Convalescent Plasma Fails to Prevent COVID-19 Progression in High-Risk Outpatients

Convalescent plasma is one of the most accessible treatments for emerging infectious diseases, but the key to unlocking its potential for the treatment of COVID-19 remains elusive.

A recent study found no clinical benefit of high-titer convalescent plasma administered to high-risk outpatients within a week of symptom onset.

The study, published in the New England Journal of Medicine, included 511 patients aged 50 or older with one or more risk factors for disease progression who were treated for COVID-19 at an emergency department within seven days of symptom onset.

The COVID-19 Convalescent Plasma in Outpatients (C3PO) trial was performed by the Strategies to Innovate Emergency Care Clinical Trials Network (SIREN). Among those enrolled at 48 hospitals in 21 states from August 2020 to February 2021, 257 received one unit of convalescent plasma with a high titer of antibodies and 254 received a placebo.

“In this randomized, controlled trial, infusion of high-titer COVID-19 convalescent plasma within 7 days after symptom onset did not prevent the progression of COVID-19 in patients at high risk for severe disease,” the study authors, led by Frederick K. Korley, MD, PhD, of the University of Michigan, wrote.

The primary outcome of disease progression within 15 days—defined as a composite of hospital admission for any reason, seeking emergency or urgent care, or death without hospitalization—occurred among 77 patients (30%) in the treatment group and in 81 patients (31.9%) in the placebo group (risk difference, 1.9 percentage points; 95% credible interval, −6.0 to 9.8; posterior probability of superiority, 0.68).

Death within 30 days occurred in five patients in the treatment group and one in the placebo group. Causes of death were pneumonia, hypoxia, respiratory failure and pulmonary embolism, and no deaths were considered to be related to the treatment product.

The study also found no statistically significant difference in secondary outcomes, which included disease severity, hospital-free days within 30 days and all-cause mortality. Three patients in the treatment group experienced serious infusion reactions.

All patients were stable for outpatient treatment. The median age was 54 and 54% of participants were women. Enrollment was stopped on Feb. 25, when a priori stopping threshold was met.

The study is consistent with other research that has shown that convalescent plasma hasn’t improved clinical outcomes. Among several studies casting doubt on the treatment, a recent study published in the journal Nature Medicine showed that patients hospitalized with COVID-19 who received convalescent plasma did not see a reduction in the risk of intubation or mortality.

However, some observational studies have shown convalescent plasma to be associated with improved outcomes.

The US Food and Drug Administration issued Emergency Use Authorization for convalescent plasma in August 2020 based on evidence suggesting it may be beneficial to patients, including research showing reduced disease progression among patients who received convalescent plasma within 72 hours of symptom onset. The authorization had been delayed because of lingering questions about efficacy of the treatment. The EUA was updated early this year to exclude the use of low-titer plasma.

More than 96% of convalescent plasma units used in the C3PO trial met high-titer levels with 50% inhibitory dilution (ID50) of 1:250 or more, the median ID50 was 641, and the study found no association between the antibody titer and disease progression.

Authors of the C3PO trial said the treatment still may be beneficial in certain cases, and more research is needed.

“Convalescent plasma may still play a role if it is administered before the development of native antibodies,” the authors wrote. “The treatment may also be efficacious in preventing symptomatic COVID-19 after exposure.”

They pointed out potential factors that may have limited the efficacy of the treatment in the trial, including insufficient doses, the timing of infusion and the selection of patients.

“Data regarding viral genotypes were not collected during this trial, and new variants emerged during the period of enrollment,” the authors wrote. “Future studies may also consider whether convalescent plasma that is collected during different epochs and from different geographic locations during a pandemic will have different therapeutic potentials.”