Interim Recommendations for the use of Tocilizumab in the Management of Patients who have Severe

COVID-19 with Suspected Hyperinflammation

This document is intended for use by healthcare professionals only.

The recommendations are specific to the management of Patients with confirmed Severe COVID-19 with Suspected Hyperinflammation. While the
recommendations are intended to strengthen clinical management of these patients they do not replace clinical judgment or specialist consultation.

Protocol: Interim Recommendations for the use of Tocilizumab in the Management of Patients who have Severe COVID-19
Published: 20 Mar 2020
with Suspected Hyperinflammation Version number: 1.0
Review: 30 Apr 2020

Contributors: Prof C Bergin, N Conlon, C Ní Choitir, R

Protocol Code: COVID19- Approved by: Dr Vida Hamilton, HSE National Clinical Advisor and Group Lead, Acute
Adams, F King, P Gilvarry. Page 1 of 14
TOCILIZUMAB Hospitals

Any clinician seeking to apply or consult these documents is expected to use independent medical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use of these
documents is the responsibly of the prescribing clinician and is subject to HSE’s terms of use available at http://www.hse.ie/eng/Disclaimer
This information is valid only on the day of printing, for any updates please check: https://www.hpsc.ie/a-z/respiratory/coronavirus/novelcoronavirus/guidance/guidanceforhealthcareworkers/

1
 Summary statement regarding the use of tocilizumab in the management of patients who have severe
COVID19 with suspected hyperinflammation

th
The evidence presented here is current as of 18 March 2020. This is a rapidly evolving area with emerging evidence accruing on a continual basis. Data
from real world experience and associated updated evidence will be considered for inclusion in updated versions of this document.

1. Tocilizumab is an experimental medicine in the context of management of severe COVID-19 disease and should only be
considered in patients who have severe COVID-19 with suspected hyperinflammation following multidisciplinary specialist input.

2. Cytokine release syndrome (CRS), also termed hyperinflammation1, is a complication of COVID-19 and is associated with high
morbidity.

3. Early identification of hyperinflammation in COVID-19 is essential. Serial monitoring of ferritin, platelet count and inflammatory
markers may identify hyperinflammation and allow early intervention. Calculation of a H score may support clinical evidence and
aid diagnosis 2.

4. The evidence continues to emerge for the use of tocilizumab in this setting and therefore every effort should be made to collect
relevant clinical outcomes.

1
Note: The terms CRS and hyperinflammation are used interchangeably in this document.
2
H score online calculator available at http://saintantoine.aphp.fr/score/
3
2
These
H scorecriteria
onlineare
calculator
drawn from
available
The SIMIT,
at http://saintantoine.aphp.fr/score/
Handbook for the care of people with COVID-19 disease (Italy) http://www.simit.org/medias/1568-covid19-vademecum-20-13-

2
 Patient selection (with input from specialist multidisciplinary team)3,4
Clinical judgment will be required for all cases; specialist consultation with local Haematology, Infectious Disease and Microbiology teams is recommended for
those cases not meeting criteria listed.

Protocol for use of IL6 inhibitor tocilizumab in severe-COVID19 with suspected hyperinflammation (RoActemra 20mg/ml)
Treatment Criteria 1. Treatment should only be initiated after discussion between critical care medicine, haematology, and infection specialists.

2. Established presence of hyperinflammation:

 Assessment of pro-inflammatory cytokines including IL-6, if available, may support the diagnosis of hyperinflammation.
 Serial monitoring of ferritin, platelet count and inflammatory markers may identify hyperinflammation and allow early intervention.
 Calculation of a H score may support clinical evidence and aid diagnosis. H score online calculator available at http://saintantoine.aphp.fr/score/
NOTE: bone marrow aspirate not required.

3. Exclude infection from sources other than SARS-CoV2 and acute severe infection.

Recommended Data continues to emerge on dosing in COVID-19; the following recommendations are adopted from China’s National Health Commission treatment
5 4
dose guidelines and The University of Michigan Inpatient Guidance for diagnosis & treatment of COVID-19 in adults & children :

Recommended dosing in adults (Specialist Paediatric advice required for patients aged under 18 years old):
- 50-60kg: 400mg as a single intravenous infusion
- >60-85kg: 600mg as a single intravenous infusion
- >85kg: 800mg as a single intravenous infusion
One additional dose may be considered if continued clinical deterioration (max 2 doses per course in severe COVID-19).

