Evaluasi TPK Pada Pasien COVID-19

Evaluasi Terapi Plasma Konvalesen
pada Pasien COVID -19
Bambang Pujo Semedi

Departemen Anestesiologi dan Reanimasi
RSUD Dr Soetomo- FK Universitas Airlangga
Surabaya
Mengapa perlu terapi plasma
konvalesen (TPK) ?
• Belum tersedia vaksin dan obat yang mujarab untuk
melawan COVID 19
• Sampai saat ini belum ada rekomendasi terapi yang memiliki
level evidence tinggi
• Menunggu terapi dengan level RCT masih terlalu lama
• Mortalitas pasien COVID-19 terutama yang
menggunakan ventilator masih tinggi
• Laporan tidak resmi mencatat mortalitas pasien yang
menggunakan ventilator ada yang mencapai 80-90%
• Perlu upaya untuk mencegah pasien pneumonia COVID-
19 sedang-berat agar tidak jatuh ke gagal nafas yang
memerlukan ventilator sehingga dapat mengurangi
mortalitas
Sejarah terapi plasma konvalesen
• Bukan konsep baru (sudah digunakan sejak tahun
1800 an)
• Uji klinis pertama : kasus difteri (1892)
Emil von Behring : The Founder of Serum Therapy

• In 1892, Behring and the Hoechst chemical and pharmaceutical
company at Frankfurt/Main, started working together, as they
recognized the therapeutic potential of the diphtheria antitoxin.
• From 1894, the production and marketing of the therapeutic
serum began at Hoechst.
Sejarah terapi plasma konvalesen
• Scarlet fever (1920-an)
• Pertussis (s/d 1970)
• Pandemi flu Spanyol pada 1918
• ..dan berbagai infeksi virus lain Emergency hospital during influenza
epidemic (NCP 1603) from National
termasuk measles, mumps, Argentine Museum of Health and Medicine.
hemorrhagic fever, influenza,

chickenpox, infeksi akibat CMV,
parvovirus B19, MERS-CoV, flu burung
(H1N1 & H5N1), Ebola, dan Severe
Acute Respiratory Infections (SARI)
viruses A hospital isolation ward in Gulu, Uganda,
during the October 2000 outbreak of
Ebola hemorrhagic fever
TPK di era modern
• Virus Ebola (terapi yang direkomendasikan oleh
WHO pada tahun 2014)
• SARS-CoV-1 (Hongkong) pada tahun 2003
• H1N1 pada tahun 2009 - 2010
• MERS-CoV pada tahun 2012
• TPK untuk COVID 19 diawali dari laporan Wuhan
(China) dan saat ini sudah dilakukan di hampir
seluruh negara yang terjangkit COVID 19
• Namun…hasil studi TPK pada COVID sampai saat ini
belum bisa disimpulkan
Efikasi TPK pada infeksi virus
• TPK hampir selalu “booming” setiap kali terjadi
outbreak infeksi, karena belum tersedia obat dan vaksin
• Studi tentang efikasi TPK
• 2006
• Metaanalisis : delapan studi tentang flu Spanyol,
dengan jumlah pasien 1703
• Kesimpulan : mengurangi risiko kematian
• 2015
• Metaanalisis : 32 studi tentang infeksi korona virus
dan influensa
• Kesimpulan : TPK menurunkan kemungkinan pasien
meninggal s/d 75%
Efikasi TPK pada infeksi virus
• 2017
• Non randomisasi, double-site, kasus serial yang
diberikan TPK dan dengan terapi standar saja di Sierra
Leone (2014-2015)
• Total pasien 69 : 44 TPK dan 25 terapi standar
• Hasil :
• TPK : 44 pasien : 31 sembuh, 12 meninggal, 1 drop out
• CFR TPK vs Standar : 27,9% vs 44%
• Odd ratio for survival from CP therapy : 2.3 (95% Cl
0,8–6,5)
• Kesimpulan :
• TPK adalah terapi yang menjanjikan untuk infeksi
Ebola pada resource-poor setting
TPK memberi harapan untuk
pencegahan dan penyembuhan
pasien COVID-19
Benefits of convalescent plasma therapy
Use of plasma convalescent was associated to
reduction in fatality rates, mortality in cases of H1N1
pandemic, Spanish Influenza A, and SARS-CoV
Manuel Rojas, et al., Autoimmunity Reviews, https://doi.org/10.1016/j.autrev.2020.102554
Use of plasma convalescent in other coronaviruses,

such as SARS-CoV, reduced days of hospital stay in
critically ill patients
Yeh K-M, et al. Experience of using convalescent plasma for severe acute respiratory syndrome among
healthcare workers in a Taiwan hospital. J Antimicrob Chemother 2005;56:919–22
In relation, to the use of mechanical ventilation, in

H1N1 pandemic, and H5N1, administration of CP
reduced the duration of invasive ventilation
Chan KKC, Lee KL, Lam PKN, Law KI, Joynt GM, Yan WW. Hong Kong’s experience
on the use of extracorporeal membrane oxygenation for the treatment of influenza A (H1N1). Hong Kong
Med J 2010;16:447–54
Karakteristik pasien yang mendapat TPK
recorded after CP transfusion. filtration, and elevated proinflammatory cytokines or even
Discussion cytokine storm in alveoli of lungs, resulting in acute pulmonary
injury and acute respiratory distress syndrome (ARDS) (17).
Our study explores the feasibility of CP therapy in COVID-19.
All enrolled severe COVID-19 patients achieved primary and Recent studies on COVID-19 demonstrated that the lymphocyte
Endpoint therapy
secondary outcomes. One dose of 200-mL CP transfusion was counts in the peripheral blood were remarkably decreased and
well tolerated, while the clinical symptoms significantly improved the levels of cytokines in the plasma from patients requiring
with the increase of oxyhemoglobin saturation within 3 d, ac- intensive care unit (ICU) support, including IL-6, IL-10, TNF-ɑ,
companied by rapid neutralization of viremia. and granulocyte-macrophage colony-stimulating factor, were
CRP Lym SaO2

patient 1
150 4 105
patient 2
100
3
100
95 patient 3
2
50
90 patient 4
1
85
patient 5
0 0 80
Before CP treatment After CP treatment Before CP treatment After CP treatment Before CP treatment After CP treatment
patient 6
ALT AST TBIL patient 7

100 60 80
patient 8
80
60
40 patient 9
60
40
patient 10
40
20
20
20
0 0 0
Before CP treatment After CP treatment Before CP treatment After CP treatment Before CP treatment After CP treatment
Fig. 2. Dynamic changes of laboratory parameters in all patients. The dotted horizontal line represents the reference value range. SaO2, oxyhemoglobin
saturation; TBIL, total bilirubin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Lym, lymphocyte.
4 of 7 | www.pnas.org/cgi/doi/10.1073/pnas.2004168117 Duan et al.

ativity after CP transfusion, accompanied by an increase of titers in CP in COVID-19 seem thus higher than those used in
oxygen saturation and lymphocyte counts, and the improve- the treatment of MERS patient (1:80) (12).
ment of liver function and CRP. The results suggest that the The second key factor associated with efficacy is the treatment
inflammation and overreaction of the immune system were time point. A better treatment outcome was observed among
alleviated by antibodies contained in CP. The case fatality rates SARS patients who were given CP before 14 dpoi (58.3% vs.
Hasil pasca TPK

