Utilization POCT in

COVID-19 Pandemic
Umi S. lnt ansari
Dept Pat ologi Klinik & Kedokt eran Laborat orium
FKKMK-UGM
 Curriculum vitae
EDUCATION
PhD Program, Universitas Gadjah Mada, 2016
Specializat ion in Clinical Pat hology (main int erest : immunology), July 2007.
Vrije Universiteit Amsterdam- Universitas Gadjah Mada, Diploma in
Immunology, April 2004
Master in Tropical Medicine, Universitas Gadjah Mada, February 1999,
Medical Doctor: Universitas Gadjah Mada February 1995,

EMPLOYMENT
Assistant Professor, Clinical Pathology-Faculty of Medicine, Universitas
Gadjah Mada,
Teach undergraduate and graduated students
Guide undergraduate and graduated student on laboratory work and
research
Consultant on clinical pathology laboratory, Sardjito's hospital
Conduct studies in immunology field
Introduction: : Covid 19 course of disease

Point of Care Testing

Laboratory test in Covid 19

POCT Biomarker in Covid 19

introduction
COVID-19 Timeline

12.31.19
O f f ic i a l s in W
u h a n , C h in a
re p o r t e d d o ze n s
o f ca se s of
1.13.20 1 . 3 0 . 2 o
The first case T h e W o r ld H e a l t h
o u t s id e o f C h in a Or g a n i z a ti o n
w a s r e p o r t e d ( W H O ) d e c la r e d t h e

j
in Thailand. outbreak a "public
p n e u m o n ia o f
h e a lt h e m e r g e n c y

conTm
u n k n o w n ca u se .

-----------------------------------------
of in te r na tional

1 I I
1.7.20 2 . 6 . 2 o 3.11.20
C h i n e s e o f f ic i a l s The first death W H O d e c la r e d
id e n t if ie d t h e n o v e l on American soil the outbreak
c o r o n a v ir u s . o c c u r r e d in a p a n d e m i c .
California.
1.21.2o
T h e U .S . a n n o u n c e d
t h e f ir s t c o n f ir m e d
c a s e in W a s h i n g t o n
state.
 Geographic distribution
g(g k
Wor ld Health
organization
search by country. Territory or Area
Covid-19 Response Fund

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~
W H O C or onav i r us D i seas e ( C O V I D - 19) D as hboar d Overview Data Table Explore
Data last updated: 2020/85, 3OOpm CEST

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Deaths

Total V

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696,147
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Source Wonid ieanth Organization

G l obal l y , as of 3: 00pm C E S T , 5 A ugust 2020, t her e have been 18, 354, 342 conf i r m ed casesO-·
COVID-19, including 696,147 deaths, reported to WHO.
 COVID-19 DI INDONESIA
INFO TERKINI: Uji PCR sebanyak 963.602 orang sudah diperiksa dan hasil negatif sebanyak 840.099
JUMLAH TERPAPAR
COVID-19 DI INDONESIA
orang. Terkonf irm asi Co v I D -19 mencap ai 123 .50 3 orang , sembuh 7 9 .306 orang , dan meninggal Update 8 Agustus 2020 PI. 12.00 WIB
dunia 5.658 orang , yang tersebar di 34 provinsi dan 480 kabu pa t e n/k ot a. Pen g ujian an t igen
berbasis real time Polymerase Chain Reaction (PC) dilakukan di selur uh Indonesia. Gunakan
masker untuk lindungi diri dan lindungi sesama, cuci tangan pakai sabun, hindari kerumunan dan @2.277 1 7 4 9 6s
DAERAH TELAH MENETAPKAN
#ProduktifAmanCovicdl9 #CuciTangan #MaskerUntukSemua #JagaJarak #AdaptasiKebiasaanBaru

UJI PCR LOGISTIK DAN RELAWAN

123.503 79.306 5.658
K O N F I R M A SI SEMBUH MENINGGAL DUNIA
TOTAL D ISTRIB USI TOTAL RELA WAN
GUG US TUGAS PEMBA TASA N SO SIA L

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@11.692 @30.565 A LM A TKES ME DIS DAN NON MEDIS TERSEBAR DI 34 PROVINSI, 480 KABUPATEN/KOTA
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9 6 3 . 6 0 2 1.693.880 38.268.451 43.114%
Surnber. K@renterian Kesehatan

ORANG Sp£SIMEN
TESE aAR DI 34 PROV INSl TESEAR DI 26 PROV INSI
UPDATE TERPAPAR COV ID -19 DI DUNIA
TE RSEBA R DI 2 6 N E G A R A DAN W IL A YA H / T E IT O R IA L
r b C u a u r e a c o o 1 f a 0 . t . t r C u fu r t o o l Updat e 8 Ag u t us 2020 Pt , 12.0 0 w I8