For infusion details see Route and method of administration section below.

Note: The dose indicated for the management of CAR-T related CRS is higher than has been used in practice for the treatment of hyperinflammation in
severe COVID19. The dose in CAR-T related CRS is 8mg/kg (12 mg/kg in patients <30 kg). Dose may be repeated every 8 hours for up to three doses in a
24-hour period. Maximum of 4 doses total over the entire course of CRS.

3
These criteria are drawn from The SIMIT, Handbook for the care of people with COVID-19 disease (Italy) http://www.simit.org/medias/1568-covid19-vademecum-20-13-
marzo-2020.pdf and
4
The University of Michigan Inpatient Guidance for diagnosis & treatment of COVOD-19 in adults & children http://www.med.umich.edu/asp/pdf/adult_guidelines/COVID-19-
treatment.pdf
5
National Health Committee of the People’s Republic of China. China’s National Health Commission treatment guidelines 7th version [Internet]. Beijing; 2020 [cited 2020 Mar
16]. Available from: http://www.nhc.gov.cn/yzygj/s7653p/202003/46c9294a7dfe4cef80dc7f5912eb1989.shtml

3
Contraindications Hypersensitivity to the active substance or to any of the excipients.
Acute, severe infections.
NB Decisions in critically ill patients must involve multidisciplinary input; treatment must only be initiated following Consultant-level multidisciplinary specialist
input. Where patients have additional co-morbidities which may negatively impact on the outcome careful consideration should be given to whether
tocilizumab should be used.
Monitoring Serial monitoring of:
 Ferritin
 Platelets
 IL-6 (if available)
 ALT or AST
 Fibrinogen
 Procalcitonin (if available; to help outrule bacterial superinfection)
 CRP

Patients with severe or life-threatening CRS frequently have cytopenias or elevated ALT or AST due to the CRS.

Side effects Most common adverse reactions (incidence of at least 5%): upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT,
injection site reactions. Transient or intermittent mild and moderate elevations of hepatic transaminases have been reported commonly with tocilizumab
treatment. See Summary of Product Characteristics (SmPC) for full list of side effects; available from: https://www.medicines.ie/medicines/roactemra-20-mg-
ml-concentrate-for-solution-for-infusion--33648/smpc
Renal impairment Dose as in normal renal function. In patients undergoing renal replacement therapies (APD/CAPD/HD/HDF/High flux/CAV/VVHD) – unknown dialysability.
GFR (mL/min) Dose as in normal renal function. Use with caution.
Hepatic The safety and efficacy of tocilizumab has not been studied in patients with hepatic impairment. The marketing authorisation holder cannot advise on any
impairment dose adjustments.
Warnings Risk of serious infection: Increased risk of serious infection including tuberculosis (TB), bacterial, invasive fungal, viral, and other opportunistic infections
have occurred in patients receiving tocilizumab.
Drug Tocilizumab (RoActemra ®) 20 mg/mL concentrate for solution for infusion. Store vials in a refrigerator (2°C–8°C)
Licence Unlicensed for the management of patients who have severe COVID-19 with suspected hyperinflammation. Tocilizumab is licensed for the management of
cytokine release syndrome following treatment with CAR-T and also in the management of rheumatoid arthritis.
Route and method Patients ≥30kg
of administration Withdraw a volume of sterile, non-pyrogenic sodium chloride 9 mg/mL (0.9%) solution for injection from a 100 mL infusion bag, equal to the volume of
Tocilizumab concentrate required for the patient’s dose, under aseptic conditions. The required amount of Tocilizumab concentrate (0.4 mL/kg) should be
withdrawn from the vial and placed in the 100 mL infusion bag. This should be a final volume of 100 mL. To mix the solution, gently invert the infusion bag to
avoid foaming. Administer by intravenous (I.V.) infusion over 60 minutes.

