Front. Med. Frontiers in Medicine Front. Med. 2296-858X Frontiers Media S.A. 10.3389/fmed.2021.624924 Medicine Systematic Review Mortality Benefit of Convalescent Plasma in COVID-19: A Systematic Review and Meta-Analysis Bansal Vikas 1 † Mahapure Kiran S. 2 † Mehra Ishita 3 † Bhurwal Abhishek 4 Tekin Aysun 1 Singh Romil 5 Gupta Ishita 6 Rathore Sawai Singh 7 Khan Hira 8 Deshpande Sohiel 9 Gulati Shivam 10 Armaly Paige 11 Sheraton Mack 12 Kashyap Rahul 1 * 1Department of Anaesthesiology and Critical Care Medicine, Mayo Clinic, Rochester, MN, United States 2Senior Resident, Department of Plastic Surgery, KAHER J. N. Medical College, Belgaum, India 3Department of Internal Medicine, North Alabama Medical Center, Florence, AL, United States 4Department of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson School of Medicine, New Brunswick, NJ, United States 5Department of Internal Medicine, Metropolitan Hospital, Jaipur, India 6Department of Internal Medicine, Dr. Rajendra Prasad Government Medical College, Tanda, India 7Department of Internal Medicine, Dr. Sampurnanand Medical College, Jodhpur, India 8Department of Internal Medicine, Riphah International University Islamic International Medical College, Rawalpindi, Pakistan 9Department of Internal Medicine, Maharashtra Institute of Medical Education and Research, Pune, India 10Department of Internal Medicine, Adesh Institute of Medical Sciences and Research, Bathinda, India 11Department of Internal Medicine, University of the West Indies, Nassau, Bahamas 12Department of Emergency Medicine, Trinity West Medical Center MSOPTI EM Program, Steubenville, OH, United States

Edited by: Chaowei Yang, George Mason University, United States

Reviewed by: Randall J. Olsen, Houston Methodist Research Institute, United States; Mohammad Saud Khan, Brown University, United States

 *Correspondence: Rahul Kashyap kashyap.rahul@mayo.edu

This article was submitted to Intensive Care Medicine and Anesthesiology, a section of the journal Frontiers in Medicine

†These authors have contributed equally to this work

 09 04 2021 2021 8 624924 20 11 2020 17 02 2021 Copyright © 2021 Bansal, Mahapure, Mehra, Bhurwal, Tekin, Singh, Gupta, Rathore, Khan, Deshpande, Gulati, Armaly, Sheraton and Kashyap. 2021 Bansal, Mahapure, Mehra, Bhurwal, Tekin, Singh, Gupta, Rathore, Khan, Deshpande, Gulati, Armaly, Sheraton and Kashyap

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Importance/Background: With a scarcity of high-grade evidence for COVID-19 treatment, researchers and health care providers across the world have resorted to classical and historical interventions. Immunotherapy with convalescent plasma (CPT) is one such therapeutic option.

Methods: A systematized search was conducted for articles published between December 2019 and 18th January 2021 focusing on convalescent plasma efficacy and safety in COVID-19. The primary outcomes were defined as mortality benefit in patients treated with convalescent plasma compared to standard therapy/placebo. The secondary outcome was pooled mortality rate and the adverse event rate in convalescent plasma-treated patients.

Results: A total of 27,706 patients were included in the qualitative analysis, and a total of 3,262 (2,127 in convalescent plasma-treated patients and 1,135 in the non-convalescent plasma/control group) patients died. The quantitative synthesis in 23 studies showed that the odds of mortality in patients who received plasma therapy were significantly lower than those in patients who did not receive plasma therapy [odds ratio (OR) 0.65, 95% confidence interval (CI) 0.53–0.80, p < 0.0001, I2 = 15%). The mortality benefit remains the same even for 14 trials/prospective studies (OR 0.59, 95% CI 0.43–0.81, p = 0.001, I2 = 22%) as well as for nine case series/retrospective observational studies (OR 0.78, 95% CI 0.65–0.94, p = 0.01, I2 = 0%). However, in a subgroup analysis for 10 randomized controlled trials (RCTs), there was no statistically significant reduction in mortality between the CPT group compared to the non-CPT group (OR 0.76, 95% CI 0.53–1.08, p = 0.13, I2 = 7%). Furthermore, the sensitivity analysis of 10 RCTs, excluding the study with the highest statistical weight, displayed a lower mortality rate compared to that of non-CPT COVID-19 patients (OR 0.64, 95% CI 0.42–0.97, p = 0.04, I2 = 0%). The observed pooled mortality rate was 12.9% (95% CI 9.7–16.9%), and the pooled adverse event rate was 6.1% (95% CI 3.2–11.6), with significant heterogeneity.

Conclusions and Relevance: Our systemic review and meta-analysis suggests that CPT could be an effective therapeutic option with promising evidence on the safety and reduced mortality in concomitant treatment for COVID-19 along with antiviral/antimicrobial drugs, steroids, and other supportive care. Future exploratory studies could benefit from more standardized reporting, especially in terms of the timing of interventions and clinically relevant outcomes, like days until discharge from the hospital and improvement of clinical symptoms.

 COVID-19 SARS-CoV 2 mortality plasma therapy systemic review and meta-analysis convalescent plasma Highlights What we Already Know About This Topic

COVID-19 is an ongoing global pandemic, for which convalescent plasma has been recommended as a possible therapeutic drug.

Preliminary clinical trial results propose that there may be a satisfactory safety profile and better clinical outcome for patients treated with convalescent plasma compared with those treated with placebo or were under standard of care; however, data are limited at the current time.

 What This Article Tells Us That Is New

This systematic review and meta-analysis provides an exhaustive summary of current literature on the efficacy and safety of convalescent plasma use in COVID-19 patients.