SEBARANKUMULA'TIF KASUSAKTIF

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c 4 Rusi
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538,164
14,725
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145,934,462
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9 ran 345,714 11,624 50,882,891 228

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2 23,503 5,658 269,603,400 21
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--IN-F-O--R-M-A-S, ICOVID-19
II : EE:
i, www co@d i9 .s o i
g!:?/
,} CENTER
119
No: 146/0100/099/0VID-19/BNP8/08082020
stages of illness & timing of therapies
Stage II Stage III
(Pulmonary Phase) (Hyperinflammation Phase)
I
llA 1 118
I
I
Viral response phase

Host inflammatory response phase

Time course

Mild constitutional symptoms ARDS

Cinical Shortness of Breath
Fever >99.6F SIRS/Shock
Syrmptons Hypoxia (Pa02/Fi02<300mm#Hg)
Dry Cough, diarrhea, headache Cardiac Failure

Lymphopenla, increased Abnormal chest imaging Elevated inflammatory markers

CinicalSigns prothrombin time, increased D• Transaminitis (CRP, LDH, IL-6, D-dimer, ferritin)
Dimer and LDH (mid) Low-normal procalcitonin Troponin, NT-proBNP elevation

Remndesivir, chloroquine, hydroxychloroquine, convalescent plasma transfusions

Corticosteroicls, human immunoglobuhin,
IL-6 inhibitors,L-2 Iinhibitors,JAK inhibitors

Siddiqu HK, Mehra MR, Journal of Heart and Lung Transplantation, 2020
 Timeline of coronavirus onset
Shortness of breath

Hospital Intensive care

Onset of symptoms admission ARDS unit admission
0----------------- -
0 1 2 3 4 5 6 7 8 9
- O
10 11

NUMBER OF DAYS°

ARDS=Acute respiratory disease syndrome

Median time from onset of symptoms, including fever (in 98% of patients),
cough (75%), myalgia or fatigue (44%), and others. THE LANCET

80% mild/ asymptomatic, 15% severe infection, 5% critical infection

 Mild vs Severe SARS-CoV-2 infection

Isolation/hospitalization
Low virus titer Supportive care...

.... Bild n r
r .....;.a..
i
Normal
mmune
response
ml> Recovery

t•
A

•• t
SARS-CoV-2

• •
CD4
Activation ~
----------►
Cytokines: CD8
IL6/IL 10/TNF/ T cell

Monocyte
Macrophage
C S F / R A N ~
Neutrop
- - - - - - - -
hil t
Anti-cytokine storm treatment:
Cytokine Cytokine antagonists/mesenchymal stem
Storm cells/convalescent plasma/chloroquine,
hydroxychloroquine/corticosteroid/
alternative medicine and others

Lung injury/septic

#
shock/organ failure/
coagu loapathy...
High virus titer ICU

FI G U R E 1 Maj or blood leukocyt e, cyt okine changes, and t her apy st rat egies in mild vs. severe SA RS-CoV-2 inf ect ion. Concept ual model of the

I
interplay between immune activation and clinical pathology from patients with mild vs. severe infection, as well as current therapeutic strategies
wit h BioRender (ht t ps:// a .biorender.com/ )
Cytokine storm induced by COVID-19 infection in some patients results in organ
damage followed by immune failure, organ failure, secondary infection, and
death.

Pre-Erstng
inflammnatory
Candrtic

cytokine
Clotting
storm 4 Renal Failure

Shock •
Cardiac
Damage

rune Failure,, Organ FfI ailure, Secondary infection

Diagnostic approach

Clinical suspicion: likelihood of COVID-19 is increased if the

patient: resides in or has traveled to a location where there is
community transmission of SARS-CoV-2; or Has had close
contact with a confirmed or suspected case of COVID-19 in the
prior 14 days,

Whom to test Symptomatic patients (priority to high risk patients, health

worker}

Select asymptomatic individuals: important for public health

or infection control purposes
• The decision to test should be based on clinical and epidemiological factors
and linked to an assessment of the likelihood of infection. PCR testing of
asymptomatic or mildly symptomatic contacts can be considered in the
assessment of individuals who have had contact with a COVID-19 case.
Screening protocols should be adapted to the local situation.
• Rapid collection and testing of appropriate specimens from patients
meeting the suspect case definition for COVID-19 is a priority for clinical
management and outbreak control and should be guided by a laboratory
expert. Suspect cases should be screened for the virus with nucleic acid
amplification tests {NAAT), such as RT-PCR.