4
Technical Appendix 1:
Tocilizumab in the management of moderate to severe COVID-19

Brief ................................................................................................................................................... 5
Introduction ..................................................................................................................................... 5
Potential mechanism of action of tocilizumab in COVID-19 ............................................... 5
 Cytokine release syndrome............................................................................................. 5
 Sepsis.................................................................................................................................... 6
 MERS-CoV, SARS-CoV ..................................................................................................... 6
Proposed place in therapy for tocilizumab in COVID-19 ..................................................... 6
Screening for hyperinflammation in patients with COVID-19 in which tocilizumab
may be efficacious ......................................................................................................................... 7
Conclusions regarding the efficacy of tocilizumab in COVID-19 ...................................... 7
Table 1 - Summary of evidence for tocilizumab in COVID-19 ............................................ 8
Table 2 - Ongoing clinical trials for tocilizumab in COVID-19 ............................................ 9
References ..................................................................................................................................... 13

Brief
To undertake a Rapid Review of the published evidence to assess the potential efficacy of
tocilizumab in the management of patients with COVID-19. A targeted literature search will
be performed to identify relevant published studies. A landscape analysis of clinical
guidelines for the management of COVID-19 will also be performed to identify international
recommendations regarding the use of tocilizumab in COVID-19.

Introduction
Tocilizumab is a humanised anti-IL6 antibody approved for the treatment of rheumatoid
arthritis, juvenile idiopathic arthritis and giant cell arteritis. It is also licensed for the induction
of the rapid reversal of cytokine release syndrome (CRS), a form of cytokine storm caused
by CAR-T treatment 1. Il-6 is a key pro-inflammatory cytokine and an important mediator of
fever and the acute phase response. Tocilizumab prevents Il-6 from binding to soluble and
cell associated Il-6 receptors inhibiting signalling 4.

Potential mechanism of action of tocilizumab in COVID-19

 Cytokine release syndrome
Cytokine release syndrome is a diverse set of conditions of pleotropic causation
associated with the clinical phenotype of exuberant systemic inflammation, multi-
organ failure, hyperferritinaemia and high mortality5. The condition is associated with
exuberant inflammation in a dysregulated positive feedback loop with elaboration of
inflammatory cytokines including IL-6. In CAR-T associated cytokine release
syndrome IL-6 is thought to be a key driver of symptoms6. IL-6 levels in this

5
 syndrome are typically several hundred pg/ml, usually one hundred-fold or more
compared with reference ranges7. There have been no RCTs however rapid clinical
improvement in several patient cohorts including symptom resolution after a single
dose led to rapid FDA approval in 2017 6. Tocilizumab has also shown efficacy after
other iatrogenic causes of cytokine release syndrome. It is worth noting that
tocilizumab does not ameliorate CNS symptoms most likely because it does not
cross the blood brain barrier6. In addition, other therapies with the potential to
modulate IL-6 may have similar effects – e.g. tofacitinib. Early introduction of anti-IL6
in the setting of cytokine release syndromes is considered vital. Iatrogenic cytokine
release syndromes share many features with primary haemophagocytic
lymphohistiocytosis syndromes and CTD related macrophage activation syndromes.
 Sepsis
Tocilizumab is not licensed in sepsis and has not been used for this indication.
However, murine models do indicate markedly reduced acute lung and injury
suggesting that modulation of IL-6 pathway might be a therapeutic target8. Similarly,
cellular models indicating suppression of inflammation have led some to propose that
tocilizumab may have a use in inflammatory cytokine phase of sepsis9.
 MERS-CoV, SARS-CoV
There is no evidence supporting the use of tocilizumab in infections with previously
emergent coronavirus strains.

