provided funding to the Ottawa Heart Institute, how
2 much was the funding and what was it for.
3 A. Every meeting ---
4 MS. TELLES-LANGDON: --- sorry, Ms. Pejovic
5 ----
6 THE DEPONENT: ---
7 MS. TELLES-LANGDON: Dr. Liu, Dr, Liu, hold
8 on. Ms. Pejovic, I’m certainly not giving an
9 undertaking to has the Ottawa Heart Institute ever in
10 its entire existence, at time of existence we see
11 funding from any of these, if you’re looking for an
12 undertaking for the timeframe when Dr. Liu has been
13 the head of the Heart Institute, we’ll take that under
14 advisement but you are aware that cross-examination is
15 not discovery.
16 MS. PEJOVIC: No, I understand that but
17 that’s where he is now, he’s the Chief Scientific
18 Officer now and if there’s a relationship -- a
19 relationship of funding, that goes to whether there
20 could be a potential conflict of interest in this
21 matter and you know whether that relationship was
22 established and formed prior to his joining, the
23 applicants have a right to know and the court ought to
24 know whether there’s a pre-existing relationship
25 between the Ottawa Heart Institute and any of the drug

AR09290
DR. PETER LIU - 23
1 companies that are providing the vaccines which are
2 part of this travel mandate.
3 MS. TELLES-LANGDON: Ms. Pejovic, we will
4 take that under advisement.
6 --- UNDER ADVISEMENT NO. 2
7 BY MR. PEJOVIC:
8 61. Q. Dr. Liu, do you receive payment from
9 any source to encourage COVID-19 vaccination?
10 A. Any source to an encourage vaccination,
11 no.
12 62. Q. Okay, and just going to go back to your
13 Affidavit -- just bare with me for a moment, please.
14 A. No problems.
15 63. Q. Okay, can you turn to Exhibit B of your
16 Affidavit please, Dr. Liu. Which is the Opinion on
17 Peckford et al v. Attorney General of Canada at page
18 two.
19 A. Exhibit B ---
20 64. Q. ---
21 A. --- that’s just a signature.
22 65. Q. Okay, it’s my PDF page 76 instead of
23 94.
24 A. Oh, 76, yeah okay because it starts on
25 page 74, okay. So, we want page 76?

AR09291
DR. PETER LIU - 24
1 66. Q. Yes, and at the bottom it says opinion
2 on Peckford, page two.
3 A. Let me just make sure I get the right
4 page. Yes, okay, I have it.
5 67. Q. And I’m looking at the last paragraph
6 on that page, it starts with in terms of, do you see
7 that paragraph Dr. Liu?
8 A. Yes, I do.
9 68. Q. Okay, so I want to go to the last
10 sentence of that paragraph which starts,
11 “...Finally in the area of COVID-19
12 associated myocarditis, I, along with the other are
13 invited members of the science expert table organized
14 by Canada’s Chief Scientist Dr. Mona Nemer...”
15 And when did you become invited to join
16 that science expert table?
17 A. I will have to double check regarding
18 the exact date but it would be around May I would say,
19 you know so but I have to say that this is an estimate
20 because you know -- if you want an exact date, I’ll
21 try to ---
22 69. Q. Is that May of 2021, Dr Liu?
23 A. May of 2021, I’m sorry.
24 70. Q. Yes.
25 A. Yes.

AR09292
DR. PETER LIU - 25
1 71. Q. Okay, and what role do you have in the
2 decision making process -- sorry, I’ll start that
3 again. What is your role at the science expert table?
4 A. To provide objective evidence that is
5 available on the myocarditis following mRNA vaccine
6 available worldwide at that time.
7 72. Q. And I’m looking at the next sentence.
8 A. Mm-hmm.
9 73. Q. And it looks like, I’m just going to --
10 it doesn’t look like a complete sentence and I’m
11 wondering what you meant to say Dr. Liu, and I’ll just
12 read it for you into the record.
13 “...Other leaders of the major federal
14 agencies such as Health Canada, Public Health Agency
15 of Canada and National Advisory Committee
16 Immunization, as well as other major academic
17 experts...”
18 What did you mean by that, it seems
19 like you wanted to say something else, maybe you could
20 just let me know what did you mean by that sentence?
21 A. I get they were present, yeah sorry.
22 Probably the page separation cut the sentence off,
23 yeah. I think the -- probably the way you should be
24 read is that Canada Chief Scientist, Dr. Mona Nemer,
25 also including other leaders -- yeah, I think that’s

AR09293
DR. PETER LIU - 26
1 probably what it should be, yeah because I’m only one
2 of many experts around the table and you know my task
3 was because we were collecting data on this area so I
4 presented data that was available at that time.
5 74. Q. And so, this science expert table, is
6 this just a group who meets about vaccine induced
7 myocarditis or they’re other issues in other experts
8 which have nothing to do with COVID-19 myocarditis?
9 A. The predominant purpose of this
10 particular meeting is regarding the myocarditis
11 related vaccine, yeah and this is actually available
12 publicly, it’s on the Chief Science Officers website.
13 75. Q. Okay and do you have a role in the
14 decision making process for the federal vaccine
15 mandates, Dr. Liu?
16 A. No.
17 76. Q. Do you provide advice to the federal
18 government as to their policies on vaccine mandates?
19 A. No.
20 77. Q. When did you have your last meeting?
21 A. Of this group?
22 78. Q. Yes.
23 A. This group had a second meeting in June
24 of 2021 and that’s when some of the action
25 recommendations that came around and one of the

AR09294
DR. PETER LIU - 27
1 recommendation was to develop a registry so they could
2 collect more data on this condition, you know hence
3 the rent that you saw.
4 79. Q. Okay, so you haven’t had a meeting in a
5 year about vaccine induced ---
6 A. --- yeah, there isn’t -- certainly not
7 organized by the chief scientist, no.
8 80. Q. Okay. So, I’m going to get into your
9 expert report now and you have indicated in your
10 Affidavit and your expert report that you’ve done a
11 lot of work in your career studying myocarditis,
12 correct?
13 A. Yes.
14 81. Q. And how in your experience, how is
15 myocarditis diagnosed?
16 A. In this patients who present with
17 myocarditis it depends on the age of presentation and
18 for younger patients, they can present with chest
19 pain, shortness of breath, palpitations you know heart
20 feels like jumping around and or you know swelling of
21 the legs which indicates heart failure.
22 And in older patients, they may only
23 have shortness of breath and they may not have any of
24 the other symptoms and then the diagnosis of
25 myocarditis is that of inclusion and exclusion.

AR09295
DR. PETER LIU - 28
1 So the -- standard for diagnosis on
2 myocarditis is cardio biopsy but that’s rarely done
3 because the patient could be very sick and you know
4 taking a piece of heart muscle out is not always the
5 safest procedure and the current diagnosis is
6 generally done with MRI scan, Magnetic Resonance
7 Imaging scan, which can pick up inflammation in the
8 heart muscle, that’s what myocarditis is.
9 If you don’t have that available, then
10 you may use echocardiogram ultrasound to look at heart
11 function, to look at fluid around the heart and you
12 also confirmed with evidence with heart injury and
13 there are blood based markers you know like troponin
14 is the classic one and you can also get
15 electrocardiogram changes but it’s kind of in that
16 order in terms of specificity but on the other hand
17 there’s also exclusion as well you know because you
18 can have patients coming in with a heart attack you
19 know presenting with the same kind of symptoms.
20 So, usually if needed one may do
21 angiogram to look at the arteries of the heart and but
22 this is more often done in older patients because the
23 chance of blockage in the arteries are more common in
24 older patients and younger patients, we usually do not
25 do that as a routine.

AR09296
DR. PETER LIU - 29
1 82. Q. Okay and in your expert report at page
2 four, both in -- just let me know if you’re there.
3 A. Page four yeah, starting with my
4 opinion, background ---
5 83. Q. --- yes, yes.
6 A. --- yes.
7 84. Q. So, in the section background preamble
8 ---
9 A. Yes.
10 85. Q. And the first sentence of the second
11 section as well, you’re describing the vaccine --
12 COVID-19 vaccines as they are proven to be safe.
13 A. Yes.
14 86. Q. And they are remarkably safe, you see
15 that, Dr. Liu?
16 A. Yes, so I do say that they’re safe.
17 87. Q. You say remarkably safe in the first
18 sentence of section two.
19 A. Yes, yes that’s in the report, yes.
20 88. Q. Dr. Liu, wouldn’t you agree with me
21 that these vaccines are not safe for everyone?
22 A. I think it’s all relevant when we
23 actually say safe because we recommend aspirin for
24 many people, is aspirin safe and aspirin is not safe
25 yet we recommend to many people so, you know in

AR09297
DR. PETER LIU - 30
1 medicine safe is a relative term and it’s not absolute
2 term so this is -- by all things considered, that you
3 have a vaccine that’s developed in less than one year
4 that is able to save millions of lives and the
5 frequency of side effects is remarkably few compared
6 to even other vaccines that we know.
7 And compared to other medicines like
8 aspirin which you know many people will take without
9 even worrying about anything, this vaccine is way
10 safer.
11 So, you know, that’s the difference --
12 context when we talk about medical safety, absolutely.
13 89. Q. But you’d agree with me Dr. Liu that
14 the COVID-19 vaccines have caused death?
15 A. Have caused -- yeah, out of the 337
16 billion doses of Pfizer and 252 billion Moderna, I
17 know of two proven cases of death, yes.
18 MS. TELLES-LANGDON: Ms. Pejovic, would it
19 be possible for you to provide some precision as far
20 as which vaccines, like at least in separating mRNA
21 vaccines from AstraZeneca vaccines unless you’re just
22 looking at ---
23 MS. PEJOVIC: Well, I mean, the travel
24 mandates don’t require a particular vaccine, so I’m
25 talking about all vaccines at this point during these

AR09298
DR. PETER LIU - 31
1 questions.
2 MS. TELLES-LANGDON: Okay.
3 BY MR. PEJOVIC:
4 90. Q. And Dr. Liu, the COVID-19 vaccines have
5 caused blood clots, have they not?
6 A. Only certain -- yes, certain types of
7 vaccines have caused blood clots.
8 91. Q. And that’s a serious condition, isn’t
9 it?
10 A. It can be, yes, it’s a whole range of
11 presentations, yes, it can be severe.
12 92. Q. And the COVID-19 vaccines have caused
13 heart inflammation, correct?
14 A. Yes, but we’re talking about two
15 different vaccines
16 93. Q. And the COVID-19 vaccines have causes
17 Bell’s Palsy, correct?
18 A. Yes, but again very rarely.
19 94. Q. And you’d agree with me Dr. Liu, that
20 these vaccines all these vaccines, COVID-19 vaccines,
21 they are new, correct?
22 A. They are new because COVID-19 is new.
23 95. Q. Right and the mRNA vaccines in
24 particular have never been used on humans before,
25 correct?

AR09299
DR. PETER LIU - 32
1 A. They have been tested in Ebola patients
2 before.
3 96. Q. But they have not been approved for use
4 on humans prior to the COVID-19 vaccines, correct?
5 A. In terms of the FDA approval, yes
6 regulatory approval, yes.
7 97. Q. And we don’t have long term safety data
8 for any of the COVID-19 vaccines, do we Dr. Liu?
9 A. The fact that we have now administered
10 over 500 billion doses around the world and the mRNA
11 vaccines has only two deaths, I think we have very
12 good safety data.
13 98. Q. But I’m asking ---
14 MS. TELLES-LANGDON: Miss ---
15 MS. PEJOVIC: --- long term safety data, I’m
16 not asking how many doses have been administered Dr.
17 Liu, do we have safety data for five years down the
18 road, for ten years down the road Dr. Liu?
19 MS. TELLES-LANGDON: So, Ms. Pejovic?
20 MS. PEJOVIC: Yes?
21 MS. TELLES-LANGDON: You established at the
22 beginning that Dr. Liu is a cardiologist, he’s not a
23 vaccinologist or an immunologist. We do have an
24 immunologist and a (inaudible) in this case, I’m just
25 wondering how many questions you’re looking to ask Dr.

AR09300
DR. PETER LIU - 33
1 Liu with respect to long term vaccine safety?
2 MS. PEJOVIC: I’m not going to go into too
3 much detail, but I think as a medical physician he can
4 provide his opinion on whether the vaccines have been
5 around long enough for people to study the long term
6 safety data for five or ten years, I don’t think we
7 need a vaccinologist to opine on that issue.
8 THE DEPONENT: On the technical turn of
9 course the vaccine haven’t been around that long.
10 MS. PEJOVIC: Okay.
11 THE DEPONENT: But on the other hand in
12 terms of as a physician do I think they are safe, I
13 think they are safe.
14 BY MR. PEJOVIC:
15 99. Q. I understand your position Dr. Liu, but
16 the question I had was do we have data from five years
17 after the vaccines were rolled out as to whether
18 they’re safe?
19 A. No, because they haven’t been out for
20 five years.
21 100. Q. Thank you and they haven’t been proven
22 to be safe in the long term have they because you have
23 in your first sentence of your report you state,
24 “...COVID-19 vaccines were proven to be
25 safe and effective...”

AR09301
DR. PETER LIU - 34
1 Proven, safe and effective but there is
2 no proof that they are safe five years after someone
3 takes them, correct Dr. Liu?
4 A. From ---
5 MS. TELLES-LANGDON: --- I -- I -- sorry,
6 I’m going to object now. We have an immunologist who
7 speaks very clearly to the -- this question. The
8 question of how vaccines function in the body and
9 would be the person -- the expert we put forward who
10 is specifically positioned to answer and address these
11 questions as an immunologist ---
12 MS. PEJOVIC: Ms. Telles-Langdon ---
13 MS. TELLES-LANGDON: --- we’ve also put
14 forward Dr. Lourenco who is the person who approved
15 these vaccines. There are witnesses that are put
16 forward to speak to this question, Dr. Liu is here as
17 a cardiologist.
18 MS. PEJOVIC: I understand that, but he’s
19 put that in his expert report and if I don’t challenge
20 him on it, it goes in as unchallenged, the statement
21 that they have been proven to be effective and safe.
22 I have to challenge him on that if I don’t agree with
23 it, that’s his evidence.
24 MS. TELLES-LANGDON: Right, that’s fine.
25 Continue, Ms. Pejovic.

AR09302
DR. PETER LIU - 35
1 BY MR. PEJOVIC:
2 101. Q. Dr. Liu, when you make the statement at
3 the first sentence of your report, COVID-19 vaccines
4 were proven to be effective and safe, you’re talking
5 about the short-term and not the long-term, correct?
6 A. Given all the data we have available
7 but you know when you use a vaccine, you are dealing
8 with a medical emergency situation, we are dealing
9 with a pandemic.
10 This is not something that you will say
11 you know, is this going to have any risk down the
12 road, right you have somebody dying in front of you,
13 you know this is -- when somebody has a cardiac
14 arrest, I don’t say you know is this drug that I’m
15 going to give, you know will actually have any impact
16 ten years down the road.
17 There is a medical compelling situation
18 we need to actually have a solution and if you, you
19 know have someone who has a heart attack in front of
20 you and you say well, I can’t actually you know treat
21 this patient because I don’t know any of these
22 treatments 10 years down the road whom have any affect
23 of not, is this how you want medicine to be practiced
24 right.
25 So, this is not how we actually make

AR09303
DR. PETER LIU - 36
1 decisions, and we know that compared to other vaccines
2 -- publishing you know sort of data in which we
3 compared you know with other vaccines available of
4 which are already accepted to be used in the entire --
5 the flu vaccine or smallpox vaccine or any of the
6 others when you do these comparisons, these are
7 extremely comfortable.
8 Right, so this is the type of standard
9 we have to use -- to decide whether something is safe
10 or not when there is actually a pandemic in front of
11 us. This isn’t something you take ten years down the
12 road, oh, I’m not going to you know sort of consider
13 treatment today simply because I don’t know what it’s
14 going to do ten years down the road.
15 Cancer patients are going to die today,
16 all my heart attack patients going to die today
17 because I don’t know how it’s going to do ten years
18 down the road.
19 You know, I just want you to -- that
20 perspective, you know think of your father, you know
21 is this how you want to actually make that medical
22 decision.
23 102. Q. I’m going to put to you Dr. Liu that
24 this research grant to study heart inflammation from
25 the vaccines is proof that the vaccines have not been

AR09304
DR. PETER LIU - 37
1 proven to be safe, nor are they remarkably safe, would
2 you agree with that?
3 A. Yes, so we want to actually collect
4 more data but keeping in mind that these are extremely
5 rare complications.
6 103. Q. And not only have you stated that the
7 vaccines are proven to be safe, you also said they’ve
8 -- they’re proven to be effective and safe and I’m
9 putting to you Dr. Liu, that they aren’t effective
10 against Omicron, are they?
11 A. I have in my second paragraph there,
12 COVID-19 extremely effective preventing death and
13 hospitalization by 85 to 90 per cent and that is
14 absolutely true for Omicron.
15 104. Q. There are many cases of vaccinated
16 people becoming effected with Omicron, correct?
17 A. Many meaning?
18 105. Q. Dr. Liu, the COVID-19 vaccines do not
19 prevent vaccinated person from getting Omicron,
20 correct?
21 A. That’s not the effectiveness we’re
22 talking about, right because the true protection we
23 want to see in the population is death in the
24 hospitalization, it doesn’t actually -- the vaccine
25 are not designed to prevent the infection because you

AR09305
DR. PETER LIU - 38
1 are kind of mixing those two parts, right so I’m
2 talking about effectiveness because the vaccines are
3 key to really prevent the death of you know we have
4 our elderly Canadians dying from COVID-19, we have to
5 do something and the vaccine very effectively
6 prevented their death and that is the effectiveness
7 because that really actually matters to Canadians.
8 The getting infected is a different
9 parameter and whether the vaccine can prevent that or
10 not, I think that is yet to be determined, you’re
11 right on that but the effectiveness that we’re talking
12 about in terms of COVID-19 is death and
13 hospitalization and that is how the effectiveness is
14 measured.
15 106. Q. And in that second paragraph, you
16 haven’t provided a source for your data, have you?
17 A. Second paragraph in terms of -- you’re
18 referring to 85/90 per cent?
19 107. Q. Yes.
20 A. Yeah, I mean it’s like you know like
21 there are so many sources, yeah if you need a source,
22 I can find one but there’s you know confirmed times
23 and times again.
24 108. Q. All right. So, we’ll go to the second
25 part of the expert report, number two, Whether the

AR09306
DR. PETER LIU - 39
1 COVID-19 Vaccines Can Cause Heart Injury and if so, to
2 what extent?
3 A. Okay.
4 109. Q. Okay so, the first sentence I’m going
5 to read it -- sorry, the second sentence.
6 “...However, with a newer mRNA based
7 vaccines which is Pfizer and Moderna, there are
8 reported cases of myocarditis reported within days of
9 receiving the vaccines starting in April and May of
10 2021...”
11 So, that’s when you first started
12 seeing reports of myocarditis from the vaccine?
13 A. Yes, correct. Yeah, around that time,
14 yeah.
15 110. Q. And was that data from all over the
16 world, was it Canadian data, where was the data from?
17 A. Yeah, it’s data from the world, Israeli
18 you know they are the first to vaccinate their
19 population, they were the first ones to report that,
20 and then you know, sort of other countries followed
21 afterwards.
22 111. Q. Okay and the second paragraph, you say,
23 “...The incidents of complications form
24 the COVID-19 vaccines is best estimated from data from
25 the U.S. and you cite a paper by the author Chouchana

AR09307
DR. PETER LIU - 40
1 and Journal of Clinical...”
2 -- is that pharmacology?
3 A. Yes, therapeutics, yes. That’s
4 actually our paper, yes.
5 112. Q. Okay.
6 A. Yeah.
7 113. Q. I’d like you to just take a look at
8 that paper, I’m going to pull it up for myself as
9 well.
10 A. Okay, let me bring that, yeah.
11 114. Q. Do you have it in front of you, Dr.
12 Liu?
13 A. Yes, I have it open now, yes.
14 115. Q. Okay, and if you can go to the
15 discussion section.
16 A. Okay.
17 116. Q. Just let me know when you’re there,
18 please.
19 A. Okay, starts on page 607.
20 117. Q. I don’t have page numbers on this PDF
21 here, but ---
22 A. Okay ---
23 118. Q. It starts,
24 “...In this global pharmacovigilance --
25 -

AR09308
DR. PETER LIU - 41
1 A. Yes, okay. The page is 607.
2 119. Q. And it states,
3 “...We report the largest case series
4 of inflammatory heart reactions following mRNA COVID-
5 19 vaccination to date...”
6 Right?
7 A. Yes.
8 120. Q. And then two sentences down, it starts,
9 “...These myocarditis and pericarditis
10 cases mostly required hospitalization, some were life-
11 threatening, and, in older patients, occasionally
12 fatal...”
13 A. Right, yeah.
14 121. Q. Right and you authored this study,
15 didn’t you, Dr. Liu?
16 A. Yes, I’m one of the authors, yes.
17 122. Q. Yeah, and so you agree with me from
18 this study, you’ve concluded that myocarditis from
19 COVID-19 vaccines can be life threatening, correct?
20 A. Can be, yes.
21 123. Q. And myocarditis from COVID-19 vaccines
22 can be fatal, correct?
23 A. Yes, but the numbers are extremely
24 small, I just want to qualify that, yes.
25 124. Q. And in the last sentence of the

AR09309
DR. PETER LIU - 42
1 paragraph you state,
2 “...This supports that myocarditis may
3 appear very rarely following mRNA vaccination, even in
4 young people, although our analysis cannot assess
5 accurate incidence...”
6 And if you go down to the next
7 paragraph, the second -- the third sentence starts,
8 “...Although our approach cannot
9 accurately assess reaction incidence owing to under-
10 reporting...”
11 You see that?
12 A. Yes.
13 125. Q. So, you’ve acknowledged that there’s an
14 under-reporting of myocarditis after COVID-19
15 vaccination?
16 A. Based on this set of data because you
17 know because these are -- especially you know we
18 include the World Health Organization which is
19 collecting data from all over the world and so it
20 really depends on the -- it’s a voluntarily reporting
21 database and so there can be barriers you know in the
22 health system you know so different countries
23 obviously have different efficiencies in terms of
24 reporting.
25 So, you know we’re just very careful in

AR09310
DR. PETER LIU - 43
1 terms of you know certainly this data is likely under-
2 reported because it’s a voluntarily basis around the
3 world.
4 126. Q. Okay, now please go to page five of
5 your expert report.
6 A. Okay, out of this paper now?
7 127. Q. Yes, yes.
8 A. Okay, yeah.
9 128. Q. Okay, are you there?
10 A. Sorry, I opened the wrong one, I opened
11 Dr. McCullough’s.
12 129. Q. The second paragraph states ---
13 A. Apologies, which page are we on?
14 130. Q. Page five of your expert report.
15 A. Page five, okay yes.
16 131. Q. It starts with fortunately, you see
17 that?
18 A. Mm-hmm.
19 132. Q. “...In contrast to COVID-19 induced
20 myocarditis or traditional viral myocarditis prior to
21 the pandemic, the natural history associated mRNA
22 vaccine induced myocarditis appears to have a
23 relatively good outcome...”
24 You consider being hospitalized for a
25 short time a good outcome, Dr. Liu?

AR09311
DR. PETER LIU - 44
1 A. Yeah, so the outcome generally that’s
2 important to the cardiologist is obviously death and
3 development of heart failure and requirement you know
4 for a heart transplantation and being hospitalized is
5 you know sort of one component of the journey but it’s
6 not necessarily you know an end point in this self in
7 terms of the myocarditis outcome and you know there’s
8 a reason for these patients that are hospitalized for
9 this so, I think I kind of -- other parts of the
10 report.
11 133. Q. And having a life threatening case of
12 myocarditis from a COVID-19 vaccine isn’t a good
13 outcome, is it Dr. Liu?
14 A. It’s not a good outcome considering if
15 you didn’t have this complication of course life is
16 better, yeah but I put this in the context of if you
17 compared to other types of myocarditis, whether it’s
18 COVID-19 related myocarditis or pre-pandemic
19 myocarditis, the outcomes for patients with vaccine
20 induced myocarditis appears to be very good by
21 comparison, yes, they are in hospital.
22 Quite often they might be in hospital
23 for four days but they are discharged home, they
24 recover, they actually do reasonably well and this is
25 you know out of this spectrum of outcomes of patients

AR09312
DR. PETER LIU - 45
1 with myocarditis, this is a good outcome.
2 134. Q. And so, your opinion that from the data
3 that you’ve seen that myocarditis, post covid vaccine
4 instances result in a good outcome for patients is
5 based on the fact that -- I’m asking you, is it based
6 on the fact that these patients are discharged from
7 the hospital after a couple of days, is that what
8 you’re basing it on?
9 A. Yeah, based on our own data, you know
10 data from CDC, data from others as well and so, the
11 classic patients with myocarditis, we got quite often
12 say that is one-third, one-third, one-third you know,
13 so one-third will actually recover, one-third will
14 actually persist with some continuing symptoms or
15 problems and one third will deteriorate you know get
16 heart failure or require heart transplantation.
17 That’s kind of the traditional outcome
18 of myocarditis you know sort of that we look after or
19 you know any major series, but for the patients coming
20 with COVID-19 -- sorry, not COVID-19 the mRNA vaccine
21 -- myocarditis, you know they can have these symptoms,
22 they come in and -- but usually within four days, they
23 have recovered the symptoms actually go away and then
24 when they are discharged home, they usually don’t need
25 to come back to hospital or any recurrence problems.

AR09313
DR. PETER LIU - 46
1 You know like the other patients and
2 for the ones that I have followed so far, you know I
3 guess now a year now, you know for certainly the
4 longest patient we follow, they all recover, which is
5 great because that is not what happens with the
6 traditional myocarditis, and so broadly speaking for
7 the patients we have to look after, this is confirmed
8 also you know the CDC experience from other colleagues
9 around the world, yes so, in the spectrum of
10 myocarditis and in terms of myocarditis recovery the
11 patient with the vaccine use myocarditis very well.
12 135. Q. And you use the word appears?
13 A. Yeah.
14 136. Q. Appears to have a relatively good
15 outcome because you don’t know the long term prognosis
16 for someone who has COVID-19 vaccine induced
17 myocarditis, do you?
18 A. No, yes, so that’s why we’re following
19 them for a long period of time, that’s why we’re doing
20 the study, but from our indication we have so far is
21 reassuring of course you know being a scientist we
22 always need to be open minded and you know that’s why
23 we follow them, let the data speak for themselves,
24 yes.
25 137. Q. And in your Affidavit and I’m happy to

AR09314
DR. PETER LIU - 47
1 take you there if you need me to take you there but
2 you have stated that in preparing this expert report,
3 you’ve referred to published literature and also
4 recent data, you agree with that?
5 A. Yes.
6 138. Q. --- Dr. Liu -- and yet, you did not
7 include a new study by Jenna Schauer in the Journal of
8 Pediatrics which was published in March of 2022 over a
9 month before you wrote your Affidavit, correct?
10 A. Could be I may have missed a paper, I’m
11 sorry, yeah. I haven’t been -- as I should.
12 139. Q. So, I have e-mailed you that paper.
13 A. Okay.
14 140. Q. It’s the Journal of Pediatrics,
15 Persistent Cardiac Magnetic Resonance Imaging Findings
16 in a Cohort of Adolescents with Post-Coronavirus
17 Disease 2019 mRNA Vaccine Myopericarditis, do you see
18 that, Dr. Liu?
19 A. Sorry, I must apologize, I’m a little
20 slow getting that particular paper for some reason, so
21 let me. What’s the first word in the title?
22 141. Q. Persistent -- oh, the e-mail.
23 A. ---
24 142. Q. --- Schauer S-C-H ---
25 A. Oh, Schauer, yes okay ---

AR09315
DR. PETER LIU - 48
1 143. Q. --- I spelt it wrong ---
2 A. Yeah, okay, okay, because it didn’t
3 have any other information on there. Yes, okay, yes.
4 144. Q. Have you seen this study before?
5 A. I don’t think so, but I’m happy to read
6 it and if you’d like to refer to it, sure.
7 145. Q. Yeah, it’s only four pages long, would
8 you like five minutes to take a look at it or ---
9 A. Yeah, so if we want to discuss it, then
10 that would be really helpful, yes.
11 MS. PEJOVIC: Is that all right with you,
12 Ms. Tells-Langdon?
13 MS. TELLES-LANGDON: That is fine, in fact
14 Ms. Pejovic, I was going to suggest that this would be
15 a good time for a ---
17 MS. TELLES-LANGDON: --- short break.
18 --- OFF THE RECORD (REPLACE) ---
19 BY MR. PEJOVIC:
20 146. Q. Dr. Liu, can I confirm with you that
21 you did not speak with anyone during the break?
22 A. No, I don’t have anybody to speak to.
23 147. Q. Okay, just as a matter of housekeeping
24 as well, I would like to mark the Chouchana study as
25 the first exhibit.

AR09316
DR. PETER LIU - 49
1 MS. PEJOVIC: Any objection Ms. Telles-
2 Langdon?
3 MS. TELLES-LANGDON: Sorry, no objection, I
4 was just trying to recall which study you were
5 speaking about.
7 --- EXHIBIT NO. 1: Chouchana Study: Features of
8 Inflammatory Heart Reactions Following mRNA COVID-19
9 Vaccination at a Global Level.
10 BY MR. PEJOVIC:
11 148. Q. Are you ready to answer some questions
12 on this Journal of Pediatrics study, Dr. Liu?
13 A. Yes, I got a chance to read it, yes.
14 149. Q. Okay, and before the break you had
15 testified that you had not seen this study before ---
16 A. Not this particular study, yes.
17 150. Q. Okay, so you were not aware of the stud
18 when you wrote your expert report then?
19 A. Not in the expert report but we have
20 our own data you know on Magnetic Resonance Imaging,
21 yeah that’s more than this study, but yeah, that’s
22 fine.
23 151. Q. Okay, so I’m going to read I don’t know
24 if you call it a head note or the first paragraph of
25 an explanation as to what the study is about, I’m

AR09317
DR. PETER LIU - 50
1 going to read that into the record.
2 “...We describe the evolution of
3 cardiac magnetic resonance imaging findings in 16
4 patients, aged 12 to 17 years, with myopericarditis
5 after the second dose of the Pfizer mRNA coronavirus
6 disease 2019 vaccine. Although all patients showed
7 rapid clinical improvement, many had persistent
8 cardiac magnetic resonance imaging findings at three
9 to eight month follow-up...”
10 And did you see in this study Dr. Liu,
11 that these patients with COVID-19 induced -- COVID-19
12 induced myopericarditis were hospitalized and the
13 median hospital stay was about two days, did you see
14 that?
15 A. I remember reading it, yes.
16 152. Q. Okay and would you agree with me Dr.
17 Liu that these patients had no intensive care
18 admission?
19 A. I think you’re correct.
20 153. Q. And none of these patients died,
21 correct?
22 A. No. Yes, no death.
23 154. Q. And all of the patients had a
24 resolution of chest pain at the time they were
25 discharged from the hospital, correct?

AR09318
DR. PETER LIU - 51
1 A. Yes.
2 155. Q. Would you agree with me Dr. Liu that
3 this study shows that beyond three months when these
4 patients were followed up, there were persistent
5 abnormal findings on cardiac MRI at follow up in most
6 patients who had clinically diagnosed vaccine induced
7 myocarditis, would you agree with that?
8 A. Yes, they did actually describe some
9 abnormalities in the context of the patients have
10 clinically improved and you’re right, yes. So, let’s
11 pause there and see how like what your next question
12 is.
13 156. Q. Sure, let’s go to the discussion
14 section of this paper.
15 A. Yes, yes.
16 157. Q. And that is at page three and in the
17 first paragraph halfway down, the sentence starts,
18 “...cardiac MRI was performed within 3-
19 6 months to guide next clinical decision-making
20 steps...”
21 See that?
22 A. Yeah.
23 158. Q. And then the next sentence starts,
24 “...Although symptoms were transient
25 and most patients appeared to respond to treatment we

AR09319
DR. PETER LIU - 52
1 demonstrated persistence of abnormal findings on
2 cardiac MRI at follow-up in most patients, albeit with
3 improvement in extent of LGE...”
4 You see that?
5 A. Yes.
6 159. Q. And Dr. Liu, for the record, what is
7 LGE, I’m assuming you know the answer to that?
8 A. Yes. Late Gadolinium Enhancement and
9 it’s a technique they use in the MRI and the idea is
10 actually to see if there is any evidence of cardiac
11 scaring and so this is a very useful technique for the
12 traditional study of patient with heart disease, the
13 only important caveat here is that the LGE importance
14 in vaccine use myocarditis is certainly not
15 established and I think that is indicated in the rest
16 of the paper as well.
17 So, yeah, it’s really an interesting
18 finding and you know the mention -- we probably didn’t
19 reference this paper because we have findings of way
20 larger patient population and it is true that a number
21 of patients do actually show these residual MRI
22 abnormalities, the major -- I know at the present time
23 is how significant they are.
24 160. Q. So, you stated that you have data from
25 your own studies that show persistent abnormalities?

AR09320
DR. PETER LIU - 53
1 A. Not persistent but residual, yeah.
2 161. Q. Residual abnormalities. How long after
3 discharge from the hospital?
4 A. Some are three months, yeah.
5 162. Q. And what sort of abnormalities have you
6 seen in your position ---
7 A. --- it’s similar you know, so you do
8 actually have some persistent LGE activation, yeah.
9 163. Q. And is this -- is that data within a
10 study that’s been published or where is that?
11 A. No, it’s not that is why I say you know
12 we have our own data on this, but the important thing
13 is that I think the general you know and I think it’s
14 reflected in this paper, it’s very interesting -- this
15 is a very interesting phenomena associated with this
16 condition in which you do actually have to be
17 persistent of LGE on some patients you know with MRI
18 with vaccine used the myocarditis and the interesting
19 aspect is that -- better, heart function improves.
20 You know I think this study shows the
21 exactly the same as well, yeah and so that’s why I
22 think most people are currently very intrigued by this
23 phenomenon but very open minded because a lot of
24 studies now we have with LGE in other patient
25 populations for example with people with cancer you

AR09321
DR. PETER LIU - 54
1 know sort of induced cancer treatment induced a heart
2 disease, we see LGE as well and but it turns out that
3 they have no impact on outcome or prognosis, you know
4 so, it’s interesting phenomenon MRI.
5 164. Q. So, a few sentences ago you said,
6 “...I think the reason why we didn’t
7 include this paper was because the study sample was
8 low...”
9 A. No, I did not -- I correct myself. I
10 missed this paper, yeah in terms of this particular
11 study yeah, so I apologize so I was jumping ahead
12 trying to mention that so you know it is a paper I
13 miss, I apologize.
14 165. Q. Okay, at the top of page three, we see
15 and I’m going to read this.
16 “...The presence of LGE is an indicator
17 of cardiac injury and fibrosis and has been strongly
18 associated with worse prognosis in patients with
19 classical acute myocarditis...”
20 And I’m going to continue.
21 “...In a meta-analysis including 8
22 studies, Yang et al5 found that presence of LGE is a
23 predictor of all cause death, cardiovascular death,
24 cardiac transplant, rehospitalization, recurrent acute
25 myocarditis, and requirement for mechanical

AR09322
DR. PETER LIU - 55
1 circulatory support. Similarly, Georgiopoulos et al8
2 found the presence and extent of LGE to be a
3 significant predictor of adverse cardiac outcomes in
4 an 11 study meta-analysis...”
5 And then at the end of the second
6 paragraph on the right hand side it says,
7 “...The prognostic meaning of LGE in
8 vaccine associated myopericarditis requires further
9 study...”
10 And so you’d agree with me Dr. Liu that
11 there is no definitive conclusion on the long term
12 outcomes of myocarditis -- sorry, COVID-19 vaccine
13 induced myocarditis patients when looking at LGE
14 results because this condition is so new, correct?
15 A. Yes, so I think you know just a few
16 clarifications, you’re actually right in terms of the
17 importance of LGE is being established but you know
18 the underscore there is classic acute myocarditis you
19 know I think -- case earlier right you know the
20 classic acute myocarditis is very different from --
21 myocarditis.
22 You know the outcome’s much worse and
23 the LGE is actually an important prognosticator and
24 then if you actually go back to the introduction you
25 know of the paper that is actually on page one of the

AR09323
DR. PETER LIU - 56
1 document and so, let’s say 12 lines down from the
2 introduction you know with the M, you know sort of
3 starting the paragraph and they put a nicely in
4 context there, there’s a sentence that starts with,
5 “...In classical myocarditis, LGE could
6 be predictive of a poor outcome...”
7 It’s after reference 3, 4.
8 166. Q. Yes, I see that.
9 A. Yeah,
10 “...Little is known about the
11 prognostic value or expected evolution of these
12 cardiac MRI abnormalities associated with post– COVID-
13 19 mRNA vaccine myopericarditis...”
14 You know, so I think it kind of
15 reflects you now the comments later in the discussion
16 as well, you know so this is an interesting
17 phenomenon, you know so that the LGE is very important
18 in classic myocarditis as we mentioned earlier and
19 then you know we track that, that’s very important and
20 you know both this study and our study and others as
21 well you know find that in fact there is LGE
22 persistence in patients with vaccine induced
23 myocarditis, these patients clinically are improved,
24 heart function improved.
25 You know there’s actually no residual

AR09324
DR. PETER LIU - 57
1 abnormalities but there is this interesting phenomenon
2 persistent you know so MRI and so, the -- and we see
3 this also as I mentioned you know in other conditions
4 -- which has no impact on outcome.
5 So, you know we’re open minded so you
6 know, yes, there is this phenomenon it’s very
7 interesting, scientifically we’re tracking it, you
8 know that’s why we’re doing a long term study and but
9 it seem to have a different significance you know in
10 this condition that’d be classic myocarditis you know
11 so this is the real fascination aspect of this
12 finding, yeah.
13 167. Q. Right and you’d agree with me Dr. Liu
14 that because the presence of LGE indicates cardiac
15 injury and worse prognosis in classical acute
16 myocarditis, the presence in LGE in patients who have
17 COVID-19 vaccine induced myocarditis warrants further
18 study going forward?
19 A. Yeah, warrants study, it may not have
20 the same significant at least right now it doesn’t
21 have the same significance you know but -- open minded
22 on that ---
23 168. Q. But it might, correct?
24 A. --- I will say that right now the data
25 doesn’t suggest that you know because clinically they

AR09325
DR. PETER LIU - 58
1 have better -- the heart functions better, you know
2 sort of all the other parameters better which we don’t
3 see you know in the other conditions so, we usually
4 look at the totality of the evidence so we reassured
5 that the patient do get better, that’s the reason that
6 I say we are optimistic that the patient do do well
7 but of course as scientists we are always open minded,
8 you know we wanted to collect the data to be
9 absolutely sure.
10 Yeah, so this is the reason we’re
11 following up on these patients and you know we want to
12 make sure that this truly means that the patient is
13 actually fine, right you know and that doesn’t have
14 the -- you know sort of the usual myocarditis in the
15 patients, right now it seem to be that -- so that it’s
16 not the same disease at all compared to traditional
17 myocarditis.
18 169. Q. And Dr. Liu, I’m looking at the third
19 paragraph on page three on the right hand side. It
20 starts with Strain Analysis by cardiac MRI. What is a
21 strain analysis, Doctor?
22 A. Strain analysis is actually looking at
23 the regional wall motion changes from baseline that is
24 you know how much movement the heart muscle actually
25 makes during the contraction, it’s a rate of movement

AR09326
DR. PETER LIU - 59
1 of the local muscle.
2 170. Q. All right and at the end of that
3 paragraph, you see the sentence,
4 “...Notably, in our cohort, although
5 there was significant reduction in LGE at follow-up,
6 abnormal strain persisted for the majority of patients
7 at follow-up...”
8 Isn’t that a concern, Dr. Liu?
9 A. Yeah, so this is also what we’re
10 studying, we’re also seeing this as well and so it’s
11 interesting that everything else improved but the
12 strain does not you know in this particular study.
13 Yeah, so that’s another parameter that we’re following
14 but you know again the question now is raised, and in
15 fact you know since we actually wrote the original MRI
16 criteria for classic myocarditis, the -- group now
17 actually want to get together to redefine these
18 significance of these in vaccine induced myocarditis,
19 you know.
20 Because people are finding these
21 abnormalities however the significance appears to be
22 very different and so in fact there is suggestion that
23 you know as more data available, we may have to
24 actually redefine the significance of these findings.
25 171. Q. And if you go down to the last

AR09327
DR. PETER LIU - 60
1 paragraph on page three on the right hand side.
2 A. Mm-hmm.
3 172. Q. I’m going to read that, it states,
4 “...In a cohort of adolescents with
5 COVID-19 mRNA vaccine related myopericarditis, a large
6 portion have persistent LGE abnormalities, raising
7 concerns for potential longer-term effects. Despite
8 these persistent abnormalities, all patients had rapid
9 clinical improvement and normalization of
10 echocardiographic measures of systolic function...”
11 So, wouldn’t you agree with me Dr. Liu,
12 that just because a patient who has myocarditis --
13 COVID-19 vaccine induced myocarditis goes home form
14 the hospital after a couple of days and has clinical
15 improvement doesn’t mean that there’s not underlying
16 issues that will present in the long term?
17 A. Yes, the possibility exists, you know
18 whether the probability exists or not it’s not clear,
19 but that’s why we’re following patients up but I do
20 want to emphasize that you know the study does
21 actually clearly indicate that all patients have rapid
22 clinical improvement, normalization or echo
23 measurements of systolic function.
24 And these are very important you know
25 both for the patient and long term outcomes, yeah, so

AR09328
DR. PETER LIU - 61
1 there are these very interesting MRI findings and
2 you’re absolutely right and that’s why we’re following
3 these patients yeah, but so far appears that these are
4 quite interesting findings but you know whether they
5 have the impact on patients (inaudible) is unknown at
6 the moment and so you know we follow up exactly as the
7 paper recommends we -- that’s the reason we’re doing
8 this study as well.
9 173. Q. Right and I’m going to read the last
10 sentence of this paper into the record.
11 “...Further follow-up assessment and
12 larger multicenter studies are needed to determine the
13 ultimate clinical significance of persistent cardiac
14 MRI abnormalities in patients with post–COVID-19
15 vaccine myopericarditis...”
16 And that is on page four and so you’d
17 agree with that conclusion, Dr. Liu?
18 A. Yes, and in fact we are doing the
19 study.
20 174. Q. And don’t you agree Dr. Liu that this
21 study is important or the discussion into whether the
22 COVID-19 vaccines cause heart injury and to what
23 extent because it is one of the only peer review
24 published studies in the medical literature to date
25 that has done a follow up of COVID-19 vaccine

AR09329
DR. PETER LIU - 62
1 myocarditis patients past three months?
2 A. I have to say that I’m not sure, this
3 is the only one, this group actually published an
4 earlier smaller part of this same population and as I
5 mentioned we have some data to suggest that you do
6 actually have this imaging phenomenon you know, but an
7 imaging phenomenon is a technical finding in the --
8 you know any clinical impact, that’s the question we
9 always have right.
10 So you know that’s always what we want
11 to find out and so, the indication at the present time
12 is that the patient all get better so, this is maybe
13 just a technical finding and that does not actually
14 have the clinical implication as you know the same
15 finding in the same classic myocarditis and I think
16 that’s exactly what the paper says as well, yeah.
17 175. Q. I’m going to move on to something else,
18 you can close that study for now, Dr. Liu, thank you.
19 A. Okay.
20 176. Q. I would ask you now to please open up -
21 --
22 MS. PEJOVIC: Sorry, for the record, Madame
23 Court Reporter, could you please have that study
24 marked as Exhibit 2 unless Ms. Telles-Langdon has an
25 objection.

AR09330
DR. PETER LIU - 63
1 MS. TELLES-LANGDON: No objection.
3 THE REPORTER: Perfect, Exhibit 2.
4 --- EXHIBIT NO. 2: The Journal of Pediatrics.
5 BY MR. PEJOVIC:
6 177. Q. Could you please open the Oster study
7 that I e-mailed to you today, I’m going to do the
8 same.
9 MS. TELLES-LANGDON: Is that the title
10 Jama_oster_2?
11 MS. PEJOVIC: --- get it here. Sounds about
12 right but I just need to find it.
13 THE DEPONENT: Jama 2022, right?
15 THE DEPONENT: I have the title -- the one I
16 have is Myocarditis Cases Reported After mRNA-Based
17 COVID-19 Vaccination in the US From ---
19 THE DEPONENT: --- yeah, 2020 to August
20 2021.
22 BY MR. PEJOVIC:
23 178. Q. And you have cited that study in
24 section two of your expert report in the section
25 whether the COVID-19 vaccines can cause heart injury

AR09331
DR. PETER LIU - 64
1 and if so to what extent, correct?
2 A. Yes.
3 179. Q. Okay and you cite in your expert report
4 that based on this study for -- and this is a U.S. CDC
5 vaccine adverse events recording system study of COVID
6 vaccine induced myocarditis, which was reported to the
7 VAERS passive reporting system, correct?
8 A. Yes.
9 180. Q. Okay, and this was published in March
10 of 2022?
11 A. Yeah, in that JAMA.
12 181. Q. Right. Okay and in your expert report,
13 you cite that based on this males aged 18 to 24 had an
14 incidence of COVID-19 vaccine induced myocarditis of
15 52.4 and that’s at page five of your expert report,
16 52.4 out of 100,000 for the second dose, correct?
17 A. Yeah, so, let me see, sorry ---
18 182. Q. Paragraph -- page five of your expert
19 report.
20 A. Okay, yeah.
21 183. Q. And you’d agree with me that the
22 incidence of COVID-19 vaccine induced myocarditis is
23 more prevalent after the second dose of and mRNA
24 vaccine, correct?
25 A. Yes.

AR09332
DR. PETER LIU - 65
1 184. Q. For young males?
2 A. For young males, yes.
3 185. Q. Okay. And at the discussion section of
4 this Oster paper at page 337 the first paragraph in
5 the discussion section, let me know when you’re there.
6 A. Okay, yes.
7 186. Q. Okay it says,
8 “...In this review of reports to VAERS
9 between December 2020 and August 2021, myocarditis was
10 identified as a rare but serious adverse event that
11 can occur after mRNA-based COVID-19 vaccination,
12 particularly in adolescent males and young men...”
13 And you agree with the authors, Dr. Liu
14 that myocarditis after COVID-19 vaccination is a
15 serious adverse event?
16 A. Yeah, so again I think it’s -- I know
17 there were you know discussions about definition of
18 serious versus rare right now and so I think these
19 technical definitions so keeping in mind that the
20 vaccine there’s the usual side effects right, you
21 know.
22 So, that’s kind of fever chills and --
23 pain and things like that so probably -- comparison
24 you know to the base line side effects, this is a
25 serious side effect and but I think the next sentence

AR09333
DR. PETER LIU - 66
1 is important right, you know so,
2 “...However, this increased risk must
3 be weighed against the benefits of COVID-19
4 vaccination...”
5 So, I think that’s context image and
6 that’s (inaudible)
7 187. Q. Okay and at page 338 on the lefthand
8 side. The third paragraph down it starts with long
9 term outcome, do you see that?
10 A. Yes.
11 188. Q. “...Long-term outcome data are not yet
12 available for COVID-19 vaccine–associated myocarditis
13 cases...”
14 And we have been discussing that for
15 the last few minutes, you agree with that statement,
16 Dr. Liu?
17 A. Yes, long term, yes outcome, yes not
18 available, yeah, the intermediate outcome actually
19 including my report you know because the CDC did share
20 some of that data with us.
21 189. Q. And you see in that same paragraph
22 about half -- quarter, no a about a third of the way
23 down, the sentence starts, for patients with
24 myocarditis, you see that?
25 A. For patients with myocarditis, yes

AR09334
DR. PETER LIU - 67
1 after reference 34.
2 190. Q. That’s right.
3 “...The American Heart Association and
4 the American College of Cardiology guidelines advise
5 that patients should be instructed to refrain from
6 competitive sports for 3 to 6 months, and that
7 documentation of a normal electrocardiogram result,
8 ambulatory rhythm monitoring, and an exercise test
9 should be obtained prior to resumption of sports...”
10 And why is that Dr. Liu?
11 A. This is a recommendation for
12 myocarditis from the American Heart Cardiology so this
13 is a fairly standard recommendation for young person
14 with pre-pandemic classic myocarditis because
15 eventually can have serious consequences for people
16 particularly engaging in sports, yeah but I think this
17 is just directly I guess transposed from that right
18 because in the absence of other information usually
19 the recommendation tends to be conservative.
20 So, you want to actually take the most
21 cautious approach and so that patients are not kind of
22 you know sort of facing any unnecessary risk or
23 anything like that in the absence right you know of
24 the data because we just don’t know yet you know what
25 to do so let’s take -- even though these are -- but

AR09335
DR. PETER LIU - 68
1 let’s take the most cautious approach and this is the
2 same for hospitalization you know we’re talking I
3 guess we’re talking -- you know so yes, these patients
4 were hospitalized mainly because we -- this is new
5 condition right you know so we want to actually be
6 absolutely sure.
7 So we admit the patient, make sure we
8 monitor them, make sure they’re safe but nowadays you
9 know the patient come into emergency department was
10 vaccine induced myocarditis, most of them we just send
11 home because we know that everybody is going to be
12 fine you know but this is how we tend to do things
13 when things are new you know because we want to be
14 cautious right, you know we don’t actually compromise
15 the patients welfare and so we take extra precautions
16 and once you know the data then you can be more
17 relaxed so I think that’s kind of the general medical
18 approach.
19 Yeah, so I think this is actually very
20 good you know because it’s very cautious approach and
21 everyone agreed that in the absence of data and
22 knowing what happens, let’s really be super careful
23 and but then you know nowadays I think there’s a
24 general assurance that this is actually a very mild
25 form of myocarditis you know people are much more

AR09336
DR. PETER LIU - 69
1 relaxed you know in terms of the concern of this
2 condition, yeah but you know this all comes with of
3 course more data, you know we still need more data as
4 you said.
5 191. Q. And you agree with the recommendation
6 for COVID-19 vaccine induced myocarditis patients who
7 are being discharged from the hospital to refrain from
8 competitive sports for approximately three to six
9 months, you agree with that?
10 A. Yes, at that time you now because
11 keeping in mind this was you know sort of -- so, data
12 to the end of last year, yeah. Nowadays we’re
13 actually much more relaxed and but you know of course
14 there’s no new guidelines yet you know we don’t have
15 you know sort of a revised new guidelines for this
16 condition certainly because it’s relatively new but I
17 think most people are now less worried so you know
18 generally we called the individualization of benefit
19 versus risk.
20 192. Q. All right, if you could please look at
21 the section called limitations on page 338.
22 A. Yes.
23 193. Q. And on the right hand side, it’s the
24 first paragraph halfway down, I’m going to read a
25 section to you, Dr. Liu.

AR09337
DR. PETER LIU - 70
1 A. Okay.
2 194. Q. “...Furthermore, as a passive system,
3 VAERS data are subject to reporting biases in that
4 both underreporting and overreporting are possible.38
5 Given the high verification rate of reports of
6 myocarditis to VAERS after mRNA based COVID-19
7 vaccination, underreporting is more likely.
8 Therefore, the actual rates of myocarditis per million
9 doses of vaccine are likely higher than estimated...”
10 You agree with that, Dr. Liu?
11 A. Yes, I agree but I didn’t want to put
12 into context you know that -- underreporting is
13 probably quite small but never less from purest point
14 of view because this is a voluntary reporting system,
15 right you know it’s always going to be -- there’s
16 always barriers right, I’m a physician, I see a case
17 and if I’m super busy and you know there are sort of
18 other emergencies of something like that you know you
19 may not get a chance to report that case, right.
20 So, I think that’s what happens but
21 from what we have seen so far because now we have more
22 data, the underreporting’s likely, quite small
23 unfortunately, it does actually mean that most
24 physicians are quite responsible and we found this in
25 Canada as well you know so people are quite

AR09338
DR. PETER LIU - 71
1 conscientious in reporting, yeah.
2 195. Q. But there could be young males with
3 myocarditis who never go to see a physician and so
4 don’t report, doesn’t get to the physician’s desk,
5 correct?
6 A. Yeah, can be, yeah so if it’s symptoms
7 are really really mild or they don’t actually get any
8 symptoms but then that may not fit the diagnosis or
9 myocarditis so I think myocarditis is generally
10 associate as pretty serious symptoms, yeah but of
11 course there will be always cases right you know
12 because we know even heart attack right, people may
13 miss it because they -- people don’t necessarily
14 always want to go to a hospital, so...
15 196. Q. Right and I see that the second
16 paragraph on the right hand side here kind of reflects
17 what you just said a minute ago,
18 “...Second, efforts by CDC
19 investigators to obtain medical records or interview
20 physicians were not always successful. And s
21 challenge limited the ability to per form case
22 adjudication and complete investigations for some
23 reports of myocarditis...”
24 A. And you can see how that would have
25 been the reality here.

AR09339
DR. PETER LIU - 72
1 A. Yes, exactly, this is always the
2 challenge for voluntary reporting you know and but for
3 major you know sort of medical conditions you know
4 this is what we tend to rely on initially but this is
5 where you know for example the block study, you know
6 the one that MMWR is you know is better because you
7 then take every case into consideration you don’t
8 depend on the voluntary reporting system.
9 197. Q. And these -- this limitation of this
10 study which indicates that it’s likely that the
11 instances of COVID-19 vaccine myocarditis was under
12 reported, you didn’t include that in this report --
13 expert report, did you, Dr. Liu?
14 A. I did refer to this paper in my report.
15 198. Q. But you didn’t discuss how these
16 numbers that you have extrapolated from this paper are
17 likely an underreporting of the real incidence of
18 COVID-19 vaccine induced myocarditis for young males,
19 correct?
20 A. Yes, I did not talk about this but I
21 did mention or I did actually because when I talk
22 about the actual incidence and in particularly in
23 relation to COVID you know relate to myocarditis you
24 know that’s kind of talking about the incidence in
25 terms of age and sexes specific comparison the MMWR

AR09340
DR. PETER LIU - 73
1 paper, you know.
2 I emphasized the strengths of that
3 study, right you know the -- itself of course is that
4 this one is not as strong but on the other hand the
5 way to estimate why is it much more accurately is
6 actually take everybody in the system and do the
7 measurement rather than a volunteer.
8 You know the analogies let’s say we
9 have a hundred people in the room, you say how many
10 people had cold symptoms yesterday right, so you
11 depend on people who actually do that, versus you
12 actually take the medical record of a hundred people
13 and actually specific examine them and then you
14 actually give accurate information, yeah.
15 So I think that’s the -- but this is
16 time -- system, you know picking up you know side
17 effects and it has worked for many many previous
18 public health you know issues, you know that’s how we
19 detect a monkeypox and things like that, right, it’s
20 all based on voluntarily reporting because there’s
21 just no other way for any new condition to do that,
22 yeah.
23 199. Q. Right and I’m looking at the conclusion
24 section of this paper at page 338.
25 A. Okay, yeah.

AR09341
DR. PETER LIU - 74
1 200. Q. And the last sentence says,
2 “...This risk should be considered in
3 the context of the benefits of COVID-19
4 vaccination...”
5 You see that, Dr. Liu?
6 A. Yes.
7 201. Q. Right, so the authors acknowledge that
8 there is a risk from the COVID-19 vaccines that they
9 can cause myocarditis, correct?
10 A. Absolutely, but there’s a second a part
11 ---
12 202. Q. --- I understand, I will get there ---
13 A. --- absolutely, as I mentioned earlier
14 right, you know everything in medicine, nothing is
15 absolute, right you know we have -- we never have a
16 hundred per cent effective treatment, we never have a
17 hundred per cent safe treatment, right you know and
18 that’s the reason I say, every time we make a medical
19 decision that we always weigh the risk versus the
20 benefit you know because that’s -- as long as the
21 benefit outweighs the risk then that is the
22 appropriate recommendation.
23 But on the other hand if it's the other
24 way around, if the risk always the benefit, then it’s
25 not worth while.

AR09342
DR. PETER LIU - 75
1 I know in legal, you always have black
2 and white yes or no right, in medicine it’s always
3 nuance in terms of you know benefit versus risk and
4 that’s how we make the decisions because you know at
5 the end of the day, we want treatments, we want
6 recommend, you know in terms of advice, it’s
7 ultimately in patient’s favor and that you know
8 there’s always risk and that’s -- we always get
9 consent for everything so...
10 203. Q. And you’d agree with e Dr. Liu that the
11 conclusion from this paper is not a recommendation
12 that young males get COVID-19 vaccines, is it ---
13 A. --- no.
14 204. Q. --- it’s a suggestion that there should
15 be a balancing of the risk in the context of the
16 benefit, correct?
17 A. Absolutely, yeah so this is -- I think
18 this is -- the purpose of the reporting is really
19 actually to you know I guess give the best information
20 available because you know this is really you know
21 sort of given what we have, given that it’s a new
22 condition, this is as good as the data we have
23 certainly from the CDC representing the whole of you
24 know the U.S. population and this is very important
25 information for the medical community to know.

AR09343
DR. PETER LIU - 76
1 And so it is always weighing risk
2 versus benefit, absolutely because for example, if
3 there are no cases of COVID-19 out there, right then
4 there’s no need for vaccination right you know because
5 that’s risk versus no benefit you know but on the
6 other hand if the -- risk for COVID-19 is quite high
7 you know right now for example the cases are
8 increasing again in the U.S. and Canada probably going
9 to get a 6th wave as well, right.
10 In that situation then this becomes a
11 very cogent consideration right you know so it’s
12 always risk versus benefit and you’re absolutely
13 right, yes.
14 205. Q. And Dr. Lou, were you aware that when
15 you cited this paper that some of the authors have
16 received funding from Pfizer and Moderna?
17 A. Yes.
18 206. Q. Okay.
19 MS. PEJOVIC: All right, I’d like to mark
20 this paper as the next exhibit, is that all right Ms.
21 Tell-Langdon?
24 --- EXHIBIT NO. 3: Jama_oster_2022: Myocarditis Cases
25 Reported After mRNA-Based COVID-19 Vaccination in the US

AR09344
DR. PETER LIU - 77
1 From December 2020 to August 2021.
2 BY MR. PEJOVIC:
3 207. Q. Okay, now we’re going to move on to the
4 next section of your report, which is entitled Whether
5 COVID-19 Can Cause Heart Injury and If So, To What
6 Extent, and that starts at page five.
7 MS. TELLES-LANGDON: Ms. Pejovic, just
8 before we move on, I just thought I would check with
9 Dr. Liu to see if he’s fine to continue or if there’s
10 any need for a break given how long we’ve been going
11 in total, we I know we have a break 40 minutes ago but
12 I wanted to check with Dr. Liu.
13 THE DEPONENT: No, I’m okay a long as the
14 counsel is okay and everybody’s okay and but if we
15 could finish slightly earlier that would be good but
16 of course this is at your pleasure.
17 MS. PEJOVIC: So, we have tomorrow morning
18 booked for the cross-examination should it be
19 necessary and I can advise that it is going to be
20 necessary by looking at where I am. So, what is --
21 what time would you like to finish today, Dr. Liu?
22 THE DEPONENT: I think if we could finish it
23 -- just I have another sort of a meeting to go to and
24 was just wanted to get -- I think something like 15
25 minutes earlier I’ll be fine, but it’s not sure ---

AR09345
DR. PETER LIU - 78
1 MS. PEJOVIC: I’m not sure what time you
2 were told this would end so can you just give me a
3 time ---
4 THE DEPONENT: Oh yeah, so let me see, I’m
5 booked to 5:30, yeah, 5:30 so if we could finish at
6 5:15 ---
7 MS. PEJOVIC: Five fifteen Eastern?
8 THE DEPONENT: Yeah, but is that okay, I
9 mean I don’t want to ---
10 MS. PEJOVIC: --- no, that’s fine, that’s
11 fine ---
12 THE DEPONENT: --- you know sort of
13 compromise your train of thought.
14 MS. PEJOVIC: No, no that’s fine and if you
15 need a break before then, please let me know.
16 THE DEPONENT: I’m okay if you are okay.
17 BY MR. PEJOVIC:
18 208. Q. Okay, so let’s keep going, okay.
19 A. Let’s go, yes.
20 209. Q. In this section of your report you
21 explain that COVID-19 can lead to myocarditis and
22 heart injury and to support your statements about
23 COVID-19 causing heart injury, you cite your own study
24 in circulation, correct?
25 A. Yes.

AR09346
DR. PETER LIU - 79
1 210. Q. Okay, all right, I’m going to pull that
2 up on my end, I would ask that you do the same, I
3 believe I sent it to you this morning.
4 A. Sorry, remind me what ---
5 211. Q. Let’s find it here. So, that would
6 have been called Liu-The Science Underlying COVID-19,
7 did I send that to you?
8 A. Oh, okay.
9 212. Q. Sorry, my Adobe is kind of freezing on
10 me, please give me a minute.
11 A. It must be in incoherent article.
12 213. Q. No, I have too many things open it
13 doesn’t like it. I’m going to try and open it with
14 something else, sorry about that. Open the version I
15 e-mailed you.
16 A. I guess we don’t share screens on
17 these, yeah, no?
18 214. Q. Okay, can you still hear me?
19 A. Absolutely, yes.
20 215. Q. Okay, I’ve got it up on a different
21 screen here on a different way. So I’m just going to
22 read this into the record, this is an article
23 entitled, The Science Underlying COVID-19 In
24 Circulation Journal and that was published April 15th
25 of 2020, correct?

AR09347
DR. PETER LIU - 80
1 A. Correct, yes.
2 216. Q. Implications for the Cardiovascular
3 System. Okay, here we go, if you can scroll down to
4 the section called the Effect of COVID-19 on the
5 Heart.
6 A. Is that bold heading or ---
7 217. Q. It’s a bold heading, yes and it starts
8 with between eight per cent and twenty eight per cent.
9 A. So, is that under the heading that
10 states Clinical Spectrum of Cardiovascular Involvement
11 in COVID-19, that’s where I found the eight to twenty
12 eight per cent?
13 MS. TELLES-LANGDON: The heading I’m seeing
14 Dr. Liu is the Effect of COVID-19 on the Heart.
15 THE DEPONENT: Where is that because I find
16 eight to twenty eight per cent under the heading, its
17 under the table but maybe ---
18 MS. TELLES-LANGDON: Perhaps further into
19 the document ---
20 THE DEPONENT: Yeah, so maybe you can like
21 say I’m looking at the bar o the side here, is that a
22 40 per cent down, 50 per cent down?
23 MS. PEJOVIC: It’s halfway down.
24 THE DEPONENT: Halfway down, okay.

AR09348
DR. PETER LIU - 81
1 THE DEPONENT: Is it before Virus --
2 interaction, it’s probably after that. Oh, yes okay,
3 got it. I should know this, right yes. The Effect of
4 COVID-19 on the Heart between eight and twenty eight
5 per cent, okay I found it. Thank you.
6 BY MR. PEJOVIC:
7 218. Q. Okay so as I’ve stated, this study you
8 are relying on in the section of your report entitled
9 Whether COVID-19 Can Cause Heart Injury and if so, To
10 What Extent, right?
11 A. Yes.
12 219. Q. Okay, and the first paragraph states,
13 “...Between 8 per cent and 28 per cent
14 of patients with COVID-19 infections show evidence of
15 cardiac injury with elevated troponin.
16 Okay and it cites a study which I have
17 also sent to you and that is called Footnote 7 to Liu
18 Circulation, can you pull that up as well?
19 A. Okay, let me -- Footnote 57?
20 220. Q. No, it’s Footnote 7. There’s two.
21 A. Oh.
22 221. Q. Did you get Footnote 7?
23 A. Oh, I see, I didn’t realize there’s a
24 second one.
25 222. Q. Yes.

AR09349
DR. PETER LIU - 82
1 A. Okay. Okay, so this one is JAMA
2 cardiology, the article is that right ---
3 223. Q. Yes.
4 A. --- Association of Cardiac Injury With
5 Mortality in Wuhan, right?
6 224. Q. Yes, yes.
7 A. Okay.
8 225. Q. And the lead author is Shaobo Shi.
9 A. Right okay, yes.
10 226. Q. And in this study, first of all, have
11 you reviewed this study before?
12 A. There are many study, I mean we even
13 study one, right so yeah there are many studies that
14 came out on these populations so I can’t remember but
15 I wont be surprised I did read it and yeah, I would
16 say that I probably aware but I would not have
17 necessary read it in detail.
18 227. Q. Okay, so I’m going to just get you to
19 look at this sort of summary section on the first page
20 ---
21 A. Okay.
22 228. Q. --- where it says results.
23 A. Yeah.
24 229. Q. And it says,
25 “...A total of 416 hospitalized

AR09350
DR. PETER LIU - 83
1 patients with COVID-19 were included in the final
2 analysis; the median age was 64 years...”
3 You see that?
4 A. Yes.
5 230. Q. You’d agree with me Dr. Liu that people
6 were -- most of the people who were hospitalize from
7 this study were not young people?
8 A. No, in this -- especially during the
9 first wave.
10 231. Q. And you could read through this further
11 -- I’m going to, I mean I can find it if we need to
12 find it but I’m going to suggest to you that the
13 median age of patients with cardiac injury was 74 and
14 had comorbidities such as hypertension, diabetes,
15 coronary heart disease, cerebrovascular disease,
16 chronic heart failure, chronic obstructive pulmonary
17 disease and cancer.
18 A. Right, yes.
19 232. Q. Does that sound accurate, Dr. Liu?
20 A. I would imagine, yes, you know -- at
21 that age, right you know so one would expect those
22 comorbidities.
23 233. Q. And the author state that,
24 “...These conditions were present more
25 often among patients with cardiac injury...”

AR09351
DR. PETER LIU - 84
1 A. Yes.
2 234. Q. So, the people who have cardiac injury
3 from COVID-19 according to this study are
4 predominantly older people, far older people who have
5 serious comorbidities, you agree with that?
6 A. The bulk of it, yeah but you know just
7 the -- you know the median right so it’s not a mean
8 and if you look at the range of the patients age, it’s
9 21 to 95 so it’s very, very broad ---
10 235. Q. --- right.
11 A. --- median, it happens to be you know
12 if you can remember 416 patients right, so 208
13 patients happen to 64 years of age, right ---
14 236. Q. --- right but the median is 74 so
15 that’s ---
16 A. --- overall, the patient population is
17 64 but anyway yeah so, you’ve got the young ones,
18 you’ve got the really old ones, this is a whole
19 spectrum right and the median just happens to be where
20 the middle person age is, right, no question median
21 age is 60 -- like older and so likely more older
22 patients nut it doesn’t exclude younger patients
23 right, so you have patients as young as 21.
24 237. Q. Okay.
25 A. But I think this is appropriate in that

AR09352
DR. PETER LIU - 85
1 we know that COVID tends to affect patients you know
2 with underlying you know potential risk factors you
3 know patient that are obese, you know have high blood
4 pressure, things like that.
5 So and that’s particularly during first
6 wave because as you know the subsequent wave get
7 younger and younger patients and it’s the older
8 patients that were particularly affected in the first
9 wave and this is during the first wave, yeah.
10 MS. PEJOVIC: Right, I would ask that that
11 study be the next exhibit, is that all right Ms.
12 Telles-Langdon?
13 MS. TELLES-LANGDON: The Footnote 7 ---
15 MS. TELLES-LANGDON: --- study. So, just to
16 be clear, the JAMA Cardiology Study Association of
17 Cardiac Injury with Mortality in Hospitalized Patients
18 with COVID-19 in Wuhan, China?
22 --- EXHIBIT NO. 4: Footnote 7: Association of Cardiac
23 Injury With Mortality in Hospitalized Patients With COVID-
24 19 in Wuhan, China.
25 BY MR. PEJOVIC:

AR09353
DR. PETER LIU - 86
1 238. Q. All right and if we go back to that
2 circulation paper.
3 A. Okay, yes.
4 239. Q. The second sentence in that paragraph
5 that we were looking at before under the Effect of
6 COVID-19 on the Heart, it states,
7 “...In a series of patients from
8 Seattle, the first major COVID-19 center in the United
9 States, several patients presented with
10 cardiomyopathy. Patients with evidence of cardiac
11 involvement had a marked increase in mortality,
12 confirming the major effect of the cardiovascular
13 system in the prognosis of these patients...”
14 You see that?
15 A. Yeah.
16 240. Q. So, I’ve pulled up the footnote which
17 is 57 and I’ve sent it to you and it’s called Footnote
18 57 to Liu Circulation Study, you see that?
19 A. Okay, yes.
20 241. Q. Okay, might be a bit obstructed by the
21 way that I’ve saved it, but it’s called COVID-19 in
22 Critically Ill Patients in the Seattle Region Case
23 Series.
24 A. Yes.
25 242. Q. And the first author is Bhatraju and

AR09354
DR. PETER LIU - 87
1 this was published in the New England Journal of
2 Medicine on May 21st of 2020, you have that there?
3 A. Yeah.
4 243. Q. All right and in the Methods section,
5 it states,
6 “...We identified patients from nine
7 Seattle-area hospitals who were admitted to the
8 intensive care unit with confirmed infection with
9 severe acute respiratory syndrome coronavirus-2. And
10 We identified 24 patients with confirmed Covid-19 age
11 of the patients was 64...”
12 And if you keep going in that
13 paragraph, it’s in the result section, it states,
14 “...58 per cent had diabetes...”
15 You see that?
16 A. Yes.
17 244. Q. Okay and in the Results section of this
18 paper, I’ll ask you to look there, that’s just below
19 table one, let me know if you find that section.
20 A. Okay so ---
21 245. Q. The sentence starts at Chronical
22 Medical Conditions, do you see that?
23 A. So, is this under table one, is that
24 right?
25 246. Q. There’s a table one but there’s a ---

AR09355
DR. PETER LIU - 88
1 A. --- yes ---
2 247. Q. --- big paragraph below that, says,
3 Chronical Medical Conditions, do you see that?
4 A. Yes, okay, yes, yes, yes.
5 248. Q. I’m going to read it.
6 A. Yes.
7 249. Q. “...Chronic medical conditions were
8 common in this critically ill population. Fourteen
9 patients (58 per cent) had diabetes mellitus and 5 (21
10 per cent) had chronic kidney disease; three patients
11 (14 per cent) had asthma...”
12 And carrying on,
13 “...Five patients (22 per cent) were
14 current or former smokers and 1 patient (4 per cent)
15 had chronic obstructive pulmonary disease; and 33 per
16 cent of the patients had more than one coexisting
17 condition...”
18 A. Right.
19 250. Q. Have you read that study, Dr. Liu?
20 A. Yes, because this was a landmark study,
21 this was the first case report of patients in the U.S.
22 and you know Seattle was the first place in which
23 patients were first identified.
24 251. Q. Right.
25 A. So, this is how you realize there’s

AR09356
DR. PETER LIU - 89
1 something going on here, yes.
2 252. Q. And the people in this study who are
3 having these issues which include heart issues, they
4 are not young healthy people, are they, Dr. Liu?
5 A. No, this is the first wave you know it
6 gets the most vulnerable population. Yeah, that’s
7 always how infections, it picks off the most
8 susceptible.
9 MS. PEJOVIC: I’d like to tender that
10 document as the next exhibit.
13 THE REPORTER: So, that’s Exhibit number 5.
15 --- EXHIBIT NO. 5: Footnote 57 to Liu Circulation Study:
16 COVID-19 in Critically Ill Patients in the Seattle Region
17 - Case Series.
18 BY MR. PEJOVIC:
19 253. Q. And just checking the time, okay.
20 A. You know what happens is we vaccinate
21 more and more of these vulnerable patients right and
22 the disease moves to younger and younger population,
23 you know that’s kind of how all these pandemics work
24 right so, it has to do with the way that we protect
25 our most vulnerable patients.

AR09357
DR. PETER LIU - 90
1 254. Q. And in the second paragraph of Section
2 3 of page five of your expert report, you state,
3 “...The frequency of COVID-19 related
4 heart injury is highly variable depending on the case
5 definition and how well cardiac involvement is
6 recognized by the clinical team. The largest series
7 published to date are that from the UK Network...”
8 And you cite a Buckley et al study in
9 the European Journal of Clinical investigation from
10 2021, you see that?
11 A. Yes.
12 255. Q. And you say,
13 “...This is a strong study because of
14 the large sample size. Network data structure and
15 propensity matching with COVID-19 patients who did not
16 have myocarditis to determine the independent
17 contribution of myocarditis to patient outcomes...”
18 Okay, I’m going to pull that study up,
19 if you could put it on your screen as well.
20 A. Okay, let’s see if we’ve got the
21 Buckley, yes. Yeah, European Journal of Clinical
22 Investigation, yes.
23 256. Q. Yes, I’m going to have to -- my
24 computer is freezing again, so I have to open this
25 another way. So, for the record, that study is in the

AR09358
DR. PETER LIU - 91
1 European Journal of Clinical Investigation and it’s
2 entitled Prevalence and Clinical Outcomes of
3 myocarditis and pericarditis in 718,365 COVID-19
4 patients and the study was published September 13th of
5 2021. Just bear with me for a minute.
6 Okay, if you go to the section called
7 Results, it’s called Number three Results.
8 A. Yes.
9 257. Q. It says in the second part of that
10 first paragraph 3.1 Character Characteristics.
11 “...Patients who developed
12 myocarditis/pericarditis had higher proportions of
13 comorbidities...”
14 See that?
15 A. Yes, yes.
16 258. Q. And the comorbidities are described
17 underneath table one which is just below that as,
18 “...Hypertensive disease, ischaemic
19 heart diseases, heart failure, cerebrovascular
20 diseases, diabetes, chronic kidney disease, diseases
21 of the respiratory system, diseases of the digestive
22 system and diseases of the nervous system...”
23 See that?
24 A. Yeah.
25 259. Q. Right.

AR09359
DR. PETER LIU - 92
1 MS. TELLES-LANGDON: I’m sorry Ms. Pejovic,
2 this is not an objection, it’s just I’m not with you
3 on the paper, so can you help me ---
4 THE DEPONENT: It’s in the note section
5 actually ---
6 MS. PEJOVIC: ---
7 THE DEPONENT: --- note section in that
8 paper.
9 MS. PEJOVIC: There’s a table one and then
10 at the bottom of table one, it says note in very small
11 print.
12 MS. TELLES-LANGDON: Okay, thank you.
14 MS. TELLES-LANGDON: I’m with you now.
15 MS. PEJOVIC: Sorry about that.
16 BY MR. PEJOVIC:
17 260. Q. Okay, so you’ve cited this study in the
18 second paragraph in Section three of your expert
19 report and at the end of that second paragraph, the
20 last sentence states,
21 “...COVID-19 is associated with a
22 significant risk of myocarditis and the outcome
23 includes significant risk in mortality...”
24 You see that, Dr. Liu?
25 A. Yes.

AR09360
DR. PETER LIU - 93
1 261. Q. And Dr. Liu, shouldn’t you have said
2 COVID-19 is associated with a significant risk of
3 myocarditis and mortality most often in people with
4 comorbidities?
5 A. That’s not the aim of the study, right
6 the aim of the study is actually to look -- because
7 the whole idea of the propensity matching is that you
8 match the underlying risk, right so that’s the -- you
9 know -- so you match for age, you match for all those
10 aspects and to see in fact that you got you know
11 COVID-19 myocarditis or not right.
12 So that’s the whole idea of matching so
13 you cancel out the -- those effects and if so then you
14 can actually look at what exactly is the net risk
15 associated with myocarditis versus no myocarditis.
16 262. Q. But from that study and the previous
17 two studies that we just went through, the Footnote 7
18 and the Footnote 57, which you’re relying on so cited
19 in your Circulation paper, those studies show that the
20 majority of people with serious outcomes from COVID-19
21 and including heart injuries are people with
22 comorbidities, correct?
23 A. Yeah, so because this is how you know
24 remember how COVID-19 affected people in the first and
25 second waves right, it effected older people, it

AR09361
DR. PETER LIU - 94
1 effected the patient with cardiovascular disease and
2 that -- this is the vulnerable population right, so
3 they are the ones actually got COVID-19 ---
4 263. Q. Right ---
5 A. --- a young person did not actually get
6 COVID-19 in that first wave, right so that’s the thing
7 but I guess if you follow larger, larger population,
8 that’s why you see the younger patients right you know
9 because the demographic changed during the waves,
10 right you know so, yeah, you remember right during in
11 Canada you know the during the first wave, the concern
12 was all in long-term care and old age homes right but
13 then we know the more recent wave, right it’s young
14 people who’s actually getting the condition because
15 the older folks all got vaccinated right.
16 So you know I think so it has to do
17 with the time of the study and because of the
18 vulnerable population changed overtime, you know we
19 know this because we’re doing COVID-19 study, you know
20 in the beginning all our patients are over 60 and now
21 patients all under 45, you know so this is just the
22 nature of this pandemic, you know because there were
23 not too many young people in the beginning.
24 And so that’s the only sample you can
25 actually study myocarditis on right, because you

AR09362
DR. PETER LIU - 95
1 didn’t have young people having the COVID-19 at the
2 time and now, you know we actually have more current
3 population and the larger sample then you will see
4 actually the amount -- the demographic shift.
5 264. Q. Right ---
6 A. Yeah.
7 265. Q. --- sorry. Studies that you’ve chosen
8 to include in this section and all we have to look at
9 in this section which is called Whether COVID-19 can
10 Cause Heart Injury and if so, To What Extent.
12 266. Q. Are these studies.
13 A. Yeah, that’s the only data that really
14 actually look at them you know with a large sample
15 size not small studies like the MRI one you know only
16 25 patients or something like that so that’s the
17 purpose you know because you want to really have a
18 reliable estimation on the impact of myocarditis.
19 So, that’s the type of data we have
20 available, you know there’s not a lot of data
21 available you know so, that’s challenge you know but
22 this type of data is helpful at least to help to
23 understand but more you know sort of this is why the
24 MMWR paper is better because it’s included younger
25 patients you know so, it’s more relevant.

AR09363
DR. PETER LIU - 96
1 267. Q. And we’ll get to talking about that ---
2 A. Yes.
3 268. Q. --- a little bit later. And just one
4 last question on this Buckley paper. Dr. Liu, are you
5 aware that Benjamin Buckley received funding from
6 Pfizer and Deirdre Lane was a speaker for Pfizer and
7 Gregory Lip was the consultant for Pfizer and a
8 speaker for Pfizer and that is the last page of the
9 study, were you aware of that?
10 A. Well, I know these investigators
11 because they are cardiologists and they also are
12 experts in anticoagulation you know for the heart not
13 related you know and Pfizer makes a -- which is an
14 excellent anticoagulant you know so I suspect that’s
15 the relationship they have because they are expert in
16 that area and Pfizer makes the anticoagulant and so
17 they declare that but they are not -- they’re
18 cardiologists like me so they (inaudible) advising on
19 vaccine policies.
20 Yeah, they have access to a large
21 patient population databases you know because they are
22 experts in doing this large epidemiology studies so
23 they have access to data and I think that’s the reason
24 they can analyze this, yeah but yes, I acknowledge
25 that, yes but I’m just saying that knowing the

AR09364
DR. PETER LIU - 97
1 investigators -- it’s good that they declare you know
2 because I think it’s absolutely important that people
3 declare conflict of interest but you know questions
4 are relevant to the conclusion.
5 MS. PEJOVIC: Okay, I’d like to mark that
6 study as the next exhibit.
7 THE REPORTER: Okay, Exhibit Number 6.
8 MS. TELLES-LANGDON: And no objection.
10 --- EXHIBIT NO. 6: European Journal of Clinical
11 Investigation: Prevalence and clinical outcome of
12 myocarditis and pericarditis in 718,365 COVID-19 patients
13 (Buckley).
14 MS. PEJOVIC: I have one more study to put
15 up in this section but I’m looking at the time and
16 it’s almost 5:12 Dr. Liu’s time ---
17 THE DEPONENT: So, depending on complex the
18 question’s going to be.
19 MS. PEJOVIC: I think we can get through it
20 in five minutes.
21 THE DEPONENT: Okay, let’s do it.
22 MS. PEJOVIC: Okay, let’s do it, it will be
23 a good place to break afterward.
25 BY MR. PEJOVIC:

AR09365
DR. PETER LIU - 98
2 A. Which study would this be?
3 270. Q. This is the Qin, I don’t know if I’m
4 pronouncing it properly.
5 A. Oh, Q-I-N, that would ben Qin, yes.
6 271. Q. Qin, okay.
7 A. Yes. Redefining Biomarkers?
8 272. Q. Yes. Redefining Cardiac Biomarkers in
9 Predicting Mortality of Inpatients With COVID-19,
10 Medicine Hypertension Journal, correct?
11 A. Yes.
12 273. Q. And in this study, you also included
13 this study in your expert report on page six, second
14 paragraph?
15 A. Yes.
16 274. Q. When you’re talking about,
17 “...If one uses the evidence of cardiac
18 biomarker troponin leakage during hospitalization for
19 COVID-19 as evidence of cardiac damage, this can occur
20 as common as 20 to 30 per cent of all patients
21 admitted with COVID-19.
22 The patients with troponin leakage
23 generally have a much higher 28 day mortality as high
24 as seven times according to one of our earlier
25 studies. Therefore it appears that cardiac

AR09366
DR. PETER LIU - 99
1 involvement in the setting of COVID-19 is more
2 frequent than commonly thought and is associated with
3 outcomes even in the short term...”
4 And when I looked at this study, Dr.
5 Lou -- sorry, my Adobe is still very slow, try to fix
6 that for tomorrow. Okay, if you go to the Result
7 section.
8 A. Okay, yeah.
9 275. Q. Okay. Says Participants and Clinical
10 Characteristics.
11 A. Okay, yes.
12 276. Q. Says,
13 “...Compared with patients without
14 cardiac injury biomarker measurement, patients with
15 biomarker values were older...”
16 A. Yes, it’s also on Table one as well.
17 277. Q. Yes -- start that again.
18 “...Compared with patients without
19 cardiac injury biomarker measurement, patients with
20 biomarker values were older and had higher percentages
21 of pre-existing comorbidities and more severe
22 symptoms...”
23 You see that?
24 A. Yes, yes and so similar to what we
25 mentioned before the other studies, it’s a context

AR09367
DR. PETER LIU - 100
1 thing right, you know if you look on Table one and you
2 actually look at the age right you know, we can see
3 the ones with biomarker release you know age 57,
4 without biomarker release it’s 54.
5 You know, so we’re talking about very
6 small differences but you know we can see the P value
7 is very, very high, that’s simply because we study a
8 large number of population and so yes, you know --
9 difference of only three years but nevertheless ---
10 278. Q. --- these are ---
11 A. --- yes ---
12 279. Q. ---
13 A. --- large samples and that’s why.
14 280. Q. And these are not young, healthy males
15 ---
16 A. --- no, again these are first wave, you
17 know patients and you know these are the more classic
18 older patients with you know typical with older
19 patients, you know comorbidities and things like that,
20 yes, absolutely.
21 281. Q. And the last question for the day, Dr.
22 Liu is in looking at this section of your expert
23 report, this section, Section three, your conclusions
24 in this section do not apply to young, healthy males,
25 do they?

AR09368
DR. PETER LIU - 101
1 A. Oh, I would not say that, I would have
2 an open mind -- because we don’t have huge database,
3 certainly at the beginning of COVID-19 where the
4 largest patient population you know had the condition
5 and certainly the you know if you -- we just asked the
6 question on myocarditis, right you know myocarditis or
7 cardiac injury -- we should say that cardiac injuries
8 to be technically correct, so does cardiac injury take
9 place, yes it does and does it actually affect
10 outcome, yes it does and but keeping in mind the
11 control population is the same right so they also have
12 comorbidities and all of that.
13 So the question is, if you add you know
14 cardiac injury on top, it doesn’t make a difference
15 and the answer is yes, so I think that’s I think the
16 main topic, but you’re absolutely right that yes these
17 are not young patients, not in that first wave, right
18 you know so tomorrow we can talk about the study that
19 include younger patients and you can see that it does
20 actually still have the same pattern but you know
21 keeping in mind that the number one predictor or death
22 is age, right.
23 You know, so in any condition so you
24 know this is the thing you know and so that’s why in
25 the beginning we have so many death because it’s in

AR09369
DR. PETER LIU - 102
1 the older population but you know for that the patient
2 infected with COVID-19, those with heart involvement
3 you know you are worse off.
4 So, of course remaining interesting
5 question, seeing younger patients you know, that’s
6 precisely you know sort of the question on your mind
7 and this is where you know the newer studies help to
8 address that more precisely you know on the age
9 equivalent issue, yeah, but you’re right in that the
10 only available data in the beginning with COVID-19
11 older patients, yeah.
12 282. Q. And my point was in that particular
13 section of your report regarding what comes after, the
14 only studies that you relied on are not focused on
15 young, healthy males?
16 A. Yes, simply because there isn’t data,
17 right you know so that’s nature -- I mean, we will
18 have more data right because now the younger patients
19 are being affected and then we will be able to collect
20 data on them right so there’s always this timeline
21 effect right you know because you don’t know the
22 outcome until that while population is being followed,
23 right, so that’s always the challenge as we are
24 learning about new things.

AR09370
DR. PETER LIU - 103
1 MS. PEJOVIC: And I would like to make that
2 study as next exhibit, Madam Court Reporter.
3 THE REPORTER: Exhibit Number 7.
4 MS. PEJOVIC: Thank you and I think this is
5 a good time to break for the day.
6 MS. TELLES-LANGDON: And no objection to it
7 being marked as an exhibit and I would agree it sounds
8 like you’re moving to the next section of this report
9 tomorrow morning.
10 MS. PEJOVIC: Yes, and thank you, Dr. Liu
11 and just remind you as I’m sure your counsel has
12 reminded you that you are not speak with anyone
13 overnight about this cross-examination.
14 THE DEPONENT: Yes.
15 --- EXHIBIT NO. 7: Qin: Redefining Cardiac Biomarkers in
16 Predicting Mortality of Inpatients With COVID-19, Medicine
17 Hypertension Journal.
18
20
21
22
23
24
25

AR09371
DR. PETER LIU - 104
4 I hereby certify that this is the
5 examination of DR. PETER LIU, taken before
6 me to the best of my skill and ability on
7 the 31st day of May, 2022.
9 ------------------------------------
11
12
13
14
15
16
17
18
19
20
21

Working o!-campus? Learn about our remote access options
AR0937211
Search 1
Search Login / Register
JOURNALS '
' ASCPT.org
Volume 111, Issue 3

March 2022
Pages 605-613
This article also appears in:
Article ! Open Access " # $ % COVID-19 in ASCPT
Features of In!ammatory Heart Reactions Following mRNA

COVID-19 Vaccination at a Global Level
- . / 0
Laurent Chouchana, Alice Blet, Mohammad Al-Khalaf, Tahir S. Ka!l, Girish Nair, James Robblee, Milou-
Figures References Related Information
Daniel Drici, Marie-Blanche Valnet-Rabier, Joëlle Micallef, Francesco Salvo, Jean-Marc Treluyer, Peter P. Liu
( … See fewer authors & &
Recommended
First published: 03 December 2021 | https://doi.org/10.1002/cpt.2499
An Analysis of Follow‐On Development in

) * New Drug Classes, January 1986–June 2018
SECTIONS PDF TOOLS + SHARE
Michael L. Lanthier, Kirk W. Kerr,
Kathleen L. Miller
Abstract Clinical Pharmacology & Therapeutics
Myocarditis and pericarditis may constitute adverse reactions of mRNA coronavirus

disease 2019 (COVID-19) vaccines. This study aimed to document these reactions and to Japan’s Special Approval for Emergency
System During the COVID‐19 Pandemic
assess the association with patient sex and age. This is as an observational retrospective
study using a case–non-case design (also called disproportionality study) on Hideki Maeda
in"ammatory heart reactions reported with mRNA COVID-19 vaccines within the World Clinical Pharmacology & Therapeutics
Health Organization (WHO) global safety database (VigiBase), up to June 30, 2021. Results
are expressed using reporting odds ratios (RORs) and their 95% con!dence interval (95%
EXOGENOUS Sex Hormones and Sex
CI). Of 716,576 reports related to mRNA COVID-19 vaccines, 2,277 were cases of
Hormone Receptor Modulators in COVID‐19:
in"ammatory heart reactions, including 1241 (55%) myocarditis and 851 (37%)
Rationale and Clinical Pharmacology
pericarditis. The main age group was 18–29 years (704, 31%), and mostly male patients Considerations
(1,555, 68%). Pericarditis onset was delayed compared with myocarditis with a median
Peng Zou, Agiua Heath, Catherine Sewell,
time to onset of 8 (3–21) vs. 3 (2–6) days, respectively (P = 0.001). Regarding myocarditis, Yanhui Lu, Doanh Tran, Shirley K. Seo
an important disproportionate reporting was observed in adolescents (ROR, 22.3, 95% CI
Clinical Pharmacology & Therapeutics
19.2–25.9) and in 18–29 years old (ROR, 6.6, 95% CI 5.9–7.5) compared with older
patients, as well as in male patients (ROR, 9.4, 95% CI 8.3–10.6). Reporting rate of
myocarditis was increased in young adults and adolescents. In"ammatory heart Cardiac complications following mRNA
reactions may rarely occur shortly following mRNA COVID-19 vaccination. Although an COVID‐19 vaccines: A systematic review of
case reports and case series
important disproportionate reporting of myocarditis was observed among adolescents
and young adults, particularly in male patients, reporting rates support a very rare risk, Asra Fazlollahi, Mahdi Zahmatyar,
Maryam Noori, Seyed Aria Nejadghaderi,
that does not seem to compromise the largely positive bene!t-risk balance of these
Mark J. M. Sullman, Reza Shekarriz-Foumani,
vaccines. Furthermore, this study con!rmed the value of disproportionality analyses for Ali-Asghar Kolahi, Kuljit Singh, Saeid Sa!ri
estimation of relative risks among subgroups of patients.
Study Highlights
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
☑ Myocarditis and pericarditis cases following mRNA coronavirus disease 2019

(COVID-19) vaccination have been reported and vaccine causality have been
con!rmed by the European Medicine Agency and the US Food and Drug
Administration.
WHAT QUESTION DID THIS STUDY ADDRESS?
☑ What are the demographic features of in"ammatory heart reactions following

mRNA COVID-19 vaccination?
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
☑ In this observational retrospective pharmacovigilance study at a global level, an

important disproportionate reporting of myocarditis following mRNA COVID-19
vaccination was observed among adolescents and young adults, particularly in
male patients. Reporting rate supports a very rare incidence, lower than reports
of myocarditis related to severe acute respiratory syndrome-coronavirus 2 (SARS-
CoV-2) infection.
HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR

TRANSLATIONAL SCIENCE?
☑ Individual risk bene!t decision making may be required for the use of COVID-
19 vaccines.
Myocarditis and pericarditis are in"ammatory heart conditions that occur in the setting of
excessive host immune response to antigenic stimuli.1 Viral myocarditis has been widely
reported after severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection and
subsequent development of coronavirus disease 2019 (COVID-19).2, 3 In some instances,
these in"ammatory reactions have been associated with some drug exposure, including
vaccines.4-6 A descriptive analysis of drug-associated myopericarditis spontaneous reports in
the United States (1990–2018) identi!ed that about 0.1% of the cases were related to
vaccines.7 In"ammatory heart reactions following vaccination have been mostly reported
with live-virus vaccines, such as the smallpox vaccine,5, 8, 9 and inactivated in"uenza
vaccines.10 Myocarditis cases have been reported following mRNA COVID-19 vaccination and
early analyses suggested it may constitute a complication of these vaccines.11-13
Vaccination is critical to contain the SARS-CoV-2 pandemic. The mRNA vaccines represent a
new generation of vaccines that can be rapidly responsive to emerging viruses.14 Pivotal
phase III randomized clinical trials were conducted on 35,654 volunteers who were exposed
to the active mRNA vaccines.15, 16 Up to July 2021, tozinameran (BNT162b2; P!zer-BioNTech)
and elasomeran (mRNA 1273; Moderna) have been distributed in 104 and 49 countries
worldwide, respectively, and more than 341 million doses have been administered in the
United States.17 Rare but severe adverse drug reactions have been highlighted in clinical
trials and thereafter reported after mRNA COVID-19 vaccination, such as anaphylaxis or
Bell’s palsy.18-20 In April and May 2021, a growing signal concerning in"ammatory heart
reactions has emerged in several regions of the world with early coverage in the press.21-24
This risk appears to concern mainly mRNA vaccines and at a less extent other COVID-19
vaccines, such as viral vector based-vaccines.25 A small case series in members of the US
Military suggested an incidence below 1 over 100,000 doses administered.26 Preliminary
analysis by national authorities in Europe and in the United States led to con!rm this safety
signal and a probable causal relationship have been established.24, 27, 28
In this study, we aimed to document the in"ammatory heart reactions reported after mRNA
COVID-19 vaccination and to further assess the association with patient sex and age.
METHODS
Study design
This is a retrospective observational study of the in"ammatory heart reactions associated
with mRNA COVID-19 vaccines registered in a global pharmacovigilance database.
Data source
VigiBase (https://www.who-umc.org/vigibase/vigibase/) is the unique World Health
Organization (WHO) global database of individual case safety reports.29 This database is
maintained, deduplicated, and deidenti!ed by Uppsala Monitoring Centre (Uppsala,
Sweden). VigiBase is the world’s largest pharmacovigilance database, with over 23 million
reports of suspected adverse drug reactions gathered from national pharmacovigilance
systems and continuously updated. More than 130 countries, over 5 continents submit
spontaneous safety reports in this database. Information concerning the reporter, the
patient, the suspected and concomitant drugs, and the suspected adverse drug reactions
and their seriousness, are reported for each case. Reactions are coded using the hierarchical
Medical Dictionary for Regulatory Activities (MedDRA; https://www.meddra.org/).
COVID-19 Data Tracker (https://covid.cdc.gov/covid-data-tracker/) is the o#cial dashboard

of the US Center for Disease Control and Prevention, allowing assessment of the number of
people vaccinated within the United States.
Ethics
This study has obtained ethics approval from the Cochin University Hospital institutional
review board (number AAA-2021-08039) in conformity with the French laws and
regulations.30
Data extraction and analysis

Reports including an mRNA COVID-19 vaccine as the suspected drug in the adverse reaction
have been extracted. From that, cases of in"ammatory heart reactions (i.e., myocarditis,
myopericarditis, pericarditis, and pleuropericarditis), were retrieved using the ad hoc high-
level terms from MedDRA, “noninfectious myocarditis” and “noninfectious pericarditis,”
coded as reactions. Cases included in this study were registered up to June 30, 2021, in
VigiBase. For each report of interest, the following data were extracted or assessed:
demographic features, continent of reporting, type of reporter, month of reporting, patient
sex, patient age, time to reaction onset, seriousness, reaction outcome, and type of heart
in"ammatory reaction. Seriousness was de!ned, according to the WHO, as the occurrence
of death, life-threatening adverse event, inpatient hospitalization or prolongation of an
existing hospitalization, signi!cant disability, or requirement of intervention to prevent any
of these.31
Disproportionality analysis
Disproportionality analyses, also called case–non-case studies, are similar to case–control
studies but for the purpose of pharmacovigilance studies. These studies are nested in a
database of spontaneous reports to assess possible disproportionality in reporting.
Disproportionality analysis compares the proportion of a speci!c adverse drug reaction
reported in a speci!c group (e.g., drug exposure, patient age, and patient sex) with the
proportion of the same adverse drug reaction for a control group.32-34 This statistical
approach has shown its value to provide an estimation of relative risks of adverse drug
reaction, that are correlated in most cases with results from meta-analyses of clinical trials.35
To assess an association between in"ammatory heart reactions after mRNA COVID-19

vaccines and patient age or sex, we performed a disproportionality analysis among di$erent
patient groups. This analysis was realized in the cohort of mRNA COVID-19 vaccine reports.
Characteristics of interest are patient sex and age groups, specially 12–17 years, 18–
29 years, and over 30 years, as reported by safety signals of concern. Cases are reports
concerning a speci!c patient group and that include the terms myocarditis, pericarditis, or
pleuropericarditis as reactions after an mRNA COVID-19 vaccine. Non-cases are reports
concerning a speci!c patient group that include all other reactions to an mRNA COVID-19
vaccine. Therefore, our analyses assessed a potential di$erence of reporting of
in"ammatory heart reactions secondary to mRNA COVID-19 vaccines in male compared with
female patients and in 12–17 years or 18–29 years old patients compared with patients over
30 years old. Thereafter, sensitivity analyses were performed, restricted to serious reports
only, and to reports originating from a healthcare professional.
Statistical analysis
Descriptive analysis of the cases was performed. Quantitative variables were expressed as
median ± interquartile range (IQR) and compared using nonparametric analysis. Qualitative
variables were expressed in number and percentages. Time to reaction onset was analyzed
using a survival Mantel-Cox model.
Disproportionality in reporting between groups is expressed using reporting odds ratio

(ROR) and its 95% con!dence interval (95% CI). ROR is a ratio similar in concept to the odds
ratio in case–control studies and corresponds to the exposure odds among reported cases
of interest over the exposure odds among reported non-cases. ROR (95% CI) were calculated
as , where a is the number of cases reported with mRNA COVID-19
vaccines in a speci!c group (e.g., male patients), b is the number of non-cases (i.e., all other
adverse drug reactions) reported with mRNA COVID-19 vaccines in a speci!c group, c is the
number of cases reported with mRNA COVID-19 vaccines in a control group (e.g., female
patients), and d is the number of non-cases reported with mRNA COVID-19 vaccines in a
control group.
Reporting rates and their 95% CI were estimated using the total count of vaccinated people
in the United States that had a complete vaccination scheme (i.e., received a second dose of
a two-dose vaccine scheme or one dose of a single-dose vaccine scheme).
RESULTS
Demographics and characteristics of cases
As of the end of June 2021, of a total of 26,258,646 reports registered in the worldwide
spontaneous report database VigiBase, 716,576 reports were related to an mRNA COVID-19
vaccine as a suspected drug, including 495,493 with tozinameran and 221,368 with
elasomeran (including 285 reports with both vaccines). Among them, 2,277 cases of
in"ammatory heart reactions were retrieved, such as 1,241 (54.5%) myocarditis, 851 (37.4%)
pericarditis, 167 (7.3%) myopericarditis, and 18 (0.8%) pleuropericarditis (Table 1). Cases
were largely reported from North America (63.4%) and Europe (35.0%). Of the cases, 1,655
(72.7%) were reported with tozinameran and 622 (27.3%) with elasomeran. Patients were of
the younger age bracket (median age 33, (21–54)) mostly from the group between 18 and
29 years old (704, 30.9%), more commonly male patients (1,555, 68.3%). Patient distribution
was di$erent according to age and sex (P < 0.0001) for both myocarditis and pericarditis
cases (Figure 1). Speci!cally, most of myocarditis cases have been reported in 12–17 and
18–29 years old male patients. Overall, the median time to onset for these in"ammatory
heart reactions was 3 (2–14) days after vaccine injection. Onset of pericarditis was delayed
compared with myocarditis with a median time to onset of 8 (3–21) vs. 3 (2–6) days,
respectively (P = 0.001; Figure 2). Seventy-three percent (764) of reported myocarditis cases
occurred before day 6 vs. 42% (312) of reported pericarditis cases. Drug other than COVID-
19 mRNA vaccines were suspected in the cardiac reaction onset in 200 (8.7%) patients. Most
of the myocarditis (1,015, 81.8%) and pericarditis (492, 57.8%) reported cases required
hospitalization; 219 (21.5%) and 101 (20.5%) were life-threatening, respectively. In 22
patients, the in"ammatory heart reaction had a fatal outcome, corresponding to 15 (1.2%)
myocarditis cases (median age 60 (56–78) years old), 5 pericarditis cases (median age 71
(67–77) years old), and 2 myopericarditis cases (age 55 and 83). Among these fatal cases, the
vaccine was the only suspected drug in all except one case in which atezolizumab, an anti-
PDL1, was another suspected drug.
Table 1. Characteristics of in"ammatory heart reactions reported with mRNA COVID-19

vaccines within the WHO global safety database
Reporting characteristics Tozinameran vaccine Elasomeran vaccine Overall

(n = 1,655) (n = 622) (n = 2,277)
Continent of reporting
North America 942 (56.9%) 502 (80.7%) 1444 (63.4%)
Europe 676 (40.8%) 120 (19.3%) 796 (35.0%)
Oceania 31 (1.9%) – 31 (1.4%)
Latin America 5 (0.3%) – 5 (0.2%)
Africa 1 (0.1%) – 1 (0.1%)
Type of reporter
Physician 383 (23.1%) 75 (12.1%) 458 (20.1%)
Pharmacist 35 (2.1%) 9 (1.4%) 44 (1.9%)
Other health professional 46 (2.8%) 2 (0.3%) 48 (2.1%)
Consumer 234 (14.1%) 34 (5.5%) 268 (11.8%)
Unknown 957 (57.8%) 502 (80.7%) 1459 (64.1%)
Sex, male (%) 1108 (66.9%) 447 (71.9%) 1555 (68.3%)
Age, years 33 (19–55) 31 (22–52) 33 (21–54)
Age, ranges
Data are presented as N (%) or median (IQR).
COVID-19, coronavirus disease 2019; IQR, interquartile range; WHO, World Health Organization.
a
Other reported suspected drugs are in"iximab (1 case with elasomeran), nicotinic acid and
hydrocodone/paracetamol (1 case with tozinameran), and antilymphocyte immunoglobulin (1 case with tozinameran).
Figure 1 Open in "gure viewer ,PowerPoint
Demographic features of in"ammatory heart reactions after mRNA coronavirus disease 2019 (COVID-19)
vaccines reported in the World Health Organization (WHO) global safety database. (a) Sex distribution
according to reaction type (myocarditis or pericarditis). (b) Reaction type (myocarditis or pericarditis)
distribution according to age. (c) Sex distribution according to reaction type (myocarditis or pericarditis) and
age. [Colour !gure can be viewed at wileyonlinelibrary.com]
Time to onset according to the type of in"ammatory heart reaction. The y-axis represents the percentage of
cases reported when “time to onset” was reported, corresponding to a total of 1,039 myocarditis and 740
pericarditis. Time to onset was earlier for myocarditis. [Colour !gure can be viewed at
wileyonlinelibrary.com]
Regarding myocarditis cases originating from the United States, they were mainly reported
after May 2021, although reactions occur alongside with vaccination achievements
(Figure 3b,c). Reporting rate (95% CI) was overall 0.61 (95% CI 0.57–0.65) per 100,000 fully
vaccinated people, with a reporting in"ation after April 2021, up to 3.57 (95% CI 3.30–3.86)
per 100,000 fully vaccinated people in June 2021 (Figure 3a, Table S2). We observed a large
increase in reporting rates in 12–17-year-old patients (3.69, 95% CI 3.25–4.18 per 100,000
persons) and in 18–29-year-old patients (1.97, 95% CI 1.80–2.16 per 100,000 persons)
compared with patients over 30 years old (0.21, 95% CI 0.19–0.24 per 100,000 persons) fully
vaccinated vaccine recipients.
Features of myocarditis reporting in the United States. (a) Myocarditis reporting rate as of June 2021
according to age. Vaccine recipients are de!ned as the total count of vaccinated people in the United States
that had a complete vaccination scheme (i.e., received a second dose of a two-dose vaccine scheme or one
dose of a single-dose vaccine scheme; see Table S2 for detailed rates according to time). (b) Number of
myocarditis cases per month according to reporting date and to reaction onset date. (c) Reported
myocarditis cases and total number of people fully vaccinated according to the age group (12–17 years old,
18–29 years old, and over 30 years old). [Colour !gure can be viewed at wileyonlinelibrary.com]
Disproportionality analysis
Compared with female patients, male patients were associated with an increased risk of
myocarditis reporting (ROR, 9.4, 95% CI 8.3–10.6) and of pericarditis reporting (ROR, 3.7, 95%
CI 3.2–4.2; Figure 4). Analysis according to age group showed a marked disproportionate
reporting of myocarditis after mRNA COVID-19 vaccines in 12–17-year-old (ROR, 22.3, 95% CI
19.2–25.9) and 18–29-year-old (ROR, 6.6, 95% CI 5.9–7.5) recipients compared with over 30-
year-old recipients. Speci!cally, this increased reporting was more marked in male than in
female patients, among all age groups (Figure 4a). Regarding pericarditis, a disproportionate
reporting in male patients among all age groups, compared with female patients was
observed (Figure 4b). Younger male patients belonging to the 12–17 and 18–29-year-old
groups were also more prone to report pericarditis after mRNA COVID-19 vaccines
compared with the over 30-year-old group. This !nding not being true in female patients in
whom no disproportionality in pericarditis reporting was observed according to age. Further
sensitivity analyses restricted to serious reports and to reports originating form healthcare
professionals showed consistent results (Tables S3–S6).
Reporting odds ratios for myocarditis and pericarditis in mRNA coronavirus disease 2019 (COVID-19) vaccine
recipients according to sex and age within the World Health Organization (WHO) global safety database. (a)
Myocarditis. (b) Pericarditis. Case–non-case approach is similar to case–control method but for the purposes
of pharmacovigilance studies. Disproportionality in adverse drug reaction reporting between groups is
expressed using RORs and their 95% CI. ROR is a ratio similar in concept to the odds ratio in case-control
studies and corresponds to the exposure odds among reported cases of in"ammatory heart disorders over
the exposure odds among reported non-cases. A lower bound of the 95% CI of the ROR over 1.0 suggests
that in"ammatory heart disorders are more frequently reported in COVID-19 mRNA vaccine recipients
speci!c group compared with control group. We performed the main analysis and a secondary analysis
strati!ed according to age groups and sex. *In"ammatory heart disorder cases were individual case safety
reports were retrieved using the high level terms “noninfectious myocarditis” and “noninfectious pericarditis”
according to the Medical Dictionary for Regulatory Activities (MedDRA, https://www.meddra.org/), coded as
reactions. Cases of myopericarditis have been considered as myocarditis. **Non-cases were reports
containing any other reaction. ROR, reporting odds-ratio; 95% CI, 95% con!dence interval. [Colour !gure can
be viewed at wileyonlinelibrary.com]
DISCUSSION
In this global pharmacovigilance retrospective observational study, we report the largest
case series of in"ammatory heart reactions following mRNA COVID-19 vaccination to date.
Our global analysis show that myocarditis is highly likely to be reported in adolescents and
young adults below 30 years old. Furthermore, we also observed a dramatically increased
disproportionate reporting risk in male patients, among all age groups. These myocarditis
and pericarditis cases mostly required hospitalization, some were life-threatening, and, in
older patients, occasionally fatal. As of June 2021, we observed overall 3.57 (from 3.30 to
3.86) myocarditis reports per 100,000 fully vaccinated persons in the United States; this rate
being higher in adolescents (5.15, from 4.45 to 5.95) and young adults (7.82, 6.89 to 8.86).
This supports that myocarditis may appear very rarely following mRNA vaccination, even in
young people, although our analysis cannot assess accurate incidence.
Overall, our !ndings are consistent with the experience !rst reported by the Israeli Ministry
of Health and thereafter by the US Centers for Disease Control and Prevention (CDC).21, 35 In
our study, among the US population, 3.57 (from 3.30 to 3.86) myocarditis reports per
100,000 persons fully vaccinated have been observed overall as of June 2021. Although our
approach cannot accurately assess reaction incidence owing to under-reporting, this
reporting rate is consistent with the !ndings from a national study in Israel, where the
excess risk of myocarditis in the 42 days following the administration of an mRNA COVID-19
vaccine has been assessed at 2.7 (from 1.0 to 4.6) events per 100,000 persons.36
Noteworthy, the authors mentioned that this risk was lower than that expected following
infection by SARS-CoV-2. One major limitation of this study was the lack of risk estimates
according to age and sex group.37 Our analysis allows to estimate a relative risk according to
patient age and sex. We found a major increased reporting for myocarditis in male patients,
and in adolescents and young adults below 30 years old, supporting a much higher risk in
these groups. In a comparable manner, an analysis from the CDC found that observed
myocarditis reports were higher than expected case rates for male patients compared with
female patients, and higher at younger ages compared with older ages.38 Otherwise, one
could hypothesize a current background risk for myocarditis probably lower than usual
along with the widespread adoption of community-based mitigation measures to reduce the
transmission of SARS-CoV-2 and thereafter other respiratory infection.39, 40
Myocarditis and pericarditis have been previously reported after vaccination, especially
smallpox and in"uenza vaccines.7 Potential mechanisms are currently unknown, but several
hypotheses may be considered. The !rst is that incidence appears to be higher in situations
related to higher immune reactivity (e.g., younger patient population, after second dose,
etc.). This may be related to greater adaptive immune response in younger individuals,
which may lead to greater increases of CD4+ Th17+ cell populations, predisposing
individuals to developing myocarditis. It would be interesting to see if the recently reported
mRNA diagnostic of Th17 activation in myocarditis is also positive in these patients.41
Second, is the possibility that mRNA in these vaccines may enhance autoimmunity.42 The
mRNA is known to be a self-adjuvant for innate immune responses, and this may help to
explain their immunogenicity, and trigger excessive immune responses in some individuals,
especially when there may be presence of a cross-reacting antigen. Optimization of mRNA
dose delivered is needed to elicit appropriate immune response while minimizing
undesirable in"ammatory reactions, re-assessing the dosing frequency and time interval
between doses, as well as optimization of all ingredients associated with the mRNA, in order
to achieve the most bene!cial outcome of e$ective immunization with the least number of
adverse e$ects to all di$erent population demographics. Finally, it has been hypothesized
that myocarditis can occur due to direct cell invasion via the spike protein interacting with
the angiotensin-converting enzyme 2 (ACE2) widely expressed and prevalent in
cardiomyocytes.43, 44 However, in case of COVID-19 related myocarditis, SARS-CoV-2 has not
been found in cardiomyocytes, but only in the remaining myocardium, thus the cell injury
was thought to be due to the generalized in"ammatory response to COVID-19, part of which
is Th1 activation.45 In two recently reported cases of myocarditis following mRNA
vaccination, only in"ammatory in!ltration was assessed in the myocardium, suggesting that
the ACE2 hypothesis is probably not relevant.46
The reason for male predominance in myocarditis cases following mRNA COVID-19
vaccination is unknown. Although, female patients usually generate higher overall antibody
levels and more adverse events following vaccination, male patients have increased
enhanced type-1 immune responses.47 These di$erences may be driven by sex hormone
di$erences and testosterone is thought to play a role in commitment to a Th1 response.38
Hence, sex di$erences observed in myocarditis could suggest a mechanism for myocarditis
occurrence involving Th1 activation.
This retrospective pharmacovigilance analysis has some limitations and strengths.

Spontaneous reports will likely feature under-reporting of total real-world cases as well as
variable data quality, all of which are inherent to any pharmacovigilance system.48 Hence, as
a limitation of this study, it is not possible to accurately assess incidence of in"ammatory
heart reactions following mRNA COVID-19 vaccination. However, in the current context of a
highly communicated risk at a global level, such as the myocarditis risk as of June 2021, the
reporting rate may be relevant to approximate incidence. Another limitation is the quality of
the data reported in pharmacovigilance databases, that could result in some cases in
misdiagnosis. However, it appears not likely that this precludes our analysis according to
patient age and sex, which was consistent after considering only reports originating from
healthcare professionals. Furthermore, VigiBase, covering more than 90% of the world’s
population, provides a unique opportunity to analyze rare adverse events at a global scale.
Disproportionality analysis on VigiBase has proven its value in detecting increased risk of
events.32 Our study con!rmed the value of disproportionality analyses in relative risk
estimation among subgroups of patients. Our analysis highlights an increased risk of
myocarditis reporting in young male patients. On one hand, myocarditis has su$ered from a
notoriety bias after media communication. On the other hand, non-cases reporting may be
in"ated as well, resulting in an underestimation of this risk. Besides, it is not clear whether,
in the current pandemic setting, the expected rate of myocarditis is di$erent from the
historical rate of 0.95 to 2.16 per 100,000 persons among the US population.49 Finally, it is
not likely that study groups in our disproportionality analysis, based on patient age and sex,
may have been imbalanced in relation with these limitations. Sensitivity analyses showing
consistent results strengthen our !ndings.
We report a global analysis on in"ammatory heart reactions occurring after mRNA COVID-19
vaccination. Reporting risk of myocarditis is highly increased in adolescents or young adults,
and in male patients. However, owing hundreds of millions of doses administered worldwide
to date, the excess risk of myocarditis following mRNA COVID-19 vaccination, supported by
the rate of reporting in our study and a recent study, appeared very rare.36 Foremost, it has
been shown that SARS-CoV-2 infection is itself a very strong risk factor for myocarditis,
higher than following vaccination.36 Absolute risk may greatly increase with the
achievements of the mass immunization campaign and the enlargement of vaccination to
young adults. Adapting the dosage, timing, and protocol of mass immunization in young
adults and children, especially male patients, should be discussed.50 Nevertheless, bene!ts
of COVID-19 vaccines still very largely outweigh their risks given the current prevalence of
SARS-CoV-2 infections around the world. As COVID-19 vaccines’ administration increases
worldwide, physicians and the public should be aware of these very rare in"ammatory heart
reactions, and follow appropriate monitoring and treatment procedures as with other cases
of myocarditis.51 Further studies are needed to support individual risk-bene!t decision
making about the use of COVID-19 vaccines. In the future, as newer formulations are being
developed, such as for vaccine boosters, the dose and timing for the at-risk cohort for
cardiac complications should be considered to maximize the bene!t to risk ratio.
ACKNOWLEDGMENTS
The authors would like to thank all the healthcare workers and the French
Pharmacovigilance Network involved in the current large immunization campaign and in its
safety monitoring, VigiBase is a fully deidenti!ed database maintained by the Uppsala
Monitoring Center (UMC). The authors are indebted to the National Pharmacovigilance
centers that contributed data. Information from VigiBase comes from a variety of sources,
and the probability that the suspected adverse e$ect is drug-related is not the same in all
cases. The information does not represent the opinion of the Uppsala Monitoring Center
(UMC) or the World Health Organization and only re"ects the authors’ opinion. According to
VigiBase access rules, no speci!c ethical approval is needed. VigiBase access is granted to
national and regional pharmacovigilance centers such our teams.
FUNDING
This work is supported in part by research grants from the Canadian Institutes of Health
Research, Heart & Stroke Foundation of Canada, Genome Canada, and University of Ottawa
of Heart Institute.
CONFLICT OF INTEREST
The authors declared no competing interests for this work.
AUTHOR CONTRIBUTIONS
L.C., A.B., M.A.-K., and P.L.L. wrote the manuscript. L.C., A.B., and P.L.L. designed the
research. L.C. and A.B. performed the research. L.C., A.B., P.P.L., M.A.-K., T.S.K., G.N., J.R., M.-
D.D., M.-B.V.-R., J.M., F.S., and J.-M.T. analyzed the data.
Open Research '

'
Supporting Information '

'
'
'
Download PDF
ASCPT.ORG MEMBERSHIP CAREER CENTER
ABOUT ASCPT MEETINGS CONTACT US
© 2022 American Society for Clinical Pharmacology and Therapeutics
About Wiley Online Library Help & Support Opportunities Connect with Wiley
Privacy Policy Contact Us Subscription Agents The Wiley Network
Terms of Use Training and Support Advertisers & Corporate Wiley Press Room
Partners
About Cookies DMCA & Reporting Piracy
Manage Cookies
Accessibility
Wiley Research DE&I

Statement and Publishing
Policies
Copyright © 1999-2022 John Wiley & Sons, Inc. All rights reserved
2
AR09373 BRIEF REPORTS
Persistent Cardiac Magnetic Resonance Imaging Findings in a Cohort of

Adolescents with Post-Coronavirus Disease 2019 mRNA Vaccine
Myopericarditis
Jenna Schauer, MD1, Sujatha Buddhe, MD, MS1, Avanti Gulhane, MD, DNB, FSCMR2, Eyal Sagiv, MD, PhD1,
Matthew Studer, MD1, Jessica Colyer, MD, MBA1, Sathish Mallenahalli Chikkabyrappa, MD1, Yuk Law, MD1,
and Michael A. Portman, MD1
We describe the evolution of cardiac magnetic resonance imaging findings in 16 patients, aged 12-17 years, with
myopericarditis after the second dose of the Pfizer mRNA coronavirus disease 2019 vaccine. Although all patients
showed rapid clinical improvement, many had persistent cardiac magnetic resonance imaging findings at 3- to
8-month follow-up. (J Pediatr 2022;-:1-5).
M
yopericarditis has emerged as an important adverse for observation with telemetry, serial troponin measure-
event following coronavirus disease 2019 ments, and repeat cardiac testing as needed. All patients
(COVID-19) mRNA vaccination, particularly in underwent cardiac MRI within 1 week of initial presentation
adolescents.1 Patients typically exhibit chest pain and an and had repeat cardiac MRI at 3-8 months’ follow-up.
elevated serum troponin level in the days following the Cardiac MRI was performed on a 1.5-T Siemens scanner
COVID-19 mRNA vaccine. They usually are hemodynami- (Siemens AG). Cardiac MRI analysis was performed using
cally stable, and symptoms and cardiac biomarkers normalize CVI42 (version 5.11.4; Circle Cardiovascular Imaging Inc).
within a few days.2 Cardiac magnetic resonance imaging Patients were excluded if they did not undergo cardiac
(MRI) studies, when performed early, frequently MRI or did not have a follow-up cardiac MRI. Initial and
demonstrate abnormalities such as edema and late gadolin- follow-up cardiac MRI data for each patient were reviewed
ium enhancement (LGE), meeting Lake Louise criteria for and compared using paired Student t tests. Statistical signif-
diagnosing myocarditis noninvasively.3,4 In classical myocar- icance was defined as a P < .05. Statistical analysis was per-
ditis, LGE can be predictive of a poor outcome.5 Little is formed using SPSS 27 (IBM Corp).
known about the prognostic value or expected evolution of
these cardiac MRI abnormalities associated with post– Results
COVID-19 mRNA vaccine myopericarditis. In this case
series, we report the evolution of cardiac MRI compared A total of 35 patients with the diagnosis of myopericarditis
with initial, acute-phase, cardiac MRI in our cohort of pa- associated with Pfizer COVID-19 mRNA vaccine were fol-
tients with myopericarditis post–COVID-19 mRNA vaccine. lowed at our institution. Twelve patients were excluded, as
they never had cardiac MRI scans due to delayed presentation
Methods after initial symptoms resolved or admission to other centers.
Six patients were excluded, as they did not have a follow up
This case review includes patients younger than 18 years of cardiac MRI, either because they followed up out of state
age presenting to Seattle Children’s Hospital with chest or a study is still pending. One patient was excluded, as initial
pain and elevated serum troponin level from April 1, 2021, cardiac MRI was performed 3 weeks after presentation.
to January 7, 2022, within 1 week of receiving the second Sixteen patients who had both acute-phase and follow-up
dose of the Pfizer COVID-19 mRNA vaccine. Institutional cardiac MRIs available for review comprised the final cohort.
review board approval was obtained. All patients were This group had a median age of 15 years (range, 12-17 years),
evaluated by a pediatric cardiologist, underwent electrocar- were mostly male (n = 15, 94%), White, and non-Hispanic
diogram (ECG) and echocardiogram, and were admitted (n = 14, 88%). One patient was Asian, and 1 patient was
American Indian. Median time to presentation from the sec-
ond dose of the Pfizer COVID-19 mRNA vaccine was 3 days
COVID-19 Coronavirus disease 2019
ECG Electrocardiogram
IVIG Intravenous immunoglobulin
LGE Late gadolinium enhancement From the 1Department of Pediatrics, Seattle Children’s Hospital, University of
LV Left ventricle Washington, Seattle, WA; and 2Department of Radiology, University of Washington,
Seattle, WA
LVEF Left ventricular ejection fraction
The authors declare no conflicts of interest.
MRI Magnetic resonance imaging
NSAID Nonsteroidal anti-inflammatory drug 0022-3476/$ - see front matter. Published by Elsevier Inc.
https://doi.org/10.1016/j.jpeds.2022.03.032
1
THE JAR09374
OURNAL OF PEDIATRICS www.jpeds.com Volume - - 2022
(range 2-4 days). All patients had chest pain. The most com- scheduled dosing (mostly, 10 mg/kg ibuprofen every
mon other presenting symptoms were fever (n = 6, 37.5%) 8 hours), with the remaining 4 receiving NSAIDs as needed
and shortness of breath (n = 6, 37.5%). All patients had for pain. The median time from vaccination to NSAID initi-
elevated serum troponin levels (median 9.15 ng/mL, range ation was 2.5 days (range 0-4 days) and from symptom onset
0.65-18.5, normal <0.05 ng/mL). Twelve patients had C- to NSAID initiation was 1 day (range 0-4 days). The 2 pa-
-reactive protein measured with median value 3.45 mg/dL, tients who presented with echocardiographic LV dysfunction
range 0-6.5 mg/dL, normal <0.08 mg/dL. were treated with intravenous immunoglobulin (IVIG) plus a
Ten (62.5%) patients had an abnormal ECG, with the most corticosteroid per our institutional pathway for treatment of
common finding being diffuse ST-segment elevation. All pa- myocarditis. One additional patient received IVIG without
tients had an echocardiogram on admission; 14 of 16 patients corticosteroids. Median hospital length of stay was 2 days
had normal left ventricular (LV) systolic function; 2 patients (range 1-4 days) with no intensive care unit admission and
demonstrated mildly reduced LV systolic function with no no significant morbidity or mortality. All patients had reso-
dilation. Left ventricular ejection fraction (LVEF) for these lution of chest pain and down-trending serum troponin level
2 patients was 45% and 53% (normal >55%). Median left before discharge.
LVEF was 59% (range 45%-69%). No patients had All patients underwent follow-up cardiac MRI at
pericardial effusion. 3-8 months after their initial study (median 3.7 months,
The initial cardiac MRIs were performed within 1 week of range 2.8-8.1 months). The results are compared in the
presentation (median 2, range 0-7 days). All were abnormal; Table. Follow-up cardiac MRI LVEF (57.7 2.8%) was
all showed evidence of edema by T2 imaging, and 15 of 16 significantly improved from initial (54.5 5.5%, P < .05),
had LGE in a patchy subepicardial to transmural pattern and none of the patients had regional wall motion
with predilection for the inferior LV free wall. Distribution abnormalities. LVEF by echocardiogram was normal for all
of LGE can be seen in Figure 1.6 LV regional wall motion patients at the time of follow-up. Eleven patients (68.8%)
abnormalities were noted in 2 patients. Cardiac MRI had persistent LGE, although there was a significant
median LVEF% was 54%, range 46%-63%. Cardiac decrease in the quantifiable LGE% (8.16 5.74%) from
MRI LVEF was mildly decreased in 7 patients. Cardiac MRI the initial study (13.77 8.53%, P < .05). Cardiac edema
global longitudinal strain (%) measurements were resolved in all but 1 patient. Global longitudinal strain (%)
abnormal in 12 patients (median 16.1%, range 13.2% remained abnormal in most patients (75%, mean
to 18.1%, normal < 18%). 16.4 2.1%) at follow-up without significant change
All patients were treated with nonsteroidal anti- from the initial study ( 16.0 1.7, P = .6). Examples of
inflammatory drugs (NSAIDs): 75% (n = 12) received initial and follow-up cardiac MRI images are shown in
Figure 1. Distribution of LGE in AHA myocardial segments.6 Shown is the number and percentage of patients with LGE in each
segment. AHA, American Heart Association.
2 Schauer et al
- 2022 BRIEF REPORTS
AR09375
The presence of LGE is an indicator of cardiac injury

Table. COVID-19 vaccine–associated myopericarditis and fibrosis and has been strongly associated with worse
findings in 16 patients prognosis in patients with classical acute myocarditis. In
Initial, Follow-up, a meta-analysis including 8 studies, Yang et al5 found
Diagnostic assessment mean ± SD mean ± SD P value that presence of LGE is a predictor of all cause death, car-
Echocardiographic LVEF % 59.4 6.0 62.6 2.8 <.05 diovascular death, cardiac transplant, rehospitalization,
Electrocardiogram
Abnormal 10 (62.5%)
recurrent acute myocarditis, and requirement for mechan-
Normal 6 (37.5%) ical circulatory support. Similarly, Georgiopoulos et al8
Peak serum troponin, ng/mL 9.0 5.2 found the presence and extent of LGE to be a significant
Cardiac MRI LVEF % 54.5 5.5 57.7 2.7 <.05
Cardiac MRI LGE % (n = 15*) 13.5 8.3 7.7 5.7 <.001
predictor of adverse cardiac outcomes in an 11 study
Cardiac MRI global longitudinal strain 16.0 1.7 16.4 2.1 .5 meta-analysis.
% (n = 15*) The persistence of LGE over time and its prognostic
Bold formatting indicates P < .05, or statistically significant. value is less well established. Ma1ek et al9 found that in
*Initial source images were not available for reanalysis for 1 patient. a cohort of 18 patients with myocarditis, nearly 70%
had persistent cardiac MRI changes at a median follow-
up time of 7 months. Dubey et al10 found similar findings
Figure 2. The patient who received IVIG alone and 1 patient in their cohort of 12 pediatric patients, with persistence of
who received IVIG plus corticosteroid had resolution of LGE, LGE in all patients despite resolution of edema. The prog-
and the other had persistence of LGE. nostic meaning of LGE in vaccine associated myopericardi-
Eight patients (5 of whom had persistent LGE) underwent tis requires further study.
24-hour cardiac rhythm monitoring, all of which were Strain analysis by cardiac MRI also has been shown to
normal. Six patients, all with persistent LGE, underwent ex- have prognostic utility in myocarditis even in the setting
ercise tests, all of which were normal. Four patients com- of normal LV function.11 Strain testing can be performed
plained of intermittent chest pain at follow up with no without use of contrast material and can be particularly
identifiable abnormality on evaluation; no therapy or inter- useful in situations in which contrast administration is
vention was required. No patient received heart failure challenging or contraindicated. Notably, in our cohort,
medication. although there was significant reduction in LGE at
follow-up, abnormal strain persisted for the majority of
Discussion patients at follow-up.
This study has certain limitations. Patients who did not
We previously reported 15 patients with clinically sus- seek medical attention during acute illness or did not present
pected COVID-19 mRNA vaccine-induced myopericardi- with significant symptoms and require hospitalization were
tis. All patients had an abnormal cardiac MRI, with not captured, and their disease course may be different.
edema and/or LGE in addition to clinical symptoms and Incomplete cardiac MRI data on other patients precludes
troponin elevation, and some had abnormal ECG or echo- extrapolation of our cardiac MRI findings to all who experi-
cardiogram.4 We have since established a clinical protocol enced mRNA vaccine-related myopericarditis. In addition,
for serial cardiac MRI performance in these patients, follow-up cardiac MRI timeframes varied from patient to pa-
consistent with the 2021 American Heart Association state- tient, making it difficult to predict the timing of cardiac MRI
ment that stressed the risk of sudden cardiac death, partic- changes over time. The total number of patients reported is
ularly with exercise, while active inflammation is present.7 small, limiting ability to draw conclusions about the effect
Our patients were restricted from exercise on discharge. of treatment modalities or to generalize regarding outcomes
Repeat cardiac MRI was performed within 3-6 months of vaccine-associated myopericarditis.
to guide next clinical decision-making steps; timing was In a cohort of adolescents with COVID-19 mRNA vaccine-
modified in some individuals based on scanner accessi- related myopericarditis, a large portion have persistent LGE
bility and safety precautions during the COVID-19 abnormalities, raising concerns for potential longer-term
pandemic. Although symptoms were transient and most effects. Despite these persistent abnormalities, all patients
patients appeared to respond to treatment (solely with had rapid clinical improvement and normalization of echo-
NSAIDS), we demonstrated persistence of abnormal find- cardiographic measures of systolic function. For patients
ings on cardiac MRI at follow-up in most patients, albeit with short acute illness, no dysfunction demonstrated by
with improvement in extent of LGE. echocardiogram at presentation and resolution of symptoms
Cardiac MRI increasingly has been identified as an impor- at follow-up, return to sports was guided by normalization of
tant diagnostic tool for myocarditis, given its ability to iden- cardiac MRI alone. In patients with persistent cardiac MRI
tify subclinical injury and fibrosis by markers of LGE and abnormalities, we performed exercise stress testing before
edema. Cardiac MRI also has been used in longitudinal sports clearance per myocarditis recommendations.7 We
follow-up of patients with myocarditis to help therapeutic plan to repeat cardiac MRI at 1-year postvaccine for our
management, although exact screening protocols remain cohort to assess for resolution or continued cardiac MRI
controversial.7 changes.
Persistent Cardiac Magnetic Resonance Imaging Findings in a Cohort of Adolescents with Post-Coronavirus 3
Disease 2019 mRNA Vaccine Myopericarditis
THE JAR09376
OURNAL OF PEDIATRICS www.jpeds.com Volume -
Figure 2. Cardiac MRI scans from 3 days after admission of a 16-year-old male patient who presented to the emergency
department with chest pain and elevated troponin 3 days after receiving the Pfizer COVID-19 mRNA vaccine. Initial cardiac MRI.
A and B, Subepicardial to midmyocardial LGE in inferior and inferolateral LV wall from base to apex (arrows). C, T2 hyperintensity
in similar segments, consistent with edema. D-F, Follow-up cardiac MRI 4.4 months later. LGE is still persistent but decreased
from 26% to 19.84% (arrows), and LVEF remained stable at 58%. There is improved T2 hyperintensity.
The Centers for Disease Control and Prevention notes that 8 weeks. Further follow-up assessment and larger multicenter
even though the absolute risk for myopericarditis following studies are needed to determine the ultimate clinical signifi-
mRNA COVID-19 vaccine is small, the relative risk is greater cance of persistent cardiac MRI abnormalities in patients
for particular groups, including male patients aged 12-39 years. with post–COVID-19 vaccine myopericarditis. n
Some studies have suggested that increasing the interval
between the first and second dose may reduce the incidence
Submitted for publication Feb 7, 2022; last revision received Mar 17, 2022;
of myopericarditis in this population.12 These data led to an accepted Mar 23, 2022.
extension in the Centers for Disease Control and Prevention– Reprint requests: Jenna Schauer, MD, 4800 Sandpoint Way NE, Seattle, WA,
recommended dosing interval between dose 1 and dose 2 to 98105. E-mail: Jenna.Schauer@seattlechildrens.org
4 Schauer et al
- 2022 BRIEF REPORTS
AR09377
References nomenclature for tomographic imaging of the heart. Circulation

2002;105:539-42. https://doi.org/10.1161/hc0402.102975
7. Law YM, Lal AK, Chen S, Cih akova D, Cooper LT, Deshpande S, et al.
1. Gargano JW, Wallace M, Hadler SC, Langley G, Su JR, Oster ME, et al. Diagnosis and management of myocarditis in children: a Scientific State-
Morbidity and Mortality Weekly Report Use of mRNA COVID-19 Vac- ment from the American Heart Association. Circulation 2021;144:E123-
cine After Reports of Myocarditis Among Vaccine Recipients: update 35. https://doi.org/10.1161/CIR.0000000000001001
from the Advisory Committee on Immunization Practices—United 8. Georgiopoulos G, Figliozzi S, Sanguineti F, Aquaro GD, di Bella G,
States, June 2021. MMWR Morb Mortal Wkly Rep 2021;70:977-82. Stamatelopoulos K, et al. Prognostic impact of late gadolinium enhance-
https://doi.org/10.15585/mmwr.mm7027e2externalicon ment by cardiovascular magnetic resonance in myocarditis: a systematic
2. Kohli U, Desai L, Chowdhury D, Harahsheh AS, Yonts AB, Ansong A, review and meta-analysis. Circ Cardiovasc Imaging 2021;14:e011492
et al. mRNA coronavirus-19 vaccine–associated myopericarditis in ado- https://doi.org/10.1161/CIRCIMAGING.120.011492
lescents: a survey study. J Pediatr 2021;243:208-13.e3. https://doi.org/10. 9. Ma1ek qA, Kami nska H, Barczuk-Fale˛cka M, Ferreira VM, W ojcicka J,
1016/j.jpeds.2021.12.025 Brzewski M, et al. Children with acute myocarditis often have persistent
3. Truong DT, Dionne A, Muniz JC, McHugh KE, Portman MA, subclinical changes as revealed by cardiac magnetic resonance. J Magn
Lambert LM, et al. Clinically suspected myocarditis temporally related Reson Imaging 2020;52:488-96. https://doi.org/10.1002/jmri.27036
to COVID-19 vaccination in adolescents and young adults. Circulation 10. Dubey S, Agarwal A, Nguyen S, Adebo D. Persistence of late gadolinium
2022;145:345-56. https://doi.org/10.1161/circulationaha.121.056583 enhancement on follow-up CMR imaging in children with acute
4. Schauer J, Buddhe S, Colyer J, Sagiv E, Law Y, Mallenahalli myocarditis. Pediatr Cardiol 2020;41:1777-82. https://doi.org/10.1007/
Chikkabyrappa S, et al. Myopericarditis after the Pfizer messenger ribo- s00246-020-02445-5
nucleic acid coronavirus disease vaccine in adolescents. J Pediatr 11. Chen Y, Sun Z, Xu L, Liu J, Li Y, Zhang N, et al. Diagnostic and prog-
2021;238:317-20. https://doi.org/10.1016/j.jpeds.2021.06.083 nostic value of cardiac magnetic resonance strain in suspected myocar-
5. Yang F, Wang J, Li W, Xu Y, Wan K, Zeng R, et al. The prognostic value ditis with preserved LV-EF: a comparison between patients with
of late gadolinium enhancement in myocarditis and clinically suspected negative and positive late gadolinium enhancement findings. J Magn Re-
myocarditis: systematic review and meta-analysis. Eur Radiol 2020;30: son Imaging 2022;55:1109-19. https://doi.org/10.1002/jmri.27873
2616-26. https://doi.org/10.1007/s00330-019-06643-5 12. Moulia D. Myocarditis and COVID-19 vaccine intervals: international
6. Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, data and policies. ACIP meeting COVID-19 Vaccines. Accessed March
Laskey WK, et al. Standardized myocardial segmentation and 1, 2022. February 4, 2022. https://stacks.cdc.gov/view/cdc/114164
Persistent Cardiac Magnetic Resonance Imaging Findings in a Cohort of Adolescents with Post-Coronavirus 5
Disease 2019 mRNA Vaccine Myopericarditis
AR09378
Research
JAMA | Original Investigation
Myocarditis Cases Reported After mRNA-Based COVID-19 Vaccination

in the US From December 2020 to August 2021
Matthew E. Oster, MD, MPH; David K. Shay, MD, MPH; John R. Su, MD, PhD, MPH; Julianne Gee, MPH; C. Buddy Creech, MD, MPH; Karen R. Broder, MD;
Kathryn Edwards, MD; Jonathan H. Soslow, MD, MSCI; Jeffrey M. Dendy, MD; Elizabeth Schlaudecker, MD, MPH; Sean M. Lang, MD;
Elizabeth D. Barnett, MD; Frederick L. Ruberg, MD; Michael J. Smith, MD, MSCE; M. Jay Campbell, MD, MHA; Renato D. Lopes, MD, PhD, MHS;
Laurence S. Sperling, MD; Jane A. Baumblatt, MD; Deborah L. Thompson, MD, MSPH; Paige L. Marquez, MSPH; Penelope Strid, MPH; Jared Woo, MPH;
River Pugsley, PhD, MPH; Sarah Reagan-Steiner, MD, MPH; Frank DeStefano, MD, MPH; Tom T. Shimabukuro, MD, MPH, MBA
Supplemental content
IMPORTANCE Vaccination against COVID-19 provides clear public health benefits, but
vaccination also carries potential risks. The risks and outcomes of myocarditis after COVID-19
vaccination are unclear.
OBJECTIVE To describe reports of myocarditis and the reporting rates after mRNA-based
COVID-19 vaccination in the US. 3
DESIGN, SETTING, AND PARTICIPANTS Descriptive study of reports of myocarditis to the
Vaccine Adverse Event Reporting System (VAERS) that occurred after mRNA-based COVID-19
vaccine administration between December 2020 and August 2021 in 192 405 448 individuals
older than 12 years of age in the US; data were processed by VAERS as of September 30, 2021.
EXPOSURES Vaccination with BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna).
MAIN OUTCOMES AND MEASURES Reports of myocarditis to VAERS were adjudicated and
summarized for all age groups. Crude reporting rates were calculated across age and sex
strata. Expected rates of myocarditis by age and sex were calculated using 2017-2019 claims
data. For persons younger than 30 years of age, medical record reviews and clinician
interviews were conducted to describe clinical presentation, diagnostic test results,
treatment, and early outcomes.
RESULTS Among 192 405 448 persons receiving a total of 354 100 845 mRNA-based
COVID-19 vaccines during the study period, there were 1991 reports of myocarditis to VAERS
and 1626 of these reports met the case definition of myocarditis. Of those with myocarditis,
the median age was 21 years (IQR, 16-31 years) and the median time to symptom onset was 2
days (IQR, 1-3 days). Males comprised 82% of the myocarditis cases for whom sex was
reported. The crude reporting rates for cases of myocarditis within 7 days after COVID-19
vaccination exceeded the expected rates of myocarditis across multiple age and sex strata.
The rates of myocarditis were highest after the second vaccination dose in adolescent males Author Affiliations: US Centers for
aged 12 to 15 years (70.7 per million doses of the BNT162b2 vaccine), in adolescent males Disease Control and Prevention,
Atlanta, Georgia (Oster, Shay, Su,
aged 16 to 17 years (105.9 per million doses of the BNT162b2 vaccine), and in young men aged
Gee, Broder, Sperling, Marquez, Strid,
18 to 24 years (52.4 and 56.3 per million doses of the BNT162b2 vaccine and the mRNA-1273 Woo, Pugsley, Reagan-Steiner,
vaccine, respectively). There were 826 cases of myocarditis among those younger than 30 DeStefano, Shimabukuro); School of
years of age who had detailed clinical information available; of these cases, 792 of 809 (98%) Medicine, Emory University, Atlanta,
Georgia (Oster, Sperling); Children’s
had elevated troponin levels, 569 of 794 (72%) had abnormal electrocardiogram results, and Healthcare of Atlanta, Atlanta,
223 of 312 (72%) had abnormal cardiac magnetic resonance imaging results. Approximately Georgia (Oster); Vanderbilt University
96% of persons (784/813) were hospitalized and 87% (577/661) of these had resolution of Medical Center, Nashville, Tennessee
(Creech, Edwards, Soslow, Dendy);
presenting symptoms by hospital discharge. The most common treatment was nonsteroidal
Cincinnati Children’s Hospital Medical
anti-inflammatory drugs (589/676; 87%). Center, Cincinnati, Ohio
(Schlaudecker, Lang); Boston Medical
CONCLUSIONS AND RELEVANCE Based on passive surveillance reporting in the US, the risk of Center, Boston, Massachusetts
myocarditis after receiving mRNA-based COVID-19 vaccines was increased across multiple age (Barnett, Ruberg); Duke University,
and sex strata and was highest after the second vaccination dose in adolescent males and young Durham, North Carolina (Smith,
Campbell, Lopes); US Food and Drug
men. This risk should be considered in the context of the benefits of COVID-19 vaccination.
Administration, Silver Spring,
Maryland (Baumblatt, Thompson).
Corresponding Author: Matthew E.
Oster, MD, MPH, US Centers for
Disease Control and Prevention,
JAMA. 2022;327(4):331-340. doi:10.1001/jama.2021.24110 1600 Clifton Rd, Atlanta, GA 30333
Corrected on March 21, 2022. (eocevent416@cdc.gov).
(Reprinted) 331
© 2022 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 05/27/2022

AR09379
Research Original Investigation Myocarditis Cases Reported After mRNA-Based COVID-19 Vaccination in the US From December 2020 to August 2021
M
yocarditis is an inflammatory condition of the heart
muscle that has a bimodal peak incidence during Key Points
infancy and adolescence or young adulthood.1-4
Question What is the risk of myocarditis after mRNA-based
The clinical presentation and course of myocarditis is vari- COVID-19 vaccination in the US?
able, with some patients not requiring treatment and others
Findings In this descriptive study of 1626 cases of myocarditis in
experiencing severe heart failure that requires subsequent
a national passive reporting system, the crude reporting rates
heart transplantation or leads to death.5 Onset of myocarditis
within 7 days after vaccination exceeded the expected rates across
typically follows an inciting process, often a viral illness; multiple age and sex strata. The rates of myocarditis cases were
however, no antecedent cause is identified in many cases.6 It highest after the second vaccination dose in adolescent males
has been hypothesized that vaccination can serve as a trigger aged 12 to 15 years (70.7 per million doses of the BNT162b2
for myocarditis; however, only the smallpox vaccine has pre- vaccine), in adolescent males aged 16 to 17 years (105.9 per million
viously been causally associated with myocarditis based on doses of the BNT162b2 vaccine), and in young men aged 18 to 24
years (52.4 and 56.3 per million doses of the BNT162b2 vaccine
reports among US military personnel, with cases typically
and the mRNA-1273 vaccine, respectively).
occurring 7 to 12 days after vaccination.7
With the implementation of a large-scale, national Meaning Based on passive surveillance reporting in the US,
COVID-19 vaccination program starting in December 2020, the risk of myocarditis after receiving mRNA-based COVID-19
vaccines was increased across multiple age and sex strata and was
the US Centers for Disease Control and Prevention (CDC)
highest after the second vaccination dose in adolescent males
and the US Food and Drug Administration began monitor- and young men.
ing for a number of adverse events of special interest, includ-
ing myocarditis and pericarditis, in the Vaccine Adverse
Event Reporting System (VAERS), a long-standing national
spontaneous reporting (passive surveillance) system.8 As the policy. The activities herein were confirmed to be nonre-
reports of myocarditis after COVID-19 vaccination were search under the Common Rule in accordance with institu-
reported to VAERS, the Clinical Immunization Safety Assess- tional procedures and therefore were not subject to institu-
ment Project,9 a collaboration between the CDC and medical tional review board requirements. Informed consent was not
research centers, which includes physicians treating infec- obtained for this secondary use of existing information; see 45
tious diseases and other specialists (eg, cardiologists), con- CFR part 46.102(l)(2), 21 CFR part 56, 42 USC §241(d), 5 USC
sulted on several of the cases. In addition, reports from sev- §552a, and 44 USC §3501 et seq.
eral countries raised concerns that mRNA-based COVID-19
vaccines may be associated with acute myocarditis.10-15 Exposure
Given this concern, the aims were to describe reports and The exposure of concern was vaccination with one of the
confirmed cases of myocarditis initially reported to VAERS af- mRNA-based COVID-19 vaccines: the BNT162b2 vaccine
ter mRNA-based COVID-19 vaccination and to provide esti- (Pfizer-BioNTech) or the mRNA-1273 vaccine (Moderna).
mates of the risk of myocarditis after mRNA-based COVID-19 During the analytic period, persons aged 12 years or older
vaccination based on age, sex, and vaccine type. were eligible for the BNT162b2 vaccine and persons aged
18 years or older were eligible for the mRNA-1273 vaccine.
The number of COVID-19 vaccine doses administered dur-
ing the analytic period was obtained through the CDC’s
Methods COVID-19 Data Tracker.17
Data Sources
VAERS is a US spontaneous reporting (passive surveillance) Outcomes
system that functions as an early warning system for poten- The primary outcome was the occurrence of myocarditis
tial vaccine adverse events.8 Co-administered by the CDC and the secondary outcome was pericarditis. Reports to
and the US Food and Drug Administration, VAERS accepts VAERS with these outcomes were initially characterized
reports of all adverse events after vaccination from patients, using the Medical Dictionary for Regulatory Activities pre-
parents, clinicians, vaccine manufacturers, and others ferred terms of myocarditis or pericarditis (specific terms
regardless of whether the events could plausibly be associ- are listed in the eMethods in the Supplement). After initial
ated with receipt of the vaccine. Reports to VAERS in- review of reports of myocarditis to VAERS and review of the
clude information about the vaccinated person, the vaccine patient’s medical records (when available), the reports were
or vaccines administered, and the adverse events experi- further reviewed by CDC physicians and public health pro-
enced by the vaccinated person. The reports to VAERS are fessionals to verify that they met the CDC’s case definition
then reviewed by third-party professional coders who have for probable or confirmed myocarditis (descriptions previ-
been trained in the assignment of Medical Dictionary for ously published and included in the eMethods in the
Regulatory Activities preferred terms. 16 The coders then Supplement).18 The CDC’s case definition of probable myo-
assign appropriate terms based on the information available carditis requires the presence of new concerning symptoms,
in the reports. abnormal cardiac test results, and no other identifiable
This activity was reviewed by the CDC and was con- cause of the symptoms and findings. Confirmed cases of
ducted to be consistent with applicable federal law and CDC myocarditis further require histopathological confirmation
332 JAMA January 25, 2022 Volume 327, Number 4 (Reprinted) jama.com

AR09380
Myocarditis Cases Reported After mRNA-Based COVID-19 Vaccination in the US From December 2020 to August 2021 Original Investigation Research
of myocarditis or cardiac magnetic resonance imaging (MRI) for each expected rate of myocarditis and for each observed
findings consistent with myocarditis. rate in a strata with at least 1 case.
Deaths were included only if the individual had met the case In cases of probable or confirmed myocarditis among those
definition for confirmed myocarditis and there was no other younger than 30 years of age, their clinical course was then
identifiable cause of death. Individual cases not involving death summarized to the extent possible based on medical review
were included only if the person had met the case definition for and clinician interviews. This clinical course included pre-
probable myocarditis or confirmed myocarditis. senting symptoms, diagnostic test results, treatment, and early
outcomes (abstraction form appears in the eMethods in the
Statistical Analysis Supplement).23
We characterized reports of myocarditis or pericarditis after When applicable, missing data were delineated in the
COVID-19 vaccination that met the CDC’s case definition results or the numbers with complete data were listed. No
and were received by VAERS between December 14, 2020 assumptions or imputations were made regarding missing
(when COVID-19 vaccines were first publicly available in the data. Any percentages that were calculated included only
US), and August 31, 2021, by age, sex, race, ethnicity, and those cases of myocarditis with adequate data to calculate
vaccine type; data were processed by VAERS as of Septem- the percentages.
ber 30, 2021. Race and ethnicity were optional fixed catego-
ries available by self-identification at the time of vaccina-
tion or by the individual filing a VAERS report. Race and
ethnicity were included to provide the most complete base-
Results
line description possible for individual reports; however, Case Characteristics
further analyses were not stratified by race and ethnicity Between December 14, 2020, and August 31, 2021, 192 405 448
due to the high percentage of missing data. Reports of peri- individuals older than 12 years of age received a total of
carditis with evidence of potential myocardial involvement 354 100 845 mRNA-based COVID-19 vaccines. VAERS re-
were included in the review of reports of myocarditis. The ceived 1991 reports of myocarditis (391 of which also in-
eFigure in the Supplement outlines the categorization of the cluded pericarditis) after receipt of at least 1 dose of mRNA-
reports of myocarditis and pericarditis reviewed. based COVID-19 vaccine (eTable 1 in the Supplement) and 684
Further analyses were conducted only for myocarditis reports of pericarditis without the presence of myocarditis
because of the preponderance of those reports to VAERS, in (eTable 2 in the Supplement).
Clinical Immunization Safety Assessment Project consulta- Of the 1991 reports of myocarditis, 1626 met the CDC’s
tions, and in published articles.10-12,19-21 Crude reporting case definition for probable or confirmed myocarditis
rates for myocarditis during a 7-day risk interval were calcu- (Table 1). There were 208 reports that did not meet the
lated using the number of reports of myocarditis to VAERS CDC’s case definition for myocarditis and 157 reports
per million doses of COVID-19 vaccine administered dur- that required more information to perform adjudication
ing the analytic period and stratified by age, sex, vaccina- (eTable 3 in the Supplement). Of the 1626 reports that met
tion dose (first, second, or unknown), and vaccine type. the CDC’s case definition for myocarditis, 1195 (73%) were
Expected rates of myocarditis by age and sex were cal- younger than 30 years of age, 543 (33%) were younger than
culated using 2017-2019 data from the IBM MarketScan 18 years of age, and the median age was 21 years (IQR, 16-31
Commercial Research Database. This database contains years) (Figure 1). Of the reports of myocarditis with dose
individual-level, deidentified, inpatient and outpatient information, 82% (1265/1538) occurred after the second vac-
medical and prescription drug claims, and enrollment infor- cination dose. Of those with a reported dose and time to
mation submitted to IBM Watson Health by large employers symptom onset, the median time from vaccination to symp-
and health plans. The data were accessed using version 4.0 tom onset was 3 days (IQR, 1-8 days) after the first vaccina-
of the IBM MarketScan Treatment Pathways analytic plat- tion dose and 74% (187/254) of myocarditis events occurred
form. Age- and sex-specific rates were calculated by deter- within 7 days. After the second vaccination dose, the
mining the number of individuals with myocarditis (Inter- median time to symptom onset was 2 days (IQR, 1-3 days)
national Statistical Classification of Diseases and Related and 90% (1081/1199) of myocarditis events occurred within
Health Problems, Tenth Revision [ICD-10] codes B33.20, 7 days (Figure 2).
B33.22, B33.24, I40.0, I40.1, I40.8, I40.9, or I51.4)22 identi- Males comprised 82% (1334/1625) of the cases of myo-
fied during an inpatient encounter in 2017-2019 relative carditis for whom sex was reported. The largest proportions
to the number of individuals of similar age and sex who of cases of myocarditis were among White persons (non-
were continually enrolled during the year in which the Hispanic or ethnicity not reported; 69% [914/1330]) and His-
myocarditis-related hospitalization occurred; individuals panic persons (of all races; 17% [228/1330]). Among persons
with any diagnosis of myocarditis prior to that year were younger than 30 years of age, there were no confirmed
excluded. Given the limitations of the IBM MarketScan cases of myocarditis in those who died after mRNA-based
Commercial Research Database to capture enrollees aged 65 COVID-19 vaccination without another identifiable cause
years or older, an expected rate for myocarditis was not cal- and there was 1 probable case of myocarditis but there was
culated for this population. A 95% CI was calculated using insufficient information available for a thorough investiga-
Poisson distribution in SAS version 9.4 (SAS Institute Inc) tion. At the time of data review, there were 2 reports of
jama.com (Reprinted) JAMA January 25, 2022 Volume 327, Number 4 333

334
Table 1. Characteristics of Reports to VAERS After mRNA-Based COVID-19 Vaccination That Met the CDC’s Case Definition for Myocarditis Between December 14, 2020, and August 31, 2021
Vaccination with BNT162b2 Vaccination with mRNA-1273

First dose Second dose Dose unknown First dose Second dose Dose unknown Overall
AR09381
No. of myocarditis reports to VAERS 147 928 61 126 337 27 1626

No. of vaccination doses administered 114 246 837 95 532 396 78 158 611 66 163 001 354 100 845
Age, median (IQR), y 19 (16-37) 18 (16-25) 22 (16-35) 31 (23-47) 26 (21-36) 29 (22-39) 21 (16-31)
Time to symptom onset, 3 (1-8) 2 (2-3) 3 (2-4) 3 (2-9) 2 (1-3) 2 (1-5) 2 (1-3)
median (IQR), d
Research Original Investigation
Reported sex, No. (%) (n = 147) (n = 928) (n = 61) (n = 125) (n = 337) (n = 27) (n = 1625)
Male 111 (76) 795 (86) 53 (87) 89 (71) 265 (79) 21 (78) 1334 (82)
Female 36 (24) 133 (14) 8 (13) 36 (29) 72 (21) 6 (22) 291 (18)
Reported race and ethnicity, (n = 123) (n = 772) (n = 40) (n = 100) (n = 277) (n = 18) (n = 1330)

No. (%)a
American Indian 1 (1) 4 (1) 0 1 (1) 0 0 6 (<1)
or Alaska Native
Asian 10 (8) 58 (8) 1 (3) 5 (5) 10 (4) 0 84 (6)
JAMA January 25, 2022 Volume 327, Number 4 (Reprinted)

Black 11 (9) 31 (4) 3 (8) 5 (5) 14 (5) 4 (22) 68 (5)
Hispanic 28 (23) 127 (16) 9 (23) 23 (23) 36 (13) 5 (28) 228 (17)
Multiple races 1 (1) 10 (1) 0 0 5 (2) 1 (6) 17 (1)
Native Hawaiian 0 5 (1) 1 (3) 1 (1) 0 0 7 (1)
or Pacific Islander
White 72 (59) 531 (69) 26 (65) 65 (65) 212 (77) 8 (44) 914 (69)
Otherb 0 6 (1) 0 0 0 0 6 (<1)
b
Abbreviations: CDC, US Centers for Disease Control and Prevention; VAERS, Vaccine Adverse Event Individuals were able to choose this category without further specification.
Reporting System.
a
Categories without ethnicity were either non-Hispanic or had no ethnicity reported.

jama.com
Myocarditis Cases Reported After mRNA-Based COVID-19 Vaccination in the US From December 2020 to August 2021
AR09382
death in persons younger than 30 years of age with poten-
12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40
Dose 2
Dose 1
tial myocarditis that remain under investigation and are not
doses and 95 532 396 second vaccination doses; and for the mRNA-1273 vaccine, there were 78 158 611 and
included in the case counts.
Reporting Rates of Myocarditis Within 7 Days

After COVID-19 Vaccination
Symptom onset of myocarditis was within 7 days after vacci-
nation for 947 reports of individuals who received the
BNT162b2 vaccine and for 382 reports of individuals who
received the mRNA-1273 vaccine. The rates of myocarditis
Age at onset of myocarditis, y

varied by vaccine type, sex, age, and first or second vaccina-
66 163 001, respectively. The y-axis range differs between panels A and B.
tion dose (Table 2). The reporting rates of myocarditis were
highest after the second vaccination dose in adolescent
males aged 12 to 15 years (70.73 [95% CI, 61.68-81.11] per mil-
lion doses of the BNT162b2 vaccine), in adolescent males
aged 16 to 17 years (105.86 [95% CI, 91.65-122.27] per million
doses of the BNT162b2 vaccine), and in young men aged 18 to
24 years (52.43 [95% CI, 45.56-60.33] per million doses of the
BNT162b2 vaccine and 56.31 [95% CI, 47.08-67.34] per mil-
lion doses of the mRNA-1273 vaccine). The lower estimate of
the 95% CI for reporting rates of myocarditis in adolescent
Vaccination with mRNA‐1273

males and young men exceeded the upper bound of the
expected rates after the first vaccination dose with the
BNT162b2 vaccine in those aged 12 to 24 years, after the sec-
ond vaccination dose with the BNT162b2 vaccine in those
aged 12 to 49 years, after the first vaccination dose with the 100
80
60
40
20
0
mRNA-1273 vaccine in those aged 18 to 39 years, and after the vaccination with mRNA‐1273
second vaccination dose with the mRNA-1273 vaccine in Reported cases of myocarditis after
B
those aged 18 to 49 years.

The reporting rates of myocarditis in females were lower
12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40
Figure 1. Cases of Myocarditis After mRNA-Based COVID-19 Vaccination by Age at Onset of Myocarditis
individual age after receiving either vaccine. For the BNT162b2 vaccine, there were 114 246 837 first vaccination
than those in males across all age strata younger than 50
cases). Among individuals older than 40 years of age, there were no more than 8 reports of myocarditis for any
The reports to the Vaccine Adverse Event Reporting System met the case definition of myocarditis (reported
years of age. The reporting rates of myocarditis were highest
after the second vaccination dose in adolescent females aged
12 to 15 years (6.35 [95% CI, 4.05-9.96] per million doses of
the BNT162b2 vaccine), in adolescent females aged 16 to 17
years (10.98 [95% CI, 7.16-16.84] per million doses of the
BNT162b2 vaccine), in young women aged 18 to 24 years
(6.87 [95% CI, 4.27-11.05] per million doses of the mRNA-
1273 vaccine), and in women aged 25 to 29 years (8.22 [95%
Age at onset of myocarditis, y
CI, 5.03-13.41] per million doses of the mRNA-1273 vaccine).

The lower estimate of the 95% CI for reporting rates of myo-
carditis in females exceeded the upper bound of the expected
rates after the second vaccination dose with the BNT162b2
vaccine in those aged 12 to 29 years and after the second vac-
cination dose with the mRNA-1273 vaccine in those aged 18
to 29 years.
Clinical Course of Myocarditis After COVID-19 Vaccination

in Persons Younger Than 30 Years of Age
Among the 1372 reports of myocarditis in persons younger
than 30 years of age, 1305 were able to be adjudicated, with
A Vaccination with BNT162b2
92% (1195/1305) meeting the CDC’s case definition. Of these,

chart abstractions or medical interviews were completed for
69% (826/1195) (Table 3). The symptoms commonly reported
in the verified cases of myocarditis in persons younger than
30 years of age included chest pain, pressure, or discomfort
140
120
100
80
60
40
20
(727/817; 89%) and dyspnea or shortness of breath (242/817; vaccination with BNT162b2
Reported cases of myocarditis after
30%). Troponin levels were elevated in 98% (792/809) of the

AR09383
Figure 2. Cases of Myocarditis After mRNA-Based COVID-19 Vaccination by Time From Vaccination to Symptom Onset
A Vaccination with BNT162b2 B Vaccination with mRNA‐1273
300 120
Dose 2

250 100
Dose 1
vaccination with mRNA‐1273

vaccination with BNT162b2
200 80
150 60
100 40
50 20
0 0
0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10
Time from vaccination to symptom onset, d Time from vaccination to symptom onset, d
The reports to the Vaccine Adverse Event Reporting System met the case known date for symptom onset and dose after 114 246 837 first vaccination
definition of myocarditis (reported cases). Among recipients of either vaccine, doses and 888 reported cases after 95 532 396 second vaccination doses.
there were only 13 reports or less of myocarditis beyond 10 days for any B, For the mRNA-1273 vaccine, there were 116 reported cases of myocarditis
individual time from vaccination to symptom onset. The y-axis range differs with known date for symptom onset and dose after 78 158 611 first vaccination
between panels A and B. doses and 311 reported cases after 66 163 001 second vaccination doses.
A, For the BNT162b2 vaccine, there were 138 reported cases of myocarditis with
Table 2. Reports to VAERS After mRNA-Based COVID-19 Vaccination That Met the CDC’s Case Definition for Myocarditis Within a 7-Day Risk Interval
per Million Doses of Vaccine Administered
Expected cases
Reported cases of myocarditis within a 7-d risk interval per million doses of vaccine administered (95% CI)a of myocarditis
Vaccination with BNT162b2 Vaccination with mRNA-1273b in a 7-d risk interval
per million doses
First dose Second dose First dose Second dose (95% CI)c
Males
Age group, y
12-15 7.06 (4.88-10.23) 70.73 (61.68-81.11) 0.53 (0.40-0.70)
16-17 7.26 (4.45-11.86) 105.86 (91.65-122.27) 1.34 (1.05-1.72)
18-24 3.82 (2.40-6.06) 52.43 (45.56-60.33) 10.73 (7.50-15.34) 56.31 (47.08-67.34) 1.76 (1.58,1.98)
25-29 1.74 (0.78-3.87) 17.28 (13.02-22.93) 4.88 (2.70-8.80) 24.18 (17.93-32.61) 1.45 (1.21-1.74)
30-39 0.54 (0.20-1.44) 7.10 (5.26-9.57) 3.00 (1.81-4.97) 7.93 (5.61-11.21) 0.63 (0.54.0.73)
40-49 0.55 (0.21-1.48) 3.50 (2.28-5.36) 0.59 (0.19-1.82) 4.27 (2.69-6.78) 0.78 (0.67-0.90)
50-64 0.42 (0.17-1.01) 0.68 (0.33-1.43) 0.62 (0.28-1.39) 0.85 (0.41-1.79) 0.77 (0.68-0.86)
≥65 0.19 (0.05-0.76) 0.32 (0.10-1.00) 0.18 (0.05-0.72) 0.51 (0.21-1.23)
Females
Age group, y
12-15 0.49 (0.12-1.98) 6.35 (4.05-9.96) 0.17 (0.11-0.29)
16-17 0.84 (0.21-3.37) 10.98 (7.16-16.84) 0.42 (0.27-0.66)
18-24 0.18 (0.03-1.31) 4.12 (2.60-6.54) 0.96 (0.31-2.96) 6.87 (4.27-11.05) 0.38 (0.30-0.49)
25-29 0.26 (0.04-1.84) 2.23 (1.07-4.69) 0.41 (0.06-2.94) 8.22 (5.03-13.41) 0.48 (0.35-0.65)
30-39 0.72 (0.32-1.60) 1.02 (0.49-2.14) 0.74 (0.28-1.98) 0.68 (0.22-2.10) 0.47 (0.39-0.57)
40-49 0.24 (0.06-0.97) 1.73 (0.98-3.05) 0.18 (0.02-1.25) 1.89 (0.98-3.63) 0.89 (0.77-1.04)
50-64 0.37 (0.15-0.88) 0.51 (0.23-1.14) 0.65 (0.31-1.36) 0.43 (0.16-1.15) 1.00 (0.89-1.13)
≥65 0.08 (0.01-0.54) 0.35 (0.13-0.92) 0.26 (0.08-0.81)
Abbreviations: CDC, US Centers for Disease Control and Prevention; VAERS, strata with cases of myocarditis after administration of mRNA-1273 in those
Vaccine Adverse Event Reporting System. younger than aged 18 years. The mRNA-1273 vaccine had not been authorized
a
Of 1453 cases of myocarditis with known vaccination dose and time to for use in the US in this age group.
c
symptom onset, 1267 had symptom onset within the 7-day risk interval. Estimated using data from the IBM MarketScan Commercial Research
b
The observed estimates were not calculated for the strata with 0 cases of Database for 2017-2019. Rates were not calculated for those aged 65 years or
myocarditis. In addition, the observed estimates were not calculated for the older due to the limitations of the database.

AR09384
Table 3. Symptoms, Treatment, and Outcomes in 826 Patients Younger Than 30 Years of Age
With Myocarditis
Cases of myocarditis,
No./total (%)
Presenting symptoms
Chest pain, pressure, or discomfort 727/817 (89.0)
Dyspnea or shortness of breath 242/817 (29.6)
Palpitations 65/817 (8.0)
Abnormal findings
Elevated troponin levela 792/809 (97.9)
Electrocardiogram 569/794 (71.7)
Echocardiogram 123/721 (17.1)
Decreased LVEF (<50%) on echocardiogram 84/721 (11.7)
Cardiac magnetic resonance imagingb 223/312 (71.5)
Hospitalized 784/813 (96.4)
Treatment
Nonsteroidal anti-inflammatory drugs 589/676 (87.1)
Glucocorticoids 81/676 (12.0)
Anticoagulant therapy 54/676 (8.0)
Antiarrhythmic therapy 18/676 (2.7)
Low- or high-flow nasal cannula oxygen support 12/676 (1.8)
Diuretics 11/676 (1.6)
Intensive therapy
Intravenous immunoglobulin 78/676 (11.5)
Vasoactive medications 12/676 (1.8)
Intubation or mechanical ventilation 2/676 (0.3)
Heart transplant 0
Extracorporeal membrane oxygenation or ventricular assist device 0
Outcome among those who were hospitalized Abbreviation: LVEF, left ventricular
Discharged from the hospital 747/762 (98.0) ejection fraction.
a
Still hospitalized at time of review 15/762 (2.0) Abnormal per the reference range
for the hospital or laboratory where
Died 0
the test was performed.
Resolution of presenting symptoms by hospital discharge 577/661 (87.3) b
Consistent with myocarditis.
cases of myocarditis. The electrocardiogram result was

abnormal in 72% (569/794) of cases of myocarditis. Of the Discussion
patients who had received a cardiac MRI, 72% (223/312) had
abnormal findings consistent with myocarditis. The echo- In this review of reports to VAERS between December 2020
cardiogram results were available for 721 cases of myocardi- and August 2021, myocarditis was identified as a rare but se-
tis; of these, 84 (12%) demonstrated a notable decreased left rious adverse event that can occur after mRNA-based COVID-19
ventricular ejection fraction (<50%). Among the 676 cases vaccination, particularly in adolescent males and young men.
for whom treatment data were available, 589 (87%) received However, this increased risk must be weighed against the ben-
nonsteroidal anti-inflammatory drugs. Intravenous immu- efits of COVID-19 vaccination.18
noglobulin and glucocorticoids were each used in 12% of the Compared with cases of non–vaccine-associated myocar-
cases of myocarditis (78/676 and 81/676, respectively). ditis, the reports of myocarditis to VAERS after mRNA-based
Intensive therapies such as vasoactive medications (12 cases COVID-19 vaccination were similar in demographic character-
of myocarditis) and intubation or mechanical ventilation istics but different in their acute clinical course. First, the
(2 cases) were rare. There were no verified cases of myocar- greater frequency noted among vaccine recipients aged 12 to
ditis requiring a heart transplant, extracorporeal membrane 29 years vs those aged 30 years or older was similar to the age
oxygenation, or a ventricular assist device. Of the 96% (784/ distribution seen in typical cases of myocarditis.2,4 This pat-
813) of cases of myocarditis who were hospitalized, 98% tern may explain why cases of myocarditis were not discov-
(747/762) were discharged from the hospital at time of ered until months after initial Emergency Use Authorization
review. In 87% (577/661) of discharged cases of myocarditis, of the vaccines in the US (ie, until the vaccines were widely
there was resolution of the presenting symptoms by hospi- available to younger persons). Second, the sex distribution in
tal discharge. cases of myocarditis after COVID-19 vaccination was similar

AR09385
to that seen in typical cases of myocarditis; there is a strong Limitations

male predominance for both conditions.2,4 This study has several limitations. First, although clinicians are
However, the onset of myocarditis symptoms after expo- required to report serious adverse events after COVID-19 vac-
sure to a potential immunological trigger was shorter for cination, including all events leading to hospitalization, VAERS
COVID-19 vaccine–associated cases of myocarditis than is typi- is a passive reporting system. As such, the reports of myocar-
cal for myocarditis cases diagnosed after a viral illness.24-26 ditis to VAERS may be incomplete, and the quality of the in-
Cases of myocarditis reported after COVID-19 vaccination were formation reported is variable. Missing data for sex, vaccina-
typically diagnosed within days of vaccination, whereas cases tion dose number, and race and ethnicity were not uncommon
of typical viral myocarditis can often have indolent courses in the reports received; history of prior SARS-CoV-2 infection
with symptoms sometimes present for weeks to months after also was not known. Furthermore, as a passive system, VAERS
a trigger if the cause is ever identified.1 The major presenting data are subject to reporting biases in that both underreport-
symptoms appeared to resolve faster in cases of myocarditis ing and overreporting are possible.38 Given the high verifica-
after COVID-19 vaccination than in typical viral cases of myo- tion rate of reports of myocarditis to VAERS after mRNA-
carditis. Even though almost all individuals with cases of myo- based COVID-19 vaccination, underreporting is more likely.
carditis were hospitalized and clinically monitored, they typi- Therefore, the actual rates of myocarditis per million doses of
cally experienced symptomatic recovery after receiving only vaccine are likely higher than estimated.
pain management. In contrast, typical viral cases of myocar- Second, efforts by CDC investigators to obtain medical
ditis can have a more variable clinical course. For example, up records or interview physicians were not always successful
to 6% of typical viral myocarditis cases in adolescents require despite the special allowance for sharing information with
a heart transplant or result in mortality.27 the CDC under the Health Insurance Portability and Account-
In the current study, the initial evaluation and treatment ability Act of 1996.39 This challenge limited the ability to per-
of COVID-19 vaccine–associated myocarditis cases was simi- form case adjudication and complete investigations for some
lar to that of typical myocarditis cases.28-31 Initial evaluation reports of myocarditis, although efforts are still ongoing
usually included measurement of troponin level, electrocar- when feasible.
diography, and echocardiography.1 Cardiac MRI was often used Third, the data from vaccination administration were lim-
for diagnostic purposes and also for possible prognostic ited to what is reported to the CDC and thus may be incom-
purposes.32,33 Supportive care was a mainstay of treatment, plete, particularly with regard to demographics.
with specific cardiac or intensive care therapies as indicated Fourth, calculation of expected rates from the IBM
by the patient’s clinical status. MarketScan Commercial Research Database relied on admin-
Long-term outcome data are not yet available for COVID-19 istrative data via the use of ICD-10 codes and there was no op-
vaccine–associated myocarditis cases. The CDC has started ac- portunity for clinical review. Furthermore, these data had lim-
tive follow-up surveillance in adolescents and young adults to ited information regarding the Medicare population; thus
assess the health and functional status and cardiac outcomes expected rates for those older than 65 years of age were not
at 3 to 6 months in probable and confirmed cases of myocar- calculated. However, it is expected that the rates in those older
ditis reported to VAERS after COVID-19 vaccination.34 For pathan 65 years of age would not be higher than the rates in those
tients with myocarditis, the American Heart Association and aged 50 to 64 years.4
the American College of Cardiology guidelines advise that pa-
tients should be instructed to refrain from competitive sports
for 3 to 6 months, and that documentation of a normal elec-
trocardiogram result, ambulatory rhythm monitoring, and an
Conclusions
exercise test should be obtained prior to resumption of sports.35 Based on passive surveillance reporting in the US, the risk of
The use of cardiac MRI is unclear, but it may be useful in evalu- myocarditis after receiving mRNA-based COVID-19 vaccines
ating the progression or resolution of myocarditis in those with was increased across multiple age and sex strata and was high-
abnormalities on the baseline cardiac MRI.36 Further doses of est after the second vaccination dose in adolescent males and
mRNA-based COVID-19 vaccines should be deferred, but may young men. This risk should be considered in the context of
be considered in select circumstances.37 the benefits of COVID-19 vaccination.
ARTICLE INFORMATION Acquisition, analysis, or interpretation of data: DeStefano, Shimabukuro.

