Association of Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis | Critical Care Medicine | JAMA | JAMA Network
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Figure 1.  Risk of Bias Assessments for the Outcomes of All-Cause Mortality, Length of Hospital Stay, and Mechanical Ventilation Use
Risk of Bias Assessments for the Outcomes of All-Cause Mortality, Length of Hospital Stay, and Mechanical Ventilation Use

Three of the trials did not have study acronyms (only trial registration numbers) and ILBS-COVID-02 and PLACID did not have expansions in the original publications. ConCOVID indicates Convalescent Plasma as Therapy for Covid-19 Severe SARS-CoV-2 Disease; ConPlas-19, Convalescent Plasma Therapy vs SOC for the Treatment of COVID-19 in Hospitalized Patients; NA, not available; PICP19, Passive Immunization With Convalescent Plasma in Severe COVID-19 Disease; PlasmAr, Convalescent Plasma and Placebo for the Treatment of COVID-19 Severe Pneumonia; RECOVERY, Randomized Evaluation of COVID-19 Therapy.

aThere was no detailed information reported regarding (1) the randomization process or (2) the concealment of randomized assignment.

bThere was no detailed information reported regarding (1) the randomization process, (2) the concealment of randomized assignment, (3) the flow of patients through the trial, and (4) possible deviations from the intended interventions due to the open-label setting of the trial.

cThe results were communicated as a press release. The assessment of this trial considered the study protocol and publications reporting results from other treatment groups of the trial.4-6,26,27

Figure 2.  Association of Convalescent Plasma With All-Cause Mortality, Length of Hospital Stay, and Mechanical Ventilation Use in Peer-Reviewed Trials and Non–Peer-Reviewed Trials (Preprints and the RECOVERY Trial)
Association of Convalescent Plasma With All-Cause Mortality, Length of Hospital Stay, and Mechanical Ventilation Use in Peer-Reviewed Trials and Non–Peer-Reviewed Trials (Preprints and the RECOVERY Trial)

Three of the trials did not have study acronyms (only trial registration numbers) and ILBS-COVID-02 and PLACID did not have expansions in the original publications. Hartung-Knapp adjustment was used for the random-effects model and the Paule-Mandel estimator was used for τ2. The weight percentages correspond to the secondary analysis for all studies. ConCOVID indicates Convalescent Plasma as Therapy for Covid-19 Severe SARS-CoV-2 Disease; ConPlas-19, Convalescent Plasma Therapy vs SOC for the Treatment of COVID-19 in Hospitalized Patients; HR, hazard ratio; NA, not available; PICP19, Passive Immunization With Convalescent Plasma in Severe COVID-19 Disease; PlasmAr, Convalescent Plasma and Placebo for the Treatment of COVID-19 Severe Pneumonia; RECOVERY, Randomized Evaluation of COVID-19 Therapy; RR, risk ratio.

aIncludes only the studies shown that were published in peer-reviewed journals or as preprints.

