• We are very confident that convalescent plasma has no benefits for the treatment of people with moderate to severe COVID-19.
• We are uncertain about the effects of convalescent plasma for treating people with mild COVID-19 or who have no symptoms.
• We found about 130 ongoing, unpublished and recently published studies. We will update our review with evidence from these studies as soon as possible. New evidence may answer our remaining questions.
What is convalescent plasma?
The body produces antibodies as one of its defences against infection. Antibodies are found in part of the blood called plasma. Plasma from people who have recovered from the COVID-19 virus contains COVID-19 antibodies, and can be used to make two preparations. Firstly, it can be used to make convalescent plasma, which is plasma that contains these antibodies. Secondly, it can be used to make hyperimmune immunoglobulin, which is more concentrated, and therefore contains more antibodies.
Convalescent plasma and hyperimmune immunoglobulin have been used successfully to treat some viruses. These treatments (given by a drip or injection) are generally well-tolerated, but can cause unwanted effects.
What did we want to find out?
We wanted to find out whether convalescent plasma or hyperimmune immunoglobulin are effective treatments for people with confirmed COVID-19. We looked at:
• deaths from any cause after treatment with convalescent plasma or hyperimmune immunoglobulin;
• improvement or worsening of patients’ condition, measured by the number of people who needed help from a ventilator (a machine that helps people breathe if they cannot breathe on their own);
• quality of life; and
• unwanted effects.
What did we do?
We searched for studies that investigated convalescent plasma or hyperimmune immunoglobulin to treat people with COVID-19. Studies could take place anywhere in the world and include participants of any age, gender or ethnicity, with mild, moderate or severe COVID-19.
Where possible we pooled the studies’ results to analyse them. We rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We found 13 studies with 48,509 participants that investigated convalescent plasma. All but one of the studies included participants with moderate to severe COVID-19. We did not find any studies that investigated hyperimmune immunoglobulin. Studies mainly took place in hospitals, in countries all over the world.
Moderate to severe COVID-19
Convalescent plasma compared to placebo or standard care:
• convalescent plasma makes no difference to deaths from any cause at up to 28 days after treatment. About 237 in 1000 people given placebo or standard care died, compared to 233 in 1000 people who had been given convalescent plasma (7 studies, 12,646 people);
• convalescent plasma makes little to no difference to the improvement of patients’ condition in terms of needing less breathing support for the overall population needing any breathing support before the start of treatment (8 studies, 12,682 people), and also not for the people that were ventilated at the beginning of the study (2 studies, 630 people);
• convalescent plasma makes no difference to the worsening of patients’ condition. About 126 in 1000 people given placebo or standard care needed invasive mechanical ventilation, compared to 123 in 1000 people who had been given convalescent plasma (4 studies, 11,765 people);
• convalescent plasma may make no difference to unwanted effects. The 8 studies that reported unwanted effects measured and reported their results very differently, so we are unable to draw any conclusions.
None of the studies reported quality of life.
We do not know if convalescent plasma compared to placebo or standard care makes a difference to number of deaths, improvement or worsening of patients’ condition, quality of life or unwanted effects. We found only one study with 160 participants that assessed people with mild COVID-19.
What are the limitations of the evidence?
• We are very confident in the evidence for deaths from any cause and improvement or worsening of patients’ condition in people with moderate to severe COVID-19.
• Our confidence in the other evidence for people with moderate and severe, and mild COVID-19 is very limited because the studies were very different and did not measure and record their results using consistent methods.
• We found little useful evidence on unwanted effects and none on quality of life.
How up to date is this evidence?
This is the fourth version of our review. The evidence is up to date to 17 March 2021.
We have high certainty in the evidence that convalescent plasma for the treatment of individuals with moderate to severe disease does not reduce mortality and has little to no impact on measures of clinical improvement. We are uncertain about the adverse effects of convalescent plasma. While major efforts to conduct research on COVID-19 are being made, heterogeneous reporting of outcomes is still problematic. There are 100 ongoing studies and 33 studies reporting in a study registry as being completed or terminated. Publication of ongoing studies might resolve some of the uncertainties around hyperimmune immunoglobulin therapy for people with any disease severity, and convalescent plasma therapy for people with asymptomatic or mild disease.
Convalescent plasma and hyperimmune immunoglobulin may reduce mortality in patients with viral respiratory diseases, and are being investigated as potential therapies for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding benefits and risks of these interventions is required.
Using a living systematic review approach, to assess whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in the treatment of people with COVID-19; and to maintain the currency of the evidence.