 Introduction

The first case of coronavirus was identified in Wuhan, China, at the end of 2019 (1). The World Health Organization (WHO) declared a public health emergency of international concern on 30th January 2020 and a global pandemic on 11th March 2020 (2). The WHO estimates that serious illness occurs in 13.8% of cases and that 6.1% cases are critical (3). As of 3rd February 2021, there have been 104,077,986 confirmed cases of COVID-19, including 2,259,391 deaths, reported worldwide (4).

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is an RNA virus that is believed to primarily affect the respiratory tract; however, numerous complications related to systems other than the respiratory system have also been noted (5). Even though certain drugs, such as remdesivir, have been repositioned for emergency use in COVID-19, no particular drugs have yet been identified as an effective treatment of COVID-19. Therefore, various clinical trials are ongoing in search for the best therapy. With a scarcity of high-grade evidence for COVID-19 treatment, researchers and health care providers across the world have resorted to classical and historical interventions. Immunotherapy with convalescent plasma (CPT) is one such therapeutic option.

Convalescent plasma uses have been well-described in various diseases such as severe acute respiratory syndrome (6), Middle East respiratory syndrome coronavirus (6), Ebola virus disease (7), pandemic influenza A (6), and avian-origin influenza A (6), and a neutralizing antibody response directed against the viral S protein of the SARS virus has been reported (8). The antibodies primarily target the trimeric spike (S) surface glycoproteins, which are used by the virus to enter the host cells (9). The antibody thus hinders the ability of the SARS-CoV-ACE2 to enter the host cells and can be detected even 24 months after the onset of infection (9). Subsequently, the Food and Drug Administration (FDA) approved the use of convalescent plasmas for patients with serious or immediately life-threatening COVID-19 infections on 24th March 2020 (10).

One of the first studies demonstrating the benefit of CPT was reported in April 2020 (11). Since then, there has been increasing interest (12, 13), and three inconclusive Cochrane reviews (14–16) revealed that unmatched cohort studies are still the most frequent reports. As the literature around CPT is evolving and newer studies are being reported across the world, we conducted a systematic review and meta-analysis to appraise the currently available data for the clinical usefulness of convalescent plasma for the treatment of COVID-19. Organizing summaries of the available clinical evidence regarding safety and effectiveness from published literature through a systematic review can provide a synopsis of clinical evidence on the potential benefits and adverse events of CPT therapy in critically ill COVID-19 patients.

 Methods

Our study has been performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement (17, 18).

Search Strategy

The search strategy was designed and conducted by the authors (IM, KM, and VB). A systematic search was conducted from COVID-19 inception through 7th August 2020 for full-length articles focusing on the efficacy and safety of convalescent plasma in COVID-19 in three major COVID-19 research article databases, namely, WHO Global Research Database, CDC COVID-19 Research Articles Downloadable Database, and LitCovid database. These databases automatically gathered for articles related to COVID-19. Other literature sources such as the Eurosurveillance, China CDC Weekly, Homeland Security Digital Library, ClinicalTrials.gov, bioRxiv (preprints), medRxiv (preprints), chemRxiv (preprints), and SSRN (preprints) were searched as well. The search strategy consisted of a combination of keywords such as “Convalescent Plasma, Plasma therapy, COVID-19, SARS-CoV 2, Mortality, Systemic, Review, Meta-analysis” across the combined COVID-19 databases. After a thorough search was performed, full-length articles meeting the inclusion criteria were evaluated. All titles and abstracts were identified by the authors and screened to accrue potentially eligible studies. A manual search of the references of the included studies was also performed to supplement the electronic search. Then, the same reviewers (AT, IG, KM, PA, RS, and SG) independently assessed all selected full-text manuscripts for eligibility.

 Eligibility Criteria

The specific inclusion criteria for the systematic review and meta-analysis were as follows: (1) all RCTs or prospective studies or retrospective studies in hospitalized patients with COVID-19, (2) the use of plasma as therapy for COVID-19, (3) all studies with information available to evaluate the incidence of mortality in COVID-19 patients with plasma use [number of events, sample size, odds ratio (OR), and confidence interval (CI)], and (4) full-text articles. Thus, reviewed studies included in our analysis were RCTs and prospective and retrospective studies evaluating the outcomes of plasma therapy in COVID-19 patients. Studies focusing on patients <18 years of age, focusing on pregnant females, and limited to particular comorbidities and organ dysfunctions were excluded to avoid selection bias. We also excluded case reports from our systematic review.

 Data Extraction

Once the studies met the inclusion criteria, four reviewers (AT, HK, IG, IM, KM, RS, or SD) independently reviewed and abstracted data for mortality rate and adverse event rate for each eligible study (Figure 1). If there were multiple reports stemming from a specific study database, data from the most robust study were extracted, with other studies contributing toward the bibliography. Subsequently, the data were collected and tabulated using Microsoft Excel. The included data were checked for accuracy by AB, KM, IG, and VB. The reviewers sorted the data separately in all stages of study collection, data extraction, and quality assessment. All discrepancies found between two reviewers were resolved with consensus and inputs from other authors.

PRISMA study flow diagram.

 Study Characteristics and Quality Assessment

Randomized trial and prospective studies were evaluated using the Cochrane risk-of-bias tool (19), and the correlation of quality measures with estimates of treatment effects in the meta-analyses of RCTs (20) was used for quality assessment of the same. We used the NIH Quality Assessment Tool for Case Series Studies (21) and the Newcastle–Ottawa Scale (NOS) (22) for case–control or non-randomized retrospective cohort studies. For each non-randomized study, we assessed the study design and content. The studies were then graded using a “star system” on the basis of (1) the selection of the study groups, (2) the comparability of the groups, and (3) the ascertainment of the outcome of interest. Quality assessments were also conducted independently, and discrepancies were resolved by consensus.