Table 1.  Characteristics of the 10 Trials
Characteristics of the 10 Trials
Table 2.  Patient Baseline Characteristics in 9 Trials
Patient Baseline Characteristics in 9 Trials
1.
Mair-Jenkins  J, Saavedra-Campos  M, Baillie  JK,  et al; Convalescent Plasma Study Group.  The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis.   J Infect Dis. 2015;211(1):80-90. doi:10.1093/infdis/jiu396 PubMedGoogle ScholarCrossref
2.
Joyner  MJ, Bruno  KA, Klassen  SA,  et al.  Safety update: COVID-19 convalescent plasma in 20,000 hospitalized patients.   Mayo Clin Proc. 2020;95(9):1888-1897. doi:10.1016/j.mayocp.2020.06.028 PubMedGoogle ScholarCrossref
3.
US Food and Drug Administration. FDA issues Emergency Use Authorization for convalescent plasma as potential promising COVID-19 treatment, another achievement in administration’s fight against pandemic. Published August 24, 2020. Accessed January 27, 2021. https://www.fda.gov/news-events/press-announcements/fda-issues-emergency-use-authorization-convalescent-plasma-potential-promising-covid-19-treatment
4.
RECOVERY Collaborative Group.  Dexamethasone in hospitalized patients with Covid-19—preliminary report.   N Engl J Med. Published online July 17, 2020. doi:10.1056/NEJMoa2021436 Google Scholar
5.
Horby  P, Mafham  M, Linsell  L,  et al; RECOVERY Collaborative Group.  Effect of hydroxychloroquine in hospitalized patients with Covid-19.   N Engl J Med. 2020;383(21):2030-2040. doi:10.1056/NEJMoa2022926PubMedGoogle ScholarCrossref
6.
Horby  PW, Mafham  M, Bell  JL,  et al.  Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.   Lancet. 2020;396(10259):1345-1352. doi:10.1016/S0140-6736(20)32013-4 Google ScholarCrossref
7.
Horby  P, Lim  WS, Emberson  J,  et al.  Effect of dexamethasone in hospitalized patients with COVID-19—preliminary report.   medRxiv. Published online June 22, 2020. doi:10.1101/2020.06.22.20137273 Google Scholar
8.
RECOVERY Trial. Press release: RECOVERY trial closes recruitment to convalescent plasma treatment for patients hospitalised with COVID-19. Published January 15, 2021. Accessed January 27, 2021. https://www.recoverytrial.net/news/statement-from-the-recovery-trial-chief-investigators-15-january-2021-recovery-trial-closes-recruitment-to-convalescent-plasma-treatment-for-patients-hospitalised-with-covid-19
9.
Page  M, McKenzie  J, Bossuyt  P,  et al.  The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.   MetaArXiv. Published online September 14, 2020. doi:10.31222/osf.io/v7gm2 Google Scholar
10.
McGowan  J, Sampson  M, Salzwedel  DM, Cogo  E, Foerster  V, Lefebvre  C.  PRESS: peer review of electronic search strategies: 2015 guideline statement.   J Clin Epidemiol. 2016;75:40-46. doi:10.1016/j.jclinepi.2016.01.021 PubMedGoogle ScholarCrossref
11.
Sterne  JAC, Savović  J, Page  MJ,  et al.  RoB 2: a revised tool for assessing risk of bias in randomised trials.   BMJ. 2019;366:l4898. doi:10.1136/bmj.l4898 PubMedGoogle ScholarCrossref
12.
Guyatt  GH, Oxman  AD, Vist  GE,  et al; GRADE Working Group.  GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.   BMJ. 2008;336(7650):924-926. doi:10.1136/bmj.39489.470347.AD PubMedGoogle ScholarCrossref
13.
Langan  D, Higgins  JPT, Simmonds  M.  Comparative performance of heterogeneity variance estimators in meta-analysis: a review of simulation studies.   Res Synth Methods. 2017;8(2):181-198. doi:10.1002/jrsm.1198 PubMedGoogle ScholarCrossref
14.
IntHout  J, Ioannidis  JP, Borm  GF.  The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method.   BMC Med Res Methodol. 2014;14:25. doi:10.1186/1471-2288-14-25 PubMedGoogle ScholarCrossref
15.
Higgins  JPT, Thompson  SG.  Quantifying heterogeneity in a meta-analysis.   Stat Med. 2002;21(11):1539-1558. doi:10.1002/sim.1186 PubMedGoogle ScholarCrossref
16.
Libster  R, Pérez Marc  G, Wappner  D,  et al; Fundación INFANT–COVID-19 Group.  Early high-titer plasma therapy to prevent severe Covid-19 in older adults.   N Engl J Med. Published online January 6, 2021. doi:10.1056/NEJMoa2033700 PubMedGoogle Scholar
17.
Agarwal  A, Mukherjee  A, Kumar  G, Chatterjee  P, Bhatnagar  T, Malhotra  P; PLACID Trial Collaborators.  Convalescent plasma in the management of moderate COVID-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial).   BMJ. 2020;371:m3939. doi:10.1136/bmj.m3939 PubMedGoogle ScholarCrossref
18.
Simonovich  VA, Burgos Pratx  LD, Scibona  P,  et al; PlasmAr Study Group.  A randomized trial of convalescent plasma in Covid-19 severe pneumonia.   N Engl J Med. Published online November 24, 2020. doi:10.1056/NEJMoa2031304 PubMedGoogle Scholar
19.
Li  L, Zhang  W, Hu  Y,  et al.  Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.   JAMA. 2020;324(5):460-470. doi:10.1001/jama.2020.10044 PubMedGoogle ScholarCrossref
20.
AlQahtani  M, Abdulrahman  A, Almadani  A,  et al.  Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease.   medRxiv. Published online November 4, 2020. doi:10.1101/2020.11.02.20224303 Google Scholar
21.
Bajpai  M, Kumar  S, Maheshwari  A,  et al.  Efficacy of convalescent plasma therapy compared to fresh frozen plasma in severely ill COVID-19 patients: a pilot randomized controlled trial.   medRxiv. Published online October 27, 2020. doi:10.1101/2020.10.25.20219337 Google Scholar
22.
Gharbharan  A, Jordans  CCE, Geurtsvankessel  C,  et al.  Convalescent plasma for COVID-19: a randomized clinical trial.   medRxiv. Published online July 3, 2020. doi:10.1101/2020.07.01.20139857 Google Scholar
23.
Avendaño-Solà  C, Ramos-Martinez  A, Muñez-Rubio  E,  et al.  Convalescent plasma for COVID-19: a multicenter, randomized clinical trial.   medRxiv. Published online September 29, 2020. doi:10.1101/2020.08.26.20182444Google Scholar
24.
Ray  Y, Paul  SR, Bandopadhyay  P,  et al.  Clinical and immunological benefits of convalescent plasma therapy in severe COVID-19: insights from a single center open label randomised control trial.   medRxiv. Published online November 29, 2020. doi:10.1101/2020.11.25.20237883 Google Scholar
25.
European Union Recover Project. Press release: REMAP-CAP: international trial of SARS-CoV-2 convalescent plasma pauses enrollment of critically ill COVID-19 patients. Published online January 11, 2021. Accessed February 1, 2021. https://www.recover-europe.eu/press-release-international-trial-of-sars-cov-2-convalescent-plasma-pauses-enrollment-of-critically-ill-covid-19-patients/
26.
RECOVERY Trial. Randomised evalution of COVID-19 therapy (RECOVERY protocol). Accessed January 27, 2021. https://www.recoverytrial.net/files/recovery-protocol-v12-1-2020-12-16.pdf
27.
Horby  PW, Roddick  A, Spata  E,  et al.  Azithromycin in hospitalised patients with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.   medRxiv. Published online December 14, 2020. doi:10.1101/2020.12.10.20245944 Google Scholar
28.
Zarin  DA, Rosenfeld  S.  Lack of harmonization of coronavirus disease ordinal scales.   Clin Trials. Published online December 15, 2020. doi:10.1177/1740774520972082 PubMedGoogle Scholar
29.
Marshall  JC, Murthy  S, Diaz  J,  et al; WHO Working Group on the Clinical Characterisation and Management of COVID-19 Infection.  A minimal common outcome measure set for COVID-19 clinical research.   Lancet Infect Dis. 2020;20(8):e192-e197. doi:10.1016/S1473-3099(20)30483-7 PubMedGoogle ScholarCrossref
30.
Petkova  E, Antman  EM, Troxel  AB.  Pooling data from individual clinical trials in the COVID-19 era.   JAMA. 2020;324(6):543-545. doi:10.1001/jama.2020.13042 PubMedGoogle ScholarCrossref
31.
Janiaud  P, Axfors  C, Saccilotto  R, Hemkens  L, Schmitt  A. COVID-evidence: a living database of trials on interventions for COVID-19. Published online April 1, 2020. Last updated August 19, 2020. Accessed February 17, 2021. https://osf.io/gehfx
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    5 Comments for this article
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    High Antibody Titres
    Paul Coppi, MD | Azienda Ospedaliera di Modena
    One cannot pool together studies using different and/or unknown titres of globulins against Covid19.
    For any effective treatment with convalescent plasma we have to use plasma having very high titres of specific globulins. A correct review would have to consider studies having these features only.
    CONFLICT OF INTEREST: None Reported
    Subgroup Analysis by Antibody Levels and Early Use
    Daniele Focosi, M.D., Ph.D., M.S. | Pisa University Hospital
    I read with interest the systematic review by Janiaud et al detailing clinical outcomes after therapeutic intervention with COVID19 convalescent plasma (CCP) [1]. The topic has become very controversial over the last months, with literature supporting both standpoints. It was well known from previous epidemics that timeliness of intervention and neutralizing antibody levels in CCP were the main drivers of efficacy, but many early randomized controlled trials (RCT) did not include stringent criteria for such parameters [2]. Those early RCTs were nevertheless published in relevant journals because of high public interest. Those early RCTs recruited huge numbers of patients, and the relative contribution of more recent RCT and propensity-score matched controlled studies which applied more stringent criteria for timeliness and antibody levels (and showed clinical benefit [3]) currently remain minoritarian in systematic reviews, potentially masking the benefit of CCP in global analyses. The 5 (out of 10) RCTs of CCP where information about both parameters has been fully investigated and disclosed can be plotted according to earliness of intervention and antibody levels, and interestingly the ones combining both high-titer and early administration have actually been able to show clinical benefit. Unfortunately, to date the few RCTs that disclosed pretransfusion neutralizing antibody titers in recipients used CCP at late stages [3].