(CFRs) in the present study were 0% (0/10), which was com- 15.6%; P < 0.01), highlighting the importance of timely rescue
parable to the CFRs in SARS, which varied from 0% (0/10) to therapy (9). The mean time from onset of illness to CP transfusion
12.5% (10/80) in four noncomparative studies using CP treat- was 16.5 d. Consistent with previous research, all three patients
ment (9, 20–22). Based on our preliminary results, CP therapy receiving plasma transfusion given before 14 dpoi (patients 1, 2,
CRP Lym SaO2
80 4 105
100
60 3
95
40 2
90
20 1
85
0 0 80
Day 0 Day 1 Day 0 Day 1 Day 3 Day 4 Day 0 Day 1
ALT AST TBIL
80 40 80
60 30 60
40 20 40
aded at Indonesia: PNAS Sponsored on April 10, 2020
20 10 20
0 0 0
Day 0 Day 1 Day 3 Day 4 Day 0 Day 1 Day 2 Day 3 Day 4 Day 0 Day 1 Day 3 Day 4
Fig. 3. Change of laboratory parameters in patient 1. The x axis represents the day post-CP transfusion. The dotted horizontal line represents the reference
value range.
Duan et al. PNAS Latest Articles | 5 of 7

CLINICAL MEMORANDUM
From: (b) (6) , OBRR/DBCD/CRS
To: (b) (6) , OBRR
Through: (b) (6) , OBRR/DBCD

(b) (6) , OBRR/DBCD
(b) (6) , OBRR/DBCD/CRS
Re: EUA 26382: Emergency Use Authorization (EUA) Request (original

request 8/12/20; amended request 8/23/20)
Product: COVID-19 Convalescent Plasma
Items reviewed: EUA request

Fact Sheet for Health Care Providers
Fact Sheet for Recipients
Sponsor: Robert Kadlec, M.D.

Assistant Secretary for Preparedness and Response (ASPR)
Office of Assistant Secretary for Preparedness and Response (ASPR)
U.S. Department of Health and Human Services (HHS)
EXECUTIVE SUMMARY
Conclusion
• COVID-19 Convalescent Plasma meets the eligibility
criteria for Emergency Use Authorization (EUA).
• COVID-19 Convalescent Plasma may be effective in the
treatment of COVID-19 and it is reasonable to believe
that the known and potential benefits of CCP
outweigh the known and potential risks of the
product for the proposed EUA.
• Current evidence suggests clinical benefit is most
likely in patients treated early in the course of the
disease (e.g., prior to intubation) and with the use of
CCP with higher antibody levels or neutralization
activity.
Conclusion
• Current data are limited by the unavailability of
validated assays of antibody levels or neutralization
activity in CCP.
• Based on the available data, it is reasonable to use
the Ortho VITROS IgG assay with an S/C cutoff of
12 or greater as a manufacturing potency test to
qualify high titer units of CCP.
Conclusion
• Based on the available evidence, CCP without a result of
12 or greater in the Ortho VITROS assay meets the
criteria for issuance of an EUA because, among other
things, it is reasonable to believe it may be effective in
treating COVID-19 and the known and potential benefits
of the product outweigh its known and potential risks.
Such units must be labeled as “COVID-19 Convalescent
Plasma of Low Titer.”
• Health care providers can decide whether to use these
units based on an individualized determination of
potential benefit and risk.
Conclusion
• The Fact Sheet for Health Care Providers and Fact
Sheet for Recipients are accurate, not misleading,
and appropriate for the intended setting.
• Randomized controlled trials are required to show
definitive evidence of safety and efficacy and to
determine the optimal product attributes and
appropriate patient populations for the use of
COVID-19 Convalescent Plasma.
EXECUTIVE SUMMARY
• COVID-19 Convalescent Plasma (CCP), an
unapproved biological product, is proposed for use
under an Emergency Use Authorization (EUA) under
section 564 of the Federal Food, Drug, and Cosmetic
Act (the Act),(21 USC 360bbb-3) as a passive
immune therapy for the treatment of hospitalized
patients with COVID-19, a serious or life-
threatening disease.
• There currently is no adequate, approved, and
available alternative to CCP for treating COVID-19
EXECUTIVE SUMMARY
• The sponsor has pointed to four lines of evidence to
support that CCP may be effective in the treatment
of hospitalized patients with COVID-19:
1. History of CP for respiratory corona virus
2. Evidence of preclinical safety and efficacy in animal
models
3. Published studies of the safety and efficacy of CCP
4. Data on safety and efficacy from the National
Expanded Access Treatment Protocol (EAP)
sponsored by the Mayo Clinic
EXECUTIVE SUMMARY
• Considering the totality of the scientific evidence
presented in the EUA, I conclude that current data
for the use of CCP in adult hospitalized patients
with COVID-19 supports the conclusion that CCP
meets the “may be effective” criterion for
issuance of an EUA from section 564(c)(2)(A) of the
Act.
• It is reasonable to conclude that the known and
potential benefits of CCP outweigh the known and
potential risks of CCP for the proposed EUA.
EXECUTIVE SUMMARY
• Current data suggest the largest clinical benefit is
associated with high-titer units of CCP
administered early in the course of disease.
Adequate and well-controlled randomized trials
remain necessary for a definitive demonstration of
CCP efficacy and to determine the optimal product
attributes and appropriate patient populations for
its use.
Recommendation: CCP meets the eligibility

criteria for EUA under section 564 of the Act.
The American Journal of Pathology, Vol. 190, No. 8, August 2020
ajp.amjpathol.org
IMMUNOPATHOLOGY AND INFECTIOUS DISEASES
Treatment of Coronavirus Disease 2019

(COVID-19) Patients with Convalescent Plasma
Eric Salazar,*y Katherine K. Perez,*z Madiha Ashraf,x Jian Chen,* Brian Castillo,* Paul A. Christensen,* Taryn Eubank,z
David W. Bernard,*y Todd N. Eagar,*y S. Wesley Long,*y{ Sishir Subedi,* Randall J. Olsen,*y{ Christopher Leveque,*
Mary R. Schwartz,* Monisha Dey,* Cheryl Chavez-East,* John Rogers,* Ahmed Shehabeldin,* David Joseph,* Guy Williams,*
Karen Thomas,* Faisal Masud,xk Christina Talley,** Katharine G. Dlouhy,** Bevin V. Lopez,** Curt Hampton,**
Jason Lavinder,yy Jimmy D. Gollihar,xx Andre C. Maranhao,yy Gregory C. Ippolito,yyzz Matthew O. Saavedra,{
Concepcion C. Cantu,{ Prasanti Yerramilli,{ Layne Pruitt,{ and James M. Musser*y{
From the Departments of Pathology and Genomic Medicine,* Pharmacy,z and Anesthesiology and Critical Carek and the Division of Infectious Diseases,x
Department of Clinical Medicine, Houston Methodist Hospital, Houston, Texas; the Department of Pathology and Laboratory Medicine,y Weill Cornell
Medical College, New York, New York; the Center for Molecular and Translational Human Infectious Diseases{ and the Academic Ofﬁce of Clinical Trials,**
Houston Methodist Research Institute, Houston, Texas; the Departments of Molecular Biosciencesyy and Oncology,zz Dell Medical School, University of Texas
at Austin, Austin, Texas; and the Combat Capabilities Development Command (CCDC) Army Research Laboratory-South,xx University of Texas at Austin,
Austin, Texas
Accepted for publication

