Novel Phenotypes of Acute Respiratory Failure and Differential Response to Awake Prone Positioning: A Multi-Cohort Study

Abstract

The heterogeneity of acute respiratory failure (ARF) in non-intubated patients remains poorly defined. This study aimed to identify novel phenotypes in non-intubated ARF patients and evaluate their prognostic and predictive ability. We analyzed data from three cohorts: a training cohort from the Chinese Database in Intensive Care, validation cohort A from a randomized controlled trial, and validation cohort B from a multicenter dataset. Latent class analysis and k-means clustering were applied independently across cohorts to identify phenotypes. A two-class model demonstrated the optimal fit in the training cohort (n = 706). Compared to Phenotype 1, Phenotype 2 exhibited worse oxygenation, higher lactate concentrations, and more severe coagulation dysfunction, along with significantly higher intubation (56.7 vs. 28.7%, p < 0.001) and mortality rates within 28 days (22.0 vs. 9.7%, p < 0.001). Similar phenotypes were verified in validation cohorts A (n = 409) and B (n = 609). Notably, Phenotype 1 patients benefited most from prolonged awake prone positioning (APP), with a significant interaction observed (p = 0.035; adjusted p = 0.048). Two parsimonious models were further developed for phenotype assignment prediction. The two novel phenotypes with both prognostic and predictive ability may help tailor APP to individual non-intubated ARF patients.

Keywords

acute respiratory failure / awake prone positioning / phenotype

References

[1] L. D. J. Bos and L. B. Ware, “Acute Respiratory Distress Syndrome: Causes, Pathophysiology, and Phenotypes,” Lancet 400, no. 10358 (2022): 1145–1156.

[2] G. Bellani, J. G. Laffey, T. Pham, et al., “Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries,” Jama 315, no. 8 (2016): 788–800.

[3] C. A. Santacruz, A. J. Pereira, E. Celis, and J.-L. Vincent, “Which Multicenter Randomized Controlled Trials in Critical Care Medicine Have Shown Reduced Mortality? A Systematic Review,” Critical Care Medicine 47, no. 12 (2019): 1680–1691.

[4] H. C. Prescott, C. S. Calfee, B. T. Thompson, D. C. Angus, and V. X. Liu, “Toward Smarter Lumping and Smarter Splitting: Rethinking Strategies for Sepsis and Acute Respiratory Distress Syndrome Clinical Trial Design,” American Journal of Respiratory and Critical Care Medicine 194, no. 2 (2016): 147–155.

[5] C. S. Calfee, K. Delucchi, P. E. Parsons, et al., “Subphenotypes in Acute Respiratory Distress Syndrome: Latent Class Analysis of Data From Two Randomised Controlled Trials,” Lancet Respiratory Medicine 2, no. 8 (2014): 611–620.

[6] H. Chen, J. Xie, N. Su, et al., “Corticosteroid Therapy Is Associated With Improved Outcome in Critically Ill Patients With COVID-19 With Hyperinflammatory Phenotype,” Chest 159, no. 5 (2021): 1793–1802.

[7] P. Sinha, D. Furfaro, M. J. Cummings, et al., “Latent Class Analysis Reveals COVID-19-Related Acute Respiratory Distress Syndrome Subgroups With Differential Responses to Corticosteroids,” American Journal of Respiratory and Critical Care Medicine 204, no. 11 (2021): 1274–1285.

[8] P.-L. Blot, B. G. Chousterman, and M. Santafè, “Subphenotypes in Patients With Acute Respiratory Distress Syndrome Treated With High-Flow Oxygen,” Critical Care 27, no. 1 (2023): 419.

[9] E. Azoulay, L. Zafrani, A. Mirouse, E. Lengliné, M. Darmon, and S. Chevret, “Clinical Phenotypes of Critically Ill COVID-19 Patients,” Intensive Care Medicine 46, no. 8 (2020): 1651–1652.

[10] M. Lu, C. Drohan, W. Bain, et al., “Trajectories of Host-Response Subphenotypes in Patients With COVID-19 Across the Spectrum of Respiratory Support,” CHEST Critical Care 1, no. 3 (2023): 100018.

[11] L. Liu, J. Xie, C. Wang, et al., “Prone Position Improves Lung Ventilation-Perfusion Matching in Non-Intubated COVID-19 Patients: A Prospective Physiologic Study,” Critical Care 26, no. 1 (2022): 193.

[12] L. Ding, L. Wang, W. Ma, and H. He, “Efficacy and Safety of Early Prone Positioning Combined With HFNC or NIV in Moderate to Severe ARDS: A Multi-Center Prospective Cohort Study,” Critical Care 24, no. 1 (2020): 28.

[13] L. Liu, Q. Sun, H. Zhao, et al., “Prolonged vs Shorter Awake Prone Positioning for COVID-19 Patients With Acute Respiratory Failure: A Multicenter, Randomised Controlled Trial,” Intensive Care Medicine 50, no. 8 (2024): 1298–1309.

[14] Y. Wang, S. Hao, J. Song, and M. Zhong, “Reflections on Awake Prone Positioning in COVID-19: Considerations on Body Inclination, Respiratory Support, and Patient Variability,” Intensive Care Medicine 51, no. 1 (2025): 237–238.

