Background Calcium release-activated calcium (CRAC) channel inhibitors block proinflammatory cytokine release, preserve endothelial integrity and may effectively treat patients with severe COVID-19 pneumonia. Methods CARDEA was a phase 2, randomized, double-blind, placebo-controlled trial evaluating the addition of Auxora, a CRAC channel inhibitor, to corticosteroids and standard of care in adults with severe COVID-19 pneumonia. Eligible patients were adults with ≥ 1 symptom consistent with COVID-19 infection, a diagnosis of COVID-19 confirmed by laboratory testing using polymerase chain reaction or other assay, and pneumonia documented by chest imaging. Patients were also required to be receiving oxygen therapy using either a high flow or low flow nasal cannula at the time of enrolment and have at the time of enrollment a baseline imputed PaO2/FiO2 ratio > 75 and ≤ 300. The PaO2/FiO2 was imputed from a SpO2/FiO2 determine by pulse oximetry using a non-linear equation. Patients could not be receiving either non-invasive or invasive mechanical ventilation at the time of enrolment. The primary endpoint was time to recovery through Day 60, with secondary endpoints of all-cause mortality at Day 60 and Day 30. Due to declining rates of COVID-19 hospitalizations and utilization of standard of care medications prohibited by regulatory guidance, the trial was stopped early. Results The pre-specified efficacy set consisted of the 261 patients with a baseline imputed PaO2/FiO2≤ 200 with 130 and 131 in the Auxora and placebo groups, respectively. Time to recovery was 7 vs. 10 days (P = 0.0979) for patients who received Auxora vs. placebo, respectively. The all-cause mortality rate at Day 60 was 13.8% with Auxora vs. 20.6% with placebo (P = 0.1449); Day 30 all-cause mortality was 7.7% and 17.6%, respectively (P = 0.0165). Similar trends were noted in all randomized patients, patients on high flow nasal cannula at baseline or those with a baseline imputed PaO2/FiO2 ≤ 100. Serious adverse events (SAEs) were less frequent in patients treated with Auxora vs. placebo and occurred in 34 patients (24.1%) receiving Auxora and 49 (35.0%) receiving placebo (P = 0.0616). The most common SAEs were respiratory failure, acute respiratory distress syndrome, and pneumonia. Conclusions Auxora was safe and well tolerated with strong signals in both time to recovery and all-cause mortality through Day 60 in patients with severe COVID-19 pneumonia. Further studies of Auxora in patients with severe COVID-19 pneumonia are warranted. Trial registration NCT04345614.

IMPORTANCEThe monoclonal antibody combination of casirivimab and imdevimab reduced viral load, hospitalization, or death when administered as a 1200-mg or greater intravenous (IV) dose in a phase 3 COVID-19 outpatient study. Subcutaneous (SC) and/or lower IV doses should increase accessibility and/or drug supplies for patients. OBJECTIVE To assess the virologic efficacy of casirivimab and imdevimab across different IV and SC doses compared with placebo. DESIGN, SETTING, AND PARTICIPANTS This phase 2, randomized, double-blind, placebocontrolled, parallel-group, dose-ranging study included outpatients with SARS-CoV-2 infection at 47 sites across the United States. Participants could be symptomatic or asymptomatic; symptomatic patients with risk factors for severe COVID-19 were excluded. Data were collected from December 15, 2020, to March 4, 2021. INTERVENTIONS Patients were randomized to a single IV dose (523 patients) of casirivimab and imdevimab at 300, 600, 1200, or 2400 mg or placebo; or a single SC dose (292 patients) of casirivimab and imdevimab at 600 or 1200 mg or placebo. MAIN OUTCOMES AND MEASURES The primary end point was the time-weighted average daily change from baseline (TWACB) in viral load from day 1 (baseline) through day 7 in patients seronegative for SARS-CoV-2 at baseline. RESULTS Among 815 randomized participants, 507 (282 randomized to IV treatment, 148 randomized to SC treatment, and 77 randomized to placebo) were seronegative at baseline and included in the primary efficacy analysis. Participants randomized to IV had a mean (SD) age of 34.6 (9.6) years (160 [44.6%] men; 14 [3.9%] Black; 121 [33.7%] Hispanic or Latino; 309 [86.1%] White); those randomized to SC had a mean age of 34.1 (10.0) years (102 [45.3%] men; 75 [34.7%] Hispanicor Latino; 6 [2.7%] Black; 190 [84.4%] White). All casirivimab and imdevimab treatments showed significant virologic reduction through day 7. Least-squares mean differences in TWACB viral load for casirivimab and imdevimab vs placebo ranged from -0.56 (95% CI; -0.89 to -0.24) log 10 copies/mL for the 1200-mg IV dose to -0.71 (95% CI, -1.05 to -0.38) log 10 copies/mL for the 2400-mg IV dose. There were no adverse safety signals or dose-related safety findings, grade 2 or greater infusionrelated or hypersensitivity reactions, grade 3 or greater injection-site reactions, or fatalities. Two serious adverse events not related to COVID-19 or the study drug were reported.

Background SARS-CoV-2 is known to induce a cytokine storm, a hyperinflammatory state driven by up-regulation of interleukin 6 (IL-6) and immunomodulatory chemokines that may result in acute heart failure. Case summary A 65-year-old woman with confirmed SARS-CoV-2 developed shock with multiorgan system failure, including acute biventricular heart failure, 2 weeks after the initial onset of fever, cough, and shortness of breath. The patient experienced myocardial recovery within 48 h after administration of tocilizumab, a humanized monoclonal anti-IL-6 receptor antibody, and multiple supportive vasoactive medications. Discussion The differential diagnosis of acute heart failure in critically ill patients with COVID-19 infection is broad, including sepsis-induced cardiomyopathy, Takotsubo syndrome, viral lymphocytic myocarditis, and acute coronary syndrome. Immunomodulatory treatment with tocilizumab may benefit patients who develop cardiogenic shock associated with SARS-CoV-2-induced cytokine storm.

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Background The role of customary diet and physical activity in development of advanced HCV-related liver disease is not well-established. Methods We conducted a retrospective association study in 91 male veterans with PCR-confirmed chronic HCV and biopsy-determined hepatic pathology. Respondents completed the Block Food Frequency and the International Physical Activity questionnaires. We conducted three independent assessments based on hepatic pathology: fibrosis (advanced=F3-F4 vs. mild=F1-F2), inflammation (advanced=A2-A3 vs. mild=A1) and steatosis (advanced=S2-S3 vs. mild=S1). Each assessment compared estimated dietary intake and physical activity in veterans with advanced disease to that in analogous veterans with mild disease. Multivariate models adjusted for total calories, age, race/ethnicity, biopsy-to-survey lag-time, BMI, pack-years smoking, and current alcohol use. Results Average veteran age was 52, with 48% African-American. Advanced fibrosis was more prevalent than advanced inflammation or steatosis (52.7% vs. 29.7% vs. 26.4% respectively). The strongest multivariate association was the suggestive 14-fold significantly decreased advanced fibrosis risk with lowest dietary copper intake (OR=0.07, 95% CI 0.01–0.60). Other suggestive associations included the 6.5-fold significantly increased advanced inflammation risk with lower vitamin E intake and 6.2-fold significantly increased advanced steatosis risk with lower riboflavin intake. The only physical activity associated with degree of hepatic pathology was a 2-fold greater weekly MET-minutes walking in veterans with mild compared to advanced steatosis (p=0.02). Conclusions Several dietary factors and walking may be associated with risk of advanced HCV-related liver disease in male veterans. However, given our modest sample size, our findings must be considered as provisional pending verification in larger prospective studies.