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RationaleUsing latent class analysis (LCA), two subphenotypes of acute respiratory distress syndrome (ARDS) have consistently been identified in five randomised controlled trials (RCTs), with distinct biological characteristics, divergent outcomes and differential treatment responses to randomised interventions. Their existence in unselected populations of ARDS remains unknown. We sought to identify subphenotypes in observational cohorts of ARDS using LCA.MethodsLCA was independently applied to patients with ARDS from two prospective observational cohorts of patients admitted to the intensive care unit, derived from the Validating Acute Lung Injury markers for Diagnosis (VALID) (n=624) and Early Assessment of Renal and Lung Injury (EARLI) (n=335) studies. Clinical and biological data were used as class-defining variables. To test for concordance with prior ARDS subphenotypes, the performance metrics of parsimonious classifier models (interleukin 8, bicarbonate, protein C and vasopressor-use), previously developed in RCTs, were evaluated in EARLI and VALID with LCA-derived subphenotypes as the gold-standard.ResultsA 2-class model best fit the population in VALID (p=0.0010) and in EARLI (pConclusionPreviously described subphenotypes are generalisable to unselected populations of non-trauma ARDS.

BackgroundPrior acute respiratory distress syndrome (ARDS) trials have identified hypoinflammatory and hyperinflammatory subphenotypes, with distinct differences in short-term outcomes. It is unknown if such differences extend beyond 90 days or are associated with physical, mental health or cognitive outcomes.Methods568 patients in the multicentre Statins for Acutely Injured Lungs from Sepsis trial of rosuvastatin versus placebo were included and assigned a subphenotype. Among 6-month and 12-month survivors (N=232 and 219, respectively, representing 243 unique survivors), subphenotype status was evaluated for association with a range of patient-reported outcomes (eg, mental health symptoms, quality of life). Patient subsets also were evaluated with performance-based tests of physical function (eg, 6 min walk test) and cognition.FindingsThe hyperinflammatory versus hypoinflammatory subphenotype had lower overall 12-month cumulative survival (58% vs 72%, pInterpretationComparing the hyperinflammatory versus hypoinflammatory ARDS subphenotype, there was no significant difference in survival beyond 90 days and no consistent findings of important differences in 6-month or 12-month physical, cognitive and mental health outcomes. These findings, when considered with prior results, suggest that inflammatory subphenotypes largely reflect the acute phase of illness and its short-term impact.

A complex myriad of aetiologies and pathologies coalesce within the clinical syndrome of acute respiratory distress syndrome (ARDS) often obfuscating our understanding of the disorder. Amidst the complexity, acute lung inflammation stands out as the fundamental unifying pathophysiology underlying ARDS. A better understanding of the mechanisms driving inflammation in the lung and the ensuing response from the innate immune system, endothelial and epithelial barriers are key to developing disease-modifying drugs in ARDS. Targeted inhibition of proinflammatory molecules such as tumour necrosis factor (TNF)-α would seem a logical and fruitful line of investigation for disease-modifying intervention in ARDS. As suggested by its name, TNF-α was first described as a mediator in abrogating malignant proliferation of cancerous cells.1 Since then, TNF-α has also been identified as a key cytokine in modulating inflammation. TNF-α is mainly produced by macrophages and monocytes, but it is released by most cells, including endothelial cells, epithelial cells and most other leucocytes. A pleiotropic cytokine, TNF-α has a wide range of biological activities. TNF-α has been implicated as a chemoattractant for neutrophils and eosinophils, as a mediator of apoptosis and a major stimulant of other proinflammatory cytokine release.2 In ARDS, elevated levels of TNF-α are found in both plasma and bronchioalveolar lavage (BAL).3 4 In the lungs, TNF-α expression directly leads to increased endothelial permeability5 6 and downregulates epithelial sodium channel expression leading to impaired alveolar fluid clearance.7 Aside from ARDS, TNF-α is also a critical mediator in other inflammatory conditions such as rheumatoid arthritis, psoriasis and Crohn’s disease. Moreover, in these diseases, inhibitors of TNF-α are now in widespread therapeutic use, setting a precedent for their use in ARDS. As a ligand, TNF-α binds to two members of TNF-receptor superfamily: TNF-receptor 1 (TNFR1) and TNF-receptor 2 (TNFR2). TNFR1 is a transmembrane receptor with …