Accepted for Publication: December 16, 2021. Oster, Shay, Su, Gee, Creech, Broder, Edwards, Statistical analysis: Oster, Su, Marquez, Strid, Woo,
Soslow, Schlaudecker, Lang, Barnett, Ruberg, Shimabukuro.
Correction: This article was corrected March 21, Smith, Campbell, Lopes, Sperling, Baumblatt, Obtained funding: Edwards, DeStefano.
2022, to change “pericarditis” to “myocarditis” in Thompson, Marquez, Strid, Woo, Pugsley, Administrative, technical, or material support: Oster,
the first row, first column of eTable 1 in the Reagan-Steiner, DeStefano, Shimabukuro. Gee, Creech, Broder, Edwards, Soslow,
Supplement. Drafting of the manuscript: Oster, Shay, Su, Gee, Schlaudecker, Smith, Baumblatt, Thompson,
Author Contributions: Drs Oster and Su had full Creech, Marquez, Strid, Woo, Shimabukuro. Reagan-Steiner, DeStefano.
access to all of the data in the study and take Critical revision of the manuscript for important Supervision: Su, Edwards, Soslow, Dendy,
responsibility for the integrity of the data and the intellectual content: Oster, Shay, Su, Creech, Broder, Schlaudecker, Campbell, Sperling, DeStefano,
accuracy of the data analysis. Edwards, Soslow, Dendy, Schlaudecker, Lang, Shimabukuro.
Concept and design: Oster, Shay, Su, Creech, Barnett, Ruberg, Smith, Campbell, Lopes, Sperling,
Edwards, Dendy, Schlaudecker, Woo, Shimabukuro. Baumblatt, Thompson, Pugsley, Reagan-Steiner,

AR09386
Conflict of Interest Disclosures: Dr Creech Charles Licata, PhD, and Bicheng Zhang, MS Israel. N Engl J Med. 2021;385(23):2140-2149. doi:
reported receiving grants from the National (for data acquisition and organization); Charles E. 10.1056/NEJMoa2109730
Institutes of Health for the Moderna and Janssen Rose, PhD (for statistical consultation); and Scott D. 15. Witberg G, Barda N, Hoss S, et al. Myocarditis
clinical trials and receiving personal fees from Grosse, PhD (for calculation of expected rates of after Covid-19 vaccination in a large health care
Astellas and Horizon. Dr Edwards reported myocarditis). We also thank the clinical staff organization. N Engl J Med. 2021;385(23):2132-2139.
receiving grants from the National Institutes of who cared for these patients and reported the doi:10.1056/NEJMoa2110737
Health; receiving personal fees from BioNet, IBM, adverse events to the Vaccine Adverse Event
X-4 Pharma, Seqirus, Roche, Pfizer, Merck, Reporting System. 16. MedDRA. Medical Dictionary for Regulatory
Moderna, and Sanofi; and receiving compensation Activities. Accessed June 30, 2021. https://www.
for being the associate editor of Clinical Infectious REFERENCES meddra.org
Diseases. Dr Soslow reported receiving personal 1. Cooper LT Jr. Myocarditis. N Engl J Med. 2009; 17. US Centers for Disease Control and Prevention.
fees from Esperare. Dr Schlaudecker reported 360(15):1526-1538. doi:10.1056/NEJMra0800028 CDC COVID-19 data tracker. Accessed June 30,
receiving grants from Pfizer and receiving personal 2021. https://covid.cdc.gov/covid-data-tracker
fees from Sanofi Pasteur. Drs Barnett, Ruberg, and 2. Vasudeva R, Bhatt P, Lilje C, et al. Trends in acute
myocarditis–related pediatric hospitalizations in the 18. Gargano JW, Wallace M, Hadler SC, et al. Use of
Smith reported receiving grants from Pfizer. Dr mRNA COVID-19 vaccine after reports of
Lopes reported receiving personal fees from Bayer, United States, 2007-2016. Am J Cardiol. 2021;149:
95-102. doi:10.1016/j.amjcard.2021.03.019 myocarditis among vaccine recipients: update from
Boehringer Ingleheim, Bristol Myers Squibb, Daiichi the Advisory Committee on Immunization
Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer, 3. Arola A, Pikkarainen E, Sipilä JO, Pykäri J, Practices—United States, June 2021. MMWR Morb
Portola, and Sanofi and receiving grants from Rautava P, Kytö V. Occurrence and features of Mortal Wkly Rep. 2021;70(27):977-982. doi:10.
Bristol Myers Squibb, GlaxoSmithKline, Medtronic, childhood myocarditis: a nationwide study in 15585/mmwr.mm7027e2
Pfizer, and Sanofi. No other disclosures were Finland. J Am Heart Assoc. 2017;6(11):e005306.
reported. doi:10.1161/JAHA.116.005306 19. Abu Mouch S, Roguin A, Hellou E, et al.
Myocarditis following COVID-19 mRNA vaccination.
Funding/Support: This work was supported by 4. Kytö V, Sipilä J, Rautava P. The effects of gender Vaccine. 2021;39(29):3790-3793. doi:10.1016/j.
contracts 200-2012-53709 (Boston Medical and age on occurrence of clinically suspected vaccine.2021.05.087
Center), 200-2012-53661 (Cincinnati Children’s myocarditis in adulthood. Heart. 2013;99(22):1681-
Hospital Medical Center), 200-2012-53663 (Duke 1684. doi:10.1136/heartjnl-2013-304449 20. Larson KF, Ammirati E, Adler ED, et al.
University), and 200-2012-50430 (Vanderbilt Myocarditis after BNT162b2 and mRNA-1273
5. Dasgupta S, Iannucci G, Mao C, Clabby M, Oster vaccination. Circulation. 2021;144(6):506-508. doi:
University Medical Center) with the US Centers for ME. Myocarditis in the pediatric population:
Disease Control and Prevention (CDC) Clinical 10.1161/CIRCULATIONAHA.121.055913
a review. Congenit Heart Dis. 2019;14(5):868-877.
Immunization Safety Assessment Project. doi:10.1111/chd.12835 21. Rosner CM, Genovese L, Tehrani BN, et al.
Role of the Funder/Sponsor: The CDC provided Myocarditis temporally associated with COVID-19
6. Pollack A, Kontorovich AR, Fuster V, Dec GW. vaccination. Circulation. 2021;144(6):502-505. doi:
funding via the Clinical Immunization Safety Viral myocarditis—diagnosis, treatment options,
Assessment Project to Drs Creech, Edwards, 10.1161/CIRCULATIONAHA.121.055891
and current controversies. Nat Rev Cardiol. 2015;12
Soslow, Dendy, Schlaudecker, Lang, Barnett, (11):670-680. doi:10.1038/nrcardio.2015.108 22. Boehmer TK, Kompaniyets L, Lavery AM, et al.
Ruberg, Smith, Campbell, and Lopes. The authors Association between COVID-19 and myocarditis
affiliated with the CDC along with the other 7. Halsell JS, Riddle JR, Atwood JE, et al; using hospital-based administrative data—United
coauthors conducted the investigations; performed Department of Defense Smallpox Vaccination States, March 2020-January 2021. MMWR Morb
collection, management, analysis, and Clinical Evaluation Team. Myopericarditis following Mortal Wkly Rep. 2021;70(35):1228-1232. doi:10.
interpretation of the data; were involved in the smallpox vaccination among vaccinia-naive US 15585/mmwr.mm7035e5
preparation, review, and approval of the military personnel. JAMA. 2003;289(24):3283-3289.
doi:10.1001/jama.289.24.3283 23. Harris PA, Taylor R, Minor BL, et al; REDCap
manuscript; and made the decision to submit the Consortium. The REDCap Consortium: building an
manuscript for publication. 8. Gubernot D, Jazwa A, Niu M, et al. US population- international community of software platform
Disclaimer: The findings and conclusions in this based background incidence rates of medical partners. J Biomed Inform. 2019;95:103208. doi:10.
article are those of the authors and do not conditions for use in safety assessment of COVID-19 1016/j.jbi.2019.103208
necessarily represent the official position of the vaccines. Vaccine. 2021;39(28):3666-3677. doi:10.
1016/j.vaccine.2021.05.016 24. Mahrholdt H, Wagner A, Deluigi CC, et al.
CDC or the US Food and Drug Administration. Presentation, patterns of myocardial damage, and
Mention of a product or company name is for 9. US Centers for Disease Control and Prevention. clinical course of viral myocarditis. Circulation.
identification purposes only and does not Clinical Immunization Safety Assessment project. 2006;114(15):1581-1590. doi:10.1161/
constitute endorsement by the CDC or the US Food Accessed August 24, 2021. https://www.cdc.gov/ CIRCULATIONAHA.105.606509
and Drug Administration. vaccinesafety/ensuringsafety/monitoring/cisa/
index.html 25. Mason JW, O’Connell JB, Herskowitz A, et al;
Additional Contributions: We thank the following Myocarditis Treatment Trial Investigators. A clinical
CDC staff who contributed to this article without 10. Marshall M, Ferguson ID, Lewis P, et al. trial of immunosuppressive therapy for myocarditis.
compensation outside their normal salaries Symptomatic acute myocarditis in 7 adolescents N Engl J Med. 1995;333(5):269-275. doi:10.1056/
(in alphabetical order and contribution specified in after Pfizer-BioNTech COVID-19 vaccination. NEJM199508033330501
parenthesis at end of each list of names): Nickolas Pediatrics. 2021;148(3):e2021052478. doi:10.1542/
Agathis, MD, MPH, Stephen R. Benoit, MD, MPH, peds.2021-052478 26. Saji T, Matsuura H, Hasegawa K, et al.
Beau B. Bruce, MD, PhD, Abigail L. Carlson, MD, Comparison of the clinical presentation, treatment,
11. Kim HW, Jenista ER, Wendell DC, et al. Patients and outcome of fulminant and acute myocarditis in
MPH, Meredith G. Dixon, MD, Jonathan Duffy, MD, with acute myocarditis following mRNA COVID-19
MPH, Charles Duke, MD, MPH, Charles Edge, MSN, children. Circ J. 2012;76(5):1222-1228. doi:10.1253/
vaccination. JAMA Cardiol. 2021;6(10):1196-1201. circj.CJ-11-1032
MS, Robyn Neblett Fanfair, MD, MPH, Nathan W. doi:10.1001/jamacardio.2021.2828
Furukawa, MD, MPH, Gavin Grant, MD, MPH, Grace 27. Ghelani SJ, Spaeder MC, Pastor W, Spurney CF,
Marx, MD, MPH, Maureen J. Miller, MD, MPH, Pedro 12. Montgomery J, Ryan M, Engler R, et al. Klugman D. Demographics, trends, and outcomes
Moro, MD, MPH, Meredith Oakley, DVM, MPH, Kia Myocarditis following immunization with mRNA in pediatric acute myocarditis in the United States,
Padgett, MPH, BSN, RN, Janice Perez-Padilla, MPH, COVID-19 vaccines in members of the US military. 2006 to 2011. Circ Cardiovasc Qual Outcomes. 2012;
BSN, RN, Robert Perry, MD, MPH, Nimia Reyes, MD, JAMA Cardiol. 2021;6(10):1202-1206. doi:10.1001/ 5(5):622-627. doi:10.1161/CIRCOUTCOMES.112.
MPH, Ernest E. Smith, MD, MPH&TM, David jamacardio.2021.2833 965749
Sniadack, MD, MPH, Pamela Tucker, MD, Edward C. 13. Diaz GA, Parsons GT, Gering SK, Meier AR, 28. Caforio ALP, Pankuweit S, Arbustini E, et al;
Weiss, MD, MPH, Erin Whitehouse, PhD, MPH, RN, Hutchinson IV, Robicsek A. Myocarditis and European Society of Cardiology Working Group on
Pascale M. Wortley, MD, MPH, and Rachael Zacks, pericarditis after vaccination for COVID-19. JAMA. Myocardial and Pericardial Diseases. Current state
MD (for clinical investigations and interviews); 2021;326(12):1210-1212. doi:10.1001/jama.2021.13443 of knowledge on aetiology, diagnosis,
Amelia Jazwa, MSPH, Tara Johnson, MPH, MS, and 14. Mevorach D, Anis E, Cedar N, et al. Myocarditis management, and therapy of myocarditis:
Jamila Shields, MPH (for project coordination); after BNT162b2 mRNA vaccine against Covid-19 in a position statement of the European Society of

AR09387
Cardiology Working Group on Myocardial and 32. Sachdeva S, Song X, Dham N, Heath DM, cardiomyopathies, and myocarditis: a scientific
Pericardial Diseases. Eur Heart J. 2013;34(33): DeBiasi RL. Analysis of clinical parameters and statement from the American Heart Association
2636-2648. doi:10.1093/eurheartj/eht210 cardiac magnetic resonance imaging as predictors and American College of Cardiology. Circulation.
29. Yancy CW, Jessup M, Bozkurt B, et al; American of outcome in pediatric myocarditis. Am J Cardiol. 2015;132(22):e273-e280. doi:10.1161/CIR.
College of Cardiology Foundation; American Heart 2015;115(4):499-504. doi:10.1016/j.amjcard.2014.11. 0000000000000239
Association Task Force on Practice Guidelines. 2013 029 36. Aquaro GD, Ghebru Habtemicael Y, Camastra
ACCF/AHA guideline for the management of heart 33. Ferreira VM, Schulz-Menger J, Holmvang G, G, et al; Cardiac Magnetic Resonance Working
failure: a report of the American College of et al. Cardiovascular magnetic resonance in Group of the Italian Society of Cardiology.
Cardiology Foundation/American Heart Association nonischemic myocardial inflammation: expert Prognostic value of repeating cardiac magnetic
Task Force on Practice Guidelines. J Am Coll Cardiol. recommendations. J Am Coll Cardiol. 2018;72(24): resonance in patients with acute myocarditis. J Am
2013;62(16):e147-e239. doi:10.1016/j.jacc.2013.05. 3158-3176. doi:10.1016/j.jacc.2018.09.072 Coll Cardiol. 2019;74(20):2439-2448. doi:10.1016/j.
019 34. US Centers for Disease Control and Prevention. jacc.2019.08.1061
30. Law YM, Lal AK, Chen S, et al; American Heart Investigating long-term effects of myocarditis. 37. US Centers for Disease Control and Prevention.
Association Pediatric Heart Failure and Accessed August 24, 2021. https://www.cdc.gov/ Interim clinical considerations for use of COVID-19
Transplantation Committee of the Council on coronavirus/2019-ncov/vaccines/safety/myo- vaccines currently authorized in the United States.
Lifelong Congenital Heart Disease and Heart Health outcomes.html Accessed August 24, 2021. https://www.cdc.gov/
in the Young and Stroke Council. Diagnosis and 35. Maron BJ, Udelson JE, Bonow RO, et al; vaccines/covid-19/clinical-considerations/covid-
management of myocarditis in children: a scientific American Heart Association Electrocardiography 19-vaccines-us.html
statement from the American Heart Association. and Arrhythmias Committee of Council on Clinical 38. Shimabukuro TT, Nguyen M, Martin D,
Circulation. 2021;144(6):e123-e135. doi:10.1161/CIR. Cardiology, Council on Cardiovascular Disease in DeStefano F. Safety monitoring in the Vaccine
0000000000001001 Young, Council on Cardiovascular and Stroke Adverse Event Reporting System (VAERS). Vaccine.
31. US Centers for Disease Control and Prevention. Nursing, Council on Functional Genomics and 2015;33(36):4398-4405. doi:10.1016/j.vaccine.2015.
Clinical considerations: myocarditis and pericarditis Translational Biology, and American College of 07.035
after receipt of mRNA COVID-19 vaccines among Cardiology. Eligibility and disqualification 39. US Centers for Disease Control and Prevention.
adolescents and young adults. Accessed August 24, recommendations for competitive athletes with HIPAA privacy rule and public health: guidance
2021. https://www.cdc.gov/vaccines/covid-19/ cardiovascular abnormalities: task force 3: from CDC and the US Department of Health and
clinical-considerations/myocarditis.html hypertrophic cardiomyopathy, arrhythmogenic Human Services. MMWR Suppl. 2003;52:1-17, 19-20.
right ventricular cardiomyopathy and other

AR09388
Research
JAMA Cardiology | Original Investigation
Association of Cardiac Injury With Mortality in Hospitalized Patients

With COVID-19 in Wuhan, China
Shaobo Shi, MD; Mu Qin, MD; Bo Shen, MD; Yuli Cai, MD; Tao Liu, MD; Fan Yang, MD; Wei Gong, MMSC; Xu Liu, MD, PhD;
Jinjun Liang, MD, PhD; Qinyan Zhao, MD, PhD; He Huang, MD, PhD; Bo Yang, MD, PhD; Congxin Huang, MD, PhD
Editorial page 751

IMPORTANCE Coronavirus disease 2019 (COVID-19) has resulted in considerable morbidity Related articles pages 811, 819,
and mortality worldwide since December 2019. However, information on cardiac injury in and 831
patients affected by COVID-19 is limited.
Supplemental content
OBJECTIVE To explore the association between cardiac injury and mortality in patients with
COVID-19.
DESIGN, SETTING, AND PARTICIPANTS This cohort study was conducted from January 20,
2020, to February 10, 2020, in a single center at Renmin Hospital of Wuhan University,
Wuhan, China; the final date of follow-up was February 15, 2020. All consecutive inpatients
4
with laboratory-confirmed COVID-19 were included in this study.
MAIN OUTCOMES AND MEASURES Clinical laboratory, radiological, and treatment data were
collected and analyzed. Outcomes of patients with and without cardiac injury were
compared. The association between cardiac injury and mortality was analyzed.
RESULTS A total of 416 hospitalized patients with COVID-19 were included in the final analysis;
the median age was 64 years (range, 21-95 years), and 211 (50.7%) were female. Common
symptoms included fever (334 patients [80.3%]), cough (144 [34.6%]), and shortness of breath
(117 [28.1%]). A total of 82 patients (19.7%) had cardiac injury, and compared with patients
without cardiac injury, these patients were older (median [range] age, 74 [34-95] vs 60 [21-90]
years; P < .001); had more comorbidities (eg, hypertension in 49 of 82 [59.8%] vs 78 of 334
[23.4%]; P < .001); had higher leukocyte counts (median [interquartile range (IQR)], 9400
[6900-13 800] vs 5500 [4200-7400] cells/μL) and levels of C-reactive protein (median [IQR],
10.2 [6.4-17.0] vs 3.7 [1.0-7.3] mg/dL), procalcitonin (median [IQR], 0.27 [0.10-1.22] vs 0.06
[0.03-0.10] ng/mL), creatinine kinase–myocardial band (median [IQR], 3.2 [1.8-6.2] vs 0.9
[0.6-1.3] ng/mL), myohemoglobin (median [IQR], 128 [68-305] vs 39 [27-65] μg/L),
high-sensitivity troponin I (median [IQR], 0.19 [0.08-1.12] vs <0.006 [<0.006-0.009] μg/L),
N-terminal pro-B-type natriuretic peptide (median [IQR], 1689 [698-3327] vs 139 [51-335]
pg/mL), aspartate aminotransferase (median [IQR], 40 [27-60] vs 29 [21-40] U/L), and
creatinine (median [IQR], 1.15 [0.72-1.92] vs 0.64 [0.54-0.78] mg/dL); and had a higher
proportion of multiple mottling and ground-glass opacity in radiographic findings (53 of 82
patients [64.6%] vs 15 of 334 patients [4.5%]). Greater proportions of patients with cardiac
injury required noninvasive mechanical ventilation (38 of 82 [46.3%] vs 13 of 334 [3.9%];
P < .001) or invasive mechanical ventilation (18 of 82 [22.0%] vs 14 of 334 [4.2%]; P < .001) than
those without cardiac injury. Complications were more common in patients with cardiac injury
than those without cardiac injury and included acute respiratory distress syndrome (48 of 82
[58.5%] vs 49 of 334 [14.7%]; P < .001), acute kidney injury (7 of 82 [8.5%] vs 1 of 334 [0.3%];
P < .001), electrolyte disturbances (13 of 82 [15.9%] vs 17 of 334 [5.1%]; P = .003),
hypoproteinemia (11 of 82 [13.4%] vs 16 of 334 [4.8%]; P = .01), and coagulation disorders (6 of
82 [7.3%] vs 6 of 334 [1.8%]; P = .02). Patients with cardiac injury had higher mortality than
those without cardiac injury (42 of 82 [51.2%] vs 15 of 334 [4.5%]; P < .001). In a Cox regression Author Affiliations: Author
model, patients with vs those without cardiac injury were at a higher risk of death, both during affiliations are listed at the end of this
article.
the time from symptom onset (hazard ratio, 4.26 [95% CI, 1.92-9.49]) and from admission to end
Corresponding Author: Bo Yang,
point (hazard ratio, 3.41 [95% CI, 1.62-7.16]).
MD, PhD (yybb112@whu.edu.cn), and
CONCLUSIONS AND RELEVANCE Cardiac injury is a common condition among hospitalized He Huang, MD, PhD (huanghe1977@
whu.edu.cn), Cardiovascular
patients with COVID-19 in Wuhan, China, and it is associated with higher risk of in-hospital Research Institute, Department of
mortality. Cardiology, Renmin Hospital of
Wuhan University, 238 Jiefang Rd,
JAMA Cardiol. 2020;5(7):802-810. doi:10.1001/jamacardio.2020.0950 Wuchang District, Wuhan 430060,
Published online March 25, 2020. Hubei, China.
802 (Reprinted) jamacardiology.com
Downloaded From: https://jamanetwork.com/ by Allison Leigh on 05/31/2022

AR09389
Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China Original Investigation Research
S
ince December 2019, coronavirus disease 2019 (COVID-
19) caused by the severe acute respiratory syndrome Key Points
coronavirus 2 (SARS-CoV-2) has resulted in consider-
Question What is the incidence and significance of cardiac injury
able morbidity and mortality in more than 30 countries world- in patients with COVID-19?
wide. Recently, COVID-19–associated clusters of severe respi-
Findings In this cohort study of 416 consecutive patients with
ratory illness have been independently associated with risk of
confirmed COVID-19, cardiac injury occurred in 19.7% of patients
mortality, and mounting evidence substantiates the pres-
during hospitalization, and it was one independent risk factor for
ence of cardiac injury in patients with COVID-19.1,2 Although in-hospital mortality.
a recent study reported that 12% of patients had COVID-19–
Meaning Cardiac injury is a common condition among patients
associated acute cardiac injury,1 manifesting as an ejection frac-
hospitalized with COVID-19, and it is associated with higher risk of
tion decline and troponin I elevation, and the American Col-
in-hospital mortality.
lege of Cardiology clinical bulletin has highlighted the cardiac
implications of COVID-19,3 the association between COVID-
19–associated cardiac injury and risk of mortality remains ties in electrocardiography and echocardiography. Acute re-
unclear. The present study therefore retrospectively ana- spiratory distress syndrome (ARDS) was defined according to
lyzed data from a single center in Wuhan, China, to examine the Berlin definition.5 Acute kidney injury was identified ac-
the potential association between cardiac injury and mortal- cording to the Kidney Disease: Improving Global Outcomes
ity among patients with COVID-19. definition.6 The clinical outcomes (ie, discharges, mortality,
and length of stay) were monitored up to February 15, 2020,
the final date of follow-up.
To confirm COVID-19, the Viral Nucleic Acid Kit (Health)
Methods was used to extract nucleic acids from clinical samples accord-
Study Participants ing to the kit instructions. A 2019-nCoV detection kit (Bioper-
Consecutive patients admitted to Renmin Hospital of fectus) was used to detect the ORF1ab gene (nCovORF1ab) and
Wuhan University with laboratory-confirmed COVID-19 the N gene (nCoV-NP) according to the manufacturer’s instruc-
were included in this retrospective cohort study, which was tions, using real-time reverse transcriptase–polymerase chain
conducted from January 20, 2020, to February 10, 2020. reaction.7 An infection was considered laboratory-confirmed
Renmin Hospital of Wuhan University, located in Wuhan, if the nCovORF1ab and nCoV-NP tests both showed positive
Hubei Province, China, was assigned responsibility for the results.
treatment of patients with severe COVID-19 by the Wuhan
government. The patients with COVID-19 enrolled in this Statistical Analysis
study were diagnosed according to World Health Organiza- Descriptive statistics were obtained for all study variables. All
tion interim guidance.4 The cases without cardiac biomark- categorical variables were compared for the study outcome by
ers, including values of high-sensitivity troponin I (hs-TNI) using the Fisher exact test or χ2 test, and continuous vari-
and creatinine kinase–myocardial band (CK-MB), were ables were compared using the t test or the Mann-Whitney U
excluded. test, as appropriate. Continuous data are expressed as mean
This study was approved by the National Health Commis- (SD) or median (interquartile range [IQR]) values. Categorical
sion of China and the institutional review board at Renmin Hos- data are expressed as proportions. Survival curves were plot-
pital of Wuhan University (Wuhan, China). Written informed ted using the Kaplan-Meier method and compared between pa-
consent was waived by the ethics commission of the desig- tients with vs without cardiac injury using the log-rank test.
nated hospital for patients with emerging infectious diseases. Multivariate Cox regression models were used to determine
the independent risk factors for death during hospitalization.
Data Collection Data were analyzed using SPSS version 25.0 (IBM). Statistical
The demographic characteristics (age and sex), clinical data charts were generated using Excel 2016 (Microsoft) or Prism 5
(symptoms, comorbidities, laboratory findings, treatments, (Graphpad). For all the statistical analyses, P < .05 was con-
complications, and outcomes), laboratory findings, and re- sidered significant.
sults of cardiac examinations (cardiac biomarkers and electro-
cardiography) for participants during hospitalization were
collected from electronic medical records by 2 investigators
(S.S. and B.S.). Cardiac biomarkers measured on admission
Results
were collected, including hs-TNI, CK-MB, and myohemoglo- Patient Characteristics
bin. The radiologic assessments included chest radiography or Figure 1 shows a flowchart for patient recruitment. Briefly, of
computed tomography. All data were independently re- all 1004 patients in the medical record system who were
viewed and entered into the computer database by 2 analysts screened initially from January 20, 2020, to February 10, 2020,
(T.L. and Y.C.). Patients were categorized according to the pres- 218 patients whose cases were not confirmed, 141 patients with-
ence or absence of cardiac injury. Cardiac injury was defined out available medical information and duplicated records, and
as blood levels of cardiac biomarkers (hs-TNI) above the 99th- 229 patients with missing core results of laboratory examina-
percentile upper reference limit, regardless of new abnormali- tion (hs-TNI and CK-MB) were excluded. The median age of
jamacardiology.com (Reprinted) JAMA Cardiology July 2020 Volume 5, Number 7 803

AR09390
Research Original Investigation Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China
Figure 1. Flowchart of Patient Recruitment

Laboratory and Radiographic Findings
The laboratory and radiologic findings are shown in Table 1.
In the overall study population of 416 patients, median (IQR)
1004 Cases in medical record system
levels of C-reactive protein (4.5 [1.4-8.5] mg/dL; to convert to
milligrams per liter, multiply by 10) and procalcitonin (0.07
218 Nonconfirmed cases excluded
[0.04-0.15] ng/L) were elevated, while the median values of
other laboratory indicators were within the normal range, such
786 Cases with confirmed COVID-19 as counts of leukocytes, lymphocytes, platelets, erythro-
cytes; hemoglobin level; cardiac indicators; alanine amino-
141 Cases excluded transferase level; aspartate aminotransferase level; creati-
No available medical information
nine concentration; and electrolyte levels. The proportion of
Duplicated records
patietns with bilateral pneumonia was 74.8% (311 patients) ac-
cording to chest radiography and computed tomography find-
645 Cases with confirmed COVID-19
ings, and 68 patients (16.3%) had multiple mottling and ground-
glass opacity. Distribution of hs-TNI based on detection time
229 Cases without core examination from hospitalization (median [IQR], 2 [1-15] days) is shown in
results
eFigure 1 in the Supplement. The duration of hospitalization
before testing was longer in patients with cardiac injury than
416 Cases with confirmed COVID-19 included
82 With cardiac injury (19.7%)
those without cardiac injury (median [range] time, 3 [1-15] days
334 Without cardiac injury (80.3%) vs 2 [1-8] days; P < .001).
In terms of laboratory findings, patients with cardiac in-
jury compared with patients without cardiac injury showed
these 229 patients was 45 years (range, 22-90 years), and 130 higher median leukocyte count (median [IQR], 9400 [6900-
(56.8%) were female; the details of baseline characteristics were 13 800] cells/μL vs 5500 [4200-7400] cells/μL), and levels of C-
presented in the eTable in the Supplement. reactive protein (median [IQR], 10.2 [6.4-17.0] mg/dL vs 3.7 [1.0-
Finally, the study population included 416 patients hos- 7.3] mg/dL), procalcitonin (median [IQR], 0.27 [0.10-1.22] ng/mL
pitalized with confirmed COVID-19: 82 patients (19.7%) with vs 0.06 [0.03-0.10] ng/mL), CK-MB (median [IQR], 3.2 [1.8-6.2]
cardiac injury and 334 patients (80.3%) without cardiac in- ng/mL vs 0.9 [0.6-1.3] ng/mL), myohemoglobin (median [IQR],
jury. The median age was 64 years (range, 21-95 years), and 211 128 [68-305] μg/L vs 39 [27-65] μg/L), hs-TNI (median [IQR], 0.19
(50.7%) were female. Among these patients, fever (334 pa- [0.08-1.12] μg/L vs <0.006 [<0.006-0.009] μg/L), N-terminal
tients [80.3%]) was the most common symptom. Cough, short- pro-B-type natriuretic peptide (NT-proBNP) (median [IQR], 1689
ness of breath, fatigue, sputum production, and muscle ache [698-3327] pg/mL vs 139 [51-335] pg/mL), aspartate aminotrans-
were present in 144 patients (34.6%), 117 patients (28.1%), 55 ferase (median [IQR], 40 [27-60] U/L vs 29 [21-40] U/L), and cre-
patients (13.2%), 23 patients (5.5%), and 19 patients (4.6%), re- atinine (median [IQR], 1.15 [0.72-1.92] mg/dL vs 0.64 [0.54-
spectively. Diarrhea (16 patients [3.8%]), chest pain (14 pa- 0.78] mg/dL) during hospitalization, but a lower median
tients [3.4%]), sore throat (12 patients [2.9%]), rhinorrhea (10 lymphocyte count (median [IQR], 600 [400-900] cells/μL vs
patients [2.4%]), and headache (9 patients [2.2%]) were rare. 1000 [800-1400] cells/μL), platelet count (median [IQR], 172 [111-
Hypertension (127 patients [30.5%]) and diabetes (60 pa- 215] cells × 103/μL vs 216 [165-273] cells × 103/μL), and albumin
tients [14.4%]) were the most common coexisting condi- level (median [IQR], 3.2 [2.9-3.4] g/dL vs 3.7 [3.3-3.9] g/dL), with
tions. Of these 416 patients, 44 (10.6%) and 22 (5.3%) had coro- significant differences in each case (all P < .001; Table 1; eFig-
nary heart disease and cerebrovascular disease, respectively. ure 1 in the Supplement). In terms of radiologic findings, bilat-
The proportion of chronic heart failure, chronic renal failure, eral pneumonia (75 of 82 patients [91.5%] vs 236 of 334 pa-
chronic obstructive pulmonary disease, cancer, pregnancy, and tients [70.7%]) and multiple mottling and ground-glass opacity
hepatitis B infection was 4.1% (17 patients), 3.4% (14 pa- (53 [64.6%] vs 15 [4.5%]) were more prevalent in patients with
tients), 2.9% (12 patients), 2.2% (9 patients), 1.7% (7 patients), than those without cardiac injury (both P < .001, Table 1).
and 1.0% (4 patients), respectively. Of patients with cardiac injury, only 22 (26.8%) under-
Compared with patients without cardiac injury, patients went examination of electrocardiogram (ECG) after admis-
with cardiac injury were older (median [range] age, 74 [34- sion, and 14 of 22 ECGs (63.6%) were performed during the
95] years vs 60 [21-90] years; P < .001), and more likely to have periods of elevation of cardiac biomarkers. All 14 ECGs were
chest pain (11 of 82 patients [13.4%] vs 3 of 334 patients [0.9%]; abnormal, with findings compatible with myocardial ische-
P < .001). Moreover, comorbidities, including hypertension (49 mia, such T-wave depression and inversion, ST-segment de-
[59.8%] vs 78 [23.4%]), diabetes (20 [24.4%] vs 40 [12.0%]), pression, and Q waves. The ECG changes in 3 patients with rep-
coronary heart disease (24 [29.3%] vs 20 [6.0%]), cerebrovas- resentative cardiac injury are shown in eFigure 2 in the
cular disease (13 [15.9%] vs 9 [2.7%]), chronic heart failure (12 Supplement.
[14.6%] vs 5 [1.5%]), chronic obstructive pulmonary disease (6
[7.3%] vs 6 [1.8%]), and cancer (7 [8.5%] vs 2 [0.6%]), were pres- Treatment, Complications, and Clinical Outcome
ent more often among patients with cardiac injury (all P < .001) The median time from symptom onset to admission was 10
(Table 1). (IQR, 1-30) days and similar between the 2 groups (P = .27;
804 JAMA Cardiology July 2020 Volume 5, Number 7 (Reprinted) jamacardiology.com

AR09391
Table 1. Baseline Characteristics and Laboratory and Radiographic Findings of 416 Patients With COVID-19
Patients, No. (%)

Cardiac injury
Characteristic All (n = 416) With (n = 82) Without (n = 334) P value
Age, median (range), y 64 (21-95) 74 (34-95) 60 (21-90) <.001
Female 211 (50.7) 38 (46.3) 173 (51.8) .39
Signs and symptoms at admission
Fever 334 (80.3) 63 (76.8) 271 (81.1) .44
Cough 144 (34.6) 28 (34.1) 116 (34.7) >.99
Shortness of breath 117 (28.1) 26 (31.7) 91 (27.2) .41
Fatigue 55 (13.2) 15 (18.3) 40 (12.0) .15
Sputum production 23 (5.5) 3 (3.7) 20 (6.0) .59
Muscle ache 19 (4.6) 5 (6.1) 14 (4.2) .55
Diarrhea 16 (3.8) 1 (1.2) 15 (4.5) .22
Chest pain 14 (3.4) 11 (13.4) 3 (0.9) <.001
Sore throat 12 (2.9) 4 (4.9) 8 (2.4) .26
Rhinorrhea 10 (2.4) 3 (3.7) 7 (2.1) .42
Headache 9 (2.2) 2 (2.4) 7 (2.1) .69
Chronic medical illness
Hypertension 127 (30.5) 49 (59.8) 78 (23.4) <.001
Diabetes 60 (14.4) 20 (24.4) 40 (12.0) .008
Coronary heart disease 44 (10.6) 24 (29.3) 20 (6.0) <.001
Cerebrovascular disease 22 (5.3) 13 (15.9) 9 (2.7) <.001
Chronic heart failure 17 (4.1) 12 (14.6) 5 (1.5) <.001
Chronic renal failure 14 (3.4) 5 (6.1) 9 (2.7) .16
Chronic obstructive pulmonary 12 (2.9) 6 (7.3) 6 (1.8) .02
disease
Cancer 9 (2.2) 7 (8.5) 2 (0.6) <.001
Pregnancy 7 (1.7) 0 7 (2.1) .35
Hepatitis B infection 4 (1.0) 2 (2.4) 2 (0.6) .18
Laboratory findings at admission,
median (IQR)
Leukocytes/μL 5800 (4300-8300) 9400 (6900-13 800) 5500 (4200-7400) <.001
Lymphocytes/μL 900 (600-1300) 600 (400-900) 1000 (800-1400) <.001
3
Platelets ×10 /μL 207 (153-265) 172 (111-215) 216 (165-273) <.001
Erythrocytes ×106/μL 4.1 (3.6-4.4) 4.0 (3.4-4.3) 4.1 (3.6-4.4) .01
Hemoglobin, g/dL 12.4 (11.1-13.4) 12.5 (10.8-13.2) 12.4 (11.2-13.5) .34
C-reactive protein, mg/dL 4.5 (1.4-8.5) 10.2 (6.4-17.0) 3.7 (1.0-7.3) <.001
Procalcitonin, ng/mL 0.07 (0.04-0.15) 0.27 (0.10-1.22) 0.06 (0.03-0.10) <.001
Creatinine kinase–myocardial 1.0 (0.7-2.0) 3.2 (1.8-6.2) 0.9 (0.6-1.3) <.001
band, ng/mL
Myohemoglobin, μg/L 47 (28-93) 128 (68-305) 39 (27-65) <.001
High-sensitivity troponin I, μg/La <0.006 0.19 (0.08-1.12) <0.006 <.001
(<0.006-0.02) (<0.006-0.009)
N-terminal pro-B-type natriuretic 219 (73-699) 1689 (698-3327) 139 (51-335) <.001
peptide, pg/mL
Alanine aminotransferase, U/L 28 (18-46) 29 (19-44) 28 (18-46) .93
Aspartate aminotransferase, U/L 30 (22-43) 40 (27-60) 29 (21-40) <.001
Albumin, g/dL 3.6 (3.2-3.8) 3.2 (2.9-3.4) 3.7 (3.3-3.9) <.001
Creatinine, mg/dL 0.67 (0.55-0.81) 1.15 (0.72-1.92) 0.64 (0.54-0.78) <.001
Potassium, mEq/L 4.0 (3.6-4.4) 4.0 (3.6-4.6) 4.0 (3.6-4.3) .65
Sodium, mEq/L 140 (138-144) 141 (138-146) 140 (138-143) .08
(continued)

AR09392
Table 1. Baseline Characteristics and Laboratory and Radiographic Findings of 416 Patients With COVID-19
(continued)
Patients, No. (%)

Cardiac injury
Characteristic All (n = 416) With (n = 82) Without (n = 334) P value
Chest radiography and computed
tomography findings
Pneumonia
Unilateral 105 (25.2) 7 (8.5) 98 (29.3) <.001
Bilateral 311 (74.8) 75 (91.5) 236 (70.7)
Multiple mottling and 68 (16.3) 53 (64.6) 15 (4.5) <.001
ground-glass opacity
Abbreviation: IQR, interquartile range.

SI conversion factors: To convert leukocytes or lymphocytes to ×109/L, multiply by 0.001; to convert platelets to ×109/L,
multiply by 1.0; to convert erythrocytes to ×1012/L, multiply by 1.0; convert hemoglobin to g/L, multiply by 10.0; to
convert C-reactive protein to mg/L, multiply by 10.0; to convert creatinine kinase–myocardial band to μg/L, multiply by
1.0; to convert troponin I to ng/mL, multiply by 1.0; to convert alanine aminotransferase or aspartate aminotransferase to
μkat/L, multiply by 0.0167; to convert albumin to g/L, multiply by 10; to convert creatinine to μmol/L, multiply by 88.4; to
convert potassium and sodium to mmol/L, multiply by 1.0.
a
Indicated that the lowest value of troponin actually measured is <0.006 ng/mL in our hospital, although the range of
reference values is 0.00 to 0.04 ng/mL.
Table 2. Treatment, Complications, and Clinical Outcome of 416 Patients With COVID-19
Patients, No. (%)

Cardiac injury
Without
Characteristic All (n = 416) With (n = 82) (n = 334) P value
Time from symptom onset to admission, 10 (1-30) 10 (1-30) 10 (1-28) .27
median (range), d
Treatment
Oxygen inhalation 316 (76.0) 26 (31.7) 290 (86.8) <.001
Noninvasive ventilation 51 (12.3) 38 (46.3) 13 (3.9) <.001
Invasive mechanical ventilation 32 (7.7) 18 (22.0) 14 (4.2) <.001
Continuous renal replacement therapy 2 (0.5) 2 (2.4) 0 .04
Antiviral treatment 403 (96.9) 82 (100) 321 (96.1) .08
Glucocorticoids 304 (73.1) 72 (87.8) 232 (69.5) <.001
Intravenous immunoglobulin therapy 259 (62.3) 68 (82.9) 191 (57.2) <.001
Antibiotic treatment 235 (56.5) 68 (82.9) 167 (50) <.001
Complications
ARDS 97 (23.3) 48 (58.5) 49 (14.7) <.001
Acute kidney injury 8 (1.9) 7 (8.5) 1 (0.3) <.001
Electrolyte disturbance 30 (7.2) 13 (15.9) 17 (5.1) .003
Hypoproteinemia 27 (6.5) 11 (13.4) 16 (4.8) .01
Anemia 13 (3.1) 4 (4.9) 9 (2.7) .30
Coagulation disorders 12 (2.9) 6 (7.3) 6 (1.8) .02
Clinical outcome
Remained in hospital 319 (76.7) 38 (46.3) 281 (72.2)
<.001
Discharged 40 (9.6) 2 (2.4) 38 (23.4)
Abbreviation: ARDS, acute
Died 57 (13.7) 42 (51.2) 15 (4.5) <.001
respiratory distress syndrome.
Table 2). A total of 399 patients (95.9%) were treated with oxy- was the highest (403 [96.9%]), followed by glucocorticoids (304
gen, and the percentages of use of oxygen inhalation, nonin- [73.1%]), intravenous immunoglobulin therapy (259 [62.3%]),
vasive ventilation, and invasive mechanical ventilation were and antibiotic therapy (235 [56.5%]). Only 2 patients (0.5%)
76.0% (316 patients), 12.3% (51 patients), and 7.7% (32 pa- among all participants were given continuous kidney therapy.
tients), respectively. The proportion of antiviral therapy use Overall, 97 patients (23.3%) had ARDS, and 8 patients (1.9%)

AR09393
had acute kidney injury during hospitalization; other com-

Figure 2. Mortality During Hospitalization Between Patients With vs
mon complications included electrolyte disturbance (30 pa- Without Cardiac Injury
tients [7.2%]), hypoproteinemia (27 [6.5%]), anemia (13 [3.1%]),
and coagulation disorders (12 [2.9%]). During follow-up, a total A Time from symptom onset
of 57 patients (13.7%) died, 40 patients (9.6%) were dis- 100
charged, and the rest (319 [76.7%]) remained hospitalized. Without cardiac injury
Compared with those without cardiac injury, patients with car- 80
diac injury required more noninvasive ventilation (38 [46.3%]
Survival rate, %
vs 13 [3.9%]; P < .001) and invasive mechanical ventilation (18 60
[22.0%] vs 14 [4.2%]; P < .001) (Table 2). The use of antibiotic With cardiac injury
40
treatment (68 [82.9%] vs 167 [50.0%]), glucocorticoids (72
[87.8%] vs 232 [69.5%]), and intravenous immunoglobulin 20
treatment (68 [82.9%] vs 191 [57.2%]) was also significant
higher in patients with cardiac injury than in those without car- 0
0 10 20 30 37
diac injury (all P < .001; Table 2). In addition to anemia, other
Days
complications were more common among patients with car-
No. at risk
diac injury than those without cardiac injury; these included With cardiac injury 82 68 46 40 40
Without cardiac injury 334 329 323 320 319
ARDS (48 [58.5%] vs 49 [14.7%]; P < .001), acute kidney in-
jury (7 [8.5%] vs 1 [0.3%]; P < .001), electrolyte disturbances
B Time from admission
(13 [15.9%] vs 17 [5.1%]; P = .003), hypoproteinemia (11 [13.4%]
100
vs 16 [4.8%]; P = .01), and coagulation disorders (6 [7.3%] vs
Without cardiac injury
6 [1.8%]; P = .02) (Table 2).
80
Survival rate, %
Cardiac Injury and Mortality 60
Patients with cardiac injury vs those without cardiac injury had
With cardiac injury
shorter durations from symptom onset to follow-up (mean, 15.6 40
[range, 1-37] days vs 16.9 [range, 3-37] days; P = .001) and ad-
mission to follow-up (6.3 [range, 1-16] days vs 7.8 [range, 1-23] 20
days; P = .039). The mortality rate was higher among pa-

0
tients with vs without cardiac injury (42 [51.2%] vs 15 [4.5%]; 0 5 10 15 20 23
P < .001) as shown in Table 2 and the Kaplan-Meier survival Days
curves in Figure 2. The mortality rate increased in associa- No. at risk
With cardiac injury 82 55 46 41 0 0
tion with the magnitude of the reference value of hs-TNI (eFig- Without cardiac injury 334 321 319 319 319 319
ure 3 in the Supplement). After adjusting for age, preexisting
cardiovascular diseases (hypertension, coronary heart dis- C Comparison of outcomes
ease, and chronic heart failure), cerebrovascular diseases, dia-
Time from symptom onset Time from admission
betes mellitus, chronic obstructive pulmonary disease, renal
Duration, Duration,
failure, cancer, ARDS, creatinine levels greater than 133 μmol/L, No. of events/ mean P value mean P value
No. of patients (range), d log-rank (range), d log-rank
and NT-proBNP levels greater than 900 pg/mL, the multivari-
With cardiac injury 42/82 15.6 (1-37) 6.3 (1-16)
able adjusted Cox proportional hazard regression model Without cardiac injury 15/334 16.9 (3-37)
<.001
7.8 (1-23)
<.001
showed a significantly higher risk of death in patients with car-

diac injury than in those without cardiac injury, either during A-B, Kaplan-Meier survival curves for mortality during the time from symptom
time from symptom onset (hazard ratio [HR], 4.26 [95% CI, onset (A) and admission (B). In (B), the maximum duration was 16 days. C,
1.92-9.49]) or time from admission to study end point (HR, 3.41 Patients with cardiac injury had a higher rate of mortality in log-rank test, both
from symptom onset and from admission.
[95% CI, 1.62-7.16]) (Table 3). Under this hazard regression
model, ARDS was another independent risk factor for mortal-
ity with COVID-19, with a high HR (7.89 [95% CI, 3.73-16.66])
in model 1 and an HR of 7.11 (95% CI, 3.31-15.25) in model 2 As of March 12, 2020, there have been a total of more than
(Table 3). 130 000 laboratory-confirmed cases of COVID-19 globally, in-
cluding more than 80 000 within mainland China. Because of
its high infectivity, this virus has managed to supersede se-
vere acute respiratory syndrome (SARS) and Middle East re-
Discussion spiratory syndrome (MERS) in death toll. Severe respiratory
The present study demonstrates the statistically significant as- distress is usually considered the main cause of coronavirus-
sociation between cardiac injury and mortality in patients with induced death. According to a recent study of the largest clini-
COVID-19. Cardiac injury, as a common complication (19.7%), cal sample in China,8 severe pneumonia was independently
was associated with an unexpected high risk of mortality dur- associated with admission to an intensive care unit, mechani-
ing hospitalization. cal ventilation, or death. It is notable that a recent report on

AR09394
Table 3. Multivariate Cox Regression Analysis on the Risk Factors Associated With Mortality
in Patients With COVID-19
From symptom onset From admission

Factor Hazard ratio (95% CI) P value Hazard ratio (95% CI) P value
Age, y 1.02 (0.99-1.05) .07 1.02 (0.99-1.04) .18
Cardiovascular diseases 1.51 (0.70-3.30) .30 1.40 (0.65-3.03) .39
Cerebrovascular diseases 1.12 (0.46-2.70) .80 1.71 (0.71-4.09) .25
Diabetes 0.79 (0.41-1.52) .48 0.75 (0.38-1.50) .42
Chronic obstructive pulmonary 0.37 (0.04-3.50) .38 0.39 (0.04-3.68) .41
disease
Renal failure 1.10 (0.49-2.44) .82 0.66 (0.29-1.46) .30
Cancer 1.75 (0.43-7.16) .44 0.82 (0.18-3.65) .79
Acute respiratory distress syndrome 7.89 (3.73-16.66) <.001 7.11 (3.31-15.25) <.001
Cardiac injury 4.26 (1.92-9.49) <.001 3.41 (1.62-7.16) .001
Creatinine ≥1.50 mg/dL 0.59 (0.29-1.23) .16 1.22 (0.60-2.50) .58
SI conversion factor: To convert
N-terminal pro-B-type natriuretic 1.16 (0.54-2.47) .70 1.52 (0.74-3.10) .25 creatinine to μmol/L, multiply by
peptide ≥900 pg/mL
88.4.
138 patients hospitalized with COVID-19 found that 7.2% of pa- COVID-19–induced cardiac injury might be mediated by
tients developed acute cardiac injury, and patients who re- ACE2. However, a recent pathological study found scarce
ceived care in the intensive care unit were more likely to have interstitial mononuclear inflammatory infiltrates in heart tis-
cardiac injury (22.2%) than non-ICU patients.2 This observa- sue without substantial myocardial damage in a patient with
tion suggests that cardiac injury is possibly associated with the COVID-19,13 suggesting that COVID-19 might not directly
clinical outcomes of COVID-19. Consistently, our study also impair the heart. The present study lacks evidence from mag-
found 19.7% of patients with cardiac injury and first demon- netic resonance imaging or echocardiography to determine
strated that cardiac injury was independently associated with the features of myocardial injury. On the basis of the present
an increased risk of mortality in patients with COVID-19. Com- results of hs-TNI and ECG findings in a subset of patients,
pared with patients without cardiac injury, patients with car- we can only estimate the severity of cardiac injury. Thus,
diac injury presented with more severe acute illness, mani- because of the current limited evidence, the question of
fested by abnormal laboratory and radiographic findings, such whether the SARS-CoV-2 virus can directly injure the heart
as higher levels of C-reactive protein, NT-proBNP, and creati- requires further demonstration.
nine levels; more multiple mottling and ground-glass opac- In contrast, a previous study found that reversible, sub-
ity; and a greater proportion requiring noninvasive or inva- clinical diastolic left ventricular impairment appears to be
sive ventilation. common in acute SARS infection, even among those without
In a study of cardiovascular complications of SARS in 121 underlying cardiac disease,14 suggesting that left ventricular
patients,9 hypertension occurred in 61 patients (50.4%) in the dysfunction in the acute phase might be attributable to the
hospital. Of these patients, 71.9% developed persistent tachy- cytokine storm syndrome. This is a serious life-threatening
cardia, including 40% with continued tachycardia during out- disease with clinical features of systemic inflammation, met-
patient follow-up. Although tachycardic cardiovascular com- hemoglobinemia, hemodynamic instability, and multiple
plications were common in patients with SARS, they were organ failure.15,16 The hallmark of cytokine storm syndrome
usually self-limiting and not associated with risk of death. In is an uncontrolled and dysfunctional immune response
contrast with that from SARS, more than half of the patients involving the continuous activation and proliferation of lym-
with cardiac injury experienced in-hospital death in this study, phocytes and macrophages. Huang et al1 found that patients
indicating that COVID-19–induced cardiac injury is associ- with COVID-19 who were admitted to the intensive care unit
ated with major adverse clinical outcomes. However, the had higher plasma levels of cytokines, including interleukin
mechanism of cardiac injury among these patients with (IL)–2, IL-7, IL-10, granulocyte-colony stimulating factor,
COVID-19 remains uncertain. IgG-induced protein 10 (also known as C-X-C motif chemo-
Evidence from a case report showed that MERS-CoV kine 10), monocyte chemoattractant protein-1, macrophage
causes acute myocarditis, manifested as myocardial edema inflammatory protein 1-alpha (also known as chemokine
and acute myocardial injury of the apical and lateral walls of ligand 3), and tumor necrosis factor α. In the present study,
the left ventricle. 10 This regional myocardial injury may we also found that markers of inflammatory response, such
result from direct viral myocardial infection. On the basis of as C-reactive protein, procalcitonin, and leukocytes, were
recent studies, angiotensin-converting enzyme 2 (ACE2) is significantly increased among patients who suffered from
a human cell receptor with a strong binding affinity to the cardiac injury. The activation or enhanced release of these
Spike protein of SARS-CoV-2, and ACE2 is also highly inflammatory cytokines can lead to apoptosis or necrosis of
expressed in heart.11,12 Thus, it is rational to hypothesize that myocardial cells.

AR09395
In addition, preexisting cardiovascular diseases might tured coronary plaque.19 Based on these lines of evidence, we
also be more susceptible COVID-19–induced heart injury, as hypothesize that an intense inflammatory response superim-
approximately 30% and 60% of patients with cardiac injury in posed on preexisting cardiovascular disease may precipitate
the present study had a history of coronary heart disease and cardiac injury observed in patients with COVID-19 infections.
hypertension, respectively, which were significantly more
prevalent than in those without cardiac injury. Similarly, in a Limitations
recent report,2 25% and 58.3% of patients who were critically Some limitations existed in the present study. First, because
ill with COVID-19 had underlying heart diseases and hyper- of the logistical limitations at the onset of these emerging
tension, respectively. According to the “Diagnosis and Treat- infections in Wuhan, some data, such as echocardiography
ment of Novel Coronavirus Pneumonia (Trial Version 4),”17 data, electrocardiography data, and cytokine level measure-
elderly patients with underlying diseases are more likely to be ments, were lacking from clinical examinations of patients in
infected with SARS-CoV-2 and tend to be severely ill, espe- isolation wards or the intensive care unit, which limits the
cially those with hypertension, coronary heart disease, and determination of potential mechanisms of cardiac injury. Sec-
diabetes. Although there are few pieces of evidence to estab- ond, because the clinical observation of patients is still ongo-
lish a direct association between cardiac injury and cardiovas- ing, many with and without cardiac injury have not reached
cular comorbidities, it is rational to presume that patients clinical end points. Third, data from larger populations and
with coronary artery disease or heart failure are susceptible to multiple centers are warranted to further confirm the out-
cardiac injury, and once such patients are infected with se- comes of cardiac injury in COVID-19.
vere pneumonia, myocardial ischemia or cardiac dysfunc-
tion are more likely to occur, ultimately leading to a sudden
deterioration. On the other hand, acute inflammatory re-
sponses can also lead to ischemia in the presence of preexist-
Conclusions
ing cardiovascular diseases. The inflammatory activity within Cardiac injury is a common condition among patients hospi-
coronary atherosclerotic plaques is exacerbated during sys- talized with COVID-19, and it is associated with a higher risk
temic inflammatory response, making them prone to rupture.18 of in-hospital mortality. Although the exact mechanism of car-
Inflammation also causes endothelial dysfunction and in- diac injury needs to be further explored, the findings pre-
creases the procoagulant activity of the blood, which can con- sented here highlight the need to consider this complication
tribute to the formation of an occlusive thrombus over a rup- in COVID-19 management.
ARTICLE INFORMATION Critical revision of the manuscript for important collation and statistical analysis. They were not
Accepted for Publication: March 9, 2020. intellectual content: Shi, Cai, F. Yang, Gong, X. Liu, compensated for their contributions.
Liang, H. Huang, B. Yang, C. Huang.
Published Online: March 25, 2020. Statistical analysis: Shi, Qin, Shen, Cai, T. Liu, REFERENCES
doi:10.1001/jamacardio.2020.0950 F. Yang, Gong. 1. Huang C, Wang Y, Li X, et al. Clinical features of
Author Affiliations: Department of Cardiology, Obtained funding: Shi. patients infected with 2019 novel coronavirus in
Renmin Hospital of Wuhan University, Wuhan, Administrative, technical, or material support: Shi, Wuhan, China. Lancet. 2020;395(10223):497-506.
China (Shi, Shen, T. Liu, Liang, Zhao, H. Huang, Shen, F. Yang, Gong, Liang, Zhao, H. Huang, B. Yang, doi:10.1016/S0140-6736(20)30183-5
B. Yang, C. Huang); Cardiovascular Research C. Huang.
Institute, Wuhan University, Wuhan, China Supervision: Shi, Qin, X. Liu, Liang, Zhao, B. Yang, 2. Wang D, Hu B, Hu C, et al. Clinical characteristics
(Shi, Shen, T. Liu, Liang, Zhao, H. Huang, B. Yang, C. Huang. of 138 hospitalized patients with 2019 novel
C. Huang); Hubei Key Laboratory of Cardiology, coronavirus-infected pneumonia in Wuhan, China.
Conflict of Interest Disclosures: None reported. JAMA. Published online February 7, 2020. doi:10.
Wuhan University, Wuhan, China (Shi, Shen, T. Liu,
Liang, Zhao, H. Huang, B. Yang, C. Huang); Shanghai Funding/Support: This research was supported by 1001/jama.2020.1585
Chest Hospital, Department of Cardiology, grants from the Nature Science Foundation of China 3. Madjid M, Solomon S, Vardeny O. ACC clinical
Shanghai Jiaotong University, Shanghai, China (Qin, (grants 81800447 and 81770324), the Nature bulletin: cardiac implications of novel Wuhan
X. Liu); Department of Endocrinology, Renmin Science Foundation of Hubei province (grant coronavirus (2019-nCoV). Published February 13,
Hospital of Wuhan University, Wuhan, China (Cai); 2017CFB204), and the Major Program of 2020. Accessed February 13, 2020. https://www.
Department of Infectious Diseases, Renmin Technological Innovation of Hubei Province (grant acc.org/latest-in-cardiology/articles/2020/02/13/
Hospital of Wuhan University, Wuhan, China 2016ACA153). 12/42/acc-clinical-bulletin-focuses-on-cardiac-
(F. Yang); Department of Radiology, Renmin Role of the Funder/Sponsor: The funders had no implications-of-coronavirus-2019-ncov
Hospital of Wuhan University, Wuhan, China (Gong) role in the design and conduct of the study; 4. World Health Organization. Clinical
. collection, management, analysis, and management of severe acute respiratory infection
Author Contributions: Drs B. Yang and H. Huang interpretation of the data; preparation, review, or when novel coronavirus (nCoV) infection is
had full access to all of the data in the study and approval of the manuscript; and decision to submit suspected: interim guidance. Published January 28,
take responsibility for the integrity of the data and the manuscript for publication. 2020. Accessed January 31, 2020. https://www.
the accuracy of the data analysis. Drs Shi, Qin, and Additional Contributions: We acknowledge all who.int/publications-detail/clinical-management-
Shen contributed to the work equally and should be medical staff involved in the diagnosis and of-severe-acute-respiratory-infection-when-novel-
regarded as co–first authors. treatment of patients with COVID-19 in Wuhan. We coronavirus-(ncov)-infection-is-suspected
Concept and design: Shi, Qin, Shen, Cai, T. Liu, thank Xu Liu, MD, PhD, Department of Cardiology, 5. Ranieri VM, Rubenfeld GD, Thompson BT, et al;
X. Liu, Liang, Zhao, H. Huang, B. Yang, C. Huang. Shanghai Chest Hospital, Shanghai Jiaotong ARDS Definition Task Force. Acute respiratory
Acquisition, analysis, or interpretation of data: Shi, University, for guidance in revision of manuscript distress syndrome: the Berlin Definition. JAMA.
F. Yang, Gong, Liang, B. Yang. and interpretation of results; we thank Min Chen, 2012;307(23):2526-2533.
Drafting of the manuscript: Shi, Qin, Shen, T. Liu, MAEng, Xuecheng Yu, MAEng, and and Zhongli Dai,
Zhao. BE, Wuhan Shinall Technology Co Ltd, for data 6. Kidney Disease: Improving Global Outcomes
(KDIGO) Acute Kidney Injury Work Group. KDIGO

AR09396
clinical practice guideline for acute kidney injury. conformation. Science. Published online February 19, 16. de Jong MD, Simmons CP, Thanh TT, et al. Fatal
Kidney Int Suppl. 2012;2:1. 2020. doi:10.1126/science.abb2507 outcome of human influenza A (H5N1) is associated
7. Wang M, Wu Q, Xu WZ, et al Clinical diagnosis of 12. Xin Z, Ke C, Zou J, et al. The single-cell RNA-seq with high viral load and hypercytokinemia. Nat Med.
8274 samples with 2019-novel coronavirus in data analysis on the receptor ACE2 expression 2006;12(10):1203-1207. doi:10.1038/nm1477
Wuhan. Published 2020. Accessed March 12, 2020. reveals the potential risk of different human organs 17. National Health Commission of People’s
https://www.medrxiv.org/content/10.1101/2020. vulnerable to Wuhan 2019-nCoV infection. Front Med. Republic of China. Diagnosis and treatment of
03.02.20030189v1.full.pdf Published online February 8, 2020. pneumonia caused by novel coronavirus (trial
8. Guan WJ, Ni ZY, Hu Y, et al Clinical characteristics 13. Xu Z, Shi L, Wang Y, et al. Pathological findings version 4). In Chinese. Published 2020. http://
of 2019 novel coronavirus infection in China. of COVID-19 associated with acute respiratory www.nhc.gov.cn/yzygj/s7653p/202001/
Published 2020. Accessed March 12, 2020. https:// distress syndrome. Lancet Respir Med. Published 4294563ed35b43209b31739bd0785e67/files/
www.medrxiv.org/content/10.1101/2020.02.06. online February 18, 2020. doi:10.1016/S2213-2600 7a9309111267475a99d4306962c8bf78.pdf
20020974v1 (20)30076-X 18. Madjid M, Vela D, Khalili-Tabrizi H, Casscells SW,
9. Yu CM, Wong RS, Wu EB, et al. Cardiovascular 14. Li SS, Cheng CW, Fu CL, et al. Left ventricular Litovsky S. Systemic infections cause exaggerated
complications of severe acute respiratory performance in patients with severe acute local inflammation in atherosclerotic coronary
syndrome. Postgrad Med J. 2006;82(964):140-144. respiratory syndrome: a 30-day echocardiographic arteries: clues to the triggering effect of acute
doi:10.1136/pgmj.2005.037515 follow-up study. Circulation. 2003;108(15):1798-1803. infections on acute coronary syndromes. Tex Heart
doi:10.1161/01.CIR.0000094737.21775.32 Inst J. 2007;34(1):11-18.
10. Alhogbani T. Acute myocarditis associated with
novel Middle east respiratory syndrome 15. Sellers SA, Hagan RS, Hayden FG, Fischer WA II. 19. Corrales-Medina VF, Musher DM, Shachkina S,
coronavirus. Ann Saudi Med. 2016;36(1):78-80. doi: The hidden burden of influenza: a review of the Chirinos JA. Acute pneumonia and the
10.5144/0256-4947.2016.78 extra-pulmonary complications of influenza cardiovascular system. Lancet. 2013;381(9865):
infection. Influenza Other Respir Viruses. 2017;11(5): 496-505. doi:10.1016/S0140-6736(12)61266-5
11. Wrapp D, Wang N, Corbett KS, et al. Cryo-EM
structure of the 2019-nCoV spike in the prefusion 372-393. doi:10.1111/irv.12470

ADVERTISEMENT
Article
AR09397 Figures/Media
Most Viewed
NEJM Group Follow Us Sign In Create Account SUBSCRIBE
5
CORRESPONDENCE M AY 1 8 , 2 0 2 2
Omicron BA.1/1.1 SARS-CoV-2

SUBSCRIBE NOW ➔ Infection among
Vaccinated Canadian Adults
P. E. Brown and Others
CASE RECORDS OF THE EDITORIAL O R I G I N A L A RT I C L E MEDICINE AND SOCIETY
MGH Audio Interview: Waning Protection and Waning of Dismantling Structural Racism
Case 16-2022: A 55-Year-Old Immunity against Covid-19 Natural and Hybrid
C O R RImmunity
E S P O N D Eto
NCE M AY 1 8 , 2 0 2in
2 the Academic Residency
Man with Fevers, Night Sweats, SARS-CoV-2 Clinic
and a Mediastinal Mas... Neutralization of the SARS-CoV-2 Deltacron and BA.3
Variants
Editor’s Note: This article was published on March 30, 2020, at NEJM.org.
J. P. Evans and Others
O R I G I N A L A RT I C L E ORIGINAL ARTICLE M AY 1 9 , 2 0 2 2
BNT162b2 Protection against the Omicron Variant in

Covid-19 in Critically Ill Patients in the Seattle Region — Case Series Children and Adolescents
A. M.K.Price
Pavan K. Bhatraju, M.D., Bijan J. Ghassemieh, M.D., Michelle Nichols, M.D., Richard Kim, M.D., Keith R. Jerome, M.D., Arun andPh.D.,
Nalla, OthersAlexander L. Greninger,
M.D., Sudhakar Pipavath, M.D., Mark M. Wurfel, M.D., Ph.D., Laura Evans, M.D., Patricia A. Kritek, M.D., T. Eoin West, M.D., M.P.H., et al.
Article Figures/Media Metrics May 21, 2020

N Engl J Med 2020; 382:2012-2022
DOI: 10.1056/NEJMoa2004500
23 References 1432 Citing Articles
Abstract A D V E RT I S E M E N T
BACKGROUND
Community transmission of coronavirus 2019 (Covid-19) was detected in the state of Washington in
February 2020.
METHODS
We identified patients from nine Seattle-area hospitals who were admitted to the intensive care unit
(ICU) with confirmed infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).
Clinical data were obtained through review of medical records. The data reported here are those
available through March 23, 2020. Each patient had at least 14 days of follow-up.
R E S U LT S
We identified 24 patients with confirmed Covid-19. The mean (±SD) age of the patients was 64±18
years, 63% were men, and symptoms began 7±4 days before admission. The most common PHYSICIAN JOBS M AY 2 7, 2 0 2 2
symptoms were cough and shortness of breath; 50% of patients had fever on admission, and 58%
had diabetes mellitus. All the patients were admitted for hypoxemic respiratory failure; 75% (18 Neurology Loma Linda, California
Academic Neurologist Opportunity in Southern California
patients) needed mechanical ventilation. Most of the patients (17) also had hypotension and needed
vasopressors. No patient tested positive for influenza A, influenza B, or other respiratory viruses.
Chiefs / Directors / Dept. Heads Boston, Massachusetts
Half the patients (12) died between ICU day 1 and day 18, including 4 patients who had a do-not- Chief of Geriatrics
resuscitate order on admission. Of the 12 surviving patients, 5 were discharged home, 4 were
discharged from the ICU but remained in the hospital, and 3 continued to receive mechanical Psychiatry Leesburg, Virginia
Child and Adolescent Psychiatrist - Outpatient
ventilation in the ICU.
CONCLUSIONS Pediatrics, General New York

Full, Associate, or Assistant Professor for the Division of
During the first 3 weeks of the Covid-19 outbreak in the Seattle area, the most common reasons for
General Pediatrics
admission to the ICU were hypoxemic respiratory failure leading to mechanical ventilation,
hypotension requiring vasopressor treatment, or both. Mortality among these critically ill patients Family Medicine Texas
was high. (Funded by the National Institutes of Health.) Family Medicine Physician
S
Anesthesiology Decatur, Illinois
evere acute respiratory Anesthesiology - Partner Track
Video
syndrome coronavirus-2
(SARS-CoV-2) is the novel Computed Tomographic Imaging
of a Patient with ARDS Due to
coronavirus first detected in Wuhan,
Covid-19. (00:07)
China, that causes coronavirus disease
2019 (Covid-19).1 Since initial detection
of the virus, more than 400,000 cases
of Covid-19 have been confirmed
worldwide, with the first reported cases in the United States occurring on January 19, 2020, in the
state of Washington.2,3 The number of cases in Washington continues to rise; as of March 27, 2020,
there had been 3700 confirmed Covid-19 cases and 175 deaths.4 Most of the cases have been in King
County, an urban county that includes Seattle and outlying suburbs and accounts for 1760 Covid-19
cases and 125 deaths. Genomic and epidemiologic analyses of sequenced virus RNA recovered in the
western Washington region5 have shown that the spread of SARS-CoV-2 has been the result of local
More Research !
community transmission — meaning that the source of infection cannot be traced back to a known
exposure. Person-to-person transmission has also been well documented in skilled nursing and
O RIG IN AL ARTI C L E MAY 26
long-term care facilities in the Seattle metropolitan area.
Tranexamic Acid in Patients Undergoing Noncardiac
Initial reports from China and Italy suggest high mortality and stressed intensive care unit (ICU) Surgery
capacity.6,7 Reports describing patients admitted to the ICU with Covid-19 in the United States are P. Devereaux and Others
limited.8 A better characterization of Covid-19 infection in critically ill patients is important to guide
decision making regarding critical care capacity and allocation of resources.9 The aim of our O RIG IN AL ARTI C L E MAY 26
multicenter report is to describe the demographic characteristics, coexisting conditions, imaging Demethylation and Up-Regulation of an Oncogene after
findings, and outcomes among critically ill patients with Covid-19 in the Seattle metropolitan area. Hypomethylating Therapy
Y.-C. Liu and Others
Methods O RIG IN AL ARTI C L E MAY 26
Evaluation of mRNA-1273 Covid-19 Vaccine in Children 6

S T U DY P O P U L AT I O N , S E T T I N G , A N D D ATA C O L L E C T I O N to 11 Years of Age
We included patients with laboratory-confirmed Covid-19 infection who were admitted to nine C.B. Creech and Others
hospital ICUs in the Seattle region between February 24 and March 9, 2020. A confirmed case of
Covid-19 was defined by a positive result on a reverse-transcriptase–polymerase-chain-reaction (RT-
PCR) assay of a specimen collected on a nasopharyngeal swab. Only laboratory-confirmed cases
were included.
Twenty-four adults (18 years of age or older) were identified from nine hospitals, including three
University of Washington (UW) Medicine Hospitals (Harborview Medical Center, UW Medical
Center–Montlake, and Northwest campuses), the Virginia Mason Medical Center, and the Swedish
Hospitals (First Hill and Cherry Hill). This group represents six of the eight adult acute care
hospitals in the city of Seattle; hospitals connected to these systems in suburbs outside Seattle (UW–
Valley Medical Center, Swedish–Issaquah, and Swedish–Edmonds) were also included in the group
of nine. Pregnant women, prisoners, and children (those younger than 18 years of age) were excluded
from the study. The UW institutional review board approved this study with the reliance agreement
(also known as an authorization agreement) of other local medical centers. The institutional review
board at Swedish Medical Center also independently approved the study. Informed consent was
waived, and researchers analyzed only deidentified (anonymized) data.
Data from each institution’s electronic medical record was obtained through a research form in
Research Electronic Data Capture software (REDCap, Vanderbilt University). We obtained
demographic data, information on clinical symptoms or signs at presentation, and laboratory and
radiologic results during ICU admission. All laboratory tests and radiologic assessments, including
plain chest radiography and computed tomography of the chest, were performed at the discretion of
the treating physician.
S T U DY D E F I N I T I O N S
Coexisting conditions were ascertained from physician documentation. Patient data were censored
at the time of data cutoff, which occurred on March 23, 2020. Acute respiratory distress syndrome
(ARDS) was defined as acute-onset hypoxemia (the ratio of the partial pressure of arterial oxygen to
the fraction of inspired oxygen [Pao2:Fio2], <300) with bilateral pulmonary opacities on chest
imaging that were not fully explained by congestive heart failure or other forms of volume
overload.10
SPECIMEN COLLECTION AND TESTING
Clinical specimens for Covid-19 diagnostic testing were obtained in accordance with Centers for
Disease Control and Prevention (CDC) guidelines. Initially, all clinical specimens were tested with
the assay developed by the CDC, targeting the N1 and N2 genes,11 which was run at the Washington
Department of Health State Public Health Laboratory. On March 2, UW began using an assay
developed by the UW School of Medicine clinical virology laboratory (see the Methods section in the
Supplementary Appendix, available with the full text of this article at NEJM.org). The assay is based
on the World Health Organization standard, and it targets the SARS-CoV-2 E gene and RdRp gene.12
If both targets are detected, the assay is reported as positive; if one target is detected, the assay is
reported as inconclusive and is later confirmed reflexively by the real-time RT-PCR assay developed
by the CDC at the Washington State Public Health Laboratory.
S TAT I S T I C A L A N A LY S I S
Descriptive statistics were used to summarize the data; results are reported as medians and
interquartile ranges or means and standard deviations, as appropriate. Categorical variables were
summarized as counts and percentages. No imputation was made for missing data. Analysis was
performed with Stata 15.1 software (StataCorp).
Results
D E M O G R A P H I C A N D C L I N I C A L C H A R A C T E R I S T I C S O F T H E P AT I E N T S
During the period from February 24 through March 9,

we identified 24 critically ill patients with confirmed
Table 1.
Covid-19 infection at the nine hospitals surveyed. This
number included all patients admitted to the ICU
under the care of an intensivist at any time during the
hospital stay. The demographic and clinical
characteristics of the patients are shown in Table 1.
The mean (±SD) age of the patients was 64±18 years
(range, 23 to 97); 63% were men. The mean duration of
symptoms before hospital admission was 7±4 days.
None of the patients had recently traveled to a country
with known transmission, such as China, South Korea,
Iran, or Italy. A slight majority of patients (13 [54%])
had had recent contact with a person known to have
been ill, but whether the sick contacts were infected
with SARS-CoV-2 was not known because of the
limited availability of testing at the time. Sixteen
patients (67%) were admitted from home, and 6
patients (25%) were admitted from a skilled nursing Clinical Characteristics of the Patients at
facility. The most common symptoms on admission to Baseline.
the hospital were shortness of breath and cough, each
of which occurred in 21 patients (88%). Documented fever was present in 12 patients (50%) on
presentation at the hospital. Patient-level data are available in the Supplementary Appendix.
Chronic medical conditions were common in this critically ill population. Fourteen patients (58%)
had diabetes mellitus and 5 (21%) had chronic kidney disease; 3 patients (14%) had asthma, and all 3
had recently received, as an outpatient, systemic glucocorticoids for a presumed asthma
exacerbation before becoming critically ill. Five patients (22%) were current or former smokers and 1
patient (4%) had chronic obstructive pulmonary disease; 8 patients (33%) had more than one
coexisting condition.
L A B O R AT O RY A N D R A D I O L O G I C F I N D I N G S
Table 2 shows the laboratory and radiologic findings in

the patients on admission and during the ICU course.
Table 2.
On admission, lymphocytopenia was common (in 75%
of the patients), with a median lymphocyte count of
720 per cubic millimeter (interquartile range, 520 to
1375). Arterial lactate was 1.5 mg per deciliter or higher
in 8 patients, and hepatic enzymes were 40 U per liter
or higher in 9 patients. Troponin concentrations were
elevated in 2 patients early in their ICU course
(maximum value, 0.80 ng per deciliter).
A chest radiograph was obtained in 23 patients (96%)

on ICU admission, and all the radiographs showed
bilateral pulmonary opacities. No pleural effusions
were seen. A computed tomographic (CT) scan of the
chest was obtained in 5 patients (21%); four of the
scans showed bilateral ground glass opacities, and one Laboratory Data at Hospital Admission and
showed pulmonary nodules. Figure 1 provides Imaging Findings.
representative images from a single patient,
illustrating the rapid evolution of pulmonary opacities
and the diffuse findings. A video showing the CT cross- Figure 1.
sectional images of the chest is available at NEJM.org.
M I C R O B I O L O G I C R E S U LT S
The performance of the local UW assay was similar to

that of the CDC assay in comparison diagnostic
testing. All patients had Covid-19 confirmed by an RT-
PCR assay of a nasal swab. The UW assay returned one
inconclusive result that was later confirmed as positive
by the Washington State Public Health Laboratory.
Of the patients with laboratory-confirmed Covid-19,

nearly all (23 patients [96%]) also had nasopharyngeal
swabs sent to test for influenza and respiratory Chest Radiographs and CT Images of a 55-
syncytial virus, and 21 patients (88%) had an extended- Year-Old Patient with SARS-CoV-2.
spectrum respiratory viral panel. None of the patients

had a coinfection with another virus (see Table S1 in the Supplementary Appendix). Sputum samples
from 15 patients were sent for bacterial culture, and all were negative for bacterial growth; blood
samples from 20 patients were sent, and all remained negative. Bronchoscopy was performed in 4
patients. Two patients had bronchoscopy performed before diagnosis of Covid-19; bacterial and viral
RT-PCR results were negative for other respiratory viruses. Two subjects had bronchoscopy
performed late in the hospitalization for mucous plugging, without additional cultures.
R E S P I R AT O RY FA I L U R E A N D S H O C K
Eighteen patients (75%) received invasive mechanical

ventilation (Table 3). For patients who received
Table 3.
mechanical ventilation, the Pao2:Fio2 ratios were
consistent with moderate-to-severe ARDS. Pulmonary
secretions were characterized as either moderate or
thick and purulent in 14 patients (77%) during the first
7 days of mechanical ventilation. The median Fio2 on
day 1 of mechanical ventilation was 0.9 (interquartile
range, 0.7 to 1.0), and the Fio2 improved on day 3 to
0.6 (interquartile range, 0.5 to 0.7). The median
driving pressure (the difference between plateau
pressure and positive end expiratory pressure [PEEP])
on day 1 of mechanical ventilation was 13 cm of water
(interquartile range, 11 to 17). During the first 3 days of
mechanical ventilation, the median driving pressure
was 12 to 13 cm of water. The median pulmonary
compliance on day 1 was 29 ml per cm of water
ICU-Level Therapies and Clinical Outcomes.
(interquartile range, 25 to 36). The pulmonary
compliance improved during the first 3 days of
mechanical ventilation, with median compliance on day 3 of 37 ml per cm of water (interquartile
range, 25 to 42). Five patients (28%) were placed in a prone position, 7 (39%) received
neuromuscular blockade, and 5 (28%) received inhaled pulmonary vasodilators to treat hypoxemic
respiratory failure in ARDS. Tracheostomy was not completed in any of the patients.
Seventeen patients (71%) presented with concurrent hypotension requiring vasopressors, without
clear evidence of secondary infection. Of these patients, 3 (18%) had transient hypotension after
intubation; 14 (82%) had hypotension that was unrelated to intubation or that persisted for more
than 12 hours after intubation. None of the echocardiograms completed in 9 patients (38%) showed
new cardiac dysfunction. Seven patients received compassionate-use remdesivir as antiviral therapy,
1 patient received hydroxychloroquine, and 1 patient received lopinavir–ritonavir; no patient received
systemic glucocorticoids or tocilizumab in the ICU.
OUTCOMES
All patients had at least 14 days of hospital follow-up.

As of March 23, of the 24 patients, 12 (50%) had died, 4
Figure 2.
(17%) had been discharged from the ICU but remained
in the hospital, 3 (13%) were receiving mechanical
ventilation and were still in the ICU, and 5 (21%) had
been discharged from the hospital (Figure 2). A greater
percentage of patients over 65 years of age had died
than patients under 65 years of age (62% vs. 37%). The
12 deaths included 4 patients (17%) who had do-not-
resuscitate orders in place before hospital admission
for use in the event of cardiac arrest, and 6 additional Outcomes for Individual Patients Included in
patients (25%) had do-not-resuscitate orders that were the Case Series.
instituted during their admission.
The median length of hospital stay among survivors was 17 days (interquartile range, 16 to 23), and
the median length of ICU stay among survivors was 14 days (interquartile range, 4 to 17) (Table 3).
The median duration of mechanical ventilation was 10 days (interquartile range, 7 to 12), and 6
patients (33%) had been extubated as of March 23, 2020. Three patients continued to receive
ventilatory support, so the durations of mechanical ventilation and ICU stay are likely to be
underestimates.
Discussion
This multicenter case series describes 24 critically ill patients who presented with acute hypoxemic
respiratory failure and laboratory-confirmed Covid-19 infection. We included all patients with Covid-
19 who were admitted to an ICU at nine Seattle-area hospitals between February 24 and March 9,
2020. All the patients had acquired Covid-19 without known exposure to a returning traveler.
Coexisting lower respiratory bacterial infections were not identified in sputum and blood cultures
obtained early in the clinical course. Overall outcomes were poor in patients who received ICU care.
The patients in our series presented with respiratory symptoms similar to those of patients
described in reports from China, which indicates a common host response to SARS-CoV-2. Cough
was the most common presenting symptom, as it was in reports from China, and the mean duration
of symptoms before ICU admission was 1 week.13 Only half the patients had fever at the time of
hospital admission, which suggests that fever may not be a useful criterion to determine the severity
of illness and that diagnostic algorithms that require fever for Covid-19 testing may delay diagnosis.
The majority of patients had chronic illnesses before their admission to the ICU, most commonly
diabetes mellitus and chronic kidney disease. Lymphocytopenia was common on hospital
admission, as it was in reports from China.13
The case fatality rate of 50% in this series (to date) is similar to that reported among critically ill
patients in Chinese hospitals but lower than that in a single-center experience reported from our
area.8,13 Although the case fatality rate was higher in persons 65 years of age or older, it was still
substantial (37%) in persons younger than 65 years of age. Our case fatality rate may be an
underestimate, given that 3 patients remained intubated at the time data were censored.
Patients who received mechanical ventilation had high oxygen requirements soon after initiation of
mechanical ventilation, with plateau pressures (mean, 25 cm of water) and driving pressures (mean,
12 to 13 cm of water) similar to those in populations of patients with ARDS enrolled in clinical
trials.14,15 For example, the mean plateau pressure in the Reevaluation of Systemic Early
Neuromuscular Blockade (ROSE) trial14 was 25 to 26 cm of water. Of the 18 patients who received
invasive mechanical ventilation in this series, 6 had been successfully extubated. The earliest
extubation occurred 8 days after initiation of invasive mechanical ventilation, which suggests that
acute respiratory failure due to Covid-19 may require prolonged mechanical ventilation lasting days
to weeks and that readiness for extubation is unlikely to occur early in patients receiving mechanical
ventilation. Of patients who were extubated, the age range was 23 to 88 years, which suggests that
age may not be the sole indicator for successful extubation.
A large proportion of patients in this series presented with shock that required vasopressor support.
In patients who had an echocardiogram, myocardial dysfunction was uncommon. The lack of
bacterial or viral coinfection suggests that the observed shock was directly related to Covid-19. In
these preliminary data, Covid-19 infection appears to differ from seasonal influenza, which is
commonly associated with bacterial coinfection due to pathogens that colonize the nasopharynx,
such as staphylococcus and streptococcus.16 Regarding antiviral interventions, 7 patients received
compassionate-use remdesivir, but we have insufficient information to report associated outcomes.
Bronchoscopy was performed in a minority of patients and did not appear to change clinical
management.
Three patients with mild asthma had received systemic glucocorticoids within 1 week before ICU
admission, as outpatients, for presumed asthma exacerbation while they had symptoms of Covid-19.
These 3 patients then presented to the hospital again, with severe respiratory failure requiring
invasive mechanical ventilation. Previous studies have shown that glucocorticoid treatment for
phylogenetically similar viruses, SARS-CoV (2003) and Middle East respiratory syndrome
coronavirus (MERS-CoV), was associated with a higher subsequent plasma viral load, longer
duration of viremia, and worse clinical outcomes.17-20 These findings are in contrast to those of a
recent nonrandomized observational study that suggested that glucocorticoids may be associated
with improved clinical outcomes in patients with Covid-19 and ARDS.21 Further research is necessary
to determine the role of systemic glucocorticoids in patients with Covid-19 infection.
Our study has several notable limitations. First, some cases had incomplete documentation of
clinical symptoms, missing laboratory testing, or both. However, given the need to provide objective
data and the urgent timeline, we did not approach patients to obtain additional history or biologic
samples for laboratory measurement. Second, 7 patients (29%) remained in hospitals at the time of
data censoring on March 23, 2020; as a result, outcomes for those patients were not known. Third,
because of our focus on the critical care needs of patients with the greatest severity of illness, our
sample size is small. Finally, it is possible that critically ill patients with established goals of care that
were not consistent with admission to an ICU were not included in this report. Specifically, this
includes patients who received care on the general medical ward that focused on comfort measures
only.
This early experience of the Covid-19 pandemic in the United States resembles the experience in
other countries, with high mortality for patients requiring care in the ICU. Patients with coexisting
conditions and older age are at risk for severe disease and poor outcomes after ICU admission. Better
information is needed to inform care for these challenging patients. Our findings also highlight the
importance of planning for mass critical care as the need for ICU care and ventilatory support to
treat patients with Covid-19 grows rapidly in the United States.22,23
Supported by a grant from the National Institutes of Health (K23DK116967, to Dr. Bhatraju).
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
This article was published on March 30, 2020, at NEJM.org.
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
We thank Adrienne Meyer from the University of Washington institutional review board for rapidly reviewing
and facilitating study protocols across many area hospitals.
Author Affiliations
From the Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine (P.K.B., B.J.G.,
M.N., R.K., M.M.W., L.E., P.A.K., T.E.W., A.L., C.M.), the Departments of Laboratory Medicine (K.R.J., A.K.N.,
A.L.G.) and Radiology (S.P.), and the Division of Allergy and Infectious Disease (J.D.G.), University of
Washington, the Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center (K.R.J.,
A.K.N., A.L.G.), the Sections of Critical Care and Pulmonary Medicine, Virginia Mason Medical Center (A.G.),
and the Divisions of Pulmonary and Critical Care (C.R.D., S.O.) and Infectious Disease (J.D.G.), Swedish
Medical Center — all in Seattle.
Address reprint requests to Dr. Bhatraju at University of Washington–Harborview Medical Center, 325 9th Ave.,
Seattle, WA 98104, or at Bhatraju@uw.edu.
Supplementary Material
Supplementary Appendix PDF 234KB
Disclosure Forms PDF 418KB
Data Sharing Statement PDF 77KB
References (23)
Citing Articles (1432)
More about P U L M O N A RY / C R I T I C A L C A R E CRITICAL CARE INFECTIOUS DISEASE VIRAL INFECTIONS
G L O B A L H E A LT H INFLUENZA
More from the week of May 21, 2020
EDITORIAL IMAGES IN CLINICAL MEDICINE C A S E R E C O R D S O F T H E M A S S A C H U S E T T S G E N E R A L H O S P I TA L
Thrombolysis before Thrombectomy — To Be or Disseminated Fusariosis Case 16-2020: A 47-Year-Old Woman with Recurrent
DIRECT-MT? J. Sevestre and L. Kopec Melanoma and Pulmonary Nodules
G.W. Albers K.A. Armstrong and Others
Tap into groundbreaking research

and clinically relevant insights.
SUBSCRIBE
B ACK TO TOP
A RT I C L E C AT E G O R I E S RESOURCES ABOUT US SUBSCRIPTIONS S TAY C O N N E C T E D FOLLOW US
Research Authors & Reviewers About NEJM Subscribe Email Alerts Facebook
Reviews Submit a Manuscript Products & Services Renew Create Account Twitter
Clinical Cases Subscribers Editors & Publishers Activate Subscription Apps Instagram
Perspective Institutions Advertising Policies Create Account NEJM CareerCenter YouTube
Commentary Media Contact Us Manage Account Podcasts LinkedIn
Other Advertisers Accessibility Pay Bill RSS Feed
Browse all Articles Agents FAQs Special Content Remote Access
Current Issue Permissions Help
Issue Index Reprints Site Feedback
NEJM CareerCenter
JOURNALS The New England Journal of Medicine NEJM Catalyst Innovations in Care Delivery NEJM Evidence
Copyright © 2022 Massachusetts Medical Society. All rights reserved. Electronic ISSN 1533-4406. Print ISSN 0028-4793.
The content of this site is intended for health care professionals. Copyright Terms Privacy Policy
Working o!-campus? Learn about our remote access options
AR09398 ( SECTIONS PDF ) TOOLS * SHARE
6
Search +
Search Login / Register
Advertisement
Volume 51, Issue 11
November 2021
e13679
ORIGINAL ARTICLE ! Free Access
Prevalence and clinical outcomes of myocarditis and pericarditis

in 718,365 COVID-19 patients
$ % &
Benjamin J.R. Buckley #, Stephanie L. Harrison, Elnara Fazio-Eynullayeva, Paula Underhill, Deirdre A. Lane
References Related Information
, Gregory Y.H. Lip
First published: 13 September 2021 | https://doi.org/10.1111/eci.13679 | Citations: 10

Recommended
Funding information:
Cardiac complications following mRNA
No speci!c funding was received for this study. TriNetX LLC. funded the acquisition of the data.
COVID‐19 vaccines: A systematic review of
case reports and case series
Asra Fazlollahi, Mahdi Zahmatyar,

Maryam Noori, Seyed Aria Nejadghaderi,
Mark J. M. Sullman, Reza Shekarriz-Foumani,
Ali-Asghar Kolahi, Kuljit Singh, Saeid Sa!ri
Abstract
Reviews in Medical Virology
Background
Myocarditis, pericarditis and
COVID-19 has a wide spectrum of cardiovascular sequelae including myocarditis and
cardiomyopathy in patients treated with
pericarditis; however, the prevalence and clinical impact are unclear. We investigated the clozapine
prevalence of new-onset myocarditis/pericarditis and associated adverse cardiovascular
P. M. Wehmeier MD, P. Heiser MD,
events in patients with COVID-19. H. Remschmidt MD PhD FRCP
Methods and results Journal of Clinical Pharmacy and Therapeutics
A retrospective cohort study was conducted using electronic medical records from a
global federated health research network. Patients were included based on a diagnosis Assessing and Managing the Patient with
of COVID-19 and new-onset myocarditis or pericarditis. Patients with COVID-19 and Chest Pain Due to either Acute Pericarditis
or Myocarditis
myocarditis/pericarditis were 1:1 propensity score matched for age, sex, race and
comorbidities to patients with COVID-19 but without myocarditis/pericarditis. The John W. Albarran
outcomes of interest were 6-month all-cause mortality, hospitalisation, cardiac arrest, Chest Pain: Advanced Assessment and
incident heart failure, incident atrial !brillation and acute myocardial infarction, Management Skills, [1]
comparing patients with and without myocarditis/pericarditis.
Of 718,365 patients with COVID-19, 35,820 (5.0%) developed new-onset myocarditis and E#usive‒Constrictive Pericarditis
10,706 (1.5%) developed new-onset pericarditis. Six-month all-cause mortality was 3.9% Eric M. Crespo, Sidney C. Smith
(n = 702) in patients with myocarditis and 2.9% (n = 523) in matched controls (p < .0001),
Cardiovascular Hemodynamics for the
odds ratio 1.36 (95% con!dence interval (CI): 1.21–1.53). Six-month all-cause mortality
was 15.5% (n = 816) for pericarditis and 6.7% (n = 356) in matched controls (p < .0001),
odds ratio 2.55 (95% CI: 2.24–2.91). Receiving critical care was associated with
signi!cantly higher odds of mortality for patients with myocarditis and pericarditis.
Patients with pericarditis seemed to associate with more new-onset cardiovascular
sequelae than those with myocarditis. This !nding was consistent when looking at pre-
COVID-19 data with pneumonia patients.
Conclusions
Patients with COVID-19 who present with myocarditis/pericarditis associate with
increased odds of major adverse events and new-onset cardiovascular sequelae.
1 INTRODUCTION
Myocarditis and pericarditis are non-ischaemic in"ammatory diseases of the myocardium
and pericardium, respectively.1, 2 The clinical presentation of these two conditions is highly
variable and may be proceeded by coryzal symptoms or non-speci!c features of general
malaise, fatigue or diarrhoea. At the other extreme, cardiac in"ammation may stimulate
myocardial infarction, symptomatic arrhythmias, heart failure, cardiogenic shock or sudden
cardiac death.3 Although the aetiology of myocarditis and pericarditis is heterogeneous,
infection is the most common cause,1 with viral pathogens the most commonly implicated in
the developed world.4
The hallmark of COVID-19 is respiratory involvement, ranging from mild upper respiratory
symptoms to acute respiratory distress syndrome.5 However, severe COVID-19 has been
implicated in multi-organ involvement, with several observational case series showing a
signi!cant proportion of cardiac involvement among hospitalised patients.6-8 Moreover,
cardiac injury seems to be signi!cantly correlated with increased in-hospital mortality in
COVID-19 patients.7 COVID-19 has a wide spectrum of cardiovascular sequelae, including
acute-onset heart failure, arrhythmias, acute coronary syndrome, myocarditis and cardiac
arrest. A growing body of evidence has described cardiac involvement in COVID-19, including
myocarditis,,9, 10 pericarditis,11 or more generally, increased biomarkers of cardiac injury,12
all of which may associate with poor prognosis.13, 14
Despite recent case reports, the prevalence and clinical impact of new-onset presentation of
myocarditis and pericarditis in adults with COVID-19 are unclear. Therefore, using a global
federated health research network, the aim of the present study was to investigate the
prevalence and associated adverse events and cardiovascular sequelae in patients with
COVID-19 who also present with new-onset myocarditis/pericarditis.
2 METHODS
2.1 Study design and participants
A retrospective observational study was conducted within TriNetX, a global federated health
research network with access to electronic medical records (EMRs) from participating
healthcare organisations including academic medical centres, specialty physician practices
and community hospitals, predominantly in the United States. The TriNetX network was
searched on 19 August 2021 for patients with COVID-19 aged 18–90 years identi!ed in EMRs
between 20 January 2020 and 1 June 2020. In addition, a pre-COVID-19 cohort was included
(between 20 January 2019 and 1 June 2019) presenting patients with an EMR of pneumonia
to validate the prevalence and associated outcomes of myocarditis/pericarditis observed in
the COVID-19 cohorts. Reporting of this study conforms to broad EQUATOR guidelines15 and
the more speci!c Strengthening the Reporting of Observational Studies in Epidemiology
(STROBE) guidelines.16
Patients with COVID-19 were identi!ed following criteria provided by TriNetX based on
Centers for Disease Control and Prevention (CDC) coding guidelines.17 Patients were
included if they had one or more of the following International Classi!cation of Diseases,
Tenth Revision, Clinical Modi!cation (ICD-10-CM) codes in patient EMRs: U07.1 COVID-19;
B97.29 other coronaviruses as the cause of diseases classi!ed elsewhere; B34.2 coronavirus
infection, unspeci!ed; or a positive test result identi!ed with COVID-19 speci!c laboratory
Logical Observation Identi!ers Names and Codes (LOINCs). Myocarditis was identi!ed with
the following ICD-10-CM codes in patient EMRs: I40, acute myocarditis; I41, myocarditis in
diseases classi!ed elsewhere; I51.4 myocarditis, unspeci!ed; B97.8 other viral agents as the
cause of diseases classi!ed elsewhere; or B89, unspeci!ed parasitic disease. Pericarditis was
identi!ed with the following ICD-10-CM codes in patient EMRs: I30, acute pericarditis; I31,
other diseases of the pericardium; I32, pericarditis in disease classi!ed elsewhere.
Pneumonia (used to validate the COVID-19 analyses) was identi!ed by ICD-10-CM code, J18.
The TriNetX platform only uses aggregated counts and statistical summaries of de-identi!ed
information. No protected health information or personal data are made available to users
of the platform. Thus, research studies using the TriNetX research network do not require
ethical approval as no identi!able patient data are received. TriNetX database performs
extensive internal data quality assessments with every refresh based on conformance,
completeness and plausibility.18 This includes the evaluation of clinical correctness and
agreements of network insights with external information.
2.2 Data collection

The TriNetX network was searched on 19 August 2020, and an anonymised data set of
patients was analysed within the online database. The COVID-19 cohort, both with and
without myocarditis/pericarditis, were aged ≥18 years with a diagnosis between 20 January
2020 (date COVID-19 !rst con!rmed in the United States)19 and 1 June 2020 (allowing for 6-
month follow-up). At the time of the search, 53 participating healthcare organisations had
data available for patients who met the study inclusion criteria.
2.3 Statistical analysis

All statistical analyses were completed within the TriNetX online platform. Baseline
characteristics were compared using chi-squared tests for categorical variables and
independent-sample t tests for continuous variables. Propensity score matching (PSM) was
used to control for di#erences in the cohorts and/or known risk factors for cardiovascular
disease and all-cause mortality. PSM was therefore used to match patients with COVID-19
and myocarditis/pericarditis to patients with COVID-19 without myocarditis/pericarditis. PSM
was also conducted for the pneumonia cohort analyses with and without
myocarditis/pericarditis. Patients were 1:1 PSM using logistic regression for age, sex, race,
hypertensive diseases, ischaemic heart diseases, heart failure, cerebrovascular diseases,
diabetes mellitus, chronic kidney disease, diseases of the respiratory system, diseases of the
digestive system and diseases of the nervous system. These variables were chosen because
they are established risk factors for cardiovascular disease and/or mortality or were
signi!cantly di#erent between the two cohorts. The TriNetX platform uses ‘greedy nearest
neighbour matching’ with a calliper of 0.1 pooled standard deviations. Following PSM,
logistic regressions produced odds ratios with 95% con!dence intervals (CIs) for 6-month
incidence of all-cause mortality, hospitalisation, cardiac arrest, incident heart failure, incident
atrial !brillation (AF) and acute myocardial infarction, comparing patients with/without
myocarditis and pericarditis. Statistical signi!cance was set at p < 0.05.
3 RESULTS
3.1 Patient characteristics
The COVID-19 cohort used in this study was distributed between the four large Census
Bureau designated regions of the United States as follows: 17% in the Northeast, 19% in the
Midwest, 45% in the South and 19% in the West. Of 718,365 patients with COVID-19, 35,820
(5.0%) developed new-onset myocarditis and 10,706 (1.5%) developed new-onset
pericarditis. Compared to propensity-matched controls, patients who developed
myocarditis/pericarditis had higher proportions of comorbidities. Although not all variables
were statistically non-signi!cant, following PSM, the myocarditis (Table S1) and pericarditis
(Table S2) cohorts were deemed well-matched.
3.2 Myocarditis and COVID-19

Following PSM, six-month all-cause mortality was 3.9% (n = 702) in patients with COVID-19
who presented with myocarditis and 2.9% (n = 523) in the matched controls without
myocarditis (p < .0001), odds ratio 1.36 (95% CI: 1.21–1.53). Associated odds of
rehospitalisation (odds ratio 1.90 (95% CI 1.80–2.01) and acute myocardial infarction (odds
ratio 1.37 (95% CI 1.17–1.61) were also higher in the myocarditis cohort compared with
controls. Associated odds of cardiac arrest, incident heart failure and incident AF were not
signi!cantly di#erent between the myocarditis cohort and controls. Among subgroups,
mortality was higher in all except those aged < 45 years and those not hospitalised following
COVID-19 (Table 1).
TABLE 1. Six-month odds ratios (95% CI) for adverse events and cardiovascular sequalae in
patients with COVID-19–associated myocarditis, following propensity score matching
Cohort Sample Mortality Hospitalisation Cardiac Heart Atrial Acute

size arrest failure !brillation myocardial
infarction
Total 35,820 1.36 1.90 (1.80, 2.01) 1.09 0.96 0.95 (0.74, 1.37 (1.17,
(1.21, (0.82, (0.79, 1.21) 1.61)
1.53) 1.46) 1.18)
Female 20,194 1.41 1.74 (1.61, 1.88) 1.13 0.86 0.83 (0.56, 1.41 (1.11,
(1.18, (0.70, (0.62, 1.22) 1.80)
1.69) 1.83) 1.17)
Male 15,592 1.41 2.12 (1.96, 2.29) 1.00 1.03 0.91 (0.66, 1.36 (1.11,
(1.21, (0.70, (0.79, 1.24) 1.67)
1.64) 1.43) 1.35)
Age <45 20,774 1.19 1.50 (1.36, 1.62) 1.72 0.96 0.77 (0.37, 1.84 (1.32,
(0.85, (1.00, (0.62, 1.58) 3.00)
1.68) 2.94) 1.49)
Age 45–70 14,444 1.24 2.12 (1.95, 2.30) 1.22 0.80 0.85 (0.59, 1.33 (1.07,
(1.03, (0.79, (0.60, 1.20) 1.64)
1.49) 1.88) 1.08)
Age >70 5,556 1.49 2.31 (2.06, 2.59) 0.64 1.02 1.02 (0.70, 1.41 (1.86,
(1.26, (0.39, (0.74, 1.48) 1.82)
1.75) 1.06) 1.40)
Note
Myocarditis based on !rst instance recorded within EMRs within the 6-month period following a COVID-19 diagnosis.
Sample size is number of patients in analysis with and without myocarditis/pericarditis, following propensity score
matching. Propensity score matched for age, sex, race and comorbidities (hypertensive diseases, ischaemic heart
diseases, heart failure, cerebrovascular diseases, diabetes mellitus, chronic kidney disease, diseases of the respiratory
system, diseases of the digestive system and diseases of the nervous system).
3.3 Pericarditis and COVID-19

Following PSM, 6-month all-cause mortality was 15.5% (n = 816) in patients with COVID-19
who presented with new-onset pericarditis and 6.7% (n = 356) in the matched controls
without pericarditis (p < .0001), odds ratio 2.55 (95% CI: 2.24–2.91). Associated odds of
rehospitalisation, cardiac arrest, incident heart failure, incident AF and acute myocardial
infarction were also signi!cantly higher in the pericarditis cohort compared with controls.
Mortality was higher among all subgroups (Table 2).
TABLE 2. Six-month odds ratios (95% CI) for adverse events and cardiovascular sequalae in
patients with COVID-19–associated pericarditis, following propensity score matching
Cohort Sample Mortality Hospitalisation Cardiac Heart Atrial Acute

size arrest failure !brillation myocardial
infarction
Total 10,706 2.55 2.77 (2.55, 3.00) 2.94 2.90 2.50 (1.90, 2.22 (1.89,
(2.24, (2.18, (2.26, 3.20) 2.61)
2.91) 3.97) 3.71)
Female 5,282 2.39 2.75 (2.44, 3.09) 4.14 2.85 2.17, (1.50, 2.38 (1.87,
(1.97, (2.43, (1.97, 3.17) 3.04)
2.90) 7.06) 4.11)
Male 5,268 2.90 2.88 (2.57, 3.24) 2.53 3.67 2.02 (1.45, 2.06 (1.66,
(2.42, (1.75, (2.55, 2.82) 2.55)
3.47) 3.67) 5.29)
Age <45 2,210 2.75 3.81 (3.15, 4.61) 3.48 6.04 1.57 (0.70, 3.29 (1.92,
(1.82, (1.71, (3.05, 5.00) 5.62)
4.14) 7.07) 11.99)
Age 45–70 5,432 3.28 2.86 (2.55, 3.21) 3.35 4.21 2.78 (1.93, 2.23 (1.81,
(2.70, (2.22, (2.81, 3.99) 2.76)
3.98) 5.06) 6.33)
Age >70 3,420 2.24 2.06 (1.79, 2.38) 1.85 1.72 1.95 (1.33, 1.91 (1.47,
(1.83, (1.11, (1.17, 2.86) 2.49)
2.74) 3.09) 2.53)
Note
Pericarditis based on !rst instance recorded within EMRs within the 6-month period following a COVID-19 diagnosis.
Sample size is number of patients in analysis with and without myocarditis/pericarditis, following propensity score
matching. Propensity score matched for age, sex, race and comorbidities (hypertensive diseases, ischaemic heart
diseases, heart failure, cerebrovascular diseases, diabetes mellitus, chronic kidney disease, diseases of the respiratory
system, diseases of the digestive system and diseases of the nervous system).
Pneumonia and myocarditis/pericarditis (pre-COVID-19 analyses).
Of the total pneumonia cases (n = 128,939), 3.1% (n = 4012) developed myocarditis and 1.9%
(n = 2,497) developed pericarditis. Myocarditis was associated with signi!cantly higher odds
of rehospitalisation compared with controls. Pericarditis was associated with signi!cantly
higher odds for mortality, rehospitalisation, cardiac arrest, heart failure, AF and myocardial
infarction. The complete prevalence and outcome data for the pneumonia cohort are
presented in Table S3.
4 DISCUSSION
Collectively, this retrospective analysis represents the largest follow-up data set of its kind
for patients with COVID-19 and presentation of new-onset myocarditis or pericarditis. The
!ndings of the present study suggest that myocarditis and pericarditis in patients with
COVID-19 associate with signi!cantly increased odds of all-cause mortality, rehospitalisation
and acute myocardial infarction. Associated odds of cardiac arrest, incident heart failure and
incident AF were higher in patients with pericarditis compared with matched controls. In
contrast, associated odds of cardiac arrest, incident heart failure and incident AF were not
higher in patients with myocarditis compared to matched controls. Therefore, although new-
onset myocarditis was more prevalent (5.0%) than pericarditis (1.5%) in patients with COVID-
19, the latter seems to be associated with more substantial adverse events and
cardiovascular sequelae.
Previous work has demonstrated that in 222 non-COVID-19, biopsy-proven, viral myocarditis
cases, the rate of mortality was 19.2% in 4.7 years of follow-up.20 In a nationwide Danish
registry of nearly 8,000 patients with pericarditis, the absolute 5-year mortality was 7.1%
compared with 4.2% in matched controls without pericarditis.21 In the present study, results
demonstrate the associated odds of adverse events and cardiovascular sequelae between
COVID-19 patients with myocarditis/pericarditis and patients with COVID-19 only. Odds of
mortality were 1.90 (95% CI 1.80–2.01) and 2.55 (95% CI: 2.24–2.91) in patients with
myocarditis and pericarditis, respectively. Although this has not been previously
investigated, these !ndings are complimentary to that of Shi et al who demonstrated that
cardiac injury was common (19.7%) among 416 hospitalised patients with COVID-19 in
Wuhan, China.7 Moreover, patients with cardiac injury had higher mortality (51.2%) than
those without cardiac injury (4.5%; p < .001), and those who received intensive care were
more likely to have cardiac injury.
Although we did not investigate cardiac injury per se, we also found an increasing magnitude
of the odds of mortality associated with COVID-19 severity, measured by proxy from
hospitalisation records. Indeed, data suggested a dose-response, with 68% (1.40–2.00) and
195% (2.19–3.97) higher odds of all-cause mortality in COVID-19 patients with myocarditis
who were either hospitalised or received critical care, respectively. Moreover, there was no
increase in the odds of mortality in COVID-19 patients with myocarditis who were not
hospitalised with COVID-19 initially. Similarly, for COVID-19 patients with pericarditis, there
were increasing odds of all-cause mortality in patients who were not hospitalised,
hospitalised and received critical care following a COVID-19 diagnosis. Thus, the clinical
importance of new-onset myocarditis/pericarditis in patients with COVID-19 seems to be
dependent on the severity of initial viral infection.
In a cohort of German patients recently recovered from COVID-19, cardiac magnetic

resonance revealed ongoing myocardial in"ammation in 60 patients (60%), independent of
pre-existing conditions, severity, overall course of the acute illness and time from the
original diagnosis.6 This aligns with previous non-COVID-19 research that demonstrated
clinical presentation with congestive heart failure, ventricular tachycardia/ventricular
!brillation or AF/atrial "utter did not predict survival in patients with myocarditis.22 In
contrast and in the present study, patients who presented with new-onset
myocarditis/pericarditis had higher proportions of comorbidities including cardiovascular,
metabolic, nervous and digestive conditions. This is in keeping with a previous study
whereby patients with pre-existing cardiovascular diseases seemed to be more susceptible
to COVID-19–induced heart injury. Speci!cally, 30% and 60% of patients with cardiac injury
had a history of coronary heart disease and hypertension, respectively, which were
signi!cantly more prevalent than in those without cardiac injury.7
In a single case of COVID-19 in a young child, it was proposed that there was a direct e#ect
of the SARS-CoV-2 infection on cardiac tissue, which in this case was a major contributor to
the presentation of new-onset myocarditis and heart failure.23 This case, among others,24, 25
provides evidence that COVID-19 may be a multisystem in"ammatory syndrome,26 and as in
the present study, its cardiovascular sequelae present a signi!cant risk to health. It has been
proposed that the pathophysiology of viral myocarditis is a combination of direct cell injury
and T-lymphocyte–mediated cytotoxicity, which can be augmented by the cytokine storm
syndrome.27 Mechanisms for COVID-19–associated myocarditis/pericarditis may therefore
be similar, given that myocardial localisation of COVID-19 has been reported in a case study
of a 69 years old who received endomyocardial biopsy.28
4.1 Limitations
A number of limitations are noteworthy. First, the data were collected from healthcare
organisation EMR databases and some health conditions may be underreported. Indeed,
recording of ICD codes in administrative data sets may vary by factors such as age, number
of comorbidities, severity of illness, length of hospitalisation and whether in-hospital death
occurred.29 Speci!cally, the method of diagnosis of myocarditis/pericarditis from EMRs is
unknown. However, we have investigated the prevalence and clinical outcomes of
myocarditis and pericarditis following a pneumonia diagnosis in January-June 2019 (i.e. pre-
COVID-19), in order to verify associations with cardiovascular outcomes in the COVID-19
cohort. Findings revealed that of the total pneumonia cases (n = 128,939), 3.1% (n = 4012)
developed myocarditis and 1.9% (n = 2,497) developed pericarditis (lower, albeit not
dissimilar from prevalence in the COVID-19 cohort). In the pneumonia cohort, myocarditis
was associated with signi!cantly higher odds of rehospitalisation only, whereas pericarditis
associated with signi!cantly higher odds for all outcomes (mortality, hospitalisation, cardiac
arrest, heart failure, atrial !brillation and myocardial infarction; Table S3). This is largely
aligned with the higher odds of cardiovascular outcomes observed with pericarditis
compared with myocarditis in the COVID-19 cohort, presented in this paper. We could also
not determine the in"uence of attending di#erent healthcare organisations due to data
privacy restrictions. In addition, outcomes which occurred outside of the TriNetX network
are not well captured. Second, the data were from multiple healthcare organisations in the
United States but may not be representative of the wider population, thus the
generalisability of the results beyond this cohort is unclear. Third, longer follow-up time
periods (beyond 6 months) would be interesting, particularly for mortality and
cardiovascular disease outcomes. Fourth, immortal time bias needs to be considered when
interpreting rates of myocarditis and pericarditis in patients with COVID-19. It is possible that
the rates reported in this study are an underrepresentation of the true prevalence. Further,
our results should not be interpreted as causal; that is, it can only be interpreted that new-
onset myocarditis/pericarditis was associated with higher mortality rates seen in the present
study; we do not know if myocarditis/pericarditis are determinants, contributors or markers
of e#ect. Indeed, residual confounding may have impacted our results, including lifestyle
factors, socio-economic status and other health markers/conditions, which were not
available from EMRs. Subsequent prospective work is needed to further investigate the
cardiac involvement of COVID-19, especially in patients presenting with severe cases.
5 CONCLUSION
Findings from the present study suggest that COVID-19 patients who present with new-
onset myocarditis/pericarditis are associated with signi!cantly higher odds of all-cause
mortality, relative to patients with COVID-19 only. Further, the severity of COVID-19 seems to
be associated with more severe outcomes among patients with myocarditis and pericarditis.
Finally, although myocarditis was more prevalent, pericarditis seemed to be associated with
higher odds of mortality and new-onset cardiovascular sequelae (a !nding that we have
con!rmed in pre-COVID-19 pneumonia analyses). Therefore, the targeting of early
intervention and monitoring for patients with new-onset myocarditis/pericarditis following a
COVID-19 diagnosis should be considered for populations with pre-existing cardiovascular
disease and risk factors.
CONFLICTS OF INTEREST
Benjamin JR Buckley has received funding from Bristol-Myers Squibb (BMS)/P!zer. Stephanie
L Harrison has received funding from BMS. Elnara Fazio-Eynullayeva and Paula Underhill are
employees of TriNetX LLC. Deirdre A Lane has received investigator-initiated educational
grants from BMS, has been a speaker for Boehringer Ingeheim and BMS/P!zer and has
consulted for BMS, Boehringer Ingelheim and Daiichi-Sankyo. Gregory YH Lip: consultant for
Bayer/Janssen, BMS/P!zer, Medtronic, Boehringer Ingelheim, Novartis, Verseon and Daiichi-
Sankyo and speaker for Bayer, BMS/P!zer, Medtronic, Boehringer Ingelheim and Daiichi-
Sankyo. No fees are directly received personally.
CONSENT TO PARTICIPATE
Not applicable.
CONSENT FOR PUBLICATION

Not applicable.
CODE AVAILABILITY
Not applicable.
Supporting Information "

"
Filename Description
eci13679-sup-0001-TableS1.docx Word document, 16.1 KB Table S1
eci13679-sup-0002-TableS2.docx Word document, 16 KB Table S2
eci13679-sup-0003-TableS3.docx Word document, 14.3 KB Table S3
Please note: The publisher is not responsible for the content or functionality of any supporting
information supplied by the authors. Any queries (other than missing content) should be directed
to the corresponding author for the article.
REFERENCES '
'
Citing Literature '

'
Download PDF
About Wiley Online Library Help & Support Opportunities Connect with Wiley
Privacy Policy Contact Us Subscription Agents The Wiley Network
Terms of Use Training and Support Advertisers & Corporate Wiley Press Room
Partners
About Cookies DMCA & Reporting Piracy
Manage Cookies
Accessibility
Wiley Research DE&I

Statement and Publishing
Policies
Copyright © 1999-2022 John Wiley & Sons, Inc. All rights reserved
ADVERTISEMENT
AR09399
7
SCIENCE VOLUNTEER WARNING SIGNS Search # Advanced Search DONATE
Hello Guest!
MY ALERTS SIGN IN JOIN
OpenAthens/Shibboleth »
Submit your article ! "
AHA Journals +
+
Journal Information +
+
All Issues +
+
Subjects +
+
Features +
+
Resources & Education +
+
For Authors & Reviewers +
+
This site uses cookies. By continuing to browse this site you are agreeing to our use of cookies.
Click here for more information. ×
Home Hypertension Vol. 76, No. 4 Redefining Cardiac Biomarkers in Predicting Mortality of Inpatients With COVID-19
$$ $$ $$
* ) ( '
Details Related References Figures
% OPEN ACCESS Redefining Cardiac Biomarkers in Predicting Mortality of Inpatients With COVID-19
RESEARCH ARTICLE
Juan-Juan Qin, Xu Cheng, Feng Zhou, Fang Lei, Gauri Akolkar, Jingjing Cai, Xiao-Jing Zhang, Alice Blet, Jing Xie, Peng Zhang,
Ye-Mao Liu, Zizhen Huang, Ling-Ping Zhao, Lijin Lin, Meng Xia, Ming-Ming Chen, Xiaohui Song, Liangjie Bai, Ze Chen, Xingyuan Zhang,
& PDF/EPUB Da Xiang, Jing Chen, Qingbo Xu, Xinliang Ma, Rhian M. Touyz, Chen Gao, Haitao Wang, Liming Liu, Weiming Mao, … See all authors +
Originally published 14 Jul 2020 https://doi.org/10.1161/HYPERTENSIONAHA.120.15528 Hypertension. 2020;76:1104–1112
Other version(s) of this article +

, Tools - Share
Jump to Abstract
October 2020
Abstract Vol 76, Issue 4
Introduction
Methods Article Information

Results
Metrics
Discussion
Perspectives
Acknowledgments
Sources of Funding See more details
Disclosures Picked up by 1 news outlets

Tweeted by 2
Supplemental Materials
158 readers on Mendeley
Footnotes
Article Metrics View all metrics
References
Novelty and
Significance Downloads Citations
Supplementary
Materials
Download figure | Download PowerPoint
The prognostic power of circulating cardiac biomarkers, their utility, and pattern of release in coronavirus disease 2019
(COVID-19) patients have not been clearly defined. In this multicentered retrospective study, we enrolled 3219 patients
with diagnosed COVID-19 admitted to 9 hospitals from December 31, 2019 to March 4, 2020, to estimate the
associations and prognostic power of circulating cardiac injury markers with the poor outcomes of COVID-19. In the
mixed-effects Cox model, after adjusting for age, sex, and comorbidities, the adjusted hazard ratio of 28-day mortality
for hs-cTnI (high-sensitivity cardiac troponin I) was 7.12 ([95% CI, 4.60–11.03] P<0.001), (NT-pro)BNP (N-terminal pro-
B-type natriuretic peptide or brain natriuretic peptide) was 5.11 ([95% CI, 3.50–7.47] P<0.001), CK (creatine Total First 30 Days 6 Months 12 Months
phosphokinase)-MB was 4.86 ([95% CI, 3.33–7.09] P<0.001), MYO (myoglobin) was 4.50 ([95% CI, 3.18–6.36]
P<0.001), and CK was 3.56 ([95% CI, 2.53–5.02] P<0.001). The cutoffs of those cardiac biomarkers for effective
prognosis of 28-day mortality of COVID-19 were found to be much lower than for regular heart disease at about 19%–
50% of the currently recommended thresholds. Patients with elevated cardiac injury markers above the newly
established cutoffs were associated with significantly increased risk of COVID-19 death. In conclusion, cardiac
biomarker elevations are significantly associated with 28-day death in patients with COVID-19. The prognostic cutoff
values of these biomarkers might be much lower than the current reference standards. These findings can assist in
better management of COVID-19 patients to improve outcomes. Importantly, the newly established cutoff levels of
COVID-19–associated cardiac biomarkers may serve as useful criteria for the future prospective studies and clinical
trials.
Take notes, share and follow articles, make comments, and

collaborate with peers! DISCUSS ADD TO LIST FOLLOW SHARE COMMENT NOTE
Introduction
The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) infection has led to >11.8 million confirmed cases with >545 000 deaths worldwide by July 9, 2020.1
Patients with preexisting cardiovascular conditions are particularly at risk and have poor prognosis.2 With ACE2
(angiotensin-converting enzyme 2)—the binding and internalization receptor for SARS-COV23—being highly expressed
in the lung, heart, and the cardiovascular system, the heart is a target organ susceptible to viral and immune-mediated
injury.2,4,5 Emerging data suggest that cardiac injury, manifested by cardiac biomarker elevation, is detected in a
sizable of COVID-19 patients and is associated with adverse outcomes and increased mortality.6,7 However, how useful
cardiac biomarkers are in COVID-19 prognosis and how to utilize these markers have not been well defined. This study
aims to establish the role of cardiac-specific injury or stress biomarker and their precise association with COVID-19
mortality, to determine their use in prognostic evaluation of risk of death and to delineate the relationship of cardiac
biomarker rise with other inflammatory markers in patients diagnosed with COVID-19.
Methods
Data, Materials, and Code Disclosure Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Study Design and Participants

This retrospective multicenter cohort study enrolled patients diagnosed as COVID-19 and admitted to 9 hospitals in
Hubei Province, China, from December 31, 2019 to March 4, 2020. COVID-19 diagnosis was confirmed by at least one
or both criteria of chest computed tomography manifestations and reverse transcription–polymerase chain reaction
according to the New Coronavirus Pneumonia Prevention and Control Program (fifth edition) published by the National
Health Commission of China and World Health Organization interim guidance.8,9 The study design and procedures
were approved by the central ethics committees, and all collaborating hospitals either approved the study protocol by
local ethics committees or accepted the approval from the central ethics committee. Individual patient informed
consent was waived by each ethics committee of participating hospitals.
For the analysis regarding the associations between increased cardiac injury markers and the risk of all-cause death of
COVID-19, patients diagnosed with COVID-19 and having available high-sensitivity cardiac troponin I (hs-cTnI) or CK
(creatine phosphokinase)-MB on admission were enrolled in this study. Participants aged <18 or >75 years, without
complete electronic medical records due to transferring, or pregnant were excluded from the study. The primary end
point was 28-day all-cause mortality, and the time of hospital admission was designed as day 0. The increase of serum
myocardial marker levels and other biochemical markers was defined as above the upper limit of normal (ULN)
according to local hospital criteria. Heart injury status was defined as a serum level of hs-cTnI or CK-MB above the
ULN. Due to variations in the examining instruments, laboratory techniques, and regents, different ULNs were applied
at different hospital sites. To guarantee the accuracy and broad-based applicability, the levels of cardiac injury
biomarkers were normalized and analyzed as relative values to their local ULNs.
Data Collection
The demographic information, preexisting comorbidities, clinical characteristics, chest computed tomography
radiological data, laboratory data, and clinical outcomes were collected from electronic medical record data. Clinical
characteristics including heart rate, breath rate, fever, cough, and dyspnea at the time of admission were analyzed.
Laboratory measurements including neutrophil count, CRP (C-reactive protein), cardiac biomarkers (hs-cTnI, CK-MB,
NT-proBNP [N-terminal pro-B-type natriuretic peptide] or BNP [brain natriuretic peptide], MYO [myoglobin], and CK),
and inflammatory cytokine IL (interleukin)-6 at admission and during hospitalization were extracted and analyzed. The
unilateral and bilateral lung lesion status was obtained from computed tomography images. Personal identifiers of
included participants were first anonymized and replaced by study ID before data collection. All the clinical data were
individually reviewed and verified by a team of experienced physicians blinded to patient identification.
Statistical Analysis
Data in this study were analyzed using R-3.6.3 (R Foundation for Statistical Computing, Vienna, Austria) and SPSS
Statistics (version 23.0; IBM, Armonk, NY). Distribution of myocardial marker levels (normalized to ULN) by age and sex
was displayed using kernel density estimation. Dynamic change of myocardial marker levels in the cumulative
proportions of patients was created and smoothed by locally weighted regression and smoothing scatterplots. The
Akaike information criterion scores and P values were calculated by the univariate logistic regression analysis to
estimate the associations of variables with 28-day all-cause death of COVID-19 and were examined by the multivariate
Cox analysis to evaluate the quality of the model. A mixed-effects Cox model analysis was conducted to determine the
association between baseline myocardial marker levels and the risk of the primary end point of COVID-19 by treating
the site as a random effect. Hazard ratios (HRs) and 95% confidence interval (CI) were calculated in the mixed-effects
model. Multivariable adjustment included age, sex, and preexisting comorbid conditions (diabetes mellitus,
hypertension, coronary heart disease, and cerebrovascular disease). Kaplan-Meier method was applied to compare the
cumulative survival between participants with normal versus increased myocardial marker levels and between those
with myocardial marker levels under or above cutoffs. The receiver operating characteristic analysis was conducted to
assess the overall performances of increased levels of myocardial injury parameters for identification of the risk of
mortality in patients with COVID-19. The area under the receiver operating characteristic curve (AUC) was computed
for evaluating the performance of each marker level. A 2-sided α-error <0.05 was considered statistically significant.
Results
Participants and Clinical Characteristics
A total of 7106 participants diagnosed with COVID-19 admitted to 9 hospitals in Hubei Province, China, were recruited
initially in this study. Of these, 277 cases were excluded due to incomplete electronic medical records during
interhospital transfer, 767 patients were excluded due to age limitation of the study design (>75 or <18 years), and 29
cases were excluded due to pregnancy. In the remaining patients, 3219 participants had measured CK-MB or hs-cTnI
levels, while 2814 cases were not. The clinical symptoms, basic comorbidities, laboratory data, and outcomes of those
patients are shown in Table 1 and Table S1 in the Data Supplement. Compared with patients without cardiac injury
biomarker measurement, patients with biomarker values were older (median age, 57 [interquartile range, 45–66] versus
54 [interquartile range, 42–64] years) and had higher percentages of preexisting comorbidities and more severe
symptoms (Tables S1 and S2). The frequencies for increase of hs-cTnI, CK-MB, (NT-pro)BNP (BNP or NT-proBNP), CK,
and MYO were 6.5%, 5.1%, 12.9%, 12.1%, and 12.0% on admission among patients with available cardiac biomarker
values, respectively. The exact values and normal ranges of laboratory examinations in patients with and without
myocardial biomarker measurements are shown in Tables S2 and S3.
Table 1. Baseline Characteristics of Patients With COVID-19
Parameters With Biomarkers (n=3219) Without Biomarkers (n=2814) P Value
Age, y; median (IQR) 57 (45–66) 54 (42–64) <0.001
Men, n (%) 1535 (47.7) 1324 (47.1) 0.640
Women, n (%) 1684 (52.3) 1490 (53.0) 0.640
Heart rate, bpm; median (IQR) 84 (78–95) 80 (76–92) <0.001
Respiratory rate, bpm; median (IQR) 20 (19–21) 20 (18–21) 0.039
SBP>140, mmHg; n/N (%) 543/2753 (19.7) 358/2224 (16.1) 0.001
Fever, n (%) 2332 (72.4) 1970 (70.0) 0.039
Cough, n (%) 2118 (65.8) 1815 (64.5) 0.304
Dyspnea, n (%) 650 (20.2) 432 (15.4) <0.001
Comorbidities
Hypertension, n (%) 895 (27.8) 634 (22.5) <0.001
Diabetes mellitus, n (%) 413 (12.8) 256 (9.1) <0.001
Coronary heart disease, n (%) 206 (6.4) 100 (3.6) <0.001
Cerebrovascular disease, n (%) 74 (2.3) 37 (1.3) 0.006
Radiological characteristics
Unilateral lung lesion, n/N (%) 292/2995 (9.8) 298/2564 (11.6) 0.027
Bilateral lung lesion, n/N (%) 2558/2995 (85.4) 2057/2564 (80.2) <0.001
Laboratory examinations
Hs-cTnI increase, n/N (%) 95/1462 (6.5) … …
CK-MB increase, n/N (%) 158/3120 (5.1) … …
BNP or NT-proBNP increase, n/N (%) 213/1650 (12.9) 69/336 (20.5) <0.001
CK increase, n/N (%) 307/2534 (12.1) 61/645 (9.5) 0.070
MYO increase, n/N (%) 228/1895 (12.0) 9/57 (15.8) 0.516
BNP indicates brain natriuretic peptide; CK, creatine phosphokinase; COVID-19, coronavirus disease 2019; hs-cTnI,
high-sensitivity cardiac troponin I; IQR, interquartile range; MYO, myoglobin; NT-proBNP, N-terminal pro-B-type
natriuretic peptide; and SBP, systolic blood pressure.
The distribution of age- and sex-specific myocardial biomarker profiles relative to those of ULN at presentation were
analyzed and presented as kernel density plots (Figure S1). The age brackets were divided into 18 to 44, 45 to 59, and
60 to 75 years. The distributions of CK-MB, CK, and MYO showed higher levels in men than in women among all 3 age
brackets, while hs-cTnI and (NT-pro)BNP had comparable distributions between male and female patients at the time
of admission.
Association of Cardiac Biomarkers With 28-Day Mortality of COVID-19

To evaluate associations between outcomes of COVID-19 and covariates including cardiac injury markers, we
performed univariate logistic regression analysis where the Akaike Information Criterion and P values were calculated.
Notably, all 5 myocardial biomarkers (hs-cTnI, CK-MB, (NT-pro)BNP, CK, and MYO) were significantly associated with
28-day all-cause death of COVID-19 (Table S4).
To evaluate the association of each myocardial marker elevation above laboratory-defined ULN with the primary end
point of all-cause mortality at 28 days post-admission, we conducted a mixed-effects Cox model analysis using the
patient’s hospital site as a random effect. Multivariables adjustments included age, sex, and coexisting comorbidities
(hypertension, diabetes mellitus, coronary heart disease, and cerebrovascular disease). Adjusted HRs for associations
of 28-day all-cause mortality of COVID-19 with abnormally elevated hs-cTnI, CK-MB, NT-proBNP, CK, and MYO were
shown in Table 2, with 95% CI. Elevation of hs-cTnI exhibited the highest adjusted HR of 7.12 ([95% CI, 4.60–11.03]
P<0.001), followed by (NT-pro)BNP of 5.11 ([95% CI, 3.50–7.47] P<0.001), CK-MB of 4.86 ([95% CI, 3.33–7.09]
P<0.001), and MYO of 4.50 ([95% CI, 3.18–6.36] P<0.001). Total CK—a much less specific cardiac biomarker—had an
adjusted HR of 3.56 ([95% CI, 2.53–5.02] P<0.001).
Table 2. Association of Increased Cardiac Injury Markers Above the Upper Limit of Normal With 28-d All-Cause
Mortality of COVID-19
Crude Model 1
HR (95% CI) P Value HR (95% CI) P Value
Hs-cTnI 9.59 (6.36–14.47) <0.001 7.12 (4.60–11.03) <0.001
CK-MB 5.30 (3.71–7.59) <0.001 4.86 (3.33–7.09) <0.001
(NT-pro)BNP 5.62 (3.99–7.93) <0.001 5.11 (3.50–7.47) <0.001
CK 4.31 (3.13–5.92) <0.001 3.56 (2.53–5.02) <0.001
MYO 6.84 (4.95–9.45) <0.001 4.50 (3.18–6.36) <0.001
Model 1: Adjusted for age, sex, and coexisting diseases (diabetes mellitus, hypertension, coronary heart disease,
and cerebrovascular disease). CK indicates creatine phosphokinase; COVID-19, coronavirus disease 2019; HR,
hazard ratio; hs-cTnI, high-sensitivity cardiac troponin I; MYO, myoglobin; and (NT-pro)BNP, N-terminal pro-B-type
natriuretic peptide or brain natriuretic peptide.
Kaplan-Meier curves illustrated that patients with increased hs-cTnI, CK-MB, (NT-pro)BNP, CK, and MYO had
significantly decreased survival rate compared with those with normal levels (Figure 1). The Kaplan-Meier curves
demonstrated an early separation of the mortality curves between patients showing elevated admission biomarker
values above ULN, versus those having normal values, underscoring the rapid onset of death among the high-risk
group of COVID-19 patients. This was particularly prominent for cardiac-specific biomarkers, such as hs-cTnI, CK-MB,
and (NT-pro)BNP.

Figure 1. Survival profiles of COVID-19 patients stratified according to cardiac biomarkers. Kaplan-Meier curves
showing cumulative survival of coronavirus disease 2019 (COVID-19) patients with increased or normal levels of
high-sensitivity cardiac troponin I (hs-cTnI; A), CK (creatine phosphokinase)-MB (B), (NT-pro)BNP (N-terminal pro-
B-type natriuretic peptide or brain natriuretic peptide; C), MYO (myoglobin; D), and CK (E) during a 28-d follow-
up. The increase of myocardial marker represents level above the upper limit of normal (ULN). HR indicates
hazard ratio.
Compared with patients without available myocardial biomarkers, patients with measured cardiac injury markers had
higher incidences of 28-day all-cause death and the occurrences of Acute Respiratory Distress Syndrome, heart
failure, disseminated intravascular coagulation (DIC), sepsis, or multiorgan failure and acute renal failure (Table S5).
However, there were no significant differences in the main causes of death between these 2 subcohorts (Table S6).
These data suggested that heart injury markers might sensitively respond to SARS-CoV-2 infection or infection-related
outcomes.
Prognostic Performance of Cardiac Injury Biomarkers in Predicting 28-Day All-Cause Mortality of COVID-19
To compare the relative accuracy, sensitivity, specificity, and positive and negative predictive values of each biomarker
based on laboratory-defined ULN, the prognostic performance of each marker was analyzed. The receiver operating
characteristic curve was used to demonstrate the ability of each cardiac biomarker in discrimination of high risk of
COVID-19 mortality, which was quantitated as AUC. Increase of MYO—an early release biomarker of cardiac injury—
showed the highest overall performance (AUC, 0.83 [95% CI, 0.80–0.86]) to predict the risk of COVID-19 mortality,
followed by (NT-pro)BNP (AUC, 0.81 [95% CI, 0.78–0.85]), hs-cTnI (AUC, 0.78 [95% CI, 0.73–0.84]), and CK-MB (AUC,
0.71 [95% CI, 0.67–0.75]). CK had the lowest performance (AUC, 0.67 [95% CI, 0.62–0.72]; Table 3; Figure S2). It is
useful to note that the overall negative predictive values are uniformly high for any of these biomarkers, at over 96% for
all of those evaluated.
The standard laboratory cutoff value of ULN is usually defined as the 99th upper percentile of biomarker distribution in
the normal population. However, our data indicated that the operational cutoff based on the biomarker distribution and
receiver operating characteristic performance curve should be redefined for each of the biomarkers to enhance the
prognostic sensitivity of the biomarkers. Indeed, the operational cutoff values of hs-cTnI, CK-MB, (NT-pro)BNP, CK,
and MYO for COVID-19 mortality prediction were markedly lower, calculated at 49.0%, 49.1%, 18.9%, 44.8%, and
49.8% of their respective ULNs. Notably, using these cutoff values of each myocardial marker in this risk prediction
model improved the balanced accuracy versus using the currently recommended ULN values (0.77 versus 0.66 for hs-
cTnI, 0.66 versus 0.59 for CK-MB, 0.75 versus 0.66 for (NT-pro)BNP, 0.75 versus 0.69 for MYO, and 0.64 versus 0.63
for CK) than using the current ULN values defined in the laboratory (Table 3; Table S7).
Accordingly, patients with biomarker levels above each recalibrated cutoff were at a significantly higher risk of 28-day
all-cause mortality of COVID-19, compared with those under the cutoff points (Figure S3). After adjusted for age, sex,
and comorbidities in the mixed-effects Cox model and treated hospital site as a random effect, patients with elevated
myocardial biomarkers over the new cutoffs were at a significantly higher risk of mortality than those having biomarker
levels under cutoff values with adjusted HR of 10.68 ([95% CI, 6.87–16.59] P<0.001) for hs-cTnI, 3.63 ([95% CI, 2.60–
5.06] P<0.001) for CK-MB, 12.01([95% CI, 6.39–22.58] P<0.001) for (NT-pro)BNP, 2.7 ([95% CI, 1.92–3.81] P<0.001) for
CK, and 5.00 ([95% CI, 3.37–7.42] P<0.001) for MYO (Table S8).
To address the potential selection bias, we further adjusted for the imbalanced variables related to disease severity
(CRP increase, neutrophil count increase, lymphocyte count decrease, D-dimer increase, and SpO2 <95%) between
patients with or without increased heart injury markers above cutoff values in the mixed-effects Cox model. The results
showed that the increased hs-cTnI (adjusted HR, 4.74 [95% CI, 3.05–7.35]; P<0.001), CK-MB (adjusted HR, 2.17 [95%
CI, 1.56–3.01]; P<0.001), CK (adjusted HR, 1.80 [95% CI, 1.28–2.53]; P<0.001), (NT-pro)BNP (adjusted HR, 5.67 [95%
CI, 2.97–10.82]; P<0.001), and MYO (adjusted HR, 2.74 [95% CI, 1.82–4.13]; P<0.001) were still significantly
associated with higher risk of all-cause mortality of COVID-19 (Table S8). The Akaike information criterion values of the
crude and adjusted analysis model were shown in Table S9, among which the model adjusted for age, sex, and
comorbidities had relatively low Akaike information criterion values for each myocardial marker.
We further performed a subgroup sensitivity analysis using patients in site 1, site 2, site 3, and site 6, where a relatively
high percentage of patients had CK-MB or hs-cTnI measured (70.0% in site 1 and site 2, 82.8% in site 3, and 68.3% in
site 6). In the mixed-effects Cox model, after adjusting for age, sex, and coexisting comorbidities, the significant
associations between increased cardiac injury biomarkers and a higher risk of COVID-19 mortality were still maintained
with adjusted HR of 4.42 ([95% CI, 2.74–7.13] P<0.001) for hs-cTnI, 2.98 ([95% CI, 1.94–4.59] P<0.001) for CK-MB,
5.46 ([95% CI, 2.55–11.73] P<0.001) for (NT-pro)BNP, 1.57 ([95% CI, 1.00–2.45] P=0.048) for CK, and 2.92 ([95% CI,
1.76–4.85] P<0.001) for MYO.
In another sensitivity analysis, we excluded patients with acute myocardial infarction to mitigate heart disease history-
related potential confounders. After adjusting for age, sex, and comorbidities, the increased CK-MB (adjusted HR, 4.39
[95% CI, 2.94–6.56]; P<0.001), hs-cTnI (adjusted HR, 6.95 [95% CI, 4.48–10.8]; P<0.001), CK (adjusted HR, 3.45 [95%
CI, 2.43–4.90]; P<0.001), (NT-pro)BNP (adjusted HR, 4.88 [95% CI, 3.31–7.20]; P<0.001), and MYO (adjusted HR, 4.20
[95% CI, 2.94–6.00]; P<0.001) remained to be significantly associated with higher risk of all-cause mortality of COVID-
19 in this subcohort.
More importantly, the patients with cardiac biomarker levels ranging from the newly established cutoffs to laboratory
reference ULNs still showed significantly lower percentage survival than those with marker levels below the newly
established cutoff values (Figure 2). The adjusted HRs for 28-day all-cause death of patients with cardiac biomarker
between cutoffs and ULNs were 8.54 ([95% CI, 4.99–14.63] P<0.001) for hs-cTnI, 2.87 ([95% CI, 1.99–4.14] P<0.001)
for CK-MB, 8.70 ([95% CI, 4.50–16.82] P<0.001) for (NT-pro)BNP, 3.55 ([95% CI, 2.20–5.73] P<0.001) for MYO, and
1.71 ([95% CI, 1.14–2.58] P=0.009) for CK compared with those with marker levels below cutoffs (Table 4). This means
patients with even borderline levels of biomarker (between ULN and the newly established cutoffs) as defined by our
current study might still have a higher risk of 28-day mortality.
Table 3. Overall Performance of Cardiac Biomarkers for Predicting COVID-19 Mortality According to Receiver
Operating Characteristic Curves
(NT-
Parameters Hs-cTnI CK-MB CK MYO CRP D-Dimer
pro)BNP
n 1462 3120 1650 2534 1895 1489 1913
Mortality 98 178 133 163 148 123 154
0.78 (0.73– 0.71 (0.67– 0.81 (0.78– 0.67 (0.62– 0.83 (0.80– 0.81 (0.77– 0.81 (0.77–
AUC (95% CI)
0.84) 0.75) 0.85) 0.72) 0.86) 0.85) 0.84)
Cutoff (relative
0.490 0.491 0.189 0.448 0.498 6.545 1.126
to ULN)
89.19 71.19 61.45 64.25 75.57 67.49 72.45

Accuracy, %
(87.49– (69.56– (59.06– (62.34– (73.57– (65.05– (70.39–
(95% CI)
90.74) 72.77) 63.81) 66.11) 77.49) 69.87) 74.44)
Sensitivity, % 63.27 60.67 91.73 64.42 75.00 81.30 74.68
Specificity, % 91.06 71.82 58.80 64.24 75.62 66.25 72.26
PPV 0.34 0.12 0.16 0.11 0.21 0.18 0.19
NPV 0.97 0.97 0.99 0.96 0.97 0.98 0.97
Balanced
0.77 0.66 0.75 0.64 0.75 0.74 0.73
accuracy
AUC indicates area under the receiver operating characteristic curves; CK, creatine phosphokinase; COVID-19,
coronavirus disease 2019; CRP, C-reactive protein; hs-cTnI, high-sensitivity cardiac troponin I; MYO, myoglobin;
NPV, negative predictive value; (NT-pro)BNP, N-terminal pro-B-type natriuretic peptide or brain natriuretic peptide;
PPV, positive predictive value; and ULN, upper limit of normal.
Table 4. Association of Cardiac Injury Markers With 28-d All-Cause Mortality of COVID-19 in Patients Divided by
Cutoffs and Upper Limit of Normal
Crude Model 1
HR (95% CI) P Value HR (95% CI) P Value
Hs-cTnI
≤Cutoff Reference Reference
Cutoff−ULN 11.33 (6.84–18.77) <0.001 8.54 (4.99–14.63) <0.001
>ULN 15.50 (9.76–24.61) <0.001 12.85 (7.79–21.19) <0.001
CK-MB
Cutoff−ULN 2.67 (1.92–3.72) <0.001 2.87 (1.99–4.14) <0.001
>ULN 7.72 (5.20–11.46) <0.001 6.81 (4.40–10.54) <0.001
(NT-pro)BNP
Cutoff−ULN 10.47 (5.52–19.83) <0.001 8.70 (4.50–16.82) <0.001
>ULN 24.94 (13.07–47.59) <0.001 22.72 (11.38–45.36) <0.001
CK
Cutoff−ULN 1.80 (1.22–2.66) 0.003 1.71 (1.14–2.58) 0.009
>ULN 5.35 (3.73–7.68) <0.001 4.79 (3.18–7.22) <0.001
MYO
Cutoff−ULN 4.53 (2.91–7.04) <0.001 3.55 (2.20–5.73) <0.001
>ULN 11.49 (7.73–17.07) <0.001 7.12 (4.60–11.02) <0.001
Model 1: Adjusted for age, sex, and coexisting diseases (diabetes mellitus, hypertension, coronary heart disease,
and cerebrovascular disease). CK indicates creatine phosphokinase; COVID-19, coronavirus disease 2019; HR,
hazard ratio; hs-cTnI, high-sensitivity cardiac troponin I; MYO, myoglobin; (NT-pro)BNP, N-terminal pro-B-type
natriuretic peptide or brain natriuretic peptide; and ULN, upper limit of normal.

Figure 2. The percentage survival of patients with cardiac biomarker levels under cutoffs, between cutoffs and
upper limits of normal (ULNs), and above ULNs of high-sensitivity cardiac troponin I (hs-cTnI; A), CK (creatine
phosphokinase)-MB; B), (NT-pro)BNP (N-terminal pro-B-type natriuretic peptide or brain natriuretic peptide); C),
MYO (myoglobin; D), and CK (E). HR indicates hazard ratio.
Overall, we found the number of patients showing biomarkers above the newly established cutoff values but below the
laboratory-defined ULNs at admission were 89 for hs-cTnI, 779 for CK-MB, 533 for (NT-pro)BNP, 308 for MYO, and 646
for CK (Figure 2). These data revealed that the prevalence of cardiac injury might be substantially underestimated by
the current laboratory-defined ULN values.
Trajectory Patterns of Cardiac Biomarkers and Inflammatory Factor Elevation in Patients With COVID-19
To further demonstrate the mechanistic cause of cardiac injury in COVID-19 patients, we determined the temporal
relationship of cardiac biomarker elevation with that of the inflammatory markers over time, we analyzed the cumulative
proportions of patients with increased cardiac biomarkers in association with inflammatory factors of CRP, neutrophil
count, and IL-6 elevation during the entire study period. This was based on the laboratory-defined ULN and analyzed
from time of symptom onset (day 0) to the end of follow-up, as illustrated in Figure S4.
Among the patients without signs of heart injury (defined by having elevated hs-cTnI or CK-MB above their ULN), the
increases of inflammatory markers were lower and slower than those with heart injury (Figure S4A). In patients showing
heart injury during the entire hospitalization, neutrophil percentage and CRP were rapidly and simultaneously increased
after disease onset, immediately followed by the increases of CK-MB, MYO, and hs-cTnI. In contrast, the significant
elevation of IL-6 occurred only after the increases of these myocardial markers and was highly elevated mainly in
patients with evidence of cardiac injury (Figure S4A).
We further divided patients into poor outcome and favorable outcome groups according to the occurrence of death,
intensive care unit treatment, and mechanical ventilation from admission to the end of follow-up, where patients with
any one of the above events were classified as in poor outcome and patients without any of the above events were in
favorable outcome group. The temporal patterns of myocardial biomarkers and inflammatory factors were
cosegregated between these 2 groups (Figure S4B). Compared with patients with favorable outcomes, the increases of
neutrophil percentage and CRP showed sharper slope in patients with poor outcome. The proportion of patients with
increased hs-cTnI was significantly higher in the poor outcome than in the favorable outcome group. Patients with
minimum levels of (NT-pro)BNP had overall a much more favorable outcome. Notably, the elevation of serum IL-6 level
was highly prognostic of poor outcome and followed slightly behind cardiac biomarker elevation such as hs-cTnI in
patients with poor outcome. In contrast, the increase of IL-6 was significantly delayed and blunted in amplitude in
those with favorable outcome (Figure S4B). Furthermore, the magnitudes of the inductions in both myocardial markers
and inflammatory factors were higher in the poor outcome patients than in the ones with favorable outcome (Figure
S5).
The increased inflammatory marker (CRP) and coagulation marker (D-dimer) levels were also significantly associated
with an increased risk of 28-day all-cause mortality of COVID-19 and had interactive effects with cardiac injury markers
in predicting the poor outcomes of COVID-19 (Table 3; Table S10).
Discussion
This retrospective study is a comprehensive evaluation of serum cardiac biomarkers with respect to 28-day all-cause
mortality of COVID-19. We demonstrated that elevations of biomarkers such as hs-cTnI, CK-MB, (NT-pro)BNP, or MYO
based on reference laboratory normal cutoff values were highly prognostic of 28-day all-cause mortality, including
deaths occurring soon after admission. However, standard cutoff values currently used for diagnosis likely
underestimated the true extent of cardiac injury. The newly established cutoffs in our study for COVID-19 prognosis
were much lower than the currently accepted laboratory cutoff thresholds (by about 50%). Dynamic pattern of cardiac
biomarker elevation showed their onset coincided with CRP and neutrophil elevation but preceded the elevation of IL-
6.
These findings are consistent with earlier reports that cardiac injury biomarkers are associated with an increased risk of
COVID-19 mortality.7,10 Elevated levels of cardiac troponin I and (NT-pro)BNP, CK-MB, and MYO are also associated
with more severe symptoms and disease progression.11–14 Our larger sample size helped to better define and to
improve the performance characteristics of these biomarkers for COVID-19, which manifest with widely divergent
outcomes from full recovery to rapid death. The cardiac-specific biomarkers, such as hs-cTnI, CK-MB, and (NT-
pro)BNP, generally have better performance than nonspecific markers such as CK. The lower levels of newly
established cutoff values of cardiac injury markers further suggest that the currently used laboratory ULNs for these
markers, based on the 99 percentiles of distribution in a normal population, might significantly underestimate the
extent of cardiac injury associated with COVID-19.
The ULNs of cardiac injury markers are primarily established and extensively recognized for diagnosis of the severity of
the cardiac injury and thus would have the satisfactory performance for predicting the prognosis of patients with
cardiovascular diseases. Therefore, it is interesting that outcomes from COVID-19—a disease associated primarily with
the lung—are also well predicted by cardiac biomarkers. While the inherent limitation of a retrospective study makes it
impossible to demonstrate the causal effect of increased cardiac injury markers with COVID-19 death, the performance
of these markers for predicting COVID-19 prognosis may indicate pathological impact of SARS-CoV-2 infection or the
infection-related pathogenesis on myocardium. In consistence with this hypothesis, Angeli et al found a wide spectrum
of ECG abnormalities during hospitalization, including persistent ST-T changes, atrial fibrillation, and brady-tachy
syndrome, in a prospective study containing 50 inpatients with COVID-19. Among those with abnormal
electrocardiogram performance, 38% of them were recorded with abnormal serum levels of hs-cTnI.15
Heart injury may likely involve multiple mechanisms, including primary injury from SARS-COV-2 infection and indirect
injury from the imbalanced immune response with dominant macrophage and neutrophil effects. This can be
augmented further by systemic or cardiac hypoxemia and microangiopathy and microthormbi.2 ACE2—the functional
receptor and a portal of entry for both SARS-COV and SARS-COV-2—is highly expressed in the heart and
vasculature.3,16,17 Previous studies indicated that SARS-COV is detectable in the heart of infected patients18 and ACE2
expression is downregulated after coronavirus infection, leading to excessive activation of the renin-angiotensin-
aldosterone system, which can further exacerbate myocardial injury.19,20 The link between SARS-COV-2 and ACE2
provides a possible mechanism that SARS-COV-2 binds to ACE2 expressed on cardiomyocytes/fibroblasts and
induces ACE2 downregulation and renin-angiotensin-aldosterone system dysfunction, which in turn leads to heart
dysfunction and pneumonia progression. Our most recent study indicated that inpatients using ACE inhibitors or
angiotensin II receptor blockers are at significantly lower risk of 28-day all-cause death compared with nonusers in
patients with hypertension hospitalized with COVID-19.21 Autopsy analysis of hearts from COVID-19 patients
suggested a potential involvement of systematic inflammation in heart injury.22 However, there are, so far, no data
directly demonstrating the presence of SARS-CoV-2 within myocardial tissue or the direct influence of renin-
angiotensin-aldosterone system inhibitors on heart injury in COVID-19 patients.
There are several limitations of our study. First, the inherent limitations of retrospective studies make it impossible to
determine whether cardiac injury is the causal effect on the prognosis of COVID-19. Second, the cutoffs of cardiac
injury markers in predicting COVID-19 outcomes were established based on a Chinese population, which will require
further external validations from other independent cohorts. Third, in the urgent circumstances during the COVID-19
pandemic, not all markers and examinations (eg, electrocardiogram, ultrasound computed tomography and magnetic
resonance imaging) related to heart injury were fully performed and collected during the entire hospitalization period
from all participants. The incomplete data collection in multiple sites might lead to confounding effects on the
magnitude of the association between cardiac injury markers and COVID-19 prognosis and the predicting performance
of those markers for COVID-19 death. Fourth, because of the limited sample size, it is unknown whether those
myocardial markers are also effective in predicting the outcomes of COVID-19 in patients with different complications
or comorbidities. Fifth, as all participants involved in this study were inpatients, findings in this study might not be fully
applicable to all individuals in the general population infected with SARS-COV-2, such as outpatients in isolation sites
or community. Sixth, there might be selection bias of the study subjects because myocardial markers may be
examined more frequently in patients with suspected heart injury or with signs of cardiovascular diseases than in the
general patient population. The imbalanced history of heart failure, the time point of admission, and the availability of
medical resources might also introduce confounding factors into our conclusion. Thus, associations between cardiac
biomarkers and COVID-19 mortality and the exact cutoffs of those markers for COVID-19 prognosis with adequate
sensitivity and specificity in the whole patient population need to be further investigated in large-scale general
population and in the rigorously designed prospective studies and randomized controlled trials.
In conclusion, the abnormal cardiac biomarker pattern in COVID-19 patients was significantly associated with
increased mortality risk, and the newly established COVID-19 prognostic cutoff values of hs-cTnI, CK-MB, (NT-
pro)BNP, CK, and MYO were found to be much lower (≈50%) than reference upper normal limits for the general
population. It is clinically meaningful that the fluctuating levels of myocardial biomarkers should be intensively
monitored, and patients with elevated levels of those biomarkers should be intervened timely to improve the prognosis
of COVID-19. Our findings support additional prospective studies and randomized controlled clinical trials to accurately
validate the risk thresholds and exact impact of myocardial injury for individuals with COVID-19.
Perspectives
To properly evaluate patients with COVID-19 at admission, the cutoff threshold of abnormality for hs-cTnI, CK-MB, (NT-
pro)BNP, CK, and MYO at admission should be lower than the currently recommended laboratory range. Using
standard reference laboratory cutoffs might underestimate the extent of cardiac injury. Measurement of cardiac-
specific biomarkers and proper interpretation on admission can help to identify COVID-19 patients with a high-risk
trajectory. The elevations can help to provide references for the management, monitoring, and enrollment for
prospective studies and randomized controlled clinical trials.
Acknowledgments
J.-J. Qin, X. Cheng, F. Zhou, and F. Lei designed the study, collected and analyzed data, and wrote the manuscript. G.
Akolkar, J. Cai, X.-J. Zhang, and A. Blet designed the study and wrote the manuscript. J. Xie, P. Zhang, Z. Huang, L.-P.
Zhao, L. Lin, M. Xia, M.-M. Chen, X. Song, L. Bai, Z. Chen, X. Zhang, and D. Xiang collected and reviewed clinical,
laboratory, and radiological data. Y.-M. Liu and J. Chen performed the statistical analysis. Q. Xu, X. Ma, R.M. Touyz, C.
Gao, and Z.-G. She edited the manuscript and provided valuable suggestions for the study design and data analysis.
H. Wang, L. Liu, W. Mao, P. Luo, Y. Yan, P. Ye, M. Chen, G. Chen, L. Zhu, X. Huang, B.-H. Zhang, and Y. Yan reviewed,
interpreted, and checked clinical data. Y. Wang, P.P. Liu, and H. Li contributed equally, designed the project, edited the
manuscript, and supervised the study. All authors have approved the final version of this article.
Sources of Funding
None.
Disclosures
None.
Supplemental Materials
Online Tables I–X
Online Figures I–V
Footnotes
This paper was sent to Theodore A. Kotchen, Guest Editor, for review by expert referees, editorial decision, and final
disposition.
*These authors contributed equally to this work.

The Data Supplement is available with this article at
AR09400 https://www.ahajournals.org/doi/suppl/10.1161/HYPERTENSIONAHA.120.15528.
Correspondence to: Peter P. Liu, Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute,
40 Ruskin St, Ottawa, Ontario K1Y 4W7, Canada, Email peter.liu@utoronto.ca or pliu@ottawaheart.ca
Yibin Wang, Department of Anesthesiology, Cardiovascular Research Laboratories, David Geffen School of Medicine,
University of California, Los Angeles, CA, Email yibinwang@mednet.ucla.edu
Hongliang Li, Department of Cardiology, Zhongnan Hospital of Wuhan University, Institute of Model Animal of Wuhan
University, 169 Donghu Rd, Wuhan 430071, China, Email lihl@whu.edu.cn
References
1.1 World Health Organization. Coronavirus disease (COVID-2019) situation reports. Coronavirus Disease (COVID-
2019) Situation Reports. 2020;2020. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-
reports. World Health Organization, Geneva. Google Scholar
2.1 Liu PP, Blet A, Smyth D, Li H. The science underlying COVID-19: implications for the cardiovascular system.
Circulation. 2020; 142:68–78. doi: 10.1161/CIRCULATIONAHA.120.047549 Link | Google Scholar
3.1 Wu F, Zhao S, Yu B, Chen Y-M, Wang W, Song Z-G, Hu Y, Tao Z-W, Tian J-H, Pei Y-Y, et al.. A new coronavirus
associated with human respiratory disease in China. Nature. 2020; 579:265–269. doi: 10.1038/s41586-020-2008-3
Crossref | Medline | Google Scholar
4.1 Akhmerov A, Marbán E. COVID-19 and the heart. Circ Res. 2020; 126:1443–1455. doi:
10.1161/CIRCRESAHA.120.317055 Link | Google Scholar
5.1 Gallagher PE, Ferrario CM, Tallant EA. Regulation of ACE2 in cardiac myocytes and fibroblasts. Am J Physiol
Heart Circ Physiol. 2008; 295:H2373–H2379. doi: 10.1152/ajpheart.00426.2008 Crossref | Medline | Google Scholar
6.1 Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, Gong W, Liu X, Liang J, Zhao Q, et al.. Association of cardiac injury with
mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol. 2020;5:802-810. doi:
10.1001/jamacardio.2020.0950 Medline | Google Scholar
7.1 Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, Wang H, Wan J, Wang X, Lu Z. Cardiovascular implications of fatal
outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020;5:1-8. doi:
10.1001/jamacardio.2020.1017 Google Scholar
8.1 World Health Organization. Laboratory Testing for 2019 Novel Coronavirus (2019-nCoV) in Suspected Human
Cases Interim Guidance. 2020. https://www.who.int/publications-detail/laboratory-testing-for-2019-novel-
coronavirus-in-suspected-human-cases. World Health Organization, Geneva. Google Scholar
9.1 National Health Commission of China. New Coronavirus Pneumonia Prevention and Control Program. 2020.
http://www.nhc.gov.cn/: National Health Commission of China. Beijing, China. Google Scholar
10.1 Zheng YY, Ma YT, Zhang JY, Xie X. Reply to: ‘interaction between RAAS inhibitors and ACE2 in the context of
COVID-19’. Nat Rev Cardiol. 2020; 17:313–314. doi: 10.1038/s41569-020-0369-9
11.1 Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, et al.. Clinical characteristics of
138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020; 323:1061–
1069. doi: 10.1001/jama.2020.1585 Crossref | Medline | Google Scholar
12.1 Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, et al.. Clinical course and risk factors for
mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet (London, England).
2020; 395:1054–1062. doi: 10.1016/S0140-6736(20)30566-3 Crossref | Medline | Google Scholar
13.1 Arentz M, Yim E, Klaff L, Lokhandwala S, Riedo FX, Chong M, Lee M. Characteristics and outcomes of 21
critically ill patients with COVID-19 in Washington state. JAMA. 2020; 323:1612–1614. doi: 10.1001/jama.2020.4326
14.1 Han H, Xie L, Liu R, Yang J, Liu F, Wu K, Chen L, Hou W, Feng Y, Zhu C. Analysis of heart injury laboratory
parameters in 273 COVID-19 patients in one hospital in Wuhan, China. J Med Virol. 2020; 92:819–823. doi:
10.1002/jmv.25809 Crossref | Medline | Google Scholar
15.1 Angeli F, Spanevello A, De Ponti R, Visca D, Marazzato J, Palmiotto G, Feci D, Reboldi G, Fabbri LM, Verdecchia
P. Electrocardiographic features of patients with COVID-19 pneumonia. Eur J Intern Med. 2020. doi:
10.1016/j.ejim.2020.06.015 Crossref | Google Scholar
16.1 Patel VB, Zhong JC, Grant MB, Oudit GY. Role of the ACE2/angiotensin 1-7 axis of the renin-angiotensin system
in heart failure. Circ Res. 2016; 118:1313–1326. doi: 10.1161/CIRCRESAHA.116.307708 Link | Google Scholar
17.1 Zhong J, Basu R, Guo D, Chow FL, Byrns S, Schuster M, Loibner H, Wang XH, Penninger JM, Kassiri Z, et al..
Angiotensin-converting enzyme 2 suppresses pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction.
Circulation. 2010; 122:717–28, 18 p following 728. doi: 10.1161/CIRCULATIONAHA.110.955369
Link | Google Scholar
18.1 Tang JW, To KF, Lo AW, Sung JJ, Ng HK, Chan PK. Quantitative temporal-spatial distribution of severe acute
respiratory syndrome-associated coronavirus (SARS-CoV) in post-mortem tissues. J Med Virol. 2007; 79:1245–1253.
doi: 10.1002/jmv.20873 Crossref | Medline | Google Scholar
19.1 Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang P, Zhang Y, Deng W, et al.. A crucial role of
angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005; 11:875–879. doi:
10.1038/nm1267 Crossref | Medline | Google Scholar
20.1 Oudit GY, Kassiri Z, Jiang C, Liu PP, Poutanen SM, Penninger JM, Butany J. SARS-coronavirus modulation of
myocardial ACE2 expression and inflammation in patients with SARS. Eur J Clin Invest. 2009; 39:618–625. doi:
10.1111/j.1365-2362.2009.02153.x Crossref | Medline | Google Scholar
21.1 Zhang P, Zhu L, Cai J, Lei F, Qin JJ, Xie J, Liu YM, Zhao YC, Huang X, Lin L, et al.. Association of inpatient use of
angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with
hypertension hospitalized with COVID-19. Circ Res. 2020; 126:1671–1681. doi: 10.1161/CIRCRESAHA.120.317134
Link | Google Scholar
22.1 Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, Liu S, Zhao P, Liu H, Zhu L, et al.. Pathological findings of
COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020; 8:420–422. doi:
10.1016/S2213-2600(20)30076-X Crossref | Medline | Google Scholar
Novelty and Significance

What Is New?
Heart injury is one of the major complications in patients with coronavirus disease 2019 (COVID-19).
However, the prognostic power of cardiac biomarkers, their utility, and pattern of release in COVID-19 patients
have not been clearly defined.
What Is Relevant?
This multicentered retrospective cohort study involving 3219 patients demonstrated that hazard ratios for
admission cardiac biomarkers such as high-sensitivity cardiac troponin I, CK (creatine phosphokinase)-MB, or
(NT-pro)BNP (N-terminal pro-B-type natriuretic peptide or brain natriuretic peptide) for 28-d mortality is high at
between 4 and 7 folds.
The established cutoff values of each cardiac biomarker to predict the risk of COVID-19 mortality are actually
much lower than standard reference laboratory cutoffs by being about 50% lower.
Trajectory analysis showed cardiac injury biomarkers are elevated early in course of disease, being parallel to
CRP (C-reactive protein) and neutrophil rise, but precedes rise in IL (interleukin)-6 and predicts mortality,
ventilator use, and intensive care unit admission.
Summary
To properly prognosticate patients with COVID-19 at admission, the cutoff threshold of abnormality for high-sensitivity
cardiac troponin I, CK-MB, (NT-pro)BNP, CK, and MYO (myoglobin) was analyzed as about 50% lower for most of the
markers. Using standard reference laboratory cutoffs might underestimate the extent of cardiac injury. Admission
cardiac biomarkers are sensitively prognostic for impending mortality in COVID-19. Their elevation tracks CRP and
neutrophil rise but precedes IL-6 elevation. Measurement of cardiac-specific biomarkers and proper interpretation on
admission can help to identify COVID-19 patients with a high-risk trajectory. The elevations provide support to guide
management, monitoring, and enrollment into prospective studies and randomized controlled clinical trials.
Previous 2 Back to top Next
AHA Journals
Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB) Circ: Cardiovascular Interventions Journal of the American Heart Association (JAHA)
Circulation Circ: Cardiovascular Quality & Outcomes Stroke

Hypertension Circ: Arrhythmia and Electrophysiology Circ: Heart Failure Stroke: Vascular and Interventional Neurology
Circ: Genomic and Precision Medicine Circulation Research AIM: Clinical Cases
Circ: Cardiovascular Imaging Hypertension
Journal Information Subjects Features Resources & Education For Authors & Reviewers
About All Subjects Acknowledgment of Reviewers AHA Guidelines and Statements Instructions for Authors
Editorial Board Arrhythmia and Electrophysiology Clinical-Pathological Conferences Scientific Councils Submission Site
Meet the Editors Basic, Translational, and Clinical Controversies in Hypertension Information for Advertisers Author Reprints
Research
Reprints Editors' Picks Instructions to Reviewers
Critical Care and Resuscitation
Customer Service and Ordering Guidelines Debate
Information Epidemiology, Lifestyle, and
Prevention Meeting Abstracts
AHA Journals RSS Feeds
Genetics Recent Advances in Hypertension
For International Users
Heart Failure and Cardiac Disease
Institutions/Librarians FAQ
Hypertension
For Subscribers
Imaging and Diagnostic Testing
Subscriber Help
Intervention, Surgery, Transplantation
Wolters Kluwer Privacy Policy
Quality and Outcomes
Stroke
Vascular Disease
ABOUT US OUR SITES TAKE ACTION ONLINE COMMUNITIES

About the AHA/ASA $ American Heart Association $ Advocate $ AFib Support $
2016-17 Annual Report $ American Stroke Association $ Donate $ Garden Community $
AHA Financial Information $ Professional Heart Daily $ Planned Giving $ Patient Support Network $
Careers $ More Sites $ Volunteer $
SHOP $
National Center
7272 Greenville Ave. Latest Heart and Stroke News $
Dallas, TX 75231
AHA/ASA Media Newsroom $
Customer Service
Global Programs $
1-800-AHA-USA-1
1-800-242-8721
Local Info
Contact Us
Follow Us: " ! . / 0
Privacy Policy Copyright Ethics Policy Conflict of Interest Policy Linking Policy Diversity Careers Suppliers & Providers Accessibility Statement
State Fundraising Notices

© American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. The American Heart Association is qualified 501(c)(3) tax-exempt organization.
*Red Dress ™ DHHS, Go Red ™; AHA; National Wear Red Day ® is registered trademark.
AR09401
TAB 61
AR09402
FEDERAL COURT
BETWEEN:
NABIL BEN NAOUM
demandeur
- and -
dèfendeur
AND BETWEEN:
demandeur
- and -
dèfendeur
AR09403
DR. PETER LIU - 104
AND BETWEEN:

MACDONALD
Applicants
- and -

Respondent
AND BETWEEN:
Applicants
- and -

Respondent
--------------------------------------------------------
This is the Continued-Examination of DR. PETER
LIU, on behalf of the Attorney General of Canada
herein, taken via Videoconference for Network Reporting
& Mediation, on the 2nd day of June, 2022.
--------------------------------------------------------

AR09404
DR. PETER LIU - 105

MAHAN KERAMATI
JAMES ELFORD
ROBERT DRUMMOND

EVA CHIPIUK
ALLISON PEJOVIC
ALSO PRESENT:

PATRICK ABBOTT
SAYAH HASSAN
HENNA PARMAR
ANDRE MEMAURI
CYNTHIA MURPHY
CHRIS NAIMI

AR09405
DR. PETER LIU - 106
DR. PETER LIU, Previously Affirmed .................... 107
EXAMINATION BY MS. PEJOVIC: ........................... 107
L I S T O F E X H I B I T S
--- EXHIBIT NO. 8: Annals of Internal Medicine: A
Longitudinal Study of COVID-19 Sequelae and Immunity:
Baseline Findings. .................................... 157
--- EXHIBIT NO. 9: CDC: MMWR study, Block et al. ..... 160
--- EXHIBIT NO. 10: Drug and Vaccine Authorizations for
COVID-19: List of authorized drugs, vaccines and expanded
indications. .........................................165
--- EXHIBIT NO. 11: Truong: Circulationaha. .......... 171
--- EXHIBIT NO. 12: Choi Study. .....................206
--- EXHIBIT NO. 13: Autopsy Histopathologic Cardiac
Findings into Adolescents Following the Second COVID-19
Vaccine Dose, James Gill. ............................. 221

AR09406
DR. PETER LIU - 107
1 --- UPON COMMENCING AT 10:35 A.M.
2 DR. PETER LIU, Previously Affirmed
3 EXAMINATION BY MS. PEJOVIC:
4 284. Q. Okay. Good morning, Dr. Liu.
5 A. Good morning.
6 285. Q. So, yesterday we left off with a
7 discussion of Section 3 of your expert report, and
8 today we're going to start off discussing Section 4.
9 And before we begin, I just want to confirm that you
10 did not speak with anyone about this Cross-Examination
11 since we last spoke yesterday.
12 A. No, no.
13 286. Q. Okay. So, you have in your expert
14 report in Section 4, relied on the Block et al
15 Morbidity and Mortality Weekly report from April 1 of
16 2021 as the best study to date, comparing the risks
17 arising from COVID-19 myocarditis versus COVID-19
18 vaccine induced myocarditis, is that fair?
19 A. Yes, it's 2022.
20 287. Q. Oh.
21 A. April 1, 2022.
22 288. Q. Okay, 2022, thank you. And can you
23 pull that study up?
24 A. Okay.
25 289. Q. Did I e-mail that to you or you have

AR09407
DR. PETER LIU - 108
1 that one handy?
2 A. I don't believe it was included in the
3 e-mail unless it's by -- who is the author?
4 290. Q. You know what, that's okay.
5 A. It's a Block, is it.
6 291. Q. I'm just going to put it on my screen.
7 That's fine.
8 A. Okay. Yeah, I think it's the first
9 name is Block, Jason Block, MMWR, yeah.
10 MS. TELLES-LANGDON: Dr. Liu, do you have
11 access to that?
12 THE DEPONENT: Yes, I have it in my kind of
13 set of documents I refer to.
14 BY MR. PEJOVIC:
15 292. Q. Can you see it now, I've just shared
16 it.
17 MS. TELLES-LANGDON: It's going to be bigger
18 than that, Alison.
20 MS. TELLES-LANGDON: It's half screen at the
21 moment.
23 THE DEPONENT: Yeah, I have a very old eyes,
24 yeah.
25

AR09408
DR. PETER LIU - 109
1 BY MR. PEJOVIC:
2 293. Q. Can you see that now?
3 A. Yeah, and I have a copy on my monitor
4 as well, yeah.
5 294. Q. Oh, all right.
6 A. Yeah, so go ahead, yeah.
7 295. Q. Okay. All right, so this is called
8 Cardiac Complications after SARS-CoV-2 Infection and
9 mRNA COVID-19 Vaccination PCORnet, United States,
10 January 2021 to January 2022. And this is a Centre
11 Board for Disease Control and Prevention MMWR,
12 Morbidity and Mortality Weekly Report.
13 All right. So, now, Dr. Liu, this is not a
14 peer reviewed study, is it?
15 A. It's internally peer reviewed by the
16 CDC internal scientists, you know, MMWR is really the
17 trusted information that's actually put out by CDC. I
18 think most physicians really use this information to
19 guide their practice.
20 And it is not kind of a broadly external
21 review, but CDC has really some of the world's best
22 scientists, you know, in terms of communicable
23 diseases, yeah.
24 296. Q. Okay. But as you said, it hasn't been
25 externally reviewed.

AR09409
DR. PETER LIU - 110
1 A. Yes, that's right. Yeah, but all MMWR
2 documents has to be internally peer reviewed. And of
3 course, you know, ultimately approved by the Director
4 General, yeah.
5 297. Q. And you said that -- you said earlier
6 that the incidence of myocarditis occurs to a
7 significantly greater extent after two doses of the
8 COVID-19 vaccine in the young male category, correct?
9 A. Yes, the mRNA vaccine, yeah, mRNA
10 vaccine, yes.
11 298. Q. And this study, just for the record,
12 looked at people who were admitted to a hospital with
13 SARS-CoV-2 infection who coded for myocarditis, and
14 people who were admitted to hospital with COVID-19
15 vaccine induced myocarditis, who were coded for that
16 as well.
17 A. Yes.
18 299. Q. And tried to assess the risks of both.
19 A. Yes.
20 300. Q. Is that fair to characterize it like
21 that?
22 A. Yes, so this is, you know, from the
23 electronic health record of 40 major health systems
24 across the US.
25 301. Q. Okay. And this study used cohorts

AR09410
DR. PETER LIU - 111
1 using EHR data among persons over five and an
2 infection cohort was defined as someone over five who
3 received a positive SARS-CoV-2 molecular or antigen
4 test, correct?
5 A. Yes.
6 302. Q. And Dr. Liu, I understand that you are
7 not -- we've established you're not a virologist, and
8 I'm guessing you're not a microbiologist either. But
9 since we are discussing the study, I'm just going to
10 ask you a couple of questions about this case
11 definition.
12 Isn't it true that someone can test
13 positives for COVID-19 on one of these PCR or antigen
14 tests, but be asymptomatic, as in they never had
15 showed symptoms?
16 A. Yes. So, particularly with the recent,
17 you know, virus, yeah, you know, the variant. But not
18 the earlier variants, yeah.
19 303. Q. Not the earlier variant?
20 A. Yeah. You know, so if we talk about
21 waves, right, in terms of the different waves of and
22 so, you know, much less frequently in the first wave
23 and much more frequently in the recent wave.
24 304. Q. And ---
25 A. Because of the virus has changed.

AR09411
DR. PETER LIU - 112
1 Yeah, the virus has changed.
2 305. Q. Okay. I wouldn't agree with that, but
3 I'll keep going. Isn't it true also that someone can
4 test positive for COVID-19 with one of these molecular
5 or antigen tests weeks and up to three months after
6 they had an active infection?
7 A. Yes. They may have fragments of the
8 virus still being around, yeah, but they may not be
9 infected in that sense.
10 306. Q. But they'd still test positive?
11 A. They can test positive, yes.
12 307. Q. So, from this definition of infection,
13 we don't really know whether these patients ever had
14 active infections with SARS-CoV-2, do we, we don't
15 know that?
16 A. There is no better way to know, right.
17 So, you know ---
18 308. Q. Well, they're ---
19 A. So, that's the best tools we have. And
20 the SARS-CoV-2 molecular testing is the standard, you
21 know, by which we actually decide whether a case is
22 positive or negative. You know, we use it for our own
23 patients, our own staff, for our own studies.
24 No test, just like what we talked about
25 yesterday, no test is perfect, and so, but it's the

AR09412
DR. PETER LIU - 113
1 best we have, and it's awfully good.
2 309. Q. But I would suggest to you that the
3 better way is a PCR or antigen test in conjunction
4 with the clinical evaluation by a physician, correct?
5 A. Yes, but I think just to mention that,
6 you know, they can be asymptomatic in certain stages.
7 310. Q. Well, that's true, but there's no
8 indication from this study that there was a clinical
9 evaluation of these patients and that they presented
10 with symptoms of SARS-CoV-2, correct?
11 A. I don't know for sure. You know, they
12 are in a hospital record, right. You know, they are
13 entered into HER, right, and so, how, you know, so I
14 wouldn't know precisely every patient.
15 But, you know, the fact that the patient is
16 actually entered into the hospital record as having a
17 test done, you know, so unless patients are just
18 curious.
19 But they won't be entered into it, you know,
20 because it's not -- you know, because for our antigen
21 testing, you know, right, if you actually get it at a
22 community centre, your name is not entering into a
23 hospital record.
24 311. Q. These patients could have been in the
25 hospital for diabetes or a pre-existing hypertension

AR09413
DR. PETER LIU - 114
1 or pre-existing condition with a positive PCR test,
2 correct?
3 A. Yes, that's possible, yes.
4 312. Q. Right. They could have had
5 comorbidities, but this study doesn't say that does
6 it, it doesn't tell us whether they had comorbidities
7 or whether they didn't.
8 A. Yeah. So, I'm sure the data is in
9 there, yeah, but that's not the focus of this
10 particular publication, yes. But you're right, yeah,
11 because the nice thing is that this is the totality of
12 the patient information, right?
13 So, that's the nice thing. And it's not,
14 you know, selected, you know, so that because it's
15 represented the total health record from 15 million
16 people, right. So, that's a really rich database to
17 study from.
18 313. Q. And the study states that the case
19 definition of myocarditis was ICD code based, but
20 nowhere in this study does it say that the diagnosis
21 of myocarditis was confirmed with an EKG or an MRI,
22 which is what you told me yesterday, is the typical
23 way to start out diagnosing myocarditis.
24 It doesn't say that anywhere that these
25 tests were done, does it?

AR09414
DR. PETER LIU - 115
1 A. Yeah. So, I think this then kind of
2 skips that stage, right. You know, so the thing is
3 that ultimately someone decided that the patient had a
4 myocarditis, right. And so, usually that will be a
5 physician and to put that code in the system.
6 And then we rely on the physician, you know,
7 to use that criteria to determine, right, because they
8 will not draw a conclusion marked by somebody just
9 came in with a cold or something like that.
10 So, the ICD-10 code, which is the standard,
11 you know, sort of disease classification. And, you
12 know, we usually, you know, that's how we code, you
13 know, the diagnosis in our EHR system, you know, based
14 on the best knowledge of the physician.
15 So, and usually physicians are very good in
16 making the right diagnosis.
17 314. Q. Okay. And on page six, I've
18 highlighted a section, and this is in a section of
19 limitations. There's no heading of limitations, but
20 earlier paragraphs here, these findings and there's
21 reports are subject to six limitations. And this is
22 listed as number four,
23 "...Case definitions for myocarditis,
24 pericarditis or MIS were ICD-10-CM code based.
25 Diagnoses were not confirmed with chart review and are

AR09415
DR. PETER LIU - 116
1 subject to misclassification..."
2 See that, Dr. Liu?
3 A. Yes. ICD codes are not accurate 100
4 per cent because, you know, physicians are not
5 perfect, but physicians from our experience are
6 awfully good.
7 315. Q. Yeah, but you don't -- you can't say
8 that the physicians out of all of these hospitals for
9 this study were good or diligent or did things
10 properly, can you?
11 A. I have no reason to think otherwise
12 either. You know, these are my colleagues, right?
13 316. Q. Well, these are -- these are -- there's
14 a -- I don't know how many hospitals that is, but it's
15 quite a few hospitals on page one of this report in
16 the starred section. Oh, that's 40, 40 PCORnet sites.
17 So, there's a lot of different people, you'd
18 agree, that are entering these codes, and we have no
19 idea on what basis they entered the code for
20 myocarditis, correct?
21 A. So, I don't know if you know about
22 PCORnet or not, you know. So, that's actually a
23 fairly selective, very high level institutions, you
24 know, that actually work together to link information
25 in order to have the ability to understand disease

AR09416
DR. PETER LIU - 117
1 changes, understand disease processes.
2 And, you know, so these are not your rural,
3 you know, hospitals in tiny town, you know. So, this
4 is a very major set of institutions that decide to
5 pull their data together, you know, for this purpose.
6 And so, there's a certain level of standard
7 when people search and to say that they don't, you
8 know, to imply that they make errors on diagnosis, I
9 think we should be very careful in terms of making
10 that kind of conclusion.
11 317. Q. My point is, though, Dr. Liu, that on
12 the basis of this study, there is no data to show us
13 on what basis they made those diagnoses.
14 A. It's based on ICD-10, which is the
15 final conclusion. If I'm seeing a patient and I've
16 discharged the patient, I put down the diagnosis, why
17 the patient was in hospital, what are all the
18 conditions, that's the ICD-10 code that I put down.
19 318. Q. Right, but the study itself, the
20 authors themselves say this diagnosis of myocarditis
21 is subject to misclassification. They actually say
22 that.
23 A. Oh, we always do that, right. As I
24 mentioned, you know, when we are actually publishing
25 anything, any responsible researcher will always put

AR09417
DR. PETER LIU - 118
1 down all the limitations, right, because no study is
2 perfect.
3 And that's the routine. It doesn't mean
4 that it's faulty, right, but, you know, we as honest
5 individuals will always put down those. It's a
6 standard routine, right. We always have a limitation
7 section. The reviewers wants it, the editors wants
8 it.
9 It doesn't mean that those are, you know,
10 means that invalidate the study, right, but this is
11 just all the good practice for good research and
12 because no study is ever perfect, you know, so we
13 always want to make sure that these things are in
14 there.
15 It doesn't mean that it invalidates the
16 study, right, because that is the value, the quality
17 of the research that we do.
18 319. Q. If you could go to or look at the
19 second page here with me, Dr. Liu. Now, talking about
20 here ---
21 MS. TELLES-LANGDON: Sorry, Ms. Pejovic, is
22 it possible for you to make it any larger?
23 MS. PEJOVIC: Is that better?
24 MS. TELLES-LANGDON: That's a little bit
25 better.

AR09418
DR. PETER LIU - 119
1 MS. PEJOVIC: It's really huge on my screen.
2 MS. TELLES-LANGDON: I see.
3 MS. PEJOVIC: I almost can't read it now.
4 BY MR. PEJOVIC:
5 320. Q. Okay, so we're on page two, and we are
6 in the first paragraph on the left hand side for the
7 record. And I have highlighted the section here that
8 starts with vaccine doses specifically coded as
9 booster or extra doses were excluded.
10 So, isn't it true, Dr. Liu, that some
11 people, and we're focusing on young males in respect
12 of the results of this study, so I'll say, isn't it
13 possible that some young males could have had a
14 booster dose and myocarditis from the vaccine, but
15 they wouldn't be included in this study?
16 It's possible to get myocarditis after a
17 booster, isn't it, Dr. Liu?
18 A. Yes, it is. But the commonest scenario
19 is on the second dose.
20 321. Q. Right. Okay, and the second sentence
21 here that I've highlighted,
22 "...persons with a positive SARS-CoV-2 test
23 results less than 30 days before receipt of an mRNA
24 COVID-19 vaccine were excluded from the vaccine
25 cohorts..."

AR09419
DR. PETER LIU - 120
1 Dr. Liu, are you aware of research and I
2 believe Dr. Bridle, Byron Bridle has talked about this
3 in his expert report, but I'm not expecting you to
4 have read that, but I'm asking you, are you aware of
5 research that shows that people who have recovered
6 from SARS-CoV-2 and then receive a mRNA COVID-19
7 vaccine are more likely to have myocarditis, are you
8 aware of that?
9 A. Yeah. So, what's the scenario. So,
10 you have -- because you're not supposed to get the
11 vaccine in that setting.
12 322. Q. Well, they're excluding people.
13 A. Yeah, because that is not standard
14 practice, right, and so, let me just imagine scenario.
15 So, you are -- you have a positive SARS-CoV-2 test and
16 then you got a vaccine?
17 323. Q. Yes.
18 A. Yeah, and within 30 days, right?
19 324. Q. Yes.
20 A. Yeah, which is not the recommended
21 practice. Yeah, so I have not seen that, but, you
22 know, nothing is impossible in medicine, so.
23 325. Q. Right. Well, it must have happened,
24 though, because they've basically said those people
25 were excluded.

AR09420
DR. PETER LIU - 121
1 A. Yeah, so they may have somebody who may
2 have received the vaccine and then subsequently, you
3 know, found out that was actually a positive, you
4 know, sort of a COVID test, right. And so then, that
5 is not the recommended practice, right? So, I think
6 in that situation, they probably exclude because it is
7 non-standard or it's really not recommended practice.
8 326. Q. So, my point ---
9 A. So it will contaminate the study.
10 327. Q. My point -- sorry. I'll let you
11 finish. But the point is that there could be cases of
12 myocarditis from the vaccine because the vaccine was
13 given after a positive -- after someone had recovered
14 from SARS-CoV-2 that didn't make it into the study.
15 They were excluded.
16 So, we're missing those numbers.
17 A. Yeah, also, there's another reason,
18 right, because then in that case, you have no idea
19 whether that's SARS-CoV-2 myocarditis versus the
20 vaccine myocarditis. Right, so because ---
21 328. Q. Yeah, that's fair but ---
22 A. Yeah, two diseases taking place at the
23 same time, yeah. But it's a very, you know, I'm sure
24 there were just very few cases because it's not one,
25 you know, the medical practice, two, is that it

AR09421
DR. PETER LIU - 122
1 probably makes the interpretation of data
2 challengeable, right. So, I think that's why they
3 also ---
4 329. Q. And then the second part of that, it
5 says,
6 "...persons who had received an mRNA COVID-
7 19 vaccine dose less than 30 days before a positive
8 SARS-CoV-2 test result were excluded from the
9 infection cohort..."
10 Again, isn't it true, Dr. Liu, that this
11 study has excluded people who could have myocarditis
12 from the vaccine and then tested positive for SARS-
13 CoV-2, which could be a lingering positive test from a
14 previous infection?
15 They're missing those people where the
16 myocarditis was actually from the vaccine and they
17 just tested positive for SARS within that 30 days?
18 A. Yeah, so that's the reason you don't
19 get vaccine during that time, right, because you don't
20 know whether patient recovered or not. And then, you
21 know, if they do have myocarditis, then you wouldn't
22 know whether it's due to whether it's due to the CoV2
23 or -- sorry, or whether it's due to the COVID-19 or
24 it's actually due to the vaccine, right.
25 330. Q. So basically, we're missing a group of

AR09422
DR. PETER LIU - 123
1 people here.
2 A. This will be tiny, I can, you know,
3 like how many patients ---
4 331. Q. Well, you don't know that. You don't
5 know that.
6 A. Yeah, we don't know that, yeah, but the
7 thing is that this is not standard practice if that's
8 not happened, right. You know, so I think this is,
9 again, one of these typical good study cautionary
10 strategies, right.
11 So, most people would not even think of
12 this, but a good set of researchers will be able to
13 actually think through to say, you know, that this is
14 just what we call the robust inclusion criteria.
15 332. Q. But the bottom line is we have no
16 number of how many of those people were excluded.
17 A. Yeah, I would not know offhand. I
18 don't know whether it's in the supplement anywhere,
19 so, you know, of course they have the data, right.
20 But I don't have that information.
21 When you look at 15 million, you know,
22 people, I don't think this will substantially affect
23 the result.
24 333. Q. But we don't know the number. I think
25 we've agreed on that.

AR09423
DR. PETER LIU - 124
1 A. I don't know the exact number, but my
2 confidence in terms of, you know, the results, you
3 know, is not going to be affected by this because it's
4 not standard practice. And I certainly don't know of
5 any patients that actually have this situation.
6 334. Q. All right. So, let's go down to the
7 bottom paragraph on page two. On the left hand side,
8 it starts with,
9 "...Incidences of three cardiac outcomes;
10 myocarditis, myocarditis or pericarditis and
11 myocarditis, pericarditis or MIS were defined using
12 International Classification of Diseases, 10th
13 Revision, Clinical Modification, ICD-10-CM diagnostic
14 codes within seven day or 21 day risk windows after
15 the index date. Persons who had received any of these
16 diagnoses during the year preceding the index date
17 were excluded..."
18 So, basically that saying that there's a
19 seven day or 21 day risk window. Can you just explain
20 what that means, Dr. Liu?
21 A. Yeah, so I think they want to make sure
22 that, you know, the event of the myocarditis or you
23 know, the myocarditis or Missy is actually potentially
24 related to the condition that we are referring to, you
25 know, whether that's COVID-19 or that's mRNA vaccine.

AR09424
DR. PETER LIU - 125
1 So, they want to make sure that there's a
2 temporal relationship, and so that, you know, that you
3 can say, you know, either testing positive for COVID-
4 19 took place, and, you know, and then, you know,
5 there's a follow up period in which then myocarditis
6 took place.
7 Then you know it's temporary related, right.
8 But if it's the other way around or is outside that
9 window, then you could, you know, sort of attribute
10 any causal relationship.
11 335. Q. But isn't it possible, Dr. Liu, that
12 somebody who was vaccinated with a COVID-19 vaccine
13 could develop myocarditis after that window and they
14 wouldn't be caught in the study, would they?
15 A. Yeah. So, that's always possible, as I
16 mentioned, sort of anything is possible in medicine,
17 but whether that's probable, that's a different
18 matter. You know, certainly all this publication to
19 date suggests after the bulk of the myocarditis
20 actually take place as early as two days, and majority
21 are presented within four days.
22 And in fact, many cases already resolved by
23 seven days, yeah. So, you know, if you actually look
24 at some of the curves of the papers that we discussed
25 yesterday, you know, in terms of the presentation, you

AR09425
DR. PETER LIU - 126
1 know, so generally, within seven days, almost no
2 further cases are identified, yeah.
3 So, it's very interesting that the
4 myocarditis cases occur very soon after the
5 vaccination and not, you know, sort of days or months
6 afterwards, or anything like that.
7 336. Q. And isn't it true, Dr. Liu, that this
8 study could be subject to under reporting of COVID-19
9 vaccine induced myocarditis cases, such as was found
10 in the Oster study and in your Chouchana study?
11 A. Oh, so this is the advantage of this
12 study, right, and versus the other studies. The other
13 studies were called volunteer based reporting. You
14 know, remember, we mentioned that there can be under
15 reporting because of, you know, sort of administrative
16 barriers or, you know, sort of, you know, the
17 reporting system, you know, not necessarily being able
18 to capture all the cases, you know, because it's
19 voluntary reporting.
20 So, the nice aspect about this is that this
21 captures all the data of 15 million people, you know,
22 all the EHR, you know, so that any medical event, you
23 know, for those patients, they are in the system
24 because they are part of the care by those system.
25 You know, just like in Ontario, we're part

AR09426
DR. PETER LIU - 127
1 of OHIP and anytime I visit a hospital, they will
2 capture it for whatever reason. So, this is, the nice
3 thing is that it doesn't depend on this volunteer
4 bias, you know, which is the thing that we worry about
5 or volunteer leakage.
6 But the nice thing is that, you know, every
7 event has been captured and they can account for, you
8 know, every vaccine that's delivered, every case of
9 myocarditis, at least, you know, that's reported
10 according to the code and, you know, through other
11 conditions, as well.
12 You know, as long as this was a medical
13 event and that has been registered in the system, is
14 there. So, you know, the nice thing, the reason I
15 like this study is because of the fact that it
16 captures the data in its completeness and that it
17 doesn't depend on, you know, any voluntary action,
18 right?
19 So, as long as a patient had an encounter,
20 as long as a patient had a vaccination, as long as a
21 patient had a diagnosis of myocarditis deemed by the
22 caring physician, they are in the system and there's
23 no way, you know, to escape, yeah. So, you're
24 captured in that system, yeah.
25 337. Q. And Dr. Liu, if we go back to the date

AR09427
DR. PETER LIU - 128
1 of this study, this study looked at myocarditis data
2 from infection, COVID-19 infection, and from the
3 vaccine from January 1st of 2021 to January 31st --
4 no, sorry. What was the last date?
5 A. Yes, that's right, yes, January 31st,
6 2022.
7 338. Q. Twenty twenty-two.
8 A. Yes.
9 339. Q. Okay. So, isn't it true then, that
10 we're actually comparing apples and oranges with these
11 data sets because people were getting myocarditis from
12 COVID-19 infection since COVID began, and that would
13 include the period starting January 1st of 2021 and
14 beyond.
15 However, as you said yesterday and in your
16 expert report, the reports of myocarditis from the
17 vaccine didn't start until April and May of 2021
18 because people weren't being vaccinated in large
19 numbers until well past January 1st of 2021.
20 So, basically, there's a five month gap from
21 when these cases of myocarditis from infection started
22 -- were accumulating for the purposes of this study,
23 where there weren't any vaccine cases of myocarditis
24 because they didn't start until people were vaccinated
25 and they weren't vaccinated.