Proposed place in therapy for tocilizumab in COVID-19

In early December 2019 a novel enveloped RNA betacoronavirus was recognised as the
cause of pneumonia cases of unknown origin. The virus is phylogenetically similar to SARS
CoV and has been designated SARS-CoV-2. Emerging studies are highlighting the
characteristics of infected patients.
Evidence continues to emerge of a dysregulated immune response as key to disease
severity with COVID-19. Qin et al elucidated a T cell lymphopaenia, with low helper and
regulatory T cells10. CRP is moderately elevated in severe cases in this cohort. IL6 is
modestly elevated at 25.2 in the severely affected group – notably this is much less than
levels typical of cytokine release syndromes (assuming at least broadly comparable assay
parameters).
From a recent retrospective, multicentre study of 150 confirmed COVID-19 cases in Wuhan,
China, a lower lymphocyte count and elevated CRP was associated with the primary
endpoint of ICU admission/ventilation/death. Predictors of fatality in this cohort identified
elevated ferritin (mean 1297·6 ng/ml in non-survivors vs 614·0 ng/ml in survivors; p<0·001)
and IL-6 (p<0·0001), suggesting that mortality might be due to virally driven
hyperinflammation. Markers of cytokine release / secondary haemophagocytosis were not
presented in this data. 11.
Corticosteroids are not routinely recommended and may exacerbate COVID-19-associated
lung injury12. However, in hyperinflammation, immunosuppression is likely to be beneficial.
Mehta et al 2020 point to accumulating evidence of a cytokine storm syndrome in a
subgroup of COVID-19 patients13. Further granular data from 41 Wuhan patients indicated
higher levels of a variety of cytokines in ICU patients including IL2, IL7, IL10, GCSF, IP10,
MCP1, MIP1A and TNFa. Other cytokines including IL6 were not elevated. Further data
indicates an elevated ferritin (a hallmark feature of secondary HLH) and elevated IL6 are
predictors of fatality11. Mehta et al advocate active screening for hyperinflammation using H

6
score and relevant basic laboratory tests to identify groups in whom targeted
immunomodulation might improve mortality13.

International Clinical guidelines which recommend tocilizumab in COVID-19

China's National Health Commission updated its treatment guidelines (7th version) to
include tocilizumab for the treatment of patients infected with COVID-19, with serious lung
damage and elevated IL-6 levels 14. A Belgian task force have identified that tocilizumab is
recommended in Switzerland in patients with critical COVID-19, who have multi-organ failure
and are receiving inotropic support. However, the original source could not be located during
this review 15 .

Screening for hyperinflammation in patients with COVID-19 in which tocilizumab may

be efficacious
A correspondence by Mehta et al 2020 makes proposals for screening of hyperinflammation
in COVID-19 based on the limited available data and experience extrapolated from other
therapy areas. The authors recommended that all patients with severe COVID-19 should be
screened for hyperinflammation using laboratory trends (e.g., increasing ferritin, decreasing
platelet counts, or erythrocyte sedimentation rate) and the H-Score to identify the subgroup
of patients for whom immunosuppression could improve mortality. The H score generates a
probability for the presence of secondary haemophagocytic lymphohistiocytosis13.

Conclusions regarding the efficacy of tocilizumab in COVID-19

A summary of the current limited evidence for tocilizumab in COVID-19 is provided in Table
1, Table 2 has the details of an on-going 12-week clinical trial for tocilizumab. It is worth
bearing in mind that the use of immunological interventions in the critical care setting
(despite supportive experimental models) has to date proven disappointing and quite
frequently led to detrimental outcomes. Actively evaluating for cytokine release states that
might benefit from immunomodulatory interventions, as suggested by Mehta et al 2020, is
advised. Extrapolation of evidence from related disorders suggests that this group could
benefit from tocilizumab, however there is still no definitive evidence to suggest that routine
use in severe COVID-19 is of benefit.
The Department of Immunology in St James’s Hospital has validated an IL-6 ELISA and a
multiplex flow-based cytokine array (Il1b, IL6, IL8, TNFa, IL10, IL12p70) for use in the setting
of COVID19 infection. Whilst these tests are not accredited it is hoped they may be useful in
risk stratification and identification of groups for targeted treatment.

