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Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
Corresponding author at: Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine, Beijing Chaoyang Hospital, Capital Medical University, No. 8, Gong Ti South Road, Chaoyang District, Beijing 100020, China.
Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
Convalescent blood product therapy has been one of the central interventions against COVID-19.
•
CBP therapy might not decrease the all-cause mortality among patients with respiratory infections of viral etiology.
•
CBP therapy did not increase the risk of adverse events.
•
Earlier initiation of convalescent blood products could decrease the all-cause mortality compared with later initiation.
•
High-quality randomized controlled trials are urgently needed to evaluate the roles of CBP therapy in patients with COVID-19.
Abstract
Objectives
The aim of this study was to determine whether convalescent blood products (CBPs) offer a survival advantage for patients with severe acute respiratory infections of viral etiology.
Methods
Up-to-date trials were identified by the authors through searches of the MEDLINE, Embase, Cochrane Library, Web of Science, ClinicalTrials.gov, and medRxiv databases from inception up to September 14, 2020. Meta-analyses were performed using a random-effects model.
Results
According to the observational studies, patients who received CBPs showed a decline in all-cause mortality compared with patients who did not receive CBPs (odds ratio (OR) 0.36, 95% confidence interval (CI) 0.23–0.56; p < 0.00001). However, the randomized controlled trials (RCTs) showed no difference between the intervention group and the control group regarding all-cause mortality (OR 0.82, 95% CI 0.57–1.19; p = 0.30). The use of CBPs did not increase the risk of adverse events (OR 0.88, 95% CI 0.60–1.29; p = 0.51). Using CBPs earlier compared with using CBPs later was associated with a significant reduction in all-cause mortality (OR 0.18, 95% CI 0.08–0.40; p < 0.0001).
Conclusions
Based on the outcomes of RCTs, CBPs may not decrease all-cause mortality. Furthermore, compared with later initiation of CBP therapy, earlier initiation of this therapy may decrease the rate of mortality.
At the time of writing, more than 29 million people had been diagnosed with coronavirus disease 2019 (COVID-19) worldwide in the ongoing pandemic, which started in December 2019, and the overall mortality was 3.1% (
). The disease progresses rapidly in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and affected patients may suffer from acute respiratory distress syndrome (ARDS), acute respiratory failure, multi-organ dysfunction, and even death within a short period (
Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.
). Current management consists of supportive therapy, including oxygen supplementation, antibiotics, antifungal treatment, and extracorporeal membrane oxygenation (ECMO) (
Convalescent plasma (CP) therapy is currently a treatment option proposed for severely affected COVID-19 patients who are experiencing a more rapid and concerning disease progression. This therapy has been one of the central interventions against COVID-19 in the absence of a vaccine and pharmacological interventions (
). The transfusion of convalescent blood products (CBPs) is a type of passive antibody therapy that has been used among patients since the time of the Spanish flu (1917–1918) (
). Antibody-rich CBPs represent the only treatment that can be applied immediately among patients with infections of viral etiology, allowing them to obtain antibodies and generate passive immunity. The antibodies from CBPs can bind to the virus directly and neutralize it. At the same time, the antibodies can also clear the virus through opsonization or antibody-dependent cell-mediated cytotoxicity (ADCC).
Recently, several observational studies have suggested that CP could decrease the risk of mortality among patients with COVID-19 (
Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.
). Many previous studies have tested the safety and clinical treatment effect of CP among patients with other viral diseases, such as severe acute respiratory syndrome (SARS), influenza, and Ebola hemorrhagic fever (EBHF) (
Due to the urgency of the epidemic, people urgently want to know whether CBPs are effective for patients with severe acute respiratory infections (SARI) of viral etiology, especially for patients with COVID-19. However, in order to develop suggestions for doctors regarding the transfusion of CBPs in patients with COVID-19, there is a need to collect and pool the results of eligible studies comprehensively. Therefore, a series of systematic reviews was performed. There is currently little direct evidence to assess the efficacy and safety of CBPs among patients with COVID-19. As the route of disease transmission and clinical features are similar in COVID-19, SARS, Middle East respiratory syndrome (MERS), and influenza, related eligible studies on these SARI were comprehensively included to provide new evidence for the clinical treatment of COVID-19 patients.
Methods
This study is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, developed by the Equator Network (Supplementary Material File S1). This work was registered in the International Prospective Register of Systematic Reviews (CRD42020172940). Ethical approval was not required.
