Convalescent plasma or hyperimmune immunoglobulin for people with COVID‐19: a living systematic review

Vanessa Piechotta; Khai Li Chai; Sarah J Valk; Carolyn Doree; Ina Monsef; Erica M Wood; Abigail Lamikanra; Catherine Kimber; Zoe McQuilten; Cynthia So-Osman; Lise J Estcourt; Nicole Skoetz

doi:10.1002/14651858.CD013600.pub2

. 2020 Jul 10;2020(7):CD013600. doi: 10.1002/14651858.CD013600.pub2

Convalescent plasma or hyperimmune immunoglobulin for people with COVID‐19: a living systematic review

Vanessa Piechotta ¹, Khai Li Chai ², Sarah J Valk ^3,⁹, Carolyn Doree ⁴, Ina Monsef ¹, Erica M Wood ², Abigail Lamikanra ⁵, Catherine Kimber ⁴, Zoe McQuilten ², Cynthia So-Osman ^6,¹⁰, Lise J Estcourt ^7,^✉, Nicole Skoetz ⁸

Editor: Cochrane Haematology Group

PMCID: PMC7389743 PMID: 32648959

Abstract

Background

Convalescent plasma and hyperimmune immunoglobulin may reduce mortality in patients with viral respiratory diseases, and are currently being investigated in trials as potential therapy for coronavirus disease 2019 (COVID‐19). A thorough understanding of the current body of evidence regarding the benefits and risks is required.

Objectives

To continually assess, as more evidence becomes available, whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in treatment of people with COVID‐19.

Search methods

We searched the World Health Organization (WHO) COVID‐19 Global Research Database, MEDLINE, Embase, Cochrane COVID‐19 Study Register, Centers for Disease Control and Prevention COVID‐19 Research Article Database and trial registries to identify completed and ongoing studies on 4 June 2020.

Selection criteria

We followed standard Cochrane methodology.

We included studies evaluating convalescent plasma or hyperimmune immunoglobulin for people with COVID‐19, irrespective of study design, disease severity, age, gender or ethnicity.

We excluded studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)) and studies evaluating standard immunoglobulin.

Data collection and analysis

We followed standard Cochrane methodology.

To assess bias in included studies, we used the Cochrane 'Risk of bias' tool for randomised controlled trials (RCTs), the Risk of Bias in Non‐randomised Studies ‐ of Interventions (ROBINS‐I) tool for controlled non‐randomised studies of interventions (NRSIs), and the assessment criteria for observational studies, provided by Cochrane Childhood Cancer for non‐controlled NRSIs.

Main results

This is the first living update of our review. We included 20 studies (1 RCT, 3 controlled NRSIs, 16 non‐controlled NRSIs) with 5443 participants, of whom 5211 received convalescent plasma, and identified a further 98 ongoing studies evaluating convalescent plasma or hyperimmune immunoglobulin, of which 50 are randomised. We did not identify any completed studies evaluating hyperimmune immunoglobulin.

Overall risk of bias of included studies was high, due to study design, type of participants, and other previous or concurrent treatments.

Effectiveness of convalescent plasma for people with COVID‐19

We included results from four controlled studies (1 RCT (stopped early) with 103 participants, of whom 52 received convalescent plasma; and 3 controlled NRSIs with 236 participants, of whom 55 received convalescent plasma) to assess effectiveness of convalescent plasma. Control groups received standard care at time of treatment without convalescent plasma.

All‐cause mortality at hospital discharge (1 controlled NRSI, 21 participants)

We are very uncertain whether convalescent plasma has any effect on all‐cause mortality at hospital discharge (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.61 to 1.31; very low‐certainty evidence).

Time to death (1 RCT, 103 participants; 1 controlled NRSI, 195 participants)

We are very uncertain whether convalescent plasma prolongs time to death (RCT: hazard ratio (HR) 0.74, 95% CI 0.30 to 1.82; controlled NRSI: HR 0.46, 95% CI 0.22 to 0.96; very low‐certainty evidence).

Improvement of clinical symptoms, assessed by need for respiratory support (1 RCT, 103 participants; 1 controlled NRSI, 195 participants)

We are very uncertain whether convalescent plasma has any effect on improvement of clinical symptoms at seven days (RCT: RR 0.98, 95% CI 0.30 to 3.19), 14 days (RCT: RR 1.85, 95% CI 0.91 to 3.77; controlled NRSI: RR 1.08, 95% CI 0.91 to 1.29), and 28 days (RCT: RR 1.20, 95% CI 0.80 to 1.81; very low‐certainty evidence).

Quality of life

No studies reported this outcome.

Safety of convalescent plasma for people with COVID‐19

We included results from 1 RCT, 3 controlled NRSIs and 10 non‐controlled NRSIs assessing safety of convalescent plasma. Reporting of adverse events and serious adverse events was variable. The controlled studies reported on adverse events and serious adverse events only in participants receiving convalescent plasma. The duration of follow‐up varied. Some, but not all, studies included death as a serious adverse event.

Grade 3 or 4 adverse events (13 studies, 201 participants)

The studies did not report the grade of adverse events. Thirteen studies (201 participants) reported on adverse events of possible grade 3 or 4 severity. The majority of these adverse events were allergic or respiratory events. We are very uncertain whether or not convalescent plasma therapy affects the risk of moderate to severe adverse events (very low‐certainty evidence).

Serious adverse events (14 studies, 5201 participants)

Fourteen studies (5201 participants) reported on serious adverse events. The majority of participants were from one non‐controlled NRSI (5000 participants), which reported only on serious adverse events limited to the first four hours after convalescent plasma transfusion. This study included death as a serious adverse event; they reported 15 deaths, four of which they classified as potentially, probably or definitely related to transfusion. Other serious adverse events reported in all studies were predominantly allergic or respiratory in nature, including anaphylaxis, transfusion‐associated dyspnoea, and transfusion‐related acute lung injury (TRALI). We are very uncertain whether or not convalescent plasma affects the number of serious adverse events.

Authors' conclusions

We are very uncertain whether convalescent plasma is beneficial for people admitted to hospital with COVID‐19. For safety outcomes we also included non‐controlled NRSIs. There was limited information regarding adverse events. Of the controlled studies, none reported on this outcome in the control group. There is only very low‐certainty evidence for safety of convalescent plasma for COVID‐19.

While major efforts to conduct research on COVID‐19 are being made, problems with recruiting the anticipated number of participants into these studies are conceivable. The early termination of the first RCT investigating convalescent plasma, and the multitude of studies registered in the past months illustrate this. It is therefore necessary to critically assess the design of these registered studies, and well‐designed studies should be prioritised. Other considerations for these studies are the need to report outcomes for all study arms in the same way, and the importance of maintaining comparability in terms of co‐interventions administered in all study arms.

There are 98 ongoing studies evaluating convalescent plasma and hyperimmune immunoglobulin, of which 50 are RCTs. This is the first living update of the review, and we will continue to update this review periodically. These updates may show different results to those reported here.

Plain language summary

Plasma from people who have recovered from COVID‐19 to treat individuals with COVID‐19

Coronavirus disease 2019 (COVID‐19) is a highly infectious respiratory illness caused by a newly recognised type of coronavirus. People infected with this virus may not show signs of the disease, others may develop symptoms, including fever, cough, shortness of breath and sore throat. In some people the infection is more severe and can cause breathing difficulties, leading to hospitalisation, admission to intensive care or death. Currently, no vaccine or specific treatment is available.

People who have recovered from COVID‐19 develop natural defences to the disease in their blood (antibodies). Antibodies are found in part of the blood called plasma. Plasma from blood donated from recovered patients, which contains COVID‐19 antibodies, can be used to make two preparations. Firstly, convalescent plasma, which is plasma that contains these antibodies. Secondly, hyperimmune immunoglobulin, which is more concentrated, and therefore contains more antibodies.

Convalescent plasma and hyperimmune immunoglobulin have been used successfully to treat other respiratory viruses. These treatments (given by a drip or injection) are generally well‐tolerated, but unwanted effects can occur.

What did we want to find?

We wanted to know whether plasma from people who have recovered from COVID‐19 is an effective treatment for people with COVID‐19, and whether this treatment causes any unwanted effects. We are continually updating this review as more evidence becomes available.

Our methods

On 4 June 2020 we searched major medical databases for clinical studies on treatment with convalescent plasma or hyperimmune immunoglobulin for people with COVID‐19. Studies could be conducted anywhere in the world and include participants of any age, gender or ethnicity, with mild, moderate or severe COVID‐19.

Key results

We included 20 completed studies with 5443 participants; 5211 participants received convalescent plasma. We found one randomised controlled trial ((RCT) 103 participants; 52 participants received convalescent plasma). RCTs are clinical studies where people are randomly allocated to receive the treatment (intervention group) or to receive a different treatment or no treatment (control group). RCTs produce the best evidence. We found three controlled non‐randomised studies of interventions ((controlled NRSIs) 236 participants; 55 participants received convalescent plasma). These controlled NRSIs did not randomly allocate participants but did include a control group of participants who did not receive convalescent plasma. The remaining 16 studies (5201 participants) were not randomised and did not include a control group (non‐controlled NRSIs) but provided information about unwanted effects of convalescent plasma.

To assess whether convalescent plasma is an effective treatment for COVID‐19, we evaluated results from the RCT and three controlled NRSIs. The control groups received standard care at the time of treatment without convalescent plasma. There was not enough evidence to determine whether or not convalescent plasma affected the risk of death due to any cause at hospital discharge, time to death, or need for breathing support.

To assess whether convalescent plasma causes unwanted effects, we also evaluated the 16 non‐controlled NRSIs (5201 participants). We identified some serious unwanted effects, which could be related to convalescent plasma, including death, allergic reactions or respiratory complications. We are very uncertain whether or not convalescent plasma affects the number of serious unwanted events.

None of the included studies reported effects on quality of life.

Certainty of the evidence

Our certainty (confidence) in the evidence was very limited because there was only one randomised study and most studies did not use reliable methods to measure their results. Furthermore, participants received various treatments alongside convalescent plasma, and some had underlying health problems.

Conclusion

We are very uncertain whether plasma from people who have recovered from COVID‐19 is an effective treatment for people hospitalised with COVID‐19. We are very uncertain whether or not convalescent plasma affects the number of serious harms. These findings could be related to the natural progression of the disease, other treatments that the participants received, or to convalescent plasma. Our searches found 98 ongoing studies evaluating convalescent plasma and hyperimmune immunoglobulin, of which 50 are randomised. This is the first living update of our review, and we will continue to update this review with results from completed studies.

Summary of findings

Background

Description of the condition

The clinical syndrome coronavirus disease 2019 (COVID‐19) is a new, rapidly emerging zoonotic infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2; WHO 2020a). On 11 March 2020, the World Health Organization (WHO) declared the current COVID‐19 outbreak a pandemic, with the outbreak resulting in more than 11.5 million cases and over 535,000 deaths worldwide as of 7 July 2020 (WHO 2020b; WHO 2020c). Although there are similarities with historic coronavirus epidemics, with severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) responsible for 813 and 858 deaths respectively, the scale and impact of the COVID‐19 pandemic presents unprecedented challenges to health facilities and healthcare workers all over the world (WHO 2007; WHO 2019).

With a preliminary hospitalisation rate of 12.3 patients per 100,000 population in the USA, COVID‐19 has taken a toll on healthcare capacity, and especially on intensive care unit (ICU) capacity (CDC 2020a). Early reports of the case fatality rate suggest that it ranges between 0.7% and 4%, with higher rates also reported (WHO 2020a; WHO 2020c). However, these numbers should be interpreted with great care due to the data pertaining to the early emergency response, which due to shortage of test kits has led to selective testing of people with severe disease, underreporting of cases and delays from confirmation of a case to time of death (Kim 2020). The median incubation period of SARS‐CoV‐2 was reported to be five days, with 97.5% of cases developing symptoms within 11.5 days of infection (Lauer 2020). Common signs and symptoms can include fever, dry cough, fatigue and sputum production (WHO 2020a). Other, less commonly reported signs and symptoms are shortness of breath, sore throat, headache, myalgia or arthralgia, chills, nausea or vomiting, nasal congestion, diarrhoea, haemoptysis and conjunctival congestion (WHO 2020a). Of the reported cases, 80% are estimated to have a mild or asymptomatic course of infection, and an estimated 5% of cases are admitted to the ICU with acute respiratory distress syndrome (ARDS), septic shock or multiple organ failure, or both (Team 2020; WHO 2020a). A risk factor for developing infection and progressing to severe disease is old age, with people aged over 80 years at highest risk of mortality. Other risk factors are cardiovascular disease, obesity, hypertension, diabetes, chronic respiratory disease, cancer and compromised immune status (Chen 2020a; Huang 2020; Liang 2020; WHO 2020a; Wu 2020a).

SARS‐CoV‐2 is a positive‐sense, single‐stranded RNA (ribonucleic acid) virus with a large genome. Although not much is known about the specific mechanisms underlying severe disease in COVID‐19, there are indications that the virus is capable of inducing an excessive immune reaction in the host, with highly activated but decreased numbers of CD4⁺ and CD8⁺ T cells detected in the peripheral blood of people with COVID‐19 (Xu 2020). Early reports also showed that people critically ill with COVID‐19 frequently exhibit a hypercoagulable state and endothelial inflammation, which is hypothesised to lead to the high burden of thromboembolic events seen in this population (Driggin 2020). Preliminary reports into the pathophysiology of SARS‐CoV‐2 have further indicated that the observed decrease in human angiotensin‐converting enzyme 2 (ACE2) activity may play a role in causing the rapid deterioration of patient lung function (Tolouian 2020; Van de Veerdonk 2020). ACE2 is a protein that functions as the receptor facilitating entry of SARS‐CoV‐2 into the host cell, and is most abundant on type II alveolar cells in the lungs.

Description of the intervention

Convalescent plasma, convalescent serum and hyperimmune immunoglobulin prepared from convalescent plasma, are interventions that have been used in the past to treat conditions when no vaccine or pharmacological interventions were available. Diphtheria, pneumococcal pneumonia, hepatitis A and B, mumps, polio, measles and rabies are conditions where convalescent plasma has been shown to be effective (Eibl 2008).

A systematic review has shown that convalescent plasma may have clinical benefit for people with influenza and SARS (Mair‐Jenkins 2015). This systematic review included observational studies and randomised controlled trials (RCTs) investigating the use of convalescent plasma, serum or hyperimmune immunoglobulin for treating severe acute respiratory infections of laboratory‐confirmed or suspected viral aetiology, and included investigations with patients of any age and sex. Control interventions consisted of sham, or placebo, therapy and no therapy. The authors concluded that, although the included studies were generally small and of low quality, with a moderate to high risk of bias, the use of convalescent plasma may reduce mortality and appears safe (Mair‐Jenkins 2015). The authors also suggested that the effectiveness of convalescent plasma in reducing hospital length of stay is dependent on early administration of the therapy, and use as prophylaxis is more likely to be beneficial than treating severe disease. However, the optimal timing and dosage of convalescent plasma therapy is unknown.

There is conflicting evidence about the effect of convalescent plasma or hyperimmune immunoglobulin for treating severe acute respiratory infections. Studies investigating the effectiveness of hyperimmune immunoglobulin for influenza have been contradictory, with some RCTs showing effectiveness (Hung 2013), whereas others show no benefit (Beigel 2017; Beigel 2019; Davey 2019).

Although convalescent plasma is generally thought to be a safe and well‐tolerated therapy, adverse events can occur. Limited information is available about specific adverse events related to convalescent plasma therapy, but symptoms that have been reported are similar to those for other types of plasma blood components, including fever or chills, allergic reactions, and transfusion‐related acute lung injury (TRALI; Beigel 2019; Chun 2016; Luke 2006). Furthermore, the transfer of coagulation factors present in plasma products is potentially harmful for people with COVID‐19, who are already at an increased risk of thromboembolic events (Driggin 2020). Plasma transfusions are also known to cause transfusion‐associated circulatory overload (TACO). TACO and TRALI are especially important to consider, because COVID‐19 patients with comorbidities, who might be eligible for experimental treatment with convalescent plasma therapy, are at an increased risk of these adverse events. There are risk‐mitigation strategies that can be implemented to prevent TRALI. These include limiting donations from female donors, especially those with a history of pregnancy, and screening of donors for antibodies that are implicated in TRALI (Otrock 2017). In addition to the aforementioned adverse events, transfusion‐transmitted infections, red blood cell alloimmunisation and haemolytic transfusion reactions have also been described following plasma transfusion, although they are less common (Pandey 2012). Pathogen inactivation can be implemented to decrease the risk of transmitting infections by transfusion (Rock 2011).

When compared to convalescent plasma, hyperimmune immunoglobulin has the advantage of preventing transfer of potentially harmful coagulation factors that are present in plasma products. The amount and antibody concentration can be more accurately dosed compared to convalescent plasma, and hyperimmune immunoglobulin can be prepared in a consistent manner (Hung 2013). Not many studies have reported on adverse events of hyperimmune immunoglobulin, but the safety profile of standard intravenous immunoglobulin is known and the adverse events reported here are also likely to occur in hyperimmune immunoglobulin therapy. Common adverse events of intravenous immunoglobulin that occur immediately after administration are: infusion site pain; swelling and erythema; and immediate systemic reactions, such as head and body aches, chills and fever (Stiehm 2013). Other, less common early adverse reactions to immunoglobulin therapy are pulmonary complications, such as pulmonary embolism, pulmonary oedema and pleural effusion, with TRALI also reported (Baudel 2020; Stiehm 2013). Anaphylactic and anaphylactoid reactions to immunoglobulin therapy are rare (Brennan 2003; Stiehm 2013). Delayed adverse events of immunoglobulin therapy, which occur within hours to days of initiation of immunoglobulin therapy, are persistent headaches (common), aseptic meningitis, renal failure, thromboembolic events, and haemolytic reactions (Sekul 1994; Stiehm 2013). Transmission of infectious agents has been described after administration of intravenous immunoglobulin, but this risk is considered to be low (Stiehm 2013). Other, severe adverse events that occur late after administration are lung disease, enteritis and dermatological disorders (Stiehm 2013).