 Outcome Measures

All the studies describing the outcomes of plasma therapy in patients with COVID-19 were analyzed in detail. Primary outcomes were mortality benefits for patients on CPT in COVID-19. The mortality rate was evaluated in comparison to that of the control group (placebo or non-CPT). The defined secondary outcome was the pooled mortality rate and pooled adverse event rate.

 Quantitative Data Synthesis

Primary outcomes were analyzed by the Review Manager (RevMan) computer program, version 5.4 for Windows (23), and the Comprehensive Meta-Analysis software package (BioStat, Englewood, NJ, USA) (24) was used for calculating the mortality and adverse event rates. The final pooled risk estimates were obtained using random effects models (25). Raw data for outcomes and non-events from each study were used to calculate crude OR with respective 95% CI for each study. The Cochrane Q and the I2 statistics were calculated to assess heterogeneity between studies (25, 26). p < 0.10 for chi-square tests and I2 <20% were interpreted as low-level heterogeneity. We planned to perform a subgroup analysis by study design (trial/prospective studies and observational) to decrease burden of selection bias of the observational studies. It is expected that the estimates from observational studies will be more overestimated than those from RCTs (26). Furthermore, we planned to conduct a sensitivity analysis for randomized trials in trial/prospective studies to check for robustness of the results. The probability of publication bias was assessed using funnel plots and Egger's tests.

 Results

The initial library search identified potentially relevant citations from the WHO Global Research Database, CDC COVID-19 Research Articles Downloadable Database, and LitCovid PubMed database comprising 174,398 articles. Subsequently, 61,487 duplicates were removed. Out of the remaining 112,911 articles, a total of 2,262 focused on convalescent plasma. A total of 2,014 articles were excluded after title and abstract reviews due to not having patient data. We added 404 articles during literature update on 18th January 2021 in the initial literature search. The remaining 652 manuscripts were scrutinized further, and 615 were further excluded because of unclear evidence and non-relevance to the objective of the manuscript. Thus, 38 studies (11, 12, 27–62) were included in their entirety, as shown in Table 1. The PRISMA flowchart is shown in Figure 1.

Study characteristics.

References Type of study Dose of convalescent plasma Hospital length of stay Antibodies titer Viral shedding Concomitant treatment with CPT Adverse events
Abolgashemi et al. (27) Trial 500 ml 9.54 days N/D N/D Lopinavir/ritonavir, hydroxychloroquine and an anti-inflammatory agent Transient mild fever and chill in one patient
Agarwal et al. (28) Trial 200 ml 14 days N/D N/D Methylprednisolone, prednisone, azithromycin, hydroxychloroquine, lopinavir, and ritonavir Pain in the local infusion site, chills, nausea, bradycardia, and dizziness reported in one patient each. Fever and tachycardia reported in three patients each. Dyspnea and intravenous catheter blockage noted in two patients each. Mortality assessed as possibly related to convalescent plasma (CP) transfusion in three patients
Ahn et al. (29) Case series 500 ml, into two doses 28 days N/D N/D Lopinavir/ritonavir, hydroxychloroquine, and methylprednisolone No adverse reactions were observed
Altuntas et al. (54) Case–control 200–600 ml 17–18 days N/D N/D Antiviral azithromycin N/A
Avenado-Sola et al. (62) Multicenter randomized clinical trial 250–300 ml N/A N/A N/A Yes Six in CP, seven in standard of care (SOC)
Bajpai et al. (59) Open-labeled randomized controlled trial (RCT) 500 ml 14 days >80 N/A Hydroxychloroquine, azithromycin, and oseltamivir Mild urticaria in one patient each of CP and fresh frozen plasma (FFP) arms
Donato et al. (30) Trial with matched cohort study 200–500 ml N/D 1:1,000–10,000 to >1:10,000 in some patients N/D Hydroxychloroquine, steroids, remdesivir, azithromycin, and tocilizumab Mild rash in one patient
Duan et al. (11) Case control 200 ml N/D 1:640 N/D Arbidol, remdesivir, and interferon-alpha Facial red spot in one patient
Gharbaran et al. (31) RCT 300 ml N/D >1:20 N/D Chloroquine, azithromycin, lopinavir/ritonavir, tocilizumab, and anakinra No adverse reactions were observed