May 21, 2020. Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, has
spread globally, and no proven treatments are available. Convalescent plasma therapy has been used
Address correspondence to
Population
• Patients (n = 25) with severe and/or life-threatening COVID-
19 disease were enrolled at the Houston Methodist hospitals
from March 28, 2020, to April 14, 2020.
Method :
• Patients were transfused with convalescent plasma, obtained
from donors with confirmed SARS CoV-2 infection who had
recovered.
• Clinical improvement was assessed on the basis of a modified
World Health Organization six-point ordinal scale and
laboratory parameters.
• Viral genome sequencing was performed on donor and
recipient strains
Measured outcome
• The primary study outcome was safety
• The secondary outcome was clinical status at day 14 after
transfusion.
Result
• At day 7 after transfusion CP
• nine patients had at least a one-point improvement in
clinical scale
• seven of those were discharged
• By day 14 after transfusion
• 19 (76%) patients had at least a one-point improvement
in clinical status
• 11 were discharged
• No adverse events related to plasma transfusion were
observed
• Whole genome sequencing data did not identify a strain
genotype-disease severity correlation
Conclusion
• The data indicate that administration of convalescent
plasma is a safe treatment option for those with severe
COVID-19 disease
Modified six-point clinical scale
(WHO Research and Development Blueprint group)
1. Discharged (alive)
2. Hospitalized, not requiring supplemental oxygen but
requiring ongoing medical care (for COVID-19 or
otherwise)
3. Hospitalized, requiring low- flow supplemental oxygen
4. Hospitalized, on noninvasive ventilation or high-flow
oxygen devices
5. Hospitalized and on invasive mechanical ventilation or
extracorporeal membrane oxygenation (ECMO)
6. Death
TEORI DASAR
SARS-CoV-2 Cell Entry Depends on ACE2 and
Graphical Abstract
CoV-2 Spike Glycoprotein

Structure, Function, and Antigenicity of the SARS-
TMPRSS2 and Is Blocked by a Clinically Proven
Protease Inhibitor
Graphical Abstract Authors
Markus Hoffmann, Hannah Kleine-Weber,
Simon Schroeder, ..., Marcel A. Müller,
Christian Drosten, Stefan Pöhlmann
Walls AC et al., 2020, Cell 180, 281–292
the SARS-CoV-2 S ectodomain trimer and reveal that it adopts et al., 2011; Matsu
Correspondence
multiple SB conformations that are reminiscent of previous re- Shulla et al., 2011
mhoffmann@dpz.eu (M.H.),
ports on both SARS-CoV S and MERS-CoV S. Finally, we We set out to
spoehlmann@dpz.eu (S.P.)
Cryo-EM structures of the SARS-CoV-2
entry receptor to invade target cells.
affinity to human ACE2 and uses it as an
spreading worldwide, binds with high
SARS-CoV-2, a newly emerged pathogen
In Brief
dveesler@uw.edu
Correspondence
Andrew T. McGuire, David Veesler

M. Alejandra Tortorici, Abigail Wall,
Alexandra C. Walls, Young-Jun Park,
Authors
• SARS-CoV-2 infection
show that SARS-CoV S mouse polyclonal sera potently in- S-mediated entry
hibited entry into target cells of SARS-CoV-2 S pseudotyped vi- (MLV) pseudotypi
In Brief
depends on the host cell
ruses. Collectively, these results pave the way for designing assess the ability o
vaccines eliciting broad protection The emerging SARS-coronavirus 2 first com
SARS-CoV, and SARSr-CoV.
against SARS-CoV-2,
(SARS-CoV-2) threatens public factors (ACE2 & TMPRSS2)
cells, we
health.
and SARS-CoV S-
Hoffmann and coworkers show pressthat
ACE2 and s
• They can be blocked by a
Article
RESULTS SARS-CoV-2 infection depends 2003;on the

Ksiazek et a
clinically proven protease
host cell factors ACE2 and TMPRSS2 and
equally well (Figur
ACE2 Is an Entry Receptor for SARS-CoV-2 can be blocked by a clinically proven
could use African
The SARS-CoV-2 S glycoprotein shares 76%
protease amino These
inhibitor. inhibitor and neutralized
acid findings
confirmmight
these res
sequence identity with the SARS-CoV S Urbani
help and 80%options
to establish by SARS convalescent sera
iden- forobserved
prevention that tra
tity with bat SARSr-CoV ZXC21 S and ZC45 S glycoprotein. The them susceptible
and treatment.
latter two SARSr-CoV sequences were identified from Rinolo- (Figure 1B). These
phus sinicus (Chinese horseshoe bats), the species from which ceptor for SARS-
Hoffmann et al., 2020, Cell 181, 271–280
KEKEBALAN TERHADAP COVID-19
https://homehealth-uk.com/all-products/coronavirus-test-kit-rapid-covid-19-igg-igm-on-site-professional-testing/
Apa yang terkandung dalam
M. Rojas, et al.
plasma konvalesen ?
Other factors ?
(viral, other pathogens, etc)
Apa manfaat TPK ?
Anti viral
IgA
Imunomodulator
• Anti inflamasi
• Regulator “badai
M. Rojas, et al, 2020, Autoimmunity Reviews 19

sitokin” ??
nt plasma components and its mechanisms of action. A. Main convalescent plasma components. B. Antiviral eﬀects of
Mekanisme netralisasi virus oleh
antibodi
1. Menghambat ikatan virus

dengan reseptor ACE2
• steric interference
• stabilisasi capsid
• perubahan struktur
2. Menghambat endositosis
3. Menghambat ”uncoating”
• stabilisasi capsid
• fusion interference
Mekanisme kerja SARS-CoV-2
neutralizing antibodies
The protruding portion of Terjadi kompetisi antara

RBD is both the ACE2 antibodi penetral virus
receptor-binding site and
the antibody epitope SARS-CoV-2 terhadap
reseptor ACE2 pada
receptor-binding domain
(RBD) untuk SARS-CoV-2
Spike protein
Anudeep TC et al., 2020 (J Clin Trials, Vol.10 Iss.3 No:1000409)

Potential mechanisms of coronavirus
COMMENT
antibody neutralization and antibody
enhancement of infection a b
Spike Receptor
protein binding
Mechanism 1 : neutralizing antibodies

could block viral infection by binding to the Mechanism 1
viral spike protein and preventing it from ACE2
interacting with the cellular receptor

angiotensin-converting enzyme 2 (ACE2) Internalization
into endosome
Mechanism 2 : neutralizing antibodies

Membrane
could bind to the viral spike protein and fusion
block the conformational changes that the

Mechanism 2
spike protein must undergo to facilitate
fusion of the viral and host cell membranes
Release of viral
Abraham J, 2020, Nature review, immunology, vol. 20 genetic material
a b v
i
Potential mechanisms of
Spike
protein
Receptor
binding Antibody binds spike
protein and FcR
i
s
coronavirus antibody i
R
neutralization and antibody