A theoretical risk related to virus‐specific antibodies, which are transferred with convalescent plasma and hyperimmune immunoglobulin administration, is antibody‐dependent enhancement of infection (Morens 1994). Here, virus‐binding antibodies facilitate the entry and replication of virus particles into monocytes, macrophages and granulocytic cells and thereby increase the risk of more severe disease in the infected host. Although antibody‐dependent enhancement has not been demonstrated in COVID‐19, it has been seen with previous coronavirus infections when the antibodies given targeted a different serotype of the virus (Wan 2020; Wang 2014). A mechanism for antibody‐dependent enhancement in COVID‐19 has recently been proposed, with non‐neutralising antibodies to variable S domains potentially enabling an alternative infection pathway via Fc receptor‐mediated uptake (Ricke 2020). Antibody‐dependent enhancement is therefore a potentially harmful consequence of convalescent plasma and hyperimmune immunoglobulin therapy for COVID‐19.

In summary, the benefits of the intervention, both for convalescent plasma or hyperimmune immunoglobulin, should be carefully considered in view of the risks of adverse events.

How the intervention might work

Convalescent plasma contains pathogen‐specific neutralising antibodies, which can neutralise viral particles, and treatment with convalescent plasma or hyperimmune immunoglobulins confers passive immunity to recipients. The duration of conferred protection can differ depending on the timing of administration, ranging from weeks to months after treatment (Casadevall 2020a).

By neutralising SARS‐CoV‐2 particles, early treatment with convalescent plasma is postulated to increase the patient’s own capacity to clear the initial inoculum (Casadevall 2020a; Robbins 1995). This could lead to a reduction in mortality and fewer hospitalised patients progressing to the ICU. Furthermore, convalescent plasma may reduce the length of ICU stay in critically ill patients (Mair‐Jenkins 2015), thus helping to lift pressure from global healthcare systems and increasing ICU capacity.

Preliminary evidence in humans and rhesus macaques has shown that reinfection with SARS‐CoV‐2 is not likely, with most (but not all) patients who recovered from COVID‐19 producing sufficient amounts of neutralising antibodies to protect against reinfection (Bao 2020a; Wu 2020b). This implies that convalescent plasma from people who have recovered from SARS‐CoV‐2 infection is capable of conferring passive immunity. A recently reported case series also indicated sufficient neutralising antibody titres in convalescent plasma to neutralise SARS‐CoV‐2 in five COVID‐19 patients, who all recovered after treatment (Shen 2020). It is important to note, however, that research in other coronavirus species has shown that immunity may not be long‐lasting, with two to three years of protection estimated from work with SARS and MERS (Mo 2006; Payne 2016). Furthermore, there are indications that the severity of infection has an impact on antibody titres, with less severe disease leading to lower neutralising antibody response in people with SARS and COVID‐19 (Ho 2005; Zhao 2020a).

Why it is important to do this review

There is a clear, urgent need for more information to guide clinical decision‐making for COVID‐19 patients. Pharmacological treatment options are being investigated in many ongoing trials, with currently only treatment of dexamethasone proven to be effective in reducing mortality (Horby 2020), and remdesivir shown to reduce time to recovery (Beigel 2020). Current treatment further consists of supportive care with extracorporeal membrane oxygenation in severe cases and oxygen supply in mild cases (CDC 2020b; WHO 2020d). Despite these treatments, people hospitalised with COVID‐19 are still at a high risk of mortality. A vaccine could aid in inducing immunity in the population and preventing transmission to those who are at risk for severe disease, but no vaccine is currently available, although multiple candidate vaccines are in development. Until these vaccines are available and distributed, convalescent plasma is a potential therapy for COVID‐19 patients. Convalescent plasma, and hyperimmune immunoglobulin to a certain extent, can be prepared and made rapidly available by blood banks and hospitals when enough potential donors have recovered from the infection, using readily available materials and methods (Bloch 2020). However, its safety and efficacy are not well characterised, and there are costs associated with pursuing the use of convalescent plasma for treatment of COVID‐19.

A multitude of clinical trials investigating the safety and effectiveness of convalescent plasma or hyperimmune immunoglobulins have been announced, and their results will need to be interpreted with care. Thus, there needs to be a thorough understanding of the current body of evidence regarding the use of convalescent plasma for people with COVID‐19, and an extensive review of the available literature is required.

Objectives

To continually assess, as more evidence becomes available, whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in the treatment of people with COVID‐19.

Methods

Criteria for considering studies for this review

Types of studies

The protocol for this review was registered with the Center for Open Science (Piechotta 2020).

To assess the benefits and safety of convalescent plasma therapy for COVID‐19 we included randomised controlled trials (RCTs), as such studies, if performed appropriately, give the best evidence for experimental therapies in highly controlled therapeutic settings. For RCT data, we used the methods recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019a), as specified in the description of the methods.

In case of insufficient evidence available from RCTs, we had planned to include prospective controlled non‐randomised studies of interventions (NRSIs), including quasi‐randomised controlled trials (e.g. assignment to treatment by alternation or by date of birth), controlled before‐and‐after (CBA) studies, and interrupted time series (ITS) studies. We had planned to use the methods proposed in the Cochrane Handbook for Systematic Reviews of Interventions for the inclusion of controlled NRSIs in systematic reviews (Reeves 2019).

As planned at the protocol stage, we further included retrospective controlled NRSIs, because of insufficient evidence (very low‐certainty evidence or no evidence) available from RCTs and prospective controlled NRSIs and adapted the methods for the inclusion of controlled NRSIs in systematic reviews as specified by the Cochrane Handbook for Systematic Reviews of Interventions (Reeves 2019).

The evidence that we found from the RCT was at unclear or high risk of bias and at serious risk of bias for the controlled NRSIs, and none of the studies reported safety data for the control arm. So we also included safety data from prospective and retrospective non‐controlled NRSIs, for example, case series (please see Differences between protocol and review), and followed the methodology as specified in the protocol (Piechotta 2020).

We followed the suggestions specified in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019a), as far as possible, and applied the methodology outlined in the following sections. We considered studies including one or more participant(s) with coronavirus disease 2019 (COVID‐19).

We included full‐text publications, abstract publications, and results published in trials registries, if sufficient information was available on study design, characteristics of participants, interventions and outcomes. We did not apply any limitation with respect to the length of follow‐up.

Types of participants

We included individuals with a confirmed diagnosis of COVID‐19, with no age, gender or ethnicity restrictions.

We excluded studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)). We also excluded studies including populations with mixed viral diseases (e.g. influenza), unless the trial authors provided subgroup data for people with COVID‐19.

Types of interventions

We included the following interventions.

Convalescent plasma from people who had recovered from SARS‐CoV‐2 infection
Hyperimmune immunoglobulin therapy

We did not include studies on standard immunoglobulin.

We included the following comparisons for studies with a control arm.

Convalescent plasma therapy versus control treatment, for example, drug treatments (including but not limited to hydroxychloroquine, remdesivir), standard immunoglobulin. Co‐interventions are allowed, but must be comparable between intervention groups.

We had planned to additionally include the following comparisons for studies with a control arm, but did not identify any studies.

Convalescent plasma versus standard care or placebo
Convalescent plasma therapy versus hyperimmune immunoglobulin
Hyperimmune immunoglobulin versus standard care or placebo
Hyperimmune immunoglobulin versus control treatment, for example, drug treatments (including but not limited to hydroxychloroquine, remdesivir). Co‐interventions are allowed, but must be comparable between intervention groups.

Types of outcome measures

We evaluated core outcomes as pre‐defined by the Core Outcome Measures in Effectiveness Trials Initiative for COVID‐19 patients (COMET 2020).

Primary outcomes

Effectiveness of convalescent plasma for people with COVID‐19

All‐cause mortality at hospital discharge
Time to death

Secondary outcomes

Effectiveness of convalescent plasma for people with COVID‐19

Improvement of clinical symptoms, assessed by need for respiratory support at up to 7 days; 8 to 15 days; 16 to 30 days:
- oxygen by mask or nasal prongs
- oxygen by non‐invasive ventilation (NIV) or high‐flow
- intubation and mechanical ventilation
- mechanical ventilation plus high‐flow oxygen
- extracorporeal membrane oxygenation (ECMO)
30‐day and 90‐day mortality
Time to discharge from hospital
Admission to the intensive care unit (ICU)
Length of stay on the ICU
Quality of life, assessed with standardised scales (e.g. WHOQOL‐100) at up to 7 days; up to 30 days, and longest follow‐up available

Safety of convalescent plasma for people with COVID‐19

Number of participants with grade 3 and grade 4 adverse events, including potential relationship between intervention and adverse reaction (e.g. transfusion‐related acute lung injury (TRALI), transfusion‐transmitted infection, transfusion‐associated circulatory overload (TACO), transfusion‐associated dyspnoea (TAD), acute transfusion reactions)
Number of participants with serious adverse events

Timing of outcome measurement

For time‐to‐event outcomes, such as mortality, discharge from hospital, and improvement of clinical symptoms, we included outcome measures representing the longest follow‐up time available.

We included all other outcome categories for the observational periods that the study publications reported. We included those adverse events occurring during active treatment and had planned to include long‐term adverse events as well. If sufficient data had been available, we planned to group the measurement time points of eligible outcomes, for example, adverse events and serious adverse events, into those measured directly after treatment (up to seven days after treatment), medium‐term outcomes (15 days after treatment) and longer‐term outcomes (over 30 days after treatment).

Search methods for identification of studies

We carry out weekly searches for completed and ongoing studies in all languages in order to limit language bias.

Electronic searches

We designed and tested search strategies for electronic databases according to methods suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2019), CD developed them and Cochrane Haematology's Information Specialist (IM) peer reviewed them. In this emerging field, we expected that at least the abstract would be in English. If studies were published in other languages than those our review team could accommodate (English, Dutch, German, French, Italian, Malay and Spanish), we involved Cochrane TaskExchange to identify people within Cochrane to translate these studies.

We searched the following databases and sources, from 1 January 2019 to 4 June 2020.

Databases of medical literature
- MEDLINE (Ovid, 23 April to 4 June 2020), Appendix 1
- Embase (Ovid, 23 April to 4 June 2020), Appendix 2
- PubMed (for epublications ahead of print only; searched 4 June 2020), Appendix 3
- Center for Disease Control and Prevention COVID‐19 Research Article Database (www.cdc.gov/library/researchguides/2019novelcoronavirus/databasesjournals.html; downloaded 4 June 2020), Appendix 4
- Cochrane COVID‐19 Study Register (covid-19.cochrane.org; searched 4 June 2020), Appendix 5
Trials registries and registry platforms to identify ongoing studies and results of completed studies
- ClinicalTrials.gov ‐ COVID‐19 subset (included in Cochrane COVID‐19 Study Register)
- WHO International Clinical Trials Registry Platform (ICTRP) ‐ COVID‐19 subset (included in Cochrane COVID‐19 Study Register)

Searching other resources

We handsearched the reference lists of all identified studies, relevant review articles and current treatment guidelines for further literature; and
contacted experts in the field, drug manufacturers and regulatory agencies in order to retrieve information on unpublished studies.

Data collection and analysis

Selection of studies

Two out of four review authors (SJV, KLC, VP, NS) independently screened the results of the search strategies for eligibility for this review by reading the abstracts using Covidence software. We coded the abstracts as either 'retrieve' or 'do not retrieve'. In the case of disagreement or if it was unclear whether we should retrieve the abstract or not, we obtained the full‐text publication for further discussion. Two review authors assessed the full‐text articles of selected studies. If the two review authors were unable to reach a consensus, they consulted a third review author to reach a final decision.

We documented the study selection process in a flow chart, as recommended in the PRISMA statement (Moher 2009), and show the total numbers of retrieved references and the numbers of included and excluded studies. We list all articles that we excluded after full‐text assessment and the reasons for their exclusion in the Characteristics of excluded studies table.

Data extraction and management

One review author (NS, SJV, KLC, or VP) performed all data extractions and assessments. Two other review authors (NS, SJV, KLC, or VP) verified the accuracy and (where applicable) the plausibility of extractions and assessment.

Two review authors (VP or NS) independently assessed eligible studies obtained in the process of study selection (as described above) for methodological quality and risk of bias. If the review authors were unable to reach a consensus, we consulted a third review author (SJV or KLC).

One review author (NS, SJV, KLC, or VP) extracted data using a customised data extraction form developed in Microsoft Excel (Microsoft Corporation 2018); please see Differences between protocol and review). Another review author (NS, SJV, KLC, or VP) verified the accuracy and (where applicable) the plausibility of extractions and assessment. We conducted data extraction according to the guidelines proposed by Cochrane (Li 2019). If the review authors were unable to reach a consensus, we consulted a third review author.

We collated multiple reports of one study so that the study, and not the report, is the unit of analysis.

We extracted the following information.

General information: author, title, source, publication date, country, language, duplicate publications
Quality assessment: study design, confounding, definition of risk estimates, selection bias, attrition bias, detection bias, reporting bias
Study characteristics: trial design, setting and dates, source of participants, inclusion/exclusion criteria, comparability of groups, treatment cross‐overs, compliance with assigned treatment, length of follow‐up
Participant characteristics: age, gender, ethnicity, number of participants recruited/allocated/evaluated, disease, severity of disease, additional diagnoses, previous treatments (e.g. experimental drug therapies, oxygen therapy, ventilation), whether the donors were tested by nasal swabs or whether the plasma was tested
Interventions: convalescent plasma therapy or hyperimmune immunoglobulin therapy, concomitant therapy, duration of follow‐up, donors' disease severity, how donations were tested for neutralising antibody
- For studies including a control group: comparator (type)
Outcomes
- Effectiveness of convalescent plasma for people with COVID‐19:
  - all‐cause mortality at hospital discharge
  - time to death
  - improvement of clinical symptoms, assessed through need for respiratory support at up to 7 days; 8 to 15 days; 16 to 30 days
  - 30‐day and 90‐day mortality
  - time to discharge from hospital
  - admission to the ICU
  - length of stay on the ICU
- Safety of convalescent plasma for people with COVID‐19:
  - number of participants with grade 3 and grade 4 adverse events, including potential relationship between intervention and adverse reaction (e.g. TRALI, TACO, TAD, acute transfusion reactions)
  - number of participants with serious adverse events

Assessment of risk of bias in included studies

Randomised controlled trials

Two review authors (VP, NS) independently assessed risk of bias for each study, using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (please see Differences between protocol and review), with any disagreements resolved by discussion (Higgins 2011). In order to rate the certainty of the evidence, we assessed risk of bias per outcome rather than per study only. We completed a 'Risk of bias' table for each included study using the 'Risk of bias' tool in Review Manager Web. Risk of bias judgements in RCTs are 'high', 'unclear' or 'low'.

Controlled non‐randomised studies of interventions

As reported above, we had planned to include controlled non‐randomised studies of intervention (NRSI) trials if there was insufficient evidence from RCTs.

Two review authors (VP, NS) independently assessed eligible studies for methodological quality and risk of bias (using the Risk Of Bias in Non‐randomised Studies ‐ of Interventions (ROBINS‐I) tool; Sterne 2016). The quality assessment strongly depends upon information on the design, conduct and analysis of the trial. The two review authors resolved any disagreements regarding quality assessments by discussion, and in case of discrepancies among their judgements, or inability to reach consensus, we had planned to consult a third review author until consensus could be reached. We asked the Cochrane Editorial and Methods Department (Theresa Moore) to review our judgements for reasonability. The categories for 'Risk of bias' judgements for controlled NRSIs using ROBINS‐I are 'low risk', 'moderate risk', 'serious risk' and 'critical risk' of bias.

We assessed the following domains of bias.

Bias due to confounding
Bias in selection of participants into the study
Bias in classification of interventions
Bias due to deviations from intended interventions
Bias due to missing data
Bias in measurement of outcomes
Bias in selection of the reported result

For every criterion we made a judgement using one of five response options.

Yes
Probably yes
Probably no
No
No information

Non‐controlled non‐randomised studies of interventions

As specified in the Types of studies section, the evidence that we found from the RCT was at unclear or high risk of bias and at serious risk of bias for the controlled NRSIs, and none of the studies reported safety data for the control arm. So we also included safety data from prospective and retrospective non‐controlled NRSIs.

Because we only included safety data from non‐controlled NRSIs, we only assessed methodological quality and risk of bias for studies reporting any safety data.

Two review authors (VP, NS) assessed eligible studies for methodological quality and risk of bias (using the 'Risk of bias' assessment criteria for observational studies tool provided by Cochrane Childhood Cancer (see Table 4; Mulder 2019). We performed and presented any 'Risk of bias' judgements per outcome per study.

1. 'Risk of bias' assessment criteria for observational studies.

