Role of convalescent plasma in the treatment of COVID-19

Between March and June 2020, there were 203,000 cases and 18,600 deaths due to COVID-19. These were scary times, marked by the consternation of physicians and public-health officials alike. With no effective therapies, experts pinned their hopes on COVID-19 convalescent plasma (CCP) due to historical successes of this intervention in addressing prior pandemics and positive results from randomized, controlled trials for diphtheria and Argentine hemorrhagic fever.

Early matched-controlled studies suggested decreased death rates after treatment of patients with COVID-19 with CCP, but since then, randomized, controlled trials have yielded mixed results A closer examination is warranted.

Recent clinical trials

 The CONTAIN COVID-19 trial  was a randomized, double-blind, placebo-controlled trial of CCP reported in December 2021. For this study, involving 941 patients, researchers tested the efficacy of a unit of 250 ml of CCP vs placebo in patients with COVID-19 who were hospitalized for 3 days or fewer or presented 7 days or fewer after symptom onset and needed oxygen supplementation.

Results of CONTAIN COVID-19 did not meet the definitions of CCP efficacy. Nevertheless, potential benefit was exhibited early during the pandemic when high-titer CCP was administered at a time when corticosteroids and remdesivir were not in use.

“This supports the concept that convalescent plasma may be a feasible treatment option at the beginning of a pandemic or when other therapies are not in use or available,” concluded the authors. “Further investigation is needed to understand the effects of corticosteroids and remdesivir on CCP efficacy and establish thresholds for antibody quantity and function that are most likely to confer a benefit.”

In issuing its guidance on the topic, the NIH cited results from the three largest randomized trials assessing the use of CCP in hospitalized patients. All three open-label trials ended early due to futility. 

In the RECOVERY trial, researchers randomized patients to receive either convalescent plasma or usual care. No differences were seen in the primary outcome of 28-day mortality, nor in the secondary endpoints of time to hospital discharge and receipt of mechanical ventilation/death.   

Similarly, in the CONCOR-1 trial, investigators randomized patients to receive convalescent plasma or standard of care. The primary outcome was intubation or death by Day 30. This outcome occurred in 32% of patients receiving convalescent plasma vs 28% of patients receiving standard of care.

Other measures did not vary between groups, such as time to intubation/death, mortality, or intensive care unit and hospital length of stay. Severe adverse events were experienced by 33% of patients receiving convalescent plasma vs 26% receiving standard of care. Notably, 35 transfusion-related complications occurred in those receiving convalescent plasma.

In the REMAP-CAP trial, researchers found that there were no differences in organ-support-free days in critically ill patients up to Day 21 in those receiving CCP vs controls. Furthermore, no differences in in-hospital mortality were observed. Results of the study exhibited the potential for harm in those receiving CCP after 7 days of hospitalization.

Recommendations

The rationale for the use of CCP is  that plasma taken from donors who have recovered from COVID-19 could harbor antibodies to SARS-CoV-2, which could inhibit viral replication. Based on this hypothesis, in August 2020, the FDA issued Emergency Use Authorization (EUA) for CCP to treat hospitalized patients with COVID-19.

In February 2021, this guidance was changed to permit authorization only for high-titer CCP in patients with COVID-19 early in their clinical trajectory or in hospitalized patients who exhibit impaired immunity. 

The EUA for convalescent plasma was related to retrospective, indirect assessments of efficacy which didn’t consider titer. Ultimately, this data proved insufficient to support the efficacy and safety of CCP due to confounding variables, lack of randomization, and the absence of control groups.

Currently, the COVID-19 Treatment Guidelines Panel advises against the use of CCP in treating COVID-19 in hospitalized patients with impaired humoral immunity. Moreover, the Panel notes insufficient evidence to advise whether to use CCP to treat COVID-19 in nonhospitalized patients without impaired humoral immunity or in either nonhospitalized or hospitalized patients who do have impaired humoral immunity.

In the 7th update of their living guidelines on COVID-19 therapeutics, the WHO noted that CCP does not enhance survival or reduce the need for mechanical ventilation; in fact. This assessment was made based on pooled data representing 16 randomized, controlled trials involving 16,236 patients with non-severe, severe, and critical COVID-19 infection.

“While the evidence that convalescent plasma has no benefit in non-severe patients was certain, it was less so in the case of severe and critically ill patients,” per the WHO. “So, randomized clinical trials for these subgroups should continue.”

Sources

Convalescent plasma. NIH. COVID-19 treatment guidelines. December 16, 2021.

Ortigoza MB. Efficacy and safety of COVID-19 convalescent plasma in hospitalized patients. A randomized clinical trial. JAMA Intern Med 2022;182(2):115-126.

WHO recommends against the use of convalescent plasma to treat COVID-19 [news release]. WHO. December 7, 2021.