Mechanism 1 s
r
enhancement of infection ACE2 FcR i
t
u
Antibodies could enhance viral
Internalization F
into endosome i
entry into immune cells by f
e
binding to the viral spike
Membrane
protein Internalization
into endosome t
t
with their Fab portionfusionand to Fc o
Membrane n
receptors (FcRs) with their Fc
Mechanism 2
fusion
F
s
domain. Release of viral t
genetic material e
Abraham J, 2020, Nature review, immunology, vol.
Release of 20
viral
o
genetic material r
Risiko dibalik manfaat TPK
Nature Reviews, Immunology, vol. 20, June 2020
The potential danger of suboptimal

antibody responses in COVID-19
Akiko Iwasaki 1,2
and Yexin Yang1
There is a desperate need for effective therapies and 55
EBioMedicine vaccines for SARS-CoV-2 to mitigate the
(2020) 102768
growing economic crisis that has ensued from societal lockdown. Vaccines are being developed
at an unprecedented speed and are already in lists
Contents clinical trials,
available without preclinical testing for safety
at ScienceDirect
and efficacy. Yet, safety evaluation of candidate vaccines must not be overlooked.
EBioMedicine
SARS- CoV-2 and SARS- CoV share 79.6% sequence independent of ACE2 expression and endosomal pH
identity, use the same entry receptorjournal (ACE2) and www.elsevier.com/locate/ebiom
homepage: and proteases, suggesting distinct cellular pathways
cause similar acute respiratory syndromes. As such, of ACE2- mediated and FcR- mediated viral entry6.
key insights from studies of the immune response to There is no evidence that ADE facilitates the spread of
Review
SARS-CoV should be considered when developing vac- SARS-CoV in infected hosts. In fact, infection of macro-
Impact
cines for SARS- of immune
CoV-2. Crucially,enhancementalthough antibody on Covid-19 phages through polyclonal
ADE does hyperimmune
not result in productive viral
titres are generally used as correlates of protection, high replication and shedding7. Instead, internalization
globulin
antibody titres therapy and vaccine
and early seroconversion are development
reported to of virus–antibody immune complexes can promote
correlate with disease severity in patients with SARS1. inflammation and tissue injury by activating myeloid
Ruklanthi de Alwisa,b, Shiwei Chena, Esther S. Gana, Eng Eong Ooi a,b,c,d,
*
The quality and quantity of the antibody response cells via FcRs5. Virus introduced into the endosome
dictates
Program in functional outcomes. High-Medical
affinity antibodies through this pathway will likely engage the RNA-sensing
a
Emerging Infectious Diseases, Duke-NUS School, Singapore
b
Viral Research and Experimental Medicine Centre, SingHealth Duke-NUS Academic Medical Centre, Singapore
ccan elicit neutralization by recognizing specific viral
Saw Swee Hock School of Public Health, National University of Singapore, Singapore Toll- like receptors (TLRs) TLR3, TLR7 and TLR8
d
epitopes
Department of . Neutralizing
Microbiology
(FIG.1a) and Immunology,antibodies areofdefined
Yong Loo Lin School Medicine, National 1c). Uptake
University
(FIG. of SARS-
of Singapore, CoV through ADE in macro-
Singapore
in vitro by their ability to block viral entry, fusion or phages led to elevated production of TNF and IL-6
egress. In vivo, neutralizing antibodies can function (REF.5). In mice infected with SARS-CoV, ADE was asso-
Potential risk of plasma therapy
In antibody-dependent
enhancement of infection,
low quality, low quantity,
non-neutralizing antibodies
bind to virus particles
through the Fab domains.
Fc receptors (FcRs)
expressed on monocytes or
macrophages bind to Fc
domains of antibodies and
facilitate viral
entry and infection.
c an anti- inflammatory response. Ectopic expres
Non-neutralizing
antibody
of FcγRIIa and FcγRIIb, but not of FcγRI or FcγR
TLR3, TLR7,
induced ADE of SARS-CoV infection6. Allelic polym
TLR8 Pro-inflammatory phisms in FcγRIIa are associated with SARS patho
Endosome cytokines and individuals with an FcγRIIa isoform that bind
both IgG1 and IgG2 were found to develop more se
disease than individuals with FcγRIIa that only bin
Risk of cytokine storm ??
IgG2 (REF.12).
Vaccine approaches
Activating It is crucial to determine which vaccines and adjuv
FcγR Anti-inflammatory can elicit protective antibody responses to SARS-Co
cytokines
Previous studies have shown that the immunizatio
Fig. 1 | Potential outcomes of antibody response to mice with inactivated whole SARS-CoV13, the imm
• In antibody-mediated
coronavirus. a | In antibody-mediated viral immune
neutralization, enhancement,
zation of rhesus macaques low9 with
quality,
MVA-encoded S
tein and the immunization of mice with DNA vac
low quantity, non-neutralizing
neutralizing antibodies binding to the receptor-binding
domain (RBD) of the viral spike protein, as well as other
antibodies bind to virus
encoding full- length S protein14 could induce A
particles.
domains, prevent virusUpon
from dockingengagement
onto its entry by the Fc
or eosinophil- domains
mediated on to s
immunopathology
receptor, ACE2. b | In antibody-dependent enhancement
antibodies, activating FcRs with ITAMs
of infection, low quality, low quantity, non-neutralizing
initiate
extent, possibly signalling
owing to low quality to
and quanti
antibody production. Additionally, we need to cons
upregulate
antibodies pro-inflammatory
bind to virus particles through the Fab domains.cytokines and downregulate
whether a vaccine is safe and effective in aged h
Fc receptors (FcRs) expressed on monocytes or macrophages
anti-inflammatory cytokines.
bind to Fc domains of antibodies and facilitate viral For instance, double- inactivated SARS- CoV vac
entry and infection. c | In antibody-mediated immune failed to induce neutralizing antibody responses in
• Immune
enhancement, complexes
low quality , low quantity,and viral RNA
non-neutralizing micein 13 the endosomes
. Furthermore, although an can
alum- adjuva
signal
antibodies bindthrough Toll-like
to virus particles. receptor
Upon engagement by 3 double-
(TLR3), TLR7SARS-
inactivated and/or TLR8elicited hi
CoV vaccine
the Fc domains on antibodies, activating FcRs with ITAMs antibody titres in aged mice, it skewed the IgG
to activate host cells, resulting in immuno-pathology.
initiate signalling to upregulate pro-inflammatory cytokines class toward IgG1 instead of IgG2, which was ass
and downregulate anti-inflammatory cytokines. Immune ated with a T helper 2 (TH2)- type immune respo
complexes and viral RNA in the endosomes can signal 13
Two Ways Convalescent Plasma Could Help Fight COVID-19
Donasi
Pasien yang sembuh Prosesing
mendonorkan
Plasma § dikirim ke pabrik à dikumpulkan à dilakukan proses
plasma mereka yang derived untuk membuang atau menginaktivasi virus à
mengandung Jalur 2 dipurifikasi untuk membuat “hyperimmune globuline”
antibodi yang dapat
therapy yang mengandung jumlah antibodi yang jumlahnya
menitralisir virus. terstandar
Uji klinis
Jalur 1 § Uji klinis dimulai saat jumlah plasma yang diproduksi
telah mencukupi à dilakukan studi apakah terapi
Transfusi tersebut aman dan efektif untuk mengobati pasien
langsung COVID-19 yang berisiko mengalami komplikasi berat
Skrining Persetujuan (Approval)