Laboratory testing strategy recommendations for COVID-19: interim guidance, 22 March 2020. https://apps.who.int
The Need for a Rapid Detection Method and Portable Detection
Devices

Lab

71ed
Lab confirmation
First case confirmation First case
T
(/) Detecti on/
1/) I
Potential cases
Response 0 90l' Detection /
0 90
go
I Reporting
&« l Reporting
Response
I

S%
I
O 70 I
I

60 I

•
6 0 I

0 50 O 50
Opportunity for 40
'0 40 control is minimal
n 30 0 30
E20 £
210
± e . 19e e e » a
10
z 1o l Z 1o 4
l a . s e e
7 10 13 16 22 25 28 31 34 37 40 7 10 13 16 19 22 25 28 31 37 40

Number of days Number of days

Impact of delayed reporting of infectious diseases Impact of early reporting of infectious diseases
in controlling and preventing an outbreak in controlling and preventing an outbreak

Nguyen T et al. 2020. Micromachines. 11(3):306

 POINT OF CARE TESTING
Definition Characteristic

• Point of care testing (POCT) is defined as • user friendly

"clinical laboratory testing conducted close • not require any extensive
to the site of pat ient care, typically by training to operate
clinical personnel whose primary training is • can be used either in
not in the clinical laboratory sciences or by hospit al environment , in the
patients {self-testing). laboratories or at patient
bedside without any
• POCT refers to any testing performed difficulty.
out side of the tradit ional, core or cent ral
laborat ory".
POINT OF CARE

TRANSPORTABLE
• a
[Ya«» initiates
To determine the actual cost ofthe
test process, each step of the service
test chain must be ident if ied and
request
evaluated for it's contribution to
T the total cost of the test performed.
M
• no.os Test Results
reviewed
by staff

r
10:10
Phlebotomist Results
dispatched reported
to draw to the
sample

LABORATORY SERVICE CHAIN turnaround time:

1 hour, SO minutes
 POCT is an increasingly popular means of delivering laboratory testing.

When used when over-utilized

appropriately or incorrectly
• POCT can improve performed
patient outcome • POCT presents a
• faster resu It patient risk.
• a shorter timeframe • False results
to therapeutic
intervention.

POCT is not freely interchangeable with traditional core lab instrumentation in all
patient care situations
Quality issue in POCT
less analytically sensitive

more at risk of
interferences

performed not by • Daily QC

laboratory trained • Instrument maintenance
individual • Troubleshooting
WHO assured criteria of ideal characteristics for a POCT
in resource-limited setting

• Affordable by those at risk of infection

• Sensitive (few false negatives)
• Specific (few false positives)
• User friendly (simple to perform and needs minimum
training)
• Rapid (t o ena ble t reat me nt at first visit ) and robust (does
not need refrigerated storage)
• No equipment
• Delivered to those who need it
 The Critical Role of Laboratory Medicine in COVID-19
(Modified from: Lippi et al, PMID: 32191623)
rs-CoV-2
Laboratory Diagnostics
Epidemiological RT-PCR, Anti•

•
· ~....- - - - - - - - - - ---= = Surveillance SARS-CoV-2
antibodies
RT-PCR
Infection Diagnosis (See Diagnostic

J
Testing)

Staging
Patient
Various IVD
Management
Overt Disease Prognostication Tests
(See
Biochemical
Monitoring)
Death Therapeutic M onitoring

Epidemiological Anti-SARS-CoV
Surveillance antibodies
Etiology diagnosis of covid 19 Infection

Virus particle

The essential role of clinical

laboratories in this pandemic
extends be and etiolo ical
diagnosis of COVID-19
Infection MW RNA

Y lgG
Nucleocapsid protein

X lgA
lgM

Fig. 1. Schematic illustration of strategies for the detection of COVID-19 patients.

 Value

• Inform individual of • Individual

infection status so they can
anticipate course of illness
Nucleic acid and take action to prevent
Current infection with
amplification test transmission
SARS-Co\V-2
for viral RNA
• Inform patient management • Healthcare or long-term
(nasopharyngeaf swab,
and actions needed to care facility
oropharyngea/ swab, sputum,
bronchoafveofar lavage fluid, prevent transmission
others)
• Inform actions needed to • Public health
prevent transmission

• Detect susceptible • Identify those potentially

individuals (antibody immune to SARS-CoV-2
negative) and those (if tests can detect
previously infected protective immunity,

•
individuals could be
Antibody Past exposure to returned to work)
SARS-CoV-2
detection • Identify individuals with • Healthcare facilities:
neutralizing antibodies Experimental therapy

