Bedside identification of subphenotypes in acute respiratory failure (PHIND): a multicentre, observational cohort study

Abstract

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a clinically defined, biologically heterogeneous condition with no proven disease-modifying therapies. Retrospective analyses have identified two biologically distinct subphenotypes (hyperinflammatory and hypoinflammatory) of ARDS, with differing outcomes and responses to therapy. Rapid identification of these subphenotypes in an actionable timeframe has previously not been possible. The PHIND study aimed to prospectively identify these subphenotypes and to demonstrate differing 60-day mortality. METHODS: The PHIND study was a prospective, multicentre, observational cohort study conducted in intensive care units (ICUs) within the National Health Service in the UK and the Health Service Executive in Ireland. Adult patients aged 18 years and older with ARDS or acute hypoxaemic respiratory failure (AHRF) were enrolled within 72 h of onset of the syndrome. Eligible patients were required to be receiving invasive mechanical ventilation, non-invasive ventilation, or high-flow nasal oxygen. Plasma interleukin (IL-6) and soluble TNF receptor-1 (TNFR1) were quantified at enrolment using a near-patient benchtop immunoanalyser (Randox multiSTAT) with a run time of approximately 1 h. Together with plasma bicarbonate measured from an arterial blood sample, these values were used to prospectively determine subphenotypes on an individual patient basis using a validated parsimonious logistic regression model. The primary outcome was 60-day mortality. The study was registered on ClinicalTrials.gov, NCT04009330. FINDINGS: Between Nov 22, 2019, and Sept 28, 2023, 1853 patients from 30 centres were screened for eligibility. Of these, 1328 were excluded and 525 were recruited into the study, with 512 individuals included. 308 (60%) patients were male, 204 (40%) were female, and mean age was 57·0 years (SD 15·1). 443 (87%) patients were white, 18 (4%) were Black, and 16 (3%) were Asian. 490 were subphenotyped using the near-patient assay: 89 (18%) were classified as hyperinflammatory and 401 (82%) as hypoinflammatory. The primary outcome of 60-day mortality was measured in 486 patients after four patients withdrew consent for confirmation of vital status. 60-day mortality was significantly higher in the hyperinflammatory group (45 [51%] of 88) than in the hypoinflammatory group (111 [28%] of 398; risk ratio 1·8 [95% CI 1·4-2·4], p<0·0001). After adjustment, hyperinflammatory patients had increased odds of 60-day mortality (adjusted odds ratio 2·7 [95% CI 1·6-4·4], p=0·0002). INTERPRETATION: Rapid identification of ARDS inflammatory subphenotypes using a near-patient assay was feasible and associated with many clinical characteristics and outcomes consistent with those described in earlier retrospective studies, including mortality, prevalence of sepsis, and incidence of metabolic acidosis. These findings support the implementation of precision medicine approaches in ARDS and the urgent need for prospective, subphenotype-stratified interventional trials. FUNDING: Innovate UK, Randox Laboratories, and Belfast Health & Social Care Trust.