Towards the identification of the correct place for convalescent plasma among COVID-19 therapies

Plasma collected from recovered individuals was utilized in the past decades to facet several infectious disease outbreaks, particularly those from respiratory viruses [1]. Likewise, during the COVID-19 pandemic, plasma from convalescent patients (COVID-19 convalescent plasma, CCP) was the first antibody-based therapy used for the emergency treatment of SARS-CoV-2 infection [2]. Since then, CCP was the most frequently utilized and the most intensively studied directly acting antiviral therapy worldwide [3]. Such research has led to the publication of dozens of randomized controlled trials and hundreds of non-randomized studies, and to the clinical real-life experience in thousands of COVID-19 patients transfused with CCP [4].

Khawaja et al. from the University Hospital of Helsinki publish in this issue a double-blinded trial which randomized 57 patients hospitalized for COVID-19 to receive high-titer CCP, low-titer CCP or placebo [5]. The study did not find any statistically significant effect on the primary outcomes: recorded intubation or starting systemic corticosteroid for aggravation of COVID-19 within 21 days post infusion nor for serious adverse events. Interestingly, patients receiving high-titer CCP necessitated less respiratory support and less frequent corticosteroid administration than the other two groups, suggesting a signal of efficacy of the former biologic treatment. After reading this article, the question that arises spontaneously is ‘Was there really a need for another RCT (precisely the forty-ninth) on CCP?’. In our opinion the answer is ‘Yes’.

Current evidence from the literature supports the efficacy of early (within five days from symptom onset) transfusion of high-titer CCP in COVID-19 outpatients, particularly those immunocompromised who are unable to mount an antibody response against the virus [6]. Less established is the clinical effect of CCP in hospitalized patients: RCTs in this setting are then welcomed. The Finnish RCT report a higher clinical benefit in recipients of CCP with a high-titer (≥1:160) of neutralizing antibodies (nAbs) against their infecting SARS-CoV-2 variants [5]. Although the effectiveness of CCP matched with patients’ variants of concerns (VOCs) has been already reported in uncontrolled studies [7], the major limitation to its practical prospective deployment is the turnaround time of the viral neutralization assays. Nevertheless, VAX-plasma (i.e. CCP collected from donors both convalescent and vaccinated against SARS-CoV-2) potentially overcomes matching, since it harbors heterologous antibodies that cross-react against most variants [8–10].

Besides these signals of CCP efficacy, the Finnish RCT suffers from some methodological flaws that may explain the lack of statistical significance in the primary endpoints between CCP and control arms. First of all, patients were recruited within 10 days from symptom onset (median time eight days), which is undoubtedly a time lapse too long for CCP transfusion. It is nowadays widely recognized, indeed, that CCP efficacy is highest when it is transfused during active viral replication, i.e. during the first 5–7 days from symptom onset. Another important limitation of this study regards the enrollment of patients, which was approximately seven times lower than that planned in the sample size calculation, due to various reasons. This issue is not new, since many formerly published RCTs on CCP recruited a number of patients lower than expected. The halts were mainly due to recruitment difficulties in interpandemic waves and reduced disease severity in immunocompetent subjects in the post-vaccine era, thus hindering the achievement of the minimum number of patients required to reach statistical significance [10–12]. Such phenomenon could be, in our opinion, at the basis of the CCP failure observed in many of such RCTs. Continuous research in this clinical setting is therefore required to definitively ascertain the therapeutic efficacy of CCP, in order to optimize its use in future pandemics.

Disclosure statement

No potential conflict of interest was reported by the authors.