Search strategy
A systematic search for relevant studies published between January 1, 1918 and September 14, 2020 was performed in the MEDLINE, Embase, Cochrane Library, Web of Science, ClinicalTrials.gov, and medRxiv databases. The search strategy combined concepts related to respiratory diseases of viral etiology (i.e., MERS coronavirus (MERS-CoV), SARS coronavirus (SARS-CoV), and SARS-CoV-2, influenza, human) and CBPs (i.e., CP, convalescent serum, convalescent blood, and immunization, passive) (Supplementary Material File S2). No filter was applied for the type of study or language.
Eligibility criteria
The inclusion criteria were as follows: (1) RCTs or observational studies; (2) patients of any age and sex who had a laboratory-confirmed or clinically suspected SARI (the definitions of influenza-like illness and severe acute respiratory infection issued by the World Health Organization (WHO) (
); (3) intravenous CP or convalescent serum or convalescent blood or hyperimmune intravenous immunoglobulin (H-IVIG) or a mixture was used in the intervention group; (4) a control group was included, with placebo, no treatment, other treatment, or later initiation of CBPs applied; (5) the donors had to have been diagnosed previously with the corresponding disease.
Study selection
First, the search results were manually screened by two authors (SS, YSW) independently to identify eligible studies for further analysis. The citations of each included study were also reviewed carefully. Any disagreement was resolved by discussion with a third author (ZHT).
Data extraction and quality assessment
The data extraction was performed by two authors using a double-entry procedure (SS, HYJK). In addition, the results of the data extraction were verified by a third author (YSW). The following data were extracted: author, publication year, country, the number of centers, study method, viral etiology, diagnostic criteria, type of CBP, treatment strategy with CBP, transfusion-related adverse events, number of patients in each group, quality score, outcome data, and treatment strategy in the intervention and control groups. The risk of bias in eligible RCTs was examined using the Cochrane Collaboration risk of bias tool (
The primary outcome was all-cause mortality. Secondary outcomes included the timing of initiation of CBPs (earlier versus later), adverse events, length of intensive care unit (ICU) stay, length of hospital stay, and days on mechanical ventilation (MV).
Statistical synthesis and analysis
Continuous variables were recorded as the mean ± standard deviation (SD). Values for categorical variables were recorded as the odds ratio (OR) with 95% confidence interval (CI). The meta-analyses were performed using random-effects models. A two-tailed p-value of less than 0.05 was considered statistically significant for all results. A correction factor (1.0) was applied to zero-event trials to enforce the effect of the OR (
). The I2 derived from Chi-square tests was applied to assess the heterogeneity between trials, with a value of >50% regarded as indicating high heterogeneity. Univariate meta-regression using a random-effects model analysis was used to reveal the potential sources of heterogeneity. The publication bias for the outcome, in analyses that included more than five studies, was judged by funnel plot and Egger’s test (
). The quality of evidence for the outcomes was further assessed according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework. A trial sequential analysis (TSA) was also performed, in which it was chosen to calculate the required information size by using an 18% relative risk reduction (RRR) for falls (calculated from the eight RCTs (
Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.
Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial.
Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection.
Convalescent plasma in the management of moderate COVID-19 in India: an open-label parallel-arm phase II multicentre randomized controlled trial (PLACID Trial).
)). The control group rate was assumed to be 10.3%. The TSA was performed with a two-sided alpha of 0.05 and a beta of 0.20 (power 80%) to limit type I errors and type II errors. The statistical analyses were completed using Review Manager version 5.3, Stata version 15.1, GRADE Profiler version 3.6, and TSA 0.9.5.10 Beta.
Subgroup and sensitivity analysis
The following variables were selected before the subgroup analysis was undertaken to explore the potential sources of heterogeneity: the type of CBP, the different types of viral disease, and the study quality score. A test of interaction was performed to judge the differences in treatment effect across these subgroups (
Clinical and molecular characteristics associated with survival among patients treated with checkpoint inhibitors for advanced non-small cell lung carcinoma: a systematic review and meta-analysis.
). When I2 ≥50%, sensitivity analyses were performed by sequentially removing one study at a time to identify the studies that influenced the results significantly.
Results
Study selection and characteristics
A flow chart of the literature search and selection process is shown in Figure 1. The Insight Flu 005 trial was not included in the present exploratory meta-analysis due to the lack of sufficient data for the outcomes that were required (
Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection.
Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection.