§ bebas virus (CMV, HIV, hepatitis,dll) § Jika badan regulasi seperti Food Drug Administration (AS)
§ kompatibilitas dan European Medicines Agency (Eropa) menyatakan
§ memastikan kandungan antibodi bahwa terapi tersebut aman dan efektif à maka metode
cukup tinggi (jumlah bervariasi) terapi tersebut dapat disetujui
§ Aliansi bisa menjajagi penggunaannya ke seluruh dunia
Transfusi dengan persetujuan otoritas negara setempat
§ resipien yang memenuhi kriteria
§ perlu volume plasma lebih besar Ketersediaan
§ terapi bersifat individual (mungkin § Sekali diproduksi dan didistribusi, maka terapi tersebut
ada yang perlu pemberian ulang) akan siap digunakan à skenario terbaik adalah bahwa
plasma yang mengandung “hyperimmune globulin”
akan tersedia tahun ini
Research Terapi yang didasarkan
based treatment PPK setempat
Asal donor plasma
• PMI
• RS yang melakukan
riset (RSDS, RSSA,
RSUA)
Indonesia
TPK
Dari siapa ? …Untuk siapa ?
Profilaksis Terapi
Pasien COVID-19 Sembuh Terpapar COVID-19 Pasien COVID-19

Sebagai pendonor
Sebagai penerima (resipien)
virus neutralizing
terapi plasma konvalesen (TPK)
antibodies
TERAPI PLASMA KONVALESEN
Manfaat : Efek samping :
1. Kekebalan instan 1. Reaksi alergi
2. Relatif lebih mudah & cepat 2. TRALI
(seperti transfusi darah) 3. TACO
3. Biaya lebih terjangkau 4. Transmisi patogen
Bahan dasar :
• Plasma
• ditransfusikan langsung
• diolah menjadi “hyperimmune globulin”
sebelum ditransfusi
• Darah Utuh
Arturo Casadevall, Liise-anne Pirofski. J Clin Invest. 2020. https://doi.org/10.1172/JCI138003.
Dosis TPK
• There is not a standard transfusion dose of CP.

• In different studies for coronaviruses the administration of CP
ranges between 200 and 500 mL in single or double scheme
dosages.
• Currently, the recommendation is to administrate 3 mL/kg per
dose in two days.
Bloch EM, Shoham S, Casadevall A, Sachais BS, Shaz B, Winters JL, et al. Deployment of convalescent plasma for the prevention and
treatment of COVID-19. J Clin Invest 2020
Efek Samping Plasma Konvalesen

Donor Plasma Konvalesen
PERSYARATAN DONOR
• Pernah didiagnosis positif COVID-19 melalui hasil pemeriksaan
gold standard (RT-PCR atau gene expert).
• Resolusi gejala secara menyeluruh mini 14 hari sebelum donasi
plasma.
• Donor wanita harus negatif terhadap antibodi HLA (jika
pemeriksaan antibodi HLA tidak tersedia maka donor dpat dari
wanita yang belum pernah hamil atau donor pria).
• Hasil negatif COVID-19 dari dua apusan, yaitu nasofaring dan
orofaring.
• Menentukan titer antibodi netralisasi SARS-CoV-2, bila
pemeriksaan bisa dilakukan (titer optimal > 1:320).
URUTAN PRIORITAS DONOR
2
Siapa RESIPIEN yang COCOK
untuk TPK ?
Kriteria Inklusi
• Usia minimal 17 tahun
• Dinyatakan COVID-19 CONFIRMED
berdasarkan hasil swab naso/orofaring
terakhir
• Derajat berat/kritis dengan tanda-tanda
• RR > 30 x/menit
• SpO2 < 93% dengan udara bebas
• P/F Ratio < 300 mmHg
• Perburukan foto thoraks dalam 24-48 jam
Kriteria Eksklusi
• Memiliki riwayat alergi terhadap darah atau
plasma (berulang)
• Penderita COVID-19 derajat berat/kritis yang
menurut kriteria klinis memiliki estimasi
prognosis jelek yakni skor SOFA > 11 yang
memiliki risiko mortalitas sebesar 53%
• Prioritas 4
• Penderita atau keluarga tidak setuju
mengikuti uji klinik
Ethical dilemma
When you have
limited stock of
donor…
Plasenter
Follow up rutin sesuai standar pelayanan RS (selain follow up wajib H-0, H3, H6, H9,
H14, H21, H28)
Interim analysis TPK di RSDS
Terapi Plasma Konvalesen (TPK)
di RSDS
(Maret – 13 Juli 2020)
100
90
80
70
60
94
50
40
30
(80,4%)
20
10
23
0 (19,6%)
Dapat TPK Tanpa TPK
Pasien COVID 19 dengan TPK
(23)
10 (43,5%) 13 (56,5%)
Meninggal Hidup
Pasien COVID-19 tanpa TPK
(94)
38 (40%)
56 (60%)
Meninggal Hidup
Total pasien ICU
(117)
TPK Tanpa TPK

23 (19,6 %) 94 (80,4 %)
Meninggal Hidup Meninggal Hidup

13 (56,5 %) 10 (43,5 %) 56 (59,6 %) 38 (40,4 %)
Chi-square = 0.42, p = 0.52 (p < 0.05)

(Tidak ada perbedaan signifikan terhadap angka
mortalitas dan kesembuhan)
TPK
(23)
Ventilator Tanpa Ventilator

15 (69,6 %) 8 (30,4 %)

13 (86,7 %) 2 (13,3 %) 0 (0 %) 8 (100 %)
• TPK mungkin bermanfaat pada kasus yang

tidak/belum menggunakan ventilator invasif
• Pasien yang diberi TPK namun memburuk dan butuh
ventilasi mekanik mungkin tidak baik prognosisnya
Survivor TPK
(10)
Ventilator
2 (20%)
HFNC
3 (30%)
HFNC - NIV
2 (20%)
TOK NIV
1 (10%) 2 (20%)
VENTILATOR TERAPI OKSIGEN HFNC NIV KOMBINASI HFNC DAN NIV
KONSERVATIF
Hidup dengan TPK
Non TPK
(94)
Ventilator Tanpa Ventilator

70 (74,46 %) 24 (26,67 %)

54 (77,14 %) 16 (22,86 %) 1 (0,42 %) 23 (99,58%)
SOFA score pasien yang mendapat TPK
5,1
HIDUP
6,36
5,75
MENINGGAL
10,5
0 2 4 6 8 10 12
SOFA Score Awal SOFA Score tertinggi
Analisis berdasarkan SOFA score awal
dan tertinggi selama perawatan
p value
Meninggal [Mean(SD)] Hidup [Mean(SD)]
P< 0.05
SOFA score awal 5.75 (2.05) 5.1 (2.39) 0.48
SOFA score tertinggi 10.50 (2.78) 6.36 (2.77) 0.0018
• SOFA score awal tidak berbeda bermakna pada

kelompok TPK yang hidup dengan yang meninggal
• SOFA score tertinggi selama perawatan secara
bermakna lebih tinggi pada pasien yang meninggal
TPK
Plus tocilizumab Tanpa tocilizumab

5 (21,7 %) 18 (78,3 %)

4 (80 %) 1 (20 %) 8 (44,4 %) 10 (55,6 %)
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; (ISSN: 1538-3598)
Li L; Zhang W; Hu Y; Tong X; Zheng S; Yang J; Kong Y; Ren L; Wei Q; Mei H; Hu C; Tao C;