AR09428
DR. PETER LIU - 129
1 So, my question is, isn't this data flawed
2 for the reason being that people weren't being
3 vaccinated and showing myocarditis from the vaccine
4 until April and May of 2021?
5 A. Okay, that's very interesting how you
6 interpret this data, because I interpreted actually in
7 a completely different fashion. The reason I like
8 this paper is really actually very, very well thought
9 out.
10 And the reason for this is that you are able
11 to do the study during that window because of the
12 following. One is that we know SARS-CoV-2 or COVID-19
13 started earlier, right. And so that you actually
14 within this data set, you have a period in which you
15 have patients exposed to the virus, developed
16 myocarditis actually without chance of being
17 contaminated by the vaccine.
18 You know, remember, we've kind of talked
19 about, you know, in terms, you know, we may actually
20 have some confusion on some cases there, right? And
21 so that's exactly right, right?
22 So, the nice thing is that you actually
23 contain this study kind of three very valuable, you
24 know, data sets, all within one study.
25 So, one is, in fact, exactly right. And so

AR09429
DR. PETER LIU - 130
1 that is that the period from January to April, for
2 example, in 2021, in which you have a huge data set of
3 people coming in with SARS-CoV-2 or COVID-19, and
4 their myocarditis will be attributed very cleanly to
5 their COVID-19 infection, right?
6 So, that's the beauty, in that you actually
7 have a bulk of data which is not contaminated with the
8 vaccine, which then, you know, can lead to some
9 confusion, as you pointed out.
10 But then, you have a period in which you
11 have vaccinated patients, and so this is, let's say
12 we, just for illustration, say from April to August,
13 and so, this is during, like, our third wave, right.
14 And but you have the vaccine in large
15 numbers. So, this then introduced this new population
16 of patients, you know, who can potentially develop a
17 vaccine use myocarditis. But that is not actually the
18 most valuable component.
19 The most valuable component to me will be
20 actually the period from September to December, you
21 know, sort of the last part. And the reason for that
22 is that, you know, just as we talked about yesterday,
23 you know, a lot of events and things like that were in
24 older patients, especially in the early phases, right?
25 And so, we don't have actually as much data

AR09430
DR. PETER LIU - 131
1 on the young folks because then, you know, that's kind
2 of the population I know you are particularly
3 interested in.
4 So, the nice thing is that including that
5 September to December period, which you know, wasn't
6 included in the other study, is that the variance, I
7 know you may not agree with this, but you know the
8 variant actually has changed, right.
9 And so that it's beginning to actually
10 affect younger people. And so this is why you begin
11 to actually have data on younger folks. And so, then
12 you will actually be in a situation to be able to look
13 at the vaccine induced myocarditis, you know, which is
14 taking place and the younger people are getting more
15 vaccine as well throughout that period, as well as the
16 fact that the virus is affecting more younger people.
17 So, that you actually don't have a
18 population you can directly compare. And that's why
19 this data is particularly valuable, because you then
20 have the younger population, right, you know, with
21 myocarditis due to either cause and for direct
22 comparison, you know, because previously you're right,
23 so a lot of studies earlier affect the older folks and
24 the myocarditis in older folks.
25 And then vaccination, you know, didn't take

AR09431
DR. PETER LIU - 132
1 place too much in the younger folks until latter part
2 of the year. And so, yeah, so absolutely, so this is
3 particularly valuable because all those three
4 components allow you to really, you know, sort of be
5 able to examine the question much more authority.
6 And that's why, you know, from design point
7 of view, I thought this is actually a very, very
8 thoughtful design from that point of view.
9 340. Q. Dr. Liu, from January until April or
10 May of 2021, there were no reports of COVID-19 induced
11 vaccination -- COVID-19 vaccination induced
12 myocarditis for the purposes of this study.
13 A. Yeah, so that's the beauty, right? So
14 that's a nice thing. You actually have a block of
15 patients who only can have virus induced the
16 myocarditis, right. So, that's the beauty, you have
17 actually that group that actually provide very clean,
18 foundational data.
19 341. Q. The data sets are different, are they
20 not, Dr. Liu?
21 A. The data sets are what we collected out
22 of the entire health system, right.
23 342. Q. But one set only starts in May, so
24 that's ---
25 A. Doesn't matter.

AR09432
DR. PETER LIU - 133
1 343. Q. You're missing seven months
2 accumulation of vaccine induced myocarditis versus
3 twelve months of myocarditis from the virus. We're
4 missing five months.
5 A. But you don't need the cases to be
6 simultaneous, right. This is not randomized trial.
7 344. Q. But we're trying to compare. The whole
8 purpose is to compare the incidences over a one year
9 period. But it's unfair. It's unfair and flawed
10 because we're missing five months of data where the
11 data couldn't have existed because these people were
12 not being vaccinated until later and the reports
13 couldn't have come on January 1st of 2021 because
14 people weren't being vaccinated at that time.
15 So, this is a comparison of apples and
16 oranges, is it not, Dr. Liu?
17 A. No. This is, no, this is the best
18 studies, you know, because you actually want to build
19 in -- because it's not randomized trial, right. So,
20 this is the thing. You are dealing with, you know,
21 this is actually a natural experiment, right, in a way
22 in which you expose the patients, right.
23 You know, so just imagine, you know, so you
24 have, let's say, a room of 100, you know, people and
25 you want to actually, you know, figure out how much,

AR09433
DR. PETER LIU - 134
1 let's say Treatment A can result in certain effects
2 versus Treatment B versus the effect, right.
3 So, the way to do it is potentially a
4 randomized trial, let's say, but you don't have that.
5 So then, the better way to do this is you actually
6 treat with A first in the group, figure out what are
7 the result is, and then you treat the group B with
8 Treatment B afterwards, right?
9 So, you can actually distinguish the two.
10 If you actually give A and B at the same time and you
11 didn't do any randomization or capture, you have no
12 idea who caused what, right. So, this study was
13 particularly clever, taking advantage of nature that
14 in one period you only have one single cause possible.
15 And so, and then the other beauty is that
16 then you have younger patients, you know, being
17 included in the latter part of the study. So,
18 essentially you have, you know, sort of the nature's
19 natural design in here for you to really be able to
20 actually capture components of the question that
21 you're interested in, right.
22 So, that's virus induced myocarditis versus
23 vaccine induced myocarditis, yeah. So, if you
24 actually have everything all the same time, makes it
25 more difficult to decipher because you may have those

AR09434
DR. PETER LIU - 135
1 overlap cases which you are just worried about, right.
2 So, that's the situation, yeah.
3 So, this is actually sort of as good as any
4 data we have and it has a very, you know, sort of
5 thoughtful design process in there. And in fact, the
6 fact that, I think it's just fortunate that during a
7 period of time in which you only have one, you know,
8 definitive cause, you know, for the population being
9 present.
10 In fact, it's just strength, right, because
11 then you have ability to really actually be sure, you
12 know, that the data regarding virus myocarditis, you
13 know, was not contaminated by vaccine.
14 345. Q. I will disagree with you, Dr. Liu, but
15 I'm going to move on.
16 A. No worries. That's why we appreciate
17 medicine, you know, sort of the ability, you know, to
18 share different opinions.
19 346. Q. Dr. Liu, on page seven of your expert
20 report, the paragraph that begins with therefore in
21 this study?
22 A. Okay. So, that's the next page. Yes,
23 okay, so which -- okay, yes.
24 347. Q. Yes. And the second sentence in that
25 paragraph says,

AR09435
DR. PETER LIU - 136
1 "...Given the excellent natural history
2 observed to date of the mRNA vaccine associated
3 myocarditis versus excess mortality observed in COVID-
4 19 associated myocarditis, the benefit still outweighs
5 the risk in young male patients with vaccination..."
6 You consider hospitalization life
7 threatening condition and death to be an excellent
8 natural history, Dr. Liu?
9 A. Yeah, as I mentioned, it's all
10 relative, right, you know, so because we're talking
11 about benefit outweigh the risk. And so,
12 hospitalization, as I mentioned, is likely due to the
13 fact that this is new condition, right.
14 As I mentioned, nowadays when patient comes
15 in with this condition, there's a known, but we
16 wouldn't be able to do that in the beginning because
17 this is a new disease, right, you know, so we actually
18 don't know and therefore as appropriate, you know,
19 action by physicians.
20 You know, in fact, everybody did the same
21 thing. That is that you admit the patients so that is
22 actually safe. But as you know, most patient
23 discharge within four days. In fact, the result was
24 within two days, which is great.
25 You know, so I think given the spectrum

AR09436
DR. PETER LIU - 137
1 myocarditis, this is really very, very safe from that
2 point of view. And, you know, the natural history as
3 far as we can see so far is really very reassuring,
4 you know, but of course, you know, there's always
5 information we can capture.
6 And from that point of view, you know, I
7 think we talked about this yesterday, you know, we
8 talked about a billion doses of this. And I will say
9 that there are only two confirmed cases of death, you
10 know.
11 So, I would say that taking aspirin gives
12 you a higher rate of death. And so, you know, this is
13 as safe as it comes. And but then, if you actually
14 compared to the fact that if the person did not get
15 vaccine but then unfortunately, you know, caught
16 COVID-19, which is, you know, unfortunately still
17 around and very contagious, then the myocarditis they
18 get does not have the same outcome, right?
19 So, that is what we are comparing with,
20 right. You know, because this paper is comparing
21 vaccine induced myocarditis with COVID-19 induced
22 myocarditis, and that's apples and oranges.
23 348. Q. Dr. Liu, young people should not have
24 inflamed hearts from taking a medication, should they?
25 A. Should means there is, like a

AR09437
DR. PETER LIU - 138
1 directive, is that, I wasn't sure what's your
2 question?
3 349. Q. Well, we are dealing with a directive
4 in this case, aren't we, Dr. Liu?
5 A. Sorry -- no, no, but you're saying ---
6 350. Q. It's not a good thing for adolescents
7 and young males to have inflamed hearts after taking a
8 drug. It's not a good thing, is it, Dr. Liu?
9 A. Oh, they get it, you know, I mean, as
10 you know, myocarditis is not just caused by the
11 vaccine.
12 351. Q. I'm talking about the vaccine. You
13 shouldn't have an inflamed heart after taking a
14 vaccine.
15 MS. TELLES-LANGDON: I'm sorry, Ms. Pejovic,
16 you cut Dr. Liu off.
17 BY MR. PEJOVIC:
18 352. Q. I'm sorry. Go ahead.
19 A. Yeah, so I'm not quite sure that
20 question. That is a very kind of a subjective
21 judgmental question and I would --
22 353. Q. Well, you're a cardiologist -- sorry,
23 go ahead.
24 A. Yeah, I go with the science. I go with
25 data. I go with, you know, sort of judgment based on

AR09438
DR. PETER LIU - 139
1 science, yeah. So, I'm not quite sure what that
2 should means. What does that mean, yeah?
3 354. Q. As a cardiologist, you don't like to
4 see your patient have inflamed hearts after taking
5 medication, correct?
6 A. Yes. Oh, I don't want my patient to
7 have any, you know, any problems at all.
8 355. Q. All right. You get into a discussion
9 at page seven of your expert report and you start
10 talking about long COVID and you do that twice in your
11 report; once at page seven, and at the very end of
12 your report on page 15.
13 And you discuss how long COVID has
14 negatively impacted and you use the term disabling
15 younger patients, correct?
16 A. Yes.
17 356. Q. Have you seen the recent study by
18 Sneller from the Internal Medicine published May 24th
19 of 2022, I believe I e-mailed that to you yesterday.
20 A. Okay, let me just see. So, which one
21 will this be?
22 357. Q. I hope I did. Let's just see.
23 A. What's the -- how does the file start?
24 358. Q. Long COVID. Did I e-mail you the one
25 that says 'Long COVID'?

AR09439
DR. PETER LIU - 140
1 A. No, I don't have one on long COVID. I
2 don't know if Sharlene ---
3 MS. TELLES-LANGDON: No, I did not receive
4 it either, Ms. Pejovic.
6 MS. PEJOVIC: Let me just check in my sent
7 items here. Okay, I must have missed that one. I
8 apologize. All right. I'm going to pull it up on my
9 screen and we can talk about it. And if you need a
10 few minutes to review it, we can do that.
11 MS. TELLES-LANGDON: Ms. Pejovic, perhaps it
12 might make sense for you to send it by e-mail and we
13 can give Dr. Liu a moment to look at it.
15 THE DEPONENT: Yeah. So, I think it depends
16 on the level of detail you want to refer to it, you
17 know, because generally, you know, certainly, you
18 know, I've seen a lot of patients with long COVID. We
19 follow the patients and study them as well.
20 Yeah, so, but on the other hand, if it's
21 very specific aspect of that paper, then you'll be
22 better to look at the paper itself.
23 MS. TELLES-LANGDON: Are you going to e-mail
24 it, Ms. Pejovic?
25 MS. PEJOVIC: Yes, I am.

AR09440
DR. PETER LIU - 141
1 MS. TELLES-LANGDON: Should we just go off
2 the record then, for a moment?
4 --- OFF THE RECORD (11:21 A.M. to 11:47 A.M.) ---
5 BY MR. PEJOVIC:
6 359. Q. All right. Before the break, Dr. Liu,
7 we had e-mailed you the study from the Annals of
8 Internal Medicine, A Longitudinal Study of COVID-19
9 Sequalae and Immunity: Baseline Findings dated May 24,
10 2022, right?
11 A. Yes.
12 360. Q. Okay. And in this study, they are
13 referring to, they call it post-acute sequalae SARS-
14 CoV-2 infection. The acronym is PASC, and that is
15 long COVID, is it not?
16 A. Yes.
17 361. Q. So, I'm going to -- it's easier for me
18 to refer to it as long COVID, is that okay with you,
19 Dr. Liu?
20 A. Yeah, that's fine.
21 362. Q. Okay. All right. So, in this study,
22 and I'm looking at the Results Section right at the
23 start,
24 "...189 persons with lab documented COVID-19
25 and 120 antibody negative control participants were

AR09441
DR. PETER LIU - 142
1 enrolled. At enrolment, symptoms consistent with long
2 COVID were reported by 55 per cent of the COVID-19
3 cohort and 13 per cent of the control participants.
4 Increased risk for long COVID was noted in women and
5 those with a history of anxiety disorder.
6 Participants with findings meeting the definition of
7 long COVID reported lower quality of life on
8 standardized testing. Abnormal findings on physical
9 examination and diagnostic testing were uncommon..."
10 And at the bottom of that paragraph, it
11 says,
12 "...Exploratory studies found no evidence of
13 persistent viral infection, autoimmunity, or abnormal
14 immune activation in participants with long COVID..."
15 See that?
16 A. Yes, yes, I see. Yes.
17 363. Q. And I'm just going to go down to this
18 section, no page number here. The bold heading is
19 called Risk Factors and Associations with PASC. It's
20 a little bit more than halfway down.
21 A. Is it in the Results Section or is it
22 in the -- which section is this?
23 364. Q. No, if you scroll down, it's own
24 heading, it's bold.
25 A. Oh, it's under Results. That's

AR09442
DR. PETER LIU - 143
1 actually under result.
2 365. Q. Yeah, risk factors in association with
3 PASC. And there's a diagram there, a chart? You see
4 that?
5 A. Yes, right, yes.
6 366. Q. Okay. So, underneath figure one,
7 there's a paragraph. It says,
8 "...We found minimal to no associations
9 between results of diagnostic testing and presence of
10 long COVID. The distance walked in six minutes, an
11 abnormal pulmonary function test results or an
12 abnormal echocardiogram were not significantly
13 associated with the presence of long COVID or the
14 presence of persistent cardiopulmonary symptoms,
15 including chest pain, cough, palpitations or
16 neurologic symptoms, concentration impairment, memory
17 impairment, headache, parosmia or paresthesia, or
18 fatigue..."
19 And then I'm just going to scroll down here
20 to the Discussion section. It has a blue bold
21 heading, do you see that?
22 A. Sorry, which section is this one?
23 367. Q. It's called Discussion. It's down ---
24 A. Oh, yeah, uh-huh, yeah.
25 368. Q. Down near the bottom. So, the first

AR09443
DR. PETER LIU - 144
1 paragraph in that section, it says,
2 "...In this COVID-19 cohort, 55 per cent of
3 participants reported one or more persistent post
4 acute symptoms such as fatigue, dyspnea, chest
5 discomfort, parosmia, headache, insomnia, memory
6 impairment, anxiety, and concentration impairment.
7 These symptoms are similar to what has been reported
8 in questionnaire based studies of long COVID. In our
9 cohort, the risk factors for developing long COVID
10 were female, gender, and pre-COVID 19 history of
11 anxiety..."
12 And if you go down to the paragraph that
13 says, 'Despite the largely normal findings', Okay.
14 A. Yeah.
15 369. Q. See that,
16 "......"Despite the largely normal findings
17 on objective testing, the presence of long COVID had a
18 significant effect on self-reported physical and
19 mental health. Participants with long COVID reported
20 lower quality of life than either participants with
21 COVID-19 without long COVID or control participants
22 And then the next sentence,
23 "...Self reported current anxiety, as
24 measured by the GAD-2 questionnaire was significantly
25 associated with long COVID. This finding suggests

AR09444
DR. PETER LIU - 145
1 that reported anxiety after COVID-19 may reflect the
2 uncertainty and worry felt by those experiencing
3 persistent, unexplained symptoms..."
4 So, I understand that that was just e-mailed
5 to you, Dr. Liu, but I'm going to suggest you that
6 based on at least the findings from this study, it's
7 possible that people who believe they have long COVID
8 actually have a history of anxiety and worry about
9 having had COVID, as opposed to COVID itself causing
10 them long term physical effects?
11 A. Yeah, so there a are large variety of
12 studies, you know, in terms of looking at long COVID.
13 This is obviously one of the major areas of, you know,
14 ongoing research. In fact, you know, we have a major
15 long COVID study, and we're part of the long COVID
16 cohort platform across Canada.
17 Yes, so the interesting aspect of long COVID
18 is that it really encompasses many different subtypes
19 of the condition. And so that it is interesting from
20 the point of view that it occurs, you know, on the
21 average of 30 per cent, you know, 30 to 40 per cent of
22 patients who had COVID.
23 And so, this is something that I think
24 people don't necessarily think about, but I see them
25 simply because the patient gets referred to me. And

AR09445
DR. PETER LIU - 146
1 it's a bit of a mysterious in terms of the exact
2 cause, again this is one of the new condition. But
3 the current, you know, information and also people who
4 died from long COVID, you know, so this is not benign
5 condition. People will die from long COVID.
6 And the analysis actually suggests that the
7 residual inflammation, particularly in the nerve and
8 in the heart, in the major organs and the GI system as
9 well. And, but it is definitely atypical in that the
10 classic findings that you expect for a serious disease
11 are difficult to identify, likely because of the fact
12 that they actually affect the small nerves and small
13 blood vessels.
14 And but obviously, it can actually have
15 major impact on the patient's function because, you
16 know, we get the descriptions of the patient and they
17 have brain fog, right. And you see that, you know,
18 very commonly, you know, even reported in regular
19 press. But also this is very, very real.
20 Patient can have residual chest pain.
21 Patient can actually have limitations. They feel
22 profound fatigue. You know, my colleagues who
23 actually had COVID-19 can't work for a whole year.
24 And these are, you know, really dedicated
25 professionals.

AR09446
DR. PETER LIU - 147
1 And we have Chiefs of Nursing who are
2 totally healthy before, sports people, young people
3 who are, you know, part of the Olympic team, having
4 COVID-19 and become totally disabled.
5 And so, we're just, you know, right now
6 finding ways to actually understanding the disease
7 process because of the problem is that likely we call
8 the microneurological inflammation and microvascular
9 inflammation, so the standard testing are difficult to
10 pick them up.
11 But they have long term consequences and we
12 have, you know, some treatments that's actually being
13 administered to these patients in terms of trials.
14 So, it is actually a condition in which there is
15 tremendous disability out of proportion to kind of the
16 traditional characterization of disease processes,
17 mainly because I think this is how the virus actually
18 affect organs after, you know, the initial condition.
19 The other interesting thing that's really
20 fascinating is that it's not related to the original
21 severity. I think, you know, this study is trying to
22 indicate that the patient can actually have very mild
23 symptoms and still end up with tremendously disabling
24 symptoms.
25 You know, I have these star students, you

AR09447
DR. PETER LIU - 148
1 know, doing Ph.D., and they can't actually continue
2 their studies. You know, they're -- they can't get
3 out of bed. You know, this is really actually very,
4 very disabling.
5 And, you know, a lot of times everybody, you
6 know, will say, well, just a malingerer, you know, and
7 there's nothing wrong with them. It's all in their
8 head, right. And this is where society has completely
9 mistreated these patients.
10 You know, and a lot of people will cut off
11 their support because they think there's nothing wrong
12 with them. And this is the bias that patient faces,
13 you know, when our medical testing cannot actually
14 detect the abnormalities.
15 And so, this study kind of indicates one
16 spectrum, you know, in which patients -- you can see
17 that actually has very significant disability. And I
18 would say there is -- I would say this conclusion is
19 somewhat discriminatory, right, you know, because it
20 actually seems to suggest that women, you know, tend
21 to have this problem, I would say.
22 But there is a reason for that, you know,
23 because there's the way the study is set up, and it
24 suggests that, you know, these are people just with
25 anxiety disorders.

AR09448
DR. PETER LIU - 149
1 You know, this is what people originally
2 described many diseases, you know, when you don't
3 understand what it is, you know, you say well, it's
4 just in your head, it's psychological. And there's a
5 reason that they may particularly end up with this
6 situation with this study, in contrast, for example,
7 other studies.
8 Like Colin Berry just last week published in
9 Nature Medicine, find out that the patient with long
10 COVID actually have significant residual abnormalities
11 when you use really sophisticated testing. And then
12 when they actually use, for example, combination MRI
13 and very sophisticated testing, they find actually,
14 you know, at least 13 per cent of those patients still
15 end up with myocarditis over long term.
16 And these are very mild symptoms, COVID
17 patients to start with. And they also have
18 significant immunological abnormalities. So, you can
19 see that there's a whole spectrum, you know, depending
20 on the patient population.
21 So, the setting of this study is very
22 important. I don't think we kind of cover that. You
23 know, if you actually look at the setting, it's
24 National Institute of Health Clinical Centre. So,
25 that's actually located in Bethesda, Maryland.

AR09449
DR. PETER LIU - 150
1 And you know, the National Institute of
2 Health is just a research centre, right. So, they
3 actually have no hospital per se. You know, it's not
4 a regular community hospital. So, the only way they
5 actually get the patients in there is by advertising
6 for volunteers.
7 So, you can see that, you know, people will
8 actually have to look at an ad or, you know, maybe
9 through social media or something like that and then
10 actually respond to it, travel to Bethesda and
11 volunteer for the study, right.
12 So, you can see that this is completely
13 volunteer population, right. It's a self selected
14 population, and so it's not a normal patient
15 population. And so, most people know that the NIH,
16 you know, recruited patient population is a bit, you
17 know, unusual.
18 And, you know, so the fact that someone
19 actually will take the trouble to travel to, you know,
20 National Institute of Health and volunteer for a
21 study, you know, and number one, they're not that sick
22 to start with, right, so they do actually have a self
23 screening process.
24 And then, you know, there's a certain type
25 of people who obviously volunteer for this study. If

AR09450
DR. PETER LIU - 151
1 you notice carefully, there are more women in this
2 study to start with. You know, that's why they have,
3 you know, the risk factors, women being more common,
4 of course, because they have more -- it's
5 disproportionate. Is not the equal sex distribution
6 of the population.
7 Yeah, so I think, so, you know, those are
8 some of the features, but I think the positive aspect
9 of this is that you do actually have the past or long
10 COVID being a real symptom complex. Two, is that it -
11 - can be very disabling, you know. So, to say that
12 they're not, you know, it's all in their head, it's
13 not real is really, you know sort of, I think,
14 misrepresentation and completely societal
15 discrimination of patients.
16 And then, but it is true that there is still
17 no good, you know, sort of understanding of the cause
18 of this condition, even though I think we'll be
19 getting better all the time. And there are many other
20 studies, of course, actually start to impact this.
21 And, you know, we do this, we now, you know,
22 as I mentioned, you know, have a lot more information
23 suggesting it's the microvascular abnormalities in the
24 nerves, in the blood vessels that's actually doing
25 this.

AR09451
DR. PETER LIU - 152
1 And this is left over immunological
2 activation as a result of virus, you know. And it is
3 a societal challenge, you know. A lot of people don't
4 think about this, but, you know, we have a huge burden
5 on our employable force.
6 You know, a lot of people -- you know, you
7 can't find people to work these days. You know, some
8 of the patients are actually disabled from leftover
9 effect from COVID. You know, people never actually
10 think about that.
11 You know, so this is a huge societal burden
12 and you, you know, you definitely don't want to get
13 affected with COVID if you can help it, yeah.
14 370. Q. Right, but just to confirm, this study
15 actually did intensive physical tests on these people
16 to see if there were any physical manifestations
17 lingering from COVID-19, and they didn't find
18 anything.
19 And you're saying it's discriminatory to say
20 that women have anxiety, but the authors actually
21 found that because there was nothing physical, there
22 was nothing physically wrong with them, even though
23 they reported memory loss, concentration problems,
24 fatigue, that the finding suggests that this is
25 reported -- this is anxiety, which is a result from,

AR09452
DR. PETER LIU - 153
1 you know, being worried that they had COVID and that
2 they might have long COVID.
3 But there's nothing -- when the studies were
4 done, there was nothing actually physically wrong with
5 them.
6 A. Yeah, so it depends on how careful you
7 do the studies, right. You know, we do routine MRIs
8 on our patients. That's the way, you know, we can
9 actually find abnormalities. They did not do that.
10 You know, we do actually bring PET imaging.
11 They did not do that. You know, so there are better
12 studies, but they don't actually do that. And, you
13 know, also always, you know, we have to keep the
14 balance in mind, right.
15 This is a self, you know, volunteer study.
16 So, if you are totally disabled, you can't breathe,
17 you're not going to volunteer for this study. You
18 can't make the trip. So, this is actually a self
19 selected artificial volunteer group, you know.
20 So, always keep that in mind, right? You
21 know, it's not representative of the total COVID
22 population. So, this is self selected because, you
23 know, if you have to actually travel long distance to
24 actually get to a place, you know, people already
25 screen themselves out, right.

AR09453
DR. PETER LIU - 154
1 371. Q. But they believe they've got long
2 COVID. They've got the same symptoms that you were
3 talking about in your report.
4 A. Yes. Yeah, just to keep in mind that
5 this does not represent the population of the total
6 COVID population, right?
7 372. Q. Right.
8 A. You know, I mentioned, there's a wide
9 spectrum, and so this is one spectrum, but it still,
10 you know, shows a number of very important aspects.
11 But the other study will show abnormalities, right.
12 That's why we do it.
13 373. Q. Right. So, I think it's important that
14 we, you know, agree that there are different studies
15 as to what long COVID is.
16 A. Yes.
17 374. Q. And how it affects people. And so that
18 conclusions cannot be made at this time as to the
19 effects that long COVID have on people who say they
20 have it and where those effects are coming from.
21 It's too soon to make definitive conclusions
22 about long COVID, is it not, Dr. Liu?
23 A. Oh, I would not say that. You know, so
24 one is that we all agree long COVID exists.
25 375. Q. Well, this study says it's actually

AR09454
DR. PETER LIU - 155
1 probably anxiety as opposed to physical causes.
2 A. So, you know, so that's -- you're not
3 implying that if you have anxiety, you have
4 disability. That's not disease?
5 376. Q. Well, this study suggests that these
6 people have anxiety disorder.
7 A. That's a condition, right? Remember,
8 mental health is just as important in our society than
9 physical health. You know, this is something that we
10 really have. I'm surprised, you know, I mean you
11 would be much more sympathetic to this issue, right.
12 So, this is the thing.
13 You know, women already been discriminated
14 the previous earlier. You know, a lot of the
15 conditions, you know, attribute to anxiety, and, you
16 know, therefore the disability, you know, is not
17 important.
18 And the fact that you can't work is not
19 important because it's just anxiety. But it's very
20 real for that patient, and it's a real condition and
21 something we need to, as a society, address.
22 And to say that anxiety and therefore it
23 doesn't matter is a discrimination.
24 377. Q. I'm not suggesting that it doesn't
25 matter, but I'm suggesting that the cause, the cause

AR09455
DR. PETER LIU - 156
1 of this long COVID is not a physical cause from COVID-
2 19.
3 A. We haven't established that, you know,
4 but I do agree that the cause of long COVID right now
5 is still being studied, right. You know, because as I
6 mentioned, there are these processes now being
7 understood.
8 And so you can imagine that you have mild
9 nerve inflammation in your brain that's going to
10 actually affect how you think, how your nerves are
11 going to function, how that nerve signal is going to
12 affect your heart, right. You're going to have to
13 feel faster heartbeat, you're going to feel more
14 depressed.
15 And but right now, unless you use very
16 sophisticated imaging like PET imaging or PET MR
17 imaging, which is very rarely available, you're not
18 going to pick that up, right.
19 You know, just examining a patient is not
20 going to find it. And therefore, all you have is the
21 physical phenomena or the mental health abnormality of
22 anxiety, right, you know, because you can't actually
23 delineate it with the tools that's available, you
24 know, in this study.
25 But there are better tools available, you

AR09456
DR. PETER LIU - 157
1 know, and that's why we're beginning to understand
2 this. Yeah, so based on this study, which is not --
3 number one, it's got flaws in it. Two, is that it's,
4 you know, very kind of a simplicity. It says it's a
5 baseline study, right.
6 You know, so this is actually -- yeah, so,
7 you know, so given these, you know, sort of attributes
8 and limitations, we can actually do that. But we
9 can't actually generalize to say that, you know,
10 that's what long COVID is.
11 MS. PEJOVIC: Okay. I'd like to mark this
12 study as the next exhibit.
15 --- EXHIBIT NO. 8: Annals of Internal Medicine: A
16 Longitudinal Study of COVID-19 Sequelae and Immunity:
17 Baseline Findings.
18 MS. PEJOVIC: And when I was on the break, I
19 realized there was one other thing I wanted to ask Dr.
20 Liu about that CDC study. So, I'd like to do that now
21 and then tender that study as an exhibit.
22 So, let's just go back to that. Hopefully
23 it won't take too long.
24 BY MR. PEJOVIC:
25 378. Q. So, Dr. Liu, let me know when you have

AR09457
DR. PETER LIU - 158
1 that study on your screen.
2 A. Yes, I have it. This is the MMWR
3 study, Block et al.
4 379. Q. Yes.
5 A. Yes.
6 380. Q. Okay. So, if you could turn to page
7 three?
8 A. Yeah.
9 381. Q. And if you could look at the chart at
10 Table 1?
11 A. Yes, okay.
12 382. Q. And you can see there is a cohort
13 entitled Unspecified Dose?
14 A. Yes.
15 383. Q. With 1,681,169 people in it?
16 A. Yes.
17 384. Q. And the definition of unspecified dose
18 in the little notes below says,
19 "...The unspecified dose cohort included
20 persons who had a single dose that was not specified
21 as a first or second dose. Doses specified as booster
22 doses were excluded..."
23 See that?
24 A. Yes.
25 385. Q. Dr. Liu, is it -- so then, it's

AR09458
DR. PETER LIU - 159
1 possible that in the unspecified dose category, there
2 could be young males with two doses of the vaccine,
3 correct?
4 A. Yes, yes.
5 386. Q. Right. And if that category didn't
6 exist and it was known, then that would be more doses
7 added into the second dose cohort. But because it's
8 unknown, there could be, as you said, second dose
9 young male sitting in that unspecified dose category,
10 which really belongs the second dose category,
11 correct?
12 A. It could be, yeah, but we don't know,
13 right, you know. So, that's the thing. We don't
14 actually know. That's the problem, right, yes.
15 387. Q. So, we don't know, but because the
16 category of unspecified dose exists, it's safe to say
17 that there are some two dose young males there in that
18 category?
19 A. Yeah, so, because we have a younger
20 patient, right, distributed into those categories in
21 the table, yeah.
22 MS. PEJOVIC: Yes. Okay. I'd like to mark
23 that as next exhibit.
24 MS. TELLES-LANGDON: No objections.

AR09459
DR. PETER LIU - 160
1 --- EXHIBIT NO. 9: CDC: MMWR study, Block et al.
2 BY MR. PEJOVIC:
3 388. Q. Okay. Dr. Liu, I'd like to go to
4 Section 5 of your expert report where you review the
5 report of Dr. McCullough.
6 A. Yes.
7 389. Q. And you obviously reviewed Dr.
8 McCullough's report. And you -- do you know who Dr.
9 McCullough is?
10 A. No.
11 390. Q. Okay.
12 A. I mean, I know from -- he has his CV,
13 yeah.
14 391. Q. Right, okay. So, let's go to -- it's
15 Part B under five, which says paragraph one. And it's
16 on page eight, the third paragraph, which starts with
17 'Please keep in mind'?
18 A. Yeah.
19 392. Q. Okay. All right. And please pull up
20 the PDF that I e-mailed you yesterday called 'Drug and
21 Vaccine Authorizations'.
22 A. Okay. So, just give me -- okay, so let
23 me just see, what does the -- oh, here is 'Drug and
24 Vaccine Authorization'.
25 393. Q. Yes.

AR09460
DR. PETER LIU - 161
1 A. Yes.
2 394. Q. Okay. So, in this paragraph of your
3 expert report, you say,
4 "...Please keep in mind that these vaccines
5 have been fully approved by regulatory agencies such
6 as the FDA, which usually requires rigorous safety
7 data that meets the standards of acceptance..."
8 Now, you don't mention Health Canada here,
9 you're mentioning the FDA. And I'd like you to look
10 at this PDF, which is a Government of Canada website
11 entitled 'Drug and Vaccine Authorizations for COVID-
12 19, List of Authorized Drugs, Vaccines and Expanded
13 Indications'.
14 And as you can see near the top, it says
15 date published is May 12th of 2022, do you see that?
16 A. Yes, I do, yeah.
17 395. Q. Okay. Any issues with this website?
18 You can see that it's a Government of Canada website,
19 Dr. Liu?
20 A. Yeah, so I assume this is a copy of
21 that website.
22 396. Q. Yes.
23 A. Yeah.
24 397. Q. So, if you scroll down, we've got --
25 we'll go to the -- what's it called here, List of --

AR09461
DR. PETER LIU - 162
1 it's a table called 'List of Authorized Drugs,
2 Vaccines and Expanded Indications for COVID-19', do
3 you see that?
4 A. Yes, right. Yeah.
5 398. Q. And on the left hand side of the table,
6 it says 'Authorization Holder'. Now, if we first
7 looked at -- there's three entries for AstraZeneca
8 Canada, Inc.
9 A. Mm-hmm.
10 399. Q. And you'd agree with me that the second
11 two in the second two boxes down, number two and three
12 are in regards to the COVID-19 vaccine, AstraZeneca?
13 A. Sorry, which boxes are we referring to?
14 400. Q. There's three AstraZeneca entries.
15 A. Yes, that's right.
16 401. Q. And second one and the third one are in
17 reference to the COVID-19 vaccine that AstraZeneca
18 makes.
19 A. Yes, vaccines for human use, right.
20 402. Q. Right. And if you look to the same
21 row, go all the way to the right hand side. It says
22 'Interim Order Authorized with Terms and Conditions'
23 for box number two and number three in the first
24 column for the AstraZeneca?
25 A. M'hmm.

AR09462
DR. PETER LIU - 163
1 403. Q. Okay. So, you'd agree with me then
2 that these vaccines are authorized with terms and
3 conditions, correct?
4 A. Yes, that's right. Yeah.
5 404. Q. And we can compare that to, if you look
6 at the bottom, Gilead Sciences Canada, Inc. with their
7 Veklury drug, it says, 'Expanded Indication' in the
8 last column of that bottom row, 'Expanded Indication,
9 Food and Drug Regulations Authorized'.
10 So, that authorization doesn't have terms
11 and conditions, does it?
12 A. I don't know, is that the full box, is
13 that the full box?
14 405. Q. I'm asking what the box says.
15 A. Yeah. So, that's a what the box, but I
16 assume that's the full box, right.
17 MS. TELLES-LANGDON: So, I'm going to object
18 to this line of questioning. You have tomorrow, Dr.
19 Celia Lourenco, who is the person of Health Canada who
20 issues these authorizations.
21 I think you should direct the questions
22 towards Dr. Lourenco as to what those authorizations
23 mean.
24 MS. PEJOVIC: All right. Well, I'll just
25 ask some questions of Dr. Liu then, because I want to

AR09463
DR. PETER LIU - 164
1 get straight to what he means in his third paragraph,
2 in his expert report.
3 BY MR. PEJOVIC:
4 406. Q. Is it your position, Dr. Liu, that the
5 COVID-19 vaccines for use in Canada are fully
6 authorized?
7 A. Yes. They are fully authorized for the
8 specific indications, right, keep in mind, you know,
9 that you have all these different ones, right, it's
10 because they have a very specific indications, right.
11 So, they're not broad indications. You
12 know, it's not just used for everybody, right. The
13 reason you have all these different components is
14 because there are actually very specific conditions,
15 right.
16 It's certain age group and all the rest,
17 right. So, that's how these things are proved, right?
18 407. Q. Yes.
19 A. So, it's not for broad open use.
20 408. Q. Yes. And I just wanted you to look at
21 this chart and agree with me that what it says there
22 is authorized with terms and conditions. And that
23 applies for the BioNTech Comirnaty Pfizer vaccines as
24 well?
25 A. Yes.

AR09464
DR. PETER LIU - 165
1 MS. PEJOVIC: Yes, thank you. I'd like to
2 tender that document as the next exhibit.
5 --- EXHIBIT NO. 10: Drug and Vaccine Authorizations for
6 COVID-19: List of authorized drugs, vaccines and expanded
7 indications.
8 BY MR. PEJOVIC:
9 409. Q. Let's go to Section 5(J) of your expert
10 report, where you refer to paragraphs ten and eleven
11 of Dr. McCullough's report.
12 A. Yes. Okay, so that's on page eleven.
13 Yes.
14 410. Q. Yes. And Dr. McCullough, you
15 acknowledge that in his expert report, he mentioned
16 the presence of heart failure after mRNA vaccination.
17 And you say,
18 "...but the true heart rate failure
19 incidence is very rare..."
20 Right?
21 A. Yes.
22 411. Q. Right. But you would admit that it
23 does occur, correct?
24 A. Yeah, but very rare.
25 412. Q. And you'd agree with me, Doctor, that

AR09465
DR. PETER LIU - 166
1 patients with heart failure from any cause have a poor
2 prognosis and a high risk of death?
3 A. Being a heart failure physician, I
4 would say, you know, there is a spectrum of outcome
5 and not all my patients die. And so, yes, so heart
6 failure is a serious diagnosis and there's a spectrum
7 outcome, and but significant majority of patients now
8 actually have excellent treatment and they actually do
9 very well.
10 413. Q. Okay. Well, then why don't we look at
11 letter N on page twelve, which is paragraph 16 of your
12 report, do you see that?
13 A. Yes.
14 414. Q. You say,
15 "...I agree that heart failure has a poor
16 survival rate...".
17 A. Yes. So, it really actually does have
18 a poor survival rate compared to normal individuals.
19 Yes.
20 415. Q. Right. So most people with heart
21 failure are not going to survive?
22 A. In what time frame, because we all die.
23 You know, so it's all time, you know, relationship,
24 right?
25 416. Q. Well, you didn't list a time frame,

AR09466
DR. PETER LIU - 167
1 just looking at your sentence there.
2 A. Yeah. So, this is for survival rates
3 compared to normal individuals, yes.
4 417. Q. Your lifespan will be shortened
5 significantly if you have heart failure, won't it, Dr.
6 Liu?
7 A. Yes, I think we can say, you know, but
8 the extent is different for everybody, right. So, I
9 think that's what it comes down to. But it is not
10 normal and I think that's what I'm referring to.
11 418. Q. Okay. At Section K, where you're
12 looking at paragraphs 12 and 13, and that's at page 11
13 of your report.
14 A. Yes, m'hmm.
15 419. Q. You're looking at the Truong study.
16 A. Yes.
17 420. Q. So, I'm going to pull that up on my
18 screen. Are you able to do that, Doctor, as well?
19 A. Yes, I remember seeing that. And I
20 think that was one that you sent as well, let me just
21 bring that up. Okay, yes.
22 421. Q. Right. And you looked at that study
23 and you noted that,
24 "...Most patients stayed only two to three
25 days in the hospital, and the left ventricular

AR09467
DR. PETER LIU - 168
1 function in all patients returned to normal..."
2 I'm reading from your report at paragraph K,
3 5(K), do you see that?
4 A. Okay. Yeah.
5 422. Q. Right. And we established yesterday
6 from that Shower pediatric study, that there's
7 evidence that just because patients only stay two to
8 three days in a hospital doesn't mean that there
9 aren't long term consequences.
10 A. Yeah. So, the patient should be
11 followed, I agree. I think that's important.
12 423. Q. And if you go down to page 349 of this
13 Truong study?
14 A. Three forty-nine, yes. Okay.
15 424. Q. And if you are on the right hand side
16 where the paragraph starts with initial CMRI, do you
17 see that?
18 A. Yes.
19 425. Q. Okay. So, why don't you go down to the
20 bottom of that paragraph, you'll see the word,
21 however, see that?
22 A. Yes.
23 426. Q. Okay. I'm going to read that,
24 "...However, six of the fifteen CMRIs
25 performed more than 30 days after symptom onset, had

AR09468
DR. PETER LIU - 169
1 findings at late gadolinium enhancement, even at up to
2 88 days..."
3 And yesterday, the pediatric study admitted
4 that there was a reduction in this LGE when they
5 looked at their patients. But here it exists more
6 than 30 days and up to 88 days after symptom onset.
7 Is that not a concern, Dr. Liu?
8 A. So actually, the two studies are quite
9 consistent with each other, and because this one did
10 not actually have serial measurements, right. So, I
11 think this is the difference between the two.
12 And so, they did not actually do kind of the
13 direct with the inpatient or same patient comparison,
14 right. You know, so, because the other study,
15 pediatric study, the design was different, they were
16 able to actually do, you know, sort of the first study
17 and second study and look at the difference.
18 And so, but I think that the findings are
19 similar, and I think it's also consistent with what we
20 find as well in that these patients clinically will
21 actually improve and heart function will be better.
22 But however, on the MRI, there is this
23 phenomena that we talked about yesterday, you know, of
24 late gadolinium enhancement, and that can be still
25 present in some of these patients.

AR09469
DR. PETER LIU - 170
1 You know, so I think the same finding with
2 the pediatric and the same finding we have. And so,
3 the -- so, I think the same conclusions, you know, are
4 consistent from the point of view that these are
5 findings after the initial presentation, and so
6 therefore, longer follow up is important.
7 But however, the significance of these are
8 unclear because the patient improves in, you know,
9 most of the other parameters in contrast to regular
10 myocarditis.
11 And so does this persistent technical
12 finding mean, you know, sort of an adverse consequence
13 down the road, we don't know, you know, because we now
14 find that the same finding in other population
15 actually doesn't have any, you know, consequence.
16 But because of the fact that this was found
17 to be abnormal in the original or, you know, I guess
18 the archetypal type of myocarditis, is not related to
19 any of these vaccines, you know, we worry about them.
20 So, we worry about them here as well. But
21 it doesn't mean that it's adverse. But it's a
22 consistent finding, you know, from yesterday's study,
23 from this study, from our own study. It's a technical
24 finding on the MRI.
25 And I think that's, you know, that's what

AR09470
DR. PETER LIU - 171
1 everybody is finding. And the meaning of which, I
2 think will need to be illustrated, with longer follow
3 up. And, you know, this is part of the reason we're
4 doing study to follow up to find the meaning of this.
5 MS. PEJOVIC: Right. I'd like to mark that
6 study as next exhibit.
9 --- EXHIBIT NO. 11: Truong: Circulationaha.121.056583
10 BY MR. PEJOVIC:
11 427. Q. Okay. Let's go to paragraph 5(N),
12 where you look at paragraph --
13 A. N, as in Norman?
14 428. Q. Yes, where you look at paragraph 16 of
15 Dr. McCullough's report?
16 A. Okay. Yes.
17 429. Q. All right. And Dr. McCullough had
18 stated in his report that heart failure caused by a
19 heart injury has a five year 50 per cent survival
20 rate, and that five year 50 per cent survival rate
21 would apply to a child or young adult who developed
22 heart failure after vaccine induced myocarditis.
23 And you'd agree with me, that is what he
24 found?
25 A. That's what he says, yeah. I don't

AR09471
DR. PETER LIU - 172
1 know how he found it because we don't have that
2 information, right.
3 430. Q. Yeah. I just want to establish ---
4 A. Yeah, it hasn't been around for five
5 years. So, it's interesting, I don't know his source,
6 you know, how he decided that, in fact, that is the
7 case, you know, because right now we only -- we're
8 only following the patients for one year, you know,
9 maximum in our whole registry.
10 Yeah, so, so it's interesting that he would
11 posit that, yeah.
12 431. Q. Right. And I think we've already
13 discussed this, but the prognosis of a person with
14 heart failure is not different depending on whether
15 the cause was a virus or a vaccine, correct? Heart
16 failure is heart failure, is it not, Dr. Liu?
17 A. So, no, the answer is no. It's totally
18 dependent on the cause, it's totally dependent on the
19 severity. And, you know, there are so many
20 parameters. You know, we have risk predictors, you
21 know, for the different types of heart failure.
22 You know, it's just like, you know, somebody
23 had a heart attack, right. Some patients have a heart
24 attack and survived for years afterwards. Some people
25 have a heart attack and die on the spot, right.

AR09472
DR. PETER LIU - 173
1 And we can't say that heart attack is a
2 heart attack is the same. Yeah, so certainly heart
3 failure is, as I mentioned, is really at your wide
4 spectrum of disease conditions.
5 And of course, you know, that's the reason
6 that, you know, we look after patients on an
7 individual basis, right. It's not, we just kind of
8 give the same drug to everybody and hope for the best.
9 And so, it's all tailored approach based on
10 their presentation, based on the cause, based on the
11 severity of the condition and based on the response to
12 treatment, you know. So, there's a whole range of
13 outcomes.
14 And so I'm very happy to report that, in
15 fact, now we have more and more patients being, let's
16 say, almost cured of heart failure, you know. This is
17 unbelievable. That never happened before.
18 And of course, we have patients who actually
19 go on and require heart transplantation, artificial
20 hearts and things like that. But fortunately, that's
21 a very small proportion, yeah. So, it's a huge
22 spectrum in terms of outcome.
23 432. Q. Right. But at the start of that
24 paragraph, you say heart failure has a poor survival
25 rate.

AR09473
DR. PETER LIU - 174
1 A. Yeah. So, if you actually take
2 everybody, you take the average, the survival rate is
3 less than normal, right. So, that's actually what we
4 refer to.
5 433. Q. Right.
6 A. Somebody has -- because the survival is
7 not the same as normal. We actually take the
8 aggregate.
9 434. Q. If your heart is failing, you're not
10 going to survive as long as a person whose heart isn't
11 failing, correct?
12 A. As a general, you know, as kind of
13 taking as most conditions, you know, sort of a
14 description, yeah. But as I mentioned, there are
15 patients who, with heart failure, now can be cured,
16 right. And I will say, remember, we mentioned that
17 the myocarditis situation, in a traditional even, it's
18 one-third, one-third, one-third, right.
19 One-third fully recovered, which means that
20 in fact, you know, their condition actually has no
21 residual versus, you know, one-third still, you know,
22 continue with some abnormality, and one-third, in
23 fact, you know, may deteriorate and therefore require
24 further treatment. That's in the traditional
25 myocarditis, you know.

AR09474
DR. PETER LIU - 175
1 So, vaccine induced myocarditis, you know,
2 now, at least, the data we have is that more than 90
3 per cent fully recovered and so, and the heart failure
4 is extremely rare, right. It's extremely rare.
5 And so, yeah, I haven't actually seen
6 patients with heart failure more than one day, I would
7 say. And, you know, certainly in our series, which is
8 the largest series in any centre, you know, so I
9 haven't seen any patients with persistent heart
10 failure.
11 But, you know, it's obviously present.
12 Sorry.
13 435. Q. Sorry. If you have a patient with, in
14 your professional opinion, Dr. Liu, a patient with
15 heart failure from a vaccine is likely to have a poor
16 survival rate, correct?
17 A. Not from any data that we have at the
18 present time to support that, no. Because as I
19 mentioned, you know, it's very rare. You know, so my
20 guess is that maybe it's about 2 per cent. You know,
21 so two out of 100 will have heart failure -- may have
22 heart failure, by definition.
23 And certainly these patients we've seen,
24 they all have fully recovered, which means that the
25 heart failure is gone. And, you know, so, it's very

AR09475
DR. PETER LIU - 176
1 fortunate in that the vaccine induced abnormalities
2 appears to be transient, at least so far, and the
3 patient fully recovered, which is really good for the
4 patient.
5 And but, you know, as someone who researched
6 the area, we always want to follow the patient always
7 want to be cautious. This is what we observe so far.
8 And, you know, this is specific because heart failure
9 is a huge spectrum, right?
10 Yeah, so this is -- this is, you know, we're
11 learning this all the time, right. This is a new
12 condition, and it appears that the vaccine induced
13 myocarditis is transient and the patient can actually
14 recover from it and heart failure is rare. And the
15 patient also recover from it.
16 436. Q. And they can also die, correct?
17 A. Two cases of three hundred. Yeah,
18 there are only two reported cases. I haven't seen a
19 single case that died our entire registry, our
20 international registry, we haven't had a case who
21 died. But, you know, there are these two cases that
22 we are aware of who died, yes.
23 437. Q. Okay. Two cases that have been
24 reported.
25 A. Yes, yes.

AR09476
DR. PETER LIU - 177
1 438. Q. You'd agree with me that there might be
2 other people out there who received a COVID-19 vaccine
3 who died from heart failure that you are not aware of?
4 A. Yes, there could always be. Yeah,
5 absolutely. My knowledge is limited, yeah.
6 439. Q. And then you look at paragraph 5(O),
7 you look at paragraph 17 to 20 of Dr. McCullough's
8 report. And that was the Gill study?
9 A. Yes, yeah.
10 440. Q. You don't say it here, but that was the
11 Gill study. And I didn't e-mail that one to you. Do
12 you happen to have that one handy, or should I put it
13 on my screen?
14 A. If you're referring to any details,
15 then it's probably better to be pointing to those very
16 specific details. In generalities, you know, I
17 describe the observations and describe my evaluation.
18 MS. TELLES-LANGDON: Ms. Pejovic, if you're
19 taking him to the study, since you did an e-mail, I
20 would appreciate seeing it on your screen.
21 MS. PEJOVIC: Yes. Yes, I will. Yes.
22 BY MR. PEJOVIC:
23 441. Q. Can you see that now?
24 A. Okay, yes. Okay. Pathology, yeah, so
25 maybe the title is most helpful.

AR09477
DR. PETER LIU - 178
1 442. Q. Yes. So, this is the Gill study that
2 Dr. McCullough refers to in his report from the
3 College of American Pathologist, Archives of Pathology
4 and Laboratory Medicine. And it's entitled Autopsy
5 Histopathologic Cardiac Findings in Two Adolescents
6 following the Second COVID-19 Vaccine Dose, and the
7 lead author is James Gill.
8 A. Yes.
9 443. Q. And this study was published, I don't
10 have the date here, but anyway, you reviewed the
11 study?
12 A. Yes. We referred to this paper, yeah.
13 444. Q. All right. And you agree that this is
14 an autopsy of two teenage boys who died within the
15 first week after receiving the Pfizer vaccine,
16 correct?
17 A. Yes. This is ---
18 445. Q. And that's at page three of this study.
19 A. Okay, yeah. Okay, yes, I think we can.
20 MS. PEJOVIC: Ms. Telles-Langdon, is that
21 large enough for you to read?
22 MS. TELLES-LANGDON: Yes, it is. Thank you.
23 BY MR. PEJOVIC:
24 446. Q. And in the results section of this
25 paper, at page four, you can see that the study refers

AR09478
DR. PETER LIU - 179
1 to the two boys as boy A and boy B,
2 "...Boy A complained of a headache and
3 gastric upset but felt better by post vaccine day
4 three. There was no history of prior medical problems
5 or prior SARS-CoV-2 infection..."
6 Do you see that?
7 A. Right, yes.
8 447. Q. Yes. And carrying on in that paragraph
9 on page four,
10 "...Boy B had no complaints, prior health
11 issues or prior SARS-CoV-2 infection. Neither boy
12 complained of fever, chest pain, palpitations or
13 dyspnea..."
14 See that?
15 A. Yeah, yeah.
16 448. Q. So, these are two teenage boys who, you
17 know, didn't have -- weren't complaining of chest pain
18 or shortness of breath after their vaccine, and they
19 didn't have any -- they didn't have any symptoms of
20 typical myocarditis.
21 A. That's right, yeah. So, that's
22 important to note, right, you know, because it's quite
23 atypical in terms of presentation, yeah.
24 449. Q. Okay.
25 A. Because they would not necessarily fit,

AR09479
DR. PETER LIU - 180
1 you know, sort of the case definition that we were
2 discussing, yeah.
3 450. Q. Okay. And at page six, the authors
4 state,
5 "...Both teenage boys had similar clinical
6 presentations with no obvious cardiac symptoms..."
7 And in that paragraph,
8 "...This injury pattern is instead similar
9 to what is seen in the myocardium of patients who are
10 clinically diagnosed with Takotsubo, toxic or stress
11 cardiomyopathy, which is a temporary myocardial injury
12 that can develop in patients with extreme physical,
13 chemical or sometimes emotional stressors..."
14 See that?
15 A. Yes, yes, absolutely.
16 451. Q. And at page seven, the authors say at
17 the last paragraph,
18 "...This post vaccine reaction may represent
19 an overly exuberant immune response and the myocardial
20 injury is mediated by similar immune mechanisms as
21 described with SARS-CoV-2 and multisystem inflammatory
22 syndrome cytokine storms..."
23 Okay. So, they're calling it a post vaccine
24 reaction.
25 A. Even though, you know, the data, as I

AR09480
DR. PETER LIU - 181
1 mentioned and, in my report, as well, it's actually
2 more similar to what we call a hyperkinetic syndrome,
3 you know, which is more of an allergic reaction.
4 Yeah, and so, I would say, you know, I think
5 I mentioned earlier, you also already, you know, read
6 that, you know, these patients had no symptoms and the
7 pathology doesn't show inflammatory infiltrate, you
8 know, which is what myocarditis is about.
9 You know, so myocarditis, which is the
10 inflammation of the heart muscle and but the
11 inflammation is not a key feature in any of these
12 findings. Yeah, so I would say they are rather
13 atypical of myocarditis, yeah.
14 452. Q. Right. And then at page nine it says
15 at the top,
16 "...These two clinical histories support the
17 etiology of the acute myocardial injury as a primary
18 factor, not a secondary agonal or post-resuscitative
19 artefact..."
20 So, Dr. Liu, you say that you only know of
21 two cases of death from a heart injury from COVID-19
22 vaccines, but isn't it true there could be people,
23 young males, there could be young males dying, and
24 like in this study, with no symptoms of anything after
25 they're vaccinated, and without an autopsy, there'd be

AR09481
DR. PETER LIU - 182
1 no indication that their heart was injured, correct?
2 A. Sorry, your question is?
3 453. Q. I'll repeat the question.
4 A. Yeah, I'm trying to figure out what the
5 ---
6 454. Q. I'll repeat the question.
7 A. Yeah, yeah.
8 455. Q. It's true that there could be, it's
9 possible that there are young males in Canada dying
10 after a vaccine, a COVID-19 vaccine, without having
11 shown any symptoms of any heart injury?
12 A. Oh. So, you mean people, young people
13 dying from the vaccine?
14 456. Q. Yes, that could be happening.
15 A. Yeah, and ---
16 457. Q. Without a doctor diagnosing them with
17 any sort of myocarditis.
18 A. So, they died in secret, I mean, you
19 know, because young people dying is -- if I find
20 somebody who died who's very young, that's usually a
21 coroner's case, right, you know, because unless I know
22 the cost, it's an automatic coroner's case.
23 You know, unless patient died in secret and
24 nobody ever found the person. You know, if you
25 encounter a young person within a home, outside, who

AR09482
DR. PETER LIU - 183
1 died, you know, you probably call the police, call the
2 ambulance. And that's an automatic coroner's case,
3 right, because you can't just leave somebody unless
4 you know the cause, right.
5 If you know the cause, then you can actually
6 fill out the death certificate with the cause. But
7 otherwise, you know, if the patient just died, then
8 you need to actually find out the cause, right,
9 because that's actually what's required, you know,
10 unless the family refuses or something like that. And
11 -- because it's unusual for young people to die out of
12 no reason.
13 458. Q. And wouldn't you agree with me that as
14 in this case, after a vaccine, after a COVID-19
15 vaccine, there can be -- it's possible there can be
16 injury to the heart that is -- doesn't manifest with
17 symptoms?
18 A. From the vaccine, you mean?
19 459. Q. Yes, it's possible.
20 A. Yeah. As I mentioned, anything is
21 possible, but it's a probable, it's unlikely, right,
22 because if you have severe inflammation, you have a
23 major heart injury and you had a vaccine and you feel
24 nothing, you don't have any abnormalities, and you
25 died or is this just walking around?

AR09483
DR. PETER LIU - 184
1 460. Q. Well, we were talking about death
2 earlier, but now I'm just talking about there could be
3 young males walking around after a COVID-19 vaccine
4 with heart problems that they don't even feel.
5 A. Yeah, that's always possible, but, you
6 know, but there's no way to find out because you have
7 no way to actually say that existed, right, you know,
8 if the patient doesn't present to anybody and you
9 haven't -- not doing any tests on them, there's no way
10 to ever confirm that's true or not, right.
11 I mean, you can hypothesize anything, right.
12 461. Q. Yeah, so what's troubling about this
13 study, Dr. Liu, is that these boys didn't have any
14 symptoms.
15 A. Yes, but there is no proof that they
16 actually died from the vaccine. You know, this is why
17 I'm saying, you know, if you actually look at case A,
18 right, so that's the reason I say these are very
19 unusual cases because you actually look at the case A,
20 there's no inflammation, right?
21 So, this is -- we're talking about
22 myocarditis subsequent to vaccine. So, there's no
23 inflammation. So, there's no myocarditis in that
24 patient, but the patient did die.
25 And you actually see that the patient has

AR09484
DR. PETER LIU - 185
1 fibrosis. This is also what we're talking about
2 earlier, patient has scar. You know, takes months,
3 years to form.
4 So, there was actually, in fact likely some
5 process going on. And the one possibility, as I
6 mentioned, is arrhythmogenic cardiomyopathy, which is
7 a genetic condition in which you actually get scarring
8 in the heart, then could cause heart rhythm
9 abnormalities, is one of the potential causes of young
10 people, you know, to die suddenly.
11 And, you know, this is why after sports,
12 some of the patients may die suddenly and, you know,
13 they may have that condition. And so that, you know,
14 of course, you know, we don't know for sure. We don't
15 have rhythm monitoring or anything like that.
16 Yeah, so there's easily other explanations.
17 And certainly myocarditis does not -- vaccine induced
18 myocarditis does not come to be top of the mind, you
19 know, because I don't think they definitively say
20 these are classic cases of vaccine induced
21 myocarditis.
22 462. Q. No, they call it a global myocardial
23 injury.
24 A. Yeah, exactly. You know, so that could
25 be anything, right.

AR09485
DR. PETER LIU - 186
1 463. Q. Right.
2 A. So, they'd be very careful because I
3 noticed that the pathology -- the folks who wrote it,
4 never, you know, mentioned that this is vaccine
5 induced myocarditis anywhere, right. You know,
6 because they're very careful to avoid actually
7 labelling that because they cannot justify it.
8 464. Q. Well, they say it's a post vaccine
9 reaction.
10 A. Yes, that could be anything, right.
11 465. Q. And this reaction resulted in death.
12 A. No, I don't think they actually said
13 that that reaction results in death, right. So,
14 that's the thing, you know, because it's very
15 difficult, you know, just like in, I think you'll be
16 very familiar with this, right, you also establishing
17 causation, right?
18 You know, it's really, really, sort of
19 robust process in which you really actually have to
20 have all the evidence, you know, being linked, you
21 know, to the result and there are no other alternative
22 explanations, right.
23 You know, so that's how you establish cause.
24 And so, this situation certainly does not meet that
25 standard. And, you know, the authors are very careful

AR09486
DR. PETER LIU - 187
1 as well. So, there's no question that there is a
2 coincidence in time.
3 And in contrast, you know, to a couple of
4 the other cases which I say, you know, are likely
5 related to vaccine, but this one has a lot of features
6 that suggested there are other processes going on and
7 that this is just temporary coincidental.
8 And so, one cannot attribute cause and
9 effect, you know, this is a mirror association. And I
10 think the authors are careful not to, you know, say
11 that this is a direct cause.
12 466. Q. So, it's your professional opinion that
13 it's more likely that these two boys had some sort of
14 pre-existing heart issues that just happened to kill
15 them on the same night as opposed to the vaccine they
16 just both got a few days prior.
17 A. Yeah, but keeping in mind, you know,
18 that this is two cases out of how, you know, many
19 young people just like them, you know, who had
20 vaccines, right. So, this is the thing. And so,
21 yeah, so, you know, these pre-existing conditions will
22 give, you know, sort of a random event, unfortunately,
23 right?
24 And they could very well be having dinner in
25 a particular restaurant and die suddenly, right. And

AR09487
DR. PETER LIU - 188
1 they may attribute that to the food they ate, for
2 example, right. So, these are coincidental
3 incidences.
4 And, you know, this happens all the time
5 when there's sudden death, right. One always want to
6 attribute it to a cause and medically very difficult
7 to establish because these all circumstantial.
8 467. Q. But the sudden death -- sorry, go
9 ahead.
10 A. Yeah, and you know, all circumstantial,
11 and you can attribute to anything to it, right. So,
12 that's the -- because, in fact, they offered
13 suggestion, I guess, to a certain extent that it could
14 be a stress cardiomyopathy, right, the Takotsubo
15 cardiomyopathy, which is usually due to emotional
16 stress.
17 So, there could actually be some emotional
18 stress conditions, you know, the boys are facing and
19 then that caused the death, which is, of course, is
20 known. And so but we would never be able to actually
21 identify what those triggers might be because we don't
22 have the history around that.
23 Yeah, they are atypical of markers, maybe
24 that's what I'm saying, you know, because it's really
25 unusual cases. They're not, certainly pathology wise,

AR09488
DR. PETER LIU - 189
1 they're not myocarditis symptoms don't convert to it
2 either.
3 468. Q. Right, but they died from a heart
4 injury. They call it a myocardial injury.
5 A. Yes, so a myocardial injury, yeah,
6 because if anything that actually is causing
7 abnormality in the heart, that's a heart injury. But
8 that can be from any cause, as I mentioned.
9 You know, so they suspect first case of
10 Takotsubo, which is, you know, stress cardiomyopathy,
11 which is, you know, due to a major emotional stressful
12 condition, which then can lead to heart injury and,
13 you know, the damage that you see there.
14 But there was a pre existing abnormality as
15 well, you know, because of the fibrosis I mentioned,
16 due to scar, right. Normal hearts should not have any
17 scar in it. So, he suggests that there was some prior
18 existing injury to the heart, you know, condition and
19 very hard to figure out without other additional
20 history to know what's the reason.
21 You know, a heart should not have a scar in
22 it.
23 469. Q. And Dr. McCullough included this case
24 study in his expert report to support his ultimate
25 conclusion that the young males should not receive

AR09489
DR. PETER LIU - 190
1 COVID-19 vaccines because of the risk.
2 So, that -- he used that study in the
3 report, and that was his ultimate conclusion. And you
4 don't have concerns, as a cardiologist looking after
5 patients, when you see something like this, when we
6 have a new vaccine which is causing this new
7 condition, you don't have concerns as a cardiologist
8 looking after patients that there could ---
9 A. Yeah, so previously ---
10 470. Q. Please let me finish.
11 A. Sorry, yes, apologies, yes.
12 471. Q. You don't have concerns as a
13 cardiologist looking after patients when you see these
14 kinds of case studies with a new vaccine, that perhaps
15 we should wait until more data is available before we
16 recommend that young people take a risk in taking this
17 vaccine?
18 A. Yeah, so, well, just kind of if we turn
19 the clock back in April or May when we actually first
20 learned about these conditions, we right away begin to
21 collect data in Canada, you know, because that's the
22 thing, sort of a responsible physician or researcher
23 would do, you know, rather than leave to chance, let's
24 collect the information. And so this is how we form
25 our registry, but, you know, we share data worldwide.

AR09490
DR. PETER LIU - 191
1 And so, of course, if this is something
2 that's really serious and this is -- was the concern,
3 and then, you know, obviously, there maybe, you know,
4 sort of appropriate, you know, sort of risk versus
5 benefit analysis, you know, in order to determine the
6 vaccine policy.
7 But the fortunate thing is that we now have
8 data to suggest that these are rare conditions, but
9 they can cause symptoms and they can cause transient,
10 you know, cardiac abnormalities. Very fortunately,
11 that patient recovery in a very short period of time.
12 The long term consequences appear to be, to
13 date, extremely limited and the motivation completely
14 recovered. So, you know, so that's kind of the risk
15 side. And we're always monitoring risk, as you know,
16 we collect data. We really objectively evaluate it.
17 We look at the worldwide data to learn about
18 this all the time. You know, so that's the key to
19 what we do. And then we have to, as I mentioned,
20 versus what is the benefit, you know, is.
21 And so, if you actually look at the benefit
22 of the vaccine, of course, you know, we talked about
23 it prevents hospitalization, it prevents, particularly
24 prevents death in the lion share of patients who
25 receive vaccine, who have no complications whatsoever.

AR09491
DR. PETER LIU - 192
1 And the key is that it's not good to have
2 COVID-19. You know, some people, you know, one of my
3 US is written up in literature. You know, there are
4 even young colleagues, you know, who are in the
5 medical profession who don't believe in vaccine, and
6 they say that the best way is actually to get COVID.
7 Well, unfortunately, they all died, and I
8 think that's too high a price to pay. So, I think
9 it's actually much more important to actually, you
10 know, put things in perspective. As I mentioned, you
11 know, getting COVID is real and COVID can result in
12 myocarditis, right, which is not as benign as vaccine.
13 So, we're already talking about a risk
14 there, and it's more frequent. And so, and we treat
15 those patients and they go our heart-lung machine for
16 support. You know, this is not anything mild and it
17 recovers within days.
18 And then we talk about, you know, the longer
19 consequences. And this is very real, whether we find
20 any abnormalities or not, it's so sad to see young
21 people, young people, you know, who are in the prime
22 of their life and they're in their golden component of
23 their learning process, careers, become totally
24 disabled. It's just heartbreaking.
25 You know, why would they, you know, face

AR09492
DR. PETER LIU - 193
1 this fate, right and so, this is why having the fact
2 that we have vaccine, we can actually prevent you from
3 it. And even nowadays, when I see six waves maybe
4 coming, people refuse to wear masks. I say why do you
5 do this, right?
6 But, you know, I guess people want to make
7 their own decisions, which is totally, you know,
8 respected. But the data just shows that this is not a
9 trivial infection. It's not just a cold. You know,
10 if you are unlucky, you get these complications and
11 it's going to be a horrible sort of years to recover.
12 And so, you've weighed the balance of risk
13 versus benefit all the time, as I mentioned, right.
14 So, I think that's the reason. Certainly, all my
15 patients, you know, there's no ifs and buts, you know,
16 because I want to make sure they are protected.
17 You know, it's up to them to ultimately
18 decide what to do, but the majority of them will be
19 vaccinated and they will do well. But for the
20 unfortunate ones who actually do have vaccine induced
21 myocarditis, right, we look after them, we make sure
22 they completely recover.
23 Fortunately, no one died and they all do
24 well so far, fingers crossed. And but we follow them.
25 We make sure that this continues to be case. But if

AR09493
DR. PETER LIU - 194
1 we find something different, you know, then we re-
2 evaluate. You know, we constantly re-evaluate.
3 This is what, sort of, the reason we do
4 medical research as well. So, we are always learning
5 and we learn together and we share this information.
6 We make sure that we do the best, you know, for our
7 fellow citizens and we don't want to compromise
8 anybody unnecessarily when we have the science to do
9 it.
10 472. Q. You said, I think you said it was
11 devastating, is that the word that you used for people
12 to have myocarditis from COVID-19, isn't it also
13 devastating for young people, young males to have
14 myocarditis from the vaccine, Dr. Liu?
15 A. I wouldn't say devastating. It's for
16 sure, not a side effect that we like to see, and but I
17 think the, in the spectrum, you know, sort of
18 complications, in the spectrum of myocarditis, you
19 know, which we look at patients with a whole variety
20 of myocarditis, that it definitely, fortunately, you
21 know, is on the mild side that I have seen, you know.
22 So, that the patients have very limited
23 symptoms and they recover in terms of heart function
24 and they do well and they're protected from COVID-19.
25 Yeah, so I think, you know, so given that,

AR09494
DR. PETER LIU - 195
1 no question, if we don't have the side effects, it
2 would be even better. So, you know, the reason we
3 look at this condition very carefully is to find out
4 why even these people have these complications, right?
5 You know, we actually want to find out the
6 reason so we can actually avoid them. We actually now
7 have some clues as to who are the people who actually
8 have risk to develop this, you know, so that we can
9 then find alternative vaccines for them. And this
10 will be even better for, you know, in terms of risk
11 management.
12 But this was a new condition. We don't know
13 that at the time, but now we're better, you know. So,
14 once we have the information, then we'll share with
15 people to even further minimize the risk.
16 But, you know, in the spectrum of
17 myocarditis, this is as good outcome as one can hope
18 for.
19 473. Q. And, you say, again, you say it's
20 devastating. Now, did you say it was devastating for
21 people to have myocarditis from COVID-19 or
22 devastating to have COVID-19?
23 A. Yeah, devastating to have -- maybe we
24 should look at the transcript. I can't remember what
25 I said now.

AR09495
DR. PETER LIU - 196
1 474. Q. I'll just ask you about that, Dr. Liu,
2 because, and there's an aspect here that we haven't
3 discussed. And let me just pull up Dr. McCullough's
4 report.
5 MS. TELLES-LANGDON: Ms. Pejovic, while
6 you're pulling up Dr. McCullough's report, I'm just
7 noting the time. And I'm wondering how much longer
8 you have because it's 1:00 for Dr. Liu now. I'm
9 wondering when we might consider taking lunch break?
10 MS. PEJOVIC: If we could just get through
11 just a few more minutes and then we can take a lunch
12 break. And then I'm going to go to a different study
13 after that.
14 BY MR. PEJOVIC:
15 475. Q. All right. Do you have Dr.
16 McCullough's expert report in front of you, Dr. Liu?
17 A. I can bring it up.
18 476. Q. Let me know when you have it in front
19 of you.
20 A. Yeah. Sorry. Okay, yeah. So, now I
21 have the file open.
22 477. Q. Yes. And I'm looking at PDF page 200
23 in my version. That is page 15 of his expert report.
24 A. Okay, 200, okay, so let me just see.
25 Two hundred on mine, it says Canadian Report Post

AR09496
DR. PETER LIU - 197
1 COVID-19 Vaccine Myocarditis.
2 478. Q. Yes. Go to the second heading there.
3 A. Yeah.
4 479. Q. You didn't actually address these
5 paragraphs in your expert report. And I'll show you
6 what you did do. At item 5(Q), you say paragraphs 22
7 to 25, you say,
8 "...The discussions in these sections refer
9 to my earlier reports of vaccine incidents..."
10 You're talking about paragraphs 22 and 23,
11 right?
12 A. Sorry. Okay, so remind me where I am?
13 480. Q. Okay. So, in your expert report on
14 page 14 at item Q.
15 A. Oh, yes, paragraph 22 to 25, yes.
16 481. Q. Yes. You say,
17 "...The discussions in these sections refer
18 to many earlier reports of vaccine incidents..."
19 But if we look at items 22 to 25, only 22
20 and 23 report -- have to do with vaccine incidents.
21 Paragraphs 24 and 25 have nothing to do with vaccine
22 incidents, correct?
23 A. Let me just take a look, yeah. So, I
24 don't have those studies in front of me. It -- I will
25 say the one that addressed the incidents most directly

AR09497
DR. PETER LIU - 198
1 will be 20 to 23, yes.
2 482. Q. Yes. Okay, so and I understand that I
3 will be cross-examining other experts about -- who are
4 virologists and with other qualifications, but we
5 can't have this discussion, Dr. Liu, in my view,
6 without acknowledging that young people have a very
7 high infection survival rate from COVID-19, would you
8 agree with that?
9 A. Compared to?
10 483. Q. Compared to older people.
11 A. Yes.
12 484. Q. And that at paragraph 25 of Dr.
13 McCullough's report, he cites the CDC and he says,
14 "...Young people aged 18 to 29 are five
15 times less likely to be hospitalized with COVID-19
16 than someone who is 65 to 74, and 65 times less likely
17 to die from COVID-19 than someone in that age
18 group..."
19 And so would you agree with me, Dr. Liu, at
20 a basic level, that young males without comorbidities
21 have a very low risk of harm from COVID-19 as compared
22 to older people with comorbidities?
23 A. Yeah, so I think if you say death, yes,
24 that's correct, yeah, absolutely. Hospitalization is
25 less, for sure. But as we just discussed earlier,

AR09498
DR. PETER LIU - 199
1 right, in terms of long COVID, that is not the case,
2 right.
3 485. Q. Well, I think we'll disagree about long
4 COVID, and that's inconclusive. So, we'll disagree
5 with that.
6 A. Yes, until you see the patient with
7 long COVID, I think you'll be, you know, really pretty
8 impressed.
9 486. Q. I mean, it's not a controversial
10 statement that young people are less likely to have
11 negative outcomes from COVID-19.
12 A. Oh, that's absolutely true. It doesn't
13 mean that they don't have complications, right, so
14 that's what it is. Yeah, but older patients, just
15 remember how many Canadians died, right, and how many
16 people are hospitalized.
17 Remember in the US, we just passed 1 million
18 deaths.
19 487. Q. Right, and you're ---
20 A. And that's not a trivial number of
21 people, right. I just don't want to trivialize this.
22 488. Q. I understand. But, you know, your
23 expert report, you chose to include certain studies in
24 your expert report, Dr. Liu, and those studies, aside
25 from the CDC MMWR study were the Buckley study,

AR09499
DR. PETER LIU - 200
1 Chouchana and the Qin study.
2 And the people that had the negative
3 outcomes from COVID, whether that was cardiac injuries
4 or otherwise, were older people with comorbidities.
5 Those are the studies you chose to include.
6 A. I chose studies that actually have
7 large sample sizes, right, you know, and I think
8 that's what it is. And so, you want to actually have
9 -- the better study, MMWR, right, which you can
10 actually directly compare age specific abnormality.
11 As I mentioned earlier, the waves of the
12 COVID-19 infection is differential in different waves,
13 you know, because the virus has actually affected
14 different populations.
15 If you actually look at the, you know,
16 Public Health Agency of Canada, you know, rates of
17 infection, you know, in different periods, you know,
18 the curves in terms of who actually gets infected, you
19 know, just changes over time.
20 And so, that's the -- that's the -- that's
21 the nature of the virus, right. The nature of virus
22 will adapt and they will adapt to you when you
23 actually have a lot of people that vaccinated, they go
24 for the unprotected. And that's how virus survives.
25 And so, you know, it has to do with the

AR09500
DR. PETER LIU - 201
1 nature of the virus infection over different periods
2 of time. And the older folks have the largest brunt,
3 but that's also where the largest amount of data
4 that's available because the additional, more recent
5 data will take time for us to actually have available
6 to refer to.
7 MS. PEJOVIC: Okay. I think it would be
8 appropriate to take a break now.
9 MS. TELLES-LANGDON: Right.
11 MS. PEJOVIC: Okay. Before the break, we
12 were talking with Dr. Liu about the Gill study from
13 the Annals of Internal Medicine. I'd like to have
14 that study tendered as the next exhibit.
15 THE DEPONENT: Yes, sorry, Archives of
16 Pathology and Laboratory Medicine.
17 MS. PEJOVIC: Oh, I'm sorry. Thank you for
18 the correction. Yes, thank you.
19 MS. TELLES-LANGDON: Ms. Pejovic, I just
20 have a question. This indicates that it's an early
21 online release and once there's a final published
22 version, it will replace the early online release
23 version.
24 Do you know if there is a final published
25 version that has completed the peer review process?

AR09501
DR. PETER LIU - 202
1 MS. PEJOVIC: Why don't we -- I'll check
2 that at the next break. Why don't we just hold off
3 and I'll check that at the next break and just look.
4 That will take me a few minutes.
5 MS. TELLES-LANGDON: That sounds good. So
6 then, we'll wait. I don't have any objections other
7 than I note that it's possible that there's a final
8 published version and it would make sense to work with
9 the most up to date version.
10 MS. PEJOVIC: Yeah, I will take a look.
11 Okay, thank you.
12 BY MR. PEJOVIC:
13 489. Q. So, next, Dr. Liu, if you could please
14 pull up the Choi study that I e-mailed you yesterday,
15 that is in the Journal of Korean Medicine.
16 A. Okay, yeah. So, let me just, Choi,
17 yes. JKMS.
18 490. Q. Yes. And you referred a study at page
19 13 of your expert report in the first paragraph, the
20 first full paragraph. And you state that,
21 "...myocarditis and vaccination were
22 'possibly related'..."
23 Right?
24 A. Yes.
25 491. Q. Yes, and that actually wasn't the

AR09502
DR. PETER LIU - 203
1 language used by the authors themselves. The authors
2 are referring to the Acknowledgment from the Korea
3 Centre for Disease Control and Prevention who said
4 that the myocarditis and vaccination were possibly
5 related, correct?
6 And that's at page three of seven. If you
7 go there and at the third paragraph down, it starts
8 off with,
9 "...The cause of death was determined to be
10 myocarditis..."?
11 A. Yeah.
12 492. Q. And the authors state,
13 "...Given that the myocarditis showed a
14 temporal relationship to vaccine administration and
15 there was no other explanation for the sudden cardiac
16 death on July 26, 2021, Korea Centre for Disease
17 Control and Prevention acknowledge that myocarditis
18 and vaccination were possibly related...".
19 A. That's right, yeah. So, that's their
20 conclusion, yeah, from the CDC, right.
21 493. Q. Right.
22 A. And I think that's what I stated as
23 well.
24 494. Q. And again, if you go to page four of
25 seven, at the first paragraph, after footnote 14? See

AR09503
DR. PETER LIU - 204
1 that?
2 A. Or reference 14.
3 495. Q. After reference 14, it states,
4 "...The deceased was previously healthy and
5 there were no signs of infective myocarditis...".
6 A. Yes. Yes, that's right.
7 496. Q. Yes. So, this was an individual where
8 there's no evidence of a pre-existing condition,
9 correct?
10 A. That's right, yeah. And that's part of
11 the reason that you can conclude that this are
12 possibly related, exactly as a concluded, yeah. And I
13 think I agree with that conclusion.
14 497. Q. So, you would agree in this particular
15 case that the vaccine caused this death?
16 A. Yes, this is, I think, possibly
17 related. And I think I mentioned in my report has
18 indeed the second published pathology case related --
19 vaccine related myocarditis following the initial
20 report by Verma, yeah. So, I agree.
21 So, that's the two cases, remember, I
22 mentioned earlier, yeah, so this is -- I think this
23 case has the required elements, you know, we discussed
24 earlier. Patients have chest pain, you know, have the
25 symptoms, no other cause, and you actually see

AR09504
DR. PETER LIU - 205
1 inflammatory infiltrate.
2 You know, that's classic myocarditis, yeah.
3 So this case, similar to the Verma case, you know,
4 would be the type of information you look for to
5 establish the cause.
6 498. Q. Right.
7 A. Yeah, so this will be the type of
8 information that will confirm that. Yeah, so this is
9 why I say there were two report cases, and this is the
10 second case, yes.
11 499. Q. And the title of this Journal is called
12 Myocarditis Induced Sudden Death after BNT162B2 mRNA
13 COVID-19 vaccination in Korea. So, you'd agree with
14 me, Dr. Liu, that there is evidence that the COVID-19
15 vaccines can cause sudden death?
16 A. The myocarditis, right, so, myocarditis
17 induced sudden death.
18 500. Q. Yes.
19 A. Yeah, so you need all three elements to
20 make that connection, yeah.
21 501. Q. So, you would agree with me that ---
22 A. Yeah, you can't take the myocarditis
23 out, it's causing death, yeah.
24 502. Q. Yeah, the vaccine caused sudden death
25 in this case, from myocarditis, right?

AR09505
DR. PETER LIU - 206
1 A. Yes.
2 503. Q. Okay. And, at -- actually, let's
3 tender that study as the next exhibit.
4 MS. PEJOVIC: Is that all right with you,
5 Ms. Telles-Langdon?
8 --- EXHIBIT NO. 12: Choi Study 0063JKMS_jkms-36-e286
9 BY MR. PEJOVIC:
10 504. Q. At page 13 of your reports, at
11 paragraph three, and this paragraph is talking about
12 athletes. And in response to Dr. McCullough's
13 concerns about athletes being more prone to having a
14 negative reaction from the COVID-19 vaccine than the
15 general population.
16 And you state near the bottom of this
17 paragraph,
18 "...Furthermore, athletes who are in trained
19 condition are usually in paradoxically hyper vagal
20 state with slow heart rate and low blood pressure,
21 thus featuring low catecholamine levels..."
22 Are you saying, Dr. Liu, that when athletes
23 are running a marathon or playing an intensive game of
24 soccer or rugby or exercising intensely for an hour or
25 more, their heart rate is low?

AR09506
DR. PETER LIU - 207
1 A. No. This is, you know, so just
2 remember that there's 24 hours in a day and that
3 athletes will compete or exercise, right, for a brief
4 period of time. And agree with you that during that
5 time the heart rate will be high, the blood pressure
6 will be high, and the catecholamine levels will be
7 high.
8 And, but that's during that brief period
9 when they're doing exercise. And then the rest of the
10 day, will be actually situation where their heart rate
11 will be actually very low because that's kind of, we
12 call the, somebody is actually in a trained condition,
13 and the blood pressure will be low.
14 And so majority of the day of the athlete,
15 they are actually in a low catecholamine state, and
16 it's only during that brief period of exercise they
17 are in a high catecholamine state.
18 Now, I just want to make sure, because we
19 usually regard athletes to be really vagal tonic,
20 which is the opposite of having catecholamine, you
21 know, vagus nerves is parasympathetic. It actually
22 slows down the heart. It actually lowers the blood
23 pressure.
24 You know, it does all the opposite of the
25 catecholamine state. And so, that's -- we call the

AR09507
DR. PETER LIU - 208
1 conditioned individual. So, but if they are prone to
2 -- I think the idea is that the athletes are prone to
3 myocarditis or to vaccine related complications.
4 They're not receiving the vaccine when they
5 are running a marathon, right. They're actually
6 receiving the vaccine when they are, you know, in a
7 resting state. And that's, you know, 23 hours a day,
8 let's say they exercise for one hour.
9 And therefore the vaccine, in fact, is
10 exposing to generally super low catecholamine state,
11 not a high catecholamine state. So, that's why the
12 theory is a little bit of at odds, you know, with
13 what's known about athletes, right?
14 Because athletes, in fact, we know they are
15 super slow in their heartbeat, you know, their blood
16 pressure is low. You know, they are not in an
17 agitated hyper-catecholamine state. A trained
18 athlete, that is, yeah.
19 505. Q. Okay. Let's go to Section 5(T) of your
20 expert report.
21 A. Okay, 5(T). Is this a page referring
22 to paragraph 30 on page 14?
23 506. Q. Yes.
24 A. Yes, okay.
25 507. Q. You say here,

AR09508
DR. PETER LIU - 209
1 "...To propose that young males without
2 comorbidities should not receive the COVID-19 vaccines
3 would only apply if there were no more cases of COVID-
4 19 in the community..."
5 See that, so, I think I know the answer, but
6 just to clarify, it is your recommendation, Dr. Liu,
7 that two young -- that young males take two doses of
8 the COVID-19 vaccine. That's your recommendation to
9 your patients?
10 A. Yes, I recommend that and, you know,
11 with a little bit of -- if I can clarify what my
12 current recommendation is? Yeah, so my current
13 recommendation is yes, you receive the two doses, you
14 know, and then, of course, depending on the new
15 variant coming, you know, in the fall and things like
16 that, may take booster as well, but it's actually very
17 important to space out the two doses.
18 You know, so it turns out to that now we
19 learn as well, as I mentioned in terms of the risk
20 factors and things like that, is that when you
21 actually put the two doses very closely together, like
22 initially, when you actually have the one month
23 interval, that's when you actually have the highest
24 risk.
25 And similarly in Canada, when you actually

AR09509
DR. PETER LIU - 210
1 have the combination of Pfizer first, Moderna second,
2 you also get highest risk. You know, so now what we
3 recommend is, in fact, you stretch that period out,
4 you know, to over two months in between and don't have
5 the Moderna as a second, at least with the existing
6 ones available.
7 And in fact, the incidence of myocarditis is
8 super, super low.
9 508. Q. And the numbers that Dr. McCullough had
10 in his expert report, which you said were, you know,
11 from last, I believe it was September, that
12 approximately one in 2,000 young males were getting
13 myocarditis from the vaccine, from the Moderna
14 vaccine.
15 And then the Ontario government recommended
16 that young males take Pfizer instead of Moderna as a
17 result of that.
18 A. Yeah, especially second dose, yes.
19 509. Q. Right. And young males, before seeing
20 that recommendation, it's likely that they would have
21 already, some of them would have already taken the
22 Moderna vaccine prior to that recommendation, correct?
23 A. I would assume so. I'm not quite sure,
24 because Canada mainly had a Pfizer, so that's kind of
25 fortunate, right, you know, because our dominant

AR09510
DR. PETER LIU - 211
1 suppliers, Pfizer. Our Moderna doses are actually
2 relatively low.
3 So, we have much less data on that. But we
4 did actually see that trend, and that's why we made
5 that recommendation, yeah. So, it's very few
6 patients, you know, but nevertheless, you know, as
7 soon as we see a signal that may be at risk, you know,
8 we immediately, so, you know, we present that data and
9 of course, the health authorities will make the
10 decision. But I think it's based on that set of data.
11 510. Q. And it's -- I understand there's a
12 definition of what is rare from, I think you said it
13 was the CDC says rare means between one in 1,000 to
14 one in 10,000?
15 A. Yes, yes.
16 511. Q. Right. I mean, 1,000 people, is not a
17 lot of people. If you're one of those 1,000 boys
18 getting myocarditis that's significant for that
19 individual, isn't it?
20 A. I agree, except, you know, the
21 frequency of myocarditis is less than that, right.
22 So, because in fact, it's not rare, these
23 complications are not rare, but in fact, they are very
24 rare, right, you know, because we're actually talking
25 about the risk of generally in one to two per 100,000,

AR09511
DR. PETER LIU - 212
1 right.
2 But it's true that in that particular
3 combination and just look at the second dose, just
4 look at the males, just look at the age, you know,
5 between 12 to 29, you know, which is the highest risk
6 category, right, you are dealing with anywhere between
7 30 to 50 per 100,000.
8 Yeah, so still less than one in 1,000, yeah.
9 But nevertheless, no question, we don't want any
10 complications to occur, you know. So, that's the
11 reason we continuously look at the data, identify the
12 risk and optimize the recommendation, so we can really
13 minimize, you know, the risk of myocarditis.
14 Even though very fortunately, as I
15 mentioned, you know, it's actually very safe in terms
16 of from the outcomes point of view. But nevertheless,
17 you know, we'll continue to -- and we, you know, we
18 will try to find out the cause as well so that the
19 manufacturers can figure out how to avoid it all
20 together.
21 512. Q. And you'd agree with me, Dr. Liu, that
22 it's possible that some unvaccinated young males in
23 Canada may never get COVID-19. That's possible, isn't
24 it?
25 A. Yes.

AR09512
DR. PETER LIU - 213
1 513. Q. So, you are comfortable as a
2 professional, advising young, unvaccinated males to
3 take the risk with a new drug that you know can cause
4 them heart injury, when you also know they may never
5 get COVID-19?
6 A. Yeah. So, you know, you take it into
7 context. I think your question is very interesting
8 because it takes the extreme cases, right, of two
9 sides. You know, so generally, you look at the
10 individual.
11 You know, there's no, you know, sort of a
12 reason to say that they particularly would get the
13 myocarditis, right. If I know they are going to be at
14 risk for myocarditis, I would not recommend the
15 vaccine.
16 And but, then to say that they are
17 definitely not going to get COVID-19, I don't think
18 anybody at the present time will actually know that,
19 right, you know, because it's so infectious, nobody
20 even knows how one even gets it.
21 And so, I think it's a balanced risk, you
22 know. So, let's say it's a young man, sort of in my
23 office, and I would advise in terms of vaccine or no
24 vaccine, I'll say here are the facts, right. So, your
25 risk of getting COVID is, you know, I mean, it's all

AR09513
DR. PETER LIU - 214
1 in the newspapers and things like that.
2 And then -- or, sorry, young people don't
3 read newspapers, you know, so on social media or
4 whatever medium they have. And then, I'll tell them
5 the risk of getting COVID-19, the risk of getting
6 complications from it, right, because COVID-19 is just
7 not just myocarditis, but all the complications that
8 can come from it.
9 And, but balance with the fact that these
10 are the best vaccines and these are the ways to take
11 the vaccines in which you get the lowest risk of
12 complications and the frequency is such and such, you
13 know, because when you actually space them apart and
14 you just stay with Pfizer, you know, in fact, it's
15 very efficacious, even safer.
16 You know, so then the individual makes that
17 decision. You know, so that's what it is. But, you
18 know, I would say that I've been impressed, you know,
19 because I have, you know, university students, you
20 know, many young people, and in fact, they actually
21 advise each other, you know, to get the vaccine.
22 I think Canadian, particularly Canadian
23 young people, are very knowledgeable and they, you
24 know, are -- they can make very reasonable decisions.
25 And, you know, we provide the information and we want

AR09514
DR. PETER LIU - 215
1 to make sure that it is actually safe for them.
2 514. Q. Dr. Liu, prior to COVID-19, have you
3 ever in your practice, recommended to your patients a
4 medical treatment that is known to cause heart injury
5 to their specific demographic?
6 A. Have I recommend treatment -- oh,
7 sorry. Without benefits, just so that it can cause
8 heart injury, I'm trying to figure out what the
9 conversation is about.
10 515. Q. I'll ask it again.
11 A. Yes.
12 516. Q. Prior to COVID-19, have you ever before
13 recommended to your patients a medical treatment that
14 is known to cause heart injury for their specific
15 demographic?
16 A. Oh, yes. Yeah, I mean, I don't
17 purposely do that, but, you know, we have heart
18 medications that reduces symptoms, save lives. But
19 when you use them, some patients will actually have
20 troponin release.
21 And we, when the patient comes in with a
22 heart attack, we want to open up their arteries with a
23 balloon and put the stent in there. The moment you
24 actually open up that balloon, right, this is a
25 standard treatment for heart attack, the moment you

AR09515
DR. PETER LIU - 216
1 open up that balloon, you block blood flow in that
2 artery for a brief minute to put the stent in there.
3 In fact, that causes heart injury right
4 there. And this is routinely done. We explained this
5 to the patient. That's why there's a risk for the
6 procedure.
7 517. Q. And those people ---
8 A. And it saves lives, but, you know,
9 there is risk. And we know that the troponin bump
10 after angioplasty or stent procedure.
11 518. Q. And so those people that you were just
12 talking about, those patients you recommended this to,
13 those were people that already had heart problems,
14 correct, that's why they're there to see you?
15 A. Yes. Maybe another example where they
16 won't have heart problems with people with cancer and,
17 you know, when the patient have cancer, they undergo
18 either radiation or cancer chemotherapy, and, you
19 know, which is not really a heart treatment.
20 But we actually now let patients know and
21 it's mainly our cancer colleagues, because I won't see
22 those patients directly, initially, that there is
23 actually risk for heart failure. They can actually
24 die from heart disease, you know, because of the
25 cancer treatment.

AR09516
DR. PETER LIU - 217
1 Now, we very clearly know that they have
2 damaged effects on the heart. And this is actually
3 one of the major areas we actually study at the
4 present time. And it's part of the treatment
5 complication.
6 Yeah, so, you now, this is known and it's a
7 measurable risk and, you know, patients will know
8 about this risk, but it's part of their cancer
9 treatment.
10 519. Q. And have you ever -- have you ever
11 recommended to anyone a med -- sorry. Have you ever
12 recommended, in your profession, to healthy people a
13 treatment that is known to cause heart injury for
14 their specific demographic prior to COVID-19?
15 A. It's a very hypothetical situation
16 because they usually don't come and see me.
17 520. Q. Would you, excluding the COVID vaccine,
18 would you recommend a treatment to healthy people that
19 you know causes heart injury for their specific
20 demographic?
21 A. I assume this is something that's
22 actually beneficial for the patient for some reason,
23 right, because I wouldn't talk to somebody if they
24 didn't come to see me for a health problem and then
25 offer them something.

AR09517
DR. PETER LIU - 218
1 Because I, you know, there has to be an
2 indication to start with and then a risk benefit
3 evaluation.
4 521. Q. Right. And you believe, Dr. Liu, as a
5 matter of medical ethics, that it's ethical to
6 recommend a medical treatment to healthy young males
7 that could kill them in order to protect them from the
8 condition they may never have?
9 A. As I mentioned, you know, the ethical
10 thing is always balancing the risk versus benefit.
11 And if the benefit outweighs the risk, then it is the
12 right thing to do, because it protects the patient, at
13 the end of day.
14 If the risk outweighs the benefit, then it's
15 not recommended because then the patient won't benefit
16 from it. At the end of the day, it's all about
17 welfare of the patient. Doing the right thing means
18 that you favour the benefit over the risk.
19 And as I mentioned, you know, yesterday, no
20 treatment is 100 per cent effective and no treatment
21 is risk free. Every decision we make is based on that
22 and there are no -- and, you know, this is always, I
23 know, it's complicated in the legal kind of terms, you
24 know, that there is no absolutes in medicine.
25 522. Q. And you agree with me, Dr. Liu, that

AR09518
DR. PETER LIU - 219
1 it's likely that there are young, unvaccinated males
2 in Canada that may have already had COVID-19 and
3 recovered?
4 A. Yes. So, asymptomatic or are you
5 talking about symptomatic individuals?
6 523. Q. Both.
7 A. Both, yeah. Yes, oh, so, yeah,
8 majority of people probably nowadays don't report to
9 the medical system.
10 MS. PEJOVIC: All right. Ms. Telles-
11 Langdon, I'd like a few minutes to confer with my
12 colleagues. I'm nearly finished here.
13 MS. TELLES-LANGDON: Should we take five
14 minutes?
17 MS. PEJOVIC: So, subject to the
18 undertakings, we don't have any further questions, but
19 I would like to clarify about that study and I'd like
20 to put it on my screen so you can see how I found that
21 study.
22 So, I'm just going to screen share here that
23 Gill study. Okay, can you see here, Ms. Telles-
24 Langdon and Dr. Liu, can you see this?
25 MS. TELLES-LANGDON: Just for the record,

AR09519
DR. PETER LIU - 220
1 this is?
2 MS. PEJOVIC: Sorry, this is the -- it says,
3 I don't know what that -- oh, Archives of Pathology
4 and Laboratory Medicine.
5 THE DEPONENT: Right.
6 MS. PEJOVIC: Autopsy Histopathologic
7 Cardiac Findings into Adolescents Following the Second
8 COVID-19 Vaccine Dose, James Gill. It's an abstract.
9 And then if you see, I click here, on this DOI button,
10 and it takes me here, which is the Archives of
11 Pathology and Laboratory Medicine.
12 And then its content is only available as a
13 PDF. So, I click on the PDF button and then I get to
14 where we were earlier, which is here.
15 THE DEPONENT: Yeah, so I think they may
16 just still post it online and have not, you know,
17 published in the final form, yes.
18 MS. PEJOVIC: Yes, so it's the same version
19 as what we discussed and what was e-mailed this
20 morning.
21 MS. TELLES-LANGDON: That's fine. I have no
22 objections to being marked as an exhibit. I guess
23 it's still in its peer review process.
24 MS. PEJOVIC: Yes. Okay. So, please mark
25 that as the next exhibit.

AR09520
DR. PETER LIU - 221
1 --- EXHIBIT NO. 13: Autopsy Histopathologic Cardiac
2 Findings into Adolescents Following the Second COVID-19
3 Vaccine Dose, James Gill.
4 MS. TELLES-LANGDON: Thank you, Ms. Pejovic
5 of it for following up to see whether it was finalized
6 or not.
7 MS. PEJOVIC: And thank you, Dr. Liu, for
8 your time and attention to this matter. And I'd ask
9 the other -- I don't know if Mr. Ben Naoum has any
10 questions?
11 MS. TELLES-LANGDON: If you could stop
12 sharing your screen?
13 MS. PEJOVIC: Oh, sure.
14 MS. TELLES-LANGDON: I don't believe Mr. Ben
15 Naoum is on.
16 MR. WILSON: Alison, I can advise -- Keith
17 Wilson here. Can you hear me?
19 MR. BACHAND: Yes.
20 MR. WILSON: Okay. I can advise that I've
21 been monitoring our other communication channel on
22 this file, and both Samuel and Mr. Ben Naoum have
23 advised that they have no questions of this witness.
24 MS. TELLES-LANGDON: Okay. Then, Dr. Liu, I
25 only have one question in redirect. Yesterday during

AR09521
DR. PETER LIU - 222
1 cross-examination, Ms. Pejovic was asking you about a
2 grant that you received from the Canadian Institute of
3 Health Research, CIHR.
5 MS. TELLES-LANGDON: And I'm just wondering
6 if you could provide a little bit more context with
7 respect to the CIHR and their role in funding health
8 research in Canada?
9 THE DEPONENT: Right, yeah. So, the federal
10 government has, certainly in the Ministry of Health
11 but also with Ministry of Innovation, have provided
12 the federal budget in order to support peer reviewed
13 research in health.
14 And this is done through Canadian Institutes
15 of Health Research. And so, the funding allocation is
16 all through peer review, as I mentioned earlier, and
17 so that all the ideas that the people actually submit
18 to the Canadian Institutes of Health Research undergo
19 extremely rigorous peer review process.
20 You know, so for example, I'm currently
21 reviewing grants for one of the panels and so the
22 investigators across the country, you know, bring
23 their best ideas forward and a panel of 20 people
24 from, you know, various institutions without conflict
25 of interest, you know, so that's one thing, which is

AR09522
DR. PETER LIU - 223
1 the first thing we have to do, but the investigators
2 have to also declare their conflict interest, so if
3 there are any -- so, all these things are pre-managed.
4 And then we evaluated the science, you know,
5 based on the most robust criteria. But as I
6 mentioned, you know, extremely competitive, right. So
7 right now, the funding success rate is 14 per cent.
8 So, I currently have about twelve grants to
9 look at, and I know that out of these twelve, maximum,
10 two will get funded. This is how selective it is.
11 And the bar of excellence is so high, right?
12 You know, so the majority, even though
13 people put in the most effort, will not be get funded.
14 So only the best of the best science will actually go
15 forward.
16 And then usually, it has to be robust
17 design. You know, we talk about sort of design issues
18 and it needs to actually answer important questions.
19 The result will have to be scientifically robust and
20 have an impact. You know, so that's kind of the bar
21 we use.
22 And this is, you know, the best system we
23 have at the present time in terms of funding research
24 and you know, it's withstood the test of time. And
25 so, you know, Canadian research punches above our

AR09523
DR. PETER LIU - 224
1 weight in terms of the number of people we have yet in
2 terms of impact on publication, because the fact that
3 we have such a selective system and dedicated people.
4 But it's no easy journey. I constantly
5 apply for grants, you know, it's a tough journey that
6 we walk.
7 MS. TELLES-LANGDON: Okay, thank you. Those
8 are all the questions that I have in redirect, I think
9 we are done, Dr. Liu.
10
12
13
14 I hereby certify that this is the Continued
15 Cross-Examination of DR. PETER LIU, taken
16 before me to the best of my skill and
17 ability on the 2nd day of June, 2022.
18
19 ------------------------------------
21

EXHIBIT No. 8
AR09524
EXAMINATION OF
Peter Liu
DATE June 2, 2022

NETWORK COURT REPORTING
ACP Journals
O
JOtrillrh I July 2022
A°'m~ainal Study of COVID-19 Sequelae and Immunity:

Baseline Findings FREE
Michael C. Sneller, MD, C. Jason Liang, PhD, Adriana R. Marques, MD, ... View all authors+
Author, Article, and Disclosure Information
https://doi .org/10.7326/M21-4905
Eligible for CME Point- of- Care
••
Visual Abstract. A Longitudinal Study of COVID-19 Sequelae and Immunity: Baseline Findings.
A substantial proportion of persons who develop COVID-19 experience postacute sequelae of SARS-CoV-2
infection (PASC). This article reports baseline findings from an ongoing longitudinal cohort study that seeks
to characterize the risk factors, clinical findings, laboratory features, and natural history of PASC.
Download figure Download PowerPoint
PDF
Abstract Help
Background:
A substantial proportion of persons who develop COVID-19 report persistent

symptoms after acute illness. Various pathophysiologic mechanisms have
been implicated in the pathogenesis of postacute sequelae of SARS-CoV-2
infection (PASC).
AR09525
Objective:
To characterize medical sequelae and persistent symptoms after recovery

from COVID-19 in a cohort of disease survivors and controls.
Design:
Cohort study. (ClinicalTrials.gov: NCT04411147)
Setting:
National Institutes of Health Clinical Center) Bethesda) Maryland.
Participants:
Self-referred adults with laboratory-documented SARS-CoV-2 infection who

were at least 6 weeks from symptom onset were enrolled regardless of
presence of PASC. A control group comprised persons with no history of
COVID-19 or serologic evidence of SARS-CoV-2 infection) recruited regardless
of their current health status. Both groups were enrolled over the same
period and from the same geographic area.
Measurements: PDF
Help
All participants had the same evaluations regardless of presence of

symptoms) including physical examination) laboratory tests and
questionnaires) cognitive function testing) and cardiopulmonary evaluation.
A subset also underwent exploratory immunologic and virologic evaluations.
Results:
AR09526
189 persons with laboratory-documented COVID-19 (12% of whom were
hospitalized during acute illness) and 120 antibody-negative control
participants were enrolled. At enrollment) symptoms consistent with PASC
were reported by 55% of the COVID-19 cohort and 13% of control
participants. Increased risk for PASC was noted in women and those with a
history of anxiety disorder. Participants with findings meeting the definition
of PASC reported lower quality of life on standardized testing. Abnormal
findings on physical examination and diagnostic testing were uncommon.
Neutralizing antibody levels to spike protein were negative in 27% of the
unvaccinated COVID-19 cohort and none of the vaccinated COVID-19 cohort.
Exploratory studies found no evidence of persistent viral infection)
autoimmunity) or abnormal immune activation in participants with PASC.
Limitations:
Most participants with COVID-19 had mild to moderate acute illness that did
not require hospitalization. The prevalence of reported PASC was likely
overestimated in this cohort because persons with PASC may have been
more motivated to enroll. The study did not capture PASC that resolve,1
PDF
before enrollment. Help
Conclusion:
A high burden of persistent symptoms was observed in persons after COVID-

19. Extensive diagnostic evaluation revealed no specific cause of reported
symptoms in most cases. Antibody levels were highly variable after COVID-
19.
AR09527
Primary Funding Source:
Division of Intramural Research, National Institute of Allergy and Infectious

Diseases.
SARS-CoV-2 is a novel coronavirus not previously known to infect humans.

COVID-19, the clinical syndrome caused by infection with SARS-CoV-2, was
first recognized in December 2019. As of April 2022, there have been more
than 496 million COVID-19 cases worldwide (1). A significant number of
persons who contract COVID-19 report symptoms that persist after the acute
illness (2). Current studies of postacute sequelae of SARS-CoV-2 infection
(PASC) have largely been based on questionnaire data and analysis of
electronic medical records (3-8). To more objectively determine the long-
term medical and mental health consequences of COVID-19, a longitudinal
cohort study of participants recovering from COVID-19 and control
participants without a history of SARS-CoV-2 infection was initiated in June
2020. The primary objectives of the study are to characterize the risk factors,
clinical findings, laboratory features, and natural history of PASC. This
article describes baseline findings from this ongoing study. PDF
Help
Methods
Study Design
The protocol (Supplement 1) was approved by the National Institutes of

Health (NIH) Institutional Review Board. Written informed consent was
AR09528
obtained from all participants. The authors were responsible for the study
design, the collection and analysis of the data, and the preparation of the
manuscript; they vouch for the accuracy and completeness of the data and
the fidelity of the study to the approved protocol.
Enrollment in this study is ongoing. This article contains findings on the 309
participants who enrolled during the first year of the study. Given the lack of
publications with detailed clinical information and diagnostic data about
PASC, we believe that the data generated by our study to date provide new
insights into the nature and severity of this syndrome and offer important
information for physicians evaluating and treating these patients.
Participants
This article is part of a longitudinal study being conducted at the NIH

Clinical Center in Bethesda, Maryland. Adults with laboratory-confirmed
SARS-CoV-2 infection were eligible if they were at least 6 weeks past onset of
COVID-19 symptoms, had no fever within 7 days before enrollment, and did
not have worsening respiratory symptoms. Persons with asymptomati
PDF
disease were eligible 4 weeks after the first positive SARS-CoV-2 revers Help
transcriptase polymerase chain reaction (RT-PCR) test result. Both study

groups were recruited from within a 100-mile radius of Bethesda, Maryland,
an area that includes Maryland, northern-central Virginia, the District of
Columbia, and parts of southern Pennsylvania. For the COVID-19 group,
there was no active study recruitment process other than posting details of
the study on ClinicalTrials.gov and the NIH Clinical Center websites.
AR09529
Participants in the COVID-19 group were enrolled regardless of the presence
of PASC. Adults with no history of COVID-19 were recruited as a control
group via the aforementioned websites and the NIH Office of Patient
Recruitment Listserv, an e-mail list maintained for persons interested in
receiving information about participation in studies being conducted at the
NIH Clinical Center. Control participants were recruited without regard for
their current health status or active medical conditions and were not
intentionally matched with the COVID-19 group for age, gender, race, or
other variables. Both groups were required to have a negative result from a
nasopharyngeal SARS-CoV-2 RT-PCR test performed at the protocol screening
visit. For the COVID-19 group, PASC was defined as any symptom or medical
condition that began or worsened after the onset of the COVID-19 illness (or
the first positive RT-PCR result for those with asymptomatic infection) and
was still present at the study enrollment visit. The mean time from onset of
COVID-19 symptoms (or positive RT-PCR result in asymptomatic cases) to
study enrollment was 162 days. To maintain balance in the amount of time
during which symptoms were counted, for control participants, the only
symptoms or conditions that were included for comparison were thos -
PDF
began or worsened no more than 162 days before their enrollment dat Help
were still present at the study enrollment visit.
Baseline Evaluation
All participants underwent evaluations at the enrollment visit, including

past medical history, a full review of systems, and physical examination. For
past medical history (including details of acute symptoms of COVID-19 and
AR09530
preexisting medical conditions), information was collected from participants
during their initial enrollment visit and from review of existing medical
records. Thus, examiners were not blinded to study group. In addition,
participants in both groups were asked about a set of 17 specific symptoms
(see Section 1.4 of Supplement 2) reported to occur after acute COVID-19 (9-
11). Blood was collected at the enrollment visit for routine chemical analysis;
hematologic assessment; measurement of D-dimer, high sensitivity C-
reactive protein, rheumatoid factor, antinuclear antibody, anticardiolipin
antibodies, troponin I, pro-B-type natriuretic peptide, serum
immunoglobulins, and SARS-CoV-2 antibodies; and research evaluations of
immunologic parameters (see Section 1.2 of Supplement 2).
Procedures done at the enrollment visit consisted of neurocognitive

assessment, pulmonary function testing, 6-minute walk test, and
echocardiography (Section 1.3 of Supplement 2). Cognition was measured
with NIH Toolbox tasks that evaluate processing speed, episodic memory,
and executive functioning (12). The NIH Toolbox is a validated
multidimensional standard set of measures assessing cognitive, emotional,
motor, and sensory function (www.healthmeasures.net/explore- PDF
Help
measurement-systems/nih-toolbox). Neurocognitive performance on eacfi

task was assessed using standardized Tscores (mean, 50 [SD, 10]) corrected
for demographic variables, including age, gender, race, ethnicity, and
education.
Participants were asked to complete online questionnaires about their

mental and physical health. This article includes survey data on health-
AR09531
related quality of life) anxiety) and depression. Quality of life was assessed
using the Short Form-36 Health Survey (SF-36)) version 2) tabulated using
QualityMetric software to yield physical and mental health component
scores. The SF-36 is an extensively validated survey that applies norm-based
scoring based on a mean score of 50 (SD) 10) in the U.S. general population)
with higher scores indicating better quality of life (13) 14). Depression and
anxiety were assessed using the ultra-brief Patient Health Questionnaire-2
(PHQ-2) and the Generalized Anxiety Disorder-2 (GAD-2). Both
questionnaires are validated and standardized assessments of anxiety and
depression (15) 16).
Only PASC that were reported by at least 1% of participants in the COVID-19

group were included and compared with the number of participants in the
control group reporting the same symptoms. For continuous variables)
unadjusted comparisons were made using the ttest or the Wilcoxon rank-
sum test) and adjusted comparisons were made using multivariate linear
regression. For binary variables) unadjusted comparisons were made PDF
Help
the Fisher exact test) and adjusted comparisons were made using
multivariate logistic regression. For the COVID-19 group) associations
between predictors and the presence of PASC were quantified using the
Fisher exact test for binary predictors and univariate logistic regression for
continuous predictors. The association between time and binding inhibition
percentage was quantified using the Spearman correlation. The Benjamini-
Hochberg procedure for controlling the expected false discovery rate at 10%
AR09532
was used to determine which results were significant. All Pvalues are 2-
sided. Adjustment variables were specified before analysis based on a
subjective synthesis of literature review and clinical experience. Missing
data were minimal and were assumed to be missing completely at random.
All analyses were performed using R, version 4.1.1 (R Foundation for
Statistical Computing). We used Fisher.exact for the Fisher exact test,
wilcox.test for the Wilcoxon rank-sum test, t.test for the ttest, car.test and
the bootstrap for the Spearman correlation, glm for multivariate regressions,
and p.adjust with method="BH" to calculate false discovery rate-adjusted P
values. The original protocol anticipated an approximately equal number of
survivors and control participants. Based on this assumption, for a binary
outcome with 5% incidence in the control group, using a univariate logistic
regression with 200 survivors and 200 control participants would allow for
detection of a relative risk of 2.6 with 80% power at a 2-sided significance
level of 0.05. Section 1.1 of Supplement 2 provides additional details on the
statistical methods, and Section 1.2 of Supplement 2 gives additional details
on the analytic methods for the high-dimensional flow cytometry data.
PDF
Role of the Funding Source Help
This study was funded by the Division of Intramural Research at the National
Institute of Allergy and Infectious Diseases and, in part, with federal funds
from the National Cancer Institute, National Institutes of Health, under
contract no. 75N91019D00024. All analyses of biological material were done
in a blinded manner at laboratories affiliated with the funding source.
AR09533
Results
Participants
From 30 June 2020 to 1 July 2021) the study enrolled 189 persons with prior
laboratory-documented SARS-CoV-2 infection and 122 control participants
with no history of COVID-19-like illness. Two of the control participants had
antibodies to SARS-CoV-2 nucleocapsid protein and were not included in the
analysis (Appendix Figure). The control group was smaller than the COVID-
19 group because of slower accrual of the former. Baseline participant
characteristics are shown in Table 1) and the period of enrollment in each
cohort is shown in Figure 1 of Supplement 2.
Table 1. Baseline Characteristics of Participants
•••
••• PDF
Help
Appendix Figure. Study flow diagram.
In the COVID-19 group) 167 participants (88%) had an illness that did not
require hospitalization. The median time from onset of COVID-19 symptoms
(or positive RT-PCR result in asymptomatic cases) to study enrollment was
AR09534
149 days (IQR, 105 to 210 days). At the time of enrollment, 104 (55%)
participants in the COVID-19 group reported 1 or more PASC (Table 1).
Because SARS-CoV-2 vaccines were introduced during the study period,

serologic testing for antibody to the SARS-CoV-2 nucleocapsid protein was
used to document prior infection. Antibody was detected in 159 participants
with COVID-19 at the time of enrollment. Of the 30 participants with COVID-
19 who were antibody-negative at enrollment, 27 had documented detection
of SARS-CoV-2 RNA by RT-PCR testing of a nasopharyngeal sample. The
remaining 3 participants had documented SARS-CoV-2 antinucleocapsid
protein antibody detected within 90 days of an acute respiratory illness
consistent with COVID-19 but tested negative for antibodies at the
enrollment visit. Fourteen of the 30 nucleocapsid antibody-negative
participants had 1 or more PASC.
Clinical and Laboratory Findings
Participants in the COVID-19 group reported more symptoms than those in

the control group. Table 2 lists the prevalence of specific symptoms re
PDF
in both groups. For participants with PASC, the median number of Help
symptoms was 2 (IQR, 1 to 4). The most frequent PASC were fatigue, dyspnea,
parosmia, concentration impairment, headache, memory impairment,
insomnia, chest discomfort, and anxiety.
Table 2. Selected Symptoms, Physical Findings, Questionnaires, and Cognitive Testing Results
•••
AR09535
Abnormal findings on physical examination were less common than

reported symptoms and did not correlate with the presence of specific
symptoms in either group (Table 2; Section 2.1 of Supplement 2). The only
significant difference in physical findings between groups was the
proportion of participants with abnormal musculoskeletal findings (8% in
the COVID-19 group vs. 1% in the control group; odds ratio [OR], 10.95 [95%
CI, 1.66 to 464.39]; P= 0.004; adjusted P= 0.014). The most common
abnormal musculoskeletal findings in the COVID-19 and control groups,
respectively, were localized bursa, muscle, or tendon tenderness (3% vs.
0.8%); unilateral bony swelling consistent with osteoarthritis (1.5% vs. 0%);
and postoperative changes (1.0% vs. 0%). No participant in either group had
physical findings of inflammatory synovitis or myositis.
Plasma levels of C-reactive protein, D-dimer, and biomarkers of cardiac

injury or dysfunction (troponin I, pro-B-type natriuretic peptide) and of
brain injury (neurofilament light chain) also did not differ significantly
between groups (Table 3). Results of laboratory measurements assessing
PDF
renal, hepatic, and hematopoietic function did not reveal clinically re:
Help
differences between groups (Table 1 of Supplement 2).
Table 3. Selected Laboratory and Diagnostic Testing Results
•••
AR09536
The prevalence of antinuclear antibodies) rheumatoid factor) and
anticardiolipin antibodies did not differ significantly between groups (Table '
3). No participant in either group who tested positive for an autoantibody
had any clinical or laboratory findings compatible with systemic lupus
erythematosus) polymyositis) rheumatoid arthritis) or thrombotic events.
The proportion of participants with abnormal findings on pulmonary

function testing (spirometry) lung volumes) and diffusion capacity) was
similar between groups (Table 3). The most common abnormality reported
in both groups was a mild defect in diffusion of carbon monoxide (8% in the
COVID-19 group and 13% in the control group) (Table 2 of Supplement 2).
Abnormal findings on transthoracic echocardiography were found in 17% of

participants in the COVID-19 group versus 18% in the control group (Table
3). The most common abnormality reported in both groups was chamber
enlargement (12% in both groups) (Table 2 of Supplement 2).
The median distance walked during standardized 6-minute walk testing was
shorter in the COVID-19 group than the control group (560 vs. 595 m; mean
difference) -24 m [CI) -41 to -7 m]; P= 0.006; adjusted P= 0.021) (Tabl1 PDF
Help
Two participants in the COVID-19 group showed a decrease in oxygen

saturation (5% for both) during the walk test) as did 2 in the control group
(7% and 4%).
In addition to protocol-defined procedures) other diagnostic testing was

performed if clinically indicated to evaluate specific symptoms. The results
of that testing are described in Section 2.2 of Supplement 2.
AR09537
Risk Factors and Associations With PASC
Of the potential pre-COVID-19 risk factors shown in panel A of Figure 1, only

female gender (OR, 2.34 [CI, 1.25 to 4.41]; P= 0.005; adjusted P= 0.033) and
self-reported history of anxiety disorder (OR, 2.78 [CI, 1.35 to 5.98]; P= 0.003;
adjusted P= 0.027) were significantly associated with increased risk for
PASC.
•••
Figure 1. Risk factors and associations with PASC.
6MWT = 6-minute walk test distance (in meters); BMI = body mass index; CRP = C-reactive protein; eGFR =
estimated glomerular filtration rate; GAD-2 = Generalized Anxiety Disorder-2; MCS = mental component
summary; NF-L = neurofi.lament light chain; NIH= National Institutes of Health; PASC = postacute sequelae of
SARS-CoV-2 infection; PCS= physical component summary; PFT = pulmonary function test; PHQ-2 = Patient
Health Questionnaire-2; pro-BNP= pro-B-type natriuretic peptide; SF-36 = Short Form-36 Health Survey
(version 2). A. Odds ratios with 95% Cis quantifying univariate associations between pre-COVID-19
characteristics and presence of any PASC at the baseline visit. Mood disorders include bipolar disorder and
depression. B. Odds ratios with 95% Cis quantifying univariate associations between results of diagnostic
testing done at the baseline visit and presence of any PASC. C. Odds ratios with 95% Cis quantifying
univariate associations between scores on health surveys completed by participants at the baseline visit and
presence of PASC.

PDF
Help
We found minimal to no associations between results of diagnostic testing

and presence of PASC (Figure 1, B) . The distance walked in 6 minutes, an
abnormal pulmonary function test result, or an abnormal echocardiogram
were not significantly associated with the presence of PASC (Figure 1, B) or
the presence of persistent cardiopulmonary symptoms (dyspnea, chest pain,
cough, palpitations), neurologic symptoms (concentration impairment,
memory impairment, headache, parosmia, paresthesia), or fatigue (Figure 2
AR09538
of Supplement 2). Laboratory biomarkers of inflammation (C-reactive
protein, D-dimer) and organ-specific tissue damage (pro-B-type natriuretic '
peptide, troponin I, neurofilament light chain, estimated glomerular
filtration rate) were also not significantly associated with PASC or with
persistent fatigue, cardiopulmonary symptoms, or neurologic symptoms
(Figure 1, B; Figure 2 of Supplement 2).
Neurocognitive Testing and Health Surveys
No significant differences were found between groups in NIH Toolbox scores

for processing speed, episodic memory, and executive functioning (Table 3).
Performance scores for the 3 NIH Toolbox domains were not significantly
associated with PASC or with persistent fatigue, neurologic symptoms, or
cardiopulmonary symptoms (Figure 1, B; Figure 2 of Supplement 2).
Quality of life was assessed using the SF-36 physical and mental health
component scores. Scores were lower in participants in the COVID-19 group
than the control group (Table 2). This difference was driven by participants
with PASC, who had significantly lower values for both the physical ar -
PDF
mental health component scores compared with those without PASC ( Help
3 of Supplement 2). Lower SF-36 scores were associated with presence of

PASC (Figure 1, G).
The GAD-2 and PHQ-2 surveys were used to screen for current anxiety and
depression symptoms, respectively. A total score of 3 or greater is a
recommended cutoff on each measure for identifying persons who warrant
further evaluation for generalized anxiety or depressive disorder (16). The
AR09539
proportion of participants with GAD-2 anxiety scores above the cutoff was
significantly higher in the COVID-19 group than in the control group (14% vs. '
3%; OR) 6.0 [CI) 1.8 to 31.9]; P< 0.001; adjusted P= 0.004) (Table 2). A GAD-2
score of 3 or above was significantly associated with the presence of any
PASC (OR) 7.97 [CI) 2.23 to 43.62]; P< 0.001; adjusted P= 0.004) (Figure 1) G).
The proportion of participants in the COVID-19 group with a PHQ-2
depression score above the cutoff was also significantly higher (11 % vs. 4%;
OR) 3.2 [CI) 1.0 to 13.4]; P= 0.040; adjusted P= 0.087) (Table 2); however) a
higher PHQ-2 score was not significantly associated with the presence of
PASC (OR) 1.94 [CI) 0.63 to 6.65]) (Figure 1) G).
Immunologic and Virologic Studies
To address the possibility that persistent activation of the immune system

might play a role in the pathogenesis of PASC) plasma samples from a
subgroup of participants were selected for inflammatory biomarker analysis.
Because recent vaccination could affect plasma levels of inflammatory
biomarkers and confound the interpretation of results) we selected samples
from a subgroup of 48 participants with PASC) 52 without PASC) and 5 PDF
Help
control participants who had not received a SARS-CoV-2 vaccine before oo

sample collection. No significant differences were detected between groups
in plasma levels of macrophage inflammatory protein-lB) interferon-y) tumor
necrosis factor-a) programmed cell death ligand-I) interferon y-induced
protein 10) interleukin-2 receptor a) interleukin-lB) interleukin-6)
interleukin-8) RANTES (regulated on activation) normal T cell expressed and
secreted), and CD40 (Figure 4 of Supplement 2). We did find that plasma
AR09540
levels of granzyme B were higher in the COVID-19 group (P< 0.001; adjusted
P< 0.001) (Figure 2, A); however, no significant difference in granzyme B
levels was found between participants with and without PASC (P= 0.53)
(Figure 2, A).
•••
Figure 2. Characterization of immune parameters in study participants.
PASC = postacute sequelae of SARS-CoV-2 infection; TEM = effector memory T cells. A. Plasma levels of
granzyme B among study participants. Pvalues were calculated using the Wilcoxon rank-sum test. B.
Comparison of the frequency of CD4+ CD25+ TEM cells (cluster 6) in the peripheral blood of study participants.
Pvalues were calculated using the Wilcoxon rank-sum test. C. Percentage inhibition of angiotensin-
converting enzyme 2 (ACE2) receptor binding to the SARS-CoV-2 receptor-binding domain (RBD) in sera from
study participants, using a surrogate neutralizing antibody binding assay (17). The dashed line represents the
assay cutoff (30% inhibition). "Not vaccinated" refers to participants who had not received a SARS-CoV-2
vaccine dose before study enrollment, and "vaccinated" refers to participants who had received 2:1 SARS-CoV-2
vaccine dose after infection but before study enrollment. Pvalues were calculated using the ttest. D.
Percentage inhibition of ACE2 receptor binding to the SARS-CoV-2 RBD as a function of time from COVID-19
symptom onset to study enrollment. The dashed line represents the assay cutoff (30% inhibition).
High-dimensional flow cytometry was performed on peripheral blood T cells

from a subset of 139 unvaccinated participants in the COVID-19 group ~nil 7'x
PDF
unvaccinated control participants to evaluate phenotypic markers of
Help
lymphocyte activation. Frequencies of CD4+ and CD8+ T-lymphocyte subsets

did not differ significantly between groups (Figure 5 of Supplement 2).
Optimized t-distributed stochastic neighbor embedding and FlowSOM
analyses identified 15 distinct T-cell clusters (Figure 6 of Supplement 2).
Among these, only the frequency of CD4+ T-cell cluster 6, an effector
memory phenotype with elevated expression of CD25, met the criteria for
significance, being higher in the COVID-19 group than in the control group
AR09541
(P= 0.002; adjusted P= 0.029) (Figure 2, B; Figure 6 of Supplement 2).
However, there was no significant difference for this T-cell subpopulation in '
the COVID-19 group between those with and those without PASC (P= 0.78)
(Figure 2, B).
To assess for evidence of persistent SARS-CoV-2 infection in the COVID-19

cohort, plasma samples from 125 participants (63 with PASC and 62 without)
were tested for SARS-CoV-2 nucleocapsid protein. One participant without
PASC had a low-level positive result (10 pg/mL [assay cutoff, 3 pg/mL]), and a
single participant with PASC had a detectable signal that was below 3 pg/mL.
No signal was detected in the remaining 121 samples.
Serologic Testing
All participants were tested for antibodies to the SARS-CoV-2 spike protein
using a surrogate neutralizing antibody binding assay (17). For the 142
participants in the COVID-19 group who had not received a SARS-CoV-2
vaccine before the enrollment visit, the median binding inhibition level was
61.5% (IQR, 28.0% to 88.8%), with 39 (27%) participants showing a lev( -
PDF
below the assay cutoff of 30% (Figure 2, C). The percentage binding Help
inhibition in the unvaccinated COVID-19 group did not correlate with time
from COVID-19 symptom onset to study enrollment (Spearman correlation,
-0.03 [CI, -0.19 to 0.13]; P= 0.71) (Figure 2, D).
Forty-seven (25%) of the participants in the COVID-19 group received a SARS-

CoV-2 vaccine after infection but before study enrollment, and 35 (29%)
control participants were vaccinated before enrollment. The median time
AR09542
from vaccination to the baseline visit was 31 days (IQR, 15.5 to 57 days) in the
COVID-19 group and 45 days (IQR, 27 to 94 days) in the control group. For the '
COVID-19 group, the percentage inhibition value in those who were
vaccinated before enrollment was higher than in those who had not been
vaccinated (mean difference, 40.3% [CI, 34.8% to 45.6%]; P< 0.001) (Figure 2,
C). The percentage inhibition was similar between vaccinated participants in
the COVID-19 group and vaccinated control participants (mean difference,
2.9% [CI, 0.1 % to 5.6%]; P= 0.041) (Figure 2, C).
Discussion
In this COVID-19 cohort, 55% of participants reported 1 or more persistent

postacute symptoms, such as fatigue, dyspnea, chest discomfort, parosmia,
headache, insomnia, memory impairment, anxiety, and concentration
impairment. These symptoms are similar to what has been reported in
questionnaire-based studies of PASC (3-7). In our cohort, the risk factors for
developing PASC were female gender and pre-COVID-19 history of anxiety.
In contrast to other reports describing persistent post-COVID-19 sym1 PDF

(3-8, 18), our study used protocol-prespecified diagnostic evaluations · Help
were conducted in all participants. We enrolled persons with a spectrum of

initial COVID-19 disease severity and without regard for the presence of
PASC. In addition, we concurrently enrolled a control group similar to the
COVID-19 group in age and demographic characteristics with no clinical
history or serologic evidence of prior SARS-CoV-2 infection. Thus, we were
able to compare findings in persons with PASC versus both a control group
AR09543
without evidence of SARS-CoV-2 infection and a COVID-19 group without
PASC.
Abnormal findings on physical examination and routine laboratory

evaluation were uncommon and occurred with similar frequency in the
COVID-19 and control groups. Levels of plasma inflammatory markers, levels
of biomarkers for cardiac and central nervous system injury, and presence of
select autoantibodies were similar between groups and were not associated
with the presence of PASC. Results of pulmonary function testing, 6-minute
walk testing, and echocardiograms were normal in the majority of
participants in both groups. Mild to moderate abnormalities on pulmonary
function testing and echocardiography were detected at a similar frequency
in both groups and were not associated with the presence of PASC. No
significant differences were found in neurocognitive testing scores between
groups, and scores were not associated with PASC or self-reported post-
COVID-19 neurocognitive symptoms.
Despite the largely normal findings on objective testing, the presence of

PASC had a significant effect on self-reported physical and mental hea PDF
Participants with PASC reported lower quality of life than either parti .L Help
with COVID-19 without PASC or control participants, as measured by the

mental and physical health components of the SF-36 Health Survey. Self-
reported current anxiety, as measured by the GAD-2 questionnaire, was
significantly associated with PASC. This finding suggests that reported
anxiety after COVID-19 may reflect the uncertainty and worry felt by those
experiencing persistent unexplained symptoms.
AR09544
Aberrant immune activation, possibly secondary to persistent SARS-CoV-2
infection, has been suggested as a cause of PASC (19, 20). We did not find
evidence of persistent viral infection when we tested for SARS-CoV-2 RNA in
nasopharyngeal specimens and the presence of viral nucleocapsid protein in
plasma. These negative results cannot rule out possible occult viral infection
in deep tissues that cannot be easily accessed. Using measurements of
soluble markers of inflammation and high-dimensional T-cell phenotyping,
we were unable to find evidence of ongoing systemic inflammation or
immune activation in participants in the COVID-19 group who had PASC.
Only plasma levels of granzyme Band a CD4+ CD2s+ T-lymphocyte subset
with an effector memory phenotype were significantly increased in the
COVID-19 group compared with control participants. However, neither of
these parameters differed significantly in participants with versus without
PASC, suggesting they reflect recent SARS-CoV-2 infection rather than being
a factor in the pathogenesis of PASC. These negative findings combined with
the lack of objective evidence of tissue damage or organ dysfunction on
diagnostic evaluations suggest that persistent, abnormal immune activation,
if present, is not causing ongoing organ damage in persons in our co,
PDF
cohort. Help
Evaluation of neutralizing antibodies using a surrogate binding inhibition

assay showed that 39 of the 142 unvaccinated participants in our COVID-19
cohort had binding inhibition levels below the cutoff of 30% and thus would
be considered antibody-negative by this emergency use-authorized test. The
47 participants in the COVID-19 cohort who were vaccinated after infection
but before study enrollment showed significantly higher antibody levels than
AR09545
the unvaccinated group, with all having binding inhibition levels greater
than 85%. These findings indicate that there may be a subpopulation of
recovered patients with antibody concentrations below a protective level and
suggest that vaccination after natural infection provides a significant boost
in neutralizing antibodies.
Our results have several limitations. First, most participants with COVID-19
in our study had mild to moderate initial illness that did not require
hospitalization. Thus, our findings may not represent the full spectrum and
severity of PASC experienced by persons with severe disease requiring
hospitalization. Second, although we enrolled participants regardless of the
presence of PASC, our study probably overestimated the prevalence of
persistent post-COVID-19 symptoms because persons with PASC were likely
more motivated to enroll. Third, control participants were not intentionally
age- or gender-matched to participants with COVID-19. Fourth, PASC that
resolved before study enrollment were not captured in our cohort. Finally,
this report contains detailed data on 189 COVID-19 survivors, a sample size
that may not fully capture all PASC.
PDF
In summary, these initial observations in a cohort of persons with Help
predominantly mild to moderate COVID-19 and control participants without

evidence of prior SARS-CoV-2 infection provide insights into the nature and
severity of PASC. For participants with PASC, an extensive diagnostic
evaluation failed to reveal a cause of reported symptoms in most cases.
Exploratory studies did not show evidence of abnormal systemic immune
activation or persistent viral infection in participants with PASC. The
AR09546
constellation of subjective symptoms in the absence of objective
abnormalities on diagnostic evaluation resembles what has been described '
with other illnesses, including chronic fatigue syndrome/myalgic
encephalomyelitis (21), postinfection syndromes described after resolution
of certain viral and bacterial infections (22-25), and mental health disorders
such as depression and anxiety (26). The pathogenesis of PASC remains
unclear and requires further study.
Comments
4Comments SIGN IN TO SUBMIT A COMMENT
Laura C. Chambers, PhD, MPH; Francesca L. Beaudoin, MD, PhD, MS • Department of Epidemiology and Long COVID
In itiative, Brown University • 13 July 2022
Our Early Work on PASC Must Not Exacerbate Stigma
Sneller and colleagues' recent article 1 received controversial coverage in social media for their conclusions
that extensive diagnostic evaluation did not identify a cause of post-acute sequelae of COVID-19 (PASC) and
people with a history of anxiety disorder are at increased risk of PASC. While we may be apt to dismiss such
critiques in the age of misinformation, it is worth further examination lest we draw erroneous inference
about anxiety and PASC.
The authors' primary analyses included 189 participants with a history of COVID-19 (104 with and 8! PDF
PASC). Ignoring power lost due to (appropriate) correction of the false discovery rate, the study sam
Help
sufficiently powered to detect an odds ratio of 4.6 (assuming 5% prevalence of the characteristic among
controls). An effect size of this magnitude is large and probably unreasonable given that PASC may represent
multiple distinct conditions with different etiologies and risk factors. Exploratory immunologic and virologic
evaluations included an even smaller subset of 100 participants further limiting power. The noted absence of
associations may be true or simply due to limited power.
Importantly, the study measured prevalent PASC at study enrollment, which occurred about five months after
COVID-19 onset. Given that some patients experience symptom resolution within five months, 2 participants
with resolved PASC at enrollment would have been misclassified as controls "without PASC," biasing results
towards the null. The design was also subject to recall and selection bias that would have been mitigated with
a prospective design or different sampling scheme. It is not surprising that people with a history of anxiety
AR09547
who thought they had PASC might be more apt to volunteer for a study about PASC. The authors acknowledge
the limitations of self-referral, but it is also important to highlight how different this sample is from the
general population. For example, 48% of participants had an advanced degree versus 13% of the US
population. 3 Finally, analyses of risk factors for PASC were unadjusted, so associations may have been
confounded by measured (e.g., female sex is associated with both PASC and anxiety disorders) and
unmeasured (e.g., genetic) characteristics. 4
This study contributes much needed data on PASC and highlights critical areas for future research. However,
we must not draw broad conclusions from a small study with important limitations, and appropriate
messaging around the science is critical. Patients' with PASC already experience stigma and difficulty
accessing care; 5 our early work on PASC should not exacerbate this.
References
l. Sneller MC, Liang CJ, Marques AR, et al. A Longitudinal Study of COVID-79 Sequelae and Immunity:
Baseline Findings. Ann Intern Med2022; Epub ahead of print.
2. UpToDate. Type, Proportion, and Duration of Persistent COVID-79 Symptoms. Available at:
https://www.uptodate.com/contents/image/print?imageKey=PULM%2Fl30356. Accessed : July 7,
2022.
3. US Census Bureau. Educational Attainment in the United States: 2078 (Table 2). Available at:
https://www.census.gov/data/ta bles/2078/demo/ed ucation-atta in ment/cps-deta i led-ta bles.htm I.
Accessed: July 7, 2022.
4. DeMartini J, Patel G, Fancher TL. Generalized Anxiety Disorder. Ann Intern Med2079; l70(7}:ITC49-64.
5. Corna R, MacDermott N, Rayner C, et al. Long COVID Guidelines Need to Reflect Lived Experience.
Lancet2027; 397(70273):455-457.
Disclosures:
The Long COVID Initiative at the Brown School of Public Health is supported by the Hassenfeld Family
Foundation. All authors declare that they have no conflicts of interest.
PDF
Michael Sneller, Tae-Wook Chun • National Institute of Allergy and Infectious Diseases, National Institutes ~f Healn
-- =
1
; •
-------- ~
Bethesda, Maryland • 26 May 2022
Author Response to Dattner
We looked for evidence of general immune activation as described in the manuscript and did not claim to
have "ruled-out" immune activation or any other process as a cause for PASC. We only indicated that we did
not find evidence of systemic immune activation using the assays described in the paper. Given the lack of
objective evidence for ongoing tissue damage in any organ system in our study to date, it is not clear what
autologous tissues should be tested for "lymphocyte activation'' and how such autologous tissue (e.g. brain,
heart, lung) could be safely and ethically obtained from protocol participants for testing.
AR09548
Disclosures:
Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfinterestForms.do?

msNum=M21-4905.
Zephan Melville, Ph.D. • Columbia University Irving Medical Center • 26 May 2022
Assessment of amyloid fiber deposits

Were you able to assess the presence of blood clots in patients in this study? I saw that the timeline of
your study predates publications regarding amyloid fiber deposits, termed microdots (Aug 2021), so it
may have gone entirely unnoticed, but I am also curious if you became aware of these results between
the end of the study and the time of publication as I think this would be a vital biomarker to discuss. If
not, I have linked the relevant articles below and would be interested in any commentary you may have
on microdots in regards to this study.
Publications by Douglas Kell showing evidence of microdots in long-covid patients:

https://pubmed.ncbi.nlm.nih.gov/34425843/
https://www.ncbi.nlm.nih.gov/pmc/artic1es/PMC8380922/
https://www.researchsquare.com/artic1e/rs-l205453/v2 (pre-print)
Alan M Dattner, MD • HolisticDermatology.com • 25 May 2022
Cross-reactive immune activation not explored
Studies of lymphocyte activation to autologus tissue) either uninfected) or modified by occult viral infection)
have not been done. The possibility of autoimmune activity causing long Covid from these mechanisms has
not really been ruled out.
PDF
( PREVIOUS ARTICLE
)( NEXT ARTICLE )
Help
AR09549
Morbidity and Mortality Weekly Report (MMWR)
Weekly / April 8, 2022 / 71(14);517-523
On April 1, 2022, this report was posted online as an MMWR Early Release.
Jason P. Block, MD1; Tegan K. Boehmer, PhD2; Christopher B. Forrest, MD, PhD3; Thomas W. Carton, PhD4; Grace M. Lee, MD5;
Umed A. Ajani, MBBS2; Dimitri A. Christakis, MD6; Lindsay G. Cowell, PhD7; Christine Draper1; Nidhi Ghildayal, PhD1; Aaron M.
Harris, MD2; Michael D. Kappelman, MD8; Jean Y. Ko, PhD2; Kenneth H. Mayer, MD9; Kshema Nagavedu, MPH1; Matthew E.
Oster, MD2,10; Anuradha Paranjape, MD11; Jon Puro, MPA12; Matthew D. Ritchey2; David K. Shay, MD2; Deepika Thacker, MD13;
Adi V. Gundlapalli, MD, PhD2 (View author affiliations)
View suggested citation
Summary Article Metrics

What is already known about this topic?
Altmetric:
Studies have found an increased risk for cardiac complications after SARS-CoV-2 infection News (185)
Blogs (4)
and mRNA COVID-19 vaccination, but few have compared these risks. Policy
documents
(1)
What is added by this report? Twitter (4280)
Facebook (5)
Wikipedia (1)
Data from 40 health care systems participating in a large network found that the risk for
Reddit (4)
cardiac complications was significantly higher after SARS-CoV-2 infection than after mRNA Video (1)
COVID-19 vaccination for both males and females in all age groups. Mendeley
(27)
What are the implications for public health practice?

Citations: 7
These findings support continued use of recommended mRNA COVID-19 vaccines among
all eligible persons aged ≥5 years. Views: 155,821
Views equals page views
plus PDF downloads
Metric Details
Tables
Table 1
Table 2
Table 3
References
 View Larger
Related
Cardiac complications, particularly myocarditis and pericarditis, have been associated with Materials
SARS-CoV-2 (the virus that causes COVID-19) infection (1–3) and mRNA COVID-19 vaccination
(2–5). Multisystem inflammatory syndrome (MIS) is a rare but serious complication of SARS-
CoV-2 infection with frequent cardiac involvement (6). Using electronic health record (EHR) PDF  [140K]
data from 40 U.S. health care systems during January 1, 2021–January 31, 2022, investigators
calculated incidences of cardiac outcomes (myocarditis; myocarditis or pericarditis; and
myocarditis, pericarditis, or MIS) among persons aged ≥5 years who had SARS-CoV-2 infection,
AR09550
stratified by sex (male or female) and age group (5–11, 12–17, 18–29, and ≥30 years). Incidences of myocarditis and
myocarditis or pericarditis were calculated after first, second, unspecified, or any (first, second, or unspecified) dose of mRNA
COVID-19 (BNT162b2 [Pfizer-BioNTech] or mRNA-1273 [Moderna]) vaccines, stratified by sex and age group. Risk ratios (RR)
were calculated to compare risk for cardiac outcomes after SARS-CoV-2 infection to that after mRNA COVID-19 vaccination.
The incidence of cardiac outcomes after mRNA COVID-19 vaccination was highest for males aged 12–17 years after the
second vaccine dose; however, within this demographic group, the risk for cardiac outcomes was 1.8–5.6 times as high after
SARS-CoV-2 infection than after the second vaccine dose. The risk for cardiac outcomes was likewise significantly higher after
SARS-CoV-2 infection than after first, second, or unspecified dose of mRNA COVID-19 vaccination for all other groups by sex
and age (RR 2.2–115.2). These findings support continued use of mRNA COVID-19 vaccines among all eligible persons aged ≥5
years.
This study used EHR data from 40 health care systems* participating in PCORnet, the National Patient-Centered Clinical
Research Network (7), during January 1, 2021–January 31, 2022. PCORnet is a national network of networks that facilitates
access to health care data and interoperability through use of a common data model across participating health care systems
(https://pcornet.org/data  ). The PCORnet Common Data Model contains information captured from EHRs and other health
care data sources (e.g., health insurance claims), including demographic characteristics, diagnoses, prescriptions, procedures,
and laboratory test results, among other elements. The study population included persons with documented SARS-CoV-2
testing, viral illness diagnostic codes, or COVID-19 vaccination during the study period. Data were obtained through a single
query that was executed by participating health care systems to generate aggregated results.
Five cohorts were created using coded EHR data among persons aged ≥5 years: 1) an infection cohort (persons who received
≥1 positive SARS-CoV-2 molecular or antigen test result); 2) a first dose cohort (persons who received a first dose of an mRNA
COVID-19 vaccine); 3) a second dose cohort (persons who received a second dose of an mRNA COVID-19 vaccine); 4) an
unspecified dose cohort (persons who received an mRNA COVID-19 vaccine dose not specified as a first or second dose); and
5) an any dose cohort (persons who received any mRNA COVID-19 vaccine dose). The any dose cohort is a combination of the
other three vaccination cohorts; persons who received 2 doses were included twice in this cohort, once for each dose.†
Vaccine doses specifically coded as booster or extra doses were excluded. Persons with a positive SARS-CoV-2 test result ≤30
days before receipt of an mRNA COVID-19 vaccine were excluded from the vaccine cohorts; persons who had received an
mRNA COVID-19 vaccine dose ≤30 days before a positive SARS-CoV-2 test result were excluded from the infection cohort. In
the infection cohort, there were no other exclusions based on vaccination status. The following index dates were used for
cohort entrance: first positive SARS-CoV-2 test result for the infection cohort; first vaccination for the first dose cohort; second
vaccination for the second dose cohort; the single vaccination for the unspecific dose cohort; and the first, second, and
unspecified vaccination for the any dose cohort. Persons could be represented twice in the any dose cohort if they received a
first and second dose; they would have a different index date for each of the doses.
Incidence of three cardiac outcomes (myocarditis; myocarditis or pericarditis; and myocarditis, pericarditis, or MIS) were
defined using International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnostic codes§
within 7-day or 21-day risk windows after the index date; persons who had received any of these diagnoses during the year
preceding the index date were excluded. The outcome including MIS was only assessed for the infection cohort because the
rare reports of MIS after mRNA COVID-19 vaccination typically had evidence of previous SARS-CoV-2 infection (8); a 42-day risk
window also was used for this outcome to allow for a possible long latency between infection and diagnosis of MIS (6).¶
Because persons with MIS who have cardiac involvement might only receive an ICD-10-CM code for MIS, rather than
myocarditis or pericarditis, this combined outcome allowed for a comprehensive capture of potential cardiac complications
after infection. Nearly 80% of cases of MIS have cardiac involvement (9). Cohorts were stratified by sex and age group.
The sex- and age-stratified incidences of the cardiac outcomes (cases per 100,000 persons) were calculated within 7-, 21-, or
42-day risk windows. Unadjusted RRs and 95% CIs were calculated as the incidences of the outcomes within the infection
cohort divided by the incidences in the first, second, unspecified, and any dose cohorts separately for each sex and age
stratum. RRs whose CIs did not include 1.0 were considered statistically significant; RRs were not compared across outcomes,
risk windows, vaccine dose, or sex and age stratum. This activity was reviewed by CDC and was conducted consistent with
applicable federal law and CDC policy.**
The study population consisted of 15,215,178 persons aged ≥5 years, including 814,524 in the infection cohort; 2,548,334 in
the first dose cohort; 2,483,597 in the second dose cohort; 1,681,169 in the unspecified dose cohort; and 6,713,100 in the any
dose cohort (Table 1).†† Among the four COVID-19 vaccination cohorts, 77%–79% of persons were aged ≥30 years; within the
SARS-CoV-2 infection cohort, 63% were aged ≥30 years.
AR09551
Among males aged 5–11 years, the incidences of myocarditis and myocarditis or pericarditis were 12.6–17.6 cases per 100,000
after infection, 0–4 after the first vaccine dose, and 0 after the second dose; incidences of myocarditis, pericarditis, or MIS
were 93.0–133.2 after infection (Table 2). Because there were no or few cases of myocarditis or pericarditis after vaccination,
the RRs for several comparisons could not be calculated or were not statistically significant. The RRs were significant when
comparing myocarditis, pericarditis, or MIS in the 42 days after infection (133.2 cases per 100,000) with myocarditis or
pericarditis after the first (4.0 cases per 100,000; RR 33.3) or second (4.7 cases per 100,000; RR 28.2) vaccine dose.
Among males aged 12–17 years, the incidences of myocarditis and myocarditis or pericarditis were 50.1–64.9 cases per
100,000 after infection, 2.2–3.3 after the first vaccine dose, and 22.0–35.9 after the second dose; incidences of myocarditis,
pericarditis, or MIS were 150.5–180.0 after infection. RRs for cardiac outcomes comparing infected persons with first dose
recipients were 4.9–69.0, and with second dose recipients, were 1.8–5.6; all RRs were statistically significant.
Among males aged 18–29 years, the incidences of myocarditis and myocarditis or pericarditis were 55.3–100.6 cases per
pericarditis, or MIS were 97.2–140.8 after infection. RRs for cardiac outcomes comparing infected persons with first dose
recipients were 7.2–61.8, and with second dose recipients, were 6.7–8.5; all RRs were statistically significant.
Among males aged ≥30 years, the incidences of myocarditis and myocarditis or pericarditis were 57.2–114.0 cases per
pericarditis, or MIS were 109.1–136.8 after infection. RRs for cardiac outcomes among infected persons compared with first
dose recipients were 10.7–67.2, and compared with second dose recipients, were 10.8–115.2; all RRs were statistically
significant.
Among females aged 5–11 years, incidences of myocarditis and myocarditis or pericarditis were 5.4–10.8 cases per 100,000
after infection, and incidences of myocarditis, pericarditis, or MIS were 67.3–94.2 after infection (Table 3). No cases of
myocarditis or pericarditis after vaccination were identified. The incidences of cardiac outcomes did not vary by age among
females aged ≥12 years. In this group, the incidences of myocarditis and myocarditis or pericarditis were 11.9–61.7 cases per
pericarditis, or MIS were 27.1–93.3 after infection. Among females aged ≥12 years, RRs for cardiac outcomes comparing
infected persons with first dose recipients were 7.4–42.6, and with second dose recipients, were 6.4–62.9; all RRs were
statistically significant.
Top
Discussion
Analysis of EHR data from 40 U.S. health care systems found that the incidences of cardiac complications after SARS-CoV-2
infection or mRNA COVID-19 vaccination were low overall but were higher after infection than after vaccination for both
males and females in all age groups. Two studies from Israel (2) and the United Kingdom (3) have found similar higher risk for
myocarditis after SARS-CoV-2 infection compared with that after mRNA COVID-19 vaccination.
Myocarditis or pericarditis incidence after mRNA COVID-19 vaccination in the current study (0–35.9 per 100,000 for males and
0–10.9 for females across age groups and vaccine cohorts) was similar to estimates found in a study from eight U.S. health
systems in the Vaccine Safety Datalink (10). Previous CDC estimates found the highest risk for post-vaccination myocarditis
among males aged 16–17 years (10.6 per 100,000) during a 7-day risk window after receipt of a second mRNA COVID-19
vaccine dose (5). Estimates from the current study (22.0 per 100,000 males aged 12–17 years) are higher, likely because
outcomes were captured using ICD-10-CM codes alone rather than through passive reporting with subsequent verification
through medical record review. Even among males aged 12–17 years, the group with the highest incidence of cardiac
complications after receipt of a second mRNA COVID-19 vaccine dose, the risk was 1.8–5.6 times as high after SARS-CoV-2
infection than after vaccination.
The findings in this report are subject to at least six limitations. First, data were obtained using a query that returned
aggregate data from sites, precluding adjustment for potential confounders. Stratification by age and sex was performed
because of their clear prior association with cardiac outcomes. Second, outcomes were rare in some cohorts, leading to wide
CIs around RR estimates. Third, only SARS-CoV-2 test results and mRNA COVID-19 vaccinations documented in EHRs were
available for assessment. SARS-CoV-2 infections were not captured if testing occurred in homes, schools, community sites, or
pharmacies. Similarly, EHR data in this study captured ≥1 dose of mRNA COVID-19 vaccine for 28% of persons aged ≥5 years.
Nationally, 82% of persons aged ≥5 years were reported to have received any COVID-19 vaccination; 97% of all vaccinations
administered were mRNA COVID-19 vaccines.§§ Underascertainment of SARS-CoV-2 infections and mRNA COVID-19
vaccinations reduced sample size and might have introduced bias if capture of infection or vaccination within the EHR
AR09552 reduced sample size and might have introduced bias if capture of infection or vaccination within the EHR
vaccinations
occurred differentially for those with cardiac outcomes.¶¶ Fourth, case definitions for myocarditis, pericarditis, or MIS were
ICD-10-CM code–based; diagnoses were not confirmed with chart review and are subject to misclassification. Fifth, cases of
MIS among persons without documented SARS-CoV-2 infection were not included (9). Finally, some overlap might have
occurred in risk windows for persons who had a SARS-CoV-2 infection soon after vaccination or a vaccination soon after
infection. Exclusions were made for persons who received COVID-19 vaccine doses ≤30 days before infection or who had
infections ≤30 days before vaccination.
Cardiac complications were rare after SARS-CoV-2 infection or mRNA COVID-19 vaccination. However, the risks for these
complications were higher after infection than after vaccination among males and females in all age groups. These findings
provide important context for balancing risks and benefits of mRNA COVID-19 vaccination among eligible persons ≥5 years.
Top
Acknowledgments
All institutions participating in this study; PCORnet, the National Patient-Centered Clinical Research Network, developed with
funding from the Patient-Centered Outcomes Research Institute (PCORI); Karen R. Broder, Samantha Chao, Joshua Denson,
Julia Fearrington, Bridget Nolan, Sonja A. Rasmussen, Tom Shimabukuro, William E. Trick, leadership of the Data, Analytics,
and Visualization Task Force, CDC COVID-19 Emergency Response Team.
Top
Corresponding author: Jason P. Block, jblock1@partners.org.
Top
1
Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, Massachusetts;
2CDC COVID-19 Emergency Response Team; 3Applied Clinical Research Center, Department of Pediatrics, Children’s Hospital
of Philadelphia, Philadelphia, Pennsylvania; 4Louisiana Public Health Institute, New Orleans, Louisiana; 5Department of
Pediatrics, Stanford University School of Medicine, Stanford, California; 6Center for Child Health, Behavior and Development,
Seattle Children’s Research Institute, Seattle Children’s Hospital, Seattle, Washington; 7Department of Population and Data
Sciences and Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas; 8Center for
Gastrointestinal Biology and Disease, University of North Carolina School of Medicine, Chapel Hill, North Carolina; 9The
Fenway Institute, Fenway Health, Harvard Medical School, Boston, Massachusetts; 10Children’s Healthcare of Atlanta, Emory
University School of Medicine, Atlanta, Georgia; 11Department of Medicine, Lewis Katz School of Medicine at Temple
University, Philadelphia, Pennsylvania; 12OCHIN, Inc., Portland, Oregon; 13Nemours Cardiac Center, Nemours Children’s Health
System, Wilmington, Delaware.
Top
All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of
potential conflicts of interest. Jason P. Block, Christopher B. Forrest, Grace M. Lee, and Thomas W. Carton report support from
the National Institutes of Health (NIH) as part of the Researching COVID to Enhance Recovery (RECOVER) program. Nidhi
Ghildayal reports NIH funding for a postdoctoral position. Michael D. Kappelman reports grants from NIH, PCORI, Helmsley
Trust, Abbvie, Arenapharm, Boehringer Ingelheim, Bristol Myers Squibb, Celtrion, Eli Lilly, Genentech, Janssen (a subsidiary of
Johnson & Johnson, Pfizer, and Takeda) and consulting fees from Abbvie, Janssen, Takeda, and Pfizer; payment for service on
a data safety monitoring board for Eli Lilly, and payment for service on the editorial board of the American Journal of
Gastroenterology. Kenneth H. Mayer reports grant support from NIH’s COVID-19 Vaccine Trials Network for a Phase III
AstraZeneca SARS-CoV-2 vaccine trial. Matthew E. Oster reports institutional support from NIH’s National Heart, Lung, and
Blood Institute. No other potential conflicts of interest were disclosed.
Top
* The 40 PCORnet sites were AdventHealth, Allina Health, Children’s Hospital Colorado, Cincinnati Children’s Hospital,
Columbia Health, Duke University, Fenway Health, Health Choice Network, Johns Hopkins University, Lurie Children’s Hospital,
Medical College of Wisconsin, Medical University of South Carolina, Montefiore Medical Center, Mount Sinai Health System,
Nationwide Children’s Hospital, Nemours Children’s Hospital, New York University Langone Medical Center, Northwestern
University, OCHIN, Inc., Ochsner Health System, Ohio State University, Orlando Health System, Penn State College of Medicine
and Penn State Health Milton S. Hershey Medical Center, Seattle Children’s Hospital, Temple University, University of Florida
Health, University of Iowa Healthcare, University of Kansas, University Medical Center New Orleans, University of Miami,
University of Michigan, University of Missouri Health Care, University of Nebraska, University of North Carolina, University of
Pittsburgh Medical Center, University of Texas Southwest Medical Center, University of Utah, Vanderbilt University Medical
Center, Wake Forest Baptist Health, and Weill Cornell Medicine. These sites represent academic and community hospitals that
serve patients who are self-pay or have public or private insurance.
AR09553
†
The first dose cohort included persons who had either the first of 2 doses ≥20 days before a second dose or a specific code
for a first dose; the second dose cohort included persons who had either the second of 2 doses ≥20 days after a first dose or
a specific code for a second dose. The unspecified dose cohort included persons who had only one code for an mRNA COVID-
19 vaccination that was not specified as a first or second dose. The any dose cohort was the combination of the first, second,
and unspecified dose cohorts; this cohort included all doses captured, with duplication of persons who received 2 doses.
Vaccination and infection exclusions were provided before but not after exposures; thus, persons who had an infection soon
after a vaccination would still be included in the vaccination cohort or vice versa. The cohorts were not mutually exclusive;
persons vaccinated and infected could be in both vaccination and infection cohorts. However, because the outcomes were
assessed in short time periods after index dates, overlap in outcomes was unlikely, unless an outcome was experienced more
than once.
§
Myocarditis was defined as presence of ICD-10-CM codes B33.22, I40, I40.0, I40.1, I40.8, I40.9, or I51.4. Pericarditis was
defined as presence of ICD-10-CM codes B33.23, I30, I30.0, I30.1, I30.8, I30.9, or I31.9. MIS was defined as presence of ICD-10-
CM code M35.81.
¶
MIS often occurs in the absence of prior positive SARS-CoV-2 test results; these cases were not captured in the infection
cohorts.
** 45 C.F.R. part 46, 21 C.F.R. part 56; 42 U.S.C. Sect. 241(d); 5 U.S.C. Sect. 552a; 44 U.S.C. Sect. Sect. 3501 et seq.
††
In the first and second dose vaccine cohorts, 27% of persons received Moderna and 73% received Pfizer-BioNTech. In the
unspecified dose cohort, 36% received Moderna and 64% Pfizer-BioNTech, and in the any dose cohort, 29% received Moderna
and 71% Pfizer-BioNTech.
§§
https://covid.cdc.gov/covid-data-tracker/#vaccinations (Accessed March 29, 2022).
¶¶
If patients who received a SARS-CoV-2–positive test result at a health care system were more likely to return to the same
health care system for myocarditis, pericarditis, or MIS treatment than were patients who had their mRNA COVID-19
vaccination documented at the health care system, then the underascertainment of outcomes might be higher in the
vaccination cohorts, introducing bias away from the null. This scenario might occur if a person was more likely to visit a
tertiary care referral center participating in this study if they were more severely ill with a cardiac complication after SARS-
CoV-2 infection than a perhaps mild cardiac complication after COVID-19 vaccination. However, if the cardiac complications
were more commonly linked to vaccination than infection in the EHR, bias would be toward the null. This scenario might
occur if clinicians were more likely to document an mRNA COVID-19 vaccination in the EHR if a cardiac complication was
noted after vaccination than if the cardiac complication occurred after SARS-CoV-2 infection.
Top
References
1. Boehmer TK, Kompaniyets L, Lavery AM, et al. Association between COVID-19 and myocarditis using hospital-based
administrative data—United States, March 2020–January 2021. MMWR Morb Mortal Wkly Rep 2021;70:1228–32.
https://doi.org/10.15585/mmwr.mm7035e5  PMID:34473684 
2. Barda N, Dagan N, Ben-Shlomo Y, et al. Safety of the BNT162b2 mRNA Covid-19 vaccine in a nationwide setting. N Engl J
Med 2021;385:1078–90. https://doi.org/10.1056/NEJMoa2110475  PMID:34432976 
3. Patone M, Mei XW, Handunnetthi L, et al. Risks of myocarditis, pericarditis, and cardiac arrhythmias associated with
COVID-19 vaccination or SARS-CoV-2 infection. Nat Med 2022;28:410–22. https://doi.org/10.1038/s41591-021-01630-0
 PMID:34907393 
4. Witberg G, Barda N, Hoss S, et al. Myocarditis after Covid-19 vaccination in a large health care organization. N Engl J Med
2021;385:2132–9. https://doi.org/10.1056/NEJMoa2110737  PMID:34614329 
5. Oster ME, Shay DK, Su JR, et al. Myocarditis cases reported after mRNA-based COVID-19 vaccination in the US from
December 2020 to August 2021. JAMA 2022;327:331–40. https://doi.org/10.1001/jama.2021.24110  PMID:35076665

6. CDC. Multisystem Inflammatory Syndrome (MIS). Atlanta, GA: US Department of Health and Human Services, CDC; 2021.
Accessed March 10, 2022. https://www.cdc.gov/mis/index.html
7. Forrest CB, McTigue KM, Hernandez AF, et al. PCORnet® 2020: current state, accomplishments, and future directions. J
Clin Epidemiol 2021;129:60–7. https://doi.org/10.1016/j.jclinepi.2020.09.036  PMID:33002635 
AR09554
8. Yousaf AR, Cortese MM, Taylor AW, et al.; MIS-C Investigation Authorship Group. Reported cases of multisystem
inflammatory syndrome in children aged 12-20 years in the USA who received a COVID-19 vaccine, December, 2020,
through August, 2021: a surveillance investigation. Lancet Child Adolesc Health 2022;S2352-4642(22)00028-1.
https://doi.org/10.1016/S2352-4642(22)00028-1  PMID:35216660 
9. Feldstein LR, Rose EB, Horwitz SM, et al.; Overcoming COVID-19 Investigators; CDC COVID-19 Response Team.
Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med 2020;383:334–46.
https://doi.org/10.1056/NEJMoa2021680  PMID:32598831 
10. Klein NP, Lewis N, Goddard K, et al. Surveillance for adverse events after COVID-19 mRNA vaccination. JAMA
2021;326:1390–9. https://doi.org/10.1001/jama.2021.15072  PMID:34477808 
Top
TABLE 1. Demographic characteristics of persons who were infected with SARS-CoV-2 or received a rst,
second, unspeci ed, or any dose of an mRNA COVID-19 vaccine* — National Patient-Centered Clinical
Research Network, United States, January 1, 2021–January 31, 2022
No. (%)
mRNA COVID-19 vaccination cohort
SARS-CoV-2 infection Second Unspecified

Characteristic cohort† First dose*,§ dose*,§ dose*,¶ Any dose*,**
Cohort total 814,524 (100) 2,548,334 2,483,597 1,681,169 (100) 6,713,100

(100) (100) (100)
Age group, yrs
5–11 76,960 (9) 48,986 (2) 41,742 (2) 30,199 (2) 120,927 (2)
12–17 70,336 (9) 190,810 (7) 179,612 (7) 113,775 (7) 484,197 (7)
18–29 151,950 (19) 308,892 (12) 297,560 (12) 241,787 (14) 848,239 (13)
30–50 255,103 (31) 665,876 (26) 652,947 (26) 490,808 (29) 1,809,631
(27)
51–65 152,243 (19) 601,615 (24) 588,873 (24) 404,445 (24) 1,594,933
(24)
≥66 107,932 (13) 732,155 (29) 722,863 (29) 400,155 (24) 1,855,173
(28)
Sex
Female 457,506 (56) 1,497,984 1,463,746 997,741 (59) 3,959,471

(59) (59) (59)
fi
Male 357,018 (44) 1,050,350 1,019,851 683,428 (41) 2,753,629
fi
(41) (41) (41)
Race/Ethnicity††
Hispanic 133,784 (16) 309,468 (12) 298,270 (12) 169,688 (10) 777,426 (12)
Asian 23,684 (3) 133,445 (5) 131,205 (5) 83,937 (5) 348,587 (5)
AR09555
No. (%)
mRNA COVID-19 vaccination cohort
SARS-CoV-2 infection Second Unspeci ed

Characteristic cohort † First dose* ,§
dose* ,§
dose*,¶ Any dose*,**
Black or African 162,434 (20) 408,657 (16) 395,283 (16) 283,534 (17) 1,087,474
American (16)
Other 34,473 (4) 93,100 (4) 90,122 (4) 54,305 (3) 237,527 (4)
White 408,152 (50) 1,441,573 1,407,974 1,001,686 (60) 3,851,233

(57) (57) (57)
Missing§§ 58,980 (7) 205,834 (8) 204,224 (8) 98,299 (6) 508,357 (8)
* In the first and second dose cohorts, 27% of persons received mRNA-1273 (Moderna) vaccine and 73% received BNT162b2
(Pfizer-BioNTech) vaccine. In the unspecified dose cohort, 36% received Moderna and 64% Pfizer-BioNTech. In the any dose
cohort, 29% received Moderna and 71% Pfizer-BioNTech.
†
Persons in the infection cohort included those who received ≥1 positive SARS-CoV-2 molecular or antigen test result.
§ The first dose cohort included persons who had either the first of 2 doses ≥20 days before a second dose or a specific code
a specific code for a second dose.
¶
The unspecified dose cohort included persons who had a single dose that was not specified as a first or second dose; doses
specified as booster doses were excluded.
** The any dose cohort is the first, second, and unspecified dose cohorts combined; persons who had 2 doses are
represented twice in the cohort but had different index dates for their first and second doses.
††
Persons of Hispanic origin could be of any race; Asian, Black or African American, White, or other (which includes American
Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, multiple race, and other race) persons are not Hispanic.
§§
Missing race category includes no information, refused to answer, unknown, or missing.
Top
TABLE 2. Incidence of cardiac outcomes among males aged ≥5 years after SARS-CoV-2 infection or mRNA
COVID-19 vaccination and risk ratios, by age group and risk window — National Patient-Centered
Clinical Research Network, United States, January 1, 2021–January 31, 2022
Risk ratio (95% CI) SARS-CoV-2 infection

Incidence* among males versus mRNA COVID-19 vaccination
SARS- mRNA COVID-19 vaccination cohort mRNA COVID-19 vaccination cohort

Age group, CoV-2
yrs/Outcome/Risk infection First Second Unspecified Any First Second Unspecified Any
window cohort †
dose §
dose §
dose¶
dose** dose §
dose §
dose ¶
dose**
5–11††
Myocarditis
7-day 12.6 0 0 0 0 NC NC NC NC
21-day 17.6 4.0 0 6.5 3.2 4.4 NC 2.7 (0.3– 5.4

(0.5– 22.1) (1.1–
35.7) 26.1)
Myocarditis or pericarditis
AR09556


Age group, CoV-2
yrs/Outcome/Risk infection First Second Unspeci ed Any First Second Unspeci ed Any
window cohort† dose§ dose§ dose¶ dose** dose§ dose§ dose¶ dose**
7-day 12.6 0 0 0 0 NC NC NC NC
21-day 17.6 4.0 0 6.5 3.2 4.4 NC 2.7 (0.3– 5.4

(0.5– 22.1) (1.1–
35.7) 26.1)
Myocarditis, pericarditis, or MIS§§
7-day 93.0 —¶¶ — — — NC NC NC NC
21-day 103.0 — — — — 25.7 NC 16.0 (2.2– 31.7

(3.5– 116.0) (7.7–
187.0) 131.2)
42-day 133.2 — — — — 33.3 28.2 10.3 (2.5– 20.5

(4.6– (3.9– 42.3) (7.4–
240.5) 203.9) 56.7)
12–17††
Myocarditis
7-day 50.1 2.2 22.0 16.7 12.9 23.0 2.3 3.0 (1.3– 3.9
(5.3– (1.2– 6.7) (2.1–
99.5) 4.4) 7.0)
21-day 59.0 3.3 26.7 20.4 16.0 18.0 2.2 2.9 (1.4– 3.7
(5.4– (1.2– 6.0) (2.1–
60.6) 4.0) 6.4)
7-day 56.0 2.2 26.7 22.3 16.0 25.7 2.1 2.5 (1.2– 3.5
(6.0– (1.1– 5.2) (2.0–
110.3) 3.9) 6.1)
21-day 64.9 3.3 35.9 29.7 21.6 19.8 1.8 2.2 (1.1– 3.0
(5.9– (1.0– 4.2) (1.8–
fi
66.2) 3.1) 5.0)
7-day 150.5 — — — — 69.0 5.6 6.8 (3.6– 9.4

(16.8– (3.5– 12.7) (6.2–
283.2) 9.2) 14.4)
21-day 159.3 — — — — 48.7 4.4 5.4 (3.1– 7.4

(15.2– (2.9– 9.4) (5.0–
155.7) 6.9) 10.8)
AR09557


Age group, CoV-2
42-day 180.0 — — — — 4.9 4.6 5.4 (3.2– 4.9

(3.2– (3.0– 9.1) (3.5–
7.4) 6.9) 6.7)
18–29
Myocarditis
7-day 55.3 0.9 6.5 7.0 4.6 61.8 8.5 7.9 (3.3– 12.0
(8.5– (3.7– 19.0) (6.4–
451.8) 19.1) 22.5)
21-day 63.7 3.6 8.4 11.6 7.5 17.8 7.6 5.5 (2.7– 8.4
(6.4– (3.7– 11.0) (5.0–
49.8) 15.7) 14.2)
7-day 85.5 2.7 12.1 22.0 11.5 31.8 7.0 3.9 (2.3– 7.4
(9.9– (3.8– 6.6) (4.8–
102.0) 12.9) 11.5)
21-day 100.6 8.1 15.0 27.8 16.1 12.5 6.7 3.6 (2.3– 6.3
(6.2– (3.9– 5.8) (4.3–
25.2) 11.7) 9.1)
7-day 97.2 — — — — 36.2 8.0 4.4 (2.6– 8.5

(11.3– (4.4– 7.4) (5.6–
115.5) 14.6) 12.9)
21-day 112.3 — — — — 13.9 7.5 4.0 (2.5– 7.0

(7.0– (4.4– 6.4) (4.8–
28.0) 13.0) 10.1)
42-day 140.8 — — — — 7.2 8.4 4.5 (2.9– 6.4

(4.5– (5.0– 6.9) (4.6–
fi
11.4) 13.9) 8.8)
≥30
Myocarditis
7-day 57.2 0.9 0.5 3.0 1.3 67.2 115.2 18.9 (11.2– 45.7
(31.4– (42.6– 31.7) (30.2–
143.8) 311.7) 69.2)
AR09558


Age group, CoV-2
21-day 63.0 1.9 1.2 4.2 2.2 32.4 50.8 15.1 (9.7– 28.3
(19.3– (26.7– 23.7) (20.4–
54.3) 96.4) 39.3)
7-day 100.2 3.8 3.1 15.0 6.3 26.6 32.3 6.7 (5.2– 16.0
(18.2– (21.3– 8.6) (12.9–
38.7) 48.8) 19.8)
21-day 114.0 7.3 7.3 20.1 10.4 15.6 15.6 5.7 (4.5– 10.9
(11.8– (11.7– 7.1) (9.1–
20.7) 20.7) 13.1)
7-day 109.1 — — — — 28.9 35.1 7.3 (5.7– 17.4

(19.9– (23.3– 9.4) (14.1–
42.0) 53.0) 21.5)
21-day 123.0 — — — — 16.8 16.8 6.1 (4.9– 11.8

(12.7– (12.7– 7.7) (9.9–
22.3) 22.2) 14.0)
42-day 136.8 — — — — 10.7 10.8 5.4 (4.4– 8.7

(8.6– (8.6– 6.7) (7.4–
13.4) 13.5) 10.1)
Abbreviations: MIS = multisystem inflammatory syndrome; NC = not calculated.
* Cases per 100,000 persons.
† Persons in the infection cohort included those who received ≥1 positive SARS-CoV-2 molecular or antigen test result.
§
The first dose cohort included persons who had either the first of 2 doses ≥20 days before a second dose or a specific code
¶ The unspecified dose cohort included persons who had a single dose that was not specified as a first or second dose; doses
fi
†† BNT162b2 (Pfizer-BioNTech) is the only mRNA COVID-19 vaccine approved for persons aged 5–17 years.
Diagnoses of myocarditis, pericarditis, or MIS after a positive SARS-CoV-2 test result compared with diagnoses of
§§
myocarditis or pericarditis after vaccination. The 42-day risk ratios were only calculated for this outcome and comparison. The
incidence of myocarditis or pericarditis in this risk window was 4.0, 37.1, 19.7, and 12.8 cases per 100,000 for males aged 5–
11, 12–17, 18–29, and ≥30 years after a first dose of an mRNA COVID-19 vaccine; 4.7, 39.4, 16.8, and 12.7 cases per 100,000
after a second dose; 12.9, 33.4, 31.3, and 25.3 cases per 100,000 after an unspecified dose; and 6.5, 37.1, 22.0, and 15.8 cases
per 100,000 after any dose.
Dashes indicate the incidence for vaccination cohorts was not applicable because the comparison for incidence of
¶¶
myocarditis, pericarditis, or MIS after infection was to myocarditis or pericarditis after vaccination.
Top
AR09559
TABLE 3. Incidence of cardiac outcomes among females aged ≥5 years after SARS-CoV-2 infection or
mRNA COVID-19 vaccination and risk ratios, by age group and risk window — National Patient-Centered
Clinical Research Network, United States, January 1, 2021–January 31, 2022

Incidence* among females versus mRNA COVID-19 vaccination

Age group, CoV-2
yrs/Outcome/Risk infection First Second Unspecified Any First Second Unspecified Any
5–11††
Myocarditis
7-day 5.4 0 0 0 0 NC NC NC NC
21-day 8.1 0 0 0 0 NC NC NC NC
7-day 8.1 0 0 0 0 NC NC NC NC
21-day 10.8 0 0 0 0 NC NC NC NC
7-day 67.3 —¶¶ — — — NC NC NC NC
21-day 80.7 — — — — NC NC NC NC
42-day 94.2 — — — — NC NC NC NC
12–17††
Myocarditis
7-day 24.7 1.0 1.1 0 0.8 24.5 23.1 NC 31.2

(3.1– (2.9– (6.7–
193.3) 182.0) 144.3)
21-day 35.7 1.0 3.2 1.7 2.0 35.4 11.1 21.4 (2.8– 18.0
(4.6– (3.2– 163.4) (6.4–
270.5) 39.0) 50.5)
7-day 24.7 2.0 2.1 0 1.6 12.2 11.5 NC 15.6

(2.6– (2.5– (4.8–
56.7) 53.4) 50.6)
21-day 35.7 2.0 5.4 3.3 3.6 17.7 6.7 10.7 (2.4– 10.0
(4.0– (2.4– 47.4) (4.3–
78.4) 18.7) 23.4)

yAR09560 p


Age group, CoV-2
7-day 63.1 — — — — 31.3 29.5 NC 39.8

(7.4– (6.9– (13.8–
132.7) 125.0) 115.2)
21-day 79.6 — — — — 39.5 14.9 23.8 (5.7– 22.3

(9.4– (5.7– 99.9) (10.6–
165.4) 38.3) 47.2)
42-day 93.3 — — — — 11.6 12.4 14.0 (5.0– 12.4

(5.4– (5.5– 39.4) (7.1–
25.0) 28.1) 21.7)
18–29
Myocarditis
7-day 11.9 0.5 1.6 3.9 1.8 23.5 7.6 3.1 (1.1– 6.5
(3.0– (2.1– 8.4) (2.8–
182.0) 27.1) 15.2)
21-day 19.5 1.0 2.1 5.8 2.8 19.2 9.3 3.4 (1.5– 7.1
(4.5– (3.1– 7.5) (3.6–
82.9) 27.5) 14.0)
7-day 23.8 2.5 3.1 7.1 4.0 9.4 7.6 3.4 (1.6– 5.9
(3.6– (3.1– 7.0) (3.3–
24.8) 18.7) 10.6)
21-day 33.6 4.6 5.2 10.9 6.6 7.4 6.4 3.1 (1.7– 5.1
(3.5– (3.1– 5.6) (3.1–
15.5) 13.1) 8.2)
7-day 27.1 — — — — 10.7 8.6 3.8 (1.9– 6.7

(4.1– (3.5– 7.8) (3.8–
fi
27.9) 21.0) 11.9)
21-day 40.1 — — — — 8.8 7.6 3.7 (2.1– 6.1

(4.2– (3.8– 6.5) (3.8–
18.2) 15.4) 9.6)
42-day 67.2 — — — — 8.3 11.6 5.2 (3.2– 7.8

(4.8– (6.1– 8.7) (5.3–
14.3) 22.1) 11.3)
≥30
AR09561


Age group, CoV-2
Myocarditis
7-day 32.6 0.8 0.5 1.0 0.7 42.6 62.9 31.3 (15.2– 44.0
(21.5– (27.6– 64.3) (27.9–
84.4) 143.6) 69.3)
21-day 36.3 1.4 0.9 1.6 1.3 25.2 38.3 23.2 (12.8– 28.2
(15.1– (20.6– 42.2) (19.6–
42.0) 71.3) 40.6)
7-day 53.8 3.1 1.7 8.2 3.9 17.1 31.2 6.6 (4.9– 13.9
(12.0– (19.6– 8.8) (11.0–
24.5) 49.7) 17.7)
21-day 61.7 6.2 4.1 10.7 6.5 10.0 14.9 5.8 (4.5– 9.4
(7.6– (10.8– 7.5) (7.7–
13.1) 20.5) 11.5)
7-day 58.6 — — — — 18.7 34.0 7.1 (5.4– 15.2

(13.1– (21.4– 9.5) (12.0–
26.6) 54.0) 19.2)
21-day 68.2 — — — — 11.0 16.5 6.4 (4.9– 10.4

(8.4– (12.0– 8.3) (8.6–
14.4) 22.6) 12.7)
42-day 79.6 — — — — 8.4 10.0 5.6 (4.5– 7.9

(6.7– (7.9– 7.0) (6.7–
10.5) 12.8) 9.4)
Abbreviations: MIS = multisystem inflammatory syndrome; NC = not calculated.
* Cases per 100,000 persons.
†
Persons in the infection cohort included those who received ≥1 positive SARS-CoV-2 molecular or antigen test result.
fi
§ The first dose cohort included persons who had either the first of 2 doses ≥20 days before a second dose or a specific code
¶
The unspecified dose cohort included persons who had a single dose that was not specified as a first or second dose; doses
††
BNT162b2 (Pfizer-BioNTech) is the only mRNA COVID-19 vaccine approved for persons aged 5–17 years.
§§ Diagnoses of myocarditis, pericarditis, or MIS after a positive SARS-CoV-2 test result compared with diagnoses of
myocarditis or pericarditis after vaccination. The 42-day risk ratios were only calculated for this outcome and comparison. The
incidence of myocarditis or pericarditis in this risk window was 0, 8.1, 8.1, 9.5 cases per 100,000 for females 5-11, 12-17, 18-29,
and ≥30 years after a first dose of an mRNA COVID-19 vaccine; 0, 7.5, 5.8, and 8.0 cases per 100,000 after a second dose; 0,
AR09562
6.7, 12.9, and 14.2 cases per 100,000 after an unspecified dose; and 0, 7.5, 8.7, and 10.1 cases per 100,000 after any dose.
Dashes indicate the incidence for vaccination cohorts was not applicable because the comparison for incidence of
¶¶
myocarditis, pericarditis, or MIS after infection was to myocarditis or pericarditis after vaccination.
Top
Suggested citation for this article: Block JP, Boehmer TK, Forrest CB, et al. Cardiac Complications After SARS-CoV-2
Infection and mRNA COVID-19 Vaccination — PCORnet, United States, January 2021–January 2022. MMWR Morb Mortal
Wkly Rep 2022;71:517-523. DOI: http://dx.doi.org/10.15585/mmwr.mm7114e1  .
MMWR and Morbidity and Mortality Weekly Report are service marks of the U.S. Department of Health and Human Services.
Use of trade names and commercial sources is for identification only and does not imply endorsement by the U.S. Department of Health and Human
Services.
References to non-CDC sites on the Internet are provided as a service to MMWR readers and do not constitute or imply endorsement of these organizations
or their programs by CDC or the U.S. Department of Health and Human Services. CDC is not responsible for the content of pages found at these sites. URL
addresses listed in MMWR were current as of the date of publication.
All HTML versions of MMWR articles are generated from final proofs through an automated process. This conversion might result in character translation or
format errors in the HTML version. Users are referred to the electronic PDF version (https://www.cdc.gov/mmwr) and/or the original MMWR paper copy for
printable versions of official text, figures, and tables.
Questions or messages regarding errors in formatting should be addressed to mmwrq@cdc.gov.