• Facilitate contact tracing • Public health

and surveillance

http://mbio.asm.org/
The challenge in covid 19 pandemic
 Current Diagnosis method available for Covid 19
''i ) [)
'4 -'

Next generation Whole genome sequencing Highly sensitive and specific, 1-2 day High expertise
sequencing Provide all related information; Equipment dependency and high cost
(NGS)
Can identify novel strain Highly sophisticated Lab required
RT-PCR Specific primer-probe based Fast results 3-4h Higher costs due to the use of expensive
detection Higher sensitivity consumables

Needs small amount of DNA Expensive lab equipment

Can be performed in a single step Detection is also complex and time

consuming
Well established methodology in
viral diagnostics
LAMP More than two sets of Highly repeatable and accurate 1h Too sensitive, highly prone to false
specific primers pair based Single working temperature positives due to carry-over or cross-
detection contamination
Serological Antigen/Antibodies IgG/ Sensitive and specific 4-6 h Testing come after 3-4 days of infection
(traditional) IgM False positive
Rapid Antigen/Antibodies IgG/ POCT 15-30 min Testing come after 3-4 days of infectio
serological IgM False ositive
Chest images Enhance sensitivity of detection if 1h Indistinguishability from other viral
findings combined with RT-PCR pneumonia and the hysteresis of
results abnormal CT
Virus isolation In vitro live virus isolation Highly (100%) specific 5-15 days Low sensitivity as isolation is not 100% Kumar et al., Virusdis. (April•
and propagation Gold standard june 2020) 31(2):97--105
 Positivity rate of SARS CoV-2 Detection in Different
Clinical Specimens

Clinical Specimen Positive Rate

Bronchoalveolar lavage fluid 93% (14/15)
72% (72/104)
63% (5/8)

Fibrobronchoscope brush biopsy 46% (6/13)

Pharyngealswabs 32%(126/398)
29% (44/153)
1% (3/307)
0% (0/72)

IFCC Information Guide on COVID-19 -IFCC. www.ifcc.org

Estimated Variation Over Time in Diagnostic Tests for Detection of SARS-CoV-2 Infection
Relative to Symptom Onset

l h l d l E E E E
( D_e_te_c_ti_o_n_u_n_lik_e_ly_a lc
) P_C_R_-_L_ik_e_ly_p_o_s_it_iv_e _,.) ( P_C_R_-_L_ik_e_ly_n_e_g_at_iv_e_b )

: (._ A_n_t_ib_o_d_y_d_et_e_c_ti_o_n ,.)

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Symptom onset

--- Nasopharyngeal swab PCR --- Bronchoalveolar lavage/sputum PCR lgM antibody
--- Virus isolation from respiratory tract Stool PCR lgG antibody
Kemkes: REV-OS Ped o m an P2 COV ID-19 13 Juli 2020

• Pemeriksaan dengan Rapid Test

Penggunaan Rapid Test tidak digunakan untuk diagnostik. Pada kondisi dengan
keterbatasan kapasitas pemeriksaan RT-PCR, Rapid Test dapat digunakan untuk
skrining pada populasi spesifik dan situasi khusus, seperti pada pelaku perjalanan
(termasuk kedatangan Pekerja Migran Indonesia, terutama di wilayah Pos Lintas
Batas Darat Negara (PLBDN), serta untuk penguatan pelacakan kontak seperti di
la pas, panti jompo, panti rehabilitasi, asrama, pondok pesantren, dan pada
kelompok-kelompok rentan.
• WHO merekomendasikan penggunaan Rapid Test untuk tujuan penelitian
epidemiologi atau penelitian lain. Penggunaan Rapid Test selanjutnya dapat
mengikuti perkembangan teknologi terkini dan rekomendasi WHO.
Types of COVID-19 rapid tests currently in use or in development:

Direct SARS-CoV-2 antigen detection

• detect viral components present during the infection in samples like
nasopharyngeal secretions.
• Viral Particle
• Nucleocapsid Protein

Indirect antibody-SARS-CoV-2 detection

• detect the antibodies that later appear in serum as part of the immune
response against the virus.
• Anti Spike Protein,
• Anti Nucleocapsid Protein,
• Antibody to Combination SP/NP
European Centre for Disease Prevention and Control. Stockholm, 2020.
 POCT Antigen:
Advice on the use of point-of-care immunodiagnostic tests for COVID-19 (WHO)

expressed only when the virus is actively replicating identify acute or early
infection.

Depend to several factors:

• the time from onset of illness, -the quality of the specimen
• the concentration of virus, -the precise formulation of the reagent

false-positive results: if the ab on the test strip also recognize antigens of viruses
other than COVID-19 .

adequate performance test could potentially be used as triage tests to rapidly

identify patients who are very likely to have COVID-19,-reducing or eliminating
the need for expensive molecular confirmatory testing.
 Performances of the COVID-19 Ag Respi-strip.

