Convalescent Plasma to Treat COVID-19: Possibilities and Challenges.

In this issue of JAMA, Shen et al report findings from a preliminary study of 5 severely ill patients with coronavirus disease 2019 (COVID-19) who were treated in the Shenzhen Third People's Hospital, China, using plasma from recovered individuals.1 All patients had severe respiratory failure and were receiving mechanical ventilation; 1 needed extracorporeal membrane oxygenation (ECMO) and 2 had bacterial and/or fungal pneumonia. Four patients without coexisting diseases received convalescent plasma around hospital day 20, and a patient with hypertension and mitral valve insufficiency received the plasma transfusion at day 10. The donor plasma had demonstrable IgG and IgM anti– SARS-CoV-19 antibodies and neutralized the virus in in vitro cultures. Although these patients continued to receive antiviral treatment primarily with lopinavir/ritonavir and interferon, the use of convalescent plasma may have contributed to their recovery because the clinical status of all patients had improvement approximately 1 week after transfusion, as evidenced by normalization of body temperature as well as improvements in Sequential Organ Failure Assessment scores and PAO2/FIO2 ratio. In addition, the patients’ neutralizing antibody titers increased and respiratory samples tested negative for SARS-CoV-2 between 1 and 12 days after transfusion. Even though the cases in the report by Shen et al are compelling and well-studied, this investigation has important limitations that are characteristic of other “anecdotal” case series. The intervention, administration of convalescent plasma, was not evaluated in a randomized clinical trial, and the outcomes in the treatment group were not compared with outcomes in a control group of patients who did not receive the intervention. Therefore, it is not possible to determine the true clinical effect of this intervention or whether patients might have recovered without this therapy. In addition, patients received numerous other therapies (including antiviral agents and steroids), making it impossible to disentangle the specific contribution of convalescent plasma to the clinical course or outcomes. Moreover, convalescent plasma was administered up to 3 weeks after hospital admission, and it is unclear whether this timing is optimal or if earlier administration might have been associated with different clinical outcomes. Despite these limitations, the study does provide some evidence to support the possibility of evaluating this well-known therapy in more rigorous investigations involving patients with COVID-19 and severe illness. The use of convalescent plasma is not new; it was used for severe acute respiratory syndrome (SARS), pandemic 2009 influenza A (H1N1), avian influenza A (H5N1), several hemorrhagic fevers such as Ebola, and other viral infections. For instance, in 2005, Cheng et al reported outcomes of patients who received convalescent plasma in Hong Kong during the 2003 SARS outbreak.2 Although this investigation was not a randomized trial, of 1775 patients, the 80 who received convalescent plasma had a lower mortality rate (12.5%) compared with the overall SARS-related mortality for admitted patients (n = 299 [17%]). The antibody titers and plasma transfusion volumes varied and did not appear to correlate with clinical response; however, patients receiving transfusion within 14 days of symptom onset (n = 33) had better outcomes. No adverse events were reported among patients receiving convalescent plasma. Despite the potential utility of passive antibody treatments, there have been few concerted efforts to use them as initial therapies against emerging and pandemic infectious threats. The absence of large trials certainly contributes to the hesitancy to employ this treatment. Also, the most effective formulations (convalescent plasma or hyperimmune globulin, H-Ig) are unknown. Convalescent plasma has the advantage that while its antibodies limit viral replication, other plasma components can also exert beneficial effects such as replenishing coagulation factors when given to patients with hemorrhagic fevers such as Ebola.3-5 On the other hand, individual convalescent plasma units demonstrate donordependent variability in antibody specificities and titers. H-Ig preparations, in contrast, contain standardized antibody doses, although fractionation removes IgM, which may be necessary against some viruses. Nonetheless, the construction of a strategic stockpile of frozen, pathogen-reduced plasma, collected from Ebola-convalescent patients with wellcharacterized viral neutralization activities, is one example of how to proceed despite existing unknowns.6 Deploying passive antibody therapies against the rapidly increasing number of COVID-19 cases provides an unprecedented opportunity to perform clinical studies of the efficacy of this treatment against a viral agent. If the results of rigorously conducted investigations, such as a large-scale randomized clinical trial, demonstrate efficacy, use of this therapy also could help change the course of this pandemic.4 Shen et al used apheresis products produced in the hospital.1 How could this be scaled to meet increased demands? One approach would be to combine the use of convalescent plasma and H-Ig in a complementary way to treat infected patients in the current COVID-19 pandemic, and subsequent infectious Related article