Liu et al. (35) Case–control 250 ml N/D ≥1:320 N/D Azithromycin, broad-spectrum antibiotics, hydroxychloroquine, antivirals, corticosteroids, interleukin-6 inhibitors, and therapeutic anticoagulation No adverse reactions were observed
Hartman et al. (32) Single-arm trial N/D 12 days N/D N/D Data unavailable N/D
Hegerova et al. (33) Case–control N/D 15 days N/D N/D Azithromycin and hydroxychloroquine No adverse reactions were observed
Joyner et al. (12) Clinical trial 200–500 ml N/D N/D N/D N/D Transfusion reactions (n = 78; <1%), thromboembolic or thrombotic events (n = 113; <1%), and cardiac events (n = 677)
Karekadavath et al. (51) Case series 200 ml 22–43 days N/D 20–42 days Remdesivir and ribavirin N/D
Li et al. (34) Trial 4–13 ml/kg of recipient body weight 7–28 days N/D N/D Antiviral, interferon, Chinese herbal medicine, antibacterial, antifungal, steroids, and human immunoglobulin Seen in two patients
Libster et al. (58) Double-blind placebo RCT 250 ml N/A >1:1,000 N/A N/A N/A
Maor et al. (36) Prospective cohort 200 ml N/D ≥1:80 N/D Tocilizumab Rash in one patient
Martinez-Resendez et al. (37) Case series 250 ml 22.5 days > 1:100 N/D Chloroquine/hydroxychloroquine, lopinavir/ritonavir, azithromycin, and ceftaroline No adverse reactions were observed
Erkurt et al. (52) Trial 200 cm3 7 days >1:640 N/D N/D No adverse reactions were observed
Olivares-Gazca et al. (38) Prospective non-randomized pilot trial 200 ml N/D N/D N/D Steroids, hydroxychloroquine, azithromycin, tocilizumab, and lopinavir/ritonavir No adverse reactions were observed
Omrani et al. (53) Retrospective cohort 400 ml N/D N/D N/A Hydroxychloroquine, azithromycin, lopinavir, ritonavir, and tocilizumab 77
Pappa et al. (39) Phase II trial 200–233 ml 21 days N/D N/D Hydroxychloroquine, remdesivir, lopinavir/ritonavir, methylprednisolone, dexamethasone, hydrocortisone, tocilizumab, heparin (UFH/LMWH), azithromycin, and intravenous immunoglobulin No adverse reactions were observed
Pei et al. (40) Case series Data unavailable 26–36 days N/D 12–29 days Data unavailable Severe anaphylactic shock
Perotti et al. (41) Trial 250–300 ml N/D >1:160 N/D Lopinavir/ritonavir, darunavir/ritonavir, darunavir/cobicistat, antibiotics, hydroxychloroquine, and anticoagulant Chills and fever during transfusion, anaphylaxis/hypersensitivity, transfusion acute lung injury, urticaria
AlQahtani et al. (60) Open-labeled RCT 400 ml NA N/A N/A Hydroxychloroquine, ribavirin, lopinavir/ritonavir, and tocilizumab One transient desaturation, one diarrhea, vomiting
Rasheed et al. (42) Randomized trial N/D 21 days N/D N/D N/D Mild skin redness and itching in one patient
Ray et al. (61) Open-labeled phase II RCT 200 ml 23 for SOC vs. 17 for CPT N/A N/A Hydroxychloroquine, azithromycin, ivermectin, doxycycline, and corticosteroids N/A
Rogers et al. (55) Matched cohort study One unit N/D N/D N/D Corticosteroid and remdesivir N/D
Salazar et al. (43) Trial with matched cohort study One or two units of COVID-19 convalescent plasma ≥1:1,350 N/D Dexamethasone and hydrocortisone N/D
Shen et al. (44) Case series 400 ml Average 46 days 1:1,000 N/D Lopinavir/ritonavir, methylprednisolone, arbidol, favipiravir, and interferon-alpha No adverse event mentioned
Simonovich et al. (56) Trial 500 ml 30 days 1:3,200 N/D Antiviral agents and glucocorticoids No adverse reactions were observed
Tan et al. (45) Case series 400 ml 17 days for one patient N/D 16 and 49 days Antiviral medicines and Chinese traditional medicines N/D
Wang et al. (46) Case series 200 ml 51 days N/D N/D Hydroxychloroquine, methylprednisolone, lopinavir, ritonavir, tocilizumab, low-molecular-weight heparin, azithromycin, and oseltamivir No adverse reactions were observed
Xia et al. (47) Case–control 200–1,200 ml 22 days N/D N/D N/D Minor allergic reactions (pruritus or erythema) in three patients
Ye et al. (48) Case series 200 ml 15–24 days N/D N/D Arbidol and levofloxacin No adverse reactions were observed
Yoon et al. (57) Retrospective cohort 200 ml N/A >1:1,000 N/A Corticosteroids N/A
Zeng et al. (49) Case–control 300 (200–600) ml N/D N/D 23.5 days Glucocorticoid and traditional Chinese medicine No adverse reactions were observed
Zhang et al. (50) Case series 200–2,400 ml 21–41 days N/D N/D Lopinavir/ritonavir, methylprednisolone, arbidol, favipiravir, interferon-alpha, and oseltamivir No adverse reactions were observed