RT-qPCR
Low performance of rapid antigen detection test as frontline testing for
COVID-19 diagnosis Detected Not detected

COVID-19 Ag Respi-Strip Detected 32 0

Not detected 74 42

Ensuring accurate diagnosis is essential to limit the spread of the virus

Little use in
Can nott pandemic
False
role out setting
SARS
Sensitivity negative CoV inf.
30,2% result
A. Scohy, et al. Journal of clinical virolo
Ec
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.oJ' = -
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--
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0
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1
0 substantially when the viral load
POSITIVE NEGATIVE
decreases with Ct values over 30,
Ag Respi-Strip Results
equivalent to 9.4 x 10 copies/mL
1. COVID-19 Ag Respi-Strip results according to viral load.

A. Scohy, et al. Journal of clinical virology 129 (2020)

 40 • Evaluation of novel antigen-based rapid
• detection test for the diagnosis of SARS-CoV-2
• • in respiratory samples
35

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• The evaluated RDT showed a high

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10
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2 3 4 5 6 7 8
Day of symptoms
9 10 11 12
to molecular methods.

Cycle threshold (Ct) values and lineal trend line of

70 RT-PCT positive samples taken on different days after symptom onset.
Dots colours represent false negative (red) and International Journal of Infectious Diseases DOI:
true positive (blue) results by antigen detection test. (10.1016/j.ijid.2020.05.098)
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 Serology: Antibody test

Serological surveys can aid investigation of an ongoing outbreak and

retrospective assessment of the attack rate or extent of an outbreak.

In cases where NAAT assays are negative and there is a strong epidemiological
link to COVID-19 inf ect io n, paired serum samples (in t he acut e and convalescent
phase} could support diagnosis once validated serology tests are available.
Serum samples can be stored for these purposes.

Paired samples are necessary for confirmation with the initial sample collected
in the first week of illness and the second ideally collected 2-4 weeks later

Cross reactivity to other coronaviruses can be challenging

 • lgM ELISA can increase the positive
detection rate when combined with
the PCR method

C -
100
98.6
• positive detection rate was only 51.9%
in a single PCR test, but significantly
c
80
7 increased (98.6%) when an lgM ELISA
9Q) 60
assay was applied to PCR-negative
Q) 40

= >
,.,, 20 patients
Ro
L. Guo et al., Clin. Infect. Dis. (2020), doi:10.1093/cid/ciaa310.
The factors that influence antibody detection performance

False
Previously infection by SARS CoV
Positive

Anti RBD
(SP): 11-14
Collecting time samples: Different time days
seroconversion
Anti NP: 7-12
False days
Negative
Host immune factors: different
immune responses to NP and SP
among people.
Hasil survey performa RDT antibodi SARS COV-2

• Tujuan melihat kondisi performa RDT covid di lapangan

• Post marketing surveillance RDT yang beredar
• Data sekunder dari komunitas dan rumah sakit
• Anonimus dan tidak ada conflict of interest
• Data sekunder sebanyak 130.693 data yang dikumpulkan dari komunitas
dan rumah sakit di seluruh cabang PDS PatKLln {30 cabang mencakup 34
provinsi)
• Didapatkan 63 merk RDT yang digunakan di seluruh Indonesia
• Baku emas yang digunakan adalah metode rRT-PCR dan TCM
 Performa ROT antibodi lgG dan lgM
SARS COV-2
5s1.m I TOTAL
PCR
[ E T. I I . ] Total
Positif Negatif Rapid Test (lgG) Total
Positif Negatif
4097 300 3797 4264 314 3950
[EIZEZI'. Rapid Test {lgG)
7/EI'E7 2327 163 2164 Reaktif 1035 183 852
[TETTEH7 1770 137 1633 Non Reaktif 3229 131 3098

95%CI 95% Cl
ETTIE] 43,84 42,32 45,36 Akurasi 76,95 75,68 78,21
58,28 52,83 63,73
EIT I E E 54,33 48,70 59,97 Sensitivitas
43,01 41,43 44,58 Spesifisitas 78,43 77,15 79,71
EH7ZIEL 7,00 4,12 7,82 PPV 17,68 13,46 18,87
EE7 92,26 91,41 93,11 NPV 95,94 95,33 96,56
AI7 0,95 -0,15 2,05 +LR 2,70 0,91 4,50
) 1,06 0,74 1,39 -LR 0,53 0,31 0,76
ETl /_ Perhimpunan Dokter Spesialis Patologi Klinik dan Kedoteran
( ) Laboratorium Indonesia
Masalah teknis yang ditemukan