Page last reviewed: April 7, 2022
10
AR09563
Français
Search Canada.ca 
MENU 
Canada.ca > Coronavirus disease (COVID-19) > COVID-19 health product industry > COVID-19 Drugs and vaccines
Drug and vaccine authorizations for COVID-19: List of authorized

drugs, vaccines and expanded indications
Overview List of applications received List of authorized products
Date published: 2022-05-12
Drugs and vaccines that have been authorized by Health Canada for use in relation to the COVID-19 pandemic are listed
here.
In the list below, the entry for each authorized drug and vaccine includes the:
authorization holder
brand name, proper name or common name, linked to the rationale for authorizing the product for use against
COVID-19
medicinal ingredient(s), strength, dosage form and route of administration
drug identification number (DIN), linked to the entry for the product in the Drug Product Database, which includes
the product monograph
therapeutic area (using the World Health Organization's coding system)
Health Canada's control number for the application
date of authorization
how the drug or vaccine was authorized
In the "authorization" column, there are 4 possible scenarios for each drug or vaccine:
The product was submitted by the company to Health Canada and authorized under the Food and Drug Regulations
The product was submitted by the company for review under section 3 of the interim order (IO) Respecting the
Importation, Sale and Advertising of Drugs for Use in Relation to COVID-19 and authorized
The product was submitted by the company for review under section 4 of the interim order and authorized
The product was added to the List of new drugs for expanded indication in relation to the COVID-19 pandemic by
Health Canada, under section 15 of the interim order
Filter items Showing 1 to 10 of 25 entries | Show 10 entries
List of authorized drugs, vaccines and expanded indications for COVID-19
Date of
Brand name, proper authorization or Authorization or
name or common Therapeutic Control expanded expanded
Authorization holder   name   area   number   indication   indication  
AstraZeneca Canada Inc Evusheld Immune sera and 258295 2022-04-14 Food and Drug
Cilgavimab and immunoglobulins, Regulations
tixagevimab solution for for human use Authorized with
injection terms and
conditions
AstraZeneca Canada Inc Vaxzevria (previously Vaccines, for 244627 2021-02-26 Interim Order
AstraZeneca COVID-19 human use Authorized with
Vaccine) terms and
ChAdOx1-S conditions
(recombinant)
solution for injection
AstraZeneca Canada Inc Vaxzevria (previously Vaccines, for 253700 2021-11-19 Food and Drug
AstraZeneca COVID-19 human use Regulations
Vaccine) Authorized with
ChAdOx1-S terms and
(recombinant) conditions
solution for injection
BioNTech Manufacturing GmbH Comirnaty (previously Vaccines, for 244906 2020-12-09 Interim Order
Pfizer-BioNTech COVID- human use Authorized with
19 Vaccine) terms and
Tozinameran (mRNA conditions
vaccine, BNT162b2)
suspension for injection
BioNTech Manufacturing GmbH Comirnaty (previously Vaccines, for 251730 2021-05-05 Pediatric indication
Pfizer-BioNTech COVID- human use (ages 12-15)
19 Vaccine) Interim Order
Tozinameran (mRNA Authorized with
vaccine, BNT162b2) terms and
suspension for injection conditions
BioNTech Manufacturing GmbH Comirnaty (previously Vaccines, for 252736 2021-09-16 Food and Drug
Pfizer-BioNTech COVID- human use Regulations
19 Vaccine) Authorized with
Tozinameran (mRNA terms and
vaccine, BNT162b2) conditions
suspension for injection
BioNTech Manufacturing GmbH Comirnaty (previously Vaccines, for 257162 2021-11-09 First booster dose
Pfizer-BioNTech COVID- human use Food and Drug
19 Vaccine) Regulations
Tozinameran (mRNA Authorized with
vaccine, BNT162b2) terms and
suspension for injection conditions
BioNTech Manufacturing GmbH Comirnaty (previously Vaccines, for 257698 2021-11-19 Pediatric indication
Pfizer-BioNTech COVID- human use (ages 5-11)
19 Vaccine) Food and Drug
Tozinameran (mRNA Regulations
vaccine, BNT162b2) Authorized with
suspension for injection terms and
conditions
Eli Lilly Canada Inc Bamlanivimab Immune sera and 244947 2020-11-20 Interim Order
Bamlanivimab solution immunoglobulins, Authorized with
for injection for human use terms and
conditions
Gilead Sciences Canada Inc. Veklury Antivirals for 250151 2022-04-22 Expanded indication
Remdesivir solution for systemic use, for Food and Drug
injection human use Regulations
Authorized
1 2 3 Next 
Report a problem or mistake on this page  Share this page
Date modified: 2022-05-12
Contact us News Prime Minister
Departments and agencies Treaties, laws and regulations About government
Public service and military Government-wide reporting Open government
Social media • Mobile applications • About Canada.ca • Terms and conditions • Privacy
11
AR09564
Circulation
ORIGINAL RESEARCH ARTICLE
Clinically Suspected Myocarditis Temporally

Related to COVID-19 Vaccination in Adolescents
and Young Adults: Suspected Myocarditis After
COVID-19 Vaccination
Dongngan T. Truong , MD, MS; Audrey Dionne , MD; Juan Carlos Muniz, MD; Kimberly E. McHugh, MD, MSCR;
Michael A. Portman, MD; Linda M. Lambert, APRN; Deepika Thacker, MD; Matthew D. Elias , MD; Jennifer S. Li, MD;
Olga H. Toro-Salazar, MD; Brett R. Anderson, MD, MBA, MS; Andrew M. Atz, MD; C. Monique Bohun , MB BCh;
M. Jay Campbell , MD, MHA; Maryanne Chrisant, MD; Laura D’Addese , MD; Kirsten B. Dummer , MD;
Daniel Forsha, MD; Lowell H. Frank, MD; Olivia H. Frosch , MD; Sarah K. Gelehrter, MD; Therese M. Giglia, MD;
Camden Hebson, MD; Supriya S. Jain, MD; Pace Johnston, MD; Anita Krishnan , MD; Kristin C. Lombardi, MD;
Brian W. McCrindle , MD, MPH; Elizabeth C. Mitchell , MD; Koichi Miyata , MD; Trent Mizzi, MD; Robert M. Parker, DO;
Jyoti K. Patel, MD; Christina Ronai , MD, MSEd; Arash A. Sabati , MD; Jenna Schauer, MD;
S. Kristen Sexson Tejtel, MD, PhD, MPH; J. Ryan Shea , MD; Lara S. Shekerdemian, MB ChB, MD, MHA;
Shubhika Srivastava, MD, MBBS; Jodie K. Votava-Smith, MD; Sarah White, MD; Jane W. Newburger , MD, MPH
BACKGROUND: Understanding the clinical course and short-term outcomes of suspected myocarditis after the coronavirus
disease 2019 (COVID-19) vaccination has important public health implications in the decision to vaccinate youth.
Downloaded from http://ahajournals.org by on June 1, 2022
METHODS: We retrospectively collected data on patients <21 years old presenting before July 4, 2021, with suspected
myocarditis within 30 days of COVID-19 vaccination. Lake Louise criteria were used for cardiac MRI findings. Myocarditis
cases were classified as confirmed or probable on the basis of the Centers for Disease Control and Prevention definitions.
RESULTS: We report on 139 adolescents and young adults with 140 episodes of suspected myocarditis (49 confirmed, 91 probable)
at 26 centers. Most patients were male (n=126, 90.6%) and White (n=92, 66.2%); 29 (20.9%) were Hispanic; and the median
age was 15.8 years (range, 12.1–20.3; interquartile range [IQR], 14.5–17.0). Suspected myocarditis occurred in 136 patients
(97.8%) after the mRNA vaccine, with 131 (94.2%) after the Pfizer-BioNTech vaccine; 128 (91.4%) occurred after the second
dose. Symptoms started at a median of 2 days (range, 0–22; IQR, 1–3) after vaccination. The most common symptom was chest
pain (99.3%). Patients were treated with nonsteroidal anti-inflammatory drugs (81.3%), intravenous immunoglobulin (21.6%),
glucocorticoids (21.6%), colchicine (7.9%), or no anti-inflammatory therapies (8.6%). Twenty-six patients (18.7%) were in the
intensive care unit, 2 were treated with inotropic/vasoactive support, and none required extracorporeal membrane oxygenation
or died. Median hospital stay was 2 days (range, 0–10; IQR, 2–3). All patients had elevated troponin I (n=111, 8.12 ng/mL;
IQR, 3.50–15.90) or T (n=28, 0.61 ng/mL; IQR, 0.25–1.30); 69.8% had abnormal ECGs and arrhythmias (7 with nonsustained
ventricular tachycardia); and 18.7% had left ventricular ejection fraction <55% on echocardiogram. Of 97 patients who underwent
cardiac MRI at a median 5 days (range, 0–88; IQR, 3–17) from symptom onset, 75 (77.3%) had abnormal findings: 74 (76.3%) had
late gadolinium enhancement, 54 (55.7%) had myocardial edema, and 49 (50.5%) met Lake Louise criteria. Among 26 patients
with left ventricular ejection fraction <55% on echocardiogram, all with follow-up had normalized function (n=25).
CONCLUSIONS: Most cases of suspected COVID-19 vaccine myocarditis occurring in persons <21 years have a mild clinical
course with rapid resolution of symptoms. Abnormal findings on cardiac MRI were frequent. Future studies should evaluate
risk factors, mechanisms, and long-term outcomes.
Key Words: adolescent ◼ COVID-19 vaccines ◼ myocarditis ◼ young adult

Correspondence to: Dongngan T. Truong, MD, MS, 81 North Mario Capecchi Drive, Salt Lake City, UT 84113. Email dongngan.truong@hsc.utah.edu
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCULATIONAHA.121.056583.
Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.
For Sources of Funding and Disclosures, see page 355.
© 2021 American Heart Association, Inc.
Circulation is available at www.ahajournals.org/journal/circ
Circulation. 2022;145:345–356. DOI: 10.1161/CIRCULATIONAHA.121.056583 February 1, 2022 345

TruongAR09565
et al Suspected Myocarditis After COVID-19 Vaccination
Immunization Practices reported a likely link between

Clinical Perspective mRNA COVID-19 vaccination and myocarditis, in par-
ORIGINAL RESEARCH
ticular, in those ≤39 years old.11 We aim to describe a

What Is New? large case series of suspected myocarditis temporally
ARTICLE
• Suspected myocarditis temporally related to coro- related to the COVID-19 vaccine in adolescents and
navirus disease 2019 (COVID-19) vaccination has young adults <21 years old across the United States
been reported in adolescents ≥12 years old and and Canada.
young adults since the emergency use authoriza-
tion of the Pfizer-BioNTech COVID-19 vaccine, in
particular, in male adolescents and young adults. METHODS
• Although the majority of patients with suspected The data that support the findings of this study are available
vaccine associated myocarditis have normal ven- from the corresponding author on reasonable request.
tricular systolic function on echocardiogram, many
have abnormal findings suggestive of myocarditis
on cardiac MRI in the setting of elevated troponin Patients
and electrocardiographic changes. We collected data retrospectively for adolescents and young
• Ventricular arrhythmias and the need for inotropic/ adults <21 years old who presented with symptoms, laboratory
vasoactive medications were rare, and no patients markers, and imaging findings concerning for myocarditis within
died or required mechanical circulatory support. 30 days of COVID-19 vaccination from 26 pediatric medical
centers across the United States and Canada before July 4,
What Are the Clinical Implications? 2021. We included patients with clinically suspected myocardi-
• Despite laboratory and cardiac MRI evidence of tis12,13 who had elevated troponin levels and abnormal ECGs, car-
myocardial injury, the majority of adolescents and diac function on noninvasive imaging, or findings consistent with
young adults with suspected myocarditis after myocarditis on cardiac MRI (cMRI), including myocardial edema
COVID-19 vaccination have rapid recovery of or late gadolinium enhancement.14 Cases of suspected vaccine-
symptoms and mild clinical course. associated myocarditis (VAM) were categorized as probable or
• Further studies are needed to better understand the confirmed using the CDC case definitions (Table 1).11
timing of the resolution of myocardial injury, mecha- We excluded patients in whom troponin levels were not
nism of myocardial injury, and long-term outcomes. measured or who had normal troponin levels or who had a plau-
sible alternative cause for suspected myocarditis. Evaluations
for alternative causes were at the discretion of sites on the
basis of local assessments (Table S1). If a patient presented

with symptoms and findings suggestive of myocarditis after >1
Nonstandard Abbreviations and Acronyms vaccine dose, the more severe presentation was added to the
cMRI cardiac MRI aggregate data for analysis. The study was approved by the
institutional review boards of each center, and waivers of con-
ICU intensive care unit
sent were granted.
IVIG intravenous immunoglobulin
LVEF left ventricular ejection fraction
MIS-C multisystem inflammatory syndrome in
Data Obtained
children associated with COVID-19 We collected deidentified and targeted demographic, clini-
cal, laboratory, imaging and ECG, and short-term outcomes
NSAID nonsteroidal anti-inflammatory drug
data. Previous COVID-19 infection was defined as having a
VAM vaccine-associated myocarditis personal history of laboratory-confirmed severe acute respira-
tory syndrome coronavirus 2 (SARS CoV-2) testing and hav-
R
ing had symptoms and immediate household family members
are cases of myocarditis have been reported who tested positive for SARS CoV-2, but the patient was not
in adults1–3 after the coronavirus disease 2019 tested. Left ventricular systolic function was categorized as
(COVID-19) vaccination in Israel4 and in the US normal if graded as normal by local assessment, or if left ven-
military,5 with most cases occurring in men <30 years tricular ejection fraction (LVEF) was ≥55%; mildly decreased
old. Since the authorization to administer the Pfizer- systolic function was defined as LVEF <45% to 54%, mod-
BioNTech COVID-19 vaccine in those as young as 12 erately decreased if 35% to 44%, and severely decreased if
years of age, suspected myocarditis temporally related <35%. The decision and timing to obtain cMRIs were at the
to the vaccine has also been reported in adolescents.6–8 discretion of the local clinical teams, and cMRIs were per-
Myocarditis has been associated with other vaccines, formed using local protocols (Table S2). Data on cMRIs were
collected retrospectively from clinical reports.
such as smallpox9 and influenza,10 although data are lim-
ited regarding symptoms, clinical course, and short-term
outcomes of suspected myocarditis after COVID-19 Statistical Analyses
vaccination. On June 23, 2021, the Centers for Disease Descriptive statistics include percentages for discrete vari-
Control and Prevention (CDC) Advisory Committee on ables and median values with range or interquartile range for
346 February 1, 2022 Circulation. 2022;145:345–356. DOI: 10.1161/CIRCULATIONAHA.121.056583

TruongAR09566
Table 1. Centers for Disease Control and Prevention Case Definitions for Probable and Confirmed Cases of
COVID-19 Vaccine-Associated Myocarditis
ORIGINAL RESEARCH
Probable case Confirmed case
ARTICLE
≥1 new or worsening symptom ≥1 new or worsening symptom:
Chest pain, pressure, or discomfort Chest pain, pressure, or discomfort
Dyspnea or shortness of breath Dyspnea or shortness of breath
Palpitations Palpitations
Syncope Syncope
AND ≥1 new finding of: AND
Elevated troponin Histological confirmation of myocarditis
Abnormal ECG or rhythm monitoring consistent with myocarditis OR
Abnormal ventricular systolic function or wall motion abnormality Elevated troponin AND cardiac MRI findings consistent with the
on echocardiogram original or revised Lake Louise criteria for myocarditis14
Cardiac MRI findings consistent with the original or revised Lake AND no other identifiable cause of the symptoms and findings
Louise criteria for myocarditis14
AND no other identifiable cause of the symptoms and findings
Adapted from Gargano et al11 with permission. Copyright © 2021, Centers for Disease Control and Prevention. COVID-19 indicates coro-
navirus disease 2019.
continuous variables. A Fisher exact test or a Wilcoxon rank- not tested again. Fifteen (10.7%) patients had evidence
sum test was used to compare markers of illness severity in of previous COVID-19 infection by history (n=5), posi-
patients who did versus did not undergo cMRI, and time to tive nucleocapsid antibodies (n=5), or both (n=5). Previ-
cMRI in those that were normal versus abnormal. Markers of ill- ous COVID-19 infection occurred <1 month to up to 10
ness severity included the need for an intensive care unit (ICU)
months before the suspected myocarditis episode in the
stay, left ventricular dysfunction on echocardiogram, and tropo-
10 patients with a known history. The majority (n=94,
nin I levels, which were performed more frequently than tropo-
nin T. All analyses were performed using Stata 11.2 (College 67.6%) had no history of previous infection and had neg-
Station, TX). ative nucleocapsid antibodies to COVID-19, although in
30 patients (21.6%) the history was unknown and no

nucleocapsid antibody testing was performed (Table 2).
Of the 12 patients who presented with myocarditis after
RESULTS the first dose of vaccine, 6 had a history of previous
As of July 4, 2021, 146 episodes of clinically suspect- COVID-19 infection or had the presence of nucleocap-
ed VAM occurred in 145 adolescents and young adults sid antibodies. Evaluation for alternative microbial causes
<21 years old at 26 centers, with 6 patients excluded for suspected myocarditis varied (Table S1), with no
because of the lack of abnormal troponin. Thus, 140 epi- plausible alternatives determined by centers. None had
sodes in 139 patients were analyzed. One patient pre- a previous history of multisystem inflammatory syndrome
sented with suspected myocarditis after both doses of in children associated with COVID-19 (MIS-C).
the Pfizer-BioNTech vaccine, with a more severe course
after the second dose; data from his second episode are
Vaccination Data, Symptoms, and Clinical
included in the aggregate analysis, as detailed later in
this article. The majority of patients were White (n=92, Course
66.2%), non-Hispanic (n=96, 69.1%), and male (n=126, Most patients with suspected myocarditis received
90.6%) with a median age of 15.8 years (range, 12.1– mRNA vaccine, with 131 (94.2%) after the Pfizer-BioN-
20.3; IQR, 14.5–17.0; Table 2). On the basis of symp- Tech and 5 (3.6%) after the Moderna vaccines. One case
toms, laboratory, and imaging data, 49 (35.0%) episodes (0.7%) occurred after the Johnson & Johnson vaccine.
of suspected myocarditis met criteria for confirmed The brand of vaccine was unknown in 2 patients. Pa-
myocarditis by CDC classification, and the remaining 91 tients presented more frequently after the second dose
(65.0%) episodes would be classified as probable. No (n=128, 91.4%; Table 3). Onset of symptoms occurred at
patients underwent endomyocardial biopsy. a median of 2 days (range, 0–22; IQR, 1–3) after vaccine
Of the 140 episodes of clinically suspected VAM, 124 administration, with 5 patients presenting with symptoms
(88.6%) were evaluated with SARS CoV-2 polymerase 7 to 20 days and only 1 presenting with symptoms ≥21
chain reaction testing at the time of presentation (Table days after vaccination. Chest pain was the most common
S1), all of which were negative. Two patients had posi- symptom, occurring in 138 patients (99.3%). Fever and
tive polymerase chain reaction testing within 32 days of shortness of breath each occurred in 30.9% and 27.3%
presentation of suspected myocarditis, and thus were of patients, respectively (Table 3).

TruongAR09567
Table 2. Demographic Variables and History of COVID-19 Table 3. COVID-19 Vaccine and Clinical Data
Infection
ORIGINAL RESEARCH
Variable Value
Variable Value
Total adolescents and young adults, n 139
ARTICLE
Total adolescents and young adults, n 139

Brand of COVID-19 vaccine, n (%)
Age, y (range; interquartile range) 15.8 (12.1–20.3; 14.5–17.0)
Pfizer-BioNTech 131 (94.2)
12 to <16, n (%) 73 (52.5)
Moderna 5 (3.6)
16 to ≤20, n (%) 66 (47.5)
Johnson & Johnson 1 (0.7)
Male sex, n (%) 126 (90.6)
Unknown 2 (1.4)
Race, n (%)
Dose of vaccine with symptoms (n=140), n (%)
White 92 (66.2)
First dose 12 (8.6)
Black 6 (4.3)
Second dose 128 (91.4)
Asian 9 (6.5)
Days from vaccine administration to symptom onset, 2 (0–22; 1–3)
Native American or Alaskan Native 2 (1.4)
n (range; interquartile range)
Other 13 (9.4)
Symptoms, n (%)
Unknown or refused to answer 17 (12.2)
Chest pain 138 (99.3)
Ethnicity, n (%)
Fever (temperature ≥100.4 °F or tactile) 43 (30.9)
Hispanic 29 (20.9)
Shortness of breath 38 (27.3)
Unknown/refused to answer 14 (10.1)
Headache 22 (15.8)
Previous COVID-19 infection
Myalgias 19 (13.7)
Yes (by history), n (%) 10 (7.2)
Vomiting 17 (12.2)
Months from known COVID-19 5 (<1–10)
infection, n (range) Fatigue 11 (7.9)
Yes (by COVID-19 nucleocapsid antibody; 10 (7.2) Palpitations 7 (5.0)
n=82), n (%)
Rash 5 (3.6)
No history and negative nucleocapsid 94 (67.6)
antibody, n (%) Diarrhea 3 (2.2)
Unknown history and no nucleocapsid 30 (21.6) Conjunctivitis 1 (0.7)

antibody tested, n (%) Intensive care unit stay, n (%) 26 (18.7)

COVID-19 indicates coronavirus disease 2019. Inotropes used, n (%) 2 (1.4)
Days in hospital, n (range, interquartile range) 2 (0–10; 2–3)
Although 26 patients (18.7%) were managed in ICUs,
inotropic/vasoactive support was used in only 2 (1.4%): Mortality, n 0
1 patient was treated with epinephrine and norepineph- COVID-19 indicates coronavirus disease 2019.
rine, and the other patient was treated with milrinone. No
patient required extracorporeal membrane oxygenation. ng/mL; IQR, 0.25–1.3 ng/mL; n=28; Table 4). Median
All patients survived. The median hospital length of stay C-reactive protein levels were mildly elevated (3.3 mg/
was 2 days (range, 0–10; IQR, 2–3). dL; IQR, 1.1–6.2 mg/dL; n=116). The median brain na-
Most patients (n=113, 81.3%) were treated with non- triuretic peptide level was within the normal range (55.0
steroidal anti-inflammatory drugs (NSAIDs); 76 (54.7%) pg/mL; IQR, 18.9–147.0 pg/mL; n=101) and median
were treated with NSAIDs alone. Intravenous immuno- NT-proBNP (N-terminal pro-B-type natriuretic peptide)
globulin (IVIG) was administered to 30 (21.6%) patients, was mildly elevated (159 pg/mL; IQR, 91.5–810.3 pg/
with glucocorticoids also given to 30 patients (Figure 1). mL; n=8; Table 4).
Glucocorticoid regimens varied, ranging from intravenous
glucocorticoids alone (n=6) at doses of 0.5 to 10 mg·kg–
·d for 1 to 3 days, to oral glucocorticoids alone (n=2)
1 –1 ECGs and Arrhythmias
at 0.5 to 0.67 mg·kg–1·d–1 for 5 to 10 days, or intravenous ECGs were obtained in 138 patients (99.3%); 97
and oral glucocorticoids (n=22) with a taper over 2 to 73 (69.8%) of the ECGs showed abnormal results. The
days. Colchicine was used in 11 patients (7.9%). Twelve most common abnormal ECG findings were ST-seg-
patients (8.6%) had complete clinical improvement with- ment and T-wave abnormalities/elevation (n=95, 97.9%;
out any anti-inflammatory therapies. Figure 2A), with low voltages also seen in some (n=5,
3.6%). Of the 5 patients with low voltages, 3 had normal
voltages within 3.5 weeks; one did not follow up with the
Laboratory Data contributing site, and thus no follow-up ECGs were avail-
All patients had elevated troponin I (median, 8.12 ng/ able; one continued to have low voltages at 5.5 weeks.
mL; IQR, 3.50–15.90 ng/mL; n=111) or T (median, 0.61 Occasional premature ventricular (n=3) or atrial (n=1)

TruongAR09568
ORIGINAL RESEARCH
ARTICLE
Figure 1. Anti-inflammatory therapies used in the treatment of suspected myocarditis temporally related to the COVID-19
vaccination.
COVID-19 indicates coronavirus disease 2019.
contractions, atrial tachycardia (n=1), first-degree atrio- and 2 (1.4%) had severe dysfunction (Table 4). Twenty-
ventricular block (n=1), and complete heart block (n=1) five patients with LVEF<55% had recovery of systolic
were observed, although uncommon. function to normal, with 1 patient awaiting outpatient
Nonsustained ventricular tachycardia occurred in 7 follow-up at the time of this submission. Only 1 patient
patients (5.0%), either on ECG, telemetry, or ambulatory had a pericardial effusion, which was small. One patient
monitoring. Six had normal LVEF on echocardiogram, and had coronary artery dilation, with further details as noted
one had mildly decreased systolic function (LVEF=50%). later on in this article.
Of the 6 patients with ventricular tachycardia who Initial cMRI was performed in 97 patients at a median
underwent cMRI, all had late gadolinium enhancement of 5 days (range, 1–88; IQR, 3–17) after symptom onset,
and myocardial edema. Two patients were treated with of whom 75 (77.3%) had abnormalities. Among patients
NSAIDs alone, 1 with IVIG and NSAIDs, 2 with IVIG and with abnormal cMRIs, late gadolinium enhancement was
glucocorticoids, 1 with glucocorticoids and NSAIDs, and noted in 74 (98.7%) and myocardial edema was present
1 with IVIG, glucocorticoids, and NSAIDs; this last patient in 54 (72.0%; Table 4, Figure 3). Among the 97 cMRIs
had a 15-beat run of nonsustained ventricular tachycar- performed, 76.3% and 55.7% had evidence of late gado-
dia on a Holter monitor (Figure 2B) and was readmitted linium enhancement or myocardial edema, respectively,
and treated with atenolol. and 49 (50.5%) met Lake Louise criteria for myocarditis
One patient presented to an emergency department (Table 4, Table S2). Of those with abnormal cMRIs, 62
with chest pain and was diagnosed with complete heart (82.7%) occurred in patients with normal left ventricular
block. He was admitted to the pediatric ICU for monitoring, systolic function on echocardiogram. Patients with versus
and no pacing was needed. Ventricular systolic function without a cMRI did not differ significantly with respect to
was normal on echocardiogram, and cMRI revealed late ICU admission (24.1% versus 16.7%, P=0.26), having
gadolinium enhancement without evidence of myocardial ≥mild left ventricular systolic dysfunction (23.2% versus
edema. This patient was treated with IVIG and steroids, 11.9%, P=0.17), or troponin I levels (9.18 versus 5.03
and his rhythm recovered within 24 hours of admission. ng/mL, P=0.08). Median days from symptom onset to
cMRI were significantly shorter for patients with abnor-
mal versus normal cMRIs (4 versus 24 days, P<0.01).
Cardiac Imaging However, 6 of the 15 cMRIs performed >30 days after
Echocardiography was performed in all patients. The symptom onset had findings at late gadolinium enhance-
majority (n=113, 81.3%) had normal systolic function, ment (even at up to 88 days), whereas 7 of the 22 normal
whereas 22 (15.8%) had mild, 2 (1.4%) had moderate, cMRIs were obtained within 7 days of symptom onset.

TruongAR09569
Table 4. Laboratory, ECG, and Imaging Data Cases of Interest

ORIGINAL RESEARCH
Variable Value
Patient With Suspected Myocarditis After the First
Peak laboratory values and Second Vaccine Doses
ARTICLE
Troponin (N=139) A 17-year-old White male patient with a history of obe-

Troponin I, ng/mL (n=111) 8.12 (IQR, 3.50–15.90) sity and hyperlipidemia and no known previous history
(Reference normal <0.04 ng/mL) of COVID-19 infection had presumed myocarditis after
Troponin T, ng/mL (n=28) 0.61 (IQR, 0.25–1.30) both the first and second doses of the Pfizer-BioNTech
(Reference normal ≤0.014 ng/mL) vaccine. He had onset of chest pain 20 days after his
Brain natriuretic peptide, pg/mL (n=101) 55.0 (IQR, 18.9–147.0) first dose and presented to the emergency department;
(Reference normal <100 pg/mL)
laboratory tests showed a peak troponin I of 0.45 ng/
NT-Pro-BNP, pg/mL (n=8) 159 (IQR, 91.5–810.3) mL. No testing for acute or previous COVID-19 infec-
(Reference normal <125 pg/mL)
tion was performed, and no other causes for myocarditis
C-Reactive protein, mg/dL (n=116) 3.3 (IQR, 1.1–6.2) were evaluated at that time. His ECG and echocardio-
(Reference normal <0.3 mg/dL)
gram were normal, and cMRI was not performed. He was
Testing/imaging
treated with NSAIDs as an outpatient. His chest pain re-
ECG (N=138), n (%) solved, with a decrease in troponin level to 0.3 ng/mL 3
Abnormal 97 (69.8) days after presentation.
Normal 41 (29.5) He received a second dose of vaccine 10 days after
Abnormal ECG findings or arrhythmias (n=97) presenting with his initial episode of suspected myo-
carditis after vaccination (ie, 30 days after receiving
ST- or T-wave changes/elevation 95 (97.9)
his first dose of vaccine). Chest pain occurred 5 days

Nonsustained ventricular tachycardia 7 (5.0)
(ECG, telemetry, or ambulatory moni-
after his second vaccine dose, with a much higher peak
toring) troponin I level of 34.5 ng/mL. His ECG showed dif-
Low-voltage QRS 5 (3.6) fuse ST-segment changes and nonsustained ventricu-
Premature ventricular contractions (ECG, 3 (2.2)
lar tachycardia. Left ventricular systolic function was
telemetry, or ambulatory monitoring) normal. cMRI showed late gadolinium enhancement
Atrial tachycardia (ECG, telemetry, or 1 (0.7) and myocardial edema. He was treated with IVIG and
ambulatory monitoring) NSAIDs. Nucleocapsid IgG testing sent before IVIG
Premature atrial contractions 1 (0.7) was negative. Thyroid peroxidase antibody group and
First-degree atrioventricular block 1 (0.7)
Sjogren syndrome-A antibodies were positive, but these
were obtained after IVIG administration, and he had no
Complete heart block 1 (0.7)
previous history of symptoms or findings suggestive of
Echocardiogram (N=139)
these disorders. He was hospitalized for 4 days, which
Left ventricular ejection fraction, n (%) included ICU admission, although no inotropic or vaso-
Normal (≥55%) 113 (81.3) active support was required.
Mild dysfunction (45%–54%) 22 (15.8) Of note, he also had a history of suspected myocardi-
Moderate dysfunction (35%–44%) 2 (1.4) tis at age 10 years, with symptoms of fever, sore throat,
and chest pain. At that time, he was admitted to the ICU,
Severe dysfunction (<35%) 2 (1.4)
with troponin I level of 0.78 ng/mL, normal ECG, and
Pericardial effusion ≥small in size, n (%) 1 (0.7)
normal function by echocardiography. No cMRI was per-
Cardiac MRI (n=97) formed associated with this episode.
Days from symptom onset to cardiac MRI 5 (range 1–88; IQR, 3–17)
Patient With Suspected Myocarditis and Coronary
Left ventricular ejection fraction 60.0% (55.0%–62.7%)
Artery Dilation
Right ventricular ejection fraction 57.3% (52.9%–62.0%)
A 16-year-old Black male patient who had a COVID-19
Abnormal findings, n (%) 75 (77.3) infection 32 days before receiving his first dose of Pfizer-
Late gadolinium enhancement 74 (98.7) BioNTech vaccine had dilated coronary arteries on pre-
Myocardial edema 54 (72.0) sentation with suspected VAM. He presented with chest
Lake Louise criteria (yes), n (%) 49 (50.5) pain 7 days after the first dose of vaccine; he had no
fevers or other organ system involvement, and he did not
Centers for Disease Control and Prevention case definition of myocarditis
(N=140), n (%) meet CDC criteria for MIS-C15 or American Heart As-
Confirmed 49 (35.0)
sociation criteria for complete or incomplete Kawasaki
disease.16 Peak C-reactive protein was 0.62 mg/dL and
Probable 91 (65.0)
peak troponin I level was 17.5 ng/mL. Nucleocapsid
IQR indicates interquartile range; and NT-proBNP, N-terminal pro-B-type na- antibody and spike antibody testing were positive. His
triuretic peptide.
ECG showed ST-segment elevation. Telemetry showed

TruongAR09570
ORIGINAL RESEARCH
ARTICLE
Figure 2. Electrocardiographic abnormalities and rhythm disturbances seen in suspected myocarditis temporally related to
vaccination.
A, Diffuse ST elevation on the ECG of a 15-year-old boy presenting with chest pain and elevated troponin levels 2 days after his second Pfizer
vaccine dose. B, Holter monitor tracing showing a 15-beat run of nonsustained ventricular tachycardia at a rate of ≈170 beats per minute in
a 17-year-old boy who had ventricular couplets and a 3-beat run of nonsustained ventricular tachycardia during hospitalization for suspected
myocarditis after his second Pfizer-BioNTech vaccine dose.
ventricular ectopy for which he was started on metopro- of 51% with a small aneurysm of the right coronary ar-
lol. He had no ventricular tachycardia or other sustained tery (Z-score of 3.8) and mild dilation of the left anterior
arrhythmias while in the hospital, but routine outpatient descending coronary artery (Z-score of 2.2) (Boston Z-
screening with a Holter monitor showed atrial ectopic score system). The left main coronary artery Z-score was
tachycardia with rare atrial and ventricular ectopy (<1%). normal. He was treated with glucocorticoids and aspirin.
His echocardiogram at presentation showed an LVEF On hospital day 3, the right coronary artery Z-score had

TruongAR09571
ORIGINAL RESEARCH
ARTICLE
Figure 3. Cardiac magnetic resonance images from a 16-year-old boy (A and C) obtained 5 days after second dose (2 days after
symptom onset) and a 15-year-old boy (B and D) 4 days after second dose (2 days after symptom onset).
T2 weighted images (A and C) show focal inferolateral wall edema. Late gadolinium enhancement images (B and D) show subepicardial and
midwall enhancement characteristic of myocarditis.
decreased to 2.6 and the left coronary artery dimensions week of vaccination and occurred in most patients after
and LVEF had normalized. One month later, the right cor- the second dose. Ventricular tachycardia and complete
onary artery Z-score was 2.9, and it remained enlarged at heart block were uncommon complications (5.8%) and
his most recent evaluation 76 days after presentation. He occurred in the absence of ventricular systolic dysfunc-
has not yet received his second dose of vaccine. tion in all but one in this series. Many patients (80.6%)
had pseudoinfarct presentation with chest pain, ST
changes on ECG, and elevated troponin with normal left
DISCUSSION ventricular systolic function.17 In the <20% of patients
In this large case series from North America, we describe with depressed LVEF on echocardiogram at presenta-
139 adolescents and young adults <21 years old who tion, systolic function normalized in all who had follow-up
had 140 episodes of clinically suspected myocarditis echocardiograms at the time of this submission. Although
temporally related to COVID-19 vaccination. The CDC only 50.5% of cMRIs performed met Lake Louise criteria
case definition11 of confirmed myocarditis after vaccina- for myocarditis, findings of late gadolinium enhancement
tion was met in 35%, with elevated troponin levels and were seen in 76.3% and myocardial edema in 55.7% of
cMRIs that met Lake Louise criteria for myocarditis, and all cMRIs performed. More than 80% of these abnormal
the remainder met criteria for probable cases. Symp- cMRIs occurred in the setting of normal systolic func-
toms and clinical findings typically developed within a tion on echocardiogram. No patients died or required

TruongAR09572
extracorporeal membrane oxygenation support, and reflect differences in vaccination rates rather than sus-
nearly 1 in 5 patients were admitted to an ICU, although ceptibility. Males outnumber females in nonvaccine forms
ORIGINAL RESEARCH
the use of inotropic/vasoactive support was rare. Similar of myocarditis in both childhood27 and adulthood,28,29 in
to patients who have myocarditis with a pseudoinfarct particular, with pseudoinfarct presentation, with the high-
ARTICLE
presentation,12,17,18 most patients had a relatively benign est incidence in adolescent and young adult males.29
clinical course. Longer-term surveillance is needed, how- Although 66% to 77% of non–COVID-19 myocardi-
ever, to determine the natural history of suspected myo- tis occurs in males,27,29 the male predominance in sus-
carditis temporally related to COVID-19 vaccines. pected VAM is strikingly higher, with males constituting
The findings in our large case series of adolescents 90.6% of cases in our series and all cases in smaller
and young adults with clinically suspected myocarditis earlier reports.6–8,19 The underlying genetic differences or
after COVID-19 vaccination add to previously reported, immune response mechanisms that underly the profound
smaller case series and case reports.6–8,19–21 Our large susceptibility of young males in VAM are uncertain.
series is similar to earlier reports in finding a predomi- Mechanisms of myocardial dysfunction posited in MIS-
nance of White and non-Hispanic men, with symptoms C, such as hyperinflammatory state and cytokine storm,30
typically within a week of the second dose of mRNA autoantibodies,31,32 or molecular mimicry,33 may play a
vaccine and cMRI abnormalities seen frequently.21 A role. Other potential mechanisms including reaction to
unique feature of our series is a patient with episodes adjuvant, nanoparticles, or other components of the vac-
of myocarditis after both his first and second doses of cine34 could also be important mechanistically. Negron et
the Pfizer-BioNTech vaccine, although there are other al35 have suggested an abundance of the SARS-CoV-2
features of this patient’s clinical history that may make Spike protein S1 subunit, produced as a result of mRNA
his case less generalizable. Nonetheless, the greater vaccines, could interact with toll-like receptor 4, activate
severity of symptoms and laboratory findings in this NF-κB (nuclear factor-κB), thereby eliciting cardiac
patient after his second versus first dose supports inflammation and myocyte toxicity. Further studies are
the consideration of withholding or deferring a sec- critically needed to elucidate risk factors and underlying
ond dose of mRNA COVID-19 vaccine in patients with mechanisms for the development of potential VAM.
suspected myocarditis after the first dose until more Optimal treatment strategies for clinically suspected
information is available.22 VAM are unknown, with treatments ranging in our series
We also describe a patient with coronary artery from no anti-inflammatory therapies to glucocorticoids
involvement that, to our knowledge, has not been previ- with or without IVIG, and even anakinra in 1 case. Glu-
ously reported in patients with post–COVID-19 vaccine cocorticoids have not been shown to be beneficial, and
myocarditis. However, coronary artery dilation has been may be harmful, in viral myocarditis. However, they have
described in non–COVID-19 viral myocarditis23 and been used in virus-negative myocarditis.12,13,36,37 Clini-
in myocarditis in the setting of COVID-19 infection.24 cians may have administered immunomodulatory agents
Because this patient had COVID-19 infection 32 days to some patients in this series because VAM results
before his vaccination, it is unclear if the coronary artery from an immune-mediated response, rather than direct
findings are related to the infection, the vaccination, a viral infection of the myocardium.34 The use of IVIG and
combination of the 2, or completely unrelated. Although glucocorticoids in ≈20% of patients in this series may
the timing of his presentation and cardiac findings are also reflect extrapolation from care strategies of MIS-C
similar to those that have been described in MIS-C, he and non–COVID-19 myocarditis. Glucocorticoids and
otherwise did not meet CDC criteria for MIS-C. Coro- IVIG, alone or in combination, are used commonly in
nary artery Z-scores, that is, coronary artery dimensions MIS-C,38 with studies suggesting recovery of cardiac
normalized for body surface area, have high inter- and function39 and decreased risk of development of left ven-
intraobserver agreement in young children.25 However, tricular dysfunction and shorter ICU stays40 when used
poor windows may limit the technical feasibility of coro- in combination. Despite equivocal data41,42 and some
nary measurements in larger children and adolescents. recommendations against its use in non–COVID-19
Until more data are available, focused echocardio- myocarditis,13,42 NSAIDs were the most commonly used
graphic coronary artery imaging in patients presenting medication in our series. However, we could not discern
with suspected myocarditis after COVID-19 vaccination whether NSAIDs were prescribed for pain manage-
may be warranted to determine the frequency and evo- ment, for anti-inflammatory effects, or for both. Likewise,
lution of this finding. although colchicine is used in the treatment of pericardial
Risk factors and mechanisms for the development of disease,43 it is not indicated for the treatment of myocar-
suspected myocarditis after COVID-19 vaccination are ditis. Its use in nearly 8% of patients in this series may
unknown. White, non-Hispanic Americans comprised reflect concerns for pericardial involvement, that is, myo-
nearly 60% of those who had at least 1 vaccine dose pericarditis. Last, we did not have sufficient sample size
in the United States before to July 4, 2021.26 Thus, to analyze the efficacy of different medical regimens with
race and ethnic distributions observed in our study likely propensity score matching.

TruongAR09573
Although VAM, even if mild in the majority, is a cause with those from severe cardiac effects in youth after
of great concern, its risk must be balanced against critical acute COVID-19 or MIS-C within each center’s catch-
ORIGINAL RESEARCH
illness and cardiovascular involvement associated with ment area. Of note, the CDC has estimated reporting
acute or postacute sequelae of COVID-19 infection,44 rates of 62.75 (0.006%) and 50.2 (0.005%) myocardi-
ARTICLE
and particularly with MIS-C in youth.44–46 In large studies tis cases per 1 million mRNA COVID-19 vaccine doses
of patients with MIS-C, 73.8% have been admitted to the administered in the 12- to 17-year and 18- to 24-year
ICU,44 30% to 62% have required inotropic/vasoactive age groups, respectively.22 Using data from Washington
support,44–46 3.3% were on extracorporeal membrane state, Schauer et al20 estimated an incidence of 0.008%
oxygenation, and 1.9% died.44 Children and adolescents in adolescents aged 16 to 17 years and 0.01% in those
with acute COVID-19 can also be quite ill; Feldstein et aged 12 to 15 years. The benefit-risk analysis presented
al44 reported that 43.8% of hospitalized patients <21 by the CDC has suggested a positive balance for all age
years old with acute COVID-19 were admitted to an ICU, groups of both sexes, although the balance varies by age
of whom 8.7% were on vasoactive support, 1.4% were and sex; assessments of benefit-risk for each individual
on extracorporeal membrane oxygenation, and 1.4% are also necessary.11,22
died. Cardiovascular injury or involvement is common Other limitations to this study relate to its retrospec-
in MIS-C, with decreased LVEF in 34.2% to 52.0%44–46 tive and descriptive nature. The evaluation for alterna-
and coronary artery aneurysms in 13.4%.44 In contrast to tive causes and management strategies for suspected
MIS-C and hospitalized pediatric patients with COVID- myocarditis, such as indications for ICU admission, was
19, the frequencies of ICU admission and of inotropic/ decided by local clinicians rather than by study protocol.
vasoactive support were only 18.7% and 1.4%, respec- Furthermore, no patients underwent endomyocardial
tively, in our suspected VAM series. Frequency of left biopsy to rule out direct viral infection of the myocar-
ventricular systolic dysfunction was lower (18.7%) than dium. Therefore, some patients included in this series
that reported in MIS-C. Some studies have suggested may have an alternative diagnosis, although the high
that diastolic dysfunction parameters persist, despite numbers of clinically suspected myocarditis presenting
normalization of systolic function in COVID-19 sus- within a week of vaccination in a 3-month period would
pected myocarditis.47,48 However, diastolic function and be unusual. Also, approaches to image acquisition of
strain parameters were not assessed in our case series, cMRIs were not standardized and relied on local pro-
so direct comparisons could not be performed. tocols. Likewise, echocardiograms and cMRIs were not
The definition of myocarditis varies somewhat in the interpreted in core laboratories, and we did not assess
literature. Endomyocardial biopsy is the current reference diastolic function parameters. Because cMRIs were
standard to confirm the diagnosis of myocarditis,12,13,49 obtained in only 69.3% of cases in our series at the
but it is used infrequently in pediatrics49 and adults.12 Fur- time of submission, we may be over- or underestimat-
thermore, a high false-negative rate has been reported ing the frequency of abnormal cMRI findings. There
in myocarditis, because biopsy samples are taken ran- may also be selection bias in who underwent cMRIs,
domly and myocarditis tends to be focal.49 In the 2021 although, in our analysis, there was no statistical dif-
American Heart Association Diagnosis and Management ference in troponin levels, frequency of LVEF<55%, or
of Myocarditis in Children Statement, a paradigm shift in ICU stays between those who underwent cMRIs and
the diagnosis of myocarditis is described, with greater those who did not. The variable timing at which cMRIs
reliance on tissue characterization through cMRI.49 None were obtained may also make findings (or lack of) find-
of the patients in our series underwent myocardial biopsy ings difficult to interpret. We only studied the acute
to confirm the diagnosis of myocarditis, likely reflecting course of patients and do not have appreciable follow-
clinical practice and an unfavorable risk/benefit ratio in up information. Patients in this series were evaluated
children and young adults who recovered quickly after at academic medical centers and may have been more
presentation with suspected myocarditis. seriously ill than patients in the community.
Although this case series cannot determine causal- In conclusion, our case series demonstrates that
ity of suspected myocarditis from COVID-19 vaccination, myocarditis temporally related to COVID-19 vaccination
the number of cases of suspected myocarditis within a is characterized by a mild illness with rapid resolution of
short time frame after COVID-19 vaccination would be symptoms in most patients. However, longer-term out-
unlikely to be secondary to chance alone. The CDC has come data are lacking. We emphasize the importance of
determined that the observed frequency of reporting of reporting suspected myocarditis cases after COVID-19
suspected myocarditis/pericarditis temporally related to vaccination to the US Vaccine Adverse Events Report-
COVID-19 vaccination is higher than the expected back- ing System or similar reporting systems for patients
ground rate of myocarditis/pericarditis.50 in other countries to better define the characteristics
Our study design did not allow us to estimate the inci- of this syndrome and its relationship to the receipt
dence or risk of myocarditis in adolescents and young of COVID-19 vaccines. Future studies that focus on
adults after COVID-19 vaccine or to compare these risks determining risk factors and mechanisms of develop-

TruongAR09574
ment of myocarditis are urgently needed, in particular, terest for covid-19 vaccines in eight countries: multinational network cohort
study. BMJ. 2021;373:n1435.
as COVID-19 vaccines become more widely available
ORIGINAL RESEARCH
4. Mevorach D, Anis E, Cedar N, Bromberg M, Haas EJ, Nadir E, Olsha-Castell
to younger children in the future. S, Arad D, Hasin T, Levi N, et al. Myocarditis after BNT162b2 mRNA vac-
cine against Covid-19 in Israel. N Engl J Med. 2021;385:2140–2149. doi:
ARTICLE
10.1056/NEJMoa2109730.
5. Montgomery J, Ryan M, Engler R, Hoffman D, McClenathan B, Collins
ARTICLE INFORMATION L, Loran D, Hrncir D, Herring K, Platzer M, et al. Myocarditis follow-
Received July 14, 2021; accepted November 2, 2021. ing immunization with mRNA COVID-19 vaccines in members of
the US military. JAMA Cardiol. 2021;6:1202–1206. doi: 10.1001/
Affiliations jamacardio.2021.2833
Division of Pediatric Cardiology, University of Utah and Primary Children’s Hospital, 6. McLean K, Johnson TJ. Myopericarditis in a previously healthy adolescent
Salt Lake City (D.T.T., L.M.L.). Department of Cardiology, Boston Children’s Hospi- male following COVID-19 vaccination: a case report. Acad Emerg Med.
tal, Department of Pediatrics; Harvard Medical School, MA (A.D., J.W.N.). Nicklaus 2021;28:918–921. doi: 10.1111/acem.14322
Children’s Hospital, Miami, FL (J.C.M.). Department of Pediatrics, Medical Univer- 7. Abu Mouch S, Roguin A, Hellou E, Ishai A, Shoshan U, Mahamid L,
sity of South Carolina, Charleston (K.E.M., A.M.A.). Seattle Children’s, Department Zoabi M, Aisman M, Goldschmid N, Berar Yanay N. Myocarditis follow-
of Pediatrics, University of Washington (M.A.P., J.S.). Nemours Cardiac Center, ing COVID-19 mRNA vaccination. Vaccine. 2021;39:3790–3793. doi:
Nemours Children’s Health, Wilmington, DE (D.T., S.S.). Division of Cardiology, The 10.1016/j.vaccine.2021.05.087
Children’s Hospital of Philadelphia, PA (M.D.E., T.M.G.). Duke University School of 8. Marshall M, Ferguson ID, Lewis P, Jaggi P, Gagliardo C, Collins JS,
Medicine, Durham, NC (J.S.L., M.J.C.). Connecticut Children's Medical Center and Shaughnessy R, Caron R, Fuss C, Corbin KJE, et al. Symptomatic acute
University of Connecticut School of Medicine, Farmington (O.H.T.-S.). Division of myocarditis in 7 adolescents after Pfizer-BioNTech COVID-19 vaccination.
Pediatric Cardiology; NewYork-Presbyterian/Columbia University Irving Medical Pediatrics. 2021;148:e2021052478. doi: 10.1542/peds.2021-052478
Center (B.R.A.). Oregon Health & Science University, Division of Pediatric Car- 9. Halsell JS, Riddle JR, Atwood JE, Gardner P, Shope R, Poland GA, Gray
diology, Department of Pediatrics, Portland (C.M.B., C.R.). The Heart Institute, Joe GC, Ostroff S, Eckart RE, Hospenthal DR, et al; Department of Defense
DiMaggio Children’s Hospital, Hollywood, FL (M.C., L.D.’A.). Division of Pediatric Smallpox Vaccination Clinical Evaluation Team. Myopericarditis following
Cardiology, Department of Pediatrics, University of California San Diego and Rady smallpox vaccination among vaccinia-naive US military personnel. JAMA.
Children’s Hospital San Diego (K.B.D.). Division of Pediatric Cardiology, Children’s 2003;289:3283–3289. doi: 10.1001/jama.289.24.3283
Mercy, Kansas City, MO (D.F.). Division of Cardiology, Children’s National Hospital, 10. Kim YJ, Bae JI, Ryoo SM, Kim WY. Acute fulminant myocarditis following in-
Washington, DC (L.H.F., A.K.). Division of Pediatric Cardiology, C.S. Mott Children’s fluenza vaccination requiring extracorporeal membrane oxygenation. Acute
Hospital, University of Michigan, Ann Arbor (O.H.F., S.K.G.). Children’s of Alabama Crit Care. 2019;34:165–169. doi: 10.4266/acc.2017.00045
Department of Pediatrics, Division of Pediatric Cardiology, University of Alabama 11. Gargano JW, Wallace M, Hadler SC, Langley G, Su JR, Oster ME, Broder
at Birmingham School of Medicine (C.H.). Maria Fareri Children’s Hospital at West- KR, Gee J, Weintraub E, Shimabukuro T, et al. Use of mRNA COVID-19
chester Medical Center/ New York Medical College, Valhalla (S.S.J.). University of vaccine after reports of myocarditis among vaccine recipients: update
North Carolina at Chapel Hill (P.J., J.R.S.). Warren Alpert Medical School of Brown from the Advisory Committee on Immunization Practices – United States,
University; Division of Pediatric Cardiology, Hasbro Children’s Hospital, Providence, June 2021. MMWR Morb Mortal Wkly Rep. 2021;70:977–982. doi:
RI (K.C.L.). Department of Paediatrics, The Hospital for Sick Children, University 10.15585/mmwr.mm7027e2
of Toronto, Canada (B.W.M., T.M.). Cohen Children’s Medical Center (Northwell 12. Caforio AL, Pankuweit S, Arbustini E, Basso C, Gimeno-Blanes J, Felix SB,
Health), New Hyde Park, NY (E.C.M.). Kawasaki Disease Research Center, De- Fu M, Heliö T, Heymans S, Jahns R, et al; European Society of Cardiology
partment of Pediatrics, University of California San Diego, La Jolla and Rady Chil- Working Group on Myocardial and Pericardial Diseases. Current state of
dren’s Hospital San Diego (K.M.). Division of Critical Care, Connecticut Children’s, knowledge on aetiology, diagnosis, management, and therapy of myocarditis:
Hartford (R.M.P.). Division of Pediatric Cardiology, Riley Children’s Hospital, India- a position statement of the European Society of Cardiology Working Group
napolis, IN (J.K.P.). Division of Pediatric Cardiology, Phoenix Children’s Hospital, on Myocardial and Pericardial Diseases. Eur Heart J. 2013;34:2636–48,
AZ (A.A.S.). Baylor College of Medicine, Texas Children’s Hospital, Houston, TX 2648a. doi: 10.1093/eurheartj/eht210
(S.K.S.T., L.S.S.). Division of Cardiology (J.K.V.-S.), Division of Hospital Medicine 13. Bozkurt B, Colvin M, Cook J, Cooper LT, Deswal A, Fonarow GC, Francis
(S.W.), Children’s Hospital Los Angeles and Keck School of USC, CA. GS, Lenihan D, Lewis EF, McNamara DM, et al; American Heart Association
Committee on Heart Failure and Transplantation of the Council on Clini-
Sources of Funding cal Cardiology; Council on Cardiovascular Disease in the Young; Council
Dr Newburger was funded in part by the McCance Foundation and the Kostin on Cardiovascular and Stroke Nursing; Council on Epidemiology and Pre-
Family Innovation Fund. vention; and Council on Quality of Care and Outcomes Research. Current
diagnostic and treatment strategies for specific dilated cardiomyopathies:
Disclosures a scientific statement from the American Heart Association. Circulation.
Dr Anderson has received research grants from the National Institutes of Health, 2016;134:e579–e646. doi: 10.1161/CIR.0000000000000455
Genentech for COVID-related research. Drs Newburger and Truong are consul- 14. Ferreira VM, Schulz-Menger J, Holmvang G, Kramer CM, Carbone I,
tants for Pfizer for vaccine-associated myocarditis (pending). The other authors Sechtem U, Kindermann I, Gutberlet M, Cooper LT, Liu P, et al. Cardio-
have no disclosures to report. vascular magnetic resonance in nonischemic myocardial inflammation:
expert recommendations. J Am Coll Cardiol. 2018;72:3158–3176. doi:
Supplemental Material 10.1016/j.jacc.2018.09.072
Tables S1 and S2 15. Centers for Disease Control and Prevention. CDC Health Advisory: multi-
system inflammatory syndrome in children (MIS-C) associated with corona-
virus disease 2019 (COVID-19). Published May 14, 2020. Accessed July
4, 2021. https://emergency.cdc.gov/han/2020/han00432.asp
REFERENCES 16. McCrindle BW, Rowley AH, Newburger JW, Burns JC, Bolger AF,
1. Ammirati E, Cavalotti C, Milazzo A, Pedrotti P, Soriano F, Schroeder JW, Gewitz M, Baker AL, Jackson MA, Takahashi M, Shah PB, et al; Ameri-
Morici N, Giannattasio C, Frigerio M, Metra M, et al. Temporal relation be- can Heart Association Rheumatic Fever, Endocarditis, and Kawasaki
tween second dose BNT162b2 mRNA Covid-19 vaccine and cardiac in- Disease Committee of the Council on Cardiovascular Disease in the
volvement in a patient with previous SARS-COV-2 infection. Int J Cardiol Young; Council on Cardiovascular and Stroke Nursing; Council on Car-
Heart Vasc. 2021:100778. doi: 10.1016/j.ijcha.2021.100774 diovascular Surgery and Anesthesia; and Council on Epidemiology and
2. Larson KF, Ammirati E, Adler ED, Cooper LT Jr, Hong KN, Saponara G, Couri Prevention. Diagnosis, treatment, and long-term management of Kawa-
D, Cereda A, Procopio A, Cavalotti C, et al. Myocarditis after BNT162b2 saki disease: a scientific statement for health professionals from the
and mRNA-1273 vaccination. Circulation. 2021;144:506–508. doi: American Heart Association. Circulation. 2017;135:e927–e999. doi:
10.1161/CIRCULATIONAHA.121.055913 10.1161/CIR.0000000000000484
3. Li X, Ostropolets A, Makadia R, Shoaibi A, Rao G, Sena AG, 17. Caforio ALP, Malipiero G, Marcolongo R, Iliceto S. Clinically suspected
Martinez-Hernandez E, Delmestri A, Verhamme K, Rijnbeek PR, et al. Char- myocarditis with pseudo-infarct presentation: the role of endomyocardial
acterising the background incidence rates of adverse events of special in- biopsy. J Thorac Dis. 2017;9:423–427. doi: 10.21037/jtd.2017.03.103

TruongAR09575
18. Fan Y, Chen M, Liu M, Yang X. Myocarditis with chest pain, normal heart 36. Chen HS, Wang W, Wu SN, Liu JP. Corticosteroids for viral myocarditis.
function and extreme increased troponin. Int J Cardiol. 2016;209:307–309. Cochrane Database Syst Rev. 2013:CD004471.
ORIGINAL RESEARCH
doi: 10.1016/j.ijcard.2016.01.037 37. Canter CE, Simpson KE, Simpson KP. Diagnosis and treatment of myo-
19. Rosner CM, Genovese L, Tehrani BN, Atkins M, Bakhshi H, Chaudhri S, carditis in children in the current era. Circulation. 2014;129:115–128. doi:
Damluji AA, de Lemos JA, Desai SS, Emaminia A, et al. Myocarditis tem- 10.1161/CIRCULATIONAHA.113.001372
ARTICLE
porally associated with COVID-19 vaccination. Circulation. 2021;144:502– 38. McArdle AJ, Vito O, Patel H, Seaby EG, Shah P, Wilson C, Broderick
505. doi: 10.1161/CIRCULATIONAHA.121.055891 C, Nijman R, Tremoulet AH, Munblit D, et al; BATS Consortium. Treat-
20. Schauer J, Buddhe S, Colyer J, Sagiv E, Law Y, Mallenahalli Chikkabyrappa ment of multisystem inflammatory syndrome in children. N Engl J Med.
S, Portman MA. Myopericarditis after the Pfizer messenger ribonucleic acid 2021;385:11–22. doi: 10.1056/NEJMoa2102968
coronavirus disease vaccine in adolescents. J Pediatr. 2021;238:317–320. 39. Belhadjer Z, Auriau J, Méot M, Oualha M, Renolleau S, Houyel L, Bonnet D.
doi: 10.1016/j.jpeds.2021.06.083 Addition of corticosteroids to immunoglobulins is associated with recovery
21. Jain SS, Steele JM, Fonseca B, Huang S, Shah S, Maskatia SA, Buddhe of cardiac function in multi-inflammatory syndrome in children. Circulation.
S, Misra N, Ramachandran P, Gaur L, et al. COVID-19 vaccination-associ- 2020;142:2282–2284. doi: 10.1161/CIRCULATIONAHA.120.050147
ated myocarditis in adolescents. Pediatrics. 2021;148:e2021053427. doi: 40. Ouldali N, Toubiana J, Antona D, Javouhey E, Madhi F, Lorrot M, Léger PL,
10.1542/peds.2021-053427 Galeotti C, Claude C, Wiedemann A, et al; French Covid-19 Paediatric In-
22. Wallace M, Oliver S. COVID-19 mRNA vaccines in adolescents and young flammation Consortium. Association of intravenous immunoglobulins plus
adults: benefit-risk discussion. Centers for Disease Control and Prevention. methylprednisolone vs immunoglobulins alone with course of fever in multi-
Published June 5, 2021. Accessed June 30, 2021. https://www.cdc.gov/ system inflammatory syndrome in children. JAMA. 2021;325:855–864. doi:
vaccines/acip/meetings/downloads/slides-2021-06/05-COVID-Wal- 10.1001/jama.2021.0694
lace-508.pdf 41. Berg J, Lovrinovic M, Baltensperger N, Kissel CK, Kottwitz J, Manka R,
23. Rached-D’Astous S, Boukas I, Fournier A, Raboisson MJ, Dahdah N. Patriki D, Scherff F, Schmied C, Landmesser U, et al. Non-steroidal anti-
Coronary artery dilatation in viral myocarditis mimics coronary artery find- inflammatory drug use in acute myopericarditis: 12-month clinical follow-up.
ings in Kawasaki disease. Pediatr Cardiol. 2016;37:1148–1152. doi: Open Heart. 2019;6:e000990. doi: 10.1136/openhrt-2018-000990
10.1007/s00246-016-1411-x 42. Meune C, Spaulding C, Mahé I, Lebon P, Bergmann JF. Risks versus
24. Ciuca C, Fabi M, Di Luca D, Niro F, Ghizzi C, Donti A, Balducci A, Rocca benefits of NSAIDs including aspirin in myocarditis: a review of the evi-
A, Zarbo C, Gargiulo GD, et al. Myocarditis and coronary aneurysms in dence from animal studies. Drug Saf. 2003;26:975–981. doi: 10.2165/
a child with acute respiratory syndrome coronavirus 2. ESC Heart Fail. 00002018-200326130-00005
2021;8:761–765. doi: 10.1002/ehf2.13048 43. Imazio M, Brucato A, Cemin R, Ferrua S, Maggiolini S, Beqaraj F, Demarie D,
25. de Zorzi A, Colan SD, Gauvreau K, Baker AL, Sundel RP, Newburger Forno D, Ferro S, Maestroni S, et al; ICAP Investigators. A randomized trial
JW. Coronary artery dimensions may be misclassified as normal in Ka- of colchicine for acute pericarditis. N Engl J Med. 2013;369:1522–1528.
wasaki disease. J Pediatr. 1998;133:254–258. doi: 10.1016/s0022- doi: 10.1056/NEJMoa1208536
3476(98)70229-x 44. Feldstein LR, Tenforde MW, Friedman KG, Newhams M, Rose EB, Dapul
26. Centers for Disease Control and Prevention. COVID Data Tracker. De- H, Soma VL, Maddux AB, Mourani PM, Bowens C, et al; Overcoming CO-
mographic trends of COVID-19 cases and deaths in the US reported VID-19 Investigators. Characteristics and outcomes of US children and
to CDC. Accessed July 4, 2021. https://covid.cdc.gov/covid-data- adolescents with multisystem inflammatory syndrome in children (MIS-C)
tracker/#demographics compared with severe acute COVID-19. JAMA. 2021;325:1074–1087. doi:
27. Vasudeva R, Bhatt P, Lilje C, Desai P, Amponsah J, Umscheid J, Parmar 10.1001/jama.2021.2091
N, Bhatt N, Adupa R, Pagad S, et al. Trends in acute myocarditis related 45. Dufort EM, Koumans EH, Chow EJ, Rosenthal EM, Muse A, Rowlands J,
pediatric hospitalizations in the United States, 2007–2016. Am J Cardiol. Barranco MA, Maxted AM, Rosenberg ES, Easton D, et al; New York State
2021;149:95–102. doi: 10.1016/j.amjcard.2021.03.019 and Centers for Disease Control and Prevention Multisystem Inflammatory
28. Fairweather D, Cooper LT Jr, Blauwet LA. Sex and gender differences in Syndrome in Children Investigation Team. Multisystem inflammatory syn-
myocarditis and dilated cardiomyopathy. Curr Probl Cardiol. 2013;38:7–46. drome in children in New York State. N Engl J Med. 2020;383:347–358.
doi: 10.1016/j.cpcardiol.2012.07.003 doi: 10.1056/NEJMoa2021756
29. Kytö V, Sipilä J, Rautava P. The effects of gender and age on occurrence of 46. Valverde I, Singh Y, Sanchez-de-Toledo J, Theocharis P, Chikermane A,
clinically suspected myocarditis in adulthood. Heart. 2013;99:1681–1684. Di Filippo S, Kuciñska B, Mannarino S, Tamariz-Martel A, Gutierrez-Larraya
doi: 10.1136/heartjnl-2013-304449 F, et al; AEPC COVID-19 Rapid Response Team*. Acute cardiovascular
30. Pesce M, Agostoni P, Bøtker HE, Brundel B, Davidson SM, Caterina R, manifestations in 286 children with multisystem inflammatory syndrome as-
Ferdinandy P, Girao H, Gyöngyösi M, Hulot JS, et al. COVID-19-related car- sociated with COVID-19 infection in Europe. Circulation. 2021;143:21–32.
diac complications from clinical evidences to basic mechanisms: opinion pa- doi: 10.1161/CIRCULATIONAHA.120.050065
per of the ESC Working Group on Cellular Biology of the Heart. Cardiovasc 47. Baruch G, Rothschild E, Sadon S, Szekely Y, Lichter Y, Kaplan A, Taieb P,
Res. 2021;117:2148–2160. doi: 10.1093/cvr/cvab201 Banai A, Hochstadt A, Merdler I, et al. Evolution of right and left ventricle
31. Consiglio CR, Cotugno N, Sardh F, Pou C, Amodio D, Rodriguez L, Tan Z, routine and speckle-tracking echocardiography in patients recovering from
Zicari S, Ruggiero A, Pascucci GR, et al; CACTUS Study Team. The immu- coronavirus disease 2019: a longitudinal study. Eur Heart J Cardiovasc Imag-
nology of multisystem inflammatory syndrome in children with COVID-19. ing. Published online September 20, 2021. doi: 10.1093/ehjci/jeab190
Cell. 2020;183:968–981.e7. doi: 10.1016/j.cell.2020.09.016 48. Matsubara D, Kauffman HL, Wang Y, Calderon-Anyosa R, Nadaraj S, Elias
32. Gruber CN, Patel RS, Trachtman R, Lepow L, Amanat F, Krammer F, MD, White TJ, Torowicz DL, Yubbu P, Giglia TM, et al. Echocardiographic
Wilson KM, Onel K, Geanon D, Tuballes K, et al. Mapping systemic findings in pediatric multisystem inflammatory syndrome associated with
inflammation and antibody responses in multisystem inflammatory COVID-19 in the United States. J Am Coll Cardiol. 2020;76:1947–1961.
syndrome in children (MIS-C). Cell. 2020;183:982–995.e14. doi: doi: 10.1016/j.jacc.2020.08.056
10.1016/j.cell.2020.09.034 49. Law YM, Lal AK, Chen S, Čiháková D, Cooper LT Jr, Deshpande S, Godown
33. Galeotti C, Bayry J. Autoimmune and inflammatory diseases follow- J, Grosse-Wortmann L, Robinson JD, Towbin JA; American Heart Associa-
ing COVID-19. Nat Rev Rheumatol. 2020;16:413–414. doi: 10.1038/ tion Pediatric Heart Failure and Transplantation Committee of the Council
s41584-020-0448-7 on Lifelong Congenital Heart Disease and Heart Health in the Young and
34. Bozkurt B, Kamat I, Hotez PJ. Myocarditis with COVID-19 mRNA vac- Stroke Council. Diagnosis and management of myocarditis in children: a
cines. Circulation. 2021;144:471–484. doi: 10.1161/CIRCULATIONAHA. scientific statement from the American Heart Association. Circulation.
121.056135 2021;144:e123–e135. doi: 10.1161/CIR.0000000000001001
35. Negron SG, Kessinger CW, Xu B, Pu WT, Lin Z. Selectively expressing 50. Shimabukuro T. COVID-19 vaccine safety updates: Vaccines and Related
SARS-CoV-2 Spike protein S1 subunit in cardiomyocytes induces cardiac Biological Products Advisory Committee (VRBPAC). US Food and Drug
hypertrophy in mice. bioRxiv. Preprint posted online June 20, 2021. doi: Administration. Published June 10, 2021. Accessed July 4, 2021. https://
10.1101/2021.06.20.448993 www.fda.gov/media/150054/download

AR09576
J Korean Med Sci. 2021 Oct 18;36(40):e286
https://doi.org/10.3346/jkms.2021.36.e286
eISSN 1598-6357·pISSN 1011-8934
Case Report
Infectious Diseases,
Myocarditis-induced Sudden Death
Microbiology & Parasitology after BNT162b2 mRNA COVID-19
Vaccination in Korea: Case Report
12 Focusing on Histopathological
Findings
Sangjoon Choi ,1 SangHan Lee ,1 Jeong-Wook Seo ,2 Min-ju Kim ,2
Yo Han Jeon ,1 Ji Hyun Park ,1 Jong Kyu Lee ,1 and Nam Seok Yeo 1
Department of Forensic Medicine, Defense Institute of Forensic Science, Criminal Investigation Command,
1
Ministry of National Defense, Seoul, Korea

2
Department of Pathology, Incheon Sejong Hospital, Incheon, Korea
Received: Aug 24, 2021

Accepted: Oct 1, 2021
ABSTRACT
Address for Correspondence: We present autopsy findings of a 22-year-old man who developed chest pain 5 days after the
SangHan Lee, MD first dose of the BNT162b2 mRNA vaccine and died 7 hours later. Histological examination of
Department of Forensic Medicine, Defense
the heart revealed isolated atrial myocarditis, with neutrophil and histiocyte predominance.
Institute of Forensic Science, Criminal
Investigation Command, Ministry of National Immunohistochemical C4d staining revealed scattered single-cell necrosis of myocytes which
Defense, 22 Itaewon-ro, Yongsan-gu, Seoul was not accompanied by inflammatory infiltrates. Extensive contraction band necrosis was
04383, Korea. observed in the atria and ventricles. There was no evidence of microthrombosis or infection
E-mail: sanghan111@gmail.com in the heart and other organs. The primary cause of death was determined to be myocarditis,
© 2021 The Korean Academy of Medical
causally-associated with the BNT162b2 vaccine.
Sciences.
Keywords: Sudden Cardiac Death; Myocarditis; Coronavirus Disease 19; Vaccination;
This is an Open Access article distributed
under the terms of the Creative Commons mRNA Vaccines; Adverse Event Following Immunization
Attribution Non-Commercial License (https://
creativecommons.org/licenses/by-nc/4.0/)
which permits unrestricted non-commercial
use, distribution, and reproduction in any INTRODUCTION
medium, provided the original work is properly
cited. The coronavirus disease 2019 (COVID-19) pandemic, which started in January 2020 has
affected people worldwide. Rapid vaccine development has enabled COVID-19 prevention.
ORCID iDs
Sangjoon Choi Two mRNA COVID-19 vaccines, BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)
https://orcid.org/0000-0003-2108-0575 demonstrated safety and efficacy in clinical trials, and were granted emergency use
SangHan Lee authorization by the US Food and Drug Administration in December 2020.1,2 As the number
https://orcid.org/0000-0003-0390-3494 of people vaccinated against COVID-19 has increased, there have been multiple reports of
Jeong-Wook Seo
myocarditis as an adverse event following immunization,3-12 which was not observed in
https://orcid.org/0000-0003-0242-1805
clinical trials.
Min-ju Kim
https://orcid.org/0000-0003-3850-9892
Yo Han Jeon Myocarditis is histologically characterized by diffuse and/or focal inflammatory infiltrates
https://orcid.org/0000-0002-0353-7255 within myocardial tissue, accompanied by myocyte damage without evidence of ischemia.13
Ji Hyun Park Little is known about the histopathological characteristics of myocarditis following COVID-19
https://orcid.org/0000-0002-1534-0070
vaccination because endomyocardial biopsy is not a routine procedure for myocarditis and,
Jong Kyu Lee
https://orcid.org/0000-0002-0492-4417 due to its generally favorable prognosis,8 opportunities for autopsy studies are rare.10
https://jkms.org 1/7
AR09577
Myocarditis-induced Sudden Death after COVID-19 Vaccination
Nam Seok Yeo We recently observed a case of sudden cardiac death in a young male six days after receiving
https://orcid.org/0000-0001-7254-6414 the first dose of the BNT162b2 mRNA vaccine and report the distinctive clinical and
pathological findings of this case.
Disclosure
The authors have no potential conflicts of
interest to disclose.
CASE DESCRIPTION
Conceptualization: Lee S. Data curation: Choi
S, Jeon YH, Park JH, Lee JK, Yeo N, Kim MJ. The deceased was 22-year-old male military recruit. His blood pressure was elevated on
Investigation: Choi S, Jeon YH, Park JH, Lee physical examination 17 and 7 months before his death (156/94 mmHg and 128/74 mmHg,
JK, Yeo N, Kim MJ. Visualization: Choi S, Seo respectively), but he was otherwise healthy. On June 13, 2021, 5 days after the first dose of
JW. Writing – original draft: Choi S. Writing BNT162b2 mRNA vaccination, he complained to a colleague of chest pain at 1:00 AM, during
– review & editing: Choi S, Lee S, Seo JW.
a smoke break, and went to bed. At 8:00 AM, he was found unconscious hunched beside the
Supervision: Lee S, Seo JW
bed. He was taken to an emergency department and was found to have ventricular fibrillation
on electrocardiography. Cardiopulmonary resuscitation was performed for two hours, but he
could not be resuscitated.
An autopsy was performed 24 hours after his death. The deceased was well-nourished with
no visible injuries on external examination. The heart weighed 470 g and had multiple
petechiae on its surface. The pericardium was smooth with no fibrin deposition or exudate.
The coronary arteries were patent, and the heart valves were unremarkable. The myocardium
was of normal thickness and there was no dilation of the atria or ventricles. The myocardium
was homogeneously brown with no obvious necrosis or fibrosis. On microscopic examination,
diffuse inflammatory infiltration, with neutrophil and histiocyte predominance, was observed
within the myocardium (Fig. 1A). Notably, the inflammatory infiltrates were dominant in the
atria (Fig. 1A and B), and around the sinoatrial (SA) and atrioventricular (AV) nodes (Fig. 1C),
A B C D
AV node
LA
RA RA
LA RA LV
LA LV
RV
Fig. 1. Histopathology of the heart. (A) Hematoxylin and eosin stains of atrial septum shows massive inflammatory infiltration with neutrophil predominance.
(B) The myocytes often show contraction band necrosis (yellow arrows), which were highlighted by Masson's trichrome staining. (C) The atrioventricular node
area shows extension of atrial myocarditis to the superficial layer of the node. (D) The ventricular myocardium is free of inflammatory infiltrates, but there are
multiple large foci of contraction band necrosis (yellow arrows) particularly in the left ventricular wall and the ventricular septum. Bars represent 100 µm. The
blue arrows in insets show where the section was taken from the low magnification views. Hematoxylin and eosin stain was used for the specimen shown in (A)
and Masson's trichrome stain was used for the specimen shown in (B-D).
RA = right atrium, LA = left atrium, RV = right ventricle, LV = left ventricle.
https://jkms.org https://doi.org/10.3346/jkms.2021.36.e286 2/7

AR09578
A B C
CD68 CD3 C4d

Fig. 2. Immunohistochemistry of the heart. (A) Immunohistochemical staining for CD68 shows that most of the inflammatory cells are histiocytes. (B) Most of
the inflammatory cells are negative for CD3 staining, indicating a paucity of lymphocytes. (C) Positive staining for C4d shows scattered single-cell necrosis of
atrial myocytes. Bars represent 100 µm.
whereas ventricular area displayed minimal or no inflammatory cells (Fig. 1D). Occasional
myocyte necrosis or degeneration was found adjacent to the inflammatory infiltrates, without
abscess formation or bacterial colonization. There was also scattered single-cell necrosis of
myocytes without accompanying inflammation. Multiple scattered foci of contraction band
necrosis (CBN) was identified throughout the myocardium, predominantly in the left ventricle.
No other specific pathological changes were found in the lung, liver, kidney, spleen, pancreas,
or brain on macroscopic or microscopic examination.
Masson's trichrome staining highlighted dense eosinophilic intracellular strips of myocytes,

consistent with CBN (Fig. 1B and D). CD68 and CD3 immunostaining showed a moderate
number of histiocytes and sparse lymphocytes in the inflammatory infiltrates (Fig. 2A and B).
Degenerated or ischemic myocytes exhibited positive C4d immunoreactivity (Fig. 2C).
The cause of death was determined to be myocarditis. Given that the myocarditis showed a
temporal relationship to vaccine administration and there was no other explanation for the
sudden cardiac death, on July 26, 2021, Korea Centers for Disease Control and Prevention
acknowledged that myocarditis and vaccination were “possibly related” in this case.
Ethics statement
Informed consent for publication of clinical data was obtained from the deceased's family.
DISCUSSION
There were three main histological findings in the heart: 1) myocarditis predominantly
involving the atrial wall, with neutrophil and histiocyte predominance; 2) non-inflammatory
single-cell necrosis; and 3) diffuse CBN throughout the myocardium, predominantly in the
left ventricle. These pathological findings were not evident on macroscopic examination. The
only abnormal gross finding was cardiac enlargement, which may have been secondary to
hypertension.
In this case, the myocarditis was histologically different from viral or immune-mediated
myocarditis in that the inflammatory infiltrates were predominantly neutrophils and
histiocytes, rather than lymphocytes. Multinucleated giant cells were not observed. The
area of myocarditis was confined to the atrial wall, but the ventricles were free of cellular

AR09579
infiltration. Inflammatory cells were also present in the SA and AV nodes. Myocyte necrosis
or degeneration was observed adjacent to the inflammatory infiltrates. Neutrophil infiltration
of the myocardium is an uncommon histological type of myocarditis, and is generally
observed in immunocompromised patients with bacterial infection.14 The deceased was
previously healthy and there were no signs of infective myocarditis. Dissemination of
infective endocarditis and pneumonia were also excluded. The underlying mechanism of
myocardial injury in this case is unclear, but it may have involved cytokine-mediated or
histiocyte-linked immunologic injury to the myocardium. Isolated atrial myocarditis is
very rare and thus is an unfamiliar disease entity to pathologists. To our knowledge, only
two case reports of sudden cardiac death caused by isolated atrial myocarditis have been
published previously.15,16 Previous reports noted that atrial myocarditis may be overlooked
on postmortem examination because sampling of atrium is not routinely performed. In
the present case, extensive myocardial sampling enabled accurate diagnosis. A total of 35
sections were examined (25 sections of ventricular and atrial myocardium and 10 sections of
the conduction system) and 9 sections had evidence of myocarditis. Myocarditis is usually
not apparent on gross examination. Even if the heart is grossly unremarkable, pathologists
should examine a sufficient number (≥ 10) of atrial and ventricular sections in order not
to overlook or misdiagnose the cause of death, especially if the deceased had myocarditis
symptoms and a recent mRNA vaccination history.
Notably, single-cell necrosis (or single-cell ischemia) of myocytes without inflammation was
observed in multiple sites throughout the atria. Several autopsy studies of the cardiovascular
pathological findings of individuals who died of COVID-19 have also found single-cell necrosis,
and this might be a distinctive pathological characteristic of COVID-19.17-19 Thus, myocardial
injury due to COVID-19 vaccination may histologically present not only as myocarditis, but also
as scattered single-cell necrosis, similar to myocardial lesions of COVID-19.
Another major histological finding was abundant CBN throughout the myocardium,
especially in the left ventricle. CBN is usually observed after irreversible myocyte injury and
is associated with ischemic heart disease or a catecholamine excess state.20 The CBN in this
case was extensive throughout the ventricular myocardium and we are cautious about drawing
a conclusion about the causality. The association between the CBN and COVID-19 vaccination
is unclear. The CBN may have occurred as a result of ventricular fibrillation or catecholamine
administration during resuscitation. There was no evidence of coronary atherosclerosis or
microthrombosis, which could explain the presence of CBN.
We were able to find only one previously published case report of a death due to myocarditis
after COVID-19 vaccination with a comprehensive clinicopathological analysis. Verma et
al.10 reported the case of a 42-year-old man, who presented with chest pain and dyspnea
2 weeks after the second dose of mRNA-1273 vaccination, and died 3 days after symptom
onset. On microscopic examination, myocyte damage with a mixed inflammatory infiltrate
of macrophages, lymphocytes, and eosinophils was observed in the myocardium of both
ventricles, whereas the atria showed no evidence of myocarditis. In contrast, our case
patient developed symptoms 5 days after the first dose of the BNT162b2 mRNA vaccine and
died 7 hours later, and showed isolated atrial myocarditis with neutrophil and histiocyte
predominance. The histopathological features described in Verma et al.'s report10 did
not include CBN or single-cell necrosis of myocytes. This suggests that myocarditis after
COVID-19 mRNA vaccination is heterogenous, both clinically and histologically.

AR09580
Table 1. Demographic and clinical features of previously reported myocarditis following coronavirus disease 2019 vaccination
No. Reference No. of Sex, Age, yr median Sx Histopathologic Outcome Vaccine Type of vaccine
Days from
patients M:F (range) (No. of patients) confirmation (No. of patients) dose (No. of patients)
vaccination
(No. of to Sx onset,
patients) median
(range)
1 Montgomery 23 23:0 25 (20–51) Chest pain Not done Resolved (23/23) 1st (3/23) BNT162b2-mRNA (7/23) 50 (12–96)a
et al.8 (23/23) 2nd (20/23) mRNA-1273 (16/23)
2 Larson et al.5 8 8:0 28.5 (21–56) Chest pain (8/8) Endomyocardial biopsyb Resolved (8/8) 1st (1/8) BNT162b2-mRNA (5/8) 3 (2–4)
Fever (5/8) 2nd (7/8) mRNA-1273 (3/8)
3 Marshall et 7 7:0 17 (14–19) Fever (5/7) Not done Resolved (7/7) 2nd (7/7) BNT162b2-mRNA (7/7) 2 (2–4)
al.7 Chest pain (7/7)
Fatigue (3/7)
4 Rosner et al.9 7 7:0 24 (19–39) Chest pain (7/7) Endomyocardial biopsyb Resolved (7/7) 1st (2/7) BNT162b2-mRNA (5/7) 3 (2–7)
Fever (2/7) 2nd (5/7) mRNA-1273 (1/7)
Ad26.CoV.S (1/7)
5 Snapiri et al.11 7 7:0 16.8 (16.2–17.6)Chest pain (7/7) Not done Resolved (7/7) 1st (1/7) BNT162b2-mRNA (7/7) 2 (1–3)
Fever (1/7) 2nd (6/7)
6 Kim et al.4 4 3:1 30 (23–70) Chest pain (4/4) Not done Resolved (4/4) 2nd (4/4) BNT162b2-mRNA (2/4) 2.5 (1–5)
Fatigue (3/4) mRNA-1273 (2/4)
Fever (3/4)
7 Mansour et 2 1:1 23 (21–25) Chest pain (2/2) Not done Resolved (2/2) 2nd (2/2) mRNA-1273 (2/2) 1.5 (1–2)
al.6 Fever (1/2)
8 Verma et al.10 2 1:1 43.5 (42–45) Chest pain (2/2) Endomyocardial biopsy Resolved (1/2) 2nd (2/2) BNT162b2-mRNA (1/2) 12 (10–14)
Autopsy Died (1/2) mRNA-1273 (1/2)
9 Ammirati et 1 1:0 56 Chest pain Not done Resolved 2nd BNT162b2-mRNA 3
al.3
10 Kim et al.12 1 1:0 24 Chest pain Not done Resolved 2nd BNT162b2-mRNA 1
11 Present study 1 1:0 22 Chest pain Autopsy Died 1st BNT162b2-mRNA 5
Fatigue
Sx = symptom, M = male, F = female.
a
The authors reported time to symptom onset as hours with mean (range); bOne patient underwent endomyocardial biopsy in each study, but myocardial
inflammation was not found.
The demographic and clinical characteristics of myocarditis after mRNA vaccination in

previous reports are summarized in Table 1. Vaccine-associated myocarditis has been
reported predominantly in young males after the second vaccination. Myocarditis was mainly
diagnosed clinically based on elevated serum troponin and cardiac magnetic resonance
imaging, and all patients except ours and the patient reported by Verma et al.10 recovered
after receiving supportive care. The patient in this case showed similar clinical features,
which supports a potential association between vaccination and myocarditis. However,
given that other reported myocarditis cases were generally mild and the symptoms usually
developed after the second vaccination, the clinical course of our case (sudden death 6 days
after the first vaccination) is an extremely rare event. Considering the short time interval
between the onset of the deceased patient's symptoms and his sudden death, the immediate
cause of death was possibly an arrhythmia, rather than heart failure.
This is the first case in South Korea that the Korea Centers for Disease Control and
Prevention acknowledged the causality of COVID-19 vaccination and myocarditis. This
unique case provides an example of a serious adverse event following COVID-19 mRNA
vaccination. It is unknown whether this case is related to the vaccine type or to a specific
vaccine component. It is also unclear whether the location (atrium), type of inflammation
(neutrophils and histiocytes), CBN, and single-cell necrosis without inflammation are
specific characteristics of COVID-19 vaccine-associated myocarditis. Comprehensive clinical
and pathological evaluation of additional cases is needed to clarify the relationship between
COVID-19 vaccination and myocarditis.

AR09581
REFERENCES
1. Oliver SE, Gargano JW, Marin M, Wallace M, Curran KG, Chamberland M, et al. The advisory committee
on immunization practices' interim recommendation for use of Pfizer-BioNTech COVID-19 vaccine -
United States, December 2020. MMWR Morb Mortal Wkly Rep 2020;69(50):1922-4.
PUBMED | CROSSREF
on immunization practices' interim recommendation for use of Moderna COVID-19 vaccine - United
States, December 2020. MMWR Morb Mortal Wkly Rep 2021;69(5152):1653-6.
PUBMED | CROSSREF
3. Ammirati E, Cavalotti C, Milazzo A, Pedrotti P, Soriano F, Schroeder JW, et al. Temporal relation between
second dose BNT162b2 mRNA Covid-19 vaccine and cardiac involvement in a patient with previous SARS-
COV-2 infection. Int J Cardiol Heart Vasc. Forthcoming 2021. DOI: 10.1016/j.ijcha.2021.100778.
PUBMED | CROSSREF
4. Kim HW, Jenista ER, Wendell DC, Azevedo CF, Campbell MJ, Darty SN, et al. Patients with acute
myocarditis following mRNA COVID-19 vaccination. JAMA Cardiol. Forthcoming 2021. DOI: 10.1001/
jamacardio.2021.2828.
PUBMED | CROSSREF
5. Larson KF, Ammirati E, Adler ED, Cooper LT Jr, Hong KN, Saponara G, et al. Myocarditis after BNT162b2
and mRNA-1273 vaccination. Circulation 2021;144(6):506-8.
PUBMED | CROSSREF
6. Mansour J, Short RG, Bhalla S, Woodard PK, Verma A, Robinson X, et al. Acute myocarditis after a second
dose of the mRNA COVID-19 vaccine: a report of two cases. Clin Imaging 2021;78:247-9.
PUBMED | CROSSREF
7. Marshall M, Ferguson ID, Lewis P, Jaggi P, Gagliardo C, Collins JS, et al. Symptomatic acute myocarditis
in seven adolescents following Pfizer-BioNTech COVID-19 vaccination. Pediatrics 2021;148(3):e2021052478.
CROSSREF
8. Montgomery J, Ryan M, Engler R, Hoffman D, McClenathan B, Collins L, et al. Myocarditis following
immunization with mRNA COVID-19 vaccines in members of the US military. JAMA Cardiol. Forthcoming
2021. DOI: 10.1001/jamacardio.2021.2833.
PUBMED | CROSSREF
9. Rosner CM, Genovese L, Tehrani BN, Atkins M, Bakhshi H, Chaudhri S, et al. Myocarditis temporally
associated with COVID-19 vaccination. Circulation 2021;144(6):502-5.
PUBMED | CROSSREF
10. Verma AK, Lavine KJ, Lin CY. Myocarditis after Covid-19 mRNA vaccination N Engl J Med
2021;385(14):1332-4.
PUBMED | CROSSREF
11. Snapiri O, Rosenberg Danziger C, Shirman N, Weissbach A, Lowenthal A, Ayalon I, et al. Transient
cardiac injury in adolescents receiving the BNT162b2 mRNA COVID-19 vaccine. Pediatr Infect Dis J
2021;40(10):e360-3.
PUBMED | CROSSREF
12. Kim IC, Kim H, Lee HJ, Kim JY, Kim JY. Cardiac imaging of acute myocarditis following COVID-19 mRNA
vaccination. J Korean Med Sci 2021;36(2):e229.
PUBMED | CROSSREF
13. Aretz HT, Billingham ME, Edwards WD, Factor SM, Fallon JT, Fenoglio JJ Jr, et al. Myocarditis. A
histopathologic definition and classification. Am J Cardiovasc Pathol 1987;1(1):3-14.
PUBMED
14. Leone O, Pieroni M, Rapezzi C, Olivotto I. The spectrum of myocarditis: from pathology to the clinics.
Virchows Arch 2019;475(3):279-301.
PUBMED | CROSSREF
15. Tse R, Garland J, Kesha K, Triggs Y, Modahl L, Milne D, et al. A rare case of isolated atrial myocarditis
causing death with no post mortem computed tomography scan correlation. Am J Forensic Med Pathol
2018;39(2):123-5.
PUBMED | CROSSREF
16. Duffy M, O'Connor K, Milne D, Ondruschka B, Tse R, Garland J. Isolated atrial neutrophilic myocarditis:
a rare cause of death and potential “Blind Spot” for postmortem computed tomography and postmortem
examination. Am J Forensic Med Pathol. Forthcoming 2021. DOI: 10.1097/PAF.0000000000000684.
CROSSREF

AR09582
17. Halushka MK, Vander Heide RS. Myocarditis is rare in COVID-19 autopsies: cardiovascular findings across
277 postmortem examinations. Cardiovasc Pathol 2021;50:107300.
PUBMED | CROSSREF
18. Jum'ah H, Loeffler A, Tomashefski JF Jr. Histopathological findings in the hearts of COVID-19 autopsies:
a letter to cardiovascular pathology journal editor in response to Halushka et al. 2020. Cardiovasc Pathol
2021;52:107333.
PUBMED | CROSSREF
19. Fox SE, Akmatbekov A, Harbert JL, Li G, Quincy Brown J, Vander Heide RS. Pulmonary and cardiac
pathology in African American patients with COVID-19: an autopsy series from New Orleans. Lancet Respir
Med 2020;8(7):681-6.
PUBMED | CROSSREF
20. Baroldi G, Mittleman RE, Parolini M, Silver MD, Fineschi V. Myocardial contraction bands. Definition,
quantification and significance in forensic pathology. Int J Legal Med 2001;115(3):142-51.
PUBMED | CROSSREF

AR09583
J Korean Med Sci. 2021 Oct 18;36(40):e286
https://doi.org/10.3346/jkms.2021.36.e286
eISSN 1598-6357·pISSN 1011-8934
Case Report
Infectious Diseases,
Myocarditis-induced Sudden Death
Microbiology & Parasitology after BNT162b2 mRNA COVID-19
Vaccination in Korea: Case Report
13
Focusing on Histopathological
Findings
Sangjoon Choi ,1 SangHan Lee ,1 Jeong-Wook Seo ,2 Min-ju Kim ,2
Yo Han Jeon ,1 Ji Hyun Park ,1 Jong Kyu Lee ,1 and Nam Seok Yeo 1
Department of Forensic Medicine, Defense Institute of Forensic Science, Criminal Investigation Command,
1
Ministry of National Defense, Seoul, Korea

2
Department of Pathology, Incheon Sejong Hospital, Incheon, Korea
Received: Aug 24, 2021

Accepted: Oct 1, 2021
ABSTRACT
Address for Correspondence: We present autopsy findings of a 22-year-old man who developed chest pain 5 days after the
SangHan Lee, MD first dose of the BNT162b2 mRNA vaccine and died 7 hours later. Histological examination of
Department of Forensic Medicine, Defense
the heart revealed isolated atrial myocarditis, with neutrophil and histiocyte predominance.
Institute of Forensic Science, Criminal
Investigation Command, Ministry of National Immunohistochemical C4d staining revealed scattered single-cell necrosis of myocytes which
Defense, 22 Itaewon-ro, Yongsan-gu, Seoul was not accompanied by inflammatory infiltrates. Extensive contraction band necrosis was
04383, Korea. observed in the atria and ventricles. There was no evidence of microthrombosis or infection
E-mail: sanghan111@gmail.com in the heart and other organs. The primary cause of death was determined to be myocarditis,
© 2021 The Korean Academy of Medical
causally-associated with the BNT162b2 vaccine.
Sciences.
Keywords: Sudden Cardiac Death; Myocarditis; Coronavirus Disease 19; Vaccination;
This is an Open Access article distributed
under the terms of the Creative Commons mRNA Vaccines; Adverse Event Following Immunization
Attribution Non-Commercial License (https://
creativecommons.org/licenses/by-nc/4.0/)
which permits unrestricted non-commercial
use, distribution, and reproduction in any INTRODUCTION
medium, provided the original work is properly
cited. The coronavirus disease 2019 (COVID-19) pandemic, which started in January 2020 has
affected people worldwide. Rapid vaccine development has enabled COVID-19 prevention.
ORCID iDs
Sangjoon Choi Two mRNA COVID-19 vaccines, BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)
https://orcid.org/0000-0003-2108-0575 demonstrated safety and efficacy in clinical trials, and were granted emergency use
SangHan Lee authorization by the US Food and Drug Administration in December 2020.1,2 As the number
https://orcid.org/0000-0003-0390-3494 of people vaccinated against COVID-19 has increased, there have been multiple reports of
Jeong-Wook Seo
myocarditis as an adverse event following immunization,3-12 which was not observed in
https://orcid.org/0000-0003-0242-1805
clinical trials.
Min-ju Kim
https://orcid.org/0000-0003-3850-9892
Yo Han Jeon Myocarditis is histologically characterized by diffuse and/or focal inflammatory infiltrates
https://orcid.org/0000-0002-0353-7255 within myocardial tissue, accompanied by myocyte damage without evidence of ischemia.13
Ji Hyun Park Little is known about the histopathological characteristics of myocarditis following COVID-19
https://orcid.org/0000-0002-1534-0070
vaccination because endomyocardial biopsy is not a routine procedure for myocarditis and,
Jong Kyu Lee
https://orcid.org/0000-0002-0492-4417 due to its generally favorable prognosis,8 opportunities for autopsy studies are rare.10
https://jkms.org 1/7
AR09584
Nam Seok Yeo We recently observed a case of sudden cardiac death in a young male six days after receiving
https://orcid.org/0000-0001-7254-6414 the first dose of the BNT162b2 mRNA vaccine and report the distinctive clinical and
pathological findings of this case.
Disclosure
The authors have no potential conflicts of
interest to disclose.
CASE DESCRIPTION
Conceptualization: Lee S. Data curation: Choi
S, Jeon YH, Park JH, Lee JK, Yeo N, Kim MJ. The deceased was 22-year-old male military recruit. His blood pressure was elevated on
Investigation: Choi S, Jeon YH, Park JH, Lee physical examination 17 and 7 months before his death (156/94 mmHg and 128/74 mmHg,
JK, Yeo N, Kim MJ. Visualization: Choi S, Seo respectively), but he was otherwise healthy. On June 13, 2021, 5 days after the first dose of
JW. Writing – original draft: Choi S. Writing BNT162b2 mRNA vaccination, he complained to a colleague of chest pain at 1:00 AM, during
– review & editing: Choi S, Lee S, Seo JW.
a smoke break, and went to bed. At 8:00 AM, he was found unconscious hunched beside the
Supervision: Lee S, Seo JW
bed. He was taken to an emergency department and was found to have ventricular fibrillation
on electrocardiography. Cardiopulmonary resuscitation was performed for two hours, but he
could not be resuscitated.
An autopsy was performed 24 hours after his death. The deceased was well-nourished with
no visible injuries on external examination. The heart weighed 470 g and had multiple
petechiae on its surface. The pericardium was smooth with no fibrin deposition or exudate.
The coronary arteries were patent, and the heart valves were unremarkable. The myocardium
was of normal thickness and there was no dilation of the atria or ventricles. The myocardium
was homogeneously brown with no obvious necrosis or fibrosis. On microscopic examination,
diffuse inflammatory infiltration, with neutrophil and histiocyte predominance, was observed
within the myocardium (Fig. 1A). Notably, the inflammatory infiltrates were dominant in the
atria (Fig. 1A and B), and around the sinoatrial (SA) and atrioventricular (AV) nodes (Fig. 1C),
A B C D
AV node
LA
RA RA
LA RA LV
LA LV
RV
Fig. 1. Histopathology of the heart. (A) Hematoxylin and eosin stains of atrial septum shows massive inflammatory infiltration with neutrophil predominance.
(B) The myocytes often show contraction band necrosis (yellow arrows), which were highlighted by Masson's trichrome staining. (C) The atrioventricular node
area shows extension of atrial myocarditis to the superficial layer of the node. (D) The ventricular myocardium is free of inflammatory infiltrates, but there are
multiple large foci of contraction band necrosis (yellow arrows) particularly in the left ventricular wall and the ventricular septum. Bars represent 100 µm. The
blue arrows in insets show where the section was taken from the low magnification views. Hematoxylin and eosin stain was used for the specimen shown in (A)
and Masson's trichrome stain was used for the specimen shown in (B-D).
RA = right atrium, LA = left atrium, RV = right ventricle, LV = left ventricle.

AR09585
A B C
CD68 CD3 C4d

Fig. 2. Immunohistochemistry of the heart. (A) Immunohistochemical staining for CD68 shows that most of the inflammatory cells are histiocytes. (B) Most of
the inflammatory cells are negative for CD3 staining, indicating a paucity of lymphocytes. (C) Positive staining for C4d shows scattered single-cell necrosis of
atrial myocytes. Bars represent 100 µm.
whereas ventricular area displayed minimal or no inflammatory cells (Fig. 1D). Occasional
myocyte necrosis or degeneration was found adjacent to the inflammatory infiltrates, without
abscess formation or bacterial colonization. There was also scattered single-cell necrosis of
myocytes without accompanying inflammation. Multiple scattered foci of contraction band
necrosis (CBN) was identified throughout the myocardium, predominantly in the left ventricle.
No other specific pathological changes were found in the lung, liver, kidney, spleen, pancreas,
or brain on macroscopic or microscopic examination.
Masson's trichrome staining highlighted dense eosinophilic intracellular strips of myocytes,

consistent with CBN (Fig. 1B and D). CD68 and CD3 immunostaining showed a moderate
number of histiocytes and sparse lymphocytes in the inflammatory infiltrates (Fig. 2A and B).
Degenerated or ischemic myocytes exhibited positive C4d immunoreactivity (Fig. 2C).
The cause of death was determined to be myocarditis. Given that the myocarditis showed a
temporal relationship to vaccine administration and there was no other explanation for the
sudden cardiac death, on July 26, 2021, Korea Centers for Disease Control and Prevention
acknowledged that myocarditis and vaccination were “possibly related” in this case.
Ethics statement
Informed consent for publication of clinical data was obtained from the deceased's family.
DISCUSSION
There were three main histological findings in the heart: 1) myocarditis predominantly
involving the atrial wall, with neutrophil and histiocyte predominance; 2) non-inflammatory
single-cell necrosis; and 3) diffuse CBN throughout the myocardium, predominantly in the
left ventricle. These pathological findings were not evident on macroscopic examination. The
only abnormal gross finding was cardiac enlargement, which may have been secondary to
hypertension.
In this case, the myocarditis was histologically different from viral or immune-mediated
myocarditis in that the inflammatory infiltrates were predominantly neutrophils and
histiocytes, rather than lymphocytes. Multinucleated giant cells were not observed. The
area of myocarditis was confined to the atrial wall, but the ventricles were free of cellular

AR09586
infiltration. Inflammatory cells were also present in the SA and AV nodes. Myocyte necrosis
or degeneration was observed adjacent to the inflammatory infiltrates. Neutrophil infiltration
of the myocardium is an uncommon histological type of myocarditis, and is generally
observed in immunocompromised patients with bacterial infection.14 The deceased was
previously healthy and there were no signs of infective myocarditis. Dissemination of
infective endocarditis and pneumonia were also excluded. The underlying mechanism of
myocardial injury in this case is unclear, but it may have involved cytokine-mediated or
histiocyte-linked immunologic injury to the myocardium. Isolated atrial myocarditis is
very rare and thus is an unfamiliar disease entity to pathologists. To our knowledge, only
two case reports of sudden cardiac death caused by isolated atrial myocarditis have been
published previously.15,16 Previous reports noted that atrial myocarditis may be overlooked
on postmortem examination because sampling of atrium is not routinely performed. In
the present case, extensive myocardial sampling enabled accurate diagnosis. A total of 35
sections were examined (25 sections of ventricular and atrial myocardium and 10 sections of
the conduction system) and 9 sections had evidence of myocarditis. Myocarditis is usually
not apparent on gross examination. Even if the heart is grossly unremarkable, pathologists
should examine a sufficient number (≥ 10) of atrial and ventricular sections in order not
to overlook or misdiagnose the cause of death, especially if the deceased had myocarditis
symptoms and a recent mRNA vaccination history.
Notably, single-cell necrosis (or single-cell ischemia) of myocytes without inflammation was
observed in multiple sites throughout the atria. Several autopsy studies of the cardiovascular
pathological findings of individuals who died of COVID-19 have also found single-cell necrosis,
and this might be a distinctive pathological characteristic of COVID-19.17-19 Thus, myocardial
injury due to COVID-19 vaccination may histologically present not only as myocarditis, but also
as scattered single-cell necrosis, similar to myocardial lesions of COVID-19.
Another major histological finding was abundant CBN throughout the myocardium,
especially in the left ventricle. CBN is usually observed after irreversible myocyte injury and
is associated with ischemic heart disease or a catecholamine excess state.20 The CBN in this
case was extensive throughout the ventricular myocardium and we are cautious about drawing
a conclusion about the causality. The association between the CBN and COVID-19 vaccination
is unclear. The CBN may have occurred as a result of ventricular fibrillation or catecholamine
administration during resuscitation. There was no evidence of coronary atherosclerosis or
microthrombosis, which could explain the presence of CBN.
We were able to find only one previously published case report of a death due to myocarditis
after COVID-19 vaccination with a comprehensive clinicopathological analysis. Verma et
al.10 reported the case of a 42-year-old man, who presented with chest pain and dyspnea
2 weeks after the second dose of mRNA-1273 vaccination, and died 3 days after symptom
onset. On microscopic examination, myocyte damage with a mixed inflammatory infiltrate
of macrophages, lymphocytes, and eosinophils was observed in the myocardium of both
ventricles, whereas the atria showed no evidence of myocarditis. In contrast, our case
patient developed symptoms 5 days after the first dose of the BNT162b2 mRNA vaccine and
died 7 hours later, and showed isolated atrial myocarditis with neutrophil and histiocyte
predominance. The histopathological features described in Verma et al.'s report10 did
not include CBN or single-cell necrosis of myocytes. This suggests that myocarditis after
COVID-19 mRNA vaccination is heterogenous, both clinically and histologically.

AR09587
Table 1. Demographic and clinical features of previously reported myocarditis following coronavirus disease 2019 vaccination
No. Reference No. of Sex, Age, yr median Sx Histopathologic Outcome Vaccine Type of vaccine
Days from
patients M:F (range) (No. of patients) confirmation (No. of patients) dose (No. of patients)
vaccination
(No. of to Sx onset,
patients) median
(range)
1 Montgomery 23 23:0 25 (20–51) Chest pain Not done Resolved (23/23) 1st (3/23) BNT162b2-mRNA (7/23) 50 (12–96)a
et al.8 (23/23) 2nd (20/23) mRNA-1273 (16/23)
2 Larson et al.5 8 8:0 28.5 (21–56) Chest pain (8/8) Endomyocardial biopsyb Resolved (8/8) 1st (1/8) BNT162b2-mRNA (5/8) 3 (2–4)
Fever (5/8) 2nd (7/8) mRNA-1273 (3/8)
3 Marshall et 7 7:0 17 (14–19) Fever (5/7) Not done Resolved (7/7) 2nd (7/7) BNT162b2-mRNA (7/7) 2 (2–4)
al.7 Chest pain (7/7)
Fatigue (3/7)
4 Rosner et al.9 7 7:0 24 (19–39) Chest pain (7/7) Endomyocardial biopsyb Resolved (7/7) 1st (2/7) BNT162b2-mRNA (5/7) 3 (2–7)
Fever (2/7) 2nd (5/7) mRNA-1273 (1/7)
Ad26.CoV.S (1/7)
5 Snapiri et al.11 7 7:0 16.8 (16.2–17.6)Chest pain (7/7) Not done Resolved (7/7) 1st (1/7) BNT162b2-mRNA (7/7) 2 (1–3)
Fever (1/7) 2nd (6/7)
6 Kim et al.4 4 3:1 30 (23–70) Chest pain (4/4) Not done Resolved (4/4) 2nd (4/4) BNT162b2-mRNA (2/4) 2.5 (1–5)
Fatigue (3/4) mRNA-1273 (2/4)
Fever (3/4)
7 Mansour et 2 1:1 23 (21–25) Chest pain (2/2) Not done Resolved (2/2) 2nd (2/2) mRNA-1273 (2/2) 1.5 (1–2)
al.6 Fever (1/2)
8 Verma et al.10 2 1:1 43.5 (42–45) Chest pain (2/2) Endomyocardial biopsy Resolved (1/2) 2nd (2/2) BNT162b2-mRNA (1/2) 12 (10–14)
Autopsy Died (1/2) mRNA-1273 (1/2)
9 Ammirati et 1 1:0 56 Chest pain Not done Resolved 2nd BNT162b2-mRNA 3
al.3
10 Kim et al.12 1 1:0 24 Chest pain Not done Resolved 2nd BNT162b2-mRNA 1
11 Present study 1 1:0 22 Chest pain Autopsy Died 1st BNT162b2-mRNA 5
Fatigue
Sx = symptom, M = male, F = female.
a
The authors reported time to symptom onset as hours with mean (range); bOne patient underwent endomyocardial biopsy in each study, but myocardial
inflammation was not found.
The demographic and clinical characteristics of myocarditis after mRNA vaccination in

previous reports are summarized in Table 1. Vaccine-associated myocarditis has been
reported predominantly in young males after the second vaccination. Myocarditis was mainly
diagnosed clinically based on elevated serum troponin and cardiac magnetic resonance
imaging, and all patients except ours and the patient reported by Verma et al.10 recovered
after receiving supportive care. The patient in this case showed similar clinical features,
which supports a potential association between vaccination and myocarditis. However,
given that other reported myocarditis cases were generally mild and the symptoms usually
developed after the second vaccination, the clinical course of our case (sudden death 6 days
after the first vaccination) is an extremely rare event. Considering the short time interval
between the onset of the deceased patient's symptoms and his sudden death, the immediate
cause of death was possibly an arrhythmia, rather than heart failure.
This is the first case in South Korea that the Korea Centers for Disease Control and
Prevention acknowledged the causality of COVID-19 vaccination and myocarditis. This
unique case provides an example of a serious adverse event following COVID-19 mRNA
vaccination. It is unknown whether this case is related to the vaccine type or to a specific
vaccine component. It is also unclear whether the location (atrium), type of inflammation
(neutrophils and histiocytes), CBN, and single-cell necrosis without inflammation are
specific characteristics of COVID-19 vaccine-associated myocarditis. Comprehensive clinical
and pathological evaluation of additional cases is needed to clarify the relationship between
COVID-19 vaccination and myocarditis.

AR09588
REFERENCES
on immunization practices' interim recommendation for use of Pfizer-BioNTech COVID-19 vaccine -
United States, December 2020. MMWR Morb Mortal Wkly Rep 2020;69(50):1922-4.
PUBMED | CROSSREF
on immunization practices' interim recommendation for use of Moderna COVID-19 vaccine - United
States, December 2020. MMWR Morb Mortal Wkly Rep 2021;69(5152):1653-6.
PUBMED | CROSSREF
3. Ammirati E, Cavalotti C, Milazzo A, Pedrotti P, Soriano F, Schroeder JW, et al. Temporal relation between
second dose BNT162b2 mRNA Covid-19 vaccine and cardiac involvement in a patient with previous SARS-
COV-2 infection. Int J Cardiol Heart Vasc. Forthcoming 2021. DOI: 10.1016/j.ijcha.2021.100778.
PUBMED | CROSSREF
4. Kim HW, Jenista ER, Wendell DC, Azevedo CF, Campbell MJ, Darty SN, et al. Patients with acute
myocarditis following mRNA COVID-19 vaccination. JAMA Cardiol. Forthcoming 2021. DOI: 10.1001/
jamacardio.2021.2828.
PUBMED | CROSSREF
5. Larson KF, Ammirati E, Adler ED, Cooper LT Jr, Hong KN, Saponara G, et al. Myocarditis after BNT162b2
and mRNA-1273 vaccination. Circulation 2021;144(6):506-8.
PUBMED | CROSSREF
6. Mansour J, Short RG, Bhalla S, Woodard PK, Verma A, Robinson X, et al. Acute myocarditis after a second
dose of the mRNA COVID-19 vaccine: a report of two cases. Clin Imaging 2021;78:247-9.
PUBMED | CROSSREF
7. Marshall M, Ferguson ID, Lewis P, Jaggi P, Gagliardo C, Collins JS, et al. Symptomatic acute myocarditis
in seven adolescents following Pfizer-BioNTech COVID-19 vaccination. Pediatrics 2021;148(3):e2021052478.
CROSSREF
8. Montgomery J, Ryan M, Engler R, Hoffman D, McClenathan B, Collins L, et al. Myocarditis following
immunization with mRNA COVID-19 vaccines in members of the US military. JAMA Cardiol. Forthcoming
2021. DOI: 10.1001/jamacardio.2021.2833.
PUBMED | CROSSREF
9. Rosner CM, Genovese L, Tehrani BN, Atkins M, Bakhshi H, Chaudhri S, et al. Myocarditis temporally
associated with COVID-19 vaccination. Circulation 2021;144(6):502-5.
PUBMED | CROSSREF
10. Verma AK, Lavine KJ, Lin CY. Myocarditis after Covid-19 mRNA vaccination N Engl J Med
2021;385(14):1332-4.
PUBMED | CROSSREF
11. Snapiri O, Rosenberg Danziger C, Shirman N, Weissbach A, Lowenthal A, Ayalon I, et al. Transient
cardiac injury in adolescents receiving the BNT162b2 mRNA COVID-19 vaccine. Pediatr Infect Dis J
2021;40(10):e360-3.
PUBMED | CROSSREF
12. Kim IC, Kim H, Lee HJ, Kim JY, Kim JY. Cardiac imaging of acute myocarditis following COVID-19 mRNA
vaccination. J Korean Med Sci 2021;36(2):e229.
PUBMED | CROSSREF
13. Aretz HT, Billingham ME, Edwards WD, Factor SM, Fallon JT, Fenoglio JJ Jr, et al. Myocarditis. A
histopathologic definition and classification. Am J Cardiovasc Pathol 1987;1(1):3-14.
PUBMED
14. Leone O, Pieroni M, Rapezzi C, Olivotto I. The spectrum of myocarditis: from pathology to the clinics.
Virchows Arch 2019;475(3):279-301.
PUBMED | CROSSREF
15. Tse R, Garland J, Kesha K, Triggs Y, Modahl L, Milne D, et al. A rare case of isolated atrial myocarditis
causing death with no post mortem computed tomography scan correlation. Am J Forensic Med Pathol
2018;39(2):123-5.
PUBMED | CROSSREF
16. Duffy M, O'Connor K, Milne D, Ondruschka B, Tse R, Garland J. Isolated atrial neutrophilic myocarditis:
a rare cause of death and potential “Blind Spot” for postmortem computed tomography and postmortem
examination. Am J Forensic Med Pathol. Forthcoming 2021. DOI: 10.1097/PAF.0000000000000684.
CROSSREF

AR09589
17. Halushka MK, Vander Heide RS. Myocarditis is rare in COVID-19 autopsies: cardiovascular findings across
277 postmortem examinations. Cardiovasc Pathol 2021;50:107300.
PUBMED | CROSSREF
18. Jum'ah H, Loeffler A, Tomashefski JF Jr. Histopathological findings in the hearts of COVID-19 autopsies:
a letter to cardiovascular pathology journal editor in response to Halushka et al. 2020. Cardiovasc Pathol
2021;52:107333.
PUBMED | CROSSREF
19. Fox SE, Akmatbekov A, Harbert JL, Li G, Quincy Brown J, Vander Heide RS. Pulmonary and cardiac
pathology in African American patients with COVID-19: an autopsy series from New Orleans. Lancet Respir
Med 2020;8(7):681-6.
PUBMED | CROSSREF
20. Baroldi G, Mittleman RE, Parolini M, Silver MD, Fineschi V. Myocardial contraction bands. Definition,
quantification and significance in forensic pathology. Int J Legal Med 2001;115(3):142-51.
PUBMED | CROSSREF

AR09590
TAB 62
AR09591
FEDERAL COURT
B E T W E E N:
NABIL BEN NAOUM
demandeur
- and -
dèfendeur
AND BETWEEN:
L'HONORABLE MAXIME BERNIER
demandeur
- and -
dèfendeur
AND BETWEEN:
THE HONOURABLE A. BRIAN PECKFORD, LEESHA
NIKKANEN, KEN BAIGENT, DREW BELOBABA, NATALKIE

GRCIC, AND AEDAN MACDONALD
Applicants
- and -
Respondent
NETWORK REPORTING & MEDIATION (416) 359-0305

AR09592
AND BETWEEN:
Applicants
- and -
Respondent
--------
--- This is the Cross-Examination of CELIA

LOURENCO on her Affidavit sworn April 22, 2022,
on behalf of the Attorney General of Canada,
taken via Videoconference for Network Reporting &
Mediation, Toronto, Ontario, on the 3rd day of
June, 2022.
--------
A P P E A R A N C E S :
SHARLENE TELLES-LANGDON - For the Respondent
MAHAN KERAMATI
ROBERT DRUMMOND
GREGORY TZEMANKIS

EVA CHIPIUK
ALLISON PEJOVIC


AR09593
June 3, 2022 Celia Lourenco - 3
1 ALSO PRESENT:
2 Shaun Rickard - observing
3 Karl Harrison observing
4 SAYAH HASSAN
5 HENNA PARMAR
6 CHRIS NAIMI
7 PATRICK ABBOTT
8
9
10 REPORTED BY: Caroline Maslin, CSR
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25

AR09594
1 I N D E X O F P R O C E E D I N G S
3 WITNESS: Celia Lourenco
4 PAGE
5 CROSS-EXAMINATION BY MR. PRESVELOS......6
7 **The following list of undertakings, advisements and
8 refusals is meant as a guide only for the assistance of
9 counsel and no other purpose**
10 INDEX OF UNDERTAKINGS
11
12 The questions/requests undertaken are noted by
13 U/T and appear on the following pages: 101:13
14
15 INDEX OF ADVISEMENTS
16
17 The questions/requests taken under advisement are

18 noted by U/A and appear on the following pages:
19 91:13, 92:14, 106:9, 137:17, 148:7
20
21 INDEX OF REFUSALS
22
23 The questions/requests refused are noted by R/F
24 and appear on the following pages: 7:8, 12:22
25

AR09595
1 I N D E X O F E X H I B I T S
3 NUMBER/DESCRIPTION PAGE/LINE NO.
5 1: Article from The Lancet..........121:9
6 2: Outcome reporting bias in COVID-19 mRNA
7 Vaccine clinical trials,
8 Ronald B. Brown...................123:23
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25

AR09596
1 -- Upon commencing at 10:35 a.m.
2 CELIA LOURENCO: Affirmed via Zoom
3 CROSS-EXAMINATION BY MR. PRESVELOS:
4 1 Q. Good morning. Can you please state
5 your name for the record?
6 A. Celia Lourenco.
7 2 Q. Okay. And so you have a Ph.D., so
8 I'm going to call you Dr. Lourenco.
9 Dr. Lourenco, you understand that you have been
10 retained by the Attorney General in support of
11 their position in this application; correct?
12 A. Yes.
13 3 Q. Okay. And you understand that you
14 have just been sworn to tell the truth; correct?
15 A. Yes.
16 4 Q. And you agree with me that you will
17 tell the truth in response to the questions that

18 I'm going to ask you today; correct?
19 A. Yes.
20 5 Q. And part of telling the truth in
21 response to the questions that I'm going to ask
22 today is giving me accurate answers; correct?
23 A. Yes.
24 6 Q. All right. And you understand that
25 the Attorney General's position on this

AR09597
1 application is that vaccines should be mandatory
2 in order for Canadians to travel by air, train,
3 or plane as regulated by the federal government;
4 correct?
5 A. Yes.
6 7 Q. Okay. And I take it that you support
7 this position; correct?
8 R/F MS. TELLES-LANGDON: I object,
9 Mr. Presvelos. Dr. Lourenco's views on the
10 policy are irrelevant.
11 MR. PRESVELOS: So either Dr. Lourenco
12 agrees or disagrees with the soundness of the
13 government's policy, your position is that that
14 is an irrelevant question?
15 MS. TELLES-LANGDON: Yes. Dr. Lourenco's
16 personal views on the policy, the soundness of
17 the policy is an irrelevant question.

18 Dr. Lourenco is the regulator who approved the
19 vaccines; she has no role in the policy itself.
21 8 Q. Well, that -- okay. So I will get to
22 those questions, just to confirm that. So
23 Dr. Lourenco, did you advise any governmental
24 department with respect to the ministerial orders
25 that are at issue in this application?

AR09598
1 A. Can you be more clear on what
2 ministerial orders you're referring to?
3 9 Q. Okay. So you understand that the
4 application today concerns ministerial orders
5 made under the Aeronautics Act that
6 effectively -- with some exceptions -- but
7 effectively prevent unvaccinated Canadians from
8 travelling by air?
9 A. Okay.
10 10 Q. Right. Yeah?
11 A. Yes.
12 11 Q. It's not a trick question. Have you
13 -- have you reviewed the ministerial orders that
14 were enacted pursuant -- or that were made
15 pursuant to the Aeronautics Act?
16 A. I have not.
17 12 Q. Okay. But you're aware that they

18 exist?
19 A. I am not aware that they exist, yes.
20 13 Q. Okay. But you knew -- before --
21 before speaking with me today, surely you knew
22 that unvaccinated Canadians, generally speaking,
23 cannot board an airplane in Canada?
24 A. Yes, I was aware of that. Yes.
25 14 Q. Right. So you knew that -- you knew

AR09599
1 that that was the -- that was in effect the
2 status -- the legal status of these ministerial
3 orders; right?
4 A. Yes. That's my understanding.
5 15 Q. Okay. And then to go back to my
6 earlier question, did you advise any governmental
7 department to implement such a policy?
8 A. No.
9 16 Q. Were you consulted by any
10 governmental department in implementing this
11 policy?
12 A. No.
13 17 Q. So I want to be clear, nobody from
14 the Canadian government -- and when I say the
15 "Canadian government," I include the Prime
16 Minister's office, the Ministry of Transport,
17 Minister of Health, no one ever consulted with

18 you as to whether or not the government should
19 enact that vaccine mandate for travel?
20 A. That's correct.
21 18 Q. Okay. From what I understand in your
22 affidavit, which is in many -- in many areas a
23 little bit too complex for me and I'm going to
24 ask for your assistance in those areas, but from
25 what I understand in your affidavit, you were

AR09600
1 largely responsible, if not, perhaps, the most
2 responsible person for approving the vaccines --
3 the COVID-19 vaccines in Canada; is that correct?
4 A. I was responsible for the
5 authorization of the vaccines. But, of course, I
6 didn't work alone in that. I have a large team
7 that has -- that supported me in that task.
8 19 Q. Who has the final say to authorize
9 any of the COVID-19 vaccines in Canada?
10 A. That would be myself.
11 20 Q. Right. So you have -- you would be
12 what we call the most responsible person for
13 authorizing the COVID-19 vaccine in Canada?
14 MS. TELLES-LANGDON: I would --
15 THE WITNESS: Go ahead, Sharlene.
16 MR. PRESVELOS: Let me put it --
17 MS. TELLES-LANGDON: If this is a bit of a

18 legal question, Sam, we can stipulate
19 Dr. Lourenco is the decision maker. The
20 regulatory authority decision maker.
22 21 Q. So -- so in other words, if you did
23 not authorize the COVID-19 vaccines, they would
24 not be in use right now?
25 A. Well, there's other ways of accessing

AR09601
1 vaccines without a regulatory authorization.
2 They would not be -- been used as authorized
3 vaccines is how I would -- I would qualify that.
4 22 Q. Right. So the authorization comes
5 ultimately from you, but you in turn rely on
6 another team and you work collaboratively in
7 authorizing these vaccines?
8 A. Yes.
9 23 Q. And as part of the authorization or
10 approval process, I imagine that you would look
11 at the vaccine -- vaccine's effectiveness;
12 correct?
13 A. We look at vaccine efficacy --
14 24 Q. Efficacy.
15 A. -- prior to the authorization, yes.
16 25 Q. Okay. And -- and how do you define
17 vaccine efficacy?
18 A. Efficacy is how well the vaccine
19 works through randomized clinical trials --
20 through clinical trials. And that's different
21 from effectiveness. Effectiveness is how well
22 vaccine works after authorization in real world
23 use of the vaccine.
24 26 Q. So efficacy and effectiveness. So
25 effectiveness is the real-world use; right?

AR09602
1 A. Yes.
2 27 Q. It's real world. And from the day
3 you authorized these COVID vaccines to today, has
4 any governmental department consulted with you
5 about the continued requirement for a vaccine to
6 travel?
7 A. No.
8 28 Q. Okay. Has the Prime Minister's
9 office ever consulted with you about the
10 continued use for the vaccine to travel?
11 A. No.
12 29 Q. Have there been any requests from any
13 governmental department to consult with you about
14 the continued use of a vaccine in order to
15 travel?
16 A. No.
17 30 Q. Would you agree with me that vaccine

18 efficacy and effectiveness would be important
19 considerations in deciding whether or not
20 unvaccinated pose a serious health and safety
21 risk to travellers?
22 R/F MS. TELLES-LANGDON: So I'm going to
23 object again, Mr. Presvelos. Dr. Lourenco's view
24 on what are the relevant considerations for the
25 decision makers with respect to the vaccine

AR09603
1 mandate are not relevant to your cross-
2 examination of Dr. Lourenco.
3 I mean, the question of relevance, Sam, is
4 border -- Mr. Presvelos, is bordering on legal
5 arguments as to what we will be supporting in
6 court, the government should or should not have
7 considered.
8 BY MR. PRESVELOS:
9 31 Q. Okay. Doctor, is there anyone that
10 you're aware of that would have better knowledge
11 than yourself as to the vaccine's effectiveness
12 or efficacy?
13 A. I -- well, certainly myself and my
14 team would have in-depth knowledge of the
15 vaccine's efficacy and effectiveness, as well,
16 through post-market monitoring. But I would say
17 that the public health agency does as well. They

18 -- they also do look at the results of the
19 clinical trials that were submitted, and then
20 they also monitor the vaccine effectiveness in
21 the post-market -- in the post-market setting.
22 They have the National Advisory Committee
23 on Immunization that is tasked with -- with
24 looking at that, along with -- along with public
25 health agency staff themselves as well.

AR09604
1 32 Q. Do you and your team communicate with
2 the Public Health Agency regarding the
3 effectiveness and efficacy of the vaccines?
4 A. Yes.
5 33 Q. And as part of those discussions have
6 you ever discussed the requirement of a vaccine
7 for travel?
8 A. No.
9 34 Q. Okay. And when you -- you made
10 reference to your team. I take it you don't do
11 all of this work alone. How large is your team?
12 A. The team that's responsible for
13 vaccine reviews is about 35 individuals or so.
14 So it would -- we have a team of scientists with
15 different backgrounds. We look at the clinical
16 aspects of the vaccine. We look at the results
17 of clinical studies, for example, and the results

18 of other types of tests and studies done on
19 animals and in laboratory -- in the laboratory
20 setting.
21 And then we have another team that looks
22 at the quality manufacturing of the vaccines.
23 35 Q. Have you and any of the 35 or so
24 individuals in your team ever discussed the
25 impact of vaccination travel?

AR09605
1 A. No.
2 36 Q. Are you aware as to whether or not
3 any of the -- if you don't know, don't guess.
4 Are you aware as to any -- as to whether any of
5 the 35 individuals that comprise your team have
6 ever advised any other government departments
7 about the -- about the -- about the vaccine
8 mandate for travel?
9 A. No.
10 37 Q. All right. I perhaps should have
11 started by -- by saying this. I'm sure your
12 lawyers have already told you. They're not --
13 I'm sure counsel has already told you, but if you
14 need a break at any time during this cross-
15 examination feel free to take it. I have a
16 tendency of speaking fast, so rather than guess
17 at what I might have said, ask me to repeat

18 myself if I'm speaking too fast. And if any of
19 my questions are unclear because they're compound
20 questions or perhaps unnecessarily robust, ask me
21 to simplify my question, and I'm more than happy
22 to do that.
23 A. Okay.
24 38 Q. Okay. Dr. Lourenco, I take it that
25 there are various aspects of your affidavit where

AR09606
1 you make statements that require -- that rely
2 upon information provided by other individuals
3 and organizations; correct?
4 A. Correct.
5 39 Q. So it's fair to say that not every
6 single item that is being discussed in your
7 affidavit reflects firsthand knowledge of that
8 information?
9 A. Yes, that's correct.
10 40 Q. Doctor, are you aware of any other
11 vaccine -- of any vaccine in Canada currently
12 that is -- that is require -- that is -- that --
13 are you aware of any other vaccine mandate in
14 Canada? In other words, there is an absolute
15 requirement to have a certain vaccine in Canada
16 in order to do something?
17 A. I can't really speak to that.

18 41 Q. But are you aware of any? Are you
19 aware of any -- are you aware of any policy in
20 place by the government -- by the federal
21 government or any provincial government that
22 requires you to be vaccinated in order to access
23 a service in order to participate in an activity,
24 anything like that?
25 MS. TELLES-LANGDON: Sam -- Mr. Presvelos,

AR09607
1 you're now asking Dr. Lourenco to speak to
2 whether legal mandates are in place in any
3 province in Canada?
4 MR. PRESVELOS: Well, as it pertains --
5 MS. TELLES-LANGDON: She said -- she said
6 she cannot speak to that, but you're asking her
7 for an opinion on what the law is in every
8 province of this country?
9 MR. PRESVELOS: I'm not asking her for an
10 opinion on what the law is. I'm asking her
11 whether or not she's aware as to whether laws
12 exist in Canada that affects something that she's
13 directly responsible for which is typical of
14 vaccines.
15 MS. TELLES-LANGDON: She's responsible for
16 the approval of vaccines.
17 MR. PRESVELOS: Right.

18 MS. TELLES-LANGDON: Not any vaccine
19 mandate. So what is the relevance of this
20 question, Mr. Presvelos?
21 MR. PRESVELOS: Well, you can't have
22 mandate without having a vaccine, and presumably
23 if you're going to have a mandate about a
24 vaccine, the person authorizing the vaccine would
25 be aware of the mandate.

AR09608
1 MS. TELLES-LANGDON: Not necessarily.
3 MS. TELLES-LANGDON: It's already been
4 established, Mr. Presvelos, on this transcript
5 that Dr. Lourenco is responsible for approving
6 the vaccines for use in Canada, that she is not
7 responsible for the decision making with respect
8 to the travel measures that are impugned in this
9 application. The decision makers are separate
10 decision makers.
11 MR. PRESVELOS: I can't wait to get to
12 them.
13 42 Q. Dr. Lourenco, do you agree that
14 unvaccinated travellers pose a health and safety
15 risk to other vaccinated travellers?
16 MS. TELLES-LANGDON: Again, Mr. Presvelos,
17 that is not within the scope of Dr. Lourenco's --

18 MR. PRESVELOS: Okay. That's offensive.
19 We have the person who is authorizing vaccines
20 for use in Canada for COVID-19, someone who
21 presumably has studied the impacts and effects of
22 vaccines, including, as Dr. Lourenco has
23 mentioned, how effective they are and their
24 efficacy, and I cannot ask her whether the very
25 product she has authorized what impact that

AR09609
1 product might have in terms of travel? What can
2 I ask her?
3 It's not a contentious -- I mean, what's
4 the problem if I ask the person who has approved
5 the vaccines whether they think that these
6 vaccines are necessary to reduce the health and
7 safety risk? Who else am I going to ask if not
8 the person who's authorized the very vaccine that
9 has brought us all here together today? Who?
10 MS. TELLES-LANGDON: You can continue,
11 Mr. Presvelos.
12 MR. PRESVELOS: So that's a refusal?
13 MS. TELLES-LANGDON: No. Go ahead and
14 answer -- ask your question.
16 43 Q. Dr. Lourenco, do you agree that
17 unvaccinated travellers pose a health and safety

18 risk to vaccinated travellers?
19 A. Let me think about that the question.
20 Whether they pose a health and safety risk to
21 vaccinated travellers? I would answer that by
22 saying that they pose a -- they pose somewhat of
23 a risk, but given that vaccinated travellers are
24 vaccinated, they're -- obviously their risk is
25 reduced because they -- they are protected by --

AR09610
1 by the vaccine.
2 44 Q. How do you understand the risk that
3 unvaccinated travellers might pose to vaccinated
4 travellers? Like, what factors would you look
5 at?
6 A. So I -- I -- I would look at factors
7 such as vaccine efficacy, vaccine effectiveness.
8 The vaccines are not a hundred percent effective,
9 so having an unvaccinated traveller who could --
10 who is at higher risk for contracting COVID and
11 then therefore a higher risk for spreading COVID
12 would pose some risk to -- to others including
13 vaccinated travellers as well.
14 45 Q. How do you quantify the risk that an
15 unvaccinated traveller might pose to a vaccinated
16 traveller in terms of transmission or infection?
17 MS. TELLES-LANGDON: I'm still concerned,

18 Mr. Presvelos, that these questions are not
19 within the scope of her role as a regulator.
20 That you're asking her to speak to quantify
21 real-world risks which are questions that are
22 more appropriately directed towards the
23 virologists and the immunologists that we have
24 put forward as an expert witness.
25 Dr. Lourenco is here to speak on -- and

AR09611
1 her affidavit speaks to her role as regulator at
2 Health Canada and in approving the vaccines for
3 use in Canada. She's not here presented as a
4 virologist speaking to quantify the risks to
5 travellers between vaccinated and unvaccinated
6 individuals.
7 BY MR. PRESVELOS:
8 46 Q. But Dr. Lourenco, aren't you
9 advocating for full vaccination of all Canadians?
10 MS. TELLES-LANGDON: Mr. Presvelos --
12 47 Q. Surely that's -- surely that's your
13 position this morning, isn't it? You recommend
14 as the individual who's authorizing COVID-19
15 vaccines in Canada, it is your preference -- it
16 is your recommendation that all Canadians get
17 vaccinated against COVID-19. Am I correct?

18 MS. TELLES-LANGDON: And, Mr. Presvelos,
19 it's already been established on the record that
20 she had no role in making that recommendation.
21 MR. PRESVELOS: I'm not saying now with
22 respect to the government or the Ministry. I'm
23 saying as a general position in this litigation,
24 do you agree with me that your position is, in
25 fact, all Canadians should be vaccinated against

AR09612
1 COVID-19?
2 MS. TELLES-LANGDON: Dr. Lourenco's
3 personal opinion is not relevant.
4 MR. WILSON: Counsel, maybe I could be of
5 some assistance. I might agree with
6 Ms. Telles-Langdon until I read paragraph 179 on
7 page 45 of the witness's affidavit wherein she
8 does appear to expressly advocate for the travel
9 mandate. So up until that point in the affidavit
10 I didn't see anything, but it certainly is there
11 and it kind of sticks out like a sore numb.
12 So I -- it is within -- I don't know, it's
13 been a while, we've all been dealing with volumes
14 and volumes of materials and many witnesses but
15 it's there at paragraph 179. Specifically talks
16 about advocating for the travel mandate as well
17 as a vaccine mandate for all federal employees

18 and says it's in the public interest to do so.
19 So I just -- I'm going to be going down
20 this line, so I thought I'd raise now that it is,
21 in fact, in the affidavit. And I'll leave it to
22 the two of you to resolve it from here.
23 MR. PRESVELOS: Thank you, counsel. And
24 just for the record, paragraph 179 is preceded by
25 a title which is called "Protecting Canadians

AR09613
1 Against COVID-19 is in the Public Interest." And
2 paragraph 179 begins with:
3 "Full vaccination forms the key component
4 of Canadian's efforts to protect
5 Canadians, including Canadians who work in
6 the federally regulated transportation
7 sector or travellers or passengers in that
8 sector against impact of COVID-19 arising
9 from the existing SARS-CoV-2 virus and
10 emerging VOCs."
11 MS. TELLES-LANGDON: Thank you,
12 Mr. Wilson, and thank you, Mr. Presvelos.
13 Dr. Lourenco, based on paragraph 179 of your
14 affidavit I will allow -- I will agree to allow
15 Mr. Presvelos to continue along this line of
16 questioning.
17 I apologize. I did not recall paragraph

18 179 of Dr. Lourenco's affidavit.
20 48 Q. So, Dr. Lourenco, when we're
21 considering the protective effects of vaccination
22 on travelling, are one of the objectives of the
23 vaccine to help reduce the onward transmission of
24 COVID-19?
25 A. As the regulator, that is not one of

AR09614
1 the endpoints that we look at when we reviewed
2 the vaccines. It's not one of the endpoints that
3 the manufacturers looked at when they conducted
4 the clinical trials. We focussed on the efficacy
5 of the vaccine against infection and against
6 severe disease. The elements of transmission is
7 something that my colleagues in the Public Health
8 Agency focus -- focus on.
9 49 Q. But aren't the --
10 A. They know more than myself.
11 50 Q. -- Aren't the elements of
12 transmission of COVID-19 virus relevant to
13 understanding the effectiveness of the vaccine?
14 A. From a regulatory perspective, the
15 key elements that we looked at -- look at is how
16 well the vaccines prevent infection and severe
17 disease in the individual who is vaccinated.

18 That that's the regulatory perspective. The
19 regulatory standpoint.
20 The element of transmission, certainly
21 it's important from a public health perspective,
22 but it's not -- it's not an endpoint that we
23 measure in order to decide whether to authorize a
24 vaccine.
25 51 Q. But you also monitor the

AR09615
1 effectiveness of the vaccines that you authorize?
2 A. Yes. We --
3 52 Q. Correct? Right.
4 A. Yes.
5 53 Q. And isn't the trans -- isn't the
6 impact of the vaccine on transmission of the
7 virus not a relevant conversation when you're
8 monitoring the effectiveness of the vaccine?
9 A. From the regulatory perspective, the
10 more relevant consideration is the effectiveness
11 against infection and especially severe disease.
12 Severe disease is the key -- the key element that
13 we look at.
14 54 Q. Okay. Do you agree with me that it
15 is relevant to understand what impact the vaccine
16 has on reducing transmission of SARS-CoV-2 virus?
17 Not that there's something more relevant. Do you

18 agree that is a relevant consideration, the
19 protective impact of the vaccine on transmission?
20 Is that a relevant consideration?
21 MS. TELLES-LANGDON: Mr. Presvelos, a
22 relevant consideration to which?
24 55 Q. To your advocacy at paragraph 179
25 that "full vaccination forms a key component of

AR09616
1 Canada's efforts to protect Canadians including
2 those who are travelling."
3 Is that a relevant consideration in that
4 context of that statement that you made that may
5 or may not have something to do with what you
6 were thinking about at the time you authorized
7 the vaccines?
8 A. In my mind, yes. That's a relevant
9 consideration from a public health perspective.
10 56 Q. Right.
11 A. Not from a regulator's perspective as
12 I've mentioned already.
13 57 Q. Paragraph 179, are you making the
14 statement as a regulator, or are you making the
15 statement as a public health advocate? What's
16 the purpose of your statement in paragraph 179?
17 A. My entire affidavit is -- is put

18 forward from the perspective of the regulator. I
19 provided this additional information as -- from
20 the perspective that it -- that it is obviously
21 important for the matter at hand. But from a
22 regulatory perspective, the key consideration as
23 I mentioned is really around protecting the
24 individual that's vaccinated; so how well the
25 vaccine protects the individual who is

AR09617
1 vaccinated.
2 Certainly, there are other elements that
3 are important such as transmission, and those are
4 considerations that the Public Health Agency, for
5 example, and other public health officials look
6 at.
7 58 Q. Dr. Lourenco, do you agree with me
8 that a vaccinated traveller who's infected with
9 COVID-19 may transmit COVID-19 to another
10 traveller who is vaccinated but not infected with
11 COVID-19?
12 A. That is possible, yes.
13 59 Q. Right. And I take it you must
14 certainly agree with me that unvaccinated
15 traveller who is infected with COVID-19 could
16 infect a vaccinated traveller who is not infected
17 with COVID-19; correct?

18 A. Can you repeat that again?
19 60 Q. Right. Do you agree with me that a
20 traveller who is not vaccinated but has
21 COVID-19 --
22 A. Mm-hmm.
23 61 Q. -- could -- could infect a vaccinated
24 passenger on a plane?
25 A. That sounds like the same question

AR09618
1 you asked before. Yes, it's possible.
2 62 Q. No. So let me be clear. Scenario
3 one contemplates a vaccinated and infected
4 traveller.
5 A. Right.
6 63 Q. Do you agree that even if you have
7 the vaccine you can still infect others?
8 Scenario two contemplates an unvaccinated
9 infected traveller.
10 A. Okay.
11 64 Q. And we agree that in both scenarios
12 there is a risk of infection?
13 A. In both scenarios there is a risk of
14 infection but the risk is likely different.
15 65 Q. And what is the differential in risk
16 between the vaccinated and the unvaccinated
17 traveller?
18 A. I don't know. It -- that speaks to
19 transmission, risk of transmission. I haven't
20 looked at the latest literature to really answer
21 that question. It's a question, again, for
22 public health officials, other -- other experts
23 to respond to.
24 66 Q. But I take it as somebody who's
25 involved in the authorization of this -- of these

AR09619
1 vaccines, you would be familiar with literature
2 on the vaccines' continued effectiveness;
3 correct?
4 A. Yes. We monitor the literature on
5 the vaccines' continued effectiveness.
6 67 Q. Do you yourself personally monitor
7 such literature?
8 A. Yes. I monitor it myself, but mainly
9 rely on my team, as well, to -- to monitor it and
10 rely on another director general within the
11 branch that I work in who was responsible for
12 pharmacovigilance in post-market monitoring of
13 the vaccines.
14 68 Q. And how often do you and your team
15 review medical or other literature on vaccine
16 effectiveness, efficacy, any of these metrics?
17 A. Weekly.
18 69 Q. And does your review also include a
19 review of literature as to how the vaccines fare
20 against different variants of concerns?
21 A. Yes, it includes that.
22 70 Q. Okay. Would you agree with me that
23 it is important to have an updated understanding
24 as to how effective the vaccines may be against
25 new and emerging variants of concern?

AR09620
1 A. Yes.
2 71 Q. And you agree with me that the
3 effectiveness of a vaccine on the ancestral
4 strain of COVID-19 or on an older strain of
5 COVID-19 may not have the same protective effect
6 on a subsequent variant of concern; correct?
7 A. We -- we are -- well, it -- we would
8 have to look at which variants of concern are we
9 talking about. So there have been several
10 variants of concern that have emerged over the
11 past two years. With regards to the most recent
12 one, the Omicron and its subvariants, it's known
13 that the vaccines are not as effective --
14 72 Q. Right.
15 A. -- against -- against infection, but
16 they maintain effectiveness against severe
17 disease.
18 73 Q. Well, wouldn't you also agree with me
19 that that observation is true not just for
20 Omicron but also Delta?
21 A. For Delta, there was a bit of a
22 decrease in effectiveness against infection but
23 not pronounced; not to the same degree as we see
24 for Omicron. So for Delta, there was still
25 pretty good effectiveness against infection and

AR09621
1 certainly effectiveness against severe disease.
2 74 Q. What preceded Delta?
3 A. Before Delta -- so we had Alpha,
4 Beta, there was mu -- Gamma mu and then Delta. I
5 don't recall exactly which one preceded Delta off
6 the top of my head. I'd have to look it up.
7 75 Q. And when the vaccines were being
8 designed, were they being designed in reference
9 to ancestral COVID-19? So I guess that would
10 be -- would that be Alpha COVID-19?
11 A. The vaccines were designed against
12 the ancestral strain which was the Wuhan.
13 76 Q. Wuhan.
14 A. The Wuhan -- the first version of the
15 virus that emerged in Wuhan, China. And so
16 that's not the Alpha. The Alpha variant emerged
17 later. I believe it was first in the U.K. where

18 it was identified.
19 77 Q. So the vaccines that are currently in
20 circulation and authorized in Canada were
21 designed as against the Wuhan strain of COVID-19?
23 78 Q. And as it pertains to Moderna or
24 Pfizer or AstraZeneca, have any of those vaccines
25 been modified to adjust for any of the subsequent

AR09622
1 variants of concern to date?
2 A. The manufacturers are working on that
3 at the moment but none of their --
4 79 Q. My question is -- my question is -- I
5 don't care what they're working. My question is
6 to date have any of the vaccines that your
7 department has -- have authorized, have they been
8 modified to accommodate any of the variants of
9 concern?
10 A. We have not authorized any of -- any
11 modifications to the current vaccines that are
12 marketed in Canada for -- for COVID-19.
13 80 Q. Okay.
14 MS. TELLES-LANGDON: Mr. Presvelos, you
15 cut Dr. Lourenco off previously. There was
16 something else, Dr. Lourenco, that you had been
17 intending to add in your response.

18 THE WITNESS: I was just going to add that
19 manufacturers are working on modifying vaccines
20 and -- but we have not yet received a submission
21 or reviewed a submission or authorized a modified
22 vaccine to deal with the variants of concern.
24 81 Q. Dr. Lourenco, can you explain to me
25 why the vaccines are not as effective at

AR09623
1 preventing transmission with Omicron as they were
2 at preventing transmission of the Wuhan ancestral
3 COVID-19 virus?
4 A. From -- from the understanding that
5 I've gathered from my team and from information
6 I've read in the literature, it appears that the
7 Omicron version of the virus is able to escape
8 the immune system more easily and therefore that
9 seems to lead to an ability to be transmissible.
10 82 Q. Is it escaping because the virus is
11 mutating?
12 A. It -- it's -- so it's escaping likely
13 because of the mutations. The -- a significant
14 degree of mutations that have been identified in
15 that strain make it sufficiently different. It's
16 different to a certain extent that the immune
17 system does not recognize it as easily as -- as

18 it would if it were the original strain, for
19 example.
20 83 Q. And would you agree with me that each
21 variant of concern represents a mutation of the
22 ancestral Wuhan SARS CoV-2 virus?
23 A. Yes, each variant of concern has
24 mutations as compared to the ancestral Wuhan
25 virus.

AR09624
1 84 Q. And I take it you agree with me that
2 the so-called booster shots are of the same
3 composition as the original COVID-19 vaccine
4 which was made in reference to ancestral
5 COVID-19; correct?
6 A. Correct, yes.
7 85 Q. So I take it that based on what
8 you've said, you would agree with me that if an
9 individual received a COVID-19 vaccine today
10 they're receiving a vaccine that was designed in
11 response to ancestral COVID-19, not to any of the
12 several variants of concern?
14 86 Q. Dr. Lourenco, do you have any
15 educational background in infectious diseases,
16 immunology, or virology?
17 A. No, not specifically in those areas.

18 87 Q. I want to take you to paragraph five
19 of your affidavit and just take a moment and read
20 that paragraph.
21 (Witness reviewing document)
22 A. Okay.
23 88 Q. And here you talk about Health
24 Canada, and you indicate that one of the
25 objectives of Health Canada is to promote

AR09625
1 healthier lifestyles. What's the purpose of
2 recounting the objectives of Health Canada in the
3 context of your affidavit?
4 A. It's just to set the context in terms
5 of what the -- the mandate -- or what the
6 responsibilities of the department are.
7 89 Q. Are -- do you work for health --
8 sorry, do you work for Health Canada? You do?
9 A. Yes, I do. I work for Health Canada.
10 90 Q. Right. And so if you look at
11 paragraph five (2), it says "to promote healthier
12 lifestyles"; right?
13 A. Yes. It says that, yes.
14 91 Q. Would you agree with me that healthy
15 individuals are generally less susceptible to
16 hospitalizations or death as a result of a
17 COVID-19 infection?
18 A. Yes, I think that's -- that's
19 generally an accurate statement.
20 92 Q. Right. And if you look at paragraph
21 five, Roman numeral six, you say that "Health
22 Canada provides health information to help
23 Canadians make informed decisions"; right?
24 A. Yes.
25 93 Q. So in the context of this sentence,

AR09626
1 it is the hope or expectation of Health Canada
2 that individuals who are considering certain
3 medical decisions will review information that is
4 publicly available from governmental authorities
5 like Health Canada?
6 A. Yes, that is the hope of this
7 statement. That Health Canada will publish
8 information, provide information that would help
9 Canadians make -- make their own informed
10 decisions.
11 94 Q. And when we say "information," what
12 type of information do you think -- or does
13 Health Canada expect Canadians to review in
14 making an informed health decision as it pertains
15 to COVID-19?
16 MS. TELLES-LANGDON: That was a very broad
17 question, Mr. Presvelos.

18 MR. PRESVELOS: Okay. That's fine. I'll
19 find a more narrow way to ask it. Just give me
20 one moment. Sorry, I'm going to get caught up.
21 95 Q. Dr. Lourenco, would you agree with me
22 that generally different age groups have a
23 different risk profile in terms of developing a
24 severe illness as a result of COVID-19 infection?
25 A. Yes. Yes, I agree with that.

AR09627
1 96 Q. And I take it you agree with that
2 generally speaking older age -- older age groups
3 have a higher risk of developing severe illness;
4 correct?
5 A. Older age groups have a higher risk
6 of developing severe illness, along with -- I
7 would say, along also with people who have other
8 conditions who are not healthy who have other
9 conditions --
10 97 Q. Right.
11 A. -- who may be younger but have other
12 conditions.
13 98 Q. Right. But generally speaking, an
14 individual who is 70 and infected with COVID-19
15 probably has a higher chance of hospitalization
16 or death than an individual person who's 20 and
17 infected with COVID-19. Would you agree with me?

18 A. Yes, I agree with that.
19 99 Q. Can you please go to paragraph 41 of
20 your affidavit?
21 A. Okay.
22 100 Q. And take a moment and read that.
24 A. Okay.
25 101 Q. What sort of information would you

AR09628
1 have reviewed from PHAC and general literature?
2 A. This is mainly information from PHAC
3 which the Public Health Agency of Canada,
4 information from their -- from their website and
5 then some literature that I have read earlier in
6 the pandemic in around 2020. I did read up some
7 -- some articles about how -- how SARS-CoV-2 is
8 spread.
9 102 Q. Would you also be reviewing
10 literature for the vaccine -- the impact of the
11 vaccine on COVID-19 transmission?
12 A. So we -- we would look at that
13 literature but, again, it's not the primary -- as
14 a regulator, it's not the primary element that
15 we're concerned about. As I mentioned earlier,
16 we're -- we're more focussed on ensuring that the
17 vaccines continue to prevent infection but

18 especially severe disease. Severe disease is the
19 key.
20 103 Q. Would you be reviewing literature on
21 the waning immunity of the vaccines that you
22 authorized?
23 A. Yes, we would -- that's vaccine
24 effectiveness. Yes, we would be looking at any
25 literature on that.

AR09629
1 104 Q. I take it as a general statement you
2 agree with me that the vaccines currently
3 authorized for use in Canada for COVID-19 have
4 waning immunity. In short, the vaccine
5 effectiveness actually decreases over time. It's
6 not steady; it's not constant.
7 A. The vaccine effectiveness decreases
8 over time with regards to infection.
9 105 Q. Right.
10 A. But with regards to severe disease,
11 we're continuing to see pretty good effectiveness
12 for the vaccines.
13 106 Q. So are you telling me that the
14 vaccine's effectiveness as it relates to severe
15 disease has not reduced over time; it has
16 remained consistent since ancestral COVID-19?
17 A. Yes, that seems to be what we're --

18 what we're observing from observational studies
19 from real-world use of the vaccines. We're
20 continuing to see pretty good effectiveness
21 against severe disease.
22 107 Q. Okay. I just want to -- I want to be
23 very careful on this point because I don't want
24 to -- I want to be fair to you. Okay. My
25 question was whether or not the vaccine's

AR09630
1 effectiveness has remained the same across the
2 variants of concern in terms of preventing severe
3 disease, the same, or with an extremely close
4 margin. Not that it still does a good job.
5 Do you know whether the vaccine's
6 effectiveness at preventing severe disease has
7 remained steady or consistent across all the
8 VOCs?
9 A. Okay. So based on the -- the data
10 that we have seen -- so I've received information
11 from the Public Health Agency, the latest report
12 that they've provided to me -- it's one of my
13 appendices, one of my exhibits -- that looks at
14 data for Delta and for Omicron. If I may refer
15 to it --
16 108 Q. Yeah.
17 A. -- quickly?
18 109 Q. What exhibit are you going to?
19 A. I'll let you know in a minute. Okay.
20 It's Exhibit "S." In Exhibit "S," you can see
21 that there is a summary of the latest literature
22 that looks at effectiveness against Delta and
23 against Omicron. And we can see that for
24 Delta --
25 110 Q. Which page -- sorry, Doctor, you have

AR09631
1 to be a little slower for me. Which page are
2 you --
3 A. Sure.
4 111 Q. Page one, two, three?
5 A. Okay. So Exhibit "S", page -- page
6 one.
7 112 Q. Yeah.
8 A. So "vaccine effectiveness against
9 Delta."
10 113 Q. Left or right-hand side?
11 A. I'm sorry?
12 114 Q. Are we looking at the left-hand side
13 or the right-hand side of this slide?
14 A. Okay. The left-hand side of the
15 slide --
16 115 Q. Yeah.
17 A. -- at the bottom of that table we see

18 "Effectiveness against severe disease" --
19 116 Q. Yeah.
20 A. -- against Delta." And we can see
21 that it's considered generally above 90 percent.
22 117 Q. Right.
23 A. Ninety percent effectiveness. So
24 that's quite -- quite high effectiveness. And
25 then on the following page for Omicron --

AR09632
1 118 Q. But sorry, Doctor, right next to it,
2 it says --
3 A. Yes.
4 119 Q. -- "decrease over time." It says,
5 "Generally maintained over time but with some
6 studies showing a decline particularly in some
7 older populations." Right? Isn't that what it
8 says? For under "severe disease vaccine
9 effectiveness against Delta two doses," it says,
10 "initial and then decrease over time."
11 A. It says at the bottom -- so the one
12 that you're looking at "after two doses," yes,
13 you're correct.
14 120 Q. Yeah.
15 A. "After two doses generally maintained
16 over time, but with some studies showing a
17 decline particularly in some older populations.

18 But after the booster dose," at the bottom --
19 121 Q. I don't -- sorry, Doctor, I don't
20 want to know about the booster dose. I'm going
21 to explain to you why.
22 MS. TELLES-LANGDON: Mr. Presvelos, please
23 don't cut the witness off when she's speaking.
25 122 Q. Well, I'm sorry to do it but we're

AR09633
1 going to be here for much longer and you probably
2 don't want that. I just want to -- I just want
3 to clarify something for today's discussions.
4 The current ministerial orders require a
5 two-dose regime of COVID-19 vaccine in order to
6 travel. So any literature as it pertains to
7 three doses or the booster dose from my
8 perspective is entirely irrelevant. And if we're
9 going to get into that conversation, I'm going to
10 stop you because I don't ask about that.
11 Okay? So my question is looking at this
12 chart that you have cited as an Exhibit "S", it
13 says, "Generally maintained over time but with
14 some studies showing a decline."
15 Have you reviewed some medical literature
16 or studies showing a decline of the effectiveness
17 of the COVID-19 vaccine as against severe

18 disease?
19 A. Not myself personally. Likely my
20 colleagues in Public Health Agency likely looked
21 at this.
22 123 Q. Okay. And in the context of this
23 chart do you know which studies it is referring
24 to?
25 A. The studies that are being referred

AR09634
1 to are on page three. Sorry, not page three.
2 Page four.
3 124 Q. Right.
4 A. Page four, you'll see the -- the list
5 of references that my colleagues looked at.
6 125 Q. Okay. Is there anything else you're
7 relying on for the notion that two doses provide
8 continued high level of protection against
9 developing severe disease?
10 A. No, I'm relying mainly on this
11 information.
12 126 Q. And when we say the 90 percent --
13 what was the word you said -- 90 percent did you
14 say effective?
15 A. Ninety percent effectiveness, yes/.
16 127 Q. So --
17 A. -- against severe disease.

18 128 Q. And is that blended across all
19 population ranges, or is that for a particular
20 population range?
21 A. This is -- this is across all
22 populations.
23 129 Q. Okay. And although I wasn't going to
24 get into this this early, I will now because it
25 looks like an opportune moment to do this, but

AR09635
1 give me one second. So 90 percent effective, is
2 that calculated -- I want to walk through that
3 calculation when we say that something is
4 90 percent effective.
5 I'm going to ask for your help so I can
6 understand your statement. And I hope you're
7 patient because I'm really bad at math. When we
8 say "90 percent effective," is that in reference
9 -- is that using a standard of what is known as
10 the relative risk reduction?
11 A. Yes, that's correct. That's using
12 relative risk reduction.
13 130 Q. Okay. Okay. And I take it the
14 relative risk reduction is the same standard or
15 metric against which you measured the how
16 effective the vaccines work in order to approve
17 them; correct?
18 A. Yes. We use that same measure.
19 131 Q. And what's the threshold for the
20 approval? Is it 50 percent effectiveness on a
21 RRR basis?
22 A. Yes, the -- the threshold for
23 approval is 50 percent with -- so around that
24 50 percent there's a confidence interval, and the
25 lower bound of that confidence interval can't go

AR09636
1 below 30 percent. So it's 50 percent with the
2 confidence interval being not less than
3 30 percent and -- and obviously the higher -- the
4 upper bound of that confidence interval would be
5 higher than 50 percent.
6 132 Q. So, in other words, if you have -- if
7 have you a vaccine that's 30 percent effect on an
8 RRR basis, that can still get authorized for
9 approval?
10 A. No, no. You need to have at least
11 50 percent --
12 133 Q. Right.
13 A. -- of efficacy to be approved.
14 134 Q. So if a vaccine were to have anything
15 under 50 percent efficacy on an RRR basis, it
16 would not be approved?
17 A. Based on our current guidelines, yes,

18 that's where we draw the line is the -- the
19 50 percent is the minimum efficacy that we want
20 to see.
21 135 Q. Right. Okay.
22 A. Now that's against infection.
23 136 Q. Okay.
24 A. Yeah.
25 137 Q. And when we say -- so we say the

AR09637
1 threshold is 50 percent on a RRR. We'll get --
2 we'll unpack what that means. But how long must
3 50 percent or greater efficacy be maintained in
4 order to approve the vaccine?
5 A. So when we authorize the vaccine,
6 the -- the clinical trials are conducted,
7 subjects are enrolled up until a certain point
8 when -- when there's -- when there are a
9 sufficient number of cases of COVID-19 in the
10 trial, and then at that point the -- the data we
11 call the -- the database is locked and then
12 analysis is conducted on -- on -- on those
13 results.
14 And at that point, that's when we
15 determine is the vaccine efficacy 50 percent or
16 higher, what is the vaccine efficacy? Once
17 that's determined, then the manufacturer submits

18 to Health Canada for -- for review and
19 consideration of the authorization. We -- we
20 don't have a -- in our standard for
21 authorization, we require the 50 percent at
22 authorization, and then after the authorization
23 we ask sponsors to monitor the vaccine
24 effectiveness in the post-market setting.
25 Especially against severe disease, we want

AR09638
1 to make sure that the vaccine continues to be
2 effective. And certainly, the 50 percent would
3 definitively be a threshold that we would
4 continue to look for to make sure the vaccine
5 continues to be effective at least 50 percent
6 for -- against severe disease.
7 138 Q. So is the criteria just against
8 severe disease, or is it also 50 percent plus --
9 at least 50 percent for, you know, general
10 effectiveness even against transmission and
11 infection?
12 A. The criteria for initial
13 authorization is the 50 percent against
14 infection. We -- in terms of the initial
15 authorization also ask that companies have
16 sufficient numbers of severe disease cases just
17 to make sure that there is also effectiveness --

18 efficacy against severe disease. But the
19 50 percent is really against infection for the
20 initial authorization.
21 139 Q. So the initial authorization does not
22 assess the vaccine as against severe disease; it
23 assesses just 50 percent against general
24 infection of COVID-19?
25 A. That is the primary endpoint. We do

AR09639
1 look at severe diseases as secondary endpoint.
2 In our guidance, we require a number -- some
3 numbers of -- I think it's -- I have look at our
4 guidance.
5 140 Q. Can you tell me what -- what the --
6 how effective it needs to be as against severe
7 disease to be approved?
8 A. Well, we need -- we need to make sure
9 there that there is -- we don't have -- we don't
10 have like a number to say it must -- it must be
11 at least 50 percent effective respiratory
12 disease, but what we ask for is for a sufficient
13 number of severe disease cases in the clinical
14 trial to show that the vaccine is also effective
15 against severe disease.
16 And that is because generally vaccines
17 that are effective against infection are also

18 effective against severe disease.
19 141 Q. So, sorry, I just want to make sure I
20 understand your evidence. Your evidence is
21 50 percent is the threshold for protection
22 against infection in terms of authorizing
23 COVID-19 vaccine?
24 A. Yeah.
25 142 Q. But you don't have a corresponding

AR09640
1 fixed-number threshold as against severe disease
2 in the approval process?
3 A. We don't have a corresponding number,
4 no.
5 143 Q. Right.
6 A. We just ask for -- we just ask that
7 the -- that the manufacturer enroll subjects in
8 the trial up to a certain point when there are
9 also some -- some cases of severe disease to see
10 how well the vaccine works against severe
11 disease. For example, for Moderna -- the Moderna
12 vaccine, there were 30 cases of severe disease in
13 the clinical trial and all of them were in the
14 placebo group and no cases in the -- in the
15 vaccinated group.
16 For the Pfizer vaccine, there were a total
17 of ten cases of severe disease in the trial; nine

18 of them were in the placebo group, and one was in
19 the control group. So we look for an indication,
20 also, that the vaccine is effective against
21 severe disease, although the primary endpoint is
22 against infection. The 50 percent against
23 infection.
24 Because as I have mentioned, demonstrating
25 efficacy against infection correlates with severe

AR09641
1 disease -- being effective also against severe
2 disease.
3 144 Q. Why would you look at -- why would
4 you reply -- why would you have a fixed threshold
5 for approving a vaccine on the basis of
6 preventing infection, but in the post-market
7 surveillance your focus shifts on reducing severe
8 disease?
9 A. We -- for the initial authorization
10 the endpoint is against infection in order to be
11 able to enroll sufficient number of subjects
12 within a certain amount of time. Given that we
13 were in a pandemic, we needed to enroll a certain
14 number of subjects fairly -- fairly quickly.
15 So -- and the endpoint of infection is not
16 unusual. This is the endpoint that we have also
17 for -- for the flu vaccine, for example.

18 145 Q. I'm not saying -- sorry, Doctor. Not
19 that it's "unusual," my -- I don't think you
20 understand my question. Why do you shift the
21 focus from understanding the protective effective
22 of the vaccine against infection as being at
23 least 50 percent, and in the post-market
24 surveillance you told me that what you become
25 more concerned about is the protective effective

AR09642
1 of the vaccine on severe disease cases?
2 A. Well, even in the authorization we're
3 concerned about severe disease as well. Sorry,
4 we're concerned about effectiveness against
5 severe disease. It's not -- it's not the primary
6 endpoint for clinical trial design reasons.
7 But -- but in the post-market, of course
8 we're concerned still about effectiveness against
9 infection, but if a vaccine is showing waning
10 protection against infection, we -- what we look
11 for is does it still protect against severe
12 disease. And if it does, then that supports our
13 analysis in terms of the benefits continuing to
14 outweigh the risks of the vaccine.
15 146 Q. And what threshold would you expect
16 to see the vaccine protecting against severe
17 disease; 50 percent in post-market -- in

18 post-market surveillance?
19 A. At least 50 percent.
20 147 Q. And that's based on an RRR
21 calculation?
22 A. Yes. Relative risk, yes.
23 148 Q. Right. Do you believe that the
24 vaccine's efficacy is currently at 50 percent as
25 against Omicron infection? Where the

AR09643
1 effectiveness of the vaccine as currently at
2 50 percent as against the Omicron infection?
3 MS. TELLES-LANGDON: For what parameter,
4 Mr. Presvelos?
5 MR. PRESVELOS: Well, presently. I'm
6 just -- I'm just asking Dr. Lourenco if she
7 understands presently what is the -- how
8 effective is COVID-19 against Omicron? And then
9 I'm going to ask you for how long you believe it
10 maintains that effectiveness.
11 THE WITNESS: So I'll refer again to -- if
12 okay with you to my Exhibit "S," page -- page
13 three where we have the table that lists the
14 effectiveness against Omicron. And we can look
15 at the -- at this -- at the effectiveness after
16 two doses. And you can see that shortly after
17 the last dose -- after the last dose the

18 effectiveness against severe disease is 65 to
19 85 percent. And then decrease in terms of --
21 149 Q. I'm sorry, what number -- what number
22 are you reading? One, two, three, four, five or
23 six?
24 MS. TELLES-LANGDON: Sorry, Mr. Presvelos,
25 I know you want to continue to question, but you

AR09644
1 have had a tendency to interrupt Dr. Lourenco,
2 and I would please ask that you do not interrupt
3 Dr. Lourenco.
4 BY MR. PRESVELOS:
5 150 Q. Sorry, Doctor. But just please help
6 me before you start reading so I know where you
7 are so I can read it together with you.
8 A. Yes. So I'm -- I'm -- sorry, what
9 page did I say?
10 151 Q. Three.
11 A. So I'm on page one, two -- page two.
12 152 Q. All right.
13 A. Okay. My apologies. So on page two
14 the table that talks about vaccine effectiveness
15 against Omicron. On the left, after two doses in
16 patients with severe disease we can see that
17 shortly after the last dose -- so within the

18 first month there is a vaccine effectiveness of
19 65 to 85 percent. And then that on the right,
20 under decrease over time, "most studies show
21 generally sustained protection over time."
22 153 Q. Now, when they say "generally
23 sustained," do you know what figure that means?
24 Or what parameter of figures that mean?
25 A. I don't know.

AR09645
1 154 Q. Do you know why those figures would
2 have been included in this chart?
3 A. These figures were included as a
4 summary of the current literature as reviewed by
5 my colleagues in the Public Health Agency who
6 prepare this summary and provided it to me.
7 155 Q. And if you look at two doses, the
8 protection it offers for a symptomatic disease,
9 in the first month it says, "50 to 80 percent";
10 correct?
12 156 Q. And then a decrease over time beyond
13 12 weeks which is three months, it says, "Vast
14 majority of studies show effectiveness below 40
15 percent with a further decline of time to
16 20 percent or less"; correct?

18 157 Q. So I take it these figures here,
19 these effectiveness figures, this wouldn't
20 qualify for authorization of this vaccine if we
21 had observed this at the trial?
22 A. It would not, no. If it's below
23 40 percent, no.
24 158 Q. Well, it's below 50.
25 A. Right. Sorry, below 50 percent.

AR09646
1 Correct.
2 MR. PRESVELOS: Let's take a break. It's
3 too many numbers for my head. We'll take a
4 15-minute break, and we will resume and have an
5 interesting discussion about relevant risk
6 reduction. Or I hope to get educated because I
7 am confused.
8 So we'll take a 15-minute break, and I'll
9 see you soon, doctor.
10 THE WITNESS: Okay.
11 --- OFF THE RECORD (11:35 A.M.)
12 --- UPON RESUMING (11:55 A.M.)
14 159 Q. Okay. Dr. Lourenco, I take it that
15 based on what has been mentioned in your
16 affidavit when you are considering the vaccine's
17 effectiveness -- and I think you confirmed this

18 earlier in your -- in response to some of the
19 questions I asked you, you were only looking at
20 the relative risk reduction; right? You're
21 assessing vaccine effectiveness on the basis of a
24 160 Q. And relative risk reduction was used
25 in the studies by the pharmaceutical companies

AR09647
1 that were designing their studies; right?
3 161 Q. Okay. And you were not looking at
4 the absolute risk reduction in assessing the
5 vaccine's effectiveness; correct?
6 A. Correct.
7 162 Q. Okay. And do you agree with me that
8 the risk of being infected and becoming ill with
9 COVID varies between populations and over time?
10 A. Yes. We spoke about that earlier.
11 163 Q. Right. And do you think that that
12 variance is a relevant consideration in
13 understanding a vaccine's effectiveness?
14 A. I have to wrap my head around that.
15 That is important, yes, to establish vaccine
16 effectiveness when we look at different age
17 ranges, for example, and that's one of the

18 reasons why we needed to see, for example,
19 sufficient numbers of older individuals enrolled
20 in the clinical trials in order to establish
21 vaccine effectiveness across the entire age range
22 of eight -- of all adults from 18 to elderly.
23 164 Q. Can you walk me through how relative
24 risk reduction assessment would work in one of
25 these clinical trials that you would have

AR09648
1 reviewed prior to approving the vaccine for use
2 -- for authorized use in Canada?
3 And I'm going to, perhaps, just to kind of
4 facilitate the conversation and move this along
5 faster. I'm going to tell you how I see it, and
6 I would like you to kind of help me through some
7 figures so I can understand what is being
8 calculated when we look at the relative risk
9 reduction and then we can walk through the same
10 figures and understand what is being calculated
11 when we're discussing absolute risk reduction.
12 Is that fair?
13 A. Sure.
14 165 Q. So my understanding of relative risk
15 reduction which, again, not to belabour the
16 point, is the metric against which you assess
17 approval of the vaccine, my understanding is the

18 pharmaceutical companies have two groups of
19 participants; is that correct?
20 A. Yes.
21 166 Q. Right. So you have -- we can say for
22 the purposes of our discussion today, which I
23 understand are just to illustrate to help me
24 understand this concept, if you have group one
25 and group two you have a finite number of

AR09649
1 participants in these groups; correct?
2 A. Yes.
3 167 Q. You're not looking at the population
4 as a whole?
5 A. You're talking about relative risk
6 reduction, right?
7 168 Q. Relative risk reduction, yeah.
8 A. So we've got the two groups and --
9 but carry on. I mean, we look at the population
10 as a whole, but carry on in terms of your
11 thinking.
12 169 Q. Okay, sure. Then you can -- you can
13 qualify and correct me where necessary on that --
14 on that particular point. Okay? I don't want to
15 restrict what you want to say with respect to
16 what I am about to say.
17 So in group one -- and in each of the

18 groups I presume that all of the individuals that
19 comprise those groups would be infected with
20 COVID-19?
21 A. So -- no. So what happens is
22 subjects are enrolled into the two groups.
23 You've got the group who received the vaccine and
24 then the group that did not receive the vaccine,
25 and received a placebo instead. And so

AR09650
1 infections will occur in the two groups
2 differentially, and then what we do at the end
3 once -- once a sufficient number of infections
4 have been reported in the trial -- and we don't
5 know whether they have happen in group one or in
6 group two, whether they have the vaccine or in
7 the placebo group -- but once there is a
8 sufficient number of infections, this is where we
9 un-blind -- we call un-blind the participants to
10 see whether they received the vaccine or received
11 the placebo and that's where we measure the
13 170 Q. So then the individuals in two of the
14 groups, the vaccine group and the placebo group,
15 it's not necessarily the case that all of them
16 have a COVID-19 vac -- have a COVID-19
17 infection -- pardon me -- you wait until, as you

18 said, there's a sufficient number of infections
19 in each of those groups.
20 A. You wait until there's a sufficient
21 number of infections overall in the trial. You
22 don't know whether a participant is in the
23 placebo group or vaccine group because everyone
24 is blinded. The participants are blinded and the
25 investigators are blinded. But you wait until

AR09651
1 there is a stuff number of cases of COVID-19, and
2 then when there's a sufficient number we un-blind
3 the subjects to see who received the vaccine and
4 who received placebo.
5 171 Q. And how is -- how is a sufficient
6 number of infections determined?
7 A. This is -- this is done through
8 statistics, making certain assumptions to -- to
9 make sure that there is enough -- enough number
10 of cases to measure -- to measure efficacy. I'm
11 trying to remember how many there were in the
12 different -- for the different vaccines, but
13 there's several hundreds. It's hundreds of cases
14 -- wait until there are hundreds of cases so that
15 you can be sure that you'll be able to have a
16 robust assessment statistically of -- of the
17 efficacy of the vaccine.

18 172 Q. Is there a threshold proportion that
19 needs to be met in order to un-blind and start
20 understanding the impact of the vaccine on the
21 group that has it and the lack of impact on the
22 group that doesn't? So, for example, do you --
23 must you wait until a certain percentage of the
24 populations get infected?
25 A. The certain percentage of the

AR09652
1 population in the trial, yes. That's enrolled in
2 the trial. I just don't remember what that is
3 for each of the vaccines. Yeah -- but...
4 173 Q. So that -- so that threshold could
5 change from study to study?
6 A. Depending on the study design, it
7 could, yes.
8 174 Q. Right. I guess my question is there
9 is no universal threshold at which the
10 individuals who are designing and conducting this
11 trial, all of them say once we've hit 20 percent
12 or 30 percent of the participants who are
13 infected, this is a sufficient number of
14 infections can now consider the impacts of the
15 vaccine. There's no standard or fixed threshold
16 proportion?
17 A. I can't answer that -- can't answer

18 that question accurately. I can't -- I would
19 have to speak to my -- my statistics team to talk
20 -- to really answer that question.
21 175 Q. Okay, that's fine. And so just --
22 just we can do an illustrative example here, if
23 that's okay. So you have two groups. One group
24 is vaccinated; one group is not vaccinated.
25 A. Right.

AR09653
1 176 Q. And do you have -- do you have an
2 equal number of participants in both of the
3 groups?
4 A. Depending on how the trial is
5 designed, but yes. For -- for Pfizer, for
6 example, and Moderna there was an equal number
7 spread between the two groups.
8 177 Q. Right. So if we are just to use
9 whole numbers -- and, again, I understand these
10 are not the numbers that was actually applicable
11 to vaccine trials, but just to make the point of
12 understanding what this shows us. If I had
13 10,000 people in each group --
14 A. Mm-hmm.
15 178 Q. -- so we have an equal number of
16 individuals in each group, and then you're
17 telling me at some point the individuals who are

18 conducting these trials decide that they have a
19 certain -- they've met a certain threshold of
20 sufficient number of infections; right?
21 A. Yes.
22 179 Q. So let's say out of 10,000 people, we
23 have four infections in the vaccinated group --
24 and we're just looking -- I think you mentioned
25 earlier that the only figures -- the primary

AR09654
1 endpoint, or the primary consideration is vaccine
2 efficacy as against the infection. So for the
3 purposes of our discussion, not to be shifty, I'm
4 just going to focus on vaccine efficacy as
5 against infection. Okay? Just general infection
6 --
7 A. Yes.
8 180 Q. -- which is what you used to approve
9 this. So let's say in group one which is the
10 vaccinated group, you have four individuals who
11 get infected with COVID-19. And in group two,
12 you have eight individuals who get infected with
13 COVID-19 --
14 MS. TELLES-LANGDON: Mr. Presvelos, is
15 this before or after unblinding? Because if it's
16 before unblinding, we would have 12 infections
17 and not know which group they belonged -- they

18 belonged in based on Dr. Lourenco's -- the
19 explanation so far.
21 181 Q. Yeah, you would have 12, and I take
22 your point, you wouldn't know where they are.
23 But you would know 12 out of 20,000 people are
24 infected; right? And I take it that these 12
25 people in our hypothetical scenario could have

AR09655
1 been infected anywhere in the community. We
2 don't know exactly how or why they were infected;
3 right?
4 A. Right.
5 182 Q. It could be somebody at home. It
6 could be at or about a grocery store, whatever;
7 right? So you have 12 people who are infected,
8 and let's say that is a sufficient number of
9 infections for you un-blind the study and start
10 analyzing -- start doing all the necessary
11 analysis to determine the relative risk
12 reduction; right?
13 What's the next step of this calculation?
14 If we were to calculate the relative risk
15 reduction based on these figures, two groups,
16 10,000 participants per group; four get infected
17 in the vaccinated group; eight get infected in

18 the placebo group. Can you slowly walk me
19 through what happens next?
20 A. Okay. So I'll caveat that with the
21 fact that I'm not a biostatistician. So this is
22 not something that's in my area of expertise.
23 But as I understand it, we look at the total
24 number of subjects -- total number of people who
25 are infected, then we un-blind and -- and see

AR09656
1 which -- which of those received the vaccine
2 versus those who received the placebo.
3 And then we look at the difference in the
4 proportion between -- between the two within --
5 within that group of 12. So in this case, it's a
6 group of 12, we -- the vaccine effectiveness in
7 this case would be eight out of 12 -- eight out
8 of 12 minus four out of 12. Whatever that comes
9 up to.
10 183 Q. All right. Could we just slow it
11 down for a minute? Slow it down. I'm not at
12 your level. So you look at the difference in
13 proportion of subjects who are infected. And
14 when you say you look at the difference in
15 proportion, look at the difference in proportion
16 between the vaccinated and placebo group?
17 A. Between the vaccinated and the

18 placebo, yes.
19 184 Q. Right. And then do you take the
20 eight and you divide that over four?
21 A. Just a second. So in this case, the
22 vaccine effectiveness is 50 percent because you
23 have doubled the cases of -- of infection in the
24 placebo group versus the vaccinated group. So
25 you have eight -- sorry about that.

AR09657
1 185 Q. It's okay.
2 A. A dog barking in the background. We
3 have eight in the -- in the placebo and four in
4 -- and half of that in the vaccinated group. So
5 that's a 50 percent --
6 186 Q. Okay. But I --
7 A. -- relative risk reduction.
8 187 Q. -- I want to understand the precise
9 calculation, how we get there. I understand that
10 double the number of people got infected in the
11 placebo group; right? And so somebody could
12 infer, maybe, that means you -- you know, the
13 vaccinated group to your point and you have
14 50 percent protection.
15 But before we get there, I want to
16 understand, the next stage here is we have equal
17 number of participants in this case. We have 12

18 total infected. We un-blind and we figure out,
19 oh, there's more people infected in the placebo;
20 there's less people infected in the vaccinated.
21 Now you're telling -- is the next stage that we
22 divide eight over four? Or four over eight?
23 What are we dividing to get 50 percent?
24 A. Right. No, I think we divide eight
25 over 12 minus four over 12, I believe that's how

AR09658
1 you would do it. Again, I'm not a
2 biostatistician. So but...
3 MS. TELLES-LANGDON: And, Mr. Presvelos,
4 Dr. Lourenco's been clear now on more than one
5 occasion that she is not a statistician.
6 Dr. Lourenco, I know you're trying to be
7 helpful but please don't speculate. So you can
8 -- in being pressed to answer questions in an
9 area where you said it's not an area of your
10 expertise.
12 188 Q. Okay. So, sorry, Doctor, I just want
13 to make some -- I'm just trying to understand.
14 You approve vaccines based on meeting a
15 certain threshold that is calculated on a
16 relative risk reduction basis; correct?
17 A. Yes, correct.
18 189 Q. So the method of calculation is
19 relative risk reduction; right? That's what you
20 look at to determine whether or not any given
21 vaccine satisfies the threshold of 50 percent for
22 authorization?
23 A. Right.
24 190 Q. So you must be very familiar with
25 relative risk reduction assessments; am I

AR09659
1 correct?
2 A. My team is familiar with relative
3 risk reduction assessments.
4 191 Q. But don't you have the ultimate
5 authority to sign off on authorizing the COVID-19
6 vaccine?
7 A. Yes, I do.
8 192 Q. Okay. So shouldn't you be very
9 familiar with how relative risk reduction is
10 actually calculated at a granular level?
11 A. Well, I have a team of experts that
12 assist in this, in the reviewing and evaluation
13 of the data and I rely on their expertise.
14 193 Q. Of when they're crunching numbers to
15 determine relative risk reduction, surely you
16 know what numbers they're crunching and why
17 they're crunching?
18 A. Yes.
19 194 Q. Okay. So that's all I'm asking. I'm
20 asking what numbers are we dividing, why are we
21 dividing them, and then what do we do to
22 understand what those numbers tell us? That's
23 all I'm asking; right?
24 So I think what you mentioned is -- and I
25 want to say just for the record, this is very

AR09660
1 relevant. Because when the government is
2 promoting a certain level of efficacy or
3 effectiveness for the vaccines, I think it's
4 relevant to the application and to the judge to
5 understand what those numbers mean.
6 Eighty percent or 90 percent or a hundred percent
7 doesn't tell me anything unless I understand what
8 it actually means and how we calculate that
9 effectiveness.
10 Would you agree with me?
11 A. Yes.
12 MS. TELLES-LANGDON: So you're asking
13 Doctor -- I'm sorry, you're asking Dr. Lourenco
14 to agree with what --
15 MR. PRESVELOS: That number --
16 MS. TELLES-LANGDON: -- the judge is
17 going to --
18 MR. PRESVELOS: No, I'm asking whether she
19 thinks the --
20 195 Q. Dr. Lourenco, do you think it is
21 relevant in understanding vaccine effectiveness
22 that to first understand how we calculate that
23 effectiveness?
24 A. Yes, it's relevant to understand how
25 to calculate the effectiveness.

AR09661
1 196 Q. Right. Okay. So let's continue
2 doing that. So we -- you tell me -- or you told
3 me you divide eight over 12; right? Eight
4 divided by 12. That's .66. And then you do four
5 over 12, which is .33. And let me just ask you,
6 when we do .66 and .33, do you also multiply
7 those figures by a hundred? So we do eight
8 divided by 12 and it is .66. Should I take that
9 number and multiply it by a hundred to give us
10 66?
11 A. Yes, you should.
12 197 Q. Okay. And I presume therefore -- I'm
13 -- this is -- I'm harping back to my maybe late
14 elementary school, early high school math. And
15 then I presume when we're -- because we're
16 dealing with fractions here, when we do four over
17 12, it's .33, we multiply that by a hundred;

18 correct?
19 A. Right.
20 198 Q. Okay. So that gives us 66 and 33.
21 And then I think the next thing you said we do is
22 we -- we take 66 and we subtract 33 and that
23 gives us 33; right?
24 A. Right. I believe that's how it's
25 done.

