Safety and Efficacy of Convalescent Plasma in COVID-19: An Overview of Systematic Reviews

Abstract

Convalescent plasma (CP) from patients recovered from COVID-19 is one of the most studied anti-viral therapies against SARS-COV-2 infection. The aim of this study is to summarize the evidence from the available systematic reviews on the efficacy and safety of CP in COVID-19 through an overview of the published systematic reviews (SRs). A systematic literature search was conducted up to August 2021 in Embase, PubMed, Web of Science, Cochrane and Medrxiv databases to identify systematic reviews focusing on CP use in COVID-19. Two review authors independently evaluated reviews for inclusion, extracted data and assessed quality of evidence using AMSTAR (A Measurement Tool to Assess Reviews) and GRADE tools. The following outcomes were analyzed: mortality, viral clearance, clinical improvement, length of hospital stay, adverse reactions. In addition, where possible, subgroup analyses were performed according to study design (e.g., RCTs vs. non-RCTs), CP neutralizing antibody titer and timing of administration, and disease severity. The methodological quality of included studies was assessed using the checklist for systematic reviews AMSTAR-2 and the GRADE assessment. Overall, 29 SRs met the inclusion criteria based on 53 unique primary studies (17 RCT and 36 non-RCT). Limitations to the method-ological quality of reviews most commonly related to absence of a protocol (11/29) and funding sources of primary studies (27/29). Of the 89 analyses on which GRADE judgements were made, effect estimates were judged to be of high/moderate certainty in four analyses, moderate in 38, low in 38, very low in nine. Despite the variability in the certainty of the evidence, mostly related to the risk of bias and inconsistency, the results of this umbrella review highlight a mortality reduction in CP over standard therapy when administered early and at high titer, without increased adverse reactions.

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Diagnostics 2021, 11, 1663. https://doi.org/10.3390/diagnostics11091663 www.mdpi.com/journal/diagnostics
Review
Safety and Efficacy of Convalescent Plasma in COVID-19:
An Overview of Systematic Reviews
Massimo Franchini
1,
*, Fabiana Corsini
2
, Daniele Focosi
3
and Mario Cruciani
1
1
Department of Hematology and Transfusion Medicine, Carlo Poma Hospital, 46100 Mantua, Italy;
crucianimario@virgilio.it
2
Santorso Hospital, AULSS7 Pedemontana, 36061 Vicenza, Italy; fabiana.corsini@aulss7.veneto.it
3
North-Western Tuscany Blood Bank, Pisa University Hospital, 56126 Pisa, Italy; daniele.focosi@gmail.com
* Correspondence: massimo.franchini@asst-mantova.it; Tel.: +39-0376-201234; Fax: +39-0376-220144
Abstract:
Convalescent plasma (CP) from patients recovered from COVID-19 is one of the most
studied anti-viral therapies against SARS-COV-2 infection. The aim of this study is to summarize
the evidence from the available systematic reviews on the efficacy and safety of CP in COVID-19
through an overview of the published systematic reviews (SRs). A systematic literature search was
conducted up to August 2021 in Embase, PubMed, Web of Science, Cochrane and Medrxiv data-
bases to identify systematic reviews focusing on CP use in COVID-19. Two review authors inde-
pendently evaluated reviews for inclusion, extracted data and assessed quality of evidence using
AMSTAR (A Measurement Tool to Assess Reviews) and GRADE tools. The following outcomes
were analyzed: mortality, viral clearance, clinical improvement, length of hospital stay, adverse
reactions. In addition, where possible, subgroup analyses were performed according to study de-
sign (e.g., RCTs vs. non-RCTs), CP neutralizing antibody titer and timing of administration, and
disease severity. The methodological quality of included studies was assessed using the checklist
for systematic reviews AMSTAR-2 and the GRADE assessment. Overall, 29 SRs met the inclusion
criteria based on 53 unique primary studies (17 RCT and 36 non-RCT). Limitations to the method-
ological quality of reviews most commonly related to absence of a protocol (11/29) and funding
sources of primary studies (27/29). Of the 89 analyses on which GRADE judgements were made,
effect estimates were judged to be of high/moderate certainty in four analyses, moderate in 38, low
in 38, very low in nine. Despite the variability in the certainty of the evidence, mostly related to the
risk of bias and inconsistency, the results of this umbrella review highlight a mortality reduction in
CP over standard therapy when administered early and at high titer, without increased adverse
reactions.
Keywords: COVID-19; convalescent plasma; overview; systematic review; therapy
1. Introduction
The Coronavirus Disease 2019 (COVID-19) pandemic, caused by the Severe Acute
Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is still a worldwide health crisis
with devastating social and economic consequences. Despite the virus known for more
than a year and a half, the management of COVID-19 remains challenging with still high
mortality rates among severely affected patients [1,2]. A number of guidelines from ex-
perts have been released during the pandemic period suggesting several treatments for
COVID-19 patients, including antiviral, hydroxychloroquine, steroid, anticoagulation
and other supportive therapies [3,4]. However, recent evidence from large-scale studies
failed to clarify the efficacy of most of the treatments proposed [5–7].
Convalescent plasma (CP), first introduced in 1890 by Emil von Behring to treat
diphtheria and pertussis and then utilized in several other serious infectious diseases,
including Ebola, severe acute respiratory syndrome (SARS), and Middle East respiratory
Citation: Franchini, M.; Corsini, F.;
Focosi, D.; Cruciani, M. Safety and
Efficacy of Convalescent Plasma in
COVID-19: An Overview of System-
atic Reviews. Diagnostics 2021, 11,
1663. https://doi.org/10.3390/
diagnostics11091663
Academic Editor: Javier Fernández
Received: 19 August 2021
Accepted: 9 September 2021
Published: 11 September 2021
Publisher’s Note: MDPI stays neu-
tral with regard to jurisdictional
claims in published maps and insti-
tutional affiliations.
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license
(http://creativecommons.org/licenses
/by/4.0/).

Diagnostics 2021, 11, 1663 2 of 25
syndrome (MERS), has been also proposed more recently as passive immunotherapy for
treatment of SARS-CoV-2 infection [1]. Convalescent plasma is nowadays among the
most studied and utilized antibody-based therapies against COVID-19 world-wide and a
number of published or ongoing clinical trials have been conducted to assess its efficacy
and safety in this challenging viral infection. Their conclusions are, however, quite con-
flicting and reflect the wide heterogeneity between different studies in terms of CP
product, patients enrolled, and disease characteristics. Because of the huge amount of
clinical data available, several systematic reviews (SRs) and meta-analysis have been
published in the last year to harmonize the results from primary clinical trials. To syn-
thesize the evidence from these SRs and meta-analyses, we have decided to apply to this
clinical setting a relatively new approach, i.e., to perform an overview of the existing SRs,
also called umbrella review.
2. Material and Methods
This umbrella review was registered at the International Prospective Register of
Systematic Reviews (PROSPERO) with the registration number CRD42021259625.
2.1. Review Question/Objective
The aim of this umbrella review is to evaluate the efficacy and safety of CP for the
treatment of COVID-19 patients.
2.2. Inclusion and Exclusion Criteria
We considered for inclusion SRs that included randomized controlled trials (RCTs)
and non-RCTs (i.e., prospective, retrospective, cross-sectional, cohort studies and case
series) evaluating the safety and efficacy of CP in COVID-19 patients. Reviews without
qualitative and/or quantitative analysis were excluded from this umbrella review. SRs
evaluating other viral infections were excluded unless they also contained data on
SARS-COV-2 infection that could be evaluated separately.
2.3. Clinical Setting and Participants
For this umbrella review, we considered SRs on COVID-19 at any stage of disease
severity, from asymptomatic/paucisymptomatic to life-threatening cases, and in any set-
ting (outpatients and hospitalized patients). In addition, we included populations of pa-
tients with no limitations of age, gender, ethnicity, or comorbidities.
2.4. Intervention and Outcomes
CP treatment at any titer, dose, timing and frequency was compared to standard of
care or placebo. We included the following outcomes: all-cause mortality, viral clearance,
clinical improvement, length of hospital stay, serious and non-serious adverse reactions.
Subgroup analyses were also performed based on the severity (i.e., non-severe versus
severe) of COVID-19 patients treated with CP and on the titer (i.e., high versus low titer)
and timing (i.e., <3 days versus >3 days of hospital admission) of CP transfusion.
2.5. Search Strategy
Relevant studies in four bibliographic databases (Embase, PubMed, Web of Science,
and Cochrane) and a preprint database MedRix were searched as of 15 August 2021. The
searches were carried-out without languages restriction using Medical Subjects Heading:
(“COVID-19” OR “SARS-CoV-2”) AND (“convalescent plasma” OR “serotherapy” OR
“hyperimmune plasma therapy” OR “convalescent plasma treatment”) AND (“system-
atic review” OR “meta-analysis”). In addition to the electronic search, we checked the
reference lists of the most relevant items (original studies and reviews) to identify po-
tentially eligible studies not captured by the initial literature search.