[15] L. Liu, Q. Sun, Y. Yang, H. Qiu, and A. S. Slutsky, “Individualized Response to Awake Prone Positioning in COVID-19 Patients: Need Deeper Insights,” Intensive Care Medicine 51, no. 1 (2025): 239–240.

[16] S. Ranjeva, R. Pinciroli, E. Hodell, et al., “Identifying Clinical and Biochemical Phenotypes in Acute Respiratory Distress Syndrome Secondary to Coronavirus Disease-2019,” EClinicalMedicine 34 (2021): 100829.

[17] F. Frantzeskaki, A. Armaganidis, and S. E. Orfanos, “Immunothrombosis in Acute Respiratory Distress Syndrome: Cross Talks Between Inflammation and Coagulation,” Respiration 93, no. 3 (2017): 212–225.

[18] L. Zhang, X. Feng, D. Zhang, et al., “Deep Vein Thrombosis in Hospitalized Patients With COVID-19 in Wuhan, China: Prevalence, Risk Factors, and Outcome,” Circulation 142, no. 2 (2020): 114–128.

[19] C. Wu, X. Chen, Y. Cai, et al., “Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China,” JAMA Internal Medicine 180, no. 7 (2020): 934–943.

[20] W. Zhang, L. Sang, J. Shi, et al., “Association of D-Dimer Elevation With Inflammation and Organ Dysfunction in ICU Patients With COVID-19 in Wuhan, China: A Retrospective Observational Study,” Aging (Albany NY) 13, no. 4 (2021): 4794–4810.

[21] M. Levi, J. Thachil, T. Iba, and J. H. Levy, “Coagulation Abnormalities and Thrombosis in Patients With COVID-19,” Lancet Haematology 7, no. 6 (2020): e438–e440.

[22] D. Huang, D. He, L. Gong, W. Jiang, R. Yao, and Z. Liang, “A Nomogram for Predicting Mortality in Patients With Pneumonia-Associated Acute Respiratory Distress Syndrome (ARDS),” Journal of Inflammation Research 17 (2024): 1549–1560.

[23] K. Dubowski, G. T. Braganza, A. Bozack, et al., “COVID-19 Subphenotypes at Hospital Admission Are Associated With Mortality: A Cross-Sectional Study,” Annals of Medicine 55, no. 1 (2023): 12–23.

[24] X. Wang, L. Jehi, X. Ji, and P. J. Mazzone, “Phenotypes and Subphenotypes of Patients With COVID-19: A Latent Class Modeling Analysis,” Chest 159, no. 6 (2021): 2191–2204.

[25] E. Schwager, K. Jansson, A. Rahman, et al., “Utilizing Machine Learning to Improve Clinical Trial Design for Acute Respiratory Distress Syndrome,” NPJ Digital Medicine 4, no. 1 (2021): 133.

[26] J.-L. Vincent, A. Q. E. Silva, L. Couto, and F. S. Taccone, “The Value of Blood Lactate Kinetics in Critically Ill Patients: A Systematic Review,” Critical Care 20, no. 1 (2016): 257.

[27] J. A. Kraut and N. E. Madias, “Lactic Acidosis,” New England Journal of Medicine 371, no. 24 (2014): 2309–2319.

[28] B. Gutiérrez-Gutiérrez, M. D. D. Toro, and A. M. Borobia, “Identification and Validation of Clinical Phenotypes With Prognostic Implications in Patients Admitted to Hospital With COVID-19: A Multicentre Cohort Study,” Lancet Infectious Diseases 21, no. 6 (2021): 783–792.

[29] J. Weatherald, K. K. S. Parhar, and Z. A. Duhailib, “Efficacy of Awake Prone Positioning in Patients With Covid-19 Related Hypoxemic Respiratory Failure: Systematic Review and Meta-Analysis of Randomized Trials,” Bmj 379 (2022): e071966.

[30] J. Li, J. Luo, I. Pavlov, et al., “Awake Prone Positioning for Non-Intubated Patients With COVID-19-Related Acute Hypoxaemic Respiratory Failure: A Systematic Review and Meta-Analysis,” Lancet Respiratory Medicine 10, no. 6 (2022): 573–583.

[31] S. Yang, Q. Sun, X. Yuan, et al., “Effect of Prone Position on Ventilation-Perfusion Matching in Patients With Moderate to Severe ARDS With Different Clinical Phenotypes,” Respiratory Research 26, no. 1 (2025): 70.

[32] J.-M. Constantin, M. Jabaudon, and J.-Y. Lefrant, “Personalised Mechanical Ventilation Tailored to Lung Morphology Versus Low Positive End-Expiratory Pressure for Patients With Acute Respiratory Distress Syndrome in France (the LIVE Study): A Multicentre, Single-Blind, Randomised Controlled Trial,” Lancet Respiratory Medicine 7, no. 10 (2019): 870–880.

[33] G. Grasselli, C. S. Calfee, L. Camporota, et al., “ESICM Guidelines on Acute Respiratory Distress Syndrome: Definition, Phenotyping and Respiratory Support Strategies,” Intensive Care Medicine 49, no. 7 (2023): 727–759.

Rights & permissions

2026 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.