An Acad Bras Cienc (2022) 94(4): e20210202 DOI 10.1590/0001-3765202220210202
Anais da Academia Brasileira de Ciências | Annals of the Brazilian Academy of Sciences
Printed ISSN 0001-3765 I Online ISSN 1678-2690
www.scielo.br/aabc | www.fb.com/aabcjournal
HEALTH SCIENCES
Comparison of safety and efficacy of
convalescent plasma with fresh frozen
plasma in severe covid-19 patients
MEENU BAJPAI, ASHISH MAHESHWARI, SURESH KUMAR, KARAN CHHABRA,
PRATIBHA KALE, ASHAD NARAYANAN, AMITA GUPTA, EKTA GUPTA, NIRUPAMA
TREHANPATI, RESHU AGARWAL, KAMINI GUPTA, ANKIT BHARDWAJ, MOJAHIDUL
ISLAM, RAVINDER SINGH, PUSHPA YADAV, GURESH KUMAR & SHIV K. SARIN
Abstract: background: Role of Convalescent plasma (COPLA) to treat severe COVID-19 is
under investigation. We compared efficacy and safety of COPLA with fresh frozen plasma
(FFP) in severe COVID-19 patients. Methods: One group received COPLA with standard
medical care (n = 14), and another group received random donor FFP, as control with
standard medical care (n = 15) in severe COVID-19 disease. Results: The proportion of
patients free of ventilation at day seven were 78.5% in COPLA group, and 93.3 % in control
group were not significant (p= 0.258). However, improved respiratory rate, O2 saturation,
SOFA score, and Ct value were observed in the COPLA group. No serious adverse events
were noticed by plasma transfusion in both groups.
Key words: COVID-19, convalescent plasma, donor plasmapheresis, ARDS, immunoglobulins, antibodies.
INTRODUCTION
The SARS-CoV-2 pandemic outbreak involves
more than 100 million people worldwide, with
almost 1.5 million deaths and counting (Huang
et al. 2020). The case-fatality rate of COVID-19
(Corona Virus disease-2019) has ranged from
1.2-13% (Huang et al. 2020, Chen et al. 2020).
The current evidence-based strategy relies on
providing supportive care in mild to moderate
cases and providing mechanical ventilation and
extracorporeal membrane oxygenation in severe
cases. There is no targeted drug therapy available
at present. Some studies have indicated benefits
with intravenous Remdesivir and a combination
of lopinavir and ritonavir for reducing severity
and duration of illness, but not mortality (Cao
et al. 2020, Grein et al. 2020, Shen et al. 2020). In
the “RECOVERY trial” dexamethasone has shown
reduced 28-day mortality among COVID-19
patients with respiratory failure requiring
oxygen supplementation and mechanical
ventilation (RECOVERY Collaborative Group et al.
2020). The plasma of convalescent patients who
have recovered from SARS-CoV-2 infection may
contain such neutralizing antibodies, which may
accelerate virus clearance in the other COVID-19
infected patients (Chen et al. 2020). Providing
passive antibody therapy through convalescent
plasma in COVID-19 infection could be one of
the approaches toward disease mitigation in
the absence of definitive treatment (Zhang et
al. 2020, Duan et al. 2020). We compared safety
and efficacy of convalescent plasma with fresh
frozen plasma (FFP) in severe COVID-19 patients.
An Acad Bras Cienc (2022) 94(4)
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TREATMENT OF COVID-19 BY CONVALESCENT PLASMA
MATERIALS AND METHODS
It was an open-labelled, phase II; pilot
randomized controlled trial conducted to assess
efficacy and safety of convalescent plasma at
the Institute of Liver and Biliary Sciences and in
collaboration with the Department of Internal
Medicine, Lok Nayak Hospital (Maulana Azad
Medical College), New Delhi. This trial was
approved by institute ethics committee and
was registered with ClinicalTrial.gov (identifier:
NCT04346446). Total 29 patients were included in
study instead of 20 patients in each group due
to premature closure of trial in severe COVID-19
patients as per the ministry of health and family
welfare guidelines to transfuse convalescent
plasma in moderate patients only. We took
Informed consent from all the patients before
enrolment in the trial. Detailed inclusion and
exclusion criteria of the trial are provided with
Supplement Material – Table SI as trial protocol.