Diagnostics 2021, 11, 1663 3 of 25
2.6. Study Selection and Data Extraction
All titles were screened by two independent assessors (MC and MF). Eligibility as-
sessment was based on the title or abstract and on the full text if required. Full texts of
possibly eligible articles were obtained and assessed independently by two reviewers
(MC and MF). Both reviewers compared the articles identified. Studies were selected
independently by two reviewers (MF and MC) with disagreements resolved through
discussion and on the basis of the opinion of a third reviewer (FC). The two assessors also
independently extracted quantitative and qualitative data from each selected study.
Findings are presented in tabular format with supporting text (Table 1). Quantitative
tabulation of results include: first author name and year of publication, the clinical con-
dition under evaluation, principal characteristics of the study population, number of
RCTs and non-RCTs included in the SR, intervention (CP versus control characteristics),
the outcomes assessed, a quantitative synthesis (when available) of the estimates of in-
terest (odds ratio (OR), risk ratio (RR), risk difference (RD), or mean difference (MD) with
the 95% confidence intervals (CI), as reported in individual reviews), and the main re-
sults and conclusions of the SR. In addition, a three-color score was used for an immedi-
ate visual inspection of the CP-related effects with regard to the four main outcomes as-
sessed: viral clearance, clinical improvement, mortality reduction and safety (green color:
CP confers advantage over standard therapy or placebo; red color: CP does not confer
advantage over standard therapy or placebo; yellow color: no clear advantage or disad-
vantage).
2.7. Assessment of Methodological Quality
We used A Measurement Tool to Assess Reviews (AMSTAR-2) critical appraisal
checklist for SRs, a tool that evaluates both quantitative and qualitative reviews [8]. The
tool is suitable for reviews including randomised and non-randomised studies. It in-
cludes 16 domains relating to the research question, review design, search strategy, study
selection, data extraction, justification for excluded studies, description of included
studies, risk of bias, sources of funding, meta-analysis, heterogeneity, publication bias,
and conflicts of interest. Two review authors (MC, MF) independently assessed the
quality of evidence in the included reviews and the methodological quality of the SRs.
We resolved discrepancies through discussion or, if needed, through a third review au-
thor (FC). We did not exclude reviews based on AMSTAR-2 ratings, but considered the
ratings in interpretation of our results.
2.8. Appraisal of the Quality of Evidence
The quality of evidence was appraised following the Grades of Recommendation,
Assessment, Development, and Evaluation (GRADE) approach. Whenever available, the
grading of the quality of evidence reported in the included reviews was considered to
determine the quality of evidence. In a situation in which the grading of evidence was not
reported by the authors of the study, the GRADE approach was applied in its five do-
mains (risk of bias, indirectness, imprecision, inconsistency, and publication bias) based
on the information available from the study [9].

Diagnostics 2021, 11, 1663 4 of 25
Table 1. Summary of the published systematic reviews and meta-analyses.
First
Author
Clinical
Setting Population
Studies Included in
Quantitative Analysis (n) Intervention
Outcomes Main Results
Overall
(Patients) RCT NRCT CP Control
Aviani [10]
MERS-CoV,
SARS-CoV-1,
SARS-CoV-2
and influenza
infections
(severe or
critically ill
patients)
Patients infected
with beta
coronaviruses or
influenza viruses
with no
limitations of age,
gender or
ethnicity
20 5 15
CP at any titer,
dose, timing
and frequency
Standard care
30-day mortality, safety, viral
clearance, clinical improvement,
discharge rate
CP significantly reduced mortality and
increased the number of discharged patients.
Less than 1% of serious transfusion-related
AEs
Bansal [11]
COVID-19 at
any stage of
disease severity
Adult (> 18 years)
patients
hospitalized for
COVID-19
23
(27,706) 10 13
CP at any titer,
dose, timing
and frequency
Placebo or
standard
therapy
Mortality, safety
CP significantly reduced mortality. A 6.1%
pooled AE rate was observed with no
CP-related fatalities
Barreira [12]
Moderate,
severe or
critical
COVID-19
Hospitalized
COVID-19
patients with no
limitations of age,
gender or
ethnicity
11
(3098) 5 6
CP at any titer,
dose, timing
and frequency
Placebo or
standard care
Mortality, safety, viral clearance,
clinical improvement, length of
hospitalization
CP significantly reduced mortality and viral
load at 72 h after CP transfusion. A 3.5% AE
rate occurred
De Candia
[13]
COVID-19 at
any stage of
disease severity
Patients with
laboratory
confirmed
COVID-19
25
(22,591) 10 15
CP at any titer,
dose, timing
and frequency
Standard
therapy Mortality
CP, independently from neutralizing titer,
significantly reduced mortality only when
administered at early stage of the disease
Elbadawi
[14]
COVID-19
pneumonia
COVID-19
patients
6
(1226) 6 0
CP at any titer,
dose, timing
and frequency
Standard care
All-cause mortality, progression to
severe respiratory illness, clinical
improvement, need for IMV, safety
CP did not reduce all-cause mortality, the
progression to sever respiratory illness or the
need for IMV. No differences in clinical
improvement and AEs
Gupta [15]
COVID-19 at
any stage of
disease severity
COVID-19
patients
12
(13,206) 12 0
CP at any titer,
dose, timing
and frequency
Placebo or
standard care
28-day mortality, clinical
improvement, viral clearance, safety
CP was not associatd with clinical
improvement or significantly reduced risk of
death. A low incidence (3.2%) of AEs was
observed

