Inflammatory subphenotypes previously identified in ARDS are associated with mortality at intensive care unit discharge: a secondary analysis of a prospective observational study
Authors: Slim Marleen A. , van Amstel Rombout B. E. , Bos Lieuwe D. J. , Cremer Olaf L. ,   MARS Consortium, de Beer Friso M. , Bos Lieuwe D. J. , Glas Gerie J. , Hoogendijk Arie J. , van Hooijdonk Roosmarijn T. M. , Horn Janneke , Huson Mischa A. , Schouten Laura R. A. , Schultz Marcus J. , Scicluna Brendon P. , Straat Marleen , van Vught Lonneke A. , Wieske Luuk , Wiewel Maryse A. , Bonten Esther Witteveen. Marc J. M. , Cremer Olaf M. , Ong David S. Y. , Frencken Jos F. , Klouwenberg Peter M. C. Klein , Koster‐Brouwer Maria E. , van de Groep Kirsten , Verboom Diana M. , Wiersinga W. Joost , van der Poll Tom , van Vught Lonneke A. 
Published: May 2024

Abstract
Background
Intensive care unit (ICU)-survivors have an increased risk of mortality after discharge compared to the general population. On ICU admission subphenotypes based on the plasma biomarker levels of interleukin-8, protein C and bicarbonate have been identified in patients admitted with acute respiratory distress syndrome (ARDS) that are prognostic of outcome and predictive of treatment response. We hypothesized that if these inflammatory subphenotypes previously identified among ARDS patients are assigned at ICU discharge in a more general critically ill population, they are associated with short- and long-term outcome.

Methods
A secondary analysis of a prospective observational cohort study conducted in two Dutch ICUs between 2011 and 2014 was performed. All patients discharged alive from the ICU were at ICU discharge adjudicated to the previously identified inflammatory subphenotypes applying a validated parsimonious model using variables measured median 10.6 h [IQR, 8.0–31.4] prior to ICU discharge. Subphenotype distribution at ICU discharge, clinical characteristics and outcomes were analyzed. As a sensitivity analysis, a latent class analysis (LCA) was executed for subphenotype identification based on plasma protein biomarkers at ICU discharge reflective of coagulation activation, endothelial cell activation and inflammation. Concordance between the subphenotyping strategies was studied.

Results
Of the 8332 patients included in the original cohort, 1483 ICU-survivors had plasma biomarkers available and could be assigned to the inflammatory subphenotypes. At ICU discharge 6% (n = 86) was assigned to the hyperinflammatory and 94% (n = 1397) to the hypoinflammatory subphenotype. Patients assigned to the hyperinflammatory subphenotype were discharged with signs of more severe organ dysfunction (SOFA scores 7 [IQR 5–9] vs. 4 [IQR 2–6], p < 0.001). Mortality was higher in patients assigned to the hyperinflammatory subphenotype (30-day mortality 21% vs. 11%, p = 0.005; one-year mortality 48% vs. 28%, p < 0.001). LCA deemed 2 subphenotypes most suitable. ICU-survivors from class 1 had significantly higher mortality compared to class 2. Patients belonging to the hyperinflammatory subphenotype were mainly in class 1.

Conclusions
Patients assigned to the hyperinflammatory subphenotype at ICU discharge showed significantly stronger anomalies in coagulation activation, endothelial cell activation and inflammation pathways implicated in the pathogenesis of critical disease and increased mortality until one-year follow up.