Yang R; Wang J; Yu Y; Guo Y; Wu X; Xu Z; Zeng L; Xiong N; Chen L; Wang J; Man N; Liu Y;
Xu H; Deng E; Zhang X; Li C; Wang C; Su S; Zhang L; Wang J; Wu Y; Liu Z
An open-label study (n = 103) of patients with

laboratory-confirmed COVID-19 in Wuhan, China,
given convalescent plasma did not result in a
statistically significant improvement in time to
clinical improvement within 28 days compared
with standard of care alone
Convalescent plasma treatment of severe COVID-19: A matched
control study
Sean T. H. Liu, Hung-Mo Lin, Ian Baine, Ania Wajnberg, Jeffrey
P. Gumprecht, Farah Rahman, Denise Rodriguez, Pranai Tandon, Adel Bassily-
Marcus, Jeffrey Bander, Charles Sanky, Amy Dupper, Allen Zheng, Deena R. Altman, Benjamin
K. Chen, Florian Krammer, Damodara Rao Mendu, Adolfo Firpo-Betancourt, Matthew
A. Levin, Emilia Bagiella, Arturo Casadevall, Carlos Cordon-Cardo, Jeffrey S. Jhang, Suzanne A. Arinsburg, David
L. Reich, Judith A. Aberg, View ORCID ProfileNicole M. Bouvier
doi: https://doi.org/10.1101/2020.05.20.20102236
A nonrandomized study transfused patients based on

supplemental oxygen needs with convalescent plasma from
donors with a SARS-CoV-2 anti-spike antibody titer of at least
1:320 dilution. Matched control patients were retrospectively
identified within the electronic health record database.
Supplemental oxygen requirements and survival were
compared between plasma recipients and controls.
Results showed convalescent plasma transfusion
improved survival in non-intubated patients (P =
0.015), but not in intubated patients (P = 0.752).
RESEARCH
Convalescent plasma in the management of moderate covid-19
BMJ: first published as 10.1136/bmj.m3939 on 22 October 2020. Downloaded from http://www.

in adults in India: open label phase II multicentre randomised
controlled trial (PLACID Trial)
Anup Agarwal,1 Aparna Mukherjee,1 Gunjan Kumar,1 Pranab Chatterjee,1 Tarun Bhatnagar,2
Pankaj Malhotra,3 on behalf of the PLACID Trial Collaborators
1
Clinical Trial and Health ABSTRACT RESULTS Accepted: 12 October 2020
Systems Research Unit, Indian OBJECTIVE Progression to severe disease or all cause mortality
OBJECTIVE
Council of Medical Research, V
Ramalingaswamy Bhawan, PO
Box 4911, Ansari Nagar, New
To investigate the effectiveness of using convalescent
plasma to treat moderate coronavirus disease 2019
at 28 days after enrolment occurred in 44 (19%)
participants in the intervention arm and 41 (18%)
• To investigate
Delhi, 110029, India
2 the effectiveness of using convalescent
ICMR School of Public Health,
DESIGN
(covid-19) in adults in India. in the control arm (risk difference 0.008 (95%
confidence interval −0.062 to 0.078); risk ratio 1.04,
Indian Council of Medical 95% confidence interval 0.71 to 1.54).
plasma to treat moderate coronavirus
Open label, parallel arm, phase II, multicentre,
Research -National Institute of
randomised controlled
Epidemiology, Chennai, Tamil, trial. CONCLUSIONdisease 2019
India Convalescent plasma was not associated with a
3
(covid-19) in andadults
SETTING
Department of Internal
39 public in across
private hospitals
Medicine, Post Graduate Institute
India India. reduction in progression to severe covid-19 or all
cause mortality. This trial has high generalisability
DESIGN
of Medical Education and PARTICIPANTS
Research, Chandigarh, India and approximates convalescent plasma use in real
464 adults (≥18 years) admitted to hospital (screened
life settings with limited laboratory capacity. A priori
Correspondence to: A Mukherjee, 22 April to 14 July 2020) with confirmed moderate
• Open label, parallel arm, phase II, multicentre,
Clinical Trial and Health Systems
Research Unit, Indian Council of
Medical Research,
covid-19 (partial pressure of oxygen in arterial blood/
fraction of inspired oxygen (PaO2/FiO2) ratio between
measurement of neutralising antibody titres in donors
and participants might further clarify the role of
convalescent plasma in the management of covid-19.
randomised controlled trial
V Ramalingaswamy Bhawan,
PO Box 4911, Ansari Nagar,
New Delhi, 110029, India
200 mm Hg and 300 mm Hg or a respiratory rate of
more than 24/min with oxygen saturation 93% or
less on room air): 235 were assigned to convalescent
TRIAL REGISTRATION
Clinical Trial Registry of India CTRI/2020/04/024775.
SETTING
aparna.sinha.deb@icmr.gov.in
(ORCID 0000-0001-7298-5097) plasma with best standard of care (intervention arm)
Additional material is published and 229 to best standard of care only (control arm). Introduction
• 39 public and private hospitals across India

online only. To view please visit
the journal online.
INTERVENTIONS With few treatment options available to manage
Cite this as: BMJ 2020;371:m3939
Participants in the intervention arm received two coronavirus disease 2019 (covid-19), the disease
http://dx.doi.org/10.1136/bmj.m3939 doses of 200 mL convalescent plasma, transfused 24 presents a unique set of challenges for healthcare
Accepted: 12 October 2020
hours apart. The presence and levels of neutralising providers globally. In addition to using non-drug
RESEARCH
BMJ: first published as 10.1136/bmj.m3939 on 22 October 2020. Downloaded from http://www.b

1
Clinical Trial and Health ABSTRACT RESULTS
464 adults (≥ 18 years) admitted to hospital

Council of Medical Research, V To investigate the effectiveness of using convalescent at 28 days after enrolment occurred in 44 (19%)
Box 4911, Ansari Nagar, New plasma to treat moderate coronavirus disease 2019 participants in the intervention arm and 41 (18%)
2 with confirmed moderate COVID-19
Indian Council of Medical
(covid-19) in adults in India.
DESIGN
in the control arm (risk difference 0.008 (95%
confidence interval −0.062 to 0.078); risk ratio 1.04,
95% confidence interval 0.71 to 1.54).
(P/F ratio between 200-300 mmHgCONCLUSION
Epidemiology, Chennai, Tamil,
India
randomised controlled trial. or RR > 24/min with
Convalescent plasma was not associated with a

3
SETTING
SaO
39 public 2 93%
and private
Medicine, Post Graduate Institute hospitalsor
acrossless
India. on room air)
reduction in progression to severe covid-19 or all
of Medical Education and PARTICIPANTS
Correspondence to: A Mukherjee, 22 April to 14 July 2020) with confirmed moderate
Clinical Trial and Health Systems measurement of neutralising antibody titres in donors
Research Unit, Indian Council of and participants might further clarify the role of
235 were assigned to CP
Medical Research,
V Ramalingaswamy Bhawan, 200 mm Hg and 300 mm Hg or a respiratory rate of 229 TRIAL
were assigned to best
convalescent plasma in the management of covid-19.
REGISTRATION
PO Box 4911, Ansari Nagar, more than 24/min with oxygen saturation 93% or
with best standard of care
aparna.sinha.deb@icmr.gov.in less on room air): 235 were assigned to convalescent standard ofofcare
Clinical Trial Registry only
India CTRI/2020/04/024775.
(ORCID 0000-0001-7298-5097) plasma with best standard of care (intervention arm)
(intervention arm)
Additional material is published
and 229 to best standard of care only (control arm). (control arm)
Introduction
the journal online.
http://dx.doi.org/10.1136/bmj.m3939
(screened
doses of 200 mL convalescent 22 April
plasma, to 14
transfused 24 July 2020)a unique set of challenges for healthcare
presents
antibodies were not measured a priori; stored interventions, health systems have devised strategies
RESEARCH