AR09662
1 199 Q. Well, take -- take a second. This is
2 a very important point. If I'm not calculating
3 this correctly, I need to know.
4 MS. TELLES-LANGDON: Just for the record,
5 Mr. Presvelos, taking Dr. Lourenco through these
6 calculations and she's already testified, again,
7 I remind you she's not a biostatistician, that
8 she has individuals on her team who are
9 biostatisticians that do these and analyses and
10 provide her with the information about the
11 outcome of those analyses. I know you still want
12 to go down this road, but I'm not sure it's fair
13 to Dr. Lourenco to continue to press her to do
14 calculations that she fairly clearly has stated
15 relative to the actual calculations. Performing
16 those calculations of relative risk reduction are
17 done by members of her team on which -- and she

18 relies on their expertise. That has been her
19 testimony so far, Mr. Presvelos.
21 200 Q. And I want to put on the record that
22 at paragraph 115 of Dr. Lourenco's affidavit, she
23 swears that "absolute risk reduction was not
24 considered in the Food and Drug Act approval
25 process for the vaccine and indicate that

AR09663
1 clinical trials are designed to assess vaccine
2 efficacy using relative risk reduction as the
3 main measure of efficacy."
4 MS. TELLES-LANGDON: She's not astute on
5 that.
6 BY MR. PRESVELOS:
7 201 Q. And -- right. And "therefore the use
8 and interpretation of the absolute risk
9 reduction, but appropriate with the data derived
10 from the COVID-19 clinical trial as explained
11 below." And goes into a difference between ARR
12 and RRR, and why RRR is considered, in your words
13 at para 159, "Given the above reasons the RRR is
14 considered a more relevant measure to assess
15 vaccine efficacy compared to the ARR for COVID-19
16 vaccine trials."
17 And you'll have to forgive me if I assume

18 that having spent four or five paragraphs on
19 explaining the difference between RRR and ARR and
20 why you use RRR and not ARR, I can at least
21 expect you to explain to me how RRR is
22 calculated, and then once we've calculated that,
23 what that actually means?
24 And -- and if I just -- just before I get
25 there, I want to -- I take it this isn't a

AR09664
1 controversial question. But, Doctor, you would
2 agree with me that when the government of Canada
3 to communicating to the Canadian public about the
4 protective effect of the vaccine it is actually
5 communicating on the basis of a relative risk
6 reduction figure and not an absolute risk
7 reduction figure; correct?
8 A. Yes. We do communicate on the basis
9 of relative risk reduction, yes.
10 202 Q. Okay. And that is how you represent
11 the vaccine's effectiveness to Canadians; right?
12 A. Right, yes.
13 203 Q. Okay. So help me -- and if you don't
14 know, that's fine. I will -- I will -- we can
15 move on from this. I just need to understand how
16 we calculate the RRR and what -- why we calculate
17 it the way we do and what that tells us. Because

18 as you've acknowledged, understanding how we
19 calculate relative risk reduction is an important
20 part of understanding efficacy.
21 A. Right.
22 204 Q. So we took in this sample -- in this
23 illustrative sample -- and, again, I want to put
24 on the record, I understand this is a
25 hypothetical. If you want we can use the real

AR09665
1 numbers, but I think it's actually going to make
2 things more complicated. We're using general
3 round numbers, 10,000 in each category, 12 total
4 infections; four vaxxed, eight unvaxxed. We
5 divided eight over 12, four over 12, and now we
6 subtract the two figures; right?
7 Or is there a different? Or is that not
8 the correct calculation?
9 A. I am not sure that that's the correct
10 calculation.
11 205 Q. Okay. And sitting here today, do you
12 know what the correct calculation is?
13 A. I'd have to consult with my team.
14 206 Q. Okay. So -- okay. Assuming in this
15 example that the relative risk reduction was in
16 fact what your initial impression of it was,
17 which is 50 percent, you agree with me that in

18 order to make sense of this efficacy we would
19 first need to understand what the baseline level
20 of risk is to any individual in these groups?
21 A. Can you repeat the question?
22 207 Q. Right. In order to understand how
23 much something reduces something else by, we need
24 to understand what your baseline level of risk
25 is; is that correct?

AR09666
1 A. Yes.
2 208 Q. Right. So to put it differently, I'm
3 30 years old. I have no comorbidities. As a
4 healthy 30-year-old with no comorbidities, I have
5 a baseline level of risk to be infected with
7 A. Right. Yes.
8 209 Q. And my level of risk of getting
9 infected is probably not the same as somebody
10 who's 70 years old; right?
11 A. Probably not.
12 210 Q. In fact, it's -- we can almost
13 certainly say it's not; right?
14 MS. TELLES-LANGDON: So you --
16 MS. TELLES-LANGDON: You asking
17 Dr. Lourenco to speculate on your level of risk

18 of becoming infected relative to a 70-year-old's
19 risk of becoming infected?
20 MR. PRESVELOS: Yeah. I think that
21 subcategories in these trials are important
22 because not -- not every subcategory as we've
23 established earlier presents the same level of
24 risk. But that's fine. You can --
25 (Simultaneous crosstalk - indiscernible)

AR09667
1 MS. TELLES-LANGDON: Sorry, have you
2 established that on the record that not every
3 subcategory is --
4 MR. PRESVELOS: Yes, yes. Awhile ago.
5 Probably an hour ago. But --
6 MS. TELLES-LANGDON: Risk of infection or
7 risk from infection?
8 MR. PRESVELOS: What -- just risk of being
9 infected. And also risk of hospitalization and
10 also risk of death.
11 MS. TELLES-LANGDON: Well, those are three
12 different things, Mr. Presvelos. I do believe
13 you established on the record earlier that for an
14 individual the risk of hospitalization and death
15 is generally higher for older individuals or
16 individuals with comorbidities. But I do not
17 think there's anything established on the record

18 so far with respect to an individual's risk of
19 becoming infected based on age.
21 211 Q. Okay. Let's just go back to this
22 idea of this baseline risk that I -- that I want
23 to talk; right? You would -- do you agree with
24 me that there is a certain baseline level of risk
25 for individuals in different age categories?

AR09668
1 A. There is a certain -- there are
2 differences in risk certainly for different age
3 categories, yes.
4 212 Q. But if I'm to understand how much the
5 vaccine protects me in a particular age category,
6 wouldn't I first have to understand what my risk
7 is of that outcome? So to be specific, if I want
8 to understand how much this vaccine protects me
9 against hospitalization, shouldn't I first know
10 what my risk is of being hospitalized if I get
11 COVID-19? Is that a crazy proposition?
12 A. If you want to know -- if you want to
13 know what your risk is -- so repeat the question.
14 I didn't quite get the question.
15 213 Q. Okay. When we say that something is
16 50 percent effective, right, it -- I take it, but
17 I'm going to ask you what it means. It provides

18 50 percent protection against you developing a
19 certain outcome; correct? Right?
20 A. Right.
21 214 Q. That 50 percent doesn't exist in a
22 vacuum. If I have a one-percent chance of
23 getting infected and dying -- and we'll get to
24 what effect -- what effect it means, but you're
25 telling me this vaccine is 50 percent effective,

AR09669
1 I take it what it actually does for me is it
2 takes the one percent and cuts it in half. It's
3 now reduced your chance by .05; right?
4 A. Right.
5 215 Q. Okay. And what I'm saying is --
6 A. No.
7 216 Q. -- don't -- no? Okay.
8 A. Just to correct it. It doesn't
9 reduce your chance by .05. What the vaccine does
10 is it reduces the risk at a -- at a population
11 level when the trial was conducted, it showed
12 that people who are -- who -- it shows that in
13 the vaccinated group, there was a 50-percent
14 reduction in the proportion of people who became
15 infected versus the placebo group.
16 So it doesn't mean that your individual
17 risk as a person, if you take the vaccine, is

18 50 percent -- is reduced by 50 percent.
19 217 Q. And how do I understand that
20 proportion based on different age categories?
21 Does relative risk reduction factor at different
22 age categories in those groups? The placebo
23 group and the vaccinated group? Does it stratify
24 for age?
25 A. Relative risk reduction doesn't

AR09670
1 stratify for -- it does -- we can calculate
2 relative risk reduction according to different
3 age groups, yes. That was done in the clinical
4 trials.
5 218 Q. Okay. And so the relative risk
6 reduction would -- could vary depending on the
7 age groups?
8 A. It could vary depending on the age
9 groups, yes.
10 219 Q. Okay. So when -- when -- when we say
11 in some of the records as we've seen in your
12 exhibit, I believe in "S," there's a 90 percent
13 relative risk reduction. I'm assuming absence --
14 absent any qualification as to which age group it
15 belongs to, that's an overall blended risk
16 reduction for all categories of ages?
17 A. Um...
18 220 Q. Because I haven't seen anything.
19 Maybe I've missed it and -- but I haven't seen
20 anything here based on relative risk reduction
21 for different age groups in your affidavit.
22 A. No, I don't think I have it in my
23 affidavit, but it was calculated for -- for the
24 vaccines.
25 221 Q. Okay. So then the -- so then what I

AR09671
1 would like to understand is this. If a vaccine
2 has as we saw in one of your exhibits a 90
3 percent effectiveness, you agree with me that
4 that does not translate into -- I should
5 understand that as meaning that the -- that I
6 have a 90 percent less chance of becoming
7 infected of COVID-19 if I have a vaccine.
8 A. Right.
9 222 Q. That's not what it means?
10 A. It -- no, it does not mean for you --
11 for any individual who receives the vaccine, it
12 doesn't mean that you're 90 percent less at risk
13 of being infected. What it means is that out of
14 -- out of -- in the clinical trial out of
15 everyone who received -- out of everyone who
16 received the vaccine versus those who received
17 placebo there was a 90 percent reduction in the

18 number of cases in the people who were vaccinated
19 in the group vaccinated versus the people who
20 received placebo.
21 223 Q. And why does the reduction in cases
22 between the vaccinated and the placebo group, why
23 does not -- why does that not get translated into
24 a corresponding reduction on an individual level?
25 A. There is a reduction on the

AR09672
1 individual level. It's just that it's not
2 necessarily -- we don't know what -- what -- it's
3 not necessarily 90 percent. It's not what the
4 trial is measuring. It's not measuring a
5 reduction on individual levels.
6 224 Q. Is there any way for me to look at
7 the RRR figure and understand how much the
8 vaccine actually reduces my risk in a particular
9 age category, how it reduces my risk of getting
10 infected of COVID-19?
11 A. That -- that likely can be done. But
12 it depends on how much data there are available
13 for -- for a certain age category and how rely --
14 so if the data are limited, it may not a reliable
15 estimate.
16 225 Q. So given that you approve vaccines on
17 the basis of an RRR rather than ARR, can you

18 comment a bit, or tell me, or flag for me what
19 are some of the limitations of using relative
20 risk reduction as a way of assessing a vaccine's
21 efficacy?
22 A. Some of the limitations?
23 226 Q. Yes.
24 A. That would be something I'd need to
25 talk to my experts about in terms of what are

AR09673
1 some of the limitations of using RRR versus ARR.
2 I did discuss with them the limitations of ARR
3 but not -- not the other way around in terms of
4 RRR.
5 227 Q. But you don't use ARR to approve or
6 authorize vaccines; right?
7 A. No, we don't use ARR to approve or
8 authorize.
9 228 Q. But that's what you had a discussion
10 about. We discussed the limiting -- the limiting
11 effects of an ARR approach to understanding
12 vaccines. But you just told me you haven't --
13 you haven't had a discussion with your team about
14 the limitations of a relative risk reduction
15 approach; right?
16 A. No, we haven't had a discussion on
17 that. No.
18 229 Q. Do you think it could be relevant to
19 understanding what the limitations are of an RRR
20 approach to assessing a vaccine's effectiveness?
21 Do you think that could be relevant to your
22 decision in terms of both how you approve a
23 vaccine and how you communicate about what that
24 vaccine does to the public?
25 A. Yes. It would be -- it is a -- an

AR09674
1 important element to be clear about and -- and in
2 how we communicate it to the public, what we mean
3 when we're talking about relative risk reduction.
4 230 Q. Do you agree with me that absolute
5 risk reduction is used to find an estimate of
6 vaccine effectiveness that requires the number
7 needed to vaccinate to prevent one more case of
8 COVID-19?
9 A. The need to vaccine is -- the
10 absolute risk reduction is used to calculate that
11 number.
12 231 Q. Right.
13 A. Yes.
14 232 Q. And would you agree with me that
15 using only relative risk reduction and not using
16 absolute risk reduction could result in a
17 reporting bias?
18 A. Not if -- as I understand it from
19 discussing with my -- with my team, the absolute
20 risk reduction itself carries a bias because of
21 the way the trials were designed. They were
22 designed to measure relative risk reduction, not
23 absolute risk reduction.
24 And so reporting on absolute risk
25 reduction when that estimate is not accurate may

AR09675
1 not be helpful.
2 233 Q. But wouldn't you agree with me that
3 the most relevant way to assess vaccine efficacy
4 is on the basis that the population understands
5 how much that vaccine reduces their risk in a
6 particular category, not how much it might reduce
7 it between two sample population groups?
8 A. Only if there is -- if there are --
9 if there is a way to measure that in an -- in an
10 accurate -- in an accurate way. And, as I said,
11 the way the clinical trials were designed, they
12 were not really designed to measure absolute risk
13 reduction.
14 234 Q. Right. So the current clinical
15 trials could not actually tell me what percentage
16 the vaccine would reduce my risk and my age
17 category of being infected with COVID-19?

18 A. No. They -- they would not.
19 MR. PRESVELOS: Okay. Can we take a --
20 can we take a ten-minute break, please? I need a
21 coffee.
22 MS. TELLES-LANGDON: Perhaps,
23 Mr. Presvelos, looking at --
24 MR. PRESVELOS: Oh, it's 12:30. We can
25 take a lunch break.

AR09676
1 MS. TELLES-LANGDON: We can take the lunch
2 break.
3 MR. PRESVELOS: Oh, I didn't even notice
4 that. Sorry. Let's go eat. Maybe that's why I
5 feel so low.
6 MS. TELLES-LANGDON: We've been taking a
7 45-minute lunch break. Just check both with
8 Dr. Lourenco and with the court reporter whether
9 that is sufficient amount of time for each of
10 you.
11 (OFF-THE-RECORD DISCUSSION)
12 --- LUNCH RECESS (12:32 P.M.)
13 --- UPON RESUMING (1:22 P.M.)
15 235 Q. Dr. Lourenco, have you looked at the
16 absolute risk reduction numbers for the vaccines
17 that you authorized for use in Canada for

18 COVID-19?
19 A. No, I have not.
20 236 Q. And do you know whether anyone in
21 your team looked or would have looked at the
22 absolute risk reduction figures for the COVID-19
23 vaccines you authorized?
24 A. No, we -- we have not looked at the
25 absolute risk reduction.

AR09677
1 237 Q. Are you familiar with the calculation
2 required in order to calculate the absolute risk
3 reduction of any or all of the COVID-19 vaccines
4 that you authorized for use in Canada?
5 A. No, I'm not really familiar with the
6 formula on how to calculate that.
7 238 Q. Do you know what information you
8 would require from the clinical studies in order
9 to calculate an absolute risk reduction?
10 A. We would need -- we would need to
11 know the -- I'll just refer to my affidavit.
12 239 Q. Yeah.
13 A. We would need to know the -- the
14 proportion of subjects who develop COVID-19 in
15 the vaccinated group and the proportion -- the
16 proportion of subjects who develop COVID-19 in
17 the control group.

18 240 Q. Okay. Do you agree with me that you
19 have this information based on the clinical
20 trials that were presented to you?
21 A. Yes.
22 241 Q. So you agree with me that you have
23 all the information you may require in order to
24 calculate the absolute risk reduction for any and
25 all of these vaccines?

AR09678
1 A. Yes, we do have the information
2 required.
3 242 Q. And do you agree with me that in --
4 do you -- do you know whether any of the
5 information you have provided in your affidavit
6 actually makes reference to the absolute risk
7 reduction of these COVID-19 vaccines?
8 A. No. I'm not aware of -- of including
9 in the affidavit reference to absolute risk
10 reduction, the actual calculation of absolute
11 risk reduction for any of the vaccines.
12 243 Q. Right. So there's nothing in your
13 affidavit that identifies what the ARR is for the
14 Moderna vaccine, for the Pfizer vaccine or for
15 the Astra-Zeneca vaccine; correct?
16 A. Correct.
17 244 Q. Okay. I am -- over the break I sent

18 you some articles to look at. They were not
19 really long except maybe one of them. One of the
20 articles was called COVID -- I'll put it up on
21 the screen for you. But one of the articles is
22 called, "COVID-19 vaccine efficacy and
23 effectiveness——the elephant (not) in the room."
24 Did you see that one during the break?

AR09679
1 at what point in time did you send these
2 articles? Today?
3 MR. PRESVELOS: Yeah. I sent them at
4 12:54 p.m., so about half an hour ago. Did any
5 of you see them?
6 MS. TELLES-LANGDON: I've not received
7 them.
8 MR. PRESVELOS: Real -- oh, you haven't
9 received them? Oh, weird.
10 MR. WILSON: You might want to hit
11 send/receive. We I haven't got -- we haven't got
12 them either.
13 MR. PRESVELOS: Yeah, maybe -- it's in my
14 sent box.
15 MR. BEN NAOUM: I have received it.
16 MR. PRESVELOS: You have or no?
17 MR. BEN NAOUM: Yeah, I have.

18 MR. PRESVELOS: Has everyone -- can
19 everyone --
20 MS. TELLES-LANGDON: Perhaps we can go off
21 the record for a moment.
22 --- OFF THE RECORD (1:26 P.M.)
25 245 Q. Dr. Lourenco, just going through your

AR09680
1 affidavit on the break, unless I missed
2 something, I don't see any of the Pfizer,
3 Moderna, or Astra-Zeneca trials in your -- as an
4 exhibit to your affidavit; is that correct?
5 A. Can you be more specific in terms of
6 trials? Like, you're looking for the -- for the
7 actual study reports? Or --
8 246 Q. Well, why don't you -- yeah, so maybe
9 I have a bit of a layman's understanding of
10 trials. Well, I'm looking at the reports that
11 you would have reviewed in making your decision
12 to authorize these vaccines for use in Canada.
13 So these reports I understand, unless I'm
14 mistaken, came from the pharmaceutical companies;
15 right?
16 A. Yes, correct.
17 247 Q. And so you would have a report from

18 Pfizer, you would have a report from Moderna, and
19 you would have had a report from -- from
20 AstraZeneca. There might be others but that's --
21 those are the main ones.
22 Did you receive reports from each of those
23 pharmaceutical companies?
24 A. Yes. We received reports on the
25 clinical study results for each of the -- for

AR09681
1 each of the companies.
2 248 Q. And you and your two -- you and your
3 team would have reviewed those results in making
4 a decision to authorize the vaccines in Canada;
5 right?
6 A. Yes, my team reviewed the results in
7 detail prior to making a recommendation for
8 authorization.
9 249 Q. Okay. I would like an undertaking to
10 produce a copy of the -- of reports and results
11 that you and your team would have reviewed for
12 AstraZeneca, for Pfizer, and for Moderna, please.
13 U/A MS. TELLES-LANGDON: We'll take that under
14 advisement. I'm not sure if there's any kinds of
15 restrictions that relate to this, and I'm also
16 not sure what the volume of that information is.
17 MR. PRESVELOS: Okay. So I guess to the

18 extent that there is a privacy concern, I guess
19 one of two things will happen. You either not --
20 you will either not give it to me or you'll
21 redact the areas that are sensitive for privacy
22 -- have privacy considerations. But in the event
23 you do that, in the event that you either deny it
24 or redact it, I would like your position as to
25 why it's being denied or redacted once you've had

AR09682
1 a chance to review these -- this information.
2 MS. TELLES-LANGDON: Dr. Lourenco, do you
3 have any sense of the volume of material we're
4 talking about here, if we provide this material
5 in response to the undertaking?
6 THE WITNESS: It would be -- it would be
7 certainly hundreds -- hundreds of pages for each
8 clinical study report. Now, we do publish -- we
9 do publish this information on our website after
10 a certain amount of redacting, it is published on
11 our website. So at minimum we can -- obviously
12 take this under advisement, but we could provide
13 at least that information.
14 U/A MS. TELLES-LANGDON: Certainly. Okay.
15 Thank you for that context, Dr. Lourenco. And
16 we'll -- Mr. Presvelos, we will take that
17 undertaking under advisement and get back to you.

19 250 Q. Sure. I want to take you -- we're
20 going to talk about the articles you just read,
21 and before we do, I just want to confirm, have
22 you had enough time to look at the articles?
23 A. Yes.
24 251 Q. Do you need more time to look at the
25 articles?

AR09683
1 A. No.
2 252 Q. Okay. For sure?
3 A. Yes.
4 253 Q. Okay. Let's go to paragraphs -- I
5 want to look at paragraphs 156, 157, and 158 of
6 your affidavit.
7 A. Okay.
8 254 Q. I'm going to give you a couple of
9 minutes to read -- just to kind of skim through
10 those paragraphs.
12 A. Mm-hmm.
13 255 Q. So in these paragraphs you're
14 explaining why relative risk reduction is being
15 used in trial -- in the vaccine -- in the vaccine
16 approval process and not absolute risk reduction.
17 And I have some questions about some of the

18 statements you make here.
19 If we go to paragraph 156, specifically at
20 the bottom sentence. I'm just going to read it
21 out:
22 "Different subjects are enrolled in the
23 clinical trial at different time points,
24 and they're consequently followed for
25 different amounts of time before the

AR09684
1 decision is taken to trigger and proceed
2 with the efficacy assessment based on the
3 overall accrued number of COVID-19 cases."
4 My first question is "the decision is
5 taken to trigger." Is that -- I think earlier we
6 had established that that decision is made when
7 there are sufficient number of infected
8 individuals in these groups; is that correct?
9 A. When there's a sufficient number of
10 infected individuals overall in the clinical
11 trial. We don't know who's enrolled in the
12 treated -- in the vaccine group versus the
13 placebo group.
14 256 Q. Right. But you do know how many
15 individuals in either of those groups at any
16 given time are infected with COVID-19?
17 A. No, you don't know that until you

18 un-blind -- you un-blind the individuals in the
19 trial and you find out whether they were given
20 the vaccine or the placebo.
21 257 Q. When do you decide when to un-blind
22 the individuals in the trial?
23 A. The decision to un-blind is taken
24 when -- when it is -- when we reach that point in
25 time when there are a sufficient number of

AR09685
1 COVID-19 cases accrued. So based on the
2 statistical analysis plan for the trial, it's
3 decided that now that we have, say, 170 cases
4 there should be enough to do a -- a proper
5 statistical analysis on vaccine efficacy.
6 258 Q. Right. So when the trial is blind,
7 you still know how many participants in that
8 trial, regardless of which group they're in, you
9 don't know because it's blind, you still know how
10 many people have a COVID-19 infection?
11 A. Yes. You know how many people have
12 COVID-19, yes.
13 259 Q. Right, okay. And so I want to ask
14 you why are subjects enrolled at different time
15 points in this clinical trial? What is the --
16 what is the methodological explanation or
17 whatever term you want to use, why do they come

18 in at different points in time?
19 A. Okay. So these clinical -- once a
20 clinical trial initiates, there are a number of
21 different clinical trial sites that will open
22 across different -- different area -- different
23 places in the world, and the rate at which
24 patients are recruited into the clinical trial
25 sites depends on how quickly you can recruit

AR09686
1 people. Some people -- some sites will recruit
2 more quickly, others will take longer. It
3 depends on finding the people who are willing to
4 participate in the trial.
5 And so the trial accruing individuals --
6 so, as you know the -- for the Pfizer trial, for
7 example, there were over 44,000 participants.
8 They were not all, like, accrued on the same day,
9 right? So it's a lot of people. They are
10 recruit -- they are enrolled into the trial
11 dynamically as they come up, as the different
12 sites are able to enroll them.
13 260 Q. So it's kind of like admissions on a
14 rolling basis?
15 A. It's -- it's -- yes, it's kind of
16 like admissions as people sign up to the trial.
17 And they're not all going to sign up on the same

18 day; they'll sign up over a period of weeks. And
19 that's why people are enrolled at different
20 times.
21 261 Q. Right. So it's not the case that
22 Pfizer waits until they have the desired number
23 of participants to start the study?
24 A. That's right. So they start to
25 enroll participants. They have a target. They

AR09687
1 have the target, we want to enroll "X" number,
2 but they start to enroll them and then once --
3 obviously they want to enroll that target, but at
4 the same time they want to enroll sufficient
5 participants in order to have a -- the required
6 number of COVID-19 cases and also have the
7 required amount of time to follow up of the
8 different participants.
9 262 Q. Okay. Got it. So that's why you say
10 that people come at different time points. Okay.
11 I didn't know that.
12 The second part here that I want to ask
13 you about, you said, and "they are consequently
14 followed for different amounts of time." So I
15 can understand why the start date and end date
16 might be different for different participants
17 depending on when they get accepted into this

18 trial. As you mentioned, you could have somebody
19 as part of the initial cohort on day one and then
20 a week later you have somebody else join,
21 right --
22 A. Right.
23 263 Q. -- in order to reach that desired
24 number. So naturally the person that joins in
25 week one was -- at the end of week one is not

AR09688
1 going to be there from the beginning, so they
2 came at different time points in the trial.
3 But are you saying in the sentence that
4 there's not a uniform length of time that you
5 follow all the subjects?
6 A. There is. There is a -- so there
7 isn't a uniform amount of time that we follow all
8 the subjects at the point in time when we do the
9 efficacy analysis. Because as I mentioned, the
10 subjects are enrolled at different time points,
11 so some of them will have been followed, let's
12 say for a month, others will have been followed
13 for two months and some for three or four or five
14 months at the point in time when we're ready to
15 do the efficacy analysis.
16 So what we look for though is to make sure
17 that all the subjects in the trial are followed

18 for a median of at least two months. So that
19 means 50 percent of the subjects are followed for
20 at least two months. That's -- that's the target
21 follow-up period. But as I mentioned, some of
22 them will not have been followed for two months,
23 others will have been followed for longer.
24 264 Q. Okay. Who determines what the median
25 follow-up time or following or surveillance time,

AR09689
1 whatever you want to say, who determines how much
2 time that is or will be?
3 A. That -- that was determined by Health
4 Canada. We issued the guidance for the COVID-19
5 vaccines requiring pharmaceutical companies to
6 follow participants for at least two months after
7 -- after the vaccine is administered. After the
8 second dose of vaccine is administered.
9 265 Q. And how --
10 A. For -- for a vaccine that requires
11 two doses, for example.
12 266 Q. And how did the government decide on
13 a median of two months?
14 A. We decided on a median of two months
15 for -- for two reasons; one, to ensure that we
16 followed subjects long enough to assess efficacy.
17 So we want to make sure that there is enough time

18 for -- for the patient to mount an immune
19 response and to be considered protected based on
20 the -- following vaccination.
21 And then the second reason is to follow
22 subjects for a sufficient amount of time for
23 adverse event monitoring as well. And we know
24 that the majority of risk events related to
25 vaccines occur within the first two months of

AR09690
1 vaccination. So that's the reason why we set it
2 at two months.
3 267 Q. Were you involved in this decision?
4 A. Yes, I was involved in this decision
5 together with my team.
6 268 Q. And how did you decide that two
7 months would be long enough to understand the
8 efficacy of the vaccine?
9 A. So we know from how vaccines work
10 that usually within one to two weeks after the
11 last dose there should be -- there should be
12 maximal antibody levels and maximal immune
13 response. And also based on earlier clinical
14 trials that were conducted, we had an idea of how
15 quickly there is -- how quickly a patient
16 responds to vaccination.
17 And then also based on the safety -- the

18 required safety monitoring. We know that -- that
19 for based on vaccines that have been developed
20 previously most adverse events happen within the
21 first two months. So we wanted to make sure that
22 at least two months was -- there was at least a
23 follow-up period of two months for -- for
24 subjects.
25 269 Q. Have you ever previously authorized a

AR09691
1 vaccine for approval that used the standard of a
2 two-month median follow up?
3 A. I have to -- I'm not sure. I'm
4 not -- don't know. I'd have to check that. It's
5 quite possible that for the H1N1 vaccine in 2009
6 that that was the case, but I'd have to verify
7 that.
8 MR. PRESVELOS: That's fine. I'll ask
9 your counsel for an undertaking to verify whether
10 the two month was ever previously used or
11 accepted by Health Canada as a sufficient length
12 of time to follow subjects.
13 U/T MS. TELLES-LANGDON: We will provide that
14 undertaking.
16 270 Q. And what -- so an aspect that I'm
17 still not quite clear on is, there is a standard

18 of median for two months. But why was it not
19 possible or why was it not -- or why did the
20 pharmaceutical companies not follow each of the
21 participants for the same amount of time?
22 A. So they --
23 271 Q. You said from day one, why did they
24 follow that individual for two months and the
25 participant on day 30, follow that individual for

AR09692
1 two months?
2 A. So they are. They're following all
3 participants for up to two years after -- after
4 vaccine administration. It's just for the
5 purpose of doing the efficacy analysis we wanted
6 to make sure that all subjects were -- not all
7 subjects -- a median of -- that subjects were
8 followed for a median of two months. Some of
9 them not two months, some of them less, some of
10 them more for the purposes of efficacy analysis
11 and registration of the vaccine in Canada.
12 But we do -- we did ask companies to
13 continue to follow subjects until the end of the
14 trial. So for Pfizer, it's two years. They're
15 following all of their subjects for two years.
16 And for Moderna, it's one year.
17 272 Q. So just to understand this correctly;

18 the subjects that you -- the data that you're
19 relying on that looked at the subjects who had
20 been followed for a median of two months, those
21 same subjects continue to be monitored by their
22 respective pharmaceutical companies; correct?
23 A. That's correct, yes.
24 273 Q. And how often do you receive reports
25 from these pharmaceutical companies on their

AR09693
1 monitoring of these subjects?
2 A. So we -- we asked the companies to
3 provide an update once they have followed the
4 subjects for six months, and then to provide us
5 the final report once all subjects have been
6 followed for -- for two years for the Pfizer
7 vaccine and one year for the Moderna vaccine.
8 Because that's how their trials were designed.
9 They were designed for Pfizer to follow
10 subjects for two years and for Moderna for one
11 year. But we also asked them to give us a report
12 at the six-month mark.
13 274 Q. And is the report at the six-month
14 mark disclosed in your affidavit anywhere as an
15 exhibit?
16 A. No, it is not. No.
17 275 Q. Is it publicly available?

18 A. Yes, we should have that on our
19 website for the Pfizer vaccine. For the Moderna
20 vaccine we have not received it yet.
21 276 Q. When you say "you," your department
22 has not received it yet?
23 A. My department has not received it
24 yet --
25 277 Q. And have you --

AR09694
1 A. -- that I'm aware of.
2 278 Q. Have you reviewed the vaccine's
3 efficacy on these subjects six months following
4 the trial?
5 A. Yes, we reviewed it for the Pfizer
6 vaccine.
7 279 Q. Okay. And what -- what does it
8 demonstrate about the vaccine's effectiveness six
9 months after?
10 A. That it's maintained. That there is
11 over -- I don't remember the exact figure, but
12 it's over 90 percent efficacy is maintained.
13 280 Q. And six months -- what, I'm assuming
14 what variant of concern would that have been?
15 That would be Delta?
16 A. I would have double -- I would have
17 to verify that, what data -- the timeframe that

18 is covered.
19 281 Q. Okay. So I will -- here's what I'll
20 say. To the extent that it's -- I'm going to
21 check that it's online. Is there any aspect of
22 the report that were -- of these reports that
23 would not be produced online to the public?
24 A. Any aspect that would not be produced
25 online?

AR09695
1 282 Q. Yes.
2 A. Just the -- just the sections that
3 would have been redacted. There's sections that
4 would have been redacted mainly for personal
5 identifying information related to subjects
6 enrolled in the trial. But that would be the
7 extent of it, yes.
8 283 Q. Okay. Other than that everything
9 else would have been reproduced online that you
10 know of?
11 A. It should be, yes. It should be
12 online.
13 284 Q. You mentioned that Pfizer's study was
14 a two-year study and Moderna study was designed
15 as a one-year study. Do you know why Moderna
16 decided to use a one-year study and why Pfizer
17 decided to use a two-year study?

18 A. I don't know why, no. I don't know
19 why the differences between the two.
20 285 Q. Did you ever ask them?
21 A. I don't know if my team asked them.
22 286 Q. I take it that individuals from your
23 team are in touch with the relevant individuals
24 from Pfizer, Moderna, and AstraZeneca that did
25 the studies, correct?

AR09696
1 A. We interact with -- with their
2 regulatory affairs and sometimes with their
3 scientific team, yes, if needed.
4 287 Q. Okay. I would like an undertaking
5 for you to speak with your colleagues to provide
6 an answer as to why certain study -- why Pfizer
7 undertook a two-year study and why Moderna
8 undertook a one-year study?
9 U/A MS. TELLES-LANGDON: We will take it under
10 advisement, Mr. Presvelos.
12 288 Q. So -- okay. The second part of the
13 question that I have here is -- I want to look at
14 paragraph 157, please. And specifically, the
15 last chunk of that paragraph, the last one -- two
16 sentences of paragraph 157.

19 289 Q. Who just hopped on? Anyways -- okay.
20 Doc, you -- you've read those last two sentences;
21 right?
22 A. Yes. Yes, I have.
23 290 Q. Have you ever been involved in
24 supervising an ARR clinical study?
25 A. No, I have not.

AR09697
1 291 Q. Have you ever been involved in
2 designing an ARR clinical study?
3 A. So -- no, I have not. So I'm trying
4 to think about your question. ARR clinical -- so
5 a clinical study where the endpoint is absolute
6 risk reduction is your question?
7 292 Q. Yeah. And where -- and where
8 assessing the efficacy of a vaccine would use
9 absolute risk reduction, yeah, as the main
10 measure of efficacy.
11 A. We don't -- as the regulator we're
12 not involved in designing clinical trials. We
13 review the design of clinical trials proposed by
14 manufacturers, but we don't design them
15 ourselves.
16 293 Q. Okay. When you say here, "The ARR
17 does not properly account for at-risk exposure

18 times to COVID-19 for each clinical trial
19 subject." And you define at-risk exposure time
20 as:
21 "[...] the amount of time the subject who
22 was followed in the clinical trial who
23 starts at the time of randomization and
24 vaccination to the time when the subject
25 is either withdrawn from the study or

AR09698
1 efficacy is assessed at the trial level,
2 whichever comes first."
3 A. Yes.
4 294 Q. Are you saying that ARR does not
5 consider how long an individual was in that
6 particular study? I'm just -- I don't
7 understand. I need to get some clarity in terms
8 of what this criticism actually means of the ARR.
9 A. Right. So ARR -- ARR varies
10 depending on the background exposure rate, the
11 background risk of anyone getting COVID-19. It
12 varies depending on that. And the way the
13 vaccine trial is designed, it's not designed to
14 be able to control for that background exposure
15 rate for that -- for the varying exposure rate in
16 order to be able to measure absolute risk
17 reduction.
18 295 Q. Sorry, which one does not control for
19 the background exposure? ARR or RRR?
20 A. ARR does not control for background
21 exposure rates, yes.
22 296 Q. Okay.
23 A. For both the exposure rate as well as
24 the time a person is at risk of exposure.
25 297 Q. How does RRR control for the time

AR09699
1 someone is at risk for exposure if they are
2 surveillance for different time periods?
3 A. ARR controls for that because it's --
4 it's -- it's a relative -- relative risk
5 reduction. So you're -- you're calculating the
6 risk reduction relative to a control group and by
7 doing that you are controlling for -- for both
8 the background event rate as well as the at-risk
9 time.
10 298 Q. But how do you control for the
11 at-risk time in the RRR group or the RRR study
12 when people are coming and going at different
13 time periods?
14 A. So it's because it's a -- you're
15 comparing it to the control. You're doing a
16 comparison to the control group at opposed to
17 absolute risk reduction where absolute risk

18 reduction taking the proportion of what happens
19 in one group and subtracting it from the other
20 group. There isn't that normalization of -- of
21 being able to compare it to the control group.
22 It's otherwise difficult to explain.
23 Again, biostatistics is not my -- my expertise,
24 so it's -- it's a bit challenging to explain.
25 299 Q. Sorry, is it different to explain

AR09700
1 because it's a complicated subject matter to
2 simplify to me or is it difficult to explain
3 because it's just difficult subject matter given
4 what you do?
5 A. It's a different subject matter for
6 me given that it's not my area of expertise.
7 300 Q. Right. And let's go to paragraph
8 158.
9 A. Yes.
10 301 Q. And in paragraph 158 towards the end
11 of the paragraph it says, "As such, it measures,"
12 and "it," I take it, if you read the paragraphs
13 as RRR -- "...measures the true benefit of the
14 vaccine and is free of limitations associated
15 with ARR given that it properly accounts to the
16 underlying COVID-19 event rates, as well as the
17 at-risk exposure time."

18 So what do you mean by the "true benefits
19 of the vaccine"?
20 A. It's a more accurate measure. It's a
21 more accurate measure of the vaccine given that
22 it's not impacted -- affected by -- by the bias
23 that can be introduced when the two different
24 groups have different underlying event rates and
25 the two different groups have different at-risk

AR09701
1 exposure times as well. The participants in the
2 different groups have -- may have different
3 at-risk exposure times.
4 So it -- because it is free from those
5 limitations it is a more accurate way of
6 measuring vaccine efficacy.
7 302 Q. So it's a more accurate way of
8 measuring vaccine efficacy. And the vaccine
9 efficacy we're talking about is the vaccine
10 efficacy in proportion to these two groups?
11 A. The relative risk reduction.
12 303 Q. Right.
13 A. Yeah.
14 304 Q. Which is a proportional analysis
15 here?
16 A. Right.
17 305 Q. Okay. Let's go to one of the

18 articles I gave you which is the "COVID-19
19 vaccine efficacy and effectiveness——the elephant
20 (not) in the room."
21 A. Yes.
22 306 Q. I'm going to put it on the screen.
23 Okay. This is a comment from The Lancet. I take
24 it this isn't the first time you've reviewed The
25 Lancet or articles from The Lancet; correct?

AR09702
1 A. Correct, yes.
2 307 Q. And I take it you would agree with me
3 that The Lancet is an authority. It's
4 authoritative scholastic academic resource or
5 publication; correct?
6 A. I don't really have an opinion on it
7 in terms of what it's -- whether The Lancet is
8 considered a prestigious journal at this point or
9 not. I just haven't looked into that recently.
10 308 Q. Do you have any reason to believe
11 that it's some sort of a fringe publication?
12 A. Not at this point.
13 309 Q. Okay. So this article discusses some
14 of the limitations simply looking at relative
15 risk reduction to the exclusion of absolute risk
16 reduction. And I take it you agree with me
17 that's what it does?

18 A. Right, yes.
19 310 Q. And I -- and you had the chance to
20 review this article?
21 A. Yes, I did review it.
22 311 Q. Okay. So if we look -- and can you
23 see where I'm highlighting by the way?
24 A. I can. I can see it, yes.
25 312 Q. So it's the bottom of the first page

AR09703
1 on the left-hand side adjacent to the -- this
2 graph here; right?
3 A. Okay.
4 313 Q. Figure -- to the figure on the
5 right-hand side. And so it says:
6 "Ranking by reported efficacy gives
7 relative risk reductions of 95 percent for
8 Pfizer-BioNTech, 94 percent for Moderna
9 NIH, 91 percent for Gamaleya," I don't
10 know what that is -- "67 percent for the
11 J&J, and 67 percent for the AstraZeneca-
12 Oxford vaccines."
13 Right?
14 A. Yes, I see. I read that.
15 314 Q. Right. And as we've established
16 earlier, these percentages doesn't actually mean
17 that Pfizer reduces your risk of COVID-19 by 95,

18 and it also doesn't mean that Moderna reduces
19 your risk of getting infected with COVID by
20 94 percent, so on and so forth; right?
21 A. Right. The individual's risk, yes.
22 315 Q. Right. Individual -- yeah, in any
23 particular age category?
24 A. Right.
25 316 Q. At the bottom it says:

AR09704
1 "ARRs tend to be ignored because they give
2 a much less impressive effect size than
3 RRRs." And it says, "1.3 percent for the
4 AstraZeneca-Oxford, 1.2 percent for the
5 Moderna NIH, 1.2 percent for the J&J,
6 .93 percent for Gamaleya, and 0.84 percent
7 for Pfizer-BioNTech vaccine."
8 Right?
9 A. Yes, I see that.
10 317 Q. So and you agree with me that both
11 RRR and ARR are two different methods of
12 calculating, understanding, and communicating the
13 efficacy of a vaccine."
14 A. They are two different ways of
15 measuring risk reduction; however, the ARR is not
16 recommended for vaccines because of the way
17 vaccine trials are designed. They're not

18 designed in order to be able to accurately
19 measure ARR.
20 318 Q. Okay.
21 A. They're designed for relative risk
22 reduction.
23 319 Q. So what's missing from the design of
24 these studies such that you could not accurately
25 determine ARR?

AR09705
1 A. Let me see if I can explain it in a
2 different way.
3 320 Q. Sure.
4 A. But the way -- so it's because of the
5 differences in exposure rate and -- and both the
6 -- the differences in the exposure rates,
7 incidents of COVID in the community, as I
8 mentioned, as well as the differences in how long
9 subjects were followed and therefore were at risk
10 of getting COVID.
11 In a vaccine trial which is a preventative
12 design, there are differences as I would have
13 talked about already in terms of when subjects
14 are enrolled and also which communities they come
15 from because there are -- there will be
16 differences in the incidents of COVID-19 in
17 different communities. And that makes it

18 difficult to establish ARR. ARR will vary
19 depending on the background incidence rate. And
20 this article -- I think it's this one or the
21 other one, one of the other ones talks about
22 that.
23 Contrast that to a different trial design
24 where all subjects have COVID, and you want to
25 treat half of them with a treatment and then

AR09706
1 treat the other half with a placebo. In that
2 setting, I mean, you're trying to treat them in
3 order to prevent hospitalization. In that
4 setting, you can more accurately measure ARR
5 because everyone is already exposed. Everyone
6 has already the virus whether you're in the
7 placebo group or you are in the control group.
8 And now you treating one group with a treatment
9 and then trying to prevent hospitalization. So
10 in that setting you are able to control for
11 exposure because everyone's been exposed.
12 So that's a different setting than in the
13 vaccine setting where you're trying to prevent
14 acquisition of the virus in the first place and
15 the -- the background variables around incidence
16 rates in the community and how long subjects are
17 followed with impact on the accuracy of the ARR.

18 321 Q. So basic...
19 A. I don't know if that kind of explains
20 it.
21 322 Q. No, I'm lost. But based on what
22 you've told me is there -- are you therefore
23 saying -- is the conclusion I'm supposed to take
24 from that is basically design studies and what
25 you would have expected to see in a study that

AR09707
1 would have -- that predominantly relies on an ARR
2 metric of vaccine efficacy, are you saying
3 therefore that these ARR figures may not be
4 accurate?
5 A. Yes, I'm saying that these ARR
6 figures reported in this Lancet article are --
7 are not to be relied upon because of inherent
8 bias in these figures.
9 323 Q. When you say "bias," what do you mean
10 by bias?
11 A. I mean that we're not able to control
12 for important factors that affect absolute risk
13 reduction, such as the incident rate in the
14 community and the at-risk exposure times. The
15 length of the time that the subjects were
16 followed in the trial.
17 324 Q. And those factors could skew the

18 data?
19 A. Those factors can skew the data with
20 regards to ARR.
21 325 Q. And what factors can skew the data
22 with respect to relative risk reduction?
23 A. With regards to relative risk
24 reduction, there isn't this concern because we're
25 able to control for these important variables

AR09708
1 with relative risk reduction when doing the
2 calculation for relative risk reduction
3 controlling -- control -- doing that comparison
4 to the control group.
5 326 Q. Okay. If you scroll down to the
6 second page in The Lancet.
7 A. Yes.
8 327 Q. Do you see where I've highlighted
9 here. It starts at the third sentence.
10 A. Right.
11 328 Q. And it says:
12 "When communicating about vaccine
13 efficacy, especially for public health
14 decisions such as choosing the type of
15 vaccine to purchase and deploy, having a
16 full picture of what the data actually
17 shows is important, and ensuring

18 comparisons are based on the combined
19 evidence that put vaccine trial results in
20 context and not just looking at one
21 summary measure, is also important."
22 Do you see that there?
23 A. Yes, I see that.
24 329 Q. And do you agree with me what they're
25 saying here is it's important to look both at

AR09709
1 relative risk reduction and absolute risk
2 reduction to get that full picture?
3 A. Well, I -- as I've mentioned, there
4 are limitations to absolute risk reduction.
5 330 Q. No, I'm sorry. Sorry, Doc, I'm just
6 saying, do you agree that's what this paragraph
7 is saying here in The Lancet?
8 A. I agree that's what the paragraph is
9 saying, yes.
10 331 Q. Okay. And do you --
11 MS. TELLES-LANGDON: But, Mr. Presvelos,
12 please allow Dr. Lourenco to finish.
13 MR. PRESVELOS: No. I'm going to allow
14 Dr. Lourenco to finish when she's responding to
15 the question. I'm not going to allow
16 Dr. Lourenco to harangue me here with a bunch of
17 information in response to questions I haven't

18 asked. That's not how cross-examination work.
19 MS. TELLES-LANGDON: Mr. Presvelos --
20 MR. PRESVELOS: So I -- if I --
21 MS. TELLES-LANGDON: Mr. Presvelos,
22 Dr. Lourenco is allowed to say yes, that's what
23 this study says but -- and provide her
24 understanding or clarification with respect to
25 what that study says. That's entirely

AR09710
1 appropriate answer to the question you asked.
2 MR. PRESVELOS: It is if that's what she
3 had done. She started off by telling me about
4 other considerations, not whether or not that's
5 what the study says.
6 332 Q. So if you want to start off by first
7 answering my question and then qualifying your
8 answer or adding context to your answer, that's
9 fine. But it's important that you begin with a
10 direct answer to my question rather than give me
11 context, a bunch of your opinions and then answer
12 my question. You're going to confuse me.
13 So my question is do you agree with the
14 statement that's being made in The Lancet with
15 respect to having a full context when
16 communicating about the efficacy of vaccines like
17 COVID-19?
18 A. Is your question whether I agree that
19 that's what's written in The Lancet or whether I
20 agree with that statement?
21 333 Q. I don't need you to confirm what I
22 can see. I need you to confirm whether or not
23 you agree with the sentiment or the proposition
24 that is being outlined in this paper.
25 A. I agree with the sentiment as long as

AR09711
1 the data that it -- or the measures that are
2 being reported are -- are accurate. That there
3 are no -- that concerns around bias can be
4 addressed.
5 334 Q. Okay. So I would like to enter this
6 -- this -- this article, this comment from The
7 Lancet as an exhibit.
9 EXHIBIT NO. 1: Article from The Lancet
11 335 Q. And if I can take you to another
12 article that was produced over the break. I'm
13 going to put that on the screen. This article is
14 "Outcome Reporting Bias in COVID-19 mRNA Vaccine
15 Clinical Trials," from Ronald B. Brown.
16 A. Yes.
17 336 Q. I think this individual is from

18 Public Health, the faculty University of
19 Waterloo. I take it that you've had the chance
20 to review this periodical or this journal; right?
21 A. Yes, I had a chance to review this
22 article.
23 337 Q. Okay. Do you need any more time to
24 review?
25 A. No.

AR09712
1 338 Q. Okay. If we go down to discussion
2 which I'm putting -- which I'm putting -- which
3 I've highlighted for you --
4 A. Okay.
5 339 Q. -- on page six of eight. It says:
6 "Medical and public health experts
7 continue to stress the need to include
8 measurements of absolute risk reduction
9 and numbers needed to treat when reporting
10 results of clinical intervention.
11 Currently, differences between relative
12 effect measures and absolute effect
13 measures in studies are 'poorly understood
14 by health professionals, and even more
15 poorly understood by patients.'"
16 If you go further down here:
17 "Reporting relative measures may be

18 sufficient to summarize evidence of a
19 study for comparison with other studies
20 but absolute measures are also necessary
21 for applying study findings to specific
22 clinical or public health circumstances."
23 Do you agree with this proposition or with
24 this sentiment?
25 A. I -- I -- I agree with the sentiment

AR09713
1 to report on measures that can be accurately
2 established as long as biases and other
3 considerations can be controlled for.
4 340 Q. And those are the biases that you
5 previously mentioned at page 157?
6 A. Yes.
7 341 Q. But I understand that those biases
8 from your perspective are inherent in any ARR
9 calculation.
10 A. They are inherent in vaccine trial --
11 342 Q. Right.
12 A. -- ARR calculations because of the
13 way vaccine trials are designed.
14 343 Q. So given what you've just said, it's
15 probably not -- you wouldn't accept this
16 proposition in the context of a COVID-19 vaccine
17 trial?
18 A. I would not accept it in the context
19 of a COVID-19 vaccine trial, no.
20 MR. PRESVELOS: Okay. I would like to
21 enter this as an exhibit.
23 EXHIBIT NO. 2: Outcome reporting bias in
24 COVID-19 mRNA vaccine clinical trials,
25 Ronald B. Brown

AR09714
1 COURT REPORTER: That's fine.
2 (Reporter appeals)
5 BY MR. PRESVELOS:
6 344 Q. Doc, I just want to confirm a couple
7 of things. We're back on the record; right?
8 COURT REPORTER: Yes.
9 BY MR. PRESVELOS:
10 345 Q. Okay. I just want to confirm a
11 couple of things. I take it that at no point in
12 time since we started our cross-examination today
13 have you spoken to anyone about the questions
14 I've asked or the answers you've given me,
15 subject to sort of general questions you may have
16 asked your lawyer about this process?
17 A. Correct, I haven't spoken to anyone.

18 346 Q. All right. And do you have any notes
19 in front of you that you're relying on throughout
20 this cross-examination?
21 A. No. I'm just relying on my
22 affidavit.
23 347 Q. Right. So is there any -- other than
24 your affidavit, there are no other materials in
25 front of you?

AR09715
1 A. No.
2 348 Q. Okay. Where did we leave off? So
3 you mentioned to me that you believe based on the
4 fact that clinical trial designs are designed in
5 a way to use RRR to assess vaccine efficacy, the
6 ARR numbers would not be accurate.
7 When we look at the ARR figures and we saw
8 in -- let me -- let me open up the particular
9 article. So when we look at the ARR figures from
10 that Lancet article that we saw, right, together,
11 and it says --
12 A. Lancet, yes.
13 349 Q. -- yeah. And it says -- it says --
14 one second. It says, for example, that the
15 absolute risk reduction for the Pfizer vaccine is
16 .84.
17 A. Yes, I saw that. Yes.

18 350 Q. What do you understand that .84 to
19 mean?
20 A. So what I understand it to mean is --
21 is that's the risk reduction for -- if -- if it
22 were an accurate assessment and an accurate
23 measure, if we could rely on absolute risk
24 reduction, this would mean the risk to an
25 individual who takes the vaccine, it would reduce

AR09716
1 their risk by .84 percent.
2 351 Q. So if I had a one percent risk of
3 getting -- of being infected with COVID-19 and I
4 took a Pfzier-BioNTech vaccine, I can expect
5 based on the ARR .84 that it would reduce -- it
6 would minimize that risk by .84?
7 A. That's my understanding.
8 352 Q. Okay. Go to page 42 of your
9 affidavit.
10 A. Okay.
11 353 Q. You state that "a number of
12 individuals infected with COVID-19 will remain
13 asymptomatic."
14 A. Which paragraph is that?
15 354 Q. Para 42. Paragraph 42.
16 A. Oh, 42. Sorry, I understood page 42.
17 355 Q. No, no, sorry. Paragraph 42, page

18 13.
19 A. Paragraph 42. Yes, okay.
20 356 Q. Okay.
21 A. I see that.
22 357 Q. And are asymptomatic COVID-19 -- are
23 individuals who have COVID-19 that are
24 asymptomatic, are they less likely, more likely,
25 or equally likely to transmit COVID-19 as a

AR09717
1 symptomatic carrier.
2 A. I don't have the latest on -- on
3 that.
4 358 Q. Based on what you've read in the
5 past, what is your understanding?
6 A. I think it depends on the variants of
7 concern. But I don't want to comment because I
8 don't want to say something that's not accurate.
9 359 Q. So paragraph 43, please.
10 A. Yes.
11 360 Q. You said, "COVID-19, like any virus,
12 changes through mutation and new variants of the
13 virus appear"; right?
14 A. Right.
15 361 Q. Give me a second to turn this. And I
16 take it that you would agree with me that each
17 variant of concern represents a mutation in the

18 virus, right, of the ancestral COVID-19?
19 A. Yes. So -- yes, each variant of
20 concern has mutations in relation to the
21 ancestral strain from Wuhan.
22 362 Q. And the vaccine doesn't prevent the
23 SARS-CoV-2 virus from mutating, does it?
24 A. So the vaccine itself doesn't prevent
25 the SARS-CoV-2 from mutating, correct. But it is

AR09718
1 understood or it is expected that with -- if
2 you're able to reduce the number of infections
3 because you have vaccination which reduces the
4 number of infections, you're also able to reduce
5 the chance that the virus will mutate. If the
6 virus needs a host, needs to be able to infect
7 people and have an opportunity to mutate through
8 infection.
9 If you reduce the number of infections
10 then you reduce the opportunity for the virus to
11 mutate.
12 363 Q. So more vaccines mean fewer
13 infections, fewer infections mean less
14 opportunity to mutate thereby decreasing the
15 chance of mutation, thereby decreasing the
16 likelihood you're going to have a subsequent VOC?
17 A. Right, yes.
18 364 Q. Okay. That makes sense. And is it
19 your position today that the COVID-19 vaccines
20 are highly effective at reducing infections of
21 COVID -- SARS-CoV-2 and the particular variant of
22 concerns that we find ourselves in which is
23 Omicron?
24 A. So no, the current vaccines are not
25 highly effective against Omicron infection.

AR09719
1 365 Q. Right.
2 A. But they -- they continue to have
3 effectiveness as we talked about earlier against
4 severe disease.
5 366 Q. Right. But earlier as it relates to
6 the VOC discussion, what we're looking at is not
7 the development of severe disease. As you
8 mentioned, what we're looking at is the number of
9 infections because it's the prevalence of
10 infection that determines the likelihood of
11 mutation; correct?
12 A. That would be a factor. Now -- yes.
13 So the prevalence of infection will give the
14 opportunity for mutation. Now, whether does it
15 change with severe disease? Is it worse with
16 severe disease? That I -- that I don't know, so
17 -- yes, I'll just leave it at that.

18 367 Q. And have you looked at recent
19 infection rates in Canada's provinces or across
20 the country based on vaccination status?
21 A. I have that in my affidavit. I don't
22 have it off the top of my head, but it's in my
23 affidavit.
24 368 Q. Right. And would you agree with me
25 that there are either the same number or more

AR09720
1 individuals who are infected with COVID-19 now
2 who are vaccinated, infected? Not hospitalized
3 or dying. But there are more individuals who
4 have the COVID-19 vaccine even on a per hundred
5 thousand population that are infected than those
6 who are unvaccinated. Would you accept that?
7 A. Well, currently -- in terms of
8 currently? I'd --
9 369 Q. Yeah.
10 A. -- I'd have to look at the data.
11 370 Q. Okay.
12 A. I don't know if we have that here.
13 I'll just take a look quickly at the data.
14 371 Q. I can save you some time if you like.
15 I can put it on the screen.
16 A. Yes. If you have the --
17 372 Q. I will. Sure, I'll put it because I

18 know what source you're -- so I'll just put it on
19 the screen here for you.
20 A. Right. Okay.
21 MS. TELLES-LANGDON: Which page?
23 373 Q. You recognize this; right?
24 A. Yes, I recognize that.
25 374 Q. And this is -- I'm just going to be

AR09721
1 fair, this is health-infobase.canada.ca/covid19/
2 epidemiological/summary.covid/19-cases and some
3 technical stuff after. Yeah, this is the same
4 exhibit -- I think it's somewhere towards the end
5 of your affidavit -- of your affidavit. And
6 figure five says, "Distribution of confirmed
7 COVID-19 cases reported to PHAC by vaccination
8 status as of May 15, 2020 [sic]."
9 Right?
10 A. Yes.
11 375 Q. Okay.
12 MS. TELLES-LANGDON: Can you make that
13 larger on the screen, Mr. Presvelos?
14 MR. PRESVELOS: You know what, I mean
15 honestly I can't because I don't know how to
16 manipulate the zoom on my screen. I can Google
17 it.
18 MS. TELLES-LANGDON: Are you on a MAC or a
19 PC?
20 MR. PRESVELOS: MAC. So control, press
21 and hold control key plus. Hold on a second.
22 Control key.
23 MS. TELLES-LANGDON: On a MAC it's not the
24 control key, it's other key that --
25 MR. PRESVELOS: Command. Ah, oh, you're

AR09722
1 good. Okay.
2 376 Q. Doc, is this better?
3 A. Yeah, I can see it.
4 377 Q. Okay. So there's three categories
5 here: One is the category of cases, one is
6 hospitalizations, and the other category is
7 deaths; correct?
8 A. Yeah, I see that.
9 378 Q. And when we -- when we look at cases,
10 I take it what we're saying is how many people
11 are infected with COVID-19; right?
12 A. Yes, how many people are infected.
13 379 Q. Okay. And we see here based on the
14 information presented to us from the federal
15 government, we see that unvaccinated is 44.5
16 percent of cases; right?
17 A. Right.
18 380 Q. And we see fully vaccinated is 34.4
19 percent of cases; right?
20 A. Right.
21 381 Q. And we see that fully vaccinated with
22 an additional dose, so a booster, is 14.3 percent
23 of cases; right?
24 A. Right, yes.
25 382 Q. Okay. So would you agree with me

AR09723
1 that if you add the fully vaccinated plus those
2 who have an additional layer of protection, they
3 actually represent a larger percent of the cases
4 in individuals who are not vaccinated?
5 A. So the way we have to look at these
6 data --
7 383 Q. Mm-hmm.
8 A. -- is that this is accumulated data
9 over time, and so over time we have more and more
10 people vaccinated in Canada. We've got a high
11 proportion of people vaccinated. And so when you
12 look -- when you start measuring the percentage
13 of cases because you've got so many people
14 vaccinated, you will see the -- an increase in
15 percentage of people with COVID in the vaccinated
16 group versus the unvaccinated.
17 384 Q. Okay. Do you know what the -- do you

18 know what the adjusted rate of the vaccination
19 would be? Or the adjusted rate of cases in the
20 population would be like on a per 100,000
21 population level?
22 A. I --
23 MS. TELLES-LANGDON: Mr. Presvelos, I'm
24 assuming it's probably on that key.
25 MR. PRESVELOS: No, it's not. It's not.

AR09724
1 But let's just give me a second.
2 385 Q. So let's look at -- we will look at
3 this figure because as you'll see it actually
4 doesn't change anything. So this here is from
5 the province of Ontario. And you'll see it up
6 here. It's data on COVID-19 vaccine; right. And
7 it's COVID-19.Ontario.ca. Right? I take it,
8 Doc, this isn't the first time you visited this
9 website; right?
10 A. I don't think I've visited this
11 website.
12 386 Q. You've never seen the COVID-19 data
13 published by the Ontario government on the
14 Ontario's government website before?
15 A. No. I usually look at the -- at the
16 federal government website for these data.
17 387 Q. I take it you understand that all the

18 data from the federal government is actually
19 pulled from the provincial governments?
20 A. Yeah, I understand that that's the
21 case. Yes.
22 388 Q. Okay. So all the federal government
23 is the doing is aggregating the data that it
24 takes from each of the individual provinces and
25 territories; correct?

AR09725
1 A. Yes, that's my understanding.
2 389 Q. In other words, the federal
3 government does not have its own independent data
4 source?
5 A. Right. They get their data from the
6 provinces, yes.
7 390 Q. Right, okay. So if we look here at
8 COVID-19 cases by vaccination status in the past
9 90 days, or I take it you will agree with me that
10 a substantial majority of the Canadian population
11 is vaccinated; correct?
12 A. Yes.
13 391 Q. Right. It's over 80 percent
14 vaccination at this point; correct?
15 A. Yeah, over 80 percent. Yes.
16 392 Q. Okay. So in the last 90 days, do you
17 agree with me that the -- on a -- consistently we

18 see more vaccinated individuals having -- being
19 infected with COVID-19 across all age categories?
20 Do you agree that this is what this chart shows
21 us?
22 MS. TELLES-LANGDON: And again,
23 Mr. Presvelos, can you make that larger, please?
24 MR. PRESVELOS: Sorry?
25 MS. TELLES-LANGDON: Could -- would you

AR09726
1 make that larger, please?
2 MR. PRESVELOS: Yeah, yeah, give me a
3 second.
4 393 Q. So let's just -- let me just take you
5 through this here. So this is COVID-19 cases by
6 vaccination status. This is a graph. There's
7 different options. You can look at the past
8 90 days. You can look at other days. We can do
9 that too. There's different age categories.
10 I've selected all ages, right, and there's
11 different colours. The green is vaccinated with
12 booster; this light pink or pink, whatever, is
13 fully vaccinated, right; and the not fully
14 vaccinated cases are in purple.
15 And this is -- this is the vaccination --
16 this is the -- this is the infection rate per
17 hundred thousand. So it's the average rate

18 COVID-19 cases per hundred thousand for each
19 vaccination status.
20 A. Okay.
21 394 Q. You agree with me that based on this
22 figure, it seems to suggest that the vaccine --
23 that the infection rate is actually higher among
24 vaccinated individuals with booster doses, and
25 it's either the same or at times -- or very close

AR09727
1 to the same between fully vaccinated and not
2 fully vaccinated cases?
3 A. That seems to be what is -- what it
4 is suggesting, but I don't know the background to
5 these data, how they were collected. Is it --
6 are there limitations in the data. So I -- I
7 wouldn't be able to confidently interpret this
8 graph without -- without having more information.
9 395 Q. Sure. So what I would like is -- I'm
10 going to send you a link of this -- of this data
11 set from the provincial government, and I would
12 like an undertaking for you to indicate whether
13 you accept these figures as accurate or
14 inaccurate representation of the number of
15 infections in the Ontario population in the past
16 90 days based on vaccination status.

18 advisement, Mr. Presvelos.
19 (Reporter appeals)
20 MS. TELLES-LANGDON: I'm sorry. I'll
21 speak more loudly. We'll take that under
22 advisement.
24 396 Q. Dr. Lourenco, do you have any idea as
25 to how doctors were treating COVID-19 patients at

AR09728
1 the outset of the pandemic?
2 A. No. It's not something I can
3 confidently speak to.
4 397 Q. So you would not know whether or not
5 there'd been any changes at the clinical level in
6 terms of how COVID-19 was managed and treated by
7 our hospitals; right?
8 A. I wouldn't be privy to that
9 information. I wouldn't want to comment on it.
10 398 Q. Right. Let's go to paragraph 53 of
11 your affidavit.
12 A. Yes.
13 399 Q. And in here you talk about the
14 Federal, Provincial, Territorial Public Health
15 Response Plan for Ongoing Management of COVID-19;
16 right?
17 A. Yes.
18 400 Q. And you talk about the goal of
19 Canada's COVID-19 pandemic response; right?
20 A. Yes.
21 401 Q. Did you contribute to this paper at
22 all? The Federal, Provincial, Territorial Public
23 Health Response Plan for Ongoing Management of
24 COVID-19?
25 A. No, not at all.

AR09729
1 402 Q. Were you consulted in any way, shape
2 or form for this paper?
3 A. No, I wasn't.
4 403 Q. Okay. Were you involved in any way
5 in establishing Canada's COVID-19 pandemic
6 response?
7 A. No, I was not.
8 404 Q. The last sentence on this page on
9 page 16, it says:
10 "The clinical measure to determine whether
11 a vaccine continues to provide benefits
12 and should therefore remain on the market,
13 is how well the vaccine prevents severe
14 COVID-19 disease and deaths in real world
15 use."
16 A. Yes.
17 405 Q. So what I find interesting is --

18 is -- it seems to me you're saying, I mean, the
19 way you decide whether this thing is going to
20 continue to be on the market is whether it
21 actually prevents people from dying and how --
22 and to what degree it prevents people from dying
23 of COVID-19. And you say "prevents severe
24 COVID-19 disease."
25 How would you define "severe COVID-19

AR09730
1 disease"?
2 A. This generally is defined as disease
3 that causes difficulty breathing, often the
4 patient will need to be hospitalized, sometimes
5 admitted to the -- to the intensive care unit.
6 So it's that kind of disease that is -- is
7 causing severe symptoms and often needing
8 hospitalization.
9 406 Q. And what do you -- what information
10 are you -- are you basing that understanding of
11 severe COVID-19 disease from?
12 A. So it was defined for the clinical
13 trials that were conducted. It was defined
14 generally along those terms that I just
15 mentioned.
16 407 Q. Right. So if that's the metric for
17 deciding whether to keep a vaccine in the market,

18 why is that not the same metric for deciding
19 whether to approve a vaccine?
20 A. It has to do with -- with how vaccine
21 clinical trials are designed. They're designed
22 for detecting first whether the vaccine can
23 prevent infection. So that -- especially in the
24 context of a pandemic, we needed to make sure
25 that we could conduct the clinical trials in a

AR09731
1 reasonable amount of time in order to be able to
2 assess the vaccine's efficacy. And if we had to
3 do that on the basis of severe disease, it would
4 take -- it would take much longer. It would take
5 much longer to enroll a sufficient number of
6 individuals with severe disease in order to be
7 able to assess the efficacy of the vaccine.
8 So relying on infection as an endpoint
9 allows for quicker conduct of the trial in the
10 context of a pandemic where we needed to assess
11 vaccine efficacy. And also we know that
12 prevention of infection of mild to moderate
13 symptoms correlates with being able to prevent as
14 well severe disease based on what we know about
15 the vaccines.
16 408 Q. But the vaccines have now been out
17 for more than a year in the general population;

18 right?
19 A. Yes.
20 409 Q. So the time pressure that you're
21 talking about at the outset of the pandemic is
22 not to the same time pressure that exists today
23 in terms of understanding the vaccine's efficacy
24 on preventing severe disease and deaths; right?
25 A. Well, the time pressure is not the

AR09732
1 same in the sense that we now have options.
2 Certainly, we have options on the market. We now
3 do have vaccine options, yes.
4 410 Q. Okay. And so why is there not a
5 threshold that's developed to assess whether or
6 not these vaccines, now that they've been out for
7 so long meet -- why is there no threshold against
8 which you assess how effective they are at
9 preventing severe COVID-19 disease and deaths?
10 A. It's -- it's the -- if -- if we -- so
11 if we were to design a trial that requires data
12 as an endpoint, it would certainly end up being
13 quite a very large -- a very large trial, and it
14 would take a long time to conduct. So,
15 generally, for infectious diseases what we look
16 at is the ability of the vaccine to prevent
17 infection.
18 These trials are still quite large. It's
19 tens of thousands of individuals to assess
20 vaccine efficacy and within a reasonable amount
21 of time to be able to answer that question.
22 411 Q. Okay. Can you please go to paragraph
23 60 of your affidavit?
24 A. Yes.
25 412 Q. Just take a second to read that --

AR09733
1 read that section or read that sentence. So you
2 say, "Vaccinations are the most effective ways to
3 protect families, communities, and individuals
4 against COVID-19."
5 What do you mean by "protect"? Is it
6 protect against infection? Protect against
7 severe illness requiring hospitalization? Or
8 protection against death, or all three of them?
9 A. Yes, it's -- it's all three. It's
10 protect -- protect against infection, against
11 severe disease, against hospitalization. Yes.
12 413 Q. Have you reviewed any literature on
13 the protected effects that natural immunity might
14 have on COVID-19 infection?
15 A. We -- my team has reviewed --
16 reviewed that as part of our -- as part of our
17 general monitoring of the literature.

18 414 Q. Have you reviewed literature on the
19 protective effects of natural immunity?
20 A. I have not -- I have not. I don't
21 have sort of a sense in my mind at the moment
22 to -- to speak to that.
23 415 Q. Do you know how much more effective,
24 if at all, immunity from a vaccine is over
25 natural immunity for any given variant of

AR09734
1 concern?
2 A. I don't have that information at this
3 point, no.
4 416 Q. Have you ever reviewed such
5 information?
6 A. Not -- I can't really speak to it
7 confidently.
8 417 Q. Okay. Can you please take a look at
9 page 62 of your affidavit?
10 A. Paragraph 62 or page?
11 418 Q. Yeah, sorry, sorry, sorry. Paragraph
12 62. Yeah, I'm sorry.
13 A. Okay. Yes.
14 419 Q. So with respect to the protective
15 effects of the vaccines you authorized on any --
16 on either the current or the previous variants of
17 concern, but I think in this case you're talking

18 about Delta. You said prior to the emergence of
19 Omicron. Okay. So with respect to the previous
20 variants of concern, what was the longest time
21 period that the vaccine's protective effect had
22 been followed or studied for?
23 A. Ever since the -- the initial rollout
24 of the vaccines. So in Canada it was in December
25 of 2020 when we first rolled out the vaccine. So

AR09735
1 we've been monitoring it since then.
2 420 Q. So are you still monitoring the
3 protective effect of ancestral SARS-Cov-2?
4 A. We don't have the ancestral
5 SARS-Cov-2 circulating in Canada at the moment.
6 It's the Omicron -- Omicron variant of concern
7 and its subvariants. But we monitor the
8 literature in terms of vaccine effectiveness
9 against -- against that circulating variant at
10 the moment.
11 421 Q. Is Delta still circulating in the
12 Canadian population?
13 A. Not based on the surveillance data
14 from the Public Health Agency. It seems to be
15 all Omicron at this stage.
16 422 Q. And had you -- and had you reviewed
17 literature that considered the effect -- the

18 vaccine's effect -- the vaccine's protected
19 effect as against Delta from the minute -- or
20 from the moment Delta was recognized as
21 circulating in the general population to the
22 moment it was replaced by Omicron?
23 A. So yes, we monitor the literature
24 when the Delta variant emerged. We monitored it
25 -- monitored the -- any information that emerged

AR09736
1 on vaccine effectiveness until it was -- until it
2 was Omicron that took over.
3 423 Q. Right. And what did you notice about
4 the vaccine's effectiveness as against preventing
5 transmission during that time period?
6 A. I'm aware that -- that there was
7 evidence to suggest that it prevents
8 transmission. But this is based on post-market
9 studies and information from the Public Health
10 Agency. I don't have, sort of, the details of
11 that information.
12 424 Q. Okay. At the bottom of page 62, you
13 say:
14 "Individuals who are fully vaccinated with
15 AstraZeneca," -- sorry -- "with a viral
16 vector vaccine had moderate levels of
17 vaccine protection and were less likely to

18 experience symptomatic illness caused by
19 most variants of concern and were less
20 likely to spread COVID-19 to others."
21 So in other words, they were less likely
22 to transmit COVID-19 to others; correct?
23 A. Yes.
24 MS. TELLES-LANGDON: Just for the sake of
25 the record, Mr. Presvelos said page 62, but I --

AR09737
1 MR. PRESVELOS: Paragraph 62. Thank you.
2 MS. TELLES-LANGDON: Thank you.
3 BY MR. PRESVELOS:
4 425 Q. What are you relying on for that
5 conclusion?
6 A. That is from -- that conclusion is
7 from Public Health Agency.
8 426 Q. What exhibit can I find as a
9 conclusion in your affidavit?
10 A. I don't think I have an exhibit
11 speaking to that.
12 427 Q. Okay. If you look at paragraph 63 of
13 your affidavit --
14 A. Yes.
15 428 Q. -- you indicated that letters were
16 sent by Health Canada to address the potential
17 risk brought by Omicron; right?

18 A. Yes.
19 429 Q. Including the effectiveness of the
20 vaccine against Omicron; right?
21 A. Yes.
22 430 Q. And you say "all manufacturers
23 responded with initial plans"; right?
24 A. Yes.
25 431 Q. Are those initial plans available to

AR09738
1 the public?
2 A. No.
3 MR. PRESVELOS: Okay. So I would like an
4 undertaking for the plans that have been
5 submitted to the government from these various
6 pharmaceutical companies, please?
7 U/A MS. TELLES-LANGDON: We will take that
8 under advisement.
9 BY MR. PRESVELOS:
10 432 Q. And you say "manufacturers are
11 working on studies to assess vaccine
12 effectiveness and final results will be provided
13 when available."
14 A. Yes.
15 433 Q. Have any of these final results been
16 produced to you or anyone in your department?
17 A. No.
18 434 Q. Okay. And I take it you agree with
19 me that these variants of concerns can change at
20 any given time; right? It's impossible to
21 predict when you're going to have a new variant
22 of concern.
23 A. It is imposs -- it is difficult --
24 impossible to predict, yes.
25 435 Q. It would be impossible to anticipate

AR09739
1 what the next variant of concern might be?
2 A. Yes. With this virus it's not
3 possible to predict.
4 436 Q. And it's impossible to predict what
5 the next variant of concern might look like in
6 terms of its composition?
7 A. Right.
8 437 Q. But despite this, you -- I understand
9 that manufacturers of these vaccines are still
10 assessing the vaccine effectiveness against
11 Omicron; right?
12 A. Yes.
13 438 Q. And I take it that the -- the reason
14 why they're assessing it is to redesign a new
15 vaccine?
16 A. Yes, the manufacturers -- the
17 manufacturers such as Pfizer and Moderna are

18 working on a redesign of their vaccine.
19 439 Q. Are they working on it or are they
20 still doing research on it?
21 A. They are working -- they've developed
22 redesigned vaccines, and they're testing them in
23 clinical trials.
24 440 Q. And -- okay. So they're redesigning
25 these vaccines, and they're redesigning it as

AR09740
1 against which of the variants?
2 A. There are different -- different
3 ones. So, for example, Moderna and Pfizer are
4 redesigning their vaccine in order to target the
5 Omicron variant, as well as the Wuhan. The
6 original ancestral strain, the Wuhan variant, at
7 the same time. So it's what we call a bivalent
8 vaccine that it will target both of those
9 variants. And Janssen -- not Janseen, sorry --
10 Sanofi is working on a vaccine that targets the
11 beta variance of concern.
12 So different manufacturers are looking at
13 different -- different strategies. Actually,
14 Moderna also has a beta variant vaccine that they
15 have under development.
16 441 Q. And I take it they keep you apprised
17 of where they are in the development of these

18 bivalent vaccines?
19 A. Yes. They -- we do have periodic
20 meetings with them to see where they're at in
21 their development process.
22 442 Q. Right. And based on your current
23 understanding of where they are in their
24 development process, how much longer do you
25 estimate they will need to submit whatever --

AR09741
1 whatever relevant materials you require to
2 authorize these new vaccines?
3 A. It's -- it's based on discussions
4 we've had with -- with the manufacturers, we may
5 be able to have an updated vaccine filed to us
6 end of summer, beginning of fall. That's a
7 possibility. Based -- just based on where
8 they're at in their development plans.
9 443 Q. But, of course, there's no way of
10 knowing what the variant of concerns that may be
11 at the time these vaccinations actually get
12 manufactured; right?
13 A. No, there's no way to know if we're
14 still going to have Omicron in the fall or if
15 it's going to be a new variant of concern.
16 444 Q. And would you agree with me that if
17 these vaccines are developed in reference to the

18 Omicron -- sorry, in reference to the Omicron
19 variant of concern and then we have a subsequent
20 variant of concern, we might see the same problem
21 here, namely the problem of waning immunity;
22 correct?
23 A. That's a possibility just based on --
24 on what we've seen with the current vaccines --
25 with the current vaccine and the variance of --

AR09742
1 and the variant of concern with Omicron. It's
2 possible that there could be. But we're
3 speculating here. We don't know, of course.
4 445 Q. I take it you would agree with me
5 that currently it's not possible to design a
6 vaccine that could protect against all future
7 variants of COVID-19; right?
8 MS. TELLES-LANGDON: We've moved into the
9 realm of quite a bit of speculation.
10 Dr. Lourenco is the regulator, not the
11 vaccine developer.
12 MR. PRESVELOS: Well, Dr. Lourenco needs
13 to know a lot about vaccine development in order
14 to regulate the vaccines. And I don't think it's
15 a --
16 MS. TELLES-LANGDON: She --

18 MS. TELLES-LANGDON: Well, you're asking
19 her to speculate on what might be possible in the
20 future with respect to vaccine development.
22 446 Q. Dr. Lourenco, are you aware of any
23 long-term studies that look at the effects of an
24 mRNA vaccine in the human population?
25 A. The -- the clinical trial that I'm

AR09743
1 aware of are the ones that are referred to in my
2 affidavit. For example, the -- the large
3 phase-three trials that were conducted and are
4 ongoing for both the Pfizer and Moderna vaccine
5 which would -- as I mentioned earlier, would
6 continue for two years, up to two years for the
7 Pfizer and one year for the Moderna. So those
8 are the two clinical trials.
9 And in addition to that we've, of course,
10 been -- been monitoring the safety of the
11 vaccines in the post-market setting since the
12 initial rollout in December for the mRNA vaccines
13 and -- and subsequent to that the other vaccines
14 that were authorized in -- in the spring of 2021.
15 447 Q. Do you agree --
16 A. Sorry, in the winter of 2021.
17 448 Q. Do you agree with me that the

18 COVID-19 vaccines were the first mRNA vaccines
19 you have ever authorized?
21 449 Q. And other than the phase three
22 clinical trials of Moderna, Pfizer, you would
23 agree with me that there are no other long-term
24 studies on the effects of mRNA vaccine in the
25 human population?

AR09744
1 A. Um...
2 450 Q. In other words, let me just be clear
3 what the question is.
4 A. Yes.
5 451 Q. The only study we have with respect
6 to the impacts of an mRNA vaccine in a human
7 population is the study that is ongoing for the
8 COVID-19 vaccines?
9 A. I actually don't know that. I know
10 that mRNA vaccines have been developed for other
11 viruses and would need to take a look and see if
12 there are longer term studies that were done with
13 those other mRNA vaccines. So I can't answer
14 that with certainty.
15 452 Q. So prior to COVID-19 your
16 understanding is there have been mRNA vaccines
17 used in the human population for other viruses?

18 A. Yes, there have been other clinical
19 trials launched for other viruses, yes, with mRNA
20 vaccines.
21 453 Q. Not clinical trials. I want to know
22 whether you believe that mRNA vaccines have
23 actually been used in the human population to
24 combat a disease. Not just in the context of a
25 trial, but in a population generally that might

AR09745
1 be suffering from that disease?
2 A. No, not -- not in the -- not in the
3 population generally, only in the context of
4 clinical trials.
5 454 Q. Right. And I take it you agree with
6 me that there are -- not yet anyways -- there are
7 no studies that look at the health impacts of
8 having repeated an accumulative vaccination of an
9 mRNA vaccine in the human population; right?
10 A. We -- we are monitoring the -- we
11 continue to monitor the safety of the vaccines
12 even through the different booster -- booster
13 administration. So there is a ton of -- a ton of
14 data that's accumulated on the safety of the
15 vaccines even through repeated -- the repeated
16 boosting strategy.
17 455 Q. But monitoring the effects of

18 continuous boosters today cannot tell us what may
19 happen two years from now; right?
20 MS. TELLES-LANGDON: You're asking her to
21 speculate again, Mr. Presvelos.
23 456 Q. Well, do you think we can extrapolate
24 from the impacts of -- or the effects of the
25 booster today what -- how someone's body may

AR09746
1 react to that vaccine many years in the future?
2 A. Well, as I've mentioned earlier, what
3 we know about -- about vaccines is that the vast
4 majority of the adverse events happen within the
5 first two months of vaccination. So we don't --
6 we don't expect long-term safety issues with the
7 vaccines. But as I've mentioned, we -- we are --
8 the companies continue to conduct the clinical
9 trial in monitoring subjects up to -- up to two
10 years and -- and they continue to monitor the
11 safety of the vaccines in the post market.
12 MR. PRESVELOS: Can we just take a break,
13 please?
15 --- Whereupon proceedings adjourned at 3:45 P.M.
16
17
18
19
20
21
22
23
24
25

AR09747
2 REPORTER'S CERTIFICATE
4 I, CAROLINE MASLIN, CSR, Certified
5 Shorthand Reporter, certify;
6 That the foregoing proceedings were taken
7 before me at the time and place therein set
8 forth, at which time the witness was put under
9 oath by me;
10 That the testimony of the witness and all
11 objections made at the time of the examination
12 were recorded stenographically by me and were
13 thereafter transcribed;
14 That the foregoing is a true and correct
15 transcript of my shorthand notes so taken.
16
17 Dated this 8th day of June, 2022.

18
19 CAROLINE MASLIN, CSR
20
21
22
23
24
25

1
AR09748
Comment
COVID-19 vaccine efficacy and effectiveness—the elephant

(not) in the room
Approximately 96 COVID-19 vaccines are at various as 1/ARR. NNVs bring a different perspective: Published Online
April 20, 2021
stages of clinical development.1 At present, we have the 81 for the Moderna–NIH, 78 for the AstraZeneca– https://doi.org/10.1016/
interim results of four studies published in scientific Oxford, 108 for the Gamaleya, 84 for the J&J, and S2666-5247(21)00069-0
journals (on the Pfizer–BioNTech BNT162b2 mRNA 119 for the Pfizer–BioNTech vaccines. The explanation This online publication
has been corrected. The
vaccine,2 the Moderna–US National Institutes of lies in the combination of vaccine efficacy and different corrected version first
Health [NIH] mRNA-1273 vaccine,3 the AstraZeneca– background risks of COVID-19 across studies: 0·9% for appeared at thelancet.
com/microbe on
Oxford ChAdOx1 nCov-19 vaccine,4 and the Gamaleya the Pfizer–BioNTech, 1% for the Gamaleya, 1·4% for June 11, 2021
GamCovidVac [Sputnik V] vaccine)5 and three studies the Moderna–NIH, 1·8% for the J&J, and 1·9% for the
through the US Food and Drug Administration AstraZeneca–Oxford vaccines.
(FDA) briefing documents (on the Pfizer–BioNTech,6 ARR (and NNV) are sensitive to background risk—
Moderna–NIH,7 and Johnson & Johnson [J&J] Ad26. the higher the risk, the higher the effectiveness—as
COV2.S vaccines).8 Furthermore, excerpts of these results exemplified by the analyses of the J&J’s vaccine on centrally
have been widely communicated and debated through confirmed cases compared with all cases:8 both the
press releases and media, sometimes in misleading numerator and denominator change, RRR does not change
ways.9 Although attention has focused on vaccine (66–67%), but the one-third increase in attack rates in the
efficacy and comparing the reduction of the number unvaccinated group (from 1·8% to 2·4%) translates in a
of symptomatic cases, fully understanding the efficacy one-fourth decrease in NNV (from 84 to 64). See Online for appendix
and effectiveness of vaccines is less straightforward
than it might seem. Depending on how the effect size 250 NNV
RRR
100
is expressed, a quite different picture might emerge 95% 94%

91%
(figure; appendix). 90
Vaccine efficacy is generally reported as a relative risk

reduction (RRR). It uses the relative risk (RR)—ie, the 200 80
ratio of attack rates with and without a vaccine—which

is expressed as 1–RR. Ranking by reported efficacy gives 70
67% 67%
relative risk reductions of 95% for the Pfizer–BioNTech,
94% for the Moderna–NIH, 91% for the Gamaleya, 150 60
RRR (%)
NNV
67% for the J&J, and 67% for the AstraZeneca–Oxford

vaccines. However, RRR should be seen against the 119
50
background risk of being infected and becoming ill 108

with COVID-19, which varies between populations and 100 40
over time. Although the RRR considers only participants 81 84

78
who could benefit from the vaccine, the absolute risk 30
reduction (ARR), which is the difference between attack

rates with and without a vaccine, considers the whole 50 20
population. ARRs tend to be ignored because they give 0 0

m h
vid a
.C on
(1 19
5)
(8 A
(1 ac
)
1)
(1 73
)
4)
a much less impressive effect size than RRRs: 1·3% for

A- H
17 S
Co d
22
Co y
21
b2 ec
RN
2.
1 n for
3·1
RN NI
·8
V
m ale
v-
26 ns
·8
12
62 NT
0·
9·
OV
m na–
Ad Joh
Ox Ox
Ga am
T1 Bio
Ad a–
er
the AstraZeneca–Oxford, 1·2% for the Moderna–NIH,

G
n&
BN zer–
Ch nec
od
so
M
Ze
Pfi
hn
1·2% for the J&J, 0·93% for the Gamaleya, and 0·84% for
tra
Jo
As
the Pfizer–BioNTech vaccines. Vaccine (attack rate without vaccine per 1000 exposed)
ARR is also used to derive an estimate of vaccine Figure: RRR and NNV with 95% CI ranked by attack rate in the unvaccinated (placebo) group for five
COVID-19 vaccines
effectiveness, which is the number needed to vaccinate The lower the NNV and the higher the RRR, the better the vaccine efficacy. Details are in the appendix (p 3).
(NNV) to prevent one more case of COVID-19 RRR=relative risk reduction. NNV=numbers needed to vaccinate. NIH=US National Institutes of Health.
www.thelancet.com/microbe Vol 2 July 2021 e279

AR09749
Comment
There are many lessons to learn from the way studies public health relevant questions with a common
are conducted and results are presented. With the use protocol will allow decisions to be made, informed
of only RRRs, and omitting ARRs, reporting bias is by common criteria and uniform assessment. These
introduced, which affects the interpretation of vaccine considerations on efficacy and effectiveness are based
efficacy.10 When communicating about vaccine efficacy, on studies measuring prevention of mild to moderate
especially for public health decisions such as choosing COVID-19 infection; they were not designed to conclude
the type of vaccines to purchase and deploy, having a on prevention of hospitalisation, severe disease, or
full picture of what the data actually show is important, death, or on prevention of infection and transmission
and ensuring comparisons are based on the combined potential. Assessing the suitability of vaccines must
evidence that puts vaccine trial results in context and not consider all indicators, and involve safety, deployability,
just looking at one summary measure, is also important. availability, and costs.
Such decisions should be properly informed by detailed We declare no competing interests.
understanding of study results, requiring access to full Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access
article under the CC BY-NC-ND 4.0 license.
datasets and independent scrutiny and analyses.
Unfortunately, comparing vaccines on the basis of *Piero Olliaro, Els Torreele, Michel Vaillant
piero.olliaro@ndm.ox.ac.uk
currently available trial (interim) data is made even more
Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine,
difficult by disparate study protocols, including primary University of Oxford, Oxford OX3 7FZ, UK (PO); Institute for Innovation and
endpoints (such as what is considered a COVID-19 Public Purpose, University College London, London, UK (ET); Competence Center
for Methodology and Statistics, Luxembourg Institute of Health, Strassen,
case, and when is this assessed), types of placebo, study Luxemburg (MV)
populations, background risks of COVID-19 during the 1 Zimmer C, Corum J, Wee S-L. Covid-19 Vaccine Tracker. https://www.
study, duration of exposure, and different definitions nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html
(accessed March 10, 2021).
of populations for analyses both within and between 2 Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2
mRNA COVID-19 Vaccine. N Engl J Med 2020; 383: 2603–15.
studies, as well as definitions of endpoints and statistical
3 Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273
methods for efficacy. Importantly, we are left with the SARS-CoV-2 Vaccine. N Engl J Med 2021; 384: 403–16.
4 Voysey M, Clemens SAC, Madhi SA, et al. Safety and efficacy of the ChAdOx1
unanswered question as to whether a vaccine with a nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of
given efficacy in the study population will have the same four randomised controlled trials in Brazil, South Africa, and the UK.
Lancet 2021; 397: 99–111.
efficacy in another population with different levels of 5 Logunov DY, Dolzhikova IV, Shcheblyakov DV, et al. Safety and efficacy of an
background risk of COVID-19. This is not a trivial question rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine:
an interim analysis of a randomised controlled phase 3 trial in Russia. Lancet
because transmission intensity varies between countries, 2021; 397: 671–81.
affected by factors such as public health interventions 6 US Food and Drug Administration. Vaccines and Related Biological Products
Advisory Committee meeting: FDA briefing document. Dec 10, 2020.
and virus variants. The only reported indication of https://www.fda.gov/advisory-committees/advisory-committee-calendar/
vaccines-and-related-biological-products-advisory-committee-december-
vaccine effectiveness is the Israeli mass vaccination 10-2020-meeting-announcement (accessed March 10, 2021).
campaign using the Pfizer–BioNTech product. Although 7 US Food and Drug Administration. Vaccines and Related Biological Products
Advisory Committee meeting: FDA briefing document. Dec 17, 2020.
the design and methodology are radically different from https://www.fda.gov/advisory-committees/advisory-committee-calendar/
vaccines-and-related-biological-products-advisory-committee-december-
the randomised trial,2 Dagan and colleagues11 report an 17-2020-meeting-announcement (accessed March 10, 2021).
RRR of 94%, which is essentially the same as the RRR of 8 US Food and Drug Administration. Vaccines and Related Biological Products
Advisory Committee meeting: FDA briefing document. Feb 26, 2021.
the phase 3 trial (95%) but with an ARR of 0·46%, which https://www.fda.gov/advisory-committees/advisory-committee-calendar/
translates into an NNV of 217 (when the ARR was 0·84% vaccines-and-related-biological-products-advisory-committee-february-
26-2021-meeting-announcement (accessed March 10, 2021).
and the NNV was 119 in the phase 3 trial). This means in 9 Olliaro P. What does 95% COVID-19 vaccine efficacy really mean?
Lancet Infect Dis 2021; published online Feb 17. https://doi.org/10.1016/
a real-life setting, 1·8 times more subjects might need S1473-3099(21)00075-X.
to be vaccinated to prevent one more case of COVID-19 10 Brown RB. Outcome reporting bias in COVID-19 mRNA vaccine clinical
trials. Medicina (Kaunas) 2021; 57: 199.
than predicted in the corresponding clinical trial. 11 Dagan N, Barda N, Kepten E, et al. BNT162b2 mRNA COVID-19 vaccine in a
Uncoordinated phase 3 trials do not satisfy public nationwide mass vaccination setting. N Engl J Med 2021; published online
Feb 24. https://doi.org/10.1056/NEJMoa2101765.
health requirements; platform trials designed to address
e280 www.thelancet.com/microbe Vol 2 July 2021

2
AR09750
medicina
Perspective
Outcome Reporting Bias in COVID-19 mRNA Vaccine
Clinical Trials
Ronald B. Brown
School of Public Health and Health Systems, University of Waterloo, Waterloo, ON N2L3G1, Canada;
r26brown@uwaterloo.ca
Abstract: Relative risk reduction and absolute risk reduction measures in the evaluation of clinical
trial data are poorly understood by health professionals and the public. The absence of reported
absolute risk reduction in COVID-19 vaccine clinical trials can lead to outcome reporting bias that
affects the interpretation of vaccine efficacy. The present article uses clinical epidemiologic tools to
critically appraise reports of efficacy in Pfzier/BioNTech and Moderna COVID-19 mRNA vaccine
clinical trials. Based on data reported by the manufacturer for Pfzier/BioNTech vaccine BNT162b2,
this critical appraisal shows: relative risk reduction, 95.1%; 95% CI, 90.0% to 97.6%; p = 0.016; absolute
risk reduction, 0.7%; 95% CI, 0.59% to 0.83%; p < 0.000. For the Moderna vaccine mRNA-1273, the
appraisal shows: relative risk reduction, 94.1%; 95% CI, 89.1% to 96.8%; p = 0.004; absolute risk
reduction, 1.1%; 95% CI, 0.97% to 1.32%; p < 0.000. Unreported absolute risk reduction measures of
0.7% and 1.1% for the Pfzier/BioNTech and Moderna vaccines, respectively, are very much lower
than the reported relative risk reduction measures. Reporting absolute risk reduction measures is
essential to prevent outcome reporting bias in evaluation of COVID-19 vaccine efficacy.
Keywords: mRNA vaccine; COVID-19 vaccine; vaccine efficacy; relative risk reduction; absolute
risk reduction; number needed to vaccinate; outcome reporting bias; clinical epidemiology; critical

appraisal; evidence-based medicine
Citation: Brown, R.B. Outcome
Reporting Bias in COVID-19 mRNA
Vaccine Clinical Trials. Medicina 2021,
57, 199. https://doi.org/10.3390/
1. Introduction
medicina57030199
Using messenger RNA (mRNA) in vaccines to produce proteins that trigger an im-
Academic Editor: Edgaras Stankevičius mune response against infectious diseases has held promise for decades, but until recently,
no clinically tested mRNA vaccine has managed to advance beyond small, early-phase
Received: 13 January 2021 trials [1]. Normally, genetic code in mRNA is transcribed from DNA in the cell nucleus,
Accepted: 22 February 2021 and the coded message is delivered by mRNA to cell ribosomes for translation during
Published: 26 February 2021 protein biosynthesis [2]. COVID-19 mRNA vaccines directly inject cells with a synthetic
genetic code to replicate the spike S protein found on the surface of the coronavirus, SARS-
Publisher’s Note: MDPI stays neutral CoV-2 [3]. Once replicated, the spike protein is proposed to trigger an immune response
with regard to jurisdictional claims in that creates antibodies against the virus [4].
published maps and institutional affil- However, several biological obstacles continue to challenge the development of mRNA
iations. vaccines, including “mRNA’s extremely large size, charge, intrinsic instability, and high
susceptibility to enzymatic degradation” [5]. To mitigate enzymatic degradation, mRNA in
the vaccines is encapsulated in lipid nanoparticles [6], but it is unclear how this encapsula-
tion affects genetic code translation in the cell ribosomes. Nevertheless, clinical results of
Copyright: © 2021 by the author. phase III trials reported for COVID-19 vaccines manufactured by Pfizer/BioNTech (New
Licensee MDPI, Basel, Switzerland. York City, NY, USA/Mainz, Germany) [7] and Moderna (Cambridge, MA, USA) [8] have
This article is an open access article far surpassed predicted performance, with vaccine efficacy rates of approximately 95%.
distributed under the terms and Curiously, “why these vaccines seem so effective while previous attempts against other
conditions of the Creative Commons pathogens haven’t appeared as promising remains an open question” [1].
Attribution (CC BY) license (https://
As noted in BMJ Opinion, 26 November 2020 [9],
creativecommons.org/licenses/by/
4.0/).
Medicina 2021, 57, 199. https://doi.org/10.3390/medicina57030199 https://www.mdpi.com/journal/medicina

AR09751
Medicina 2021, 57, 199 2 of 8
“There may be much more complexity to the ‘95% effective’ announcement than
meets the eye—or perhaps not. Only full transparency and rigorous scrutiny of
the data will allow for informed decision making. The data must be made public.”
As was also noted in the BMJ Opinion, Pfizer/BioNTech and Moderna reported the relative
risk reduction of their vaccines, but the manufacturers did not report a corresponding
absolute risk reduction, which “appears to be less than 1%” [9]. Absolute risk reduction
(ARR) and relative risk reduction (RRR) are measures of treatment efficacy reported in
randomized clinical trials. Because the ARR and RRR can be dramatically different in the
same trial, it is necessary to include both measures when reporting efficacy outcomes to
avoid outcome reporting bias. In the present article, a critical appraisal of publicly available
clinical trial data verifies that absolute risk reduction percentages for Pfizer/BioNTech
vaccine BNT162b2 [7] and Moderna vaccine mRNA-1273 [8] are, respectively, 0.7%; 95% CI,
0.59% to 0.83%; p = 0.000, and 1.1%; 95% CI, 0.97% to 1.32%; p = 0.000. The same publicly
available data, without absolute risk reduction measures, were reviewed and approved
by the roster of members serving on the U.S. Food and Drug Administration’s (FDA’s)
Vaccines and Related Biological Products Advisory Committee (VRBPAC) for emergency
use authorization (EUA) of the mRNA vaccines [10]. Ironically, the omission of absolute
risk reduction measures in data reviewed by the VRBPAC overlooks FDA guidelines for
communicating evidence-based risks and benefits to the public [11]. The FDA’s advice for
information providers includes:
“Provide absolute risks, not just relative risks. Patients are unduly influenced
when risk information is presented using a relative risk approach; this can result
in suboptimal decisions. Thus, an absolute risk format should be used.”
The New England Journal of Medicine also published clinical trial data on safety and efficacy
for the BNT162b2 vaccine [12] and the mRNA-1273 vaccine [13], but with no mention of
absolute risk reduction measures.
The present article uses epidemiologic tools to critically appraise absolute and relative
risk reduction measures for vaccine efficacy in phase III clinical trials of the COVID-19
mRNA vaccines. Microsoft Excel was used to analyze data and chart risk reduction out-
comes. The article further clarifies how selective reporting of vaccine efficacy measures can
cause a type of outcome reporting bias that misrepresents health information disseminated
to the public.
2. Critical Appraisal of Vaccine Efficacy

The application of epidemiologic and biometric methods to clinical diagnosis and
treatment is known as clinical epidemiology [14]. Clinical epidemiologic tools can be
applied in evidence-based medicine (EBM) to critically appraise research evidence for
validity, size of effect, and usefulness in clinical practice [15]. Clinical treatment effects in
groups of participants are measured by comparing probabilities of an event, known as
event rates [16].
Figure 1 shows an example of a vaccine clinical trial for an infectious disease. The
vaccine and placebo groups in Figure 1 each have 100 randomly assigned individuals with
no history of infection, and an event is defined as the incidence of infection among all
individuals during the course of the trial. The percentage of events in the vaccine group is
the experimental event rate (EER) or the risk of infection in the vaccine group (1/100 = 1%),
and the percentage of events in the placebo group is the control event rate (CER) or the risk
of infection in the placebo group (2/100 = 2%). Absolute risk reduction (ARR) is the disease
risk difference between the placebo and vaccine groups, i.e., the CER minus the EER (2% −
1% = 1%). The ARR is also known as the vaccine disease preventable incidence (VDPI) [17].
Relative risk reduction (RRR) or vaccine efficacy (VE) is the reduced risk from vaccination,
the ARR or VDPI, relative to or divided by the risk in unvaccinated individuals, the CER
(1%/2% = 50%) [18].
AR09752
Medicina 2021, 57, x FOR PEER REVIEW 3 of 9
Medicina 2021, 57, 199 3 of 8

duced risk from vaccination, the ARR or VDPI, relative to or divided by the risk in un-
vaccinated individuals, the CER (1%/2% = 50%) [18].
Figure 1.
Figure 1. Example
Example of
of aa vaccine
vaccine clinical
clinical trial
trial for
for an
an infectious
infectiousdisease.
disease.
3. 22 ×
3. × 22Contingency
ContingencyTablesTablesandandEpidemiologic
EpidemiologicEquations
Equations
The following 2 × 2 contingency tables for SARS-CoV-2 infection are based on re-
The following 2 × 2 contingency tables for SARS-CoV-2 infection are based on reported
ported clinical
clinical trial
trial data fordata for the Pfzier/BioNTech
the Pfzier/BioNTech BNT162b2BNT162b2
vaccinevaccine
[12] and [12]
theand the Moderna
Moderna mRNA-
mRNA-1273
1273 vaccine vaccine
[13]. The[13]. The
table tableshown
rows, rows, shown
in Tablein1,Table 1, list
list the the vaccine
vaccine and placebo
and placebo groups
groups
and and the
the table table columns
columns list the participants’
list the participants’ outcomesoutcomes of either SARS-CoV-2
of either SARS-CoV-2 infection orin-
no
fection orTables
infection. no infection.
2 and 3 listTable 2 andtrial
the clinical Table
data3 for
listthethe clinical trial data
Pfzier/BioNTech for the
and Moderna
Pfzier/BioNTech
vaccines, and Moderna
respectively. As shownvaccines,
in Table respectively. As shown
1, the total number in Table 1,inthe
of participants total
a group,
number of participants in a group, known as n, is represented by a +
known as n, is represented by a + b for the vaccine group and c + d for the placebo group. b for the vaccine
group and c + d for the placebo group.
Table 1. 2 × 2 contingency table for SARS-CoV-2 infection in vaccine clinical trials.
Table 1. 2 × 2 contingency table for SARS-CoV-2 infection in vaccine clinical trials.
Infection No Infection
Vaccine
Vaccine a a b a + bb a+b
Placebo c d c+d
Placebo c d c+d
Table2.2. 22 ×
Table × 22 contingency
contingencytable
tablefor
forSARS-CoV-2
SARS-CoV-2infection
infectionininPfzier/BioNTech
Pfzier/BioNTechvaccine
vaccine clinical
clinical trial.
trial.
Infection Infection No No Infection

Infection
BNT162b2
BNT162b2 8 8 21,712
21,712 21,720
21,720
PlaceboPlacebo 162 162 21,564
21,564 21,726
21,726
Table3.3. 22 ×
Table × 22 contingency
contingencytable
tablefor
forSARS-CoV-2
SARS-CoV-2infection
infectionininModerna
Modernavaccine
vaccineclinical
clinicaltrial.
trial.
mRNA-1273 11 15,199 15,210
Placebo 185 15,025 15,210
AR09753
Medicina 2021, 57, 199 4 of 8
The following epidemiologic equations use data from the 2 × 2 contingency tables
(Tables 1–3) to calculate relative and absolute measures of COVID-19 mRNA vaccine efficacy.
Risk ratio (RR):
a/( a + b)
RR = (1)
c/(c + d)
The risk ratio, also known as the relative risk, in a randomized controlled trial is the
ratio calculated by dividing the experimental event rate (EER), a/(a + b), by the control
event rate (CER), c/(c + d) [19]. Dividing the EER by the CER equals 1 if the rates do not
differ, in which case the RR has the null value 1. RRs below 1 indicate a protective effect
and a decreased risk (EER < CER), and RRs above 1 indicate an increased risk (EER > CER).
Risk ratio 95% confidence interval (CI):
s s
b/a d/c 1 1 1 1
CI = eˆ(Ln(RR) ± 1.96 ∗ SE) where SE = + or − + − (2)
( a + b) (c + d) a ( a + b) c (c + d)
The risk ratio 95% confidence interval predicts the range of probable risk ratios if the
experiment or trial was repeated 95 out of 100 times. The narrower the range between
the upper and lower CI values, the more precise the CI. If the range includes the RR null
value, 1, the risk ratio is considered statistically insignificant. The equation calculates the
standard error (SE) [20,21], and the natural logarithm (Ln) is used, along with the antilog
expressed as an exponent of the base e, to normally distribute the data when calculating
the 95% probability.
Absolute risk reduction (ARR):
c a
ARR (%) = − (3)
(c + d) ( a + b)
The absolute risk reduction is a percentage equal to the arithmetic difference when
subtracting the EER from the CER [19]. The difference equals zero if the rates do not differ,
in which case the ARR has the null value zero. The difference is negative if the EER is
higher than the CER.
Absolute risk reduction 95% confidence interval (CI upper, lower):
s
EER∗(1 − EER) CER∗(1 − CER)
ARR CI = ARR ± 1.96 ∗ SE, where SE = + (4)
( a + b) (c + d)
The standard error in the absolute risk reduction 95% confidence interval measures
the square root of the sum of the group variances [22]. If the ARR CI includes the null
value zero, the ARR is not statistically significant.
Number needed to vaccinate (NNV):
1
NNV = (5)
ARR
The NNV, or the number needed to vaccinate to prevent one infection, is the reciprocal
of the ARR [17]. Note that the numerator is multiplied by 100 when the ARR is expressed
with a percentage sign. The NNV is also usually rounded up to the next individual.
NNV 95% confidence interval (CI):
1
NNV CI = (6)
ARR CI
The CI of the NNV is calculated by dividing 1 by the ARR CI [22], again multiplying
by 100 in the numerator when the ARR is expressed with a percentage sign.
Relative risk reduction (RRR) or vaccine efficacy (VE):
RRR, VE (%) = 1 − RR (7)

Medicina 2021, 57, x FOR PEER REVIEW 5 of 9
AR09754
Medicina 2021, 57, 199 5 of 8

Relative risk reduction (RRR) or vaccine efficacy (VE):
RRR, VE (%) = 1 − RR (7)
The relative risk
The risk reduction
reduction isisthe
thesame
sameasasvaccine
vaccineefficacy (VE)
efficacy [17].
(VE) TheThe
[17]. RRRRRR
is cal-
is
culated by by
calculated subtracting thethe
subtracting RR RR
from the the
from nullnull
value 1, or1,by
value ordividing the ARR
by dividing by the
the ARR byCER
the
[22]. [22].
CER
RRR,VE
RRR, VE95%
95%confidence
confidenceinterval
interval(CI):
(CI):
RRR,
RRR,VEVE = 1=− 1RR
CICI − CI
RR CI (8)
(8)
The CI
The CI for
for the
the relative
relative risk
risk reduction
reduction is is calculated
calculated by by subtracting
subtracting thethe RR
RR CI
CI from
from the
the
null value
null value 1.1.
Pvalues, which
Pvalues, which measure
measure thethe probability
probability that
that aa trial
trial result
result occurred
occurredby bychance,
chance,cancanbebe
calculated from the confidence interval for the difference between two
calculated from the confidence interval for the difference between two proportions, as in proportions, as in
the ARR,
the ARR,andandfrom
fromthe theconfidence
confidenceinterval
intervalforfor a ratio,
a ratio, as as in the
in the RRR RRR [23].
[23]. Online
Online calcula-
calculators
torsalso
are are also available
available thatthat compare
compare group
group proportions
proportions [24]and
[24] andcalculate
calculateepidemiological
epidemiological
equations [25],
equations [25], which
which are are useful
useful for
for measuring
measuring vaccine
vaccine efficacy.
efficacy. Figure
Figure22shows
showsaachart
chartofof
the present critical appraisal of mRNA COVID-19 vaccine efficacy.
the present critical appraisal of mRNA COVID-19 vaccine efficacy. Note that the verticalNote that the vertical
axis of
axis of the
the chart
chart is
is aa logarithmic
logarithmic scale,
scale, base
base 10.
10.
Figure 2. The chart shows critical appraisal results of mRNA COVID-19 vaccine efficacy.
Figure 2. The chart shows critical appraisal results of mRNA COVID-19 vaccine efficacy.
Clinical epidemiologic tools can be used to critically appraise the efficacy of new
Clinical
COVID-19 epidemiologic
vaccines tools can mechanisms
having biological be used to critically appraise
that differ from the themRNA
efficacy of new
vaccines,
COVID-19 vaccines having biological mechanisms that differ from
such as AstraZeneca-Oxford’s ChAdOx1 adenoviral vector vaccine [26] and Johnson &the mRNA vaccines,
such as AstraZeneca-Oxford’s
Johnson’s ChAdOx1 vaccine
Janssen Biotech Ad26.COV2.S adenoviral
[27].vector vaccine
(As this article[26] and
goes to Johnson
press, the&
Johnson’s Janssen Biotech Ad26.COV2.S vaccine [27]. (As this article
FDA VRBPAC is scheduled to review the Janssen Biotech vaccine for EUA.) As well, re-goes to press, the
FDA VRBPAC
ported is scheduled
efficacy for randomized toclinical
reviewtrials
the Janssen Biotech
involving vaccine for
any treatment, EUA.) As well,
intervention, re-
disease,
ported efficacy
disorder, for randomized
or illness clinical
can be critically trials involving
appraised any treatment,
using clinical intervention,
epidemiologic tools. Indis-
a
ease, disorder,
similar manner,or illness can be
observational critically
studies thatappraised usingand
report vaccine clinical
otherepidemiologic tools. In a
treatment effectiveness
similar
in manner,
reducing observational
disease studiesa that
incidence within report vaccine
population can alsoand other treatment
be critically appraisedeffective-
using
clinical epidemiologic tools.
AR09755
Medicina 2021, 57, 199 6 of 8
4. Discussion
Medical and public health experts continue to stress the need to include measurements
of absolute risk reduction and number needed to treat when reporting results of clinical
interventions [28]. Currently, differences between relative effect measures and absolute
effect measures in studies are “poorly understood by health professionals, and even more
poorly understood by patients.” [29] In addition,
“ . . . critical appraisal knowledge and skills are limited among physicians,”
and “use of relative effect measures was associated with greater perceptions
of medication effectiveness and intent to prescribe, compared with the use of
absolute effect measures.” [29]
Reporting relative measures may be sufficient to summarize evidence of a study for com-
parisons with other studies, but absolute measures are also necessary for applying study
findings to specific clinical or public health circumstances [22]. Omitting absolute risk
reduction findings in public health and clinical reports of vaccine efficacy is an example of
outcome reporting bias, which ignores unfavorable outcomes and misleads the public’s
impression and scientific understanding of a treatment’s efficacy and benefits [30]. Fur-
thermore, the ethical and legal obligation of informed consent requires that patients are
educated about the risks and benefits of a healthcare procedure or intervention [31].
Similar to the critical appraisal in the present article, critical appraisals of reported
vaccine efficacy in other studies reveals clinically significant insights. For example, a 2018
review of 52 randomized trials for influenza vaccines that studied over 80,000 healthy
adults reported an overall influenza vaccine EER of 0.9% and a 2.3% CER, which calculates
to a RRR of 60.8% [32]. This vaccine efficacy is consistent with a 40% to 60% reduction in
influenza reported by the Centers for Disease Control and Prevention (CDC) [33]. However,
critically appraising data from the 2018 review shows an overall ARR of only 1.4%, which
reveals vital clinical information that is missing in the CDC report. A 1.4% ARR works out
to a NNV of approximately 72 people, meaning that 72 individuals need to be vaccinated
to reduce one case of influenza. By comparison, Figure 2 of the present article shows that
the NNV for the Pfzier-BioNTech and Moderna vaccines are 142 (95% CI 122 to 170) and 88
(95% CI 76 to 104), respectively.
The mRNA vaccine manufacturers reported that infections in most subgroups in
phase III clinical trials were similar for both vaccines after two doses. Vaccine clinical trial
case definitions for SARS-CoV-2 infection included COVID-19 clinical symptoms; thus
the trials were not designed to provide evidence of vaccine efficacy for protection against
asymptomatic infections. In addition to outcome reporting bias, information bias may have
also affected COVID-19 vaccine trial outcomes due to misclassification of SARS-CoV-2
infections as mild adverse effects of the vaccines. For example, several COVID-19 clinical
symptoms are similar to the vaccines’ adverse effects such as fever, pain, and fatigue, which
could potentially lead to missed diagnoses of viral infections.
A limitation of this article is that it only critically appraised mRNA vaccine efficacy
in healthy individuals who were randomized to two groups under strictly controlled
conditions. The critical appraisal did not include vaccine safety and effectiveness outcomes
within a general population that includes unhealthy people and that lacks control over
confounding factors. For example, healthy vaccinee bias occurs when people who are in
better health are more likely to follow vaccination recommendations in order to protect
their health [34].
5. Conclusions
A critical appraisal of phase III clinical trial data for the Pfizer/BioNTech vaccine
BNT162b2 and Moderna vaccine mRNA-1273 shows that absolute risk reduction measures
are very much lower than the reported relative risk reduction measures. Yet, the manufac-
turers failed to report absolute risk reduction measures in publicly released documents.
As well, the U.S FDA Advisory Committee (VRBPAC) did not follow FDA published
guidelines for communicating risks and benefits to the public, and the committee failed
AR09756
Medicina 2021, 57, 199 7 of 8
to report absolute risk reduction measures in authorizing the BNT162b2 and mRNA-1273
vaccines for emergency use. Such examples of outcome reporting bias mislead and distort
the public’s interpretation of COVID-19 mRNA vaccine efficacy and violate the ethical and
legal obligations of informed consent.
Funding: This research received no external funding.

Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Data for Pfzier/BioNTech BNT162b2: https://doi.org/10.1056/nejmoa2
034577; data for Moderna mRNA-1273: https://doi.org/10.1056/NEJMoa2035389 (accessed on 10
January 2021).
Acknowledgments: Special thanks to Richard J. Cook from the University of Waterloo, whose
foundational work with David L. Sackett in clinical epidemiology is cited in this manuscript.
Conflicts of Interest: The author declares no conflict of interest.
References
1. Kwon, D. The Promise of mRNA Vaccines. Available online: https://www.the-scientist.com/news-opinion/the-promise-of-
mrna-vaccines-68202 (accessed on 23 December 2020).
2. Genome. Messenger RNA (mRNA). Available online: https://www.genome.gov/genetics-glossary/messenger-rna (accessed on
23 December 2020).
3. Garde, D. The Story of mRNA: How a Once-Dismissed Idea Became a Leading Technology in the Covid Vaccine Race. Available
online: https://www.statnews.com/2020/11/10/the-story-of-mrna-how-a-once-dismissed-idea-became-a-leading-technology-
in-the-covid-vaccine-race/ (accessed on 5 January 2021).
4. Centers for Disease Control and Prevention. Understanding mRNA COVID-19 Vaccines. Available online: https://www.cdc.
gov/coronavirus/2019-ncov/vaccines/different-vaccines/mrna.html (accessed on 22 December 2020).
5. Wadhwa, A.; Aljabbari, A.; Lokras, A.; Foged, C.; Thakur, A. Opportunities and Challenges in the Delivery of mRNA-based
Vaccines. Pharmaceutics 2020, 12, 102. [CrossRef] [PubMed]
6. Reichmuth, A.M.; Oberli, M.A.; Jaklenec, A.; Langer, R.; Blankschtein, D. mRNA vaccine delivery using lipid nanoparticles. Ther.
Deliv. 2016, 7, 319–334. [CrossRef] [PubMed]
7. Food and Drug Administration. Pfizer-BioNTech COVID-19 Vaccine VRBPAC Briefing Document. Available online: https:
//www.fda.gov/media/144246/download (accessed on 23 December 2020).
8. Food and Drug Administration. FDA Briefing Document: Moderna COVID-19 Vaccine. Available online: https://www.fda.gov/
media/144434/download (accessed on 23 December 2020).
9. Doshi, P. Peter Doshi: Pfizer and Moderna’s ”95% effective” Vaccines—Let’s Be Cautious and First See the Full Data. Available
online: https://blogs.bmj.com/bmj/2020/11/26/peter-doshi-pfizer-and-modernas-95-effective-vaccines-lets-be-cautious-and-
first-see-the-full-data/ (accessed on 23 December 2020).
10. Food and Drug Administration. Roster of the Vaccines and Related Biological Products Advisory Committee. Available
online: https://www.fda.gov/advisory-committees/vaccines-and-related-biological-products-advisory-committee/roster-
vaccines-and-related-biological-products-advisory-committee (accessed on 23 December 2020).
11. Fischhoff, B.; Brewer, N.; Downs, J. Communicating Risks and Benefits: An Evidence-Based User’s Guide; Food and Drug Administra-
tion (FDA), US Department of Health and Human Services: Silver Spring, MA, USA, 2011.
12. Polack, F.P.; Thomas, S.J.; Kitchin, N.; Absalon, J.; Gurtman, A.; Lockhart, S.; Perez, J.L.; Pérez Marc, G.; Moreira, E.D.; Zerbini, C.
Safety and efficacy of the BNT162b2 mRNA covid-19 vaccine. N. Engl. J. Med. 2020, 383. [CrossRef] [PubMed]
13. Baden, L.R.; El Sahly, H.M.; Essink, B.; Kotloff, K.; Frey, S.; Novak, R.; Diemert, D.; Spector, S.A.; Rouphael, N.; Creech, C.B.; et al.
Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 2020, 384. [CrossRef]
14. Sackett, D.L. Clinical epidemiology. Am. J. Epidemiol. 1969, 89, 125–128. [CrossRef] [PubMed]
15. Sackett, D.; Straus, S.; Scott Richardson, W.; Rosenberg, W.; Haynes, R. Evidence-Based Medicine: How to Practice and Teach EBM,
2nd ed.; Churchill Livingstone: Edinburgh, UK; London, UK, 2000.
16. Cook, R.J.; Sackett, D.L. The number needed to treat: A clinically useful measure of treatment effect. BMJ 1995, 310, 452–454.
[CrossRef] [PubMed]
17. Dasgupta, S. A Review of Vaccine Efficacy Measures. Vaccin Res. Open J. 2019, 1, 61–64.
18. Irwig, L.; Irwig, J.; Revena, L.; Sweet, M. Relative risk, relative and absolute risk reduction, number needed to treat and confidence
intervals. In Smart Health Choices: Making Sense of Health Advice; Hammersmith Press: London, UK, 2008; Chapter 18.
19. Kremer, L.; Moyer, V. Tips and tricks for understanding and using SR results—No 1: Relative risk, risk difference, and number
needed to treat. Evidence-Based Child Health Cochrane Rev. J. 2009, 4, 1146–1148. [CrossRef]
AR09757
Medicina 2021, 57, 199 8 of 8
20. Sullivan, L. Confidence Intervals for the Risk Ratio (Relative Risk). Available online: https://sphweb.bumc.bu.edu/otlt/mph-
modules/bs/bs704_confidence_intervals/bs704_confidence_intervals8.html#:~{}:text=Therefore%2C%20computing%20the%
20confidence%20interval,confidence%20interval%20for%20the%20RR (accessed on 26 December 2020).
21. Morris, J.A.; Gardner, M.J. Calculating Confidence Intervals For Relative Risks (Odds Ratios) And Standardised Ratios And Rates.
BMJ 1988, 296, 1313–1316. [CrossRef] [PubMed]
22. Schechtman, E. Odds ratio, relative risk, absolute risk reduction, and the number needed to treat—Which of these should we use?
Value Health 2002, 5, 431–436. [CrossRef] [PubMed]
23. Altman, D.G.; Bland, J.M. How to obtain the P value from a confidence interval. BMJ 2011, 343, d2304. [CrossRef] [PubMed]
24. Azzopardi, D. Group Comparison Calculator. Available online: https://www.neoweb.org.uk/Additions/compare.htm (accessed
on 6 January 2021).
25. Heidel, E. Epidemiology. Available online: https://www.scalestatistics.com/epidemiology.html (accessed on 6 January 2021).
26. Voysey, M.; Clemens, S.A.C.; Madhi, S.A.; Weckx, L.Y.; Folegatti, P.M.; Aley, P.K.; Angus, B.; Baillie, V.L.; Barnabas, S.L.;
Bhorat, Q.E. Safety and Efficacy of the ChAdOx1 nCoV-19 Vaccine (AZD1222) against SARS-CoV-2: An Interim Analysis of Four
Randomised Controlled Trials in Brazil, South Africa, and the UK. Lancet 2021, 397, 99–111. [CrossRef]
27. Sadoff, J.; Le Gars, M.; Shukarev, G.; Heerwegh, D.; Truyers, C.; de Groot, A.M.; Stoop, J.; Tete, S.; Van Damme, W.; Leroux-Roels, I.
Interim Results of a Phase 1–2a Trial of Ad26. COV2. S Covid-19 Vaccine. N. Engl. J. Med. 2021. [CrossRef] [PubMed]
28. Elliott, M.H.; Skydel, J.J.; Dhruva, S.S.; Ross, J.S.; Wallach, J.D. Characteristics and Reporting of Number Needed to Treat, Number
Needed to Harm, and Absolute Risk Reduction in Controlled Clinical Trials, 2001–2019. JAMA Intern. Med. 2020, 181.
29. Kahwati, L.; Carmody, D.; Berkman, N.; Sullivan, H.W.; Aikin, K.J.; DeFrank, J. Prescribers’ Knowledge and Skills for Interpreting
Research Results: A Systematic Review. J. Contin. Educ. Health Prof. 2017, 37, 129–136. [CrossRef]
30. Thomas, E.T.; Heneghan, C. Outcome Reporting Bias. Available online: https://catalogofbias.org/biases/outcome-reporting-
bias/ (accessed on 23 November 2020).
31. Shah, P.; Thornton, I.; Turrin, D.; Hipskind, J.E. Informed Consent. Available online: https://www.ncbi.nlm.nih.gov/books/
NBK430827/#:~{}:text=Informed%20consent%20is%20the%20process,undergo%20the%20procedure%20or%20intervention (ac-
cessed on 8 February 2021).
32. Demicheli, V.; Jefferson, T.; Ferroni, E.; Rivetti, A.; Di Pietrantonj, C. Vaccines for preventing influenza in healthy adults. In
Cochrane Database Of Systematic Reviews; Cochrane Library: Hoboken, NJ, USA, 2018. Available online: https://pubmed.ncbi.nlm.
nih.gov/29388196 (accessed on 7 January 2021).
33. Centers for Disease Control and Prevention. Vaccine Effectiveness: How Well Do the Flu Vaccines Work? Available online:
https://www.cdc.gov/flu/vaccines-work/vaccineeffect.htm (accessed on 26 November 2020).
34. Remschmidt, C.; Wichmann, O.; Harder, T. Frequency and impact of confounding by indication and healthy vaccinee bias in
observational studies assessing influenza vaccine effectiveness: A systematic review. BMC Infect. Dis. 2015, 15, 429. [CrossRef]
[PubMed]
AR09758
TAB 63
AR09759
FEDERAL COURT
B E T W E E N:
NABIL BEN NAOUM
demandeur
- and -
dèfendeur
AND BETWEEN:
demandeur
- and -
dèfendeur
AND BETWEEN:
NIKKANEN, KEN BAIGENT, DREW BELOBABA, NATALIE

Applicants
- and -
Respondent

AR09760
AND BETWEEN:
Applicants
- and -
Respondent
--------
--- This is the continued Cross-Examination of

CELIA LOURENCO, on her Affidavit sworn April 22,
2022, on behalf of the Attorney General of
Canada, taken via Videoconference for Network
Reporting & Mediation, Toronto, Ontario, on the
6th day of June, 2022.
--------
MAHAN KERAMATI
JAMES ELFORD
ROBERT DRUMMOND
EVA CHIPIUK
ALLISON PEJOVIC

ALSO PRESENT:
Shaun Rickard observing

Sayah Hassan
Patrick Abbot
REPORTED BY: Caroline Maslin, CSR

AR09761
WITNESS: Celia Lourenco
PAGE
CROSS-EXAMINATION BY MR. PRESVELOS..........162
CROSS-EXAMINATION BY MR. WILSON.............223
RE-DIRECT EXAMINATION BY MS. TELLES-LANGDON.328
**The following list of undertakings, advisements and
refusals is meant as a guide only for the assistance of
counsel and no other purpose**
The questions/requests undertaken are noted by
U/T and appear on the following pages: 209:16,
210:6, 261:24
INDEX OF ADVISEMENTS
The questions/requests taken under advisement are

noted by U/A and appear on the following pages:
182:24, 204:8, 216:1, 219:14, 241:24, 242:25,
268:21, 269:11, 271:16, 273:12
INDEX OF REFUSALS
The questions/requests refused are noted by R/F
and appear on the following pages: 172:7, 237:3,
278:19, 283:25, 289:16, 296:3, 333:21, 339:13

AR09762
I N D E X O F E X H I B I T S
NUMBER/DESCRIPTION PAGE/LINE NO.
3: Drug and vaccine authorizations for COVID-19:

List of authorized drugs, vaccines and expanded
indications, Government of Canada website..256:25
4: Health Canada Advisory, April 26/21.....262:20
5: Health Canada Advisory - Updates Pfizer and

Moderna COVID-19 vaccine labels to include
information on myocarditis/pericarditis....263:23
6: Health Canada Advisory, Aug. 2, 2021....266:4
7: Health Canada Advisory, Nov. 9, 2021....269:23
8: FDA Advisory Janssen.PDF 2022...........278:15
9: New England Journal of Medicine, Safety and

efficacy of the BNT162b2 MRNA COVID-19 vaccine
through six months.........................285:4
10: Supplement to New England Journal of

Medicine...................................285:8
11: Cumulative analysis of post-authorization

adverse effect reports, Feb. 28, 2021......286:16
12: NHS Vaccinations and when to have them.290:18

13: Janssen (Johnson & Johnson) COVID-19 vaccine
- Canada.PDF, May 5, 2022..................309:5
14: AstraZeneca Vaxzevria COVID-19 Vaccine

Canada.PDF.................................314:25
15: Ontario recommends the use of Pfizer-BioNTech

COVID-19.PDF...............................316:5
16: Travel to England - Gov.UK.PDF.........323:6
17: WHO Pharmaceuticals Newsletter 1, '22..326:1
18: Moderna Spikevax COVID-19 Vaccine -

Canada.PDF.................................328:10

AR09763
1 --- Upon commencing at 10:30 a.m.
2 CELIA LOURENCO: Previously affirmed
3 EXAMINATION CONTINUED BY MR. PRESVELOS:
4 457 Q. Good morning, Dr. Lourenco.
5 A. Good morning.
6 458 Q. It's nice to see you again. I'm
7 probably going to have -- Sharlene, I'm probably
8 going to be another max hour and a half I think
9 with questions, and then I'll turn it over to the
10 JCC and I understand they have a couple of hours
11 of questions so I'm going to try my best to move
12 this along fairly quickly but I just wanted to
13 give you a sense of my timing.
14 Dr. Lourenco, how many vaccines do you
15 think Canadians should get right now?
16 A. I'm not -- I'm not sure I understand
17 the question how many vaccines.

18 459 Q. Yes. So right now there are --
19 there's a possibility of I think up to four shots
20 of the vaccine; correct?
21 MS. TELLES-LANGDON: So, Mr. Presvelos,
22 Dr. Lourenco is -- is the -- is not a public
23 health expert. She's not part of NACI, the
24 National Advisory Committee on Immunizations.

AR09764
1 460 Q. Well, Dr. Lourenco, do you have any
2 role to play in terms of recommending how many
3 dosages of any of the vaccines you approve
4 Canadians should take?
5 A. My role as the regulator is to review
6 the submissions that are filed by the
7 manufacturers in terms of recommendations for
8 number of doses and intervals between doses, and
9 then that information is incorporated into a
10 product monograph that is made available to
11 healthcare professionals including the National
12 Advisory Committee on Immunization who then takes
13 that information and makes recommendations for
14 how the vaccines -- for how many doses and
15 intervals should be used for the different
16 vaccines.
17 So it's more the public health

18 professionals who then make the actual
19 recommendations for implementation of the
20 vaccines in Canada.
21 461 Q. Are you consulted at all in terms of
22 providing a recommendation in terms of how many
23 doses of the vaccines Canadians should get?
24 A. No.
25 462 Q. So you mentioned, sorry, it's the

AR09765
1 National Advisory Committee of Immunization?
2 A. Yes.
3 463 Q. And that committee does not consult
4 with you in terms of determining how many dosages
5 -- or how many doses, sorry, of the vaccine
6 Canadian should get and at what stage?
7 A. No, that committee does not consult
8 with me. I do participate on the committee as an
9 ex officio member observing the activities of the
10 committee and provide updates to the committee
11 for their information, but it's their decisions
12 and their recommendations.
13 464 Q. And is it the National Advisory
14 Committee that also decides on the definition of
15 "fully vaccinated"?
16 A. I don't know.
17 465 Q. Are you involved at all as a

18 stakeholder in discussing and advising the
19 government on what the definition of a "fully
20 vaccinated person" is?
21 A. No, I'm not involved in that.
22 466 Q. Do you know who is involved in the
23 determination of what a fully vaccinated person
24 is?
25 A. I don't know who is involved. I

AR09766
1 don't want to speculate.
2 467 Q. No, I'm not asking you to. If you
3 don't know, you don't know. That's fair. So I
4 just want to be clear the National Advisory
5 Committee has never sought your input in
6 recommending how many dosages of the vaccines
7 Canadians should get and what intervals?
8 A. No, they haven't.
9 468 Q. Okay. Are you consulted with any
10 governmental department in terms of the messaging
11 around the COVID-19 vaccines; how you communicate
12 about the COVID-19 vaccines?
13 A. Can you be more specific in terms of
14 communicating in the sense of what types of areas
15 exactly, what types of --
16 469 Q. Well --
17 A. -- what type of information?

18 470 Q. Well, you know, we spent a fair bit
19 of time last week talking about absolute risk
20 reduction and relative risk reduction and how
21 those two figures can communicate something quite
22 different to the public.
23 Are you -- would you be involved or would
24 you be consulted in terms of how the government
25 might communicate to the public about the

AR09767
1 vaccines' effectiveness?
2 A. When we first -- when we authorized
3 the vaccine when I -- when -- when I first
4 authorized the vaccines, I was involved in
5 preparing the documents that were published to
6 communicate on the authorization of the vaccines
7 including efficacy and safety and that's really
8 where it stops.
9 My role as the regulator is communicating
10 on the results of the clinical trials and what
11 they showed in terms of efficacy and safety and
12 then what -- what is recommended in terms of
13 doses, number of doses and dosing intervals. And
14 that information is published on our website, we
15 have our vaccines, COVID-19 vaccines and
16 treatments portal where that information is
17 published and there are also some general landing

18 pages on Canada.ca where we have very high level
19 information about -- about the vaccines.
20 That's the extent to which I participate
21 in communication.
22 471 Q. Okay. Do you review studies of
23 vaccine efficacy in other countries?
24 A. As the regulator -- did you say do
25 you do or do you review? Sorry, can you repeat

AR09768
1 that?
2 472 Q. Do you review -- do you review
3 studies of vaccine efficacy in other countries,
4 say America, the U.K.?
5 A. Right. So the submissions that are
6 filed to us can include vaccine clinical trial
7 results from studies conducted in any country.
8 So for the majority of the vaccines that we
9 authorize, in fact the trials were conducted
10 elsewhere outside of Canada.
11 473 Q. So I wasn't -- I wasn't clear with my
12 question and I'm sorry. What I'm referring to
13 specifically is sort of the ongoing surveillance
14 of the vaccine efficacy. So we discussed last
15 time that you do review from time to time
16 literature on the vaccines. There was two
17 different terms, there's efficacy and what was

18 the other one? Is it efficient? It's not
19 efficiency. Is it efficiency?
20 A. Effectiveness.
21 474 Q. Effectiveness. Thank you. Efficacy
22 and effectiveness. So in terms of ongoing
23 surveillance of the effectiveness of the vaccine
24 in the general population, do you review studies
25 that are conducted on this issue in other

AR09769
1 countries or from other countries?
2 A. Yes. So when we're monitoring the
3 literature we do look at vaccine studies in other
4 countries as well, but we're obviously interested
5 in results from studies in Canada.
6 475 Q. And do you yourself personally --
7 because I know you have a team of about 35
8 people, but do you yourself personally review
9 studies on vaccine effectiveness in other
10 countries?
11 A. Personally? Generally, no. I rely
12 on my team to do those -- those reviews; I rely
13 on the Public Health Agency to do those reviews
14 and provide information to me.
15 476 Q. Okay. From your understanding and
16 perspective, what is the objective of the
17 COVID-19 vaccines? Is it -- is it to complete

18 eliminate the COVID-19 virus in the population?
19 A. From my perspective, my role as the
20 regulator the objective is to reduce the risk of
21 people contracting COVID-19 especially in such a
22 way that will lead to severe disease, so
23 decreasing infection and -- and severe disease.
24 477 Q. Right. But I take you probably agree
25 with me that the vaccines are unlikely to

AR09770
1 completely eliminate COVID-19 from the community.
2 Is that a fair statement?
3 A. I don't think we have enough
4 information to say that at this point, that it
5 will be able to completely eliminate or not
6 completely eliminate SARS-CoV-2 from the
7 community.
8 478 Q. And what information is missing in
9 order for you to decide whether or not that
10 statement could be true and accurate?
11 A. Well, I think we just need more time
12 to see how this virus behaves epidemiologically.
13 To date it appears to come and go in waves, but
14 we've had the virus for two years; it's -- I
15 don't think we can speculate in saying that
16 vaccines will never be able to eliminate the
17 virus.
18 479 Q. To date, are you aware as to whether
19 or not the vaccines have shown any ability to
20 eliminate the virus? Are you aware of any
21 studies that might suggest that that's the case?
22 A. No, I'm not -- I'm not aware of that,
23 no.
24 480 Q. And you mentioned that from your
25 perspective as the regulator, one of the

AR09771
1 objectives would be to reduce severe disease,
2 right, as a result of a COVID-19 infection?
3 A. Right.
4 481 Q. Is there a certain target that your
5 department has in mind when they're thinking
6 about the reduction of severe disease? Is there
7 a certain parameter within which would be an
8 ideal parameter for you to see individuals
9 developing severe disease from COVID-19?
10 A. At this point, we would use expect at
11 least -- at least a 50-percent reduction in
12 severe disease but it is an area for further
13 discussion. And moving forward, if that's a bar
14 that we should raise, have a higher bar or not, I
15 think it's an active area of discussion in terms
16 of what's the bar for severe disease. As we
17 talked about on Friday, the bar for infection is

18 50 percent -- at least a 50-percent reduction,
19 but for severe disease it would be at least that.
20 It could be -- it could be set higher, but
21 it's up for -- up for discussion at this point.
22 482 Q. But assuming that the vaccine does
23 reduce severe disease by 50 percent, which I take
24 it you mean 50 percent that are relative risk
25 reduction; correct?

AR09772
1 A. Yes, 50 percent relative risk
2 reduction.
3 483 Q. How much longer do you believe
4 Canadians will need to continue receiving
5 vaccines assuming we have a fully vaccinated
6 population right new?
7 R/F MS. TELLES-LANGDON: Sam, I'm going to
8 speculate -- sorry, I'm going to object to that
9 question. I've let a lot of questions go where
10 you've asked Dr. Lourenco to speculate, but it's
11 time to reframe from those types of questions.
13 484 Q. Can we go to your affidavit, please,
14 and go to page -- go to paragraph 179?
15 A. Okay.
16 485 Q. Just take a moment and read this
17 paragraph because I want you just to be familiar

18 with that. And, in particular -- because I know
19 it's a little bit long -- I'm going to ask you to
20 look at paragraph 179 on.
21 And in the last sentence you put, "PHAC
22 data continue to indicate that unvaccinated
23 people are much more likely to be admitted to
24 hospital than fully vaccinated people."
25 Right?

AR09773
1 A. Yes.
2 486 Q. Do you know how much more likely an
3 unvaccinated individual is to be hospitalized
4 than a vaccinated individual?
5 A. Not off the top of my head.
6 487 Q. And is this -- would you -- are you
7 saying that this statement is true across all age
8 categories or does this -- or does this
9 observation apply only with respect to certain
10 age categories?
11 A. I'm not sure. I don't know.
12 488 Q. Over the weekend I was trying to make
13 sense of something I saw online and I'm hoping
14 you might be able to help me make sense of this.
15 On Friday, we saw some information that's made
16 available through the federal government on the
17 health-infobase which is also an exhibit to your

18 affidavit and just -- just to simplify this, I'm
19 going to share my screen with you so we can look
20 at it together and if you have a hard time seeing
21 this information let me know and I will try to
22 maximize it.
23 Hold on a second, let me see if I can --
24 can you see that, Dr. Lourenco?
25 A. I can see it, yes.

AR09774
1 489 Q. Do you need a moment to take a look
2 at this?
3 A. Yes, just give me a moment.
4 490 Q. Yeah. I can scroll down if you like.
6 A. Okay. Okay.
7 491 Q. So we have three different set --
8 three different data sets; right? We have cases
9 of individuals who are infected with COVID-19 and
10 I think this is since the vaccination campaign
11 began -- I might be wrong, we can check that --
12 the second data set we have is number of
13 hospitalizations and the third one is deaths;
14 correct?
15 A. Yeah, that seems to be the case.
16 492 Q. And you remember that we went through
17 this -- this data set -- these data set, if my

18 conjugation is correct, on Friday; correct?
19 A. We very briefly looked at this and
20 then we quickly switched to the Ontario data.
21 493 Q. Right. And -- and part of the data
22 in here incorporates the Ontario data; correct?
23 A. I would expect so, but I can't
24 confirm that for you.
25 494 Q. Okay. One thing I've noticed --

AR09775
1 yeah, sorry.
2 MS. TELLES-LANGDON: Just -- sorry, just
3 for the record, Sam, these are total numbers,
4 correct, as opposed to range per hundred
5 thousand?
6 MR. PRESVELOS: Yeah, I think these are
7 total numbers as of -- yeah, I think these are
8 total numbers. I mean, this is an exhibit so we
9 can always -- we can always get some
10 clarification on this. It's like not this isn't
11 disappearing any time soon, but I'm pretty sure
12 these are total numbers.
13 495 Q. One of the questions I have for you,
14 Dr. Lourenco, is one of the observations I've
15 made when looking at these charts is that
16 individuals who are partially vaccinated, which
17 -- my understanding from reading this, means one

18 -- having a single dose of the vaccine seemed to
19 consistently fare better both in terms of having
20 fewer infections, fewer hospitalizations and
21 fewer deaths than those who are both fully
22 vaccinated and those who are fully vaccinated
23 with an additional dose.
24 Would you -- would you agree with that
25 observation?

AR09776
1 A. I don't think we can make that
2 conclusion from these data, --
3 496 Q. Yeah.
4 A. -- so I would say no. These are --
5 these are just the raw numbers of cases that are
6 being reported; we would need to look at
7 additional information to really interpret these
8 data.
9 497 Q. Yeah. So figure five, you agree with
10 me, shows the aggregate number of individuals who
11 are infected with COVID-19; right?
12 A. Yeah.
13 498 Q. And it shows me the aggregate number
14 of individuals who have been hospitalized with
15 COVID-19.
16 A. Right.
17 499 Q. And it shows me the aggregate number

18 of individuals who have died as a result of
20 A. Right.
21 500 Q. And you agree with me that when we
22 look at the aggregate number, so the total amount
23 of people in each of these categories, those who
24 are partially vaccinated there are fewer cases of
25 partially vaccinated individuals who have

AR09777
2 A. There are fewer cases that haven't
3 reported, it appears, yes, --
4 501 Q. Correct. Yeah, well --
5 A. -- on these graphs.
6 502 Q. Correct. And, similarly, you would
7 agree with me that there are fewer individuals
8 who are partially vaccinated that haven't been
9 admitted to the hospital as compared to those who
10 are fully vaccinated and those who are fully
11 vaccinated with an additional dose; correct?
12 A. Based on these raw numbers. Again,
13 we -- we would need to look at additional
14 information to --
15 503 Q. Well, we'll get to that. I'm just
16 asking you to confirm what we're seeing on the
17 screen. And then also I take it --

18 MS. TELLES-LANGDON: Mr. Presvelos, you
19 just interrupted Dr. Lourenco.
20 MR. PRESVELOS: I'm asking a question and
21 Dr. Lourenco's telling me there's more
22 information needed.
23 MS. TELLES-LANGDON: Yes.
24 MR. PRESVELOS: She's already stated that
25 there's more information needed. We will get

AR09778
1 into what information is needed. My question is
2 very straightforward and the witness, frankly, is
3 being evasive. These are aggregate numbers on
4 the government's website. I'm simply asking for
5 a very simple observational confirmation that the
6 number of individuals across all categories who
7 are partially vaccinated are lower than those who
8 are fully and those with an additional dose. It
9 doesn't have to be a difficult exercise.
10 MS. TELLES-LANGDON: Yes. Well,
11 Mr. Presvelos, you can ask the question but if
12 the witness says yes, the aggregate is a smaller
13 but there's an explanation, the witness is
14 entitled to provide that explanation and provide
15 any answer. She's allowed to answer the
16 questions as she thinks is appropriate.
17 There is nothing evasive about the way in

18 which Dr. Lourenco was responding to your
19 questions.
20 MR. PRESVELOS: Okay. Well, I disagree.
21 504 Q. And, Dr. Lourenco, I'm going to give
22 you the opportunity to provide a full answer
23 because I -- I take it that you believe that
24 there's additional information necessary to
25 interpret this data and we will talk about that;

AR09779
1 I'm going to ask you about that.
2 I would just like you to confirm that what
3 I'm observing on these aggregate numbers are
4 true. So we went through the number of cases;
5 we've gone through the number of
6 hospitalizations, and I take it that you will
7 also agree with me that the total number of
8 Canadians who are partially vaccinated and who
9 have died are fewer than the total number of
10 Canadians who are fully vaccinated and died and
11 those who are fully vaccinated with an additional
12 dose; is that correct?
13 A. Based on these data, yes.
14 505 Q. Right. And this is data that the
15 federal government has collected and aggregated
16 from each of the provinces and territories;
17 correct?
18 A. I -- yes, that's my understanding.
19 506 Q. Right. And so when I asked you to
20 explain to me earlier why it is that we're
21 observing that those who are partially vaccinated
22 -- i.e., have one dose of the vaccines -- fare
23 better in terms of being infected with COVID-19,
24 being hospitalized as a result of COVID-19 or
25 dying result of COVID-19, you told me that

AR09780
1 additional information is required to interpret
2 this data; correct?
3 A. Yes.
4 507 Q. What is missing to make sense of why
5 those who are partially vaccinated on an -- on an
6 individual -- on an aggregate number basis are
7 faring much better in terms of not being
8 infectious -- or infected, not being hospitalized
9 and not dying?
10 This is your opportunity to tell me
11 exactly what you think is missing.
12 A. So these are just raw numbers, crude
13 numbers that are being reported over time and my
14 understanding is this is cumulative information
15 that's being collected since -- ever since the
16 pandemic started or ever since vaccination was
17 rolled out in December of 2020.

18 508 Q. Right.
19 A. And -- and so these are just very
20 crude raw numbers of cases that are being
21 collected and it's being sampled from different
22 -- different numbers of people. So at the
23 beginning of the campaign we had the vast
24 majority of the country where no one was
25 vaccinated, so you -- you would have many more

AR09781
1 cases coming from unvaccinated individuals. As
2 we move through the vaccination campaign, then
3 you started to have some people partially
4 vaccinated and then others fully vaccinated.
5 And so where these numbers come from, like
6 the -- the -- sort of the pool of people where
7 these numbers come from is constantly changing
8 and so you can't just draw conclusions from these
9 graphs without doing further analysis. What we
10 really need to look at is properly conducted
11 observational studies in the post-market setting
12 that look at how well partially vaccinated versus
13 unvaccinated versus fully vaccinated people do.
14 And as I have in my Exhibit "S" which was
15 provided to me by the Public Health Agency, you
16 can see there that vaccines are still providing
17 protection against -- against severe disease,

18 including with Omicron.
19 509 Q. So are you aware of government
20 figures that would be more accurate than the data
21 or more accurate in order for somebody to
22 interpret the data and the information that's
23 presented on this website?
24 A. More accurate data will come from
25 those observational studies.

AR09782
1 510 Q. Okay. And have you reviewed
2 observational studies comparing partially
3 vaccinated to vaccinated individuals?
4 A. Not -- not myself personally. It's
5 something I would have to go back and check with
6 the team.
7 511 Q. Do you know whether your team would
8 have reviewed observational studies of comparing
9 partially vaccinated to fully vaccinated
10 individuals?
11 A. I'm not sure. I'd have to -- I'd
12 have to check.
13 MR. PRESVELOS: Okay. So I will ask for
14 an undertaking that Dr. Lourenco consults with
15 her team to ascertain whether or not anyone in
16 the team would have reviewed studies comparing
17 partially vaccinated from fully vaccinated, and

18 also to provide an undertaking to disclose the
19 studies that they would have reviewed and relied
20 upon.
21 MS. TELLES-LANGDON: Those are two
22 separate undertakings, Sam.
24 U/A MS. TELLES-LANGDON: We'll take them both
25 under advisement.

AR09783
1 BY MR. PRESVELOS:
2 512 Q. Okay. But, Dr. Lourenco, you'd
3 mentioned earlier that part of your concern about
4 these figures is that this began -- these numbers
5 reflect numbers from the beginning of the
6 campaign -- of the vaccine campaign to the
7 present time.
8 But you agree with me right now in Canada
9 that there are vaccines available for any
10 Canadian who wishes to be vaccinated; correct?
11 A. Not for children under -- under six
12 years of age -- five years of age. That's --
13 children under five years of age we don't have
14 vaccines currently authorized for that age group,
15 but for everyone else above that age range yes,
16 we do have.
17 513 Q. So you agree with me that the

18 children under five would also not be partially
19 vaccinated?
20 A. Right. Children under five would not
21 be. They would be under the unvaccinated
22 category unless they were vaccinated off-label --
23 is what we call "off-label" using a current
24 vaccine at the decision of their treating
25 physician.

AR09784
1 514 Q. Right. Dr. Lourenco, you agree with
2 me that you, in your affidavit, have relied on
3 some of the figures contained in this -- from the
4 government's website here; correct?
5 A. Yes, I have relied on some of the
6 figures. Yes.
7 515 Q. And some of the figures you relied on
8 include the hospitalization and death figures;
9 correct?
10 A. Yes, I included -- I included those
11 figures as part of one of my exhibits. Yes.
12 516 Q. How come your affidavit didn't
13 qualify the level of caution that you just
14 advised we should have when reviewing raw or, as
15 you put it, crude numbers?
16 A. The -- the information was provided
17 for information as -- as in terms of the context.

18 I could have elaborated further, I just didn't --
19 didn't decide to do that.
20 517 Q. But clearly you agree with me that
21 you think this is important context what you just
22 told me; right?
23 A. It is. It is important context, yes.
24 I agree.
25 518 Q. Could we go to paragraph 119 of your

AR09785
1 affidavit, please?
3 which paragraph?
4 MR. PRESVELOS: One, one, nine which
5 appears on page 31 of Dr. Lourenco's affidavit.
6 THE WITNESS: Yes.
7 BY MR. PRESVELOS:
8 519 Q. Just take a moment and review that,
9 please.
11 A. Yes.
12 520 Q. So you state that "authorization may
13 be revoked if new information does not support
14 the safe and effective use of the product."
15 Right?
16 A. Yes.
17 521 Q. So can you just elaborate on what

18 would -- what would -- what you would mean by the
19 "effective use of the product" here?
20 A. Effective we mean -- I mean the
21 effectiveness -- the effectiveness of the
22 product. So if we observe that over time the
23 vaccine no longer shows effectiveness, then we
24 could engage with the manufacturer to assess
25 whether the vaccine should -- continues to show a

AR09786
1 positive benefit risk ratio.
2 522 Q. And is this -- are you considering
3 effectiveness here only in terms of being
4 infected with COVID-19 or adverse or developing
5 -- developing a severe illness in response to
6 COVID-19? What metric are you using?
7 A. It's the severe illness, yes.
8 523 Q. Why is that not --
9 A. Severe illness.
10 524 Q. Why is that not stated in your
11 affidavit?
12 A. I do believe I refer to that in other
13 areas of my affidavit where I talk about how
14 severe disease is an important endpoint that we
15 -- that we continue to monitor in the -- in the
16 post-market. I don't remember exactly which
17 paragraph, but it's in my affidavit.

18 525 Q. You do. But you agree with me that
19 it would be very relevant to know the criteria
20 against which your department may revoke the
21 vaccines from use; correct?
22 A. It -- yes, it's important to know the
23 criteria. We know what the criteria are.
24 Certainly the criteria would be if we start to
25 see a significant decrease in effectiveness of

AR09787
1 the vaccine; that would prompt us to take action
2 with the -- with the manufacturers.
3 526 Q. And what's the threshold level in
4 terms of the effectiveness at preventing severe
5 illness before you decide -- before you
6 potentially decide to revoke the authorization?
7 Is that the 50 percent that you mentioned
8 earlier?
9 A. Certainly if we start to see it below
10 50 percent, that would -- that would prompt the
11 discussion.
12 527 Q. So, 50 percent on an RR basis of the
13 vaccines' effectiveness at preventing severe
14 illness, that's the threshold at which you may
15 consider to revoke the authorization of the
16 vaccines; correct?
17 A. That would be the threshold at which

18 we would engage with the manufacturer to have a
19 discussion. We would likely also engage with the
20 public health officials to have a discussion
21 around that finding and seeing if -- what would
22 -- what will be the general recommendation or
23 consensus on whether to maintain the vaccine on
24 the market or not.
25 528 Q. And how would you decide between

AR09788
1 revoking the vaccine or simply requiring a
2 booster shot?
3 A. Right. That's a good question. So I
4 think the way we would do that is if we note that
5 booster shots are no longer being effective, so
6 it would need to be in the context of booster
7 shots as well. So if a booster shot is no longer
8 showing effectiveness, that's -- that would be
9 the context that we would then engage with the
10 manufacturer.
11 529 Q. So if I understand this correctly, if
12 you have the vaccine plus a booster and it
13 provides 50 percent or less effectiveness against
14 severe disease, that would trigger
15 reconsideration of whether or not you're going to
16 authorize these drugs?
17 A. It -- it could. So if we -- if we
18 notice that after -- so we've got the primary
19 series, then we've got booster shots. If we
20 notice that the booster shot is no longer
21 providing protecting to that 50 percent against
22 severe disease, I think that would be a situation
23 that would prompt us to take further action.
24 Yeah.
25 530 Q. And what studies is the Canadian --

AR09789
1 as far as you're aware, what studies is the
2 Canadian government currently doing to continue
3 to monitor the effectiveness of the COVID-19
4 vaccines as against preventing severe illness?
5 A. So on my side as the regulator, we
6 don't conduct studies ourselves. We may engage
7 other -- others to conduct studies, for example,
8 the Drug Safety & Effectiveness Network is an
9 organization we may engage to conduct studies on
10 behalf of the government.
11 What we -- what we do is we monitor
12 studies that are emerging in the literature and
13 the Public Health Agency may have their own
14 network; I'm not familiar exactly where they
15 engage with different -- different public health
16 professionals to -- to monitor vaccine
17 effectiveness.
18 531 Q. Okay. To date, have you had a
19 discussion with the drug manufacturers and other
20 governmental departments about possibly revoking
21 the authorization for any of the COVID-19
22 vaccines?
23 A. No, we have not had those
24 discussions. The data that we continue to see
25 and the observational studies continue to show

AR09790
1 that the vaccines are effective against the
2 Omicron variant.
3 532 Q. Well, I'm going to help you here a
4 little bit. When you say "effective," do you
5 mean effective against severe disease or
6 effective against infection?
7 A. Effective against severe disease,
8 yes.
9 533 Q. Right. Because that's an important
10 distinction; right?
11 A. Yes, agree.
12 534 Q. Right. Let's go back to paragraph
13 179 of your affidavit for a moment.
14 A. Okay.
15 535 Q. And mid-sentence -- sort of
16 mid-sentence, you say "Vaccination is one of the
17 most effective ways to protect against COVID-19

18 and the emergence of new VOCs" -- so new variants
19 of concern; correct?
20 A. Right.
21 536 Q. What percentage of the Canadian
22 population do you believe would need to be
23 vaccinated in order to help prevent against the
24 emergence of new VOCs?
25 A. I don't know the answer to that.

AR09791
1 537 Q. Do you know whether this is something
2 that your team has considered?
3 A. No, this is not something my team
4 would have considered.
5 538 Q. So paragraph 179, Roman numeral six,
6 it's the bottom of page 46.
7 A. Yes.
8 539 Q. Take a moment and read that sentence,
9 please.
11 A. Yes.
12 540 Q. Okay. You indicate that based on the
13 information provided to you by PHAC, which you
14 reviewed, it is "...recommended having as many
15 people vaccinated as possible to possibly reduce
16 the risk -- the impact of COVID-19 on the
17 healthcare system." Right?

18 A. Yes.
19 541 Q. Have you reviewed any studies
20 detailing what impact COVID-19 has had on the
21 Canadian healthcare system?
22 A. No, I have not personally reviewed
23 studies on the impact on the healthcare system.
24 This would be something that Public Health Agency
25 would -- would be very familiar with.

AR09792
1 542 Q. Okay. And if you look at Roman
2 numeral five:
3 "The studies show having as many people
4 vaccinated as possible may reduce the risk
5 both of ongoing circulation of the virus
6 and the appearance of future variants."
7 We've dealt with the latter topic; now
8 let's deal with the former one. How do you
9 reconcile waning immunity with a reduction in the
10 ongoing circulation of the virus?
11 A. Okay. Right. So this has to do with
12 transmission --
13 543 Q. Right.
14 A. -- may reduce the risk. So there's a
15 chance that it may reduce the risk of ongoing
16 circulation through transmission; so that's what
17 we're trying to -- what I'm trying to say there.

18 544 Q. Okay. Can you please go to paragraph
19 188 of your affidavit?
20 A. Okay.
21 545 Q. Just take a moment and review that,
22 please.
24 what paragraph?
25 MR. PRESVELOS: Paragraph one, eight,

AR09793
1 eight, which appears on page 49 of Dr. Lourenco's
2 affidavit.
3 MS. TELLES-LANGDON: All right. Thank
4 you.
7 BY MR. PRESVELOS:
8 546 Q. So these figures are the figures that
9 you would have taken from the same website that
10 we looked at together; correct?
11 A. Yes.
12 547 Q. And you would agree with me that the
13 same qualification you stated on the record
14 earlier about the figures I was using in figure
15 five would equally apply to these statement,
16 i.e., that there was a vaccine rollout and
17 therefore there's a period of time where certain

18 people in the population could not have been
19 vaccinated at an -- at earlier periods of time;
20 correct?
21 A. Right. And then the number --
22 correct. The number of individuals in each of
23 those categories changes over time.
24 548 Q. Right. So there would have
25 necessarily been a higher risk of people being

AR09794
1 unvaccinated and infected because, at the
2 beginning of the pandemic, there was a
3 prioritization of the vaccines, right, for those
4 most at risk?
5 A. There would have been a higher risk
6 because there were -- there were much fewer
7 people vaccinated. You're correct, because there
8 was a prioritization of the amount of supply that
9 we had available, which was very limited, was
10 prioritized to higher-risk individuals --
11 549 Q. Right.
12 A. -- at the beginning.
13 550 Q. Okay. Do you monitor vaccine uptake
14 on an ongoing basis in the Canadian population?
15 A. No, that's the role of the Public
16 Health Agency together with the provinces and
17 territories.
18 551 Q. Okay. So vaccine uptake is not
19 something that you would -- you would pay
20 particular attention to in your day-to-day job?
21 A. No, it's not -- as the regulator,
22 it's not -- it's not something that we -- that we
23 monitor. We do look at -- when we're looking at
24 analyzing the safety of the vaccines, we look at
25 number of doses that have been administered from

AR09795
1 that perspective to look -- to look at them in
2 terms of the safety, putting it in the context of
3 number of doses administered.
4 But that's as far as we go in terms of
5 monitoring vaccine uptake. We don't delve into
6 areas that are more public health -- of public
7 health concern around vaccine uptake.
8 552 Q. So I take it you'll agree with me,
9 then, you are not consulted by any other
10 governmental department or agency on ways in
11 which the government could improve vaccine uptake
12 in the Canadian population?
13 A. Correct. I'm not consulted on that.
14 553 Q. Okay. I'm going to take you back to
15 the website that we were looking at earlier; just
16 give me a second. I refreshed it just to make
17 sure our numbers are up to date.

18 So can you see -- can you see my screen?
19 A. I can.
20 554 Q. Okay. So we have key updates on the
21 left-hand side is total cases; right?
22 A. Yes.
23 555 Q. On the right-hand side are total
24 deaths; correct?
25 A. Right.

AR09796
1 556 Q. I take it that you're familiar with
2 the terms "case fatality rate"?
3 A. Yes.
4 557 Q. And I take it you'll agree with me
5 that the way you determine case fatality rate is
6 you divide the number of cases by the number of
7 deaths?
8 A. Yes.
9 558 Q. Okay. And do you agree with me that
10 the total cases that are represented in the
11 left-hand box do not include asymptomatic cases?
12 A. That, I'm not sure. I'm not sure if
13 it includes asymptomatic cases that happen to be
14 detected. Certain of the -- by chance is what I
15 meant to say. Detected by chance people
16 sometimes are admitted to hospital and they may
17 be screened for COVID-19 and then the case will

18 be detected by chance.
19 So even though they may have been
20 hospitalized for another reason, so there may be
21 cases like that as well that are asymptomatic.
22 559 Q. Right. Okay. And I'm glad that you
23 went there, because that's -- that's my next
24 question. Is all this data comes from the
25 provinces and territories of Canada; right?

AR09797
1 A. Right.
2 560 Q. And each province and territory has a
3 different manner in which they define "death," is
4 that correct, as it pertains to COVID statistics?
5 A. That, I'm not familiar with. I can't
6 comment on that in terms of their definitions.
7 561 Q. So do you know -- sorry, I take it
8 you do not know which provinces have included
9 deaths as a result of COVID-19 or deaths with
10 COVID-19? You don't know which provinces adopt
11 either approach?
12 A. I don't know, no.
13 562 Q. Okay. So to the extent there are
14 provinces that count a death as somebody dying
15 with COVID-19 that --
16 MS. TELLES-LANGDON: So -- sorry,
17 Mr. Presvelos.
19 MS. TELLES-LANGDON: I'll let you finish
20 your question, but it really is looking like
21 you're -- she said she doesn't know. You're now
22 asking her to speculate.
24 563 Q. Okay. Okay. I don't have too many
25 more questions. Just a few questions for you,

AR09798
1 Doctor. But I take it as part of your role you
2 look at therapeutics for COVID-19; right?
3 A. Yes. The -- just --
4 564 Q. Okay.
5 A. -- for the biologics. The biologic
6 therapeutics, yes.
7 565 Q. Okay. What other therapeutics are
8 there?
9 A. There's also pharmaceutical small
10 molecule therapeutics. You may have heard the
11 drug Paxlovid --
12 566 Q. Yeah.
13 A. -- that was authorized. So that --
14 that one was not under my responsibility. I'm
15 responsible for the monoclonal antibody biologic
16 therapeutics for COVID-19. Remdesivir is another
17 one that would not be under my responsibility.

18 567 Q. Okay. You're going to have to --
19 you're going to have to walk me through this a
20 bit more. So there are biological therapeutics
21 and you gave us an example of monoclonal
22 antibodies?
23 A. Yes. Monoclonal antibodies is a
24 class, biologic therapies and --
25 568 Q. What else have you looked at?

AR09799
1 A. Those would be all. Those -- the
2 monoclonal antibodies would be all that we looked
3 at so for -- for COVID-19 therapeutics.
4 569 Q. Okay. So -- and that's under the
5 biological therapeutics?
6 A. Yes.
7 570 Q. I'll stop sharing my screen, it's a
8 distraction. And what's the second category of
9 therapeutics you mentioned to me?
10 A. Pharmaceuticals. So small molecule
11 pharmaceutical therapeutics. Those -- I --
12 they're not of biologic origin. Those are not
13 within my responsibilities just the way we're
14 organized at Health Canada in terms of where the
15 products are -- are regulated.
16 571 Q. And so for the pharmaceutical
17 therapeutics, Remdesivir was one of them?

18 A. Right. Remdesivir and Paxlovid is
19 another one that both of them have been
20 authorized by Health Canada but they were not
21 under my responsibility.
22 572 Q. Whose responsibility is it for the
23 pharmaceutical therapeutics?
24 A. It's a different director general
25 within the same branch that I work in, but a

AR09800
1 different director general. At the moment the --
2 the person just retired, the director general, so
3 there's a rotational acting at the moment for
4 that position.
5 573 Q. So this director general, I take it,
6 is your colleague; right?
7 A. Yes.
8 574 Q. You're both sort of in the department
9 but slightly different scope of -- of
10 responsibilities, let's say --
11 A. Correct.
12 575 Q. -- or product; right?
13 A. Yeah.
14 576 Q. And I take it you communicate with
15 this other director general with respect to these
16 pharmaceutical therapeutics that might be
17 available for COVID-19?

18 A. Yes, we communicate and discuss.
19 Yeah.
20 577 Q. So I take it you're familiar with
21 some of these pharmaceuticals, if not all of the
22 pharmaceutical therapeutics that might be
23 available in Canada to treat COVID-19; correct?
24 A. I'm familiar. I'm familiar. If we
25 get into details around efficacy of safety, then

AR09801
1 I would not be able to really comment on those --
2 on those aspects.
3 578 Q. Well, do the two of you not update
4 each other as to the efficacy of these
5 therapeutics both that you are developing or
6 responsible for overseeing in response to
7 COVID-19?
8 A. No, we don't get into those details.
9 579 Q. Okay. Are you -- do you -- are you
10 aware as to what the effectiveness of Remdesivir
11 or Paxlovid is at reducing severe illness from
12 COVID-19?
13 A. No, I'm not aware of that. I'm not
14 aware of the -- of those metrics.
15 580 Q. So I take it you've never looked at
16 any studies that might demonstrate how effective
17 either of those two therapeutics are at

18 preventing severe illness or disease?
19 A. No, I have not. I have not looked at
20 metrics.
21 581 Q. Okay. And in terms of what you're
22 responsible for just biologic therapeutics --
23 biological therapeutics; right?
24 A. Yes.
25 582 Q. You mentioned the only one is mono --

AR09802
1 monoclonal antibodies.
2 A. So the monoclonal antibody is the
3 class. We -- we did authorize a number of
4 different ones. We -- would you like me to list
5 them?
6 583 Q. How many are there?
7 A. There are -- so there's Sotrovimab,
8 Ronapreve, Bamlanivimab and Evusheld. Four.
9 584 Q. So there's four of them that are
10 currently authorized for use in Canada?
11 A. Yes, correct. Three are them are
12 authorized for treatment and one of them -- the
13 last one, Evusheld, is authorized for prevention
14 of COVID-19.
15 585 Q. And I take it that the biological
16 therapeutics and the pharmaceutical therapeutics
17 both have the same objective, right, which is to

18 reduce severe disease and death of COVID-19 among
19 Canadians?
20 A. The -- so the ones that are --
21 586 Q. Well, three of the four that you
22 mentioned, to be fair to you, because you said
23 one was about prevention, three was about actual
24 therapeutics; right?
25 A. Three -- the three that are to treat,

AR09803
1 yes. They're to -- they are meant to treat mild
2 to moderate --
3 587 Q. Okay.
4 A. -- COVID-19. So yes, it's to make
5 sure that patients don't progress in their
6 disease and they can make it through their
7 infection without going -- without progressing to
8 severe disease or hospitalization and so on and
9 so forth.
10 588 Q. And I take it you reviewed studies on
11 the effectiveness of the three of the four
12 monoclonal antibodies?
13 A. On the -- yes, we reviewed studies on
14 the efficacy. On the efficacy --
15 589 Q. Yeah.
16 A. -- so clinical trials on the efficacy
17 of all four monoclonal antibodies.

18 590 Q. And what about on the effectiveness
19 in the population? Have you reviewed studies on
20 that?
21 A. Effectiveness in the population, I'm
22 not -- I'm not sure we have --
23 591 Q. Okay.
24 A. -- reviewed results of those. I'd
25 have to check with the team.

AR09804
1 MR. PRESVELOS: If you could. I will ask
2 for that as an -- as an undertaking, please, any
3 studies that they would have considered in terms
4 of the monoclonal -- mono whatever -- antibodies'
5 effectiveness in the population. I don't have
6 the patience for multisyllabic words maybe, I
7 don't know.
9 advisement.
11 592 Q. And in terms of the efficacy of these
12 antibodies, what did you observe for the three
13 that are used for the treatment of COVID, not for
14 the one that's used for prevention? Did you --
15 can you recall sitting here today? And if it's
16 -- if you can't, that's fine, I'll just ask for
17 an undertaking. I don't want you to guess and be

18 wrong.
19 A. I'll just speak in general terms that
20 we observed that the treatments reduced the risk
21 of progressing to severe disease, but I can't
22 remember off the top of my head what the figures
23 were in terms of the percent reduction.
24 593 Q. And would that have been on an RR
25 basis?

AR09805
1 A. Yes, that's RR -- RR basis, yes.
2 594 Q. And what threshold would it have to
3 have to reduce the disease by in order for you to
4 approve it?
5 A. For treatments, it is different.
6 It's -- we didn't set a threshold. It's a
7 different kind of setting than for vaccines.
8 595 Q. Okay.
9 A. What we were looking for there is we
10 wanted to make sure that there was a significant
11 decrease in the risk between the treated patients
12 and the patients who were not treated. That
13 there was a statistically significant decrease.
14 We would need to make sure that there was enough
15 patients enrolled in the trial, and that the
16 outcome was statistically significant in terms of
17 the impact on reducing the risk of progressing to

18 severe disease or hospitalization.
19 596 Q. But do you know what threshold that
20 would have been?
21 A. We didn't set a -- there wasn't a
22 threshold that was set.
23 597 Q. Right. Because in the -- for the
24 vaccines, I think you told me that the threshold
25 is 50-percent reduction infection on an RR basis;

AR09806
1 right?
2 A. Right. Because we're dealing with
3 healthy people, so you're giving the vaccine to
4 healthy individuals; you want to make sure that
5 it's going to at least prevent 50 percent reduce
6 the risk of infection in people who are
7 vaccinated in a group of vaccinated individuals
8 by at least 50 percent.
9 For treatment, it's different. You're
10 treating an individual; you want to make sure the
11 treatment shows significant efficacy versus --
12 versus a non-treated group, but we don't have a
13 threshold for that.
14 598 Q. It's different because in one
15 instance you're inoculating healthy people; in
16 another instance, you're introducing a drug to
17 unhealthy people and so the risk sort of profile

18 -- the risk scenarios are different between those
19 two categories of people; right?
20 A. The risk scenarios are different.
21 They are, yes.
22 599 Q. Right. And you mentioned that one of
23 these antibodies actually is being used for
24 prevention.
25 A. Yes.

AR09807
1 600 Q. So the treatment; right?
2 A. Right.
3 601 Q. So I take it has a similar objective
4 as the vaccines, then?
5 A. It has a similar objective as the
6 vaccines, yes.
7 602 Q. Sitting here today, do you recall how
8 -- do you recall what the efficacy was of that
9 antibody in preventing COVID-19 infection?
10 A. I don't remember it off the top of my
11 head, sorry.
12 603 Q. I'm going to include this as part of
13 the previous undertaking because I'm interested
14 in all of this.
15 And would you have applied the same
16 threshold to that antibody as you did to the
17 vaccines, the 50-percent RR reduction of

18 infection threshold?
19 A. Right. I have to check that. I have
20 to see what the -- what was applied there in
21 terms of making sure that we had an efficacy rate
22 that we were agreeing to, so I'd have to check on
23 that one.
24 604 Q. Okay.
25 MS. TELLES-LANGDON: Sam?

AR09808
1 MR. PRESVELOS: Yes.
2 MS. TELLES-LANGDON: Sorry, Mr. Presvelos.
3 MR. PRESVELOS: It's okay.
4 MS. TELLES-LANGDON: You just said I'm
5 going to include this in the previous
6 undertaking. Which undertaking, to be clear for
7 the record, please?
8 MR. PRESVELOS: Yeah. Now I'm not clear.
9 I think I might have asked for all the
10 information on the efficacy and effectiveness of
11 the monoclonal antibodies, the three that are
12 used for therapeutics, the one that is used for
13 prevention.
14 So I guess that's under the umbrella of I
15 would like to have all the research or data that
16 Dr. Lourenco would have review -- would have
17 reviewed and considered in approving these

18 monoclonal antibodies.
19 MS. TELLES-LANGDON: So before I even take
20 that undertaking under advisement --
22 MS. TELLES-LANGDON: -- as we recall from
23 Friday similar that type of -- that data was
24 available on Health Canada's website for the
25 vaccines. Dr. Lourenco, is that information

AR09809
1 available at least efficacy, the information that
2 was reviewed to approve those treatments
3 available on Health Canada's website?
4 THE WITNESS: It -- it should be
5 available. I'll need to check for Evusheld as
6 that's the latest one that we authorized, and it
7 takes us some time to publish the results. But
8 the intent is to publish all the results on our
9 website.
11 605 Q. If -- you know, if it's there, rather
12 than produce what's already produced, if you
13 could just direct me to send me the link.
14 Because I -- as a lawyer, I find it difficult to
15 navigate your website.
16 U/T A. Okay.
17 606 Q. So I can't -- I can't imagine other

18 people. But it's tough for me to find it; I was
19 trying to go through the studies and stuff over
20 the weekend -- nothing better to do -- and I
21 found it took me probably about 20 minutes to get
22 to where I thought I needed to go. So if -- if
23 it's out there, that's fine; I'm not going to ask
24 you to produce what's already published.
25 But if you can just assist me by way of

AR09810
1 undertaking just give me the link specifically to
2 each of these monoclonal antibodies, the studies,
3 the -- the efficacy studies and the effectiveness
4 studies assuming the latter is published, that
5 would be helpful.
6 U/T MS. TELLES-LANGDON: Okay. Thank you,
7 Mr. Presvelos, for that clarification. So that
8 for any of the information where you've requested
9 that Dr. Lourenco provide it by way of
10 undertaking, if it's available on Health Canada's
11 website we will provide links to that data rather
12 than providing you with the what I'm anticipating
13 by now are hundreds pages of data.
14 MR. PRESVELOS: Yeah. Unless -- unless
15 there is something Dr. Lourenco would have
16 reviewed that's not published or has not yet been
17 published such that you cannot give me a link to

18 it, then obviously I would -- I would -- I would
19 require that information since it's not publicly
20 available.
21 MS. TELLES-LANGDON: Okay. And --
22 MR. PRESVELOS: Excuse me.
23 MS. TELLES-LANGDON: -- I don't know how
24 much longer you have, Mr. Presvelos. Is this --
25 would this be an appropriate moment for a short

AR09811
1 break?
2 MR. PRESVELOS: It's a very appropriate
3 moment for a short break, and I was going to
4 suggest it myself. So why don't we take ten
5 minutes if that's okay with everybody. We'll
6 come right back at, let's say, 11:45?
7 MS. TELLES-LANGDON: Okay. We'll go off
8 the record, then.
9 --- OFF THE RECORD (11:33 A.M.)
10 --- UPON RESUMING (11:50 A.M.)
12 607 Q. All right. Dr. Lourenco.
13 A. Hello.
14 608 Q. If we can go to tab C -- Exhibit "C"
15 to your affidavit.
16 A. Okay.
17 609 Q. So did you author this letter?

18 A. No. So, this I did not author, and
19 it is a -- not a formal letter. It's a table
20 compiling all of the different terms and
21 conditions that we have imposed on the Moderna
22 Spikevax Vaccine.
23 610 Q. Were you involved in imposing some of
24 the terms and conditions on the Moderna vaccine?
25 A. Yes, I was involved in imposing all

AR09812
1 of them.
2 611 Q. All of them.
3 A. Yes.
4 612 Q. Right. And what was -- if you can
5 just explain to me, what was the -- what is --
6 maybe there's more than one -- what's the purpose
7 of having imposed the terms and conditions that
8 you have summarized in this exhibit?
9 A. It's to deal with any remaining
10 uncertainties around the vaccine. It could have
11 -- it could be, for example, uncertainties around
12 the longer term efficacy or safety of the vaccine
13 or in additional information that may be needed
14 related to the manufacturing of the vaccine and
15 also to deal with the -- the safety monitoring of
16 the vaccine.
17 So those are some examples of why we --

18 why we impose the terms and conditions.
19 613 Q. Right. And some of these terms and
20 conditions, like you said, require further
21 information, further studies about several issues
22 pertaining to the vaccine.
23 A. Further information from ongoing
24 studies or from new studies, yes.
25 614 Q. Right. So you agree with me, then,

AR09813
1 that as to -- as it stands today, we have
2 imperfect knowledge as to all of the potential
3 long-term consequences of COVID-19 vaccines.
4 It's not yet complete.
5 A. There is additional information
6 needed for long term. It's considered -- yes,
7 it's considered missing information in the data
8 that's available.
9 615 Q. Right. And I take it that the
10 missing information is -- is -- would be relevant
11 to your continued authorization of these trials?
12 A. It would be relevant to the continued
13 authorization, yes.
14 616 Q. And where I see this for the other
15 drugs, so I think you've -- let's see, that's for
16 Moderna. I have here for Pfizer Bio -- so you
17 have here for BioNTech at Exhibit "B"; right?

18 A. Yes.
19 617 Q. And all the comments you made with
20 respect to Exhibit "C" would apply to Exhibit
21 "B"; right?
22 A. That's right. Yes, it would.
23 618 Q. Can you please go to Exhibit "D"?
24 A. Okay.
25 619 Q. Who prepared this?

AR09814
1 A. This was prepared by the
2 manufacturer, by Pfizer together with BioNTech.
3 620 Q. Right. So this was prepared by the
4 pharmaceutical company and submitted to you?
5 A. Correct.
6 621 Q. What's the purpose of the risk
7 management plan?
8 A. The purpose of the risk management
9 plan is to have a structured plan for the
10 monitoring of the vaccine in the post-market, it
11 will identify certain adverse events of special
12 interest and will identify also areas where there
13 are data gaps, there's missing information that
14 the sponsor will address in the post-market
15 either through monitoring of ongoing trials or
16 monitoring of the safety of the vaccine through
17 real-world use or by conducting new studies in

18 the post-market.
19 622 Q. And -- and do you or anyone from your
20 team -- do you or anyone from your team review
21 this and provide feedback to the authors of this
22 risk management plan?
23 A. Yes, we review it. Now, it's not my
24 team, it's a team that works in the Marketed
25 Health Products Directorate which is a sister

AR09815
1 directorate that is responsible for the
2 pharmacovigilance of products once they're
3 marketed. So it's another director general
4 colleague of mine who's responsible and it's her
5 team that reviews these documents.
6 623 Q. Would you -- are you copied on any
7 discussion threads concerning the review of this
8 document?
9 A. My team is copied. Myself
10 personally? No. I just receive the final
11 recommendation after the document is reviewed.
12 But my team is involved in the discussion
13 process, and there is a report that's prepared by
14 my DG colleague, director general teams -- team
15 prepares a report that is sent to my team for
16 consideration.
17 624 Q. And your -- and that's an internal

18 report. Not -- this report would not be prepared
19 by anyone from the pharmaceutical companies?
20 A. Correct. It's an internal report
21 from the review of the risk management plan.
22 MR. PRESVELOS: Wonderful. So, Sharlene,
23 I will -- or sorry, counsel, I will ask for an
24 undertaking for a copy of that report that would
25 be prepared.

AR09816
2 advisement. And also, Mr. Presvelos, before the
3 break just to be clear the other undertaking we
4 were discussing is also taken under advisement of
5 the review and all these undertakings afterwards.
6 MR. PRESVELOS: Sure.
7 625 Q. Doc, can you go to page 17 of this
8 risk management plan?
9 A. Which one? The one that --
10 626 Q. The same one that we're on. Exhibit
11 --
12 A. Exhibit "D"? Okay. And 17?
13 627 Q. Mm-hmm.
14 A. Okay.
15 628 Q. So there's table five here says,
16 "Additional pharmacovigilance activities for
17 addressing missing information specific for

18 Canada."
19 So this is a chart of certain studies or
20 certain data that the pharmaceutical companies
21 anticipate on gathering and introducing?
22 A. Yes.
23 629 Q. Okay. And I take it that some of
24 these studies could not yet be produced because
25 they are due to be completed the following year;

AR09817
1 right?
2 A. Some of these may have been produced
3 subsequently because this is the initial. Let me
4 just check. I believe this is the initial risk
5 management plan for the vaccine, so they may have
6 been produced. This is the August 2021 version
7 of the risk management plan which -- which -- it
8 would have been before we, for example, reviewed
9 the -- the studies for children under 12 years of
10 age as an example.
11 So some of these studies could have been
12 already produced to us.
13 MR. PRESVELOS: Okay. For those studies
14 -- so this is for your -- so this is for counsel.
15 For those studies that are 2022 and beyond I
16 would like an undertaking to identify whether
17 those studies have been produced ahead of the

18 expected delivery and an undertaking for the
19 information that would have been produced in
20 that.
21 I'm going to ask for that in respect of
22 Exhibit "D" and also when expected Exhibit "E"
23 from Moderna which is also a risk management
24 plan. And I take it you're probably going to
25 take it under advisement?

AR09818
1 MS. TELLES-LANGDON: Sorry, Exhibit "D"
2 and Exhibit "E"?
3 MR. PRESVELOS: Mm-hmm.
4 MS. TELLES-LANGDON: Can you be a little
5 bit more specific, Mr. Presvelos, about what it
6 is you're seeking?
7 MR. PRESVELOS: Yes. So tab D is a
8 document called "Risk Management Plan, Canada
9 specific addendum" and this is prepared by
10 Pfizer. It's dated August 2021. On page 17
11 there's a table and it's table five and there are
12 certain studies with milestones for completion.
13 And I'm asking that to the extent that the
14 completion due date is 2022 or beyond -- so this
15 year or beyond -- I would like an undertaking to
16 advise whether the study has been completed and
17 to produce a copy of the study so completed.

18 So that's for Exhibit "D" and in Exhibit
19 "E" this is Moderna's version of the risk
20 management plan.
21 630 Q. Oh, do they not have a similar table?
22 Dr. Lourenco, do you know why they don't have a
23 specific? Am I missing something here?
24 A. They -- the risk management plans are
25 prepared independently by the manufacturers, so

AR09819
1 they may -- they may have different
2 information -- they may display the information
3 differently. There's table two with missing
4 information.
5 631 Q. Oh, "Moderna promises to provide a
6 monthly safety report for the period of the
7 interim order." Is the interim order still in
8 effect?
9 A. No, the interim order is no longer in
10 effect.
11 MR. PRESVELOS: Okay. So then I guess it
12 will be -- I guess it will be in respect of
13 exhibit -- Exhibit "D" from Pfizer.
14 U/A MS. TELLES-LANGDON: Thank you for your
15 clarifications and positions, Mr. Presvelos, and
16 we will take that under advisement.
18 632 Q. Dr. Lourenco, I think, like, two or
19 three more questions and you're finished -- you
20 know, we're finished, at least with me. Can we
21 go to Exhibit "K"?
22 A. Okay.
23 633 Q. This is "Guidance for market
24 authorization requirements for COVID-19
25 vaccines."

AR09820
1 A. Correct.
2 634 Q. Did you or your team prepare this
3 document?
4 A. Yes, my team prepared this document.
5 635 Q. Okay. So take it you're familiar
6 with the contents of the document?
7 A. Yes, I am familiar.
8 636 Q. And I take it that part of what this
9 document discusses is how you communicate about
10 the COVID-19 vaccine which is something you and I
11 touched upon earlier?
12 A. That is correct, we -- we do have a
13 section in the document that discusses that on
14 page 11.
15 637 Q. Yeah. Can you go to page nine,
16 please?
17 A. Okay.
18 638 Q. Actually, sorry. To be fair, let's
19 go back -- let's go back to page eight for a
20 second.
21 A. Okay.
22 639 Q. Page eight starts with a label --
23 with a title called "Labelling and post-market
24 requirements." Right?
25 A. Right.

AR09821
1 640 Q. And there are several sub-titles:
2 Brand name, assessment, risk management plan,
3 safety specification, pharmacovigilance plan and
4 there's something called a risk minimization
5 plan; correct?
6 A. Yes.
7 641 Q. And you agree with me that part of
8 the risk minimization plan is "robust labelling
9 with warnings and precautions"?
10 A. Yes.
11 642 Q. Why is that part of a risk
12 minimization plan?
13 A. So that's reflect -- that is
14 highlighting or reflecting on the fact that we
15 require the product monograph for each of the
16 vaccines which should be sufficiently
17 comprehensive to include all the warnings and

18 precautions for the vaccine. So that's part of
19 the risk minimization plan when we're looking at
20 an overall risk management plan for the product
21 that includes also the product labelling, which
22 -- including the product monograph.
23 643 Q. And -- and what purpose do warnings
24 serve on a label?
25 A. Warnings serve the purpose of

AR09822
1 informing the healthcare provider and the patient
2 around potential risks associated with the
3 vaccine.
4 644 Q. And you agree with me that it's
5 important to inform the potential user of a
6 particular vaccine what risks may be associated
7 with using that vaccine; right?
8 A. Yes, agree.
9 645 Q. And it's important because that, in
10 turn, might inform their design as to whether or
11 not they want to be vaccinated with that vaccine?
12 A. Yes, agree.
13 646 Q. Right. And you have here education
14 materials. What -- what sort of -- what type of
15 education materials is being contemplated as part
16 of the risk minimization plan?
17 A. The educational materials refer to

18 materials that the manufacturer may develop for
19 the vaccine administration sites to use when
20 administering the vaccine. It could be
21 educational materials around how to prepare the
22 vaccine, how to administer it, what type of
23 information to communicate to subjects or to
24 people who are getting vaccinated.
25 So those kinds of materials.

