Convalescent plasma cuts death in mechanically ventilated patients with COVID-19-induced ARDS

In the CONFIDENT trial, convalescent plasma (CCP) conferred a mortality benefit for patients with COVID-19-induced acute respiratory distress syndrome (ARDS) who were on invasive mechanical ventilation (IMV).

“In this trial involving patients with COVID-19-induced ARDS admitted to the intensive care unit (ICU), the administration of CCP with neutralizing antibody (nAb) titres of at least 1:160 against SARS-CoV-2 early after IMV initiation reduced mortality at day 28,” said the researchers.

Day 28 saw a lower mortality in the CCP arm than the standard-care arm (35.4 percent vs 45.0 percent; p=0.03). This effect was mirrored on prespecified analysis, mainly among patients who underwent randomization ≤48 hours after IMV initiation (32.7 percent vs 46.8 percent). [N Engl J Med 2023;389:1590-1600]

The 45-percent mortality in the standard-care arm correlates with that observed in previous trials, the researchers noted. “This high mortality may be due to the age of the population and the direct nature of the pulmonary injury.” [Chest 2017;151:755-763]

There were 711 adverse events (AEs) reported, 209 of which were classified as serious. About 90 percent of the 209 serious AEs were considered fatal. “All 711 AEs were attributed to COVID-19 or complications of organ support, and none were directly attributed to CCP,” the researchers said. The incidence of serious AEs was numerically lower in the CCP vs the standard-care arm (n=93 vs 116).

Passive immunization with CCP

Seventy percent of ICU-admitted COVID-19 patients have received IMV for ARDS, and mortality in the ICU among COVID-19 patients receiving IMV was nearly 50 percent. [PLoS One 2021;16: e0246318; Am J Respir Crit Care Med 2021;203:54-66 ] CCP reportedly provides passive immunization to COVID-19 patients, but data on its use in patients with COVID-19-induced ARDS receiving IMV remain scarce. [JAMA 2020;323:1582-1589]

“We conducted the CONFIDENT trial to test the hypothesis that passive immunization with CCP with a nAb titre of at least 1:320 would cut mortality when administered early after the initiation of IMV in [this patient subgroup],” the researchers said.

This open-label trial included 475 adult patients (median age 64 years, 68 percent male) with COVID-19-induced ARDS who had been receiving IMV for <5 days in 17 sites in Belgium. Participants were randomized from September 2020 through March 2022 (during the predominance of the ancestral virus, B.1.1.7, B.1.617.2, and B.1.1.529 variants in Belgium) 1:1 to receive either CCP with a nAb titre of at least 1:320 or standard care alone.

Thirty-nine and 32 percent of CCP recipients were given CCP with nAb titres of 1:320 and 1:640, respectively. Due to CCP shortage, about 18 percent of CCP recipients were administered a nAb titre of 1:160. More than half (58 percent) of the ARDS cases were moderate, 32 percent were severe, while 10 percent were mild. Almost all participants received glucocorticoids.

“Our interpretation of the [mortality benefit] is that CCP is directed against the cause of COVID-19-induced ARDS in patients receiving IMV. CCP may reduce the quantity of virus alive in the lungs of patients who continue to shed the virus,” the researchers explained. [Crit Care 2020;24:610; Clin Infect Dis 2022;75:e82-e88]

“We believe our trial has a good potential for generalizability to most patients with COVID-19-induced ARDS, because almost 50 percent of such patients were included in the centres during their participation in the trial,” they said.

However, the results should still be confirmed in patients with ARDS induced by COVID-19 variants other than what they’ve studied, the researchers pointed out. “The reduced virulence of new variants may limit the immediate effect of our results, but future SARS-CoV-2 variants with increased virulence may occur.”