Early convalescent plasma fails to prevent COVID-19 progression in high-risk outpatients
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COVID-19 convalescent plasma administered within 7 days of symptom onset did not appear to prevent disease progression among high-risk outpatients with COVID-19, according to study results published in The New England Journal of Medicine.
“Administering convalescent plasma from patients who have recovered from an infection has been a strategy for treating patients newly infected for more than 100 years, but this strategy has rarely undergone rigorous testing,” Clifton W. Callaway, MD, PhD, professor and executive vice-chair of emergency medicine and Ronald D. Stewart chair of emergency medicine research at University of Pittsburgh, told Healio. “Particularly in emerging infections, where no known therapeutic exists, convalescent plasma may be the first available treatment to try.”
This strategy was employed at the beginning of the COVID-19 pandemic, when many patients received convalescent plasma, Callaway added.
“We took advantage of this situation to test whether COVID-19 convalescent plasma actually reduces disease progression,” he said. “We set up our trial to test if the plasma was effective early on in the illness, when we thought it would have the best chance of working. We selected patients at risk for severe illness, including those with risk factors and/or who were aged older, so that we would have enough events to study.”
The randomized, multicenter, single-blind trial included 511 patients (median age, 54 years) with COVID-19 symptoms across 48 hospital EDs in 21 states. All patients presented to the ED within 7 days of symptom onset (median symptom duration, 4 days) and were in stable condition for outpatient management. Study participants received either one unit of convalescent plasma with high-titer antibodies against severe acute respiratory syndrome COVID-19 (n = 257; 52.5% women; 66.9% white) or placebo (n = 254; 54.7% women; 65% white). Median titer of COVID-19 neutralizing antibodies was 1:641 among the donor convalescent plasma samples.
Common risk factors for severe COVID-19 among those in the convalescent plasma group and placebo group included age 50 years or older (60.3% vs. 61%) BMI of 30 kg/m2 or greater (59.1% for both), hypertension (40.9% vs. 43.7%), current or former tobacco use (31.5% vs. 28%), diabetes (29.6% vs. 26%) and chronic obstructive pulmonary disease or asthma (21.8% vs. 26.8%).
Disease progression within 15 days after randomization served as the primary outcome. Worst severity of illness on an eight-category ordinal scale, hospital-free days within 30 days after randomization and death of any cause served as secondary outcomes.
Results showed disease progression occurred among 30% of patients in the convalescent plasma group compared with 31.9% of the placebo group, for a risk difference of 1.9 percentage points (95% CI, 6 to 9.8; posterior probability of superiority of convalescent plasma, 0.68).
Five patients who received convalescent plasma died, compared with one in the placebo group. Researchers observed similar outcomes between the convalescent plasma and placebo groups with regard to worst illness severity and mean number of hospital-free days (28.3 vs. 28.6; mean percentage-point difference, 0.3; 95% CI, 0.4 to 1.1).
“Time to worsening, worst disease severity, mortality and hospital-free days did not differ between the convalescent plasma and placebo groups, and we did not see any subgroup with differential treatment response,” Callaway said. “This was all surprising, because we expected that providing passive immunization with convalescent plasma would modify the course of the illness to some extent. These data may indicate that the severity of illness after infection is related more to the host response to the infection — how much inflammation occurs in the lung — rather than the clearance of the virus by antibodies, since most patients will generate their own antibodies throughout time.”
Future research will entail assessment of COVID-19 antibody levels after infusion among the banked plasma samples of patients in the current trial, Callaway added.
“We will examine whether convalescent plasma altered endogenous antibody response, whether baseline antibody levels modified treatment response, and to what extent the transfused plasma actually increased recipient humoral immunity,” Callaway said. “These same plasma samples also allow us to examine inflammatory responses to the infection, and whether transfusion modified this at all.”
For more information:
Clifton W. Callaway, MD, PhD, can be reached at University of Pittsburgh, 400A Iroquois, 3600 Forbes Ave., Pittsburgh, PA 15260; email: callawaycw@upmc.edu.
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