AR09823
1 647 Q. Would you ever allow a vaccine
2 product be developed without labelling that
3 includes the warnings involved in taking a
4 particular vaccine?
5 A. No, we would not -- the labelling is
6 something that's required as per the Food and
7 Drugs Drugs Act and regulations, and so products
8 are required to have appropriate labelling so
9 that -- and instructions for use so both the
10 healthcare professional as well as patients can
11 be properly informed.
12 648 Q. Dr. Lourenco, did you write your
13 affidavit?
14 A. Yes, I wrote my affidavit.
15 649 Q. So each of the paragraphs that appear
16 in your affidavit are paragraphs which you have
17 written yourself?
18 A. Yes.
19 MR. PRESVELOS: Okay. So subject to the
20 undertakings, under advisements and refusals,
21 those are my questions and I thank you very much
22 for being patient with me.
23 THE WITNESS: No problem.
24 MR. PRESVELOS: Thanks.
25 MS. TELLES-LANGDON: So we will take a

AR09824
1 lunch break now and then resume in -- is
2 45 minutes sufficient for you, Dr. Lourenco, and
3 for you madam court reporter?
4 THE WITNESS: Yes, that will fine with me.
5 COURT REPORTER: Yes, that's fine.
6 MS. TELLES-LANGDON: Is that fine with
7 you, Mr. Wilson?
8 MR. WILSON: Certainly. What time would
9 you like to resume?
12 CROSS-EXAMINATION BY MR. WILSON:
13 650 Q. Good afternoon, Dr. Lourenco. Can
14 you hear me okay?
15 A. Good afternoon. Yes, I can hear you
16 well.
17 651 Q. Thank you. My name is Keith Wilson;

18 I'm legal counsel for one of the applicant groups
19 known as the Peckford group.
20 You understand that you're still under
21 oath?
22 A. I understand.
23 652 Q. Thank you. And that you're required
24 to give truthful answers to my questions?
25 A. Yes.

AR09825
1 653 Q. Thank you. I'm going to use my best
2 efforts to not cover the same questions that
3 you've answered from my friend Mr. Presvelos, but
4 I may occasionally need to sort of lay a
5 foundation that may have some overlap, but your
6 counsel will catch me if I'm going too far.
7 I'd understood that you testified that
8 it's your position that Canadians who've received
9 COVID-19 vaccines can still become infected with
11 A. Correct, they can still be infected
12 with the -- with the virus that causes COVID-19.
13 654 Q. Right. And they can still transmit
14 it; right?
15 A. Yes, they can still transmit it.
16 655 Q. So my question is when you initially
17 issued the authorizations, the approvals for the

18 COVID-19 vaccines, was it your understanding at
19 that time that the administration of the vaccine
20 would prevent people from becoming infected and
21 transmitting?
22 A. My understanding at the time of the
23 authorization was -- was that the vaccines could
24 prevent infection, but we did not receive any
25 data in the submissions filed by the

AR09826
1 manufacturers that addressed the question of
2 transmission.
3 656 Q. Okay. So when you issued your
4 authorization, it was your understanding that if
5 a Canadian was vaccinated that they would not
6 become infected; correct?
7 A. When we authorized the vaccines we
8 based the authorization on data that showed a
9 relative risk reduction or that -- showed data
10 that would reduce the risk of people in the
11 community becoming infected if they're
12 vaccinated.
13 657 Q. That it would simply reduce the risk
14 or that a vaccinated person would not become
15 infected?
16 A. That it reduces the risk. So
17 vaccines are not a hundred percent effective, so

18 even if one person -- if a person is vaccinated,
19 it doesn't mean that they will not be -- become
20 infected with the virus.
21 658 Q. So the -- you're aware that there was
22 statements from public health leaders and
23 political leaders in our country that encouraging
24 and the President of the United State, Joe Biden,
25 that by getting vaccinated people would stop

AR09827
1 infections.
2 Were you aware of those statements at the
3 time? They were prevalent.
4 A. I may have heard those statements,
5 but preventing people from -- that would prevent
6 people from being infected. It's not an
7 incorrect statement, it's just that it's not a
8 hundred percent -- the vaccines are not a hundred
9 percent effective so some people can still be
10 infected for sure.
11 659 Q. But that wasn't part of the message,
12 though, was it? It was that by taking the
13 vaccine, we would stop COVID-19; correct?
14 MS. TELLES-LANGDON: Mr. Wilson, sorry --
15 THE WITNESS: Yes.
16 MS. TELLES-LANGDON: -- part of whose
17 message?
18 MR. WILSON: The message of the Government
19 of Canada, of which she is a part.
20 MS. TELLES-LANGDON: Well, I would ask,
21 Mr. Wilson, that you be more specific. Health
22 Canada's messaging? The -- she isn't a -- she
23 isn't part of the Government of Canada. She's a
24 public servant; there's a distinction.
25 MR. WILSON: What's that distinction?

AR09828
1 MS. TELLES-LANGDON: The Government of
2 Canada consists of elected officials that are
3 serving them as a parliament. The public service
4 serves the government of the day with a duty of
5 full and frank advice and loyal implementation
6 and the public service is nonpartisan.
7 MR. WILSON: Excellent. That's a
8 distinction I'd not heard before. But -- so
9 thank you for sharing that.
10 660 Q. Did Health Canada, in the messaging
11 that you were involved in, seek to make it clear
12 that the -- getting a vaccine for COVID-19 would
13 not actually prevent people from getting
14 infected?
15 A. In the messaging that I was involved
16 in as we -- we did issue press statements and we
17 also had -- we held pressers with our

18 spokespeople, Dr. Sharma and Dr. Berthiaum. We
19 talked about vaccine efficacy in those pressers
20 and -- and we always highlighted what the vaccine
21 efficacy was and we did not indicate that it's a
22 hundred percent effective; we provided the actual
23 numbers that came out of the clinical trials.
24 So 95-percent effective, for example, for
25 -- for the Pfizer and the Moderna vaccines, a bit

AR09829
1 less effective for some of the other vaccines.
2 661 Q. And you'd agree with me that the
3 Canada-wide use of COVID-19 vaccines has not
4 prevented the continued spread of COVID-19 within
5 Canada; correct?
6 A. It has not prevented the continued
7 spread. It -- if we're talking about spread and
8 transmission, it's -- there's certainly data that
9 show that there are -- there's a decrease in --
10 there's an effect of the vaccines on decreasing
11 severe disease. In terms of spread, we're seeing
12 at the -- well, spread, I can't speak to it, but
13 we can -- I can speak to the fact that we're
14 saying data in terms of infections, in terms of
15 infection that -- that the vaccines are not as
16 effective anymore against infection with -- with
17 the Omicron variant.

18 662 Q. Thank you. And we've had lots of
19 discussion and there's been lots written both by
20 the various medical experts for the applicants in
21 this case as well as in the -- a number of the 16
22 affidavits that the respondent Attorney General
23 has filed about the efficacy and effectiveness.
24 You've testified, is my understanding,
25 that the approval threshold for you to issue the

AR09830
1 authorization was a 50-percent reduction in
2 infections; correct?
3 A. A 50-percent reduction in infections
4 in the vaccinated group compared to the control
5 group, yes.
6 663 Q. Right. And that we -- the evidence
7 is now that the efficacy is much lower than that,
8 correct, much lower than 50 percent?
9 MS. TELLES-LANGDON: Mr. Wilson, can you
10 please specify a timeframe for that efficacy
11 because the document that Dr. Lourenco pointed to
12 earlier breaks that down based on periods of time
13 relative to when that second dose is provided.
14 BY MR. WILSON:
15 664 Q. Okay. You would agree with me that
16 in the present timeframe that the 50-percent
17 threshold is no longer being met and it's a much

18 lower efficacy percentage; correct?
19 MS. TELLES-LANGDON: But, Mr. Wilson, in a
20 timeframe relative to -- because I'm assuming
21 we're talking about the Omicron variant, not
22 present time, but in a timeframe relative to when
23 doses are provided.
24 MR. WILSON: I don't think I need to get
25 that precise. Either -- either it's still -- if

AR09831
1 she wants to break down the categories to her
2 answer, that's fine. But I -- it's either at
3 50 percent or it's not, and I'm pretty sure the
4 evidence has come out a number of times that it's
5 much lower because I'm leading to my -- to my
6 next question from that. The precision of the
7 categories isn't critical to what I'm getting at
8 here.
9 665 Q. It's just we're not at 50 percent
10 anymore; is that true?
11 A. Yes. So the data with regards to
12 identification to efficacy against -- or effect
13 -- effectiveness in observational studies that
14 are -- that have been done in the post-market
15 suggest that the vaccines are really there is an
16 initial response, but people who are vaccinated
17 initially within the first few weeks still show

18 efficacy -- effectiveness, however, that wanes
19 very quickly. That decreases very quickly.
20 666 Q. So why not make it an expectation for
21 continued authorization that that 50-percent
22 threshold be maintained throughout its use? Why
23 is it suddenly 50 percent is the threshold for an
24 authorization but dropping below 50 percent is
25 not a threshold for withdrawal?

AR09832
1 A. Right. So because we -- in the
2 post-market setting when we're looking at vaccine
3 effectiveness, the key measure that we're looking
4 for is against severe disease. And when we're
5 looking at effectiveness against severe disease
6 the vaccines continue to -- to meet a threshold
7 and surpass -- surpass the 50-percent threshold.
8 667 Q. Is that true, though? Has it always
9 been the thresh -- the target being severe
10 disease? Is it not the case that the original
11 objective of the development of COVID-19 vaccines
12 was to stop the spread?
13 A. The original submissions that were
14 filed by the manufacturers had the primary
15 endpoint of identification -- of preventing
16 identification. We did not receive any data that
17 looked at the spread of transmission. It was

18 focussing on identification, and we used the
19 infection endpoint as that in the context of a
20 pandemic.
21 It's a much more feasible endpoint to
22 assess vaccine efficacy, and we know that if a
23 vaccine is effective against infection then it is
24 expected that it will also be effective against
25 severe disease. In the clinical trials -- so we

AR09833
1 have the primary endpoint as infection, and then
2 we also wanted to make sure that there were some
3 cases of severe disease in the trials. All the
4 companies had to demonstrate that their vaccine
5 was also effective against severe disease as a
6 primary -- as a secondary endpoint.
7 Now, in the post-market setting after the
8 vaccines are out and being used, severe disease
9 is certainly an important -- the most important
10 endpoint that we're looking for. Absolutely we
11 would like to see the vaccines prevent infection
12 as well, but if the vaccines are not preventing
13 infection to the -- in an effective way,
14 certainly they -- severe disease is the primary
15 endpoint that we look for. Prevention of that
16 severe -- severe condition.
17 668 Q. Thank you. So my understanding

18 you've been working with Health Canada I believe
19 for 20 years; is that correct?
20 A. About 21 years now, yes.
21 669 Q. Yeah. And throughout that time the
22 primary focus of your work has been related to
23 approving pharmaceutical drugs, vaccines and
24 those types of things?
25 A. Correct.

AR09834
1 670 Q. Okay. And you'd agree with me that
2 there's a general process that's followed not
3 just in Canada, but in other countries by
4 pharmaceutical companies when they want to seek
5 approval from you as the regulator for a new
6 product; correct?
7 A. Correct.
8 671 Q. And would you agree with me that --
9 that one of the steps that you would expect a
10 pharma company to take would be in-vitro and
11 animal models on testing of their drugs?
12 A. Yes, generally that's our
13 requirement.
14 672 Q. And is that one of the reasons why we
15 see experts in this field having the word
16 veterinary in their CVs quite frequently is
17 because the initial testing phase is often on

18 animals and not humans?
19 MS. TELLES-LANGDON: You're asking
20 Dr. Lourenco to speak to the experts that are in
21 this case?
22 MR. WILSON: I'm speaking generally about
23 the people in her profession who are involved in
24 medical research for pharmacological drugs and
25 vaccines. Is it -- is one of the reasons why we

AR09835
1 tend to see people with experience in veterinary
2 research involved in this field?
3 MS. TELLES-LANGDON: I'm not sure you've
4 established that as a factual -- as a factual
5 foundation. Generally people are --
6 MR. WILSON: Well, she just acknowledged
7 that animal testing is part of the first phase of
8 testing; animals are looked after by
9 veterinarians, so...
10 MS. TELLES-LANGDON: Yeah. That's the --
11 that's the piece, Mr. Wilson, that you have not
12 established as a factual foundation. Animal
13 studies are done by many, not just veterinarians.
14 I mean, that's -- many of the experts have spoken
15 about clinical and preclinical work with the
16 distinction being treatment of those animals in
17 clinical and human trials, but they're not

18 necessarily veterinarians.
19 You have not established that as a factual
20 foundation.
21 BY MR. WILSON:
22 673 Q. Doctor, what disciplines in -- when
23 you're reviewing an application for approval and
24 you're looking at the early phases of the
25 research, would it be normal for you to see the

AR09836
1 animal elements of the research conducted perhaps
2 by veterinary colleges?
3 A. I can't really comment on that. I --
4 the -- the -- what we receive from the
5 pharmaceutical companies is studies that are
6 conducted either by the manufacturers themselves
7 or contracted to a third party, and I can't
8 really speak to whether the third parties are
9 veterinary colleges or the angle that you're
10 asking in terms of veterinary college or
11 veterinarian involvement.
12 674 Q. So veterinary medicine has nothing to
13 do with the approval process for animal research?
14 You've never seen that in all the studies you've
15 reviewed? You're under oath.
16 A. Yes. I can't say. I can't say
17 exactly how many studies we receive that were

18 conducted by veterinarians, for example, versus
19 other types of expertise. It -- it -- it's just
20 not -- I'm not -- I'm not sure the answer to
21 that.
22 675 Q. Yeah. And I -- and I wouldn't even
23 expect you to have an answer to how many because
24 that wasn't my question. But it is something
25 that you would see as part of your work in

AR09837
1 reviewing the animal studies for veterinary -- or
2 for pharmaceutical drugs and vaccines; right?
3 R/F MS. TELLES-LANGDON: Mr. Wilson, asked and
4 answered. She already said she can't speak to
5 that.
6 MR. WILSON: No, she said she can't speak
7 to the number of reports. I didn't ask her about
8 the number of reports. I've asked her within the
9 many studies she's reviewed whether she has seen
10 reference to people with -- that conduct
11 veterinary medical research in those studies.
12 MS. TELLES-LANGDON: So the nature of your
13 question from the beginning to the end of this
14 line has changed from "is it common" to now has
15 she ever seen.
16 MR. WILSON: That's correct, because you
17 objected to my question about it being common so

18 I narrowed the scope of it.
19 MS. TELLES-LANGDON: No, I -- sorry, I
20 object that you hadn't established the factual
21 foundation for the assumption of your question --
22 MR. WILSON: Well --
23 MS. TELLES-LANGDON: -- that it was
24 common.
25 MR. WILSON: -- I don't know we're going

AR09838
1 to --
2 MS. TELLES-LANGDON: And she already
3 answered the question when you narrowed the scope
4 to just does she see it and it was asked and
5 answered. She said she couldn't -- she said she
6 couldn't speak to it; she then said she had no
7 idea of the numbers.
8 And if you're asking has she ever seen,
9 that's obviously a much narrower question but
10 that's not how you -- has she ever seen is not a
11 question she's answered.
12 BY MR. WILSON:
13 676 Q. So what is -- what types of -- when
14 you review the adequacy of the work that's been
15 done by a pharmaceutical company in applying for
16 an authorization and you're looking at the animal
17 models, what kinds of things would you like to

18 see to satisfy yourself that the animal models
19 meet your expectation?
20 A. I'll speak to that in general terms
21 as that is something that is -- can get very
22 technical. It's more my team that would have the
23 expertise to really respond to that question.
24 But in general we want to make sure that the
25 studies are well-conducted, they're conducted

AR09839
1 under good laboratory practices, that there is an
2 appropriate study design, that the endpoints of
3 the study are clearly outlined, that we
4 understand what the test -- what the test item
5 is, what are we testing in this study and what is
6 it that we're going to measure in that study, and
7 that the methods that are being used to make
8 those measurements are -- are qualified and
9 validated.
10 677 Q. And the reason we do testing on
11 animals first is because we don't want to cause
12 harm to humans if there's adverse effects not yet
13 known from a drug in development; correct?
14 A. Yes, we start -- correct. We start
15 with animal studies first to -- as an initial
16 step to look for any potential risks, any
17 potential safety toxic effects of the -- of the

18 drug under development.
19 678 Q. Sure. And sometimes the standard
20 procedure is to increase the dosing quite high to
21 exaggerate the conditions to get another
22 opportunity for an early warning of an adverse
23 effect potential; correct?
24 A. That is correct. In the animal
25 toxicology studies -- in general in the animal

AR09840
1 studies, we administer a dose that's several-fold
2 higher than what is expected to be administered
3 in humans in order to establish a margin of
4 safety.
5 679 Q. Thank you. And after that, the
6 animal model phase, the next phase you'd agree
7 with me is the human trials phase one; correct?
8 A. Yes. In general after we -- we test
9 the new drug on animals and if we don't see any
10 particular safety concerns, then we move on to
11 studies in humans.
12 680 Q. And after the phase one, there is
13 human trial phase two; correct?
14 A. Yes, they can -- they can -- usually
15 when we launch a phase one, we would like it to
16 progress to a certain stage before starting phase
17 two. They can overlap to a certain extent, but

18 there is a bit of a -- a bit of a progression
19 starting with phase one, then phase one, then
20 phase three.
21 There can be overlaps, but there needs to
22 be information that comes out of the phase one
23 that is support -- that is sufficient to support
24 moving on to phase two.
25 681 Q. Understood, thank you. And phase two

AR09841
1 isn't the end of it. The final phase is human
2 trials phase three; correct?
3 A. That is the final phase in terms of
4 the progression of a product through clinical
5 testing before submitting the results to the
6 regulator for -- for review.
7 682 Q. Okay. The -- Health Canada in 2009
8 approved Prevnar 13, a pneumonia vaccine. Are
9 you aware of - of that -- of that approval at
10 all?
11 A. I don't have it -- I'm not aware of
12 -- I'm aware that it may have been authorized,
13 but I don't have any details around that
14 authorization.
15 683 Q. Okay. Do you know if it was approved
16 prior to the completion of phase three clinical
17 trials?
18 A. I don't -- I don't know that
19 information.
20 MR. WILSON: Could you undertake to
21 provide us the answer to that question --
22 MS. TELLES-LANGDON: We'll take it --
23 MR. WILSON: -- through your counsel?
24 U/A MS. TELLES-LANGDON: We will take that
25 under advisement.

AR09842
2 684 Q. The -- a further pneumonia vaccine --
3 MS. TELLES-LANGDON: Sorry, Mr. Wilson.
4 Sorry, Mr. Wilson, just before you go on. Can
5 you set out for me why you consider that to be
6 relevant?
7 MR. WILSON: What's that?
8 MS. TELLES-LANGDON: The undertaking that
9 you just requested, can you provide for me -- can
10 you set out for me why it is that you think the
11 approval of the Prevnar 13 vaccine is relevant?
12 MR. WILSON: I can, but I'm not going do
13 that right now. I'm going to do that in a moment
14 and I think it will become clear, but I will come
15 back to that.
16 685 Q. Now, Dr. Lourenco, in 2013 Pneumovax
17 23 was approved by Health Canada as a -- as a

18 pneumonia vaccine. Was that authorized for use
19 prior to completing the phase three clinical
20 trials?
21 A. I don't know the answer.
22 MR. WILSON: Could you undertake to
23 provide an answer to that through your counsel,
24 please?
25 U/A MS. TELLES-LANGDON: Again, we'll take

AR09843
1 that undertaking under advisement. But, Keith,
2 both of those undertakings are now subject to
3 some articulation of relevance.
4 MR. WILSON: You will have that in a
5 moment, madam. Thank you.
6 686 Q. The Shingles vaccine was approved in
7 2017. Was that vaccine -- had that vaccine
8 completed the phase three clinical trials prior
9 to being approved by Health Canada?
10 A. I don't know. We'll need to get
11 information on that.
12 MR. WILSON: Okay. I'm asking for an
13 undertaking to confirm whether that vaccine was
14 approved for use prior to completion of clinical
15 three -- phase three clinical trial.
16 687 Q. Was the HPV, the human papillomavirus
17 -- pardon my pronunciation there -- approved --

18 which was approved in 2006, was it approved and
19 authorized for use on the Canadian population
20 prior to completing phase three clinical trials?
21 A. I don't know the -- the answer as
22 well.
23 688 Q. Okay. And I'm going to ask for an
24 undertaking on that one.
25 The last ones that I wanted to ask you

AR09844
1 about are hepatitis B vaccine, was it approved
2 for use in Canada prior to completion of phase
3 three clinical trials?
4 A. The same answer there, I don't -- I
5 don't recall.
6 689 Q. Okay. And what about the annual flu
7 vaccine, was it approved prior to completion of
8 phase three clinical trials?
9 A. So the annual flu vaccine -- the
10 initial authorization of the flu vaccine
11 undergoes phase three clinical trials and is
12 authorized after the clinical trials are
13 completed. And then what happens subsequent to
14 that is as the strain changes year after year,
15 the manufacturers do what we call strain updates
16 and those strain updates don't require clinical
17 trials, so they just require the manufacturing

18 changes which they submit to us for our review
19 prior to authorization in the fall.
20 Because we rely on the initial
21 authorization of the vac -- of the initial
22 vaccine through its initial authorization of that
23 particular vaccine and the platform that it's
24 manufactured under.
25 690 Q. And that initial approval that you've

AR09845
1 just indicated underwent a -- completed its phase
2 three clinical trials before it was authorized;
3 correct?
4 A. Yes, it under -- underwent phase
5 three clinical trials before it was authorized.
6 691 Q. You'd agree with me that the phase
7 three clinical trial for the Pfizer COVID-19
8 vaccine is not scheduled to complete and is
9 ongoing until December of 2023; correct?
10 A. That's correct, the clinical trial is
11 ongoing. However, it has completed the phase --
12 the reporting-out phase for the purposes of
13 regulatory authorization. So for regulatory
14 authorization they needed to complete the phase
15 of the trial where they were able to provide data
16 on efficacy and safety up to a median of two
17 months of follow up of all the participants in

18 the clinical trial.
19 So once that was achieved, they submitted
20 the information to us for review and
21 authorization and initial authorization of the
22 vaccine if everything looked acceptable. The
23 trial, however, is continuing in order to collect
24 longer term safety and efficacy data.
25 692 Q. And you'd agree with me that with

AR09846
1 respect to the Moderna COVID-19 vaccine, that its
2 phase three clinical trial is ongoing until
3 December 29th, 2022; correct?
4 A. It is ongoing with the same
5 explanation as I gave for the Pfizer vaccine
6 where it met the readout that was required from
7 the trial in order to have regulatory review and
8 authorization -- initial authorization of the
9 vaccine, and then after that it continues in
10 order to collect longer term efficacy and safety
11 data to make sure that obviously that there are
12 no concerns in terms of longer term safety and
13 efficacy for the vaccine.
14 693 Q. And what about AstraZeneca, is it
15 still undergoing clinical phase three trials?
16 A. For the AstraZeneca, I believe so as
17 well the same -- the same situation where we're

18 following subjects for longer after the trial --
19 after the initial readout is provided for
20 regulatory review and authorization.
21 694 Q. Thank you. And finally the J&J
22 vaccine, what's its status? Is it still
23 undergoing clinical phase three trials?
24 A. I believe that is the status of that
25 one as well, the same explanation where the --

AR09847
1 the initial endpoint of the trial for the
2 purposes of regulatory authorization was reached
3 and we received the submission package with that
4 primary endpoint data around vaccine efficacy and
5 safety with subjects being followed for at least
6 a median of two months before we could consider
7 them all the data for authorization, then after
8 authorization continuing to monitor all the
9 subjects in the trial for longer term results.
10 MR. WILSON: Thank you. Counsel, do you
11 still need me to speak to relevance?
12 MS. TELLES-LANGDON: I would ask you to
13 still speak to relevance, Mr. Wilson.
14 MR. WILSON: Sure. The witness's
15 affidavit is replete with references to the
16 COVID-19 vaccines being safe and effective. The
17 witness has sought to assure us and the court

18 that there are processes and these are
19 long-established processes and they're widely
20 used, and so I am seeking evidence to confirm one
21 way or the other what the normal processes are
22 through other common widely-used vaccines in
23 Canada and how they compare to the steps that
24 were taken with respect to COVID-19 vaccine
25 approval which, is our submission, is highly

AR09848
1 relevant.
2 And so I'm giving you the courtesy of that
3 explanation for when you consider later whether
4 you're going to grant us the undertaking answers
5 to those questions or whether we're going to have
6 to fight out about it in a motion. So that's my
7 comment on that.
8 MS. TELLES-LANGDON: Thank you for that
9 articulation, Mr. Wilson, that will help with our
10 consideration.
12 695 Q. One of the -- Dr. Lourenco, what is
13 the status of immunity to the pharma --
14 pharmacological companies for the four COVID-19
15 vaccines that we've discussed? Has Health Canada
16 granted them an immunity from liability if
17 there's any future problems from being sued? Is

18 that part of your terms and conditions?
19 A. So that doesn't fall within my role
20 as the regulator; it would be another part of the
21 government, I believe the Public Health Agency,
22 that deals with that.
23 696 Q. So you don't have control over
24 whether a pharma -- pharmacological company
25 becomes liable for problems with their product or

AR09849
1 whether they're granted a legal immunity, you're
2 saying your understanding is that's the Public
3 Health Agency of Canada that makes those
4 decisions?
5 A. I -- I know that it's not mine. It's
6 not my role --
7 697 Q. Fair enough.
8 A. -- as a regulator. Yeah.
9 MR. WILSON: Thank you. It was either Eva
10 or Allison's going to help me with screen shares,
11 and if they could bring up the document -- the
12 web page "Drug and vaccine authorizations for
13 COVID-19; list of authorized drugs, vaccines and
14 expanded indications." I think Eva's going to do
15 that if the court reporter needs to give her
16 screen share permissions.
17 And this is one of the documents that was

18 sent earlier as well, counsel.
19 MS. TELLES-LANGDON: And what is the title
20 of the document, Mr. Wilson?
21 MR. WILSON: Let me see here. Maybe it
22 wasn't in there. In any event, we'll bring the
23 website up on the screen if we can, Eva. If you
24 need me to send you the link again, I can because
25 I had it open.

AR09850
1 MS. CHIPIUK: If you could just tell me
2 the name of the link again, please?
3 MR. WILSON: I will do better than that.
4 I will send it to you right now.
5 MS. TELLES-LANGDON: Yeah, Mr. Wilson,
6 could you please put the link into the chat for
7 the Zoom call?
8 MR. WILSON: Yeah, that's smart. Thank
9 you. Well, it's actually much more complicated
10 for me than it would seem. I'm operating off one
11 laptop and then I have a machine with all screens
12 and I'm operating that and the mouse doesn't go
13 from that to my laptop. But I have just e-mailed
14 Eva and I'll see if I can bring it up and paste
15 it into the chat.
16 The title is "Drug and vaccine
17 authorizations" and it's from the Government of

18 Canada list of authorized drugs and vaccines.
19 You had originally sent this one to me, Eva.
20 MS. CHIPIUK: It always sounds so easy in
21 the background. I didn't get your e-mail just
22 now and --
23 MR. WILSON: Okay.
24 MS. CHIPIUK: Sorry about that.
25 MS. TELLES-LANGDON: Mr. Wilson, should we

AR09851
1 just go off the record for a few minutes until we
2 get --
3 MR. WILSON: Yes, let's go off the record.
4 Thanks. Sorry about this.
5 MS. TELLES-LANGDON: -- this technical
6 piece sorted out.
9 BY MR. WILSON:
10 698 Q. So we've brought up on the screen a
11 Government of Canada website, the title of the
12 page is "Drug and vaccine authorizations for
13 COVID-19: List of authorized drugs, vaccines and
14 expanded indications." Scroll down, please.
15 Now, when I look at the -- so on the left
16 there's a table on this document; the table
17 comprise of six columns, the first column is the

18 authorization holder. So, for example, Pfizer,
19 AstraZeneca, et cetera. It then has a brand name
20 of the product, some other description of its
21 use, a control number, a date the authorization,
22 and then the final column -- and that's the one I
23 want to focus on -- is the authorization or
24 expanded indication.
25 And you'll notice, everyone looking at

AR09852
1 this screen, that you can see pretty much
2 everything in the column says "authorized with
3 terms and conditions" but when we go to the
4 second page I noticed that some just say
5 "authorized with no terms and conditions." Can
6 you help us, Dr. Lourenco, understand the
7 difference between a pharmacological or a vaccine
8 that is authorized versus one that is authorized
9 with terms and conditions?
10 MS. TELLES-LANGDON: Just before -- so,
11 Mr. Wilson, can you flag one that says it is
12 authorized and it doesn't show?
13 MR. WILSON: Sorry, I'm just having a hard
14 time hearing you, Sharlene.
15 MS. TELLES-LANGDON: Sorry. I -- I've not
16 found. You said some are authorized and they
17 don't have -- they're not authorized with terms

18 and conditions, I mean. So I see many --
19 MR. WILSON: Eva, can you --
20 MS. TELLES-LANGDON: -- that are
21 authorized.
22 MR. WILSON: There you go. There's one
23 right there.
24 MS. TELLES-LANGDON: There we go. I
25 hadn't seen that one.

AR09853
1 MR. WILSON: No problem. I understand.
2 699 Q. So, Dr. Lourenco, could you help us
3 understand the difference between one that's just
4 simply authorized and one that's authorized with
5 terms and conditions, please?
6 A. Sure. So for the ones that are just
7 authorized, the example that you have highlighted
8 there from Gilead Sciences Veklury, that
9 particular drug was filed under our normal
10 pathway for -- for drugs -- for drug submissions.
11 That's our division eight under the Food and Drug
12 regulations.
13 And under that normal pathway we don't
14 have the option for terms and conditions; we can
15 issue a notice of compliance and we can have
16 negotiations with the sponsor about additional
17 commitments that they can make, but there isn't

18 the regulatory authority to impose terms and
19 conditions under the normal pathway. Whereas --
20 as the reason why that's the case for Veklury
21 it's because it was filed before we had amended
22 our Food and Drug regulations, division eight,
23 with amendments that allowed terms and
24 conditions.
25 Those amendments were done in March of

AR09854
1 2021 -- March 18th, specifically, of 2021 -- and
2 so they came into effect at that point which was
3 after the initial filing of the -- of the Veklury
4 submission. Now, I note here that it was also --
5 so it was initially authorized under that pathway
6 and that's the reason why it doesn't have terms
7 and conditions, whereas for the ones that were
8 filed under the amended pathway, those have terms
9 and conditions.
10 There can also be circumstances where
11 we've decided not to issue terms and conditions;
12 maybe there were no -- no additional -- there was
13 no additional need for a term and condition on
14 the authorization.
15 700 Q. Okay. And so the other -- so we have
16 a normal pathway and then we have an amended
17 pathway; correct?
18 A. Right. Correct.
19 701 Q. And the -- the normal pathway that
20 existed prior to March 2021 was there, prior to
21 March 2021, ever an amended or alternative
22 pathway or was there only the normal pathway?
23 A. There was an interim order. There
24 was an interim order in effect from September of
25 2020 until September of 2021. So that interim

AR09855
1 order was used for a large number of the initial
2 authorizations of the vaccines and for some of
3 the treatments before the amended pathway was
4 introduced in March of 2021.
5 702 Q. Okay. So the interim order was
6 implemented in September 2020; correct?
7 A. Correct, yes.
8 703 Q. Prior to September 2020 -- that will
9 read better than it sounded -- the -- my question
10 is was there any alternative than the normal
11 pathway prior to the interim order of
12 September 2020?
13 A. Right. There was no -- no other
14 pathway prior to the interim order. It was the
15 regular pathway is what we had available for
16 authorizing a drug under the Food and Drugs Act.
17 704 Q. Okay. And so --

18 MS. TELLES-LANGDON: So for clarification,
19 do you mean ever or in the time period leading up
20 to the authorization of COVAX? Like ever in the
21 history of the Food and Drug Act? I just want to
22 know how to --
24 MR. WILSON: I'm going to -- I'm going to
25 object to that question of my witness, but I will

AR09856
1 narrow the scope of the question.
2 705 Q. In the previous five years, was there
3 an alternative to the normal pathway prior to the
4 interim order of September 2020?
5 A. In the previous five years, no, there
6 would not have been an alternative pathway. The
7 pathway we have for authorization is the division
8 eight of the Food and Drug regulations, the new
9 drug submission process. We have other pathways
10 for access, but they're not authorization
11 pathways.
12 706 Q. And you've been with Health Canada
13 for 21 years; has the normal pathway been in
14 place as far as you can recall for those
15 21 years --
16 A. Yes.
17 707 Q. -- prior to September 2020?

18 A. Yes, the normal pathway has been --
19 has been in effect for -- for -- yes, going back
20 to at least 21 years.
21 708 Q. And is it fair to say that the reason
22 for deviating from the longstanding normal
23 pathway and Health Canada being involved in a
24 change involving an interim order in September of
25 2020 and then an amended pathway through

AR09857
1 regulation in March of 2021, was solely because
2 of COVID-19?
3 A. COVID-19 was the trigger. We -- we
4 realized that, first of all, needed a pathway
5 that provided more flexibility and tools such as
6 terms and conditions, for example, the
7 requirement to -- the ability to impose terms and
8 conditions. So the way we did that was initially
9 through the interim order and then the amendment
10 of the Food and Drug regulations to introduce the
11 same tools in the actual regulations.
12 That said, we have used interim orders in
13 the past for the H1N1 pandemic in 2009, we also
14 had an interim order at that time to assist with
15 the regulatory process for the flu vaccine for
16 that -- for that -- for that pandemic.
17 MR. WILSON: Thank you. Unless counsel

18 objects, I'd like to have that web page marked as
19 -- as an exhibit. And we'll -- if it's not in
20 the e-mail package before the end of the day I'll
21 make sure a clean PDF of that document is
22 e-mailed.
25 EXHIBIT NO. 3: Drug and vaccine

AR09858
1 authorizations for COVID-19: List of
2 authorized drugs, vaccines and expanded
3 indications, Government of Canada website.
4 BY MR. WILSON:
5 709 Q. I thought I heard you say on Friday
6 -- and I may be mistaken -- in your
7 testimony that you require -- Health Canada
8 requires as part of the authorization to Moderna
9 for them to provide adverse events and
10 effectiveness updates as part of their
11 authorization; correct?
12 A. Yes, as part of their authorization
13 it's part of the terms and conditions to provide
14 us periodic updates.
15 710 Q. And did I understand correctly that
16 you indicated that Moderna has not in fact
17 provided those updates?

18 A. They -- no, they're continuing to
19 provide their updates. They provide monthly
20 safety report updates and they provide -- they
21 will provide, once available, the -- for example,
22 the results of their ongoing clinical trial
23 that's to be provided once available.
24 So I think what I spoke about on Friday
25 was in relation to the six-month follow-up data.

AR09859
1 For Pfizer, we have received the six-month
2 follow-up data. From Moderna, we have not yet,
3 but we should be receiving it soon. I don't have
4 a timeline, but it's -- it's on their terms and
5 conditions for them to file it once it's
6 available.
7 711 Q. Okay. So but it's -- but it's late?
8 Moderna's late?
9 A. I wouldn't say that they're late, I
10 would just need to check to see what -- is it --
11 is it because they haven't -- they don't have all
12 subjects followed for six months. I'm not sure
13 exactly what the -- what the issue is there. I
14 don't think that's the case, but I don't want to
15 speculate exactly why they haven't filed yet.
16 MR. WILSON: Can you undertake to provide
17 us a clear answer as to why Moderna has not yet

18 filed this required information?
19 MS. TELLES-LANGDON: Dr. Lourenco has
20 indicated that she doesn't think they're late at
21 this point.
22 MR. WILSON: Sorry, Sharlene, I couldn't
23 hear you.
24 MS. TELLES-LANGDON: I'm sorry.
25 Dr. Lourenco just said she doesn't think they're

AR09860
1 late at this point.
2 MR. WILSON: Well, that's not what I
3 heard. I heard that she hasn't received it yet
4 because she doesn't believe they've completed
5 some of the steps they were planning to complete
6 which is -- boy, I would have wished I had that
7 one in high school. That would have been great.
8 So my homework's done, it's just not all my steps
9 are complete. So I just --
10 MS. TELLES-LANGDON: Have you established
11 when it was due, Mr. Wilson?
12 MR. WILSON: No, I haven't.
13 MS. TELLES-LANGDON: So you're asking why
14 they haven't provided a report when you haven't
15 established that that report is yet due.
16 BY MR. WILSON:
17 712 Q. Dr. Lourenco, is that report yet due?

18 A. The -- the due date was when
19 available.
20 713 Q. All right. And is that the same due
21 date that the other pharma companies have?
22 A. Yes.
23 714 Q. How important is this information to
24 your ongoing review of the safety and
25 effectiveness of the four vaccines?

AR09861
1 A. For -- in terms of our ongoing safety
2 and effectiveness, we're certainly relying quite
3 significantly on the post-market safety data
4 that's emerging and post-market effectiveness
5 data as well especially given the changes in --
6 in the variants of concern, we're really
7 interested in seeing what's happening in the real
8 world now rather than necessarily the follow-up
9 of the subjects who were vaccinated with the
10 original -- with a vaccine during a time when the
11 original variant was circulating.
12 So we're more concerned about now the
13 post-market safety and the effectiveness as data
14 that we're seeing now in people in the real
15 world.
16 715 Q. And when -- when was the start date
17 for this for Moderna?

18 A. I don't know off the top of my head
19 when it -- when they started. Definitely in
20 2020, I just don't know exactly which month they
21 started.
22 MR. WILSON: Okay. Would you undertake to
23 get us the answer to that start date?
24 U/T MS. TELLES-LANGDON: Yes.
25 MR. WILSON: If Eva could bring up one of

AR09862
1 the public -- Health Canada public advisories
2 that we e-mailed earlier -- there's four in total
3 -- and perhaps start with the first one which I
4 believe is April 26th and put that on the screen,
5 please.
6 716 Q. So are you familiar with the document
7 that's on the screen, Dr. Lourenco?
8 A. Yes, I'm familiar.
9 717 Q. And how would you describe this
10 document? It reads at the top "Health
11 professional risk communication Janssen COVID-19
12 vaccine and the risk of thrombosis" and another
13 big medical word.
14 What am I looking at here?
15 A. This is a risk communication
16 targeting healthcare professionals who would be
17 involved in the -- in vaccinating individuals

18 with the COVID-19 vaccines and other healthcare
19 professionals to inform them about a safety issue
20 with the Janssen COVID-19 vaccine. The risk of
21 thrombosis with thrombocytopenia.
22 718 Q. So this is a warning that's issued by
23 Health Canada to -- to health professionals;
24 correct?
25 A. It's a warning that is issued by the

AR09863
1 manufacturer and posted by Health Canada. So the
2 manufacturer works very closely with Health
3 Canada on this, issues the risk communication
4 through their networks of healthcare
5 professionals and Health Canada does the same.
6 We publish it on our website and issue it
7 to our network of healthcare professionals.
8 719 Q. But you only do that because you
9 agree it's a warning that needs to be publicized;
10 correct?
11 A. Yes.
12 MR. WILSON: All right. If Ms. Chipuik
13 could bring up the next one, please? I believe
14 it's June 30th. And -- and while that's
15 happening, any objection, counsel, to the
16 April 26th Health Canada Advisory being marked as
17 an exhibit?
20 EXHIBIT NO. 4: Health Canada Advisory,
21 April 26, 2021
22 BY MR. WILSON:
23 720 Q. So this one's dated June 30th; it's
24 in the same format as the screen we looked at
25 previously. A public advisory, "Health Canada

AR09864
1 updates Pfizer and Moderna COVID-19 vaccine
2 labels to include information on myocarditis and
3 pericarditis."
4 Again, is this -- this -- so -- so is it
5 the same as the previous one? This would be
6 something that was identified by Pfizer and
7 Moderna and communicated to Health Canada?
8 A. This one -- this one is slightly
9 different in that is it a public advisory so the
10 audience is different. It's targeting the
11 general public; the previous one was targeting
12 healthcare professionals. And in terms of the
13 public advisory is it is generated by Health
14 Canada -- exclusively by Health Canada.
15 But based on certainly the safety data
16 that -- that we've come to become aware of
17 through post-market surveillance of the vaccine

18 in Canada and internationally.
19 MR. WILSON: Got it. Thank you for that.
20 I'd like to have this one marked as an exhibit as
21 well if that's okay?
23 EXHIBIT NO. 5: Health Canada Advisory -
24 Updates Pfizer and Moderna COVID-19
25 vaccine labels to include information on

AR09865
1 myocarditis/pericarditis
2 BY MR. WILSON:
3 721 Q. The next one on the list will be
4 August 6th, I believe -- yes, August 6th -- and
5 this one reads at the top "Public Advisory -
6 Health Canada updates Pfizer COVID vaccine labels
7 to reflect very rare reports of Bell's Palsy" and
8 it's dated August 6, 2021.
9 What would the origins of this warning be?
10 A. Also Health Canada's. We developed
11 and published this one.
12 722 Q. So the information you would get to
13 lead to Health Canada making the decision to
14 issue this public notice, is that from the
15 manufacturer or from the -- the pharmaceutical
16 company or is that from public health departments
17 in the provinces?
18 Like, help -- help us understand how you
19 find yourself issuing something like this.
20 A. It would come from multiple sources;
21 definitely the manufacturer, as well as reports
22 of adverse events that are filed -- that are
23 reported through the provinces and territories.
24 They report these adverse events directly to the
25 Public Health Agency and we would receive those

AR09866
1 adverse events as well through our collaboration
2 with the Public Health Agency.
3 It would also be reports that can be filed
4 by Canadians directly. They can file those
5 reports directly with us through our Canada
6 Vigilance database and then finally also
7 international. There would be international
8 reports that we would look at; we definitely want
9 to look at what the safety data look like in the
10 Canadian context but also internationally.
11 So all of that would be compiled in our
12 analysis that would lead then to this public
13 advisory.
14 723 Q. So you, as part of your normal
15 surveillance activity with respect to the safety
16 and effectiveness of drugs and vaccines that you
17 approve, you -- you pay attention to what's

18 happening in other jurisdictions and what your
19 colleagues there are finding, is that fair?
20 A. Yes, we do.
21 724 Q. And the last one I wanted to bring up
22 is dated November 9th. And did I have that last
23 one -- the most recent one -- the August one
24 marked as an exhibit? I've lost track. My -- my
25 brain's ahead of myself here.

AR09867
1 MS. TELLES-LANGDON: Not yet, but no
2 objection.
5 August 2, 2021
6 BY MR. WILSON:
7 725 Q. So this one is a public advisory. It
8 reads, "Health Canada is updating the labels of
9 Janssen and Vaxzevria AstraZeneca COVID-19
10 vaccines" and it's dated November 9th. So this
11 is also a public advisory as opposed to an
12 advisory to the -- to medical doctors?
13 A. Correct. This is also a broader
14 public advisory.
15 726 Q. Okay. And -- okay. Just go back up;
16 I just need to read that. Right there, stop.
17 Down a bit. So this is relating to -- it appears

18 that you had a concern -- Health Canada had a
19 concern about unexplained bleeding, unexplained
20 bruising, shortness of breath, chest pain, leg
21 pain and swelling following vaccination; is that
22 correct?
23 A. Yes, this is -- this is reflecting
24 the concern we had about cases of blood clots as
25 well as cases of -- cases of blood clots as well

AR09868
1 as cases of low blood platelets that can lead to
2 bleeding and blood clots that can lead to
3 shortness of breath or stroke, for example, that
4 can be a serious outcome. So we wanted to make
5 sure that the public was informed about -- about
6 this.
7 727 Q. Are you aware in your role at Health
8 Canada of any similar public warnings, public
9 advisory or a notification to medical
10 practitioners being issued for the Shingles
11 vaccine?
12 A. I'm -- I'm not. I can't say. I'm
13 not aware. I'd have to look into it to see if we
14 have issued any for the Shingles vaccine.
15 MR. WILSON: Would you undertake through
16 your counsel to make that inquiry and provide us
17 the answer as to whether similar public and

18 medical advisories, warnings had been issued for
19 the Shingles vaccine and, if so, to provide us
20 copies of those warnings?
21 U/A MS. TELLES-LANGDON: We'll take it under
22 advisement.
23 BY MR. WILSON:
24 728 Q. The same question with respect to the
25 two pneumonia vaccines; are you aware of any

AR09869
1 public -- Health Canada issuing a public advisory
2 or notification to medical practitioners with a
3 warning regarding those two new -- relatively new
4 -- pneumonia vaccines?
5 A. I'm -- I would have to verify. I'm
6 not -- off the top of my head, I don't know.
7 MR. WILSON: Fair enough. Would you
8 undertake through your counsel to provide the
9 answer to that question and copies of any such
10 advisories, if found?
12 advisement. Mr. Wilson, I just note we've been
13 going for approximately an hour since the lunch
14 break.
15 MR. WILSON: Sorry?
16 MS. TELLES-LANGDON: I'm sorry.
17 MR. WILSON: Sorry, I didn't hear you.

18 MS. TELLES-LANGDON: I note -- I note that
19 we've been going approximately an hour since the
20 lunch break. I'm not saying take a break now,
21 I'm just wondering if you just keep in mind when
22 there's an appropriate spot in your questioning
23 that --
24 MR. WILSON: Now would be. I'm about to
25 do a big shift, so now would be a good time.

AR09870
1 MS. TELLES-LANGDON: Okay. Then would ten
2 minutes be sufficient?
3 MR. WILSON: Yes, unless the -- I'm
4 actually -- pardon me. Dr. Lourenco, is ten
5 minutes sufficient for you? If you would like
6 longer time, I -- I want you to have that.
7 THE WITNESS: Ten minutes is sufficient
8 and I -- I do have a hard stop at 3 p.m. today.
9 MR. WILSON: Okay.
10 THE WITNESS: Yeah.
11 MR. WILSON: Thank you for letting us know
12 that. We'll be back in ten.
14 MS. TELLES-LANGDON: Thank you.
17 MR. WILSON: Welcome back. Just as a

18 housekeeping matter, I don't believe I had the
19 November 9th, 2021 Public Health Advisory --
20 Health Canada Advisory marked as an exhibit.
21 Could we mark that as an exhibit?
24 November 9, 2021.
25 BY MR. WILSON:

AR09871
1 729 Q. And just having a chance to review my
2 notes over the break, Dr. Lourenco, I'd
3 previously asked you whether you were aware of
4 any similar public health or public advisories
5 and warnings to the public and medical
6 professionals for certain vaccines; I'd like to
7 ask that same question with respect to the
8 hepatitis B vaccine.
9 Are you aware of any public health
10 advisories or warning being issued for that
11 vaccine?
12 A. I don't know off the top of my head.
13 MR. WILSON: Will you undertake through
14 your counsel to make an inquiry and provide same
15 if you find there is one?
16 U/A MS. TELLES-LANGDON: I'll take it under
17 advisement.
18 BY MR. WILSON:
19 730 Q. And finally the same question with
20 respect to the flu shot, can you advise as to
21 whether -- are you aware of whether any public
22 health advisory warning was issued to the public
23 from Health Canada or to medical professionals
24 with respect to the flu vaccine?
25 A. I don't know off the top of my head.

AR09872
1 MR. WILSON: If you could undertake
2 through your counsel to make inquiries and
3 provide an answer and copies of any said
4 advisories if they exist, please?
5 MS. TELLES-LANGDON: I'm sorry,
6 Mr. Wilson, --
7 MR. WILSON: Yes.
8 MS. TELLES-LANGDON: -- which flu vaccine?
9 Because the flu vaccine was initially approved --
10 Dr. Lourenco's evidence already was that the flu
11 vaccine initially was approved after phase three
12 trials, but then the annual variants are -- have
13 a different regulatory approval. But the flu
14 vaccine has been around for many, many, many
15 years.
16 BY MR. WILSON:
17 731 Q. Dr. Lourenco, when was the flu

18 vaccine initially approved for use in Canada by
19 Health Canada?
20 A. I don't have the date off the top of
21 my head. Many years for sure; I just don't have
22 the date.
23 732 Q. Would it be prior to your involvement
24 in 21 years of experience?
25 A. So I haven't been in this role all

AR09873
1 the 21 years, I've been in other roles. It may
2 have occurred while I was in other roles.
3 733 Q. Okay.
4 A. I don't know. We would have to get
5 that information.
6 MR. WILSON: I can -- I can -- that's a
7 fair concern that counsel's raised. I can narrow
8 it to review Health Canada's public and medical
9 advisory warnings with respect to the flu vaccine
10 for the last ten years and provide us with copies
11 of any public warning notices if they exist.
12 U/A MS. TELLES-LANGDON: Okay. We'll take
13 that under advisement.
15 734 Q. Dr. Lourenco, you've testified
16 earlier to me, actually in the last few minutes
17 prior to the break, how one of the things that

18 Health Canada does and that you do is look to
19 what's happening internationally with -- with
20 your colleagues in -- in other jurisdictions;
21 right?
22 A. Yes.
23 735 Q. So you're aware that the FDA had
24 requested that the documentation that Pfizer
25 provided in support of approval of the Pfizer

AR09874
1 COVID-19 vaccine be sealed for 75 years. Are you
2 aware of that?
3 A. No, I wasn't aware of that.
4 736 Q. Okay. And are you aware that U.S.
5 court earlier this year ordered the FDA and
6 Pfizer to make those documents available
7 including releasing them in 55,000-page tranches
8 beginning in March 1st of 2022?
9 Were you aware of that -- that event?
10 A. No, I wasn't really aware of that.
11 No.
12 737 Q. So then you'd agree with me that the
13 documents -- well, I guess I -- scratch that.
14 Have you seen the documents that were
15 submitted by Pfizer to the FDA in support of
16 their application for approval of COVID-19
17 vaccines?
18 A. So I have not personally seen the
19 documents, but what we did -- my team is the one
20 that will review the documents in detail that are
21 filed by the company. We did receive some
22 aspects of the same application that went to the
23 U.S. FDA, we also received it here. I just don't
24 know exactly which components, but some of them
25 are the same as what was filed to the U.S. FDA

AR09875
1 under their emergency use authorization process.
2 MR. WILSON: Thank you. Ms. Chipuik,
3 could you bring up the FDA advisory regarding
4 Janssen, please? And that would have been in the
5 e-mail package.
6 MS. TELLES-LANGDON: And which is the
7 title of the document, please?
8 MR. WILSON: It's entitled "FDA Advisory
9 Janssen.PDF." It's got a date of 2022 in front
10 of it. If someone else has it readily more
11 handy, that would be -- oh, here we go.
12 738 Q. So this is a news release from
13 May 5th of 2022 and it's an announcement by the
14 FDA limiting the use of Janssen COVID-19 vaccine
15 to certain individuals and it talks about the
16 risks of thrombosis, blood clotting and other
17 concerns that, according to the words of the FDA,

18 warrants "...limiting the authorized use of the
19 Janssen COVID-19 vaccine in certain individuals."
20 Were you aware of this?
21 A. Yes, yes, I was aware of this.
22 739 Q. And just so I'm clear, because I
23 confess I'm confused about this, is the Janssen
24 COVID-19 vaccine one of the vaccines that
25 Canadians can take in Canada?

AR09876
1 A. It is one of the vaccines that is
2 authorized for use in Canada. Whether they can
3 currently access it, that's a different question.
4 Given that the National Advisory Committee on
5 Immunization and the provinces and territories
6 are preferentially recommending the mRNA
7 vaccines, so the -- the Janssen vaccine may not
8 be readily available.
9 740 Q. Okay. So has Health Canada issued
10 any similar warning or limitation on use of
11 Janssen COVID-19 vaccine to certain individuals
12 the same individuals the FDA has said should not
13 receive it?
14 A. So we -- we have not. And the reason
15 for that is because the National Advisory
16 Committee on Immunization makes those
17 recommendations in terms of preferential use

18 whether some vaccines should be preferred over
19 others. The National Advisory Committee on
20 Immunization does that.
21 That said, we are looking at this
22 internally, we're reviewing this recommendation
23 from the U.S. FDA and the plan is to discuss it
24 also with other international regulators and see
25 if there's anything else we want to do in terms

AR09877
1 of our labelling and our recommendations for the
2 Janssen vaccine. But in the -- in the interim --
3 in the meantime, it is already well covered by
4 the fact that National Advisory Committees on
5 Immunization already does not recommend the use
6 of the Janssen vaccine unless the mRNA vaccines
7 are not available for use.
8 741 Q. So you've used throughout a term
9 throughout your affidavit as well as in your
10 testimony on Friday and today about your
11 authority to withdraw a -- a vaccine or a drug.
12 You have that authority; correct?
13 A. Yes.
14 742 Q. Okay. And why not issue a
15 restriction just like the FDA did for this
16 particular vaccine given what you know?
17 A. The -- the restriction's already in

18 effect given the recommendations from the
19 National Advisory Committee. They already
20 preferentially recommend the mRNA vaccines and
21 the availability of the Janssen vaccine -- I'm
22 not sure where it's at at the moment, but my
23 understanding is is may not even be available
24 anymore in Canada.
25 It's really the mRNA vaccines that are

AR09878
1 available along with the Novavax vaccine.
2 743 Q. So whose -- who decides? Is it -- do
3 you require the permission of this National
4 Committee before you issue a withdrawal or issue
5 a restriction on use similar to what the FDA has
6 done in the United States?
7 A. No. No, we don't need. We're
8 independent from the committee; we can take
9 independent -- we take independent steps as the
10 regulator. We are looking at this, as I -- as I
11 mentioned, but at the moment the risk to
12 Canadians is -- is very low given that the
13 vaccine is virtually not -- not available in
14 Canada.
15 744 Q. But how can you not know whether
16 there's some pharmacist in -- on Vancouver Island
17 who's got a case of this in his freezer or his

18 fridge?
19 R/F MS. TELLES-LANGDON: Mr. Wilson, you're
20 asking Dr. Lourenco to speculate.
21 MR. WILSON: Well, I'm asking her about
22 what assumptions she's making about distribution.
23 She's saying that well, this committee recommends
24 against it so, you know, nothing to see here.
25 And I just -- that just, with all due respect,

AR09879
1 seems somewhat a little careless given what the
2 FDA has done.
3 745 Q. And she -- you've confirmed,
4 Dr. Lourenco, that you have the authority to
5 issue a restriction on uses in addition to a
6 withdrawal; correct?
7 A. Yes.
8 746 Q. And you know there's a problem with
9 this vaccine but you haven't issued the
10 withdrawal or the restriction; correct?
11 A. We have not, no.
12 MR. WILSON: Thank you. I'd like to have
13 the FDA document marked as an exhibit, please.
15 EXHIBIT NO. 8: FDA Advisory Janssen.PDF
16 2022
17 MR. WILSON: I'm going to ask Mr. Abbott

18 to screen share. It's very important that law
19 students get to experience everything, so we --
20 we promised Mr. Abbott that we would do that.
21 747 Q. So I'm showing you a New England
22 Journal of Medicine report or article and it's
23 entitled "Safety and Efficacy of the BNT162b2
24 mRNA COVID-19 Vaccine through six months."
25 Are you -- are you familiar with this --

AR09880
1 this study?
2 A. Yes, I have -- I have seen this
3 before, yes.
4 748 Q. So is this the six-months -- Pfizer
5 six-month report?
6 A. This reflects the six-month report,
7 reflects the data that they have after following
8 their vaccine trial participants for six months.
9 749 Q. Right. And if Mr. Abbott could go
10 down to the page that shows 1767 on the bottom
11 right, and you'd agree with me that when -- and
12 you may have this just in your general knowledge
13 from your review of Pfizer's work, that after
14 unblinding the groups five more people were
15 listed as people who had died who got vaccinated;
16 correct.
17 You're aware of that?

18 A. I don't remember those details. That
19 would be information that my team would have
20 reviewed, but I can't -- I can't confirm.
21 750 Q. Okay. Fine. Now, if we could move
22 this six-month report prepared by Pfizer that
23 appears in the New England Journal of Medicine
24 has a supplementary appendix, and if we could
25 bring that up and if we go to table S-3 -- and if

AR09881
1 Mr. Abbott is able to with this document to
2 highlight some of the key information.
3 So, for example, you'd agree with me that
4 under adverse event in table S-3 on PDF page
5 11 --
6 MS. TELLES-LANGDON: Mr. Wilson, I'm just
7 going to interrupt you for a moment. Although
8 you did establish that Dr. Lourenco was aware of
9 the first document that you showed, you've not
10 established that Dr. Lourenco was aware of this
11 document.
12 She may well be, but you just haven't
13 established it.
14 MR. WILSON: Fair enough.
15 751 Q. Dr. Lourenco, did you have prior
16 knowledge of this appendix to the six-month
17 post-consumer report from Pfizer?

18 A. I have not seen this --
19 752 Q. Okay.
20 A. -- this post-report, no.
21 753 Q. All right. Well, I'd like to show
22 you a couple of things that's in it.
23 A. Okay.
24 754 Q. Under "adverse events" and "severe"
25 on the left-hand side, you see the word "severe,"

AR09882
1 you agree with me that what it shows is that
2 there were 262 instances of a severe adverse
3 event in those that were vaccinated but only 150
4 severe adverse events in those that were not
5 vaccinated with Pfizer; correct?
6 A. That seems to be what the table is
7 showing.
8 755 Q. Okay. And then the group -- there's
9 a further category of any -- "any serious adverse
10 event" and, again, it's showing, according to
11 Pfizer in their supplement to their six-month
12 report, 127 in the vaccinated group and only 116
13 in the placebo group; correct?
14 A. That's what I see in the table.
15 756 Q. All right. And the top line "any
16 event of adverse" it shows that there's 6,617
17 individuals who had an adverse event in the

18 vaccinated group but less than half, only 3,048
19 in the -- the unvaccinated placebo group;
20 correct?
21 A. Yes, that's what I see.
22 757 Q. So -- so you'd agree with me there's
23 risks involved in taking vaccine, isn't there?
24 A. Well, this table is listing these
25 events, but then these were events that were

AR09883
1 reported in the clinical trial and what we need
2 to do is do an assessment of each event to see if
3 the event could be possible or plausibly
4 associated with the vaccine or caused by the
5 vaccine. So these are just the raw numbers of
6 what was reported and then there needs to be an
7 additional assessment of each event.
8 758 Q. And is this normal when you're
9 reviewing an application for a drug or a vaccine
10 to see the adverse events to be very
11 significantly higher numerically in the study
12 group versus the placebo control group? Is this
13 normal?
14 A. Yes, we can see that and we do see
15 that very often where -- and it's an indication
16 of which group received the treatment or the
17 vaccine is the fact that there are adverse events

18 versus the group that received the -- it could
19 have been saline or something that is a placebo
20 that doesn't have the -- the active ingredient.
21 759 Q. I'm not -- maybe I wasn't clear. Are
22 you saying it is normal for there to be much more
23 adverse events in those who receive a proposed
24 drug or vaccine?
25 R/F MS. TELLES-LANGDON: Mr. Wilson, I'm going

AR09884
1 to --
2 MR. WILSON: Yeah.
3 MS. TELLES-LANGDON: -- object to the
4 qualifier "much." That's a normative statement.
5 The numbers are there.
6 MR. WILSON: Okay.
7 MS. TELLES-LANGDON: I'm not sure what the
8 level of --
9 MR. WILSON: Well, I'll be more precise.
10 Is it --
11 MS. TELLES-LANGDON: -- significance is.
12 You know, is it small number that might --
13 MR. WILSON: Fair enough. I'll -- I'll
14 restate my question, counsel.
15 760 Q. Is it normal in your experience of
16 reviewing and approving and issuing
17 authorizations for drugs and vaccines in Canada

18 to see double the number of adverse events in the
19 group that received the drug or vaccine relative
20 to the placebo group?
21 A. It -- it's not unexpected, I would
22 say and I'm not -- I would say that it's normal,
23 but it's not -- it's not unexpected that can
24 happen especially with a vaccine which is
25 expected to cause local -- what we call

AR09885
1 reactogenicity, a local -- a local reaction where
2 the vaccine is administered. That's much more
3 likely to occur in the vaccinated group than in
4 the placebo group, hence the reason for seeing
5 higher number of any event in -- in the -- in the
6 vaccinated group versus the placebo.
7 MR. WILSON: Thank you. I'd like to bring
8 up the -- the other attachment that shows the
9 adverse events from the other document. I'm not
10 sure if Ms. Chipuik or -- or Mr. Abbott's going
11 to bring this up on the screen for me. I know
12 I'm suffering from too much paper right now.
13 Here it is.
14 This would be the "Cumulative analysis of
15 post-authorization adverse effect reports of
16 Pfizer" February 28th, 2021.
17 MS. TELLES-LANGDON: The document -- the

18 document -- the name of the document begins
19 "Pfizer post-marketing experience."
20 MR. WILSON: There we go, that's the one.
21 Oh, and I forgot to have the two -- the document
22 from the New England Journal of Medicine, the
23 six-month post study and its supplement marked as
24 an exhibit.
25 MS. TELLES-LANGDON: We'll mark them as

AR09886
1 separate exhibits. No objection.
4 EXHIBIT NO. 9: New England Journal of
5 Medicine, Safety and efficacy of the
6 BNT162b2 MRNA COVID-19 vaccine through six
7 months.
8 EXHIBIT NO. 10: Supplement to New England
9 Journal of Medicine.
10 BY MR. WILSON:
11 761 Q. If we go down to page seven of this
12 document, please, table one, Doctor, you'd agree
13 with me that this shows that there was 1,223 --
14 it's the second-last line -- of fatal outcomes
15 associated with this vaccine; correct?
16 A. I see that there are 1,223 number of
17 fatal cases. I don't know that it's associated

18 with the vaccine.
19 762 Q. Thank you. And if we could go
20 forward to page one of the appendix, list of
21 adverse event -- adverse events of special
22 interest, is this a list that you would have
23 reviewed as part of your ongoing assessment of
24 the safety of the Pfizer vaccine, this seven-page
25 list that lists all the adverse events of special

AR09887
1 interest?
2 A. So this is a very long list, appears
3 to be all-encompassing of any adverse event that
4 could occur. If this document was filed to my
5 team, they would have looked at this certainly.
6 763 Q. Thank you.
7 MS. TELLES-LANGDON: Would it be
8 appropriate to give Dr. Lourenco a moment to look
9 at this document if you have any further
10 questions on it?
11 MR. WILSON: No, I don't have any more
12 questions on it. I think she's answered as much
13 as I can ask her given her -- what she's just
14 said. So I'd like to have it marked as an
15 exhibit, please.
16 EXHIBIT NO. 11: Cumulative analysis of
17 post-authorization adverse effect reports,

18 February 28, 2021
19 BY MR. WILSON:
20 764 Q. When -- when Health Canada and your
21 group made the decision to authorize the mRNA
22 vaccine, would you agree with me that your
23 assumption was that spike proteins would not end
24 up in the ovaries of women?
25 A. So when -- when we reviewed the --

AR09888
1 the data that was submitted for the vaccines, we
2 looked at with regards to distribution of the
3 vaccine into different tissues, we looked at
4 animal studies that were conducted for that and
5 my team would have reviewed the details of that.
6 And then also we looked at what we call
7 repeat-dose toxicity studies where the animals
8 are treated with repeat dose -- doses of the
9 vaccine and then assessed for any toxic effects
10 and that would have included the ovaries as well.
11 765 Q. So was it your expectation that the
12 spike protein would not end up in the ovaries?
13 MS. TELLES-LANGDON: Mr. Wilson, have you
14 established the factual foundation that the spike
15 protein does end up in the ovaries?
16 MR. WILSON: The evidence of three of our
17 medical experts and their affidavits and their

18 cross-examination, that was their evidence. It's
19 in Dr. Bridle's report, it's in Dr. Pellech's
20 report and it's in Dr. Cvetic's report.
21 MS. TELLES-LANGDON: Right. You asked
22 Dr. Lourenco if she had an assumption or an
23 expectation with respect to spike proteins. Your
24 question was sort of very broad, high level. Can
25 you be a little bit more specific?

AR09889
1 MR. WILSON: I can try.
2 766 Q. When you approved the vaccine, the
3 mRNA vaccines, did you or did you not believe
4 that spike proteins would end up in the ovaries
5 of women?
6 A. When we reviewed the data that was
7 submitted, there was no -- no cause for concern
8 in terms of toxicity to the ovaries of women
9 based on the nonclinical data that we reviewed
10 and the clinical data as well.
11 767 Q. Are you aware of the emerging
12 evidence referred to in the expert reports filed
13 in this court case that indicate that spike
14 proteins are finding their way into women's
15 ovaries?
16 R/F MS. TELLES-LANGDON: Mr. Wilson, I am
17 going to object because that is a point that is

18 highly contentious among the experts.
19 MR. WILSON: All right. Could one of
20 those helping me bring up the link to the
21 National Health Service of the United Kingdom's
22 website regarding vaccines and the link for that
23 would have been in the e-mail earlier. There's
24 two; there's one entitled "Withdraw" and then
25 there's one generally about vaccines. I'd like

AR09890
1 the one generally about vaccines brought up
2 first, please. Thank you.
3 Can you clear that cookie? Just say I'm
4 okay with the cookies or do not -- yeah.
5 Whatever you want. Just click "I'm okay" on the
6 left there. Yeah, that one. Unless this is a
7 PDF.
8 MS. TELLES-LANGDON: I'd say this is a PDF
9 that was shared, Mr. Wilson.
10 MR. WILSON: Okay. All right, thank you.
11 768 Q. So what I'm showing you is this
12 document was retrieved today, it's the "National
13 Health Services Vaccinations and when to have
14 them" page and it's a very high-level document
15 and it divides their citizens into categories
16 include babies under one year of age. It has the
17 vaccination schedule. It does indicate, for

18 example, in children one to 15 and what vaccines
19 they can get.
20 You'll see, Doctor, that it says for five
21 to 15-year-olds, they can get a COVID-19 vaccine.
22 If you scroll further down, you'll see in adults
23 it talks about COVID-19 vaccine, first, second
24 and booster dose for persons 16 years of age and
25 over and then you'll see the category of pregnant

AR09891
1 women.
2 You'll see -- and you'll agree with me,
3 Doctor, that a COVID-19 vaccine is no longer on
4 the list for the U.K. National Health Service as
5 a recommended vaccine; right?
6 A. I can't really speak to that because
7 I'm not familiar with what they may have had on
8 the list before versus what they have removed
9 from the list. Again, --
10 769 Q. Right.
11 A. -- I can't really speak to that.
13 this marked as an exhibit.
14 MS. TELLES-LANGDON: On what basis? The
15 witness said she can't speak to it.
16 MR. WILSON: That's evidence. And then
17 let's bring up to next one, please.

18 EXHIBIT NO. 12: NHS Vaccinations and when
19 to have them.
20 MS. TELLES-LANGDON: I think Mr. -- well,
21 yeah.
22 MR. WILSON: This is a document from the
23 Government of the U.K. that was retrieved from
24 their website today from their Department of
25 Health and Social Care. The -- the reference

AR09892
1 title is in reference to Coronavirus-19 advice
2 for pregnant employees, I see how they manage to
3 avoid using the word "people" and "women" there,
4 and it says "withdrawn" and it says it was
5 withdrawn on April 1st, 2022.
6 Were you aware that the U.K. government
7 has issued this withdrawal of recommendation for
8 pregnant people -- sorry, pregnant women to be
9 vaccinated with COVID-19 vaccines?
10 A. No, I was not -- not aware of this.
11 I haven't been following what that U.K.
12 government is recommending in terms of
13 vaccination for their citizens.
14 770 Q. And you can see on the document that
15 it says this guidance was withdrawn on April 1st,
16 2022. Can you see that?
17 A. Yes, I can see that.

19 this marked as an exhibit, please.
20 MS. TELLES-LANGDON: Again, Mr. Wilson, on
21 what basis? The witness said she hasn't been
22 following this and can't speak to it.
23 MR. WILSON: On the basis that the witness
24 has testified that part of their decision-making
25 and their standard practice is to look to what's

AR09893
1 happening internationally with other health
2 authorities and that's its relevant. And I'm
3 providing this to her to see if she is aware of
4 what is happening recently in the U.K. with
5 respect to vaccines on pregnant women and her
6 answer is she doesn't know about it.
7 So that's -- that's the relevance and
8 that's the evidence, and I think having these two
9 documents available to contextualize that answer
10 is -- is reasonable, proper and relevant.
11 MS. TELLES-LANGDON: Well, Dr. Lourenco
12 has testified that they review safety and
13 efficacy data, not necessarily recommendations
14 made by non-regulators. You haven't established
15 that the -- sorry, the National Health Service in
16 the U.K. is a regulator as opposed to playing a
17 similar role to NACI, and we haven't established

18 who published these documents, who made these
19 decisions. There's really no foundation for
20 these to be entered into evidence, Mr. Wilson.
21 MR. WILSON: Well, I'd prefer the
22 witness's answer.
23 771 Q. But the -- the -- Doctor, you would
24 agree with me that you know who the National
25 Health Service is in -- in England; right?

AR09894
1 A. I've -- I have heard of the National
2 Health Service. I can't speak to what exactly
3 their role is and their mandate.
4 MR. WILSON: Wow, okay. I'll take that.
5 It's our position this is a highly-relevant
6 exhibit. You can object to it. We can bring a
7 motion, but it's our view that if you want to
8 just take it under advisement for now so I can
9 move on because I'm mindful that I just found out
10 a few minutes ago that this witness has a hard
11 out and I'm down to 14 minutes, so I'd prefer us
12 to not prevent me from completing --
13 MS. TELLES-LANGDON: Well, I -- and I
14 actually do have questions in re-direct as well,
15 so...
16 MR. WILSON: Pardon me?
17 MS. TELLES-LANGDON: And you did find out

18 over an hour ago. I think that was consistent
19 with the time that we advised Dr. Lourenco her
20 cross-examination would end today, but...
21 MR. WILSON: Sorry, I'd understood it was
22 four, but let's -- counsel, can I move on,
23 please, so I can try to finish?
24 MS. TELLES-LANGDON: Yes, we can move on.
25 MR. WILSON: Thank you. So you're taking

AR09895
1 it -- just so we're clear, your position is are
2 -- are you allowing me to put the exhibit in or
3 are you reserving or what are we doing here?
4 MS. TELLES-LANGDON: I think our position
5 is -- is no, Mr. Wilson, you haven't -- haven't
6 established the foundation, but we can reserve
7 and move on and discuss it later.
9 772 Q. So you have indicated, I understand,
10 through your testimony and in your affidavit that
11 if you or Health Canada becomes concerned about
12 the safety and the effectiveness of these
13 COVID-19 vaccines, that -- and let's say that
14 happened, you know, on -- on July 15th, you could
15 withdraw them; right?
16 A. If we -- if we are concerned about
17 the safety or effectiveness of the vaccines in

18 such a way that the benefits may no longer
19 outweigh the risks, we can take steps to address
20 that and with -- and withdraw these products --
21 the product from the market if warranted.
22 773 Q. Okay. And so let's say you were to
23 reach that point and it does turn out that the
24 spike protein is impacting women's ovaries, that
25 withdrawal that you might issue at some future

AR09896
1 date doesn't take the spike proteins out of the
2 ovaries? It doesn't undue the harm; correct?
3 R/F MS. TELLES-LANGDON: Okay. Mr. Wilson,
4 I'm going to object to that question. That's
5 total speculation and also we still have not
6 established that fact.
7 BY MR. WILSON:
8 774 Q. Okay. Well, let's deal with some
9 basic science. You'd agree with me, Doctor, that
10 stopping the use of a pharmaceutical product or
11 removing it from the market won't undue harm that
12 it may have done. That's not how physiology
13 works; you don't un-program it correctly --
14 correct?
15 A. It depends on what -- what harm we're
16 talking about. If it is a harm that is
17 irreversible, then yes, correct. If it's

18 irreversible, then you won't be able to undue
19 that harm. But if it is time-limited,
20 reversible, goes away after a certain amount of
21 time, then -- then that harm can be reversed and
22 that harm no longer exists.
23 775 Q. So, for example -- sorry. So, for
24 example --
25 A. And that harm no longer exists.

AR09897
1 Sorry, go ahead.
2 776 Q. Right. So with thalidomide, which
3 you would agree with me that it was discovered
4 that it was causing birth defects four years
5 after it was approved for use, you're aware of
6 that? Surely you studied that in your
7 undergraduate work.
8 A. Yes, I'm aware of thalidomide. It
9 was -- it was developed many years ago in the
10 1950s and when the unfortunate events occurred it
11 was at the end of 1950s, early 60s.
12 777 Q. And the announcement by the
13 regulators to remove it from the market didn't
14 have the effect of reversing the birth defects;
15 right?
16 A. Right. In that -- in that setting,
17 it did not. Unfortunately, there were congenital

18 abnormalities of the individuals who were born
19 from mothers who took thalidomide and they --
20 they live to the current day with those
21 abnormalities. But that was in a time when the
22 standards were very different from the standards
23 for drug development today including the
24 nonclinical toxicology studies that are required
25 to be conducted today to screen for risk to -- to

AR09898
1 congenital anomalies like that.
2 778 Q. And -- and -- and you'd agree with me
3 that the processes that are being used with
4 COVID-19 approvals are very different than those
5 normal processes and the normal pathway; right?
6 A. No, no. They're not different.
7 They're very much in line with what the
8 guidelines require for the development of
9 vaccines. We require the same type of
10 nonclinical toxicology studies as we would
11 require for -- for any other vaccine.
12 779 Q. So everything you said about normal
13 pathway versus interim order and amended pathway
14 was wrong?
15 A. So those were in terms of the -- of
16 the process, the regulator review process --
17 780 Q. Yes.
18 A. -- but not -- we did not change the
19 requirements in terms of the evidence standard.
20 The -- the evidence and criteria for
21 authorization for review -- for assessing the
22 safety of the vaccines were not changed. What we
23 changed with the interim order was to allow
24 greater flexibility in terms of the review
25 process, allow for, for example, rolling

AR09899
1 submissions to occur, so as data become available
2 the manufacturers were able to submit it to
3 Health Canada -- which is not something that can
4 happen in the normal process -- and then allow
5 for other tools like terms and conditions that
6 could be imposed on the authorization.
7 781 Q. And you've allowed the phase three
8 clinical trials to still be going on ongoing
9 right now even though you have authorized
10 millions of Canadians to receive these vaccines;
11 correct?
12 A. The phase three clinical trials are
13 ongoing, but that's part of the normal process in
14 product development where as soon as the phase
15 three clinical trial reaches the endpoint for
16 assessing the efficacy it's quite normal for a
17 company to file the results at that point to

18 Health Canada, but for the trial to still
19 continue to proceed afterwards for -- in order to
20 collect long-term efficacy, long-term safety from
21 that clinical trial.
22 782 Q. And you'd agree with me that there is
23 no long-term data available for the effects on
24 pregnant women and as-yet-to-be pregnant women
25 from taking COVID-19 because it's only been

AR09900
1 around for a year, right, COVID-19 vaccine?
2 A. We have data from the clinical trials
3 that began in 2020 -- earlier in 2020, and then
4 data from the post-market use of the vaccines
5 from December 2020.
6 783 Q. But we don't know what --
7 A. So about a year and a half.
8 784 Q. Yeah. So we don't know what the
9 impact might be two years or four years later as
10 was the case when we discovered it with -- with
11 thalidomide, for example, right? It took four
12 years. So we don't know.
13 MS. TELLES-LANGDON: Mr. Wilson, have we
14 established the four years?
15 MR. WILSON: I think so.
16 MS. TELLES-LANGDON: I don't know, I'm not
17 sure where that four years is from.

18 MR. WILSON: It's referred to in
19 Dr. Pellech's report and then there's a footnote
20 leaking -- linking it to a medical journal
21 article that describes thalidomide.
22 MS. TELLES-LANGDON: Okay.
23 BY MR. WILSON:
24 785 Q. So your confidence level is that --
25 that young women and women in childbearing age

AR09901
1 should not be concerned about impacts on their
2 fertility is based solely on the year and a half
3 worth of work that's been done to date; correct?
4 A. The confidence comes from certainly
5 the post-market data as for a year and a half,
6 but also from the clinical trials, as well as the
7 nonclinical toxicology studies that were
8 conducted that did not reveal any risks to
9 reproductive health, to fertility and then to
10 impacts to offspring based on animals studies.
11 So we didn't find any issues in the
12 clinical studies that -- nonclinical studies that
13 were conducted that suggested a concern with
14 regards to both fertility as well as risks to a
15 fetus or an embryo.
16 786 Q. The -- from the studies that you've
17 reviewed, does the COVID-19 virus behave

18 differently in Canada than other geopolitical
19 boundaries around the world such as Europe and
20 England?
21 A. It depends on the variant of concern.
22 But generally if it's the same variant of concern
23 circulating here versus other areas of the world,
24 it should behave similarly. It should behave in
25 a similar -- in a similar manner. There may be

AR09902
1 individual factors, different population factors
2 that could impact that, access to healthcare,
3 genetic factors across different populations, so
4 it -- so we would need to caveat it with that.
5 But if it is the same -- the same virus, then we
6 would expect it to behave in a similar way.
7 787 Q. The -- is there anything different
8 that you found from your review of the studies
9 and the applications and the literature and the
10 data that suggest Canadians are somehow
11 physiologically different, our cells are
12 different than -- and we react differently to
13 disease and vaccine than citizens of Europe and
14 England, for example?
15 A. So there's always going to be host
16 factors -- what I call host factors is the
17 individual who's infected and how they will react

18 to an infection and those can be different across
19 -- across the globe. There can also be
20 differences because of the way public health
21 measures are applied differently across -- across
22 the globe or access to healthcare that could be
23 different and differences in comorbidities that
24 may occur in different parts of the world that
25 will impact how the virus affects different

AR09903
1 populations.
2 MR. WILSON: I've just been provided a
3 document that needs to be put on the screen and I
4 would ask Ms. Chipuik to do that now. It's a
5 document that says "Health Canada ponders U.K.
6 model on easing bio similar study requirements"
7 and it quotes you, Dr. Lourenco.
8 MS. TELLES-LANGDON: Keith, I don't mean
9 to -- Mr. Wilson, I don't mean to interrupt, I
10 just -- Dr. Lourenco, you noted that you had a
11 hard stop at three but obviously Mr. Wilson is
12 not done and I also have some questions in
13 redirect. I'm wondering if there's anything we
14 can do to work with you with your schedule?
15 THE WITNESS: Yes. Are you looking for
16 this week or would next week be okay?
17 MS. TELLES-LANGDON: Or later today.

18 THE WITNESS: Later today only if it's
19 after -- I have to appear before HESA committee,
20 so only if it's after 5:45.
21 MS. TELLES-LANGDON: I'm wondering,
22 Mr. Wilson, if we're able to break, hopefully
23 bring the other witness forward so that we can
24 try to get her cross-examination completed and is
25 -- if it's possible, I guess it also depends on

AR09904
1 the court reporter if it's possible to try to
2 finish this today. I don't know how much more
3 time you have, Mr. Wilson.
4 MR. WILSON: I'm fine with it subject to
5 the court reporter. Caroline, did you hear that?
6 COURT REPORTER: Yes, I heard that. Can
7 we go off the record?
8 MS. TELLES-LANGDON: Sure.
11 MR. WILSON: Ms. Pejovic, did you have a
12 chance to e-mail those aids?
13 MS. PEJOVIC: No, I did not. I can do
14 that right now.
15 MR. WILSON: Yes, please.
17 MR. WILSON: And if you could bring up J&J

18 or -- either you or Eva, that would be great.
19 MS. PEJOVIC: I can -- I can bring it up
20 and also send it by e-mail. So I'll just bring
21 it up.
22 MR. WILSON: Okay, thank you.
23 MS. PEJOVIC: Mm-hmm.
24 BY MR. WILSON:
25 788 Q. Dr. Lourenco, on the screen is a

AR09905
1 Government of Ontario website and it describes
2 vaccine for COVID-19 and the topical heading is
3 "Janssen (Johnson & Johnson) COVID-19 vaccine."
4 It says that its status is approved by Health
5 Canada.
6 Are you familiar generally with this type
7 of website of Health Canada?
8 A. Yes, I am.
9 789 Q. And I previously shared with you the
10 FDA document that expresses concerns about
11 Johnson & Johnson's COVID-19 vaccine and makes
12 recommendations on limitations of its use.
13 I'm looking at this website from your
14 department and I see that it says, "All COVID
15 vaccines authorized by Canada are proven safe,
16 effective and high quality," but I don't see the
17 warning that the FDA has issued.

18 Why is that?
19 A. The warning -- the warning that the
20 FDA has issued is already covered in our product
21 monograph where we talk about the concerns with
22 the Johnson & Johnson vaccine, or the Janssen
23 vaccine, with regards to the thrombosis with
24 thrombocytopenia events. That safety issue is
25 already described in the -- in the product

AR09906
1 monograph for healthcare professionals.
2 And we have also issued both public --
3 public advisories as well as health product risk
4 communications in that regard to inform both
5 healthcare professionals as well as Canadians in
6 general about that safety issue. And then it is
7 further addressed in the National Advisory
8 Committee on Immunization guidance on the use of
9 vaccines in Canada where the Janssen vaccine is a
10 vaccine of third choice. The -- the first
11 vaccines that are recommended are the mRNA
12 vaccines, followed by the Novavax vaccine and
13 then if -- if those vaccines are not available,
14 then the Janssen vaccine could be an option.
15 And this aligns very well with the U.S.
16 FDA's recommendations for the vaccine.
17 790 Q. Would you agree with me to put bold

18 at the top of the document to the reader to say
19 "are proven safe and effective and high quality"
20 given the known serious adverse effect is
21 misleading?
22 A. No, I don't agree with -- with that
23 given that I don't agree that it's misleading,
24 given that at this time we continue to consider
25 the benefits to outweigh the risks for the

AR09907
1 vaccine. Yes, there are those safety concerns
2 with the vaccine, but those are well labelled in
3 the product labelling and they're well known by
4 healthcare professionals given the communications
5 that we have issued and the recommendations from
6 -- from the National Advisory Committee on
7 Immunization.
8 791 Q. So when you speak of the benefits
9 outweighing the risks, you're talking about a
10 generalized basis; right?
11 A. When we speak about benefits
12 outweighing the risks we consider the emerging
13 safety profile in the post-market setting and
14 consider the -- the known benefits of the vaccine
15 and weigh the two to see if the -- if that ratio
16 of benefit versus risk is still considered
17 acceptable, still considered to be positive and,

18 if so, then the vaccine continues to be allowed
19 to be marketed in Canada.
20 792 Q. In the exhibit that I showed you from
21 the FDA -- so the Federal Drug Administration --
22 they're your equivalent agency in the United
23 States of America; correct?
24 A. The Food and Drug Administration,
25 yes, that is correct.

AR09908
1 793 Q. And you're familiar with the FDA?
2 You know who that is?
3 A. Yes, I am familiar with the -- with
4 the U.S. FDA.
5 794 Q. So why is it that the FDA has shown
6 an ability to identify risk to certain
7 individuals in their materials but you have not?
8 MS. TELLES-LANGDON: So, Mr. Wilson, I've
9 let this go on for a little while, but I would
10 note that you've highlighted one line at the top
11 and yet on this page is a linked directly to
12 possible side-effects which is also visible to --
13 to -- immediately on the portion -- the small
14 portion of the page that you're screen sharing.
15 MR. WILSON: Thank you. That's my point.
16 The FDA put it right at the top of their page to
17 warn individuals that there's risk to them apart

18 from a generalized population. But what we've
19 heard from this witness is you have to go read a
20 monograph; you have to be familiar with the
21 National Advisory Committee, you have to talk to
22 a doctor even though we have widespread walk-in
23 clinics for vaccinations where people don't get a
24 chance to talk to a doctor.
25 795 Q. So I'm -- my question was why is it

AR09909
1 that the FDA can warn of individualized risks but
2 Health Canada continues to promote in bold words
3 at the top of the page that they're "proven safe,
4 effective and of high quality" and it says right
5 underneath it "approved for ages 18 and older."
6 There are no asterisk, there's no star; there's
7 no footnote.
8 Why -- why has Health Canada not taken
9 greater steps to warn individuals who fall into
10 specified risk categories that you've developed
11 of the risks that they face?
12 A. So -- so we have taken steps. We --
13 we have updated our labelling, as I've mentioned,
14 we -- we have communicated on these risks. And,
15 in fact, Canada was way ahead of the U.S. in
16 addressing this issue. The National Advisory
17 Committee on Immunization, as I mentioned, which

18 makes recommendations on how each vaccine should
19 be used based on their efficacy and safety
20 profile, based on supply considerations and other
21 considerations has taken steps way before the
22 U.S. FDA to make recommendations on preferential
23 use of the mRNA vaccines over both the
24 AstraZeneca and the Janssen vaccine because of
25 the safety issues with these two other latter

AR09910
1 vaccines.
2 MR. WILSON: I'd like to have this marked
3 as an exhibit, please.
5 EXHIBIT NO. 13: Janssen (Johnson &
6 Johnson) COVID-19 vaccine - Canada.PDF,
7 May 5, 2022.
8 MR. WILSON: Allison, could you bring up
9 the equivalent document for AstraZeneca, please?
10 796 Q. I'm showing you a similar document on
11 the screen; it's got the Government of Canada
12 logo at the top of the page. It indicates that
13 the page is about vaccines for COVID-19 and that
14 Astra -- the main detailed heading is
15 "AstraZeneca COVID-19 vaccine."
16 You can see again, Doctor, that underneath
17 it says, "Proven safe, effective and of high

18 quality," correct?
19 MS. TELLES-LANGDON: Mr. Wilson, can you
20 please read the full sentence?
21 BY MR. WILSON:
22 797 Q. "All COVID-19 vaccines authorized in
23 Canada are proven safe, effective and of high
24 quality." That's what that sentence reads,
25 correct, Doctor?

AR09911
2 798 Q. And the words "are proven safe,
3 effective and of high quality" are bolded; right?
4 A. Yes, those words are bolded.
5 799 Q. Now, there seems to be confusion in
6 the evidentiary record so far; is it true that
7 the AstraZeneca vaccine is no longer used in
8 Canada due to serious blood clot issues?
9 A. The AstraZeneca vaccine is -- is not
10 one of the preferred vaccines in Canada. So,
11 again, going back to the National Advisory
12 Committee on Immunization and their
13 recommendations, they recommend the mRNA vaccines
14 as -- as a -- as the preferred vaccines as a
15 result of the -- both the efficacy as well as the
16 safety profile of the mRNA vaccines being
17 superior to -- to the -- both AstraZeneca and

18 Janssen vaccines.
19 So for that reason, my understanding is
20 Canada has primarily focussed on procuring the
21 mRNA vaccines, so the AstraZeneca vaccine is no
22 longer being procured at this point and not
23 available in Canada.
24 800 Q. Now, there's nothing on this website
25 to say that, is there? All those things you just

AR09912
1 said about preference -- the word "preference"
2 doesn't appear anywhere, does it? And if you'd
3 like, I'm happy to take a moment so you can
4 carefully review it.
5 MS. TELLES-LANGDON: I -- I would -- I
6 would like you to put the link into the chat and
7 allow Dr. Lourenco to review this page, please.
8 MR. WILSON: Certainly. Allison, could
9 you put the link into the chat?
10 MS. PEJOVIC: Yeah. It's a -- it's a PDF,
11 so just give me a minute, please, to get the
12 link. I'll get it, just a minute.
13 BY MR. WILSON:
14 801 Q. And while -- but before -- while
15 we're dealing with that technical aspect of
16 things just to be efficient with everyone's time;
17 Dr. Lourenco, your affidavit doesn't talk about

18 preferential vaccines and the dangers of other
19 vaccines, does it?
20 A. No, because that in general is not a
21 role that we play in terms of recommending which
22 vaccines are preferred over other vaccines.
23 That's the role of the National Advisory
24 Committee on Immunization. We review each
25 vaccine independently, determine if benefits

AR09913
1 outweigh the risks and issue authorizations on
2 that basis. And then the National Advisory
3 Committee reviews similar data as we do but take
4 into consideration other -- other -- other
5 considerations and make their recommendations on
6 which vaccines are preferred over others.
7 802 Q. Thank you. And you --
8 MS. PEJOVIC: I can advise that the link
9 is in the chat now.
10 THE WITNESS: Yes. Okay.
11 BY MR. WILSON:
12 803 Q. So you agree with me there's nothing
13 in there about preference and not being
14 recommended relative to others which are
15 preferred for certain groups of people or even
16 the natural -- the National Advisory Committee on
17 vaccinations; correct?
18 A. No. On this web page we don't
19 indicate anything about preference because it
20 goes back to what I mentioned around the role of
21 Health Canada where we don't make those
22 recommendations; the National Advisory Committee
23 does. So it -- the preference is absolutely
24 found in the National Advisory Committee
25 recommendations published on the Public Health --

AR09914
1 Public Agency of -- Public Health Agency of
2 Canada's website.
3 804 Q. And who is your intended audience for
4 this document on your website?
5 A. This is a general audience.
6 805 Q. If you could just scroll back up to
7 the top? So the headings are "Canada.ca
8 Coronavirus disease COVID-19" and then "Vaccines
9 for COVID-19" and then "COVID-19 vaccines:
10 Authorized vaccines."
11 You see that?
12 A. Yes.
13 806 Q. And you'd agree with me there's
14 nothing -- that's the last I'm going to ask this
15 question -- there's nothing there to indicate
16 that the Canadian who's trying to make an
17 informed medical choice needs to go look

18 somewhere else, is there?
19 MS. TELLES-LANGDON: Dr. Lourenco, have
20 you taken -- have you had enough time --
21 MR. WILSON: I'm sorry, I can't hear you,
22 counsel.
23 MS. TELLES-LANGDON: I'm sorry. I'm just
24 wanting to make sure that Dr. Lourenco has had
25 time to review the entire document.

AR09915
1 BY MR. WILSON:
2 807 Q. Oh, sure. Absolutely. Thank you.
3 A. It does -- it does say under mixed
4 dose schedules that the National Advisory
5 Committee on Immunization recommends an mRNA
6 vaccine should be offered for the second dose and
7 this is the case even if you got a viral vector
8 vaccine as the first dose.
9 And then it does say that the viral vector
10 vaccine, like AstraZeneca, may be recommended by
11 your healthcare provider depending on your unique
12 -- unique health situation, for example, if
13 you're allergic to an mRNA vaccine. So that
14 speaks to the recommendations for preferential
15 treatment of mRNA -- professional -- preferential
16 recommendation for the mRNA vaccine over the
17 other vaccines.
18 MR. WILSON: Thank you. Allison, could
19 you put up the Ontario document, please?
20 MS. TELLES-LANGDON: Do you want to mark
21 this as an exhibit, Keith?
22 MR. WILSON: Yes. Could we please have
23 this document relating to AstraZeneca from Health
24 Canada marked as an exhibit?
25 EXHIBIT NO. 14: AstraZeneca Vaxzevria

AR09916
1 COVID-19 Vaccine Canada.PDF
2 BY MR. WILSON:
3 808 Q. What's on the screen currently is a
4 document from the Ontario government website from
5 their newsroom and this -- it's dated
6 September 29th, 2021, and it's the statement
7 title is dated "Ontario recommends the use of
8 Pfizer COVID-19 vaccine for individuals aged 18
9 to 24 years old."
10 If we scroll down, there is a discussion
11 about concern Ontario is issuing a preferential
12 recommendation of the use of Pfizer for
13 individuals aged 18 to 24 but Health Canada
14 hasn't issued a similar advisory, has it?
15 A. So Health Canada has not issued a
16 similar advisory but, again, the National
17 Advisory Committee on Immunization has. In their

18 guidance document they talk about recommending
19 the use of the Pfizer vaccine over Moderna for
20 this age -- age range -- actually, an age rage
21 younger than this from 12 to about 30 years of
22 age because of slightly higher incidents of
23 myocarditis and pericarditis with Moderna
24 compared to Pfizer.
25 So then therefore Pfizer is -- is the

AR09917
1 preferred vaccine for this younger age group.
2 MR. WILSON: I'd like to have this
3 document marked as an exhibit, please.
5 EXHIBIT NO. 15: Ontario recommends the
6 use of Pfizer-BioNTech COVID-19.PDF
7 MR. WILSON: Earlier today I'd sent a
8 World Health Organization document and I'd like
9 to have that one put on the screen now if
10 possible, please.
11 MS. TELLES-LANGDON: I note, Mr. Wilson,
12 that this is a 43-page document. I imagine
13 Dr. Lourenco has not had an opportunity to review
14 this document either.
15 MR. WILSON: I am going to take -- you'll
16 be pleased to know I will take you to a very
17 specific place and if what I'm asking her is not

18 fair, I know you will object as you should. Once
19 the document's up, if we could go to page 18.
20 809 Q. So we're on page 18 and I just want
21 to go to the title of the document if you could
22 scroll up a little bit so I can see that. There
23 we go. This is a World Health Organization
24 newsletter.
25 You're familiar with the world horse --

AR09918
1 the -- the World Health Organization,
2 Dr. Lourenco?
3 A. Yes, I am.
4 810 Q. Thank you. And if we can go back to
5 -- and this is from -- it's number one and it's
6 from 2022; if we could go to page 18. So the
7 World Health Organization has identified tinnitus
8 and hearing loss as an event of concern and has
9 identified it with respect to the Pfizer, the
10 Moderna and the AstraZeneca.
11 Are you aware of this work of the worth --
12 the World Health Organization?
13 A. I'm not aware of this specific work,
14 no. I'm aware of this signal through my
15 colleagues at the Market Health Products
16 Directorate, and also tinnitus has been added to
17 the product labelling for both AstraZeneca and

18 Janssen vaccines so already -- we already have
19 that on our product labels.
20 But my colleagues in the Market Health
21 Products Directorate would -- would have more
22 information on this.
23 811 Q. Then would they bring that concern to
24 your attention?
25 A. Yes, they would bring it to my

AR09919
1 attention following review of international cases
2 and any Canadian cases that may have happened
3 related to hearing loss and tinnitus.
4 812 Q. All right. Is there a threshold of
5 the number of deaths that you would need to see
6 attributable to the vac -- the COVID-19 vaccines
7 before you would withdraw one from the market?
8 A. No, there isn't. There isn't a
9 threshold. We -- a product could be removed from
10 the market even on the basis of a single death.
11 It really depends on the -- on the circumstances;
12 it depends on the condition in question that the
13 product is being used for, or it may be on
14 another of -- it could be -- it could be removed
15 from the market on the basis of more than -- more
16 than one death.
17 But certainly deaths are of really grave

18 concern for us. If we can confirm that a -- that
19 a product causes a death, that would be a very
20 serious outcome and we would certainly look at
21 that very seriously and consider whether the
22 product should stay on the market or not.
23 813 Q. The -- in your affidavit at paragraph
24 179 you say full -- under the heading "Protecting
25 Canadians against COVID-19 is in the public

AR09920
1 interest," you --
2 A. Yes.
3 814 Q. -- say:
4 "Full vaccination forms a key component of
5 Canada's efforts to protect Canadians
6 including Canadians who work in federally
7 regulated transportation sector or our
8 travellers or passengers in that sector
9 against the impact of COVID-19 arising
10 from the existing SARS-CoV-2 virus and
11 emergence -- emerging VOCs."
12 What do you mean by "protect"?
13 A. Here as I'm speaking in terms of my
14 role as the regulator, so in terms of protect is
15 it is to help decrease the risk of getting
16 infected but, more importantly, acquiring serious
17 -- serious disease, serious COVID-19.

18 815 Q. Okay. So we've already agreed a
19 number of times that getting any one of these
20 vaccines does not prevent either a vaccinated or
21 unvaccinated person from getting infected; right?
22 MS. TELLES-LANGDON: Well, Mr. Wilson,
23 we've agreed to a certain extent there -- there
24 was evidence that Dr. Lourenco pointed to at
25 Exhibit "S," I believe, of her affidavit that

AR09921
1 showed the proportion of protection that remained
2 against infection.
3 MR. WILSON: Okay.
4 MS. TELLES-LANGDON: We haven't agreed
5 that it provides no protection.
6 MR. WILSON: But we have agreed that the
7 vaccinated and unvaccinated both can contract --
8 become infected with COVID and both can spread
9 it; correct?
10 MS. TELLES-LANGDON: We have agreed that,
11 yes.
13 816 Q. And, Dr. Lourenco, you adopt the
14 answer of your counsel there?
15 A. Yes.
16 817 Q. Thank you. So the -- are you aware
17 that the European countries, that England, that

18 Iceland, that the Scandinavian countries, Doctor,
19 do not require their citizens to be vaccinated to
20 get on planes, trains and ships? Are you aware
21 of that?
22 MS. TELLES-LANGDON: I'm not sure we've
23 established that in evidence, Mr. Wilson.
24 MR. WILSON: Pardon me?
25 MS. TELLES-LANGDON: I'm not sure we've

AR09922
1 established that in evidence, Mr. Wilson.
2 MR. WILSON: Hmm. All right. Well, then
3 maybe we should. Can we just go off the record
4 for a minute?
5 MS. TELLES-LANGDON: Yes.
7 MR. WILSON: We can go back on. I'm going
8 to have brought up on the screen an excerpt from
9 the -- England's official government website and
10 as soon as Ms. Chipuik has that at her disposal,
11 you'll see it on the screen.
12 MS. TELLES-LANGDON: And just to be clear,
13 Mr. Wilson, Dr. Lourenco has no expertise in
14 international law.
15 MR. WILSON: I'm not expecting her to have
16 expertise. She's testified in her affidavit that
17 one of the things that she considers is the

18 practices of other governments and -- and
19 international organizations as part of her
20 decision-making.
21 MS. TELLES-LANGDON: Yes. She said that
22 for the purposes of regulatory authorizations.
23 There was a --
24 MR. WILSON: Fair enough.
25 MS. TELLES-LANGDON: There was a clear

AR09923
1 caveat on -- on that.
2 MR. WILSON: Right. And then in paragraph
3 179 she went beyond that and said about
4 protecting Canadians against COVID-19 is in the
5 public interest and that requiring full
6 vaccination for travellers is required, and I'm
7 trying to understand how she reached that
8 conclusion when every other government in the
9 developed world did not.
10 818 Q. So I'll just scroll down and this was
11 retrieved on May 30th, 2022 and on the screen,
12 Doctor, you can see that it says:
13 "Travel to England rules. When you travel
14 to England, you: -- three bullets -- Do
15 not need to complete a U.K. passenger
16 locator form before you travel; do not
17 need to take any COVID-19 tests before you

18 travel or after you arrive; do not need to
19 quarantine when you arrive. This applies
20 whether you are vaccinated or not. It
21 includes people who are transitioning
22 [sic] through England."
23 Do you -- are you now aware, Doctor, that
24 England does not require people to be vaccinated
25 to travel?

AR09924
1 A. That seems to be the case based on
2 the document you just showed.
4 that marked as an exhibit.
5 MS. TELLES-LANGDON: No -- no objections.
6 EXHIBIT NO. 16: Travel to England -
7 Gov.UK.PDF
8 BY MR. WILSON:
9 819 Q. So in your discussion -- have you had
10 any discussions with your international
11 colleagues about why they are not requiring their
12 citizens to be vaccinated, their travellers and
13 passengers, as you phase it in your paragraph
14 179, to be vaccinated?
15 A. No, I have not because it's not in my
16 role to -- to delve into vaccine mandates or
17 requirements. My role is really about regulating

18 vaccines on the basis of safety, efficacy and
19 quality. So when I interact with my
20 international colleagues it's really within the
21 confines of that role, not going beyond that.
22 820 Q. Have -- have they reached out to you
23 and said we've lifted -- for example, in England,
24 have officials from that government and your
25 colleagues reached out to you to say -- to ask

AR09925
1 why you're continuing to support a vaccination
2 requirement for travelling? Have they asked you
3 if you're aware of something in the science that
4 they've missed?
5 A. No, I have not received any such
6 questions or -- or reached out for that kind of
7 question.
8 MS. TELLES-LANGDON: And, Mr. Wilson, just
9 to be fair with respect to 179 of Dr. Lourenco's
10 affidavit, she doesn't say anywhere in that
11 paragraph that vaccination is required or it
12 should be mandated. It states, "Full vaccination
13 forms a key component of Canada's efforts to
14 protect Canadians, including Canadians who work
15 in the federally regulated transportation
16 sector."
17 But she nowhere in there suggests that she

18 is expressing any opinion with respect to whether
19 or not the vaccinations should be mandated; she's
20 just expressing a view on the value of
21 vaccination.
22 MR. WILSON: She says in the public
23 interest; it's her evidence, not mine
24 821 Q. So I'm not going to dwell on this
25 much further. Did you recommend -- and

AR09926
1 Mr. Presvelos might have asked you this and I'm
2 tired, so I'm not trying to ask a question twice
3 and I'll defer to your counsel if she has a
4 clearer memory than mine -- but did you make a
5 recommendation to the Prime Minister or the
6 Minister of Health that a vaccine mandate
7 requirement remain in place in Canada?
8 A. No, I did not.
9 822 Q. Okay. And I believe you've confirmed
10 that you were not part of that decision-making
11 process; correct?
12 A. Correct, I was not.
13 MR. WILSON: Okay. So I just need to
14 check in with my colleagues real quick. If I
15 could just have three to four minutes, we'll just
16 mute and turn our cameras off, I think I might be
17 just about finished. So off the record.

20 MR. WILSON: Counsel, I think I might have
21 neglected to have the World Health Organization
22 Newsletter marked as an exhibit.
23 MS. TELLES-LANGDON: If that's the case,
24 then I have no objection.
25 MR. WILSON: Right.

AR09927
1 EXHIBIT NO. 17: WHO Pharmaceuticals
2 Newsletter No. 1, 2022.
3 MR. WILSON: And I'd just ask one of those
4 helping me to bring up one last document and then
5 we're done -- it's more of a housekeeping thing
6 than anything -- and it is the Health Canada
7 document relating to Moderna which was similar in
8 format to the documents that we looked at for
9 Pfizer and others.
10 823 Q. Dr. Lourenco, I'm showing you a
11 document on the screen from the Government of
12 Canada and it's similar to the one for
13 AstraZeneca and Pfizer and it's relating to
14 authorized vaccines and the descriptive title is
15 the "Moderna Spikevax COVID-19 Vaccine."
16 Can you see that on the screen?
17 A. Yes, I can.
18 824 Q. Are you aware of whether the warning
19 from the Ontario government about this not being
20 preferred is in this document?
21 A. I --
22 825 Q. And we can scroll down or provide you
23 the hyperlink in the text -- or the chat, rather.
24 MS. PEJOVIC: Okay, I'll get that ready.
25 Whoops, I've got to stop screen sharing and then

AR09928
1 I can do that. Okay, there it is in the chat.
3 THE WITNESS: Okay, thank you. Okay, I've
4 reviewed it.
5 BY MR. WILSON:
6 826 Q. You'd agree with me the warning that
7 the Ontario government issued in September 2021
8 against young men avoiding Moderna and using
9 Pfizer instead because of the myocarditis risk is
10 not identified on this document, is it?
11 A. On this document we don't refer -- we
12 don't make any reference to a preferential
13 recommendation for Pfizer versus Moderna. The
14 Ontario recommendation was as they've stated out
15 of an abundance of caution -- they made the
16 recommendation out of an abundance of caution
17 that the Pfizer vaccine is recommended to be used

18 instead of the Moderna vaccine.
19 MR. WILSON: Doctor, that concludes the
20 Peckford applicants' cross-examination. Thank
21 you very much for your time and your
22 professionalism in participating in this
23 cross-examination. I hand it back to the
24 Attorney General's counsel at this point.
25 MS. PEJOVIC: And, Mr. Wilson, I'm sorry

AR09929
1 to interrupt. Could we -- I imagine we want that
2 one marked as an exhibit?
3 MR. WILSON: Yes. I'm sorry, guys, yes.
5 MS. TELLES-LANGDON: I would -- I would --
6 MR. WILSON: Could we please have that
7 last one marked as an exhibit --
9 MR. WILSON: -- as my final exhibit?
10 EXHIBIT NO. 18: Moderna Spikevax COVID-19
11 Vaccine - Canada.PDF
12 MS. TELLES-LANGDON: No objections,
13 Mr. Wilson. And I, in fact, was going to note
14 the same thing. I know we're all getting tired;
15 it's been a very long day for everybody. I hope
16 to not take particularly long in -- in redirect
17 but I do definitely have some questions.

18 RE-DIRECT EXAMINATION BY MS.
19 TELLES-LANGDON:
20 827 Q. First, thinking back to last Friday,
21 Dr. Lourenco, during Mr. Presvelos's
22 cross-examination of you he asked a number of
23 questions regarding relative risk reduction and I
24 have a few questions arising from that line of
25 questioning.

AR09930
1 First, Mr. Presvelos put to you
2 hypothetical numbers in which there were 10,000
3 participants in each of the vaccine and placebo
4 group for a total of 20,000 participants, and in
5 his hypothetical example the study was unblinded
6 after a total of 12 infections. In an actual
7 trial, would 12 infections out of 20,000
8 participants be a significant proportion of
9 infections to un-blind a trial?
10 A. Extremely unlikely. We would very
11 much likely need more -- more numbers in order to
12 be able to have sufficient reliability in that
13 data to have an appropriate estimate of vaccine
14 efficacy. So you -- you really need many more
15 cases than -- than just 12 to be able to estimate
16 vaccine efficacy with an appropriate power, with
17 appropriate confidence interval and ability to

18 really measure with statistical significance.
19 828 Q. Mr. Presvelos then asked you to do a
20 relative risk reduction calculation using his
21 hypothetical numbers despite your indication that
22 you are not a biostatistician. Are there one or
23 more biostatisticians experts in the team of
24 experts who advise you to support you in your
25 decision-making role?

AR09931
1 A. Yes, absolutely, I have a team of
2 about of seven biostatisticians who participate
3 -- who are part of my team and advise me on
4 biostatistics including for the COVID-19
5 vaccines.
6 829 Q. All right. Are you confident in
7 relying on these biostatisticians to perform for
8 you the relative risk reduction calculation on
9 the trial data submitted by the vaccine
10 manufacturers?
11 A. Yes, I'm very confident.
12 830 Q. At the time that you approved the
13 vaccines, do you recall being briefed by your
14 team regarding the use of relative risk reduction
15 as the means to assess vaccine efficacy?
16 A. At the time I approved the vaccines
17 the issue of using relative risk reduction didn't

18 come up because that is the measure that's always
19 used to assess vaccines. So it's not -- it's not
20 an issue up for discussion, it's -- that's the
21 right measure of vaccine efficacy.
22 But when I was briefed, they talked -- we
23 talked about the actual measurements and -- and
24 what the outcome of the data was, what the data
25 show in terms of efficacy.

AR09932
1 831 Q. And then Mr. Presvelos spent some
2 time focussed on the calculation of absolute risk
3 reduction and asked you questions about why
4 relative risk reduction controls for the at-risk
5 time while absolute risk reduction cannot do so.
6 In the recruitment for this study for either
7 Pfizer or Moderna when participating in the
8 design what participants are randomized to either
9 the vaccine group or the control group, does this
10 randomization occur throughout the recruitment
11 process?
12 (Mr. Presvelos enters Zoom)
13 A. Yes. This recommend -- this
14 randomization occurs throughout the recruitment
15 process. As -- as individuals are identified,
16 they're randomized to either one or the other
17 group.
18 832 Q. Is this aspect of the study design
19 relevant to your explanation about why relative
20 risk reduction controls for the at-risk time
21 while absolute risk reduction cannot do so?
22 A. It is, because it -- it has to do
23 with time, the time that subjects are in the
24 trial and that time varies from subject to
25 subject. The relative risk reduction accounts

AR09933
1 for that, whereas absolute risk reduction -- the
2 measurement of absolute risk reduction cannot --
3 does not account -- does not control for the
4 differences in time that different subjects
5 participate in the trial.
6 833 Q. In The Lancet article, which I
7 believe is marked as Exhibit 1, Mr. Presvelos
8 took you to a statement that said, "Absolute risk
9 reduction tends to be ignored because they give a
10 much less impressive effect size than relative
11 risk reduction."
12 You explained that absolute risk reduction
13 is not considered for vaccine authorization
14 because of the study designs; one of the reasons
15 you mentioned is the differences in exposure
16 rates. Does this mean that the absolute risk
17 reduction calculation would differ depending on

18 whether there was a high rate of infection such
19 as at the peak of a wave versus a low rate of
20 infection in the community?
21 R/F MR. PRESVELOS: Counsel you're putting
22 evidence to the -- to the -- to the witness. You
23 know, you're -- you're -- you're adducing facts
24 that were not -- that did not come from the
25 witness and you're putting it to her. What are

AR09934
1 you relying on that for those -- for that
2 particular interpretation of what Dr. Lourenco
3 said in response to The Lancet article?
4 I don't recall -- I don't recall the
5 evidentiary basis of her making those statements.
6 MS. TELLES-LANGDON: Okay. So,
7 Mr. Presvelos, the first portion of my sentence
8 was a statement in The Lancet article that you
9 put to her.
10 MR. PRESVELOS: I heard it. It was the
11 latter portion that was nowhere to be found
12 except whatever notes you're reading from. And
13 so that's improper and I'm going to put that on
14 the record.
15 MS. TELLES-LANGDON: I'm sorry, well -- I
16 mean, we will ultimately have the transcript, my
17 recollection is that Dr. Lourenco's response was

18 that absolute risk reduction is not considered
19 for vaccine authorization because of the study
20 design. I was trying to set the context for my
21 question -- my question and --
22 MR. PRESVELOS: And what did you -- what
23 did you say?
25 MS. TELLES-LANGDON: And -- and -- and one

AR09935
1 of the reasons she mentioned was -- is
2 differences in exposure rates.
3 834 Q. Maybe -- I'll do this; what does that
4 mean, Dr. Lourenco? What did you mean when you
5 say one of the reasons is because of differences
6 in exposure rates?
7 A. Differences in exposure rates because
8 there are -- there will be differences in the --
9 in the risk of exposure in the community because
10 there will be different rates of SARS-CoV-2
11 occurring in different communities. So depending
12 on where the subject is -- is recruited from,
13 their risk of exposure will -- will -- will be
14 different.
15 You've got different rates of COVID
16 occurring in different cities and different
17 communities and depending on where the subject

18 are coming from, that will impact their risk of
19 contracting SARS-CoV-2.
20 835 Q. Does use of the relative risk
21 reduction approach allow for comparisons between
22 efficacy results for different vaccine even if
23 the trials are done in different communities or
24 at different times?
25 A. Relative risk reduction allows for

AR09936
1 the comparison of the efficacy of the vaccine
2 across different -- across different sites, yes.
3 Across different regions of the world, for
4 example, if you wanted to do that because it does
5 allow to control for the -- the differences in
6 incidents of -- of SARS-CoV-2 across different
7 regions.
8 836 Q. This may seem like an obvious
9 question, Dr. Lourenco, but in asking you
10 questions about paragraph 60 of your affidavit
11 which states "vaccination is one of the most
12 effective ways to protect families, communities
13 and individuals against COVID-19," Mr. Presvelos
14 then asked you about infection-induced immunity.
15 Is it fair to say, Dr. Lourenco, that in
16 order to have infection-induced immunity an
17 individual would necessarily have had to have had

18 a COVID-19 infection?
19 A. Yes, it is fair to say that. They --
20 yes, they would have to have been exposed to the
21 virus and -- and been infected whether it's
22 asymptomatic or symptomatic.
23 837 Q. In cross-examination, Mr. Presvelos
24 asked you about others studies of mRNA
25 vaccinations in human populations and in response

AR09937
1 to that question you indicated that you were
2 aware of clinical trials for mRNA vaccinations
3 for other viruses.
4 And can you explain, Dr. Lourenco, what is
5 a clinical trial in very broad terms? What is
6 the distinction between clinical and nonclinical
7 trial?
8 A. A clinical trial involves enrollment
9 of human subjects in order to test an
10 intervention, a drug, a treatment and assess
11 whether it is able to treat disease or prevent
12 disease, but it involves human subject versus
13 nonclinical where nonclinical involves usually
14 the testing of a treatment, an intervention, a
15 drug either in animals or in other types of
16 models could be cell cultures or it could be
17 other types of -- types of laboratory tests that

18 don't involve human subjects.
19 838 Q. And are those sometimes called
20 preclinical trials?
21 A. Or preclinical, yes.
22 839 Q. Today Mr. Presvelos took you to
23 figure five of the COVID-19 daily epidemiology
24 update. Let's just see if I can put that up on
25 my screen.

AR09938
1 Are you able to see that, Dr. Lourenco?
2 A. Yes.
3 840 Q. Dr. Lourenco, please take a moment to
4 review figure five and the text immediately
5 following figure five including the three bullet
6 points.
8 A. Okay.
9 841 Q. In taking you to the aggregate number
10 of people, the total number of people in figure
11 five with confirmed cases of COVID-19,
12 Mr. Presvelos pointed out to you that there are
13 fewer total number of cases the number of people
14 admitted to the hospital and number of deaths
15 among the partially vaccinated group than for the
16 fully vaccinated or fully vaccinated with a
17 booster dose group and he suggested to you that

18 this data shows that partially vaccinated
19 individuals are faring better.
20 Dr. Lourenco, in assessing this raw data
21 as you described it, is the denominator being the
22 total number of people within a particular --
23 with a particular vaccination status important
24 context for interpreting the data?
25 MR. PRESVELOS: Sorry, it's the

AR09939
1 denominator for what?
2 BY MS. TELLES-LANGDON:
3 842 Q. Is the denominator being the number
4 of people with that -- with a particular
5 vaccination status important context for
6 interpreting the aggregate data?
7 A. Yes. Yes, the denominator is
8 important context.
9 843 Q. To your knowledge, is it fair to say
10 that a majority of people who are partially
11 vaccinated with one dose go on to become fully
12 vaccinated?
13 R/F MR. PRESVELOS: Well, what kind of a
14 question is that? You literally have statistics
15 on who's partially vaccinated as of May 15th and
16 you're asking Dr. Lourenco to speculate whether
17 the partially vaccinated who already have -- you

18 have statistics on hospitalizations and deaths
19 are going to go on to be -- well, the person who
20 died can't go on to be fully vaccinated and
21 presumably the person who's hospitalized is not
22 going to get out of the hospital and take the
23 second vaccine. This is ridiculous.
24 MS. TELLES-LANGDON: Well, Mr. Presvelos,
25 you put to her aggregate numbers and --

AR09940
2 MR. PRESVELOS: I put to her numbers of
3 individuals in each category from which the
4 government is interpreting and making health
5 recommendations and decisions. And if there's
6 further contextualization that's required, maybe
7 one of the individuals who you've adduced as a
8 witness about these numbers should have spoken to
9 it.
10 Dr. Lourenco just authorizes the
11 pharmaceuticals and apparently does not
12 contribute to these figures anyways based on her
13 own recollection.
14 MS. TELLES-LANGDON: Okay. Well -- so,
15 Mr. Presvelos, you chose to put them to her.
16 Perhaps I'll read into the record the text that
17 is immediately below the figures you put to her.

18 MR. PRESVELOS: Sure.
19 MS. TELLES-LANGDON: (Reading):
20 "Among the 12 jurisdictions and reported
21 case level vaccine history data to fact, a
22 total of 25.1 million people have received
23 at least one dose of the COVID-19 vaccine
24 as of May 15th, 2022. Of these,
25 25.1 million achieved partial vaccination

AR09941
1 status, of which 93,950 or .37 percent
2 were diagnosed with COVID-19 while
3 partially vaccinated, 2.4 million achieved
4 full vaccination" --
5 MR. PRESVELOS: No, it's 24 million -- 24
6 million achieved it.
7 MS. TELLES-LANGDON: I'm sorry, 24
8 million.
9 MR. PRESVELOS: It doesn't even make
10 sense.
11 MS. TELLES-LANGDON: No, we're all --
12 "achieved full vaccination status of which" --
13 well, you -- you put the -- this document to her
14 and I'm providing some context and I was trying
15 to lay the groundwork for the question. Here's
16 my question --
17 MR. PRESVELOS: You're asking her to

18 speculate whether the -- whether the partially
19 vaccinated go on to become fully vaccinated, and
20 there's nothing in this document that would
21 support that theory. And as I've pointed out to
22 you, it is impossible in at least one of the
23 three scenarios -- in fact, I would say in at
24 least two of the three scenarios.
25 Because if you're infected and your status

AR09942
1 is partially vaccinated, the fact is you've
2 already been partially vaccinated while you're
3 infected. So the only possibility is that
4 somebody perhaps is hospitalized and receives a
5 second dose, so I'm objecting because it's
6 improper speculation that's not supported by
7 anything on this website.
8 MS. TELLES-LANGDON: Well, does --
9 MR. PRESVELOS: How does Dr. Lourenco --
10 how does Dr. Lourenco know if the partially
11 vaccinated go on to get vaccinated? She doesn't
12 know. I don't know; you don't know, no one
13 knows. Maybe the government doesn't know.
14 MS. TELLES-LANGDON: Well, in fact that is
15 established in the record through a different
16 witness.
17 844 Q. But in any event, Dr. Lourenco, would

18 the amount of time that an individual spends with
19 partially vaccinated status be important context
20 to interpret the numbers in paragraph -- in -- in
21 figure five?
22 A. Yes, the amount of time as being
23 partially vaccinated would -- would be important
24 context.
25 845 Q. I'll stop sharing my screen; just

AR09943
1 give me a moment. And just for the sake of the
2 record -- record, Exhibit "X" of Dr. Lourenco's
3 affidavit includes figure five from the COVID-19
4 daily epidemiological update as well as table two
5 which follows immediately after as of March 27th,
6 2022.
7 Dr. Lourenco, in asking about Exhibits "B"
8 and "C" to your affidavit --
9 A. Yes.
10 846 Q. -- which were the authorization terms
11 and conditions for Pfizer and Moderna
12 respectively, Mr. Presvelos asked you about
13 outstanding information in connection with the
14 approval of these vaccines.
15 Is it unusual for there to be long-term
16 data outstanding for vaccines at the time of
17 their approval in your experience as a regulator?

18 A. No, it's not unusual. The -- it --
19 it is expected that clinical trials may continue
20 after the initial authorization and further data
21 would be filed later as those data become
22 available.
23 847 Q. And based on your experience as a
24 regulator with previous vaccine approvals, what
25 is the expectation regarding the likelihood that

AR09944
1 significant adverse events not already identified
2 will appear in the long term?
3 A. "Long term" meaning?
4 848 Q. Well, the vaccines have been approved
5 now for a year or so, --
6 A. Yes.
7 849 Q. -- a year and a half. You know what,
8 I'll just -- I'll just move on from this
9 question.
10 A. Yeah.
11 850 Q. Turning to Mr. Wilson's
12 cross-examination today he asked you about
13 whether vaccines for Shingles, pneumonia and
14 hepatitis B -- and hepatitis B had completed
15 their phase three clinical trials prior to
16 approval to your recollection. You didn't
17 recall, but I'm wondering do you recall if any of

18 those vaccines were developed and approved in the
19 context of a public health emergency of
20 international concern?
21 A. No, I don't -- I don't believe so.
22 851 Q. Now, in his questions, Mr. Wilson
23 asked you whether in your time at Health Canada
24 prior to COVID there are alternative routes to
25 vaccines' authorization other than what we

AR09945
1 reference as the normal route; you answered no to
2 that question but then later you mentioned that
3 there was -- and, sorry, I can't remember whether
4 it was H1N1 or bird flu vaccine, but you
5 mentioned that one of those vaccines was
6 initially approved under an interim order.
7 Did I understand that correctly?
8 A. Yes, that's correct, the -- the
9 vaccine for the H1N1 pandemic in 2009 was
10 approved under an interim order.
11 852 Q. And can a public health emergency of
12 international concern then in that context impact
13 the regulatory approach to vaccine approval?
14 A. Yes, it can. It certainly can as --
15 as it did with the H1N1 pandemic and with the
16 COVID-19 pandemic now as well.
17 853 Q. Returning to the Shingles and

18 pneumonia vaccines -- and it's okay if you don't
19 know, but have these vaccines been widely
20 administered either in Canada or globally in any
21 way that is comparable to the COVID-19 mRNA
22 vaccines?
23 A. No, no. The COVID-19 mRNA vaccines
24 is really unprecedented in terms of the -- the
25 global rollout of vaccines.

AR09946
1 854 Q. And during his cross-examination of
2 you, Mr. Wilson showed you a document entitled --
3 I'll just find that -- "Supplementary appendix
4 re: BNT126b2" which he said is a document from
5 Pfizer, I believe it's Exhibit 7, and he took you
6 to table S-3 on page ten of that document and had
7 you note some -- and had you note that some
8 adverse events are higher in the vaccine group
9 than in the placebo group.
10 I'm just going to share my screen again to
11 put that table in front of you. Can you see that
12 table, Dr. Lourenco?
13 A. I can see it.
14 MS. TELLES-LANGDON: Mr. Wilson, you're
15 content that this is the same table to which you
16 took Dr. Lourenco earlier to in your
17 cross-examination?
18 MR. WILSON: I am.
19 BY MS. TELLES-LANGDON:
20 855 Q. Mr. -- Dr. Lourenco, Mr. Wilson took
21 you to certain lines to show that the adverse
22 events for the vaccinated group were higher than
23 for the placebo group; I'd like you to take you
24 to some additional lines on this document. Any
25 serious adverse events life-threatening, how many

AR09947
1 -- it says -- shows that there were 21 in the --
2 can we agree to call it the BNT126b2 column the
3 Pfizer vaccinated group?
4 A. Yes. I see that 21 versus 26 in the
5 placebo.
6 856 Q. So this line, the incident -- it's --
7 the number of adverse events were higher in the
8 placebo group, is that the correct way to read
9 this?
10 A. Yes.
11 857 Q. And any -- and under the any adverse
12 events leading to withdrawal for the severe
13 events, and I'm reading it correctly that there
14 were an equal number ten in the vaccinated group
15 and ten in the placebo group?
16 A. Yes, that's right.
17 858 Q. And, again, any adverse events

18 leading to withdrawal life-threatening there were
19 three in the vaccination group and seven in the
20 placebo group?
21 A. Yes, that's what I see as well.
22 859 Q. And for deaths there were three in
23 the vaccination group and five in the placebo
24 group?
25 A. Yes.

AR09948
1 860 Q. Would it be fair to assume,
2 Dr. Lourenco, that the life-threatening adverse
3 events and deaths that occurred following the
4 placebo were not caused by the placebo?
5 A. Yes, it would be fair to assume that.
6 861 Q. What does the fact that the number of
7 reported life-threatening adverse events in the
8 placebo group -- that that number was higher than
9 for the vaccination group mean to you as the
10 regulator?
11 A. That the number of life-threatening
12 events in the placebo were higher than in the
13 vaccine? Well, we wouldn't necessarily be
14 concerned about the life-threatening events in
15 the placebo group; we would certainly look at the
16 life-threatening events in the -- in the vaccine
17 group.
18 However, on -- on balance, we would
19 certainly conclude that there are -- there isn't
20 a signal that's coming out in terms of
21 life-threatening events for the vaccine compared
22 to the placebo. But we would look at all the
23 events in great detail with regards to the
24 vaccine group for sure.
25 862 Q. Okay. I'm going to continue to share

AR09949
1 my screen, Dr. Lourenco. Do you see Appendix 1,
2 list of adverse events of special interest?
3 A. I see, yes.
4 863 Q. For context, I believe this was
5 Exhibit 8, it's the "Cumulative analysis of
6 post-authorization adverse event reports of
7 Pfizer" -- again, it's the long number --
8 received through 28 February, 2021. And
9 Mr. Wilson took you to Appendix 1, this list of
10 adverse events of special interest.
11 In asking you about -- in his asking you
12 about this list, you said that this is a list of
13 every potential adverse event of special
14 interest. What did you mean by that statement?
15 A. This appears to be an extremely long
16 list of adverse events that -- that -- that are
17 not -- not necessarily associated with the

18 vaccine but any -- any adverse event that the
19 manufacturer -- the manufacturer was likely
20 looking out for or noting as part of their
21 pharmacovigilance activities. So this is not our
22 typical list of adverse events of special
23 interest.
24 The adverse events of special interest are
25 -- are very specific events that we would ask the

AR09950
1 manufacturer to follow very closely due to
2 concerns either in the early clinical trials or
3 in the animal studies or basically concerns in
4 the clinical trials we would ask the sponsors to
5 follow the adverse events of special interest
6 very closely.
7 This other list just appear -- appears to
8 be a complete catch-all of all sorts of different
9 adverse events; I wouldn't call them adverse
10 events of special interest but just any adverse
11 event that could possibly be reported in
12 associated -- in association with any vaccine.
13 864 Q. Just one more question, Dr. Lourenco.
14 Mr. Wilson asked you questions about the
15 discovery of the tragic adverse events from the
16 use of thalidomide in pregnant women in the late
17 1950s. Was thalidomide a vaccine?

18 A. No, thalidomide is not a vaccine.
19 MS. TELLES-LANGDON: Just give me a minute
20 to consult with my colleagues; I think I might be
21 done. If we can just go off camera for maybe two
22 minutes.
25 MS. TELLES-LANGDON: Thank you,

AR09951
1 Dr. Lourenco, those are all the questions that I
2 have in redirect for you today. I appreciate
3 your willingness to come back and -- and finish;
4 I recognize it's now 7:00 p.m. for you in Ottawa.
5 THE WITNESS: No problem.
6 MS. TELLES-LANGDON: And I think that ends
7 the cross-examination, Dr. Lourenco.
8 THE WITNESS: Okay. Thank you very much,
9 have a good evening.
10 MS. TELLES-LANGDON: You, too.
11 MR. WILSON: Good evening.
12
13 -- Whereupon proceedings adjourned at 7:01 p.m.
14
15
16
17
18
19
20
21
22
23
24
25

AR09952
2 REPORTER'S CERTIFICATE
4 I, CAROLINE MASLIN, CSR, Certified
5 Shorthand Reporter, certify;
6 That the foregoing proceedings were taken
7 before me at the time and place therein set
8 forth, at which time the witness was put under
9 oath by me;
10 That the testimony of the witness and all
11 objections made at the time of the examination
12 were recorded stenographically by me and were
13 thereafter transcribed;
14 That the foregoing is a true and correct
15 transcript of my shorthand notes so taken.
16
17 Dated this 8th day of June, 2022.

18
19 CAROLINE MASLIN, CSR
20
21
22
23
24
25

EXHIBIT No ._ _ _3 _ _ __
AR09953 EXAMINATION OF_
Celia Lourenco
l♦I
Government Gouvernement
of Canada du Canada DATE June 6, 2022
Canada.ea > Coronavirus disease (COVID-19). > COVID-19 health P-roduct industry
> COVID-19 Drugs and vaccines
Drug and vaccine authorizations for COVID-19:

List of authorized drugs, vaccines and expanded
indications
Overview
List of aP-J2lications received
List of authorized products
Date published: 2022-06-01
Drugs and vaccines that have been authorized by Health Canada for use in relation to
the COVID-19 pandemic are listed here.
In the list below, the entry for each authorized drug and vaccine includes the:
• authorization holder
• brand name, proper name or common name, linked to the rationale for authorizing
the product for use against COVID-19
• medicinal ingredient(s}, strength, dosage form and route of administration
• drug identification number (DIN}, linked to the entry for the product in the Drug
Product Database, which includes the product monograph
• therapeutic area (using the World Health Organization's coding~stem)
• Health Canada's control number for the application
• date of authorization
AR09954
• how the drug or vaccine was authorized
• The product was submitted by the company to Health Canada and authorized
under the Food and Drug Regulations
• The product was submitted by the company for review under section 3 of the
interim order (10) ResP-ecting the lmP-ortation, Sale and Advertising of Drugs for
Use in Relation to COVID-19 and authorized
interim order and authorized
• The product was added to the List of new drugs for exP-anded indication in relation
to the COVID-19 P-andemic by Health Canada, under section 15 of the interim order
I________I
Filter items .... I
Showing 1 to 1O of 26 entriesShow 10 v Ientries
Brand name, Date of

proper name authorization Authorization
Authorization or common Therapeutic Control or expanded or expanded
holder name l"t!.J.I area l"t!.J.I number l"t!.J.I indication l"t!.J.I indication l"t!.J.I
AstraZeneca Evusheld Immune sera and 258295 2022-04-14 Food and Drug
Canada Inc Cilgavimab immunoglobulins, Regulations
and for human use Authorized with
tixagevimab terms and
solution for conditions
injection
AstraZeneca Vaxzevria Vaccines, for 244627 2021-02-26 Interim Order

Canada Inc (weviouslY. human use Authorized with
AstraZeneca terms and
COVID-19 conditions
Vaccine).
ChAdOx1-S
(recombinant)
solution for
injection
AR09955
Brand name, Date of
holder name lt-1....,1 area lt-1....,1 number It-I ....,I indication lt-1....,1 indication lt-1....,1
AstraZeneca Vaxzevria Vaccines, for 253700 2021-11-19 Food and Drug

Canada Inc .(previously human use Regulations
AstraZeneca Authorized with
COVID-19 terms and
Vaccine) conditions
ChAdOx1-S
(recombinant)
solution for
injection
BioNTech ComirnatY. Vaccines, for 244906 2020-12-09 Interim Order

Manufacturing _
( previously human use Authorized with
GmbH Pfizer- terms and
BioNTech conditions
COVID-19
Vaccine).
Tozinameran
(mRNA
vaccine,
BNT162b2)
suspension
for injection
BioNTech ComirnatY. Vaccines, for 251730 2021-05-05 Pediatric

Manufacturing .(previously human use indication (ages
GmbH Pfizer- 12-15)
BioNTech Interim Order
COVID-19 Authorized with
Vaccine). terms and
Tozinameran conditions
(mRNA
vaccine,
BNT162b2)
suspension
for injection
AR09956
Brand name, Date of
holder name lt-1....,1 area lt-1....,1 number It-I ....,I indication lt-1....,1 indication lt-1....,1
BioNTech ComirnatY. Vaccines, for 252736 2021-09-16 Food and Drug

Manufacturing .(previously human use Regulations
GmbH Pfizer- Authorized with
BioNTech terms and
COVID-19 conditions
Vaccine).
Tozinameran
(mRNA
vaccine,
BNT162b2)
suspension
for injection
BioNTech ComirnatY. Vaccines, for 257162 2021-11-09 First booster

Manufacturing .(previously human use dose
GmbH Pfizer- Food and Drug
BioNTech Regulations
COVID-19 Authorized with
Vaccine). terms and
Tozinameran conditions
(mRNA
vaccine,
BNT162b2)
suspension
for injection
BioNTech ComirnatY. Vaccines, for 257698 2021-11-19 Pediatric

Manufacturing .(previously human use indication (ages
GmbH Pfizer- 5-11)
BioNTech Food and Drug
COVID-19 Regulations
Vaccine). Authorized with
Tozinameran terms and
(mRNA conditions
vaccine,
BNT162b2)
suspension
for injection
AR09957
Brand name, Date of
holder name lt-1..a.l area It- I ..a.I number It-I ..a.I indication lt- 1..a.l indication lt- 1..a.l
BioNTech Comirnacy. Vaccines, for 261729 2022-06-01 First booster

Manufacturing {P-reviouslY. human use dose {ages 16-
GmbH Pfizer- 17)
BioNTech Food and Drug
Tozinameran terms and
{mRNA conditions
vaccine,
BNT162b2)
suspension
for injection
Eli Lilly Canada Bamlanivimab Immune sera and 244947 2020-11-20 Interim Order
Inc Bamlanivimab immunoglobulins, Authorized with
solution for for human use terms and
injection conditions
~ 2 3 Next~
Date modified:
2022-06-01
AR09958
• The product was submitted by the company to Health Canada and authorized under
the Food and Drug Regulations
• The product was submitted by the company for review under section 3 of the interim
order (10) ResP-ecting the lmP-ortation, Sale and Advertising of Drugs for Use in
Relation to COVID-19 and authorized
• The product was submitted by the company for review under section 4 of the interim
order and authorized
• The product was added to the List of new drugs for exP-anded indication in relation to
the COVID-19 P-andemic by Health Canada, under section 15 of the interim order
Filter items I....__________.I Showing 11 to 20 of 26 entriesShow 10 I v Ientries

Brand name, Date of

proper name authorization Authorization or
Authorization or common Therapeutic Control or expanded expanded
holder [t]l!I name lt l..J.l area lt l..J.l number t indication lt l..J.l indication lt l..J.l
Gilead Sciences Veklu[Y. Antivirals for 250151 2022-04-22 Expanded
Canada Inc. Remdesivir systemic use, for indication
solution for human use Food and Drug
injection Regulations
Authorized
Gilead Sciences Veklury Antivirals for 240551 2020-07-27 Food and Drug
Canada Inc. Remdesivir systemic use, for Regulations
solution for human use Issued Notice of
injection Compliance under
the NOC/c
Guidance
GlaxoSmithKline Sotrovimab Immune sera and 251285 2021-07-30 Interim Order

Inc Sotrovimab immunoglobulins, Authorized with
for injection for human use terms and
conditions
AR09959
Brand name, Date of
holder [t]l!I name !t +,J.I area 1-tl..a.1 number 1-tl.a.I indication 1-tl..a.1 indication 1-tl..a.1
Hoffmann-La Casirivimab Immune sera and 249830 2021-06-09 Interim Order
Roche Limited and immunoglobulins, Authorized with
imdevimab for human use terms and
Casirivimab conditions
and
imdevimab
solution for
injection
Janssen Inc Janssen Vaccines, for 246758 2021-03-05 Interim Order

COVID-19 human use Authorized with
Vaccine terms and
AD26.COV2.S conditions
(recombinant)
suspension
for injection
Janssen Inc Janssen Vaccines, for 253702 2021-11-23 Food and Drug
COVID-19 human use Regulations
Vaccine Authorized with
AD26.COV2.S terms and
(recombinant) conditions
suspension
for injection
Janssen Inc Janssen Vaccines, for 259715 2022-05-11 First booster dose
COVID-19 human use Food and Drug
Vaccine Regulations
AD26.COV2.S Authorized with
(recombinant) terms and
conditions
suspension
for injection
Medicago Inc Covifenz Vaccines, for 254598 2022-02-24 Food and Drug
Virus-like human use Regulations
particles (VLP) Authorized with
of SARS-CoV-2 terms and
spike protein conditions
emulsion for
injection
AR09960
Brand name, Date of
holder [tI !I name lf-!-l,I area lf-!-l,I number lt-!-l,I indication lf- !-l,I indication lf- !-l,I
ModernaTX, Inc S.P-ikevax Vaccines, for 244946 2020-12-23 Interim Order
.(P-reviouslY. human use Authorized with
Moderna terms and
COVID-19 conditions
Vaccine).
Elasomeran
suspension
for injection
ModernaTX, Inc S.P-ikevax Vaccines, for 253430 2021-08-27 Pediatric

.(P-reviouslY. human use indication (ages
Moderna 12-17)
COVID-19 Interim Order
Elasomeran terms and
suspension conditions
for injection
+- Previous 1
0 3 Next-+
Date modified:
2022-06-01
AR09961
• date of authorization
• how the drug or vaccine was authorized
In the "authorization" column, there are 4 possible scenarios for each drug or
vaccine:
• The product was submitted by the company to Health Canada and authorized
under the Food and Drug Regulations
interim order (IO) ResP-ecting the lmP-ortation, Sale and Advertising of Drugs for
Use in Relation to COVID-19 and authorized
interim order and authorized
• The product was added to the List of new drugs for exP-anded indication in
relation to the COVID-19 P-andemic by Health Canada, under section 15 of the
interim order
I___________.
Filter items .... Showing 21 to 26 of 26 entriesShow 10 I v Ientries
Brand name, Date of

holder name lt !.J.I area lt !.J.I number lt !.J.I indication lt !.J.I indication lt !.J.I
ModernaTX, Inc .SP-ikevax Vaccines, for 252733 2021-09-16 Food and Drug
.(P-reviouslY. human use Regulations
Moderna Authorized with
COVID-19 terms and
Vaccine). conditions
Elasomeran
suspension
for injection
AR09962
Brand name, Date of
holder name lt !.J.I area It !.J.I number It !.J.I indication lt !.J.I indication lt !.J.I
ModernaTX, Inc .SP-ikevax Vaccines, for 257293 2021-11-12 First booster
.(P-reviouslY. human use dose
Moderna Food and Drug
Elasomeran terms and
for injection
ModernaTX, Inc .SP-ikevax Vaccines, for 258658 2022-03-17 Pediatric

.(P-reviouslY. human use indication (ages
Moderna 6-11)
COVID-19 Food and Drug
Vaccine). Regulations
Elasomeran Authorized with
suspension terms and
for injection conditions
Novavax Inc. Nuvaxovid Vaccines, for 255370 2022-02-17 Food and Drug
SARS-CoV-2 human use Regulations
recombinant Authorized with
spike protein terms and
for injection
Pfizer Canada Paxlovid Antivirals for 259186 2022-01-17 Food and Drug
ULC Nirmatrelvir systemic Regulations
and ritonavir use, for Authorized with
tablets for human use terms and
oral conditions
administration
Verity Covishield Vaccines, for 248651 2021-02-26 Interim Order

Pharmaceuticals ChAdOx1-S human use (expired 2021- Authorized with
Inc/Serum (recombinant) 09-16) terms and
Institute of solution for conditions
India (in injection
partnership
with
AstraZeneca
Canada Inc)
AR09963
+ Previous 1
Date modified:
2022-06-01
4
AR09964
Health professional risk communication
Janssen COVID-19 Vaccine and the Risk

of Thrombosis with Thrombocytopenia
Starting date: April 26, 2021

Posting date: April 26, 2021
Type of Dear Healthcare
communication: Professional Letter
Subcategory: Biologic/vaccine
Source of recall: Health Canada
Issue: New safety
information
Audience: Healthcare
Professionals
Identification RA-75479
number:
Last updated:
2021-04-26
Issue Who is affected

Report health or Related AWRs
safety concerns
IMPORTANT: Janssen COVID-19 Vaccine

and the risk of thrombosis in combination
with thrombocytopenia
AR09965
Please note: Important safety information on the importation of
Janssen COVID-19 Vaccine with two types of English-only vial and
carton labels was also published on April 26, 2021
Audiences
Healthcare professionals including infectious disease physicians, family
physicians, emergency room physicians, hematologists, neurologists,
pharmacists, public health officials, nurses and nurse practitioners, and
healthcare professionals at the identified points of use.
Key messages
Very rare cases of thrombosis in combination with
thrombocytopenia, in some cases accompanied by bleeding, have
been observed following vaccination with Janssen COVID-19
Vaccine. A causal relationship with the vaccine is considered
plausible.
Health Canada has assessed the available data on the reported
events and has determined that the benefits of Janssen COVID-19
Vaccine outweigh the risks of thrombosis and thrombocytopenia.
Healthcare professionals are advised to:
be alert to the signs and symptoms of thrombosis and
thrombocytopenia in individuals.
instruct those being vaccinated to seek immediate medical
attention if they develop signs and symptoms of thrombosis
and/or thrombocytopenia following vaccination (see the
Information for healthcare professionals section).
consult with current guidance and hematologic specialists to
diagnose and treat this post-vaccine event.
Health Canada has worked with Janssen Inc. to update the Product
Monograph for Janssen COVID-19 Vaccine to include this new safety
AR09966
information.
Health Canada continues to work closely with international
regulators to review data as it becomes available on these very rare
events and will make further updates to product labelling or take
other actions as needed.

Issue
Janssen COVID-19 Vaccine was authorized for use in Canada on March 5,
2021 in accordance with the Interim Order Respecting the Importation,
Sale and Advertising of Drugs for Use in Relation to COVID-19. Since the
time of authorization, there have been very rare reports of thrombosis with
thrombocytopenia following administration of Janssen COVID-19 Vaccine.
Products affected
Janssen COVID-19 Vaccine (5 Ã 1010 virus particles/0.5 mL) suspension for
intramuscular injection, multiple dose vials. Each vial contains 5 doses
(each dose is 0.5 mL).
DIN: 02513153
Manufacturer, Importer and Distributor: Janssen Inc.
Logistics Services Provider: Innomar Strategies Inc.
Background information
Janssen COVID-19 Vaccine is indicated for active immunization for the
prevention of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2
virus in individuals 18 years of age and older.
AR09967
Very rare cases of thrombosis in combination with thrombocytopenia, in
some cases accompanied by bleeding, have been observed following
vaccination with Janssen COVID-19 Vaccine. This includes severe cases
presenting in unusual sites such as cerebral venous sinus thrombosis
(CVST) and splanchnic vein thrombosis, as well as arterial thrombosis,
concomitant with thrombocytopenia. The majority of cases occurred within
three weeks following vaccination. Some cases had a fatal outcome. No
specific risk factors have been identified at this time.
Health Canada has assessed the available data on the reported events and
has determined that the benefits of Janssen COVID-19 Vaccine outweigh
the risks of thrombosis and thrombocytopenia.
Janssen COVID-19 Vaccine is expected to be distributed and administered in

Canada in early May 2021.
Who is affected
Information for consumers

A combination of blood clots with low levels of platelets (elements in the
blood that help it to clot), in some cases together with bleeding, has been
observed very rarely following vaccination with Janssen COVID-19 Vaccine.
For the majority of people who developed these blood clots and low levels
of platelets, symptoms began one to three weeks following vaccination.
Patients should seek immediate medical attention if they develop any of

the following symptoms within the first month after receiving Janssen
COVID-19 Vaccine:
New severe headaches, worsening or persistent headaches, blurred

vision, confusion or seizures;
AR09968
Shortness of breath, chest pain, leg swelling, leg pain or persistent
abdominal pain;
Unusual skin bruising or pinpoint round spots under the skin beyond
the site of injection.
The benefits of Janssen COVID-19 Vaccine in protecting Canadians from

COVID-19 continue to outweigh the risks. Canadians are encouraged to get
immunized with any of the COVID-19 vaccines that are offered to them.
Information for healthcare professionals

The Janssen COVID-19 Vaccine Product Monograph has been updated to
include the risk of thrombosis with thrombocytopenia.
Healthcare professionals are advised to:
be alert to the signs and symptoms of thrombosis and

thrombocytopenia and report cases through their respective
jurisdiction’s Adverse Events Following Immunization (AEFI) surveillance
system.
instruct individuals vaccinated with Janssen COVID-19 Vaccine to seek
immediate medical attention if they develop symptoms such as
shortness of breath, chest pain, leg pain or swelling, or progressive
abdominal pain following vaccination. Additionally, anyone with
neurological symptoms including sudden onset of severe headaches,
persistent or worsening headaches, blurred vision, confusion or seizure
after vaccination, or who experiences unusual skin bruising or petechiae
beyond the site of vaccination after a few days, should seek prompt
medical attention.
consult with current guidance and hematologic specialists to diagnose
and treat this post-vaccine event.
Action taken by Health Canada

AR09969
Health Canada has worked closely with international regulators and
reviewed the available data. Health Canada will continue to gather
Canadian and international information from the manufacturer,
international regulators, and other experts, and will communicate any new
information as needed.
Health Canada worked with the manufacturer to update the Product

Monograph for Janssen COVID-19 Vaccine to reflect current knowledge of
this safety issue in a timely manner. Further updates will be made or other
actions will be taken, if required, based on emerging evidence.
Health Canada has worked with Janssen Inc. to prepare this alert. Health
Canada is communicating this important safety information to healthcare
professionals and Canadians via the Recalls and Safety Alerts Database on
the Healthy Canadians Web Site. This communication will be further
distributed through the MedEffectâ¢ e-Notice email notification system,
as well as through social media channels, including LinkedIn and Twitter.
Report health or safety concerns

Managing marketed health product-related side effects depends on
healthcare professionals and consumers reporting them. Any serious or
unexpected side effects in patients receiving Janssen COVID-19 Vaccine
should be reported to your local Health Unit or Janssen Inc.
Janssen Inc.
19 Green Belt Drive
Toronto, ON
M3C 1L9
To correct your mailing address or fax number, contact Janssen Inc. at

1-800-565-4008 (toll free) or 1-908-455-9922 (US toll).
AR09970
If a patient experiences a side effect following immunization, please
complete the Adverse Events Following Immunization (AEFI) Form
appropriate for your province/territory and send it to your local Health
Unit.
For other health product inquiries related to this communication, contact

Health Canada at:
Biologic and Radiopharmaceutical Drugs Directorate
E-mail: hc.brdd.dgo.enquiries.sc@canada.ca
Original signed by
Katherine Tsokas
Vice President Regulatory Affairs
Janssen Inc.
Related AWRs
Importation of Janssen COVID-19 Vaccine with Two Types of English-only

Vial and Carton Labels
2021-04-26 | Health products, COVID-19
Advisory
Authorization of Janssen COVID-19 Vaccine with English-only Vial and

Carton Labels
2021-03-05 | Health products, COVID-19
Advisory
AR09971
Date modified:
2021-04-26
5
AR09972
Public advisory
Health Canada updates Pfizer-BioNTech

and Moderna COVID-19 vaccine labels to
include information on myocarditis and
pericarditis
Starting date: June 30, 2021

Posting date: June 30, 2021
Type of Advisory
communication:
Issue: Product Safety
Audience: General Public
number:
Last updated:
2021-06-30
Summary
Product:
Pfizer-BioNTech and Moderna COVID-19 vaccines

Issue:
Health Canada has updated the product monographs (labels) for the
Pfizer-BioNTech and Moderna COVID-19 vaccines to describe very rare
reports of myocarditis and pericarditis following vaccination.
AR09973
What to do:
Seek medical attention immediately if you experience any of the

following symptoms within several days of vaccination: chest pain,
shortness of breath, or feelings of having a fast beating, fluttering or
pounding heart.
Issue What you should do

What industry Media enquiries
professionals should Public enquiries
do
Issue
Health Canada has updated the product monographs (labels) for the Pfizer-
BioNTech and Moderna COVID-19 vaccines to describe very rare reports of
myocarditis (inflammation of the heart muscle) and pericarditis
(inflammation of the tissue surrounding the heart) following vaccination.
Cases of myocarditis and/or pericarditis following immunization with

COVID-19 vaccines have been reported in a small number of people in
Canada and internationally. These reports are very rare. Health Canada and
other international regulators are continuing to investigate the potential
relationship between COVID-19 vaccines and these rare events. Most
reported cases to date have followed vaccination with an mRNA vaccine
(Pfizer-BioNTech and Moderna) and, based on an analysis of international
cases, have occurred more often after the second dose and in younger
male adults and adolescents. The Canadian evidence is expected to evolve
as more people in these populations are vaccinated. Available short-term
follow-up data show that these events were typically mild and treatable;
however, information on long-term outcomes is not yet available.
AR09974
Myocarditis is an inflammation of the heart muscle, while pericarditis is an
inflammation of the lining around the heart. Both conditions can result
from an infection (including COVID-19), exposure to a toxic substance or
radiation, or other health events. Symptoms can include chest pain,
shortness of breath, or palpitations (feelings of having a fast-beating,
fluttering or pounding heart). In many cases, these conditions are mild and
require little to no treatment. However, more severe cases can lead to heart
muscle damage.
Health Canada has updated the product labels for the Pfizer-BioNTech and
Moderna COVID-19 vaccines to inform Canadians and healthcare
professionals of these possible side effects and to provide information
about the signs and symptoms and when to seek prompt medical attention
following vaccination.
Health Canada will continue to work with manufacturers, as well as

domestic and international partners, to gain a better understanding of the
relationship between COVID-19 vaccines and these events. In addition,
Health Canada and the Public Health Agency of Canada will continue to
monitor Canadian and international reports of myocarditis and/or
pericarditis, particularly as more adolescents and young adults are
vaccinated and more second doses are administered. The Department will
take appropriate action will be taken if any new safety issues are identified.
Health Canada reassures Canadians that COVID-19 vaccines continue to be

safe and effective at protecting them against COVID-19. The benefits of
COVID-19 vaccines continue to outweigh their potential risks, as scientific
evidence shows that they reduce deaths and hospitalizations due to COVID-
19. The Government of Canada encourages people to get vaccinated and to
complete their vaccine series as soon as they are eligible.
AR09975
For further information on COVID-19 vaccines in Canada, please visit Health
Canada’s COVID-19 vaccines and treatments portal.
What you should do

If you have received the Pfizer-BioNTech and Moderna COVID-19
vaccines:
Seek medical attention immediately if you experience any of the following

symptoms within several days of vaccination:
chest pain
shortness of breath
feelings of having a fast-beating, fluttering or pounding heart.
Report any adverse events after immunization to your healthcare

professional.
What industry professionals should do

Be alert to the signs and symptoms of myocarditis and pericarditis when
individuals present with chest pain, shortness of breath, palpitations or
other signs and symptoms following immunization with a COVID-19
vaccine. This could allow for early diagnosis and treatment. Cardiology
consultation for management and follow-up should be considered.
When deciding whether to administer the Pfizer-BioNTech or Moderna
COVID-19 vaccine to an individual with a history of myocarditis or
pericarditis, consider the individual's clinical circumstances.
Report any event potentially related to a vaccine. To report a side effect
to Health Canada contact your local health unit or visit Health Canada's
Web page on Adverse Reaction Reporting for information on how to
report online, by mail or by fax.
AR09976
Media enquiries
Health Canada
(613) 957-2983
hc.media.sc@canada.ca
Public enquiries
(613) 957-2991
1-866 225-0709
Date modified:
2021-06-30
6
AR09977
Public advisory
Health Canada updates Pfizer-BioNTech

COVID-19 vaccine label to reflect very
rare reports of Bell's Palsy
Starting date: August 6, 2021

Type of Advisory
communication:
Issue: Product label update
Audience: General Public,
Healthcare
Professionals
number:
Last updated:
2021-08-06
Summary
Product:
Pfizer-BioNTech COVID-19 vaccine

Issue:
Health Canada has updated the product information for the Pfizer-
BioNTech COVID-19 vaccine to describe very rare reports of Bell’s Palsy
(typically temporary weakness or paralysis on one side of the face)
following vaccination.
AR09978
What to do:
Seek medical attention if you experience any combination of the

following symptoms after vaccination: uncoordinated movement of the
muscles that control facial expression; loss of feeling in the face;
headache; tearing from the eye; drooling; lost sense of taste on the
front two-thirds of the tongue; hypersensitivity to sound in one ear; or
inability to close an eye on one side of the face.
Issue What you should do

What industry Media enquiries
professionals should Send us your
do feedback
Issue
Health Canada has updated the product information for the Pfizer-
BioNTech COVID-19 vaccine to describe very rare reports of Bell’s Palsy
(typically temporary weakness or paralysis on one side of the face)
following vaccination. Cases have been reported in a small number of
people in Canada and internationally.
The Moderna COVID-19 vaccine label already contains safety information

about reported cases of Bell’s Palsy following vaccination and the
Department is continuing to assess this issue for all authorized COVID-19
vaccines in Canada.
Bell's Palsy is an episode of facial muscle weakness or paralysis. The

condition is typically temporary. Symptoms appear suddenly and generally
start to improve after a few weeks. The exact cause is unknown. It's
believed to be the result of swelling and inflammation of the nerve that
controls muscles on one side of your face.
AR09979
Health Canada reassures Canadians that COVID-19 vaccines continue to be
safe and effective at protecting them against COVID-19. The benefits of
COVID-19 vaccines continue to outweigh their potential risks, as scientific
evidence shows that they reduce deaths and hospitalizations due to COVID-
19.
Health Canada will continue to work with manufacturers, as well as

domestic and international partners, to gain a better understanding of the
potential relationship between COVID-19 vaccines and adverse events. The
Department will take further action if necessary.
For further information on COVID-19 vaccines in Canada, please visit Health

Canada’s COVID-19 vaccines and treatments portal.
What you should do

Seek medical attention if you experience any combination of the following
symptoms after vaccination:
uncoordinated movement of the muscles that control facial expressions,

such as smiling, squinting, blinking or closing the eyelid
loss of feeling in the face
headache
tearing from the eye
drooling
lost sense of taste on the front two-thirds of the tongue
hypersensitivity to sound in the one ear
inability to close an eye on one side of the face
Report any adverse events after immunization to your healthcare

professional.
AR09980
What industry professionals should do
Be alert to the signs and symptoms of side effects following vaccination
with COVID-19 vaccines.
Report any event potentially related to a vaccine to your local public
health unit.
Media enquiries
Health Canada
(613) 957-2983
hc.media.sc@canada.ca
Send us your feedback

(613) 957-2991
1-866 225-0709
Date modified:
2021-08-06
EXHIBIT No . 7
AR09981 EXAMINATION OF
Celia Lourenco
-------
Public advisory
DATE June 6, 2022
Health Canada is updating the labels of

the Janssen and Vaxzevria (AstraZeneca)
COVID-19 vaccines
Last updated: 2021-11-09
Summary
Product: Janssen and Vaxzevria (AstraZeneca) COVID-19 vaccines
Issue: Health products - Product safety
COVID
What to do: Seek medical attention immediately if you have any of
the following symptoms after vaccination with the Janssen and
Vaxzevria COVID-19 vaccines: unexplained bleeding, unexplained
bruising, small purplish spots beyond the site of vaccination,
shortness of breath, chest pain, leg pain and/or swelling, and
persistent abdominal pain.
Issue
Health Canada is informing Canadians and healthcare professionals about
changes to the product labels of the Janssen and Vaxzevria (AstraZeneca)
COVID-19 vaccines.
AR09982
The Department is updating the label of the Janssen COVID-19 Vaccine to
provide additional information about the very rare risk of immune
thrombocytopenia (ITP), an autoimmune condition, and the rare risk of
venous thromboembolism (VTE) following vaccination.
Health Canada is also updating the label of the Vaxzevria (AstraZeneca)

COVID-19 vaccine to provide additional information about the very rare risk
of thrombocytopenia, including the very rare risk of ITP, following
vaccination.
Immune thrombocytopenia
Very rare cases of ITP, an autoimmune condition, have been reported
internationally after receiving the Janssen COVID-19 vaccine. Similarly,
cases of thrombocytopenia including ITP have been reported after
receiving Vaxzevria.
ITP is a disorder that can lead to easy or excessive bruising and bleeding.
The bleeding results from unusually low levels of platelets the cells that
help blood clot. These cases typically occur within the first four weeks after
vaccination. Some of these cases occurred in individuals with a history of
ITP. Cases with a fatal outcome have been reported abroad.
Individuals should seek immediate medical attention if they develop

symptoms, such as unexplained bleeding, unexplained bruising, or small
purplish spots beyond the site of vaccination.
Venous thromboembolism
Rare cases of VTE have been reported following vaccination with the
Janssen COVID-19 vaccine. VTE is a condition where a blood clot forms in a
deep vein, usually in a leg, arm or groin, and may travel to the lungs
AR09983
causing a blockage of the blood supply, with possible life-threatening
consequences.
The risk of VTE should be considered for individuals who are at increased
risk for thromboembolism. Healthcare professionals should be alert to the
signs and symptoms of VTE. Individuals should seek immediate medical
attention if they develop symptoms, such as shortness of breath, chest
pain, leg pain, leg swelling, or persistent abdominal pain following
vaccination.
The risk of VTE should be considered for individuals who are at increased
risk for thromboembolism. Healthcare professionals should be alert to the
signs and symptoms of VTE. Individuals should seek immediate medical
attention if they develop symptoms, such as shortness of breath, chest
pain, leg pain, leg swelling, or persistent abdominal pain following
vaccination.
What you should do

If you have received the Janssen or Vaxzevria COVID-19 vaccine:
• Seek prompt medical attention immediately if you have any of the

following symptoms after vaccination:
0 unexplained bleeding
0 unexplained bruising
0 small purplish spots beyond the site of vaccination
0 shortness of breath
0 chest pain
0 leg pain and/or swelling
0 persistent abdominal pain
• Talk to your healthcare professional if you have any questions about the
Janssen or Vaxzevria COVID-19 vaccines.
AR09984
• Report any adverse events after immunization to your healthcare
professional.
If you are a healthcare professional:
• Be alert to the signs and symptoms of thromboembolism and

thrombocytopenia to promptly treat these conditions according to
available evidence and clinical guidelines.
• Inform people receiving the vaccine to seek medical attention if they
develop any of the following symptoms:
0 ITP symptoms include spontaneous bleeding, unusual bruising or
small red, purple or brown spots that appear under the skin.
0 VTE symptoms include shortness of breath, chest pain, leg pain, leg
swelling, or persistent abdominal pain following vaccination.
• Consider consultation with a specialist if you suspect the patient has
post-vaccine thrombosis.
• If an individual has a history of a thrombocytopenic disorder, such as
immune thrombocytopenia, the risk of developing low platelet levels
should be considered before administering the vaccine and platelet
monitoring is recommended after vaccination.
Additional information
► What is being done
► Details
► Media and public enquiries
Date modified:
2021-11-09
8 _ __
EXHIBIT No . _ _ _ _ _

Celia Lourenco
FDA NEWS RELEASE DATE June 6, 2022

Coronavirus (COVID-19) Update: FDA Limits Use of Janssen COVID-

19 Vaccine to Certain Individuals
For Immediate Release:
May 05, 2022
Español (/news-events/press-announcements/actualizacion-sobre-el-coronavirus-covid-19-la-fda-limita-el-uso-de-la-vacuna-contra-el-covid-19-de)
Today, the U.S. Food and Drug Administration has limited the authorized use of the Janssen COVID-19
Vaccine to individuals 18 years of age and older for whom other authorized or approved COVID-19 vaccines
are not accessible or clinically appropriate, and to individuals 18 years of age and older who elect to receive
the Janssen COVID-19 Vaccine because they would otherwise not receive a COVID-19 vaccine.
Key Points:
• After conducting an updated analysis, evaluation and investigation of reported cases, the FDA has
determined that the risk of thrombosis with thrombocytopenia syndrome (TTS), a syndrome of rare
and potentially life-threatening blood clots in combination with low levels of blood platelets with onset
of symptoms approximately one to two weeks following administration of the Janssen COVID-19
Vaccine, warrants limiting the authorized use of the vaccine.
• The FDA has determined that the known and potential benefits of the vaccine for the prevention of
COVID-19 outweigh the known and potential risks for individuals 18 years of age and older for whom
other authorized or approved COVID-19 vaccines are not accessible or clinically appropriate, and for
individuals 18 years of age and older who elect to receive the Janssen COVID-19 Vaccine because they
would otherwise not receive a COVID-19 vaccine.
• The Fact Sheet for Healthcare Providers Administering Vaccine

(https://www.fda.gov/media/146304/download) now reflects the revision of the authorized use of the
Janssen COVID-19 Vaccine and includes a warning statement at the beginning of the fact sheet for
prominence which summarizes information on the risk for TTS. Additionally, information on the
revision to the authorized use of the vaccine and updated information on this risk of blood clots with
low levels of blood platelets has been added to the Fact Sheet for Recipients and Caregivers
(https://www.fda.gov/media/146305/download).
“We recognize that the Janssen COVID-19 Vaccine still has a role in the current pandemic
response in the United States and across the global community. Our action reflects our
updated analysis of the risk of TTS following administration of this vaccine and limits the use
of the vaccine to certain individuals,” said Peter Marks, M.D., Ph.D., director of the FDA’s
Center for Biologics Evaluation and Research. “Today’s action demonstrates the robustness
of our safety surveillance systems and our commitment to ensuring that science and data
guide our decisions. We’ve been closely monitoring the Janssen COVID-19 Vaccine and
occurrence of TTS following its administration and have used updated information from our
AR09986
safety surveillance systems to revise the EUA. The agency will continue to monitor the safety
of the Janssen COVID-19 Vaccine and all other vaccines, and as has been the case throughout
the pandemic, will thoroughly evaluate new safety information.”
Background
The Janssen COVID-19 Vaccine was authorized for emergency use (https://www.fda.gov/news-
-- ---- -- ---------
events/press-announcements/fda-issues-emergency-use-authorization-third-covid-19-vaccine) on Feb. 27,
2021. On April 13, 2021, the FDA and the Centers for Disease Control and Prevention (CDC), announced a
recommended pause in administration (https://www.fda.gov/news-events/press-announcements/joint-cdc-
and-fda-statement-johnson-johnson-covid-19-vaccine) of the vaccine to investigate six reported cases of
TTS, and to help ensure that health care providers were made aware of the potential for TTS and could plan
for proper recognition and management due to the unique treatment required for TTS.
On April 23, 2021, following a thorough safety evaluation, including two meetings of the CDC’s Advisory
Committee on Immunization Practices (ACIP), the FDA and CDC lifted the recommended pause
(https://www.fda.gov/news-events/press-announcements/fda-and-cdc-lift-recommended-pause-johnson-
johnson-janssen-covid-19-vaccine-use-following-
thorough#:~:text=Following%20a%20thorough%20safety%20review,Johnson%20(Janssen)%20COVID%2D19)
regarding the use of the Janssen COVID-19 Vaccine. The agencies confirmed a total of 15 cases of TTS had
been reported to the Vaccine Adverse Event Reporting System (VAERS), including the original six reported
cases, out of approximately 8 million doses administered.
These data, plus the deliberations and recommendations by the ACIP, helped with FDA’s assessment that
the known and potential benefits of Janssen COVID-19 Vaccine outweighed its known and potential risks in
individuals 18 years of age and older. The available data suggested the chance of TTS occurring was remote,
but investigation into the level of potential excess risk due to vaccination and specific risk factors continued.
At that time the Fact Sheet for Healthcare Providers Administering Vaccine was revised to include a warning
pertaining to the risk of TTS and the Fact Sheet for Recipients and Caregivers was also revised to include
information about blood clots in combination with low blood platelets after receiving the Janssen COVID-19
Vaccine.
In December 2021, after reviewing updated vaccine effectiveness and safety data, the ACIP made a
preferential recommendation for the use of mRNA COVID-19 vaccines over the Janssen COVID-19 Vaccine
in all persons 18 years of age and older in the United States. The ACIP recommended and CDC endorsed that
the Janssen COVID-19 Vaccine may be considered in some situations: when a person has a contraindication
to receipt of mRNA COVID-19 vaccines, when a person would otherwise remain unvaccinated for COVID-19
due to limited access to mRNA COVID-19 vaccines, and when a person wants to receive the Janssen COVID-
19 Vaccine despite the safety concerns identified.
Current Status
The FDA and CDC have continuously monitored for and investigated all suspected cases of TTS reported to
VAERS. In an updated analysis of TTS cases following administration of the Janssen COVID-19 Vaccine that
were reported to VAERS through March 18, 2022, the FDA and CDC have identified 60 confirmed cases,
including nine fatal cases. The FDA has determined that the reporting rate of TTS is 3.23 per million doses
of vaccine administered and the reporting rate of TTS deaths is 0.48 per million doses of vaccine
administered.
AR09987
In making the determination to limit the authorized use of the Janssen COVID-19 Vaccine, the agency
considered that reporting rates of TTS and TTS deaths following administration of the Janssen COVID-19
Vaccine are not appreciably lower than previously reported. Furthermore, the factors that put an individual
at risk for TTS following administration of Janssen COVID-19 Vaccine remain unknown. The FDA also
considered that individuals with TTS may rapidly deteriorate, despite prompt diagnosis and treatment, that
TTS can lead to long-term and debilitating health consequences and that TTS has a high death rate. The
agency also considered the availability of alternative authorized and approved COVID-19 vaccines which
provide protection from COVID-19 and have not been shown to present a risk for TTS.
Examples of individuals who may still receive the Janssen COVID-19 Vaccine include: individuals who
experienced an anaphylactic reaction after receipt of an mRNA COVID-19 vaccine, individuals who have
personal concerns with receiving mRNA vaccines and would otherwise not receive a COVID-19 vaccine and
individuals who would remain unvaccinated for COVID-19 due to limited access to mRNA COVID-19
vaccines.
Ongoing Safety Monitoring
The FDA has a robust safety surveillance system in place to monitor the safety of COVID-19 vaccines
approved and authorized for emergency use. The FDA is monitoring COVID-19 vaccine safety through both
passive and active safety surveillance systems in collaboration with the CDC, the Centers for Medicare and
Medicaid Services, the Department of Veterans Affairs and other academic and large non-government
healthcare data systems.
The revised EUA for the Janssen COVID-19 Vaccine was issued to Janssen Biotech Inc., a Janssen
Pharmaceutical Company of Johnson & Johnson.
Related Information
• Janssen COVID-19 Vaccine (https://www.fda.gov/emergency-preparedness-and-
-- - -- ----------
response/coronavirus-disease-2019-covid-19/janssen-covid-19-vaccine)
• COVID-19 Vaccines (https://www.fda.gov/emergency-preparedness-and-response/coronavirus-

-- - -- ------------ ------------
disease-2019-covid-19/covid-19-vaccines)
• Emergency Use Authorization for Vaccines Explained (https://www.fda.gov/vaccines-blood-

biologics/vaccines/emergency-use-authorization-vaccines-explained)
###
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health
by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other
biological products for human use, and medical devices. The agency also is responsible for the safety and
security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic
radiation, and for regulating tobacco products.
Inquiries
Media:
AR09988

FDA Office of Media Affairs (mailto:fdaoma@fda.hhs.gov)
 301-796-4540
Consumer:
 888-INFO-FDA
[  More Press Announcements (/news-events/newsroom/press-announcements)

9
AR09989 The n e w e ng l a n d j o u r na l of m e dic i n e
EXHIBIT No.
EXAMINATION OF
.:........:..__:_:..
Celia Lourenco _____
Original Article DATE June 6, 2022
Safety and Efficacy of the BNT162b2 mRNA

Covid-19 Vaccine through 6 Months
S.J. Thomas, E.D. Moreira, Jr., N. Kitchin, J. Absalon, A. Gurtman, S. Lockhart,
J.L. Perez, G. Pérez Marc, F.P. Polack, C. Zerbini, R. Bailey, K.A. Swanson,
X. Xu, S. Roychoudhury, K. Koury, S. Bouguermouh, W.V. Kalina, D. Cooper,
R.W. Frenck, Jr., L.L. Hammitt, Ö. Türeci, H. Nell, A. Schaefer, S. Ünal, Q. Yang,
P. Liberator, D.B. Tresnan, S. Mather, P.R. Dormitzer, U. Şahin, W.C. Gruber,
and K.U. Jansen, for the C4591001 Clinical Trial Group*
A BS T R AC T
BACKGROUND
BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine The authors’ full names, academic de-
encoding a prefusion-stabilized, membrane-anchored severe acute respiratory syn- grees, and affiliations are listed in the
Appendix. Dr. Dormitzer can be contact-
drome coronavirus 2 (SARS-CoV-2) full-length spike protein. BNT162b2 is highly ed at philip.dormitzer@pfizer.com or at
efficacious against coronavirus disease 2019 (Covid-19) and is currently approved, Pfizer, 401 N. Middletown Rd., Pearl River,
conditionally approved, or authorized for emergency use worldwide. At the time of NY 10965.
initial authorization, data beyond 2 months after vaccination were unavailable. *A list of the investigators in the C4591001
Clinical Trial Group is provided in the
METHODS Supplementary Appendix, available at
NEJM.org.
In an ongoing, placebo-controlled, observer-blinded, multinational, pivotal efficacy
trial, we randomly assigned 44,165 participants 16 years of age or older and 2264 This article was published on September 15,
2021, at NEJM.org.
participants 12 to 15 years of age to receive two 30-μg doses, at 21 days apart, of
BNT162b2 or placebo. The trial end points were vaccine efficacy against laboratory- N Engl J Med 2021;385:1761-73.
DOI: 10.1056/NEJMoa2110345
confirmed Covid-19 and safety, which were both evaluated through 6 months after Copyright © 2021 Massachusetts Medical Society.
vaccination.
CME
RESULTS at NEJM.org
BNT162b2 continued to be safe and have an acceptable adverse-event profile. Few
participants had adverse events leading to withdrawal from the trial. Vaccine ef-
ficacy against Covid-19 was 91.3% (95% confidence interval [CI], 89.0 to 93.2)
through 6 months of follow-up among the participants without evidence of previ-
ous SARS-CoV-2 infection who could be evaluated. There was a gradual decline in
vaccine efficacy. Vaccine efficacy of 86 to 100% was seen across countries and in
populations with diverse ages, sexes, race or ethnic groups, and risk factors for
Covid-19 among participants without evidence of previous infection with SARS-
CoV-2. Vaccine efficacy against severe disease was 96.7% (95% CI, 80.3 to 99.9). In
South Africa, where the SARS-CoV-2 variant of concern B.1.351 (or beta) was pre-
dominant, a vaccine efficacy of 100% (95% CI, 53.5 to 100) was observed.
CONCLUSIONS
Through 6 months of follow-up and despite a gradual decline in vaccine efficacy,
BNT162b2 had a favorable safety profile and was highly efficacious in preventing
Covid-19. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.)
n engl j med 385;19 nejm.org November 4, 2021 1761

The New England Journal of Medicine
Downloaded from nejm.org on June 3, 2022. For personal use only. No other uses without permission.
Copyright © 2021 Massachusetts Medical Society. All rights reserved.
T
he coronavirus disease 2019 (Covid-19) population (all participants ≥12 years of age)
pandemic continues, with recent estimates reported here.
of more than 187 million cases diagnosed Participants who were healthy or had stable
and more than 4 million deaths.1 Vaccines are chronic medical conditions were eligible. An ac-
currently available by means of full approval, tive immunocompromising condition or recent
A Quick Take
is available at conditional marketing approval, and emergency immunosuppressive therapy was an exclusion
NEJM.org use authorization pathways.2-5 BNT162b2 is a criterion. Participants with a history of Covid-19
lipid nanoparticle–formulated,6 nucleoside-mod- were excluded, although evidence of current or
ified RNA7 encoding the severe acute respiratory previous SARS-CoV-2 infection on laboratory test-
syndrome coronavirus 2 (SARS-CoV-2) full-length ing of trial-obtained samples was not an exclu-
spike glycoprotein in a prefusion stabilized con- sion criterion. Trial-related responsibilities and
formation.8 To date, more than 1 billion doses ethical conduct are summarized in the Supplemen-
of BNT162b2 have been distributed. tary Appendix, available with the full text of this
We previously reported safety and efficacy article at NEJM.org. The protocol contains addi-
data obtained through a median of 2 months of tional details of the trial and is available at
postimmunization follow-up from a global NEJM.org. The first draft of the manuscript was
phase 1–2–3 trial of BNT162b2 involving persons written by the fourth author. The authors had
16 years of age or older. Vaccine efficacy against the opportunity to review the data included in
Covid-19 was 95%. BNT162b2 had a favorable this article and confirm the accuracy of the data
safety profile in diverse populations.9 These data presented through the specified data cutoff date.
formed the basis for BNT162b2 emergency or The authors vouch for the accuracy and complete-
conditional authorizations globally.10 Safety, ef- ness of the data and for the fidelity of the trial to
ficacy, and immunogenicity data from partici- the protocol.
pants 12 to 15 years of age in this trial have been
reported.11 Here, we report safety and efficacy Procedures
findings from a prespecified analysis of the The participants were randomly assigned in a
phase 2–3 portion of the trial through approxi- 1:1 ratio to receive two 30-μg intramuscular in-
mately 6 months of follow-up. These additional jections, 21 days apart, of BNT162b2 (0.3 ml
data contributed to the full approval of BNT162b2 volume per dose) or saline placebo. Random-
in the United States. ization was performed with an interactive Web-
based system. Starting in December 2020, after
BNT162b2 became available under emergency or
Me thods
conditional use authorizations, participants 16
Objectives, Participants, and Oversight years of age or older who became eligible for
This randomized, placebo-controlled, observer- Covid-19 vaccination according to national or
blinded, phase 1–2–3 trial assessed the safety, local recommendations were given the option to
efficacy, and immunogenicity of the BNT162b2 learn their trial assignment. Those who had been
vaccine in adolescents and adults. The current randomly assigned to receive placebo were of-
report of the findings from the phase 2–3 portion fered BNT162b2. After unblinding of the group
of the trial focuses on safety assessments among assignments, participants were followed in an
participants 16 years of age or older and prespeci- open-label trial period.
fied assessments of vaccine efficacy among par-
ticipants 12 years of age or older through 6 months Safety
of follow-up after immunization. Because the en- Safety end points included solicited, prespecified
rollment of participants 12 to 15 years of age local reactions, systemic events, and antipyretic
began on October 15, 2020, 6-month postim- or pain medication use during the first 7 days
munization data are currently unavailable for after receipt of each vaccine or placebo dose,
this age cohort. Shorter-duration safety, immu- which were recorded in an electronic diary; unso-
nogenicity, and efficacy data for participants 12 licited adverse events after receipt of the first dose
to 15 years of age are reported separately11; through 1 month after the second dose; and seri-
however, data for this cohort are included in ous adverse events after receipt of the first dose
the analyses of vaccine efficacy in the overall through 1 and 6 months after the second dose
1762 n engl j med 385;19 nejm.org November 4, 2021

AR09991 Safety and Efficacy of BNT162b2 through 6 Months
was received. Safety data are presented for the od, with adjustment for surveillance time, which
blinded follow-up and open-label periods. accounts for potential differential follow-up be-
tween the two trial groups. As described in the
Efficacy statistical analysis plan, available with the pro-
BNT162b2 efficacy against laboratory-confirmed tocol, hypothesis-testing analyses were performed
Covid-19 with an onset of 7 days or more after with the use of a Bayesian approach, and the
the second dose was assessed and summarized descriptive analyses presented here were per-
descriptively in participants without serologic or formed with a frequentist approach for clarity of
virologic evidence of SARS-CoV-2 infection within communication. Because the percentage of par-
7 days after the second dose and in participants ticipants who reported symptoms but were miss-
with or without evidence of previous infection. ing a valid polymerase-chain-reaction test result
Efficacy against severe Covid-19 was also assessed. was small and slightly higher in the placebo group,
Lineages of SARS-CoV-2 detected in midturbinate data for these participants were not imputed in the
specimens are reported here for Covid-19 cases analysis.
that occurred 7 days or more after the second The previously reported primary efficacy ob-
dose in South African participants without evi- jective was achieved on the basis of an analysis of
dence of previous infection. Methods for deter- 170 accrued cases of Covid-19 that could be evalu-
mining SARS-CoV-2 lineages and case definitions ated (data cutoff date, November 14, 2020).9 The
for confirmed and severe cases of Covid-19 are current report provides updated efficacy analyses
summarized in the Supplementary Appendix. that were performed with data from cases that
had accrued up to March 13, 2021.
The analysis populations are summarized in R e sult s
Table S1 in the Supplementary Appendix. Safety
analyses included participants 16 years of age or Participants
older without known human immunodeficiency Between July 27, 2020, and October 29, 2020, a
virus (HIV) infection who provided informed total of 45,441 participants 16 years of age or
consent and received at least one BNT162b2 or older underwent screening, and 44,165 underwent
placebo dose. The results of the safety analyses, randomization at 152 sites (130 sites in the
which are descriptive and not based on formal United States, 1 site in Argentina, 2 sites in Brazil,
hypothesis testing, are presented as counts, per- 4 sites in South Africa, 6 sites in Germany, and
centages, and associated Clopper–Pearson 95% 9 sites in Turkey) in the phase 2–3 portion of the
confidence intervals for adverse events, according trial. Of these participants, 44,060 received at
to terms in the Medical Dictionary for Regulatory Ac- least one dose of BNT162b2 (22,030 participants)
tivities, version 23.1, and reactogenicity events for or placebo (22,030), and 98% (21,759 in the
each trial group. Safety data that were reported BNT162b2 group and 21,650 in the placebo group)
up to March 13, 2021, are summarized here. The received the second dose (Fig. 1). During the
95% confidence intervals in this report were not blinded period of the trial, 51% of the partici-
adjusted for multiplicity. pants in each group had 4 to less than 6 months
The analysis of vaccine efficacy during the of follow-up after the second dose; 8% of the
blinded period of the trial included all partici- participants in the BNT162b2 group and 6% of
pants 12 years of age or older without known those in the placebo group had 6 months of
HIV infection who received at least one BNT162b2 follow-up or more after the second dose. During
or placebo dose. Vaccine efficacy was calculated the combined blinded and open-label periods,
as 100 × (1 – IRR), where IRR (incidence rate ra- 55% of the participants in the BNT162b2 group
tio) is the ratio of the rate (number per 1000 had 6 months of follow-up or more after the
person-years of follow-up) of confirmed cases of second dose. A total of 49% of the participants
Covid-19 in the BNT162b2 group to the corre- were female, 82% were White, 10% were Black,
sponding rate in the placebo group. Descriptive and 26% were Hispanic or Latinx; the median age
analyses of vaccine efficacy were performed and was 51 years. A total of 34% of the participants
associated 95% confidence intervals were calcu- had a body-mass index (the weight in kilograms
lated with the use of the Clopper–Pearson meth- divided by the square of the height in meters) of

I 45,441 Participants underwent screening I

~~1
1276 Were excluded
-
1173 Did not pass screening
103 Withdrew
44,165 Underwent randomization

I
!
22,085 Were assigned to receive BNT162b2
l
22,080 Were assigned to receive placebo
I 11 I
55 Did not receive BNT162b2 50 Did not receive placebo

26 Withdrew 26 Withdrew
15 Had protocol deviation 12 Had protocol deviation
7 No longer met eligibility criteria 3 No longer met eligibility criteria
3 Had adverse event 2 Had adverse event
4 Had other reason 7 Had other or unknown reason
22,030 Received the first dose 22,030 Received the first dose
I 11 I
380 Discontinued trial after the first

271 Discontinued trial after the first
dose and before the second dose
dose and before the second dose
108 Withdrew
108 Withdrew
90 Were lost to follow-up
89 Were lost to follow-up
119 No longer met eligibility criteria
25 No longer met eligibility criteria
25 Had adverse event
25 Had adverse event
6 Became pregnant
6 Became pregnant
7 Were withdrawn by physician
3 Were withdrawn by physician
2 Died
2 Died
2 Had medication error without
2 Had medication error without
associated adverse event
associated adverse event
1 Had protocol deviation
11 Had other or unknown reason
20 Had other or unknown reason
21,759 Received the second dose 21,650 Received the second dose
I 11 I
167 Discontinued trial after the second
dose 273 Discontinued trial after the second
81 Were lost to follow-up dose
54 Withdrew 125 Withdrew
14 Died 96 Were lost to follow-up
11 Had protocol deviation 24 Had protocol deviation
3 Were withdrawn by physician 13 Died
1 Had medication error without 3 Were withdrawn by physician
associated adverse event 4 No longer met eligibility criteria
1 Was withdrawn by parent 1 Had adverse event
or guardian 1 Became pregnant
1 No longer met eligibility criteria 6 Had other reason
1 Had other reason
20,334 Entered open-label follow-up 20,794 Entered open-label follow-up

I 11 I

Figure 1 (facing page). Screening, Randomization, evidence, and 49 who lacked the data needed to
and Follow-up. determine previous infection status.
The diagram represents all enrolled participants 16 More participants in the BNT162b2 group
years of age or older through the data cutoff date than in the placebo group reported local reac-
(March 13, 2021). The diagram includes two deaths tions, the most common of which was mild-to-
that occurred after the second dose in human immu-
moderate pain at the injection site (Fig. S1A).
nodeficiency virus (HIV)–infected participants (one
in the BNT162b2 group and one in the placebo group; Local reactions were reported with similar fre-
these deaths were not reported in the Results section quency among the participants with or without
of this article because the analysis of HIV-infected par- evidence of previous SARS-CoV-2 infection, and
ticipants is being conducted separately). Information the reactions were of similar severity. No local
on the screening, randomization, and follow-up of the
reactions of grade 4 (according to the guidelines
participants 12 to 15 years of age has been reported
previously.11 of the Center for Biologics Evaluation and Re-
search12) were reported.
More participants in the BNT162b2 group
than in the placebo group reported systemic
30.0 or more, 21% had at least one underlying events, the most common of which was fatigue
medical condition, and 3% had baseline evidence (Fig. S1B). Systemic events were mostly mild to
of a previous or current SARS-CoV-2 infection moderate in severity, but there were occasional
(Table 1 and Table S2). severe events. Systemic reactogenicity was similar
Between October 15, 2020, and January 12, among those with or without evidence of previous
2021, a total of 2306 participants 12 to 15 years SARS-CoV-2 infection, although BNT162b2 re-
of age underwent screening, and 2264 underwent cipients with evidence of previous infection re-
randomization at 29 U.S. sites. Of these partici- ported systemic events more often after receipt
pants, 2260 received at least one dose of BNT162b2 of the first dose, and those without evidence
(1131 participants) or placebo (1129), and 99% reported systemic events more often after receipt
(1124 in the BNT162b2 group and 1117 in the of the second dose. For example, 12% of recipi-
placebo group) received the second dose.11 Among ents with evidence of previous SARS-CoV-2 in-
participants who received at least one dose of fection and 3% of those without evidence report-
BNT162b2 or placebo, 58% had at least 2 months ed fever after receipt of the first dose; 8% of
of follow-up after the second dose, 49% were those with evidence of previous infection and
female, 86% were White, 5% were Black, and 12% 15% of those without evidence reported fever
were Hispanic or Latinx. Full details of the de- after the second dose. The highest temperature
mographic characteristics of the participants reported was a transient fever of higher than
have been reported previously.11 40.0°C on day 2 after the second dose in a
BNT162b2 recipient without evidence of previ-
Safety ous infection.
Reactogenicity
The subgroup that was evaluated for reactogenic- Adverse Events
ity in the current report, in which reactions were Analyses of adverse events during the blinded
reported in an electronic diary, included 9839 period included 43,847 participants 16 years of
participants 16 years of age or older. In this sub- age or older (Table S3). Reactogenicity events
group, 8183 participants had been included in among the participants who were not in the re-
the previous analysis, and 1656 were enrolled actogenicity subgroup were reported as adverse
after the data cutoff for that analysis.9 The reac- events, which resulted in imbalances between
togenicity profile of BNT162b2 in this expanded the BNT162b2 group and the placebo group with
subgroup did not differ substantially from that respect to adverse events (30% vs. 14%), related
described previously.9 This subgroup included adverse events (24% vs. 6%), and severe adverse
364 participants who had evidence of previous events (1.2% vs. 0.7%). New adverse events at-
SARS-CoV-2 infection, 9426 who did not have tributable to BNT162b2 that were not previously

Table 1. Demographic Characteristics of the Participants at Baseline.*
BNT162b2 Placebo Total

Characteristic (N = 22,026) (N = 22,021) (N = 44,047)
Sex — no. (%)
Male 11,322 (51.4) 11,098 (50.4) 22,420 (50.9)
Female 10,704 (48.6) 10,923 (49.6) 21,627 (49.1)
Race or ethnic group — no. (%)†
White 18,056 (82.0) 18,064 (82.0) 36,120 (82.0)
Black or African American 2,098 (9.5) 2,118 (9.6) 4,216 (9.6)
Asian 952 (4.3) 942 (4.3) 1,894 (4.3)
American Indian or Alaska Native 221 (1.0) 217 (1.0) 438 (1.0)
Native Hawaiian or other Pacific Islander 58 (0.3) 32 (0.1) 90 (0.2)
Multiracial 550 (2.5) 533 (2.4) 1,083 (2.5)
Not reported 91 (0.4) 115 (0.5) 206 (0.5)
Ethnicity†
Hispanic or Latinx 5,704 (25.9) 5,695 (25.9) 11,399 (25.9)
Not reported 111 (0.5) 114 (0.5) 225 (0.5)
Country — no. (%)
Argentina 2,883 (13.1) 2,881 (13.1) 5,764 (13.1)
Brazil 1,452 (6.6) 1,448 (6.6) 2,900 (6.6)
Germany 249 (1.1) 250 (1.1) 499 (1.1)
South Africa 401 (1.8) 399 (1.8) 800 (1.8)
Turkey 249 (1.1) 249 (1.1) 498 (1.1)
United States 16,792 (76.2) 16,794 (76.3) 33,586 (76.3)
Age group at vaccination — no. (%)
16–55 yr 13,069 (59.3) 13,095 (59.5) 26,164 (59.4)
>55 yr 8,957 (40.7) 8,926 (40.5) 17,883 (40.6)
Age at vaccination — yr
Median 51.0 51.0 51.0
Range 16–89 16–91 16–91
SARS-CoV-2 status — no. (%)‡
Positive 689 (3.1) 716 (3.3) 1,405 (3.2)
Negative 21,185 (96.2) 21,180 (96.2) 42,365 (96.2)
Missing data 152 (0.7) 125 (0.6) 277 (0.6)
Body-mass index — no. (%)§
≥30.0: obese 7,543 (34.2) 7,629 (34.6) 15,172 (34.4)
Missing data 7 (<1) 6 (<1) 13 (<1)
* Data are summarized for participants 16 years of age or older in the safety population. The demographic characteristics
of participants 12 to 15 years of age were reported previously.11 Percentages may not total 100 because of rounding.
SARS-CoV-2 denotes severe acute respiratory syndrome coronavirus 2.
† Race and ethnicity were reported by the participants. The categories shown are those that were used to collect the data.
‡ Positive status was defined as a positive N-binding antibody result or a positive nucleic acid amplification test (NAAT)
result at visit 1 or medical history of coronavirus disease 2019 (Covid-19). Negative status was defined as a negative
N-binding antibody result or a negative NAAT result at visit 1 and no medical history of Covid-19.
§ The body-mass index is the weight in kilograms divided by the square of the height in meters.