To identify completed and ongoing studies, we searched the World Health Organization (WHO) COVID-19 Global literature on coronavirus disease Research Database, MEDLINE, Embase, the Cochrane COVID-19 Study Register, the Epistemonikos COVID-19 L*OVE Platform, and trial registries. Searches were done on 17 March 2021.
We included randomised controlled trials (RCTs) evaluating convalescent plasma or hyperimmune immunoglobulin for COVID-19, irrespective of disease severity, age, gender or ethnicity. For safety assessments, we also included non-controlled non-randomised studies of interventions (NRSIs) if 500 or more participants were included.
We excluded studies that included populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)), as well as studies evaluating standard immunoglobulin.
We followed standard Cochrane methodology.
To assess bias in included studies, we used the Cochrane 'Risk of Bias 2' tool for RCTs, and for NRSIs, the assessment criteria for observational studies, provided by Cochrane Childhood Cancer. We rated the certainty of evidence, using the GRADE approach, for the following outcomes: all-cause mortality, improvement and worsening of clinical status (for individuals with moderate to severe disease), development of severe clinical COVID-19 symptoms (for individuals with asymptomatic or mild disease), quality of life (including fatigue and functional independence), grade 3 or 4 adverse events, and serious adverse events.
We included 13 studies (12 RCTs, 1 NRSI) with 48,509 participants, of whom 41,880 received convalescent plasma. We did not identify any completed studies evaluating hyperimmune immunoglobulin. We identified a further 100 ongoing studies evaluating convalescent plasma or hyperimmune immunoglobulin, and 33 studies reporting as being completed or terminated.
Individuals with a confirmed diagnosis of COVID-19 and moderate to severe disease
Eleven RCTs and one NRSI investigated the use of convalescent plasma for 48,349 participants with moderate to severe disease. Nine RCTs compared convalescent plasma to placebo treatment or standard care alone, and two compared convalescent plasma to standard plasma (results not included in abstract).
Effectiveness of convalescent plasma
We included data on nine RCTs (12,875 participants) to assess the effectiveness of convalescent plasma compared to placebo or standard care alone.
Convalescent plasma does not reduce all-cause mortality at up to day 28 (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.92 to 1.05; 7 RCTs, 12,646 participants; high-certainty evidence). It has little to no impact on clinical improvement for all participants when assessed by liberation from respiratory support (RR not estimable; 8 RCTs, 12,682 participants; high-certainty evidence). It has little to no impact on the chance of being weaned or liberated from invasive mechanical ventilation for the subgroup of participants requiring invasive mechanical ventilation at baseline (RR 1.04, 95% CI 0.57 to 1.93; 2 RCTs, 630 participants; low-certainty evidence). It does not reduce the need for invasive mechanical ventilation (RR 0.98, 95% CI 0.89 to 1.08; 4 RCTs, 11,765 participants; high-certainty evidence). We did not identify any subgroup differences.
We did not identify any studies reporting quality of life, and therefore, do not know whether convalescent plasma has any impact on quality of life. One RCT assessed resolution of fatigue on day 7, but we are very uncertain about the effect (RR 1.21, 95% CI 1.02 to 1.42; 309 participants; very low-certainty evidence).
Safety of convalescent plasma
We included results from eight RCTs, and one NRSI, to assess the safety of convalescent plasma. Some of the RCTs reported on safety data only for the convalescent plasma group.
We are uncertain whether convalescent plasma increases or reduces the risk of grade 3 and 4 adverse events (RR 0.90, 95% CI 0.58 to 1.41; 4 RCTs, 905 participants; low-certainty evidence), and serious adverse events (RR 1.24, 95% CI 0.81 to 1.90; 2 RCTs, 414 participants; low-certainty evidence).
A summary of reported events of the NRSI (reporting safety data for 20,000 of 35,322 transfused participants), and four RCTs reporting safety data only for transfused participants (6125 participants) are included in the full text.
Individuals with a confirmed diagnosis of SARS-CoV-2 infection and asymptomatic or mild disease
We identified one RCT reporting on 160 participants, comparing convalescent plasma to placebo treatment (saline).
Effectiveness of convalescent plasma
We are very uncertain about the effect of convalescent plasma on all-cause mortality (RR 0.50, 95% CI 0.09 to 2.65; very low-certainty evidence). We are uncertain about the effect of convalescent plasma on developing severe clinical COVID-19 symptoms (RR not estimable; low-certainty evidence).
We identified no study reporting quality of life.
Safety of convalescent plasma
We do not know whether convalescent plasma is associated with a higher risk of grade 3 or 4 adverse events (very low-certainty evidence), or serious adverse events (very low-certainty evidence).
This is a living systematic review. We search weekly for new evidence and update the review when we identify relevant new evidence. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.