In Reply—How Safe Is COVID-19 Convalescent Plasma?

Abstract

We would like to thank Franchini and Cruciani for their letter in response to our systematic review and meta-analysis studying the effect of convalescent plasma therapy on the mortality of patients diagnosed with coronavirus disease 2019 (COVID-19).1Klassen S.A. Senefeld J.W. Johnson P.W. et al.The effect of convalescent plasma therapy on mortality among patients with COVID-19: systematic review and meta-analysis.Mayo Clin Proc. 2021; 96: 1262-1275Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar This letter highlights important new meta-analytical data based on 30 controlled studies (including 14 randomized clinical trials) demonstrating that convalescent plasma transfusion does not increase the risk of adverse events, including thromboembolic events, compared with patients diagnosed with COVID-19 who either were not transfused or were transfused with standard fresh frozen plasma. This new safety analysis supports the viewpoint that human convalescent plasma has a favorable risk-benefit ratio, particularly when it is reviewed in the context of the mosaic of evidence supporting some degree of effectiveness of convalescent plasma therapy for COVID-19.2Klassen S.A. Senefeld J.W. Senese K.A. et al.Convalescent plasma therapy for COVID-19: a graphical mosaic of the worldwide evidence.Front Med (Lausanne). 2021; 8: 684151Crossref PubMed Scopus (32) Google Scholar Taken as a whole, these data support the continued use of convalescent plasma as the COVID-19 pandemic endures, especially in regions with limited vaccine access and in immunocompromised patients who cannot mount effective immune responses to vaccines.3Boyarsky B.J. Werbel W.A. Avery R.K. et al.Antibody response to 2-dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients.JAMA. 2021; 325: 2204-2206Crossref PubMed Scopus (566) Google Scholar At the onset of the COVID-19 pandemic, several theoretical safety risks regarding convalescent plasma therapy were raised, including the potentiation of COVID-19 respiratory deterioration through antibody-dependent enhancement or cytokine storms, transfusion-associated circulatory overload, and enhanced thromboembolic risk.4Dzik S. COVID-19 convalescent plasma: now is the time for better science.Transfus Med Rev. 2020; 34: 141-144Crossref PubMed Scopus (52) Google Scholar However, the meta-analytical safety data presented in the letter by Franchini and Cruciani along with the consistent signatures of safety emerging from worldwide use of convalescent plasma, including in the United States under the Expanded Access Program and Emergency Use Authorization, have generally allayed these safety concerns.5US Food and Drug AdministrationClinical memorandum for the emergency use authorization of COVID-19 convalescent plasma.https://www.fda.gov/media/141480/downloadGoogle Scholar,6Joyner M.J. Bruno K.A. Klassen S.A. et al.Safety update: COVID-19 convalescent plasma in 20,000 hospitalized patients.Mayo Clin Proc. 2020; 95: 1888-1897Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar Convalescent plasma safety can also be inferred from the mortality benefit and rapid clinical improvement in patients with several forms of immunosuppression following convalescent plasma transfusion.7Senefeld J.W. Klassen S.A. Ford S.K. et al.Use of convalescent plasma in COVID-19 patients with immunosuppression.Transfusion. 2021; https://doi.org/10.1111/trf.16525Crossref PubMed Scopus (40) Google Scholar These positive safety data are promising, given that immunocompromised patients will continue to represent a vulnerable population throughout the duration of the COVID-19 pandemic and may be among those medically advised to not receive vaccination or unable to mount a robust humoral response to vaccination.3Boyarsky B.J. Werbel W.A. Avery R.K. et al.Antibody response to 2-dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients.JAMA. 2021; 325: 2204-2206Crossref PubMed Scopus (566) Google Scholar Given the link between COVID-19 and thromboembolic diseases and plasma serving as a source of both procoagulant and anticoagulant factors, there may be lingering concerns that convalescent plasma escalates thromboembolic risk, especially among severely ill patients.8Cui S. Chen S. Li X. Liu S. Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.J Thromb Haemost. 2020; 18: 1421-1424Crossref PubMed Scopus (1101) Google Scholar At present, the aggregate epidemiologic data suggest that convalescent plasma does not increase the thromboembolic risk in patients with COVID-19. To support and confirm these findings, future experimental studies should assess the impact of convalescent plasma on a panel of coagulation factors in patients with COVID-19 or evaluate whether the coagulation profile of COVID-19 convalescent plasma poses a greater thromboembolic risk than standard fresh frozen plasma. The importance of the work by Franchini and Cruciani is that they have broadly shown there is a consistent safety profile for the use of human convalescent plasma in the treatment of COVID-19. Whereas there are mixed interpretations on the effectiveness of convalescent plasma, the lack of safety concerns must be carefully weighed in the context of the potential for benefit the treatment may offer during the remainder of the COVID-19 pandemic. The Effect of Convalescent Plasma Therapy on Mortality Among Patients With COVID-19: Systematic Review and Meta-analysisMayo Clinic ProceedingsVol. 96Issue 5PreviewTo determine the effect of COVID-19 convalescent plasma on mortality, we aggregated patient outcome data from 10 randomized clinical trials, 20 matched control studies, 2 dose-response studies, and 96 case reports or case series. Studies published between January 1, 2020, and January 16, 2021, were identified through a systematic search of online PubMed and MEDLINE databases. Random effects analyses of randomized clinical trials and matched control data demonstrated that patients with COVID-19 transfused with convalescent plasma exhibited a lower mortality rate compared with patients receiving standard treatments. Full-Text PDF Open AccessHow Safe Is COVID-19 Convalescent Plasma?Mayo Clinic ProceedingsVol. 96Issue 8PreviewWe read with interest the systematic review and meta-analysis by Klassen and colleagues,1 recently published in Mayo Clinic Proceedings. The investigators included in their analysis 30 randomized clinical trials (RCTs) and matched control studies, documenting that COVID-19 convalescent plasma (CP) transfusion, especially when it is given within 3 days of hospital admission, is associated with lower mortality of patients with COVID-19 compared with standard treatment. Adverse events analysis, in combination with benefits analysis, is essential to make an informed decision about health intervention. Full-Text PDF