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ImportanceImmune dysregulation contributes to poorer outcomes in COVID-19.ObjectiveTo investigate whether abatacept, cenicriviroc, or infliximab provides benefit when added to standard care for COVID-19 pneumonia.Design, Setting, and ParticipantsRandomized, double-masked, placebo-controlled clinical trial using a master protocol to investigate immunomodulators added to standard care for treatment of participants hospitalized with COVID-19 pneumonia. The results of 3 substudies are reported from 95 hospitals at 85 clinical research sites in the US and Latin America. Hospitalized patients 18 years or older with confirmed SARS-CoV-2 infection within 14 days and evidence of pulmonary involvement underwent randomization between October 2020 and December 2021.InterventionsSingle infusion of abatacept (10 mg/kg; maximum dose, 1000 mg) or infliximab (5 mg/kg) or a 28-day oral course of cenicriviroc (300-mg loading dose followed by 150 mg twice per day).Main Outcomes and MeasuresThe primary outcome was time to recovery by day 28 evaluated using an 8-point ordinal scale (higher scores indicate better health). Recovery was defined as the first day the participant scored at least 6 on the ordinal scale.ResultsOf the 1971 participants randomized across the 3 substudies, the mean (SD) age was 54.8 (14.6) years and 1218 (61.8%) were men. The primary end point of time to recovery from COVID-19 pneumonia was not significantly different for abatacept (recovery rate ratio [RRR], 1.12 [95% CI, 0.98-1.28]; P = .09), cenicriviroc (RRR, 1.01 [95% CI, 0.86-1.18]; P = .94), or infliximab (RRR, 1.12 [95% CI, 0.99-1.28]; P = .08) compared with placebo. All-cause 28-day mortality was 11.0% for abatacept vs 15.1% for placebo (odds ratio [OR], 0.62 [95% CI, 0.41-0.94]), 13.8% for cenicriviroc vs 11.9% for placebo (OR, 1.18 [95% CI 0.72-1.94]), and 10.1% for infliximab vs 14.5% for placebo (OR, 0.59 [95% CI, 0.39-0.90]). Safety outcomes were comparable between active treatment and placebo, including secondary infections, in all 3 substudies.Conclusions and RelevanceTime to recovery from COVID-19 pneumonia among hospitalized participants was not significantly different for abatacept, cenicriviroc, or infliximab vs placebo.Trial RegistrationClinicalTrials.gov Identifier: NCT04593940

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The D-dimer fragment of fibrin degradation has been a useful adjunct in the diagnosis of venous thromboembolism (VTE). In conjunction with predictive algorithms, the high negative predictive value (NPV) of D-dimer measurements has provided this analyte with a prominent position in the diagnosis of pulmonary embolism (PE). The purpose of this study was to determine if D-dimer levels correlate with ventilation/perfusion (V/Q) derangements as assessed by the alveolar-arterial oxygen tension gradient (DeltaA-a) and to ascertain if quantitative measurements of D-dimer on admission have prognostic value in terms of during-admission mortality and recurrence over a 60-week period. The study utilized a retrospective cohort of 108 subjects admitted to a single institution and studied longitudinally. The cohort was divided into 4 groups representing degree of severity assessed by computed tomographic (CT) angiography: mild, moderate, severe, and very severe. Differences in D-dimer levels among these groups were strongly significant (P < .0001). A strong correlation was observed between D-dimer concentration and DeltaA-a (P < .0001). Logistic methods were used to calculate a "cut-off" level that would distinguish mild-moderate from severe-very severe PE. At a concentration of 12.35 mug/mL, this level yielded an odds ratio (OR) of 12.64 (P = .006) for during-admission mortality and a hazard ratio (HR) of 0.13 (P < .0001) for 60-week recurrence. These data suggest that D-dimer levels have utility beyond their NPV and should be considered as potential prognostic markers in subjects presenting with acute PE.

Background: We investigated whether abatacept, a selective costimulation modulator, provides additional benefit when added to standard-of-care for patients hospitalized with Covid-19. Methods: We conducted a master protocol to investigate immunomodulators for potential benefit treating patients hospitalized with Covid-19 and report results for abatacept. Intravenous abatacept (one-time dose 10 mg/kg, maximum dose 1000 mg) plus standard of care (SOC) was compared with shared placebo plus SOC. Primary outcome was time-to-recovery by day 28. Key secondary endpoints included 28-day mortality. Results: Between October 16, 2020 and December 31, 2021, a total of 1019 participants received study treatment (509 abatacept; 510 shared placebo), constituting the modified intention-to-treat cohort. Participants had a mean age 54.8 (SD 14.6) years, 60.5% were male, 44.2% Hispanic/Latino and 13.7% Black. No statistically significant difference for the primary endpoint of time-to-recovery was found with a recovery-rate-ratio of 1.14 (95% CI 1.00-1.29; p=0.057) compared with placebo. We observed a substantial improvement in 28-day all-cause mortality with abatacept versus placebo (11.0% vs. 15.1%; odds ratio [OR] 0.62 [95% CI 0.41-0.94]), leading to 38% lower odds of dying. Improvement in mortality occurred for participants requiring oxygen/noninvasive ventilation at randomization. Subgroup analysis identified the strongest effect in those with baseline C-reactive protein >75mg/L. We found no statistically significant differences in adverse events, with safety composite index slightly favoring abatacept. Rates of secondary infections were similar (16.1% for abatacept; 14.3% for placebo). Conclusions: Addition of single-dose intravenous abatacept to standard-of-care demonstrated no statistically significant change in time-to-recovery, but improved 28-day mortality. Trial registration: ClinicalTrials.gov (NCT04593940).