Patients were enrolled for convalescent plasma
transfusion and the standard treatment
protocol in one group and fresh frozen plasma
[FFP] and the standard treatment protocol in
another group using block randomization. FFP
transfused in the study was collected before the
emergence of the virus in our country to avoid
any chance of providing COVID-19 convalescent
plasma in the control group. The primary
outcome measure was the proportion of patients
remaining free of mechanical ventilation in both
groups on day seven. The secondary outcome
measures included mortality at day seven and
day 28, improvement in PaO2/FiO2, and the
SOFA scores reduction at 48 hours and day 7,
duration of hospital stay, duration of Intensive
Care Unit stay, requirements of vasopressors,
and days free of dialysis up to 28 days from
randomization. COPLA was collected from
COVID-19 recovered patients after 14 days of
complete resolution of symptoms following the
national guidelines for plasma donation (Drugs
and Cosmetics Act, 1940). The determination
of serum neutralization antibodies in donors
was done by SARS-CoV-2 Surrogate Virus
Neutralization Test Kit (Genscript, USA) and the
minimum neutralization titre was 1:80 on ELISA
method (Department of Health). The test was
used to detect circulating neutralizing antibodies
against SARS-CoV-2 which blocks the interaction
between the receptor-binding domains of the
viral spike glycoprotein (RBD) with the ACE2
cell surface receptor. The S1 RBD IgG antibody
titres were determined in recipient samples at
baselines and a day after transfusion in both
treatment groups.
Clinical and laboratory monitoring was
done as per trial protocol and ABO blood group
compatible 250 ml plasma in two doses on
consecutive days. Continuous variables were
expressed as Mean (± SD) or median (range) and
compared by Student’s t-test or Mann- Whitney
U test as appropriate. Categorical data were
analyzed by Chi-Square test. To compare pre
and post results, a paired t-test test was used.
Cox-proportional hazard regression analysis
was applied to find the predictor in survival
analysis. The actuarial probability of survival
was calculated by the Kaplan-Meier graph and
compared by the log-rank test. The p-value <
0.05 was considered statistically significant. All
statistical tests were performed using SPSS for
Windows version 22 (SPSS IBM Corp. Ltd. Armonk,
NY)
RESULTS
Total 29 patients were randomized, as shown
in figure 1, were comparable in their baseline
parameters. The baseline demographic details
are provided in table I). The primary outcome
shows no statistically significant difference in
the proportion of patients free of ventilation on
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TREATMENT OF COVID-19 BY CONVALESCENT PLASMA
Figure 1. Patient selection and randomization.
day seven. The secondary outcome, including
median reductions in respiratory rate per min,
earlier improvement in O2 saturation, and
median reduction in SOFA score, favoured the
use of convalescent plasma. No statistical
improvement was noticed in ICU and Hospital
stay in any treatment group, as shown in table II.
On laboratory evaluation, the median increment
in the Cycle threshold values on day seven
showed a higher reduction in the viral load in
the COPLA group, although the difference was
insignificant (p=0.11), as shown in figure S1 of
the supplementary material. The SARS CoV-2
S1 RBD IgG antibody titres of the 14 recipients
ranged between 10 and 640 a day after the
convalescent plasma transfusion and 0 to 640
after FFP transfusion, as shown in table I of the
supplementary material. There was a significant
time-dependent increase in the IgG antibody
titres in 85.71% (12 out of 14) of the convalescent
plasma recipients as compared to 20% (3 out
of 15) FFP recipients (p= 0.001).On convalescent
plasma transfusion, median post-transfusion IL6, IL-10, and TNF-α levels were reduced while IL-1β
level was increased at day 7. In the FFP group, the
median post-transfusion levels of IL-1β and TNF-α
were reduced while IL-6 and IL-10 increased, as
shown in table II of the supplementary material.
All these differences did not attain statistical
significance post-transfusion. (Details of
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Table I. Baseline characteristics of patients in the study.