Heading	Internal validity	External validity
Study group	Selection bias (representative: yes/no) if the described study group consisted of > 80% of individuals with COVID‐19 treated with convalescent plasma therapy or hyperimmune globulin in the original cohort or if it was a random sample with respect to the treatment and important prognostic factors	Reporting bias (well defined: yes/no) if the study population was well described (e.g. severity of disease, age, risk factors) and the intervention was well described (e.g. number of doses, volume)
Follow‐up	Attrition bias (adequate: yes/no) if the outcome was assessed for > 90% of the study group of interest (++) or if the outcome was assessed for 60% to 90% of the study group of interest (+)	Reporting bias (well defined: yes/no) if the length of follow‐up was mentioned
Outcome	Detection bias (blind: yes/no) if the outcome assessors were blinded to the investigated determinant	Reporting bias (well defined: yes/no) if the outcome definition was objective and precise, and the method of detection was provided
Risk estimation	Confounding (adjustment for other factors: yes/no) if important prognostic factors (i.e. age, co‐treatment, comorbidities) or follow‐up were taken adequately into account	Analyses (well defined: yes/no) if a risk ratio, odds ratio, attributable risk, linear or logistic regression model, mean difference or Chi² statistic was calculated

Study ID	Title	Link	Design	Planned number of participants	Planned completion date	Completed/terminated	Results available	Other study ID
ChiCTR2000029850	Efficacy and safety of convalescent plasma treatment for severe patients with novel coronavirus pneumonia (COVID‐19): a prospective cohort study	www.chictr.org.cn/showproj.aspx?proj=49533	Controlled NRSI	20	15 February 2022
ChiCTR2000030010	A randomized, double‐blind, parallel‐controlled, trial to evaluate the efficacy and safety of anti‐SARS‐CoV‐2 virus inactivated plasma in the treatment of severe novel coronavirus pneumonia patients (COVID‐19)	www.chictr.org.cn/showproj.aspx?proj=49777	RCT	100	31 May 2020
ChiCTR2000030039	Clinical study for infusing convalescent plasma to treat patients with new coronavirus pneumonia (COVID‐19)	www.chictr.org.cn/showproj.aspx?proj=49544	Controlled NRSI	60	1 February 2020
ChiCTR2000030179	Experimental study of novel coronavirus pneumonia rehabilitation plasma therapy severe novel coronavirus pneumonia (COVID‐19)	www.chictr.org.cn/showproj.aspx?proj=50059	RCT	100	24 February 2020
ChiCTR2000030627	Study on the application of convalescent plasma therapy in severe COVID‐19	www.chictr.org.cn/showproj.aspx?proj=50727	RCT	30	30 May 2020
ChiCTR2000030702	Convalescent plasma for the treatment of common COVID‐19: a prospective RCT	www.chictr.org.cn/showproj.aspx?proj=50537	RCT	30	15 August 2020
ChiCTR2000030929	A randomized, double‐blind, parallel‐controlled trial to evaluate the efficacy and safety of anti‐SARS‐CoV‐2 virus inactivated plasma in the treatment of severe novel coronavirus pneumonia (COVID‐19)	www.chictr.org.cn/showproj.aspx?proj=50696	RCT	30	16 June 2020
ChiCTR2000031501	The efficacy of convalescent plasma in patients with critical novel coronavirus pneumonia (COVID‐19): a pragmatic, prospective cohort study	www.chictr.org.cn/showproj.aspx?proj=50254	Controlled NRSI	20	17 July 2020
EUCTR2020‐001310‐38	A randomized, prospective, open label clinical trial on the use of convalescent plasma compared to best supportive care in patients with severe COVID‐19	www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2020-001310-38	RCT	106	NR
IRCT20151228025732N53	Therapeutic effects of plasma of recovered people from COVID‐19 on hospitalized patients with this disease	en.irct.ir/trial/46931	Controlled NRSI	12	20 June 2020
IRCT20200310046736N1	Comparison of the therapeutic effect of convalescent plasma and plasma‐derived immunoglobulin‐enriched solution on COVID‐19 patients	en.irct.ir/trial/46424	RCT	45	24 July 2020
IRCT20200325046860N1	Convalescent plasma therapy for COVID‐19 patients	en.irct.ir/trial/46759	Non‐controlled NRSI	200	20 August 2020
IRCT20200404046948N1	Efficacy and safety of convalescent plasma in the treatment of COVID‐19	en.irct.ir/trial/46973	RCT	60	20 June 2020
IRCT20200409047007N1	Effect of COVID 19 survivors plasma in COVID 19 patients with ARDS	en.irct.ir/trial/47058	RCT	32	15 August 2020
IRCT20200413047056N1	Comparison between the efficacy of intravenous immunoglobulin and convalescent plasma in COVID‐19	en.irct.ir/trial/47212	RCT	15	19 June 2020
NCT04264858	An exploratory clinical study on the treatment of acute severe 2019‐nCoV pneumonia with immunoglobulin from cured 2019‐nCoV pneumonia patients	clinicaltrials.gov/show/NCT04264858	Non‐controlled NRSI	10	31 May 2020			ChiCTR2000030841
NCT04292340	The efficacy and safety of anti‐SARS‐CoV‐2 inactivated convalescent plasma in the treatment of novel coronavirus pneumonia patient (COVID‐19): an observational study	clinicaltrials.gov/show/NCT04292340	Non‐controlled NRSI	15	31 July 2020
NCT04327349	Investigating effect of convalescent plasma on COVID‐19 patients outcome: a clinical trial	clinicaltrials.gov/show/NCT04327349	Non‐controlled NRSI	30	30 September 2020
NCT04332380	Convalescent plasma for patients with COVID‐19: a pilot study	clinicaltrials.gov/show/NCT04332380	Non‐controlled NRSI	10	31 December 2020
NCT04332835	Convalescent plasma for patients with COVID‐19: a randomized, open label, parallel, controlled clinical study	clinicaltrials.gov/show/NCT04332835	RCT	80	31 December 2020
NCT04333251	Evaluating convalescent plasma to decrease coronavirus associated complications. A phase I study comparing the efficacy and safety of high‐titer anti‐Sars‐CoV‐2 plasma vs best supportive care in hospitalized patients with interstitial pneumonia due to COVID‐19	clinicaltrials.gov/show/NCT04333251	RCT	115	31 December 2022
NCT04333355	Phase 1 study to evaluate the safety of convalescent plasma as an adjuvant therapy in patients with SARS‐CoV‐2 infection	clinicaltrials.gov/show/NCT04333355	Non‐controlled NRSI	20	30 Apr 2021
NCT04338360	Expanded access to convalescent plasma for the treatment of patients with COVID‐19	ClinicalTrials.gov/show/NCT04338360	Expanded access	NR	NR		Preprint, subset of data
NCT04340050	COVID‐19 convalescent plasma	ClinicalTrials.gov/show/NCT04340050	Non‐controlled NRSI	10	31 December 2021
NCT04342182	Convalescent plasma as therapy for Covid‐19 severe SARS‐CoV‐2 disease (CONCOVID Study) (ConCoVid‐19	ClinicalTrials.gov/show/NCT04342182	RCT	426	1 July 2020
NCT04343261	Convalescent plasma in the treatment of COVID 19	ClinicalTrials.gov/show/NCT04343261	Non‐controlled NRSI	15	1 April 2021
NCT04343755	Convalescent plasma as treatment for hospitalized subjects with COVID‐19 infection	ClinicalTrials.gov/show/NCT04343755	Non‐controlled NRSI	55	1 April 2021
NCT04344535	Convalescent plasma vs. standard plasma for COVID‐19	ClinicalTrials.gov/show/NCT04344535	RCT	500	31 August 2021
NCT04345289	Efficacy and safety of novel treatment options for adults with COVID‐19 pneumonia (CCAP)	ClinicalTrials.gov/show/NCT04345289	RCT	1500	15 June 2021			EUCTR2020‐001367‐88
NCT04345523	Convalescent plasma therapy vs. SOC for the treatment of COVID19 in hospitalized patients (ConPlas‐19)	ClinicalTrials.gov/show/NCT04345523	RCT	278	1 July 2020
NCT04345679	Anti COVID‐19 convalescent plasma therapy	ClinicalTrials.gov/show/NCT04345679	Non‐controlled NRSI	20	1 April 2021
NCT04345991	Efficacy of convalescent plasma to treat COVID‐19 patients, a nested trial in the CORIMUNO‐19 cohort	ClinicalTrials.gov/show/NCT04345991	RCT	120	1 June 2020
NCT04346446	Efficacy of convalescent plasma therapy in severely sick COVID‐19 patients	ClinicalTrials.gov/show/NCT04346446	RCT	20	20 June 2020
NCT04346589	Convalescent antibodies infusion in critically ill COVID 19 patients	ClinicalTrials.gov/ct2/show/NCT04346589	Non‐controlled NRSI	10	1 July 2020
NCT04347681	Potential efficacy of convalescent plasma to treat severe COVID‐19 and patients at high risk of developing severe COVID‐19	ClinicalTrials.gov/show/NCT04347681	Non‐controlled NRSI	40	11 April 2021
NCT04348656	Convalescent plasma for hospitalized adults with COVID‐19 respiratory illness (CONCOR‐1)	ClinicalTrials.gov/show/NCT04348656	RCT	1200	31 December 2020
NCT04348877	Plasma rich antibodies from recovered patients from COVID19	ClinicalTrials.gov/show/NCT04348877	Non‐controlled NRSI	20	1 December 2020
NCT04352751	Experimental use of convalescent plasma for passive immunization in current COVID‐19 pandemic in Pakistan in 2020	ClinicalTrials.gov/show/NCT04352751	Non‐controlled NRSI	2000	1 April 2021
NCT04353206	Convalescent plasma in ICU patients with COVID‐19‐induced respiratory failure	ClinicalTrials.gov/show/NCT04353206	Non‐controlled NRSI	90	1 May 2021
NCT04354831	A study evaluating the efficacy and safety of high‐titer anti‐SARS‐CoV‐2 plasma in hospitalized patients with COVID‐19 infection	ClinicalTrials.gov/ct2/show/NCT04354831	Non‐controlled NRSI	106	1 May 2023
NCT04355767	Convalescent plasma vs. placebo in emergency room patients with COVID‐19	ClinicalTrials.gov/ct2/show/NCT04355767	RCT	206	1 December 2022
NCT04355897	CoVID‐19 plasma in treatment of COVID‐19 patients	ClinicalTrials.gov/ct2/show/NCT04355897	Non‐controlled NRSI	100	1 August 2020
NCT04356482	Convalescent plasma for ill patients by COVID‐19	ClinicalTrials.gov/show/NCT04356482	Non‐controlled NRSI	90	1 December 2020
NCT04356534	Convalescent plasma trial in COVID ‐19 patients	ClinicalTrials.gov/show/NCT04356534	RCT	40	30 June 2020
NCT04357106	COPLA study: treatment of severe forms of coronavirus infection with convalescent plasma	ClinicalTrials.gov/show/NCT04357106	Non‐controlled NRSI	10	1 August 2020
NCT04358211	Expanded access to convalescent plasma to treat and prevent pulmonary complications associated with COVID‐19	ClinicalTrials.gov/show/NCT04358211	Expanded access	NR	NR
NCT04358783	Convalescent plasma compared to the best available therapy for the treatment of SARS‐CoV‐2 pneumonia	ClinicalTrials.gov/show/NCT04358783	RCT	30	30 May 2020
NCT04359810	Plasma therapy of COVID‐19 in critically ill patients	ClinicalTrials.gov/show/NCT04359810	RCT	105	1 April 2021
NCT04360486	Treatment of COVID‐19 with Anti‐Sars‐CoV‐2 convalescent plasma (ASCoV2CP)	ClinicalTrials.gov/show/NCT04360486	Expanded access	NR	NR
NCT04361253	Evaluation of SARS‐CoV‐2 (COVID‐19) antibody‐containing plasma therapy	ClinicalTrials.gov/show/NCT04361253	RCT	220	1 December 2021
NCT04362176	Passive immunity trial of Nashville II	ClinicalTrials.gov/show/NCT04362176	RCT	500	1 April 2021
NCT04363034	Arkansas expanded access COVID‐19 convalescent plasma treatment program	ClinicalTrials.gov/ct2/show/NCT04363034	Expanded access	NR	NR
NCT04364737	Convalescent plasma to limit COVID‐19 complications in hospitalized patients	ClinicalTrials.gov/show/NCT04364737	RCT	300	30 April 2023
NCT04365439	Convalescent plasma for COVID‐19	ClinicalTrials.gov/show/NCT04365439	Non‐controlled NRSI	10	30 June 2020
NCT04366245	Clinical trial to evaluate the efficacy of treatment with hyperimmune plasma obtained from convalescent antibodies of COVID‐19 infection	ClinicalTrials.gov/show/NCT04366245	RCT	72	1 December 2021
NCT04372368	Convalescent plasma for the treatment of patients with COVID‐19	ClinicalTrials.gov/show/NCT04372368	Expanded access	NR	NR
NCT04372979	Efficacy of convalescent plasma therapy in the early care of COVID‐19 patients	ClinicalTrials.gov/show/NCT04372979	RCT	80	1 May 2021
NCT04373460	Convalescent plasma to limit SARS‐CoV‐2 associated complications	ClinicalTrials.gov/show/NCT04373460	RCT	1344	31 January 2023
NCT04374370	SARSCoV2 (COVID‐19) convalescent plasma (CP) expanded access protocol (EAP)	ClinicalTrials.gov/show/NCT04374370	Expanded access	NR	NR
NCT04374487	A phase II, open label, RCT to assess the safety and efficacy of convalescent plasma to limit COVID‐19 associated complications	ClinicalTrials.gov/show/NCT04374487	RCT	100	9 May 2021
NCT04374526	Early transfusion of convalescent plasma in elderly COVID‐19 patients to prevent disease progression	ClinicalTrials.gov/show/NCT04374526	RCT	182	30 June 2021
NCT04374565	Convalescent plasma for treatment of COVID‐19 patients with pneumonia	ClinicalTrials.gov/show/NCT04374565	Non‐controlled NRSI	29	5 April 2021
NCT04375098	Efficacy and safety of early COVID‐19 convalescent plasma in patients admitted for COVID‐19 infection	ClinicalTrials.gov/show/NCT04375098	RCT	30	1 December 2021
NCT04376034	Convalescent plasma collection and treatment in pediatrics and adults	ClinicalTrials.gov/show/NCT04376034	Non‐controlled NRSI	240	30 Mar 2021
NCT04376788	Exchange transfusion versus plasma from convalescent patients with methylene blue in patients with COVID‐19	ClinicalTrials.gov/show/NCT04376788	RCT	15	1 June 2020
NCT04377568	Efficacy of human coronavirus‐immune convalescent plasma for the treatment of COVID‐19 disease in hospitalized children	ClinicalTrials.gov/show/NCT04377568	RCT	100	1 May 2022
NCT04377672	Human convalescent plasma for high risk children exposed or infected with SARS‐CoV‐2	ClinicalTrials.gov/show/NCT04377672	Non‐controlled NRSI	30	18 May 2022
NCT04380935	Effectiveness and safety of convalescent plasma therapy on COVID‐19 patients with acute respiratory distress syndrome	ClinicalTrials.gov/show/NCT04380935	RCT	60	31 August 2020
NCT04381858	Convalescent plasma vs human immunoglobulin to treat COVID‐19 pneumonia	ClinicalTrials.gov/show/NCT04381858	RCT	500	30 September 2020
NCT04381936	Randomised evaluation of COVID‐19 therapy (RECOVERY)	ClinicalTrials.gov/ct2/show/NCT04381936	RCT	12000	30 June 2021			ISRCTN50189673
NCT04383535	Convalescent plasma and placebo for the treatment of COVID‐19 severe pneumonia	ClinicalTrials.gov/show/NCT04383535	RCT	333	20 August 2020
NCT04383548	Clinical study for efficacy of anti‐corona VS2 immunoglobulins prepared from COVID19 convalescent plasma prepared by VIPS mini‐pool IVIG medical devices in prevention of SARS‐CoV‐2 infection in high risk groups as well as treatment of early cases of COVID	ClinicalTrials.gov/show/NCT04383548	Non‐controlled NRSI	100	1 January 2021
NCT04384497	Convalescent plasma for treatment of COVID‐19: an exploratory dose identifying study	ClinicaltTrials.gov/show/NCT04384497	Non‐controlled NRSI	50	1 December 2020
NCT04384588	COVID19‐convalescent plasma for treating patients with active symptomatic COVID 19 infection (FALP‐COVID)	ClinicalTrials.gov/show/NCT04384588	Controlled NRSI	400	6 April 2021
NCT04385043	Hyperimmune plasma in patients with COVID‐19 severe infection	ClinicalTrials.gov/show/NCT04385043	RCT	400	15 May 2021
NCT04385186	Inactivated convalescent plasma as a therapeutic alternative in patients with CoViD‐19	ClinicalTrials.gov/show/NCT04385186	RCT	60	30 November 2020
NCT04385199	Convalescent plasma for patients with COVID‐19	ClinicalTrials.gov/show/NCT04385199	RCT	30	1 August 2020
NCT04388410	Safety and efficacy of convalescent plasma transfusion for patients with SARS‐CoV‐2 infection	ClinicalTrials.gov/show/NCT04388410	RCT	250	31 December 2020
NCT04388527	COVID‐19 convalescent plasma for mechanically ventilated population	ClinicalTrials.gov/show/NCT04388527	Non‐controlled NRSI	50	30 September 2020
NCT04389710	Convalescent plasma for the treatment of COVID‐19	ClinicalTrials.gov/show/NCT04389710	Non‐controlled NRSI	100	14 April 2021
NCT04389944	Amotosalen‐ultraviolet a pathogen‐inactivated convalescent plasma in addition to best supportive care and antiviral therapy on clinical deterioration in adults presenting with moderate to severe COVID‐19	ClinicalTrials.gov/show/NCT04389944	Non‐controlled NRSI	15	30 June 2020
NCT04390178	Convalescent plasma as treatment for acute coronavirus disease (COVID‐19)	ClinicalTrials.gov/show/NCT04390178	Non‐controlled NRSI	10	1 December 2020
NCT04390503	Convalescent plasma for COVID‐19 close contacts	ClinicalTrials.gov/ct2/show/NCT04390503	RCT	200	1 April 2021
NCT04391101	Convalescent plasma for the treatment of severe SARS‐CoV‐2 (COVID‐19)	ClinicalTrials.gov/show/NCT04391101	RCT	231	31 December 2021
NCT04392232	A phase 2 study of COVID 19 convalescent plasma in high risk patients with COVID 19 infection	ClinicalTrials.gov/show/NCT04392232	Non‐controlled NRSI	100	31 December 2020
NCT04392414	Hyperimmune convalescent plasma in moderate and severe COVID‐19 disease	ClinicalTrials.gov/show/NCT04392414	RCT	60	15 September 2020
NCT04393727	Transfusion of convalescent plasma for the early treatment of pneumonia due to SARSCoV2	ClinicalTrials.gov/show/NCT04393727	RCT	126	30 August 2020
NCT04395170	Convalescent plasma compared to anti‐COVID‐19 human immunoglobulin and standard treatment (TE) in hospitalized patients	ClinicalTrials.gov/show/NCT04395170	RCT	75	1 June 2021
NCT04397523	Efficacy and safety of COVID‐19 convalescent plasma	ClinicalTrials.gov/show/NCT04397523	Non‐controlled NRSI	20	29 April 2021
NCT04397757	COVID‐19 convalescent plasma for the treatment of hospitalized patients with pneumonia caused by SARS‐CoV‐2	ClinicalTrials.gov/show/NCT04397757	RCT	80	13 November 2020
NCT04403477	Convalescent plasma therapy in severe COVID‐19 infection	ClinicalTrials.gov/show/NCT04403477	RCT	20	30 October 2020
NCT04404634	Convalescent plasma to limit coronavirus associated complications	ClinicalTrials.gov/show/NCT04404634	RCT	300	31 January 2023
NCT04405310	Convalescent plasma of Covid‐19 to treat SARS‐COV‐2 a randomized double blind 2 center trial	ClinicalTrials.gov/show/NCT04405310	RCT	80	20 July 2020
NCT04407208	Convalescent plasma therapy in patients with COVID‐19	ClinicalTrials.gov/show/NCT04407208	Non‐controlled NRSI	10	1 August 2020
NCT04408040	Use of convalescent plasma for COVID‐19	ClinicalTrials.gov/show/NCT04408040	Non‐controlled NRSI	700	1 June 2022
NCT04408209	Convalescent plasma for the treatment of patients with severe COVID‐19 infection	ClinicalTrials.gov/show/NCT04408209	Non‐controlled NRSI	60	15 September 2021
NCT04412486	COVID‐19 convalescent plasma (CCP) transfusion	ClinicalTrials.gov/show/NCT04412486	Non‐controlled NRSI	100	31 May 2022
U1111‐1251‐9286	Effect of convalescent plasma in patients with severe COVID‐19	www.ensaiosclinicos.gov.br/rg/RBR-4vm3yy/	Non‐controlled NRSI	20	31 May 2022
NR: not reported; RCT: randomised controlled trial; NRSI: non‐randomised study of intervention