•
• Garis hasil samar / tidak jelas (Biolidies, Boson, Eagteeare, Edan, Genbody,
Hasil Tidak Wondfo, Vazyme, VivaDiag, Livzon, High Top, SD Biosensor, Star)
Jelas • Hasil sangat tebal seperti kotoran ulang = non reaktif (Egens)

• False positive (VivaDiag, Edan, SD Biosensor, Setro, Wondfo)

• High Top: pasien geriatri dengan komorbid & gravid
Hasil • False negative (High Top, Biozek)
Invalid • Pasien swab (+), hasil non reaktif, duplo merk lain don Abbott(+)
• Garis kontrol tidak muncul (Aero, High Top, Lungene, Vazyme, Wondfo)
• Munc ul 5 garis da la m 1 alat uji (Viva Diag)

{
• Strip sangat kecil (Aero)
Kit Kurang • Pipet sulit digunakan (High Top, Livzon)
Lengkap • Jumlah lgM don lgG tidak sama (Livzon)
• Tidak ado buffer don pipet (Edan, New Test)

Prosedur
unclear { • SOP rumit (Aero, Edan)
• buffer ditetes 20-30 detik sesudah sampel, strip sangat kecil (Aero)
Perhimpunan Dokter Spesialis Patologi Klinik dan Kedoteran
Laboratorium Indonesia
Kesimpulan
Banyak ROT beredar yang tidak memiliki rekomendasi/ sertifikasi gugus
tugas/ FDA/ CE

Validitas ROT antibodi SARS COV-2 yang bervariasi

lgG sensitivitas 33-96% dan spesifistas 19-100% -

lgM sensitivitas 16-100% dan spesifisitas 7-97%

• Performa lgG secara umum lebih baik dibanding lgM anti SARS COV-2
• Ditemukan hasil PCR positif disertai hasil lgG reaktif, yang mengindikasikan lgG dapat
timbul pada fase akut
• Dijumpai banyak masalah teknis terkait pemakaian ROT COVID-19
 Rekomendasi
• Pem ilihan RDT per lu dipert im bangkan dengan mem per hat ikan perf or ma dan masalah
teknis yang timbul
• Perlunya diadakan post marketing surveillance dari user untuk setiap masalah yang
ditemukan di lapangan
• Perlunya pelatihan untuk petugas (SDM) yang akan melakukan pemeriksaan RDT
terutama dalam hal pengerjaan dan interpretasi
• Berkaitan dengan rendahnya validitas RDT, tidak direkomendasikan penggunaan RDT
secara tunggal, namun dikombinasikan dengan parameter lain yaitu klinis (formulir
sesuai buku pedoman Kememkes) serta pemeriksaan lab lain (PCR, CBC)
• Tidak merekomendasikan penggunaan RDT antibody tunggal untuk skrining dan
diagnosis COVID-19 namun untuk surveilans (seroprevalence) dengan
mempertimbangkan performa RDT yang akan digunakan
Main laboratory abnormalities observed in adult patients with
unfavorable COVID-19 progression (Modified 1-30)
aboratory Test bnormalities otential clinical significance
Bacterial (super)infection
Increased white bloodcell
Bacterial (superinfection
omplete blood Increase neutrophil count
Decreased immunological response to
ount Decreased lymphoc yte count the virus
Decreased platelet count Consumption (disseminated)
coagulopa thy
lo o d ases Estimated modifications Important in critical care managment
l bum l n Decreased Impairment of liver function
Pulmonary injury and/or widespread
Increased
organ damage
Increased Liver injury and/or organ damage
Increased Liver injury and/or organ damage
otal bilirubin Increased Liver injury
reatinin Increased Kidney injury
rea Estimated Increase Kidney Injury
ardiac tror nin Increased Cardiac injury
Activation of blood coagulation and/or
Increased
disseminated coagulopathy
Activation of blood coagulation and/or
rothrombin Time Increased
disseminated coag ulo pathy
rocalcitonin Increased Bacterial (super)infection
Increased Severe viral infection/viremia/viral
reactive protein
sepsis
erritin Increased Severe inflammation IFCC Information
Guide on COVID-19
okines IL-6 Increased Cytokine storm syndrome
- IFCC. www.ifcc.org
 C-REACTIVEPROTEIN

• Synthesized within 6-8 hours of exposure to an infective process or tissue

damage
• Half life 19hrs and may reach to 1000 fold during an acute phase
response
• Peaks at 36-50 hours. It decreased when there was no stimuli

• It has higher sensitivity and specificity than total neutrophils and I/T
ratio (immature granulocyte to total).
 3#
Respiratory
tract infection