    Similar reasoning should apply to systematic reviews of anti-SARS-CoV-2 monoclonal antibodies, which, as expected, have initially failed to show benefit when treating patients with advanced stage COVID19 [4], but have later proven effective in outpatients without pre-treatment anti-spike antibodies [5].

    We hence feel that subgroup analyses, separately analyzing the outcomes of RCTs administering high-titer CCP within 72 hours from symptom onset from the rest of RCTs, should be used in future systematic reviews of CCP, and could help fine-tune the usage of CCP.

    References

    1. Janiaud P, Axfors C, Schmitt AM, et al. Association of Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis. JAMA. 2021.
    2. Focosi D, Anderson AO, Tang JW, Tuccori M. Convalescent Plasma Therapy for COVID-19: State of the Art. Clinical microbiology reviews. 2020;33(4):e00072-00020.
    3. Focosi D, Franchini M. COVID-19 convalescent plasma therapy: hit fast, hit hard! . Vox sanguinis. 2021.
    4. ACTIV-3/TICO LY-CoV555 Study Group. A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19. The New England journal of medicine. 2020.
    5. Weinreich DM, Sivapalasingam S, Norton T, et al. REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19. The New England journal of medicine. 2020;384(3):238-251.
    CONFLICT OF INTEREST: Co-investigator in the TSUNAMI (NCT04393727) randomized controlled trial.
    READ MORE
    Plasma Therapy Effective in Certain Subgroups
    Abhaya Indrayan, PhD | Department of Clinical Research, Max Healthcare, Dew Delhi
    Previous studies generally analyze all the patients together and get the result that plasma therapy does not offer any benefit. This happened in our study as well (1). However in a subgroup analysis, females aged 60-74 with one co-morbidity in the ICU were found to have statistically significantly less mortality vs equivalent controls (23.1% vs 53.5%; p = 0.013; OR = 0.26, 95% CI: 0.09-0.78). Moreover, patients on a ventilator had lower mortality in the plasma arm (37.2% vs 49.3%; p = 0.009; OR = 0.61, 95% CI: 0.42-0.89); particularly so for patients on invasive mechanical ventilation (63.9% vs 82.9%; p = 0.014; OR = 0.37, 95% CI: 0.16-0.83). This study is based on 333 cases on plasma therapy and 361 controls on standard care.

    Reference
    1. Budhiraja S, Dewan A, Aggarwal R, et al. Effectiveness of convalescent plasma in Indian patients with COVID-19 [published online ahead of print, 2021 Feb 18]. Blood Cells Mol Dis. 2021;88:102548. doi:10.1016/j.bcmd.2021.102548
    CONFLICT OF INTEREST: None Reported
    READ MORE
    What If Convalescent Plasma Were Used Appropriately?
    Rafael de la Camara, Haematologist | Hospital de la Princesa, Madrid (Spain)
    We have read with interest the systematic Review and Meta-analysis of convalescent plasma for COVID-19 treatment by Janiaud et al. (1).

    The review shows that convalescent plasma used without restriction in titer, time since symptom onset, and need of mechanical ventilation, compared with placebo or standard of care, was not significantly associated with a decrease in all-cause mortality or with any benefit for other clinical outcomes. But it doesn't reply to the question of its utility if it is used according to what now is considered an appropriate treatment. Two requirements seem to be essential for convalescent plasma
    to be effective (2): the use of only high titer COVID-19 convalescent plasma, and early administration in the disease course (prior to respiratory failure requiring intubation and mechanical ventilation). The use of convalescent plasma in the appropriate way is essential in order to know if it has an impact on mortality. If, for example, we use an antibiotic with a low dose and very late in the course of a bacterial infection, nobody will find it unexpected that this therapy fails.