N/A, not available; N/D, not defined/not mentioned.

 Study Characteristics

A total of 38 studies (11, 12, 27–62) were included in the qualitative analysis (Tables 1A,B). Out of which, 23 studies (11, 27, 28, 30, 31, 33–35, 41–43, 47, 49, 53–62) compared the mortality in convalescent plasma-treated patients vs. that in patients treated by standard therapy/placebo. Out of 14 trials/prospective studies, 10 trials (28, 31, 34, 42, 56, 58–62) conducted proper randomization, and six trials/prospective studies matched with the cohort retrospectively (27, 30, 41, 43). Zhang et al. (50) concluded that seroconversion occurred in 5–24 days, while Zeng et al. (49) mentioned that all six patients tested negative within 3 days of starting convalescent plasma. Tan et al. (45) evaluated the viral shedding period in convalescent plasma-treated patients, which was 16–46 days. Joyner et al. conducted the largest interventional case study with 20,000 convalescent plasma-treated patients and evaluated the safety profile (12).

Study characteristic outcomes.

References Mortality CPT arm Total CPT patient Mortality Non-CPT arm Total Non-CPT patient Adverse event CPT ICU admission ARDS Mechanical ventilation ECMO
Abolgashemi et al. (27) 17 115 18 74 1 N/A N/A 8 0
Agarwal et al. (28) 34 235 31 229 9 N/A N/A 18 0
Ahn et al. (29) 0 2 0 2 2 2 0
Altuntas et al. (54) 219 888 245 888 0 21 N/A 926 N/A
Avenado-Sola et al. (62) 0 38 4 43 6 N/A N/A N/A N/A
Bajpai et al. (59) 3 14 1 15 1 N/A N/A 4 0
Donato et al. (30) 11 47 565 1,340 1 N/A N/A 15 0
Duan et al. (11) 0 10 3 10 1 2 2 3 0
Gharbaran et al. (31) 6 43 11 43 0 31 31 31 5
Liu et al. (35) 5 39 38 156 0 4 4 4 0
Hartman et al. (32) 4 31 0 6 15 10 0
Hegerova et al. (33) 2 20 6 20 4 6 6 6 0
Joyner et al. (12) 1,711 20,000 1,282 11,560 9,729 6,864 0
Karekadavath et al. (51) 0 4 0 4 4 1 0
Li et al. (34) 8 51 12 50 2 29 N/A 14 14
Libster et al. (58) 2 80 4 80 0 8 7 6 0
Maor et al. (36) 9 49 1 28 28 0
Martinez-Resendez et al. (37) 0 8 0 8 8 5 0
Erkurt et al. (52) 6 26 0 0 0 0 0 6 0
Olivares-Gazca et al. (38) 2 10 0 10 5 5 0
Omrani et al. (53) 1 40 5 40 N/A 80 N/A 69 0
Pappa et al. (39) 0 9 1 9 9 2 0
Pei et al. (40) 0 3 1 0 0 0 0
Perotti et al. (41) 3 46 7 23 4 16 43 7 2
AlQahtani et al. (60) 1 20 2 20 3 N/A N/A 10 0
Rasheed et al. (42) 1 21 8 28 2 21 21 21 0
Ray et al. (61) 10 40 14 40 0 N/A N/A N/A N/A
Rogers et al. (55) 8 64 28 177 85 0 28 0
Salazar et al. (43) 5 136 19 251 0 161 21 21 1
Shen et al. (44) 0 5 0 5 5 5 1
Simonovich et al. (56) 25 228 12 105 220 8 0 19 0
Tan et al. (45) 0 2 0 0 0 0 0
Wang et al. (46) 3 5 0 5 5 5 0
Xia et al. (47) 3 138 59 1,430 0 3 22 28 2
Ye et al. (48) 0 6 0 1 0 4 0
Yoon et al. (57) 23 73 28 73 0 N/A N/A 18 0
Zeng et al. (49) 5 6 14 15 0 6 6 5 1
Zhang et al. (50) 0 4 0 4 4 2 2

N/A, not available/not mentioned.

 Primary Outcome Mortality Comparison Between Plasma Therapy and Placebo

Twenty-three studies reported the mortality rate in COVID-19 patients on plasma and non-CPT therapy (11, 27, 28, 30, 31, 33–35, 41–43, 47, 49, 53–62). This yielded a sample size of 7,542 patients, with 2,392 patients on plasma therapy and 5,150 patients in the control group. In the CPT therapy cohort, 392 patients died, while 1,135 patients died in the placebo/non-CPT cohort. The meta-analysis of these mortality rates showed that the odds of mortality on plasma therapy were significantly lower than those in patients who did not receive plasma therapy (OR 0.65, 95% CI 0.53–0.80, p < 0.0001, I2 = 15%). This is shown in a Forrest plot (Figure 2A). We performed a subgroup analysis by study designs and observed similar mortality benefits in 14 trial/prospective studies (27, 28, 30, 31, 34, 41–43, 56, 58–62) (OR 0.59, 95% CI 0.43–0.81, p = 0.001, I2 = 22%) (Figure 2B) as well as for nine case series/retrospective observational studies (11, 33, 35, 47, 49, 53–55, 57) (OR 0.78, 95% CI 0.65–0.94, p = 0.01, I2 = 0%) (Figure 2C). However, during the sensitivity analysis of 10 randomized trials (28, 31, 34, 42, 56, 58–62), no statistically significant reduction of COVID-19 deaths was shown (OR 0.76, 95% CI 0.53–1.08, p = 0.13, I2 = 7%) (Figure 2D). Agarwal et al. (28) demonstrated a different effect and had a large statistical weight (34.3%). Therefore, a sensitivity analysis was performed by excluding the study by Agarwal et al. (28). This revealed a significant reduction in the odds of mortality with COVID-19 (OR 0.64, 95% CI 0.42–0.97, p = 0.04, I2 = 0%) (Figure 2E).

(A) Overall comparison of mortality rate in patients on CPT vs. non-CPT treatment. (B) Subgroup analysis of mortality rate in patients on CPT vs. non-CPT treatment (trial/prospective studies). (C) Subgroup analysis of mortality rate in patients on CPT vs. non-CPT treatment (observational). (D) Sensitivity analysis for mortality rate in patients on CPT vs. non-CPT treatment (trial/prospective studies) true randomized controlled trial (removed pseudorandomized or trial with matched cohort). (E) Sensitivity analysis for mortality rate in patients on CPT vs. non-CPT treatment (trial/prospective studies) true randomized controlled trial [removed Agarwal et al. (28)].

 Secondary Outcome Pooled Mortality Rate

Thirty-eight studies (11, 12, 27–62) reported the mortality rate in COVID-19 patients on plasma therapy, as shown in Figure 3. A total of 22,556 patients with CPT were included in the analysis, of which a total of 2,127 patients died. This yielded a pooled post CPT mortality rate of 12.9% (95% CI 9.7–16.9) with a substantial amount of heterogeneity (I2 = 89.6) in the analysis (Figure 3).

Pooled mortality rate with use of CPT in COVID-19.

 Pooled Adverse Event Rate

Similarly, 37 studies (11, 12, 27–53, 55–62) reported the adverse event rate in COVID-19 patients on plasma therapy, as shown in Figure 4. A total of 21,668 patients with CPT were included in the analysis, of which a total of 1,506 patients had adverse events. This yielded a pooled adverse event rate of 6.1% (95% CI 3.2–11.6) with significant heterogeneity in the analysis (I2 = 94.9) (Figure 4).

Pooled adverse event rate with use of CPT in COVID-19.

 Risk-of-Bias Assessment

Two authors (KM and AT) independently assessed the risk of bias of each study included. All disagreements were discussed with all the authors, and decisions were made via a consensus. The Cochrane tool for risk of bias (19) was used for RCTs (Table 2A), and the correlation of quality measures with estimates of treatment effects in meta-analyses of RCTs (20) was used for quality assessment of the same (Table 2B). Non-randomized studies were evaluated using the NOS for the case–control/cohort (22) (Tables 2C,D) and the NIH Quality Assessment Tool for Case Series Studies (21) (Table 2E). Quality assessments were conducted independently, and discrepancies were resolved by consensus. Overall, risk-of-bias assessment showed that the included studies had low to medium risk of bias.