7
Table 1 - Summary of evidence for tocilizumab in COVID-19
Study Title Methodology Population Outcome assessed Efficacy data Reference
(location)
Analysis of clinical Retrospective observational Patients (n=29) were To analyse the clinical There were statistically significant differences in the expression Chen L, Liu HG, Liu W,
features of 29 analysis of chart data. stratified into three characteristics of levels of interleukin-2 receptor (IL-2R) and IL-6 in the serum of Liu J, Liu K, Shang J, et
patients with groups according to 2019 the three groups (P<0.05), among which the critical group was al. [Analysis of clinical
2019 novel Intervention: tocilizumab degree of severity: novel coronavirus (20 higher than the severe group and the severe group was higher features of 29
coronavirus mild (15 cases), severe 19-nCoV) pneumonia than the mild group. The authors claim that the increased patients with 2019
pneumonia (9 cases) and critical (5 and to investigate the expression of IL-2R and IL-6 in serum is expected to predict the novel coronavirus
16 16
(China) cases). correlation between severity of the 2019-nCoV pneumonia and the prognosis of pneumonia].
serum inflammatory patients. However, patient numbers in this study are small. No
cytokines and severity criteria were provided to define severity in COVID-19. Baseline
of the disease. and change in IL-6 levels were not presented in the publication.
No a priori definition was provided which defined magnitude or
range of IL-6 to be measured. The study has not been peer-
reviewed.
Effective Retrospective observational Patients (n=20) To retrospectively Preliminary data was reported from a small study demonstrated Xu X, Han M, Li T, Sun
Treatment of analysis of chart data. diagnosed as severe or analyse the changes that 15 of the 20 patients reduced their oxygen therapy and one W, Wang D, Fu B, et
Severe COVID-19 critical COVID-19. of clinical patient did not require oxygen therapy following treatment with al. Effective
Patients with Intervention: tocilizumab Severity was defined if manifestations, CT tocilizumab. The body temperature of all patients returned to Treatment of Severe
Tocilizumab 400mg once as an IV any of the following scans, and laboratory normal on the first day after receiving tocilizumab and remained Covid-19 Patients
17
(China) infusion. conditions was met: (1) examinations. stable then after. The authors report that inflammatory markers with Tocilizumab.
(Note: n =3/21 had a second respiratory rate ≥ 30 including CRP, lymphocytes all normalised or decreased ChinaXiv [Internet].
dose within 12 hours) breaths/min; (2) SpO2 ≤ significantly. In total nineteen patients (90.5%) have been 2020 Mar 5 [cited
93% while breathing discharged on average 13.5 days after the treatment with 2020 Mar 16];
All patients were treated room air; (3) PaO2/FiO2 tocilizumab. The study has not been peer-reviewed. The study Available from:
with standard of care prior to ≤ 300 mmHg. A critical sample is small. Patients were also being treated with other https://www.ser.es/w
initiation of tocilizumab case was diagnosed if therapies during the study including lopinavir which may have p-
which included lopinavir, any of: (1) respiratory contributed to the positive outcomes. It is noted that based on content/uploads/202
methylprednisolone, other failure which requiring these results, China recently updated its COVID-19 treatment 0/03/TCZ-and-COVID-
17
supportive therapies and mechanical ventilation; guidelines, approving the use of tocilizumab to treat patients 19.pdf
oxygen therapy. (2) shock; (3) combined with severe or critical disease
with other organ
failure, need to be
admitted to ICU

8
Table 2 - Ongoing clinical trials for tocilizumab in COVID-19
Study NCT04306705 Start date – 20/02/2020 Primary completion date – 30/05/2020 Study completion date- 20/06/2020

Title A Retrospective Study of Evaluating Safety and Efficacy of Tocilizumab Compared to Continuous Renal Replacement
Therapy in Controlling CRS Triggered by COVID-19
Location China, Hubei - Tongji Hospital
Methodology Observational, retrospective study
Treatments Arm 1: Tocilizumab + standard of care
Tocilizumab: Subjects received 8 mg/kg (body weight) Tocilizumab once in 100 ml 0.9% saline solution and administered
intravenously within no less than 60 minutes.
Arm 2: Continuous Renal Replacement Therapy (CRRT) + standard of care
CRRT: Femoral vein catheterization was performed to complete continuous renal replacement therapy for consecutive 3 times or
more.
Standard of care: Standard of care therapy per local written policies or guidelines and includes balancing of electrolytes and acid-
base, the provision of enteral or parenteral nutrients support, antibiotics therapy, oxygen therapy and non-invasive ventilation.

