Convalescent Plasma for COVID-19: An Old Therapy for a Novel Pathogen

The concept of passive immunization, including use of convalescent plasma (CP) to treat an infectious disease, originated more than 100 years ago.¹  In 1890, physiologists from Germany treated patients with diphtheria, initially, with sera from immunized animals, and subsequently, with sera or whole blood from recovered patients.²  Until the development of antimicrobials in the 1940s, the use of passive immunization became one of the mainstays of therapy for infectious disease. Numerous reports during the Spanish flu pandemic of 1918 to 1920 demonstrated efficacy of CP in cases of that highly lethal viral infection. A meta-analysis of 1,703 patients with Spanish Flu treated with CP in eight different studies, suggested markedly reduced mortality.³  Since that time, CP has been used for dozens of infectious diseases, including varicella, measles, and Ebola, with largely anecdotal studies suggesting some benefit.¹ 

Recently, multiple outbreaks of different coronaviruses with high mortality rates, including SARS-CoV-1 in 2003, MERS in 2012, and SARS-CoV-2 in the present day, have renewed interest in passive immunization with CP. Use of CP was trialed in MERS and more extensively in SARS-CoV-1.^4-6  The largest study was from Hong Kong and included 80 patients with SARS-CoV-1 who were treated with CP. This nonrandomized series of cases found that patients treated before day 14 were more likely to be discharged from the hospital compared with untreated patients or those treated later in the disease course.⁴  While such studies suggest a possible benefit for use of CP, the actual efficacy is difficult to ascertain, owing to lack of control groups, use of other therapies, and other confounders and biases. Nonetheless, meta-analyses of these case series did not reveal adverse effects.^7,8 

Studies Using CP in COVID-19

There have been six reports thus far on the use of CP for patients with COVID-19.^9-14  These reports all included adult patients with moderate to severe disease. Not all of these studies included information about the titers of anti–SARS-CoV-2 antibodies in CP preparations. In all but one report,¹⁴  most patients were reported to have experienced clinical improvements, as evidenced by resolution in fever, normalization of laboratory values (C-reactive protein and proinflammatory cytokines), and resolution of radiographic abnormalities. Successful extubation from mechanical ventilation (10 of 12 patients) and decannulation from extracorporeal membrane oxygenation (2 of 3 patients) were noted in critically ill patients. In one study, however, five of six patients treated with CP eventually died, even though use of CP was associated with viral clearance. It should be noted that in this study, the median time to administration of CP was 21.5 days from the detection of viral shedding.¹⁴  Given that each of these reports included a small number of patients, and approaches that were not uniform, caution is needed in interpreting the results. Nonetheless, these existing reports do suggest that if CP is to be effective, it may need to be used earlier in the course of disease.

Potential Risks

Use of CP carries several potential risks beyond those associated with the transfusion of human blood products (e.g., infection with blood borne pathogens, allergic reactions, and transfusion-related acute lung injury). Additional risks include antibody-mediated enhancement (ADE) of infection, the potential inhibition of the development of effective humoral immunity, and the exacerbation of harmful immune responses, including worsening acute respiratory distress syndrome or systemic inflammatory response syndrome. In ADE, virus-specific antibodies increase the entry of virus into cells expressing Fc or complement receptors. ADE has been identified in preclinical studies with numerous viruses and could in theory occur with coronaviruses including SARS-CoV-2,¹⁵  though it has not been reported in patients with SARS-CoV-1, MERS, or SARS-CoV-2. ADE is believed to most likely occur with sub-neutralizing or non-neutralizing antibodies and at higher viral loads. While initial reports claimed that a proportion of those who recovered from COVID-19 did not develop significant titers of neutralizing antibodies,¹⁶  two subsequent studies showed that all patients with COVID-19 do eventually produce antibodies, though the patterns of antibody production were not uniform across different patients.^17,18  If the donor CP being used carries suboptimal titers of neutralizing antibodies, this may theoretically impose a higher chance of harm. This is especially germane as not all CP-use protocols mandate the measurement or the use of cut-offs for total or neutralizing antibody titers against SARS-CoV-2 in the donor plasma. Of note, none of the aforementioned studies reported serious adverse events directly attributable to the CP.^9-14  Nevertheless, because there are risks, the use of CP is currently only recommended for patients who are critically ill with COVID-19. As safety and efficacy data mature, its use in high-risk populations with mild infections may eventually be considered, but such approaches should be pursued in the context of clinical trials.

Practical Considerations and Conclusion

In the United States, the U.S. Food and Drug Administration has recently given guidance on the use of CP as an investigational product that can be employed as part of a clinical trial, under a single-patient emergency Investigational New Drug, or through a National Expanded Access Treatment Protocol through the Mayo Clinic.¹⁹  To donate plasma, a patient must have documented evidence of a history of infection with SARS-CoV-2 by viral polymerase chain reaction (PCR) and have fully recovered from the infection. Currently, full recovery is defined as being symptom-free for at least four weeks or for at least two weeks and with a negative viral reverse transcriptase-PCR. Donors who have been previously transfused and female donors who have been pregnant are tested and must be negative for anti-HLA/HPA/HNA antibodies. Similar processes occur in other countries, including the European Union.²⁰ 

CP from patients who have recovered from COVID-19 is a limited resource. Persons who meet the criteria and are otherwise healthy are encouraged to donate in order to help others during this pandemic, until other therapeutic modalities become available. Detailed information for such donations is available from the American Red Cross.²¹