Table 2. Vaccine Efficacy against Covid-19 from 7 Days after Receipt of the Second Dose during the Blinded, Placebo-Controlled Follow-up
Period.*
Vaccine Efficacy
Efficacy End Point BNT162b2 Placebo (95% CI)‡
No. of Surveillance No. at No. of Surveillance No. at

Cases Time† Risk Cases Time† Risk
1000 person-yr 1000 person-yr percent

(N = 20,998) (N = 21,096)
First occurrence of Covid-19 from 77 6.247 20,712 850 6.003 20,713 91.3
7 days after receipt of the sec- (89.0–93.2)
ond dose among participants
without evidence of previous
infection
(N = 22,166) (N = 22,320)
First occurrence of Covid-19 from 81 6.509 21,642 873 6.274 21,689 91.1
7 days after receipt of the sec- (88.8–93.0)
ond dose among participants
with or without evidence of
previous infection
* This analysis included participants who had no serologic or virologic evidence (within 7 days after receipt of the second dose) of previous
SARS-CoV-2 infection (i.e., negative N-binding antibody [serum] test at visit 1 and SARS-CoV-2 not detected by NAAT [nasal swab] at visits
1 and 2) and had a negative NAAT at any unscheduled visit up to 7 days after receipt of the second dose.
† The surveillance time is the total time (in 1000 person-years) at risk for the given end point across all participants within each group. The
time period for the accrual of Covid-19 cases was from 7 days after the second dose to the end of the surveillance period.
‡ Vaccine efficacy was calculated as 100 × (1 – IRR), where IRR (incidence rate ratio) is the ratio of the rate (number per 1000 person-years of
follow-up) of confirmed cases of Covid-19 in the BNT162b2 group to the corresponding rate in the placebo group. The 95% confidence in-
terval for vaccine efficacy was derived with the use of the Clopper–Pearson method, with adjustment for surveillance time.
identified in earlier reports included decreased and 2 in the original placebo group who received
appetite, lethargy, asthenia, malaise, night sweats, BNT162b2 after unblinding died. None of these
and hyperhidrosis. Few participants had serious deaths were considered to be related to BNT162b2
adverse events or adverse events that led to trial by the investigators. Causes of death were bal-
withdrawal. No new serious adverse events were anced between BNT162b2 and placebo groups
considered by the investigators to be related to (Table S4).
BNT162b2 after the data cutoff date of the previ- Safety monitoring will continue according to
ous report.9 the protocol for 2 years after the second dose for
During the combined blinded and open-label participants who originally received BNT162b2 and
periods, cumulative safety data during follow-up for 18 months after the second BNT162b2 dose for
were available through 6 months after the sec- placebo recipients who received BNT162b2 after
ond dose for 12,006 participants who were origi- unblinding.
nally randomly assigned to the BNT162b2 group.
No new safety signals relative to the previous Efficacy
report were observed during the longer follow- Among 42,094 participants 12 years of age or
up period in the current report, which included older who could be evaluated and had no evidence
open-label observation of the original BNT162b2 of previous SARS-CoV-2 infection, Covid-19 with
recipients and placebo recipients who received an onset of 7 days or more after the second dose
BNT162b2 after unblinding.9 was observed in 77 vaccine recipients and in 850
During the blinded, placebo-controlled peri- placebo recipients up to the data cutoff date
od, 15 participants in the BNT162b2 group and (March 13, 2021), corresponding to a vaccine ef-
14 in the placebo group died; during the open- ficacy of 91.3% (95% confidence interval [CI],
label period, 3 participants in the BNT162b2 group 89.0 to 93.2) (Table 2). Among 44,486 participants

with or without evidence of previous infection subgroups defined according to age, sex, race,
who could be evaluated, cases of Covid-19 were ethnic group, presence or absence of coexisting
observed in 81 vaccine recipients and in 873 medical conditions, and country was generally
placebo recipients, corresponding to a vaccine consistent with that observed in the overall
efficacy of 91.1% (95% CI, 88.8 to 93.0). population (Table 3 and Table S7).
Among the participants with evidence of pre- Given the concern about the SARS-CoV-2
vious SARS-CoV-2 infection based on a positive B.1.351 (or beta) variant, which appears to be
baseline N-binding antibody test, Covid-19 was neutralized less efficiently by BNT162b2-immune
observed in 2 vaccine recipients after the first sera than many other lineages,14 whole-viral-
dose and in 7 placebo recipients. Among the genome sequencing was performed on midturbi-
participants with evidence of previous SARS- nate samples from Covid-19 cases observed in
CoV-2 infection based on a positive nucleic acid South Africa, where this lineage was prevalent.
amplification test at baseline, cases of Covid-19 Nine cases of Covid-19 were observed in South
were observed in 10 vaccine recipients and in 9 African participants without evidence of previ-
placebo recipients (Table S5). Covid-19 was less ous SARS-CoV-2 infection, all of whom were
common among the placebo recipients with placebo recipients; this finding corresponds with
positive N-binding antibodies at trial entry (7 of a vaccine efficacy of 100% (95% CI, 53.5 to 100)
542 participants, for an incidence of 1.3%) than (Table 3). Midturbinate specimens from 8 of 9
among those without evidence of infection at cases contained sufficient viral RNA for whole-
trial entry (1015 of 21,521, for an incidence of genome sequencing. All viral genomes were the
4.7%); these findings indicate that previous infec- beta variant (Global Initiative on Sharing All
tion conferred approximately 72.6% protection. Influenza Data accession codes are provided in
Among the participants with or without evi- the Supplementary Appendix).
dence of previous infection, cases of Covid-19
were observed in 46 vaccine recipients and in
Discussion
110 placebo recipients from receipt of the first
dose up to receipt of the second dose, corre- In this update to the preliminary safety and effi-
sponding to a vaccine efficacy of 58.4% (95% CI, cacy report of two 30-μg doses, at 21 days apart,
40.8 to 71.2) (Fig. 2). During the interval from of BNT162b2, 91.1% vaccine efficacy against
the approximate start of observed protection at Covid-19 was observed from 7 days to 6 months
11 days after receipt of the first dose up to re- after the second dose in participants 12 years of
ceipt of the second dose, vaccine efficacy in- age or older. Vaccine efficacy against severe dis-
creased to 91.7% (95% CI, 79.6 to 97.4). From its ease with an onset after receipt of the first dose
peak after the second dose, observed vaccine effi- was approximately 97%. This finding, combined
cacy declined. From 7 days to less than 2 months with the totality of available evidence, including
after the second dose, vaccine efficacy was 96.2% real-world effectiveness data,15-18 alleviates theo-
(95% CI, 93.3 to 98.1); from 2 months to less than retical concerns over potential enhancement of
4 months after the second dose, vaccine effi- vaccine-mediated disease.19
cacy was 90.1% (95% CI, 86.6 to 92.9); and The benefit of BNT162b2 immunization start-
from 4 months after the second dose to the data ed approximately 11 days after receipt of the first
cutoff date, vaccine efficacy was 83.7% (95% CI, dose, with 91.7% vaccine efficacy from 11 days
74.7 to 89.9). after receipt of the first dose up to receipt of the
Severe Covid-19, as defined by the Food and second dose. The trial cannot provide informa-
Drug Administration,13 with an onset after receipt tion on persistence of protection after a single
of the first dose occurred in 31 participants, of dose, because 99% of the participants received
whom 30 were placebo recipients; this finding the second dose as scheduled during the blinded
corresponds with a vaccine efficacy of 96.7% trial period. A recent trial showed that although
(95% CI, 80.3 to 99.9) against severe Covid-19 nonneutralizing viral antigen–binding antibody
(Fig. 2 and Table S6). Although the trial was not levels rise between the first and second BNT162b2
powered to definitively assess efficacy according dose, serum neutralizing titers are low or unde-
to subgroup, supplemental analyses indicated tectable during this interval.20 Early protection
that vaccine efficacy after the second dose in against Covid-19 without strong serum neutral-

100.0
1 0.5
0.4
Placebo
__ p,-J
,,__,•-·
•
8.0 .....
0.3 ......,...t'-"'
.,...J
7.0
0.2 ..........
..... Placebo
.... BNT162b2
Cumulative Incidence (%)
....
6.0 0.1 _'!".J""
0.0
5.0 0 3 6 9 12 15 18 21
4.0
3.0
2.0
1.0 BNT162b2
0.0
0 14 28 42 56 70 84 98 112 126 140 154 168 182 196 210 224 238
Days since Receipt of First Dose
BNT162b2 Placebo
Efficacy End Point (N=23,040) (N=23,037) Vaccine Efficacy
cases time risk cases time risk
1000 person-yr 1000 person-yr % (95% CI)
Overall: first occurrence of Covid-19 after receipt of first dose 131 8.412 22,505 1034 8.124 22,434 87.8 (85.3 to 89.9)
After receipt of first dose up to receipt of second dose 46 1.339 22,505 110 1.331 22,434 58.4 (40.8 to 71.2)
<11 Days after receipt of first dose 41 0.677 22,505 50 0.675 22,434 18.2 (−26.1 to 47.3)
≥11 Days after receipt of first dose up to receipt of second dose 5 0.662 22,399 60 0.656 22,369 91.7 (79.6 to 97.4)
After receipt of second dose to <7 days after 3 0.424 22,163 35 0.422 22,057 91.5 (72.9 to 98.3)
≥7 Days after receipt of second dose 82 6.649 22,132 889 6.371 22,001 91.2 (88.9 to 93.0)
≥7 Days after receipt of second dose to <2 mo after 12 2.923 22,132 312 2.884 22,001 96.2 (93.3 to 98.1)
≥2 Mo after receipt of second dose to <4 mo after 46 2.696 20,814 449 2.593 20,344 90.1 (86.6 to 92.9)
≥4 Mo after receipt of second dose 24 1.030 12,670 128 0.895 11,802 83.7 (74.7 to 89.9)
Figure 2. Efficacy of BNT162b2 against Covid-19 after Receipt of the First Dose (Blinded Follow-up Period).
The top of the figure shows the cumulative incidence curves for the first occurrence of coronavirus disease 2019 (Covid-19) after receipt
of the first dose (efficacy analysis population of participants ≥12 years of age who could be evaluated). Each symbol represents Covid-19
cases starting on a given day, and filled symbols represent severe Covid-19 cases. Because of overlapping dates, some symbols repre-
sent more than one case. The inset shows the same data on an enlarged y axis through 21 days. The bottom of the figure shows the
time intervals for the first occurrence of Covid-19 in the efficacy analysis population, as well as the surveillance time, which is given as
the total time (in 1000 person-years) at risk for the given end point across all participants within each group. The time period for the ac-
crual of Covid-19 cases was from after receipt of the first dose to the end of the surveillance period for the overall row and from the start
to the end of the range stated for each time interval. Vaccine efficacy was calculated as 100 × (1 – IRR), where IRR (incidence rate ratio) is
the ratio of the rate (number per 1000 person-years of follow-up) of confirmed cases of Covid-19 in the BNT162b2 group to the corre-
sponding rate in the placebo group. The 95% confidence interval for vaccine efficacy was derived with the use of the Clopper–Pearson
method, with adjustment for surveillance time.
ization indicates that neutralizing titers alone do and antibody-dependent cytotoxicity) may con-
not appear to explain early BNT162b2-mediated tribute to protection.21-26
protection from Covid-19. Other immune mech- Efficacy peaked at 96.2% during the interval
anisms (e.g., innate immune responses, CD4+ or from 7 days to less than 2 months after the sec-
CD8+ T-cell responses, B-cell memory responses, ond dose and declined gradually to 83.7% from

Table 3. Vaccine Efficacy against Covid-19 up to 7 Days after Receipt of the Second Dose among Participants without Evidence of Infection.*
First Occurrence of
Covid-19 after Receipt BNT162b2 Placebo Vaccine Efficacy
of the First Dose (N = 20,998) (N = 21,096) (95% CI)‡
Cases Time† Risk Cases Time† Risk
1000 person-yr 1000 person-yr percent
Overall population 77 6.247 20,712 850 6.003 20,713 91.3 (89.0 to 93.2)
Age group — yr
16 or 17 0 0.061 342 10 0.057 331 100 (58.2 to 100)
16 to 55 52 3.593 11,517 568 3.439 11,533 91.2 (88.3 to 93.5)
≥55 25 2.499 8,194 266 2.417 8,208 90.9 (86.3 to 94.2)
≥65 7 1.233 4,192 124 1.202 4,226 94.5 (88.3 to 97.8)
≥75 1 0.239 842 26 0.237 847 96.2 (76.9 to 99.9)
Sex
Male 42 3.246 10,637 399 3.047 10,433 90.1 (86.4 to 93.0)
Female 35 3.001 10,075 451 2.956 10,280 92.4 (89.2 to 94.7)
Race or ethnic group§
White 67 5.208 17,186 747 5.026 17,256 91.3 (88.9 to 93.4)
Black or African 4 0.545 1,737 48 0.527 1,737 91.9 (78.0 to 97.9)
American
Asian 3 0.260 946 23 0.248 934 87.6 (58.9 to 97.6)
American Indian or 0 0.041 186 3 0.037 176 100 (–119.0 to 100)
Alaska Native
Native Hawaiian 0 0.015 54 1 0.008 30 100 (–1961.2 to 100)
or other Pacific
Islander
Multiracial 3 0.151 518 22 0.128 476 88.5 (61.6 to 97.8)
Not reported 0 0.026 85 6 0.030 104 100 (2.8 to 100)
Ethnicity§
Hispanic or Latinx 29 1.786 5,161 241 1.711 5,120 88.5 (83.0 to 92.4)
Non-Hispanic and 47 4.429 15,449 609 4.259 15,484 92.6 (90.0 to 94.6)
non-Latinx
Not reported 1 0.032 102 0 0.033 109 NA
Country
Argentina 15 1.012 2,600 108 0.986 2,586 86.5 (76.7 to 92.7)
Brazil 12 0.406 1,311 80 0.374 1,293 86.2 (74.5 to 93.1)
Germany 0 0.047 236 1 0.048 242 100 (–3874.2 to 100)
South Africa 0 0.080 291 9 0.074 276 100 (53.5 to 100)
Turkey 0 0.027 228 5 0.025 222 100 (–0.1 to 100)
United States 50 4.674 16,046 647 4.497 16,046 92.6 (90.1 to 94.5)
* This analysis of vaccine efficacy during the blinded, placebo-controlled follow-up period included all participants who had undergone ran-
domization and were 12 years of age or older without baseline evidence of previous infection who had undergone randomization. NA de-
notes not applicable.
† Surveillance time is the total time (in 1000 person-years) at risk for the given end point across all participants within each group. The time
period for the accrual of Covid-19 cases was from 7 days after the second dose to the end of the surveillance period.
‡ Vaccine efficacy was calculated as 100 × (1 – IRR). The 95% confidence interval for vaccine efficacy was derived with the use of the Clopper–
Pearson method, with adjustment for surveillance time.
§ Race and ethnicity were reported by the participants. The categories shown are those that were used to collect the data.

4 months after the second dose to the data cut- of safety follow-up data after a second BNT162b2
off date — an average decline of approximately dose. The safety profile observed at a median of
6% every 2 months. Ongoing follow-up is need- 2 months after immunization was confirmed
ed to understand persistence of the vaccine ef- through 6 months after immunization in the cur-
fect over time, the need for booster dosing, and rent analysis. No cases of myocarditis were noted.
timing of such a dose. Most participants who Before immunization, 3% of the participants
initially received placebo have now been immu- 16 years of age or older had evidence of SARS-
nized with BNT162b2, ending the placebo-con- CoV-2 infection. Although this group had a slight-
trolled period of the trial. Nevertheless, ongoing ly higher incidence of systemic reactogenicity
observation of participants through 2 years in events after receipt of the first dose than those
this trial, together with real-world effectiveness without evidence of previous infection, the group
data,15-18 will determine whether a booster is had a slightly lower incidence of reactogenicity
likely to be beneficial after a longer interval. events after the second dose than those without
Booster trials to evaluate safety and immunoge- previous infection. Thus, there was minimal ob-
nicity of BNT162b2 are under way to prepare for served difference in the overall reactogenicity
this possibility. profile on the basis of infection status at baseline.
From 7 days after the second dose, 86 to 100% Nine cases of Covid-19 were observed among
efficacy was observed across diverse demographic participants with previous serologically defined
profiles, including age, sex, race or ethnic group, natural infection: two cases were observed among
and factors that increase the risk of Covid-19, the vaccine recipients and seven among the pla-
such as high body-mass index and other coexist- cebo recipients. These data support the current
ing medical conditions. BNT162b2 was also practice of immunizing without screening for
highly efficacious in various geographic regions evidence of previous infection.
including North America, Europe, South Africa, This report has several limitations. Duration
and Latin America. Although vaccine efficacy of protection and safety data that could be col-
was slightly lower in Latin American countries, lected in a blinded, placebo-controlled manner
BNT162b2 had a high efficacy of approximately were limited by the ethical and practical need to
86% in Argentina and Brazil. Circulation of immunize eligible initial placebo recipients un-
SARS-CoV-2 variants — some of which are as- der emergency use authorization and according
sociated with more rapid transmission and po- to the recommendations of public health authori-
tentially greater pathogenicity27 — has raised ties. The data presented here do not address
concerns that such variants could evade vaccine- whether vaccination prevents asymptomatic in-
mediated protection. Our studies of in vitro fection; however, evaluation of that question is
neutralization of a variety of SARS-CoV-2 vari- ongoing in this trial, and real-world data sug-
ants have, to date, showed that all tested gest that BNT162b2 prevents asymptomatic in-
BNT162b2-immune sera neutralize all tested fection.33,34 Preliminary analyses of breakthrough
variants.14,28-32 The beta variant, which has shown cases have not yet identified a correlate of pro-
the greatest reduction in neutralization and was tection, since vaccine protection rates remain high.
the dominant strain in South Africa during the This report does not address vaccine efficacy and
reported observation period, is still neutralized safety in pregnant women and in children younger
at serum titers higher than those observed at the than 12 years of age. Studies evaluating BNT162b2
onset of protection against Covid-19 after the in these populations are ongoing.
first vaccine dose.9,14,20 We found that BNT162b2 The data in this report show that BNT162b2
had an observed efficacy of 100% (95% CI, 53.5 prevents Covid-19 effectively for up to 6 months
to 100) against Covid-19 in South Africa (9 cases after the second dose across diverse populations,
occurred in the placebo recipients and 0 cases in despite the emergence of SARS-CoV-2 variants,
the BNT162b2 recipients), and 8 of 9 cases for including the beta variant, and the vaccine con-
which sequence information could be obtained tinues to show a favorable safety profile.
involved the beta variant of SARS-CoV-2. Supported by BioNTech and Pfizer.
Safety data are now available for approxi- Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
mately 44,000 participants 16 years of age or A data sharing statement provided by the authors is available
older; 12,006 participants have at least 6 months with the full text of this article at NEJM.org.

We thank all the participants who volunteered for this trial; roko, Jason McKinley, Tracey Mellelieu, Neda Aghajani Memar,
the investigators in the C4591001 Clinical Trial Group for their Farheen Muzaffar, Brendan O’Neill, Jason Painter, Elizabeth
contributions; the members of our data monitoring committee Paulukonis, Allison Pfeffer, Katie Puig, Kimberly Rarrick, Balaji
(Jonathan Zenilman [chair], Robert Belshe, Kathryn Edwards, Prabu Raja, Christine Rainey, Kellie Lynn Richardson, Elizabeth
Stephen Self, and Lawrence Stanberry) for their review of the Rogers, Melinda Rottas, Charulata Sabharwal, Uzma Sarwar,
data; Tricia Newell, Sheena Hunt, and Philippa Jack of ICON Vilas Satishchandran, Harpreet Seehra, Judy Sewards, Huiqing
(North Wales, PA) for editorial support, which was funded Si, Helen Smith, David Swerdlow, James Trammel, Elisa Har-
by Pfizer; the following Pfizer staff: Greg Adams, Negar Ali- kins Tull, Sarah Tweedy, Erica Weaver, John Wegner, Jenah West,
abadi, Mohanish Anand, Fred Angulo, Ayman Ayoub, Melissa Christopher Webber, David C. Whritenour, Fae Wooding, Em-
Bishop-Murphy, Mark Boaz, Christopher Bowen, Donna Boyce, ily Worobetz, Nita Zalavadia, and Liping Zhang, as well as the
Sarah Burden, Andrea Cawein, Patrick Caubel, Darren Cowen, Vaccines Clinical Assay Team, the Vaccines Assay Development
Kimberly Ann Cristall, Michael Cruz, Daniel Curcio, Gabriela Team, and all the Pfizer colleagues not named here who contrib-
Dávila, Carmel Devlin, Gokhan Duman, Niesha Foster, Maja uted to the success of this trial; the following BioNTech staff:
Gacic, Juleen Gayed, Ahmed Hassan, Luis Jodar, Stephen Kay, Corinna Rosenbaum, Christian Miculka, Andreas Kuhn, Ferdia
William Lam, Esther Ladipo, Joaquina Maria Lazaro, Marie- Bates, Paul Strecker, Ruben Rizzi, Martin Bexon, Eleni Lagkadi-
Pierre Hellio Le Graverand-Gastineau, Kwok Lee, Zhenghui Li, nou, and Alexandra Kemmer-Brück; and Dietmar Katinger and
Jacqueline Lowenberg, Hua Ma, Rod MacKenzie, Robert Ma- Andreas Wagner at Polymun.
Appendix
The authors’ full names and academic degrees are as follows: Stephen J. Thomas, M.D., Edson D. Moreira, Jr., M.D., Nicholas Kitchin,
M.D., Judith Absalon, M.D., Alejandra Gurtman, M.D., Stephen Lockhart, D.M., John L. Perez, M.D., Gonzalo Pérez Marc, M.D., Fer-
nando P. Polack, M.D., Cristiano Zerbini, M.D., Ruth Bailey, B.Sc., Kena A. Swanson, Ph.D., Xia Xu, Ph.D., Satrajit Roychoudhury,
Ph.D., Kenneth Koury, Ph.D., Salim Bouguermouh, M.D., Ph.D., Warren V. Kalina, Ph.D., David Cooper, Ph.D., Robert W. Frenck, Jr.,
M.D., Laura L. Hammitt, M.D., Özlem Türeci, M.D., Haylene Nell, M.D., Axel Schaefer, M.D., Serhat Ünal, M.D., Qi Yang, Ph.D., Paul
Liberator, Ph.D., Dina B. Tresnan, D.V.M., Ph.D., Susan Mather, M.D., Philip R. Dormitzer, M.D., Ph.D., Uğur Şahin, M.D., William C.
Gruber, M.D., and Kathrin U. Jansen, Ph.D.
The authors’ affiliations are as follows: the State University of New York, Upstate Medical University, Syracuse (S.J.T.), and Vaccine
Research and Development, Pfizer, Pearl River (J.A., A.G., K.A.S., K.K., S.B., W.V.K., D.C., Q.Y., P.L., P.R.D., W.C.G., K.U.J.) — both
in New York; Associação Obras Sociais Irmã Dulce and Oswaldo Cruz Foundation, Bahia (E.D.M.), and iTrials-Hospital Militar Central
(G.P.M.) and Fundacion INFANT, Buenos Aires (F.P.P.) — all in Brazil; Centro Paulista de Investigação Clinica, São Paulo (C.Z.); Vac-
cine Research and Development, Pfizer, Hurley, United Kingdom (N.K., S.L., R.B.); Vaccine Research and Development (J.L.P., X.X.)
and Worldwide Safety, Safety Surveillance, and Risk Management (D.B.T., S.M.), Pfizer, Collegeville, PA; Global Product Development,
Pfizer, Peapack, NJ (S.R.); Cincinnati Children’s Hospital, Cincinnati (R.W.F.); Johns Hopkins Bloomberg School of Public Health,
Baltimore (L.L.H.); BioNTech, Mainz (Ö.T., U.Ş.) and Medizentrum Essen Borbeck, Essen (A.S.) — both in Germany; Tiervlei Trial
Centre, Karl Bremer Hospital, Cape Town, South Africa (H.N.); Hacettepe University, Ankara, Turkey (S.Ü.); and Worldwide Safety,
Safety Surveillance, and Risk Management, Pfizer, Groton, CT (D.B.T., S.M.).
References
1. COVID-19 dashboard. 2021 (https:// et al. Incorporation of pseudouridine into clinical trials. Rockville, MD:Center for
coronavirus.jhu.edu/map.html). mRNA yields superior nonimmunogenic Biologics Evaluation and Research. Sep-
2. Food and Drug Administration. vector with increased translational capac- tember 2007 (https://www.fda.gov/media/
COVID-19 vaccines. Silver Spring, MD:Food ity and biological stability. Mol Ther 2008; 7
3679/download).
and Drug Administration. 2021 (https:// 16:1833-40. 13. COVID-19: developing drugs and bi-
www.fda.gov/emergency-preparedness-and 8. Wrapp D, Wang N, Corbett KS, et al. ological products for treatment or pre-
-response/coronavirus-disease-2019-covid Cryo-EM structure of the 2019-nCoV spike vention: guidance for industry. Silver
-19/covid-19-vaccines). in the prefusion conformation. Science Spring, MD:Food and Drug Administration.
3. Medicines and Healthcare Products 2020;367:1260-3. May 2020 (https://www.fda.gov/regulatory
Regulatory Agency. Decision: conditions 9. Polack FP, Thomas SJ, Kitchin N, et al. -i nformation/search-fda-g uidance
of authorisation for COVID-19 vaccine Safety and efficacy of the BNT162b2 -documents/covid-19-developing-d rugs
AstraZeneca (regulation 174). 2021 (https:// mRNA Covid-19 vaccine. N Engl J Med -a nd-biological-products-t reatment-or
www.gov.u k/government/publications/ 2020;383:2603-15. -prevention).
regulatory-approval-of-covid-19-vaccine 10. Pfizer, BioNTech. Pfizer-BioNTech 14. Liu Y, Liu J, Xia H, et al. Neutralizing
-astrazeneca/conditions-of-authorisation COVID-19 vaccine. FDA briefing docu- activity of BNT162b2-elicited serum. N Engl
-for-covid-19-vaccine-astrazeneca). ment. Presented at the Vaccines and Re- J Med 2021;384:1466-8.
4. Baraniuk C. What do we know about lated Biological Products Advisory Com- 15. Haas EJ, Angulo FJ, McLaughlin JM,
China’s covid-19 vaccines? BMJ 2021;373: mittee Meeting, virtual, December 10, et al. Impact and effectiveness of mRNA
n912. 2020 (https://www.fda.gov/media/144245/ BNT162b2 vaccine against SARS-CoV-2
5. Baraniuk C. Covid-19: what do we d
ownload). infections and COVID-19 cases, hospitali-
know about Sputnik V and other Russian 11. Frenck RW Jr, Klein NP, Kitchin N, sations, and deaths following a nation-
vaccines? BMJ 2021;372:n743. et al. Safety, immunogenicity, and effica- wide vaccination campaign in Israel: an
6. Pardi N, Tuyishime S, Muramatsu H, cy of the BNT162b2 Covid-19 vaccine in observational study using national sur-
et al. Expression kinetics of nucleoside- adolescents. N Engl J Med 2021;385:239- veillance data. Lancet 2021;397:1819-29.
modified mRNA delivered in lipid nanopar- 50. 16. Abu-Raddad LJ, Chemaitelly H, Butt AA.
ticles to mice by various routes. J Control 12. Guidance for industry: toxicity grad- Effectiveness of the BNT162b2 Covid-19
Release 2015;217:345-51. ing scale for healthy adult and adolescent vaccine against the B.1.1.7 and B.1.351
7. Karikó K, Muramatsu H, Welsh FA, volunteers enrolled in preventive vaccine variants. N Engl J Med 2021;385:187-9.

17. Lopez Bernal J, Andrews N, Gower C, sulated mRNA vaccines induce protective E484K and N501Y variants by BNT162b2
et al. Effectiveness of the Pfizer-BioNTech memory CD8 T cells against a lethal viral vaccine-elicited sera. Nat Med 2021; 27:
and Oxford-AstraZeneca vaccines on infection. Mol Ther 2021 May 14 (Epub 620-1.
covid-19 related symptoms, hospital ad- ahead of print). 29. Zou J, Xie X, Fontes-Garfias CR, et al.
missions, and mortality in older adults in 24. Tauzin A, Nayrac M, Benlarbi M, et al. The effect of SARS-CoV-2 D614G muta-
England: test negative case-control study. A single BNT162b2 mRNA dose elicits tion on BNT162b2 vaccine-elicited neu-
BMJ 2021;373:n1088. antibodies with Fc-mediated effector tralization. NPJ Vaccines 2021;6:44.
18. Vasileiou E, Simpson CR, Shi T, et al. functions and boost pre-existing humoral 30. Muik A, Wallisch A-K, Sänger B, et al.
Interim findings from first-dose mass and T cell responses. March 18, 2021 Neutralization of SARS-CoV-2 lineage
COVID-19 vaccination roll-out and (https://www.biorxiv.org/content/10.1101/ B.1.1.7 pseudovirus by BNT162b2 vaccine-
COVID-19 hospital admissions in Scotland: 2021.03.18.435972v1). preprint. elicited human sera. Science 2021; 371:
a national prospective cohort study. Lan- 25. Gallagher KME, Leick MB, Larson 1152-3.
cet 2021;397:1646-57. RC, et al. SARS-CoV-2 T-cell immunity to 31. Liu Y, Liu J, Xia H, et al. BNT162b2-
19. Haynes BF, Corey L, Fernandes P, et al. variants of concern following vaccina- elicited neutralization against new SARS-
Prospects for a safe COVID-19 vaccine. Sci tion. May 3, 2021 (https://www.biorxiv CoV-2 spike variants. N Engl J Med 2021;
Transl Med 2020;12(568):eabe0948. .org/content/10.1101/2021.05.03.442455v1). 385:472-4.
20. Walsh EE, Frenck RW Jr, Falsey AR, preprint. 32. Liu J, Liu Y, Xia H, et al. BNT162b2-
et al. Safety and immunogenicity of two 26. Painter MM, Mathew D, Goel RR, elicited neutralization of B.1.617 and
RNA-based Covid-19 vaccine candidates. et al. Rapid induction of antigen-specific other SARS-CoV-2 variants. Nature 2021
N Engl J Med 2020;383:2439-50. CD4+ T cells guides coordinated humoral June 10 (Epub ahead of print).
21. Sahin U, Muik A, Vogler I, et al. and cellular immune responses to SARS- 33. Dagan N, Barda N, Kepten E, et al.
BNT162b2 vaccine induces neutralizing CoV-2 mRNA vaccination. April 22, 2021 BNT162b2 mRNA Covid-19 vaccine in a na-
antibodies and poly-specific T cells in hu- (https://www.biorxiv.org/content/10.1101/ tionwide mass vaccination setting. N Engl J
mans. Nature 2021;595:572-7. 2
021.04.21.440862v1). preprint. Med 2021;384:1412-23.
22. Goel RR, Apostolidis SA, Painter MM, 27. Centers for Disease Control and Pre- 34. Tande AJ, Pollock BD, Shah ND, et al.
et al. Distinct antibody and memory B cell vention. SARS-CoV-2 variant classifications Impact of the COVID-19 vaccine on asymp
responses in SARS-CoV-2 naïve and recov- and definitions. 2021 (https://www.cdc.gov/ tomatic infection among patients under-
ered individuals following mRNA vacci- c oronavirus/2019-ncov/cases-updates/variant going pre-procedural COVID-19 molecu-
nation. Sci Immunol 2021;6(58):eabi6950. -surveillance/variant-info.html#print). lar screening. Clin Infect Dis 2021 March
23. Knudson CJ, Alves-Peixoto P, Mura- 28. Xie X, Liu Y, Liu J, et al. Neutralization 10 (Epub ahead of print).
matsu H, et al. Lipid-nanoparticle-encap- of SARS-CoV-2 spike 69/70 deletion, Copyright © 2021 Massachusetts Medical Society.
TRACK THIS ARTICLE’S IMPACT AND REACH

Visit the article page at NEJM.org and click on Metrics for a dashboard
that logs views, citations, media references, and commentary.
NEJM.org/about-nejm/article-metrics.

10_ _ __
EXHIBIT No ._ _ _ _
Celia Lourenco
DATE June 6, 2022

Supplementary Appendix
This appendix has been provided by the authors to give readers additional information about their work.
Supplement to: Thomas SJ, Moreira ED Jr, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19
vaccine through 6 months. N Engl J Med 2021;385:1761-73. DOI: 10.1056/NEJMoa2110345
AR10003
SUPPLEMENTARY APPENDIX
List of Investigators ...................................................................................................................................... 2
Ethical Conduct of the Study ........................................................................................................................ 6
Study Responsibilities ................................................................................................................................... 6
Testing for SARS-CoV-2 Virus and Antibodies........................................................................................... 6
Determination of SARS-CoV-2 Lineage ...................................................................................................... 6
Definitions of Confirmed and Severe COVID-19 Cases .............................................................................. 7
Table S1 | Explanation of the Changes in Denominator Numbers in Various Analyses. ............................. 8
Table S2 | Baseline Comorbidities in Participants ≥16 Years of Age........................................................... 9
Table S3 | Participants Reporting at Least 1 Adverse Event from Dose 1 to 1 Month After Dose 2 During
the Blinded Follow-up Period. .................................................................................................................... 10
Table S4 | Causes of Death from Dose 1 to Unblinding (Safety Population, ≥16 Years Old).................... 11
Table S5 | Vaccine Efficacy Overall and by Subgroup after Dose 1 During the Blinded Placebo
Controlled Follow-up Period (All-Available Population)........................................................................... 13
Table S6 | Vaccine Efficacy against Severe COVID-19 Occurrence after Dose 1 (All-Available
Population) .................................................................................................................................................. 14
Table S7 | Vaccine Efficacy from 7 Days after Dose 2 by Underlying Comorbidities (Risk Status) among
Participants Without Evidence of Infection Prior to 7 Days after Dose 2 (Evaluable Efficacy Population)
.................................................................................................................................................................... 15
Figure S1 | Local Reactions and Systemic Events Reported within 7 Days after Receipt of BNT162b2 or
Placebo by Baseline SARS-CoV-2 Status. ................................................................................................. 16
1
AR10004
List of Investigators
Name Institute Location
Aberg, Judith Icahn School of Medicine at Mount Sinai New York, NY, USA
Addo, Marylyn Universitätsklinikum Hamburg-Eppendorf Hamburg, Germany
Akhan, Sıla Kocaeli University Med Kocaeli, Turkey
Albertson, Timothy University of California, Davis Sacramento, CA, USA
Al-Ibrahim, Mohamed SNBL Clinical Pharmacology Center Baltimore, MD, USA
Yedikule Chest Diseases and Thoracic Surgery Training and
Altın, Sedat Istanbul, Turkey
Research Hospital
Anderson, Corey Clinical Research Consortium Tempe, AZ, USA
Andrews, Charles Diagnostics Research Group San Antonio, TX, USA
Arora, Samir Aventiv Research Columbus, OH, USA
Balik, Ismail Ankara University Medical School Ankara, Turkey
Barnett, Elizabeth Boston Medical Center Boston, MA, USA
Bauer, George Benchmark Research Metairie, LA, USA
Baumann-Noss, Sybille CRS Clinical Research Services Berlin Berlin, Germany
Berhe, Mezgebe North Texas Infectious Diseases Consultants Dallas, TX, USA
Bradley, Paul Meridian Clinical Research Savannah, GA, USA
Brandon, Donald California Research Foundation San Diego, CA, USA
Brune, Daniel Optimal Research Peoria, IL, USA
Burgher, Abram The Pain Center of Arizona Peoria, AZ, USA
Butcher, Bain Sterling Research Group Cincinnati, OH, USA
Butuk, David Solaris Clinical Research Meridian, ID, USA
Cannon, Kevin PMG Research of Wilmington Wilmington, NC, USA
Cardona, Jose Indago Research and Health Center Hialeah, FL, USA
Cavelli, Rachael State University of New York Upstate Medical University Syracuse, NY, USA
Chalhoub, Fadi CNS Healthcare Jacksonville, FL, USA
Christensen, Shane J. Lewis Research Salt Lake City, UT, USA
Christensen, Tom Waterway Family Medicine Little River, SC, USA
Chu, Laurence Benchmark Research Austin, TX, USA
Cox, Steven Lynn Institute of Norman Norman, OK, USA
Crook, Gretchen Austin Regional Clinic: ARC Wilson Parke Austin, TX, USA
Davis, Matthew Rochester Clinical Research Rochester, NY, USA
Davit, Rajesh Sterling Research Group Cincinnati, OH, USA
Denham, Douglas Clinical Trials of Texas (CTT) San Antonio, TX, USA
Dever, Michael Clinical Neuroscience Solutions Orlando, FL, USA
Donskey, Curtis Louis Stokes Cleveland VA Medical Center Cleveland, OH, USA
Doust, Matthew Hope Research Institute Phoenix, AZ, USA
Dunn, Michael Quality Clinical Research Omaha, NE, USA
Earl, John PMG Research of Hickory Hickory, NC, USA
Eder, Frank United Medical Associates - Meridian Clinical Research Binghamton, NY, USA
Eich, Andreas IKF Pneumologie Frankfurt, Germany
Ensz, David Meridian Clinical Research Dakota Dunes, SD, USA
Essink, Brandon Meridian Clinical Research Omaha, NE, USA
Falcone, Robert Amici Clinical Research Raritan, NJ, USA
Falsey, Ann University of Rochester/Rochester General Hospital Rochester, NY, USA
Farrington, Cecil PMG Research of Salisbury Salisbury, NC, USA
2
AR10005
Finberg, Robert University of Massachusetts Medical School Worcester, MA, USA

Finn, Daniel Kentucky Pediatric/Adult Research Bardstown, KY, USA
Fitz-Patrick, David East-West Medical Research Institute Honolulu, HI, USA
Fortmann, Stephen Kaiser Permanente Center for Health Research Portland, OR, USA
Fouche, Leon Tambotie Medical Centre Thabazimbi, South Africa
Fragoso, Veronica Texas Center for Drug Development Houston, TX, USA
Frenck, Robert Cincinnati Children’s Hospital Cincinnati, OH, USA
Fried, David Omega Medical Research Warwick, RI, USA
Fuller, Gregory Ventavia Research Group Keller, TX, USA
Fussell, Suzanne Long Beach Clinical Trials Services Long Beach, CA, USA
Garcia-Diaz, Julia Ochsner Health New Orleans, LA, USA
Gentry, Andrew Bozeman Health Clinical Research Bozeman, MT, USA
Glover, Richard Alliance for Multispecialty Research Newton, KS, USA
Greenbaum, Carla Benaroya Research Institute at Virginia Mason Seattle, WA, USA
Grubb, Stephen Main Street Physicians Little River, SC, USA
Hammitt, Laura Johns Hopkins Center for American Indian Health Whiteriver, AZ, USA
Johns Hopkins Center for American Indian Health Chinle, AZ, USA
Johns Hopkins Center for American Indian Health Shiprock, NM, USA
Johns Hopkins Center for American Indian Health Gallup, NM, USA
Harper, Charles Meridian Clinical Research Norfolk, NE, USA
Harper, Wayne Wake Research Raleigh, NC, USA
Hartman, Aaron Virginia Research Center Midlothian, VA, USA
Heller, Robert Bayview Research Group Valley Village, CA, USA
Hendrix, Ernest North Alabama Research Center Athens, AL, USA
Herrington, Darrell Benchmark Research San Angelo, TX, USA
Jennings, Timothy Clinical Research Professionals Chesterfield, MO, USA
Karabay, Oğuz Sakarya University Faculty of Medicine Sakarya, Turkey
Kaster, Steven Confluence Health/Wenatchee Valley Hospital & Clinics Wenatchee, WA, USA
Katzman, Steven Michigan Center for Medical Research Farmington Hills, MI, USA
Kingsley, Jeffrey Columbus Regional Research Institute Columbus, GA, USA
Klein, Nicola Kaiser Permanente, Northern California Santa Clara, CA, USA
Sacramento, CA, USA
Klein, Tracy Heartland Research Associates Wichita, KS, USA
Koch, Mark Ventavia Research Group Fort Worth, TX, USA
Köksal, Iftahar Acibadem University Hospital Atakent Istanbul, Turkey
Koren, Michael Jacksonville Center for Clinical Research Jacksonville, FL, USA
Kutner, Mark Suncoast Research Group Miami, FL, USA
Lee, Marcus Trinity Clinical Research Tullahoma, TN, USA
Leibowitz, Mark National Research Institute Huntingdon Park, CA, USA
Levin, Michael Clinical Research Center of Nevada Las Vegas, NV, USA
Libster, Romina Fundacion INFANT Buenos Aires, Argentina
Lillestol, Michael Lillestol Research Fargo, ND, USA
Lucasti, Christopher South Jersey Infectious Disease Somers Point, NJ, USA
Studienzentrum Brinkum Dr. Lars Pohlmeier und Torsten
Luttermann, Matthias Stuhr, Germany
Drescher
Manning, Mary Beth Velocity Clinical Research Cleveland, OH, USA
Martin, Earl Martin Diagnostic Clinic Tomball, TX, USA
Matherne, Paul MedPharmics Gulfport, MS, USA
3
AR10006
McMurray, James Medical Affiliated Research Center (MARC) Huntsville, AL, USA
Mert, Ali Medipol University Hospital Istanbul, Turkey
Middleton, Randle Optimal Research Huntsville, AL, USA
Mitha, Essack Newtown Clinical Research Johannesburg, South Africa
Morawski, Emily Holston Medical Group Kingsport, TN, USA
Associação Obras Sociais Irmã Dulce and Oswaldo Cruz
Moreira, Edson Bahia, Brazil
Foundation
Murray, Alexander PharmQuest Greensboro, NC, USA
Mussaji, Murtaza LinQ Research Houston, TX, USA
Musungaie, Dany Jongaie Research Pretoria, South Africa
Nell, Haylene Tiervlei Trial Centre, Karl Bremer Hospital Cape Town, South Africa
Odekirk, Larry Lynn Institute of Denver Denver, CO, USA
Ogbuagu, Onyema Yale University School of Medicine New Haven, CT, USA
Paolino, Kristopher State University of New York, Upstate Medical University Syracuse, NY, USA
Patel, Suchet Regional Clinical Research Endwell, NY, USA
Peterson, James J. Lewis Research Salt Lake City, UT, USA
Pickrell, Paul Tekton Research Austin, TX, USA
Polack, Fernando Fundacion INFANT Buenos Aires, Argentina
Poretz, Donald Clinical Alliance for Research and Education Annandale, VA, USA
Raad, George PMG Research of Charlotte Charlotte, NC, USA
Randall, William PriMed Clinical Research Dayton, OH, USA
Rankin, Bruce Accel Research Sites - DeLand Clinical Research Unit DeLand, FL, USA
Reynolds, Steven Collaborative Neuroscience Network Long Beach, CA, USA
Riesenberg, Robert Atlanta Center for Medical Research Atlanta, GA, USA
Rodriguez, Hector Acevedo Clinical Research Associates Miami, FL, USA
Rosen, Jeffrey Clinical Research of South Florida Coral Gables, FL, USA
Rubino, John Raleigh Medical Group, PA Raleigh, NC, USA
Rupp, Richard University of Texas Galveston, TX, USA
Saiger, Salma Research Across America Mesquite, TX, USA
Salata, Robert University Hospitals Cleveland Medical Center Cleveland, OH, USA
Saleh, Jamshid Northern California Neurological Surgery Redding, CA, USA
Schaefer, Axel Medizentrum Essen Borbeck Essen, Germany
Schear, Martin Dayton Clinical Research Dayton, OH, USA
Schultz, Armin CRS Clinical Research Services Mannheim Mannheim, Germany
Schwartz, Howard Research Centers of America Hollywood, FL, USA
Segall, Nathan Clinical Research Atlanta Stockbridge, GA, USA
Seger, William HealthFirst Medical Group Fort Worth, TX, USA
Senders, Shelly Senders Pediatrics South Euclid, OH, USA
Sharp, Stephan Clinical Research Associates Nashville, TN, USA
Shoffner, Sylvia PMG Research of Cary Cary, NC, USA
Simsek Yavuz, Serap Istanbul Faculty of Medicine, Istanbul University Istanbul, Turkey
Sligh, Teresa Providence Clinical Research North Hollywood, CA, USA
Smith, William New Orleans Center for Clinical Research New Orleans, LA, USA
Stacey, Helen Diablo Clinical Research Walnut Creek, CA, USA
Stephens, Michael Fleming Island Center for Clinical Research Fleming Island, FL, USA
Studdard, Harry Coastal Clinical Research Mobile, AL, USA
Tabak, Fehmi Istanbul University Cerrahpaşa Medical School Istanbul, Turkey
Talaat, Kawsar Johns Hopkins School of Medicine Baltimore, MD, USA
4
AR10007
Thomas, Stephen State University of New York, Upstate Medical University Syracuse, NY, USA
Towner, William Kaiser Permanente Los Angeles, CA, USA
Tran, Van Ventavia Research Group Houston, TX, USA
Ünal, Serhat Hacettepe University Ankara, Turkey
Usdan, Lisa CNS Healthcare Memphis, TN, USA

Vanchiere, John Louisiana State University Health Shreveport Shreveport, LA, USA
Varano, Susann Clinical Research Consulting Milford, CT, USA
Wadsworth, L. Tyler Sundance Clinical Research St Louis, MO, USA
Walsh, Edward University of Rochester/Rochester General Hospital Rochester, NY, USA
Walter, Emmanuel Duke Human Vaccine Institute Durham, NC, USA
Wappner, Diego Fundacion INFANT Buenos Aires, Argentina
Whiles, Rick Holston Medical Group Bristol, TN, USA
Williams, Hayes Achieve Clinical Research Birmingham, AL, USA
Wilson, Jonathan Piedmont Medical Research of Winston-Salem Winston-Salem, NC, USA
Winkle, Peter Anaheim Clinical Trials Anaheim, CA, USA
Winokur, Patricia University of Iowa Iowa City, IA, USA
Wolf, Thomas Prairie Fields Family Medicine Fremont, NE, USA
Yozviak, Joseph Lehigh Valley Hospital Cedar Crest Allentown, PA, USA
Zerbini, Cristiano Centro Paulista de Investigaçăo Clínica - CEPIC São Paulo, Brazil
5
AR10008
Ethical Conduct of the Study
The trial was conducted in accordance with the protocol, the ethical principles derived from international
guidelines including the International Council for Harmonisation Good Clinical Practice Guidelines, the
Declaration of Helsinki and Council for International Organizations of Medical Sciences International
Ethical Guidelines, and applicable laws and regulations (including applicable privacy laws). An
independent data monitoring committee reviewed efficacy and unblinded safety data.
Study Responsibilities
Pfizer was responsible for the design, study conduct, data collection, data analysis, data interpretation,
and writing of this manuscript. Both Pfizer and BioNTech manufactured clinical trial material. BioNTech
was the sponsor of the study and contributed to data interpretation and writing of the manuscript. All
study data were available to all authors who vouch for its accuracy and adherence of the study to the
protocol.
Testing for SARS-CoV-2 Virus and Antibodies
Testing for SARS-CoV-2 virus was conducted using the Cepheid Xpert Xpress SARS-CoV-2 RT-PCR
test. Testing for SARS-CoV-2 antibodies was conducted using the Roche Elecsys® Anti-SARS-CoV-2
antibody test.
Determination of SARS-CoV-2 Lineage
For determination of SARS-CoV-2 lineage, nucleic acid extraction of midturbinate swab specimens was
performed using the MagMAX™ Viral/Pathogen Ultra Nucleic Acid Isolation Kit processed on a
KingFisher™ Presto.
SARS-CoV-2 viral genome sequencing was performed using the Ion Torrent and Illumina NextSeq
platforms. For the Ion Torrent sequencing platform, the Ion AmpliSeq™ SARS-CoV-2 Research Panel
was used, which consists of 2 primer pools targeting a total of 237 PCR amplicons specific to SARS-
CoV-2 and 5 human expression controls in each pool. Oligonucleotide primers based on available SARS-
CoV-2 nucleotide sequences direct the amplification of the viral genome with amplicon lengths of 125–
275 bp. The panel provides >99% coverage of the SARS-CoV-2 genome (~30 kb). To determine the
optimal number of target amplification cycles, SARS-CoV-2 viral RNA content in the nucleic acid
purified from the midturbinate specimens was quantified using the TaqMan™ 2019-nCoV Assay Kit v1,
the TaqMan™ 2019-nCoV Control Kit v1, and TaqPath™ 1-Step RT-qPCR Master Mix, CG. cDNA was
synthesized with the SuperScript VILO cDNA synthesis kit. Libraries were prepared using the Ion
AmpliSeq™ Library Kit plus the Ion AmpliSeq™ SARS-CoV-2 Research Panel according to the
manufacturer’s instructions (ThermoFisher. Ion AmpliSeq™ Library Kit Plus USER GUIDE. Publication
MAN0017003 version C.0.). Libraries underwent template preparation with Ion Chef according to the
manufacturer’s instructions. Prepared templates were loaded onto an Ion 530 chip for semiconductor
sequencing on the Ion GeneStudio™ S5 plus sequencer according to the manufacturer’s instructions. Raw
sequencing reads generated by the Ion Torrent sequencer were quality and adaptor trimmed by Ion
6
AR10009
Torrent Suite and the resulting reads were then mapped to the complete genome of the SARS-CoV-2
Wuhan-Hu-1 isolate (GenBank accession number MN908947.3) using TMAP 5.14.0. Variant calling was
carried out with the Torrent Variant Caller using the BAM file from the mapping of the cleaned sequence
reads onto the reference sequence of SARS-CoV-2.
SARS-CoV-2 viral genome sequencing performed using the Illumina NextSeq platform used the
AmpliSeq for Illumina SARS-CoV-2 panel of PCR primers to enrich for SARS-CoV-2 in the biological
specimen. This was a 2-pool design, containing a total of 237 SARS-CoV-2 specific amplicon/primer
pairs plus 5 human expression controls in each pool. Oligonucleotide primers based on available SARS-
CoV-2 nucleotide sequences directed the amplification of overlapping amplicons with lengths of 125–275
bp that cover >99% of the viral genome. Nucleic acid extracted from the midturbinate specimens was
digested initially with DNase (Invitrogen TURBO DNA-free™ Kit, AM1907), and RNA was purified
using MagMAX™ beads before cDNA synthesis. Synthesis of cDNA using random sequence primers
and downstream steps were as described by the manufacturer. SARS-CoV-2 amplicons were generated
from the cDNA, followed by ligation of Universal Next Generation Sequencing Adaptors to the ends of
the amplicons. Amplicon libraries were purified with magnetic beads and loaded onto a flow cell for
sequence determination using the Illumina NextSeq instrument, according to the manufacturer’s
instructions. Sequences with ≥30-fold coverage across the entire spike gene were advanced for viral
lineage assignment. Single nucleotide variants were called using the “Low Frequency Variant Detection”
function with the cut-off for sequence heterogeneity set at >10%.
SARS-CoV-2 lineage assignment was based on Pangolin 2.0 software, which runs a multinomial logistic
regression model trained against lineage assignments based on isolate data from the Global Initiative on
Sharing All Influenza Data (GISAID), a global science initiative established in 2008 that provides open-
access to genomics data of influenza virus and SARS-CoV-2.
Definitions of Confirmed and Severe COVID-19 Cases
The definition of SARS-CoV-2-related cases was the presence of ≥1 of the following symptoms and
SARS-CoV-2-NAAT positivity during or within 4 days before or after the symptomatic period: fever,
new or increased cough, new or increased shortness of breath, chills, new or increased muscle pain, new
loss of taste or smell, sore throat, diarrhea, and/or vomiting. The onset date of the case was the date that
symptoms were first experienced by the participant. If new symptoms were reported ≤4 days after
resolution of all previous symptoms, they were considered part of a single illness.
Confirmed severe COVID-19 required confirmation of COVID-19 and the presence of ≥1 of the
following: clinical signs at rest indicative of severe systemic illness (respiratory rate ≥30 breaths per
minute, heart rate ≥125 beats per minute, SpO2 ≤93% on room air at sea level, or PaO2/FiO2 <300
mmHg); respiratory failure (defined as needing high-flow oxygen, non-invasive ventilation, mechanical
ventilation, or extracorporeal membrane oxygenation); evidence of shock (systolic blood pressure <90
mmHg, diastolic blood pressure <60 mmHg, or requiring vasopressors); significant acute renal, hepatic,
or neurologic dysfunction; intensive care unit admission; and/or death
(https://www.fda.gov/media/137926/download).
7
AR10010
Figure/Table
Number Figure/Table Title Population(s)/Sample Size Explanation
Figure 1 Disposition of Participants All enrolled safety population ≥16 Per protocol
years of age
N=44,165
Figure 2 Efficacy of BNT162b2 against N=46,077 (all available) All randomized participants
COVID-19 Occurrence after Dose 1 ≥12 years of age
During the Placebo-controlled
Follow-up Period
Table 1 Demographics Participants ≥16 years of age Includes HIV-infected
N=44,047 individuals
Table 2 Vaccine Efficacy against COVID-19 a. Efficacy endpoint including Evaluable population:
from 7 Days after Dose 2 During the individuals without evidence of  received 2 vaccinations
Blinded Placebo Controlled Follow- prior infection (N=42,094) as randomized
up Period (Evaluable Efficacy
 no major protocol
Population, ≥12 Years Old) b. Efficacy endpoint including deviations
individuals with and those Excludes HIV+ participants
without evidence of prior infection
(N=44,486)
Table 3 Vaccine Efficacy Overall and by N=42,094 (same as efficacy
Subgroup in Participants Without endpoint in Table 2, participants
Evidence of Infection Prior to 7 ≥12 years of age)
Days After Dose 2 During the
Blinded Placebo Controlled Follow-
up Period
Table S2 Baseline Comorbidities in N=44,047 Includes HIV-infected
Participants ≥16 Years of Age individuals
Table S3 Participants Reporting at Least 1 Participants ≥16 years of age Vaccinated minus 200 HIV-
Adverse Event From Dose 1 to 1 N=43,847 infected participants
Month After Dose 2 During the
Blinded Follow-up Period
Table S4 Causes of Death from Dose 1 to Participants ≥16 years of age Vaccinated minus 200 HIV-
Unblinding (Safety Population, ≥16 N=43,847 infected participants
Years Old)
Table S5 Vaccine Efficacy Overall and by N=46,077 (all available)
Subgroup after Dose 1 During the
Blinded Placebo Controlled Follow-
up Period (All-Available
Population)
Table S6 Vaccine Efficacy against Severe N=46,077 (all available,
COVID-19 Occurrence after Dose 1 participants ≥12 years of age)
(All-Available Population)
Table S7 Vaccine Efficacy from 7 Days after N=42,094 (same as efficacy
Dose 2 by Underlying endpoint in Table 2, participants
Comorbidities (Risk Status) among ≥12 years of age)
Participants without Evidence of
Infection Prior to 7 Days after Dose
2 (Evaluable Efficacy Population)
Figure S1 Local Reactions and Systemic Reactogenicity subset of Per protocol
Events Reported within 7 Days after participants ≥16 years of age (ie,
Receipt of BNT162b2 or Placebo by participants who used an electronic
Baseline SARS-CoV-2 Status diary for reporting local reactions
and systemic events)
N=9839
Table S1 | Explanation of the Changes in Denominator Numbers in Various Analyses.
8
AR10011
BNT162b2 Placebo Total

Charlson Comorbidity Index Category (Na=22,026) (Na=22,021) (Na=44,047)
nb (%) nb (%) nb (%)
Participants with any Charlson comorbidity 4628 (21.0) 4511 (20.5) 9139 (20.7)
AIDS/HIV 100 (0.5) 100 (0.5) 200 (0.5)
Any malignancy 812 (3.7) 757 (3.4) 1569 (3.6)
Cerebrovascular disease 227 (1.0) 198 (0.9) 425 (1.0)
Chronic pulmonary disease 1783 (8.1) 1775 (8.1) 3558 (8.1)
Congestive heart failure 109 (0.5) 102 (0.5) 211 (0.5)

Dementia 7 (0.0) 11 (0.0) 18 (0.0)
Diabetes with chronic complication 116 (0.5) 130 (0.6) 246 (0.6)
Diabetes without chronic complication 1700 (7.7) 1699 (7.7) 3399 (7.7)
Hemiplegia or paraplegia 15 (0.1) 25 (0.1) 40 (0.1)

Leukemia 14 (0.1) 11 (0.0) 25 (0.1)
Lymphoma 26 (0.1) 36 (0.2) 62 (0.1)

Metastatic solid tumor 4 (0.0) 3 (0.0) 7 (0.0)
Mild liver disease 152 (0.7) 115 (0.5) 267 (0.6)
Moderate or severe liver disease 2 (0.0) 3 (0.0) 5 (0.0)
Myocardial infarction 225 (1.0) 218 (1.0) 443 (1.0)
Peptic ulcer disease 63 (0.3) 84 (0.4) 147 (0.3)
Peripheral vascular disease 144 (0.7) 139 (0.6) 283 (0.6)
Renal disease 140 (0.6) 153 (0.7) 293 (0.7)
Rheumatic disease 75 (0.3) 71 (0.3) 146 (0.3)
Table S2 | Baseline Comorbidities in Participants ≥16 Years of Age. Baseline comorbid conditions are
classified according to the Charlson Comorbidity Index (Charlson M, Szatrowski TP, Peterson J, Gold J.
Validation of a combined comorbidity index. J Clin Epidemiol 1994;47:1245-51.). a. N=number of
participants in the specified group. This value is the denominator for the percentage calculations. b.
n=number of participants with the specified characteristic. Participants with multiple occurrences within
each category are counted only once. For ‘Participants with any Charlson comorbidity’, n=number of
participants reporting ≥1 occurrence of any Charlson comorbidity.
9
AR10012
BNT162b2 Placebo
(Na=21,926) (Na=21,921)
Adverse Event nb (%) nb (%)
Any event 6617 (30.2) 3048 (13.9)
Relatedc 5241 (23.9) 1311 (6.0)
Severe 262 (1.2) 150 (0.7)
Life-threatening 21 (0.1) 26 (0.1)
Any serious adverse event 127 (0.6) 116 (0.5)
c,d
Related 3 (0.0) 0
Severe 71 (0.3) 66 (0.3)
Any adverse event leading to withdrawal 32 (0.1) 36 (0.2)
c
Related 13 (0.1) 11 (0.1)
Severe 10 (0.0) 10 (0.0)
Death 3 (0.0) 5 (0.0)
Table S3 | Participants Reporting at Least 1 Adverse Event from Dose 1 to 1 Month After Dose 2
During the Blinded Follow-up Period. The population included all ≥16-year-old participants who
received ≥1 dose of vaccine irrespective of follow-up time. a. N=number of participants in the specified
group. This value is the denominator for the percentage calculations. b. n=Number of participants
reporting ≥1 occurrence of the specified event category. For ‘any event’, n=number of participants
reporting ≥1 occurrence of any event. c. Assessed by the investigator as related to investigational product.
d. Shoulder injury related to vaccine administration, right axillary lymphadenopathy, and paroxysmal
ventricular arrhythmia (as previously reported). Adverse events for 12‒15-year-old participants were
reported previously.11
10
AR10013
BNT162b2 Placebo
(N=21,926) (N=21,921)
Reported Cause of Deatha n n
Deaths 15 14
Acute respiratory failure 0 1
Aortic rupture 0 1
Arteriosclerosis 2 0
Biliary cancer metastatic 0 1
COVID-19 0 2
COVID-19 pneumonia 1 0
Cardiac arrest 4 1
Cardiac failure congestive 1 0
Cardiorespiratory arrest 1 1
Chronic obstructive pulmonary disease 1 0
Death 0 1
Dementia 0 1
Emphysematous cholecystitis 1 0
Hemorrhagic stroke 0 1
Hypertensive heart disease 1 0
Lung cancer metastatic 1 0
Metastases to liver 0 1
Missing 0 1
Multiple organ dysfunction syndrome 0 2
Myocardial infarction 0 2
Overdose 0 1
Pneumonia 0 2
Sepsis 1 0
Septic shock 1 0
Shigella sepsis 1 0
Unevaluable event 1 0
Table S4 | Causes of Death from Dose 1 to Unblinding (Safety Population, ≥16 Years Old). a.
Multiple causes of death could be reported for each participant. There were no deaths among 12‒15-year-
old participants.
11
AR10014
BNT162b2 Placebo
(Na=23,040) (Na=23,037)
First COVID-19 Occurrence Surveillance Surveillance
after Dose 1 n1b Timec (n2d) n1b Timec (n2d) VE (%) (95% CIe)
Overall (≥12 years old) 131 8.412 1034 8.124 87.8 (85.3, 89.9)
(22,505) (22,434)
Efficacy endpoint by subgroup
Select age groups (years)
16 to 17 3 0.094 (373) 19 0.090 (370) 84.8 (48.4, 97.1)
16 to 55 95 4.845 693 4.669 86.8 (83.6, 89.5)
(12,645) (12,626)
>55 33 3.310 (8740) 306 3.204 (8689) 89.6 (85.0, 92.9)
≥65 12 1.645 (4455) 138 1.596 (4437) 91.6 (84.8, 95.7)
≥75 2 0.326 (905) 26 0.310 (877) 92.7 (70.7, 99.2)
Sex
Male 70 4.355 (11,560) 500 4.115 86.8 (83.0, 89.9)
(11,312)
Female 61 4.057 (10,945) 534 4.009 88.7 (85.3, 91.5)
(11,122)
Race
White 115 6.957 (18,538) 916 6.719 87.9 (85.3, 90.1)
(18,479)
Black or African American 6 0.783 (2042) 53 0.770 (2063) 88.9 (74.1, 96.1)
American Indian or Alaska 1 0.061 (216) 7 0.055 (209) 86.9 (–1.6, 99.7)
Native
Asian 4 0.348 (995) 26 0.337 (990) 85.1 (57.0, 96.2)
Native Hawaiian or other 0 0.021 (58) 1 0.011 (32) 100.0 (–2000.0, 100.0)
Pacific Islander
Multiracial 5 0.208 (565) 25 0.190 (546) 81.8 (51.6, 94.6)
Not reported 0 0.035 (91) 6 0.042 (115) 100.0 (–0.7, 100.0)
Ethnicity
Hispanic/Latinx 52 2.351 (5701) 302 2.282 (5673) 83.3 (77.5, 87.8)
Non-Hispanic/non-Latinx 78 6.018 (16,692) 730 5.799 89.7 (87.0, 92.0)
(16,647)
Not reported 1 0.043 (112) 2 0.043 (114) 49.4 (–872.9, 99.1)
Country
Argentina 32 1.282 (2846) 146 1.269 (2840) 78.3 (68.0, 85.7)
Brazil 14 0.554 (1430) 95 0.520 (1420) 86.1 (75.6, 92.7)
Germany 2 0.067 (246) 1 0.069 (250) –104.5 (–11,965.9, 89.4)
South Africa 0 0.128 (367) 11 0.125 (365) 100.0 (61.1, 100.0)
Turkey 3 0.048 (246) 12 0.045 (244) 76.4 (12.4, 95.7)
USA 80 6.333 769 6.095 90.0 (87.4, 92.1)
(17,370) (17,315)
Baseline SARS-CoV-2 status
Positivef 13 0.250 (692) 17 0.265 (736) 19.2 (–76.6, 63.9)
Positive N-binding only 2 0.192 (521) 7 0.198 (542) 70.5 (–54.7, 97.0)
12
AR10015
Positive NAAT only 10 0.020 (66) 9 0.020 (69) –10.5 (–207.3, 59.7)
Positive NAAT and N- 1 0.038 (105) 1 0.046 (124) –20.5 (–9359.2, 98.5)
binding
Negativeg 116 8.101 (21,615) 1015 7.804 (21,521) 89.0 (86.6, 91.0)
Unknown 2 0.061 (198) 2 0.055 (177) 9.7 (–1145.4, 93.5)
Table S5 | Vaccine Efficacy Overall and by Subgroup after Dose 1 During the Blinded Placebo
Controlled Follow-up Period (All-Available Population). Efficacy data are presented for participants
≥12 years old. a. N=number of participants in the specified group. b. n1=Number of participants meeting
the endpoint definition. c. Total surveillance time in 1000 person-years for the given endpoint across all
participants within each group at risk for the endpoint. Time period for COVID-19 case accrual is from
dose 1 to the end of the surveillance period. d. n2=number of participants at risk for the endpoint. e. CI
for vaccine efficacy is derived based on the Clopper and Pearson method adjusted for surveillance time.
f. Positive N-binding antibody result at Visit 1, positive NAAT result at Visit 1, or medical history of
COVID-19. g. Negative N-binding antibody result at Visit 1, negative NAAT result at Visit 1, and no
medical history of COVID-19.
13
AR10016
BNT162b2 Placebo
(Na=23,040) (Na=23,037)
Efficacy Endpoint Surveillance Surveillance
Subgroup n1b Timec (n2d) n1b Timec (n2d) VE (%) (95% CIe)
First severe COVID-19 occurrence after 1 8.439 (22,505) 30 8.288 (22,435) 96.7 (80.3, 99.9)
dose 1
After dose 1 to before dose 2 0 1.351 (22,505) 6 1.360 (22,435) 100.0 (14.5, 100.0)
Dose 2 to 7 days after dose 2 0 0.425 (22,170) 1 0.423 (22,070) 100.0 (–3783.5, 100.0)
≥7 Days after dose 2 1 6.663 (22,142) 23 6.505 (22,048) 95.7 (73.9, 99.9)
Table S6 | Vaccine Efficacy against Severe COVID-19 Occurrence after Dose 1 (All-Available
Population). Efficacy data are presented for participants ≥12 years old. a. N=number of participants in
the specified group. b. n1=number of participants meeting the endpoint definition. c. Total surveillance
time in 1000 person-years for the given endpoint across all participants within each group at risk for the
endpoint. Time period for severe COVID-19 case accrual is from dose 1 to the end of the surveillance
period for the overall row, and from the start to the end of the range stated for each time interval. d.
n2=number of participants at risk for the endpoint. e. CI for vaccine efficacy is derived based on the
Clopper and Pearson method adjusted for surveillance time. Severe COVID-19 as defined by the US FDA
[https://www.fda.gov/media/137926/download]).
14
AR10017
BNT162b2 Placebo
(Na=20,998) (Na=21,096)
Efficacy Endpoint Surveillance Surveillance VE
Subgroup n1b Timec (n2d) n1b Timec (n2d) (%) (95% CIe)
First COVID-19 occurrence from 7 days

after dose 2
Overall (≥12 years old) 77 6.247 (20,712) 850 6.003 (20,713) 91.3 (89.0, 93.2)
f
At risk
Yes 35 2.797 (9167) 401 2.681 (9136) 91.6 (88.2, 94.3)
No 42 3.450 (11,545) 449 3.322 (11,577) 91.0 (87.6, 93.6)
Age group (years) and at risk
16−64 and at risk 29 2.083 (6632) 325 1.993 (6629) 91.5 (87.5, 94.4)
≥65 and at risk 6 0.680 (2322) 71 0.656 (2304) 91.8 (81.4, 97.1)
g
Obese
Yes 27 2.103 (6796) 314 2.050 (6875) 91.6 (87.6, 94.6)
No 50 4.143 (13,911) 536 3.952 (13,833) 91.1 (88.1, 93.5)
Age group (years) and obese
16−64 and obese 24 1.680 (5303) 266 1.624 (5344) 91.3 (86.7, 94.5)
≥65 and obese 3 0.404 (1370) 45 0.410 (1426) 93.2 (78.9, 98.7)
Table S7 | Vaccine Efficacy from 7 Days after Dose 2 by Underlying Comorbidities (Risk Status)
among Participants Without Evidence of Infection Prior to 7 Days after Dose 2 (Evaluable Efficacy
Population). Efficacy data are presented for participants ≥12 years old. a. N=number of participants in the
specified group. b. n1=number of participants meeting the endpoint definition. c. Total surveillance time in
1000 person-years for the given endpoint across all participants within each group at risk for the endpoint.
Time period for COVID-19 case accrual is from 7 days after dose 2 to the end of the surveillance period. d.
n2=number of participants at risk for the endpoint. e. CI for vaccine efficacy is derived based on the
Clopper and Pearson method adjusted for surveillance time. f. Includes participants who had ≥1 Charlson
Comorbidity Index (CMI) category or obesity (body mass index [BMI] ≥30 kg/m2 [≥16 years old] or BMI
≥95th percentile [12–15 years old]). g. Participants who had BMI ≥30 kg/m2 (≥16 years old) or BMI ≥95th
percentile (12–15 years old; refer to the CDC growth charts at
https://www.cdc.gov/growthcharts/html_charts/bmiagerev.htm).
15
AR10018
Figure S1 | Local Reactions and Systemic Events Reported within 7 Days after Receipt of
BNT162b2 or Placebo by Baseline SARS-CoV-2 Status. Local reactions and systemic events and
medication use were collected with electronic diaries for 7 days after each vaccination from ≥16-year-old
participants in the reactogenicity subset (n=9839; ie, participants who used an electronic diary for
reporting local reactions and systemic events). A. Solicited injection-site (local) reactions. Pain at the
injection site scale: mild, does not interfere with activity; moderate: interferes with activity; severe,
prevents daily activity; Grade 4, emergency room visit or hospitalization). Redness and swelling scale:
mild, 2.0 to 5.0 cm in diameter; moderate, >5.0 to 10.0 cm in diameter; severe, >10.0 cm in diameter;
Grade 4, necrosis or exfoliative dermatitis for redness and necrosis for swelling. B. Systemic events and
medication use. Fever scale as indicated in the key. Medication use is not graded. Fatigue, headache,
chills, new or worsened muscle pain, new or worsened joint pain scale: mild, does not interfere with
activity; moderate, some interference with activity; severe, prevents daily activity; Grade 4, emergency
room visit or hospitalization. Vomiting scale: mild, 1 to 2 times in 24 hours; moderate, >2 times in 24
hours; severe, requires intravenous hydration; Grade 4, emergency room visit or hospitalization. Diarrhea
scale: mild, 2 to 3 loose stools in 24 hours; moderate, 4 to 5 loose stools in 24 hours; severe, 6 or more
loose stools in 24 hours; Grade 4, emergency room visit or hospitalization. Whiskers represent 95% CIs.
Numbers above the whiskers are the overall percentage of participants in each group reporting the
specified local reaction or systemic event. One participant who received BNT162b2 reported a fever of
>40.0⁰C, but this is not visible on the graph. Local reactions and systemic events for 12-15-year-old
participants have been reported previously (Frenck RW, et al. N Engl J Med 2021;385(3):239-250).
Baseline SARS-CoV-2 Posit ive, Dose 1 Baseline SARS-CoV-2 Negative, Dose 1
A. 100 100
73 78
80 80
j!J
.,C: c.,"'
c. c.
·;:; 60 60
t:., ~.,
...c.
0
40 ...c.
0
40
~ 13 ~
20 20 12
0 0 n ~
5 7
N
~ ~
N
~ ~
N
~ ~
N
~
g
~
N
~ ..
g N
~
g
..
~
a,
l ~
a,
l ~
a,
l ~
a,
ii: ~
a,
~
ii: ~
a,
~
ii:
Pain at Redness Swelling Pain at Redness Swellin g

injection injection
si te site
Baseline SARS-CoV-2 Positive, Dose 2 Baseline SARS-CoV-2 Negative, Dose 2

100 100
80 80 74
c.,"' 61 c.,"'
c. c.
·;:; 60 ·;:; 60
~., f:
.,
c. 40 c. 40
0 0
~ ~
20 7 20 10
4 6 7
0
±, 0 n ,......, 0
N
~
;::
g
~
N
~
;::
~
l;l
N
~
;::
~
~
N
~
;::
..
g
~
..
N
ll
;::
~
~
N
~
;::
g
..
~
z ii: z ii: z ii: z ii: z ii: z ii:
a, a, a, a, a, a,
Pain at Redness Swelling Pain at Redness Swelli ng

injection injectio n
s ite site
Severity: - Mid - Moderate Severe - Grade 4
16
AR10019
B. Baseline SARS,CoV,2 Positive, Oose 1 Baseline SARS,CoV,2 Negative, Oose 1

100 100
1/) 80 80
i: .l!l
C
<a <a
.e-
(.) 60 45
.e-
(.) 60
~ 38 i: 43
<a
-
<a
-
a.. 31 a..
40 40 36
0 0 29 28
24
0~ 0~ 19
20 11 20
6 7
I,rl1 ~
0
N
~
8
;:: Ii:~
N
~
8
;:: Ii:~
N
~
8
;:: Ii:~
N
~
8
;:: Ii:~
2 2
~
8
;:: Ii:~
N
~
8
;:: Ii:~
N
~
8
;:: Ii:~
N
~
8
;:: Ii:~
N
~
8
;:: Ii:~
0
-3 1
!;:: 8
~ ~ 8
;:: Ii:~
~ 8
;:: Ii:~
!;:: 8
~ ~ 8
;:: Ii:~
!;:: 8
~ ~ 8
;:: Ii:~
~ 8
;:: Ii:~
!;:: 8
~
z
m
Few,
z
m
Fatigue
-
z
m
z
m
O.ls
z
m
Vomiting
Baseline SARS,CoV,2 Posit ive, Oose 2

--
z
m
z
m
pan
z
m
Joint
pan
z
m
Ampyn<ic
use
zm
._
Ii: zm
Fatigue
-
z
m
z
m
Olils
Ii: z
m
Vonili~
Baseline SARS,CoV,2 Negative, Oose 2

--
z
m
Ii: z
m
pan
z
m
JOW'lt
pan
z
m
Arq,ym;c
use
Ii:
100 100
.l!l 80 J!l 80
C C
....
<a <a
Q. Q. 58
(.) 60 (.) 60 ::c
:e<a 37 35
49
E 42
-
<a
a..
0
~
0
40
31
-
a..
0
~
0
40 32
::E
35
22
20 20 15 11
0
0 0
I:! 8 .. I:! 8 I:! 8 I:! 8 .. I:! 8 I:! 8 I:! 8 I:! 8 I:! 8 .. ~ 8 ~ 8 ~ 8 ~ 8 ~ 8 ~ 8 ~ 8 ~ 8 ~ 8
~ ~
I.! ii! I.! ~ I.! ii! I.! ~ I.! ~ I.! ~ I.! ~ I.! ii! ~ ~ ~ ~ ~ ~ ~ ~ ~
~ ii: ~ ~ ~ ~ ~ ~ ~ ~
~ ~
-
~ ~ ~
--
~ ~ ~
- -
ii: ii: ii: ii: ii: ii: ii: ii: ii: ii: ii: ii: ii: ii: ii: ii: ii:
m m m m m m m m m m m m m m m m m m
Few, Fatigue Chils Vomiting Joint Am,,,..«ic

._ Fatigue Olils Vonili~ Di- J oc,t Ampymjc
pan pan use pan pan use
Severity: - Mild - Moderate Severe - Grade4

Fever: - 38.0"C--384-C - >38.4°C-38.9°C >38.9°C-40.0°c • >4o.o•c
17
11_ __
EXHIBIT No . _ _ _ _
BNT162b2
5.3.6 Cumulative Analysis of Post-authorization Adverse Event Reports
Celia Lourenco
DATE June 6, 2022

5.3.6 CUMULATIVE ANALYSIS OF POST-AUTHORIZATION ADVERSE EVENT

REPORTS OF PF-07302048 (BNT162B2) RECEIVED THROUGH 28-FEB-2021
090177e196ea1800\Approved\Approved On: 30-Apr-2021 09:26 (GMT)
Report Prepared by:
Worldwide Safety
Pfizer
The information contained in this document is proprietary and confidential. Any disclosure, reproduction,
distribution, or other dissemination of this information outside of Pfizer, its Affiliates, its Licensees, or
Regulatory Agencies is strictly prohibited. Except as may be otherwise agreed to in writing, by accepting or
reviewing these materials, you agree to hold such information in confidence and not to disclose it to others
(except where required by applicable law), nor to use it for unauthorized purposes.
CONFIDENTIAL
Page 1
AR10021
BNT162b2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................3
APPENDICES ...........................................................................................................................3
LIST OF ABBREVIATIONS....................................................................................................4
1. INTRODUCTION .................................................................................................................5
2. METHODOLOGY ................................................................................................................5
3. RESULTS ..............................................................................................................................6
3.1. Safety Database .........................................................................................................6
3.1.1. General Overview.........................................................................................6
3.1.2. Summary of Safety Concerns in the US Pharmacovigilance Plan ...............9
3.1.3. Review of Adverse Events of Special Interest (AESIs) .............................16
3.1.4. Medication error .........................................................................................26
4. DISCUSSION ......................................................................................................................28
5. SUMMARY AND CONCLUSION ....................................................................................29
CONFIDENTIAL
Page 2
AR10022
BNT162b2
LIST OF TABLES
Table 1. General Overview: Selected Characteristics of All Cases Received
During the Reporting Interval.....................................................................7
Table 2. Events Reported in ≥2% Cases...................................................................8
Table 3. Safety concerns ...........................................................................................9
Table 4. Important Identified Risk..........................................................................10
Table 5. Important Potential Risk ...........................................................................11
Table 6. Description of Missing Information .........................................................12
Table 7. AESIs Evaluation for BNT162b2.............................................................16
Table 8. ME PTs by seriousness with or without harm co-association
(Through 28 February 2021) ....................................................................27
LIST OF FIGURES
Figure 1. Total Number of 13vPnC AEs by System Organ Classes and Event
Seriousness .................................................................................................8
APPENDICES
APPENDIX 1 LIST OF ADVERSE EVENTS OF SPECIAL INTEREST ............................30
CONFIDENTIAL
Page 3
AR10023
BNT162b2
LIST OF ABBREVIATIONS
Acronym Term
AE adverse event
AESI adverse event of special interest
BC Brighton Collaboration
CDC Centers for Disease Control and Prevention
COVID-19 coronavirus disease 2019
DLP data lock point
EUA emergency use authorisation
HLGT (MedDRA) High Group Level Term
HLT (MedDRA) High Level Term
MAH marketing authorisation holder
MedDRA medical dictionary for regulatory activities
MHRA Medicines and Healthcare products Regulatory Agency
PCR Polymerase Chain Reaction
PT (MedDRA) Preferred Term
PVP pharmacovigilance plan
RT-PCR Reverse Transcription-Polymerase Chain Reaction
RSI reference safety information
TME targeted medically event
SARS-CoV-2 severe acute respiratory syndrome coronavirus 2

SMQ standardised MedDRA query
SOC (MedDRA) System Organ Class
UK United Kingdom
US United States
VAED vaccine-associated enhanced disease
VAERD vaccine-associated enhanced respiratory disease
VAERS vaccine adverse event reporting system
CONFIDENTIAL
Page 4
AR10024
BNT162b2
1. INTRODUCTION
Reference is made to the Request for Comments and Advice submitted 04 February 2021
regarding Pfizer/BioNTech’s proposal for the clinical and post-authorization safety data
package for the Biologics License Application (BLA) for our investigational COVID-19
Vaccine (BNT162b2). Further reference is made to the Agency’s 09 March 2021 response to
this request, and specifically, the following request from the Agency.
“Monthly safety reports primarily focus on events that occurred during the reporting interval
and include information not relevant to a BLA submission such as line lists of adverse events
by country. We are most interested in a cumulative analysis of post-authorization safety data
to support your future BLA submission. Please submit an integrated analysis of your
cumulative post-authorization safety data, including U.S. and foreign post-authorization
experience, in your upcoming BLA submission. Please include a cumulative analysis of the
Important Identified Risks, Important Potential Risks, and areas of Important Missing
Information identified in your Pharmacovigilance Plan, as well as adverse events of special
interest and vaccine administration errors (whether or not associated with an adverse event).
Please also include distribution data and an analysis of the most common adverse events. In
addition, please submit your updated Pharmacovigilance Plan with your BLA submission.”
This document provides an integrated analysis of the cumulative post-authorization safety

data, including U.S. and foreign post-authorization adverse event reports received through 28
February 2021.
2. METHODOLOGY
Pfizer is responsible for the management post-authorization safety data on behalf of the
MAH BioNTech according to the Pharmacovigilance Agreement in place. Data from
BioNTech are included in the report when applicable.
Pfizer’s safety database contains cases of AEs reported spontaneously to Pfizer, cases
reported by the health authorities, cases published in the medical literature, cases from
Pfizer-sponsored marketing programs, non-interventional studies, and cases of serious AEs
reported from clinical studies regardless of causality assessment.
The limitations of post-marketing adverse drug event reporting should be considered when
interpreting these data:
• Reports are submitted voluntarily, and the magnitude of underreporting is unknown.

Some of the factors that may influence whether an event is reported include: length of
time since marketing, market share of the drug, publicity about a drug or an AE,
seriousness of the reaction, regulatory actions, awareness by health professionals and
consumers of adverse drug event reporting, and litigation.
• Because many external factors influence whether or not an AE is reported, the

spontaneous reporting system yields reporting proportions not incidence rates. As a
result, it is generally not appropriate to make between-drug comparisons using these
CONFIDENTIAL
Page 5
AR10025
BNT162b2
proportions; the spontaneous reporting system should be used for signal detection
rather than hypothesis testing.
• In some reports, clinical information (such as medical history, validation of diagnosis,

time from drug use to onset of illness, dose, and use of concomitant drugs) is missing
or incomplete, and follow-up information may not be available.
• An accumulation of adverse event reports (AERs) does not necessarily indicate that a
particular AE was caused by the drug; rather, the event may be due to an underlying
disease or some other factor(s) such as past medical history or concomitant
medication.
• Among adverse event reports received into the Pfizer safety database during the
cumulative period, only those having a complete workflow cycle in the safety database
(meaning they progressed to Distribution or Closed workflow status) are included in the
monthly SMSR. This approach prevents the inclusion of cases that are not fully processed
hence not accurately reflecting final information. Due to the large numbers of
spontaneous adverse event reports received for the product, the MAH has prioritised the
processing of serious cases, in order to meet expedited regulatory reporting timelines and
ensure these reports are available for signal detection and evaluation activity. The
increased volume of reports has not impacted case processing for serious reports, and
compliance metrics continue to be monitored weekly with prompt action taken as needed
to maintain compliance with expedited reporting obligations. Non-serious cases are
entered into the safety database no later than 4 calendar days from receipt. Entrance into
the database includes the coding of all adverse events; this allow for a manual review of
events being received but may not include immediate case processing to completion.
Non-serious cases are processed as soon as possible and no later than 90 days from
receipt. Pfizer has also taken a multiple actions to help alleviate the large increase of
adverse event reports. This includes significant technology enhancements, and process
and workflow solutions, as well as increasing the number of data entry and case
■
(b) (4)
processing colleagues. To date, Pfizer has onboarded approximately additional full-
-
time employees (FTEs). More are joining each month with an expected total of more than
(b) (4) additional resources by the end of June 2021.
3. RESULTS
3.1. Safety Database
-
3.1.1. General Overview
It is estimated that approximately (b) (4) doses of BNT162b2 were shipped worldwide
from the receipt of the first temporary authorisation for emergency supply on 01 December
2020 through 28 February 2021.
Cumulatively, through 28 February 2021, there was a total of 42,086 case reports (25,379
medically confirmed and 16,707 non-medically confirmed) containing 158,893 events. Most
cases (34,762) were received from United States (13,739), United Kingdom (13,404) Italy
(2,578), Germany (1913), France (1506), Portugal (866) and Spain (756); the remaining
7,324 were distributed among 56 other countries.
CONFIDENTIAL
Page 6
AR10026
BNT162b2
Table 1 below presents the main characteristics of the overall cases.
Table 1. General Overview: Selected Characteristics of All Cases Received During

the Reporting Interval
Characteristics Relevant cases (N=42086)
Gender: Female 29914
Male 9182
No Data 2990
Age range (years): ≤ 17 175a
0.01 -107 years 18-30 4953
Mean = 50.9 years 31-50 13886
n = 34952 51-64 7884
65-74 3098
≥ 75 5214
Unknown 6876
Case outcome: Recovered/Recovering 19582

Recovered with sequelae 520
Not recovered at the time of report 11361
Fatal 1223
Unknown 9400
a. in 46 cases reported age was <16-year-old and in 34 cases <12-year-old.
As shown in Figure 1, the System Organ Classes (SOCs) that contained the greatest number
(≥2%) of events, in the overall dataset, were General disorders and administration site
conditions (51,335 AEs), Nervous system disorders (25,957), Musculoskeletal and
connective tissue disorders (17,283), Gastrointestinal disorders (14,096), Skin and
subcutaneous tissue disorders (8,476), Respiratory, thoracic and mediastinal disorders
(8,848), Infections and infestations (4,610), Injury, poisoning and procedural complications
(5,590), and Investigations (3,693).
CONFIDENTIAL
Page 7
AR10027
BNT162b2
Figure 1. Total Number of BNT162b2 AEs by System Organ Classes and Event
Seriousness
I
I I I I lid
-+-----+---+----+-----+---+-----l
-¼=-----+---+----+-----+---+-----l
lymphatic~E----+----+-1---+-1----+-1----+1-1
;
gcl
I
I
I
I
I ~
H:::.::1
Skin
Immune
Endocrine
Co ngenital & genetic
Nervous system
Re11al & urinary

Reproduc tive & breast
lnvestigati011s
Cardiac
Musculoskeletal
General disorders
Eye
Soc ial circums tances

Gas trointes tinal
Ear & labyrinth
Smgical & medical procedures

Respiratory
Melabolism & nutrition

Product issues
lnfec tio11s
Psychiatric
comp11cal:to11s
, .
Blood &
d ua1
, proce l
.m J
IllJlu.,
Table 2 shows the most commonly (≥2%) reported MedDRA (v. 23.1) PTs in the overall
dataset (through 28 February 2021),
Table 2. Events Reported in ≥2% Cases
Cumulatively Through 28
February 2021
MedDRA SOC MedDRA PT AEs (AERP%)
N = 42086
Blood and lymphatic system
disorders
Lymphadenopathy 1972 (4.7%)
Cardiac disorders
Tachycardia 1098 (2.6%)
Gastrointestinal disorders
Nausea 5182 (12.3%)
Diarrhoea 1880 (4.5%)
Vomiting 1698 (4.0%)
General disorders and administration site conditions
Pyrexia 7666 (18.2%)
Fatigue 7338 (17.4%)
Chills 5514 (13.1%)
Vaccination site pain 5181 (12.3%)
CONFIDENTIAL
Page 8
AR10028
BNT162b2
Table 2. Events Reported in ≥2% Cases

Cumulatively Through 28
February 2021
MedDRA SOC MedDRA PT AEs (AERP%)
N = 42086
Pain 3691 (8.8%)
Malaise 2897 (6.9%)
Asthenia 2285 (5.4%)
Drug ineffective 2201 (5.2%)
Vaccination site erythema 930 (2.2%)
Vaccination site swelling 913 (2.2%)
Influenza like illness 835 (2%)
Infections and infestations
COVID-19 1927 (4.6%)
Injury, poisoning and procedural complications
Off label use 880 (2.1%)
Product use issue 828 (2.0%)
Musculoskeletal and connective tissue disorders
Myalgia 4915 (11.7%)
Pain in extremity 3959 (9.4%)
Arthralgia 3525 (8.4%)
Nervous system disorders
Headache 10131 (24.1%)
Dizziness 3720 (8.8%)
Paraesthesia 1500 (3.6%)
Hypoaesthesia 999 (2.4%)

Respiratory, thoracic and mediastinal disorders
Dyspnoea 2057 (4.9%)
Cough 1146 (2.7%)
Oropharyngeal pain 948 (2.3%)
Skin and subcutaneous tissue disorders
Pruritus 1447 (3.4%)
Rash 1404 (3.3%)
Erythema 1044 (2.5%)
Hyperhidrosis 900 (2.1%)
Urticaria 862 (2.1%)
Total number of events 93473
3.1.2. Summary of Safety Concerns in the US Pharmacovigilance Plan
Table 3. Safety concerns

Important identified risks Anaphylaxis
Important potential risks Vaccine-Associated Enhanced Disease (VAED), Including Vaccine-associated

Enhanced Respiratory Disease (VAERD)
Missing information Use in Pregnancy and lactation
Use in Paediatric Individuals <12 Years of Age
Vaccine Effectiveness
CONFIDENTIAL
Page 9
AR10029
BNT162b2
Table 4. Important Identified Risk

Topic Description
Important Post Authorization Cases Evaluation (cumulative to 28 Feb 2021)

Identified Total Number of Cases in the Reporting Period (N=42086)
Risk
Anaphylaxis Since the first temporary authorization for emergency supply under Regulation 174 in the UK
(01 December 2020) and through 28 February 2021, 1833 potentially relevant cases were retrieved from
the Anaphylactic reaction SMQ (Narrow and Broad) search strategy, applying the MedDRA algorithm.
These cases were individually reviewed and assessed according to Brighton Collaboration (BC)
definition and level of diagnostic certainty as shown in the Table below:
Brighton Collaboration Level Number of cases

BC 1 290
BC 2 311
BC 3 10
BC 4 391
BC 5 831
Total 1833
Level 1 indicates a case with the highest level of diagnostic certainty of anaphylaxis,
whereas the diagnostic certainty is lowest for Level 3. Level 4 is defined as “reported
event of anaphylaxis with insufficient evidence to meet the case definition” and Level
5 as not a case of anaphylaxis.
There were 1002 cases (54.0% of the potentially relevant cases retrieved), 2958 potentially relevant
events, from the Anaphylactic reaction SMQ (Broad and Narrow) search strategy, meeting BC Level 1 to
4:
Country of incidence: UK (261), US (184), Mexico (99), Italy (82), Germany (67), Spain (38), France
(36), Portugal (22), Denmark (20), Finland, Greece (19 each), Sweden (17), Czech Republic ,
Netherlands (16 each), Belgium, Ireland (13 each), Poland (12), Austria (11); the remaining 57 cases
originated from 15 different countries.
Relevant event seriousness: Serious (2341), Non-Serious (617);
Gender: Females (876), Males (106), Unknown (20);
Age (n=961) ranged from 16 to 98 years (mean = 54.8 years, median = 42.5 years);
Relevant even outcomea: fatal (9)b, resolved/resolving (1922), not resolved (229), resolved with sequelae
(48), unknown (754);
Most frequently reported relevant PTs (≥2%), from the Anaphylactic reaction SMQ (Broad and Narrow)
search strategy: Anaphylactic reaction (435), Dyspnoea (356), Rash (190), Pruritus (175), Erythema
(159), Urticaria (133), Cough (115), Respiratory distress, Throat tightness (97 each), Swollen tongue
(93), Anaphylactic shock (80), Hypotension (72), Chest discomfort (71), Swelling face (70), Pharyngeal
swelling (68), and Lip swelling (64).
Conclusion: Evaluation of BC cases Level 1 - 4 did not reveal any significant new safety information.
Anaphylaxis is appropriately described in the product labeling as are non-anaphylactic hypersensitivity
events. Surveillance will continue.
a Different clinical outcome may be reported for an event that occurred more than once to the same individual.
b There were 4 individuals in the anaphylaxis evaluation who died on the same day they were vaccinated.
Although these patients experienced adverse events (9) that are potential symptoms of anaphylaxis, they all had serious
underlying medical conditions, and one individual appeared to also have COVID-19 pneumonia, that likely contributed to
their deaths
CONFIDENTIAL
Page 10
AR10030
BNT162b2
Table 5. Important Potential Risk

Topic Description
Important Post Authorization Cases Evaluation (cumulative to 28 Feb 2021)

Potential Total Number of Cases in the Reporting Period (N=42086)
Risk
Vaccine- No post-authorized AE reports have been identified as cases of VAED/VAERD, therefore, there is no
Associated observed data at this time. An expected rate of VAED is difficult to establish so a meaningful
Enhanced observed/expected analysis cannot be conducted at this point based on available data. The feasibility of
Disease conducting such an analysis will be re-evaluated on an ongoing basis as data on the virus grows and the
(VAED), vaccine safety data continues to accrue.
including
Vaccine- The search criteria utilised to identify potential cases of VAED for this report includes PTs indicating a
Associated lack of effect of the vaccine and PTs potentially indicative of severe or atypical COVID-19a.
Enhanced
Respiratory Since the first temporary authorization for emergency supply under Regulation 174 in the UK (01
Disease December 2020) and through 28 February 2021, 138 cases [0.33% of the total PM dataset], reporting 317
(VAERD) potentially relevant events were retrieved:
Country of incidence: UK (71), US (25), Germany (14), France, Italy, Mexico, Spain, (4 each), Denmark
(3); the remaining 9 cases originated from 9 different countries;
Cases Seriousness: 138;
Seriousness criteria for the total 138 cases: Medically significant (71, of which 8 also serious for
disability), Hospitalization required (non-fatal/non-life threatening) (16, of which 1 also serious for
disability), Life threatening (13, of which 7 were also serious for hospitalization), Death (38).
Gender: Females (73), Males (57), Unknown (8);
Age (n=132) ranged from 21 to 100 years (mean = 57.2 years, median = 59.5);
Case outcome: fatal (38), resolved/resolving (26), not resolved (65), resolved with sequelae (1), unknown
(8);
Of the 317 relevant events, the most frequently reported PTs (≥2%) were: Drug ineffective (135),
Dyspnoea (53), Diarrhoea (30), COVID-19 pneumonia (23), Vomiting (20), Respiratory failure (8), and
Seizure (7).
Conclusion: VAED may present as severe or unusual clinical manifestations of COVID-19. Overall, there
were 37 subjects with suspected COVID-19 and 101 subjects with confirmed COVID-19 following one
or both doses of the vaccine; 75 of the 101 cases were severe, resulting in hospitalisation, disability,
life-threatening consequences or death. None of the 75 cases could be definitively considered as
VAED/VAERD.
In this review of subjects with COVID-19 following vaccination, based on the current evidence,
VAED/VAERD remains a theoretical risk for the vaccine. Surveillance will continue.
a. Search criteria: Standard Decreased Therapeutic Response Search AND PTs Dyspnoea; Tachypnoea; Hypoxia;
COVID 19 pneumonia; Respiratory Failure; Acute Respiratory Distress Syndrome; Cardiac Failure; Cardiogenic shock;
Acute myocardial infarction; Arrhythmia; Myocarditis; Vomiting; Diarrhoea; Abdominal pain; Jaundice;
Acute hepatic failure; Deep vein thrombosis; Pulmonary embolism; Peripheral Ischaemia; Vasculitis; Shock;
Acute kidney injury; Renal failure; Altered state of consciousness; Seizure; Encephalopathy; Meningitis;
Cerebrovascular accident; Thrombocytopenia; Disseminated intravascular coagulation; Chillblains;
Erythema multiforme; Multiple organ dysfunction syndrome; Multisystem inflammatory syndrome in children.
CONFIDENTIAL
Page 11
AR10031
BNT162b2
Table 6. Description of Missing Information

Topic Description
Missing Post Authorization Cases Evaluation (cumulative to 28 Feb 2021)

Information Total Number of Cases in the Reporting Period (N=42086)
Use in
Pregnancy • Number of cases: 413a (0.98% of the total PM dataset); 84 serious and 329 non-serious;
and lactation • Country of incidence: US (205), UK (64), Canada (31), Germany (30), Poland (13), Israel
(11); Italy (9), Portugal (8), Mexico (6), Estonia, Hungary and Ireland, (5 each), Romania (4),
Spain (3), Czech Republic and France (2 each), the remaining 10 cases were distributed among
10 other countries.
Pregnancy cases: 274 cases including:
• 270 mother cases and 4 foetus/baby cases representing 270 unique pregnancies (the 4
foetus/baby cases were linked to 3 mother cases; 1 mother case involved twins).
• Pregnancy outcomes for the 270 pregnancies were reported as spontaneous abortion (23),
outcome pending (5), premature birth with neonatal death, spontaneous abortion with
intrauterine death (2 each), spontaneous abortion with neonatal death, and normal outcome (1
each). No outcome was provided for 238 pregnancies (note that 2 different outcomes were
reported for each twin, and both were counted).
• 146 non-serious mother cases reported exposure to vaccine in utero without the occurrence of
any clinical adverse event. The exposure PTs coded to the PTs Maternal exposure during
pregnancy (111), Exposure during pregnancy (29) and Maternal exposure timing unspecified
(6). Trimester of exposure was reported in 21 of these cases: 1st trimester (15 cases), 2nd
trimester (7), and 3rd trimester (2).
• 124 mother cases, 49 non-serious and 75 serious, reported clinical events, which occurred in
the vaccinated mothers. Pregnancy related events reported in these cases coded to the PTs
Abortion spontaneous (25), Uterine contraction during pregnancy, Premature rupture of
membranes, Abortion, Abortion missed, and Foetal death (1 each). Other clinical events which
occurred in more than 5 cases coded to the PTs Headache (33), Vaccination site pain (24),
Pain in extremity and Fatigue (22 each), Myalgia and Pyrexia (16 each), Chills (13) Nausea
(12), Pain (11), Arthralgia (9), Lymphadenopathy and Drug ineffective (7 each), Chest pain,
Dizziness and Asthenia (6 each), Malaise and COVID-19 (5 each). Trimester of exposure was
reported in 22 of these cases: 1st trimester (19 cases), 2nd trimester (1 case), 3rd trimester (2
cases).
• 4 serious foetus/baby cases reported the PTs Exposure during pregnancy, Foetal growth
restriction, Maternal exposure during pregnancy, Premature baby (2 each), and Death neonatal
(1). Trimester of exposure was reported for 2 cases (twins) as occurring during the 1st
trimester.
Breast feeding baby cases: 133, of which:
• 116 cases reported exposure to vaccine during breastfeeding (PT Exposure via breast milk)
without the occurrence of any clinical adverse events;
• 17 cases, 3 serious and 14 non-serious, reported the following clinical events that occurred in
the infant/child exposed to vaccine via breastfeeding: Pyrexia (5), Rash (4), Infant irritability
(3), Infantile vomiting, Diarrhoea, Insomnia, and Illness (2 each), Poor feeding infant,
Lethargy, Abdominal discomfort, Vomiting, Allergy to vaccine, Increased appetite, Anxiety,
Crying, Poor quality sleep, Eructation, Agitation, Pain and Urticaria (1 each).
Breast feeding mother cases (6):

• 1 serious case reported 3 clinical events that occurred in a mother during breast feeding (PT
Maternal exposure during breast feeding); these events coded to the PTs Chills, Malaise, and
Pyrexia
• 1 non-serious case reported with very limited information and without associated AEs.
CONFIDENTIAL
Page 12
AR10032
BNT162b2

Topic Description

• In 4 cases (3 non-serious; 1 serious) Suppressed lactation occurred in a breast feeding women
with the following co-reported events: Pyrexia (2), Paresis, Headache, Chills, Vomiting, Pain
in extremity, Arthralgia, Breast pain, Scar pain, Nausea, Migraine, Myalgia, Fatigue and
Breast milk discolouration (1 each).
Conclusion: There were no safety signals that emerged from the review of these cases of use in
pregnancy and while breast feeding.
Use in
Paediatric Paediatric individuals <12 years of age
Individuals • Number of cases: 34d (0.1% of the total PM dataset), indicative of administration in paediatric
<12 Years of subjects <12 years of age;
Age • Country of incidence: UK (29), US (3), Germany and Andorra (1 each);
• Cases Seriousness: Serious (24), Non-Serious (10);
• Gender: Females (25), Males (7), Unknown (2);
• Age (n=34) ranged from 2 months to 9 years, mean = 3.7 years, median = 4.0;
• Case outcome: resolved/resolving (16), not resolved (13), and unknown (5).
• Of the 132 reported events, those reported more than once were as follows: Product
administered to patient of inappropriate age (27, see Medication Error), Off label use (11),
Pyrexia (6), Product use issue (5), Fatigue, Headache and Nausea (4 each), Vaccination site
pain (3), Abdominal pain upper, COVID-19, Facial paralysis, Lymphadenopathy, Malaise,
Pruritus and Swelling (2 each).
Conclusion: No new significant safety information was identified based on a review of these cases
compared with the non-paediatric population.
Vaccine Company conventions for coding cases indicative of lack of efficacy:

Effectiveness
The coding conventions for lack of efficacy in the context of administration of the COVID-19 vaccine
were revised on 15 February 2021, as shown below:
• PT “Vaccination failure” is coded when ALL of the following criteria are met:
o The subject has received the series of two doses per the dosing regimen in local
labeling.
o At least 7 days have elapsed since the second dose of vaccine has been administered.
o The subject experiences SARS-CoV-2 infection (confirmed laboratory tests).
• PT “Drug ineffective” is coded when either of the following applies:
o The infection is not confirmed as SARS-CoV-2 through laboratory tests
(irrespective of the vaccination schedule). This includes scenarios where LOE is
stated or implied, e.g., “the vaccine did not work”, “I got COVID-19”.
o It is unknown:
Whether the subject has received the series of two doses per the dosing
regimen in local labeling;
How many days have passed since the first dose (including unspecified
number of days like” a few days”, “some days”, etc.);
If 7 days have passed since the second dose;
o The subject experiences a vaccine preventable illness 14 days after receiving the
first dose up to and through 6 days after receipt of the second dose.
Note: after the immune system as had sufficient time (14 days) to respond to the vaccine, a report of
COVID-19 is considered a potential lack of efficacy even if the vaccination course is not complete.
Summary of the coding conventions for onset of vaccine preventable disease versus the vaccination
date:
CONFIDENTIAL
Page 13
AR10033
BNT162b2

Topic Description

1st dose (day 1-13) From day 14 post 1st dose to Day 7 post 2nd dose
day 6 post 2nd dose
Code only the events Code “Drug ineffective” Code “Vaccination failure”
describing the SARS-CoV-2
infection
Scenario Not considered Scenario considered LOE as Scenario considered LOE as
LOE “Drug ineffective” “Vaccination failure”
Lack of efficacy cases

• Number of cases: 1665b (3.9 % of the total PM dataset) of which 1100 were medically
confirmed and 565 non medically confirmed;
• Number of lack of efficacy events: 1665 [PT: Drug ineffective (1646) and Vaccination failure
(19)f].
• Country of incidence: US (665), UK (405), Germany (181), France (85), Italy (58), Romania
(47), Belgium (33), Israel (30), Poland (28), Spain (21), Austria (18), Portugal (17), Greece
(15), Mexico (13), Denmark (8), Canada (7), Hungary, Sweden and United Arab Emirates (5
each), Czech Republic (4), Switzerland (3); the remaining 12 cases originated from 9 different
countries.
• COVID-19 infection was suspected in 155 cases, confirmed in 228 cases, in 1 case it was
reported that the first dose was not effective (no other information).
• COVID-19 infection (suspected or confirmed) outcome was reported as resolved/resolving
(165), not resolved (205) or unknown (1230) at the time of the reporting; there were 65 cases
where a fatal outcome was reported.
Drug ineffective cases (1649)

• Drug ineffective event seriousness: serious (1625), non-serious (21)e;
• Lack of efficacy term was reported:
o after the 1st dose in 788 cases
o after the 2nd dose in 139 cases
o in 722 cases it was unknown after which dose the lack of efficacy occurred.
• Latency of lack of efficacy term reported after the first dose was known for 176 cases:
o Within 9 days: 2 subjects;
o Within 14 and 21 days: 154 subjects;
• Latency of lack of efficacy term reported after the second dose was known for 69 cases:
o Within 23 and 36 days: 5 subjects.
• Latency of lack of efficacy term reported in cases where the number of doses administered was
not provided, was known in 409 cases:
o Within 0 and 7 days after vaccination: 281 subjects.
According to the RSI, individuals may not be fully protected until 7 days after their second dose of
vaccine, therefore for the above 1649 cases where lack of efficacy was reported after the 1st dose or the
CONFIDENTIAL
Page 14
AR10034
BNT162b2

Topic Description

2nd dose, the reported events may represent signs and symptoms of intercurrent or undiagnosed COVID-
19 infection or infection in an individual who was not fully vaccinated, rather than vaccine
ineffectiveness.
Vaccination failure cases (16)

• Vaccination failure seriousness: all serious;
• Lack of efficacy term was reported in all cases after the 2nd dose:
• Latency of lack of efficacy was known for 14 cases:
o Within 15 and 29 days: 6 subjects.
COVID-19 (10) and Asymptomatic COVID-19 (6) were the reported vaccine preventable infections that
occurred in these 16 cases.
Conclusion: No new safety signals of vaccine lack of efficacy have emerged based on a review of these
cases.
a. From a total of 417 cases, 4 cases were excluded from the analysis. In 3 cases, the MAH was informed
that a 33-year-old and two unspecified age pregnant female patients were scheduled to receive bnt162b2 (PT
reported Off label use and Product use issue in 2 cases; Circumstance or information capable of leading to
medication error in one case). One case reported the PT Morning sickness; however, pregnancy was not
confirmed in this case.
b. 558 additional cases retrieved in this dataset were excluded from the analysis; upon review, 546 cases
cannot be considered true lack of efficacy cases because the PT Drug ineffective was coded but the subjects
developed SARS-CoV-2 infection during the early days from the first dose (days 1 – 13); the vaccine has not
had sufficient time to stimulate the immune system and, consequently, the development of a vaccine
preventable disease during this time is not considered a potential lack of effect of the vaccine; in 5 cases the
PT Drug ineffective was removed after data lock point (DLP) because the subjects did not develop COVID-
19 infection; in 1 case, reporting Treatment failure and Transient ischaemic attack, the Lack of efficacy PT
did not refer to BNT162b2 vaccine; 5 cases have been invalidated in the safety database after DLP; 1 case
has been deleted from the discussion because the PTs reported Pathogen resistance and Product preparation
issue were not indicative of a lack of efficacy. to be eliminated.
c. Upon review, 31 additional cases were excluded from the analysis as the data reported (e.g. clinical
details, height, weight, etc.) were not consistent with paediatric subjects
d. Upon review, 28 additional cases were excluded from the analysis as the data reported (e.g. clinical
details, height, weight, etc.) were not consistent with paediatric subjects.
e. Different clinical outcomes may be reported for an event that occurred more than once to the same
individual
f. In 2 cases the PT Vaccination failure was replaced with Drug ineffective after DLP. Another case was
not included in the discussion of the Vaccination failure cases because correct scheduling (21 days apart
between the first and second dose) cannot be confirmed.
CONFIDENTIAL
Page 15
AR10035
BNT162b2
3.1.3. Review of Adverse Events of Special Interest (AESIs)

Please refer to Appendix 1 for the list of the company’s AESIs for BNT162b2.
The company’s AESI list takes into consideration the lists of AESIs from the following
expert groups and regulatory authorities: Brighton Collaboration (SPEAC), ACCESS
protocol, US CDC (preliminary list of AESI for VAERS surveillance), MHRA (unpublished
guideline).
The AESI terms are incorporated into a TME list and include events of interest due to their
association with severe COVID-19 and events of interest for vaccines in general.
The AESI list is comprised of MedDRA PTs, HLTs, HLGTs or MedDRA SMQs and can be
changed as appropriate based on the evolving safety profile of the vaccine.
Table 7 provides a summary review of cumulative cases within AESI categories in the Pfizer
safety database. This is distinct from safety signal evaluations which are conducted and
included, as appropriate, in the Summary Monthly Safety Reports submitted regularly to the
FDA and other Health Authorities.
Table 7. AESIs Evaluation for BNT162b2

a
AESIs Post-Marketing Cases Evaluationb
Category Total Number of Cases (N=42086)
Anaphylactic Reactions Please refer to the Risk ‘Anaphylaxis’ included above in Table 4.
Search criteria: Anaphylactic
reaction SMQ (Narrow and Broad,
with the algorithm applied),
selecting relevant cases according
to BC criteria
Cardiovascular AESIs • Number of cases: 1403 (3.3% of the total PM dataset), of which
Search criteria: PTs Acute 241 are medically confirmed and 1162 are non-medically
myocardial infarction; confirmed;
Arrhythmia; Cardiac failure; • Country of incidence: UK (268), US (233), Mexico (196), Italy
Cardiac failure acute; (141), France (128), Germany (102), Spain (46), Greece (45),
Cardiogenic shock; Coronary Portugal (37), Sweden (20), Ireland (17), Poland (16), Israel (13),
artery disease; Myocardial Austria, Romania and Finland (12 each), Netherlands (11),
infarction; Postural orthostatic Belgium and Norway (10 each), Czech Republic (9), Hungary and
tachycardia syndrome; Stress Canada (8 each), Croatia and Denmark (7 each), Iceland (5); the
cardiomyopathy; Tachycardia remaining 30 cases were distributed among 13 other countries;
• Subjects’ gender: female (1076), male (291) and unknown (36);
• Subjects’ age group (n = 1346): Adultc (1078), Elderlyd (266)
Childe and Adolescentf (1 each);
• Number of relevant events: 1441, of which 946 serious, 495
non-serious; in the cases reporting relevant serious events;
• Reported relevant PTs: Tachycardia (1098), Arrhythmia (102),
Myocardial infarction (89), Cardiac failure (80), Acute myocardial
infarction (41), Cardiac failure acute (11), Cardiogenic shock and
Postural orthostatic tachycardia syndrome (7 each) and Coronary
artery disease (6);
• Relevant event onset latency (n = 1209): Range from <24 hours to
21 days, median <24 hours;
CONFIDENTIAL
Page 16
AR10036
BNT162b2

AESIsa Post-Marketing Cases Evaluationb
• Relevant event outcomeg: fatal (136), resolved/resolving (767),
resolved with sequelae (21), not resolved (140) and unknown
(380);
Conclusion: This cumulative case review does not raise new safety
issues. Surveillance will continue
COVID-19 AESIs • Number of cases: 3067 (7.3% of the total PM dataset), of which
Search criteria: Covid-19 SMQ 1013 are medically confirmed and 2054 are non-medically
(Narrow and Broad) OR PTs confirmed;
Ageusia; Anosmia • Country of incidence: US (1272), UK (609), Germany (360),
France (161), Italy (94), Spain (69), Romania (62), Portugal (51),
Poland (50), Mexico (43), Belgium (42), Israel (41), Sweden (30),
Austria (27), Greece (24), Denmark (18), Czech Republic and
Hungary (17 each), Canada (12), Ireland (11), Slovakia (9), Latvia
and United Arab Emirates (6 each); the remaining 36 cases were
distributed among 16 other different countries;
• Subjects’ age group (n= 1880): Adult (1315), Elderly (560),
Infanth and Adolescent (2 each), Child (1);

non-serious;
• Most frequently reported relevant PTs (>1 occurrence): COVID-
19 (1927), SARS-CoV-2 test positive (415), Suspected COVID-19
(270), Ageusia (228), Anosmia (194), SARS-CoV-2 antibody test
negative (83), Exposure to SARS-CoV-2 (62), SARS-CoV-2
antibody test positive (53), COVID-19 pneumonia (51),
Asymptomatic COVID-19 (31), Coronavirus infection (13),
Occupational exposure to SARS-CoV-2 (11), SARS-CoV-2 test
false positive (7), Coronavirus test positive (6), SARS-CoV-2 test
negative (3) SARS-CoV-2 antibody test (2);
374 days, median 5 days;
• Relevant event outcome: fatal (136), not resolved (547),
resolved/resolving (558), resolved with sequelae (9) and unknown
(2110).
Dermatological AESIs • Number of cases: 20 cases (0.05% of the total PM dataset), of
Search criteria: PT Chillblains; which 15 are medically confirmed and 5 are non-medically
Erythema multiforme confirmed;
• Country of incidence: UK (8), France and Poland (2 each), and the
remaining 8 cases were distributed among 8 other different
countries;
• Subjects’ gender: female (17) male and unknown (1 each);
• Subjects’ age group (n=19): Adult (18), Elderly (1);
• Number of relevant events: 20 events, 16 serious, 4 non-serious
CONFIDENTIAL
Page 17
AR10037
BNT162b2

• Reported relevant PTs: Erythema multiforme (13) and Chillblains
(7)
• Relevant event onset latency (n = 18): Range from <24 hours to 17
days, median 3 days;
• Relevant event outcome: resolved/resolving (7), not resolved (8)
and unknown (6).
issues. Surveillance will continue.
Haematological AESIs • Number of cases: 932 (2.2 % of the total PM dataset), of which
Search criteria: Leukopenias NEC 524 medically confirmed and 408 non-medically confirmed;
(HLT) (Primary Path) OR • Country of incidence: UK (343), US (308), France (50), Germany
Neutropenias (HLT) (Primary (43), Italy (37), Spain (27), Mexico and Poland (13 each),
Path) OR PTs Immune Sweden (10), Israel (9), Netherlands (8), Denmark, Finland,
thrombocytopenia, Portugal and Ireland (7 each), Austria and Norway (6 each),
Thrombocytopenia OR SMQ Croatia (4), Greece, Belgium, Hungary and Switzerland (3 each),
Haemorrhage terms (excl Cyprus, Latvia and Serbia (2 each); the remaining 9 cases
laboratory terms originated from 9 different countries;
• Subjects’ gender (n=898): female (676) and male (222);
• Subjects’ age group (n=837): Adult (543), Elderly (293), Infant

(1);
non-serious;
• Most frequently reported relevant PTs (≥15 occurrences) include:
Epistaxis (127), Contusion (112), Vaccination site bruising (96),
Vaccination site haemorrhage (51), Petechiae (50), Haemorrhage
(42), Haematochezia (34), Thrombocytopenia (33), Vaccination
site haematoma (32), Conjunctival haemorrhage and Vaginal
haemorrhage (29 each), Haematoma, Haemoptysis and
Menorrhagia (27 each), Haematemesis (25), Eye haemorrhage
(23), Rectal haemorrhage (22), Immune thrombocytopenia (20),
Blood urine present (19), Haematuria, Neutropenia and Purpura
(16 each) Diarrhoea haemorrhagic (15);
33 days, median = 1 day;
• Relevant event outcome: fatal (34), resolved/resolving (393),
(371).
Hepatic AESIs • Number of cases: 70 cases (0.2% of the total PM dataset), of
Search criteria: Liver related which 54 medically confirmed and 16 non-medically confirmed;
investigations, signs and symptoms • Country of incidence: UK (19), US (14), France (7), Italy (5),
(SMQ) (Narrow and Broad) OR Germany (4), Belgium, Mexico and Spain (3 each), Austria, and
PT Liver injury Iceland (2 each); the remaining 8 cases originated from 8 different
countries;
CONFIDENTIAL
Page 18
AR10038
BNT162b2

non-serious;
• Most frequently reported relevant PTs (≥3 occurrences) include:
Alanine aminotransferase increased (16), Transaminases increased
and Hepatic pain (9 each), Liver function test increased (8),
Aspartate aminotransferase increased and Liver function test
abnormal (7 each), Gamma-glutamyltransferase increased and
Hepatic enzyme increased (6 each), Blood alkaline phosphatase
increased and Liver injury (5 each), Ascites, Blood bilirubin
increased and Hypertransaminasaemia (3 each);
resolved with sequelae (1), not resolved (14) and unknown (47).
Facial Paralysis • Number of cases: 449i (1.07% of the total PM dataset), 314
Search criteria: PTs Facial medically confirmed and 135 non-medically confirmed;
paralysis, Facial paresis • Country of incidence: US (124), UK (119), Italy (40), France (27),
Israel (20), Spain (18), Germany (13), Sweden (11), Ireland (9),
Cyprus (8), Austria (7), Finland and Portugal (6 each), Hungary
and Romania (5 each), Croatia and Mexico (4 each), Canada
(3),Czech Republic, Malta, Netherlands, Norway, Poland and
Puerto Rico (2 each); the remaining 8 cases originated from 8
different countries;
• Subjects’ gender: female (295), male (133), unknown (21);
• Subjects’ age group (n=411): Adult (313), Elderly (96), Infantj
and Child (1 each);
• Number of relevant eventsk: 453, of which 399 serious, 54
non-serious;
• Reported relevant PTs: Facial paralysis (401), Facial paresis (64);
• Relevant event outcome: resolved/resolving (184), resolved with
sequelae (3), not resolved (183) and unknown (97);
Overall Conclusion: This cumulative case review does not raise new
safety issues. Surveillance will continue. Causality assessment will be
further evaluated following availability of additional unblinded data
from the clinical study C4591001, which will be unblinded for final
analysis approximately mid-April 2021. Additionally, non-
interventional post-authorisation safety studies, C4591011 and
C4591012 are expected to capture data on a sufficiently large
vaccinated population to detect an increased risk of Bell’s palsy in
vaccinated individuals. The timeline for conducting these analyses will
be established based on the size of the vaccinated population captured
in the study data sources by the first interim reports (due 30 June
CONFIDENTIAL
Page 19
AR10039
BNT162b2

2021). Study C4591021, pending protocol endorsement by EMA, is
also intended to inform this risk.
Immune-Mediated/Autoimmune • Number of cases: 1050 (2.5 % of the total PM dataset), of which
AESIs 760 medically confirmed and 290 non-medically confirmed;
Search criteria: Immune- • Country of incidence (>10 cases): UK (267), US (257), Italy (70),
mediated/autoimmune disorders France and Germany (69 each), Mexico (36), Sweden (35), Spain
(SMQ) (Broad and Narrow) OR (32), Greece (31), Israel (21), Denmark (18), Portugal (17),
Autoimmune disorders HLGT Austria and Czech Republic (16 each), Canada (12), Finland (10).
(Primary Path) OR PTs Cytokine The remaining 74 cases were from 24 different countries.
release syndrome; Cytokine storm; • Subjects’ gender (n=682): female (526), male (156).
Hypersensitivity • Subjects’ age group (n=944): Adult (746), Elderly (196),
Adolescent (2).
non‑serious.
• Most frequently reported relevant PTs (>10 occurrences):
Hypersensitivity (596), Neuropathy peripheral (49), Pericarditis
(32), Myocarditis (25), Dermatitis (24), Diabetes mellitus and
Encephalitis (16 each), Psoriasis (14), Dermatitis Bullous (13),
Autoimmune disorder and Raynaud’s phenomenon (11 each);

30 days, median <24 hours.
• Relevant event outcomel: resolved/resolving (517), not resolved
(215), fatal (12), resolved with sequelae (22) and unknown (312).
Musculoskeletal AESIs • Number of cases: 3600 (8.5% of the total PM dataset), of which
Search criteria: PTs Arthralgia; 2045 medically confirmed and 1555 non-medically confirmed;
Arthritis; Arthritis bacterialn; • Country of incidence: UK (1406), US (1004), Italy (285), Mexico
Chronic fatigue syndrome; (236), Germany (72), Portugal (70), France (48), Greece and
Polyarthritis; Polyneuropathy; Poland (46), Latvia (33), Czech Republic (32), Israel and Spain
Post viral fatigue syndrome; (26), Sweden (25), Romania (24), Denmark (23), Finland and
Rheumatoid arthritis Ireland (19 each), Austria and Belgium (18 each), Canada (16),
Netherlands (14), Bulgaria (12), Croatia and Serbia (9 each),
Cyprus and Hungary (8 each), Norway (7), Estonia and Puerto
Rico (6 each), Iceland and Lithuania (4 each); the remaining 21
cases originated from 11 different countries;
• Subjects’ gender (n=3471): female (2760), male (711);
• Subjects’ age group (n=3372): Adult (2850), Elderly (515), Child
(4), Adolescent (2), Infant (1);
non-serious;
• Reported relevant PTs: Arthralgia (3525), Arthritis (70),
Rheumatoid arthritis (26), Polyarthritis (5), Polyneuropathy, Post
viral fatigue syndrome, Chronic fatigue syndrome (4 each),
Arthritis bacterial (1);
32 days, median 1 day;
CONFIDENTIAL
Page 20
AR10040
BNT162b2

• Relevant event outcome: resolved/resolving (1801), not resolved
(959), resolved with sequelae (49), and unknown (853).
Neurological AESIs (including • Number of cases: 501 (1.2% of the total PM dataset), of which
demyelination) 365 medically confirmed and 136 non-medically confirmed.
Search criteria: Convulsions • Country of incidence (≥9 cases): UK (157), US (68), Germany
(SMQ) (Broad and Narrow) OR (49), Mexico (35), Italy (31), France (25), Spain (18), Poland (17),
Demyelination (SMQ) (Broad and Netherlands and Israel (15 each), Sweden (9). The remaining 71
Narrow) OR PTs Ataxia; cases were from 22 different countries.
Cataplexy; Encephalopathy; • Subjects’ gender (n=478): female (328), male (150).
Fibromyalgia; Intracranial • Subjects’ age group (n=478): Adult (329), Elderly (149);
pressure increased; Meningitis; • Number of relevant events: 542, of which 515 serious, 27
Meningitis aseptic; Narcolepsy non‑serious.
• Most frequently reported relevant PTs (˃2 occurrences) included:
Seizure (204), Epilepsy (83), Generalised tonic-clonic seizure
(33), Guillain-Barre syndrome (24), Fibromyalgia and Trigeminal
neuralgia (17 each), Febrile convulsion, (15), Status epilepticus
(12), Aura and Myelitis transverse (11 each), Multiple sclerosis

relapse and Optic neuritis (10 each), Petit mal epilepsy and Tonic
convulsion (9 each), Ataxia (8), Encephalopathy and Tonic clonic
movements (7 each), Foaming at mouth (5), Multiple sclerosis,
Narcolepsy and Partial seizures (4 each), Bad sensation,
Demyelination, Meningitis, Postictal state, Seizure like
phenomena and Tongue biting (3 each);
• Relevant events outcome: fatal (16), resolved/resolving (265),
resolved with sequelae (13), not resolved (89) and unknown (161);
Other AESIs • Number of cases: 8152 (19.4% of the total PM dataset), of which
Search criteria: Herpes viral 4977 were medically confirmed and 3175 non-medically
infections (HLT) (Primary Path) confirmed;
OR PTs Adverse event following • Country of incidence (> 20 occurrences): UK (2715), US (2421),
immunisation; Inflammation; Italy (710), Mexico (223), Portugal (210), Germany (207), France
Manufacturing laboratory (186), Spain (183), Sweden (133), Denmark (127), Poland (120),
analytical testing issue; Greece (95), Israel (79), Czech Republic (76), Romania (57),
Manufacturing materials issue; Hungary (53), Finland (52), Norway (51), Latvia (49), Austria
Manufacturing production issue; (47), Croatia (42), Belgium (41), Canada (39), Ireland (34), Serbia
MERS-CoV test; MERS-CoV test (28), Iceland (25), Netherlands (22). The remaining 127 cases
negative; MERS-CoV test positive; were from 21 different countries;
Middle East respiratory syndrome; • Subjects’ gender (n=7829): female (5969), male (1860);
Multiple organ dysfunction • Subjects’ age group (n=7479): Adult (6330), Elderly (1125),
syndrome; Occupational exposure Adolescent, Child (9 each), Infant (6);
to communicable disease; Patient
CONFIDENTIAL
Page 21
AR10041
BNT162b2

isolation; Product availability • Number of relevant events: 8241, of which 3674 serious, 4568
issue; Product distribution issue; non‑serious;
Product supply issue; Pyrexia; • Most frequently reported relevant PTs (≥6 occurrences) included:
Quarantine; SARS-CoV-1 test; Pyrexia (7666), Herpes zoster (259), Inflammation (132), Oral
SARS-CoV-1 test negative; SARS- herpes (80), Multiple organ dysfunction syndrome (18), Herpes
CoV-1 test positive virus infection (17), Herpes simplex (13), Ophthalmic herpes
zoster (10), Herpes ophthalmic and Herpes zoster reactivation (6
each);
• Relevant event onset latency (n =6836): Range from <24 hours to
• Relevant events outcome: fatal (96), resolved/resolving (5008),
(1685).
Pregnancy Related AESIs For relevant cases, please refer to Table 6, Description of Missing
Search criteria: PTs Amniotic Information, Use in Pregnancy and While Breast Feeding
cavity infection; Caesarean
section; Congenital anomaly;

Death neonatal; Eclampsia;
Foetal distress syndrome; Low
birth weight baby; Maternal
exposure during pregnancy;
Placenta praevia; Pre-eclampsia;
Premature labour; Stillbirth;
Uterine rupture; Vasa praevia
Renal AESIs • Number of cases: 69 cases (0.17% of the total PM dataset), of
Search criteria: PTs Acute kidney which 57 medically confirmed, 12 non-medically confirmed;
injury; Renal failure. • Country of incidence: Germany (17), France and UK (13 each),
US (6), Belgium, Italy and Spain (4 each), Sweden (2), Austria,
Canada, Denmark, Finland, Luxembourg and Norway (1 each);
• Subjects’ gender: female (46), male (23);
• Subjects’ age group (n=68): Adult (7), Elderly (60), Infant (1);
• Number of relevant events: 70, all serious;
• Reported relevant PTs: Acute kidney injury (40) and Renal failure
(30);
• Relevant event outcome: fatal (23), resolved/resolving (10), not
resolved (15) and unknown (22).
Respiratory AESIs • Number of cases: 130 cases (0.3% of the total PM dataset), of
Search criteria: Lower respiratory which 107 medically confirmed;
tract infections NEC (HLT)
CONFIDENTIAL
Page 22
AR10042
BNT162b2

(Primary Path) OR Respiratory • Countries of incidence: United Kingdom (20), France (18), United
failures (excl neonatal) (HLT) States (16), Germany (14), Spain (13), Belgium and Italy (9),
(Primary Path) OR Viral lower Denmark (8), Norway (5), Czech Republic, Iceland (3 each); the
respiratory tract infections (HLT) remaining 12 cases originated from 8 different countries.
(Primary Path) OR PTs: Acute • Subjects’ gender (n=130): female (72), male (58).
respiratory distress syndrome; • Subjects’s age group (n=126): Elderly (78), Adult (47),
Endotracheal intubation; Hypoxia; Adolescent (1).
Pulmonary haemorrhage; • Number of relevant events: 137, of which 126 serious, 11
Respiratory disorder; Severe acute non-serious;
respiratory syndrome • Reported relevant PTs: Respiratory failure (44), Hypoxia (42),
Respiratory disorder (36), Acute respiratory distress syndrome
(10), Chronic respiratory syndrome (3), Severe acute respiratory
syndrome (2).
• Relevant event onset latency (n=102): range from < 24 hours to 18
days, median 1 day;
• Relevant events outcome: fatal (41), Resolved/resolving (47), not
recovered (18) and unknown (31).
Thromboembolic Events • Number of cases: 151 (0.3% of the total PM dataset), of which
Search criteria: Embolism and 111 medically confirmed and 40 non-medically confirmed;
thrombosis (HLGT) (Primary • Country of incidence: UK (34), US (31), France (20), Germany
Path), excluding PTs reviewed as (15), Italy and Spain (6 each), Denmark and Sweden (5 each),
Stroke AESIs, OR PTs Deep vein Austria, Belgium and Israel (3 each), Canada, Cyprus, Netherlands
thrombosis; Disseminated and Portugal (2 each); the remaining 12 cases originated from 12
intravascular coagulation; different countries;
Embolism; Embolism venous; • Subjects’ gender (n= 144): female (89), male (55);
Pulmonary embolism • Subjects’ age group (n=136): Adult (66), Elderly (70);
non-serious;
• Most frequently reported relevant PTs (>1 occurrence) included:
Pulmonary embolism (60), Thrombosis (39), Deep vein
thrombosis (35), Thrombophlebitis superficial (6), Venous
thrombosis limb (4), Embolism, Microembolism,
Thrombophlebitis and Venous thrombosis (3 each) Blue toe
syndrome (2);
Stroke • Number of cases: 275 (0.6% of the total PM dataset), of which
Search criteria: HLT Central 180 medically confirmed and 95 non-medically confirmed;
nervous system haemorrhages and • Country of incidence: UK (81), US (66), France (32), Germany
cerebrovascular accidents (21), Norway (14), Netherlands and Spain (11 each), Sweden (9),
CONFIDENTIAL
Page 23
AR10043
BNT162b2

(Primary Path) OR HLT Israel (6), Italy (5), Belgium (3), Denmark, Finland, Poland and
Cerebrovascular venous and sinus Switzerland (2 each); the remaining 8 cases originated from 8
thrombosis (Primary Path) different countries;
• Subjects’ gender (n= 273): female (182), male (91);
• Subjects’ age group (n=265): Adult (59), Elderly (205), Childm
(1);
• Number of relevant events: 300, all serious;
• Most frequently reported relevant PTs (>1 occurrence) included:
o PTs indicative of Ischaemic stroke: Cerebrovascular
accident (160), Ischaemic stroke (41), Cerebral infarction
(15), Cerebral ischaemia, Cerebral thrombosis, Cerebral
venous sinus thrombosis, Ischaemic cerebral infarction
and Lacunal infarction (3 each) Basal ganglia stroke,
Cerebellar infarction and Thrombotic stroke (2 each);
o PTs indicative of Haemorrhagic stroke: Cerebral
haemorrhage (26), Haemorrhagic stroke (11),
Haemorrhage intracranical and Subarachnoid
haemorrhage (5 each), Cerebral haematoma (4), Basal
ganglia haemorrhage and Cerebellar haemorrhage (2
each);

• Relevant event outcome: fatal and resolved/resolving (61 each),
Vasculitic Events • Number of cases: 32 cases (0.08% of the total PM dataset), of
Search criteria: Vasculitides HLT which 26 medically confirmed and 6 non-medically confirmed;
• Country of incidence: UK (13), France (4), Portugal, US and
Spain (3 each), Cyprus, Germany, Hungary, Italy and Slovakia
and Costa rica (1 each);
• Subjects’ gender: female (26), male (6);
• Number of relevant events: 34, of which 25 serious, 9 non-serious;
• Reported relevant PTs: Vasculitis (14), Cutaneous vasculitis and
Vasculitic rash (4 each), (3), Giant cell arteritis and Peripheral
ischaemia (3 each), Behcet’s syndrome and Hypersensitivity
vasculitis (2 each) Palpable purpura, and Takayasu’s arteritis (1
each);
• Relevant event outcome: fatal (1), resolved/resolving (13), not
resolved (12) and unknown (8).
CONFIDENTIAL
Page 24
AR10044
BNT162b2

a. For the complete list of the AESIs, please refer to Appendix 5;
b. Please note that this corresponds to evidence from post-EUA/conditional marketing authorisation
approval data sources;
c. Subjects with age ranged between 18 and 64 years;
d. Subjects with age equal to or above 65 years;
e. Subjects with age ranged between 2 and 11 years;
f. Subjects with age ranged between 12 and less than 18 years;
g. Multiple episodes of the same PT event were reported with a different clinical outcome within some
cases hence the sum of the events outcome exceeds the total number of PT events;
h. Subjects with age ranged between 1 (28 days) and 23 months;
i. Twenty-four additional cases were excluded from the analysis as they were not cases of peripheral facial
nerve palsy because they described other disorders (stroke, cerebral haemorrhage or transient ischaemic
attack); 1 case was excluded from the analysis because it was invalid due to an unidentifiable reporter;
j. This UK case report received from the UK MHRA described a 1-year-old subject who received the
vaccine, and had left postauricular ear pain that progressed to left-sided Bell’s palsy 1 day following
vaccination that had not resolved at the time of the report;
k. If a case included both PT Facial paresis and PT Facial paralysis, only the PT Facial paralysis was
considered in the descriptions of the events as it is most clinically important;
l. Multiple episodes of the same PT event were reported with a different clinical outcome within some
cases hence the sum of the events outcome exceeds the total number of PT events
m. This UK case report received from the UK MHRA described a 7-year-old female subject who received
the vaccine and had stroke (unknown outcome); no follow-up is possible for clarification.
n. This PT not included in the AESIs/TME list was included in the review as relevant for ACCESS
protocol criteria;
CONFIDENTIAL
Page 25
AR10045
BNT162b2
3.1.4. Medication error

Cases potentially indicative of medication errors1 that cumulatively occurred are summarized
below.
• Number of relevant medication error cases: 20562 (4.9%) of which 1569 (3.7%) are
medically confirmed.
• Number of relevant events: 2792
• Top 10 countries of incidence:
− US (1201), France (171), UK (138), Germany (88), Czech Republic (87), Sweden
(49), Israel (45), Italy (42), Canada (35), Romania (33), Finland (21), Portugal (20),
Norway (14), Puerto Rico (13), Poland (12), Austria and Spain (10 each).
Medication error case outcomes:
• Fatal (7)3,
• Recovered/recovering (354, of which 4 are serious),

• Recovered with sequelae (8, of which 3 serious)
1
MedDRA (version 23.1) Higher Level Terms: Accidental exposures to product; Product administration
errors and issues; Product confusion errors and issues; Product dispensing errors and issues; Product label
issues; Product monitoring errors and issues; Product preparation errors and issues; Product selection errors and
issues; Product storage errors and issues in the product use system; Product transcribing errors and
communication issues, OR Preferred Terms: Accidental poisoning; Circumstance or information capable of
leading to device use error; Circumstance or information capable of leading to medication error;
Contraindicated device used; Deprescribing error; Device use error; Dose calculation error; Drug titration error;
Expired device used; Exposure via direct contact; Exposure via eye contact; Exposure via mucosa; Exposure via
skin contact; Failure of child resistant product closure; Inadequate aseptic technique in use of product; Incorrect
disposal of product; Intercepted medication error; Intercepted product prescribing error; Medication error;
Multiple use of single-use product; Product advertising issue; Product distribution issue; Product prescribing
error; Product prescribing issue; Product substitution error; Product temperature excursion issue; Product use in
unapproved therapeutic environment; Radiation underdose; Underdose; Unintentional medical device removal;
Unintentional use for unapproved indication; Vaccination error; Wrong device used; Wrong dosage form;
Wrong dosage formulation; Wrong dose; Wrong drug; Wrong patient; Wrong product procured; Wrong product
stored; Wrong rate; Wrong route; Wrong schedule; Wrong strength; Wrong technique in device usage process;
Wrong technique in product usage process.
2
Thirty-five (35) cases were exclude from the analysis because describing medication errors occurring in
an unspecified number of individuals or describing medication errors occurring with co suspects were
determined to be non-contributory.
3
All the medication errors reported in these cases were assessed as non-serious occurrences with an
unknown outcome; based on the available information including the causes of death, the relationship between
the medication error and the death is weak. .
CONFIDENTIAL
Page 26
AR10046
BNT162b2
• Not recovered (189, of which 84 are serious),
• Unknown (1498, of which 33 are serious).
1371 cases reported only MEs without any associated clinical adverse event. The PTs most
frequently reported (≥12 occurrences) were: Poor quality product administered (539),
Product temperature excursion issue (253), Inappropriate schedule of product administration
(225), Product preparation error (206), Underdose (202), Circumstance or information
capable of leading to medication error (120), Product preparation issue (119), Wrong
technique in product usage process (76), Incorrect route of product administration (66),
Accidental overdose (33), Product administered at inappropriate site (27), Incorrect dose
administered and Accidental exposure to the product (25 each), Exposure via skin contact
(22), Wrong product administered (17), Incomplete course of vaccination, and Product
administration error (14 each) Product administered to patient of inappropriate age (12).
In 685 cases, there were co-reported AEs. The most frequently co- associated AEs (˃ 40
occurrences) were: Headache (187), Pyrexia (161), Fatigue (135), Chills (127), Pain (107),
Vaccination site pain (100), Nausea (89), Myalgia (88), Pain in extremity (85) Arthralgia
(68), Off label use (57), Dizziness (52), Lymphadenopathy (47), Asthenia (46) and Malaise
(41). These cases are summarized in Table 8.
Table 8. ME PTs by seriousness with or without harm co-association (Through 28

February 2021)
Serious Non-Serious
ME PTs With Harm Without Harm With Harm Without Harm
Accidental exposure to 0 0 0 5
product
Accidental overdose 4 1 9 6
Booster dose missed 0 0 0 1
Circumstance or information 0 0 5 11
capable of leading to
medication error
Contraindicated product 1 0 0 2
administered
Expired product administered 0 0 0 2
Exposure via skin contact 0 0 0 5
Inappropriate schedule of 0 2 8 264

product administration
Incorrect dose administered 1 1 0 0
CONFIDENTIAL
Page 27
AR10047
BNT162b2
Table 8. ME PTs by seriousness with or without harm co-association (Through 28

February 2021)
Serious Non-Serious
ME PTs With Harm Without Harm With Harm Without Harm
Incorrect route of product 2 6 16 127

administration
Lack of vaccination site 1 0 0 0

rotation
Medication error 0 0 0 1
Poor quality product 1 0 0 34

administered
Product administered at 2 1 13 29
inappropriate site
Product administered to 0 4 0 40
patient of inappropriate age
Product administration error 1 0 0 3

Product dose omission issue 0 1 0 3
Product preparation error 1 0 4 11
Product preparation issue 1 1 0 14
Overall, there were 68 cases with co-reported AEs reporting Harm and 599 cases with co-
reported AEs without harm. Additionally, Intercepted medication errors was reported in 1
case (PTs Malaise, clinical outcome unknow) and Potential medication errors were reported
in 17 cases.
4. DISCUSSION
Pfizer performs frequent and rigorous signal detection on BNT162b2 cases. The findings of
these signal detection analyses are consistent with the known safety profile of the vaccine.
This cumulative analysis to support the Biologics License Application for BNT162b2, is an
integrated analysis of post-authorization safety data, from U.S. and foreign experience,
focused on Important Identified Risks, Important Potential Risks, and areas of Important
Missing Information identified in the Pharmacovigilance Plan, as well as adverse events of
special interest and vaccine administration errors (whether or not associated with an adverse
event). The data do not reveal any novel safety concerns or risks requiring label changes and
support a favorable benefit risk profile of to the BNT162b2 vaccine.
CONFIDENTIAL
Page 28
AR10048
BNT162b2
5. SUMMARY AND CONCLUSION

Review of the available data for this cumulative PM experience, confirms a favorable
benefit: risk balance for BNT162b2.
Pfizer will continue routine pharmacovigilance activities on behalf of BioNTech according to

the Pharmacovigilance Agreement in place, in order to assure patient safety and will inform
the Agency if an evaluation of the safety data yields significant new information for
BNT162b2.
CONFIDENTIAL
Page 29
AR10049
BNT162b2
APPENDIX 1. LIST OF ADVERSE EVENTS OF SPECIAL INTEREST

1p36 deletion syndrome;2-Hydroxyglutaric aciduria;5'nucleotidase increased;Acoustic
neuritis;Acquired C1 inhibitor deficiency;Acquired epidermolysis bullosa;Acquired epileptic
aphasia;Acute cutaneous lupus erythematosus;Acute disseminated encephalomyelitis;Acute
encephalitis with refractory, repetitive partial seizures;Acute febrile neutrophilic
dermatosis;Acute flaccid myelitis;Acute haemorrhagic leukoencephalitis;Acute
haemorrhagic oedema of infancy;Acute kidney injury;Acute macular outer retinopathy;Acute
motor axonal neuropathy;Acute motor-sensory axonal neuropathy;Acute myocardial
infarction;Acute respiratory distress syndrome;Acute respiratory failure;Addison's
disease;Administration site thrombosis;Administration site vasculitis;Adrenal
thrombosis;Adverse event following immunisation;Ageusia;Agranulocytosis;Air
embolism;Alanine aminotransferase abnormal;Alanine aminotransferase increased;Alcoholic
seizure;Allergic bronchopulmonary mycosis;Allergic oedema;Alloimmune
hepatitis;Alopecia areata;Alpers disease;Alveolar proteinosis;Ammonia abnormal;Ammonia
increased;Amniotic cavity infection;Amygdalohippocampectomy;Amyloid
arthropathy;Amyloidosis;Amyloidosis senile;Anaphylactic reaction;Anaphylactic
shock;Anaphylactic transfusion reaction;Anaphylactoid reaction;Anaphylactoid
shock;Anaphylactoid syndrome of pregnancy;Angioedema;Angiopathic
neuropathy;Ankylosing spondylitis;Anosmia;Antiacetylcholine receptor antibody
positive;Anti-actin antibody positive;Anti-aquaporin-4 antibody positive;Anti-basal ganglia
antibody positive;Anti-cyclic citrullinated peptide antibody positive;Anti-epithelial antibody

positive;Anti-erythrocyte antibody positive;Anti-exosome complex antibody positive;Anti-
GAD antibody negative;Anti-GAD antibody positive;Anti-ganglioside antibody
positive;Antigliadin antibody positive;Anti-glomerular basement membrane antibody
positive;Anti-glomerular basement membrane disease;Anti-glycyl-tRNA synthetase antibody
positive;Anti-HLA antibody test positive;Anti-IA2 antibody positive;Anti-insulin antibody
increased;Anti-insulin antibody positive;Anti-insulin receptor antibody increased;Anti-
insulin receptor antibody positive;Anti-interferon antibody negative;Anti-interferon antibody
positive;Anti-islet cell antibody positive;Antimitochondrial antibody positive;Anti-muscle
specific kinase antibody positive;Anti-myelin-associated glycoprotein antibodies
positive;Anti-myelin-associated glycoprotein associated polyneuropathy;Antimyocardial
antibody positive;Anti-neuronal antibody positive;Antineutrophil cytoplasmic antibody
increased;Antineutrophil cytoplasmic antibody positive;Anti-neutrophil cytoplasmic
antibody positive vasculitis;Anti-NMDA antibody positive;Antinuclear antibody
increased;Antinuclear antibody positive;Antiphospholipid antibodies
positive;Antiphospholipid syndrome;Anti-platelet antibody positive;Anti-prothrombin
antibody positive;Antiribosomal P antibody positive;Anti-RNA polymerase III antibody
positive;Anti-saccharomyces cerevisiae antibody test positive;Anti-sperm antibody
positive;Anti-SRP antibody positive;Antisynthetase syndrome;Anti-thyroid antibody
positive;Anti-transglutaminase antibody increased;Anti-VGCC antibody positive;Anti-
VGKC antibody positive;Anti-vimentin antibody positive;Antiviral prophylaxis;Antiviral
treatment;Anti-zinc transporter 8 antibody positive;Aortic embolus;Aortic
thrombosis;Aortitis;Aplasia pure red cell;Aplastic anaemia;Application site
thrombosis;Application site vasculitis;Arrhythmia;Arterial bypass occlusion;Arterial bypass
thrombosis;Arterial thrombosis;Arteriovenous fistula thrombosis;Arteriovenous graft site
stenosis;Arteriovenous graft thrombosis;Arteritis;Arteritis
CONFIDENTIAL
Page 1
Page 30
AR10050
BNT162b2
coronary;Arthralgia;Arthritis;Arthritis enteropathic;Ascites;Aseptic cavernous sinus

thrombosis;Aspartate aminotransferase abnormal;Aspartate aminotransferase
increased;Aspartate-glutamate-transporter deficiency;AST to platelet ratio index
increased;AST/ALT ratio abnormal;Asthma;Asymptomatic COVID-
19;Ataxia;Atheroembolism;Atonic seizures;Atrial thrombosis;Atrophic thyroiditis;Atypical
benign partial epilepsy;Atypical pneumonia;Aura;Autoantibody positive;Autoimmune
anaemia;Autoimmune aplastic anaemia;Autoimmune arthritis;Autoimmune blistering
disease;Autoimmune cholangitis;Autoimmune colitis;Autoimmune demyelinating
disease;Autoimmune dermatitis;Autoimmune disorder;Autoimmune
encephalopathy;Autoimmune endocrine disorder;Autoimmune enteropathy;Autoimmune eye
disorder;Autoimmune haemolytic anaemia;Autoimmune heparin-induced
thrombocytopenia;Autoimmune hepatitis;Autoimmune hyperlipidaemia;Autoimmune
hypothyroidism;Autoimmune inner ear disease;Autoimmune lung disease;Autoimmune
lymphoproliferative syndrome;Autoimmune myocarditis;Autoimmune myositis;Autoimmune
nephritis;Autoimmune neuropathy;Autoimmune neutropenia;Autoimmune
pancreatitis;Autoimmune pancytopenia;Autoimmune pericarditis;Autoimmune
retinopathy;Autoimmune thyroid disorder;Autoimmune thyroiditis;Autoimmune
uveitis;Autoinflammation with infantile enterocolitis;Autoinflammatory disease;Automatism
epileptic;Autonomic nervous system imbalance;Autonomic seizure;Axial
spondyloarthritis;Axillary vein thrombosis;Axonal and demyelinating
polyneuropathy;Axonal neuropathy;Bacterascites;Baltic myoclonic epilepsy;Band
sensation;Basedow's disease;Basilar artery thrombosis;Basophilopenia;B-cell

aplasia;Behcet's syndrome;Benign ethnic neutropenia;Benign familial neonatal
convulsions;Benign familial pemphigus;Benign rolandic epilepsy;Beta-2 glycoprotein
antibody positive;Bickerstaff's encephalitis;Bile output abnormal;Bile output
decreased;Biliary ascites;Bilirubin conjugated abnormal;Bilirubin conjugated
increased;Bilirubin urine present;Biopsy liver abnormal;Biotinidase deficiency;Birdshot
chorioretinopathy;Blood alkaline phosphatase abnormal;Blood alkaline phosphatase
increased;Blood bilirubin abnormal;Blood bilirubin increased;Blood bilirubin unconjugated
increased;Blood cholinesterase abnormal;Blood cholinesterase decreased;Blood pressure
decreased;Blood pressure diastolic decreased;Blood pressure systolic decreased;Blue toe
syndrome;Brachiocephalic vein thrombosis;Brain stem embolism;Brain stem
thrombosis;Bromosulphthalein test abnormal;Bronchial oedema;Bronchitis;Bronchitis
mycoplasmal;Bronchitis viral;Bronchopulmonary aspergillosis allergic;Bronchospasm;Budd-
Chiari syndrome;Bulbar palsy;Butterfly rash;C1q nephropathy;Caesarean section;Calcium
embolism;Capillaritis;Caplan's syndrome;Cardiac amyloidosis;Cardiac arrest;Cardiac
failure;Cardiac failure acute;Cardiac sarcoidosis;Cardiac ventricular thrombosis;Cardiogenic
shock;Cardiolipin antibody positive;Cardiopulmonary failure;Cardio-respiratory
arrest;Cardio-respiratory distress;Cardiovascular insufficiency;Carotid arterial
embolus;Carotid artery thrombosis;Cataplexy;Catheter site thrombosis;Catheter site
vasculitis;Cavernous sinus thrombosis;CDKL5 deficiency disorder;CEC syndrome;Cement
embolism;Central nervous system lupus;Central nervous system vasculitis;Cerebellar artery
thrombosis;Cerebellar embolism;Cerebral amyloid angiopathy;Cerebral arteritis;Cerebral
artery embolism;Cerebral artery thrombosis;Cerebral gas embolism;Cerebral
microembolism;Cerebral septic infarct;Cerebral thrombosis;Cerebral venous sinus
thrombosis;Cerebral venous thrombosis;Cerebrospinal thrombotic
CONFIDENTIAL
Page 2
Page 31
AR10051
BNT162b2
tamponade;Cerebrovascular accident;Change in seizure presentation;Chest discomfort;Child-

Pugh-Turcotte score abnormal;Child-Pugh-Turcotte score
increased;Chillblains;Choking;Choking sensation;Cholangitis sclerosing;Chronic
autoimmune glomerulonephritis;Chronic cutaneous lupus erythematosus;Chronic fatigue
syndrome;Chronic gastritis;Chronic inflammatory demyelinating
polyradiculoneuropathy;Chronic lymphocytic inflammation with pontine perivascular
enhancement responsive to steroids;Chronic recurrent multifocal osteomyelitis;Chronic
respiratory failure;Chronic spontaneous urticaria;Circulatory collapse;Circumoral
oedema;Circumoral swelling;Clinically isolated syndrome;Clonic convulsion;Coeliac
disease;Cogan's syndrome;Cold agglutinins positive;Cold type haemolytic
anaemia;Colitis;Colitis erosive;Colitis herpes;Colitis microscopic;Colitis ulcerative;Collagen
disorder;Collagen-vascular disease;Complement factor abnormal;Complement factor C1
decreased;Complement factor C2 decreased;Complement factor C3 decreased;Complement
factor C4 decreased;Complement factor decreased;Computerised tomogram liver
abnormal;Concentric sclerosis;Congenital anomaly;Congenital bilateral perisylvian
syndrome;Congenital herpes simplex infection;Congenital myasthenic syndrome;Congenital
varicella infection;Congestive hepatopathy;Convulsion in childhood;Convulsions
local;Convulsive threshold lowered;Coombs positive haemolytic anaemia;Coronary artery
disease;Coronary artery embolism;Coronary artery thrombosis;Coronary bypass
thrombosis;Coronavirus infection;Coronavirus test;Coronavirus test negative;Coronavirus
test positive;Corpus callosotomy;Cough;Cough variant asthma;COVID-19;COVID-19
immunisation;COVID-19 pneumonia;COVID-19 prophylaxis;COVID-19 treatment;Cranial

nerve disorder;Cranial nerve palsies multiple;Cranial nerve paralysis;CREST
syndrome;Crohn's disease;Cryofibrinogenaemia;Cryoglobulinaemia;CSF oligoclonal band
present;CSWS syndrome;Cutaneous amyloidosis;Cutaneous lupus erythematosus;Cutaneous
sarcoidosis;Cutaneous vasculitis;Cyanosis;Cyclic neutropenia;Cystitis interstitial;Cytokine
release syndrome;Cytokine storm;De novo purine synthesis inhibitors associated acute
inflammatory syndrome;Death neonatal;Deep vein thrombosis;Deep vein thrombosis
postoperative;Deficiency of bile secretion;Deja vu;Demyelinating
polyneuropathy;Demyelination;Dermatitis;Dermatitis bullous;Dermatitis
herpetiformis;Dermatomyositis;Device embolisation;Device related thrombosis;Diabetes
mellitus;Diabetic ketoacidosis;Diabetic mastopathy;Dialysis amyloidosis;Dialysis membrane
reaction;Diastolic hypotension;Diffuse vasculitis;Digital pitting scar;Disseminated
intravascular coagulation;Disseminated intravascular coagulation in newborn;Disseminated
neonatal herpes simplex;Disseminated varicella;Disseminated varicella zoster vaccine virus
infection;Disseminated varicella zoster virus infection;DNA antibody positive;Double cortex
syndrome;Double stranded DNA antibody positive;Dreamy state;Dressler's syndrome;Drop
attacks;Drug withdrawal convulsions;Dyspnoea;Early infantile epileptic encephalopathy with
burst-suppression;Eclampsia;Eczema herpeticum;Embolia cutis medicamentosa;Embolic
cerebellar infarction;Embolic cerebral infarction;Embolic pneumonia;Embolic
stroke;Embolism;Embolism arterial;Embolism venous;Encephalitis;Encephalitis
allergic;Encephalitis autoimmune;Encephalitis brain stem;Encephalitis
haemorrhagic;Encephalitis periaxialis diffusa;Encephalitis post
immunisation;Encephalomyelitis;Encephalopathy;Endocrine disorder;Endocrine
ophthalmopathy;Endotracheal intubation;Enteritis;Enteritis leukopenic;Enterobacter
pneumonia;Enterocolitis;Enteropathic spondylitis;Eosinopenia;Eosinophilic
CONFIDENTIAL
Page 3
Page 32
AR10052
BNT162b2
fasciitis;Eosinophilic granulomatosis with polyangiitis;Eosinophilic

oesophagitis;Epidermolysis;Epilepsy;Epilepsy surgery;Epilepsy with myoclonic-atonic
seizures;Epileptic aura;Epileptic psychosis;Erythema;Erythema induratum;Erythema
multiforme;Erythema nodosum;Evans syndrome;Exanthema subitum;Expanded disability
status scale score decreased;Expanded disability status scale score increased;Exposure to
communicable disease;Exposure to SARS-CoV-2;Eye oedema;Eye pruritus;Eye
swelling;Eyelid oedema;Face oedema;Facial paralysis;Facial paresis;Faciobrachial dystonic
seizure;Fat embolism;Febrile convulsion;Febrile infection-related epilepsy syndrome;Febrile
neutropenia;Felty's syndrome;Femoral artery embolism;Fibrillary
glomerulonephritis;Fibromyalgia;Flushing;Foaming at mouth;Focal cortical resection;Focal
dyscognitive seizures;Foetal distress syndrome;Foetal placental thrombosis;Foetor
hepaticus;Foreign body embolism;Frontal lobe epilepsy;Fulminant type 1 diabetes
mellitus;Galactose elimination capacity test abnormal;Galactose elimination capacity test
decreased;Gamma-glutamyltransferase abnormal;Gamma-glutamyltransferase
increased;Gastritis herpes;Gastrointestinal amyloidosis;Gelastic seizure;Generalised onset
non-motor seizure;Generalised tonic-clonic seizure;Genital herpes;Genital herpes
simplex;Genital herpes zoster;Giant cell arteritis;Glomerulonephritis;Glomerulonephritis
membranoproliferative;Glomerulonephritis membranous;Glomerulonephritis rapidly
progressive;Glossopharyngeal nerve paralysis;Glucose transporter type 1 deficiency
syndrome;Glutamate dehydrogenase increased;Glycocholic acid increased;GM2
gangliosidosis;Goodpasture's syndrome;Graft
thrombosis;Granulocytopenia;Granulocytopenia neonatal;Granulomatosis with

polyangiitis;Granulomatous dermatitis;Grey matter heterotopia;Guanase increased;Guillain-
Barre syndrome;Haemolytic anaemia;Haemophagocytic
lymphohistiocytosis;Haemorrhage;Haemorrhagic ascites;Haemorrhagic
disorder;Haemorrhagic pneumonia;Haemorrhagic varicella syndrome;Haemorrhagic
vasculitis;Hantavirus pulmonary infection;Hashimoto's
encephalopathy;Hashitoxicosis;Hemimegalencephaly;Henoch-Schonlein purpura;Henoch-
Schonlein purpura nephritis;Hepaplastin abnormal;Hepaplastin decreased;Heparin-induced
thrombocytopenia;Hepatic amyloidosis;Hepatic artery embolism;Hepatic artery flow
decreased;Hepatic artery thrombosis;Hepatic enzyme abnormal;Hepatic enzyme
decreased;Hepatic enzyme increased;Hepatic fibrosis marker abnormal;Hepatic fibrosis
marker increased;Hepatic function abnormal;Hepatic hydrothorax;Hepatic
hypertrophy;Hepatic hypoperfusion;Hepatic lymphocytic infiltration;Hepatic mass;Hepatic
pain;Hepatic sequestration;Hepatic vascular resistance increased;Hepatic vascular
thrombosis;Hepatic vein embolism;Hepatic vein thrombosis;Hepatic venous pressure
gradient abnormal;Hepatic venous pressure gradient increased;Hepatitis;Hepatobiliary scan
abnormal;Hepatomegaly;Hepatosplenomegaly;Hereditary angioedema with C1 esterase
inhibitor deficiency;Herpes dermatitis;Herpes gestationis;Herpes oesophagitis;Herpes
ophthalmic;Herpes pharyngitis;Herpes sepsis;Herpes simplex;Herpes simplex
cervicitis;Herpes simplex colitis;Herpes simplex encephalitis;Herpes simplex gastritis;Herpes
simplex hepatitis;Herpes simplex meningitis;Herpes simplex meningoencephalitis;Herpes
simplex meningomyelitis;Herpes simplex necrotising retinopathy;Herpes simplex
oesophagitis;Herpes simplex otitis externa;Herpes simplex pharyngitis;Herpes simplex
pneumonia;Herpes simplex reactivation;Herpes simplex sepsis;Herpes simplex
viraemia;Herpes simplex virus conjunctivitis neonatal;Herpes simplex visceral;Herpes virus
CONFIDENTIAL
Page 4
Page 33
AR10053
BNT162b2
infection;Herpes zoster;Herpes zoster cutaneous disseminated;Herpes zoster infection

neurological;Herpes zoster meningitis;Herpes zoster meningoencephalitis;Herpes zoster
meningomyelitis;Herpes zoster meningoradiculitis;Herpes zoster necrotising
retinopathy;Herpes zoster oticus;Herpes zoster pharyngitis;Herpes zoster
reactivation;Herpetic radiculopathy;Histone antibody positive;Hoigne's syndrome;Human
herpesvirus 6 encephalitis;Human herpesvirus 6 infection;Human herpesvirus 6 infection
reactivation;Human herpesvirus 7 infection;Human herpesvirus 8
infection;Hyperammonaemia;Hyperbilirubinaemia;Hypercholia;Hypergammaglobulinaemia
benign monoclonal;Hyperglycaemic seizure;Hypersensitivity;Hypersensitivity
vasculitis;Hyperthyroidism;Hypertransaminasaemia;Hyperventilation;Hypoalbuminaemia;H
ypocalcaemic seizure;Hypogammaglobulinaemia;Hypoglossal nerve paralysis;Hypoglossal
nerve paresis;Hypoglycaemic seizure;Hyponatraemic seizure;Hypotension;Hypotensive
crisis;Hypothenar hammer syndrome;Hypothyroidism;Hypoxia;Idiopathic CD4
lymphocytopenia;Idiopathic generalised epilepsy;Idiopathic interstitial pneumonia;Idiopathic
neutropenia;Idiopathic pulmonary fibrosis;IgA nephropathy;IgM nephropathy;IIIrd nerve
paralysis;IIIrd nerve paresis;Iliac artery embolism;Immune thrombocytopenia;Immune-
mediated adverse reaction;Immune-mediated cholangitis;Immune-mediated
cholestasis;Immune-mediated cytopenia;Immune-mediated encephalitis;Immune-mediated
encephalopathy;Immune-mediated endocrinopathy;Immune-mediated enterocolitis;Immune-
mediated gastritis;Immune-mediated hepatic disorder;Immune-mediated hepatitis;Immune-
mediated hyperthyroidism;Immune-mediated hypothyroidism;Immune-mediated
myocarditis;Immune-mediated myositis;Immune-mediated nephritis;Immune-mediated

neuropathy;Immune-mediated pancreatitis;Immune-mediated pneumonitis;Immune-mediated
renal disorder;Immune-mediated thyroiditis;Immune-mediated uveitis;Immunoglobulin G4
related disease;Immunoglobulins abnormal;Implant site thrombosis;Inclusion body
myositis;Infantile genetic agranulocytosis;Infantile spasms;Infected vasculitis;Infective
thrombosis;Inflammation;Inflammatory bowel disease;Infusion site thrombosis;Infusion site
vasculitis;Injection site thrombosis;Injection site urticaria;Injection site vasculitis;Instillation
site thrombosis;Insulin autoimmune syndrome;Interstitial granulomatous
dermatitis;Interstitial lung disease;Intracardiac mass;Intracardiac thrombus;Intracranial
pressure increased;Intrapericardial thrombosis;Intrinsic factor antibody abnormal;Intrinsic
factor antibody positive;IPEX syndrome;Irregular breathing;IRVAN syndrome;IVth nerve
paralysis;IVth nerve paresis;JC polyomavirus test positive;JC virus CSF test positive;Jeavons
syndrome;Jugular vein embolism;Jugular vein thrombosis;Juvenile idiopathic
arthritis;Juvenile myoclonic epilepsy;Juvenile polymyositis;Juvenile psoriatic
arthritis;Juvenile spondyloarthritis;Kaposi sarcoma inflammatory cytokine
syndrome;Kawasaki's disease;Kayser-Fleischer ring;Keratoderma blenorrhagica;Ketosis-
prone diabetes mellitus;Kounis syndrome;Lafora's myoclonic epilepsy;Lambl's
excrescences;Laryngeal dyspnoea;Laryngeal oedema;Laryngeal rheumatoid
arthritis;Laryngospasm;Laryngotracheal oedema;Latent autoimmune diabetes in adults;LE
cells present;Lemierre syndrome;Lennox-Gastaut syndrome;Leucine aminopeptidase
increased;Leukoencephalomyelitis;Leukoencephalopathy;Leukopenia;Leukopenia
neonatal;Lewis-Sumner syndrome;Lhermitte's sign;Lichen planopilaris;Lichen planus;Lichen
sclerosus;Limbic encephalitis;Linear IgA disease;Lip oedema;Lip swelling;Liver function
test abnormal;Liver function test decreased;Liver function test increased;Liver
induration;Liver injury;Liver iron concentration abnormal;Liver iron concentration
CONFIDENTIAL
Page 5
Page 34
AR10054
BNT162b2
increased;Liver opacity;Liver palpable;Liver sarcoidosis;Liver scan abnormal;Liver

tenderness;Low birth weight baby;Lower respiratory tract herpes infection;Lower respiratory
tract infection;Lower respiratory tract infection viral;Lung abscess;Lupoid hepatic
cirrhosis;Lupus cystitis;Lupus encephalitis;Lupus endocarditis;Lupus enteritis;Lupus
hepatitis;Lupus myocarditis;Lupus myositis;Lupus nephritis;Lupus pancreatitis;Lupus
pleurisy;Lupus pneumonitis;Lupus vasculitis;Lupus-like syndrome;Lymphocytic
hypophysitis;Lymphocytopenia neonatal;Lymphopenia;MAGIC syndrome;Magnetic
resonance imaging liver abnormal;Magnetic resonance proton density fat fraction
measurement;Mahler sign;Manufacturing laboratory analytical testing issue;Manufacturing
materials issue;Manufacturing production issue;Marburg's variant multiple
sclerosis;Marchiafava-Bignami disease;Marine Lenhart syndrome;Mastocytic
enterocolitis;Maternal exposure during pregnancy;Medical device site thrombosis;Medical
device site vasculitis;MELAS syndrome;Meningitis;Meningitis aseptic;Meningitis
herpes;Meningoencephalitis herpes simplex neonatal;Meningoencephalitis
herpetic;Meningomyelitis herpes;MERS-CoV test;MERS-CoV test negative;MERS-CoV test
positive;Mesangioproliferative glomerulonephritis;Mesenteric artery embolism;Mesenteric
artery thrombosis;Mesenteric vein thrombosis;Metapneumovirus infection;Metastatic
cutaneous Crohn's disease;Metastatic pulmonary
embolism;Microangiopathy;Microembolism;Microscopic polyangiitis;Middle East
respiratory syndrome;Migraine-triggered seizure;Miliary pneumonia;Miller Fisher
syndrome;Mitochondrial aspartate aminotransferase increased;Mixed connective tissue
disease;Model for end stage liver disease score abnormal;Model for end stage liver disease
score increased;Molar ratio of total branched-chain amino acid to tyrosine;Molybdenum
cofactor deficiency;Monocytopenia;Mononeuritis;Mononeuropathy
multiplex;Morphoea;Morvan syndrome;Mouth swelling;Moyamoya disease;Multifocal
motor neuropathy;Multiple organ dysfunction syndrome;Multiple sclerosis;Multiple sclerosis
relapse;Multiple sclerosis relapse prophylaxis;Multiple subpial transection;Multisystem
inflammatory syndrome in children;Muscular sarcoidosis;Myasthenia gravis;Myasthenia
gravis crisis;Myasthenia gravis neonatal;Myasthenic syndrome;Myelitis;Myelitis
transverse;Myocardial infarction;Myocarditis;Myocarditis post infection;Myoclonic
epilepsy;Myoclonic epilepsy and ragged-red fibres;Myokymia;Myositis;Narcolepsy;Nasal
herpes;Nasal obstruction;Necrotising herpetic retinopathy;Neonatal Crohn's disease;Neonatal
epileptic seizure;Neonatal lupus erythematosus;Neonatal mucocutaneous herpes
simplex;Neonatal pneumonia;Neonatal seizure;Nephritis;Nephrogenic systemic
fibrosis;Neuralgic amyotrophy;Neuritis;Neuritis cranial;Neuromyelitis optica pseudo
relapse;Neuromyelitis optica spectrum disorder;Neuromyotonia;Neuronal
neuropathy;Neuropathy peripheral;Neuropathy, ataxia, retinitis pigmentosa
syndrome;Neuropsychiatric lupus;Neurosarcoidosis;Neutropenia;Neutropenia
neonatal;Neutropenic colitis;Neutropenic infection;Neutropenic sepsis;Nodular rash;Nodular
vasculitis;Noninfectious myelitis;Noninfective encephalitis;Noninfective
encephalomyelitis;Noninfective oophoritis;Obstetrical pulmonary embolism;Occupational
exposure to communicable disease;Occupational exposure to SARS-CoV-2;Ocular
hyperaemia;Ocular myasthenia;Ocular pemphigoid;Ocular sarcoidosis;Ocular
vasculitis;Oculofacial paralysis;Oedema;Oedema blister;Oedema due to hepatic
disease;Oedema mouth;Oesophageal achalasia;Ophthalmic artery thrombosis;Ophthalmic
herpes simplex;Ophthalmic herpes zoster;Ophthalmic vein thrombosis;Optic neuritis;Optic
CONFIDENTIAL
Page 6
Page 35
AR10055
BNT162b2
neuropathy;Optic perineuritis;Oral herpes;Oral lichen planus;Oropharyngeal

oedema;Oropharyngeal spasm;Oropharyngeal swelling;Osmotic demyelination
syndrome;Ovarian vein thrombosis;Overlap syndrome;Paediatric autoimmune
neuropsychiatric disorders associated with streptococcal infection;Paget-Schroetter
syndrome;Palindromic rheumatism;Palisaded neutrophilic granulomatous
dermatitis;Palmoplantar keratoderma;Palpable
purpura;Pancreatitis;Panencephalitis;Papillophlebitis;Paracancerous pneumonia;Paradoxical
embolism;Parainfluenzae viral laryngotracheobronchitis;Paraneoplastic
dermatomyositis;Paraneoplastic pemphigus;Paraneoplastic thrombosis;Paresis cranial
nerve;Parietal cell antibody positive;Paroxysmal nocturnal haemoglobinuria;Partial
seizures;Partial seizures with secondary generalisation;Patient isolation;Pelvic venous
thrombosis;Pemphigoid;Pemphigus;Penile vein thrombosis;Pericarditis;Pericarditis
lupus;Perihepatic discomfort;Periorbital oedema;Periorbital swelling;Peripheral artery
thrombosis;Peripheral embolism;Peripheral ischaemia;Peripheral vein thrombus
extension;Periportal oedema;Peritoneal fluid protein abnormal;Peritoneal fluid protein
decreased;Peritoneal fluid protein increased;Peritonitis lupus;Pernicious anaemia;Petit mal
epilepsy;Pharyngeal oedema;Pharyngeal swelling;Pityriasis lichenoides et varioliformis
acuta;Placenta praevia;Pleuroparenchymal fibroelastosis;Pneumobilia;Pneumonia;Pneumonia
adenoviral;Pneumonia cytomegaloviral;Pneumonia herpes viral;Pneumonia
influenzal;Pneumonia measles;Pneumonia mycoplasmal;Pneumonia necrotising;Pneumonia
parainfluenzae viral;Pneumonia respiratory syncytial viral;Pneumonia viral;POEMS
syndrome;Polyarteritis nodosa;Polyarthritis;Polychondritis;Polyglandular autoimmune

syndrome type I;Polyglandular autoimmune syndrome type II;Polyglandular autoimmune
syndrome type III;Polyglandular disorder;Polymicrogyria;Polymyalgia
rheumatica;Polymyositis;Polyneuropathy;Polyneuropathy idiopathic progressive;Portal
pyaemia;Portal vein embolism;Portal vein flow decreased;Portal vein pressure
increased;Portal vein thrombosis;Portosplenomesenteric venous thrombosis;Post procedural
hypotension;Post procedural pneumonia;Post procedural pulmonary embolism;Post stroke
epilepsy;Post stroke seizure;Post thrombotic retinopathy;Post thrombotic syndrome;Post viral
fatigue syndrome;Postictal headache;Postictal paralysis;Postictal psychosis;Postictal
state;Postoperative respiratory distress;Postoperative respiratory failure;Postoperative
thrombosis;Postpartum thrombosis;Postpartum venous thrombosis;Postpericardiotomy
syndrome;Post-traumatic epilepsy;Postural orthostatic tachycardia syndrome;Precerebral
artery thrombosis;Pre-eclampsia;Preictal state;Premature labour;Premature
menopause;Primary amyloidosis;Primary biliary cholangitis;Primary progressive multiple
sclerosis;Procedural shock;Proctitis herpes;Proctitis ulcerative;Product availability
issue;Product distribution issue;Product supply issue;Progressive facial
hemiatrophy;Progressive multifocal leukoencephalopathy;Progressive multiple
sclerosis;Progressive relapsing multiple sclerosis;Prosthetic cardiac valve
thrombosis;Pruritus;Pruritus allergic;Pseudovasculitis;Psoriasis;Psoriatic
arthropathy;Pulmonary amyloidosis;Pulmonary artery thrombosis;Pulmonary
embolism;Pulmonary fibrosis;Pulmonary haemorrhage;Pulmonary microemboli;Pulmonary
oil microembolism;Pulmonary renal syndrome;Pulmonary sarcoidosis;Pulmonary
sepsis;Pulmonary thrombosis;Pulmonary tumour thrombotic microangiopathy;Pulmonary
vasculitis;Pulmonary veno-occlusive disease;Pulmonary venous thrombosis;Pyoderma
gangrenosum;Pyostomatitis vegetans;Pyrexia;Quarantine;Radiation leukopenia;Radiculitis
CONFIDENTIAL
Page 7
Page 36
AR10056
BNT162b2
brachial;Radiologically isolated syndrome;Rash;Rash erythematous;Rash pruritic;Rasmussen

encephalitis;Raynaud's phenomenon;Reactive capillary endothelial proliferation;Relapsing
multiple sclerosis;Relapsing-remitting multiple sclerosis;Renal amyloidosis;Renal
arteritis;Renal artery thrombosis;Renal embolism;Renal failure;Renal vascular
thrombosis;Renal vasculitis;Renal vein embolism;Renal vein thrombosis;Respiratory
arrest;Respiratory disorder;Respiratory distress;Respiratory failure;Respiratory
paralysis;Respiratory syncytial virus bronchiolitis;Respiratory syncytial virus
bronchitis;Retinal artery embolism;Retinal artery occlusion;Retinal artery thrombosis;Retinal
vascular thrombosis;Retinal vasculitis;Retinal vein occlusion;Retinal vein thrombosis;Retinol
binding protein decreased;Retinopathy;Retrograde portal vein flow;Retroperitoneal
fibrosis;Reversible airways obstruction;Reynold's syndrome;Rheumatic brain
disease;Rheumatic disorder;Rheumatoid arthritis;Rheumatoid factor increased;Rheumatoid
factor positive;Rheumatoid factor quantitative increased;Rheumatoid lung;Rheumatoid
neutrophilic dermatosis;Rheumatoid nodule;Rheumatoid nodule removal;Rheumatoid
scleritis;Rheumatoid vasculitis;Saccadic eye movement;SAPHO
syndrome;Sarcoidosis;SARS-CoV-1 test;SARS-CoV-1 test negative;SARS-CoV-1 test
positive;SARS-CoV-2 antibody test;SARS-CoV-2 antibody test negative;SARS-CoV-2
antibody test positive;SARS-CoV-2 carrier;SARS-CoV-2 sepsis;SARS-CoV-2 test;SARS-
CoV-2 test false negative;SARS-CoV-2 test false positive;SARS-CoV-2 test negative;SARS-
CoV-2 test positive;SARS-CoV-2 viraemia;Satoyoshi
syndrome;Schizencephaly;Scleritis;Sclerodactylia;Scleroderma;Scleroderma associated
digital ulcer;Scleroderma renal crisis;Scleroderma-like reaction;Secondary

amyloidosis;Secondary cerebellar degeneration;Secondary progressive multiple
sclerosis;Segmented hyalinising vasculitis;Seizure;Seizure anoxic;Seizure cluster;Seizure
like phenomena;Seizure prophylaxis;Sensation of foreign body;Septic embolus;Septic
pulmonary embolism;Severe acute respiratory syndrome;Severe myoclonic epilepsy of
infancy;Shock;Shock symptom;Shrinking lung syndrome;Shunt thrombosis;Silent
thyroiditis;Simple partial seizures;Sjogren's syndrome;Skin swelling;SLE arthritis;Smooth
muscle antibody positive;Sneezing;Spinal artery embolism;Spinal artery thrombosis;Splenic
artery thrombosis;Splenic embolism;Splenic thrombosis;Splenic vein
thrombosis;Spondylitis;Spondyloarthropathy;Spontaneous heparin-induced
thrombocytopenia syndrome;Status epilepticus;Stevens-Johnson syndrome;Stiff leg
syndrome;Stiff person syndrome;Stillbirth;Still's disease;Stoma site thrombosis;Stoma site
vasculitis;Stress cardiomyopathy;Stridor;Subacute cutaneous lupus erythematosus;Subacute
endocarditis;Subacute inflammatory demyelinating polyneuropathy;Subclavian artery
embolism;Subclavian artery thrombosis;Subclavian vein thrombosis;Sudden unexplained
death in epilepsy;Superior sagittal sinus thrombosis;Susac's syndrome;Suspected COVID-
19;Swelling;Swelling face;Swelling of eyelid;Swollen tongue;Sympathetic
ophthalmia;Systemic lupus erythematosus;Systemic lupus erythematosus disease activity
index abnormal;Systemic lupus erythematosus disease activity index decreased;Systemic
lupus erythematosus disease activity index increased;Systemic lupus erythematosus
rash;Systemic scleroderma;Systemic sclerosis
pulmonary;Tachycardia;Tachypnoea;Takayasu's arteritis;Temporal lobe epilepsy;Terminal
ileitis;Testicular autoimmunity;Throat tightness;Thromboangiitis
obliterans;Thrombocytopenia;Thrombocytopenic
purpura;Thrombophlebitis;Thrombophlebitis migrans;Thrombophlebitis
CONFIDENTIAL
Page 8
Page 37
AR10057
BNT162b2
neonatal;Thrombophlebitis septic;Thrombophlebitis superficial;Thromboplastin antibody

positive;Thrombosis;Thrombosis corpora cavernosa;Thrombosis in device;Thrombosis
mesenteric vessel;Thrombotic cerebral infarction;Thrombotic microangiopathy;Thrombotic
stroke;Thrombotic thrombocytopenic purpura;Thyroid disorder;Thyroid stimulating
immunoglobulin increased;Thyroiditis;Tongue amyloidosis;Tongue biting;Tongue
oedema;Tonic clonic movements;Tonic convulsion;Tonic posturing;Topectomy;Total bile
acids increased;Toxic epidermal necrolysis;Toxic leukoencephalopathy;Toxic oil
syndrome;Tracheal obstruction;Tracheal oedema;Tracheobronchitis;Tracheobronchitis
mycoplasmal;Tracheobronchitis viral;Transaminases abnormal;Transaminases
increased;Transfusion-related alloimmune neutropenia;Transient epileptic
amnesia;Transverse sinus thrombosis;Trigeminal nerve paresis;Trigeminal
neuralgia;Trigeminal palsy;Truncus coeliacus thrombosis;Tuberous sclerosis
complex;Tubulointerstitial nephritis and uveitis syndrome;Tumefactive multiple
sclerosis;Tumour embolism;Tumour thrombosis;Type 1 diabetes mellitus;Type I
hypersensitivity;Type III immune complex mediated reaction;Uhthoff's
phenomenon;Ulcerative keratitis;Ultrasound liver abnormal;Umbilical cord
thrombosis;Uncinate fits;Undifferentiated connective tissue disease;Upper airway
obstruction;Urine bilirubin increased;Urobilinogen urine decreased;Urobilinogen urine
increased;Urticaria;Urticaria papular;Urticarial vasculitis;Uterine
rupture;Uveitis;Vaccination site thrombosis;Vaccination site vasculitis;Vagus nerve
paralysis;Varicella;Varicella keratitis;Varicella post vaccine;Varicella zoster
gastritis;Varicella zoster oesophagitis;Varicella zoster pneumonia;Varicella zoster

sepsis;Varicella zoster virus infection;Vasa praevia;Vascular graft thrombosis;Vascular
pseudoaneurysm thrombosis;Vascular purpura;Vascular stent thrombosis;Vasculitic
rash;Vasculitic ulcer;Vasculitis;Vasculitis gastrointestinal;Vasculitis necrotising;Vena cava
embolism;Vena cava thrombosis;Venous intravasation;Venous recanalisation;Venous
thrombosis;Venous thrombosis in pregnancy;Venous thrombosis limb;Venous thrombosis
neonatal;Vertebral artery thrombosis;Vessel puncture site thrombosis;Visceral venous
thrombosis;VIth nerve paralysis;VIth nerve paresis;Vitiligo;Vocal cord paralysis;Vocal cord
paresis;Vogt-Koyanagi-Harada disease;Warm type haemolytic anaemia;Wheezing;White
nipple sign;XIth nerve paralysis;X-ray hepatobiliary abnormal;Young's syndrome;Zika virus
associated Guillain Barre syndrome.
CONFIDENTIAL
Page 9
Page 38
AR10058 12
Cookies on the NHS website
We've put some small files called cookies on your device to make our site work.
We'd also like to use analytics cookies. These send information about how our site is used to services called
Adobe Analytics, Hotjar and Google Analytics. We use this information to improve our site.
Let us know if this is OK. We'll use a cookie to save your choice. You can read more about our cookies
before you choose.
I'm OK with analytics cookies Do not use analytics cookies
Search My account
Health A-Z Live Well Mental health Care and support Pregnancy NHS services
Home Health A to Z Vaccinations
NHS vaccinations and when

to have them
It's important that vaccines are given on time for the best protection,
but if you or your child missed a vaccine, contact your GP to catch up. Vaccinations
Your child's appointment
Coronavirus (COVID-19) update Booking your child's vaccination
appointment
Routine vaccinations for babies, pre-school children and adults Vaccination tips for parents
are continuing as normal.