    For these reasons, we would like to know the mortality results if the analysis is done with high titer plasma vs low titer or placebo/ standard of care, administered early in the course of the disease (≤72h since symptom onset and/or no need for intubation and mechanical ventilation). It would be optimum if high titer plasma is classified according to the FDA requirements (2).

    References
    1. Janiaud P, Axfors C, Schmitt AM, Gloy V, Ebrahimi F, Hepprich M, et al. Association of Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis. JAMA. 2021.
    2. FDA. Letter of Authorization for COVID-19 convalescent plasma 2021 [Available from: https://www.fda.gov/media/141477/download.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Meta-analysis of Convalescent Plasma in Hospitalized COVID-19 Patients
    Binh Ngo, M.D. | Keck USC School of Medicine
    The lack of early treatment of COVID-19 constitutes the great failure of Western medicine (1), and publications such as Janiaud et al continue to support this unfortunate course. Symptomatic COVID-19 exhibits a characteristic sequence of phases beginning with a primary viral attack, manifesting as an influenza-like illness. Then, within seven to 10 days of onset of symptoms, an inflammatory phase develops in up to 20% of infected individuals, typically heralded by an organizing pneumonia (2). At this stage, viral levels are typically falling as a result of antibody response.

    The publication of this meta-analysis by Janiaud
    et al perpetuates the misunderstanding that COVID-19 is a homogeneous disease. Dr. de la Camara in his Comment has made it clear that convalescent plasma as well monoclonal antibody treatment and other antiviral therapy should be appropriate to the phase of the disease, which is that of viral proliferation. The other Comments on this article have made the same points. This meta-analysis is essentially based on the RECOVERY Trial of hospitalized patients. By the time patients reach the hospital, they are typically in the inflammatory phase by which time viral titers are falling. That is a time when anti-inflammatory agents, not anti-virals, are more likely to have some benefit.

    The evidence that early treatment of diagnosed patients with high titer convalescent plasma is strong (3,4). Based on safety studies in over 20,000 patients, the U.S. FDA has issued emergency authorization for use of convalescent plasma (5). Passive immunization in the early viral replication phase of COVID-19 has been further pursued with synthetic monoclonal antibodies. Treatment of ambulatory patients with the Lilly neutralizing antibodies and the Regeneron combination of two antibodies early in the course of infection, but not later, has shown success in reducing the frequency of hospitalization (6-8). Just as with convalescent plasma, synthetic monoclonal antibodies to the spike protein have not benefited hospitalized patients.

    References

    1) Ngo BT, Marik P, Pierre Kory P, et al. The time to offer treatments for COVID-19. medRxiv, 16 Dec20 doi: 10.1101/2020.05.27.20115238

    2) Griffin DO, Brennan-Rieder D, Ngo B et al. The importance of understanding the stages of COVID-19 in treatment and trials. AIDS Rev. 2021 Feb 8. doi: 10.24875/AIDSRev.200001261. Online ahead of print

    3) Joyner MJ, Carter RE, Senefeld JW, et al. Convalescent plasma antibody levels and the risk of death from Covid-19. N Engl J Med. DOI: 10.1056/NEJMoa2031893.

    4) Libster R, Pérez Marc G, Wappner D, et al. Early high-titer plasma therapy to prevent severe Covid-19 in older adults. N Engl J Med. DOI: 10.1056/NEJMoa2033700

    5) Joyner MJ, Bruno KA, Klassen SA, et al, Safety update: COVID-19 convalescent plasma in 20,000 hospitalized patients Mayo Clin Proc. 2020;95 (9):1888-1897

    6) ACTIV-3/TICO LY-CoV555 Study Group, Lundgren JD, Grund B, Barkauskas CE et al. A neutralizing monoclonal antibody for hospitalized patients with Covid-19. N Engl J Med. 2020 Dec 22:NEJMoa2033130.

    7) Chen P, Nirula A, Heller B, et al SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19. N Engl J Med. 2021;384:229-237

    8) Weinreich DM, Sivapalasingam S, Norton T, et al. REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19. N Engl J Med 2021;384:238-251
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Original Investigation
    February 26, 2021

    Association of Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis

    Author Affiliations
    • 1Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland
    • 2Meta-Research Innovation Center at Stanford, Stanford University, Stanford, California
    • 3Department for Women’s and Children’s Health, Uppsala University, Uppsala, Sweden
    • 4Department of Medical Oncology, University of Basel, Basel, Switzerland
    • 5Department of Gastroenterology and Hepatology, University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland
    • 6Clinic of Endocrinology, Diabetes and Metabolism, University Hospital Basel, Basel, Switzerland
    • 7Clinic of Endocrine and Metabolic Disorders, Cantonal Hospital Olten, Olten, Switzerland
    • 8Milken Institute School of Public Health, Department of Global Health, George Washington University, Washington, DC
    • 9Division of Infectious Diseases and Hospital Hygiene and Infection Biology Laboratory, University Hospital Basel, University of Basel, Basel, Switzerland
    • 10Centre for Journalology, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
    • 11Department of Medicine, School of Medicine, Stanford University, Stanford, California
    • 12Department of Epidemiology and Population Health, School of Medicine, Stanford University, Stanford, California
    • 13Department of Biomedical Data Science, School of Medicine, Stanford University, Stanford, California
    • 14Department of Statistics, School of Humanities and Sciences, Stanford University, Stanford, California
    • 15Meta-Research Innovation Center Berlin, Berlin Institute of Health, Berlin, Germany
    JAMA. 2021;325(12):1185-1195. doi:10.1001/jama.2021.2747
    Key Points

    Question  Is treatment with convalescent plasma associated with improved clinical outcomes?

