Late Administration and Corticosteroid Usage Explain Inefficacy in COVID-19 Convalescent Plasma Trial
Year: 2023
Type: article
Abstract: To the Editor—We commend Nurmi et al [1] for carrying out a comparative study of antibody titers to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the convalescent plasma used in the REMAP [2] and Argentinean outpatient trial [3]. This is precisely the type of post hoc analysis that needs to be done to understand conflicting results among studies. Knowing the conditions when plasma with high levels of SARS-CoV-2 antibodies is effective is critically important because we can anticipate that it will be rolled out again at the next infectious disease emergency for which there is no specific therapy. The major finding of the Nurmi et al study is that the specific antibody titers used in the convalescent plasma units used in the 2 trials were comparable, which, as the authors imply, would suggest that the differences in efficacy reflect early use in the Argentinean trial and late use in REMAP. This conclusion is further supported by the fact that, historically, antibody therapies were effective when used early in disease [4] and by the efficacy observed in the 5 randomized controlled trials for outpatient coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) therapy [5]. In the REMAP trial, over 90% of participants received supplemental oxygen with a large proportion being on either invasive mechanical ventilation or high-flow nasal cannulas, which indicates a high prevalence of pulmonary compromise in this population. Antibody therapy works primarily as an antiviral and, like small-molecule antiviral drugs, is most effective early in infection. The primary cause of death in COVID-19 is pulmonary insufficiency caused by lung inflammation that interferes with gas exchange and there is no known immunological mechanism by which specific antibody can reverse this inflammation, thus providing an explanation for the inefficacy of CCP in hospitalized patients with advanced disease. Although we agree that the major difference in CCP efficacy observed in the REMAP and Argentinean trial is likely to be the timing of CCP administration relative to disease progression, we note that differences in corticosteroid use could have affected the lack of efficacy observed in REMAP, where 94% of the participants received glucocorticoids [2]. The prevalence of corticosteroid use in the Argentinean trial was not stated but is very likely to have been low to none because the participants were outpatients, and the study was done before these drugs became widely used for COVID-19. Corticosteroids downregulate Fc receptors [6] and are known to interfere with antibody function by inhibiting phagocytosis [7] and antibody-dependent cellular cytotoxicity (ADCC) [8], which have been shown to be important components of CCP activity against SARS-CoV-2 [9]. Both phagocytosis and ADCC are Fc-related antibody functions. In the intervening years since these studies were done, we have learned that antibody Fc-related action is critically important for the efficacy of CCP [10]. Given that we can rule out differences in plasma quality based on the work of Nurmi et al [1], the most likely explanation for the inefficacy of CCP in REMAP was its use beyond the point in disease progression when antibody therapy could be effective and perhaps antibody antagonism from concomitant corticosteroid usage. Financial support. No financial support was received for this work.
Authors: Arturo Casadevall, David J Sullivan
Institution: Johns Hopkins University
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funder: Johns Hopkins University
OpenAlex ID: W4388688185