Convlescent plasma for people with COVID‐19
Patients or population: people with COVID‐19 Settings: inpatient Intervention: convalescent plasma transfusion Comparison: no convalescent plasma transfusion
Outcomes and study design	Anticipated absolute effects (95% CI)		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence	Comments
Outcomes and study design	Control group risk (without convalescent plasma)^a	Risk with convalescent plasma	Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence	Comments
All‐cause mortality at hospital discharge
Randomised controlled trials	NA	NA	NA	0	NA
Controlled non‐randomised studies of interventions	933 per 1000	830 per 1000 (569 to 1000)	RR 0.89 (95% CI 0.61 to 1.31)	21 (1 study)	⊕⊝⊝⊝ Very low^b,c
Time to death
Randomised controlled trials (follow‐up 28 days)	240 per 1000 dead	184 per 1000 (79 to 393)	HR 0.74 (95% CI 0.30 to 1.82)	103 (1 study)	⊕⊝⊝⊝ Very Low^c,d
Controlled non‐randomised studies of interventions  (follow‐up 11 days)	243 per 1000 dead	120 per 1000 (59 to 235)	HR 0.46, 95% CI 0.22 to 0.96	195 (1 study)	⊕⊝⊝⊝ Very low^b,e
Improvement of clinical symptoms, assessed by need for respiratory support Follow‐up: 7 days
Randomised controlled trials at day 7	98 per 1000	96 per 1000 (29 to 312)	RR 0.98 (95% CI 0.30 to 3.19)	103 (1 study)	⊕⊝⊝⊝ Very Low^c,d
Controlled non‐randomised studies of interventions	NA	NA	NA	0	NA	None of the identified studies reported this outcome.
Improvement of clinical symptoms, assessed by need for respiratory support Follow‐up: 15 days
Randomised controlled trials at day 14	176 per 1000	326 per 1000 (160 to 663)	RR 1.85 (95% CI 0.91 to 3.77)	103 (1 study)	⊕⊝⊝⊝ Very Low^c,d
Controlled non‐randomised studies of interventions	756 per 1000	817 per 1000 (688 to 975)	RR 1.08 (95% CI 0.91 to 1.29)	195 (1 study)	⊕⊝⊝⊝ Very low^b,c
Improvement of clinical symptoms, assessed by need for respiratory support Follow‐up: 30 days
Randomised controlled trials at day 28	431 per 1000	523 per 1000 (344 to 780)	RR 1.20 (95% CI 0.80 to 1.81)	103 (1 study)	⊕⊝⊝⊝ Very Low^c,d
Controlled non‐randomised studies of interventions	NA	NA	NA	0	NA	None of the identified studies reported this outcome.
Quality of Life
Randomised controlled trials	NA	NA	NA	0	NA	None of the identified studies reported this outcome.
Controlled non‐randomised studies of interventions	NA	NA	NA	0	NA	None of the identified studies reported this outcome.
Grade 3 or 4 adverse events^f
Randomised controlled trials	NR	NR in a comparative design	NA	NA	NA	All included controlled trials reported safety data for the intervention group only, so we included the results here under non‐controlled non‐randomised studies of interventions.
Controlled non‐randomised studies of interventions	NR	NR in a comparative design	NA	NA	NA
Non‐controlled non‐randomised studies of interventions	NA	NA	NA	201 (13 studies)	⊕⊝⊝⊝ Very low^g,h	We were unable to summarise numerical data in any meaningful way. We have provided an overview of the reported adverse events for each study in Table 2. Studies did not report the grade of adverse events. The majority of these adverse events were allergic or respiratory events.
Serious adverse events
Randomised controlled trials	NR	NR in a comparative design	NA	NA	NA	All included controlled trials reported safety data for the intervention group only, so we included the results here under non‐controlled non‐randomised studies of interventions.
Controlled non‐randomised studies of interventions	NR	NR in a comparative design	NA	NA	NA
Non‐controlled non‐randomised studies of interventions	NA	NA	NA	5201 (14 studies)	⊕⊝⊝⊝ Very low^g,h	We were unable to summarise numerical data in any meaningful way. An overview of the reported serious adverse events is provided in Table 3 per study. The majority of participants were from one non‐controlled non‐randomised study of intervention (5000 participants), which reported only on serious adverse events limited to the first four hours after convalescent plasma transfusion. This study included death as a serious adverse event; they reported 15 deaths, four of which they classified as potentially, probably or definitely related to transfusion. Other serious adverse events reported in all studies were predominantly allergic or respiratory in nature, including: anaphylaxis; transfusion‐associated dyspnoea; and transfusion‐related acute lung injury (TRALI).
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect. CI: confidence interval; HR: hazard ratio; NA: not available; NR: not recorded; RR: risk ratio

Study	Number of participants	Grade 3 or 4 adverse events^a
Ahn 2020	2	0
Duan 2020^b	10 (convalescent plasma group)	0
Jin 2020	6	0
Li 2020	52 (convalescent plasma group)	3 (in 2 participants) 1 possible severe transfusion‐associated dyspnoea (participant had "shortness of breath, cyanosis, and severe dyspnoea within 6 hours of transfusion. The patient was given dexamethasone, aminophylline, and other supportive care immediately and gradually improved after 2 hours"). 1 non‐severe allergic transfusion reaction and 1 probable non‐severe febrile non‐haemolytic transfusion reaction (participant developed chills and rashes within 2 hours of transfusion but recovered fully after treatment with dexamethasone and promethazine).
Liu 2020	39 (convalescent plasma group)	0
Pei 2020	3	1 (anaphylactic shock)
Perotti 2020	46	5 (in 4 participants) chills and fever during transfusion (relation likely) urticaria (relation likely) anaphylaxis/hypersensitivity (relation possible) transfusion‐related acute lung injury (relation possible) subsegmental pulmonary embolism (relation unlikely/excluded)
Salazar 2020^c	25	0
Tan 2020	1	1 (fever)
Ye 2020	6	0
Zeng 2020	6 (convalescent plasma group)	0
Zhang 2020a^d	4	0
Zhang 2020b	1	0

Date	Event	Description
3 June 2020	New citation required and conclusions have changed	We included results from one RCT and three controlled NRSIs and added further safety data from non‐controlled NRSIs.
31 May 2020	New search has been performed	We included eight new studies.

'Risk of bias' assessment of Li 2020
Domain	Assessed outcomes	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Mortality Clinical improvement Adverse events	Low	Quote: "Patients were randomly assigned via computer‐generated random numbering (1:1) to receive standard treatment coupled with convalescent plasma transfusion or standard treatment alone (control group) (Figure 1). The randomization was stratified based on the severity of COVID‐19 (severe or life‐threatening) and a randomization schedule was generated using block randomization with block size of 4 for each type of COVID‐19 by SAS software."
Allocation concealment (selection bias)	Mortality Clinical improvement Adverse events	Low	Quote: "This random number will connect the subject to the designated treatment group (experimental group or control group) for treatment. [...] Staff responsible for randomization will only be responsible for the assignment of random groups and will not be involved in any specific trial operations."
Blinding of participants and personnel (performance bias)	Mortality Clinical improvement Adverse events	High	Quote: "open‐label" Co‐interventions not balanced across arms
Blinding of outcome assessment (detection bias)	Mortality	Low	Quote: "To avoid assessment bias, the evaluation of clinical outcomes was performed by an investigator who was blind to the study group allocation."
Blinding of outcome assessment (detection bias)	Clinical improvement Adverse events	Low	Quote: "To avoid assessment bias, the evaluation of clinical outcomes was performed by an investigator who was blind to the study group allocation."
Selective reporting (reporting bias)	Mortality	Low	Reported as determined at protocol stage
	Clinical improvement	Unclear	Quote: "A post hoc analysis was added to compare rates of improvement at days 7, 14, and 28."
	Adverse events	High	Only transfusion‐related adverse events reported
Incomplete outcome data (attrition bias)	Mortality	Low	ITT population reported
	Clinical improvement	Low	ITT population reported
	Adverse events	High	No safety data for control group available
Other bias	Mortality Clinical improvement Adverse events	Unclear	Quote: "Due to the containment of the COVID‐19 epidemic in Wuhan, China, the numbers of patients with COVID‐19 decreased in late March 2020. [...] The trial was terminated early after 103 of a planned 200 patients were enrolled." The study expressed effect estimates as odds ratios. Therefore we recalculated relative effects as risk ratios. We noticed that our calculation arrived at the same numerical values, and therefore highlight that effect estimates, which are indicated as odds ratios in the primary study, are in fact risk ratios.

'Risk of bias' assessment of Duan 2020
Domain	Assessed outcomes	Authors' judgement	Support for judgement
Bias due to confounding	Mortality Clinical improvement	Serious	Quote: "Historic control group was formed by random selection of 10 patients from the cohort treated in the same hospitals and matched by age, gender, and severity of the diseases to the 10 cases in our trial." Not adjusted for co‐morbidities, previous treatments, time of disease onset, etc.
Bias due to confounding	Adverse events	Not applicable	Paper only reports transfusion‐related adverse events for intervention group
Bias in selection of participants into the study	Mortality Clinical improvement	Critical	Small sample size, unclear how participants were selected into intervention group, unclear how long participants of historical control group were followed
Bias in selection of participants into the study	Adverse events	Not applicable	Paper only reports transfusion‐related adverse events for intervention group
Bias in classification of interventions	Mortality Clinical improvement	Critical	Assignment to control group was done retrospectively. Treatment details of control group are not provided, and it is unclear whether patients were treated during the same period or at a time when less was known about the disease and the treatment options. Knowledge of patients' outcomes at the time of assignment to the control group could have had a major impact on the selection.
Bias in classification of interventions	Adverse events	Not applicable	Paper only reports transfusion‐related adverse events for intervention group
Bias due to deviations from intended interventions	Mortality Clinical improvement Adverse events	Low	All participants received the intended intervention.
Bias due to missing data	Mortality	Serious	Mortality is reported for participants in intervention group until day 3 of follow‐up. Unclear how long control group was followed and how clinical status was assessed
	Clinical improvement	Critical	Unclear how long control group was followed and clinical status in terms of respiratory support was not assessed
	Adverse events	Critical	No safety data for control group reported
Bias in measurement of outcomes	Mortality	Critical	Unclear whether follow‐up was comparable between groups
	Clinical improvement	Critical	Clinical course is reported for participants in intervention group until day 3 of follow‐up
	Adverse events	Critical	Only transfusion‐related adverse events reported
Bias in selection of the reported results	Mortality Clinical improvement	Critical	Study was registered as single‐arm trial and control group was retrospectively selected
Bias in selection of the reported results	Adverse events	Critical	Observation period unclear; only transfusion‐related adverse events assessed and reported
Overall bias	Mortality	Critical	The study is too problematic to provide any useful evidence, however better evidence is yet insufficient.
	Clinical improvement	Critical	The study is too problematic to provide any useful evidence, however better evidence is yet insufficient.
	Adverse events	Critical	The study is too problematic to provide any useful evidence, however better evidence is yet insufficient.

Risk of bias assessment of Liu 2020
Domain	Assessed outcomes	Authors' judgement	Support for judgement
Bias due to confounding	Mortality Clinical improvement	Serious	Only adjusted for hydroxychloroquine and azithromycin, intubation status and duration, length of hospital stay, and oxygen requirement on the day of transfusion. Not adjusted for e.g. age and gender
Bias due to confounding	Adverse events	Not applicable	Paper only reports transfusion‐related adverse events for intervention group
Bias in selection of participants into the study	Mortality Clinical improvement	Moderate	Selection into the study may have been related to intervention and outcome, but the study authors used appropriate methods to adjust for the selection bias. Quote: "propensity score‐matched analysis using The Mount Sinai Hospital’s COVID‐19 confirmed patient pool from the same calendar period (24 March 2020 105 to 8 April 2020). A logistic regression was fit to predict the potential for plasma therapy based on time series data obtained at baseline upon admission, prior to transfusion, and the day of 107 transfusion."
Bias in selection of participants into the study	Adverse events	Not applicable	Paper only reports transfusion‐related adverse events for intervention group
Bias in classification of interventions	Mortality Clinical improvement	Critical	Assignment to control group was done retrospectively. Treatment details of control group are not provided. Knowledge of participants' outcomes at the time of assignment to the control group could have had a major impact on the selection.
Bias in classification of interventions	Adverse events	Not applicable	Paper only reports transfusion‐related adverse events for intervention group
Bias due to deviations from intended interventions	Mortality Clinical improvement	Low	All participants received the intended intervention. Most common co‐interventions (hydroxychloroquine and azithromycin, intubation status and duration, length of hospital stay, and oxygen requirement on the day of transfusion) were propensity score‐matched. Other co‐interventions were administered too infrequently to enforce exact matching
Bias due to deviations from intended interventions	Adverse events	Low
Bias due to missing data	Mortality Clinical improvement	Low	Data were reasonably complete
Bias due to missing data	Adverse events	Critical	No safety data for control group available
Bias in measurement of outcomes	Mortality Clinical improvement	Moderate	Median follow‐up comparable between groups. However, outcome assessors were not blinded to intervention and the study was performed retrospectively.
Bias in measurement of outcomes	Adverse events	Critical	Only transfusion‐related adverse events reported
Bias in selection of the reported results	Mortality Clinical improvement	Critical	Retrospective study; selection of all reported results are likely biased
Bias in selection of the reported results	Adverse events	Critical	Observation period unclear, non‐occurrence of transfusion‐related adverse events only reported in discussion section
Overall bias	Mortality	Critical	The study is too problematic to provide any useful evidence, however better evidence is yet insufficient.
	Clinical improvement	Critical	The study is too problematic to provide any useful evidence, however better evidence is yet insufficient.
	Adverse events	Critical	The study is too problematic to provide any useful evidence, however better evidence is yet insufficient.