·
Lr

··w
0 0

Figure 1]Functional CRPpatways. In response to cytolines suchas IL6 and IL 1$. hepatic expression of CRPincreases
dramatically. CirculatingCRPopsonie s bacteria andapoptotic cells, facilitatingtheir clearancevia the complement
system and Foy/mediated phagocytosis. CRPligation might controute to the releaseby phagocytic cells of
immunomodulatory cytolioes such as IL10. Evidence is mountingtat plasma CRPdeposited onto inflamed tssue
breaks into biologcaly active monomeric subunits, to whichhave been attributed arangeof proinflammatoryeffects .
Abbreviations. CRP
foeti nwnt ale p lnhaenhaihritrlre
 Original article
C-reactive protein levels in the early stage of COVID-19
L Wang

IN FO AR T I C L E A B S T R A C T

Hitorigue de tarncie Ba oiground c0OVID 19 is a new infect ious dise ase , for w hich there
ru le 26 mar a0U th er efo re necessary to explore biomarkers to determine the ext ent of lu
Accept& e 30 mars 20.20 Objective. We ai m ed to a ssess the use fulness c& CP leve ls in the e a r l y s t,
Dispou ble sur Interre t le 11 Mr« h 20t th em w ith tung lesions and severe prese nt at io n

At the early stage of COVID-19, CRP levels were

positively correlated with lung lesions. CRP levels
could reflect disease severity and should be used
as a key indicator for disease monitoring.

Mild group Moderate group Severe group Critical group

-CRP levels - Diameter of the largest lung lesion

C-reactive protein correlates with computed tomographic , T i i W IL E

findings and predicts severe COVID-19 early

I
(E) (F)

,
C reactive protein
CT scores

%z ·
15
- S e v e n t y group - Seventy group
-« Mild group -« Mild group
compared with severity 10 compared withseverity
5«
%
group.P<0.05 group.P<0 05
c:i.

Stage l ·. stage s
: Initial
•£ z0 •
•
Stage 2 : Progression stag
A v , r a g e d se e sf.e d
3 4 Stage 4 : Recove ry stage 2 3
Stage of illness Stage of illness

"CRP increased significantly at the initial stage in

severe COVID-1 9 patients; while still no significant
diffe rence in the CT scores were found between the
severe and mild groups" Tan et al, 2020. DOI 10.1002/mv.25871
•
Procalcitonin
,,Ho rm o kines''
Hormones expressed like Cytokines
Healthy Se
Thyroid
Leukocytes Inflammation
Perit. Macrophages Bacterial Inte rfer on
Toxins
i-1» tat.a
Spleen
Lung
Liver TNFa
Kidney
Adrenals
Brain Procalcitonin
Spine
Stomach
Pancreas
Small intestine
Thyrocytes c-Cells Colon

! ~
Thyroxine Calcitonin
Heart
Muscle
Skin
Adipose Tissue
e $ Testes

Muller B. et al. J CIin Endocrinol Metab 200

 Co-infection with respiratory pathogens among COVID-2019 cases
Xiaojuan Zhu, Yiyue Ge', Tao Wu, Kangchen Zhao, Yin Chen, Bin Wu, Fengcai Zhu,
Baoli Zhu"", Lunbiao Cui
- - - - ·----- -
Characteristics of respiratory pathogens with the SARS-CoV-2 co-infection.

No. (%)

Characteristic
Total Asymptomatic l\Iild Moderate
(n =257) (n=22) (n = 78) (n= 140) (n= 17)
Co-infections 242 21 (95.5) 75 129 (92.1) 17 (100)
(94.2) (96.2)
any virus isolated 81 (31.5) 4(8.2) 26 45 (32.1 6(35.3)
(33.3)
any bacteria 236 21(95.5) 75 124(88.6) 16 (94.1)
isolated' (91.8) (96.2)
any fungi isolated° 60 (23.3) 6 (27.3) 18 31 (22.1) 5(29.9)
(23.8)
Bacteria-virus 77 (30.0) 4 (18.2) 26 42 (30) 5(29.5)
(33.3)
Bacteria-fungi 61 (23.7) 6 027.3) 20 30 (21.9 5 (29.5)
(25.6)
Virus-fungi 24 (9.3) 1(4.5) 11 11 (7.9) 1(5.9)
(14.1)
Bacteria- virus-fungi 23 (8.9) 1(4.5) 10 (7.1) 1(5.9)
Procalcitonin
Contents lists available at ScienceDirect
serial procalcitonin measurement may play
Clinica Chimica Acta
journal homepage: www.elsevier.com/locate/cca
a role for predicting evolution towards a
more severe form of disease
reflect bacterial coinfection in those
£ 2 a T % 7 4_ $ } "