IV; two units of ABO-compatible plasma (volume range 225–350 ml/unit or 8 ml/kg pediatric equivalent) on study day 0 (HI titer of at least 1:40)
42/45
Anti-influenza plasma plus standard care (included a NAI)
Standard care alone (included a NAI)
ARDS, stroke, hyperglycemia, increased AST, diarrhea, anemia, and fever
High risk of bias
Beigel 2019
USA
41 ICUs
RCT
Influenza A(H1N1), A(H3N2) virus
Rapid antigen or PCR
Plasma
IV; infusion rate ≤500 ml/h; pediatric patients weighing <30 kg received 8 ml/kg plasma in one infusion, and those weighing ≥30 kg received two infusions of 4 ml/kg
91/47
High-titer anti-influenza plasma (antibody titer ≥1:80) plus standard care (a licensed anti-influenza antiviral drug)
Low-titer anti-influenza plasma (antibody titer ≤1:10) plus standard care (a licensed anti-influenza antiviral drug)
ARDS, allergic transfusion reactions, anemia, and respiratory distress
Unclear risk of bias
Davey 2019
USA
34 ICUs
RCT
Influenza A (i.e., A(H1N1) pdm09, A(H3N2)) or B virus
Nucleic acid testing or by rapid antigen test
H-IVIG
IV; 500 ml; one dose of 0.4 g/kg of H-IVIG was given after randomization over a period of approximately 2 h
156/152
Received 500 ml H-IVIG and standard care (95% patients received oseltamivir)
Received 500 ml saline and standard care (95% patients received oseltamivir)
Adverse events always found in respiratory system and mediastinum
High risk of bias
Insight Flu 005 2015
USA
8 ICUs
RCT
Influenza A or B
RT-PCR or rapid antigen testing of upper respiratory tract specimens
H-IVIG
IV; 500 ml; one dose of 0.25 g/kg of H-IVIG
16/15
Received 500 ml H-IVIG and standard care
Received 500 ml placebo and standard care
One patient had elevated bilirubin level, elevated platelet count, and renal failure; the other two experienced hyperkalemia and worsened dysthymic disorder, respectively
Unclear risk of bias
Li 2020
China
7 ICUs
RCT
SARS-CoV-2
RT-PCR
Plasma
IV; approximately 4–13 ml/kg of recipient body weight; plasma units with an S-RBD-specific IgG titer of ≥1:640; the median plasma infusion volume was 200 ml (IQR 200–300 ml), and 96% of patients received a single dose of plasma infusion
51/50
CP plus standard care (antiviral drug, antibacterial drug, steroids, human Ig, Chinese herbal medicines)
Standard care alone (antiviral drug, antibacterial drug, steroids, human Ig, Chinese herbal medicines)
One patient in the severe COVID-19 group had chills and rashes within 2 h of transfusion; the other one in the life-threatening group presented with shortness of breath, cyanosis, and severe dyspnea within 6 h of transfusion
High risk of bias
Hung 2013
China (Hong Kong)
5 ICUs
RCT
Influenza A(H1N1) pdm09 virus
RT-PCR
H-IVIG
IV; one dose of 0.4 g/kg of H-IVIG
17/17
Received 0.4 g/kg H-IVIG (NAT >1:40) plus oseltamivir
Received 0.4 g/kg normal IV Ig (NAT <1:10) plus oseltamivir
None
High risk of bias
12/5
Received 0.4 g/kg H-IVIG within 5 days of symptom onset
Received 0.4 g/kg H-IVIG after 5 days of symptom onset
Gharbharan 2020 (medRxiv)
Holland
14 ICUs
RCT
SARS-CoV-2
RT-PCR
Plasma
IV; 300 ml of plasma with anti-SARS-CoV-2 NAT of ≥1:80
43/43
CP plus standard care (e.g. chloroquine, azithromycin, LPV/r, tocilizumab, anakinra)
Standard care alone (e.g. chloroquine, azithromycin, LPV/r, tocilizumab, anakinra)
None
High risk of bias
Avendaño-Solà 2020 (medRxiv)
Spain
14 ICUs
RCT
SARS-CoV-2
RT-PCR
Plasma
IV; received one dose (250–300 ml) of plasma from donors with IgG anti-SARS-CoV-2
38/43
CP plus standard care (e.g. chloroquine, azithromycin, LPV/r, tocilizumab, anakinra)
Standard care alone (e.g. chloroquine, azithromycin, LPV/r, tocilizumab, anakinra)
Sixteen serious or grade 3–4 adverse events were reported in 13 patients, 6 in the intervention group and 7 in the control group
High risk of bias
Agarwal 2020 (medRxiv)
India
39 ICUs
RCT
SARS-CoV-2
RT-PCR
Plasma
IV; two doses of 200 ml CP was transfused 24 h apart in the intervention arm
235/229
CP plus standard care (including antiviral drug, broad-spectrum antibiotics, immuno-modulators and supportive management)
Standard care alone (including antiviral drug, broad-spectrum antibiotics, immuno-modulators and supportive management)