'Risk of bias' assessment of Zeng 2020
Domain	Assessed outcomes	Authors' judgement	Support for judgement
Bias due to confounding	Mortality Clinical improvement	Serious	Not adjusted for confounding factors
Bias due to confounding	Adverse events	Not applicable	Paper only reports adverse events after plasma transfusion for intervention group
Bias in selection of participants into the study	Mortality Clinical improvement	Moderate	Allocation to intervention and control group based on donor‐availability Quote: "A total of 21 contemporaneous critically ill patients with COVID‐19 were enrolled in the current study (Table 1), and all of them required intensive care unit admission. Six of the patients received convalescent plasma treatment based on the limited availability of convalescent plasma and ABO compatibility. Five of 6 patients in the convalescent plasma treatment group and 11 of 15 in the non–convalescent plasma treatment (control) group were male."
Bias in selection of participants into the study	Adverse events	Not applicable	Paper only reports adverse events after plasma transfusion for intervention group
Bias in classification of interventions	Mortality Clinical improvement	Critical	Retrospective study design. Despite missingness of donors, unclear how control group was selected. Treatment details of control group are provided, but knowledge of participants' outcomes at the time of assignment to the control group could have had a major impact on the selection.
Bias in classification of interventions	Adverse events	Not applicable	Paper only reports adverse events after plasma transfusion for intervention group
Bias due to deviations from intended interventions	Mortality Clinical improvement	Low	All participants received intended intervention. Co‐interventions (e.g. antiviral therapy, traditional Chinese medicine, etc.) seem to be balanced across treatment groups.
Bias due to deviations from intended interventions	Adverse events	Low	All assessed participants received intended intervention
Bias due to missing data	Mortality	Low	Data were reasonably complete
	Clinical improvement	Low	Living participants discharged
	Adverse events	Critical	No safety data for control group available
Bias in measurement of outcomes	Mortality Clinical improvement	Low	Follow‐up until death or discharge
Bias in measurement of outcomes	Adverse events	Critical	Only adverse events after plasma transfusion reported
Bias in selection of the reported results	Mortality Clinical improvement	Critical	Retrospective study; selection of all reported results are likely biased
Bias in selection of the reported results	Adverse events	Critical	Retrospective study; selection of all reported results are likely biased; only transfusion‐related adverse events reported; no safety data for control group available
Overall bias	Mortality	Critical	The study is too problematic to provide any useful evidence, however better evidence is yet insufficient.
	Clinical improvement	Critical	The study is too problematic to provide any useful evidence, however better evidence is yet insufficient.
	Adverse events	Critical	The study is too problematic to provide any useful evidence, however better evidence is yet insufficient.

'Risk of bias' assessment of Ahn 2020
Domain	Assessed outcomes	Authors' judgement	Support for judgement
Representative study group (selection bias)	Not available	High	2 participants only
Outcome detectors blinded to intervention (detection bias)	Adverse events	High	Not blinded, awareness of intervention can bias assessment of subjective outcomes
Complete outcome assessment/follow‐up (attrition bias)	Adverse events	Low	Assessed and reported for both cases
Well‐defined study group (reporting bias)	Not available	Low	Population and intervention are well described
Well‐defined outcome (reporting bias)	Adverse events	High	No adverse reaction occurred after the administration of convalescent plasma in both cases. Observation period not reported
Well‐defined risk estimates (analyses)	Adverse events	Not applicable	No analyses performed
Important prognostic factors or follow‐up taken adequately into account (confounding)	Not available	High	Not adjusted for confounding factors

'Risk of bias' assessment of Jin 2020
Domain	Assessed outcomes	Authors' judgement	Support for judgement
Representative study group (selection bias)	Not available	High	6 of 146 COVID‐19 patients in Guizhou Jiangjunshan Hospital who received convalescent plasma therapy included in report
Outcome detectors blinded to intervention (detection bias)	Adverse events	High	Not blinded, awareness of intervention can bias assessment of subjective outcomes
Complete outcome assessment/follow‐up (attrition bias)	Adverse events	Unclear	Assessed for all participants over study period, observation period unclear
Well‐defined study group (reporting bias)	Not available	Unclear	Study population well described, but intervention scarcely described
Well‐defined outcome (reporting bias)	Adverse events	High	Reported for all participants, but observation period unclear
Well‐defined risk estimates (analyses)	Adverse events	Not applicable	No analyses performed
Important prognostic factors or follow‐up taken adequately into account (confounding)	Not available	High	Not adjusted for confounding, results only reported for 6 of 146 participants receiving convalescent plasma

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Improvement of clinical symptoms at up to 7 days (assessed by need for respiratory support)	1	103	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.30, 3.19]
1.2 Improvement of clinical symptoms at 8 to 15 days (assessed by need for respiratory support)	1	103	Risk Ratio (M‐H, Random, 95% CI)	1.85 [0.91, 3.77]
1.3 Improvement of clinical symptoms at 16 to 30 days (assessed by need for respiratory support)	1	103	Risk Ratio (M‐H, Random, 95% CI)	1.20 [0.80, 1.81]
1.4 Improvement of clinical symptoms at up to 7 days (assessed by need for respiratory support): subgroup severity of disease	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.4.1 Severe disease	1	45	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.18, 2.85]
1.4.2 Life‐threatening disease	1	58	Risk Ratio (M‐H, Random, 95% CI)	2.00 [0.19, 20.86]
1.5 Improvement of clinical symptoms at 8 to 15 days (assessed by need for respiratory support): subgroup severity of disease	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.5.1 Severe disease	1	45	Risk Ratio (M‐H, Random, 95% CI)	2.23 [1.05, 4.76]
1.5.2 Life‐threatening disease	1	58	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.22, 4.55]
1.6 Improvement of clinical symptoms at 16 to 30 days (assessed by need for respiratory support): subgroup severity of disease	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.6.1 Severe disease	1	45	Risk Ratio (M‐H, Random, 95% CI)	1.34 [0.98, 1.83]
1.6.2 Life‐threatening disease	1	58	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.33, 2.24]
1.7 30‐day mortality	1	101	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.29, 1.46]

*Study characteristics*
Methods	Trial design: case series Type of publication: journal publication Setting: ICU Recruitment dates: 22 February 2020‐29 March 2020 Country: South Korea Language: English Number of centres: 1 Trial registration number: NR Date of trial registration: NR
Participants	Age: 67 and 71 Gender: 1 male, 1 female Ethnicity: NR Number of participants (recruited/allocated/evaluated): 2 Severity of disease: critical Co‐morbidities: case 2 ‐ medical history of hypertension Inclusion criteria: NR Exclusion criteria: NR Previous treatments (e.g. experimental drug therapies, oxygen therapy, ventilation): 400 mg of hydroxychloroquine once daily and lopinavir/ritonavir 400 mg/100 mg twice daily, empirical antibiotics, 4 L/min oxygen flow via nasal cannula, high‐flow oxygen therapy
Interventions	Intervention(s): CP therapy Details of CP: Type of plasma: apheresis plasma, collected with Spectra Optia apheresis system (CMNC software; Spectra Optia IDL Tubing set; Terumo BCT, Lakewood, CO, USA) Volume: 500 mL total Number of doses: 2 Type of antibody test(s) and antibody‐titre(s): anti‐SARS‐CoV‐2 IgG antibody in plasma was measured by ELISA (Novel Coronavirus COVID‐19 IgG ELISA kit; Epitope Diagnostics, San Diego, CA, USA) and OD ratio for IgG Pathogen inactivated: NR RT‐PCR tested: NR Details of donors: Gender: male HLA and HNA antibody‐negative: NR Severity of disease: pneumonia Timing from recovery from disease: 18‐21 days RT‐PCR tested: yes in 1 participant Treatment details, including time of plasma therapy (e.g. early stage of disease): administered 7 (case 2) and 22 (case 1) days after admission Comparator: not applicable Concomitant therapy: 400 mg of hydroxychloroquine once daily and lopinavir/ritonavir 400 mg/100 mg twice daily, empirical antibiotics, intubation and mechanical ventilator care, IV methylprednisolone (0.5/1 mg/kg/day daily). Unclear whether these treatments were stopped before plasma transfusion or continuously given Duration of follow‐up: up to 26 days Treatment cross‐overs: not applicable Compliance with assigned treatment: good (all compliant)
Outcomes	Primary study outcome(s): NR Primary review outcomes All‐cause mortality at hospital discharge: reported Time to death: not applicable Secondary review outcomes Number of participants with grade 3 and grade 4 AEs, including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions): reported Number of participants with SAEs: reported Improvement of clinical symptoms, assessed through need for respiratory support at up to 7 days; 8‐15 days; 16‐30 days: reported 30‐day and 90‐day mortality: not applicable Admission to the ICU: reported Length of stay on the ICU: reported Time to discharge from hospital: reported QoL: NR Additional study outcomes: SARS‐CoV‐2 RNA by rRT‐PCR, IL‐6 and CRP, white blood cell count, lymphocyte count, arterial blood gas analysis (PaO2/FiO2), chest X‐ray, overall improvement of clinical symptoms
Notes	Sponsor/funding: funding was provided by: Ministry of Health and Welfare (HI14C1324), Korea HIV/AIDS Cohort Study (2019‐ER5101‐00) COIs: the authors have no potential conflicts of interest to disclose Other: "this study was approved by the IRB of Severance Hospital (IRB No. 4‐2020‐0076) and with participants' written informed consent. The images are published under agreement of the patients."

*Study characteristics*
Methods	Trial design: case report Type of publication: case reports in Women's Health Setting: teaching hospital Recruitment dates: NR Country: USA Language: English Number of centres: 1 Inclusion/exclusion criteria: NR Trial registration no.: NR Date of trial registration: NR
Participants	Age: 35 years Gender: female Ethnicity: NR Number of participants (recruited/allocated/evaluated): 1 Severity of disease: critical Co‐morbidities: type 2 diabetes mellitus, asthma, and class III obesity, 22 weeks pregnant Inclusion criteria: NR Exclusion criteria: NR Previous treatments (e.g. experimental drug therapies, oxygen therapy, ventilation): 6 L nasal cannula, high‐flow non‐invasive positive‐pressure ventilation
Interventions	Intervention(s): CP therapy Details of CP: Type of plasma: NR Volume: NR Number of doses: 1 Type of antibody test(s) and antibody‐titre(s): NR Pathogen inactivated: NR RT‐PCR tested: NR Details of donors: Gender: NR HLA and HNA antibody‐negative: NR Severity of disease: NR Timing from recovery from disease: NR RT‐PCR tested: NR Treatment details, including time of plasma therapy (e.g. early stage of disease): on admission day Comparator: not applicable Concomitant therapy: 6 L nasal cannula, high‐flow non‐invasive positive‐pressure ventilation. Rocephin 2 g IV daily and azithromycin, 500 mg IV for concern for possible superimposed bacterial pneumonia. Unclear whether these treatments were stopped before plasma transfusion or continuously given. Hydroxychloroquine 400 g twice daily was initiated on the day of admission, followed by 400 mg daily for 3 days. Patient received a therapeutic dose of low molecular weight heparin for the duration of admission. Patient was intubated and placed on mechanical ventilation. Intermittent pressure support with IV ephedrine was provided as needed for hypotension. Prone ventilation was attempted on hospital day 4 and discontinued. A short course of IV glucocorticoids with hydrocortisone 50 mg IV which was started as a 3‐times‐daily dose and tapered over the course of 5 days was initiated. Steps to establish management of hyperglycaemia were also initiated. Patient was started on remdesivir on hospital day 5 with a 200 mg IV dose. Remdesivir therapy continued with 100 mg IV doses every 24 h for an additional 9 days. Supplemental oxygen via nasal cannula was initiated following extubation. Duration of follow‐up: 14 days Treatment cross‐overs: not applicable Compliance with assigned treatment: good
Outcomes	Primary study outcome(s): NR Primary review outcomes All‐cause mortality at hospital discharge: reported Time to death: not applicable Secondary review outcomes Number of participants with grade 3 and grade 4 AEs, including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions): periods of intermittent hypertension and hypotension on day 2 cardiac arrhythmia (torsades de pointes) on day 4 Number of participants with SAEs: NR Improvement of clinical symptoms, assessed through need for respiratory support at up to 7 days; 8‐15 days; 16‐30 days: reported 30‐day and 90‐day mortality: not applicable Admission to the ICU: reported Length of stay on the ICU: reported Time to discharge from hospital: reported QoL: NR Additional study outcomes: blood pressure, AST and ALT, renal dysfunction, vital signs, cardiac arrhythmia
Notes	Sponsor/funding: no funding COIs: the authors have no potential conflicts of interest to disclose Other: patient consent: obtained. This case report was peer reviewed.

*Study characteristics*
Methods	Trial design: case report Type of publication: epub, ahead of print Setting: hospital Recruitment dates: 16 February‐19 March 2020 Country: China Language: English Number of centres: 1 Trial registration number: NR Date of registration: NR
Participants	Age: 38 Gender: male Ethnicity: NR Number of participants (recruited/allocated/evaluated): 1 Severity of disease: severe Co‐morbidities: nil Inclusion criteria: NR Exclusion criteria: NR Previous treatments (e.g. experimental drug therapies, oxygen therapy, ventilation): NR
Interventions	CP therapy or hyperimmune immunoglobulin therapy: CP therapy Details of CP: Type of plasma: ABO‐compatible Volume: 150ml to 200 mL each dose Number of doses: 2 Antibody test and antibody‐titre: NR Pathogen inactivated or not: NR RT‐PCR tested: NR Details of donors: Gender: NR HLA and HNA antibody‐negative: NR Severity of disease: NR Timing from recovery from disease: NR RT‐PCR tested: NR Treatment details, including time of plasma therapy (e.g. early stage of disease): administered between 9 and 24 days after admission For studies including a control group: comparator (type): not applicable Concomitant therapy: antibiotics, haemostatic drugs were administered, low‐temperature noradrenaline dilution solution and low‐temperature thrombin solution, antifungals, antivirals, tracheostomy, ventilation, craniotomy, mannitol Duration of follow‐up: up to 32 days Treatment cross‐overs: not applicable Compliance with assigned treatment: not applicable
Outcomes	Primary study outcome(s): NR Primary review outcomes All‐cause mortality at hospital discharge: reported Time to death: not applicable Secondary review outcomes Number of participants with grade 3 and grade 4 AEs, including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions): NR Number of participants with SAEs: NR Improvement of clinical symptoms, assessed through need for respiratory support at up to 7 days; 8‐15 days; 16‐30 days: reported 30‐day and 90‐day mortality: not applicable Admission to the ICU: reported Length of stay on the ICU: NR Time to discharge from hospital: NR QoL: NR Additional study outcomes: NR
Notes	Sponsor/funding: no funding received COIs: all study authors declare no competing interests Other: nil

'Risk of bias' assessment of Joyner 2020
Domain	Assessed outcomes	Authors' judgement	Support for judgement
Representative study group (selection bias)	Not available	Low	Large population size, prospective study, interim analysis of first 5000 patients
Outcome detectors blinded to intervention (detection bias)	Adverse events	High	Not blinded, awareness of intervention can bias assessment of subjective outcomes
Complete outcome assessment/follow‐up (attrition bias)	Adverse events	Unclear	Preliminary results; only serious adverse events assessed, 4‐h follow‐up
Well‐defined study group (reporting bias)	Adverse events	Unclear	Study population well described, intervention scarcely described
Well‐defined outcome (reporting bias)	Adverse events	Unclear	Preliminary results; serious adverse events only
Well‐defined risk estimates (analyses)	Adverse events	Not available	No analyses performed
Important prognostic factors or follow‐up taken adequately into account (confounding)	Not available	High	Not adjusted for confounding factors

'Risk of bias' assessment of Pei 2020
Domain	Assessed outcomes	Authors' judgement	Support for judgement
Representative study group (selection bias)	Not available	High	3 participants only
Outcome detectors blinded to intervention (detection bias)	Adverse events	High	Not blinded, awareness of intervention can bias assessment of subjective outcomes
Complete outcome assessment/follow‐up (attrition bias)	Adverse events	Unclear	Serious adverse events reported for 1 participant, not reported whether other participants experienced any adverse events
Well‐defined study group (reporting bias)	Not available	High	Study population and intervention insufficiently described
Well‐defined outcome (reporting bias)	Adverse events	High	Observation period not described
Well‐defined risk estimates (analyses)	Adverse events	Not available	No analyses performed
Important prognostic factors or follow‐up taken adequately into account (confounding)	Not available	High	Comorbidities and disease presentation and course not clearly reported; not adjusted for confounding factors

'Risk of bias' assessment of Perotti 2020
Domain	Assessed outcomes	Authors' judgement	Support for judgement
Representative study group (selection bias)	Not available	High	46 participants only
Outcome detectors blinded to intervention (detection bias)	Adverse events	High	Not blinded, but awareness of intervention can bias assessment of subjective outcomes
Complete outcome assessment/follow‐up (attrition bias)	Adverse events	Low	Assessed and reported for all participants, 7‐day follow‐up
Well‐defined study group (reporting bias)	Not available	Low	Study population and intervention well described
Well‐defined outcome (reporting bias)	Adverse events	Low	Assessed and reported for all participants, 7‐day follow‐up
Well‐defined risk estimates (analyses)	Adverse events	Not available	No analyses performed
Important prognostic factors or follow‐up taken adequately into account (confounding)	Not available	High	Not adjusted for confounding factors

'Risk of bias' assessment of Salazar 2020
Domain	Assessed outcomes	Authors' judgement	Support for judgement
Representative study group (selection bias)	Not available	High	25 participants only
Outcome detectors blinded to intervention (detection bias)	Adverse events	High	Not blinded, but awareness of intervention can bias assessment of subjective outcomes
Complete outcome assessment/follow‐up (attrition bias)	Adverse events	Low	All participants observed for occurrence of adverse events
Well‐defined study group (reporting bias)	Not available	Low	Study population and intervention well described
Well‐defined outcome (reporting bias)	Adverse events	Low	All observed adverse events described
Well‐defined risk estimates (analyses)	Adverse events	Not available	No analyses performed
Important prognostic factors or follow‐up taken adequately into account (confounding)	Not available	High	Not adjusted for confounding factors

'Risk of bias' assessment of Tan 2020
Domain	Assessed outcomes	Authors' judgement	Support for judgement
Representative study group (selection bias)	Not available	High	1 participant only
Outcome detectors blinded to intervention (detection bias)	Adverse events	High	Not blinded, but awareness of intervention can bias assessment of subjective outcomes
Complete outcome assessment/follow‐up (attrition bias)	Adverse events	Unclear	Only fever reported, not reported whether other adverse events occurred
Well‐defined study group (reporting bias)	Not available	High	1 participant only, not much information (e.g. age, comorbidities, clinical symptoms), intervention not described in detail
Well‐defined outcome (reporting bias)	Adverse events	High	Only fever reported, not reported whether other adverse events occurred
Well‐defined risk estimates (analyses)	Adverse events	Not available	No analyses performed
Important prognostic factors or follow‐up taken adequately into account (confounding)	Not available	High	Not adjusted for confounding factors

