Reproducible clinical archetypes in acute respiratory failure: a multi-cohort trajectory analysis
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Purpose
Acute hypoxemic respiratory failure (AHRF) is common and biologically heterogeneous. Static phenotyping at a single time point does not capture illness evolution and risks stage-mixing; reproducible clinical course archetypes may address this. We aimed to identify, externally validate, and predict trajectory classes (TCs) of persistent AHRF.
Methods
We analyzed MIMIC-IV (derivation; n = 3938) and two external validation cohorts (UK/Netherlands; n = 6480) comprising adults with PaO2/FiO2 < 300 mmHg and PEEP ≥ 5 cmH2O for ≥ 72 h. Daily mean PaO2/FiO2 to day 14 and time to ICU discharge/death were jointly modelled using a competing-risk latent class mixed model. Early TC prediction used a 12-variable XGBoost model. We explored prevalence of ARDS and hyperinflammatory subphenotypes between TCs.
Results
A four-class model provided optimal fit: (TC1) early recovery (0.3% 14-day mortality); (TC2) stable persistence (8% 14-day mortality); (TC3) biphasic improvement–deterioration (17% 14-day mortality); and (TC4) rapid decline (100% 14-day mortality). These archetypes generalized to external cohorts with high assignment certainty. TCs demonstrated distinct patterns in other clinical biomarker trajectories. TC4 was enriched for the hyperinflammatory subphenotype (41–53%), while TC2 was most common in patients with ARDS (50%). Early TC prediction models achieved mean AUCs ≥ 0.78 (0.70–0.86) by day 3 in external validation.
Conclusions
Four reproducible oxygenation archetypes capture the 14-day course of persistent respiratory failure. By providing early prognostic value distinct from static baseline severity, these trajectories have the potential to guide therapeutic strategies, reduce patient heterogeneity in trials, and direct biological phenotyping.
Acute hypoxemic respiratory failure (AHRF) is common and biologically heterogeneous. Static phenotyping at a single time point does not capture illness evolution and risks stage-mixing; reproducible clinical course archetypes may address this. We aimed to identify, externally validate, and predict trajectory classes (TCs) of persistent AHRF.
Methods
We analyzed MIMIC-IV (derivation; n = 3938) and two external validation cohorts (UK/Netherlands; n = 6480) comprising adults with PaO2/FiO2 < 300 mmHg and PEEP ≥ 5 cmH2O for ≥ 72 h. Daily mean PaO2/FiO2 to day 14 and time to ICU discharge/death were jointly modelled using a competing-risk latent class mixed model. Early TC prediction used a 12-variable XGBoost model. We explored prevalence of ARDS and hyperinflammatory subphenotypes between TCs.
Results
A four-class model provided optimal fit: (TC1) early recovery (0.3% 14-day mortality); (TC2) stable persistence (8% 14-day mortality); (TC3) biphasic improvement–deterioration (17% 14-day mortality); and (TC4) rapid decline (100% 14-day mortality). These archetypes generalized to external cohorts with high assignment certainty. TCs demonstrated distinct patterns in other clinical biomarker trajectories. TC4 was enriched for the hyperinflammatory subphenotype (41–53%), while TC2 was most common in patients with ARDS (50%). Early TC prediction models achieved mean AUCs ≥ 0.78 (0.70–0.86) by day 3 in external validation.
Conclusions
Four reproducible oxygenation archetypes capture the 14-day course of persistent respiratory failure. By providing early prognostic value distinct from static baseline severity, these trajectories have the potential to guide therapeutic strategies, reduce patient heterogeneity in trials, and direct biological phenotyping.
Date Issued
2026-07-01
Date Acceptance
2026-04-10
Citation
Intensive Care Medicine, 2026, 52 (7)
ISSN
0342-4642
Publisher
Springer
Journal / Book Title
Intensive Care Medicine
Volume
52
Issue
7
Copyright Statement
© 2026 The Author(s) Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/42149243
Subjects
Acute hypoxemic respiratory failure
Subphenotyping
Trajectories
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2026-05-17