Assessment of the trials included in the study.

References Abolgashemi et al. (27) Agarwal et al. (28) AlQahtani et al. (60) Avenado-Sola et al. (62) Bajpai et al. (59) Donato et al. (30) Erkurt et al. (52) Hartman et al. (32) Gharbaran et al. (31) Joyner et al. (12)
Study question well-defined in introduction/methods Yes Yes Yes Yes No Yes Yes Yes Yes Yes
Study question well-defined anywhere in the article Yes Yes Yes Yes No Yes Yes Yes Yes Yes
Placebo control No No No No No No No No No No
Appropriate outcome studied Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Multicenter study Yes Yes Yes Yes No No No No Yes Yes
Study country Iran India Bahrain Spain India USA Turkey USA Netherlands USA
Adequate selection criteria Yes Yes Yes Yes Yes Yes No Yes Yes Yes
Randomization methods described N/A Yes Yes Yes Yes N/A N/A N/A Yes N/A
Central randomization site N/A Yes N/D N/D N/A N/A N/A N/A N/D N/A
Allocation concealment N/D Yes No Yes Yes N/D N/A N/D No N/D
Patients blinded N/D No No No No N/D N/A N/D No N/D
Caregivers blinded N/D No No No No N/D N/A N/D No N/D
Outcome assessors blinded N/D No N/D N/D N/D N/D N/A N/D N/D N/D
Data analysts blinded N/D N/D N/D N/D N/D N/D N/A N/D N/D N/D
Double blinded N/D No No No No N/D N/A N/D N/D N/D
Vital statistical measures Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Statistician author or acknowledged No Yes No Yes N/D Yes No No No Yes
Intention-to-treat analysis No Yes No No No No No No No No
Power calculation reported No Yes Yes Yes N/D Yes No No Yes No
Stopping rules described No No No Yes N/D No No No Yes No
Baseline characteristics reported Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Groups similar at baseline No Yes Yes N/D Yes N/A N/A No No N/A
Confounders accounted for Yes Yes Yes No Yes Yes No Yes Yes No
Percentage dropouts N/A Yes N/A Yes Yes N/A N/A N/A N/A N/A
Reasons for dropout given N/A Yes N/A Yes Yes N/A N/A N/A N/A N/A
Findings support conclusion Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
References Li et al. (34) Libster et al. (58) Olivares-Gazca et al. (38) Pappa et al. (39) Perotti et al. (41) Rasheed et al. (42) Ray et al. (61) Salazar et al. (43) Simonovich et al. (56)
Study question well-defined in introduction/methods Yes Yes Yes Yes Yes Yes Yes Yes Yes
Study question well-defined anywhere in the article Yes Yes Yes Yes Yes Yes Yes Yes Yes
Placebo control No Yes No No No No No No Yes
Appropriate outcome studied Yes Yes Yes Yes Yes Yes Yes Yes Yes
Multicenter study Yes Yes No Yes Yes Yes No Yes Yes
Study country China Argentina Mexico Greece Italy Iraq India USA Argentina
Adequate selection criteria Yes Yes Yes Yes Yes Yes Yes Yes Yes
Randomization methods described Yes Yes N/A N/A No Yes No N/A Yes
Central randomization site Yes Yes N/A N/A No No N/D N/A N/D
Allocation concealment N/D Yes N/D N/D N/D N/D No N/D Yes
Patients blinded N/D Yes N/D N/D N/D N/D No N/D Yes
Caregivers blinded N/D Yes N/D N/D N/D N/D No N/D Yes
Outcome assessors blinded N/D N/D N/D N/D N/D N/D N/D N/D Yes
Data analysts blinded N/D N/D N/D N/D N/D N/D N/D N/D No
Double blinded N/D Yes N/D N/D N/D N/D No N/D Yes
Vital statistical measures No Yes No Yes No No Yes Yes Yes
Statistician author or acknowledged Yes N/D No No Yes No No No Yes
Intention-to-treat analysis Yes Yes No No Yes No No No Yes
Power calculation reported No Yes No No No No No No Yes
Stopping rules described No Yes No No No No No No No
Baseline characteristics reported Yes Yes Yes Yes Yes Yes Yes Yes Yes
Groups similar at baseline Yes No N/A N/A Yes Yes N/D Yes No
Confounders accounted for Yes Yes Yes Yes Yes No No Yes Yes
Percentage dropouts N/A Yes N/A N/A N/A N/A N/A N/A N/A
Reasons for dropout given N/A Yes N/A N/A N/A N/A N/A N/A N/A
Findings support conclusion Yes Yes Yes Yes Yes Yes Yes Yes Yes

N/A, not available/not applicable; N/D, not defined.

Risk-of-bias assessment of the trials included in the study.

References Sequence generation risk of bias Allocation concealment risk of bias Selective reporting risk of bias Other sources of risk of bias Blinding participants and personnel risk of bias Blinding outcome assessors' risk of bias Incomplete outcome data risk of bias
Abolgashemi et al. (27) High High Low Low High High Low
Agarwal et al. (28) Low High Low Low High High Low
AlQahtani et al. (60) Low High Low Low High Unclear Low
Avenado-Sola et al. (62) Unclear High Low Low High High Low
Bajpai et al. (59) Low High Low Low High High Low
Donato et al. (30) High High Low Low High High Low
Erkurt et al. (52) High High Low Low High High Low
Hartman et al. (32) High High Low Low High High Low
Gharbaran et al. (31) Low High Low Low High High Low
Joyner et al. (12) High High Low Low High High Low
Li et al. (35) Low Moderate Low Low Low Low Low
Libster et al. (58) Low Low Low Low Low Unclear Low
Olivares-Gazca et al. (38) High High Low Low High High Low
Pappa et al. (39) High High Low Low High High Low
Perotti et al. (41) Low Low Low Low Low Low Low
Rasheed et al. (42) High High Low Low High High Low
Ray et al. (61) High High Low Low High Unclear Low
Salazar et al. (43) High High Low Low High High Low
Simonovich et al. (56) Low Low Low Low Low Low Low

Quality assessment for case–control studies included in the study.

