By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University

SYNOPSIS: Administration of convalescent plasma obtained from survivors of COVID-19 within 72 hours of onset of mild symptoms in elderly patients with COVID-19 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 underwent randomization to receive a single infusion of either 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 that patients were symptomatic for  72 hours and were either 65-74 years of age with one of a series of specified comorbid conditions or were > 75 years of age with or without a comorbid condition. There were several exclusion criteria, including, e.g., 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 of the trial was the develop-ment of severe respiratory disease, defined as a respiratory rate 30 breaths per minute, an oxygen saturation < 93% while breathing ambient air, or both. A power analysis had estimated a requirement to enroll a total of 210 patients to achieve an 80% power to detect a difference between treatment groups at an α = 0.05. Enrollment was discontinued after only 76% of the target population was enrolled as the local epidemic waned.

The mean age of the cohort was 77.2 ± 8.6 years (55% were 75 years of age) and 60% were women; approximately four-fifths of the cohort had comorbidities. In an intent-to-treat analysis, severe respiratory disease occurred in 13 (16%) of 80 patients assigned convalescent plasma and 25 (31%) of 80 patients assigned placebo, resulting in a calculated relative risk of 0.52 (95% confidence interval [CI], 0.29 to 0.94; P = 0.03). This represented a 48% risk reduction and a number needed to treat of 7. In modified intent-to-treat analysis that excluded six patients who reached the primary end point prior to receiving their designated infusion, relative risk favoring plasma was 0.40 (95% CI, 0.20 to 0.81). The response was greater in those who received plasma with the highest antibody titers. No adverse reactions were observed.

COMMENTARY

This study provides evidence that 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 very large 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 and colleagues pointed out that those studies enrolled adults as young as 18 years of age and that the median duration of symptoms prior to 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 was halted 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 that seen with convalescent plasma in the study reviewed here. In their trials, however, they were administered to a population that was as young as 18 years of age, and could be affected by a variety of comorbidities. In addition, the participants received their infusions after a median duration of symptoms of 4.0 days and 3.0 days — meaning that more than half of 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 that 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 study by Libster and colleagues. Furthermore, their results may provide lessons for the use of monoclonals until there is more direct evidence related to the use of these products. Among these is that there is a greater likelihood of benefit the earlier the infusion is administered. This knowledge would be especially useful in circumstances of shortage, as currently exist. 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 have little or no benefit if the virus is no longer replicating, something that can be determined using a polymerase chain reaction (PCR) test specific for negative-strand ribonucleic acid (RNA).