Diagnostics 2021, 11, 1663 5 of 25
Janiaud [16]
COVID-19 at
any stage of
disease severity
Patients with
confirmed or
suspected
COVID-19 in any
treatment setting
10
(11,782) 10 0
CP at any titer,
dose, timing
and frequency
Placebo +
standard
therapy or
standard
therapy
Clinical improvement, all-cause
mortality, no. of patients requiring
IMV, rate of serious adverse events
CP did not reduce the need for IMV and
all-cause mortality. A subgroup analysis
showed a mortality reduction in patients
receiving high-titer CP [17]
Juul [18]
COVID-19 at
any stage of
disease severity
COVID-19
patients with no
limitations of age,
gender or
ethnicity
33
(13,312)
33
(2 CP) 0
Various
interventions
for treatment of
COVID-19,
including CP,
were analyzed
Standard care All-cause mortality, admission to ICU,
need for IMV, non-serious AEs CP did not reduce all-cause mortality
Keikha [19]
MERS-CoV (2
studies),
SARS-CoV-1 (5
studies),
SARS-CoV-2 (8
studies)
infections
Patients infected
with beta
coronaviruses
15
(5240) 1 14
CP at any titer,
dose, timing
and frequency
Placebo or
standard
therapy
Clinical improvement, viral clearance,
hospital discharge mortality
The clinical improvement was significantly
increased in CP group versus control group
Kim [20] Moderate-sever
e COVID-19
Adult (> 18 years)
patients
hospitalized for
COVID-19
110
(4 CP)
40
(2 CP)
70
(2 CP)
Various
pharmacologic
al interventions
against
COVID-19,
including CP,
were analyzed
Placebo or
standard care
Mortality, progression to severe
disease, viral clearance, serious
adverse events
CP was associated with significantly reduced
mortality rate in non-ICU setting and
improved viral clearance rate at 2 weeks
compared to standard care
Klassen [21]
COVID-19 at
any stage of
disease severity
COVID-19
patients with no
limitations of age,
gender or
ethnicity
30 10 20
CP at any titer,
dose and
timing (<3 days
versus >3 days
of hospital
admission)
Standard care Mortality
CP significantly reduced mortality rate
compared with standard care. CP transfusion
within 3 days of hospital admission resulted in
greater mortality reduction. A subgroup
analysis documented the safety of CP [22]
Kloypan [23]
COVID-19 at
any stage of
disease severity
COVID-19
patients 47 14 33
CP at any titer,
dose, timing
and frequency
Placebo or
standard
treatment
28-day mortality, length of hospital
stay, clinical improvement, discharge
rate
CP significantly reduced the risk of all-cause
mortality compared to standard care
Meher [24] Moderate-sever
e COVID-19
Hospitalized
adult patients of
6
(474) 2 4
CP at any titer,
dose, timing Standard care Mortality, clinical improvement, viral
clearance
CP significantly reduced all-cause mortality
and viral detection by day 7 with no clinical

Diagnostics 2021, 11, 1663 6 of 25
both gender with
moderate to
severe COVID-19
and frequency improvement by day 7
Peng [25]
Prophylaxis
and treatment
of
COVID-19
COVID-19
patients with no
limitations of age,
gender, ethnicity
or underlying
diseases
13
(2984) 2 11
CP at any titer,
dose, timing
and frequency
Placebo or
standard care Mortality, clinical improvement, safety CP significanlty reduced mortality and
increased viral clearance
Piechotta
[26]
COVID-19 at
any stage of
disease severity
(asymptomatic
or
symptomatic)
COVID-19
patients with no
limitations of age,
gender or
ethnicity
13
(48,509) 12 1
CP at any titer,
dose, timing
and frequency
Placebo or
standard care
All-cause mortality, clinical
improvement, need for IMV, viral
clearance, safety
CP did not reduce the need for IMV and
28-day all-cause mortality, but increased 7-day
viral clearance. In a subgroup analysis, CP
decreased disease progression and all-cause
mortality in individuals with asymptomatic or
mild COVID-19
Prasad [27]
Severe and
non-severe
COVID-19
Hospitalized
COVID-19
patients with no
limitations of age,
gender or
ethnicity
22
(9622) 9 13
CP at any titer,
dose, timing
and frequency
Placebo or
standard care
Mortality, clinical improvement, need
for IMV, viral clearance,
length of ICU or hospital stay, safety
Inconclusive effects of CP on mortality, clinical
improvement, need for mechanical ventilation
and faster viral clearance
Rabelo-da-P
onte [28]
COVID-19 at
any stage of
disease severity
COVID-19
patients with no
limitations of age,
gender or
ethnicity
9
(149) 1 8
CP at any titer,
dose, timing
and frequency
Standard
treatment Viral clearance, clinical improvement CP reduced viral load and was associated with
clinical status improvement
Sarkar [29]
COVID-19 at
any stage of
disease severity
COVID-19
patients with no
limitations of age,
gender or
ethnicity
7
(5444) 2 5
CP at any titer,
dose, timing
and frequency
Standard
treatment
Mortality, viral clearance, clinical
improvement
CP reduced mortality
,
increased viral clearance
and was associated with clinical improvement
Sun [30]
Different types
of infectious
diseases
including
severe
Patients with viral
infections with no
limitations of age
and sex
15 3
(1 CP) 12
CP at any titer,
dose, timing
and frequency
Standard
treatment
Mortality, symptom duration, hospital
length of stay, antibody levels, viral
load, adverse events
There was a significantly lower mortality rate
in the group treated with CP compared with
control groups

Diagnostics 2021, 11, 1663 7 of 25
COVID-19
Talaie [31]
COVID-19 at
any stage of
disease severity
Adult COVID-19
patients
26
(3263)
14
(1 CP)
12
(5 CP)
Various
pharmacologic
al interventions
against
COVID-19,
including CP,
were analyzed
Standard
treatment
Mortality, viral clearance, clinical
improvement, ICU entry, need for
IMV
CP had a beneficial effect on clinical
improvement and negative seroconversion and
tended to decrease mortality
Vegivinti
[32]
COVID-19 at
any stage of
disease severity
COVID-19
patients with no
limitations of age,
gender or
ethnicity
15
(4898) 5 10
CP at any titer,
dose, timing
and frequency
Standard care Mortality, clinical improvement,
length of hospital stay
CP was associated with a significantly reduced
mortality and higher clinical improvement
Wang [33]
COVID-19 at
any stage of
disease severity
Adult (>18 years)
COVID-19
patients
42
(8 CP)
10
(1 CP)
32
(7 CP)
CP at any titer,
dose, timing
and frequency
Standard care Mortality,
viral clearance
CP tended to decrease the mortality risk and
was associated with a higher viral nucleic acid
negative rate
Wang [34]
COVID-19 at
any stage of
disease severity
COVID-19
patients with no
limitations of age,
gender or
ethnicity
45
(44,068) 4 41
CP at any titer,
dose, timing
and frequency
Placebo,
standard care,
no
intervention
Mortality,
clinical improvement, safety
CP reduced (NRCTs) or not (RCTs) mortality
and improved (NRCTs) or not (RCTs) clinical
symptoms
Wardhani
[35]
Mild and severe
COVID-19
COVID-19
patients
12
(5342) 3 9
CP at any titer,
dose, timing
and frequency
Standard care All-cause mortality, subgroup analysis
based on disease severity
All and severe COVID-19 patients not
receiving CP were at increased mortality risk
compared to those treated with CP
Wenjing [36]
Severe and
critical
COVID-19
Severely and
critically ill
COVID-19
patients with no
limitations of age,
gender or
ethnicity
9 3 6
CP at any titer,
dose, timing
and frequency
NA Mortality, clinical improvement,
safety
CP significantly reduced mortality. A
qualitative analysis showed a beneficial effect
of CP in reducing viral load, on clinical
improvement and on safety
Yuwono
Soeroto [37]
COVID-19 at
any stage of
disease severity
COVID-19
patients
18
(5658) 7 11
CP at any titer,
dose, timing
and frequency
Standard care Mortality CP use was associated with significantly
decreased mortality
Zhang [38] Severe
COVID-19
Critically ill
COVID-19 19 1 18
CP at any titer,
dose, timing
Placebo or
standard care Mortality, safety, viral clearance A significantly reduced mortality rate and a
higher negative rate of PCR was found in the

Diagnostics 2021, 11, 1663 8 of 25
patients with no
limitations of age,
gender or
ethnicity
and frequency CP versus control group
Abbreviations: RCT, randomized controlled trial; NRCT, non-randomized controlled trial; CP, convalescent plasma; NA, not available; IMV, invasive mechanical ventilation; Severe
acute respiratory syndrome coronavirus: SARS; Middle East respiratory syndrome: MERS; ICU, intensive care unit; PCR, polymerase chain reaction; AE, adverse event.