About vaccinations
It's important to go to your appointments unless you or your Why vaccination is safe and important
child have symptoms of COVID-19.
6-in-1 vaccine
Vaccinations usually given in school are being rescheduled. 6-in-1 vaccine overview
6-in-1 vaccine: side effects
Pneumococcal (PCV) vaccine
NHS vaccination schedule Pneumococcal vaccine overview
Pneumococcal vaccine side effects
Who should have the pneumococcal

Babies under 1 year old vaccine?
MenB vaccine
Age Vaccines MenB vaccine overview
MenB vaccine side effects

8 weeks 6-in-1 vaccine Which babies should have the MenB
Rotavirus vaccine vaccine?
MenB
Rotavirus vaccine
12 weeks 6-in-1 vaccine (2nd dose) Rotavirus vaccine overview
Pneumococcal (PCV) vaccine Rotavirus vaccine side effects

Rotavirus vaccine (2nd dose) Rotavirus vaccine FAQs
16 weeks 6-in-1 vaccine (3rd dose) Hib/MenC

MenB (2nd dose) Hib/MenC vaccine overview
Hib/MenC vaccine side effects
Hib/MenC vaccine FAQs
MMR vaccine
MMR (measles, mumps and rubella)
vaccine
Children aged 1 to 15
Children's flu vaccine
Age Vaccines Children's flu vaccine
4-in-1 preschool booster

1 year Hib/MenC (1st dose)
4-in-1 pre-school booster overview
MMR (1st dose)
4-in-1 pre-school booster side effects
Pneumococcal (PCV) vaccine (2nd dose)
MenB (3rd dose)
HPV vaccine
HPV vaccine overview
2 to 10 years Flu vaccine (every year)
HPV vaccine side effects
HPV vaccine safety

3 years and 4 months MMR (2nd dose)
How is the HPV vaccine given?
4-in-1 pre-school booster
Who should have the HPV vaccine?
5 to 15 years COVID-19 vaccine (1st and 2nd dose) 3-in-1 teenage booster
3-in-1 teenage booster overview
12 to 13 years HPV vaccine
3-in-1 teenage booster side effects
3-in-1 teenage booster FAQs

14 years 3-in-1 teenage booster
MenACWY MenACWY vaccine
MenACWY vaccine overview
Pneumococcal (PPV) vaccine

Pneumococcal vaccine overview
Pneumococcal vaccine side effects

Adults Who should have the pneumococcal
vaccine?
Age Vaccines Flu vaccine

Flu vaccine
16 years and over COVID-19 vaccine (1st, 2nd and
booster dose) Shingles vaccine
Shingles vaccine overview
50 years (and every Flu vaccine Shingles vaccine side effects
year after) Shingles vaccine FAQs
Who can have the shingles vaccine?

65 years Pneumococcal (PPV) vaccine
BCG (TB) vaccine
BCG vaccine for tuberculosis (TB)
70 years Shingles vaccine
overview
BCG (TB) vaccine side effects
BCG vaccine for tuberculosis (TB) FAQs
Who should have the BCG (TB) vaccine?
Hepatitis B vaccine
Pregnant women
Hepatitis B vaccine overview
When it's offered Vaccines Chickenpox vaccine

Chickenpox vaccine overview
Chickenpox vaccine side effects

During flu season Flu vaccine
Chickenpox vaccine FAQs
From 16 weeks pregnant Whooping cough (pertussis) vaccine Who should have the chickenpox
vaccine?
Extra vaccines for at-risk people

Some vaccines are only available on the NHS for groups of people who
need extra protection.
See vaccines for at-risk babies and children
See vaccines for people with underlying health conditions
See vaccines for children and adults at high risk from COVID-19
Important
If you're starting college or university you should make sure

you've already had:
the MenACWY vaccine – which protects against serious

infections like meningitis. You can still ask your GP for this
vaccine until your 25th birthday.
2 doses of the MMR vaccine – as there are outbreaks of
mumps and measles at universities. If you have not
previously had 2 doses of MMR you can still ask your GP for
the vaccine.
Speak to your GP surgery if:
you think you or your child have missed any vaccinations

you or your child have a vaccination appointment – but
you've missed it or cannot attend
They can book or rearrange the next available appointment.
It’s best to have vaccines on time, but you can still catch up on
most vaccines if you miss them.
Coronavirus (COVID-19) update: how to

contact a GP
It's still important to get help from a GP if you need it.

To contact your GP surgery:
visit their website

use the NHS App
call them
Find out about using the NHS during COVID-19
Page last reviewed: 30 July 2019

Next review due: 30 July 2022
Back to Vaccinations
Home NHS App Contact us About us
Health A to Z Find my NHS number Other NHS websites Accessibility statement
Live Well Your health records Profile editor login Our policies
Mental health About the NHS Cookies
Care and support Healthcare abroad
Pregnancy
NHS services
Coronavirus (COVID-19)
© Crown copyright
AR10059
13 Français
MENU 
Canada.ca > Coronavirus disease (COVID-19) > Vaccines for COVID-19 > COVID-19 Vaccines: Authorized vaccines
Janssen (Johnson & Johnson) COVID-19 vaccine

All COVID-19 vaccines authorized in Canada are proven safe, effective and of high quality.
Name: Janssen COVID-19 Vaccine Approved for: Age 18 and older
Manufacturer: Janssen Inc How it's given: Injection in muscle (usually the upper arm)
Type: Viral vector-based Number of doses: 1 dose
Status: Approved by Health Canada
On this page
Who the vaccine is approved for
Effectiveness
Dosage
Vaccine ingredients
Possible side effects
Vaccine review, approval and monitoring
Get vaccinated

The vaccine is approved for people who are 18 years of age and older. Its safety and effectiveness in people younger than
18 years of age have not yet been established.
Effectiveness
Clinical trials showed that beginning 2 weeks after the single dose, the Janssen COVID-19 vaccine was 66% effective in
protecting trial participants against COVID-19.
Dosage
This vaccine requires a single dose.
A booster dose of the Janssen (Johnson & Johnson) COVID-19 vaccine may be given to individuals 18 years of age and
older at least 2 months after completing their primary vaccine series.
Some people may have a contraindication (for example, an allergy) to an mRNA vaccine or the Novavax Nuvaxovid
vaccine, or any of their components. For these cases only, NACI recommends that they may be offered viral vector
COVID-19 vaccines, including the Janssen COVID-19 vaccine, as a booster dose.
Vaccine ingredients
Medicinal ingredient
adenovirus vector vaccine
Other ingredients
2-hydroxypropyl-β-cyclodextrin (HBCD)
citric acid monohydrate
ethanol
hydrochloric acid
polysorbate 80
sodium chloride
sodium hydroxide
trisodium citrate dihydrate
water for injection

After getting vaccinated, it's common to have temporary side effects. These can last a few hours to a few days after
vaccination.
This is the body's natural response, as it's working hard to build protection against the disease.
Common vaccine side effects may include:

Symptoms at the injection site, such as: More general symptoms, such as:
redness chills
soreness fatigue
swelling joint pain
headache
mild fever
muscle aches
A severe allergic reaction (anaphylaxis) is also rare. Signs and symptoms of anaphylaxis may include:
hives (bumps on the skin that are often very itchy)

swelling of the lips, face, tongue or airway
difficulty breathing
increased heart rate
loss of consciousness
sudden low blood pressure
abdominal pain, vomiting and diarrhea
Call emergency services if you develop or witness any serious symptoms that could be an allergic reaction after
vaccination.
Talk to your doctor about any serious allergies or health conditions you may have before you get a vaccine.
This vaccine does not contain common food allergens, such as eggs, shellfish, gluten or nuts.
Rare vaccine side effects

Some rare reactions that have been reported and confirmed after taking a viral vector vaccine are:
Blood clots with low levels of blood platelets

Capillary leak syndrome
Guillain-Barré syndrome (GBS)
Talk to your health care provider about which vaccine is recommended for you. They will take into consideration your risk
of:
exposure to COVID-19
more severe disease or outcomes if you get COVID-19
Reporting a possible side effect or serious reaction

Contact your health care provider if you experience:
a side effect following vaccination with a COVID-19 vaccine

any persistent, new or worsening symptoms
Health care providers must report possible reactions following vaccination to their local public health authority. The
public health authority then reports them to the Public Health Agency of Canada.
Reported allergic reactions and side effects to COVID-19 vaccines are published weekly in our Reported side effects
following COVID-19 vaccination report.

Health Canada's independent drug review and approval process is recognized around the world for its high standards
and rigor. Our decisions are based only on scientific and medical evidence showing that vaccines are safe and effective.
The benefits must also outweigh any risks.
The Janssen COVID-19 vaccine was authorized for use in Canada under the Interim Order respecting the importation, sale
and advertising of drugs for use in relation to COVID-19. On November 23, 2021, Janssen COVID-19 vaccine transitioned
to an authorization under the Food and Drug Regulations.
Find detailed technical information such as the product monograph and the regulatory decision summary:
Janssen (Johnson & Johnson) vaccine regulatory information
As COVID-19 vaccines are administered across Canada, our safety monitoring is ongoing. The Public Health Agency of
Canada, Health Canada, and provincial and territorial health authorities continue to:
monitor the use of all COVID-19 vaccines closely

examine and assess any new safety concerns
Learn about the side effects we're currently monitoring.
Get vaccinated
How to get vaccinated near you
Related links
COVID-19: Proof of vaccination
Number of doses given in Canada
Canada’s vaccine supply
All drugs and vaccines approved for COVID-19
COVID-19 vaccines for children and youth
COVID-19: How provinces and territories make decisions about how, who and when to vaccinate
Interim Order respecting the importation, sale and advertising of drugs for use in relation to COVID-19
Did you find what you were looking for? Yes No  Share this page
14
AR10060
Français
MENU 
AstraZeneca Vaxzevria COVID-19 vaccine

Name: AstraZeneca Vaxzevria® COVID-19 vaccine Approved for: Age 18 and older
Manufacturer: AstraZeneca Canada Inc and Verity/SII How it's given: Injection in muscle (usually the upper arm)
(COVISHIELD)
Number of doses: 2 doses
Type: Viral vector-based
Note: The COVISHIELD version of this vaccine provided a temporary supply to Canadians through the Interim Order
respecting the importation, sale and advertising of drugs for use in relation to COVID-19. It was not transitioned to the
Food and Drug Regulations when the interim order expired on September 16, 2021.
The AstraZeneca Vaxzevria® COVID-19 vaccine is authorized for use in Canada under the Food and Drug Regulations.
On this page
Effectiveness
Dosage
Vaccine ingredients
Get vaccinated

Effectiveness
U.S. Clinical trials showed that beginning 2 weeks after the second dose, the AstraZeneca Vaxzevria® COVID-19 vaccine
was 74% effective in protecting trial participants against COVID-19.
Dosage
This vaccine requires 2 doses for maximum protection.
The dosing schedule approved by Health Canada is to give the 2 doses 4 to 12 weeks apart, based on evidence from
clinical trials.
Your province or territory decides when people receive their first and second doses of the vaccine.
These decisions are based on public health recommendations and the latest evidence.
Find out how provinces and territories are making COVID-19 vaccine decisions
Mixed dose schedules

A different vaccine may be offered for your second dose. This is known as a mixed vaccine series.
The National Advisory Committee on Immunization (NACI) recommends an mRNA vaccine (Pfizer-BioNTech Comirnaty®
or Moderna Spikevax®) should be offered for your second dose. This is the case even if you got a viral vector vaccine as a
first dose.
A viral vector vaccine, like AstraZeneca Vaxzevria®, may be recommended by your health care provider depending on
your unique health situation. For example, if you're allergic to an mRNA vaccine.
Learn more about:
mRNA vaccines
Viral vector vaccines
Vaccine ingredients
Adenovirus vector vaccine
Other ingredients
disodium edetate dihydrate (EDTA)
ethanol
L-histidine
L-histidine hydrochloride monohydrate
magnesium chloride hexahydrate
polysorbate 80
sodium chloride
sucrose
water for injection

vaccination.

redness chills
soreness fatigue
swelling joint pain
headache
mild fever
muscle aches

Some rare reactions that have been reported and confirmed after taking a viral vector vaccine are:
Blood clots with low levels of blood platelets

Capillary leak syndrome
Guillain-Barré syndrome
A severe allergic reaction (anaphylaxis) is also rare. Signs and symptoms of anaphylaxis may include:

vaccination.
Talk to your doctor about any serious allergies or health conditions you may have before you get a vaccine.
This vaccine does not contain common food allergens, such as eggs, shellfish, gluten or nuts.
Reporting a possible side effect or serious reaction



Health Canada's independent drug review and approval process is recognized around the world for its high standards
and rigor. Our decisions are based only on scientific and medical evidence showing that vaccines are safe and effective.
The benefits must also outweigh any risks.
AstraZeneca Vaxzevria® vaccine regulatory information

Get vaccinated
Related links
Canada’s vaccine supply
AR10061 Français Subscribe
15
Newsroom Search Menu
Follow the COVID-19 restrictions and public health measures and

X
book your appointment to get vaccinated.
STATEMENT
Ontario Recommends the use of

Pfizer-BioNTech COVID-19 Vaccine
for Individuals Aged 18-24 Years
Old
September 29, 2021
Health
Table of Contents Share

1. Content 2. Related Topics
TORONTO — Today, Dr. Kieran Moore, Chief Medical O!cer of Health, issued the following
statement on COVID-19 vaccines for individuals aged 18-24 years old: Media Contacts
“Health Canada authorized COVID-19 vaccines are safe, e"ective and signi#cantly reduce the risk Alexandra Hilkene
of infection and serious illness, including hospitalization. Minister Elliott’s O!ce
alexandra.hilkene@ontario.ca
Out of an abundance of caution, Ontario is issuing a preferential recommendation of the use of
P#zer-BioNTech vaccine for individuals aged 18-24 years old e"ective immediately based on the David Jensen
current available analysis from Ontario’s adverse events following immunization (AEFI) Communications Division
surveillance system. media.moh@ontario.ca
416-314-6197
This recommendation was based on the advice of Ontario’s Children COVID-19 Vaccine Table,
Ontario Vaccine Clinical Advisory Group, and Public Health Ontario and is due to an observed
increase in Ontario of the very rare heart condition called pericarditis/myocarditis following
vaccination with Moderna compared to P#zer in the 18 to 24 year old age group, particularly
among males. The majority of reported cases have been mild with individuals recovering quickly,
normally with anti-in$ammatory medication. Symptoms have typically been reported to start
within one week after vaccination, more commonly after the second dose.
This decision is also based on the increased and reliable supply of the P#zer vaccines and the fact
that individuals who received Moderna for their #rst dose can safely take the P#zer-BioNTech
vaccine for their second dose. Mixing vaccines is safe and e"ective, and full vaccination with two
doses of the mRNA vaccine o"ers the greatest protection you can have against COVID-19 and the
Delta variant.
Based on the signi#cantly higher risks of COVID-19 hospitalizations, ICU admissions and death
among the unvaccinated, those who received a #rst dose of the Moderna vaccine absolutely did
the right thing to protect themselves, their loved ones and communities. Vaccination is the best
way to protect against COVID-19 related complications, and the risk of contracting myocarditis
and other serious adverse events including pericarditis, arrhythmia, deep-vein thrombosis,
pulmonary embolism, myocardial infarction, intracranial hemorrhage and thrombocytopenia is 18
times higher among patients with COVID-19. Should individuals aged 18 to 24-year old wish to
receive Moderna they can continue to do so with informed consent. The province will continue
using the P#zer vaccine for youth ages 12-17 (including those turning 12 in 2021).
The health and safety of Ontarians remains our top priority, and we will continue to monitor the
latest available data regarding the use of Moderna for this population moving forward.
As Ontario continues to respond to the fourth wave driven by the highly transmissible Delta
variant, we encourage all eligible Ontarians to sign up to receive their #rst and second dose of the
COVID-19 vaccine today.”
Related Topics
Government
Learn about the government services available to you and how government works. Learn more
Health and Wellness

Get help navigating Ontario’s health care system and connecting with the programs or services
you’re looking for. Learn more
Accessibility Privacy Contact us
© Queen's Printer for Ontario, 2012-2022

5/30/22, 11:43 PM Travel to England from another country during coronavirus (COVID-19) - GOV.UK
AR10062
You have accepted additional cookies. You can change your cookie settings
(/help/cookies) at any time.
16
Hide this message

GOV.UK
1. Home (https://www.gov.uk/)
2. Coronavirus (COVID-19) (https://www.gov.uk/coronavirus-taxon)
3. International travel, immigration and repatriation during coronavirus
(https://www.gov.uk/coronavirus-taxon/international-travel-immigration-repatriation)
4. Entering England during coronavirus (https://www.gov.uk/coronavirus-taxon/entering-england)
Guidance
Travel to England from another country during
coronavirus (COVID-19)
You do not need to complete a UK passenger locator form before you travel, take any COVID-19
tests or quarantine when you arrive in England.
From:
Department for Transport (/government/organisations/department-for-transport) and Department of
Health and Social Care (/government/organisations/department-of-health-and-social-care)
Published
22 June 2021
Last updated
18 March 2022
—
Applies to England
Guidance for Wales (https://gov.wales/international-travel-and-wales-coronavirus)
Guidance for Scotland (https://www.gov.scot/publications/coronavirus-covid-19-international-
travel-quarantine/)
Guidance for Northern Ireland (https://www.nidirect.gov.uk/articles/coronavirus-covid-19-
travel-advice)
Contents
Travel to England rules
How to stay safe while in the UK and on public transport
https://www.gov.uk/guidance/travel-to-england-from-another-country-during-coronavirus-covid-19 1/5
AR10063
Red list countries and territories
Travel abroad from England
Travel to England rules

When you travel to England, you:
do not need to complete a UK passenger locator form before you travel

do not need to take any COVID-19 tests before you travel or after you arrive
do not need to quarantine when you arrive
This applies whether you are vaccinated or not.
It includes people who are transiting through England.
Other countries may have rules about what you need to do to leave the country to travel to England.
You should check travel advice for the country you are travelling from.
How to stay safe while in the UK and on public transport

Check separate public health guidance on how to stay safe and help prevent the spread of
Coronavirus while you are in the UK (https://www.gov.uk/guidance/living-safely-with-respiratory-infections-
including-covid-19).
Travel provider and transport hub rules
Your travel provider, or the transport hub you travel through, may have COVID-19 rules in place. For
example they may require or advise you to wear a face covering.
You should follow any COVID-19 rules and guidance from:
your travel provider – airline, ferry, coach or train company

the transport venue – airport, port, coach or railway station
Red list countries and territories

There are currently no red list restrictions in place for travel to England.
Travel abroad from England

Other countries have rules about what you must do to travel there from England.
Read separate guidance about what you need to do to travel abroad from England
(https://www.gov.uk/guidance/travel-abroad-from-england-during-coronavirus-covid-19).
Published 22 June 2021
Last updated 18 March 2022

+ show all updates
1. 18 March 2022
AR10064
When you arrive in England from abroad you do not need to take any COVID-19 tests or fill in a
UK passenger locator form.
2. 14 March 2022
If you will arrive in England after 4am, Friday 18 March, you do not need to take any COVID-19
tests or fill in a UK passenger locator form.
3. 5 March 2022
If you began your journey in Russia, you do not need to complete a passenger locator form, or
take a COVID-19 test before travel to England or on arrival.
4. 2 March 2022
If you began your journey in Ukraine, you do not need to complete a passenger locator form, or
take a COVID-19 test before travel to England or on arrival.
5. 28 February 2022
From 9am Monday 28 February, you can fill in the UK passenger locator form up to 3 days
before you arrive in England.
6. 24 February 2022
From 24 February, there is no legal requirement to self-isolate if you get a positive day 2 test
result.
7. 11 February 2022
You do not need to take any COVID-19 travel tests or self-isolate on arrival in England if you
qualify as fully vaccinated.
8. 24 January 2022
The testing and quarantine rules for international travel to England will change 11 February
2022.
9. 9 January 2022
You can now choose a lateral flow test or a PCR test as your post arrival test.
10. 7 January 2022
From 4am 7 January you do not have to quarantine on arrival in England if you qualify as fully
vaccinated for travel to England.
11. 5 January 2022
Changes to rules for fully vaccinated people travelling to England from 4am 7 January 2022.
12. 24 December 2021
People who qualify as fully vaccinated for travel to England can now end self-isolation after 7
days with 2 negative lateral flow tests.
13. 20 December 2021
Further information about quarantine rules for children aged 4 and under.
14. 7 December 2021
People aged 12 years and over must COVID-19 test before they travel to England from abroad.
15. 4 December 2021
From 4am, Tuesday 7 December all people aged 12 years and over must also take a PCR or
LFD COVID-19 test before they travel to England from abroad.
16. 30 November 2021
People who qualify as fully vaccinated must quarantine and take a PCR test before the end of
day 2 after they arrive in England. Lateral flow tests will not be accepted.
From 4am 30 November 2021, fully vaccinated people must self-isolate and take a PCR test
before the end of day 2 after they arrive in England. They may leave self-isolation if their PCR
result is negative. Lateral flow tests will not be accepted.
AR10065
South Africa, Botswana, Eswatini, Lesotho, Namibia and Zimbabwe will move onto the red list
at 12.00 midday Friday 26 November. A temporary flight ban will be in place and all travellers
who have been in these countries must quarantine and take tests.
Travel to England rules for children no longer depend on their place of residence.
Clarification about unclear or inconclusive test results.
21. 8 November 2021
From 4am 22 November 2021, all children aged 17 and under will not have to quarantine on
arrival in England.
22. 22 October 2021
People who qualify as fully vaccinated for travel to England can book a lateral flow test for use
from 24 October instead of a PCR test.
23. 15 October 2021
From 22 October, if you qualify as fully vaccinated for travel to England, you will be able to
book an antigen lateral flow device (LFD) test instead of a PCR for your ‘on arrival’ test.
24. 4 October 2021
Rule changes for international travel to England for people who qualify as fully vaccinated.
25. 19 July 2021
Changes to amber list rules on quarantine and testing.
26. 22 June 2021
First published.
Related content
Travel abroad from England during coronavirus (COVID-19) (/guidance/travel-abroad-from-
england-during-coronavirus-covid-19)
Using the NHS COVID Pass to demonstrate COVID-19 status (/guidance/nhs-covid-pass)
Coronavirus (COVID-19): guidance and support (/coronavirus)
Report a COVID-19 rapid lateral flow test result (/report-covid19-result)
Passport rules for travel to Europe (/guidance/passport-rules-for-travel-to-europe)
Detailed guidance
Travel abroad from England during coronavirus (COVID-19) (/guidance/travel-abroad-from-

england-during-coronavirus-covid-19)
Collection
Coronavirus (COVID-19): guidance for local government (/government/collections/coronavirus-

covid-19-guidance-for-local-government)
Coronavirus (COVID-19): transport and travel guidance (/government/collections/coronavirus-covid-
19-transport-and-travel-guidance)
AR10066
Explore the topic
Entering England during coronavirus (/coronavirus-taxon/entering-england)
All content is available under the Open Government Licence

v3.0, except where otherwise stated © Crown copyright
17
AR10067 AR10067
WHO Pharmaceuticals 2022
NEWSLETTER No. 1
The WHO Pharmaceuticals Newsletter provides you

WHO Vision for Safety of
Medicinal Products with the latest information on the safety of medicinal
No country left behind: products and legal actions taken by regulatory
worldwide pharmacovigilance authorities around the world. It also provides signals
for safer medicinal products,
safer patients based on information from the WHO global database of
individual case safety reports, VigiBase.
In addition, this edition of the Newsletter includes a

The aim of the Newsletter is short article on the recent Advisory Committee on
to disseminate regulatory
information on the safety of Safety of Medicinal Products (ACSoMP) meeting.
medicinal products,
based on communications
received from our network of
national pharmacovigilance centres
and other sources such as
specialized bulletins and journals,
as well as partners in WHO.
The information is produced in

the form of résumés in English,
full texts of which may be obtained
on request from:
Pharmacovigilance,
MHP/RPQ,
World Health Organization,
1211 Geneva 27, Switzerland, Contents
E-mail address:
pvsupport@who.int
This Newsletter is also available at: Regulatory matters
https://www.who.int/teams/regula
tion-prequalification Safety of medicines
Signal
Feature
AR10068
WHO Pharmaceuticals Newsletter No. 1, 2022
ISBN 978-92-4-004245-2 (electronic version)

ISBN 978-92-4-004246-9 (print version)
© World Health Organization 2022
Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO
licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo).
Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the
work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any
specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must
license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should
add the following disclaimer along with the suggested citation: “This translation was not created by the World Health
Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall
be the binding and authentic edition”.
Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the
World Intellectual Property Organization (http://www.wipo.int/amc/en/mediation/rules/).
Suggested citation. WHO Pharmaceuticals Newsletter No. 1, 2022. Geneva: World Health Organization; 2022. Licence:
CC BY-NC-SA 3.0 IGO.
Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris.
Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/bookorders. To submit requests for
commercial use and queries on rights and licensing, see https://www.who.int/copyright.
Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or
images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the
copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely
with the user.
General disclaimers. The designations employed and the presentation of the material in this publication do not imply the
expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or
of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent
approximate border lines for which there may not yet be full agreement.
The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or
recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the
names of proprietary products are distinguished by initial capital letters.
All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the
published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the
interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use.
AR10069
Table of Contents
Regulatory Matters
Bisphosphonates, denosumab and romosozumab ........................................... 5
Cefoperazone and sulbactam .......................................................................... 5
Chloral hydrate, cloral betaine ........................................................................ 5
COVID-19 vaccine NRVV Ad (ChAdOx1 nCoV-19) .......................................... 6
COVID-19 vaccine NRVV Ad26 (JNJ 78436735) ............................................. 6
Eperisone ....................................................................................................... 7
Erenumab ....................................................................................................... 7
Fingolimod ...................................................................................................... 7
Gadolinium-based contrast agents .................................................................. 8
Hydrocortisone................................................................................................ 8
Ivermectin ....................................................................................................... 8
Magnesium sulfate .......................................................................................... 9
Methylphenidate ............................................................................................. 9
Minocycline ..................................................................................................... 9
Nifedipine ....................................................................................................... 9
Ocrelizumab ................................................................................................. 10
Parenteral iron products ................................................................................ 10
Pentosan polysulfate sodium ........................................................................ 10
Pregabalin .................................................................................................... 11
Remdesivir .................................................................................................... 11
Sertraline ...................................................................................................... 11
Statins .......................................................................................................... 12
Tetanus, diphtheria and pertussis (Tdap) vaccine ......................................... 12
Tinidazole ..................................................................................................... 12
Tofacitinib, Baricitinib and Upadacitinib ......................................................... 12
Topical corticosteroids .................................................................................. 13
Tramadol ...................................................................................................... 14
Safety of medicines
Aflibercept .................................................................................................... 15
Atezolizumab ................................................................................................ 15
Bevacizumab ................................................................................................ 15
Cefuroxime ................................................................................................... 15
WHO Pharmaceuticals Newsletter No. 1, 2022 • 3
AR10070
Table of Contents
Colchicine ..................................................................................................... 15
Empagliflozin ................................................................................................ 15
Finasteride .................................................................................................... 16
Infliximab ...................................................................................................... 16
Octreotide ..................................................................................................... 16
Propylthiouracil and carbimazole................................................................... 16
Selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline
reuptake inhibitors (SNRIs) ........................................................................... 17
Signal
Covid-19 vaccines AND hearing loss and tinnitus .......................................... 18
Methotrexate and muscle spasm ................................................................... 31
Tocilizumab and Gastric perforation .............................................................. 35
Feature
Advisory Committee on Safety of Medicinal Products (ACSoMP) Eighteenth
meeting ......................................................................................................... 42
All the previous issues of the WHO Pharmaceuticals Newsletter can be accessed from our website at:
https://www.who.int/publications/i?healthtopics=c896df17-29f4-4e3a-b81f-302f999ed12d,9bc69cb6-e97e-
4ae9-adf3-76d5b171ff08,5f7b6914-1953-48b6-aabe-9b997a16999e&publishingoffices=a511529e-adb5-49ea-
bbde-546a3c26cba7&healthtopics-hidden=true&publishingoffices-hidden=true&regionscountries-hidden=true

AR10071
Regulatory Matters
Bisphosphonates, Japan. The MHLW and the and pharmacological). The

PMDA have announced that the product information is being
denosumab and product information for the amended to clarify the
products containing both restricted use.
romosozumab
cefoperazone and sulbactam
(Sulperazon®) should be Chloral hydrate (Welldorm
Risk of atypical fracture in
revised to include the risk of Elixir®) and cloral betaine
non-femur sites (Welldorm®) are indicated for
acute coronary syndrome
accompanying allergic reaction. severe insomnia that is
Japan. The Ministry of Health,
interfering with normal daily
Labour and Welfare (MHLW) Cefoperazone and sulbactam life and where other therapies
and the Pharmaceuticals and are indicated for the treatment have failed, as an adjunct to
Medical Devices Agency of infectious diseases which are non-pharmacological therapies.
(PMDA) have announced that strains of genus susceptible to Chloral hydrate is licensed for
the product information for the substances. use in adults and in children
bisphosphonates, denosumab
The MHLW and the PMDA aged two years and older.
(Ranmark®) and
reviewed two cases of acute Cloral betaine tablets are
romosozumab (Evenity®)
coronary syndrome licensed for use in adults and
should be revised to include
accompanying allergic reaction adolescents aged 12 years and
the risk of atypical fracture in
in patients treated with the older.
non-femur sites.
products reported in Japan.
Bisphosphonates (including The MHRA conducted a review
alendronate, ibandronate, Reference: of safety and efficacy data and
etidronate, zoledronic, Revision of Precautions, sought independent expert
pamidronate, minodronic acid MHLW/PMDA, 12 October 2021 advice including for paediatric
and risedronate), denosumab (link to the source within sleep disorders. No new safety
and romosozumab are www.pmda.go.jp/english/) concerns were identified;
indicated for the treatment of however, in view of the
osteoporosis. carcinogenicity data in animals
Chloral hydrate, and the lack of long-term
The MHLW and the PMDA
studies, a risk in humans for
reviewed reports of atypical cloral betaine
long-term use was not
fracture in non-femur sites
excluded. As such, the above
(such as ulna or tibia) following Restriction of paediatric
restriction was recommended
administration of those indication
where the benefits of short-
products.
United Kingdom. The term use outweigh any
Reference: Medicines and Healthcare potential risk, reflecting current
Revision of Precautions, Products Regulatory Agency clinical practice.
MHLW/PMDA, 20 June 2021 (MHRA) has announced that
(link to the source within In addition, the maximum
the paediatric indication for
www.pmda.go.jp/english/) treatment period for these
chloral hydrate (for children
medicines in all patients has
(See WHO Pharmaceuticals aged two years and older) and
now been defined as two
Newsletter No.3, 2019: Risk of cloral betaine (children aged 12
hypercalcaemia and multiple weeks in the product
years and older) has been
vertebral fractures for denosumab information because their
restricted to short-term
in UK) prolonged use is associated
treatment (maximum two
with tolerance and the risks of
weeks) of severe insomnia only
dependence and abuse.
when the child or adolescent
Cefoperazone and has a suspected or definite
Repeated courses are not
recommended and can only be
sulbactam neurodevelopmental disorder
administered following medical
and when the insomnia is
specialist re-assessment.
Risk of acute coronary interfering with normal daily
Following prolonged treatment,
syndrome accompanying life after treatment failure with
the dose should be slowly
other therapies (behavioural
allergic reaction tapered before discontinuation

AR10072
Regulatory Matters
to avoid delirium. within www.ema.europa.eu) within www.ema.europa.eu)
Reference:
Drug Safety Update, MHRA, 6
COVID-19 vaccine 2. Risk of immune
October 2021 (link to the source thrombocytopenia (ITP)
within www.gov.uk/mhra) NRVV Ad26 (JNJ
Europe. The PRAC has
78436735)
recommended a change to the
product information for COVID-
1. Risk of venous
COVID-19 vaccine thromboembolism (VTE)
19 vaccine NRVV Ad26 (JNJ
78436735) (COVID-19 vaccine
NRVV Ad (ChAdOx1 Janssen®) to include a warning
Europe. The PRAC has
nCoV-19) recommended that on immune thrombocytopenia
thromboembolism (VTE) should (ITP) as an adverse reaction
Risk of immune be listed as a rare side effect in with an unknown frequency.
thrombocytopenia (ITP) the product information for ITP is a condition in which the
COVID-19 vaccine NRVV Ad26 immune system mistakenly
Europe. The (JNJ 78436735) (COVID-19 targets platelets in blood.
Pharmacovigilance Risk vaccine Janssen®). VTE is a The PRAC assessed cases of
Assessment Committee (PRAC) condition in which a blood clot ITP reported following
has recommended a change to forms in a deep vein, usually in vaccination and evidence from
the product information for a leg, arm or groin, and may the scientific literature.
COVID-19 vaccine NRVV Ad travel to the lungs causing a
(ChAdOx1 nCoV-19) blockage of the blood supply, Healthcare professionals should
(Vaxzevria®) to include a with possible life-threatening consider the risk of developing
warning on immune consequences. low platelet levels prior to
thrombocytopenia (ITP) as an administering the vaccine if an
adverse reaction with an COVID-19 vaccine NRVV Ad26 individual has a history of ITP.
unknown frequency. ITP is a (JNJ 78436735) is indicated for They are recommended to
condition in which the immune preventing COVID-19. monitor platelet levels
system mistakenly targets The PRAC reviewed data form following vaccination in
platelets in blood. two large clinical studies and individuals with a history of
post marketing surveillance ITP.
COVID-19 vaccine NRVV Ad
(ChAdOx1 nCoV-19) is a and concluded that there is a Reference:
vaccine for preventing COVID- possible link to rare cases of Patients and carers, EMA, 1
19. VTE with COVID-19 vaccine October 2021 (link to the source
NRVV Ad26 (JNJ 78436735). within www.ema.europa.eu)
The PRAC assessed cases of
ITP reported following The PRAC has also
vaccination and evidence from recommended to provide a
warning to raise awareness 3. Risk of dizziness and
the scientific literature.
among healthcare professionals tinnitus
Healthcare professionals should and people taking the vaccine,
consider the risk of developing Europe. The PRAC has
especially those who may have
low platelet levels prior to recommended that dizziness
an increased risk of VTE, and
administering the vaccine if an and tinnitus should be listed as
to assess a potential diagnosis
individual has a history of ITP adverse reactions in the
of thrombosis with
and are recommended to product information of COVID-
thrombocytopenia syndrome
monitor platelet levels 19 vaccine NRVV Ad26 (JNJ
(TTS) when signs are present
following vaccination in 78436735) (COVID-19 vaccine
within three weeks after
individuals with a history of Janssen®). Tinnitus is ringing
vaccination.
ITP. or other noises in one or both
Reference: ears.
Reference: Patients and carers, EMA, 1
Patients and carers, EMA, 1 The PRAC assessed the
October 2021 (link to the source
October 2021 (link to the source available evidence including

AR10073
Regulatory Matters
cases of dizziness identified in cutaneous symptoms. 9 September 2021 (link to the

spontaneous reports and cases source within www.tga.gov.au)
Reference:
of tinnitus identified in clinical
Based on the communication
trials and spontaneous reports
from MFDS and KIDS,
and concluded that cases of
November 2021 Fingolimod
dizziness and tinnitus are
linked to the administration of Risk of liver injury
COVID-19 vaccine NRVV Ad26
(JNJ 78436735). Erenumab New Zealand. The Medsafe
has announced that the
Reference: Risk of hypertension
product information for
Patients and carers, EMA, 6
Australia. The Therapeutic fingolimod (Gilenya®) has
August 2021 (link to the source
Goods Administration (TGA) been updated to include the
within www.ema.europa.eu)
has announced that the risk of liver injury, to require
product information for liver function monitoring during
and after treatment, and to
Eperisone erenumab (Aimovig®) has
include criteria for stopping
been updated with a warning
statement about a potential treatment to prevent serious
Risk of Stevens-Johnson
causal relationship between the drug-induced liver injury.
syndrome (SJS) and toxic
epidermal necrolysis (TEN) drug and hypertension.
Fingolimod is an
Erenumab is indicated for immunomodulating drug
Republic of Korea. The
prophylaxis of migraine in indicated for the treatment of
Ministry of Food and Drug
adults. relapsing multiple sclerosis.
Safety (MFDS) has updated the
product information for The TGA reviewed cases of the
Clinically significant liver injury
eperisone products (oral) to development of hypertension
and cases of acute liver failure
include the risk of Stevens- and worsening of pre-existing
requiring liver transplant have
Johnson syndrome (SJS) and hypertension reported following
been reported in patients
toxic epidermal necrolysis use of the drug in the
treated with fingolimod and the
(TEN). postmarketing setting
Centre for Adverse Reactions
internationally. Hypertension
Eperisone is a centrally-acting Monitoring (CARM) received
can occur at any time during
muscle relaxant used for four adverse reaction reports of
treatment, but it was most
relieving painful muscle spasms increased hepatic enzymes
frequently reported within
or rigidity in musculoskeletal where fingolimod was the
seven days of dose
and neuromuscular disorders. suspected medicine.
administration. In the majority
Healthcare professionals are
The Korea institute of Drug of cases, the onset or
advised to check recent
safety and Risk Management worsening of hypertension was
transaminase and bilirubin
(KIDS) reviewed one report, reported after the first dose of
levels before initiation of
which suggested a causal link erenumab.
treatment, to promptly
between oral eperisone and Healthcare professionals should
measure transaminase and
SJS/TEN, and information monitor patients treated with
bilirubin levels if the patient
from a foreign regulatory erenumab for new-onset
treated with fingolimod reports
authority and a medical hypertension or worsening of
signs and symptoms of liver
database. pre-existing hypertension. If
injury, and not to resume the
hypertension is observed and
Healthcare professionals should treatment unless a plausible
evaluation fails to establish an
be aware of the signs and alternative aetiology for the
alternative etiology, they
symptoms of SJS and TEN to signs and symptoms of liver
should consider whether
allow early diagnosis and injury can be established.
discontinuation of erenumab is
prompt treatment. Patients are Reference:
warranted.
advised to seek immediate Prescriber Update, Medsafe,
medical attention if they September 2021 (link to the
Reference:
experience these severe source within
Medicines Safety Update, TGA,

AR10074
Regulatory Matters
www.medsafe.govt.nz/) harm to fetuses and infants. Ivermectin

(See WHO Pharmaceuticals In the review process, case
Newsletter No.1, 2021: Risk of reports of congenital anomalies 1. Risk of disturbed
serious liver injury and herpes consciousness
with the use of GBCAs were
meningoencephalitis in UK)
also assessed but no link was
Japan. The MHLW and the
found between the use of
PMDA have announced that the
GBCAs during pregnancy and
Gadolinium-based the risk of congenital
ivermectin (Stromectol®)
anomalies.
contrast agents should be revised to include
Reference: the risk of disturbed
Potential risk of stillbirth Summary Safety Review, consciousness.
Health Canada, 22 September
and neonatal death
2021 (link to the source within Ivermectin is indicated for the
Canada. Health Canada
www.hc-sc.gc.ca) treatment of intestinal
announced that it will work strongyloidiasis and scabies.
with the manufacturers of The MHLW and the PMDA
gadolinium-based contrast reviewed four cases of
agents (GBCAs) to include the
Hydrocortisone
disturbed consciousness
potential risks of stillbirth and reported in patients treated
Risk of hypertrophic
neonatal death in their with ivermectin in Japan and
cardiomyopathy in neonates
Canadian Product Monographs other countries.
(CPMs) to raise awareness and infants
among healthcare professionals Reference:
Japan. The MHLW and the Revision of Precautions,
and encourage reporting of
PMDA have announced that the MHLW/PMDA, 12 October 2021
these potential safety issues.
product information for (link to the source within
GBCAs are used to make hydrocortisone preparations www.pmda.go.jp/english/)
certain body tissues easier to (oral and injectable dosage
see during a magnetic forms) should be revised to
resonance imaging (MRI) or a include the risk of hypertrophic 2. Potential risk of
magnetic resonance cardiomyopathy in neonates encephalopathy
angiography (MRA) scan. and infants.
Gadopentetate dimeglumine, Saudi Arabia. The Saudi Food
Hydrocortisone preparations
gadobenate dimeglumine, & Drug Authority (SFDA) has
are used for various indications
gadodiamide, gadoxetate announced that healthcare
including endocrine and allergic
disodium, gadoterate professionals should be aware
diseases.
meglumine, gadobutrol and of the potential risk of
gadoteridol are authorized as The MHLW and the PMDA encephalopathy associated with
GBCAs. reviewed cases of hypertrophic the use of ivermectin and to
cardiomyopathy reported in monitor any signs or symptoms
Health Canada reviewed
neonates and infants treated in treated patients.
information from databases
with hydrocortisone
(Canada Vigilance database The SFDA reviewed eight case
preparations overseas.
and VigiBase), where reports of reports, of which two
stillbirths or neonatal deaths Reference: suggested possible association
with the use of GBCAs during Revision of Precautions, of encephalopathy with
pregnancy are received, and MHLW/PMDA, 20 June 2021 ivermectin and one case
literature and concluded that (link to the source within positive dechallenge reaction
there is not enough information www.pmda.go.jp/english/) reported, as well as the
to rule out a link between the literature.
use of GBCAs during pregnancy
Reference:
and the risks of stillbirth and
Safety Alerts, SFDA, 17 August
neonatal death. The measure
2021 (link to the source within
will be taken as a precaution, www.sfda.gov.sa)
given the potential for serious
AR10075
Regulatory Matters
Magnesium sulfate included and the pregnancy The TGA reviewed four cases of
category has now been agranulocytosis reported
Risk of rickets-like bone changed so that following treatment with
methylphenidate should not be minocycline. One case had a
lesion in neonates at birth
prescribed for women of positive dechallenge while
Japan. The MHLW and the childbearing age unless, in the another was a fatal case
PMDA have announced that the opinion of the physician, the reported as tetracycline-
product information for potential benefits outweigh the induced agranulocytosis. In the
magnesium sulfate (injection) possible risks. other two cases, minocycline-
indicated for eclampsia should induced agranulocytosis could
Methylphenidate is a central
be revised to include the risk of not be ruled out, as the cases
nervous system stimulant. It is
rickets-like bone lesion in were confounded by other
available in the forms of
neonates at birth with medicines known to cause
immediate-release tablets
prolonged administration of agranulocytosis.
(Ritalin 10®), modified-release
this drug during pregnancy. Healthcare professionals should
capsules (Ritalin LA®) and
be aware of the potential risk
The MHLW and the PMDA modified-release tablets
of agranulocytosis associated
reviewed cases of rickets-like (Concerta®) and is indicated
with minocycline and the
bone lesion reported in for the treatment of ADHD.
importance of early recognition
neonates born to patients The TGA reviewed large and monitoring of full blood
treated with magnesium sulfate observational studies and count and liver function tests
in Japan and concluded that a observed a small increased during treatment. Prior to
causal relationship between the occurrence of foetal cardiac treatment with minocycline,
drug and event was reasonably malformations in women who patients should be made aware
possible in all the cases. The received methylphenidate of the risk, including signs and
shortest duration of during the first trimester of symptoms, and what to do in
administration with magnesium pregnancy, compared with the event of suspected
sulfate (injections) to the non-exposed pregnancies. agranulocytosis.
mother was 18 days.
Reference:
Reference: Reference:
Revision of Precautions, Medicines Safety Update, TGA,
26 July 2021 (link to the source
MHLW/PMDA, 20 June 2021 30 August 2021 (link to the
within www.tga.gov.au)
(link to the source within source within www.tga.gov.au)
www.pmda.go.jp/english/)
Nifedipine
(See WHO Pharmaceuticals Minocycline
Newsletter No.4, 2019: Risk of Risk of pulmonary oedema
skeletal adverse effects in neonates
Risk of agranulocytosis when used in pregnancy
in UK)
Australia. The TGA has Australia. The TGA has
announced that the product announced that the product
Methylphenidate information for minocycline information for nifedipine
(Minomycin®, Akamin®) is in products has been updated to
Potential risk of birth the process of being updated to provide new information about
defects and malformations include information about the risk of acute pulmonary
agranulocytosis, a rare but oedema when used as a
Australia. The TGA has potentially life-threatening tocolytic agent (inhibiting
announced that the product adverse event, where there is myometrial smooth muscle
information for an extremely low number of contractions) for the treatment
methylphenidate products has granulocytes (a type of white of preterm labor in pregnancy.
been updated with new blood cell) in the blood.
information about use in Nifedipine is a calcium channel
pregnancy. Updated safety Minocycline is a tetracycline blocker and indicated for the
information relating to birth antibiotic used to treat management of chronic stable
defects and malformations is bacterial infections. angina pectoris and vasospastic

AR10076
Regulatory Matters
angina pectoris (Prinzmetal's recognition and treatment. impractical; and iron sucrose
angina, variant angina) due to Signs and symptoms of late (Venofer®) is for the treatment
coronary heart disease and the onset neutropenia may not be of iron deficiency anaemia in
treatment of hypertension. apparent initially and can occur patients undergoing chronic
Nifedipine is contraindicated in at least four weeks after the haemodialysis and who are
pregnancy and during last administration of receiving supplemental
lactation. ocrelizumab. erythropoietin therapy.
The TGA reviewed four adverse Reference: Hypersensitivity is a class

event reports involving off- Medicines Safety Update, TGA, effect that is well documented
label use of nifedipine in 26 July 2021 (link to the source in the product information of all
pregnancy. The risk was higher within www.tga.gov.au) parenteral iron products. The
in cases of multiple pregnancy TGA concluded that fetal
(twins or more), with an bradycardia and Kounis
intravenous administration Parenteral iron syndrome are biologically
route or concomitant use of plausible as a result of
beta-2 agonists. products hypersensitivity reactions.
Reference: Risk of fetal bradycardia Reference:

Medicines Safety Update, TGA, and Kounis syndrome Medicines Safety Update, TGA,
within www.tga.gov.au) Australia. The TGA has
within www.tga.gov.au)
announced that the product
information for parenteral iron
Ocrelizumab products has been updated
Pentosan polysulfate
class-wide to include
Risk of late onset information about fetal sodium
neutropenia bradycardia and Kounis
syndrome, which is the Potential risk of pigmentary
Australia. The TGA has concurrence of acute coronary maculopathy
announced that the product syndromes with conditions
information for ocrelizumab associated with mast cell Australia. The TGA has
(Ocrevus®) has been updated activation. Both conditions can announced that the product
to include a warning and have serious clinical information for pentosan
further information about late implications. polysulfate sodium (Elmiron®)
onset neutropenia. has been updated with a
There are four parenteral iron
warning about potential
Ocrelizumab is a recombinant products marketed in Australia:
pigmentary maculopathy,
humanised anti-CD20 ferric carboxymaltose
especially after long-term use.
monoclonal antibody (IgG1 (Ferinject®) and ferric
subtype) that is indicated for derisomaltose (Monofer®) are Pentosan polysulfate sodium is
patients with relapsing forms of indicated for iron deficiency indicated for the treatment of
multiple sclerosis and primary where oral administration is bladder pain syndrome
progressive multiple sclerosis. ineffective or contraindicated, (interstitial cystitis).
or where there is a need to
The TGA reviewed four The TGA reviewed rare cases of
deliver iron rapidly; iron
reported cases of neutropenia pigmentary maculopathy with
polymaltose (Ferrosig
associated with ocrelizumab. the use of pentosan polysulfate
injection®) is for the treatment
Cases of late onset of sodium, especially after long-
of iron deficiency anaemia
neutropenia have been term use, reported in the
when oral iron therapy is
reported at least four weeks literature. Visual symptoms
contraindicated, enteric
after the last Ocrevus infusion. could include complaints of
absorption of iron is defective,
difficulty to read and slow
Healthcare professionals should or when patient non-
adjustment in low or reduced
be advised that late onset compliance or persistent
light environments.
neutropenia is a serious safety gastrointestinal intolerance
concern and requires prompt makes oral therapy Healthcare professionals should

AR10077
Regulatory Matters
be aware of this potential and without other risk factors reports of sinus bradycardia in
adverse event and advise for respiratory depression. patients receiving remdesivir in
patients receiving pentosan their database and in the
polysulfate sodium of the risks. Healthcare professionals should literature and concluded that a
All patients should have regular be advised that patients with link between the use of
ophthalmic examinations for risk factors (compromised remdesivir and the risk of sinus
early detection of pigmentary respiratory function, bradycardia is possible.
maculopathy, particularly those respiratory or neurological
Reference:
on long-term use of pentosan disease, renal impairment,
Summary Safety Review,
polysulfate sodium. concomitant use of CNS Health Canada, 18 August
depressants and older age (> 2021 (link to the source within
Reference:
65 years)) may be at higher www.hc-sc.gc.ca)
risk of experiencing respiratory
11 October 2021 (link to the (See also WHO Pharmaceuticals
depression with pregabalin and
source within www.tga.gov.au) Newsletter No.4, 2021: Risk of
dose adjustment may be
sinus bradycardia in Europe)
(See WHO Pharmaceuticals necessary. Patients taking the
Newsletter No.6, 2019: Rare risk of medicine should be advised to
pigmentary maculopathy in UK)
contact their doctor if they
experience trouble breathing or Sertraline
have shallow breaths and not
Pregabalin to drink alcohol while taking Potential risk of microscopic
pregabalin. colitis
Risk of severe respiratory
depression Reference: Singapore. The Health
Newsletters and Reports, Sciences Authority (HSA) has
Ireland. The Health Products HPRA, 16 September 2021 (link
announced that it is working
Regulatory Authority (HPRA) to the source within www.hpra.ie)
with the manufacturers of
has announced that the
(See also WHO Pharmaceuticals sertraline-containing products
Newsletter No.2, 2021: Risk of to update the product
pregabalin-containing
severe respiratory depression in information to include
medicinal products will be UK) microscopic colitis as an
updated to include a warning
adverse event. Microscopic
on respiratory depression and
colitis is a rare inflammatory
to add it as a possible adverse
disorder of the colon.
reaction with unknown Remdesivir
frequency, following the Sertraline is a selective
conclusions of the PRAC. Potential risk of sinus serotonin reuptake inhibitor
bradycardia (SSRI) indicated for the
Pregabalin-containing medicinal treatment of depression,
products are indicated for the Canada. Health Canada has obsessive compulsive disorder,
treatment of neuropathic pain announced that it will work panic disorder, post-traumatic
in adults, as adjunctive therapy with the manufacturer of stress disorder, social phobia
in adults for specific forms of remdesivir (Veklury®) to and pre-menstrual dysphoric
epilepsy and for generalized update the product information disorder.
anxiety disorder in adults. to include a warning on the
The HSA reviewed a case-
potential risk of sinus
The PRAC reviewed safety data control study, three case
bradycardia. Sinus bradycardia
and concluded that pregabalin reports of microscopic colitis
occurs when the heart beats
is associated with reports of related to the use of sertraline
slower than normal.
respiratory depression in the and the decisions by other
Remdesivir is indicated to treat regulatory authorities.
absence of concomitant
COVID-19 in adults with
therapy with opioids or other Healthcare professionals should
pneumonia who require
central nervous system (CNS) be advised to consider the
oxygen.
depressants, in patients with possibility of microscopic colitis
Health Canada assessed case in patients on sertraline who

AR10078
Regulatory Matters
present with prolonged or most pregnant patients, or with recent vaccination history.
severe diarrhoea. Diarrhoea is they can consider the ongoing
a common adverse drug therapeutic needs of the Reference:
reaction associated with the individual patient, particularly Based on the communication
use of sertraline. those at very high risk for from MFDS and KIDS,
cardiovascular events during November 2021
Reference:
pregnancy. Patients taking
Safety Alerts, HSA, 18 October
statins should notify their
www.hsa.gov.sg)
healthcare professionals if they Tinidazole
become pregnant or suspect
(See also WHO Pharmaceuticals they are pregnant. Those who Risk of fixed eruption
Newsletter No.4, 2021: potential require statins after giving
risk of microscopic colitis in birth should not breastfeed and India. The National
Singapore) should use alternatives such as Coordination Centre –
infant formula. Pharmacovigilance Programme
of India (NCC-PvPI), Indian
Reference:
Pharmacopoeia Commission
Statins MedWatch, US FDA, 20 July
(IPC) has advised the Central
Drugs Standard Control
Removal of contraindication www.fda.gov)
Organization (CDSCO) to revise
for pregnant women the prescribing information
leaflet (PIL) for tinidazole to
USA. The US Food and Drug
include fixed eruption as an
Administration (FDA) has Tetanus, diphtheria
adverse drug reaction.
requested revisions to the and pertussis (Tdap)
information in the prescribing Tinidazole is indicated for the
information for the entire class vaccine treatment of intestinal
of statin medicines about use amoebiasis, giardiasis,
in pregnancy. These changes Risk of Guillain-Barré trichomoniasis and anaerobic
include removing the syndrome infections.
contraindication against using NCC-PvPI, IPC reviewed 71
Republic of Korea. The MFDS
these medicines in all pregnant case reports of tinidazole
patients. has updated the product
information for tetanus, associated fixed eruption and a
Statins are a class of medicines diphtheria and pertussis (Tdap) strong causal relationship
that have been used to lower vaccine (Boostrix®) to include between them was found.
low-density lipoprotein the risk of Guillain-Barré Reference:
cholesterol (LDL-C) in the syndrome (GBS). Based on the communication
blood. Medicines in the statin from IPC, India, November
class include atorvastatin, Tdap vaccine is indicated for
2021 (ipc.gov.in)
fluvastatin, lovastatin, booster immunization against
pitavastatin, pravastatin, tetanus, diphtheria and
pertussis in individuals aged 10
rosuvastatin, and simvastatin. Tofacitinib,
years and older.
It was concluded that Baricitinib and
contraindicating these drugs in The KIDS reviewed one report,
all pregnant women is not Upadacitinib
which suggested a causal link
appropriate because the between Tdap vaccine
Risk of serious heart-related
benefits of statins may include administration and GBS, and
prevention of serious or events, cancer, blood clots,
other information from a
potentially fatal events in a foreign regulatory authority
and death
small group of very high-risk and a medical database.
1. USA. The US FDA has
pregnant patients.
requested that the boxed
Healthcare professionals should Healthcare professionals should
warnings for tofacitinib
discontinue statin therapy in be aware of the signs and
(Xeljanz®/Xeljanz XR®),
symptoms of GBS in patients
AR10079
Regulatory Matters
baricitinib (Olumiant®) and the information that tofacitinib withdrawal reactions

upadacitinib (Rinvoq®), are should not be used in patients
updated to include the risk of older than 65 years of age, United Kingdom. The MHRA
serious heart-related events, people who are current or past has warned that rare, severe
cancer, blood clots, and death. smokers, or individuals with adverse effects can occur on
other cardiovascular (e.g., stopping treatment with topical
Tofacitinib, baricitinib and diabetes or coronary artery corticosteroids, often after
upadacitinib are janus kinase disease) or malignancy risk long-term continuous or
(JAK) inhibitors and are used to factors unless there are no inappropriate use of moderate
treat inflammatory conditions suitable alternative treatments. to high potency products.
such as rheumatoid arthritis. Information about the risks and
The MHRA reviewed the results characteristics of topical steroid
A review of safety data for of a clinical safety trial to withdrawal reactions will be
tofacitinib was recently evaluate the safety of added to the product
completed in USA. Based on tofacitinib compared with TNF information for topical
this review increased risks of blockers and identified these corticosteroid medicines.
serious heart-related events, risk factors.
cancer, blood clots, and death Topical corticosteroids are used
were identified for tofacitinib Reference: for treatments of skin
compared with TNF blockers in Drug Safety Update, MHRA, 6 conditions such as eczema,
the treatment of patients with October 2021 (link to the source psoriasis, and atopic
rheumatoid arthritis. within www.ema.europa.eu) dermatitis. They are available
in four different levels of
Baricitinib and upadacitinib,
potencies.
also used for inflammatory
3. Japan. The MHLW and the
conditions in the same class, The MHRA reviewed 55 reports
PMDA have announced that the
are considered to have a risk indicative of topical steroid
package insert for tofacitinib
similar to that of tofacitinib. withdrawal reactions, most of
should be revised to include
Healthcare professionals should the risk of cardiovascular which were reported by
consider the benefits and risks events, such as myocardial patients, and information
for individual patients prior to infarction. available in the literature and
initiating or continuing therapy from other regulators and
with these medicines. Patients The MHLW and the PMDA sought advice from clinical
should be advised to seek reviewed the results of a experts. Although it was not
emergency medical attention if clinical safety trial to evaluate possible to estimate the
they experience signs and the safety of tofacitinib frequency of these reactions,
symptoms of a heart attack, compared with TNF blockers given the number of patients
stroke, or blood clot. Patients and identified these risk who use topical corticosteroids,
should tell their healthcare factors. it was understood that reports
professional their history and of severe withdrawal reactions
Reference:
risk factors for those events were very infrequent.
Revision of Precautions,
and seek emergency help
MHLW/PMDA, 12 October 2021 To reduce the risks of these
immediately if they have any of
(link to the source within events, it is recommended that
those symptoms.
www.pmda.go.jp/english/) healthcare professionals should
Reference: (See also WHO Pharmaceuticals prescribe the lowest potency of
MedWatch, US FDA, 1 Newsletter No.4, 2021: Risk of topical corticosteroid needed
September 2021 (link to the cardiovascular events and cancer in and ensure patients know how
source within www.fda.gov) Europe)
to use it safely and effectively.
Reference:
Topical Drug Safety Update, MHRA, 15
2. United Kingdom. The
September 2021 (link to the
MHRA has announced that the corticosteroids source within www.gov.uk/mhra)
tofacitinib will be updated with Risk of topical steroid
AR10080
Regulatory Matters
Tramadol
Risk of urinary retention
India. The NCC-PvPI, IPC has

advised the CDSCO to revise
the PIL for tramadol to include
urinary retention as an adverse
drug reaction.
Tramadol is indicated for the

treatment of moderate to
severe pain, diagnostic
procedures and surgical pain.
NCC-PvPI, IPC reviewed seven

reports of tramadol-associated
urinary retention and a causal
relationship between them was
found.
Reference:
Based on the communication
from IPC, India, November
2021 (ipc.gov.in)

AR10081
Safety of Medicines
Aflibercept Bevacizumab Colchicine

Potential risk of Fournier’s Potential risk of Fournier’s Potential risk of pneumonia
gangrene gangrene
Saudi Arabia. The SFDA has
Saudi Arabia. The SFDA has Saudi Arabia. The SFDA has released a potential safety
released a potential safety released a potential safety signal concerning pneumonia
signal concerning Fournier’s signal concerning Fournier’s associated with the use of
gangrene associated with the gangrene associated with the colchicine.
use of aflibercept. use of bevacizumab.
Colchicine is indicated for
Aflibercept is indicated for the Bevacizumab is a monoclonal prophylaxis of gout flares in
treatment of neovascular (wet) antibody inhibiting VEGF-A and adults.
age-related macular indicated for the treatment of
The SFDA reviewed 40 case
degeneration and metastatic non-small cell lung cancer and
reports, four of which
colorectal cancer. other cancers.
supported the association, and
The SFDA reviewed five case The SFDA reviewed 35 case the literature.
reports, two of which reports, nine of which
Reference:
supported the association, and supported the association, and
the literature. the literature.
Reference: Reference: www.sfda.gov.sa)
Safety Alerts, SFDA, 21 Safety Alerts, SFDA, 9 August
September 2021 (link to the 2021 (link to the source within
source within www.sfda.gov.sa) www.sfda.gov.sa) Empagliflozin
Risk of ketoacidosis and

Atezolizumab Cefuroxime Fournier’s gangrene
Potential risk of keratitis Potential risk of Kounis New Zealand. The Medsafe
syndrome has announced that
Saudi Arabia. The SFDA has empagliflozin is associated with
released a potential safety Saudi Arabia. The SFDA has the risk of ketoacidosis and
signal concerning keratitis released a potential safety Fournier’s gangrene
associated with the use of signal concerning Kounis (necrotising fasciitis of the
atezolizumab. syndrome associated with the perineum).
use of cefuroxime.
Atezolizumab is a monoclonal
antibody inhibiting PD-L1 and Empagliflozin is a sodium
Cefuroxime is cephalosporin
indicated for the treatment of glucose co-transporter 2
antibacterial drug indicated for
locally advanced or metastatic (SGLT2) inhibitors and is used
the treatment of infectious
urothelial carcinoma after prior for the treatment of type two
diseases caused by sensitive
chemotherapy or that are diabetes mellitus.
bacteria.
considered cisplatin ineligible. The CARM received three
The SFDA reviewed 11 case reports of ketoacidosis and two
The SFDA reviewed four case reports, three of which reports of Fournier’s gangrene
reports, one of which supported the association, and following initiation of
supported the association, and the literature. empagliflozin.
the literature.
Reference:
Reference: Safety Alerts, SFDA, 21 June For the risk of ketoacidosis,
Safety Alerts, SFDA, 9 August 2021 (link to the source within healthcare professionals are
2021 (link to the source within www.sfda.gov.sa) advised to consider stopping
www.sfda.gov.sa) empagliflozin temporarily
during an acute illness,
particularly if patients are
unwell, febrile or vomiting and
AR10082
Safety of Medicines
not eating. Empagliflozin Infliximab indications, while one product

should also be temporarily (Sandostatin LAR®) may only
stopped before undergoing Potential risk of bursitis be administered by deep
medical procedures or surgery. intragluteal injection.
For the risk of Fournier’s Saudi Arabia. The SFDA has
The TGA evaluated the risk of
gangrene, patients should be released a potential safety
atrioventricular blocks
advised to seek immediate signal concerning bursitis
associated with octreotide
medical attention if they associated with the use of
treatment using the product
experience pain, tenderness, infliximab.
information in European Union
redness or swelling of the
Infliximab is a monoclonal and clinical guidelines in
genital or perineal area,
antibody inhibiting the function Australia.
particularly with associated
of TNFα and indicated for the
fever or malaise. Healthcare professionals should
treatment of rheumatoid
be advised of the identified risk
arthritis and other
Reference: of atrioventricular block in
inflammatory diseases.
Prescriber Update, Medsafe, patients receiving off-label high
September 2021 (link to the The SFDA reviewed 30 case doses of continuous infusion
source within reports, 18 of which supported (100 micrograms/hour) of
www.medsafe.govt.nz/) the association and the octreotide and in patients
(See WHO Pharmaceuticals literature. receiving bolus octreotide
Newsletter No.3, 2020: Risk of intravenously (50 micrograms
Reference:
diabetic ketoacidosis for SGLT2 bolus followed by 50
Safety Alerts, SFDA, 8 July
inhibitors in UK) micrograms/hour continuous
infusion).
www.sfda.gov.sa)
Reference:
Finasteride (See WHO Pharmaceuticals
Newsletter No.4, 2018: Potential
risk of linear IgA bullous 25 October 2021 (link to the
Potential risk of diabetes
dermatosis in Canada) source within www.tga.gov.au)
mellitus

released a potential safety Octreotide Propylthiouracil and
signal concerning diabetes
Risk of atrioventricular carbimazole
mellitus associated with the
use of finasteride. block
Use in pregnancy
Finasteride is a 5α-reductase Australia. The TGA has
Australia. The TGA has
inhibitor and indicated for the announced that intravenous
announced that the pregnancy
treatment of symptomatic infusion of octreotide, which is
category for both
benign prostatic hyperplasia used off-label in Australia, is
propylthiouracil (PTU®) and
(BPH) in men with an enlarged linked to the risk of
carbimazole (Neo-Mercazole®)
prostate. atrioventricular block.
is being changed from being
The SFDA reviewed 62 case Octreotide is an octapeptide suspected of harmful effects on
reports, two of which that mimics natural the human foetus by the
supported the association, and somatostatin pharmacologically pharmacological effects to the
the literature. and is indicated for being associated with an
symptomatic control and increased incidence of human
Reference:
reduction of growth hormone foetal malformations.
and IGF-1 plasma levels in
2021 (link to the source within Propylthiouracil is an
patients with acromegaly etc.
www.sfda.gov.sa) antithyroid drug indicated for
The approved route of
the treatment of
administration for octreotide
hyperthyroidism or prior to
products is only subcutaneous
surgery or radioactive iodine
injection for the registered
therapy in these patients.

AR10083
Safety of Medicines
Carbimazole is also an announced to healthcare

antithyroid drug indicated for professionals that there is a
hyperthyroidism. It is used as a small increased risk of
definitive therapy for the postpartum hemorrhage
induction of a permanent associated with use of selective
remission in either primary or serotonin reuptake inhibitors
secondary thyrotoxicosis. It is (SSRIs) and serotonin-
also used in preparation for noradrenaline reuptake
thyroidectomy before and after inhibitors (SNRIs)
radioactive iodine treatment. antidepressants when used
The risks relating to congenital during the last month before
abnormalities in neonates are delivery.
known for these medicines.
The SFDA reviewed the result
from observational studies
The TGA reviewed reported
suggesting the risk.
cases of congenital
abnormalities for Healthcare professionals are
propylthiouracil and advised to carefully assess the
carbimazole in the safety of antidepressants use
postmarketing setting. during pregnancy against the
benefits, especially in later
Healthcare professionals should stages, and consider the
be advised that propylthiouracil patient’s risk factors for
and carbimazole should not be bleeding or thrombotic events.
prescribed for women of
Reference:
childbearing age unless, in the
Safety communication, SFDA,
opinion of the physician, the
potential benefits outweigh the
within www.sfda.gov.sa)
possible risks.
(See also WHO Pharmaceuticals
Newsletter No.4, 2021: Increased
Reference:
risk of postpartum haemorrhage in
New Zealand)
15 September 2021 (link to the
source within www.tga.gov.au)
(See WHO Pharmaceuticals
Newsletter No.3, 2020: Potential
risk of birth defects in Canada)
Selective serotonin
reuptake inhibitors
(SSRIs) and
serotonin-
noradrenaline
reuptake inhibitors
(SNRIs)
Increased risk of
postpartum hemorrhage

AR10084
Safety of Medicines
A signal is defined by WHO as reported information on a possible causal relationship between an adverse event and a drug,
the relationship being unknown or incompletely documented previously. Usually more than a single report is required to
generate a signal, depending on the seriousness of the event and the quality of the information. A signal is a hypothesis
together with data and arguments and it is important to note that a signal is not only uncertain but also preliminary in
nature.
The signals in this Newsletter are based on information derived from reports of suspected adverse drug reactions available
in the WHO global database of individual case safety reports (ICSRs), VigiBase. The database contains over 27 million
reports of suspected adverse drug reactions, submitted by National Pharmacovigilance Centres participating in the WHO
Programme for International Drug Monitoring. VigiBase is maintained by the Uppsala Monitoring Centre (UMC) on behalf
of WHO and periodic analysis of VigiBase data is performed in accordance with UMC’s current routine signal detection
process. International pharmaceutical companies, when identified as uniquely responsible for the drug concerned, are
invited to comment on the signal text. Signals are thereafter communicated to National Pharmacovigilance Centres, before
being published in this Newsletter. Signal texts from UMC might be edited to some extent by WHO and may differ from the
original version. More information regarding the ICSRs, their limitations and proper use, is provided in the UMC caveat
document available at the end of Signal (page 41). For information on the UMC Measures of Disproportionate reporting
please refer to WHO Pharmaceuticals Newsletter Issue No. 1, 2012.
UMC, a WHO Collaborating Centre, is an independent foundation and a centre for international service and scientific
research within the field of pharmacovigilance. For more information, on the UMC Measures of Disproportionate Reporting
etc., visit www.who-umc.org. To leave a comment regarding the signals in this Newsletter, please contact: the Uppsala
Monitoring Centre, Box 1051, SE-751 40 Uppsala, Sweden. E-mail: signals@who-umc.org.
Covid-19 vaccines and hearing loss and tinnitus
Christian Rausch, MD and Qun-Ying Yue, MD, Uppsala Monitoring Centre
Summary Awareness of this possible link may help

healthcare professionals and those
A recent signal detection activity at the vaccinated to monitor symptoms and seek
Uppsala Monitoring Centre (UMC) identified care, as appropriate. As there is still only
hearing loss (including sudden cases) and limited data in the literature providng
tinnitus following COVID-19 vaccination as a evidence for this link, further monitoring is
preliminary signal to be further assessed. Up required.
to 22 February 2021 i, there were 164 unique
individual case safety reports (ICSRs) which Introduction
reported ‘hearing losses’ (MedDRA High Level
Term, HLT), and 367 ICSRs which reported
The emergence of the novel severe acute
‘tinnitus’ (Preferred Term, PT) with ‘COVID-
respiratory syndrome coronavirus 2 (SARS-
19 vaccine’ in the WHO global database of
CoV-2) and the World Health Organization’s
ICSRs, VigiBase. The cases were from 10
declaration of the associated coronavirus
countries, most had no co-morbidities. Time-
disease 2019 (COVID-19) as a global
to-onset varied between 0 and 19 days with
pandemic, have led to a worldwide
a median of 1 day. Based on well-
prioritization of research and development of
documented cases, alternative causes were
protective vaccines. To date, several
not identified for most of the patients,
potential vaccines are under development
although some may have had contributing
and a few have received market
morbidities (e.g., allergies, high blood
authorization or emergency use
pressure, prior hearing loss, auto-immune
authorization, including ChAdOx1-S -
related disorders). The most common co-
(AZD1222) (Covishield) developed by
reported symptoms were tinnitus, followed
AstraZeneca/University of Oxford, mRNA-
by headache, dizziness and nausea, and
1273 developed by Moderna and the National
many patients experienced quick recovery,
Institute of Allergy and Infectious Diseases,
while some needed steroid treatment. A
and BNT162 developed by BioNTech, Pfizer
plausible mechanism of action involving the
and Fosun Pharma. At the time of this report,
vestibulocochlear nerve has been suggested.
the current vaccines used have different
iRenewed search was conducted on 18 November 2021

(see Adendum on 24 November 2021)
AR10085
Safety of Medicines
mechanisms to provide protection against Hearing loss

COVID-19.1–3
Among the 172 ICSRs reporting hearing loss,
Hearing loss generally refers to the partially 8 were duplicate cases, resulting in a total of
or completely diminished ability to hear in 164 unique ICSRs. Of these 164 ICSRs, 104
one or both ears. Hearing loss includes (63%) were for females and 59 (36%) for
deafness, i.e. the inability to comprehend males, in one case sex was not provided. The
aural/verbal language, as well as age in the reported cases ranged from 19 to
sensorineural hearing loss which is defined 93 years with a median of 49. Reports were
by a hearing acuity below 30 dB and received from 10 countries including the USA
generally involves damage to the inner ear, (66), UK (36), and Italy (15). More than a
cochlear nerve or vestibulocochlear nerve, or third of the ICSRs (62, 38%) were from
brain.4,5 Sensorineural hearing loss can occur healthcare professionals; ‘reporter category
suddenly within three days or less, and it unknown’ was stated in 66 reports (40%),
may be associated with tinnitus and vertigo.4 and ‘consumer/non health professionals’ in
Tinnitus can also occur as an isolated 37 (23%). Some consumer reports were
symptom and is defined as perception of an from physicians or other healthcare
auditory sensation despite the absence of a professionals who had been vaccinated. The
auditory trigger.6 Incidence of sensorineural most reported COVID-19 vaccines in these
hearing loss in the US is estimated at 27 per cases were Pfizer/BioNTech (142 cases),
100,000 persons per annum, with the followed by Moderna (15 cases) and
incidence increasing with age.7 AstraZeneca (7 cases).
Depending on the aetiology, the age of onset While most of the cases were recorded as
for hearing loss can vary.8 Hearing loss can non-serious (93 cases, 57%), 71 cases
be congenital, e.g. Alport-syndrome, or (43%) were recorded as serious. Seriousness
acquired through infections and criteria were most often ’Other medically
inflammations due to viruses, as well as important condition’ (37 case reports), and
systemic disorders, such as hypertension.9–12 ‘Disabling/incapacitating’ (29), followed by
Specific medications, e.g., aminoglycoside ‘Caused/prolonged hospitalization’ (5), and
antibiotics, are known to be ototoxic and can ‘Life threatening’ (2).
cause direct damage to the vestibulocochlear
apparatus. 13 Of the 164 ICSRs the most commonly co-
reported PTs were tinnitus (56), headache
Reports in VigiBase (26), dizziness (19), nausea (19), fatigue
(14), hypoaesthesia (12), pyrexia (12),
In a signal detection activity on 22 February acoustic stimulation tests abnormal (11),
2021 screening for COVID-19 vaccines in the vertigo (11), and ear discomfort (11).
WHO global database of ICSRs, VigiBase,
disproportional reporting was detected for Only a few reports included information on
‘COVID-19 vaccine’ associated with MedDRA concomitant treatments and the most
Preferred Terms (PTs) ‘Sudden hearing loss’ commonly reported was the influenza vaccine
(24 observed and 8 expected; lower limit of (four reports), which had been given at least
the 95% credibility interval (IC025=0.9) and 30 days prior to the COVID-19 vaccine,
‘Tinnitus’ (367 observed and 259 expected; according to the narratives. Other
IC025=0.4). In addition to the PT ‘Sudden medications mentioned included omeprazole,
hearing loss’ the search was extended to the acetylsalicylic acid, propranolol, estradiol,
High Level Term (HLT) ‘Hearing losses’ which calcium carbonate, dexamethasone,
included an additional 148 relevant cases, paracetamol, rivaroxaban, iron, and folic
among which the PT ‘Deafness unilateral’ (31 acid. All appeared in less than four reports
observed and 15 expected; IC025=0.4), and and were only reported as concomitant. In
PT ‘Deafness neurosensory’ (19 observed and some reporting interfaces there are limited
9 expected; IC025=0.4) also showed options for reporters to note concomitant
disproportional reporting. Other PTs within medication, so this may be underreported.
the HLT Hearing losses considered, but not
disproportionate, were: Hypoacusis, Time-to-onset (TTO) varied between the
Deafness, Deafness transitory and same day, i.e., several minutes, to 19 days,
Neurosensory hypoacusis. with a median of one day. Of the 164 ICSRs,
95 provided narratives for in-depth analysis.
Table 1 presents the characteristics of the
reports for sudden hearing loss (23), and
Table 2 the selected reports of hearing loss
AR10086
Safety of Medicines
(HLT) with informative narratives (25) in and vestibular neuritis. In five cases with
association with a COVID-19 vaccine. information on the recovery of hearing
following steroid treatment, two reported
Based on Tables 1 and 2, the TTO is similar recovery after three days of steroids and
for all 164 reports. In 31 cases of the 48 another experienced hearing loss subsiding
reports displayed in Table 1 and 2, there spontaneously after the first COVID-19
were no apparent risk factors . In seven vaccine dose but requiring steroid treatment
cases the reports specified hearing loss after the second COVID-19 vaccine dose,
related to the second dose, and of these, two with partial recovery (report was received 18
reported onset of hearing loss within half an days post-vaccination). A fourth case
hour to several hours, three within one to described mild improvements with steroid
two days, and another two six or seven days treatment (report received five days post-
after the second dose of COVID-19 vaccine. vaccination) and another had mild
In three cases the reports described hearing improvements five days after steroid
loss as occurring with the first COVID-19 treatment (report received 17 days post-
vaccine dose and re-occurring and worsening vaccination).
after administration of the second dose. One
case of tinnitus following the first dose Of the 164 cases, at the time of the report 51
decreased over a couple of days but hearing (31%) were recovering or recovered from
loss recurred after the second dose, and the their symptoms and 50 (30%) had not
patient was started on steroid treatment; no recovered. In the remaining 63 (38%) cases
risk factors were recorded. Another case no outcome information was recorded.
described bilateral tinnitus more than a week
after the first dose and worsening 1.5 weeks Tinnitus
after the second dose. Receipt of unspecified
medications were recorded, and the patient There were 367 ICSRs reporting tinnitus with
consulted an ear, nose and throat (ENT) COVID-19 vaccines, of which 56 were also
physician. Another described hearing loss grouped into hearing losses (HLT). Of these
occurring which decreased within two days 367, 268 (73%) were in females and 92 in
after the first dose, but re-occurring with the males (25%), sex was missing in 7. Their
second dose, which required steroid ages ranged from 19 to 91 years with a
treatment. median of 48. They came from 27 countries
with the UK (115), the US (113), and Italy
In 29 cases, patients contacted a physician (42) having the most reports. More than a
or ENT specialist within a few days after third of the ICSRs (160, 44%) were from
receiving the vaccination due to hearing loss. healthcare professionals. Reporter category
Some of the reports were provided by was unknown in 113 reports (31%) and
consumers who were themselves physicians consumer/non healthcare professionals in 97
or other healthcare professionals. Seven (26%). The vaccines received were
patients confirmed an abnormal audiogram Pfizer/BioNTech (293, 80%), Moderna (39,
conducted by their physician, and 20 were 11%) AstraZeneca (31, 8.4%), and Sinovac
treated with systemic steroids. (1, 0.3%). The TTO ranged from several
minutes to 30 days after vaccination, with a
In the narratives of these cases where median one of 1 day. Of the 367 reports, 90
information on medical history and potential were recorded as not recovered (25%), 164
risk factors was present, the following are of as recovered (45%) and 112 were unknown
note: prior history of hearing loss (n=6), (31%).
hypothyroidism (n=3) and previous
autoimmune thyroiditis (n=1), high blood Most cases were recorded as non-serious
pressure and cardio-vascular diseases (n=4), (270, 74%), but 97 cases (26%) were
allergies, including nut allergy (n=2), and recorded as serious. Seriousness criteria
one case each of diabetes mellitus, included ’other medically important condition’
antiphospholipid syndrome, prior COVID-19, (59, 16%), ‘disabling/incapacitating’ (33,
hearing loss related to another viral infection, 9.0%), ‘caused/prolonged hospitalization’ (8,
and unspecified auto-immune reaction or 2.2%) and ‘life threatening’ (2, 0.5%). The
disease. most co-reported PTs with tinnitus were
headache (131, 36%), dizziness (65, 18%),
Of the 164 cases of hearing loss, four also fatigue (65, 18%), nausea (65, 18%),
described the feeling of numbness of the face pyrexia (60, 16%), myalgia (54, 15%), chills
on the affected side. In two narratives, the (47, 13%), arthralgia (37, 10%), asthenia
patients had consulted an ENT physician and (33, 9.0%) and pain in extremity (30, 8.2%).
received a potential diagnosis of labyrinthitis Eight case narratives reported progression

AR10087
Safety of Medicines
from tinnitus to hearing loss, i.e., inability to In addition, several patients reported other
hear in the affected ear. co-occurring reactions such as headaches,
nausea, and dizziness. The additional
Labelling and literature description of dizziness and nausea may
suggest the involvement not only of the
The product labelling for COVID-19 vaccines cochlear nerve, but also the vestibular nerve.
does not refer to hearing loss. 1–3 However, Furthermore, among the ICSRs reporting
for both mRNA vaccines, acute peripheral hearing loss, two also reported facial
facial paralysis is listed as a rare adverse paralysis, and four narratives a feeling of
reaction. Apart from headaches, no other numbness in the face, both of which would
form of nerve or cranial nerve involvement is point to the potential involvement of other
listed under adverse reactions. cranial nerves apart from the
vestibulocochlear, i.e., the facial nerve and
No additional information exists in the trigeminal nerve. The product information for
scientific literature of an association between the COVID-19 vaccines does include the rare
COVID-19 vaccines and hearing loss. occurrence of acute facial nerve paralysis. No
other reactions specific to other cranial
Discussion and conclusion nerves, including hearing loss, are listed. In a
study on motor palsies of cranial nerves after
vaccination the need for further studies was
This analysis of reports in VigiBase includes
recommended.14 The TTO for cranial nerve
164 unique cases of hearing loss with
palsies was reported to be a median of 9-10
COVID-19 vaccines.
days, and with patients of all age groups.
The TTO ranged from 0 to 19 days. However,
To date, no studies assessing novel COVID-
97 (59%) cases indicated a TTO ranging from
19 vaccines and hearing loss or cranial nerve
0 to 1 day. The narratives contain
involvement have been reported. The
information about relatively quick reactions,
literature provides anecdotal references to an
occurring from minutes to several hours after
association between other vaccines and
the injections, often described with tinnitus-
hearing loss.15–18 In addition, there has been
like or muffled-hearing sensations, and in
some publications about the potential role of
some instance headaches, vertigo, and
vaccines in adverse reactions involving other
nausea. Some patients described the
cranial nerves.14,19 However, a case-centred
muffled-hearing or tinnitus progressing into
analysis of sudden-onset sensorineural
partial or complete hearing loss. Some well
hearing loss after immunization did not
documented cases recorded an audiogram
report any significant association for 28
confirming the sudden hearing loss diagnosis,
different vaccines.20 The study used a large
and in many cases, the need for treatment
medical records database and analyzed the
with high dose steroids.
first episodes of sensorineural hearing loss in
patients who had been vaccinated in the
Half of the cases noted that the patient was
preceding nine months between 2007 and
recovering or had recovered from their
2013. The study identified 1,929 cases of
hearing loss, while no (or limited) additional
sensorineural hearing loss within nine
information on follow-up was recorded for
months of receiving a vaccine, and 57 that
the other cases. The evidence for long-term
occurred within a week.14 In addition, in
hearing loss is therefore incomplete.
2020 the Brighton Collaboration published a
case definition of sensorineural hearing loss
The analysis also shows that ICSRs with to aid investigation of adverse events
hearing loss came from ten countries and following immunization.12
that most cases were young healthy adults
with no comorbidities. The median age was
A potential mechanism for COVID-19
47 years, which appears young and reflects
vaccine-associated hearing loss could be an
several countries’ prioritization of healthcare
autoimmune process involving molecular
worker vaccination. Some cases describe
mimicry related to the vaccine’s antigen, or
patients with a medical history of prior
bystander activation of autoreactive T-cells
hearing loss, high blood pressure,
that may involve the vestibulocochlear nerve
environmental or seasonal allergies, as well
(vestibular nerve is involved in balance and
as thyroid dysfunction. In seven cases the
equilibrium functions, and cochlear nerve in
reaction of hearing loss was reported with
hearing function).21–24 Involvement of this
the second dose of the COVID-19 vaccine,
nerve can contribute to symptoms related to
and in two cases a positive re-challenge was
labyrinthitis, which involves both vestibular
described.
and cochlear branches of the nerve or

AR10088
Safety of Medicines
vestibular neuritis, which involves vertigo, vaccinees, and the median age is just over
dizziness and nausea.25 Two cases in the 40 years. Most of the cases were young
VigiBase analysis mentioned the potential healthy adults with no comorbidities. A close
diagnosis of labyrinthitis and vestibular temporal relationship has been observed,
neuritis made by ENT specialists. and based on well-documented cases, most
Furthermore, analysis of VigiBase in patients of the patients did not have alternative
vaccinated with COVID-19 vaccine showed a causes identified, although some patients
disproportionality for vestibular neuronitis may have had contributing morbidities (e.g.,
(13 observed and 2 expected) and high blood pressure, allergies, prior hearing
labyrinthitis (19 observed and 6 expected). loss, auto-immune related disorders). The
Studies on vaccinations and neurological most common co-reported symptoms were
disorders, including cranial nerve tinnitus, followed by headache, dizziness and
involvement reported the potential time nausea, and many patients experienced a
windows for symptom onset as being several quick recovery, although some patients
hours to several weeks depending on the needed steroid treatment. A plausible
neurological disorder.14,20,21,26 Currently, mechanism of action has been suggested and
clinical evidence and studies on potential awareness of this possible link may help
mechanisms and the relation between healthcare professions and those vaccinated
vaccines and neurological disorders, cranial to monitor symptoms and seek care as
nerve palsies and hearing loss, remain appropriate. As the literature and ICSR data
limited. are still limited for this link, further
monitoring is required.
Under-reporting is a well-known limitation of
spontaneous adverse drug reaction reporting. Addendum on 24 November 2021
However, there is high interest in COVID-19
and COVID-19 vaccines, which may Tinnitus is only listed as an adverse reaction
contribute to increased reporting and for the Janssen COVID-19 vaccine.
therefore, potentially an overestimation of
the risk. Additionally, the observed versus An updated search of VigiBase has been
expected numbers and IC025 values need to performed for the PTs included in this signal
be interpreted with caution, since reporting assessment (Table-A) and for the terms with
by healthcare providers and the sites is a a positive (>0) IC025 values for each COVID-
requirement under the terms of the 19 vaccine (Table-B).
Emergency Use Authorizations for COVID-19
vaccines in some places (e.g., the USA where In brief, the terms selected for hearing
most of the cases were reported). For disorders included sudden hearing loss,
approved medicinal products this is not the tinnitus, deafness unilateral, neurosensory
case. Therefore, when an expected number is hypoacusis, deafness, deafness transitory,
estimated using other medicinal products and hypoacusis. On 18 November 2021 there
prior to the pandemic and then compared were 37 529 deduplicated cases, for which at
with the observed cases for COVID-19 least one of these terms was reported, from
vaccines, the result may overestimate the 86 countries: 21 countries reported more
risk. It may be useful to approach the than 100 cases; another 22 countries
individual countries for more in-depth reported 10-99 cases; 15 countries reported
information and could be considered in future 5-9 cases and 28 countries reported 1-4
signal investigations. cases.
In summary, cases of (sudden) hearing loss It seems that hearing disorders have been
following COVID-19 vaccination have been reported for most of the COVID-19 vaccines,
reported to VigiBase from ten countries. Most but with different IC025 values. More in-depth
of the patients were females (62%) and the assessment of narratives has not been
age range was 19 to 93 years with a median performed for the recently reported cases..
of 49. However, it should be noted that 75% The limitations and precautions for the data
of the COVID-19 virus vaccine adverse and its interpretation mentioned above need
reactions included in VigiBase concern female to be taken into consideration.

AR10089
Safety of Medicines
Table-A. The observed and expected numbers of selected hearing disorders with positive (>0)
IC025 values in VigiLyze on 22 February 2021 and in a repeated search on 18 November 2021.
Search on 22 February 2021 Search on 18 November 2021

Observed Expected IC025 Observed Expected IC025
Sudden hearing loss 24 8 0.9 1290 284 2.1
Tinnitus’ 367 259 0.4 31 644 8549 1.9
Deafness unilateral 31 15 0.4 1676 495 1.7
Neurosensory hypoacusis ND* 55 20 1.1
Deafness ND* 3167 2378 0.4
Deafness transitory ND* 97 70 0.2
Hypoacusis ND* 3278 3608 ND*
*Not disproportionate
Table-B. The observed and expected numbers of selected hearing disorders with positive (>0)
IC025 values for each COVID-19 vaccine in VigiLyze on 18 November 2021.
Observed Expected IC025

Sudden hearing loss 1290 284 2.1
Tozinameran 837 135 2.5
Elasomeran 218 53 1.8
COVID-19 vaccine NRVV Ad (ChAdOx1 nCoV-19) 199 74 1.2
COVID-19 vaccine NRVV Ad26 (JNJ 78436735) 28 12 0.6
Tinnitus 31 644 8549 1.9
COVID-19 vaccine inact (Vero) HB02 1507 142 3.3
COVID-19 vaccine NRVV Ad (ChAdOx1 nCoV-19) 7131 2215 1.7
Deafness unilateral 1676 495 1.7
Neurosensory hypoacusis 55 20 1.1
Deafness 3167 2378 0.4
Deafness transitory 97 70 0.2
Hypoacusis 3278 3608 ND*
*Not disproportionate

AR10090
Safety of Medicines
References 10. van Beeck Calkoen EA, Engel MSD, van

de Kamp JM, Yntema HG, Goverts ST,
1. EMA Committee for Medicinal Products Mulder MF, et al. The etiological
for Human Use (CHMP). Summary of evaluation of sensorineural hearing loss
product characteristics for COVID-19 in children. Eur J Pediatr. 2019
vaccine Moderna [website]. 2021 [cited Aug;178(8):1195–205.
2021 Feb 7]. Available from:
https://www.ema.europa.eu/en/docume 11. Korver AMH, Smith RJH, Van Camp G,
nts/product-information/covid-19- Schleiss MR, Bitner-Glindzicz MAK,
vaccine-moderna-epar-product- Lustig LR, et al. Congenital hearing loss.
information_en.pdf Nat Rev Dis Primer. 201712;3:16094.
2. EMA Committee for Medicinal Products 12. Carol Liu Y-C, Ibekwe T, Kelso JM, Klein
for Human Use (CHMP). Summary of NP, Shehu N, Steuerwald W, et al.
product characteristics for Comirnaty. Sensorineural hearing loss (SNHL) as an
[website]. 2021 [cited 2021 Feb 7]. adverse event following immunization
Available from: (AEFI): Case definition & guidelines for
https://www.ema.europa.eu/en/docume data collection, analysis, and
nts/product-information/comirnaty-epar- presentation of immunization safety
product-information_en.pdf. data. Vaccine. 2020;38(30):4717–31.
3. EMA Committee for Medicinal Products 13. Guthrie OW. Aminoglycoside induced
for Human Use (CHMP). Summary of ototoxicity. Toxicology. 2008;249(2–
product characteristics for COVID-19 3):91–6.
vaccine AstraZeneca. [website]. 2021
[cited 2021 Feb 7]. Available from: 14. Woo EJ, Winiecki SK, Ou AC. Motor
https://www.ema.europa.eu/en/docume palsies of cranial nerves (excluding VII)
nts/product-information/covid-19- after vaccination. Hum Vaccin
vaccine-astrazeneca-product- Immunother. 2014;10(2):301–5.
information-approved-chmp-29-january-
2021-pending-endorsement_en.pdf 15. Kolarov C, Löbermann M, Fritzsche C,
Hemmer C, Mlynski R, Reisinger EC.
4. Schreiber BE, Agrup C, Haskard DO, Bilateral deafness two days following
Luxon LM. Sudden sensorineural hearing influenza vaccination: a case report.
loss. Lancet. 2010 Apr Hum Vaccin Immunother.
3;375(9721):1203–11. 2019;15(1):107–8.
5. Roeser RJ, Valente M, Hosford-Dunn H, 16. Huang H-H, Huang C-C, Hsueh P-Y, Lee
editors. Audiology. Diagnosis. 2nd ed. T-J. Bilateral sudden deafness following
New York: Thieme; 2007. 602 p. H1N1 vaccination. Otolaryngol Head
Neck Surg. 2010;143(6):849–50.
6. Nondahl DM, Cruickshanks KJ, Huang G-
H, Klein BEK, Klein R, Nieto FJ, et al. 17. De Marco F, De Cesare DP, Di Folco F,
Tinnitus and its risk factors in the Massoni F, Tomei G, Di Luca NM, et al.
Beaver Dam offspring study. Int J Post vaccinal temporary sensorineural
Audiol. 2011 May;50(5):313–20. hearing loss. Int J Environ Res Public
Health. 2018;15(8):1780.
7. Alexander TH, Harris JP. Incidence of
sudden sensorineural hearing loss. Otol 18. Okhovat S, Fox R, Magill J, Narula A.
Neurotol. 2013 Dec;34(9):1586–9. Sudden onset unilateral sensorineural
hearing loss after rabies vaccination.
8. Shi X. Physiopathology of the cochlear BMJ Case Rep. 2015 bcr2015211977
microcirculation. Hear Res. 2011
Dec;282(1–2):10–24. 19. Mutsch M, Zhou W, Rhodes P, Bopp M,
Chen RT, Linder T, et al. Use of the
9. Ibekwe TS, Okokhere PO, Asogun D, inactivated intranasal influenza vaccine
Blackie FF, Nwegbu MM, Wahab KW, et and the risk of Bell’s palsy in
al. Early-onset sensorineural hearing Switzerland. N Engl J Med.
loss in Lassa fever. Eur Arch Otorhino- 2004;350(9):896–903.
Laryngol . 2011;268(2):197–201.

AR10091
Safety of Medicines
20. Baxter R, Lewis N, Bohrer P, Harrington Vaccin Immunother. 2015;11(9):2274–

T, Aukes L, Klein NP. Sudden-onset 80.
sensorineural hearing loss after
immunization: a case-centered analysis. 24. Institute of Medicine 2012. Adverse
Otolaryngol Head Neck Surg. effects of vaccines: evidence and
2016;155(1):81–6. causality. Washington, DC: The National
Academies Press.
21. Principi N, Esposito S. Do vaccines have https://doi.org/10.17226/13164.
a role as a cause of autoimmune
neurological syndromes? Front Public 25. Baloh RW. Clinical practice. Vestibular
Health. 2020;8:361. neuritis. N Engl J Med.
2003;348(11):1027–32.
22. Ozonoff A, Nanishi E, Levy O. Bell’s
palsy and SARS-CoV-2 vaccines. Lancet 26. Paul R, Stassen LFA. Transient facial
Infect Dis. 2021;21(4):450-2 nerve paralysis (Bell’s palsy) following
administration of hepatitis B
23. Liang Y, Meng F-Y, Pan H-F, Ye D-Q. A recombinant vaccine: a case report. Br
literature review on the patients with Dent J. 2014;216(2):69–71.
autoimmune diseases following
vaccination against infections. Hum

AR10092
Signal
Table 1. Individual characteristics of reports in VigiBase of sudden hearing loss in association with COVID-19 vaccines (n=23).
Relevant reactions
Age / Dose Time to Type of
Case Type of vaccine (MedDRA preferred Outcome Additional information
sex number onset reporter
terms)
Pfizer/BioNTech - Tinnitus 7 days Not Physician -
1. 46/M
Sudden hearing loss recovered
Pfizer/BioNTech - Headache 0 days Recovered Physician -
Myalgia
2. 52/F Tinnitus
Chest pain
Sudden hearing loss
Moderna - Deafness neurosensory 3 days - - Lost hearing in left ear three days after the vaccination, diagnosed by an
3. -/F Deafness unilateral ENT with "sudden sensory nerve severe hearing loss".
Sudden hearing loss
Pfizer/BioNTech - Acoustic stimulation tests 1 day - - Sudden total hearing loss, left ear; numbness in face and outer ear.
abnormal
4. 61/F
Deafness
Sudden hearing loss
Pfizer/BioNTech - Tinnitus 1 day Not Pharmacist One day after the vaccine tinnitus in ear, 14 days later still constant
5. 54/M
Sudden hearing loss recovered tinnitus in ear, sudden hearing loss left diagnosed by a physician.
Pfizer/BioNTech Deafness unilateral 18 hours - Consumer woke up with vertigo and imbalance, clogged left ear and tinnitus, started
Nausea hyperventilating, went to the hospital with CT and MRI not showing any
Sudden hearing loss abnormalities, later referred to ENT, who started high dose steroids after
6. 70/M
Tinnitus audiogram showed abnormal findings, no improvements five days after
Vertigo treatment initiation.
Vision blurred
Pfizer/BioNTech - Acoustic stimulation tests 1 day - Consumer No medical history, arm tender after injection, one day later tinnitus right
abnormal ear, two days after the vaccine consultation with an ENT for earwax
Deafness unilateral removal, few minutes later reoccurrence of tinnitus and humming, three
7. 77/F
Injection site pain days after the vaccination complete hearing loss right ear and started on
Sudden hearing loss prednisolone 40 mg from ENT, four days after the treatment initiation
Tinnitus still no improvement.
Pfizer/BioNTech - Injection site inflammation 1 day Recovered Consumer Movicolon, pantoprazole
8. 61/F Injection site pain
Sudden hearing loss
Pfizer/BioNTech - Sudden hearing loss 5 days Not Consumer -
9. 46/M
recovered
10. 52/F Pfizer/BioNTech - Sudden hearing loss 6 days Recovering Consumer -

AR10093
Signal
Hyperacusis
Pfizer/BioNTech - Sudden hearing loss Same day Not Physician Previously known with acoustic neuroma right, cyberknife treated 2019,
11. 57/M
recovered Last MRI November 2020 without new abnormalities.
Pfizer/BioNTech - Sudden hearing loss 30 min Not Physician 30 min post-vaccination sudden hearing loss, recovered three days after
12. 25/M
recovered high dose steroid treatment.
Pfizer/BioNTech - Sudden hearing loss 5 days Not Consumer -
13. 52/M
recovered
Moderna - Acoustic stimulation tests Same day - - Sudden sensorineural hearing loss in left ear, day later sudden pop in left
Deafness neurosensory ear, two days after the vaccine could barely hear, hearing test proved
14. 68/F Hypoacusis SSHL and patient was started on steroid treatment plus local steroid
Sudden hearing loss treatment in ear, doctors feel it is a side effect due to compromised
Tinnitus immune system, patient had a similar reaction 15 years ago from a virus.
Moderna - Deafness 3 days - - Three days after vaccination tinnitus and muffled hearing that went away
Deafness unilateral and next day complete hearing loss left ear, still has tinnitus and muffled
15. 19/M Hypoacusis hearing at time of report.
Sudden hearing loss
Tinnitus
Pfizer/BioNTech - Sudden hearing loss Same day - Consumer Rash over face and even over the ears, uses rivaroxaban.
16. 70/M
Rash
AstraZeneca - Sudden hearing loss Same day Not Physician Not tested positive for COVID-19.
17. 89/M
recovered
18. 39/F Pfizer/BioNTech - Sudden hearing loss 2 days Recovered Consumer -
Pfizer/BioNTech - Sudden hearing loss 1 day Not Consumer Sudden hearing loss, one day after vaccination.
19. 52/F
recovered
Moderna - Acoustic stimulation tests 10 days - - Sudden hearing loss right, accompanied by tinnitus.
abnormal
20. 37/F Deafness unilateral
Sudden hearing loss
Tinnitus
Pfizer/BioNTech - Dizziness 12 days Recovering Consumer 13 days after vaccination developed sudden hearing loss and dizziness
21. 31/M Sudden hearing loss and hypoesthesia, lasting four days.
Hypoaesthesia
Pfizer/BioNTech - Sudden hearing loss 6 days - Consumer Six days after vaccine started on high dose prednisone for one week,
22. -/M
high dose 250 mg for three days then daily reduction by 50 mg.
Pfizer/BioNTech - Sudden hearing loss 1 day Not Physician Reporter is patient and healthcare professional, second dose with febrile
recovered reaction, and systemically ill, 20 hours later woke up due to tinnitus left
23. 40/F ear, got prednisone from ENT after confirmed sensorineural hearing loss
left, ENT believes inflammatory response to vaccination is possible,
concomitant medications include estrogel, propranolol, utrogestran.

AR10094
Signal
Table 2. Individual characteristics of selected reports in VigiBase of hearing loss (HLT) in association with COVID-19 vaccines (n=25).
Relevant reactions
Age / Dose Time to Type of
Case Type of vaccine (MedDRA preferred Outcome Additional information
sex number onset reporter
terms)
Past medical history with COVID in November and high blood
Balance disorder pressure, 8 hours after injection feeling of ear "closing up", few days
1. 68/F Pfizer/BioNTech - Deafness unilateral 8 hours Recovering Consumer later hearing loss in right ear same side as the injected arm, had
Hypoaesthesia problems with hearing and equilibrium, contacted physician and was
started on prednisone with partial improvement five days later.
Deafness unilateral Immediate loss of hearing right ear which recovered after six hours, next
2. 71/M Moderna - 3 days - -
Hypoacusis day partial loss of hearing left ear which did not return to normal.
Patient received the first dose and experienced hearing loss left ear, had
Deafness unilateral only 60% of hearing, unspecified treatment was initiated, and hearing
3. 63/M Pfizer/BioNTech - 2 days - Consumer
Malaise returned to 90%, physician informed that hearing loss could be due to
stress or a virus but was not sure if it was due to the vaccine.
Audiogram
Acute left sensorineural hearing loss with tinnitus, significant hearing
Deafness neurosensory
4. 40/M Moderna 2 1 day - - impairment noted on audiometric evaluation, symptoms began a day
Hypoacusis
after receiving the second dose of the vaccine.
Tinnitus
Deafness Four days after the vaccine sudden onset of bilateral fullness in ears,
Deafness neurosensory tinnitus, hearing loss, hyperacusis without vertigo. Weber's test did not
5. 69/M Pfizer/BioNTech - Ear discomfort 4 days Recovered - lateralize. Rinne's test showed air conduction greater than bone
Hyperacusis conduction consistent with neurosensory loss, initiated treatment with
Tinnitus dexamethasone 8 mg a day for three days and symptoms resolved.
Approximately 11 days after receiving the first dose woke up with
Audiogram decreased hearing, went to audiologist and otolaryngologist, both
6. 40/F Pfizer/BioNTech - 11 days - -
Hypoacusis concerned symptoms are related to having antibodies for COVID-19 or
having had the vaccine.
Acoustic stimulation tests
7. 37/F Pfizer/BioNTech - abnormal 7 days - - Sudden onset right sensorineural hearing loss.
Nervous system disorder
One day post-vaccination sudden vertigo and nausea. Two days post
Deafness unilateral
vaccination sudden hearing loss right ear and feeling of fullness, no
8. 28/F Pfizer/BioNTech - Vertigo 2 days Recovering -
pain, hearing loss confirmed with audiogram and started on steroids for
Endolymphatic hydrops
several days, differential diagnosis is endolymphatic hydrops.
Nausea
Left sudden sensorineural hearing loss and ear numbness 48 hours after
Deafness neurosensory injection, five days after vaccination started on prednisolone and trans-
9. 63/M Pfizer/BioNTech - 2 days Recovered -
Thyroid function test normal tympanic dexamethasone shots due to hearing loss, partial recovery after
3 weeks.
AR10095
Signal
Took unspecified medications and stopped several of them prior to
second vaccination, no prior medical history, worked as registered
Hypoacusis -
nurse, first vaccination dose in mid-December and second dose in
SARS-CoV-2 test negative
10. 32/M Pfizer/BioNTech 2 - - January, bilateral tinnitus end of December and beginning of January,
Tinnitus
tinnitus got worse after the second dose, consultation with ENT who
VIIIth nerve injury
assumed it was the nerve, but could not explain bilateral hearing
problem, COVID-19 test was negative.
abnormal 19 days after the first dose hearing loss and muffled sounds left,
Audiogram abnormal anaemia in past medical history and no medications, no prior hearing
11. 39/F Pfizer/BioNTech - Deafness unilateral 19 days - - problems, contacted ENT who diagnosed 20% decreased hearing in
Fear affected ear and was started on steroid treatment without recovery at
Hypoacusis time of report, took COVID-19 test which was negative.
SARS-CoV-2 test negative
Acute sudden hearing loss left with dizziness, audiology confirmed
acute sudden hearing loss left with normal ear canals, started on
prednisone treatment with improvements in dizziness symptoms, day
Dizziness later fall accident with worsening dizziness, ENT suspected viral
12. 89/F Pfizer/BioNTech - 4 days Not recovered Physician
Deafness labyrinthitis, likely to be viral infection but occurred four days after
vaccination, did not test positive for COVID-19, CT head was nil,
concomitant medications: influenza virus vaccine, furosemide,
latanoprost, omeprazole, simvastatin, THEICAL-D3.
Few hours after vaccination tinnitus right ear, recovered after a couple
Audiogram
of days, after 2nd dose muffled hearing and did not subside and severe
13. 34/F Pfizer/BioNTech 2 Deafness Few hours - -, -
right sided low frequency hearing loss was noted, patient was started on
Hypoacusis
high dose steroids with partial recovery.
Arm pain two days on injection site, day after injection right ear felt
Deafness
uncomfortable, felt like hearing loss and constant buzzing and fullness
14. 52/F Pfizer/BioNTech - Headache 1 day - -
feeling, consulted ENT who started patient on prednisone, no
Injection site pain
information on recovery.
Tinnitus
Deafness unilateral
After nine days awoke with deafness and was started on high dose
Fatigue
15. 79/M Pfizer/BioNTech - 9 days - - steroids 60 mg prednisone, ENT consulted severe neurosensory hearing
Headache
loss right ear.
Myalgia
Tinnitus
Acoustic stimulation tests Fullness right ear, felt like fluid in ear, hearing loss right ear, soreness
abnormal left arm, hearing loss two days after vaccination and subsided, then
16. 34/F Pfizer/BioNTech 2 1 day - -
Audiogram abnormal received second dose followed by myalgia, chills back pain, and
Deafness unilateral constant ringing right ear, hearing loss had worsened, prescribed

AR10096
Signal
Myalgia prednisone and local injections dexamethasone by ENT due to abnormal
Tinnitus audiogram right ear, only 52% acuity, tested negative for COVID-19.
Sudden hearing loss right ear, currently treated with steroids, audiology
17. 25/F Moderna - Deafness neurosensory 9 days - -
and ENT assessment performed.
Audiogram abnormal
Auditory disorder
Physician self-reports, after second dose of the vaccine severe myalgias,
Balance disorder
high fever and fatigue, two days after vaccine got vertigo, did not hear
Deafness
well in left ear, had hearing aid which was functioning, three days after
Deafness bilateral
18. 57/F Pfizer/BioNTech 2 1 day - Physician vaccine severe vertigo and hearing loss, Epley’s manoeuvre with no
Fatigue
effect, could not work and was admitted to emergency department,
Myalgia
audiogram showed profound hearing loss both ears, got prednisone,
Pyrexia
MRI negative, mild improvement after steroids.
Tinnitus
Vertigo
Headache 24-48 hours after vaccine, 1 week after vaccine complete
Deafness neurosensory sensorineural hearing loss left ear, penicillin allergy, no other
19. 37/F Pfizer/BioNTech - 1 day - -
Headache medications, started on prednisone via medical doctor, not recovered so
far.
Four hours after vaccination acute hearing loss, went to ENT and was
20. 36/F Pfizer/BioNTech - Deafness 4 hours Not recovered -
started on high dose prednisolone 250 mg for three days.
Audiogram abnormal
One day later woke up with ringing both ears, called pcp, consulted
Hypoacusis
21. 58/M Pfizer/BioNTech - 1 day - - ENT diagnosed abnormality left inner ear, started on prednisolone high
Inner ear disorder
dose, two weeks in the tinnitus got worse.
Tinnitus
Deafness unilateral Lost hearing right ear and right-side face was numb hours after
22. 58/F Pfizer/BioNTech - Same day - -
Hypoaesthesia vaccination.
Acoustic neuritis
Deafness neurosensory Sudden onset acoustic neuritis without labyrinthitis, hyperacusis, loss of
23. 69/M Pfizer/BioNTech - Dizziness 5 days - - hearing and tinnitus, atrial fibrillation in history. No medications. Nerve
Hyperacusis related hearing loss recovered.
Tinnitus
Left sided hearing loss, physician was the patient, Antiphospholipid
24. 42/F Pfizer/BioNTech - Deafness unilateral 6 days - -
syndrome in history.
Right ear tinnitus and sensorineural hearing loss, left arm injection,
diabetes type 2, latex allergy and asthma, woke up with tinnitus, MD did
abnormal -
25. 45/M Pfizer/BioNTech - 1 day - test and found right sided hearing loss, prescribed prednisone for 10
days 60 mg, not recovered, concomitant medications, metformin and
Tinnitus
glipizide.

AR10097
Signal
Methotrexate and muscle spasm

Rosa María Papale, Argentina and Mónica Tarapués, Ecuador
Summary hypokalaemia, hypocalcaemia, or hypomagnesemia.

Muscle spasm can accompany myopathy, which has
Methotrexate is a structural analogue of folic acid. As been associated with numerous drug classes,
a folic acid antagonist, it blocks the synthesis of including antimalarials and statins. Other
purines by inhibiting numerous regulatory enzymes. medications can cause muscle spasms, including
It produces an intense anti-inflammatory action and beta-agonists, acetylcholinesterase inhibitors (often
inhibits cell division. A screening of VigiBase, the used for the treatment of myasthenia gravis),
WHO global database of individual case safety cimetidine, steroids, morphine, penicillamine,
reports (ICSRs), identified the association of the cardiotropic medications, antiretrovirals, and
MedDRA Preferred Term (PT) ‘muscle spasm’ with psychotropic medications.6,7
methotrexate. A qualitative analysis of 47 cases was
undertaken with a completeness score of over 0.70. Reports in VigiBase
The similarity of characteristics with respect to time
to onset, the biological plausibility, the improvement As of May 2020, there were 397 reports for the
after drug withdrawal, all provide evidence of this MedDRA Preferred Term ‘muscle spasms’ associated
association. The muscle spasms could be associated with methotrexate. Due to the large number of
with methotrexate, especially in patients on long- cases, a completeness score over 0.7 was set for this
term low doses. Prescribers and patients need to be analysis so as to identify the causality patterns that
aware that muscle spasms could be present with the strengthen the signal. In the present case series, 47
use of methotrexate. This adverse reaction could cases were evaluated.
impair the patients’ quality of life, especially long-
term users with chronic diseases. The reports came from 18 countries, most of them in
Europe but also from the Americas, Africa, and Asia.
Introduction There were 30 females and 17 males. The age was
recorded for 45 patients, ranged from 13 to 87 years
Methotrexate was granted US FDA approval in (median 57); 31 were adults. Thirty-six cases (76%)
December 1953. Since then, it has been used via oral, were reported by health professionals (20 by
intramuscular, intravenous, subcutaneous, physicians and 16 by pharmacists). Sixteen cases
intrapleural, and intrathecal routes of administration. were considered serious, mainly under the criterion
Methotrexate acts by inhibiting enzymes responsible of other medically important condition (10 cases).
for nucleotide synthesis. It is used for the treatment The last report was received in March 2020. Thirty-
of several neoplasmic conditions, such as acute three of the cases had a narrative; their
leukaemia, lymphomas, osteosarcoma, breast characteristics are summarized in Table 1.
cancer, and in autoimmune diseases, such as
rheumatoid arthritis and psoriasis. In addition, it is The most frequent therapeutic indication was
used to treat gestational choriocarcinoma, rheumatoid arthritis (17 cases), followed by psoriasis
chorioadenoma, hydatiform mole, and advanced or psoriatic arthritis.8 There were also cases with
mycosis fungoides.1,2 neoplastic indications (6) and with polymyositis,
meningitis, and Crohn’s Disease (one of each). In 13
Muscle spasm covers several overlapping concepts of reports the therapeutic indications were not given.
true spasm and cramps. Spasms are involuntary Methotrexate was administered orally in 26 (55%)
muscle contractions. When these are prolonged and patients, parenterally in 8 patients (6 intravenous
painful, they are often referred to as cramps. Muscle and 2 intrathecal), and subcutaneously in four
cramps are sustained, painful contractions of muscle patients. The time to onset was highly variable in the
which occur in individuals with or without medical whole group, ranging from one day to six years.
conditions. Muscle cramps are common in the However, 26 patients received a weekly dose: 17
general population and can be disabling. This orally, 4 subcutaneously, and 5 were unknown. In
description distinguishes muscle cramps from other this subgroup of 26 patients, the time to onset,
painful muscle disorders that either do not include reported for 14, ranged from 1 day to 18 months,
shortening of the muscle, e.g., myositis and myalgia, with a median of 29 days. A daily dose was reported
or that include involuntary shortening of muscle but for five patients who developed muscle spasms on
do not cause pain, e.g., myotonia and tetany.3 the day of administration.
Myalgia and arthralgia are listed in the Summary of
Product Characteristics (SPC) of methotrexate as Methotrexate was the only suspected drug in 28
rare adverse drug reactions (ADRs).4,5 Other drugs patients, and in 18 others, it was the only drug
such as diuretics may cause muscle spasm through reported. Adalimumab was reported as a co-
dehydration or an electrolyte imbalance, especially suspected drug in five patients, but methotrexate

AR10098
Signal
was the last medication taken for two patients, and and 1 was recovered with sequelae. In the remaining
the other three patients were on chronic three patients the dose was reduced, and the
methotrexate treatment when adalimumab was reported outcome was recovered. Individual
administered. Etanercept was a co-suspected drug in causality assessment was undertaken for 16 patients,
two patients. Dates were available for only one (10 using the Naranjo algorithm and 6 using the
patient who was a chronic user of methotrexate and UMC/WHO global introspection method). The
etanercept was recently administered. Proton pump reported result was ‘possible’, for 15 patients and not
inhibitors (PPIs), were reported in five patients as co- assessable by the UMC/WHO method for the
suspected (lansoprazole (1), pantoprazole (2), and remaining patient.
esomeprazole (2)). In additions PPIs were reported
as concomitant medication, in eight patients but only Rechallenge was undertaken in 8 of the 47patients,
four had dates that suggest that the PPI and in three there was a positive rechallenge;
administration came before the ADR and was however, there were no narratives for these patients.
concurrent with the use of methotrexate. The outcome was reported as unknown for the other
Esomeprazole was used after the occurrence of the rechallenged patients, although they reported some
ADR in one patient. Non-steroidal anti-inflammatory interesting details. For example, a 57 year-old man,
drugs (NSAIDs) were concomitant drugs for three whose physician described muscle cramps and
patients (diclofenac (2), naproxen (1)) . Three cases increased blood creatine phosphokinase with the use
reported concomitant statins, (atorvastatin and of methotrexate and lansoprazole. In the narrative,
simvastatin). the physician wrote: “This patient is being followed
for non-erosive rheumatoid arthritis. Treatment with
Another ADR, decreased levels of calcium and methotrexate 10 mg/week was introduced in
magnesium was reported for one patient. Diarrhoea February. The patient reports from the start of his
or vomiting were reported at the same time as treatment disabling muscle cramps preventing any
muscle spasms in seven patients. The LLT term used sporting activity. He has also been treated with
for 31 patients was muscle cramps, and for some lansoprazole since February. This patient was also on
patients the location of the cramps was reported as hydrochlorothiazide- irbesartan, stopped in
a limb, legs, hand, or foot. The reported LLT was November of the same year, but without
muscle spasms for 16 patients some of which were improvement in muscle symptoms”. It is worth
described as a cervical or back muscle spasm. The noting that the rechallenge had an unknown outcome.
intensity of this ADR for a 63 year-old male patient, However, with the dates given in the original report,
reported by a pharmacist, was described as “very it is possible to deduce that the rechallenge was
intense, disabling and painful on the arms or the legs, without the lansoprazole, because at the beginning
with frequency variable, 1 to 3 times a day”. . in February the patient was exposed to both drugs,
Methotrexate and pantoprazole were reported as but for the rechallenge, only methotrexate was
suspected drugs. This patient also had concomitant reintroduced.
diltiazem, digoxin, and paracetamol. Methotrexate
was first used subcutaneously for rheumatoid A 33 year-old woman, reported by a physician, with
arthritis. After about six months, the patient pain, muscle spasm, and tetany was rechallenge. The
presented with muscle cramps, and five months later suspected drugs were methotrexate and adalimumab
methotrexate was changed to an oral route. The (both subcutaneous, weekly) and opipramol (daily,
patient was reported as not recovered. oral). The medical history included former smoker,
adiposity, allergic bronchial asthma, depression,
Another 65 year-old patient, reported by a onychomycosis, bilateral gonalgia, and psoriatic
pharmacist, had muscle cramps that occurred at arthritis. The starting date for methotrexate was
night following the administration of methotrexate January and for adalimumab, March of the same year.
(15 mg a week) for rheumatoid arthritis, with a The muscle cramps began on 30 April and the tetany
latency of 14 days after increasing the dose. The on 4 May. Complete tetany of the right leg, which
dose was subsequently reduced to 7.5 mg a week was not resolved by administration of tetrazepam
and the patient felt better with fewer complaints. was reported for this patient. The patient was
Only methotrexate was reported as suspected. The reported as rechallenged with an unknown outcome.
concomitant medications were carbasalate,
diclofenac, misoprostol, amlodipine, isosorbide
dinitrate, folic acid, metoprolol, alendronic acid, and
simvastatin. The patient had never had a muscle Literature and labelling
disorder in association with simvastatin. The national
centre mentioned that the official product The main risks with the use of methotrexate are
information of methotrexate only describes myalgia. related to haematological toxicity, and reduced
immunity in the presence of infections. However,
Positive dechallenge was reported for 21 patients. neither the SPC in the US nor in Europe describe
Methotrexate was stopped in 18 patients, of whom muscle spasm or cramps as ADRs. Myalgia,
16 were reported as recovered, 1 was recovering,

AR10099
Signal
arthralgia, osteonecrosis, and osteoporosis are listed properties, however, this also acts on the skeletal
as musculoskeletal ADRs. muscle by the adenosine monophosphate-activated
protein kinase (AMPK). Hence, the potential action of
There are several special warnings and precautions the methotrexate on the skeletal muscle is a concern.
for use of methotrexate regarding potential Recent research suggests that methotrexate could
interactions with other drugs. There is a warning for reduce the threshold for AMPK activation by AICART.
the concomitant use with NSAIDs, because it has AMPK has recently emerged as a novel target for the
been found to decrease the tubular secretion of treatment of pain, with the exciting potential for
methotrexate and possibly to increase its toxicity. disease modification. AMPK activators inhibit
Likewise, there is a precaution in the concomitant signalling pathways that are known to promote
use of omeprazole and pantoprazole because of their changes in the function and phenotype of peripheral
potential impact on methotrexate elimination .5 nociceptive neurons and promote chronic pain.2,10–12
However, there are no warnings regarding
concomitant use of statins or adalimumab, or other The literature suggests that muscle spasms could be
drugs that can cause musculoskeletal disorders. associated with peripheric neuropathy and
hypothyroidism, which were not identified in this
There are no case reports about muscle cramps in case series due to the intrinsic limitations of
the literature, although there are two case reports spontaneous reporting. Other causes could be
about musculoskeletal ADRs. One describes two electrolyte imbalances, and calcium and magnesium
cases of acute diffuse muscular pain following imbalances were reported for one patient. It is well
initiation of weekly low dose oral methotrexate in known that hypokalaemia can be associated with
rheumatoid arthritis (women 70 and 49 years old).8 muscle cramps or other muscle disorders, however,
The other report concerns a 59-year-old man with a hypokalaemia was not reported for any of the
folliculotropic cutaneous T-cell lymphoma taking low patients.
dose pulse methotrexate (15 mg intramuscularly,
once a week), at the same time as being treated with The concomitant drugs found in the case reports
pantoprazole (20 mg/day, orally). After the first raise concerns about an incomplete profile of
injection of methotrexate the patient presented with methotrexate interactions. Some drugs, such as
generalized myalgia and bone pain. The symptoms adalimumab, or statins, could be strongly associated
recurred over the following four methotrexate cycles. with the muscle ADRs, however, it is not possible to
Pantoprazole was replaced by ranitidine and the rule out the suspected role of methotrexate as its
muscle symptoms disappeared. The report administration fits the same timeframe. Also, results
mentioned a positive rechallenge, during which a with animal models and some pharmacokinetics
laboratory test showed an elevation in the serum studies suggest that other drugs such as NSAIDs and
concentration of the 7-hydroxymethotrexate, which PPIs can decrease renal elimination and tubular
the authors interpreted as an interaction in renal secretion. Some studies that have analysed this
elimination, rather than a metabolic interaction.9 interaction with low and high doses of methotrexate
concluded that the elevation in methotrexate
Discussion concentration as a consequence of the interaction
has a low clinical impact, however, it is important to
Muscle spasms or cramps may sometimes overlap carefully assess the risk-benefit balance before
with myalgia, and myalgia has already been deciding to prescribe it, and to follow-up the patients,
identified as an ADR. Nevertheless, this analysis especially those who are long-term users of
presents a group of patients who suffered from methotrexate.5,13,14
spasm or cramp, with most cases reported by
physicians. For that reason, it is plausible to think the Conclusion
muscle spasm or cramp is a worrisome clinical event
that may prevent some patients from performing Muscle spasms or muscle cramps are not currently
daily activities. mentioned in the SPC for methotrexate, and this ADR
could have an impact on the quality of life of patients
Methotrexate inhibits aminoimidazole caboxamide undergoing treatment with methotrexate. Patients,
ribonucleotide transformylase (AICART). This as well as physicians, should be aware of these ADRs
inhibition leads to the accumulation of AICART to avoid a reaction that could affect the quality of life
ribonucleotide, which inhibits adenosine deaminase, of patients. For this reason, it is reasonable to
leading to an accumulation of adenosine consider an in-depth clinical analysis when the
triphosphate and adenosine in the extracellular space, patient mentions these complaints, especially
stimulating adenosine receptors. This action is well- patients on low doses.
known as the basis for its anti-inflammatory

AR10100
Signal
Table 1. Summary characteristics of 47 cases in VigiBase of muscle cramps in association with methotrexate
with a completeness score over 0.70.
Characteristic 47 cases with completeness score over 0.70

Age (mean / range) 53 years / 13-87
Patient sex distribution 30 females / 17 males, ratio 2:1
Top ten countries Netherlands (15), France (6), Canada (5), Australia (2), Republic of Korea (2), Sweden (2), Croatia (2)
Germany (2), Italy (2), Costa Rica (1)
Reporters Physician (26), Pharmacist (10), Consumer (7), Other Healthcare Professional (4)
Single suspected drug 28 reports (59%)
Single reported drug 18 reports
Time-to-onset 1 day to 6 years
The action taken with the drug 25 cases with drug withdrawn / 16 recovered, 1 recovered with sequelae, 1 recovering, and 1 outcome
/outcome unknown.
4 cases with dose reduced / 3 recovered and 1 not recovered.
12 cases with the drug not changed / 3 recovered, 1 recovered with sequelae, 7 not recovered and 1
outcome unknown.
6 drug action unknown / 3 recovered and 3 outcomes unknown
References
1. Cipriani P, Ruscitti P, Carubbi F, Liakouli V, pain following initiation of methotrexate

Giacomelli R. Methotrexate in rheumatoid therapy. Ann Rheum Dis. 1994;53(7): 478–
arthritis: optimizing therapy among different 9.
formulations. Current and emerging
paradigms. Clin Ther. 2014;36(3):427–35. 9. Tröger U, Stötzel B, Martens-Lobenhoffer J,
Gollnick H, Meyer FP. Drug points: severe
2. Inoue K, Yuasa H. Molecular basis for myalgia from an interaction between
pharmacokinetics and pharmacodynamics of treatments with pantoprazole and
methotrexate in rheumatoid arthritis methotrexate. BMJ. 2002;324(7352):1497.
therapy. Drug Metab Pharmacokinet.
2014;29(1):12–9. 10. Dolinar K, Jan V, Pavlin M, Chibalin AV,
Pirkmajer S. Nucleosides block AICAR-
3. Jansen PHP, Gabreëls FJM, van Engelen stimulated activation of AMPK in skeletal
BGM. Diagnosis and differential diagnosis of muscle and cancer cells. Am J Physiol Cell
muscle cramps: A clinical approach. J Clin Physiol. 2018;315(6):C803–17.
Neuromuscul Dis. 2002;4(2):89–94.
11. Asiedu MN, Dussor G, Price TJ. Targeting
4. Methotrexate 2.5 mg Tablets - Summary of AMPK for the alleviation of pathological pain.
Product Characteristics (SmPC). In: 2016;107:257–85.
Electronic Medicines Compendium (emc)
[website]. 2020 12. Pirkmajer S, Kulkarni SS, Tom RZ, Ross FA,
(https://www.medicines.org.uk/emc/product Hawley SA, Hardie DG, et al. Methotrexate
/511/smpc, accessed 30 November 2021). promotes glucose uptake and lipid oxidation
in skeletal muscle via AMPK activation.
5. DailyMed - METHOTREXATE- methotrexate Diabetes. 2015;64(2):360–9.
sodium tablet [website]. In: US National
Library of Medicine, Dailymed2021 13. Reeves DJ, Moore ES, Bascom D, Rensing B.
(https://dailymed.nlm.nih.gov/dailymed/dru Retrospective evaluation of methotrexate
gInfo.cfm?setid=8f1260de-b60c-4f0e-8af6- elimination when co-administered with
0e957b0a281b, accessed 30 November proton pump inhibitors. Br J Clin Pharmacol.
2021). 2014;78(3):565–71.
6. Stamford B. Muscle cramps. Phys 14. Hall JJ, Bolina M, Chatterley T, Jamali F.
Sportsmed. 1993;21(7):115–6. Interaction between low-dose methotrexate
and nonsteroidal anti-inflammatory drugs,
7. Miller TM, Layzer RB. Muscle cramps. Muscle penicillins, and proton pump inhibitors: a
Nerve. 2005:;32:431–42. narrative review of the literature. Ann
Pharmacother. 2017;51(2):163–78.
8. Eames P, Jones AC. Acute diffuse muscular
AR10101
Signal
Tocilizumab and gastric perforation

Dr Qun-Ying Yue and Dr Elenor Kaminsky, Uppsala Monitoring Centre
Summary with glucocorticoids or MTX. TCZ reduces

progression rate of joint damage and improves
Tocilizumab (TCZ), a humanized monoclonal physical function when given in combination with
antibody acting as an interleukin6 (IL-6) receptor MTX. It is also indicated for treatment of juvenile
antagonist, belongs to an important group of idiopathic polyarthritis in patients from two years of
biological agents that has revolutionized the anti- age who have not responded to previous MTX
inflammatory therapy of rheumatoid arthritis (RA). treatment. More recently, TCZ has been discussed
However, drugs that block IL-6 are reported to be and tested as an alternative treatment for COVID-
associated with increased risk of gastrointestinal 19 patients with a risk of cytokine storms, since it
(GI) perforation, mainly intestinal. Gastric has been suggested that IL-6 is one of the most
perforation associated with TCZ was identified as a important cytokines in the storms.5
potential signal in a screening of VigiBase, the WHO Gastrointestinal (GI) perforation is a hole in the wall
global database of individual case safety reports. As of GI tract which could include the oesophagus,
of March 2020, there were 20 unique patients stomach, small intestine and large intestine.
(compared with 3 expected), from 9 countries, Underlying causes of GI perforation may be gastric
reporting gastric perforation with TCZ as a ulcers, duodenal ulcers, appendicitis, GI cancer,
suspected medicine, in VigiBase. These cases diverticulitis, inflammatory bowel disease, and use
occurred with a time to onset ranging from 0.5 to of medicines such as NSAIDs. Surgical intervention
36 months (median 5 months); 17/20 (85%) were is usually required for haemostasis, and closure of
considered as serious, 1 with a fatal outcome. The perforation and conservative treatment is indicated
indication (known in 18 patients) for TCZ treatment only in selected patients who are clinically stable.6
was RA in 16 and temporalis arthritis, or giant cell
arthritis (GCA), in two patients. The outcome was Gastrointestinal perforation is mentioned in both
unknown for 7 patients, 11 patients recovered or the EMA and FDA labelling. However, the labelling is
were recovering, including four where a surgical focused on intestinal perforation, and as a
procedure was reported, and two did not recover, complication of diverticulitis. This was why gastric
including the fatal case. Known risk factors for perforation was identified as a potential signal in a
gastric perforation existed in 10 patients, including screening of VigiBase.
co-mobilities or a history of GI disorders, smoking;
The objective of this study was to analyze the
and concomitant treatment with methotrexate
pattern and clinical features of gastric perforation
(MTX), rituximab, steroids, NSAIDs, or a
associated with TCZ in the VigiBase cases, and to
combination of these. There seemed to be more
assess the causality alongside literature findings.
patients with a high body weight than with a low
body weight, when information was available.
Considering the seriousness of this reaction, it
Reports in VigiBase
would be prudent to recommend close monitoring of
patients when treated with TCZ, in particular those
A clinical review of reports with gastric perforation
with risk factors for GI perforation as well as those
(PT) associated with TCZ retrieved from VigiBase up
with a high body weight, as its dose is determined
to March 2020 was performed.
by the patient’s total body weight.
VigiBase contained 20 unique patients reporting
gastric or stomach perforation with TCZ as a
Introduction suspected or interacting medicine, compared with 3
expected. Table 1 shows the patients’ demographics
Tocilizumab (TCZ) is a humanized monoclonal and their characteristics. The reports came from
antibody that acts as an interleukin6 (IL-6) receptor nine countries (Japan (5), USA (5), Colombia (3),
antagonist. Thus, it is an immunosuppressive and Austria (2), and 1 each from UK, Ireland, Greece,
interleukin repressive medicine, indicated for adult Portugal and Hungary). The indications of TCZ,
treatment of severe active and progressive available for 18 patients, were RA (n=16) and GCA
rheumatoid arthritis (RA), especially in combination (n=2). There were 13 females, 6 males and one
with methotrexate (MTX),1 and giant cell arteritis gender information missing, which reflects the
(GCA).2, 3 TCZ is often given to patients responding population treated under the indications. Their ages
inadequately or being intolerant to previous therapy ranged from 37 to 83 years (median: 61 years).
with disease-modifying anti-rheumatic drugs or When reporter category information was available,
tumour necrosis factor (TNF) antagonists.4 Further, most reports came from physicians (n=16). Of the
it can be given as monotherapy in case of 20 cases, 17 (85%) were serious, including 4 life-
intolerance to, or inappropriate continued treatment threatening and one with a fatal outcome. In 11
AR10102
Signal
cases (55%) there were narratives, although some ranging from 49 to 114 kg (49, 52, 53, 75, 88, 90,
of these were considered not informative. 98, 100 and 114 kg, respectively).
In addition to gastric perforation, seven patients The time to onset (TTO) was reported for 13
had co-reported reactions such as acute coronary patients, and ranged from 0.5 to 36 months (mean:
syndrome, pulmonary embolism, cerebrovascular 10; SD: 11; median: 5). The reaction led to
accident, neutropenia, transaminases increased, withdrawal of TCZ in seven patients, when
respiratory or urinary tract infections, while some information was available. The outcome was
patients had multiple co-reported reactions. TCZ reported as recovery for 11 patients, no recovery
was the only suspected drug in 15 patients (75%),. for 1, fatal for 1, and unknown for 7. Positive
In the remaining five cases the co-reported dechallenge was reported for four patients and
suspected drugs included MTX, prednisolone, rechallenge for one patient , who had no gastric
hormones (unspecified) and celecoxib, and two of symptoms reported two weeks after the restart of
these patients, on NSAIDs or steroid, no TCZ, at the time of reporting. Surgery was
gastroprotection (such as antacids) was mentioned. specifically mentioned in the management of the
Where information was provided, 12 patients were reaction for four patients.
taking concomitant medications.
Where information on the medical history and
TCZ dosing information was available for eight concomitant medications was available, known risk
patients: the mean dose, corresponding to four- factors for gastric perforation were reported for 10
weekly intervals, was 7.9 (SD 1.1; median 8.0) patients, including GI disorders, smoking;
mg/kg, ranging from 6.0 to 10.0 mg/kg, based on concomitant treatment with MTX, rituximab,
the highest dose if different doses had been given. steroids, NSAIDs, or a combination of these.
When information was available (n=9), the mean
body weight was 80 kg (SD 24; median 89),
Table 1. Patients’ demographics and characteristics of gastric perforations associated with tocilizumab in
VigiBase.
Age/sex Indication Other suspected (S) or Time to Outcome Co-reported Relevant medical
Case /body / Dose concomitant drugs onset Recovery: adverse history and
weight (mg /4 w) (months) Yes/No/ events concomitant medicines
unknown
1 -/-/- Unknown - Unknown Unknown - -
/-
2 55/F/ RA / - Calcium carbonate, Unknown Unknown Acute PPI; BW 88 kg
88 kg levothyroxine, losartan, coronary
omeprazole, vitamin D syndrome,
nos UGI
haemorrhage
3 53/F/- RA / 560 - 5 Yes - -
(sequelae)
4 70/F/- RA / 400 - 3 Yes - -
(sequelae)
5 50/F/- RA / 504 - 36 Yes - -
6 37/F/ RA / 780 Etoricoxib 2 Yes, - NSAID,
98 kg leflunomide after surgery diverticulitis,
hydroxychloroquine BW 98 kg
tramadol
7 -/F/- RA / - - Unknown Unknown - -
8 67/-/- RA / - Rituximab (S), Unknown Unknown Oesophagitis, Steroid high dose,
beclometasone, pulmonary MTX, PPI, rituximab,
budesonide, fluticasone, embolism, higher than max dose
folic acid, formoterol, tongue
furosemide, gabapentin, ulceration
ipratropium, metformin,
MTX, montelukast,
pantoprazole, prednisone,
ranitidine, salbutamol,
salmeterol, simvastatin,
sitagliptin, warfarin
9 65/F/- RA / 400 13 Yes - -

AR10103
Signal
10 49/F/ RA / - DMARDs, NSAIDs 17 Unknown GI NSAID

52 kg haemorrhage,
neutropenia
11 55/M/ RA / Folic acid (S), hydroxy- 27 Yes, Transaminase Smoking, MTX,
90 kg 680/35-40 chloroquine (S), MTX. after surgery s increased, steroids; PPI; high dose;
Corticosteroids, PPI URTI BW 90 kg
12 58/M/ RA / 400 MTX (S), Prednisol (S), 3 Yes - MTX, steroids, max
49 kg alfacalcidol allpurinol, dose
aspartate calcium,
diclofenac, dimeticone,
etizolam, iron,
lansoprazol,
mizoribine, risedronic
acid, tacrolimus,
zopiclone
13 46/M/ RA / 800 Diclofenac, leflunomide 3 Yes, Abscess, NSAID, steroids, PPI,
100 kg omeprazole, prednisolone after surgery (probably BW 100 kg
tamponated)
14 -/F/- Unknown - Unknown Unknown -
/-
15 73/M/ RA / 600 Meloxicam, MTX, PPI. 11 Yes, - NSAID, PPI, MTX. No
75 kg after surgery history of GI disorders
(ulcers, diverticulosis
etc).
16 62/F/ RA / - Folic acid, metoprolol, Unknown Unknown UTI, influenza (Rivaroxaban), PPI,
113 kg oxybutynin, pravastatin, BW 113.5 kg. Mg/kg
rivaroxaban, omeprazole unknown.
17 79/M/- GCATemp - Unknown No - -
.art/-
18 83/M/- RA/162/1o Hormones (S), 8 Yes - -
r2v = iguratimod, Sulfasalazine
19 76/F/- Temp.art / Prednisone 3 Death Cerebrovascul Steroids; fatal
162/1v ar accident
(=648?)
s.c./i.m.
20 50/F/ RA Celecoxib (S), 0.5 Yes - NSAID, steroids, MTX
53 kg /162/2v prednisolone (S), folic
(= 324 acid, MTX, paracetamol,
mg?) tramadol
BW: Body weight; DMARDs: Disease-modifying antirheumatic drugs; F:Female; GCA: Giant cell arteritis; GI: Gastrointestinal; M: Male; MTX:
Methotrexate; NSAIDs: Nonsteroidal anti-inflammatory drugs; PPI: Proton pump inhibitor; RA: Rheumatoid arthritis; TCZ: Tocilizumab; URTI: Upper
respiratory tract infection;
Literature and labelling laboratory abnormalities (liver enzyme

abnormalities, low absolute neutrophil count, and
Tocilizumab (RoActemra) EU summary of low platelet count) are found. No dose adjustment
product characteristics (SPC)4 is required in elderly patients >65 years of age, or
in patients with mild renal impairment.
Posology and method of administration
Special warnings and precautions for use
Treatment should be initiated by healthcare
professionals experienced in the diagnosis and Complications of diverticulitis: perforations as
treatment of RA, systemic juvenile idiopathic complications of diverticulitis have been reported
arthritis (sJIA), juvenile idiopathic polyarthritis uncommonly with TCZ in RA patients. TCZ should
(pJIA) or cytokine release syndrome (CRS). TCZ be used with caution in patients with a previous
should be administered as an intravenous infusion history of intestinal ulceration or diverticulitis.
over one hour. Patients presenting with symptoms potentially
indicative of complicated diverticulitis, such as
For RA patients, the recommended posology is abdominal pain, haemorrhage or unexplained
8 mg/kg body weight, given once every four weeks. change in bowel habits with fever should be
For individuals whose body weight is more than evaluated promptly for early identification of
100 kg, doses exceeding 800 mg per infusion are diverticulitis, which can be associated with
not recommended. Dose adjustments are needed if gastrointestinal perforation.

AR10104
Signal
Adverse drug reactions relevant to the signal are

presented in Table 2.
Table 2. Adverse drug reactions (relevant to the signal, selected by the authors).
MedDRA System Organ Class Frequency categories with preferred terms
Infections and infestations Uncommon: diverticulitis
Gastrointestinal disorders Common: abdominal pain, mouth ulceration, gastritis

Uncommon: stomatitis, gastric ulcer
Gastrointestinal perforation: during the 6-month controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events
per 100 patient years with TCZ therapy. The overall rate of gastrointestinal perforation was 0.28 events per 100 patient years in the long-
term exposure population. Reports of gastrointestinal perforation in patients taking TCZ were primarily reported as complications of
diverticulitis including generalized purulent peritonitis, lower gastrointestinal perforation, fistulae and abscess.
Discussion study. It has been reported that chronic dosing

using total body weight can lead to drug toxicity in
TCZ, a monoclonal antibody targeting the IL-6 obese adults.14 Although the body composition (lean
receptor, has been reported to increase the risk of versus adipose weight) and the body mass index
GI perforation.7 The risk for lower GI perforation were not reported, it seems prudent to recommend
associated with TCZ was estimated to be more than close monitoring of patients, in particular, those
twice that for anti-tumour necrosis factor agents.8 with a high body weight when the drug is dosed
In a registry of lower intestinal perforation (LIP), according to total body weight.
the crude incidence rate of LIP was found to be
significantly higher in patients taking TCZ (2.7/1000 The findings in the present case series are in line
person-years), compared with all other treatments with the literature reporting the commonly used
(0.2−0.6/1000 person-years).9 In the literature, concomitant medicines in RA, e.g. MTX, NSAIDs,
more data are available for the risk of for lower GI and corticosteroids, all known to present risks for
tract perforation. More recently, based on updated GI disorders, in particular gastric perforation.7 As
data it was reported that, although data are limited, shown in Table 1, in five patients MTX was used, in
drugs that block IL-6 are associated with a greater five cases NSAIDs, and in six cases steroids,
increased risk of GI perforation, than other RA including one with higher dose of steroids. In
therapies.7 In our current study, 20 patients with addition, one patient concomitantly used
gastric perforation in VigiBase were reviewed with a rivaroxaban which is known to increase the risk of
focus on the clinical features. TTO ranged from 0.5 GI bleeding. Therefore, these drugs may also have
to 36 months (mean 10; median 5). About 2/3 of contributed to the adverse events. In addition, six
the patients were females, reflecting the treatment patients had also concomitantly used PPI, although
indication of RA where a female to male prevalence it is unknown if it was used to prevent or treat GI
ratio of 2-3:1 has been reported.10 problems.
When TCZ (RoActemra) was approved in the EU Diverticulosis, was specifically mentioned for only
(2009), the Member States were required to two patients, one where it was reported present,
implement an educational pack to inform physicians and another where it was absent. Diverticular
and patients about the risks of serious infections inflammation was reported for 0.8% of patients,
and complications of diverticulitis.11 In the summary who underwent colonoscopy but who lacked
of the Risk Management Plan (RMP) it was stated symptoms or clinical evidence of diverticulitis.15 Up
that the rate of serious infections appeared to to 40% of the Western population may have
increase with body weight.12 The dose of TCZ is diverticulosis.16 It is unclear if patients with known
dependant on body weight: 8 mg/kg body weight, severe diverticulosis should be excluded from TCZ
given once every four weeks. For individuals whose treatment, or if they should have a colonoscopy
body weight is more than 100 kg, doses exceeding before starting TCZ to assess whether they have
800 mg per infusion are not recommended.13 diverticulosis. 17 It has also been suggested that IL-
6 blockers should be avoided in patients with a
In the current study, the mean body weight was history of diverticulitis, as they are known to
about 80 kg. However, no patient weighed 80 kg. increase the risk of subsequent intestinal
Only one patient weighed 75 kg, which was close to perforation.7 The impact of diverticulitis on gastric
the mean body weight, while five patients were perforation is unclear.
heavier (88.2, 90, 98, 100 and 113.5 kg) and three
were lighter (49, 52.2 and 53 kg). It would seem One patient was a smoker, which could induce
that heavier patients are over-represented in this pathogenic and carcinogenic processes in the GI

AR10105
Signal
tract.18 This is because active compounds in 2. Toussirot É, Martin A, Soubrier M, Redeker S,

cigarette smoke can damage GI tract structure Régent A. Rapid and sustained response to
through cellular apoptosis induction, and hamper tocilizumab in patients with polymyalgia
the mucosal cell renewal. Cigarette smoke also rheumatica resistant or intolerant to
interferes with the protective mechanisms of the GI glucocorticoids: a multicenter open-label study.
tract through modulating the mucosal immune J Rheumatol. 2016;43(1):249-51.
system, and reducing the mucosa blood flow. In
addition, it inhibits the synthesis and release of EGF
3. Stone JH, Tuckwell K, Dimonaco S, Klearman M,
and polyamines, which reduces mucus secretion,
which may compromise the integrity of the mucosal Aringer M, Blockmans D, et al. Trial of
defence. Tocilizumab in Giant-Cell Arteritis. N Eng JMed.
2017;377(4)317-28.
Eleven patients, when information was provided,
had at least one factor that may have contributed 4. Summary of Product Characteristics for
to the occurrence of gastric damage, such as
Tocilizumab. In: Electronic Medicines
concomitant drugs (e.g., MTX, NSAIDs, steroids,
rivaroxaban), or conditions (e.g., smoking, high Compendium [website].
body weight and associated high dose of TCZ). (https://www.medicines.org.uk/emc/product/66
Eight of these patients had more than one of the 73/smpc, accessed 5 April 2019
factors, suggesting compounded risk for the
reaction to occur.
5. Luo P, Liu Y, Qiu L, Liu X, Liu D, Li J.
Only four reports specifically mentioned surgery for Tocilizumab treatment in COVID‐19: A single
the ADR. The current treatment of perforated peptic center experience. J Med Virol. 2020;1–5.
ulcer is surgical repair, although conservative
treatment can be adopted in selected patients.6 It is 6. Hanumanthappa MB, Gopinathan S, Guruprasad
unclear in our case series whether the perforations Rai D, Dsouza N. A non-operative treatment of
without surgery mentioned in the reports were perforated peptic ulcer: a prospective study
‘microperforation’ (see definition of GI perforation7)
with 50 sases. JClinDiagn Res. 2012;6(4):696-
for which surgery is not indicated, or if surgery was
9.
performed but not noted in the reports.
7. Jagpal A, Curtis J. Gastrointestinal perforations

Conclusion with biologics in patients with rheumatoid
arthritis: implications for clinicians. Drug Saf.
Gastrointestinal perforation is an important 2018;41(6):545–53
identified risk of TCZ treatment which may be life-
threatening. However, the current labelling is 8. Xie F, Yun H, Bernatsky S, Curtis JR. Risk of
focused on intestinal perforation, and as a gastrointestinal perforation among rheumatoid
complication of diverticulitis. In VigiBase, cases of arthritis patients receiving tofacitinib,
gastric perforation have been reported, particularly tocilizumab, or other biologic treatments.
in patients with high body weight and taking Arthritis Rheumatol., 2016;68(11);2612–7.
concomitant medications known to cause gastric
perforation. Healthcare professionals should be
9. Strangfeld A, Richer A, Siegmund B, Herzer P,
aware of this potential risk and closely monitor
Rockwitz K, Demary W, et al. Risk for lower
patients, in particular those with risk factors for GI
intestinal perforations in patients with
perforation, as well as those with high body weight,
during treatment with TCZ, which is dosed rheumatoid arthritis treated with tocilizumab in
according to total body weight. comparison to treatment with other biologic or
conventional synthetic DMARDs. Ann Rheum
Dis. 2017;76(3):504-10.
We acknowledge with thanks the pharmacovigilance
centres that provided additional case information 10. Tedeschi SK, Bermas B, Costenbader KH.
upon request. Sexual disparities in the incidence and course of
SLE and RA. Clin Immunol. 2013;149(2):211-8.
References 11. European Medicines Agency. 2011. Conditions

or restrictions with regard to the safe and
1. Dhillon, S. Intravenous tocilizumab: a review of effective use of medicinal product to be
its use in adults with rheumatoid arthritis. implemented by the member states – Annex IV.
BioDrugs. 2014;28:75–106. Available from:
https://www.ema.europa.eu/en/documents/con

AR10106
Signal
ditions-member-states/roactemra-epar- colonoscopy patients without clinical acute

conditions-imposed-member-states-safe- diverticulitis: prevalence and endoscopic
effective-use-annex-iv_en.pdf, accessed 1 spectrum. Am J Gastroenterol. 2003;98(4):802-
December 2021 6.
12. European Medicines Agency. 2020. Summary of 16. Storz C, Rothenbacher T, Rospleszcz S,
risk management plan for RoActemra Linseisen J, Messmann H, DeCecco CN, et al.
(tocilizumab). Characteristics and associated risk factors of
(https://www.ema.europa.eu/en/documents/rm diverticular disease assessed by magnetic
p-summary/roactemra-epar-risk-management- resonance imaging in subjects from a Western
plan-summary_en.pdf, accessed 1 December general population. Eur Radiol.
2021). 2019;29(3):1094–103
13. European Medicines Agency. 2021. EPAR, 17. Giang J, Settergren N, Lute M, Fernandez, H.
(EMA/686079/2018, EMEA/H/C/000955; Tocilizumab associated hemorrhagic shock from
https://www.ema.europa.eu/en/medicines/hum gastrointestinal bleeding: Abstract 2606. Am J
an/EPAR/roactemra, accessed 1 December Gastroenterol. 2016;111(suppl):S1311-3
2021).
18. Li LF, Chan RLY, Lu L, Shen J, Zhang L, Wu
14. Barras M, Legg A. Drug dosing in obese adults. WKK, et al. Cigarette smoking and
Aust Prescr. 2017;40(5):189–93. gastrointestinal diseases: the causal
relationship and underlying molecular
15. Ghorai S, Ulbright TM, Rex DK. Endoscopic mechanisms (review) Int J Mol Med.
findings of diverticular inflammation in 2014;34(2):372-80.

AR10107
Signal
CAVEAT DOCUMENT
Statement of reservations, limitations and conditions relating to data released from
VigiBase, the WHO global database of individual case safety reports (ICSRs).
Understanding and accepting the content of this document are formal conditions for the use of
VigiBase data.
Uppsala Monitoring Centre (UMC) in its role as the World For these reasons, interpretations of adverse effect
Health Organization (WHO) Collaborating Centre for data, and particularly those based on comparisons
International Drug Monitoring receives reports of between medicinal products, may be misleading.
suspected adverse reactions to medicinal products from The data comes from a variety of sources and the
National Centres in countries participating in the WHO likelihood of a causal relationship varies across
Programme for International Drug Monitoring. The reports. Any use of VigiBase data must take these
information is stored in VigiBase, the WHO global significant variables into account.
database of individual case safety reports (ICSRs). It is
Prohibited use of VigiBase Data includes, but is not
important to understand the limitations and qualifications
limited to:
that apply to this information and its use.
• patient identification or patient targeting
Tentative and variable nature of the data
• identification, profiling or targeting of general
Uncertainty: The reports submitted to UMC generally
practitioners or practice
describe no more than suspicions which have arisen from
observation of an unexpected or unwanted event. In most Any publication, in whole or in part, of information
instances it cannot be proven that a specific medicinal obtained from VigiBase must include a statement:
product is the cause of an event, rather than, for example,
(i) recording ‘VigiBase, the WHO global database of
underlying illness or other concomitant medication.
individual case safety reports (ICSRs)’ as the source
Variability of source: Reports submitted to national of the information
centres come from both regulated and voluntary sources.
(ii) explaining that the information comes from a variety
Practice varies: some national centres accept reports only
of sources, and the probability that the suspected
from medical practitioners; others from a broader range of
adverse effect is drug-related is not the same in all
reporters, including patients, some include reports from
cases
pharmaceutical companies.
(iii) affirming that the information does not represent the
Contingent influences: The volume of reports for a
opinion of the UMC or the World Health Organization.
particular medicinal product may be influenced by the
extent of use of the product, publicity, the nature of the Omission of this statement may exclude the
adverse effects and other factors. responsible person or organization from receiving
further information from VigiBase.
No prevalence data: No information is provided on the
UMC may, in its sole discretion, provide further
number of patients exposed to the product, and only a
instructions to the user, responsible person and/or
small part of the reactions occurring are reported.
organization in addition to those specified in this
Time to VigiBase: Some national centres make an statement and the user, responsible person and/or
assessment of the likelihood that a medicinal product organization undertakes to comply with all such
caused the suspected reaction, while others do not. Time instructions.
from receipt of an ICSR by a national centre until
submission to UMC varies from country to country. Uppsala Monitoring Centre (UMC)
Information obtained from UMC may therefore differ from Box 1051, SE-751 40 Uppsala, Sweden
that obtained directly from national centres. Tel: +46-18-65 60 60, E-mail: info@who-umc.org
www.who-umc.org

AR10108
Feature
Advisory Committee on Safety of Medicinal Products (ACSoMP)

Eighteenth meeting
World Health Organization, Geneva (virtual Meeting)
26-27th October 2021
The WHO Advisory Committee on Safety of Medicinal Products (ACSoMP) was established in 2003, to provide
advice to WHO, including its Collaborating Centre for International Drug Monitoring (the UMC), and through it,
to the Member States, on safety issues relating to medicinal products. Topics discussed in the 18th meeting of
ACSoMP consisted of updates on previously discussed safety issues such as the safety of sodium valproate in
pregnancy, and request for advice on new topics such as integrating pharmacovigilance into the global leprosy
programme. A full list of topics discussed is below:
1. Update on therapeutic investigational drugs for treatment of COVID-19 and latest vaccine safety
issues.
2. Update on results of studies investigating neural tube defects and the use of dolutegravir.
3. Update on the use of sodium valproate during pregnancy.
4. Monitoring the safety of drugs used in leprosy.
5. Safety signal of hallucinations with the use of delamanid in children for tuberculosis.
6. Ocular adverse events with the use of miltefosine for visceral leishmaniasis and post-kala-azar dermal
leishmaniasis.
7. Update on the safety of fexinidazole used for African trypanosomiasis in the Democratic Republic of
Congo.
An overview of recommendations from the meeting will be published in a following issue of the
Pharmaceuticals Newsletter.

AR10109
AR10110
Français
18
MENU 
Moderna Spikevax COVID-19 vaccine

Name: Moderna Spikevax® COVID-19 vaccine Approved for: Age 6 and older
Manufacturer: ModernaTX, Inc. How it's given: Injection in muscle (usually the upper arm)
Type: mRNA Number of doses: 2 doses
On this page
Effectiveness
Dosage
Vaccine ingredients
Get vaccinated

Effectiveness
Clinical trials showed that beginning 2 weeks after the second dose, the Moderna Spikevax® COVID vaccine was:
94.1% effective in protecting trial participants aged 18 and above against COVID-19
100% effective in trial participants 12 to 17 years old
as effective in trial participants 6 to 11 years old as young adults (18 to 25 years old)
Dosage
The dosing schedule approved by Health Canada is to give 2 doses (100 micrograms each for ages 12 and older or 50
micrograms each for ages 6 to 11) 1 month apart, based on evidence from clinical trials.
A booster dose (50 micrograms) of the Moderna Spikevax® COVID-19 vaccine may be administered in individuals 18
years of age and older at least 6 months after completing their primary vaccine series.
Dose volume depends on which series of the vaccine is being administered. The dose for individuals 12 years of age and
older (100 micrograms) is twice the dose used for children 6 to 11 years of age (50 micrograms). The booster dose is also
50 micrograms.
Check the colour of the vial cap and the corresponding dose volumes to select the appropriate dose volume for the
vaccine series being administered. The 0.2 mg/mL multi-dose vial has a red plastic cap. The 0.1 mg/mL multi-dose vial
has a royal blue plastic cap. The vials with royal blue caps make it easier to administer smaller doses.
Your province or territory decides when people receive their doses of the vaccine. These decisions are based on public
health recommendations and the latest evidence.
Learn more about:
how provinces and territories make decisions about how, who and when to vaccinate
Mixed dose schedules

A different vaccine may be offered for your second dose. For example, you may have received Pfizer-BioNTech
Comirnaty® as your first dose and be offered Moderna Spikevax® as your second. This is known as a mixed vaccine
series.
The National Advisory Committee on Immunization (NACI) recommends an mRNA vaccine (Pfizer-BioNTech Comirnaty®
or Moderna Spikevax®) should be offered for your second dose.
Learn more about:
mRNA vaccines
Viral vector vaccines
Vaccine ingredients
Vials with a red cap contain 10 doses of 0.5 mL. One dose (0.5 mL) contains 100 micrograms of COVID-19 mRNA
vaccine.
Vials with a red cap contain 20 doses of 0.25 mL. One dose (0.25 mL) contains 50 micrograms of COVID-19 mRNA
vaccine.
Vials with a royal blue cap contain 5 doses of 0.5 mL. One dose (0.5 mL) contains 50 micrograms of COVID-19 mRNA
vaccine.
mRNA
Other ingredients
Acetic acid
Cholesterol
DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine)
Lipid SM-102
PEG2000-DMG (1,2-dimyristoyl-rac-glycerol,methoxy-polyethyleneglycol)
Sodium acetate trihydrate
Sucrose
Trometamol
Trometamol hydrochloride
Water for injection
This vaccine does not contain any:
preservatives
antibiotics
adjuvants
human materials
animal-derived materials
common food allergens

vaccination.

redness chills
soreness fatigue
swelling joint pain
headache
mild fever
muscle aches
nausea
vomiting

Rare reactions that have been reported and confirmed after taking an mRNA vaccine are:
Myocarditis and pericarditis

Bell's palsy (facial paralysis)
A severe allergic (anaphylaxis) reaction is also rare. Signs and symptoms of anaphylaxis may include:

vaccination.
Reporting a possible serious reaction



Health Canada's independent drug review process is recognized around the world for its high standards and rigor. Our
decisions are based only on scientific and medical evidence showing that vaccines are safe and effective. The benefits
must also outweigh any risks.
The Moderna COVID-19 vaccine was authorized for use in Canada under the Interim Order respecting the importation,
sale and advertising of drugs for use in relation to COVID-19. The interim order expired on September 16, 2021. On this
date, Moderna Spikevax® transitioned to an authorization under the Food and Drug Regulations.
Moderna Spikevax® vaccine regulatory information

Get vaccinated
Related links
Canada's vaccine supply
What to expect at your vaccination
AR10111
TAB 64
AR10112
FEDERAL COURT
B E T W E E N:
NABIL BEN NAOUM
demandeur
- and -
dèfendeur
AND BETWEEN:
demandeur
- and -
dèfendeur
AND BETWEEN:
NIKKANEN, KEN BAIGENT, DREW BELOBABA, NATALKIE

Applicants
- and -
Respondent

AR10113
AND BETWEEN:
Applicants
- and -
Respondent
--------
--- This is the Cross-Examination of JULIE

LAROCHE, on her Affidavit sworn on April 22,
2022, on behalf of the Attorney General of
Canada, taken via Videoconference for Network
Reporting & Mediation, Toronto, Ontario, on the
6th day of June, 2022.
--------
MAHAN KERAMATI
ROBERT DRUMMOND

EVA CHIPIUK
ALLISON PEJOVIC
ALSO PRESENT:
Patrick Abbott
Sayah Hassan
REPORTED BY: Caroline Maslin, CSR

AR10114
WITNESS: Julie Laroche
PAGE
CROSS-EXAMINATION BY MR. PRESVELOS......6
CROSS-EXAMINATION BY MR. WILSON........18
**The following list of undertakings, advisements and
refusals is meant as a guide only for the assistance of
counsel and no other purpose**
The questions/requests undertaken are noted by
U/T and appear on the following pages: None
INDEX OF ADVISEMENTS
The questions/requests taken under advisement are
noted by U/A and appear on the following pages:
19:16
INDEX OF REFUSALS
The questions/requests refused are noted by R/F
and appear on the following pages: None

AR10115
I N D E X O F E X H I B I T S
NUMBER/DESCRIPTION PAGE/LINE NO.
None entered

AR10116
June 6, 2022 Julie Laroche - 5
1 --- Upon commencing at 3:45 p.m.
2 JULIE LAROCHE: Affirmed via Zoom
3 CROSS-EXAMINATION BY MR. PRESVELOS:
4 1 Q. Okay. Good afternoon, Dr. Laroche.
5 How are you?
6 A. Good, thank you.
7 2 Q. Dr. Laroche, you understand that
8 you've been sworn to tell the truth today?
9 A. Yes.
10 3 Q. You understand I'm going to ask you a
11 series of questions about your affidavit?
12 A. Yes.
13 4 Q. And you promise me that you're going
14 to answer truthfully and accurately in response
15 to questions I'm going to ask you; correct?
16 A. Yes.
17 5 Q. Good. That's good. So I just want

18 to get a sense of what you do at PHAC. You say,
19 "I am responsible for the surveillance of
20 vaccination coverage and effectiveness." And
21 I've spoken with a colleague of yours a few days
22 ago who seem to do something similar.
23 When you say "surveillance," I take it
24 that's a -- that's a term to mean you observe,
25 you review information on vaccine coverage and

AR10117
1 effectiveness in Canada?
2 A. Yes. So in the -- in terms of public
3 health, what I mean by "surveillance" is that we
4 estimate and we monitor and we report data
5 related to vaccine coverage.
6 6 Q. So you're not looking at any
7 peer-reviewed scientific papers on vaccine
8 effectiveness; you're just looking at data from
9 the Canadian population?
10 A. So in terms of vaccine coverage, we
11 are looking at data from the Canadian population
12 in terms of effectiveness, which is not related
13 to this affidavit. There is one section in my
14 group that does look at peer-reviewed published
15 articles related to vaccine effectiveness, yes.
16 7 Q. Do you belong to that section? Is
17 that something that you do?

18 A. Can you clarify your question,
19 please?
20 8 Q. Yes. You said that there is a
21 section in your group that would look at
22 peer-reviewed articles for vaccine effectiveness.
23 A. Yes.
24 9 Q. Right. Do you belong to that group?
25 A. I'm the director of that group.

AR10118
1 10 Q. So then you, yourself, also look at
2 peer-reviewed articles for vaccine effectiveness;
3 correct?
4 A. So epidemiologists in my group look
5 at the data, They synthesize it in our review of
6 the synthesis that they provide.
7 11 Q. I see. So you just review the
8 synthesis of what's been prepared by other
9 individuals in your group?
10 A. Exactly.
11 12 Q. And as far as you're aware, does the
12 synthesis of information also include periodicals
13 and information from other countries?
14 A. Yes.
15 13 Q. And would the -- would the United
16 Kingdom be one of those countries? Or one of
17 those -- well, would the U.K. be one of those

18 jurisdictions where you would review information
19 relating to vaccine effectiveness?
20 A. If it's published in peer-reviewed
21 scientific articles, yes.
22 14 Q. Okay. And when you're reviewing
23 information regarding vaccine effectiveness, what
24 are you doing with that information?
25 A. So the role of my group as it relates

AR10119
1 to vaccine effectiveness is to review what's in
2 the peer-reviewed scientific literature to make
3 synthesis' summaries and to circulate those
4 summaries to other groups.
5 15 Q. Okay. Are there any action items or
6 recommendations based on the synthesis of these
7 summaries that you circulate to other groups?
8 A. No.
9 16 Q. Why not?
10 A. It's not our role.
11 17 Q. I see. So your role is to review and
12 synthesize and distribute?
13 A. Exactly.
14 18 Q. Okay. And when you send it to other
15 groups, do you know which other groups you send
16 it to?
17 A. There are several groups at the

18 agency, within the agency, and a few external
19 research groups in the provinces and territories.
20 19 Q. Can you tell me which groups are in
21 the agency that would review and -- that would
22 rely and review upon the summaries that you
23 prepare and distribute?
24 A. Sure. There's the Centre for
25 Immunization and Respiratory Infectious Diseases,

AR10120
1 the Centre for Immunization Readiness, colleagues
2 in the Infectious Disease Prevention and Control
3 Branch.
4 20 Q. Is there anything else?
5 A. I would have to go and verify other
6 groups on our distribution list. It's relatively
7 far and wide across the agency.
8 21 Q. And do you have a dialogue with these
9 other departments about the research that you're
10 distributing to them? Do you have any discussion
11 about the research papers that you're
12 synthesizing and passing forward?
13 A. Not formally, no. There -- if there
14 are questions, they're circulated between the
15 groups at a working level but I never get
16 questions.
17 22 Q. And do you know how these other

18 departments use the information that you're
19 distributing to them?
20 A. I just want to clarify that they're
21 not other departments; they are within the Public
22 Health Agency which is the same department.
23 23 Q. Right. That's a good clarification.
24 Well do you know how other groups within the same
25 department rely and use the information that you

AR10121
1 distribute?
2 A. Not fully, no. I know it's -- we've
3 been told that it's useful to them, but I don't
4 know the extent to which they use it for their
5 specific purposes.
6 24 Q. Okay. You're aware that this
7 particular litigation deals with the mandatory
8 vaccination for travel; right?
9 A. Yes.
10 25 Q. And I take it that you were not
11 consulted with by any governmental agency or
12 department with respect to this particular
13 policy; right?
14 A. No.
15 26 Q. Are you aware as to whether or not
16 any of the research you synthesized and
17 distributed was relied upon in making this

18 policy?
19 A. No.
20 27 Q. Okay. Are you aware of any data that
21 the Canadian government may collect that might
22 demonstrate how many Canadians have asymptomatic
23 infection of COVID-19?
24 A. No.
25 28 Q. We have looked with other individuals

AR10122
1 that are -- that are involved or connected with
2 the PHAC. We looked at a website which I'm sure
3 you're familiar with, and it's the health-
4 infobase.canada.ca. And I think you describe
5 some collection methods with respect to this
6 website; is that correct?
7 A. For infobase, yes.
8 29 Q. Right. You know, and just to be
9 fair, I'll do a screen share quickly just so
10 you're -- you can confirm that you and I are
11 talking about the same thing. It's this -- it's
12 this website; right? Give me one second. I'm
13 just refreshing.
14 You're familiar with this; right?
15 A. I know of this website, but my group
16 does not provide data to this particular part of
17 the website.
18 30 Q. Is there any part of this website
19 that your group provides data to?
20 A. Not this one, no.
21 31 Q. Okay. But part of the information
22 you review -- or not -- all of the information, I
23 take it that you review, the data that you review
24 comes from Canada's provinces and territories; is
25 that correct?

AR10123
1 A. In terms of the data for vaccine
2 coverage, yes.
3 MR. DRUMMOND: Counsel, just before we go
4 on, I'm wondering if you could just give me --
5 give the name of this document you put up for the
6 record. I think you may have referred to it
7 differently.
8 MR. PRESVELOS: Sure. It is the COVID-19
9 daily epidemiology update.
10 MR. DRUMMOND: Thank you.
11 MR. PRESVELOS: And updated as of
12 June 6th, 2022.
15 32 Q. Yeah. Dr. Laroche, are you aware
16 that each province and territory across Canada
17 may define death as it pertains to COVID-19

18 differently?
19 A. No.
20 33 Q. Do you know how each province and
21 territory considers a COVID-19 death?
22 A. No.
23 34 Q. So you are not aware that some
24 provinces consider a COVID-19 death as dying with
25 COVID and other provinces classify a COVID-19

AR10124
1 death as dying because of COVID? Are you aware
2 of that?
3 A. I may have heard about this, but this
4 is not my -- my line of expertise of work.
5 35 Q. Can you go to paragraph nine of your
6 affidavit, please?
7 A. Yes.
8 36 Q. Just take a moment and read that
9 paragraph.
10 A. "The federal government is
11 responsible" --
12 37 Q. You -- you could read it to yourself.
13 You don't have to read it on the record. It's
14 okay.
16 A. Yes.
17 38 Q. Have you had a chance to read it?

18 A. Yes.
19 39 Q. Okay. I take it that you're not part
20 of the regulatory approval of vaccines -- that's
21 not part of the -- part of your role; correct?
22 A. Correct.
23 40 Q. Okay. Do you communicate with anyone
24 who is involved in the regulatory approval of
25 vaccines in Canada?

AR10125
1 A. Not directly.
2 41 Q. Do you communicate with them
3 indirectly?
4 A. We do share some of our vaccine
5 coverage data upon request.
6 42 Q. Okay. And do you know what the
7 purpose of sharing the vaccine coverage data with
8 the -- with these individuals are?
9 A. No.
10 43 Q. Okay. You state, "The federal
11 government also provides scientific guidance on
12 the use of vaccines," correct?
13 A. Yes.
14 44 Q. You're not involved in providing such
15 scientific guidance; right?
16 A. No.
17 45 Q. So I take it that the purpose of this

18 paragraph is you're just explaining what the
19 federal government does with respect to
20 regulatory approval process of vaccines and how
21 to use those vaccines and who it reports to with
22 respect to those vaccines, but you're not
23 involved in any of these things?
24 A. I am involved with reporting data to
25 the World Health Organization and the Pan

AR10126
1 American Health Organization.
2 46 Q. I see. And that's the same data that
3 you're talking about earlier; right? That's the
4 data that you report to the WHO and the Pan
5 American Health Organization; right?
6 A. Vaccine coverage data, yes.
7 47 Q. As part of reporting to these
8 organizations, do you give them any
9 recommendations or any action items or any
10 insights when you're reporting this information
11 to them?
12 A. No.
13 48 Q. Okay. Can you read paragraph 12 of
14 your affidavit for a second? And I have some
15 questions to ask you on that paragraph.
17 A. Yes.
18 49 Q. So in this paragraph, you are
19 discussing the purpose of the surveillance
20 system, and it seems to me that there are several
21 action items as a result of the surveillance
22 system. One of them could be to inform the
23 vaccine program delivery, to make public health
24 recommendations, and to build trust through
25 timely and transparent communications; right?

AR10127
1 A. Yes.
2 50 Q. Are you involved in any of these
3 things? Are you part of -- are you part of
4 setting the direction or the strategy of the
5 vaccine program delivery?
6 A. No.
7 51 Q. Do you -- are you involved in making
8 any public health recommendations?
9 A. No.
10 52 Q. Right. Are you consulted on how to
11 build public trust through timely and transparent
12 communications regarding the vaccines?
13 A. No. My only role is to put the data
14 out there and to make it available.
15 53 Q. Okay. Now, in paragraph 13, you said
16 that the data that you received from the
17 provinces and territories is standardized; right?

18 A. Yes.
19 54 Q. And you said:
20 Standardization refers to a set of common
21 rules followed by the surveillance system
22 partners to ensure the data submit is
23 comparable."
24 Where can I find these rules that you
25 follow to standardize the data received from

AR10128
1 provinces and territories?
2 A. So what we mean by that is that we
3 agree with the provinces and territories on
4 common definitions.
5 55 Q. What would those definitions include?
6 A. For instance, that we will report for
7 certain age groups across the country for which
8 people are eligible, that we will agree between
9 the provinces and territories that we'll -- we
10 will report on certain vaccines that are
11 available.
12 56 Q. Is the -- is the definition of deaths
13 and hospitalizations something that's been
14 standardized across the provinces and territories
15 as far as you're aware?
16 A. I don't know.
17 57 Q. Who would know?

18 A. Presumably my colleagues in another
19 group who work on this. This is not my -- my
20 line of work or expertise.
21 58 Q. Okay. I just want to confirm that
22 the -- earlier I showed you the -- the COVID-19
23 -- the COVID-19, well, more specifically, the
24 health-infobase.canada COVID-19 website. Are you
25 aware these -- the starting point of the

AR10129
1 collection of that data is? Is that the
2 beginning of the vaccine rollout which would have
3 been December 14th, 2021? Is that your
4 understanding?
5 A. The page that you showed me had the
6 daily epidemiology update which is not the
7 vaccine-related data.
8 59 Q. So none of the information that you
9 -- that you're responsible to survey would go
10 into this website that I showed you?
11 A. Yes, not into this particular page.
12 60 Q. I'm just looking at paragraph 18 of
13 your affidavit. Is there a reason why there's --
14 partially vaccinated is not a defined term?
15 A. No.
16 61 Q. Okay. Is it a -- is partially
17 vaccinated a term that you would work with in

18 your department?
19 A. Yes, we have.
20 MR. PRESVELOS: Okay. Those are all my
21 questions subject to questions from the -- from
22 Mr. Wilson and his team. Thank you, Doc.
24 CROSS-EXAMINATION BY MR. WILSON:
25 62 Q. Good afternoon, Dr. Laroche. Can you

AR10130
1 hear me?
2 A. Yes, I can. Good afternoon.
3 63 Q. My name is Keith Wilson; I'm one of
4 the lawyers for one of the group of applicants in
5 this case known as the Peckford group.
6 Are you able to tell me based on your
7 review of vaccination coverage data the number of
8 Canadians who are 12 years of age or older and
9 are unvaccinated?
10 A. No.
11 64 Q. Your data collection is pretty
12 comprehensive including demographics on age
13 categories and people's vaccination status.
14 Through your counsel will you undertake to make
15 that calculation?
16 U/A MR. DRUMMOND: Well, I'm going to take
17 that under advisement because of two reasons.

18 It's not discovery and this would be creation
19 evidence, but I will take it under advisement.
20 MR. WILSON: Well, I mean, I can do it
21 long and slow. I have the stats Canada data and
22 I can put them all up and we can all do math
23 together. The issue here for the court is to
24 understand the scope of the problem, which is how
25 many Canadians are unvaccinated and unable to

Untitled

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Untitled

Uploaded by

Copyright:

Available Formats

AR08681

JML TRANSCRIPTION BRIEF REPORT • CID 2022:74 (IS February) • 715

716 • cid 2022:74 (15 February) • BRIEF REPORT

BRIEF REPORT • cid 2022:74 (15 February) • 717

718 • cid 2022:74 (15 February) • BRIEF REPORT

~ FactCheck.0 rg ,I ProfN:I o{T/w,~mm/wg P11b/JcPoli,y(e/llPr 11rJ

SciCheck's C0VID-19/Vaccination Project

FACTCHECK POSTS > FEATURED POSTS > SCICHECK

11 a a a a pcopft" "110 have bet-n Ya('Cio:ated?

A: At1 unva«i.uat.ed person who is iufei1ed

Rr-ad the full gue-stion and ,:mS\ver

Jason-'1cLellan~ asmKturalbiologist at the Umversit~• of Texas at Austin who has b(>en

1. 4 4 • • •,. • I/ . _ / '"' A '"' "1 JA ,-, / _ • 0

with minimal transfer of vaccine mRNA

Amin(MBBS, MHFE, FAAP)1.2, Le Ye Lee(MMed, MRCPCH)1.2, Yvonne Peng Mei

Wang(PhD)5*, Youjia Zhong(MRCPCH (UK), MMed (Paeds), MCI) 1h

Joint firstA, joint last*

National University Health System, Singapore

University of Singapore, Singapore

Liang Wei Wang

Singapore Immunology Network,

Agency for Science, Technology and Research,

Immunos Building, Level 4, Singapore 138648

Word count: 2884

vaccination, 90% produced SARS-CoV-2 immunoglobulin A, and 100% produced

immunoglobulin G in human milk, with minimal amounts of vaccine mRNA transfer.

Meaning: Lactating individuals should continue breastfeeding in an uninterrupted manner after

receiving SARS-CoV-2 mRNA vaccination.

Importance: To examine the impact of SARS-CoV-2 vaccination of lactating mothers on human

Objective: (1) To quantify SARS-CoV-2-specific immunoglobulin A (IgA) and

February 2021 and 9th February 2021.

Setting: Lactating healthcare workers living in Singapore

Exposure: Two doses of the BNT162b2 vaccine 21 days apart.

mRNA in human milk after BNT162b2 vaccination.

breastfeeding in an uninterrupted manner after receiving mRNA vaccination for SARS-CoV-2.

Trial Registration: Registered at clinicaltrials.gov (NCT04802278).

influenza and tetanus in lactating mothers.4,5

premature cessation of breastfeeding.10

post vaccination;11-14 however, the amount of immunoglobulin G (IgG) and immunoglobulin A

and quantify vaccine mRNA in human milk after vaccination.

We hypothesize that BNT162b2, an mRNA vaccine encoding the immunogenic SARS-CoV-2

into human milk.

We conducted a prospective cohort study of a convenience sample of lactating healthcare

study protocol was registered at clinicaltrials.gov (NCT04802278).16 Participants were recruited

recent immunomodulatory medication. Demographic details and clinical outcomes of lactating

following mother’s second dose of vaccine.

pregnancy confirmed with real-time polymerase-chain-reaction (RT-PCR) assay, and then

served as the “healthy cohort”.

determined up to 28 days through a structured questionnaire after ingestion of post-vaccination

(details available in eMethods in the Supplement).

quantitative PCR (qPCR; details available in eMethods in the Supplement).

the STROBE reporting guidelines for cohort studies.17

Maternal and infant characteristics

days after ingestion of post-vaccination human milk.

reference cohort are available in the eTables 1 and 2 in the Supplement.

Levels of SARS-CoV-2-specific IgA and IgG in in human milk of lactating mothers

A human monoclonal antibody binding to SARS-CoV-2 was recombinantly engineered and

CoV-2 spike and RBD (Figure 1; eFigure 2 in the Supplement).

(Figure 1C, D; eFigure 2C, D in the Supplement).

IgG detected in healthy unvaccinated lactating women.

IgG than IgA.

However, in order to perform direct cross-comparison between different antibody isotypes,

concentration of antibodies. Here, breaking-down the analysis by individual mothers, we report a

(Figure 3A) and anti-RBD (Figure 3B) antibodies.