    Findings  In a meta-analysis of 4 peer-reviewed and published randomized clinical trials including 1060 patients with COVID-19 treated with convalescent plasma vs control, the risk ratio for mortality was 0.93 and after the addition of 6 unpublished randomized clinical trials and 10 722 patients, the risk ratio for mortality was 1.02; neither finding was statistically significant. No significant associations with benefit were shown for hospital length of stay, mechanical ventilation use, clinical improvement, or clinical deterioration.

    Meaning  Among patients with COVID-19, treatment with convalescent plasma compared with control was not associated with improved survival or other positive clinical outcomes.

    Abstract

    Importance  Convalescent plasma is a proposed treatment for COVID-19.

    Objective  To assess clinical outcomes with convalescent plasma treatment vs placebo or standard of care in peer-reviewed and preprint publications or press releases of randomized clinical trials (RCTs).

    Data Sources  PubMed, the Cochrane COVID-19 trial registry, and the Living Overview of Evidence platform were searched until January 29, 2021.

    Study Selection  The RCTs selected compared any type of convalescent plasma vs placebo or standard of care for patients with confirmed or suspected COVID-19 in any treatment setting.

    Data Extraction and Synthesis  Two reviewers independently extracted data on relevant clinical outcomes, trial characteristics, and patient characteristics and used the Cochrane Risk of Bias Assessment Tool. The primary analysis included peer-reviewed publications of RCTs only, whereas the secondary analysis included all publicly available RCT data (peer-reviewed publications, preprints, and press releases). Inverse variance–weighted meta-analyses were conducted to summarize the treatment effects. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation.

    Main Outcomes and Measures  All-cause mortality, length of hospital stay, clinical improvement, clinical deterioration, mechanical ventilation use, and serious adverse events.

    Results  A total of 1060 patients from 4 peer-reviewed RCTs and 10 722 patients from 6 other publicly available RCTs were included. The summary risk ratio (RR) for all-cause mortality with convalescent plasma in the 4 peer-reviewed RCTs was 0.93 (95% CI, 0.63 to 1.38), the absolute risk difference was −1.21% (95% CI, −5.29% to 2.88%), and there was low certainty of the evidence due to imprecision. Across all 10 RCTs, the summary RR was 1.02 (95% CI, 0.92 to 1.12) and there was moderate certainty of the evidence due to inclusion of unpublished data. Among the peer-reviewed RCTs, the summary hazard ratio was 1.17 (95% CI, 0.07 to 20.34) for length of hospital stay, the summary RR was 0.76 (95% CI, 0.20 to 2.87) for mechanical ventilation use (the absolute risk difference for mechanical ventilation use was −2.56% [95% CI, −13.16% to 8.05%]), and there was low certainty of the evidence due to imprecision for both outcomes. Limited data on clinical improvement, clinical deterioration, and serious adverse events showed no significant differences.

    Conclusions and Relevance  Treatment with convalescent plasma compared with placebo or standard of care was not significantly associated with a decrease in all-cause mortality or with any benefit for other clinical outcomes. The certainty of the evidence was low to moderate for all-cause mortality and low for other outcomes.

    Introduction

    Patients with COVID-19 have frequently been treated with convalescent plasma (ie, plasma from persons who have recovered from SARS-CoV-2 infection), but the clinical evidence of benefits or harms is limited.1 Preliminary reports indicating that convalescent plasma is well tolerated with low risk of adverse events2 led to Emergency Use Authorization in the US in August 2020.3 Despite the large number of clinical trials being conducted since the start of the pandemic, only a few have been published in peer-reviewed journals and some have posted preliminary results on preprint servers.

    The Randomized Evaluation of COVID-19 Therapy (RECOVERY) platform trial is by far the largest clinical trial on COVID-19 treatments, and has provided important evidence for several promising treatments, including dexamethasone,4 hydroxychloroquine,5 lopinavir-ritonavir,6 and azithromycin.7 The part of the trial investigating treatment with convalescent plasma was halted based on the recommendation of the RECOVERY data monitoring committee. Communicated as a press release on January 15, 2021, the preliminary reported results based on data from 10 406 patients indicate no significant association of a benefit with convalescent plasma in reducing all-cause mortality compared with standard of care (risk ratio [RR], 1.04; 95% CI, 0.95-1.14).8

    Given the previously reported clinical trials and this recent announcement,8 a systematic review and meta-analysis was conducted to summarize and assess all published evidence from randomized clinical trials (RCTs) on the association between treatment with convalescent plasma compared with standard of care or placebo on clinical outcomes in patients with COVID-19.

    Methods

    This review has been reported in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis.9

    Search Strategy and RCT Selection

    Two reviewers (P.J. and C.A.) systematically searched PubMed (using peer-review of electronic search strategies10), the Cochrane COVID-19 trial registry, and the Living Overview of Evidence platform for all published RCTs as of January 29, 2021, aiming to assess the benefits and harms of convalescent plasma to treat patients with COVID-19. Search strategies were designed with terms related to convalescent plasma and COVID-19 along with standard RCT filters (eMethods in the Supplement).

    In addition, we searched for press releases presenting results of RCTs assessing convalescent plasma. Peer-reviewed publications, preprints, and press releases were eligible for inclusion. There were no restrictions on language or geographic region.

    The selected RCTs included patients with suspected or confirmed SARS-CoV-2 infection randomly allocated to receive convalescent plasma, placebo together with standard of care, or only standard of care. The RCTs were included regardless of the level of plasma titer (ie, low or high antibody titer) or health care setting. The RCTs aimed at preventing the occurrence of COVID-19 were excluded.

    Outcomes

    The outcomes were all-cause mortality at any time point, length of hospital stay, number of patients with clinical improvement or deterioration, number of patients requiring mechanical ventilation, and number of patients experiencing serious adverse events.