Baseline parameters
Overall
(n=29)
Convalescent
Plasma group
(n=14)
Fresh frozen
Plasma group
(n=15)
p-value
Mean Age (Years)
48.21 ± 9.79
48.14 ± 9.05
48.27 ± 10.75
0.96
Male (n, %)
22 (75.86)
11 (78.6)
11 (73.3)
1.0
Chest X-ray changes (n, %)
25 (86.20)
12 (85.7)
13 (86.67)
0.94
BMI
26.31 ± 2.29
26.28 ± 2.52
26.13 ± 2.22
0.78
Respiratory rate/min
34.9 ± 2.55
35.36 ± 2.65
34.47 ± 2.47
0.38
PaO2 (mmHg)
61.76 ± 4.96
62.71 ± 3.87
61.13 ± 5.74
0.58
O2 Saturation (%)
85.03 ± 4.03
85 ± 4.29
85.07 ± 3.92
0.53
FiO2 (mmHg)
0.38 ± 0.04
0.38 ± 0.03
0.38 ± 0.04
0.89
PaO2/FiO2 ratio
162.92 ± 13.77
164.92 ± 15.85
161.06 ± 11.77
0.43
Baseline Neutrophils (N) (per microliter)
3375 (2626, 6928)
3083 (2700, 7512)
3782 (2432,7520)
0.87
Baseline Lymphocytes (L) (per
microliter)
968 (758, 1874)
935 (747, 1872)
1240 (760, 1950)
0.90
N / L ratio
3.8(3.37, 4.67)
3.67 (3.26, 4.46)
4(3.5, 5)
0.60
Platelet count (in lakh per microliter)
1.8 ± 1.20
2.05 ± 1.42
1.58 ± 0.95
0.49
Baseline Ct value
31.91 ± 3.44
30.83 ± 4.07
32.93 ± 2.46
0.12
SOFA Score
7.44 ± 1.86
7.71 ± 1.59
7.20 ± 2.11
0.32
laboratory findings, including cytokines, Ct value,
and donor information of convalescent plasma,
are provided in table SII). Both the treatment
groups were compared for survival analysis
using Cox-proportional hazard regression. In
the COPLA group, three events of mortality were
observed, while in the FFP group, one event was
observed, the difference was statistically not
significant (HR, 4.23 [95% CI, 0.43-41.6]; P = 0.22).
One patient in each of the groups showed signs
of mild urticaria during plasma transfusion.
DISCUSSION
Like our pilot trial, many other clinical trials
show varying effects of COPLA transfusion
in COVID-19, but the safety of convalescent
plasma transfusion was on each trial card,
including the findings reported by Joyner et al.
on 20000 patients with only few transfusion
reactions (Joyner et al. 2020). In this novel
study, the purpose of using FFP in the control
group was to supplement and balance the
beneficial and adverse effects of plasma on
coagulation abnormalities developing in severe
COVID-19 patients to study the added benefits
of transfusing SARS-CoV-2 antibodies present
in COPLA in compare to FFP. Although no
significant results were observed in the
primary outcome of weaning of ventilation and
mortality, early and significant improvement in
O2 saturation, a reduction in respiratory rate,
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Table II. Changes in clinical outcome parameters.
Variable
Convalescent
plasma (n=14)
Normal plasma
(n=15)
p-value
Median Reduction in Respiratory Rate/min at 48 hours
-6.5 (-10.25, -5)
-3 (-5,-1)
0.004
Median Reduction in Respiratory Rate/min at 7 days
-14.5 (-18.75, -13)
-10 (-14,-9)
0.008
Median Improvement in O2 Saturation at 48 hour
6.5 (5, 7.25)
2 (1, 2)
<0.001
Median Improvement in O2 Saturation at 7 days
10 (8.2, 11)
7.5(4.75, 9.25)
0.026
Mechanical Ventilation within 7 days (n) %
3 (21.4)
1 (6.7)
0.258
Median reduction in SOFA Score 48 hours
-2 (-2.25,-1)
-1 (-1, 0.0)
0.01
Median Reduction in SOFA Score 7 days
-5 (-6.5,-4.0)
-3 (-5.25,-2.75)
0.04
Median improvement in PaO2/FiO2 at 48 hour
41.94 (1.25, 55.58)
5.55 (-9.318, 11.11)
0.009
Median improvement in PaO2/FiO2 at 7 days
231.15(183.37, 245.20)
77.01 (56.93, 96.20)
<0.001
Median ICU stay
5 (4,7)
5 (4, 5.7)
0.72
Mean duration of Hospital stay (days)
12.07 ± 4.1
16.07 ± 5.6
0.08
Increase in S1 RBD IgG antibody titre post transfusion
12 (85.7%)
4(26.7%)
0.001
Median Improvement in Lymphocyte count at 7 days
896.5 (524.5, 1351.5)
105(-8, 523)
0.15
Transfusion reactions (n)
1 (7.1%)
1 (6.7%)
1
Median Improvement in Ct value at 7 days
7.7 (3.4, 9.2)
5.15 (3.3, 6.27)
0.11
Mortality till 7 days (n) %
2 (14.28%)
1 (6.7%)
0.60
Mortality till 28 days (n) %
3 (21.4%)
1 (6.7%)
0.25
and SOFA scoring were observed. We found a
significant time-dependent increase in the S1
RBD IgG antibody titres and an early increase
in the Ct values in patients who received COPLA
compared to FFP, similar to Shen et al. specific
effectiveness in terms of neutralizing antibodies
in the COPLA (Shen et al. 2020). We could also
find an increase in S1 RBD IgG antibody titres in
FFP group patients, which reflects the natural
immune response toward infection. In this pilot
trial, early increment in Ct values demonstrated
a speedy reduction in the viral load, a laboratory
marker for assessing the effectiveness of
therapy similar to previous studies done on it
(Ng et al. 2018, Wu & McGoogan 2019). Although,
few observational studies favored outcome with
COPLA transfusion (Shen et al. 2020, Zhang et al.
