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Systematic review and meta‐analysis of randomised controlled trials testing the safety and efficacy of convalescent plasma in the treatment of coronavirus disease 2019 (COVID‐19): Evidence‐base for practise and implications for research

Abstract Background Despite scientific advances, there is no effective medical therapy for coronavirus disease 2019 (COVID‐19). This systematic review and meta‐analysis aimed to evaluate the safety and efficacy of convalescent plasma therapy in COVID‐19. Methods This review was carried out in accordance with Cochrane methodology including risk of bias assessment and grading of the quality of evidence. Only prospective clinical trials randomly assigning COVID‐19 patients to convalescent plasma plus standard of care therapy (test arm) versus placebo/standard of care (control arm) were included. Two reviewers independently read each preprint/publication and extracted relevant data from individual studies. Data were pooled using the random‐effects model and expressed as risk ratio (RR) with 95% confidence interval (CI). Results A total of 13 206 patients from 12 randomised controlled trials were included. There was no significant difference in clinical improvement rate (RR = 1.00, 95% CI: 0.98–1.02, p = 0.96) or time to clinical improvement (median difference of 1.08 days with 95% CI ranging from −0.15 to +2.30 days) between convalescent plasma versus placebo/standard of care therapy. The use of convalescent plasma was not associated with significantly reduced risk of death (RR = 0.81, 95% CI: 0.65–1.02, p = 0.08). Reassuringly, overall incidence of infusion‐related serious adverse events was low (3.25%) and not significantly different (RR = 1.14, 95% CI: 0.93–1.40, p = 0.22) for convalescent plasma transfusion compared to placebo/standard of care therapy. Conclusions There is low to moderate certainty evidence that the addition of convalescent plasma to current standard of care therapy is generally safe but, does not result in any significant clinical benefit or reduction of mortality in COVID‐19.

aim to generate high-quality evidence to inform and guide clinical practise during the ongoing pandemic. 3 However, even a year and half after it was initially described, COVID-19 is still largely managed empirically worldwide with few effective or proven therapies. Dexamethasone was the first drug to demonstrate significant reduction in mortality in COVID-19 patients requiring ventilatory support or supplemental oxygen. 4 Recently, remdesivir become the first drug to receive United States (US) Food and Drug Administration (FDA) approval for the treatment of hospitalised COVID-19 patients based on significant reduction in the duration of hospitalisation 5 for COVID-19 patients of varying disease severity. Amongst various other promising therapies, convalescent plasma 6,7 enriched in human antibodies against COVID-19 from recovered patients and humanised monoclonal antibodies 8 have received emergency use authorization (EUA) from US FDA till date.
The use of convalescent blood products (whole blood, plasma, serum, and isolates such as immunoglobulins and antibodies) collected from recovered patients to confer passive immunity in the recipients is not entirely new and has strong scientific rationale and historical precedence. 9,10 Convalescent plasma therapy is a passive antibody therapy that involves the transfusion of plasma rich in antibodies against a given pathogen to a susceptible individual for the purpose of preventing or treating an infectious disease. Efficacy of such therapy largely correlates with titres of anti-SARS-CoV-2 specific neutralising antibodies present in convalescent plasma. 7,10,11 In addition to the neutralising antibodies, other components in donor plasma such as anti-inflammatory cytokines, clotting factors, natural antibodies, defensins, and pentraxins may also provide further benefit through their immunomodulatory effects and amelioration of systemic inflammatory response. 11 Convalescent plasma with neutralising antibodies has previously demonstrated clinical efficacy 9,10 against other virus-borne illnesses such as Ebola, human influenza A (H1N1), SARS, and Middle East respiratory syndrome (MERS). Over 50 RCTs are currently underway testing convalescent plasma against the present standard of care therapy in COVID-19 disease. However, many of these trials have limitation of numbers (small sample size) which would be inadequate to detect clinically meaningful and/or statistically significant differences, if any. Timely provision of COVID-19 convalescent plasma in resourceconstrained settings poses significant logistic difficulties, challenges, and impediments in clinical trial accrual. 12,13 In addition, the unexpected presence of neutralising immunoglobulin G (IgG) antibodies against SARS-CoV-2 in recipients can even result in premature termination of the study, affecting statistical power and rigour. Given the context, a structured systematic review with appropriate statistical pooling of data in a direct comparison meta-analysis of all RCTs evaluating the safety and efficacy of convalescent plasma therapy in COVID-19 was necessary to create an evidence-base and facilitate rapid translation of research findings into clinical practise to inform and guide therapeutic decision-making globally.

| MATERIALS AND METHODS
This systematic review was carried out in accordance with Cochrane methodology for systematic reviews of interventional studies. 14

| RESULTS
The flow-diagram of study selection and inclusion in the meta-analysis as per the PRISMA guidelines is depicted in Figure 1. Detailed PRI-SMA cheque-list is also provided as online a  Tables 1 and 2  Based on the above, there is low to moderate certainty evidence that the addition of convalescent plasma to standard of care therapy is not associated with significant clinical benefit or harm in patients with COVID-19 (Table 3).  Most studies were open-label with no placebo-control resulting in potential performance bias. b The 95% CI straddles the line of unity and increases/decreases the RR by more than 25% in several studies.
antibodies targeting the spike protein or convalescent plasma with low levels of neutralising antibodies for COVID-19 infection can potentiate immune escape allowing newer and novel mutations 38,39 with potential for increased infectivity, disease severity and even mortality. Consequent to the EUA, it has now become increasingly difficult to recruit patients on clinical trials evaluating convalescent plasma therapy clearly reflecting a missed opportunity to firmly establish its efficacy in COVID-19. 35 An updated living Cochrane review 40   Since the press release declaring closure of RECOVERY trial to The next generation of convalescent plasma trials should also determine desirable product attributes, optimal dose and timing of administration, as well as appropriate patient population for its usage. 46,50 All reported RCTs evaluating convalescent plasma in COVID-19 till date have included only hospitalised adults with mild/ moderate to severe/critical disease, excepting one study conducted in the outpatient setting for elderly patients with milder disease to prevent symptomatic worsening. If the main mechanism of action of convalescent plasma is through virus neutralisation, it would possibly be most efficacious when used very early in the course of the disease and/or even for prophylaxis in high-risk individuals. 50 In addition, there may be specific groups who are more likely to benefit such as those with impaired immune responses secondary to an immuno-

| CONCLUSIONS
There is low to moderate certainty evidence that the addition of convalescent plasma to current standard of care therapy is generally safe with low risk of transfusion-associated serious adverse events but does not result in significant clinical benefit or reduction of mortality in patients with COVID-19 infection. An updated meta-analysis including other ongoing large RCTs of convalescent plasma therapy may help improve this evidence-base in the future.

CONFLICT OF INTEREST
None of the authors have any conflicts of interest to declare.