    Data Extraction and Risk of Bias Assessment

    We extracted the following information for each RCT: trial design characteristics (randomization procedure and blinding), descriptions of the experimental and control groups, baseline characteristics of the patients, eligibility criteria for plasma donors, and trial location. High antibody titer was defined in this meta-analysis as S-protein receptor-binding domain–specific IgG antibody titer of 1:640 or higher or serum neutralization titer of 1:40 or higher. For each outcome, we collected either the number of events for the convalescent plasma and control groups or the effect size and corresponding 95% CI (only hazard ratios [HRs] were consistently reported for length of hospital stay). Data on outcomes (F.E. and M.H.) and characteristics (A.M.S. and V.G.) were extracted independently by 2 reviewers.

    For each RCT, 2 reviewers (A.M.S. and V.G.) independently assessed the risk of bias for all-cause mortality, mechanical ventilation use, and length of hospital stay using version 2 of the Cochrane Risk of Bias Assessment Tool (low risk, some concerns, or high risk of bias).11 We also used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE)12 to assess the certainty of the evidence for the summarized outcomes regarding the treatment effect of convalescent plasma on patients with COVID-19.

    Disagreements among reviewers were discussed with a third reviewer (P.J.) until a consensus was reached.

    Statistical Analyses

    The primary analysis included only RCTs published in peer-reviewed journals. A secondary analysis included all the RCTs (peer-reviewed, preprints, and information from the press release for the RECOVERY trial).

    For outcomes with available data (all-cause mortality, length of hospital stay, and mechanical ventilation use), we conducted meta-analyses to summarize the treatment effects using RRs and HRs when applicable. The treatment effects for clinical improvement, clinical deterioration, and serious adverse events were not summarized due to inconsistent definitions of these outcomes and insufficient reporting of relevant details. When possible (based on the available data), we also estimated and summarized the treatment effects across the RCTs on an absolute risk difference scale.

    We conducted inverse variance–weighted random-effects meta-analyses using the Paule and Mandel τ2 estimator for heterogeneity.13 We applied the Hartung-Knapp adjustment14 to account for uncertainties due to large variations in sample size and in the number of outcome events across the RCTs. Heterogeneity across the RCTs was described using the I2 and τ2 metrics.15

    We conducted sensitivity analyses to assess the robustness of the results using the following meta-analytic models: Sidik-Jonkman τ2 estimator (instead of the Paule and Mandel estimator), the profile likelihood model, and the inverse variance–weighted fixed-effects model.

    All tests were 2-sided and statistical significance was based on the 95% CIs excluding the null. All analyses were conducted using R version 3.6.2 meta and metafor packages (R Foundation for Statistical Computing).

    Results

    A total of 4357 records were identified in databases, registries, and other sources. There were 4 RCTs published in peer-reviewed journals16-19 and 5 RCTs published as preprints20-24 that were included. In addition, press releases were identified for 2 RCTs (the RECOVERY trial8 and the Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia [REMAP-CAP]25) but only the reported results from the RECOVERY trial8 (NCT04381936) were included, stating 1873 deaths among 10 406 patients randomized (eFigure 1 in the Supplement).

    Of the 10 included RCTs, 3 were conducted in India, 2 in Argentina, and 1 each in Bahrain, China, the Netherlands, Spain, and the UK (Table 1). Five RCTs were terminated early; 2 were terminated early due to futility (Convalescent Plasma as Therapy for Covid-19 Severe SARS-CoV-2 Disease [ConCOVID; NCT04342182]22 and RECOVERY [NCT04381936]8) and 3 were terminated early due to slow recruitment (Convalescent Plasma Therapy vs SOC for the Treatment of COVID-19 in Hospitalized Patients [ConPlas-19; NCT04345523],23 ChiCTR2000029757,19 and NCT04479163).16 There were 2 double-blind RCTs (NCT04479163 and Convalescent Plasma and Placebo for the Treatment of COVID-19 Severe Pneumonia [PlasmAr; NCT04383535]),18 whereas the other 8 were open-label RCTs.

    From the 4 RCTs published in peer-reviewed journals, there were 1060 patients (595 randomized to convalescent plasma and 465 to placebo together with standard of care or only standard of care). From the 5 RCTs published as preprints, there were 316 patients (155 randomized to convalescent plasma and 161 to placebo together with standard of care or only standard of care). From the RECOVERY trial, there were 10 406 patients (the number of patients randomized per group was not reported in the press release information).

    Of the 10 RCTs, 9 included only patients with confirmed SARS-CoV-2 infection but the RECOVERY trial included those with either confirmed or suspected SARS-CoV-2 infection. Only 1 RCT included outpatients, 5 included inpatients requiring supplemental oxygen, and 4 included inpatients regardless of need for supplemental oxygen (Table 1). Patients were administered a single convalescent plasma transfusion in 5 of the RCTs and were administered 2 transfusions 24 hours apart in the other 5 RCTs (Table 1). Of the 10 RCTs, high plasma titer was used in 4, low titer was used in 1, a minimum plasma titer cutoff was not used in 3, and it was unclear in 2 (Table 1). Six RCTs used donated plasma from men, nulliparous women, or women testing negative for HLA antibodies (this type of description was not reported for 4 RCTs: RECOVERY [NCT04381936], NCT04479163, ChiCTR2000029757, and ConPlas-19 [NCT04345523]). Only 3 RCTs (PlasmAr [NCT04383535], NCT04356534, and PLACID [CTRI/2020/04/024775]) reported the COVID-19 severity of plasma donors.

    Detailed information on patient characteristics were available for 9 of the 10 RCTs (Table 2). The mean age of patients was younger than 70 years and they were typically male (≤80%); these generalizations did not apply to NCT04479163. Comorbidities at randomization were common when reported in the trials and only 2 RCTs reported the concurrent treatments at randomization.