Diagnostics 2021, 11, 1663 9 of 25
3. Results
The electronic and manual search retrieved 244 references. At the first stage of
screening titles and abstracts, 52 references were selected. The Preferred Reporting Items
for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram is reported in Figure
1. After the full texts were scrutinized against the inclusion and exclusion criteria, 29 SRs
were included in the umbrella review [10–38] and 23 SRs were excluded [39–61]. Reasons
for exclusion were: SRs not covering or with no informative data on CP therapy in
COVID-19 [39–42,44,45,47–49,54] and reviews on CP therapy in COVID-19 with no
quantitative and/or qualitative analysis [43,46,50–52,53,55–61].
Figure 1. PRISMA flow diagram of study selection.

Diagnostics 2021, 11, 1663 10 of 25
3.1. Description of the Studies
Of the 29 SRs included in the overview, 26 were focused exclusively on COVID-19
[11–18,20–29,31–38], while three were focused on respiratory pandemics and on beta
coronaviruses infections [10,19,30]. Two SRs [17,22] were a subgroup analysis of other
reviews [16,21]. The 29 SRs included 653 overlapping reports (237 RCTs and 416
non-RCTs), based on 53 individual primary studies. The primary studies included 17
RCTs, 26 controlled non-RCTs, and 10 uncontrolled studies (single arm studies, including
case series and case reports). Twenty-eight SRs were focused on CP treatment of
COVID-19, while one study [25] was focused on both CP prophylaxis and treatment. The
majority of the SRs analyzed COVID-19 at any stage of disease severity, while four
studies [10,30,36,38] were focused on more advanced (severe and/or critical) stages. Most
SRs analyzed COVID-19 patients with no limitation of age, gender or ethnicity, while
four SRs were focused only on adult (> 18 years) COVID-19 patients [11,20,31,33]. The
main characteristics of the SRs included are summarized in Table 1.
3.2. Methodological Quality
Of the included reviews, the majority (19/29; 65.5%) had ≥ 2 (from 2 to 12) unmet
AMSTAR-2 methodological requirements, and nine (31.0%) had one unmet methodo-
logical requirement; one Cochrane review met all the methodologic requirements (Table
2). Sixteen reviews (55.2%) had one or more methodological requirements partly met.
Twenty-seven reviews (93.1%) did not report on the source of funding for the studies in-
cluded in the review; 11 reviews (39.2%) did not register or publish a protocol. Eight re-
views (27.6%) did not mention publication bias in methods and results, and failed to
discuss the possible impact of publication bias on review findings. In five reviews, par-
ticipants, interventions, comparators, and outcomes (PICO) were not clearly made ex-
plicit, and in 3 reviews design was not fully explained. In six reviews, the search strategy
was not comprehensive. More than 85% of author teams perform study selection and
screening in duplicate. Other unmet domains were related to the list of excluded reviews
and reasons (seven reviews, 24.1%), assessment of risk of bias (three reviews), and
sources of conflict of interest, including any funding that the authors receive for con-
ducting the review (four reviews).
Table 2. The AMSTAR-2 checklist.
Author [Reference] AMSTAR-2 DOMAIN
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Aviani [10]
Bansal [11]
Barreira [12]
De Candia [13]
Elbadawi [14]
Gupta [15]
Janiaud [16]
Cruciani [17]
Juul [18]
Keikha [19]
Kim [20]
Klassen [21]
Franchini [22]
Kloypan [23]
Meher [24]
Peng [25]

Diagnostics 2021, 11, 1663 11 of 25
Piechotta [26]
Prasad [27]
Rabelo-da-Ponte [28]
Sarkar [29]
Sun [30]
Talaie [31]
Vegivinti [32]
Wang M [33]
Wang Y [34]
Wardhani [35]
Wenjing [36]
Yuwono Soeroto [37]
Zhang [38]
Footnotes: Methodological requirement met, Methodological requirement partly met, Methodological require-
ment unmet. AMSTAR-2 domains: 1. Did the research questions and inclusion criteria for the review include the com-
ponents of PICO? 2. Did the report of the review contain an explicit statement that the review methods were established
prior to the conduct of the review and did the report justify any significant deviations from the protocol? 3. Did the re-
view authors explain their selection of the study designs for inclusion in the review? 4. Did the review authors use a
comprehensive literature search strategy? 5. Did the review authors perform study selection in duplicate? 6. Did the re-
view authors perform data extraction in duplicate? 7. Did the review authors provide a list of excluded studies and justify
the exclusions? 8. Did the review authors describe the included studies in adequate detail? 9. Did the review authors use a
satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review? 10. Did
the review authors report on the sources of funding for the studies included in the review? 11. If meta-analysis was per-
formed did the review authors use appropriate methods for statistical combination of results? 12. If meta-analysis was
performed, did the review authors assess the potential impact of RoB in individual studies on the results of the me-
ta-analysis or other evidence synthesis? 13. Did the review authors account for RoB in individual studies when inter-
preting/ discussing the results of the review? 14. Did the review authors provide a satisfactory explanation for, and dis-
cussion of, any heterogeneity 15. If they performed quantitative synthesis did the review authors carry out an adequate
investigation of publication bias (small study bias) and discuss its likely impact on the results of the review? 16. Did the
review authors report any potential sources of conflict of interest, including any funding they received for conducting the
review? Although AMSTAR-2 consists of 16 items, critical domains include items 2, 4, 7, 9, 11, 13, and 15.
3.3. Summary of the Effect of CP on the Main Outcomes
3.3.1. (a) Outcome “Overall Mortality”
Overall mortality was the most common reported outcome. Great heterogeneity was
ascertained in several SRs; thus, we performed subgroup analyses to control for sources
of heterogeneity such as design of studies included in the review (e.g., RCTs and
non-RCTs), titre of SARS-CoV-2 neutralizing antibodies (high or low), and time of ad-
ministration (early or late). The results of our analyses are summarized in Table 3. Sixteen
SRs reported the outcome mortality in RCTs and non-RCT. In 14 of these SRs the effect
size favoured the CP arm compared to controls, while in two SRs it was unclear whether
CP reduced mortality compared to controls; the quality of the evidence was very low in 2
SRs, low in four, moderate in nine, and from moderate to high in one. Eleven SRs ana-
lysed the outcome mortality in RCTs only, and all were consistent in concluding that CP
did not reduce mortality compared to controls (moderate certainty of evidence in 10 SRs,
from moderate to high certainty in one SR). The analysis of results from non-RCTs
showed higher reduction in mortality in CP group compared to control in six out of
seven SRs (low quality of evidence in four, very low in one, moderate in two).