ABSTRACT RESULTS
RESULTS
1
Clinical Trial and Health
Progression to severe disease or all cause mortality
2
ICMR School of Public Health, confidence interval −0.062 to 0.078); risk ratio 1.04,
at 28 days after enrolment occurred in
DESIGN
randomised controlled trial.
CONCLUSION
India
3 • 44 (19%)
participants in the intervention arm
SETTING
39 public and private hospitals across India.
41 (18%) in the control arm

•
of Medical Education and
PARTICIPANTS
Research, Chandigarh, India
and approximates convalescent plasma use in real
• Risk difference
Clinical Trial and Health Systems 0.008 (95% confidence interval −0.062
22 April to 14 July 2020) with confirmed moderate
Correspondence to: A Mukherjee,
and participants might further clarify the role of
to 0.078)
Medical Research, fraction of inspired oxygen (PaO /FiO ) ratio between
2
200 mm Hg and 300 mm Hg or a respiratory rate of
2 convalescent plasma in the management of covid-19.
TRIAL REGISTRATION
• Risk ratio
less on
aparna.sinha.deb@icmr.gov.in 1.04, 95%
room air): 235 confidence
were assigned to convalescent interval
plasma with best standard of care (intervention arm)
(ORCID 0000-0001-7298-5097)
0.71 to 1.54).
Clinical Trial Registry of India CTRI/2020/04/024775.
the journal online.
RESEARCH

ABSTRACT RESULTS
CONCLUSION
1
• Although the use of convalescent plasma seemed
2
ICMR School of Public Health, confidence interval −0.062 to 0.078); risk ratio 1.04,
to improve resolution of shortness of breath and
DESIGN
CONCLUSION
India
3 fatigue in patients with moderate covid-19 and
SETTING
39 public and private hospitals across India.
led to higher negative conversion of SARS-CoV-2

PARTICIPANTS
RNA on day 7 post-enrolment, but..
Clinical Trial and Health Systems measurement of neutralising antibody titres in donors
Research Unit, Indian Council of and participants might further clarify the role of
• this did not translate into a reduction in 28 day
Medical Research, convalescent plasma in the management of covid-19.
V Ramalingaswamy Bhawan, 200 mm Hg and 300 mm Hg or a respiratory rate of
PO Box 4911, Ansari Nagar, more than 24/min with oxygen saturation 93% or TRIAL REGISTRATION
New Delhi, 110029, India Clinical Trial Registry of India CTRI/2020/04/024775.
mortality or progression to severe disease.
(ORCID 0000-0001-7298-5097)
less on room air): 235 were assigned to convalescent
and 229 to best standard of care only (control arm).
Additional material is published Introduction
the journal online.
RESEARCH

ABSTRACT RESULTS
CONCLUSION
1
• Areas of future research could include effectiveness of
convalescent
DESIGN plasma among neutralising antibody negative confidence interval −0.062 to 0.078); risk ratio 1.04,
2
Indian Council of Medical 95% confidence interval 0.71 to 1.54).
India patients and the use of

SETTING
convalescent plasma
CONCLUSION
Convalescent
with high
plasma was not associated with a
neutralising antibody titres.

3
Department of Internal reduction in progression to severe covid-19 or all
39 public and private hospitals
Medicine, Post Graduate Institute across India.
PARTICIPANTS
• The challenge
Research, Chandigarh, India
will
464 adults (≥18 be
years) to
admitted find
to hospitalboth
(screened suitable patients and
and approximates convalescent plasma use in real
suitable plasma
Clinical Trial and Health Systems
donors. Additionally,
Medical Research,fraction of inspired oxygen (PaO /FiO ) ratio between
and this challenge
participants could
might further clarify the role of
2 convalescent plasma in the management of covid-19.
2
limit the 200

use of convalescent plasmaTRIAL
mm Hg and 300 mm Hg or a respiratory rate of
toREGISTRATION
a small subset of
New Delhi, 110029, India Clinical Trial Registry of India CTRI/2020/04/024775.
patients.less on room air): 235 were assigned to convalescent
(ORCID 0000-0001-7298-5097)
the journal online.
Summary recommendation
There are insufficient data for the COVID-19
Treatment Guidelines Panel (the Panel) to
recommend either for or against the use of
the following blood-derived products for the
treatment of COVID-19 :
• COVID-19 convalescent plasma
• Severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2) immunoglobulins
Prinsip Tatalaksana COVID-19
Antivirus Anti inflamasi Tindakan suportif
• Lopinavir/ritonavir + • Steroids • Terapi oksigen dan

interferon • Anti-IL-6 : ventilasi mekanik
• Favipiravir (Avigan) • Nutrisi
Tocilizumab
• Remdesivir • Organ support (CRRT,
• Kombinasi CQ atau Anti oksidan ECMO, ECCO2R)
HCQ plus Azithromycin • Precise fluid management
• High dose Vit C
• IVIg dosis tinggi • Antikoagulan
• High dose NAC
• TPK • Pencegahan HAIs
• Omega 3 plus
Glutation 85
Apa penyebab kematian pada
pasien COVID 19 ?
HIPOKSIA BERAT
Gagal Gagal Organ Gagal
nafas Lain Sirkulasi
Hepatic
failure Septik Hipovolemik Kardiogenik
AKI
plus
• Komorbid
• Usia
Terapi TPK yang rasional
• Berikan pada waktu yang tepat (timing dependent)
• Sebelum Ab tubuh terbentuk (jumlahnya adekwat)
mungkin adalah waktu yang paling tepat
• Selalu pertimbangkan untung – rugi
• Pasien dengan gejala ringan mungkin mendapat
“mudhorot” lebih banyak
• Pasien dengan skor SOFA tinggi atau end-state disease
bukan kandidat TPK
• Optimalisasi organ support
• Cegah infeksi sekunder
Plus TPK pH : 7.03
pO2 : 48 (FiO2 100%)
pCO2 : 99
HCO3 : 26.2
SO2 : 62%
BE : -4.5
Laktat : 2.3
Pasien meninggal walau diberi TPK