    Risk of Bias

    The risk of bias for mortality, length of hospital stay, and mechanical ventilation use was deemed low for 7 of the 10 RCTs. For 2 of the RCTs, the risk of bias was classified as having some concerns (NCT04356534 and ConPlas-19 [NCT04345523]) and for 1 RCT it was deemed high (Passive Immunization With Convalescent Plasma in Severe COVID-19 Disease [PICP19; CTRI/2020/05/025209]; Figure 1). Loss to follow-up was less than 10% when reported in 9 RCTs (data were unavailable for the RECOVERY trial).

    The RECOVERY trial was deemed as having probably low risk of bias based on the trial protocol and published information for other treatments assessed by the trial (Figure 1).4-6,26,27

    Data Availability

    Mortality was assessed in all 10 RCTs and for 8 of the trials it was assessed between 15 to 30 days after randomization (1 RCT assessed mortality at 60 days and 1 RCT did not report length of follow-up; eTable 1 in the Supplement). Length of hospital stay was assessed in 7 RCTs; 3 used medians or means (1 published in a peer-reviewed journal and 2 published as preprints), 1 used HRs (published as a preprint), and 3 used both medians and HRs (2 published in peer-reviewed journals and 1 published as a preprint). The need for mechanical ventilation use was reported in 5 RCTs (3 peer-reviewed and 2 preprints). Data on clinical deterioration and clinical improvement were available in 5 RCTs (3 peer-reviewed and 2 preprints) and 3 RCTs reported data on serious adverse events (1 peer-reviewed and 2 preprints).

    Association of Convalescent Plasma With Clinical Outcomes

    In the primary analysis including only peer-reviewed RCTs, the mortality in patients receiving convalescent plasma was 11.6% (69/595) and 12.7% (59/465) in control patients. The summary RR for all-cause mortality with convalescent plasma was 0.93 (95% CI, 0.63 to 1.38; P = .60) and the absolute risk difference was −1.21% (95% CI, −5.29% to 2.88%). There was no significant between-trial heterogeneity (I2 = 0%; τ2 = 0 [95% CI, 0 to 1.35]) (Figure 2A). In the RECOVERY trial, the reported 28-day mortality rates were 18% with convalescent plasma and 18% for usual care (control).

    Across the 10 RCTs, the summary RR for all-cause mortality with convalescent plasma was 1.02 (95% CI, 0.92 to 1.12]; P = .68). There was no significant between-trial heterogeneity (I2 = 0%; τ2 = 0 [95% CI, 0 to 0.86]). In this meta-analysis of the 10 RCTs for all-cause mortality, the RECOVERY trial accounted for 90.2% of the weight and 88.3% (10 406/11 782) of the patients (Figure 2). The results of the sensitivity analyses were consistent with the main results (eTable 2 in the Supplement).

    The 4 peer-reviewed RCTs showed no significant associations between treatment with convalescent plasma and reductions in length of hospital stay (summary HR, 1.17 [95% CI, 0.07 to 20.34], P = .61 for analysis of 436 patients) or mechanical ventilation use (summary RR, 0.76 [95% CI, 0.20 to 2.87], P = .35 for analysis of 957 patients) (Figure 2). The absolute risk difference for mechanical ventilation use was −2.56% (95% CI, −13.16% to 8.05%). Similar results were observed for the peer-reviewed and preprint RCTs for length of hospital stay (HR, 1.07 [95% CI, 0.79 to 1.45], P = .87 for analysis of 603 patients) and for mechanical ventilation use (RR, 0.81 [95% CI, 0.42 to 1.58], P = .88 for analysis of 1026 patients; Figure 2). The absolute risk difference for mechanical ventilation use was −2.21% (95% CI, −8.94% to 4.51%) (eFigure 2 in the Supplement).

    For clinical improvement and clinical deterioration, the RRs were not summarized across RCTs due to inconsistent definitions and insufficient reporting of relevant details for these outcomes (eTable 1 and eFigure 3 in the Supplement). Of the 5 RCTs (3 peer-reviewed and 2 preprints) that reported such data, none demonstrated statistically significant clinical deterioration or improvement in patients who received convalescent plasma compared with the control group and the 95% CIs were wide (eFigure 3 in the Supplement).

    No meta-analysis was conducted on serious adverse events due to inconsistencies in the reporting. PlasmAr (NCT04383535), ConPlas-19 (NCT04345523), and ConCOVID (NCT04342182) were the RCTs that reported data on serious adverse events (eFigure 4 in the Supplement); 60 serious adverse events were reported for the 309 patients in the convalescent plasma groups and 26 serious adverse events were reported for the 191 patients in the control groups. Even though ConCOVID (NCT04342182) included all-cause mortality in its definition of serious adverse events and 17 patients died, only plasma-related serious adverse events were reported (with 0 events). Similarly, PLACID (CTRI/2020/04/024775) and NCT04356534 reported recording serious adverse events including all-cause mortality but no clear data were shown.

    The Certainty of the Evidence

    For the primary analysis that only included the 4 RCTs published in peer-reviewed journals, the certainty of the evidence (using GRADE) for mortality was low due to very serious imprecision concerns regarding the wide 95% CI for the summary RR, which would be compatible with substantial benefit or harm. For the secondary analysis that included all 10 RCTs (published in peer-reviewed journals, published as preprints, and the RECOVERY trial), the concern regarding imprecision was reduced and the certainty of the evidence was rated as moderate (eTable 3 in the Supplement).

    For length of hospital stay and mechanical ventilation use, the certainty of the evidence was rated as low for peer-reviewed trials only and when considering all publicly available trials due to very serious imprecision concerns (wide 95% CIs for the summary RR estimates; eTable 3 in the Supplement).

