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.

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.

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Monozygotic twin and other epidemiologic studies indicate that epigenetic processes may play an important role in the pathogenesis of inflammatory bowel diseases that commonly affect the colonic mucosa. The peak onset of these disorders in young adulthood suggests that epigenetic changes normally occurring in the colonic mucosa shortly before adulthood could be important etiologic factors. We assessed developmental changes in colitis susceptibility during the physiologically relevant period of childhood in mice [postnatal day 30 (P30) to P90] and concurrent changes in DNA methylation and gene expression in murine colonic mucosa. Susceptibility to colitis was tested in C57BL/6J mice with the dextran sulfate sodium colitis model. Methylation specific amplification microarray (MSAM) was used to screen for changes in DNA methylation, with validation by bisulfite pyrosequencing. Gene expression changes were analyzed by microarray expression profiling and real time RT-PCR. Mice were more susceptible to chemically induced colitis at P90 than at P30. DNA methylation changes, however, were not extensive; of 23 743 genomic intervals interrogated, only 271 underwent significant methylation alteration during this developmental period. We found an excellent correlation between the MSAM and bisulfite pyrosequencing at 11 gene associated intervals validated (R(2) = 0.89). Importantly, at the genes encoding galectin-1 (Lgals1), and mothers against decapentaplegic homolog 3 or Smad3, both previously implicated in murine colitis, developmental changes in DNA methylation from P30 to P90 were inversely correlated with expression. Colonic mucosal epigenetic maturation continues through early adulthood in the mouse, and may contribute to the age-associated increase in colitis susceptibility. Transcript Profiling: Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/), accession numbers: GSE18031 (DNA methylation arrays), GSE19506 (gene expression arrays).

Rationale & Objective Acute kidney injury treated with kidney replacement therapy (AKI-KRT) occurs frequently in critically ill patients with COVID-19. We examined the clinical factors that determine kidney recovery in this population. Study Design Multicenter cohort study. Setting & Participants 4221 adults with COVID-19 not receiving kidney replacement therapy who were admitted to intensive care units at 68 US hospitals with COVID-19 from March 1 to June 22, 2020 (the “ICU cohort”). Among these, 876 developed AKI-KRT after admission to the ICU (the “AKI-KRT subcohort”). Exposure(s) The ICU cohort was analyzed using AKI severity as the exposure. For the AKI-KRT subcohort, exposures included demographics, comorbidities, initial mode of KRT, and markers of illness severity at the time of dialysis initiation. Outcome(s) The outcome for the ICU cohort was estimated glomerular filtration rate (GFR) at hospital discharge. A three-level outcome including death, kidney nonrecovery, and kidney recovery at discharge, was analyzed for the AKI-KRT subcohort. Analytical approach The ICU cohort was characterized using descriptive analyses. The AKI-KRT subcohort was characterized with both descriptive analyses and multinomial logistic regression to assess factors associated with kidney nonrecovery while accounting for death. Results Among a total of 4221 patients in the ICU cohort, 2361 (56%) developed AKI, including 876 (21%) who received KRT. More severe AKI was associated with higher mortality. Among survivors, more severe AKI was associated with an increased rate of kidney nonrecovery and lower kidney function at discharge. Among the 876 patients with AKI-KRT, 588 (67%) died, 95 (11%) had kidney nonrecovery, and 193 (22%) had kidney recovery by the time of discharge. The odds of kidney nonrecovery was greater for lower estimated GFR with odds ratios (ORs) of 2.09 (95% CI, 1.09-4.04), 4.27 (95% CI, 1.99-9.17), and 8.69 (95% CI, 3.07-24.55) for CKD GFR categories 3, 4, and 5, respectively, compared to estimated GFR > 60 mL/min/1.73 m2. Oliguria at the time of KRT initiation was also associated with nonrecovery (OR 2.10 [95% CI, 1.14-3.88] and 4.02 [95% CI, 1.72-9.39] for patients with 50-499 and <50 mL urine/day respectively, compared to ≥500 mL urine/day). Limitations Later recovery events may not have been captured due to lack of post-discharge follow-up. Conclusions Lower baseline eGFR and reduced urine output at the time of KRT initiation are each strongly and independently associated with kidney nonrecovery among critically ill patients with COVID-19.