Convalescent plasma: is there still a role in the treatment of COVID-19?

Since the late 1800s, the use of convalescent plasma (CP) has been reported to treat a myriad of infectious diseases, including diphtheria, influenza pandemics and severe acute respiratory syndrome.[1] It works on the basis of passive transfer of neutralising antibodies from the plasma of recovered individuals to infected patients without immunity. Its use in novel diseases is especially valuable and of interest when other treatment options are limited or unavailable. Numerous meta-analyses have examined the use of CP for treatment of coronavirus disease 2019 (COVID-19), but its impact on mortality has been inconsistent.[2,3,4] These inconsistencies are due to several factors, including heterogeneity in neutralising antibody titres and volume of CP used, timing of administration in the course of disease, and information on COVID-19 variants in donor and recipient (typically unknown).[2,3,4] In addition, most studies were conducted before widespread vaccination. The effect of hybrid immunity (Vax-plama)[5] is still understudied. As such, current international guidelines generally recommend against the routine use of CP.[6,7] For instance, the Infectious Diseases Society of America (IDSA) COVID-19 guidelines advise against the routine use of CP for both immunocompetent and immunocompromised hospitalised patients.[5] Similarly, the latest Singapore COVID-19 guidelines do not recommend routine use of CP.[7] The European Conference on Infections in Leukaemia has, however, suggested that high-titre CP might be of benefit in seronegative immunocompromised patients, particularly if administered early during the infection.[8] In particular, patients with B-cell depletion due to anti-CD20 monoclonal antibody treatment for haematological malignancies, autoimmune diseases or primary immunodeficiencies (e.g. common variable immunodeficiency) may benefit. The IDSA COVID-19 guidelines also conditionally recommend it for ambulatory patients with mild to moderate COVID-19 who are at high risk of progression to severe disease, within 8 days of symptom onset, or when no other treatment options are available.[5] Case series have shown positive outcomes in patients with profound B-cell lymphopenia and prolonged COVID-19 clinical course, with many receiving prior COVID-19 antivirals without improvement.[9,10] A study by Hueso et al.[9] found that patients with severe B-cell depletion experienced protracted COVID-19 symptoms for a median of 56 days, but showed rapid clinical improvement after receiving CP. Fever resolved within 48 h, and patients were able to be weaned off oxygen support or non-invasive ventilation within a median of 5 days.[9] In addition, a recent meta-analysis on the use of CP in immunocompromised COVID-19 patients suggested a mortality benefit.[11] Therefore, there may still be a role in its use. Other forms of passive immunity, such as monoclonal antibodies (e.g. casirivimab/imdevimab, sotrovimab, tixagevimab–cilgavimab), became available from November 2020[12] and subsequently negated the need for CP. However, frequent mutations in the virus have rendered these monoclonal antibodies ineffective against new variants.[13] The time required to develop new monoclonal antibodies makes it difficult to keep up with evolving variants. In contrast, CP can adapt over time, as donors are exposed to new variants and vaccinations. In this issue of SMJ, Tay et al.[14] reported on Singapore’s experience in using CP for COVID-19 patients during the first year of the pandemic, as part of the country’s national expanded access (investigational therapy) programme. The study involved 27 plasma donors and seven recipients, most of whom were severely or critically ill and required mechanical ventilation, including five who required proning. These patients received CP early, between the 6th and 11th day of their illness. All except one were alive at 28 days. A large US national registry study showed that transfusion of high-antibody titre CP was associated with a lower risk of death compared to low-antibody titre plasma.[15] In the subgroup analyses, there was no mortality benefit for patients on mechanical ventilation,[15] suggesting that the effectiveness of CP is the greatest when administered early in the disease and when high titres of neutralising antibodies are used. Given the availability of antivirals, widespread vaccinations and hybrid immunity, the role of CP is likely limited to the severely immunocompromised patient. However, some questions remain unanswered. For instance, what is the optimal level of neutralising antibodies, and what is the best dosing strategy? Would Vax-plasma with hybrid immunity be more effective? The theoretical benefit needs to be tested in a well-designed randomised control trial, which will likely not be performed this late into the pandemic. Despite the above uncertainties, severely immunocompromised patients have reasons to remain hopeful. This is because Singapore now has the expertise to develop some form of early treatment for novel pathogens, particularly in managing future pandemics before vaccines (for which they may be poor responders) and other treatments (which they may not tolerate) become available.