Study 0R(95%.0 %Weight

Guanetal,2020 4,14( 206, 8,33) 38.0 contributing to complicate the clinical

2Zangetal, 2020
Hangetal,2020
3,25 (1,48, 7,15) 29.8
350 (0,82,14,93) 8.8
picture
Wangetal,2020 10,91 ( 4,48,26.56) 234

Overal 4,76 (274, 8.29) 100.0

0=456,p-0.21,02-34%

10 12 14 16 18 20 22 24 26
OR

l i K ] [t,l e t + ; i [i
 Abnormal Clotting Optimal time for
B
D-Dimer
f o g
Fibrin(ogen)

t
t Bleeding and Thr omb oc ytopenia
v - »
Normal to t t Fibrin(ogen)

4
slightly D-dimer
increased

..
but
increasing
P-selectin

D -di mer

COVID-19 Personalized Treatment

COVID-19 Point-Of-Care Options
TEG
*Platelet function tests

Int. J. Mol. Sci. 2020, 21, 5168

F ibrinogen, P-selectin and vWF concentrations
Other circulat ing inflammatory marker
concentrations
t cytokine storm
Why are D-dimer levels elevated in severe courses of COVID-19 patients?

activated
Inflammatory This high
Immune
processes number of
cells and a
and blood clots is
potential
infections degraded by
influence of
(COVID-19) fibrinolysis.
cytokines
 D-dimer
a marker for increased coagulation processes in the body.

D-dimer levels correlate with D-dimer is commonly elevated in patients

disease severity with COVID-19 and reliable prognostic
marker for in-hospital mortality .

Table 4 Test characteristics of D-dimer for predicting in-hospital

mortality with the optimal sensitivity and specificity scores
Cutoff point for D-dimer (mg/L) 2.14
Area under curve 0.85
95% Cl 0.77-0.92
Subjects with D-dimer > 2.14 mg/L (6) 77 (31.2%)
Sensitivity (%) 88.2
Specificity (%) 71.3
Likelihood ratio 3.08

Correlations of D-dimer levels with clinical staging

Yao et al. Journal of Intensive Care (2020) 8:49
 Possible approach to empiric anticoagulation in COVID-19

'
No
Is D-dimer above 1,000-2,000 ng/ml?
fpvr prophylactic anticoagulation (consider
higher dose than normal, if D-dimer is
moderately elevated).
]rs
Follow serial D-dimer (If D-dimer rises above
Yes 1,000-2,000 ng/mu, then re-consider
Contraindication to anticoagulation?
anticoagulation).

]
Check fibrinogen level and/or thromboelastography (TEG)

Normal or hyper-coagulable pattern (nearly always) Hypo-coagulable pattern (rare, late-stage)

- R-time low or normal on thromboelastogrophy - R-time prolonged on thromboelastography
- Fibrinogen level is normal or elevated • Fibrinogen level low

Therapeutic anticoagulation, e.g.:

- Normal renal function: therapeut ic dose low molecular weight heparin
- Renal failur e heparin infu sion
[ No anticoagulation
]
f

. Follow fibrinogen level and/ or throm boelastogr aphy

"
occasionally. Discontinue anticoagulation if evidence of hypo•
. coagulable pat tern.
For severe hypercoagulability, consider addition of aspirin
'- ,)

The role of anticoagulation remains unknown and highly controversial. This is one general approach which could
be reasonable, but treatment decisions should always be individualized.
f ltrnt Seel el Critical Care, ty r ut C r it
15TH interim guidance on recognition and management of coagulopathy in COVID-19

1. D-dimer* I
I
2. Prothrombin time
I
3. Platelet count I
4. Fibrinogen**
vI

1. D-dimer markedly raised 1. D-dimer not markedly raised

2. Prothrombin time prolonged 2. Prothrombin time normal
3. Platelet count 100 x 109/L 3. Platelet count normal
4. Fibrinogen <2.0 g/L 4. Fibrinogen elevated

I
V

Admit (even if no other If admitted for other clinical reasons, If discharged, use as baseline
concerns) Monitor daily for
Monitor once or twice daily if re-presenting with symptoms

l
•
In all patients

Start prophylactic dose

Worsening
low molecular weight heparin In non-bleeding patients, keep
► platelet count above 20 x 10/L
► fibrinogenabove2.0 g/L

In bleeding patients, keep

• Blood products as per protocol (see box on the ► platelet count above 50 10/L
right) ► fibrinogenabove2.0 g/L
• Consider experimental therapies » PT ratio <1.5 (not the same as INR)
Patklin
Terima
kasih