IMPORTANCE The US is currently an epicenter of the coronavirus disease 2019 (COVID-19) pandemic, yet few national data are available on patient characteristics, treatment, and outcomes of critical illness from COVID-19. OBJECTIVES To assess factors associated with death and to examine interhospital variation in treatment and outcomes for patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTS This multicenter cohort study assessed 2215 adults with laboratory-confirmed COVID-19 who were admitted to intensive care units (ICUs) at 65 hospitals across the US from March 4 to April 4, 2020. EXPOSURES Patient-level data, including demographics, comorbidities, and organ dysfunction, and hospital characteristics, including number of ICU beds. MAIN OUTCOMES AND MEASURES The primary outcome was 28-day in-hospital mortality. Multilevel logistic regression was used to evaluate factors associated with death and to examine interhospital variation in treatment and outcomes. RESULTS A total of 2215 patients (mean [SD] age, 60.5 [14.5] years; 1436 [64.8%] male; 1738 [78.5%] with at least 1 chronic comorbidity) were included in the study. At 28 days after ICU admission, 784 patients (35.4%) had died, 824 (37.2%) were discharged, and 607 (27.4%) remained hospitalized. At the end of study follow-up (median, 16 days; interquartile range, 8-28 days), 875 patients (39.5%) had died, 1203 (54.3%) were discharged, and 137 (6.2%) remained hospitalized. Factors independently associated with death included older age (Ն80 vs <40 years of age: odds ratio [OR], 11.15; 95% CI, 6.19-20.06), male sex (OR, 1.50; 95% CI, 1.19-1.90), higher body mass index (Ն40 vs <25: OR, 1.51; 95% CI, 1.01-2.25), coronary artery disease (OR, 1.47; 95% CI, 1.07-2.02), active cancer (OR, 2.15; 95% CI, 1.35-3.43), and the presence of hypoxemia (PaO 2 :FIO 2 <100 vs Ն300 mm Hg: OR, 2.94; 95% CI, 2.11-4.08), liver dysfunction (liver Sequential Organ Failure Assessment score of 2 vs 0: OR, 2.61; 95% CI, 1.30-5.25), and kidney dysfunction (renal Sequential Organ Failure Assessment score of 4 vs 0: OR, 2.43; 95% CI, 1.46-4.05) at ICU admission. Patients admitted to hospitals with fewer ICU beds had a higher risk of death (<50 vs Ն100 ICU beds: OR, 3.28; 95% CI, 2.16-4.99). Hospitals varied considerably in the risk-adjusted proportion of patients who died (range, 6.6%-80.8%) and in the percentage of patients who received hydroxychloroquine, tocilizumab, and other treatments and supportive therapies. CONCLUSIONS AND RELEVANCE This study identified demographic, clinical, and hospital-level risk factors that may be associated with death in critically ill patients with COVID-19 and can facilitate the identification of medications and supportive therapies to improve outcomes.

Key PointsQuestionDoes prior COVID-19 vaccination reduce hospitalizations for COVID-19, and among patients hospitalized for COVID-19, does prior vaccination reduce disease severity?FindingsIn a case-control study that included 4513 hospitalized adults in 18 US states, hospitalization for a COVID-19 diagnosis compared with an alternative diagnosis was associated with an adjusted odds ratio (aOR) of 0.15 for full vaccination with an authorized or approved mRNA COVID-19 vaccine. Among adults hospitalized for COVID-19, progression to death or invasive mechanical ventilation was associated with an aOR of 0.33 for full vaccination; both ORs were statistically significant.MeaningVaccination with an mRNA COVID-19 vaccine was significantly less likely among patients with COVID-19 hospitalization and with disease progression, consistent with risk reduction among vaccine breakthrough infections.

Objectives To characterize the clinical severity of covid-19 associated with the alpha, delta, and omicron SARS-CoV-2 variants among adults admitted to hospital and to compare the effectiveness of mRNA vaccines to prevent hospital admissions related to each variant. Design Case-control study. Setting 21 hospitals across the United States. Participants 11 690 adults (≥18 years) admitted to hospital: 5728 with covid-19 (cases) and 5962 without covid-19 (controls). Patients were classified into SARS-CoV-2 variant groups based on viral whole genome sequencing, and, if sequencing did not reveal a lineage, by the predominant circulating variant at the time of hospital admission: alpha (11 March to 3 July 2021), delta (4 July to 25 December 2021), and omicron (26 December 2021 to 14 January 2022). Main outcome measures Vaccine effectiveness calculated using a test negative design for mRNA vaccines to prevent covid-19 related hospital admissions by each variant (alpha, delta, omicron). Among patients admitted to hospital with covid-19, disease severity on the World Health Organization’s clinical progression scale was compared among variants using proportional odds regression. Results Effectiveness of the mRNA vaccines to prevent covid-19 associated hospital admissions was 85% (95% confidence interval 82% to 88%) for two vaccine doses against the alpha variant, 85% (83% to 87%) for two doses against the delta variant, 94% (92% to 95%) for three doses against the delta variant, 65% (51% to 75%) for two doses against the omicron variant; and 86% (77% to 91%) for three doses against the omicron variant. In-hospital mortality was 7.6% (81/1060) for alpha, 12.2% (461/3788) for delta, and 7.1% (40/565) for omicron. Among unvaccinated patients with covid-19 admitted to hospital, severity on the WHO clinical progression scale was higher for the delta versus alpha variant (adjusted proportional odds ratio 1.28, 95% confidence interval 1.11 to 1.46), and lower for the omicron versus delta variant (0.61, 0.49 to 0.77). Compared with unvaccinated patients, severity was lower for vaccinated patients for each variant, including alpha (adjusted proportional odds ratio 0.33, 0.23 to 0.49), delta (0.44, 0.37 to 0.51), and omicron (0.61, 0.44 to 0.85). Conclusions mRNA vaccines were found to be highly effective in preventing covid-19 associated hospital admissions related to the alpha, delta, and omicron variants, but three vaccine doses were required to achieve protection against omicron similar to the protection that two doses provided against the delta and alpha variants. Among adults admitted to hospital with covid-19, the omicron variant was associated with less severe disease than the delta variant but still resulted in substantial morbidity and mortality. Vaccinated patients admitted to hospital with covid-19 had significantly lower disease severity than unvaccinated patients for all the variants.

