By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University

SYNOPSIS: Administering convalescent plasma obtained from survivors of COVID-19 within 72 hours of onset of mild symptoms in elderly patients with the virus was associated with a significant reduction in the risk of development of severe respiratory disease.

SOURCE: Libster R, Pérez Marc G, Wappner D, et al; Fundación INFANT–COVID-19 Group. Early high-titer plasma therapy to prevent severe Covid-19 in older adults. N Engl J Med 2021; Jan 6. doi: 10.1056/NEJMoa2033700. [Online ahead of print].

In this clinical trial performed in Argentina, 160 patients with COVID-19 were randomized to a single infusion of convalescent plasma that had been obtained with high titers (> 1:1,000) of immunoglobulin G (IgG) antibody to SARS-CoV-2 spike protein from individuals who had recovered from COVID-19 or a normal saline placebo. Study entry required patients to be symptomatic for 72 hours or fewer and were either age 65-74 years with one of a series of specified comorbid conditions or were older than age 75 years with or without a comorbid condition. There were several exclusion criteria, including severe respiratory disease, primary hypogammaglobulinemia, lymphoproliferative disorders, cancer with treatment in the previous six months, immunosuppressive therapy, solid organ transplant, chronic liver or lung disease, and receipt of anticoagulants.

The primary endpoint was the development of severe respiratory disease, defined as a respiratory rate 30 breaths or more per minute, an oxygen saturation < 93% while breathing ambient air, or both. A power analysis estimated a requirement to enroll 210 patients to achieve an 80% power to detect a difference between treatment groups at an α = 0.05. The authors ended enrollment after only 76% of the target population joined the trial as the local epidemic waned. The mean age was 77.2 ± 8.6 years (55% were 75 years of age) and 60% were women; approximately four-fifths of the cohort presented with comorbidities. In an intent-to-treat analysis, severe respiratory disease occurred in 13 of 80 patients assigned convalescent plasma and 25 of 80 patients assigned placebo, resulting in a calculated relative risk of 0.52 (95% CI, 0.29-0.94; P = 0.03). This represented a 48% risk reduction and a number needed to treat of 7. In a modified intent-to-treat analysis that excluded six patients who reached the primary endpoint before receiving their designated infusion, relative risk favoring plasma was 0.40 (95% CI, 0.20-0.81). The response was greater in those who received plasma with the highest antibody titers. No adverse reactions were observed.

COMMENTARY

This study shows a highly selected group of patients with COVID-19 benefit from receipt of convalescent plasma. These include patients with mild symptoms of no more than 72 hours duration who were > 75 years of age and/or 65-74 years of age with limited specified comorbidities. It excluded patients with a long list of other comorbidities, a factor that significantly limits the applicability of the results.

The results also may be considered possibly surprising based on prior published experience. Thus, in a supplementary appendix, the authors listed five previous randomized, controlled trials that enrolled between 81 and 333 patients and that failed to demonstrate benefit from administration of convalescent plasma in the treatment of patients with COVID-19. However, Libster et al noted those studies enrolled adults as young as age 18 years and the median duration of symptoms before enrollment in these studies ranged from eight to 30 days. In addition, the evaluation of convalescent plasma in COVID-19 patients admitted to intensive care as part of the REMAP-CAP adaptive trial ended recently because of futility.

In contrast to these negative results, the apparent benefit of monoclonal antibodies, bamlanivimab as well as the combination of casirivimab and imdevimab, is more modest than seen with convalescent plasma in the study reviewed here. However, in their trials, they were administered to a population that was as young as age 18 years and could be affected by a variety of comorbidities. Further, the participants received their infusions after a median duration of symptoms of four days and three days, meaning more than half the subjects would not have been eligible for the convalescent plasma study, in which the plasma was administered within 72 hours of symptom onset. Of note is the emergency use authorizations for these monoclonals allow for infusion to patients with symptom durations as long as 10 days.

Thus, convalescent plasma with high IgG antibody titers should be considered for administration to patients who match the entry/exclusion criteria in the Libster et al study. Furthermore, their results may provide lessons for using monoclonals until there is more direct evidence related to the use of these products. Among these is the greater likelihood of benefit the earlier the infusion is administered. This knowledge would be especially useful in circumstances of shortage. It also is apparent from the study evaluating casirivimab/imdevimab that patients who lack antibody at the time of intervention are most likely to benefit, but this would require the availability of an antibody test with rapid turnaround time.

Another factor that has not been evaluated in this context relates to the usual disappearance of viable (replication competent) SARS-CoV-2 after approximately eight days, at least in patients without severe immunocompromise. Presumably, antibody administration would produce little or no benefit if the virus is no longer replicating, something that can be determined using a polymerase chain reaction test specific for negative-strand ribonucleic acid.