2020, Duan et al. 2020).
Further, Libster et al. found that early
transfusion of high-titer convalescent plasma
in COVID-19 infection can reduce the disease’s
progression (Libster et al. 2021). We did not
find statistically significant improvement in
severe and critically ill COVID-19 patients in
terms of need of ventilation and mortality after
28 days of monitoring, similar to the findings
observed by Li et al., PLACID trial, and PlasmAr
Study Group (Li et al. 2020, Agarwal et al. 2020,
and Simonovich et al. 2020). Libster et al. found
that early transfusion of high-titer convalescent
plasma in COVID-19 infection can reduce the
disease’s progression (Libster et al. 2021). The
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appearance of the anti-inflammatory marker IL10 and reduction in levels of pro-inflammatory
markers (IL-1, IL-6, and TNF- TNF-α) has been well
correlated with the disappearance of clinical
symptoms. Further, the decrease in the level
of pro-inflammatory markers (IL-6 and TNF-α)
and increase in anti-inflammatory marker IL10 after COPLA transfusion shows it may limit
immune-mediated damage in the COPLA group,
while in FFP group, we found only a decrease in
TNF-α level with the beneficial effect of FFP on
endothelium lining and coagulation system (de
Brito et al. 2016, Velazquez-Salinas et al. 2019,
Straat et al. 2015).
COPLA therapy is safe and may be beneficial
for COVID-19 patients (in terms of clinical
and laboratory parameters). More extensive
clinical trials are needed to be conducted
with Convalescent plasma in different drugs
combination and at different timing (early and
delayed) in patients to explore the role and
efficacy of COPLA transfusion.
CHEN L, XIONG J, BAO L & SHI Y. 2020. Convalescent plasma
as a potential therapy for COVID-19. Lancet Infect Dis
20(4): 398-400.
CHEN N ET AL . 2020. Epidemiological and clinical
characteristics of 99 cases of 2019 novel coronavirus
pneumonia in Wuhan, China: a descriptive study. Lancet
395(10223): 507-513.
DE BRITO RC, LUCENA-SILVA N, TORRES LC, LUNA CF, CORREIA JB &
DA SILVA GA. 2016. The balance between the serum levels
of IL-6 and IL-10 cytokines discriminates mild and severe
acute pneumonia. BMC Pulm Med 16(1): 170.
DRUGS AND COSMETICS ACT AND RULES. 1940. Section XB
and XIIB, Ministry of Health and Family Welfare Govt.
of India. 1940. https://cdsco.gov.in/opencms/opencms/
en/Acts-Rules/.
DUAN ET AL. 2020. Effectiveness of convalescent plasma
therapy in severe COVID-19 patients. ProcNatlAcadSci
USA 117(17): 9490-9496.
GREIN ET AL. 2020. Compassionate Use of Remdesivir
for Patients with Severe Covid-19. N Engl J Med 382(24):
2327-2336.
HUANG ET AL. 2020. Clinical features of patients infected
with 2019 novel coronavirus in Wuhan, China. Lancet
395(10223): 497-506.
JOYNER ET AL. 2020. Safety update: COVID-19 convalescent
plasma in 20,000 hospitalized patients. Mayo ClinProc
95: 1888-1897.
CONCLUSION
COPLA therapy is safe and may be beneficial
for COVID-19 patients (in terms of clinical and
laboratory parameters), and more extensive
clinical trials are needed to draw more robust
conclusions.
LIBSTER ET AL. 2021. Early high-titer plasma therapy to
prevent severe Covid-19 in older adults. N Engl J Med
384: 610-618.
LI ET AL. 2020. Effect of Convalescent Plasma Therapy on
Time to Clinical Improvement in Patients With Severe
and Life-threatening COVID-19: A Randomised Clinical
Trial. JAMA 324(5): 460-470.