16% of treated patients had chills, shakes, and temporary increase; transfusion reaction may have hastened death in 4 seriously ill patients
5
31/25
Treated within 48 h after the development of the pneumonia
Treated at >48 h after the development of the pneumonia
Gould 1918
USA
1 ICU
OS
Spanish influenza A(H1N1) virus
Clinical diagnosis
Serum
IV; convalescent serum 100 ml; 1–3 doses every 24 h
30/290
Convalescent serum plus standard care
Standard care alone
NA
5
Ross 1919
USA
1 ICU
OS
Spanish influenza A(H1N1) virus
Clinical diagnosis
Blood
IV; convalescent blood 250–500 ml; 1–3 doses every 12–24 h
28/21
Convalescent blood plus standard care (e.g. sodium salicylate)
Standard care alone (e.g. sodium salicylate)
Slight chills followed by profuse perspiration and drop in temperature; a feeling of constriction in the chest and slight respiratory distress occurred
5
21/7
Transfusion within 7 days of symptom onset
Transfusion after 7 days of symptom onset
Sanborn 1920
USA
NA
OS
Spanish influenza A(H1N1) virus
Clinical diagnosis
Serum
IV; convalescent serum 100 ml for adults, 50 ml for children (8–24-h intervals); 1–6 doses every 24 h
55/46
Received convalescent serum within the second day of pneumonia onset
Received convalescent serum after the second day of pneumonia onset
10% of the treated patients experienced a mild chill reaction
5
Maclachlan 1918
USA
1 ICU
OS
Spanish influenza A(H1N1) virus
Clinical diagnosis
Blood
IV; convalescent blood 75–100 ml; 1–4 doses
40/7
Received convalescent blood within 2.5 days of pneumonia onset
Received convalescent blood after 2.5 days of pneumonia onset
Some treated patients developed a chill reaction with a body temporary increase
5
Cheng2005
China (Hong Kong)
1 ICU
OS
SARS-CoV
CDC case definition and serology
Plasma
IV; 200–400 ml (4–5 ml/kg)
48/32
Received CP before day 14 of illness onset
Received CP after day 14 of illness onset
None
7
McGuire and Redden 1919
United Kingdom
1 ICU
OS
Spanish influenza A(H1N1) virus
Clinical diagnosis
Serum
IV; 100–250 ml; 1–7 doses every 8–16 h
151/400
Convalescent serum plus standard care
Standard care alone
Experienced chills and temporary increase; jaundice and phlebitis
5
Duan 2020
China
1 ICU
OS
SARS-CoV-2
RT-PCR
Plasma
IV; 200 ml; one dose of inactivated plasma with neutralization activity of >1:640 within 4 h
10/10
CP plus standard care (antibiotic treatment, antifungal treatment, glucocorticoid, and oxygen support)
Standard care alone (antibiotic treatment, antifungal treatment, glucocorticoid, and oxygen support)
Just one patient showed an evanescent facial red spot
7
Sahra2016
Sierra Leone (Freetown)
2 ICUs
OS
Ebola virus
RT-PCR
Blood
IV; 450 ml of ABO-compatible blood; transfusion over a period of 1–4 h
43/25
Convalescent blood plus standard care (multivitamins, antipyretics, analgesics, antibiotics, anthelmintics, and antimalarial drugs)
Standard care alone (multivitamins, antipyretics, analgesics, antibiotics, anthelmintics, and antimalarial drugs)
None
7
Abolghasemi 2020
Iran
6 ICUs
OS
SARS-CoV-2
RT-PCR
Plasma
IV; 500 ml was infused within 4 h
115/74
CP plus standard care (antiviral drug)
Standard care alone (antiviral drug)
Only one patient had transient mild fever and chills after transfusion
7
Zeng 2020
China
2 ICUs
OS
SARS-CoV-2
RT-PCR
Plasma
IV; median volume 300 ml
6/15
CP plus standard care (antiviral drug, antibacterial drug, steroids, human Ig, Chinese herbal medicines)
Standard care alone (antiviral drug, antibacterial drug, steroids, human Ig, Chinese herbal medicines)
None
8
ARDS, acute respiratory distress syndrome; AST, aspartate aminotransferase; C, control; CBP, convalescent blood product; CDC, US Centers for Disease Control and Prevention; COVID-19, coronavirus disease 2019; CP, convalescent plasma; ETU, Ebola treatment unit; HI, hemagglutination inhibition; H-IVIG, hyperimmune intravenous immunoglobulin; I, intervention; ICU, intensive care unit; Ig, immunoglobulin; IQR, interquartile range; IV, intravenous; LPV/r, lopinavir/ritonavir; NA not available; NAI, neuraminidase inhibitor; NAT, neutralizing antibody titer; OS, observational study; RCT, randomized controlled trial; SARS, severe acute respiratory syndrome; SARS-CoV, severe acute respiratory syndrome coronavirus; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; S-RBD, USA, .
Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.
Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial.
Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection.
) (Supplementary Material File S3 and File S4). More details are shown in Table 3. The quality of the 19 observational studies was assessed according to the NOS. Seven studies (
The losses to follow-up appeared to be higher in the control group compared to the intervention group, although the authors did not think it would affect the outcomes.
Seventeen patients from one site were excluded as their eligibility could not be confirmed. According to the sensitivity analyses, their exclusion had little impact on estimated odds ratios for the primary endpoint.
The antibody titers in convalescent plasma could not be measured before transfusion.
a Study used an unblinded design.
b The losses to follow-up appeared to be higher in the control group compared to the intervention group, although the authors did not think it would affect the outcomes.
c Insufficient information to judge.
d Seventeen patients from one site were excluded as their eligibility could not be confirmed. According to the sensitivity analyses, their exclusion had little impact on estimated odds ratios for the primary endpoint.
e The subgroup with influenza B only included 27% of all participants in the trial (84 patients).
f The sample size was small (34 patients).
h Missing data for secondary outcomes and adverse events were not imputed.
i The study was stopped prematurely.
j The antibody titers in convalescent plasma could not be measured before transfusion.
Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection.
). All of them used a time-point to define ‘earlier’ and ‘later,’ but the specific time-point cut-offs were not the same among the studies. Specifically, the median time-point of ‘earlier’ treatments when patients received CBPs after symptom onset was 3.8 days (IQR 2.1–6.5 days) (
Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection.
). As a result, earlier treatment was defined as receiving CBPs within 4 days of illness onset and later treatment was defined as receiving CBPs at ≥4 days following illness onset.
Definition of ‘high dose of CBPs’ versus ‘low dose of CBPs’
Two studies provided the mean total volume of CBP transfusion (125 ml (
Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial.
Convalescent plasma in the management of moderate COVID-19 in India: an open-label parallel-arm phase II multicentre randomized controlled trial (PLACID Trial).
). The median volume of CBP was 400 ml (IQR 200–500 ml). A low dose was defined as a total volume of less than 200 ml, because one unit of CBP was almost 200 ml. Greater volumes were considered a high dose.
Synthesis of results
Primary outcome
The pooled data extracted from the RCTs revealed that there was no significant reduction in all-cause mortality in the intervention group when compared with the control group (OR 0.82, 95% CI 0.57–1.19; p = 0.30; I2 = 0%) (Figure 2A ) (
Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.
Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial.
Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection.
Convalescent plasma in the management of moderate COVID-19 in India: an open-label parallel-arm phase II multicentre randomized controlled trial (PLACID Trial).
). After the eight studies were divided into COVID-19 and influenza subgroups, CBPs did not significantly reduce all-cause mortality either in patients with COVID-19 (
Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.
Convalescent plasma in the management of moderate COVID-19 in India: an open-label parallel-arm phase II multicentre randomized controlled trial (PLACID Trial).
Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial.
Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection.
) (OR 0.87, 95% CI 0.42–1.80; p = 0.71; I2 = 0%) when compared to the control group (Supplementary MaterialFile S6). However, the data on all-cause mortality extracted from the observational studies revealed a significant decrease in mortality in the intervention group when compared with the control group (OR 0.36, 95% CI 0.23–0.56; p < 0.00001; I2 = 52%) (Figure 2B) (
), the results revealed that the heterogeneity decreased from 52% to 14% (OR 0.48, 95% CI 0.35–0.66; p < 0.00001; I2 = 14%) (Supplementary Material File S7). This may be because the patients in the intervention group and the patients in the control group did not come from the same time period, although they all came from the same hospital. As a result, it was best to exclude this trial to ensure the robustness of the outcome of all-cause mortality (Table 4).
Table 4Outcomes or subgroup analysis of included studies [Au?19].
Outcomes or subgroup analysis or sensitivity analysis
Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.
Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial.
Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection.
Convalescent plasma in the management of moderate COVID-19 in India: an open-label parallel-arm phase II multicentre randomized controlled trial (PLACID Trial).
Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection.
Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.
Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial.
Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection.
Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection.
Convalescent plasma in the management of moderate COVID-19 in India: an open-label parallel-arm phase II multicentre randomized controlled trial (PLACID Trial).
Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection.
Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.
Convalescent plasma in the management of moderate COVID-19 in India: an open-label parallel-arm phase II multicentre randomized controlled trial (PLACID Trial).
Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial.
Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection.
Potential sources of heterogeneity were explored by subgroup analysis (Figure 3). The results of the subgroup analysis revealed that CP (OR 0.43, 95% CI 0.25–0.71; p = 0.001; I2 = 28%), convalescent serum (OR 0.11, 95% CI 0.05–0.23; p < 0.00001; I2 = 0%), and convalescent blood (OR 0.41, 95% CI 0.18–0.90; p = 0.03; I2 = 0%) could decrease all-cause mortality when compared with the control group. The interaction test showed that there might be differences between the subgroups of the various types of CBP compared with control group for this outcome (p = 0.002). The type of viral etiology and the quality of the study were not the source of heterogeneity (Supplementary Material File S8).
Figure 3Subgroup analysis of all-cause mortality according to the types of convalescent blood products.
The meta-regression regarding all-cause mortality of observational studies observed that the treatment effect was not affected by the dose of CBP (high or low dose) (p = 0.697), publication year (p = 0.329), study sample size (p = 0.945), race (p = 0.896), mean age (p = 0.324), proportion of males (%) (p = 0.117), proportion of pregnant women (%) (p = 0.866), or the proportion of patients under 18 years old (%) (p = 0.535). The funnel plot for RCTs, which compared the CBPs with placebo (or no treatment), showed an absence near the bottom right, but the Egger linear regression test did not show any evidence of potential publication bias (p = 0.077) (Figure 4A ). The same situation was found for the results of all-cause mortality in the observational studies, and the Egger linear regression test did not find any evidence of substantial publication bias (p = 0.195) (Figure 4B).
Figure 4Funnel plots for all-cause mortality in RCTs and observational studies: (A) funnel plot for all-cause mortality in RCTs; (B) funnel plot for all-cause mortality in observational studies.
In terms of the optimal timing of initiation of CBPs, the pooled results revealed that there might be an improvement in the ‘earlier’ group when compared with the ‘later’ group (OR 0.18, 95% CI 0.08–0.40; p < 0.0001; I2 = 39%) (Figure 5) (
Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection.
The pooled analysis revealed no significant difference between the groups in the length of ICU stay (mean difference (MD) 0.35, 95% CI − 0.70 to 1.40; p = 0.51; I2 = 0%) (
Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection.
Convalescent plasma in the management of moderate COVID-19 in India: an open-label parallel-arm phase II multicentre randomized controlled trial (PLACID Trial).
Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection.
Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.
Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial.
Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection.
) (Figure 6). However, there was a significant improvement in the intervention group versus the control group regarding days on MV (MD − 4.20, 95% CI − 7.45 to −0.94; p = 0.01; I2 = 19%) (
Visual inspection indicated symmetry in the funnel plots of the secondary outcomes of the optimal timing of initiation of CBPs and adverse events, and the p-value of Egger linear regression was 0.768 and 0.679, respectively (Supplementary Material File S10).
Quality of the evidence in this meta-analysis
The quality of the evidence for the five outcomes ranged from very low to moderate. The quality of the evidence for all-cause mortality in RCTs was assessed as low (Table 5). Furthermore, the quality of evidence for all-cause mortality in the observational studies was assessed as very low (Table 5). Details for the secondary outcomes can be found in Supplementary Material File S11.
Table 5Quality of evidence for primary outcomes by GRADE system.
Mortality following treatment with CBPs for severe acute respiratory infections of viral etiology
Patient or population: patients with severe acute respiratory infections of viral etiology Intervention: Mortality following treatment with CBPs
The basis for the assumed risk (e.g., the median control group risk across studies) is provided in the footnotes below. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
GRADE Working Group grades of evidence: ‘high quality’: further research is very unlikely to change our confidence in the estimate of effect; ‘moderate quality’: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; ‘low quality’: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; ‘very low quality’: we are very uncertain about the estimate.
Seven RCTs were categorized as having a high risk of bias. The other one was evaluated as having an unclear risk of bias, due to insufficient information to judge whether there was other bias in the RCT.
Only 34 patients were included in the study of Hung et al., which was published in 2013, and only 21 patients were included in the study of Li et al., which was published in 2020.