    Discussion

    In this meta-analysis that included 4 RCTs published in peer-reviewed journals for the primary analysis and an additional 6 RCTs not published in peer-reviewed journals (5 preprints and 1 press release) for the secondary analysis, treatment with convalescent plasma compared with placebo in combination with standard of care or only standard of care was not significantly associated with a decrease in all-cause mortality or with any benefit for other clinical outcomes among patients with COVID-19.

    The certainty of the evidence on all-cause mortality was low when only the peer-reviewed trials were included and then moderate when the evidence from the RCTs published as preprints and the RECOVERY trial was added. The evidence was largely dominated by the RECOVERY trial, which accounted for 90.2% of the weight in the meta-analysis, although the pooled results from the 4 peer-reviewed trials were similar. The results from the RECOVERY trial published as a press release warrant cautious interpretation until the trial results are fully analyzed and reported in a peer-reviewed journal.

    There also was no significant association of convalescent plasma with benefits on other patient-relevant clinical outcomes, including reduction in the length of hospital stay or mechanical ventilation use; however, summarized sample sizes were considerably smaller (range, 603-1026 patients) than for all-cause mortality (11 782 patients). Data on clinical improvement or deterioration were limited and inconclusive due to the use of inconsistent definitions for the outcomes and insufficient reporting of the relevant details for these outcomes. Similarly, the safety of convalescent plasma regarding serious adverse events could not be reliably assessed because only 3 RCTs reported data and there were inconsistencies in the definitions used. Although it was identified during the literature search, the press release for the REMAP-CAP trial25 was not included because it did not present quantitative results. However, according to their reported preliminary analysis including 912 participants requiring intensive care unit support, treatment with convalescent plasma did not show a beneficial effect on the number of days requiring intensive support or on mortality. The REMAP-CAP preliminary findings are consistent with our summarized results and, given the relatively small sample size of REMAP-CAP compared with the RECOVERY trial,8 the data would likely not change our interpretation.

    Difficulties in synthesizing evidence across COVID-19 trials because of heterogeneous outcome measures were anticipated by Zarin and Rosenfeld28 who identified 351 unique descriptions for outcome measures among 232 trials registered until June 2020, including 14 unique ordinal scales. Besides precluding a meaningful overview, unnecessary variation in outcome measures makes precise conclusions more challenging. To aid the development of uniform outcome measurement across trials, core outcome sets involving patients may be a fruitful way forward.29

    Limitations

    This study has several limitations. First, 3 of the 10 RCTs had some concerns or high risk of bias. However, those 3 RCTs only contributed to 1.8% of the weight of the meta-analysis on all-cause mortality, which was highly dominated by data from the RECOVERY trial. Although access to full publication of the results was not yet available, the mortality results from the RECOVERY trial appear likely to be at low risk of bias and without a specific reason to downgrade the certainty of evidence based on previously published treatment group results and the RECOVERY trial protocol.4-6,26,27

    Second, the reporting of clinical outcomes, other than all-cause mortality, for RECOVERY was insufficient and inconsistent regarding the use of definitions and relevant details across its COVID-19 treatment trials.

    Third, the data were too limited to perform meaningful subgroup analyses. The observations reported in the literature regarding a benefit with early high-titer plasma1 administration in observational studies call for further analyses based on individual patient data such as the Continuous Monitoring of Pooled International Trials of Convalescent Plasma for COVID-19 Hospitalized Patients (COMPILE) project.30

    Fourth, except for 1 RCT with outpatients,16 all patients were hospitalized with or without oxygen supplementation, indicative of moderate to critical COVID-19. The generalizability of the results to patients with milder COVID-19 is unclear.

    Fifth, the primary focus of this meta-analysis was on published RCTs. There are many ongoing trials (>100) assessing convalescent plasma that are at risk of being terminated early or never published, but a collaborative meta-analysis of all these data is underway.31

    Conclusions

    Treatment with convalescent plasma compared with placebo or standard of care was not significantly associated with a decrease in all-cause mortality or with any benefit for other clinical outcomes. The certainty of the evidence was low to moderate for all-cause mortality and low for other outcomes.

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    Article Information

    Corresponding Author: Lars G. Hemkens, MD, MPH, Department of Clinical Research, University Hospital Basel, Spitalstrasse 12, CH-4031 Basel, Switzerland (lars.hemkens@usb.ch).

    Accepted for Publication: February 15, 2021.

    Published Online: February 26, 2021. doi:10.1001/jama.2021.2747

    Author Contributions: Drs Janiaud and Hemkens had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Janiaud and Axfors contributed equally to this study.

    Concept and design: Janiaud, Axfors, Smith, Khanna, Moher, Ioannidis, Hemkens.

    Acquisition, analysis, or interpretation of data: Janiaud, Axfors, Schmitt, Gloy, Ebrahimi, Hepprich, Haber, Khanna, Moher, Goodman, Ioannidis, Hemkens.

    Drafting of the manuscript: Janiaud, Axfors, Hepprich, Hemkens.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Janiaud, Hepprich, Haber, Moher, Ioannidis, Hemkens.

    Obtained funding: Hemkens.

    Administrative, technical, or material support: Janiaud, Axfors, Gloy, Ebrahimi, Hepprich, Smith.

    Supervision: Ioannidis, Hemkens.

    Conflict of Interest Disclosures: None reported.

    Funding/Support: The Meta-Research Innovation Center at Stanford (Stanford University) is supported by a grant from the Laura and John Arnold Foundation. Dr Axfors is supported by postdoctoral grants from the Knut and Alice Wallenberg Foundation, Uppsala University, the Swedish Society of Medicine, the Blanceflor Foundation, and the Sweden-America Foundation. Dr Khanna is supported by the Swiss National Science Foundation and the National Center of Competence in Research. Drs Janiaud and Hemkens are supported by grants from Swiss National Science Foundation.

    Role of the Funder/Sponsor: The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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