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.

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.

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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 strategy: 

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.

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