Diagnostics 2021, 11, 1663 12 of 25
Table 3. Effects of convalescent plasma on overall mortality.
Review
[Reference]
No. Studies
No. Subjects
(CP/Controls)
Effect Size (RR,
OR or RD) and
95% CIs
GRADE
Assessment Comment Effect
Direction
Outcome:
Mortality
Overall
Analysis
(RCTs +
non-RCTs)
Aviani [10] 12 (4/8) 4306 (724/3582) RR 0.62 (0.46/0.82) ⊕⊕⊝⊝
Low1
CP reduces mortality
compared to controls
Bansal [11] 23 (11/12) 7542 (2392/5150) OR 0.65
(0.53/0.80)
⊕⊕⊝⊝
Low1
CP reduces mortality
compared to controls
Barreira [12] 11 (5/6) 2998 (823/2175) RR 0.71 (0.57/0.90) ⊕⊕⊝⊝
Low1
CP reduces mortality
compared to controls
De Candia
[13] 25 (10/15) 24772
(13470/11302) RR 0.78 (0.68/0.90) ⊕⊕⊝⊝
Low1
CP reduces mortality
compared to controls
Klassen [21] 30 (10/20) 12982 (1425/11467) OR 0.58
(0.47/0.71)
From moderate
⊕⊕⊕⊝
to high⊕⊕⊕⊕3
CP reduces mortality
compared to controls
Kloypan [23] 20 (11/9) 16533 (7753/8780) RR 0.69 (0.56/0.86) ⊕⊕⊝⊝
Low1
CP reduces mortality
compared to controls
Meher [24] 6 (2/4) 469 (167/302) RR 0.61 (0.37/0.99) ⊕⊝⊝⊝
Very low4
CP reduces mortality
compared to controls
Peng [25] 13 (4/9) 2984 (695/2289) OR 0.48
(0.34/0.67)
⊕⊕⊝⊝
Low1
CP reduces mortality
compared to controls
Sarkar [29] 7 (2/5) 5454 (5169/285) OR 0.44
(0.25/0.77)
⊕⊕⊝⊝
Low1
CP reduces mortality
compared to controls
Talaie [31] 3 (1/2) 163 (82/81) RR 0.52 (0.26/1.03) ⊕⊝⊝⊝
Very low 5
It is unclear whether
CP reduces mortality
compared to controls
Vegivinti
[32] 15 (5/10) 4858 (2208/2650) OR 0.58
(0.44/0.78)
⊕⊝⊝⊝
Very low4
CP reduces mortality
compared to controls
Wang Y [34] 3 (1/2) 319 (97/222) RR 0.65 (0.42/1.02) ⊕⊝⊝⊝
Very low5
It is unclear whether
CP reduces mortality
compared to controls
Wardhani
[35] 12 (3/9) 5342(1937/3405) OR 1.92
(1.33/2.77)
⊕⊕⊝⊝
Low1
Mortality higher in
controls
Wenjing [36] 10 (3/7) 2835 (2271/564) RR 0.57 (0.44/0.74) ⊕⊝⊝⊝
Very low4
CP reduces mortality
compared to controls
Yuwono
Soeroto [37] 18 (6/12) 5657 (2168/3489) OR 0.64
(0.49/0.84)
⊕⊕⊝⊝
Low1
CP reduces mortality
compared to controls
Zhang [38] 4 (1/3) 182 (87/95) RR 0.59 (0.37/0.94) ⊕⊝⊝⊝
Very low5
CP reduces mortality
compared to controls
RCTs only
Bansal [11] 10 1413 (770/653) OR 0.75
(0.53/1.08)
⊕⊕⊕⊝
Moderate2
It is unclear whether
CP reduces mortality
compared to controls
Barreira [12] 5 1065 (595/470) OR 0.85
(0.62/1.16)
⊕⊕⊕⊝
Moderate2
It is unclear whether
CP reduces mortality
compared to controls

Diagnostics 2021, 11, 1663 13 of 25
De Candia
[13] 10 13470 (6579/6891) RR 0.96 (0.91/1.03) ⊕⊕⊕⊝
Moderate2
It is unclear whether
CP reduces mortality
compared to controls
Elbadawi
[14] 6 1307 (737/550)
OR 0.83
(0.58/1.18)
⊕⊕⊕⊝
Moderate2
It is unclear whether
CP reduces mortality
compared to controls
Gupta [15] 12 13204 (6715/6489) RR 0.81 (0.65/1.02) ⊕⊕⊕⊝
Moderate2
It is unclear whether
CP reduces mortality
compared to controls
Janiaud [16] 9 1384 (758/626) RR 1.02 (0.92/1.12) ⊕⊕⊕⊝
Moderate6
It is unclear whether
CP reduces mortality
compared to controls
Klassen [21] 10 1425 (771/654) OR 0.76
(0.54/1.09)
From moderate
⊕⊕⊕⊝
to high⊕⊕⊕⊕3
It is unclear whether
CP reduces mortality
compared to controls
Meher [24] 2 187 (94/93) RR 0.60 (0.33/1.10) ⊕⊕⊕⊝
Moderate6
It is unclear whether
CP reduces mortality
compared to controls
Prasad [27] 8 1336 (730/606) OR 0.85
(0.61/1.18)
⊕⊕⊕⊝
Moderate2
It is unclear whether
CP reduces mortality
compared to controls
Wang M
[33] 2 167 (81/86)
OR 0.40
(0.14/1.11)
⊕⊕⊕⊝
Moderate6
It is unclear whether
CP reduces mortality
compared to controls
Yuwono
Soeroto [37] 6 1142 ()647/495) RR 0.85 (0.71/1.02) ⊕⊕⊕⊝
Moderate2
It is unclear whether
CP reduces mortality
compared to controls
Non-RCTs
only
Bansal [11] 9 4087 (1278/2809) OR 0.78
(0.65/0.94)
⊕⊕⊝⊝
Low1
CP reduces mortality
compared to controls
Barreira [12] 6 2033 (328/1705) RR 0.56 (0.39/0.81) ⊕⊕⊝⊝
Low1
CP reduces mortality
compared to controls
Klassen [21] 20 11467 (3150/8317) OR 0.57
(0.45/0.72)
From moderate
⊕⊕⊕⊝
To high⊕⊕⊕⊕3
CP reduces mortality
compared to controls
Meher [24] 4 273 (73/200) OR 0.48
(0.17/1.36)
⊕⊝⊝⊝
Very low4
It is unclear whether
CP reduces mortality
compared to controls
Prasad [27] 13 8267 (2621/5646) OR 0.66
(0.53/0.82)
⊕⊕⊝⊝
Low1
CP reduces mortality
compared to controls
Wang M
[33] 11 7779 (1649/6130) RR 0.59 (0.53/0.66) ⊕⊝⊝⊝
Very low5
CP reduces mortality
compared to controls
Yuwono
Soeroto [37] 12 4515 (1521/2994) RR 0.48 (0.34/0.70) ⊕⊕⊕⊝
Moderate2
CP reduces mortality
compared to controls
Subgroup
analysis:
High
antibody titre
Aviani [10] High titre 1186 (98/1088) RR 0.42 (0.22/0.78) ⊕⊕⊕⊝ -In pts with severe

Diagnostics 2021, 11, 1663 14 of 25
(>640)
-3 studies (2
RCTs) in
severely ill
pts
-2 studies (1
RCT) in
critical ill pts
388 (43/345) RR 0.72 (0.46/1.12) Moderate2
⊕⊕⊝⊝
Low7
illness, high titre CP
reduces mortality
compared to controls.
The reduction in
mortality in study with
lower antibody titre
(neutralizing titre ≤
1:320) was less marked
(RR 0.80, 95% CI
0.47/1.34).
-In pts with critical
illness, it is unclear
whether CP reduces
mortality compared to
controls
Barreira [12]
High titre
(>1:297) (4
studies, 2
RCTs)
650 (329/321) RR 0.68 (0.44/1.04) ⊕⊕⊝⊝
Low7
It is unclear whether
high titre CP reduces
mortality compared to
controls. In studies
with lower titre
(<1:297) CP the RR was
higher: 0.85 (0.58/1.25)
Cruciani
[17]
High titre, 3
RCTs 374 (170/174) RD −0.06
(−0.12/0.00)
⊕⊕⊕⊝
Moderate2
High titre CP reduces
mortality compared to
controls
De Candia
[13]
High titre
(different
cut-off) (14
studies, 7
RCTs)
20744 (11711/9033) RR 0.93 (0.88/0.99) ⊕⊕⊕⊝
Moderate2
High titre CP reduces
mortality compared to
controls
Klassen [21] 2 non-RCTs
1125 (534 high
titre, 591 lower
titre)
22% high titre CP,
29% lower titre
⊕⊕⊝⊝
Low7
Mortality higher in
those receiving lower
CP titre transfusion
Subgroup
analysis:
early CP
transfusion
Barreira [12] 3 studies (2
RCTs) 2118 (416/1702) RR 0.71 (0.53/0.96) ⊕⊕⊕⊝
Moderate2
Mortality was reduced
in pts receiving early
(within 7 days) CP
transfusion compared
to controls. In pts
receiving late (> 7 days)
CP transfusion
mortality was similar
to that observed in
control group (RR 0.60,
95% CI 0.30/1.17)
De Candia
[13]
11 studies (5
RCTs) 19007 (8018/10989) OR 0.72
(0.68/0.77)
⊕⊕⊕⊝
Moderate2
Mortality was reduced
in pts receiving early
(within 3 days) CP