'Risk of bias' assessment of Ye 2020
Domain	Assessed outcomes	Authors' judgement	Support for judgement
Representative study group (selection bias)	Not available	High	6 participants only
Outcome detectors blinded to intervention (detection bias)	Adverse events	High	Not blinded, but awareness of intervention can bias assessment of subjective outcomes
Complete outcome assessment/follow‐up (attrition bias)	Adverse events	Low	None occurred (3‐day follow‐up)
Well‐defined study group (reporting bias)	Not available	Low	Study population and intervention well described
Well‐defined outcome (reporting bias)	Adverse events	Low	3‐day follow‐up
Well‐defined risk estimates (analyses)	Adverse events	Not available	No analyses performed
Important prognostic factors or follow‐up taken adequately into account (confounding)	Not available	High	Not adjusted for confounding factors

'Risk of bias' assessment of Zhang 2020a
Domain	Assessed outcomes	Authors' judgement	Support for judgement
Representative study group (selection bias)	Not available	High	4 participants only
Outcome detectors blinded to intervention (detection bias)	Adverse events	High	Not blinded, but awareness of intervention can bias assessment of subjective outcomes
Complete outcome assessment/follow‐up (attrition bias)	Adverse events	Unclear	Clinical course reported, but not whether adverse events occurred
Well‐defined study group (reporting bias)	Not available	Unclear	Study group well described but not intervention
Well‐defined outcome (reporting bias)	Adverse events	High	Not described in detail, unclear whether adverse events occurred
Well‐defined risk estimates (analyses)	Adverse events	Not available	No analyses performed
Important prognostic factors or follow‐up taken adequately into account (confounding)	Not available	High	Not adjusted for confounding factors

*Study characteristics*
Methods	Trial design: prospective single‐arm pilot study Type of publication: journal publication Setting: inpatient Recruitment dates: 23 January 2020‐19 February 2020 Country: China Language: English Number of centres: 3 Trial registration number: ChiCTR2000030046 Date of trial registration: 21 February 2020
Participants	Age: median age 52.5 years (IQR 45.0‐59.5 years) Gender: 6 male, 4 female Ethnicity: NR Number of participants (recruited/allocated/evaluated): 10 Severity of disease: severe Co‐morbiditities: cardiovascular and/or cerebrovascular diseases and essential hypertension Inclusion criteria: 1 of the conditions 2‐4 plus condition 1: 1) age ≥ 18 years; 2) respiratory distress, respiratory rate ≥ 30 breaths/min; 3) oxygen saturation level < 93% in resting state; and 4) PaO2/FiO2 ≤ 300 mmHg (1 mmHg = 0.133 kPa) Exclusion criteria: 1) previous allergic history to plasma or ingredients (sodium citrate); 2) cases with serious general conditions, such as severe organ dysfunction, who were not suitable for CP transfusion Previous treatments (e.g. experimental drug therapies, oxygen therapy, ventilation): oxygen support (9/10 before CP therapy, 8/10 after CP therapy): mechanical ventilation, high‐flow nasal cannula oxygenation, conventional low‐flow nasal cannula oxygenation antiviral treatments (10/10): arbidol 0.2 g every 8 h) by mouth, monotherapy or combination therapy with remdesivir 0.2 g/day IV or ribavirin 0.5 g/day IV or peramivir 0.3 g/day IV, or ribavirin 0.5 g/day IV monotherapy, IFN‐ɑ 500 MIU/day inhalation, oseltamivir 75 mg every 12 h by mouth, peramivir 0.3 g/day IV antibacterial or antifungal treatment (8/10): when participants had coinfection corticosteroids 6/10): IV methylprednisolone (20 mg every 24 h)
Interventions	CP therapy or hyperimmune immunoglobulin therapy: CP therapy Details of CP: Type of plasma: apheresis plasma. Apheresis was performed using a Baxter CS 300 cell separator (Baxter). A 200‐ to 400‐mL ABO‐compatible plasma sample was harvested from each donor depending on age and body weight, and each sample was divided and stored as 200 mL aliquots at 4 °C without any detergent or heat treatment. The CP was then treated with methylene blue and light treatment for 30 min in the medical plasma virus inactivation cabinet (Shandong Zhongbaokang Medical Appliance Co, Ltd) Volume: 200 mL Number of doses: 1 Type of antibody test(s) and antibody‐titre(s): the neutralising activity against SARS‐CoV‐2 was evaluated by classical plaque reduction test using a recently isolated viral strain. Antibody titre: > 1:160 Pathogen inactivated or not: methylene blue photochemistry RT‐PCR tested: NR Details of donors: CP for treatment was collected from 40 donors. The median age was 42.0 years (IQR 32.5‐49 years). Gender: NR HLA and HNA antibody‐negative: NR Severity of disease: NR Timing from recovery from disease: NR RT‐PCR tested: NR Treatment details, including time of plasma therapy (e.g. early stage of disease): administered between 10 and 20 days after admission (median: 16.5 days) For studies including a control group: comparator (type): historic control, matched by age, gender and severity of disease Concomitant therapy: mechanical ventilation, high‐flow nasal cannula oxygenation, conventional low‐flow nasal cannula oxygenation, arbidol 0.2 g every 8 h by mouth, monotherapy or combination therapy with remdesivir 0.2 g/day IV or ribavirin 0.5 g/day IV or peramivir 0.3 g/day IV, or ribavirin 0.5 g/day IV monotherapy, IFN‐ɑ 500 MIU/day inhalation, oseltamivir 75 mg every 12 h by mouth, peramivir 0.3 g/day IV, antibacterial or antifungal treatment when participants had coinfection, IV methylprednisolone (20 mg every 24 h) Duration of follow‐up: NR Treatment cross‐overs: not applicable Compliance with assigned treatment: good (all compliant)
Outcomes	Primary study outcome The changes of clinical symptom, laboratory and radiological data 3 days after CP transfusion Primary review outcomes All‐cause mortality at hospital discharge: NR Time to death: NR Secondary review outcomes Number of participants with grade 3 and grade 4 AEs, including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions): only CP transfusion‐related AEs reported (evanescent facial red spot) Number of participants with SAEs: reported, none occurred Improvement of clinical symptoms, assessed through need for respiratory support at up to 7 days; 8‐15 days; 16‐30 days: reported; up to day 4 30‐day and 90‐day mortality: NR Admission on the ICU: NR Length of stay on the ICU: NR Time to discharge from hospital: NR QoL: NR Additional study outcomes: lymphocyte count, CRP, ALT, AST, total bilirubin, SaO₂, clinical symptoms improvement, clinical outcome, defined as: death, stable, improved, discharged, neutralising antibody titres, SARS‐CoV‐2 RNA by RT‐PCR, reduction of pulmonary lesions on chest CT
Notes	Sponsor/funding: this study was funded by Key projects of the Ministry of Science and Technology China 'Preparation of specific plasma and specific globulin from patients with a recovery period of COVID‐19 infection' (Project 2020YFC0841800). This work was also supported by Shanghai Guangci Translational Medicine Development Foundation. We thank all patients and donors involved in this study. COIs: study authors declare no competing interests Other: "written informed consent according to the Declaration of Helsinki was obtained from each patient or legal relatives. This study was approved by the Ethics Committee of the China National Biotec Group Co., Ltd. (Approval number 2020‐0001)."

*Study characteristics*
Methods	Trial design: expanded access Type of publication: preprint publication Setting: hospital, 66% ICU Recruitment dates: 13 April‐11 May 2020 Country: USA Language: English Number of centres: 12 Trial registration number: NCT04338360 Date of trial registration: 08 April 2020
Participants	Age: median age 62 years (18‐97 years) Gender: 3153 men, 1824 women and 23 people in other gender/sex categories Ethnicity: Asian (6%), American Indian or Alaskan Native (< 1%), black (18%), white (49%), Native Hawaiian or Pacific Islander (< 1%) and multi‐racial (< 1%) Number of participants (recruited/allocated/evaluated): recruited: 14,288 patients; allocated: 8932 patients; evaluated: the first 5000 patients Severity of disease: hospitalised adults with severe or life‐threatening COVID‐19 At the time of enrolment, 4051 (81%) patients had severe or life‐threatening COVID‐19 72% had respiratory failure 63% reported dyspnoea 62% had a blood oxygen saturation ≤ 93% 43% had lung infiltrates > 50% within 24‐28 h of enrolment 38% had a respiratory frequency ≥ 30 breaths/min‐1 34% had partial pressure of arterial oxygen to fraction of inspired oxygen ratio < 300 18% had multiple organ dysfunction or failure 15% had septic shock 949 (19%) were judged to have a high risk of progressing to severe or life‐threatening COVID‐19 Prior to CP transfusion, 3316 patients (66%) were admitted to the ICU Co‐morbidities: NR Inclusion criteria: Age ≥ 18 years Laboratory‐confirmed diagnosis of infection with SARS‐CoV‐2 Admitted to an acute care facility for the treatment of COVID‐19 complications Severe or life‐threatening COVID‐19, or judged by the treating provider to be at high risk of progression to severe or life‐threatening disease. (Severe COVID‐19 is defined by one or more of the following: dyspnoea, respiratory frequency ≥ 30/min, blood oxygen saturation ≤ 93%, PaO2/FiO2 < 300, lung infiltrates > 50% within 24‐48 h. Life‐threatening COVID‐19 is defined as one or more of the following: multiple organ dysfunction or failure, septic shock, respiratory failure.) Informed consent provided by the patient or healthcare proxy Exclusion criteria: NR Previous treatments (e.g. experimental drug therapies, oxygen therapy, ventilation): NR
Interventions	CP therapy or hyperimmune immunoglobulin therapy: CP therapy Details of CP: Type of plasma: ABO‐compatible COVID‐19 CP Volume: 200‐500 mL; according to institutional transfusion guidelines Number of doses: 1 Type of antibody test(s) and antibody‐titre(s): NR Pathogen inactivated or not: NR RT‐PCR tested: NR Details of donors: Gender: NR HLA and HNA antibody‐negative: NR Severity of disease: NR Timing from recovery from disease: NR RT‐PCR tested: NR Treatment details, including time of plasma therapy (e.g. early stage of disease): NR Comparator: none Concomitant therapy: NR Duration of follow‐up: 4‐h follow‐up for SAEs, 7‐day follow‐up for mortality Treatment cross‐overs: not applicable Compliance with assigned treatment: NR
Outcomes	Primary study outcome(s): key safety metrics after transfusion of ABO‐compatible human COVID‐19 CP Primary review outcomes All‐cause mortality at hospital discharge: 7‐day mortality rate Time to death: NR Secondary review outcomes Number of participants with grade 3 and grade 4 AEs, including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions): serious transfusion‐related AEs reported Number of participants with SAEs: reported; 4h observation period Improvement of clinical symptoms, assessed through need for respiratory support at up to 7 days; 8‐15 days; 16‐30 days: NR 30‐day and 90‐day mortality: NR Admission on the ICU: NR Length of stay on the ICU: NR Time to discharge from hospital: NR QoL: NR Additional study outcomes: none
Notes	Sponsor/funding: US Department of Health and Human Services (HHS), Biomedical Advanced Research and Development Authority (BARDA) grant 75A50120C00096 (to MJJ), National Center for Advancing Translational Sciences (NCATS) grant UL1TR002377, National Heart, Lung, and Blood Institute (NHLBI) grant 5R35HL139854 (to MJJ), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 5T32DK07352 (to JWS and CCW), Natural Sciences and Engineering Research Council of Canada (NSERC) PDF‐532926‐2019 (to SAK), National Institute of Allergy and Infectious Disease (NIAID) grants R21 AI145356 and R21 AI152318 (to DF), R01 AI152078 9 (to AC), National Heart Lung and Blood Institute RO1 HL059842 (to AC), Schwab Charitable Fund (Eric E Schmidt, Wendy Schmidt donors), United Health Group, National Basketball Association (NBA), Millennium Pharmaceuticals, Octopharma USA, Inc, and the Mayo Clinic COIs: NR Other: preliminary analysis, study still ongoing

*Study characteristics*
Methods	Trial design: RCT Type of publication: journal publication Setting: hospital Recruitment dates: 14 February 2020‐1 April 2020 Country: China Language: English Number of centres: 7 Trial registration number: ChiCTR2000029757 Date of registration: NR
Participants	Age: median 70 years, IQR 62‐78 years Gender: 60 male (58.3%), 43 female (41.7%) Ethnicity: NR Number of participants (recruited/allocated/evaluated): 103 (52 CP, 51 standard treatment) Severity of disease: severe or life‐threatening Co‐morbidities: hypertension, cardiovascular disease, cerebrovascular disease, diabetes, liver disease, cancer, kidney disease Inclusion criteria: signed informed consent aged at least 18 years COVID‐19 diagnosis based on PCR testing positive PCR result within 72 h prior to randomisation pneumonia confirmed by chest imaging clinical symptoms meeting the definitions of severe or life‐threatening COVID‐19 acceptance of random group assignment hospital admission willingness to participate in all necessary research studies and be able to complete the study follow‐up no participation in other clinical trials, such as antiviral trials, during the study period Exclusion criteria: pregnancy or lactation immunoglobulin allergy IgA deficiency pre‐existing comorbidity that could increase the risk of thrombosis life expectancy < 24 h disseminated intravascular coagulation severe septic shock PaO2/FIO2 of < 100 severe congestive heart failure detection of high titre of S protein–RBD‐specific IgG antibody (≥ 1:640) other contraindications as determined by the patient’s physicians participation in any antiviral clinical trials for COVID‐19 within 30 days prior to enrolment Previous treatments (e.g. experimental drug therapies, oxygen therapy, ventilation): antivirals, antibiotics, steroids, human Ig, Chinese herbal medicines, interferon
Interventions	CP therapy or hyperimmune immunoglobulin therapy: CP therapy Details of CP: Type of plasma: plasmapheresis Volume: 4‐13 mL/kg of recipient body weight, median 200 mL, IQR 200‐300 mL Number of doses: 1 (96%) or more Antibody test and antibody‐titre: only the plasma units with an S‐RBD–specific IgG titre of at least 1:640 were used correlating to serum neutralisation titre of 1:80 Pathogen inactivated or not: NR RT‐PCR tested: NR Details of donors: Gender: both, 18‐55 years suitable for blood donation HLA and HNA antibody‐negative: NR Severity of disease: NR Timing from recovery from disease: discharged from hospital > 2 weeks RT‐PCR tested: lab‐confirmed COVID‐19 diagnosis, 2 negative PCR results from nasopharyngeal swabs at least 24 h apart prior to hospital discharge Treatment details, including time of plasma therapy (e.g. early stage of disease): severe to life‐threatening For studies including a control group: comparator (type): standard therapy Concomitant therapy: antivirals, antibiotics, steroids, human Ig, Chinese herbal medicines, interferon Duration of follow‐up: 28 days Treatment cross‐overs: none Compliance with assigned treatment: 1 participant in control arm received CP, 1 participant in CP arm discontinued study
Outcomes	Primary study outcome(s): clinical improvement within 28 days (patient discharged alive or reduction of 2 points on a 6‐point disease severity scale) Primary review outcomes All‐cause mortality at hospital discharge: reported Time to death: reported Secondary review outcomes Number of participants with grade 3 and grade 4 AEs, including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions): reported Number of participants with SAEs: reported Improvement of clinical symptoms, assessed through need for respiratory support at up to 7 days; 8‐15 days; 16‐30 days: reported 30‐day and 90‐day mortality: reported Admission on the ICU: NR Length of stay on the ICU: NR Time to discharge from hospital: reported QoL: NR Additional study outcomes: rate of viral PCR to negative at up to 72 h
Notes	Sponsor/funding: this work was supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS) grants 2020‐I2M‐CoV19‐006, 2016‐I2M‐3‐024 (Dr Z. Liu), and 2017‐I2M‐1‐009 (Dr L. Li) and the Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences grant 2018PT32016 (Dr Z. Liu) COIs: Dr Liu reports holding a pending patent on COVID‐19 testing. Dr Wu reports consulting for Verax Medical and Grifols, receiving royalties from UptoDate and AABB, and being a volunteer visiting professor and receiving travel support for giving medical education from the Chinese Institute of Blood Transfusion. No other disclosures were reported. Other: nil

PERMALINK

Convalescent plasma or hyperimmune immunoglobulin for people with COVID‐19: a living systematic review

Vanessa Piechotta

Khai Li Chai

Sarah J Valk

Carolyn Doree

Ina Monsef

Erica M Wood

Abigail Lamikanra

Catherine Kimber

Zoe McQuilten

Cynthia So-Osman

Lise J Estcourt

Nicole Skoetz

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Effectiveness of convalescent plasma for people with COVID‐19

Secondary outcomes

Effectiveness of convalescent plasma for people with COVID‐19

Safety of convalescent plasma for people with COVID‐19

Timing of outcome measurement

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Randomised controlled trials

Controlled non‐randomised studies of interventions

Non‐controlled non‐randomised studies of interventions

1. 'Risk of bias' assessment criteria for observational studies.

Measures of treatment effect

Randomised controlled trials

Controlled non‐randomised studies of interventions

Non‐controlled non‐randomised studies of interventions

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Results

Description of studies

Results of the search

1.