References Altuntas et al. (54) Duan et al. (11) Hegerova et al. (33) Liu et al. (35) Xia et al. (47) Zeng et al. (49)
Selection Case definition – * * * – –
Representativeness of cases * - * * * *
Selection of controls * * * * * *
Definition of controls * * * * * *
Comparability of cohorts ** ** ** ** – –
Exposure Ascertainment of exposures * * * * * *
Same method for both groups * * * * * *
Non-response rate * – – – – –
Total number of stars 8/9 7/9 8/9 8/9 5/9 5/9

Note: A study can be awarded a maximum of one star for each numbered item within the Selection and Exposure categories. A maximum of two stars can be given for Comparability.

Quality assessment for cohort studies included in the study.

References Maor et al. (36) Omrani et al. (53) Rogers et al. (55) Yoon et al. (57)
Selection Representativeness of cohort * * * *
Selection of non-exposed cohort – * * *
Ascertainment of exposure * * * *
Outcome not present at the beginning – * * *
Comparability of cohorts – ** ** **
Outcome Assessment of outcome * * * *
Follow-up length - * - *
Adequacy of follow-up * * * *
Total number of stars 4/9 9/9 8/9 9/9

Note: A study can be awarded a maximum of one star for each numbered item within the Selection and Exposure categories. A maximum of two stars can be given for Comparability.

Quality assessment of the case studies included in the study.

References Ahn et al. (29) Karekadavath et al. (51) Martinez-Resendez et al. (37) Pei et al. (40) Shen et al. (44) Tan et al. (45) Wang et al. (46) Ye et al. (48) Zhang et al. (50)
1. Was the study question or objective clearly stated? Yes Yes Yes Yes Yes Yes Yes Yes Yes
2. Was the study population clearly and fully described, including a case definition? Yes No Yes Yes Yes Yes No Yes Yes
3. Were the cases consecutive? No Yes N/D N/D No N/D N/D No No
4. Were the subjects comparable? Yes Yes Yes Yes Yes No Yes No Yes
5. Was the intervention clearly described? Yes Yes Yes No Yes No Yes Yes Yes
6. Were the outcome measures clearly defined, valid, reliable, and implemented consistently across all study participants? Yes Yes Yes No Yes No Yes Yes Yes
7. Was the length of follow-up adequate? Yes Yes No Yes Yes No No No Yes
8. Were the statistical methods well-described? N/A N/A Yes N/A N/A N/A Yes N/A N/A
9. Were the results well-described? Yes Yes Yes Yes Yes Yes Yes Yes Yes
Quality rating Good Good Good Fair Good Poor Fair Fair Good

N/A, not applicable; N/D, not defined.

 Discussion

In this systematic review and meta-analysis of CPT in COVID-19 patients, 38 studies (11, 12, 27–62) were included and critically evaluated. All included studies reported excellent outcomes for CPT in COVID-19. Our systemic review and meta-analysis is one of the first ones to summarize all such existing evidence on the efficacy and safety of CPT in humans with COVID-19. According to the results of our systematic review and meta-analysis, CPT is effective in reducing the mortality rate and has low incidence of serious adverse events during and after convalescent plasma infusion, which are mostly controllable.

CPT confers immediate immunity via interruption of the viral entry into the cells. Additionally, in the context of COVID-19, neutralizing antibodies are anticipated to be the primary active agent in convalescent plasma and the marker of plasma potency (9). In the past, CPT has been shown to provide benefits in severe acute respiratory syndromes (6). Prior studies have also reported promising outcomes in Spanish influenza A (H1N1) infection (63), avian influenza A (H5N1) (64), viral hemorrhagic fevers such as Ebola (65), influenza A (H1N1) infections in 2009/2010 (66), and SARS-CoV infections in 2003 (67). A systematic review and meta-analysis revealed a consistent reduction in mortality with the use of plasma therapy (6). The results are similar to our findings. One of the possible hypotheses for the observed decreased mortality could be due to antibodies that can hamper virus reproduction in the active phase of infection and help clear the virus, which is advantageous to the rapid recovery of the disease (67). Mechanistic and clinical data also support the observed mortality reduction benefit associated with convalescent plasma administration (68, 69).

There was no significant reduction in mortality rate between patients with CPT and controls based on data from RCTs. However, sensitivity analysis [excluding the study by Agarwal et al. (28)] revealed that patients transfused with CPT had a lower mortality rate. The Agarwal et al. (28) trial comprised ~70% of the patients in the CPT cohort who received plasma with low levels of SARS-CoV-2 antibodies. Additionally, the remaining 30% of the patients received plasma with no detectable antibodies. Thus, there were strong methodical and clinical rationales to exclude this study from statistical models during sensitivity analysis. Nevertheless, Agarwal et al. (28) did observe a positive effect of CPT on clinical symptoms and viral clearance.

It is worth noting that the doses of CPT vary between the included studies. However, the Chinese study (11) described the use of a single dose of 200 ml of convalescent plasma, whereas Bin Zhang et al. (50) reported a maximum of 2,400 ml of convalescent plasma. The optimal dose of CPT for COVID-19, therefore, could not be estimated.