Diagnostics 2021, 11, 1663 15 of 25
transfusion compared
to controls. In pts
receiving late (> 7 days)
CP transfusion
mortality was similar
to that observed in
control group (OR 0.94,
95% CI 0.86/1.04)
Klassen [21] 8 studies (3
RCTs) 1561 (656/905) OR 0.44
(0.32/0.61)
⊕⊕⊕⊝
Moderate2
Mortality reduction
associated with
convalescent plasma
transfusion was greater
in studies that
transfused patients
within 3 days of
hospital admission
(OR, 0.44; 95% CI 0.32–
0.61) compared with
studies that transfused
patients more than 3
days after hospital
admission (OR, 0.79;
95% CI 0.62/0.98)
Piechotta
[26]
1 RCT
(Recovery
trial)
4466 RR 0.93 (0.84/1.02)
⊕⊕⊕⊝
Moderate2
It is unclear whether
early CP transfusion
(within 7 days of
symptoms onset)
reduces mortality
compared to controls.
Transfusion of CP after
7 days of symptoms
onset resulted in a RR
of 1.04 (0.95/1.15)
Subgroup
analysis
according
to severity
of infection
-Moderate
COVID-19
Barreira [12] 3 (2 RCTs) 545 (275/272) RR 0.96 (0.62/1.48) ⊕⊕⊝⊝
Low1
It is unclear whether
CP transfusion reduces
mortality in pts with
moderate illness
Kim [20] 3 non-RCTs Not available OR 0.67
(0.16/2.74)
⊕⊕⊝⊝
Low8
It is unclear whether
CP transfusion reduces
mortality in pts with
moderate illness
Piechotta
(from
moderate to
1 RCT 77 (36/41) RR 0.98 (0.68/1.41) ⊕⊕⊝⊝
Low9
It is unclear whether
CP transfusion reduces
mortality in pts with

Diagnostics 2021, 11, 1663 16 of 25
severe) [26] moderate/severe illness
Yuwono
Soeroto
(from
moderate to
severe) [37]
6 (3 RCTs) 938 (430/508) RR 0.51 (0.26/1.02) ⊕⊕⊝⊝
Low8
It is unclear whether
CP transfusion reduces
mortality in pts with
moderate/severe illness
- Severe/
critical
COVID-19
Aviani
(Severe vs.
critical) [10]
4 (1 RCT) 166 (80/86) RR 4.64 (2.12/10.0) ⊕⊕⊝⊝
Low7
In pts receiving CP,
mortality higher in
critical ill pts compared
to severely illness
Barreira [12] 4 (2 RCTs) 1889 (240/1649) RR 0.84 (0.54/1.32) ⊕⊕⊕⊝
Moderate2
It is unclear whether
CP transfusion reduces
mortality in pts with
severe/critical illness
Wardhani
[35]
9 trials (3
RCTs) 4164 (1458/2706) OR 1.32
(1.09/1.60)
⊕⊕⊕⊝
Moderate2
In pts with severe
disease, mortality
higher in controls
compared to CP
recipients
Wenjing [36]
Severe: 4
trials (1 RCT)
Critical: 3
trials (1 RCT)
1420 (168/1252)
171 (78/93)
RR 0.54 (0.36/0.80)
RR 0.72 (0.35/1.47)
⊕⊕⊕⊝
Moderate2
⊕⊝⊝⊝
very low5
CP reduces mortality
in pts with severe
illness
It is unclear whether
CP transfusion reduces
mortality in pts with
critical illness
Yuwono
Soeroto [37] 13 (6 RCTs) 4899 (1718/3181) RR 0.68 (0.51/0.91) ⊕⊕⊝⊝
Low8
In pts with
severe/critical illness,
CP reduces mortality
compared to controls
Footnotes: Favouring CP, Not clear effect of CP compared to controls, favouring controls. 1. Downgraded for
risk of bias and heterogeneity. 2. Downgraded for risk of bias. 3. This judgment was based on the consistency of the re-
sults between RCTs and matched control studies and the corroborating evidence from dose–response studies and other
uncontrolled case data. In aggregating data from all controlled studies, the meta-analyses provided precise estimates, did
not demonstrate substantial heterogeneity, and demonstrated no evidence of publication bias. The inherent limitations of
the included studies rendered the certainty of evidence judgment to be moderate to high. 4. Downgraded for risk of bias,
heterogeneity and publication bias. 5. Downgraded for risk of bias, imprecision and heterogeneity. 6. Downgraded for
imprecision. 7. Downgraded for risk of bias and imprecision. 8. Downgraded twice for risk of bias (confounding and
publication bias). 9. Downgraded for imprecision and clinical heterogeneity.
Due to the clinical heterogeneity observed in many of the primary studies and sta-
tistical heterogeneity in many of the SRs, we performed subgroup analyses as specified in
the protocol. High titre CP was more effective than lower titre in reducing mortality
(moderate certainty of evidence in three SRs, low in one). In two SRs, it was unclear
whether high titre CP reduces mortality compared to controls (low certainty of evidence).
Subgroup analysis according to time to CP transfusion showed a reduction in mortality
in early CP recipients compared to controls in three SRs (moderate certainty of evidence);
by contrast a Cochrane review based on a single RCT (RECOVERY trial) [62] concluded
that it is unclear whether early CP transfusion reduces mortality compared to controls