Included studies

Design and sample size

Efficacy outcomes

Safety outcomes

Setting

Participants

Interventions

Outcomes

Ongoing studies

2. Summary: design and planned completion date of ongoing studies.

Excluded studies

*Study characteristics*
Methods	Trial design: matched control study Type of publication: preprint Setting: hospitalised patients Recruitment dates: 24 March 2020‐8 April 2020 Country: USA Language: English Number of centres: 1 Trial registration number: NR Date of trial registration: NR
Participants	Age: 55 (± 13) years Gender: 2/3rd male, 1/3rd female Ethnicity: NR Number of participants (recruited/allocated/evaluated): 45 recruited, 39 allocated and evaluated (matched retrospectively to controls) Severity of disease: severe or life‐threatening disease and consented to therapy Co‐morbidities: 21 (54%) obese, 7 (18%) current or former history of tobacco use, 1 (3%) participant had end‐stage renal disease requiring peritoneal dialysis, asthma in 3 (8%), cancer in 2 (5%), COPD in 1 (3%), diabetes in 8 (21%), OSA in 2 (5%) Inclusion criteria: severe or life‐threatening disease and consented to therapy Exclusion criteria: NR improvement of disease (4 of the 45 recruited patients did not receive plasma transfusion because they improved) Previous treatments (e.g. experimental drug therapies, oxygen therapy, ventilation): azithromycin, broad‐spectrum antibiotics, hydroxychloroquine, therapeutic anticoagulants, corticosteroids, directly acting antivirals, stem cells, and interleukin 1 and interleukin 6 inhibitors
Interventions	Intervention(s): CP therapy Details of CP: Type of plasma: plasmapheresis ABO‐matched Volume: 250 mL each dose (500 mL total) Number of doses: 2, each unit infused over 1 to 2 h Type of antibody test(s) and antibody‐titre(s): 2‐step Spike protein‐directed ELISA, anti‐spike antibody titre of ≥ 1:320 dilution Pathogen inactivated: NR RT‐PCR tested: NR Details of donors: Gender: NR HLA and HNA antibody‐negative: NR Severity of disease: NR Timing from recovery from disease: NR RT‐PCR tested: NR Treatment details, including time of plasma therapy (e.g. early stage of disease): severe to life‐threatening disease, median time between admission and transfusion was 4 (1 to 7) days Comparator: propensity‐score matched cohort from the same hospital and calendar period matching was performed on the following variables: administration of hydroxychloroquine and azithromycin, intubation status and duration, length of hospital stay, oxygen requirement on the day of transfusion; control patients were matched to plasma recipients by length of stay prior to transfusion Concomitant therapy: azithromycin, broad‐spectrum antibiotics, hydroxychloroquine, therapeutic anticoagulants, corticosteroids, directly acting antivirals, stem cells, and interleukin 1 and interleukin 6 inhibitors, oxygen therapy (87%), mechanical ventilation (10%), 69.2% were receiving high‐flow oxygen Duration of follow‐up: median follow‐up time was 11 (1 to 28) days for the plasma group and 9 (0 to 31) 186 days for the control group Treatment cross‐overs: not applicable Compliance with assigned treatment: good (all compliant)
Outcomes	Primary study outcome(s): supplemental oxygen requirements Primary review outcomes All‐cause mortality at hospital discharge: reported (survival at 3 time points: days 1, 7, and 14 post‐transfusion) Time to death: reported Secondary review outcomes Number of participants with grade 3 and grade 4 AEs, including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions): reported; assessed every 15 minutes after transfusion Number of participants with SAEs: reported Improvement of clinical symptoms, assessed through need for respiratory support at up to 7 days; 8‐15 days; 16‐30 days: reported (supplemental oxygen requirements three time points: days 1, 7, and 14 post‐transfusion) 30‐day and 90‐day mortality: NR (survival at 3 time points: days 1, 7, and 14 post‐transfusion) Admission on the ICU: reported Length of stay on the ICU: reported Time to discharge from hospital: reported QoL: NR Additional study outcomes: none
Notes	Sponsor/funding: Dr. Krammer reports that patent applications have been filed for the assay used to select plasma donors, and Mount Sinai has licensed its use to several companies. Dr. Aberg reports grants and personal fees from Gilead, grants and personal fees from Merck, grants and personal fees from Janssen, personal fees from Theratech, personal fees from Medicure, grants from Regeneron, grants and personal fees from Viiv, outside the submitted work. No external funding COIs: all other study authors have nothing to disclose Other: all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.

*Study characteristics*
Methods	Trial design: single‐arm, open‐label Type of publication: preprint Setting: hospital Recruitment dates: 25 March 2020‐21 April 2020 Country: Italy Language: English Number of centres: 3 Trial registration number: NCT 04321421 Date of registration: 25 March 2020
Participants	Age: mean 63 years (SD 12) Gender: 28 male (61%), 18 female (39%) Ethnicity: NR Number of participants (recruited/allocated/evaluated): planned sample size: 49, recruited: 46 Severity of disease: moderate to severe Co‐morbidities: 19 (41%) had ≥ 2 comorbidities, including diabetes, hypertension, cancer Inclusion criteria: Age ≥ 18 years Positive SARS‐CoV‐2 RT‐PCR on nasal swab or deep respiratory sample Moderate‐severe ARDS for ≤ 10 days as per Berlin definition Increase in the PCR value of approximately 3.5 times the upper reference limit or above 1.8 mg/dL Need for mechanical ventilation and/or CPAP Patients who signed the informed consent. If there is no possibility of obtaining informed consent for the clinical condition (e.g. patients sedated and treated for acute respiratory failure and consequent mechanical ventilation), the patient's consent will be assumed until manifestly stated otherwise. Exclusion criteria: Diagnosis of moderate‐severe ARDS >10 days Proven hypersensitivity or allergic reaction to blood products or immunoglobulin Manifest willingness to participate Previous treatments (e.g. experimental drug therapies, oxygen therapy, ventilation): antibiotics (84%), hydroxychloroquine (86%), antivirals (42%), anticoagulants (98%), oxygen therapy (CPAP (70%), intubation (16%), high‐flow (12%), low‐flow (2%))
Interventions	CP therapy or hyperimmune immunoglobulin therapy: CP therapy Details of CP Type of plasma: plasma collection was performed with the latest generation cell separator (Trima Accel –Terumo BCT and Amicus – Fresenius Kabi) devices. A plasma volume of about 660 mL was collected during each procedure and immediately equally divided into 2 bags using a sterile tubing welder. The collected units were stored at a controlled temperature ranging from −40 to −25 °C. ABO‐compatible Volume: approx 330 mL Number of doses: up to 3 over 5 days (1 (49%), 2 (49%), 3 (2%)) Antibody test and antibody‐titre: 1:80‐1:640. Neutralising antibodies (NT‐Abs) titers against SARS‐CoV2 was defined according to the following protocol. Briefly, 50 μl of sample from each patient, starting from 1:10 in a serial fourfold dilution series, were added in two wells of a flat bottom tissue culture microtiter plate (COSTAR, Corning Incorporated, NY 14831, USA), mixed with an equal volume of 50 TCID50 of a SARS‐CoV‐2 strain isolated from a symptomatic patient. Neutralising titre was the maximum dilution with the reduction of 90% of CPE. A positive titre was ≥ 1/10. Positive and negative controls were included in all tests run. Pathogen inactivated or not: yes, by INTERCEPT processing system (Cerus Europe BV) or the Mirasol PRT System (Terumo BCT, Lakewood, CO, USA) RT‐PCR tested: negative novel coronavirus nucleic acid test Details of donors Gender: both, females with no previous pregnancy included, age ≥ 18 HLA and HNA antibody‐negative: NR Severity of disease: NR Timing from recovery from disease: 2 consecutive negative nasopharyngeal swabs performed 7‐30 days before RT‐PCR tested: 2 consecutive negative nasopharyngeal swabs performed 7‐30 days before tested by RT‐PCR Treatment details, including time of plasma therapy (e.g. early stage of disease): moderate to severe For studies including a control group: comparator (type): not applicable Concomitant therapy: antibiotics (84%), hydroxychloroquine (86%), antivirals (42%), anticoagulants (98%), oxygen therapy (CPAP; 70%), intubation (16%), high‐flow (12%), low‐flow (2%)) Duration of follow‐up: 7 days Treatment cross‐overs: not applicable Compliance with assigned treatment: good
Outcomes	Primary study outcome: 7‐day mortality Primary review outcomes All‐cause mortality at hospital discharge: reported Time to death: reported Secondary review outcomes Number of participants with grade 3 and grade 4 AEs, including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions): reported Number of participants with SAEs: reported Improvement of clinical symptoms, assessed through need for respiratory support at up to 7 days; 8‐15 days; 16‐30 days: reported 30‐day and 90‐day mortality: NR Admission on the ICU: reported Length of stay on the ICU: reported Time to discharge from hospital: reported QoL: NR Additional study outcomes: laboratory parameters (CRP, ferritin, LDH, viral load), radiological changes (chest X‐ray)
Notes	Sponsor/funding: no funding received COIs: all study authors declare no competing interests Other: nil

*Study characteristics*
Methods	Trial design: single‐arm intervention Type of publication: journal preproof Setting: hospital Recruitment dates: 28 March–14 April 2020 Country: USA Language: English Number of centres: 1 Trial registration number: NR Date of trial registration: NR
Participants	Age: 19‐77 years (median 51, IQR 42.5 to 60) Gender: 11 male, 14 female Ethnicity: NR Number of participants (recruited/allocated/evaluated): 25 Severity of disease: severe or life‐threatening Co‐morbidities: diabetes (10 patients), hypertension (9 patients), hyperlipidaemia (5 patients), and gastrointestinal reflux disease (4 patients) Inclusion criteria: severe and/or life‐threatening COVID‐19 disease severe disease was defined as one or more of the following: shortness of breath (dyspnoea), respiratory rate ≥ 30/min, blood oxygen saturation ≤ 93%, partial pressure of arterial oxygen to fraction of inspired oxygen ratio < 300, and/or pulmonary infiltrates > 50% within 24 to 48 hours. life‐threatening disease was defined as one or more of the following: respiratory failure, septic shock, and/or multiple organ dysfunction or failure Exclusion criteria: NR Previous treatments (e.g. experimental drug therapies, oxygen therapy, ventilation)
Interventions	Intervention(s): CP therapy Details of CP: Type of plasma: obtained by apheresis using the Trima Accel automated blood collection system (Terumo BCT) Volume: 300 mL Number of doses: 1‐2 (1 patient had 2 doses 6 days apart) Type of antibody test(s) and antibody‐titre(s): to assess antibody titers, we used 2 ELISAs, 1 based on recombinant purified ectodomain (ECD) of the spike protein and the second using recombinant RBD of the spike protein. The titers of the CP used for transfusion ranged from 0‐1350 for the RBD and ECD domains. Pathogen inactivated: NR RT‐PCR tested: NR Details of donors: Gender: male and female HLA and HNA antibody‐negative: yes Severity of disease: all symptomatic, 1 hospitalised Timing from recovery from disease: > 14 days RT‐PCR tested: yes Treatment details, including time of plasma therapy (e.g. early stage of disease): median time from symptom onset to transfusion was 10 days (IQR, 7.5 to 12.5), and from hospitalisation to transfusion was 2 days (IQR, 2 to 4) Comparator: not applicable Concomitant therapy: tocilizumab and steroids, hydroxychloroquine, azithromycin, ribavirin, lopinavir/ritonavir, remdesivir, 12 participants on mechanical ventilation, 10 on low‐flow oxygen, 3 on high‐flow oxygen, 1 on ECMO Duration of follow‐up: up to 27 days Treatment cross‐overs: not applicable Compliance with assigned treatment: good (all compliant)
Outcomes	Primary study outcome(s): safety Primary review outcomes All‐cause mortality at hospital discharge: reported Time to death: reported Secondary review outcomes Number of participants with grade 3 and grade 4 AEs, including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions): reported (none) Number of participants with SAEs: reported (1 patient developed a morbilliform rash 1 day post‐transfusion that lasted for several days) Improvement of clinical symptoms, assessed through need for respiratory support at up to 7 days; 8‐15 days; 16‐30 days: reported (of 25 participants, 9 showed improvement by day 7, and by day 14 post‐transfusion, 19 participants showed improvement, as assessed by discharge or at least a 1‐point improvement on a modified clinical scale) 30‐day and 90‐day mortality: reported Admission on the ICU: NR Length of stay on the ICU: NR Time to discharge from hospital: reported QoL: NR Additional study outcomes: improvement in the modified 6‐point WHO ordinal scale at day 14 post‐transfusion, blood results (white blood count, liver function tests, ferritin, CRP, LDH)
Notes	Sponsor/funding: this study was supported by the National Institutes of Health grants AI146771‐01 and AI139369‐01, and the Fondren Foundation, Houston Methodist Hospital and Research Institute (to JMM). This research has been funded in whole or part with federal funds under a contract from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Contract Number 75N93019C00050 (to JL and GCI). A portion of this work was funded through Cooperative Agreement W911NF‐12‐1‐0390 by the Army Research Office (to JDG). COIs: the study authors have no potential conflicts of interest to disclose Other: all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.

*Study characteristics*
Methods	Trial design: retrospective matched controlled study Type of publication: journal online, ahead of print Setting: ICU Recruitment dates: NR Country: China Language: English Number of centres: 2 Trial registration number: NR Date of trial registration: NR
Participants	Age: median 61.5 years in CP group, median 73 years in control group Gender: 5 male, 1 female in CP group; 11 males, 4 females in control group Ethnicity: NR Number of participants (recruited/allocated/evaluated): 21 (6 received CP, 15 in control group) Severity of disease: critical (admitted to ICU) Co‐morbidities: pregnancy, diabetes, hypertension, cardiovascular disease (CP group) Inclusion criteria: critically ill patients Exclusion criteria: NR Previous treatments (e.g. experimental drug therapies, oxygen therapy, ventilation): antibiotics (100%), antiviral therapy (67%), traditional Chinese medicine (50%), IVIG (83%), steroid therapy (67%), high‐flow oxygen therapy (100%), mechanical ventilation (83%), renal replacement therapy (33%), ECMO (67%) in the CP group
Interventions	Intervention(s): CP therapy Details of CP: Type of plasma: NR Volume: median 300 mL (range 200‐600mL) Number of doses: 1‐2 Type of antibody test(s) and antibody‐titre(s): Gold immunochromatography for SARS‐CoV‐2 IgM and IgG tests were performed using blood sample (New Coronavirus [2019‐nCoV] Antibody Detection Kit, Shanghai Outdo Biotech and Tangshan Innovita Biotech). Pathogen inactivated: NR RT‐PCR tested: NR Details of donors: Gender: NR HLA and HNA antibody‐negative: NR Severity of disease: NR Timing from recovery from disease: NR RT‐PCR tested: NR Treatment details, including time of plasma therapy (e.g. early stage of disease): critically ill patients Comparator: Not applicable Concomitant therapy: antibiotics (100%), antiviral therapy (67%), traditional Chinese medicine (50%), IVIG (83%), steroid therapy (67%), high‐flow oxygen therapy (100%), mechanical ventilation (83%), renal replacement therapy (33%), ECMO (67%) in the CP group. Unclear whether these treatments were stopped before plasma transfusion or continuously given Duration of follow‐up: NR Treatment cross‐overs: Not applicable Compliance with assigned treatment: good (all compliant)
Outcomes	Primary study outcome(s): survival Primary review outcomes All‐cause mortality at hospital discharge: reported (5 of 6 patients died) Time to death: reported Secondary review outcomes Number of participants with grade 3 and grade 4 AEs, including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions): none Number of participants with SAEs: none Improvement of clinical symptoms, assessed through need for respiratory support at up to 7 days; 8‐15 days; 16‐30 days: NR 30‐day and 90‐day mortality: reported Admission on the ICU: reported (all admitted) Length of stay on the ICU: NR Time to discharge from hospital: reported (1 discharged) QoL: NR Additional study outcomes: duration of viral shedding
Notes	Sponsor/funding: supported by The National Natural Science Foundation of China (No. 81970517), Zhongyuan (Henan) Thousands Outstanding Talents Plan (No. ZYQR201912179), Foundation for Distinguished Young Talents of Zhengzhou University Medical School (No.2020ZQLMS), and The Key Scientific Research Project of Henan Higher Education Institutions of China (No. 20B320028). COIs: the authors have no potential conflicts of interest to disclose. Other: written informed consents were obtained from all the family members of patients who received plasma.