123 per 1000
103 per 1000 (74–143)
Moderate
111 per 1000
87 per 1000 (54–146)
Mortality following treatment with CBPs – observational studies
The quality of 16 observational studies was assessed according to the Newcastle–Ottawa Scale; six studies were classified as high quality and 10 studies were classified as moderate quality.
a The basis for the assumed risk (e.g., the median control group risk across studies) is provided in the footnotes below. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
b GRADE Working Group grades of evidence: ‘high quality’: further research is very unlikely to change our confidence in the estimate of effect; ‘moderate quality’: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; ‘low quality’: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; ‘very low quality’: we are very uncertain about the estimate.
c Seven RCTs were categorized as having a high risk of bias. The other one was evaluated as having an unclear risk of bias, due to insufficient information to judge whether there was other bias in the RCT.
d Only 34 patients were included in the study of Hung et al., which was published in 2013, and only 21 patients were included in the study of Li et al., which was published in 2020.
e The quality of 16 observational studies was assessed according to the Newcastle–Ottawa Scale; six studies were classified as high quality and 10 studies were classified as moderate quality.
f The experimental results were inconsistent.
g Half of the eligible studies included fewer than 50 participants.
A TSA was performed for all-cause mortality for the eight RCTs. The Z-curve of all-cause mortality between the intervention group and the control group did not cross the trial sequential monitoring boundary, the conventional boundary, or the line of estimated information size, revealing that the result may be a false-negative and that more RCTs are needed to prove it (Figure 7).
Figure 7Trial sequential analysis of all-cause mortality.
In this meta-analysis, a reduction in all-cause mortality associated with CBPs was found for the observational studies but not for the RCTs. Moreover, the results indicate that earlier treatment, when compared with later treatment, might decrease the all-cause mortality of SARI patients. In terms of days on MV, the pooled results revealed that there might be an improvement for patients receiving CBPs when compared to those not receiving this treatment. The pooled estimates of eligible studies indicated that no significant difference could be found between the groups with regard to the length of ICU stay, length of hospital stay, or risk of adverse events.
Discussion of the important differences in the results
The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis.
The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis.
Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.
Efficacy and safety of convalescent plasma for severe COVID-19 based on evidence in other severe respiratory viral infections: a systematic review and meta-analysis.
Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.
Convalescent plasma in the management of moderate COVID-19 in India: an open-label parallel-arm phase II multicentre randomized controlled trial (PLACID Trial).
Efficacy and safety of convalescent plasma for severe COVID-19 based on evidence in other severe respiratory viral infections: a systematic review and meta-analysis.
) included four RCTs, and the pooled results showed that CP did not decrease mortality in the intervention group compared with the control group, which is similar to the result of the present study. However, this finding differs from that for all-cause mortality derived from observational studies. Possible reasons for this difference are as follows. According to the TSA, the RCT analysis might have led to false-negative results, and more patients are needed to clarify the therapeutic effect of CBPs. In addition, three RCTs used H-IVIG with a high hemagglutination inhibition titer (HAI) in the intervention groups (
Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial.
). However, although the HAI can indicate the quantity of antibodies, it cannot determine the quality of antibodies very well. At the same time, the HAI in these three studies might not have been high enough to treat patients with SARI of viral etiology (
). Also, standard care, including neuraminidase inhibitors, antibiotic treatment, antifungal treatment, etc., was used in both groups, but whether these concomitant therapies could have influenced the clinical outcomes was unclear. Although there might be several limitations in these RCTs, the limitations of observational studies, including the lack of randomization to contemporary control groups, is a far greater concern, and this cannot be ignored. As a result, more high quality and large sample size RCTs should be performed in the future.
In theory, CBPs might improve the clinical outcomes of patients by increasing antibody titers, decreasing the viral load, and reducing the levels of inflammatory factors in the patient’s body. A recent study observed that five COVID-19 patients, after receiving CP, had higher antibody titers than did pre-transfusion patients (range 40–60 before transfusion and 80–320 on day 7 after transfusion) (
). A similar outcome was found in another study, which showed that 87.2% of the CP group was negative for viral nucleic acid at 72 hours after transfusion, while this rate was only 37.5% in the control group (
Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.
). Moreover, several studies have found that the cytokine storm mediated by interleukin (IL)-2, IL-7, IL-10, G-SCF, IP10, MCP-1, MIP (macrophage inflammatory protein)-1A, and tumor necrosis factor alpha (TNF-α) was the crucial mechanism of disease progression in patients with severe COVID-19 (
). In a cohort study that recruited patients with influenza A(H1N1) pdm09, a subgroup analysis of 44 patients revealed that the corresponding day 5 IL-6, day 5 IL-10, day 5 TNF-α, day 7 IL-10, and day 9 IL-10 levels were significantly lower in patients who received CP than in the patients in the control group (
Additionally, the present study results indicated that the earlier usage of CBPs could offer a greater improvement for patients with SARI when compared with the later usage of CBPs, which is consistent with the results of previous meta-analyses (
The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis.