Diagnostics 2021, 11, 1663 17 of 25
(low quality of evidence), although transfusion after the first week of illness resulted in
higher risk of mortality compared to early transfusion. We also performed subgroup
analysis of mortality according to baseline severity of COVID-19, but there was hetero-
geneity in defining the clinical condition. In patients with moderate/severe infection, the
effect of CP was unclear (three SRs, low-quality of evidence), while in patients with se-
vere/critical infection, the results were more heterogeneous in the comparison, effect size
and certainty of the evidence (Table 3).
3.3.2. (b) Outcome “Viral Clearance”
The outcome viral clearance (rate of patients with negative reverse transcription
polymerase chain reaction (RT-PCR) test for SARS-CoV-2 after a positive test at baseline)
was reported in 6 SRs after 3 days, and in two SRs after 7–14 days (Table 4). On day 3,
four out of six SRs reported an increase in viral clearance in CP recipients compared to
controls (from low to moderate certainty of evidence), while in two SRs it was unclear
whether CP reduced the viral clearance compared to controls (from low to moderate
certainty of evidence). On day 14, CP showed significantly higher viral clearance rate
compared to standard supportive therapy in one SR (low certainty of evidence), while in
a Cochrane review based on two RCTs it was unclear whether CP increases viral clear-
ance compared to controls (low certainty of evidence). It was not possible to perform
subgroup analyses for these outcomes due to the relatively low number of primary
studies and SRs available.
Table 4. Effects of convalescent plasma on viral clearance, clinical improvement and length of hospital stay.
Review
[Reference]
No. Studies
No. Subjects
(CP/Controls)
Effect Size (RR,
OR, HR or MD)
and 95% CIs
GRADE
Assessment Comment Effect
Direction
Outcome:
viral clearance
-on day 3
Barreira [12] 4 trials (3
RCTs) 552 (276/276) RR 0.61
(0.38/0.98)
⊕⊕⊕⊝
Moderate1
Compared to standard
treatment, CP increases
rate of viral clearance after
3 days
Peng [25] 3 trials (2
RCTs) 128 (63/65) OR 26.21
(4.36/157.66)
⊕⊕⊕⊝
Moderate2
CP increases viral
clearance compared to
controls
Piechotta [26] 4 RCTs 552 (279/273) RR 1.73
(0.98/3.04)
⊕⊕⊕⊝
Moderate1
In patients with
moderate/severe disease, it
is unclear whether CP
increases rate of viral
clearance compared to
controls
Prasad [27] 2 RCTs 551 (282/269) OR 3.62
(0.43/30.49)
⊕⊕⊝⊝
Low3
It is unclear whether CP
increases rate of viral
clearance compared to
controls
Wang Y [34] 2 trials (1
RCT) 108 (53/55) RR 2.47
(1.70/3.57)
⊕⊕⊝⊝
Low4
CP increases viral
clearance compared to
controls
Zhang [38] 2 trials (1
RCT) 108 (53/55) RR 2.55
(1.76/3.70)
⊕⊕⊝⊝
Low4
CP increases viral
clearance compared to

Diagnostics 2021, 11, 1663 18 of 25
controls
-on day 7–14
Kim [20] 3 trials (1
RCT) NA OR 11.39
(3.91/33.18)
⊕⊕⊝⊝
Low5
On day 14, CP showed
significantly higher viral
clearance rate compared to
standard supportive
therapy
Piechotta [26] 2 RCTs 149 (79/70) RR 1.59
(0.74/3.43)
⊕⊕⊝⊝
Low3
On day 14, it is unclear
whether CP increases viral
clearance rate compared to
standard supportive
therapy
Outcome:
clinical
improvement
Elbadawi [14] 3 RCTs 267 (130/137) OR 1.31
(0.78/2.22)
⊕⊕⊝⊝
Low5
It is unclear whether CP
increases rate of clinical
improvement compared to
controls
Gupta [15] 6 RCTs 1106 (616/490) RR 1.02
(0.82/1.28)
⊕⊕⊕⊝
Moderate6
It is unclear whether CP
increases rate of clinical
improvement compared to
controls after 7, 14 and 28
days from administration
Peng [25] 4 trials (2
RCTs) 404 (144/260) OR 1.54
(0.79/3.01)
⊕⊕⊝⊝
Low5
It is unclear whether CP
increase rate of clinical
improvement compared to
controls
Piechotta [26] 1 RCT 77 (36/41) RR 1.10
(0.83/1.48)
⊕⊕⊕⊝
Moderate2
In patients with
moderate/severe disease, it
is unclear whether CP
increases rate of clinical
improvement (liberation
from supplemental
oxygen) compared to
controls
Prasad [27] 3 RCTs 421 (322/199) OR 1.07
(0.86/1.34)
⊕⊕⊝⊝
Low5
It is unclear whether CP
increases rate of clinical
improvement compared to
controls
Sarkar [29] 7 trials (2
RCTs) 5454 OR 0.44
(0.25/0.77)
⊕⊕⊕⊝
Moderate 6
CP increase rate of clinical
improvement compared to
controls
Talaie [31] 3 trials (2
RCTs) Not available RR 1.41
(1.01/1.98)
⊕⊕⊝⊝
Low5
CP increase rate of clinical
improvement compared to
controls
Vegivinti [32] 7 trials (2
RCTs) 1581 OR 2.02
(1.54/2.65)
⊕⊕⊝⊝
Low5
CP increase rate of clinical
improvement compared to
controls
Wang M [33] 2 RCTs 189 (95/94) OR 1.21 ⊕⊕⊕⊝
Moderate 2 It is unclear whether CP

Diagnostics 2021, 11, 1663 19 of 25
(0.68/2.16) increase rate of clinical
improvement compared to
controls
Outcome:
length of
hospital stay
Barreira [12] 3 trials (1
RCT) 2221 (488/1733) MD 1.94
(−3.69/7.58)
⊕⊕⊝⊝
Low5
It is unclear whether CP
decreases length of
hospital stay compared to
controls
Janiaud [16]
4 RCTs (2
published as
preprints)
603 (361/242) HR 1.07
(0.79/1.45)
⊕⊕⊝⊝
Low4
It is unclear whether CP
decreases length of
hospital stay compared to
controls
Peng [25] 6 trials (1
RCT) 2101 (366/1735) MD 0.84
(−3.35/5.02)
⊕⊕⊝⊝
Low5
It is unclear whether CP
decreases length of
hospital stay compared to
controls
Piechotta [26] 5 RCTs 683 (401/282) HR 1.15
(0.95/1.40)
⊕⊕⊕⊝
Moderate2
It is unclear whether CP
decreases length of
hospital stay compared to
controls
Prasad [27] 4 trials (3
RCTs) 2602 (1365/1237) MD 0.12
(−1.69/1.93)
⊕⊕⊕⊝
Moderate7
It is unclear whether CP
decreases length of
hospital stay compared to
controls
Vegivinti [32] 6 trials (2
RCTs) 2157 MD −0.5
(−3.1/2.1)
⊕⊕⊝⊝
Low5
It is unclear whether CP
decreases length of
hospital stay compared to
controls
Footnotes: Favouring CP, Not clear effect of CP compared to controls, favouring controls. 1. Downgraded for
heterogeneity. 2. Downgraded for imprecision. 3. Downgraded for inconsistency and imprecision. 4. Downgraded for
ROB and imprecision. 5. Downgraded for ROB and inconsistency. 6. Downgraded for ROB. Downgraded for incon-
sistency.
3.3.3. (c) Outcome “Clinical Improvement”
Clinical improvement was reported in nine SRs. Six SRs concluded that it is unclear
whether CP increases rate of clinical improvement compared to controls (in three SRs
moderate certainty of evidence, in three low certainty of evidence). Three SRs showed
that CP increase rate of clinical improvement compared to controls (low certainty of ev-
idence in two SRs, moderate certainty of evidence in one SR) (see Table 4).
3.3.4. (d) Outcome “Length of Hospital Stay”
Length of hospital stay was reported in six SRs. All concluded that it is unclear
whether CP decreases length of hospital stay compared to controls (low quality of cer-
tainty in four SRs, moderate certainty of evidence in two SRs) (Table 4).
3.3.5. (e) Outcome “Adverse Events”
Serious adverse events to CP transfusion were reported in five SRs and overall ad-
verse events in two SRs. All SRs concluded that the frequency of adverse reactions was
similar in CP and control groups (low quality of certainty in four SRs, moderate certainty
of evidence in one SR) (Table 5).