IMPORTANCE Therapies that improve survival in critically ill patients with coronavirus disease 2019 (COVID-19) are needed. Tocilizumab, a monoclonal antibody against the interleukin 6 receptor, may counteract the inflammatory cytokine release syndrome in patients with severe COVID-19 illness. OBJECTIVE To test whether tocilizumab decreases mortality in this population. DESIGN, SETTING, AND PARTICIPANTS The data for this study were derived from a multicenter cohort study of 4485 adults with COVID-19 admitted to participating intensive care units (ICUs) at 68 hospitals across the US from March 4 to May 10, 2020. Critically ill adults with COVID-19 were categorized according to whether they received or did not receive tocilizumab in the first 2 days of admission to the ICU. Data were collected retrospectively until June 12, 2020. A Cox regression model with inverse probability weighting was used to adjust for confounding. EXPOSURES Treatment with tocilizumab in the first 2 days of ICU admission. MAIN OUTCOMES AND MEASURES Time to death, compared via hazard ratios (HRs), and 30-day mortality, compared via risk differences. RESULTS Among the 3924 patients included in the analysis (2464 male [62.8%]; median age, 62 [interquartile range {IQR}, 52-71] years), 433 (11.0%) received tocilizumab in the first 2 days of ICU admission. Patients treated with tocilizumab were younger (median age, 58 [IQR, 48-65] vs 63 [IQR, 52-72] years) and had a higher prevalence of hypoxemia on ICU admission (205 of 433 [47.3%] vs 1322 of 3491 [37.9%] with mechanical ventilation and a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of <200 mm Hg) than patients not treated with tocilizumab. After applying inverse probability weighting, baseline and severity-of-illness characteristics were well balanced between groups. A total of 1544 patients (39.3%) died, including 125 (28.9%) treated with tocilizumab and 1419 (40.6%) not treated with tocilizumab. In the primary analysis, during a median follow-up of 27 (IQR, 14-37) days, patients treated with tocilizumab had a lower risk of death compared with those not treated with tocilizumab (HR, 0.71; 95% CI, 0.56-0.92). The estimated 30-day mortality was 27.5% (95% CI, 21.2%-33.8%) in the tocilizumab-treated patients and 37.1% (95% CI, 35.5%-38.7%) in the non-tocilizumab-treated patients (risk difference, 9.6%; 95% CI, 3.1%-16.0%). CONCLUSIONS AND RELEVANCE Among critically ill patients with COVID-19 in this cohort study, the risk of in-hospital mortality in this study was lower in patients treated with tocilizumab in the first 2 days of ICU admission compared with patients whose treatment did not include early use of tocilizumab. However, the findings may be susceptible to unmeasured confounding, and further research from randomized clinical trials is needed.

IMPORTANCE Data on the efficacy of hydroxychloroquine for the treatment of coronavirus disease 2019 are needed. OBJECTIVE To determine whether hydroxychloroquine is an efficacious treatment for adults hospitalized with COVID-19. DESIGN, SETTING, AND PARTICIPANTSThis was a multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US. Adults hospitalized with respiratory symptoms from severe acute respiratory syndrome coronavirus 2 infection were enrolled between April 2 and June 19, 2020, with the last outcome assessment on July 17, 2020. The planned sample size was 510 patients, with interim analyses planned after every 102 patients were enrolled. The trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients.INTERVENTIONS Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237). MAIN OUTCOMES AND MEASURESThe primary outcome was clinical status 14 days after randomization as assessed with a 7-category ordinal scale ranging from 1 (death) to 7 (discharged from the hospital and able to perform normal activities). The primary outcome was analyzed with a multivariable proportional odds model, with an adjusted odds ratio (aOR) greater than 1.0 indicating more favorable outcomes with hydroxychloroquine than placebo. The trial included 12 secondary outcomes, including 28-day mortality. RESULTS Among 479 patients who were randomized (median age, 57 years; 44.3% female; 37.2% Hispanic/Latinx; 23.4% Black; 20.1% in the intensive care unit; 46.8% receiving supplemental oxygen without positive pressure; 11.5% receiving noninvasive ventilation or nasal high-flow oxygen; and 6.7% receiving invasive mechanical ventilation or extracorporeal membrane oxygenation), 433 (90.4%) completed the primary outcome assessment at 14 days and the remainder had clinical status imputed. The median duration of symptoms prior to randomization was 5 days (interquartile range [IQR], 3 to 7 days). Clinical status on the ordinal outcome scale at 14 days did not significantly differ between the hydroxychloroquine and placebo groups (median [IQR] score,[6][7] vs 6 [4-7]; aOR, 1.02 [95% CI, 0.73 to 1.42]). None of the 12 secondary outcomes were significantly different between groups. At 28 days after randomization, 25 of 241 patients (10.4%) in the hydroxychloroquine group and 25 of 236 (10.6%) in the placebo group had died (absolute difference, −0.2% [95% CI, −5.7% to 5.3%]; aOR, 1.07 [95% CI, 0.54 to 2.09]).CONCLUSIONS AND RELEVANCE Among adults hospitalized with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14. These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults.