The COVID STEROID 2 Trial Group IMPORTANCE A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease. OBJECTIVE To assess the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. DESIGN, SETTING, AND PARTICIPANTS A multicenter, randomized clinical trial was conducted between August 2020 and May 2021 at 26 hospitals in Europe and India and included 1000 adults with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation. End of 90-day follow-up was on August 19, 2021. INTERVENTIONS Patients were randomized 1:1 to 12 mg/d of intravenous dexamethasone (n = 503) or 6 mg/d of intravenous dexamethasone (n = 497) for up to 10 days. MAIN OUTCOMES AND MEASURESThe primary outcome was the number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days and was adjusted for stratification variables. Of the 8 prespecified secondary outcomes, 5 are included in this analysis (the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and Ն1 serious adverse reactions at 28 days). RESULTSOf the 1000 randomized patients, 982 were included (median age, 65 [IQR, 55-73] years; 305 [31%] women) and primary outcome data were available for 971 (491 in the 12 mg of dexamethasone group and 480 in the 6 mg of dexamethasone group). The median number of days alive without life support was 22.0 days (IQR, 6.0-28.0 days) in the 12 mg of dexamethasone group and 20.5 days (IQR, 4.0-28.0 days) in the 6 mg of dexamethasone group (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days]; P = .07). Mortality at 28 days was 27.1% in the 12 mg of dexamethasone group vs 32.3% in the 6 mg of dexamethasone group (adjusted relative risk, 0.86 [99% CI, 0.68-1.08]). Mortality at 90 days was 32.0% in the 12 mg of dexamethasone group vs 37.7% in the 6 mg of dexamethasone group (adjusted relative risk, 0.87 [99% CI, 0.70-1.07]). Serious adverse reactions, including septic shock and invasive fungal infections, occurred in 11.3% in the 12 mg of dexamethasone group vs 13.4% in the 6 mg of dexamethasone group (adjusted relative risk, 0.83 [99% CI, 0.54-1.29]).CONCLUSIONS AND RELEVANCE Among patients with COVID-19 and severe hypoxemia, 12 mg/d of dexamethasone compared with 6 mg/d of dexamethasone did not result in statistically significantly more days alive without life support at 28 days. However, the trial may have been underpowered to identify a significant difference.

Background and aims: Expression of inducible nitric oxide synthase (iNOS) is greatly upregulated in the colonic mucosa of patients with collagenous and ulcerative colitis. As the transcription factor nuclear factor kB (NFkB) is a major inducer of iNOS gene expression, we compared activation and transcriptional activity of NFkB in colonic mucosal biopsies from these patients. Patients: Eight patients with collagenous colitis, six with relapsing ulcerative colitis, and eight with uninflamed bowel were studied. Methods: NFkB DNA binding activity was assessed by electrophoretic mobility shift assay and inhibitor of NFkB (IkB) kinase (IKK) activity by immunocomplex kinase assay. In vivo recruitment of NFkB to the iNOS promoter was determined by chromatin immunoprecipitation analysis and transcriptional activity by NFkB gene expression profiling arrays. Cells showing NFkB activation were identified by immunohistochemistry. Results: In collagenous and ulcerative colitis, as opposed to uninflamed bowel, IKKb activity and strong NFkB DNA binding gave rise to activation of identical NFkB subunits and recruitment of transcriptionally active p65 to the iNOS promoter. In collagenous colitis, activated NFkB was observed only in epithelial cells while up to 10% of lamina propria macrophages showed activation in ulcerative colitis. Conclusions: In collagenous and ulcerative colitis, colonic mucosal NFkB is activated and recruited to the iNOS promoter in vivo via an IKKb mediated pathway. As collagenous colitis is not associated with tissue injury, these data challenge the prevailing view that activation of NFkB per se mediates tissue injury. Our results suggest that downstream inflammatory reactions leading to tissue damage originate in lamina propria immune cells, as increased NFkB activity in collagenous colitis was localised solely in epithelial cells, but present also in macrophages in ulcerative colitis.

Background Most data on intensive care unit (ICU) patients with COVID‐19 originate in selected populations from stressed healthcare systems with shorter term follow‐up. We present characteristics, interventions and longer term outcomes of the entire, unselected cohort of all ICU patients with COVID‐19 in Denmark where the ICU capacity was not exceeded. Methods We identified all patients with SARS‐CoV‐2 admitted to any Danish ICU from 10 March to 19 May 2020 and registered demographics, chronic comorbidities, use of organ support, length of stay, and vital status from patient files. Risk factors for death were analyzed using adjusted Cox regression analysis. Results There were 323 ICU patients with confirmed COVID‐19. Median age was 68 years, 74% were men, 50% had hypertension, 21% diabetes, and 20% chronic pulmonary disease; 29% had no chronic comorbidity. Invasive mechanical ventilation was used in 82%, vasopressors in 83%, renal replacement therapy in 26%, and extra corporeal membrane oxygenation in 8%. ICU stay was median 13 days (IQR 6‐22) and hospital stay 19 days (11‐30). Median follow‐up was 79 days. At end of follow‐up, 118 had died (37%), 15 (4%) were still in hospital hereof 4 in ICU as of 16 June 2020. Risk factors for mortality included male gender, age, chronic pulmonary disease, active cancer, and number of co‐morbidities. Conclusions In this nationwide, population‐based cohort of ICU patients with COVID‐19, longer term survival was high despite high age and substantial use of organ support. Male gender, age, and chronic co‐morbidities, in particular chronic pulmonary disease, were associated with increased risk of death.

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