Diagnostics 2021, 11, 1663 20 of 25
Table 5. Adverse reactions related to convalescent plasma transfusion.
Review
[Referenc
e]
No.
Studie
s
No. Events/No. Patients in CP and
Controls
Effect size (RR
or RD) and 95%
CIs
GRADE
Assessmen
t
Comment
Effect
Directio
n
Outcome:
Adverse
Events
(AE)
-Serious
AE
Gupta
[15]
11
RCTs 200/6164 (3.2%) 161/5826 (2.87) RR 1.14
(0.93/1.40)
⊕⊕⊕⊝
Moderate1
Serious AE were rare
and with similar
frequency in CP and
controls
Janiaud
[16] 3 RCTs 60/329 (18.2%) 26/191
(13.6%)
RR 0.97
(0.36/2.63)
⊕⊕⊝⊝
Low2
Serious AE had
similar frequency in
CP and controls
Juul [18] 3 RCTs 46/249 (18.4%) 49/262 (18.7%) RR 0.93
(0.36/2.63)
⊕⊕⊕⊝
Moderate1
Serious AE had
similar frequency in
CP and controls
Franchini
[22] 9 RCTs 106/853 (12.4%) 52/616 (8.4%) RD 0.00
(−0.03/0.03)
⊕⊕⊕⊝
Moderate1
Serious AE had
similar frequency in
CP and controls
Piechotta
[26] 2 RCTs 60/206 (29.1%) 26/148 (17.5%) RR 1.73
(0.98/3.04)
⊕⊕⊕⊝
Moderate3
Serious AE were
more common in CP
compared to
controls (29.1 vs
17.5%) but the
difference was not
statistically
significant
-Overall
AE
Franchini
[22] 8 RCTs 1692/5848 (28.9%) 1535/5471
(28.0%)
RD 0.01
(−0.02/0.03)
⊕⊕⊕⊝
Moderate1
Overall AE had
similar frequency in
CP and controls
(28%)
Piechotta
[26] 1 RCT 153/228 (67%) 66/104 (63.4%) RR 1.06
(0.89/1.26)
⊕⊕⊕⊝
Moderate3
Overall AE had
similar frequency in
CP and controls
(>60%). Likewise,
grade 3–4 AE had
similar frequency in
CP recipients and
controls (8.5 and
6.3%, respectively)
Footnotes: Favouring CP, Not clear effect of CP compared to controls, favouring controls. 1. Downgraded for
ROB. 2. Downgraded for ROB and imprecision. 3. Downgraded for imprecision.

Diagnostics 2021, 11, 1663 21 of 25
3.4. GRADE Assessment
Of the 89 analyses on which GRADE judgements were made, effect estimates were
judged to be of high/moderate certainty in four analyses, moderate in 38, low in 38, and
very low in nine. For the outcome mortality, the judgment was very low in nine analyses,
low in 19, moderate in 19 and moderate/high in four.
4. Discussion
The outbreak of the COVID-19 pandemic has greatly accelerated the clinical trial
research evaluating the safety and efficacy of CP as emergency therapy. According to the
study by Muller-Olling and colleagues [63], CP is the second most frequent investiga-
tional medicinal product evaluated in COVID-19-related clinical trials and increasing
interest in this form of immunotherapy is documented by the fact that more than 140
clinical trials specifically evaluating CP in COVID-19 have been registered to date
worldwide [63]. Studies on CP as treatment for COVID-19 have qualitatively evolved
during the COVID-19 pandemic period in response to the advances in the knowledge of
this disease and to the results of the published clinical trials [64]. They can be generally
classified into three generations: the first-generation clinical trials, performed at the be-
ginning of the first pandemic wave, utilized CP with high-titer anti-SARS-CoV-2 neu-
tralizing antibodies usually in hospitalized patients with severe, advanced COVID-19
[65,66]. However, it soon became evident that, since CP was working by blocking the
viral replication, the earlier it was used the more effective it was in preventing the disease
progression [1]. Thus, second generation clinical trials were focused on the use of
high-titer CP early in the course of COVID-19 (within 3 days from symptom onset or
hospitalization) [67]. Finally, to optimize the possible beneficial effect of plasma, the more
recent third generation trials are evaluating the CP infusion in particular populations of
patients at high risk of development of severe or critical COVID-19, such as those with
impaired humoral immunity, onco-hematological disorders or other severe cardiovas-
cular or respiratory co-morbidities [68–70]. Moreover, some of these trials encompass the
pre-transfusion evaluation of recipients’ anti-SARS-CoV-2 antibody levels in order to
capture those patients with lack or insufficient antibody response and therefore most
likely to benefit from CP passive immunotherapy [1]. Based on the above, it is evident
that the clinical trials conducted during the 18-month COVID-19 pandemic are widely
heterogeneous in terms of study design and CP administration schedule, disease and
patients characteristics. In this extremely uncertain and changing context, typical of
emergency situations such as those of the COVID-19 pandemic, it is evident that even the
systematic reviews and meta-analyses have produced heterogeneous results. This over-
view of reviews includes data from twenty-nine systematic reviews, based on more than
600 overlapping reports and 53 individual primary studies (43 controlled trials, including
17 RCTs and 26 non-RCTs, and 10 uncontrolled trials (single arm studies). We believe
that makes this the largest review to date within this subject area, and hope this will
make it particularly helpful to decision makers. The results of RCTs are not always con-
sistent with the results of observational studies, and differences in estimated magnitude
of treatment effect are very common, often resulting in overestimation of treatment ef-
fects in observational studies [71]. Interpretation of the results obtained from both RCTs
and observational studies, as well as from systematic reviews including both types of
study design, can help understand the efficacy/effectiveness and safety of a therapeutic
option [72]. For this reason we performed, where available, subgroup analyses of the ef-
fect size obtained in the overall comparison, in RCTs and in observational studies. For the
outcome most commonly reported, overall mortality, it was possible to perform sub-
group analysis of SRs according to study design, antibodies titre and time of transfusion.
While the majority of SRs reporting this outcome in non-RCTs and in non-RCTs + RCTs
showed a reduction in mortality in CP recipients compared to controls, when the analysis
was limited to RCTs it was unclear whether CP reduced mortality compared to controls.

Diagnostics 2021, 11, 1663 22 of 25
It was also clear that most of the included studies (both RCTs and non-RCTs) were at risk
of bias and showed significant clinical, methodological and statistical heterogeneity.
Overall the certainty of the evidence was from low to moderate in the majority of the SRs.
Subgroup analyses according to neutralizing antibody titres and time of CP transfusion
showed a reduction in mortality in the majority of SRs when high titres of antibody and
early transfusions were administered (from low to moderate certainty of the evidence).
The other secondary outcomes (i.e., viral clearance, clinical improvement and length of
hospital stay) were addressed by only a minority of SRs with a high level of uncertainty,
so that no definitive conclusions can be drawn. However, CP seemed to be effective in
increasing viral clearance as compared with standard therapy, particularly within the
first three days from CP transfusion (from low to moderate certainty of the evidence).
Additionally, CP did not increase the risk of adverse events between intervention and
control groups, confirming the safety of this procedure [22]. Although the SRs tried to
address, at least in part, the heterogeneity of the results (on the basis of neutralizing titre,
time of CP infusion and study design) it was almost impossible to evaluate in this over-
view the clinical heterogeneity of primary studies, related to different disease conditions
at baseline, concomitant therapies, patients characteristics. Limitations to the methodo-
logical quality of reviews most commonly related to absence of a protocol (11/29) and
funding sources of primary studies (27/29).
In conclusion, despite these limitations and based on the analysis of the main out-
come mortality, this overview of systematic reviews supports the safety and efficacy of
the clinical use of CP over standard therapy when administered at high titer and early
during the course of COVID-19. Further pooled qualitative and quantitative analyses
from a new systematic review based on individual patients data rather than on aggregate
data (that are often insufficient for a thorough analysis) or from adequately powered
third generation clinical trials (i.e., assessing the early use of high titer CP administered in
populations of patients with inadequate antiviral response and at increased risk of de-
veloping severe COVID-19) are needed to pinpoint exactly where and when CP can give
the greatest clinical benefit in COVID-19.
Author Contributions: Conceptualization: M.C and M.F. Methodology: M.C. Validation: M.F. and
F.C. Writing—preparation original draft: M.C. and M.F. Writing—review and editing: F.C. and
D.F. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest in regard to this work.
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