Number of patients 120

Inclusion criteria 1. Agrees to the collection of oropharyngeal or anal swabs and venous blood per protocol.
2. Male or non-pregnant female adult ≥18 years of age at time of enrolment.
3. Has laboratory-confirmed novel coronavirus infection as determined by polymerase chain reaction (PCR), or other
commercial or public health assay in oropharyngeal or anal specimen within 72 hours prior to hospitalization.
4. Illness of any duration, and at least one of the following:
a. Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR
b. Clinical assessment (evidence of rales/crackles on physical examination) AND SpO2 ≤93% on room air, OR
c. Requiring mechanical ventilation and/or supplemental oxygen, OR
d. Sustained fever in the past 24 hours and unresponsive to NSAID or steroid
5. Serum IL-6 ≥3 times the upper limit of normal
Exclusion criteria 1. Alanine transaminase/aspartate transaminase (ALT/AST) > 5 times the upper limit of normal.
2. Stage 4 severe chronic kidney disease or requiring dialysis (i.e. estimated glomerular filtration rate (eGFR) < 30 ml
/min/1.73 m^2)
3. Haemoglobin<80 g/L
4. Leukocytes<2.0×10^9
5. Platelets<50×10^9
6. Pregnancy or breast feeding.
7. Anticipated transfer to another hospital which is not a study site within 72 hours.
8. Expected life span does not exceed 7 days.
9. Allergy to any study medication.
Primary endpoints Proportion of Participants With Normalization of Fever and Oxygen Saturation Through Day 14 [ Time Frame: First dose date up to

9
 14 days ]. This is a composite outcome measure. Criteria for fever normalization: Temperature < 36.6 °C armpit, < 37.2 °C oral
sustained for at least 72 hours and criteria for oxygen normalization: peripheral capillary oxygen saturation (Sp02) > 94% sustained
for at least 72 hours.
Secondary 1. Duration of hospitalization [ Time Frame: Up to 28 days ]
endpoints 2. Proportion of Participants With Normalization of Fever Through Day 14 [ Time Frame: First dose date up to 14 days ].
Criteria for: Temperature < 36.6 °C armpit, < 37.2 °C oral, or < 37.8 °C rectal sustained for at least 72 hours.
3. Change from baseline in white blood cell and differential count [ Time Frame: Day 1 through Day 28 ]
4. Time to first negative in 2019 novel Corona virus RT-PCR test [ Time Frame: Up to 28 days ]. Oropharyngeal or anal swabs
5. All-cause mortality [ Time Frame: up to 12 weeks ]
6. Change from baseline in hsCRP [ Time Frame: Day 1 through Day 28 ].
7. Change from baseline in cytokines IL-1β, IL-10, sIL-2R, IL-6, IL-8 and TNF-α [ Time Frame: Day 1 through Day 28 ]
8. Change from baseline in proportion of CD4+CD3/CD8+CD3 T cells [ Time Frame: Day 1 through Day 28 (if applicable) ]
Exploratory None specified
endpoints
Reference https://clinicaltrials.gov/ct2/show/NCT04306705?cond=covid-19&draw=3&rank=45

10
Technical Appendix 2:H Score
The H score generates a probability for the presence of secondary haemophagocytic lymphohistiocytosis (sHLH). HScores greater than 169
are 93% sensitive and 86% specific for HLH. Note that bone marrow haemophagocytosis is not mandatory for a diagnosis of HLH. HScores
can be calculated using an online HScore calculator which is available at http://saintantoine.aphp.fr/score/

HScore for secondary HLH, by clinical parameter

Clinical Parameter Number of points

Temperature
<38·4°C 0
38·4–39·4°C 33
>39·4°C 49
Organomegaly
None 0
Hepatomegaly or splenomegaly 23
Hepatomegaly and splenomegaly 38
Number of cytopenias*
One lineage 0
Two lineages 24
Three lineages 34
Triglycerides (mmol/L)
<1.5 mmol/L 0
1-5 – 4.0 mmol/L 44
≥4.0 mmol/L 64
Fibrinogen (g/L)
>2·5 g/L 0
≤2·5 g/L 30
Ferritin ng/ml
<2000 ng/ml 0
2000-6000 ng/ml 35
>6000 ng/ml 50
Serum aspartate aminotransferase
< 30 IU/L 0
≥ 30 IU/L 19
Haemophagocytosis on bone marrow aspirate
No 0

11
 Yes 35
†
Known immunosuppression
No 0
Yes 18

*defined as either haemoglobin concentration of 9·2 g/dL or less (≤5·71 mmol/L), a white blood cell count of 5000 white blood cells per mm³ or less, or platelet
count of 110000 platelets per mm³ or less, or all of these criteria combined

†HIV positive or receiving long-term immunosuppressive therapy (i.e., glucocorticoids, cyclosporine, azathioprine).

The table above is from publication by Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm
syndromes and immunosuppression. Lancet [Internet]. 2020 Mar [cited 2020 Mar 17];0(0). Available from:
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30628-0/fulltext

12
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