Convalescent plasma reduced mortality in COVID-19 patients with acute respiratory distress syndrome (ARDS) when provided within 5 days of invasive mechanical ventilation, the randomized open-label CONFIDENT trial showed.
Mortality at 28 days was 35.4% among patients who received donated convalescent plasma with at least 1:160 neutralizing antibody titer, compared with 45% in patients who received standard care (P=0.03), reported Benoît Misset, MD, of University Hospital of Liège at the Domaine Universitaire du Sart Tilman in Belgium, and colleagues in the New England Journal of Medicine. The effect primarily occurred in patients who were randomized within 48 hours after initiation of invasive mechanical ventilation.
“The survival curves in both the overall population and the patients who underwent randomization 48 hours or less after ventilation initiation separated near day 17,” the authors reported. “Among the secondary outcomes, the results for inflammation, vasopressor support, and the number of adverse events tended to be better in the convalescent-plasma group.”
Todd Rice, MD, MSc, of Vanderbilt University School of Medicine, who was not involved in the study, was surprised by the findings, noting that numerous previous studies of convalescent plasma, including his own, did not show much benefit in patients hospitalized with COVID-19.
“The study suggests that convalescent plasma might be one treatment option in the sickest patients with COVID, especially in ones who there is concern that they have not mounted an adequate immune response and do not already have their own antibodies against COVID,” Rice told MedPage Today. “Mortality is a really hard outcome to improve, especially in patients who are already sick enough to need a ventilator. These findings will make us reconsider convalescent plasma in our patients.”
He added, however, that the study occurred in patients during earlier phases of COVID with “variants that act a bit differently than the variants that we are seeing today,” and that most participants were not vaccinated against COVID. “So it is not clear if this therapy will work for vaccinated patients – who may have already produced their own antibodies to the vaccine – or in patients who have antibodies from prior infections,” he said.
An estimated 20-25% of patients hospitalized with COVID-19 had been admitted to ICU during the early part of the pandemic, and 70% of them received invasive mechanical ventilation, according to a 2021 study, the authors noted. Mortality for COVID-19 patients receiving invasive mechanical ventilation in the ICU hovered around 45% in a separate 2021 meta-analysis.
To assess the effect of convalescent plasma in patients like these, researchers enrolled 475 patients from 17 sites in Belgium from September 2020 to March 2022. The patients had an average age of 64, and two-thirds were male. Vaccination rates were 11.4% in the plasma group and 8% in the control group. Rates of hypertension, congestive heart failure, diabetes, COPD, asthma, chronic renal failure and cancer did not statistically differ between groups.
All the patients had been admitted to an ICU with COVID-19-induced ARDS and had received invasive mechanical ventilation for no more than 5 days. Only patients with a Clinical Frailty Score less than 6 (range 1-9) were included, and COVID-19-induced ARDS was defined as “extended interstitial pneumonia on a computed tomographic scan or a chest radiograph within 10 days before inclusion and a positive result of a clinical SARS-CoV-2 nasopharyngeal polymerase-chain-reaction (PCR) test within 15 days before inclusion.”
The convalescent plasma donors had a previous SARS-CoV-2 infection and had fully recovered between 28 days to 10 months earlier. Although the researchers sought to use plasma with a 1:320 antibody titer ratio, they accepted a 1:160 ratio during shortages for 17.7% of the plasma group.
Most patients (57.5%) had moderate ARDS, with 9.9% classified with mild ARDS and 32.4% with severe ARDS. Around 6% in both groups received remdesivir (Veklury), and nearly all the patients (around 98%) received glucocorticoids. Enrollment included 41.4% of patients when the ancestral virus was circulating, 34.3% during the Alpha wave, 20.8% during Delta, and 3.4% during Omicron.
Most participants (72%) were randomized within 48 hours of invasive mechanical ventilation, and they were evenly distributed in the intervention and control groups. All of the 237 patients randomized to receive two units of convalescent plasma received it except one who died before infusion began. None of the 238 patients in the standard care group received plasma.
Mortality rates of 35.4% in the plasma group and 45% in the standard care group were significantly different both before and after accounting for the better outcomes in those who were randomized within 48 hours of ventilation. For only those randomized within 48 hours of ventilation, mortality was 32.7% in the plasma group and 46.8% in the standard care group. However, mortality was 42% in the plasma group and 40% in the standard care group among those randomized more than 48 hours after ventilation. Titer levels of the plasma were not associated with mortality.
No adverse effects were attributed to the plasma, and secondary bacteremia, pneumonia, organ support duration, and length of hospital stay did not differ between the groups. A greater effect occurred among patients with a higher Sequential Organ Failure Assessment (SOFA) score.
Aside from uncertainty about the findings’ generalizability to vaccinated and previously infected patients, Rice noted that convalescent plasma is difficult to obtain given the timing needs in donors.
“Patients who donate have to be recovered from their infection with COVID, but not so long after that their antibody levels have decreased, so we have to find patients between 1 and 6 months after they recover from their COVID,” Rice said. “Then we have to make sure that they have a high enough level of the antibodies to be able to pass along immunity.”
Most U.S. blood banks have stopped offering convalescent plasma because of the difficulty of finding donors and past studies’ disappointing results, Rice said, but “this trial will likely result in some blood banks starting to offer convalescent plasma again.”
The research was funded by the Belgian Health Care Knowledge Center.
Study authors reported relationships with Boehringer Ingelheim, Merck, Roche, ViiV Healthcare Company, Grand Medical Pty Ltd, Transgene SA, and AM Pharma.
Rice had no disclosures.
New England Journal of Medicine
Source Reference: Misset B, et al “Convalescent plasma for Covid-19-induced ARDS in mechanically ventilated patients ” N Engl J Med 2023; DOI: 10.1056/NEJMoa2209502