In this issue of Blood, Hegerova et al report on a study of 20 hospitalized patients with severe or critical coronavirus disease 2019 (COVID-19) who were transfused with convalescent plasma (CP); the authors suggest a favorable, albeit modest, benefit as compared with 20 matched (ie, nontransfused) controls, particularly when transfusion was undertaken within the first 7 days of hospitalization.1 

CP that has been collected from individuals who have recovered from COVID-19 (ie, COVID-19 convalescent plasma [CCP]) has emerged as a leading treatment of COVID-19. Early studies in China reported benefits of CCP transfusion in patients with COVID-19, including viral clearance, radiological resolution of pulmonary disease, improved oxygenation, and survival.2,3  This spurred efforts by the US Food and Drug Administration (FDA) and the US blood-banking community to collect and transfuse CCP on an unprecedented scale.4  To date, over 26 000 patients have been transfused with CCP in the United States alone, primarily through a government-led expanded access program.5  Data gleaned from this program have shown CCP to be well tolerated, with comparable risk to standard (ie, nonimmune) plasma.6 

Hegerova et al add to a growing number of observational studies that have reported on the use of CCP to treat COVID-19. The outcomes of the collective studies span dramatic examples of recovery to the absence of demonstrable effect,2,3,7,8  highlighting the challenges of CP in general. Like many infectious diseases for which CP has been applied, clinical trial data are lacking. CP is typically deployed in times of emergency when the design and execution of randomized clinical trials is most complex. Beyond the administrative, regulatory, and logistical barriers of initiating trials in times of crisis, timing is critical: once epidemics wane, enrollment goals risk going unfulfilled. There is already at least 1 example of this with COVID-19: in a clinical trial in China, critically ill patients with COVID-19 were randomized to CCP with standard therapy vs standard therapy alone.9  Despite encouraging signals of benefit in earlier—severe rather than life-threatening disease, the trial failed to show a significant difference in clinical improvement 28 days following randomization, its primary outcome. With only 103 of its targeted 200 subjects enrolled, the study was ultimately underpowered.

Currently, we are reliant on observational data of CCP to guide practice.2,3,7,8  Observational studies have proven invaluable to the CCP initiative but they share a host of methodologic limitations. Some are constrained by small sample sizes and lack of controls. All have selected for severe COVID-19 in which most patients have received other therapies, in addition to CCP, such as steroids, antibiotics, and antivirals, blurring interpretation of the findings. Hegerova et al acknowledged this as a limitation in their study in which one-half of their control group had received remdesivir, an investigational antiviral that could well have masked the differential effect of CCP if indeed one were present. Beyond concomitant therapies, the investigators highlight 2 other elements that have not been standardized across studies: dosage and titering. Dosing of CCP has been gleaned from studies of severe acute respiratory syndrome; the pharmacokinetics of CP in the context of COVID-19 are not well understood. Most studies of COVID-19 have reported use of 1 to 2 U (∼200-500 mL) of CCP to treat COVID-19; while practical, this fails to account for differences in the volumes of distribution or acuity of disease. Furthermore, the approaches that have been used to qualify donors and/or the transfused units of CCP have varied enormously, from qualitative assessments of immunoglobulin G to formal viral neutralization assays and associated titers.4 

Independent of the study design, the patient population that is being targeted for CCP use may be suboptimal. An enduring finding across studies of CP is the need for early intervention.1,4,7,9  Yet, the overwhelming majority, if not all, CCP to date has been transfused to patients with advanced COVID-19. At inception, the US expanded access program required severe or life-threatening COVID-19 for enrollment.6  Although the desire to help those who are most sick is intuitive, this is the population for which evidence of benefit from CP is weakest. Late intervention also fails to abrogate the societal burden of disease. In short, intervention likely needs to occur earlier in the disease process.4 

In conclusion, observational studies and compassionate use programs have been instrumental in the mobilization of CCP to contend with a global health emergency. Although safety has been addressed, efficacy data are critically needed to transition CCP’s status from an investigational product to a standard therapy. The latter has practical ramifications, offering a formal mechanism for reimbursement and thus a durable treatment strategy. Broadly, COVID-19 presents a rare opportunity to study CP. If shown to be effective, CP would offer a scalable model that could be applied both to the current pandemic as well as to future emerging infectious diseases. It could also facilitate development of hyperimmune globulin and vaccine design. Clinical trials are already under way to address the uncertainty of use. Nonetheless, harmonization of efforts is needed along with creative approaches to overcome looming obstacles, such as pairing of trials of similar design and/or metanalysis. We must not be left wondering whether the intervention worked after the pandemic wanes.

Conflict-of-interest disclosure: E.M.B. reports personal fees and nonfinancial support from Terumo BCT and Grifols Diagnostics Solutions outside of the submitted work.

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