NG ET AL. 2018. Viral Load and Sequence Analysis Reveal
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NIRUPAMA TREHANPATI6
RESHU AGARWAL5
https://orcid.org/0000-0002-9207-3607
KAMINI GUPTA5
https://orcid.org/0000-0003-2091-1007
ANKIT BHARDWAJ7
https://orcid.org/0000-0002-5380-2782
MOJAHIDUL ISLAM6
https://orcid.org/0000-0001-7219-9686
RAVINDER SINGH6
https://orcid.org/0000-0003-0603-8328
SUPPLEMENTARY MATERIAL
Figure S1. Reduction in viral load after transfusion (ct
value).
Table SI. Convalescent Plasma Donation Details (n=14).
Table SII. Median baseline and post transfusion
cytokine level.
PUSHPA YADAV6
https://orcid.org/0000-0001-5285-7936
GURESH KUMAR8
https://orcid.org/0000-0002-8864-3849
SHIV K. SARIN4
https://orcid.org/0000-0002-0544-5610
How to cite
1
BAJPAI M ET AL. 2022. Comparison of safety and efficacy of convalescent
plasma with fresh frozen plasma in severe covid-19 patients. An Acad
Bras Cienc 94: e20210202. DOI 10.1590/0001-3765202220210202.
Manuscript received on February 15, 2021;
accepted for publication on April 07, 2021
MEENU BAJPAI
1
https://orcid.org/0000-0002-4872-7845
Institute of Liver and Biliary Sciences, Department
of Transfusion Medicine, D1 ilbs, D-1, Vasant Kunj
Rd, Ghitorni, 110070 New Delhi, Delhi, India
2
Lok Nayak Jai Prakash Hospital, Department of Medicine,
J6QP+PRR, Jawaharlal Nehru Marg, Maulana Azad Medical
College Campus, Delhi Gate, 110002 New Delhi, Delhi, India
3
Institute of Liver and Biliary Sciences, Department
of Microbiology, D1 ilbs, D-1, Vasant Kunj Rd,
Ghitorni, 110070 New Delhi, Delhi, India
4
ASHISH MAHESHWARI
1
https://orcid.org/0000-0002-0716-939X
SURESH KUMAR2
https://orcid.org/0000-0001-8766-6937
KARAN CHHABRA2
https://orcid.org/0000-0001-5710-7026
PRATIBHA KALE3
https://orcid.org/0000-0002-5172-0193
ASHAD NARAYANAN4
https://orcid.org/0000-0003-2531-1094
AMITA GUPTA
1
https://orcid.org/0000-0003-1369-9853
Institute of Liver and Biliary Sciences, Department
of Hepatology, D1 ilbs, D-1, Vasant Kunj Rd,
Ghitorni, 110070 New Delhi, Delhi, India
5
Institute of Liver and Biliary Sciences,Department
of HepatoVirology, D1 ilbs, D-1, Vasant Kunj Rd,
Ghitorni, 110070 New Delhi, Delhi, India
6
Institute of Liver and Biliary Sciences, Department of
Molecular and Cellular Medicine, D1 ilbs, D-1, Vasant
Kunj Rd, Ghitorni, 110070 New Delhi, Delhi, India
7
Institute of Liver and Biliary Sciences, Department
of Clinical Research, D1 ilbs, D-1, Vasant Kunj Rd,
Ghitorni, 110070 New Delhi, Delhi, India
8
Institute of Liver and Biliary Sciences, Department
of Research, D1 ilbs, D-1, Vasant Kunj Rd,
Ghitorni, 110070 New Delhi, Delhi, India
An Acad Bras Cienc (2022) 94(4)
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MEENU BAJPAI et al.
TREATMENT OF COVID-19 BY CONVALESCENT PLASMA
Correspondence to: Shiv Kumar Sarin
E-mail: shivsarin@gmail.com
Author contributions
1.Study concept and design: Shiv K Sarin, Meenu Bajpai, Ashish
Maheshwari, Suresh Kumar and Ekta Gupta.
2.Acquisition of data: Karan Chhabra, Ashad Narayan, Pratibha
Kale, Amita Gupta, Reshu Agarwal, Kamini Gupta, Mojahidul
Islam, Ravinder Singh and Pushpa Yadav.
3. Statistical analysis: Guresh Kumar, Ankit Bhardwaj.
4.Initial Drafting of the Manuscript: Suresh Kumar, Ashish
Maheshwari, Pratibha Kale, Ekta Gupta, Nirupama Trehanpati,
Karan Chhabra, Ankit Bhardwaj, Ashad Narayan, Amita Gupta,
Reshu Agarwal, Kamini Gupta, Mojahidul Islam, Ravinder Singh
and Pushpa Yadav.
5.Critical revision of manuscript done for important intellectual
content: Meenu Bajpai, Guresh Kumar and Shiv K Sarin,
6.Administrative and technical support: Shiv K Sarin.
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