The acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in critically ill patients and is defined by the acute onset of noncardiogenic pulmonary edema, hypoxemia, and the need for mechanical ventilation. ARDS occurs most often in the setting of pneumonia, sepsis, aspiration of gastric contents or severe trauma, and is present in ~10% of all intensive care unit patients worldwide. Despite some improvements over the past decades, mortality remains high at 30–40% in most studies. Pathologic specimens from patients with ARDS most frequently reveal diffuse alveolar damage, and laboratory studies have demonstrated both alveolar epithelial and lung endothelial injury, resulting in accumulation of protein-rich inflammatory edema fluid in the alveolar space. Diagnosis is based on consensus syndromic criteria, with recent proposed modifications for under-resourced settings and for pediatric patients. Patient management focuses on implementing a lung-protective ventilation strategy; no specific pharmacotherapies have been identified. Long-term outcomes of patients with ARDS are increasingly recognized as important research targets, as many patients survive ARDS only to suffer ongoing functional and/or psychologic sequelae. Future directions include efforts to facilitate earlier recognition of ARDS, prognostic and/or predictive enrichment in clinical studies to identify responsive subsets, and ongoing efforts to understand fundamental mechanisms of lung injury that may respond to specific treatments.

Background Subphenotypes have been identified within heterogeneous syndromes such as asthma and breast cancer, with important therapeutic implications. Whether subphenotypes exist within the acute respiratory distress syndrome (ARDS), another heterogeneous syndrome, is unknown. Methods We applied latent class modeling to identify subphenotypes using clinical and biological data from two NHLBI ARDS randomized controlled trials; modeling was conducted independently in each cohort. We then tested the association of subphenotypes with clinical outcomes in both cohorts and with the response to positive end-expiratory pressure (PEEP) in the second cohort. Findings Independent latent class models indicated that a two-class (i.e. two subphenotype) model was optimal for both cohorts. In both cohorts, we identified a hyperinflammatory subphenotype (Phenotype 2) that was characterized by higher plasma levels of inflammatory biomarkers, a higher prevalence of vasopressor use, lower serum bicarbonate, and a higher prevalence of sepsis, compared to Phenotype 1. Subjects in Phenotype 2 had higher mortality and fewer ventilator-free and organ failure-free days in both cohorts. In the second cohort, the effects of ventilation strategy on mortality, ventilator and organ failure-free days differed significantly by phenotype (p=0.003–0.049 for interactions). Interpretation Latent class models identify two subphenotypes within ARDS, one of which is characterized by more severe inflammation, shock, and metabolic acidosis and by significantly worse clinical outcomes. Response to treatment in a randomized trial of PEEP strategies differed based on subphenotype. Identification of ARDS subphenotypes may be useful in selecting patients for clinical trials. Funding National Institutes of Health

The description of a so-called cytokine storm in patients with COVID-19 has prompted consideration of anti-cytokine therapies, particularly interleukin-6 antagonists. However, direct systematic comparisons of COVID-19 with other critical illnesses associated with elevated cytokine concentrations have not been reported. In this Rapid Review, we report the results of a systematic review and meta-analysis of COVID-19 studies published or posted as preprints between Nov 1, 2019, and April 14, 2020, in which interleukin-6 concentrations in patients with severe or critical disease were recorded. 25 COVID-19 studies (n=1245 patients) were ultimately included. Comparator groups included four trials each in sepsis (n=5320), cytokine release syndrome (n=72), and acute respiratory distress syndrome unrelated to COVID-19 (n=2767). In patients with severe or critical COVID-19, the pooled mean serum interleukin-6 concentration was 36•7 pg/mL (95% CI 21•6-62•3 pg/mL; I²=57•7%). Mean interleukin-6 concentrations were nearly 100 times higher in patients with cytokine release syndrome (3110•5 pg/mL, 632•3-15 302•9 pg/mL; p<0•0001), 27 times higher in patients with sepsis (983•6 pg/mL, 550•1-1758•4 pg/mL; p<0•0001), and 12 times higher in patients with acute respiratory distress syndrome unrelated to COVID-19 (460 pg/mL, 216•3-978•7 pg/mL; p<0•0001). Our findings question the role of a cytokine storm in COVID-19-induced organ dysfunction. Many questions remain about the immune features of COVID-19 and the potential role of anti-cytokine and immune-modulating treatments in patients with the disease.

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