It is also important to note that the included patients were critically ill and received ICU admission (n = 12,095) or underwent mechanical ventilation (n = 8,200) and that all COVID-19 patients described in our meta-analysis received concomitant antiviral drugs and steroids including CPT; also, many patients received antibacterial/antifungal drugs for co-infection. All included studies described little mortality with the use of CPT, and the pooled analysis suggests a mortality rate of 12.9% (95% CI 9.7–16.9). However, the individual impact of CPT could not be determined as patients also received multiple other agents (including antiviral medications). Therefore, further studies evaluating the use of CPT alone are warranted.

The safety profile of CPT in COVID-19 has not been described in detail. The observed pooled adverse event rate was 6.1% (95% CI 3.2–11.6). This suggests that CPT was well-tolerated by the participants in the included studies. It is important to note that no fatality was reported as adverse event with the use of CPT. Human plasma transfusion is routinely performed in hospitals. Human anti-SARS-CoV-2 plasma differs from standard plasma as it contains antibodies against SARS-CoV-2. The risks to transfusion recipients are similar to those of standard plasma. The risk of transfusion-transmissible infection is low in developed countries. The incidence rates of infections such as HIV, hepatitis B, and hepatitis C are less than one infection per 2 million donations (70). Other adverse events with plasma therapy include allergic transfusion reactions, transfusion-associated circulatory overload (TACO), and transfusion-related acute lung injury (TRALI) (71). Even though TRALI occurs in <1 for every 5,000 transfused units, it is concerning in COVID-19 patients. Donor screening including HLA antibody screening decreases the risk of TRALI (72).

A risk benefit analysis based on age, symptoms, comorbidities, and COVID-19 transmission parameters was published in a recent review by Bloch et al. (73). Five hundred simulations were carried out, assuming varying degrees of effectiveness of convalescent plasma treatment. The model revealed that convalescent plasma was beneficial in COVID-19 infection even at the lowest estimates of 25% effectiveness. In other words, the model suggests that the potential benefit of plasma therapy outweighs the risk of transfusion in COVID-19 infection (73).

The important strengths of our study are a comprehensive search of the already published clinical studies and the large number of patients included in the analysis. This is one of the first meta-analyses on CPT use in COVID-19 patients showing an overwhelming positive result. The review of sample of articles by two co-authors is again a testimony of the quality check of data collection in this review. The generalizability of these results is also a strength of this article.

Despite the numerous strengths of the meta-analysis, there are certain limitations. One of the limitations of the meta-analysis is integral to the methodology. The summarization of varying pieces of information may ignore important differences between studies. Nonetheless, this is a controversial aspect of the meta-analysis (74). Additionally, a meta-analysis generalizes results despite differences in primary research and does not simply report a summary effect. The heterogeneity is high in our studies, especially regarding the pooled adverse event rate and pooled mortality rate. Further studies may be needed to confirm the findings and explain the mechanisms. A lack of high-quality RCT studies and relevant literature paucity limited our analyses. All the reported studies were predominately case reports or series, had no proper control groups, and had a moderate to high risk of bias. Most studies in our meta-analysis were observational studies with a high risk of bias, which are subject to inherent limitations of the study design with unmeasured differences in the study population and residual confounders despite all adjustments. The currently available evidence on the safety and effectiveness of convalescent plasma for treatment of people with COVID-19 is of very low strength. Our study predominantly describes the clinical data and incidence rates in hospitalized patients. Also, we could not register the review. We tried to prospectively register our systematic review but decided to go against it as it was taking an unreasonably longer time than expected due to the increased pool of COVID-19-related articles. Another limitation of our study is the inclusion of 12 studies (30, 31, 37, 39, 40, 42, 45, 57–59, 61, 62) from the preprint databases which have not been peer reviewed and are necessary for a thorough evaluation of the currently available data on CPT in our meta-analysis. Preprint articles possibly indicate the undetermined quality of available literature and biased articles on CPT; however, we will update the status of these above-mentioned studies in the risk-of-bias table. Lastly, many studies were determined to have a significant risk of bias. This was related to a combination of factors such as non-randomized design, confounding, poor methodological conduct, and limited information on dose and duration of the CPT. Importantly, many of the patients enrolled in the studies included in the present analysis received convalescent plasma transfusions later in their disease course. As a result, our analysis may underestimate the mortality reduction achievable through early administration of high-titer convalescent plasma for COVID-19. Based on low-quality evidence, there is no suggestion that convalescent plasma would cause any serious adverse events in patients with COVID-19 and lower the mortality in COVID-19 patients. Thus, any conclusions that are drawn based on these data are of limited value, and these conclusions are subject to change as more reliable results become available.

 Conclusion

Based on the consolidated clinical data derived from the systemic review and meta-analysis, it is suggested that, in addition to antiviral/antimicrobial drugs and steroids, CPT could be an effective concomitant therapeutic option as the use of CPT decreased mortality with a safe clinical profile and promising evidence on the safety and reduced mortality. We recognize that a definitive conclusion cannot be drawn regarding optimal doses and treatment time point for the CPT. Future larger observational studies (75) and clinical trials could benefit from more standardized reporting, especially in terms of the timing of intervention and clinically relevant outcomes, like days until discharge from hospital and improvement of clinical symptoms.

 Data Availability Statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

 Author Contributions

Data review and collection were done by KM, IG, SG, RS, AT, PA, HK, and SD. Statistical analysis was done by VB, AB, and MS. Study design and distribution of articles for critical review were done by IM and RK. VB and KM are the guarantors of the paper, taking responsibility for the integrity of the work as a whole, and from inception to publication of the article. Final approval was given by all authors. All authors contributed to the article and approved the submitted version.

 Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Coronavirus Disease 2019

 CPT

immunotherapy with convalescent plasma

 FDA

Food and Drug Administration

 HIV

human immunodeficiency virus

 RNA

ribonucleotide acid

 SARS-CoV-2

Severe Acute Respiratory Syndrome Coronavirus 2

 TRALI

transfusion-related acute lung injury

 WHO

World Health Organization.