• HCQ plus..
• Terapi suportif
• TPK
Tanpa :
• anti IL-6
• IVIg
• high dose NAC
• high dose Vit C
Take home message
• TPK merupakan salah satu modalitas terapi
yang menjanjikan untuk COVID 19
• TPK bukan “obat dewa”
• Masih tahap uji klinis
• “Timing” pemberian TPK sangat mungkin
mempengaruhi outcome
• TPK tanpa terapi suportif optimal akan sia-sia
• Seleksi pasien yang tepat (donor terbatas)
• Perlu analisis lebih dalam tentang manfaat,
efektifitas dan keamanan TPK
Convalescent Plasma for COVID-19. A randomized clinical trial
medRxiv preprint doi: https://doi.org/10.1101/2020.07.01.20139857; this version posted July 3, 2020. 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.
It is made available under a CC-BY-NC-ND 4.0 International license .
Authors:
Methods
Arvind Gharbharan (*)1
TheC.E.Convalescent-plasma-for-COVID
• Convalescent
Carlijn Plasma
Jordans (*)1for COVID-19. A randomized(ConCOVID)
clinical trial study was a
randomized
Corinne Geurtsvankesseltrial comparing
1 convalescent plasma with
standard
JanAuthors:
G. of care2 therapy in patients hospitalized for COVID-19
den Hollander
(*)1
Arvind Gharbharan
Faiz in the Netherlands.
Karim 3
Carlijn C.E. Jordans(*)1
Femke Patients
• Corinne were randomized
P.Geurtsvankessel
N. Mollema 14 1:1 and received 300 ml of plasma
2 5
Janneke
Janwith
G. denE.anti-SARS-
Stalenhoef
Hollander – Schukken
CoV-2 neutralizing antibody titers of at least
Faiz Karim3 6
Anthonius
1:80P. N.Dofferhoff
Femke Mollema4
7
Inge Ludwig
• Primary endpoint
Janneke E. Stalenhoef :
– Schukken day-60
5
mortality
6
Anthonius Dofferhoff 8
Adrianus Koster endpoints were hospital stay and WHO 8-point
Secondary
• Inge Ludwig7
9
Robert-Jan
Adrianus Hassing
disease severity
Koster 8
scale improvement on day 15.
10
Jeannet
Robert-JanC. Hassing
Bos 9
Jeannet C. Bos10 11
Geert R. van Pottelberge
Geert R. van Pottelberge 11
Imro
ImroN. Vlasveld12 12
N. Vlasveld
Authors:
Results
TheC.E.trial
• Convalescent
Carlijn was
Plasma
Jordans halted prematurely
(*)1for COVID-19. after 86
A randomized patients
clinical trial were
enrolled
Corinne Geurtsvankessel1
53den
• Authors:
Jan G. of 66 patients
Hollander 2 tested had anti-SARS-CoV-2 antibodies at
(*)1
Arvind Gharbharan
Faiz baseline,
Karim 3 although
symptomatic for only 10 days (IQR 6-15) at
Femke theP.time
Corinne of inclusion
N. Mollema
Geurtsvankessel 14
• JanAG.SARS-CoV-2 plaque reduction

5
neutralization test showed
2
Janneke denE.3Hollander
Stalenhoef – Schukken
Faiz Karim 6
Anthonius
Femke P. N.Dofferhoff
neutralizing Mollemaantibodies
4 in 44 of the 56 (79%) patients tested
7
Inge Ludwig
with
Janneke E.median
Stalenhoef titers comparable
– Schukken 5
to the 115 donors (1:160 vs
6
Adrianus
1:160,
Inge Ludwig
Koster
7p=0.40).
9
Robert-Jan
• No difference
Adrianus Hassing
Koster 8
in mortality (p=0.95), hospital stay (p=0.68) or
10
Jeannet C. Hassing
Robert-Jan Bos 9
Jeannet C. Bosdisease
day-15 10 severity (p=0.58) was observed between
11
Geert
Geert R.
plasma van Pottelberge
treated
R. van Pottelberge patients and patients on standard of care.
11
12 12
Imro
ImroN.N. Vlasveld
Vlasveld
Authors:
Conclusion
Convalescent
Carlijn C.E. JordansPlasma (*)1for COVID-19. A randomized clinical trial
• Most COVID-19 patients 1 already have high neutralizing
Corinne Geurtsvankessel
antibody titers at hospital admission
G. den Hollander2
JanAuthors:
Screening for antibodies and prioritizing convalescent
(*)1
Arvind Gharbharan
•
Faiz Karim 3
Femke plasma
Corinne to risk1 4 groups with recent symptom onset will
P.Geurtsvankessel
N. Mollema
2 5
Janneke
Jan G. den
be E.
key Stalenhoef
Hollander
to identify – Schukken
patients that may benefit from
Faiz Karim3 6
Anthonius
Femke P. N. Dofferhoff
convalescent
Mollema 4
plasma
7
Inge Ludwig
Janneke E. Stalenhoef – Schukken5
6
Adrianus Koster
Inge Ludwig7
9
Robert-Jan
Adrianus KosterHassing
8
10 9
Jeannet C. Hassing
Robert-Jan Bos
Jeannet C. Bos10 11
Geert R. van Pottelberge
Geert R. van Pottelberge 11
Imro
ImroN. Vlasveld12 12
N. Vlasveld
Terima kasih
Perawat ICU RSDS,

survivor COVID 19 yang
telah 3 kali mendonorkan
plasmanya

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hemorrhagic fever, influenza,

Use of plasma convalescent in other coronaviruses,

In relation, to the use of mechanical ventilation, in

CRP Lym SaO2

ALT AST TBIL patient 7

4 of 7 | www.pnas.org/cgi/doi/10.1073/pnas.2004168117 Duan et al.

Hasil pasca TPK

CRP Lym SaO2

ALT AST TBIL

Duan et al. PNAS Latest Articles | 5 of 7

From: (b) (6) , OBRR/DBCD/CRS

To: (b) (6) , OBRR

Through: (b) (6) , OBRR/DBCD

Re: EUA 26382: Emergency Use Authorization (EUA) Request (original

Product: COVID-19 Convalescent Plasma

Items reviewed: EUA request

Sponsor: Robert Kadlec, M.D.

Recommendation: CCP meets the eligibility

IMMUNOPATHOLOGY AND INFECTIOUS DISEASES

Treatment of Coronavirus Disease 2019

Accepted for publication

CoV-2 Spike Glycoprotein

Andrew T. McGuire, David Veesler

RESULTS SARS-CoV-2 infection depends 2003;on the

M. Rojas, et al, 2020, Autoimmunity Reviews 19

1. Menghambat ikatan virus

The protruding portion of Terjadi kompetisi antara

Anudeep TC et al., 2020 (J Clin Trials, Vol.10 Iss.3 No:1000409)

Mechanism 1 : neutralizing antibodies

viral spike protein and preventing it from ACE2

interacting with the cellular receptor

Mechanism 2 : neutralizing antibodies

block the conformational changes that the

neutralization and antibody

The potential danger of suboptimal

Skrining Persetujuan (Approval)

Pasien COVID-19 Sembuh Terpapar COVID-19 Pasien COVID-19

Manuel Rojas, et al., Autoimmunity Reviews, https://doi.org/10.1016/j.autrev.2020.102554

• There is not a standard transfusion dose of CP.

Manuel Rojas, et al., Autoimmunity Reviews, https://doi.org/10.1016/j.autrev.2020.102554

TPK Tanpa TPK

Meninggal Hidup Meninggal Hidup

Chi-square = 0.42, p = 0.52 (p < 0.05)

Ventilator Tanpa Ventilator

Meninggal Hidup Meninggal Hidup

• TPK mungkin bermanfaat pada kasus yang

Ventilator Tanpa Ventilator

Meninggal Hidup Meninggal Hidup

SOFA score tertinggi 10.50 (2.78) 6.36 (2.77) 0.0018

• SOFA score awal tidak berbeda bermakna pada

Plus tocilizumab Tanpa tocilizumab

Meninggal Hidup Meninggal Hidup

Li L; Zhang W; Hu Y; Tong X; Zheng S; Yang J; Kong Y; Ren L; Wei Q; Mei H; Hu C; Tao C;

An open-label study (n = 103) of patients with

A nonrandomized study transfused patients based on

Convalescent plasma in the management of moderate covid-19

BMJ: first published as 10.1136/bmj.m3939 on 22 October 2020. Downloaded from http://www.

• 39 public and private hospitals across India

Convalescent plasma in the management of moderate covid-19

BMJ: first published as 10.1136/bmj.m3939 on 22 October 2020. Downloaded from http://www.b