Articles

Biological subphenotypes in severe acute hypoxaemic respiratory failure and acute respiratory distress syndrome using rapid prospective classification (SPARC) in the USA: a multicentre, observational, study

D Clark Files, Michael A Matthay, Andrew G Chapple, et al

Lancet Respir Med Available online 15 May 2026

https://doi.org/10.1016/S2213-2600(26)00083-4

Summary

Background

Two biological subphenotypes in acute respiratory distress syndrome (ARDS) have been identified in retrospective analyses, with differential clinical outcomes and post-hoc responses to investigational treatments. The ability to identify biological subphenotypes in real-time is unknown. We aimed to evaluate the feasibility of using the multisite ISPY COVID Network to prospectively evaluate biological subphenotypes in real-time.

Methods

This prospective, observational, cohort study enrolled patients with ARDS and severe acute hypoxaemic respiratory failure (AHRF) and assessed the feasibility of real-time stratification into biological subphenotypes using plasma concentrations of IL-6, soluble tumour necrosis factor-1 (TNFR1), and clinical variables. Participants were eligible if they were receiving mechanical ventilation, non-invasive positive pressure ventilation, or heated high flow nasal oxygen (at flow rates ≥30 L/min); had severe AHRF (defined by an SpO₂ to FiO₂ ratio ≤315, calculated with SpO₂ ≤97%, or PaO₂ to FiO₂ ratio <300 if arterial blood gas was available); and the presence of these criteria for less than 48 h. Key exclusion criteria were being younger than 18 years, known pregnancy, being incarcerated, ARDS secondary to trauma, and rapidly improving hypoxaemia. Enrolled patients had to meet inclusion and exclusion criteria at the time of consent and blood draw. Enrolled patients were stratified into either a severe AHRF group (unilateral infiltrate) or an ARDS group (bilateral infiltrates) based on chest imaging at enrolment, determined by the study team. After enrolment, a blood sample (up to 6 mL) was collected and immediately taken to the local laboratory for plasma analysis. Following biomarker quantification participants were allocated to the hypoinflammatory or hyperinflammatory groups. Feasibility was defined a priori as successful real-time biological subphenotyping in greater than 75% of the final 100 enrolled participants.

Findings

From June 15, 2023, to Oct 31, 2024, 844 patients at 17 hospitals in the ISPY COVID Network across the USA were screened for the study. After 504 exclusions and two withdrawals of consent, 338 patients were enrolled. 124 (37%) of the enrolled cohort were classified as AHRF, and 214 (63%) were classified as ARDS. 199 (59%) of patients were male and 138 (41%) were female, and the median age at enrolment was 64 years (IQR 54–74). The majority of patients were white (239 [71%]). 250 (74%) of the enrolled cohort completed subphenotype assignment using fresh plasma and were defined as successfully subphenotyped. Successful real-time subphenotyping increased from 59 for the first 100 enrolled participants (59% [95% CI 49–69]) to 82 for the last 100 enrolled participants (82% [73–89]), meeting the predefined feasibility threshold. Median time to subphenotype assignment from blood collection in the overall cohort and the successfully subphenotyped subgroup was 2·2 h (IQR 1·5–19·8) and 1·9 h (1·3–2·3) from the time of blood collection, respectively. The hyperinflammatory subphenotype was identified in 61 (29%) of 214 participants with ARDS and 29 (23%) of the 124 participants with severe AHRF. Clinical outcomes including mortality, organ support-free days and ventilator-free days were worse in patients with hyperinflammatory ARDS compared with those with hypoinflammatory ARDS.

Interpretation

Rapid real-time biological subphenotyping for ARDS and severe AHRF in a multisite US hospital network is feasible; and successful real-time subphenotyping both improved over the study time-course and was completed within 2·2 h from study blood collection. These results support the feasibility of real-time precision trials of therapies targeting biological subphenotypes in ARDS.

Funding

COVID R&D Consortium, Allergan, Amgen, Takeda Pharmaceutical Company, Ingenus Pharmaceuticals, Implicit Bioscience, Johnson & Johnson, Pfizer, Roche-Genentech, Apotex, FAST Grant from Emergent Venture George Mason University, and The Grove Foundation. This work was supported by the US Defense Threat Reduction Agency (MCDC-2013–001). This project has been funded in whole or in part with Federal funds from the US Department of Health and Human Services; Administration for Strategic Preparedness and Response; and Biomedical Advanced Research and Development Authority (MCDC-2014–001).