Study	Reason for exclusion
Alzoughool 2020	Review
Barone 2020	Review
Bloch 2020	Review
Brasil Ministerio 2020	Standard operating procedure
Budhai 2020	Feasibility of plasma collection only
Cao 2020a	Ineligible intervention
Cao 2020b	Review
Casadevall 2020a	Review
Casadevall 2020b	Editorial
Chen 2020a	Review
Chen 2020b	Ineligible intervention
Chen 2020c	Ineligible intervention
ChiCTR2000030312	Study cancelled before starting recruitment
ChiCTR2000030381	Study cancelled before starting recruitment
ChiCTR2000030442	Study cancelled before starting recruitment
Datta 2020	Review
de Assis 2020	Ineligible indication
Dzik 2020	Review
Díez 2020	Ineligible intervention
Fleming 2020	Letter
Franchini 2020	Standard operating procedure
Hammarström 2020	Review
Hu 2020	Ineligible intervention
ISRCTN86534580	Ineligible intervention
Jawhara 2020	Review
Jiang 2020	Ineligible intervention
Kesici 2020	Letter
Khanna 2020	Review
Knudson 2020	Letter
Kominers 2020	Review
Kumar 2020	Review
Lancet Haematology 2020	Editorial
Lanza 2020	Letter
Lin 2020	Ineligible intervention
Ministerio de Salud 2020	Standard operating procedure
NCT04261426	Ineligible intervention
NCT04323800	Ineligible participant population (participants exposed to COVID‐19)
NCT04325672	Study cancelled before starting recruitment
NCT04344015	Feasibility of plasma collection only
NCT04344379	Ineligible intervention
NCT04344977	Feasibility of plasma collection only
NCT04350580	Ineligible intervention
NCT04360278	Feasibility of plasma collection only
NCT04368013	Ineligible intervention
Pawar 2020	Review
Qiu 2020	No use of convalescent plasma. Reporting on generalised collection of information about Covid‐19 infection relating to aetiology, pathology, symptoms, clinical presentation and some generalised pharmacological treatment methods. The papers do not contain patient data that we required. Article translated by Rujan Shrestha and Ya‐Ying Wang via Cochrane TaskExchange
Roback 2020	Review
Robbiani 2020	Ineligible intervention
Rubin 2020	Review
Seghatchian 2020	Review
Sheridan 2020	Review
Shi 2020	Ineligible intervention
Syal 2020	Review
Tanne 2020	Review
Tiberghien 2020	Review
Tu 2020	No use of convalescent plasma. Reporting on generalised collection of information about Covid‐19 infection relating to aetiology, pathology, symptoms, clinical presentation and some generalised pharmacological treatment methods. The papers do not contain patient data that we required. Article translated by Rujan Shrestha and Ya‐Ying Wang via Cochrane TaskExchange
Wong 2020	Review
Xie 2020	Ineligible intervention
Yoo 2020	Review
Zeng 2020a	Letter
Zhao 2020b	Review
Zhu 2020	Letter

Study name	Study on convalescent plasma treatment for severe patients with novel coronavirus pneumonia (COVID‐19)
Methods	Trial design: prospective cohort study, controlled Sample size: 10 in each arm (20) Setting: inpatient Country: China Language: translated to English Number of centres: 1
Participants	Inclusion criteria Laboratory‐confirmed diagnosis of COVID‐19 infection by RT‐PCR Aged > 18 years Written informed consent given by the patient or next‐of‐kin Clinical deterioration despite conventional treatment that required intensive care Exclusion criteria Hypersensitive to immunoglobulin IgA deficiency
Interventions	CP therapy or hyperimmune immunoglobulin therapy: CP Details of CP: NR type of plasma: NR volume: NR number of doses: NR antibody‐titre: NR pathogen inactivated or not: NR Treatment details, including time of plasma therapy (e.g. early stage of disease): NR For studies including a control group: comparator (type): standardised comprehensive treatment Concomitant therapy: NR Treatment cross‐overs: NR
Outcomes	Primary study outcome: fatality rate Primary review outcomes All‐cause mortality at hospital discharge: yes (fatality rate) Time to death: NR Secondary review outcomes Number of participants with grade 3 and grade 4 AEs, including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions): NR Number of participants with SAEs: NR Improvement of clinical symptoms, assessed through need for respiratory support at up to 7 days; 8‐15 days; 16‐30 days: NR 30‐day and 90‐day mortality: yes Admission on the ICU: NR Length of stay on the ICU: yes Time to discharge from hospital: hospital stay duration QoL: NR Additional study outcomes Viral titres in respiratory samples Incubation period PaO2/FiO2 Cytokines/chemokines
Starting date	15 February 2020
Contact information	Liang Yu The First Affiliated Hospital of Zhejiang University, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Disease, 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, 310003, yu‐liang@zju.edu.cn Xiaowei Xu 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang, China, 310003, xxw69@126.com
Notes	Recruitment status: recruiting Prospective completion date: 15 February 2022 Sponsor/funding: The First Affiliated Hospital of Zhejiang University School of Medicine, Key Research and Development Project of Zhejiang Province

Study name	A randomized, double‐blind, parallel‐controlled, trial to evaluate the efficacy and safety of anti‐SARS‐CoV‐2 virus inactivated plasma in the treatment of severe novel coronavirus pneumonia patients (COVID‐19)
Methods	Trial design: randomised, double‐blind, parallel‐controlled trial Sample size: 50 in each arm (100) Setting: inpatient Country: China Language: translated to English Number of centres: 1
Participants	Inclusion criteria Aged 18‐70 years old, inpatients, male or female Patients with severe novel coronavirus infection: according to the "Pneumonitis Diagnosis and Treatment Guideline for the Novel Coronavirus Infection (Trial Version 5)", clinically diagnosed cases (suspected cases with pneumonia imaging features) or suspected cases. Severe patients must also meet any of the following: 1) respiratory distress, respiratory rate ≥ 30 times/min; 2) In the resting state, the oxygen saturation is ≤ 93%; 3) PaO2/FiO2 ≤ 300 mmHg (1 mm Hg = 0.133 kPa) Participants and/or legal guardians of the participants volunteered to participate in the study and voluntarily signed informed consent Exclusion criteria The clinical classification of patients with severe novel coronavirus infection is to meet any of the following: 1) respiratory failure occurs and requires mechanical ventilation; 2) shock occurs; 3) combined failure of other organs requires ICU monitoring and treatment Those who are allergic to blood products or plasma components and auxiliary materials (sodium citrate) There is multiple organ failure, and the estimated survival time is < 3 days Those who tested positive for HIV antibodies before enrolment Women who are pregnant or breastfeeding or have a birth plan within the past year Participants in other clinical trials within 3 months before screening Poor adherence or other conditions that the study author believes are not suitable for inclusion (such as poor physical condition)
Interventions	CP therapy or hyperimmune immunoglobulin therapy: Anti‐SARS‐CoV‐2 virus inactivated plasma Details of CP: type of plasma: NR volume: NR number of doses: NR antibody‐titre: NR pathogen inactivated or not: yes Treatment details, including time of plasma therapy (e.g. early stage of disease): NR For studies including a control group: comparator (type): ordinary plasma Concomitant therapy: NR Treatment cross‐overs: NR
Outcomes	Primary study outcome: improvement of clinical symptoms (clinical improvement is defined as a reduction of 2 points on the 6‐point scale of the patient's admission status or discharge from the hospital) Primary outcomes All‐cause mortality at hospital discharge: 14‐ and 28‐day all‐cause mortality Time to death: NR Secondary outcomes Number of participants with grade 3 and grade 4 AEs, including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions): NR Number of participants with SAEs: NR Improvement of clinical symptoms, assessed through need for respiratory support at up to 7 days; 8‐15 days; 16‐30 days: NR 30‐day and 90‐day mortality: 14‐ and 28‐day all‐cause mortality Admission on the ICU Length of stay on the ICU: ICU hospitalisation days Time to discharge from hospital QoL: NR Additional study outcomes Improvement of clinical symptoms (clinical improvement is defined as a reduction of 2 points on the 6‐point scale of the patient's admission status or discharge from the hospital) Main clinical manifestations subsided or significantly improved (fever, dry cough, fatigue, etc.)
Starting date	19 February 2020
Contact information	Liu Ying Wuhan Jinyintan Hospital (Wuhan Infectious Diseases Hospital) , 1 Yintan Road, Dongxihu District, Wuhan, Hubei, China , 430023, whsjytyy_gcp@163.com Zhang Dingyu 1 Yintan Road, Dongxihu District, Wuhan, Hubei, China, 430023, 1813886398@qq.com
Notes	Recruitment status: not yet recruiting Prospective completion date: 31 May 2020 Sponsor/funding: Wuhan Jinyintan Hospital (Wuhan Infectious Diseases Hospital), Sinopharm Wuhan Blood Products Co., Ltd., Sinopharm Wuhan Blood Products Co., Ltd

Study name	Clinical study for infusing convalescent plasma to treat patients with new coronavirus pneumonia (COVID‐19)
Methods	Trial design: non‐randomised controlled study Sample size: 30 experimental, 60 control group Setting: inpatient Country: China Language: translated into English Number of centres: 8
Participants	Inclusion criteria Diagnosis conforms to the diagnostic criteria of "pneumonia diagnosis and treatment program for new coronavirus infection (trial version 5)" Clinical classification is normal, severe or critical Patient aged ≥ 18 years old Patient or his/her legal guardian will participate voluntarily and sign the informed consent Exclusion criteria Highly allergic constitution or history of severe allergy, especially plasma allergy Doctor believes that there are other reasons not to include the patient
Interventions	CP therapy or hyperimmune immunoglobulin therapy: CP Details of CP type of plasma: CP volume: 200‐500 mL number of doses: 2 infusions are recommended antibody‐titre: NR pathogen inactivated or not: NR Treatment details, including time of plasma therapy (e.g. early stage of disease): NR For studies including a control group: comparator (type): conventional therapy Concomitant therapy: NR Treatment cross‐overs: NR
Outcomes	Primary study outcome: SARS‐CoV‐2 DNA, antibody levels Primary outcomes All‐cause mortality at hospital discharge: NR Time to death: NR Secondary outcomes Number of participants with grade 3 and grade 4 AEs, including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions): NR Number of participants with SAEs: NR Improvement of clinical symptoms, assessed through need for respiratory support at up to 7 days; 8‐15 days; 16‐30 days: NR 30‐day and 90‐day mortality: NR Admission on the ICU: NR Length of stay on the ICU: NR Time to discharge from hospital: NR Additional study outcomes SARS‐CoV‐2 DNA: infusion day 1 and recheck according to the participant's condition SARS‐CoV‐2 antibody levels: infusion day 1 and recheck according to the participant's condition CRP: hospitalised day 1, day 3, day 7, day 14, infusion day 1, day 2, 14 days after discharge IL‐6: hospitalised day 1, day 3, day 7, day 14, infusion day 1, day 2, 14 days after discharge LDH: hospitalised day 1, day 3, day 7, day 14, infusion day1, day 2, 14 days after discharge CPK: hospitalised day 1, day 3, day 7, day 14, infusion day 1, day 2, 14 days after discharge Liver function: hospitalised day 1, day 3, day 7, day 14, infusion day 1, day 2, 14 days after discharge Renal function: hospitalised day 1, day 3, day 7, day 14, infusion day 1, day 2, 14 days after discharge Respiratory rate: hospitalised day 1, day 3, day 7, day 14, infusion day 1, day 2, 14 days after discharge SiO2: hospitalised day 1, day 3, day 7, day 14, infusion day 1, day 2, 14 days after discharge Thoracic spiral CT: hospitalised day 1, day 3, day 7, day 14, infusion day 1, day 2, 14 days after discharge
Starting date	1 February 2020
Contact information	Liping Wang Affiliated Hospital of Xuzhou Medical University, 9 Kunpeng Road, Gulou District, Xuzhou, Jiangsu, 163wangliping@163.com China Xuebing Yan 9 Kunpeng Road, Gulou District, Xuzhou, Jiangsu, China, yxbxuzhou@126.com
Notes	Recruitment status: recruiting Prospective completion date: 1 February 2020 Sponsor/funding: Affiliated Hospital of Xuzhou Medical University, Affiliated Hospital of Xuzhou Medical University, the working unit

Study name	Study for using the healed novel coronavirus pneumonia (COVID‐19) patients plasma in the treatment of severe critical cases
Methods	Trial design: RCT Sample size: 15 in each arm (30) Setting: inpatient Country: China Language: translated to English Number of centres: 1
Participants	Inclusion criteria Patients who were diagnosed as COVID‐19 by nucleic acid test and were in accordance with the clinical classification of severe or critically illness. (Refer to the clinical classification criteria in the pneumonia diagnosis and treatment program of novel coronavirus infection, General Office of the National Health Commission (trial version 4)) Exclusion criteria Patients with hypersensitivity to plasma products; patients with severe transfusion reactions in the past; patients with acute pulmonary oedema, congestive heart failure, PE, malignant hypertension, polycythaemia vera, extreme renal failure and other diseases
Interventions	CP therapy or hyperimmune immunoglobulin therapy: CP Details of CP: NR type of plasma: NR volume: NR number of doses: NR antibody‐titre: NR pathogen inactivated or not: NR Treatment details, including time of plasma therapy (e.g. early stage of disease): NR For studies including a control group: comparator (type): routine treatment Concomitant therapy: no Treatment cross‐overs: no
Outcomes	Primary study outcomes: temperature, virus nucleic acid detection Primary review outcomes All‐cause mortality at hospital discharge: mortality rate Time to death Secondary review outcomes Number of participants with grade 3 and grade 4 AEs, including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions): incidence of AEs in blood transfusion Number of participants with SAEs Improvement of clinical symptoms, assessed through need for respiratory support at up to 7 days; 8‐15 days; 16‐30 days: NR 30‐day and 90‐day mortality: yes Admission on the ICU: NR Length of stay on the ICU: NR Time to discharge from hospital: length of admission QoL: NR Additional study outcomes Laboratory examination
Starting date	1 February 2020
Contact information	Guojun Zhang The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Road East, Zhengzhou, He'nan, China, zlgj‐001@126.com Guojun Zhang 1 Jianshe Road East, Zhengzhou, He'nan, China, zlgj‐001@126.com
Notes	Recruitment status: recruiting Prospective completion date: 30 May 2020 Sponsor/funding: The First Affiliated Hospital of Zhengzhou University, Science and Technology Department of He'nan Province

Study name	Plasma of the convalescent in the treatment of novel coronavirus pneumonia (COVID‐19) common patient: a prospective clinical trial
Methods	Trial design: open‐label, RCT Sample size: 25 in each arm (50) Setting: inpatient Country: China Language: translated to English Number of Centres: 4
Participants	Inclusion criteria Patient signed an informed consent form to participate in the study of CP therapy Patient age ≥ 18 years old COVID‐19 patients diagnosed by PCR Nucleic acid positive within 72 h before blood transfusion Pneumonia confirmed by imaging Hospitalisation for fever (axillary temperature ≥ 36.7 °C, or oral temperature ≥ 38.0 °C, or anal or ear temperature ≥ 38.6 °C) and respiratory rate > 24 breaths/min or cough (at least 1 of the 2) Severe clinical warning indicators: such as a progressive decrease in peripheral blood lymphocytes, a progressive increase in peripheral blood inflammatory factors, a progressive increase in lactic acid, and rapid progress of lung lesions in the short term, et al Accept random grouping into any group Hospitalised before the end of the clinical study Willing to participate in all necessary research directions and be able to participate in follow‐up During the period of participating in this study, they will no longer participate in clinical trials such as other antiviral drugs Exclusion criteria Doctor believes that the patient is not suitable to participate in this trial, including those who may not co‐operate, do not comply with the requirements of the procedure, or participating in this trial may put the patient in an unsafe situation Pregnant or lactation periods women Immunoglobulin allergy IgA deficiency Clinical symptoms are mild (no pneumonia on imaging) Clinical symptoms are severe or critical where severe patients meet any of the following: 1) respiratory distress, respiratory rate ≥ 30 breaths/min; 2) in resting state, oxygen saturation ≤ 93%; 3) partial PaO2/FiO2 ≤ 300 mmHg (1 mmHg = 0.133 kPa); and critically ill patients meet any of the following: 1) respiratory failure and need mechanical ventilation; 2) shock; 3) patients with other organ failure need ICU monitoring treatment Diseases that may increase the risk of thrombosis, such as cold globulinaemia, severe refractory hypertriglyceridaemia, clinically defined monoclonal gamma globulinaemia, etc Detection of high titre of anti‐novel coronavirus antibody RBDIgG (> 1) Received any experimental treatment for novel coronavirus infection within 30 days before screening Researchers judged that the patients had the following life‐threatening conditions, including, but not limited to, Phammer F < 100 mmHg, near‐death state or expected survival time < 24 h, severe septic shock or disseminated intravascular coagulation ((DIC)), etc Severe congestive heart failure, or other relative contraindications for plasma transfusion determined by study authors
Interventions	CP therapy or hyperimmune immunoglobulin therapy: conventional treatment and CP therapy Details of CP: type of plasma: NR volume: NR number of doses: NR antibody‐titre: NR pathogen inactivated or not: NR Treatment details, including time of plasma therapy (e.g. early stage of disease): NR For studies including a control group: conventional treatment Concomitant therapy: symptomatic treatment, antiviral treatment, and antibacterial treatment Treatment cross‐overs: NR
Outcomes	Primary study outcome: time to clinical recovery after randomisation Primary review outcomes reported All‐cause mortality at hospital discharge: 28‐day mortality Time to death: NR Secondary review outcomes reported Number of participants with grade 3 and grade 4 adverse events, including potential relationship between intervention and adverse reaction (e.g. TRALI, transfusion‐transmitted infection, TACO, TAD, acute transfusion reactions): yes (cumulative incidence of AEs (AE), grades 3 and 4 AE): cumulative incidence of severe AEs, incidence of adverse plasma transfusion reactions Number of participants with SAEs: cumulative incidence of severe AEs (SAE) Improvement of clinical symptoms, assessed through need for respiratory support at up to 7 days; 8‐15 days; 16‐30 days: invasive mechanical ventilation during infection; ECMO duration during infection: 28‐day assisted oxygen therapy or non‐invasive mechanical ventilation rate 30‐day and 90‐day mortality: 28‐day mortality Admission on the ICU: yes Length of stay on the ICU: yes (ICU hospitalisation) Time to discharge from hospital: yes (hospitalisation time) QoL: NR Additional study outcomes Incidence of breathing exacerbations Time for conscious cough relief during infection (cough present when enrolled) Time to remission of conscious dyspnea during infection (existed dyspnea upon enrolment) Proportion of viral nucleic acid negative
Starting date	15 February 2020
Contact information	Liu Zhong Institute of Blood Transfusion, Chinese Academy of Medical Sciences, 26 Huacai Road, Chenghua District, Chengdu, Sichuan, China, 610000, Liuz@ibt.pumc.edu.cn Cao Bin 2 Yinghua Street East, Chaoyang District, Beijing, China, 100029, caobin_ben@163.com
Notes	Recruitment status: recruiting Prospective completion date: 15 August 2020 Sponsor/funding: China‐Japan friendship hospital, Beijing, Institute of Blood Transfusion, Chinese Academy of Medical Sciences, Beijing, Government