). The newest study focusing on COVID-19 patients showed that those who received CP before 14 days post-onset of illness had better treatment outcomes than those who received transfusions later (
). This may be because, in the early stage of infection, the body’s immune response is not severe, and the tissues and organs are not severely damaged. At this time, the antibody could neutralize the virus’ infectivity directly and bring clinical benefits to the patient through antibody-mediated pathways like complement activation and ADCC. Using CBPs later might allow the course of the illness to progress too far for the patient to benefit from the treatment. Although the neutralizing antibody could still bind to the pathogen through the mechanisms mentioned above, the tissues and organs of the patient might have been damaged irreversibly due to virus reproduction and a severe inflammatory reaction. Serious complications, such as sepsis and coagulation dysfunction, may have occurred at the same time.
According to the existing study results, CBPs seem to be safe in treating patients with SARI of viral etiology, and no study has reported life-threatening CBP-related adverse events. Joyner et al. analyzed safety metrics in 5000 hospitalized adults with severe or life-threatening COVID-19 after the transfusion of ABO-compatible CP (
). Thirty-six patients (<1%) reported severe adverse events (SAEs), and half of them were transfusion-associated circulatory overload (TACO) (seven patients) or transfusion related acute lung injury (TRAIL) (11 patients). Simultaneously, according to the judgment of the treating physician, only two of 18 SAEs were directly related to the transfusion of CP. ‘Antibody-dependent enhancement’ (ADE) is another concern for the transfusion of CP in COVID-19 patients. This is largely a theoretical risk of severe COVID-19 patients experiencing ADE after previous exposure to one or more strains of the coronavirus with heterogeneity of the antigenic epitope (
). In theory, if enough neutralizing antibodies are present in the CP from donors, and the patient who receives the CP is infected with the same SARS-CoV-2 strain of virus, the virus may be destroyed (
). However, if the protective neutralizing antibody titer in the CP is low or the recipient is infected with a different SARS-CoV-2 strain (e.g., RBD mutant), low levels of SARS-CoV-2/antibody complexes may be induced (
). This complex could bind to angiotensin-converting enzyme 2 (ACE2), and ADE can subsequently be observed through internalization of the complex and IgG-induced stimulation (
). The potential threat of ADE needs to be investigated further, especially given the many survivors who have developed immunity.
Strengths and limitations of this study
To our knowledge, this meta-analysis recruited the largest number of relevant studies by far, and seven studies on patients with COVID-19 were included (
). We updated the outcomes, such as the optimal timing of CBP initiation. TSA software was applied in the present study to assess the robustness of the relevant results. However, there are some limitations. First, several eligible studies involved very few patients, so we cannot ignore the possibility of a ‘small sample effect,’ and their sampling error should be fully considered (
). In addition, the current results may not be conclusive. The TSA analysis revealed that more patients were required to validate the use of CBPs in patients with SARI. Moreover, three of the RCTs have not been peer-reviewed, which might affect the robustness of the result (
). Although this meta-analysis recruited studies including multiple types of viral CBP, which might be non-specific for any viral disease, subgroup analyses were performed to resolve this problem. As we know little about the treatment effects of CP in COVID-19, more high-quality RCTs with a larger sample size are needed to assess the efficacy, safety, optimal time of initiation, and best dose of CP in COVID-19 patients.
Conclusions
Taken together, the low-quality evidence in this study shows that the transfusion of CBPs may not reduce all-cause mortality. Although the transfusion of CP is associated with a low rate of adverse events, the widespread use of CP in patients should be based on high-quality RCTs. If clinicians decide to transfuse CP to patients, earlier initiation might be better.
Author contributions
Shuai Shao developed the initial idea for this study and conducted a comprehensive search of the databases. Shuai Shao and Yishan Wang were responsible for the study selection. Shuai Shao extracted the data. All authors made contributions to the research design, interpretation of results, and ideas for writing studies. Shuai Shao synthesized and analyzed the data and drafted the manuscript. Yishan Wang, Hanyujie Kang, and Zhaohui Tong reviewed the study and provided suggestions. All authors carefully examined this manuscript and agreed with the ideas presented in the study.
Funding
Zhaohui Tong received support for this study from the National Natural Science Foundation of China (grant number 81870004).
Ethical approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Availability of data and materials
The datasets generated and/or analyzed during the current study are available in the MEDLINE, Embase, Cochrane Library, Web of Science, ClinicalTrials.gov, and medRxiv databases.
Conflict of interest
None of the authors has any competing interests.
Acknowledgement
Zhaohui Tong received support for this study from the National Natural Science Foundation of China (grant number 81870004).
Appendix A. Supplementary data
The following are Supplementary data to this article:
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