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Clinical Research and Public HealthIn-Press PreviewClinical ResearchInflammationPulmonology Open Access | 10.1172/JCI196290

Longitudinal multi-omic signatures of ARDS and sepsis inflammatory phenotypes identify pathways associated with mortality

Narges Alipanah-Lechner,1 Lucile Neyton,1 Pratik Sinha,2 Carolyn Leroux,1 Kim Bardillon,3 Sidney A. Carrillo,1 Suzanna Chak,3 Olivia Chao,3 Taarini Hariharan,1 Carolyn Hendrickson,4 Kirsten Kangelaris,5 Charles R. Langelier,6 Deanna Lee,3 Chelsea Lin,1 Kathleen Liu,7 Liam Magee,3 Angelika Ringor,3 Aartik Sarma,1 Emma Schmiege,1 Natasha Spottiswoode,6 Kathryn Sullivan,1 Melanie F. Weingart,1 Andrew Willmore,1 Hanjing Zhuo,3 Angela J. Rogers,8 Kathleen A. Stringer,9 Michael A. Matthay,1 and Carolyn S. Calfee1

1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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1Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Departme, University of California San Francisco, San Francisco, United States of America

2Division of Clinical and Translational Research, Department of Anesthesia, Washington University School of Medicine, St. Louis, United States of America

3Cardiovascular Research Institute, University of California San Francisco, San Francisco, United States of America

4Division of Pulmonary and Critical Care, Department of Medicine, Zuckerberg San Francisco General Hospital, San Francisco, United States of America

5Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, United States of America

6Division of Infectious Disease, Department of Medicine, University of California San Francisco, San Francisco, United States of America

7Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, United States of America

8Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, United States of America

9Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, United States of America

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Published December 2, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI196290.
Copyright © 2025, Alipanah-Lechner et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published December 2, 2025 - Version history
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Abstract

BACKGROUND. Critically ill patients with acute respiratory distress syndrome (ARDS) and sepsis exhibit distinct inflammatory phenotypes with divergent clinical outcomes, but the underlying molecular mechanisms remain poorly understood. These phenotypes, derived from clinical data and protein biomarkers, were associated with metabolic differences in a pilot study.

METHODS. We performed integrative multi-omics analysis of blood samples from 160 ARDS patients in the ROSE trial, randomly selecting 80 patients from each latent class analysis-defined inflammatory phenotype (Hyperinflammatory and Hypoinflammatory) with phenotype probability >0.9. Untargeted plasma metabolomics and whole blood transcriptomics at Day 0 and Day 2 were analyzed using multi-modal factor analysis (MEFISTO). The primary outcome was 90-day mortality, with validation in an independent critically ill sepsis cohort (EARLI).

RESULTS. Multi-omics integration revealed four molecular signatures associated with mortality: (1) enhanced innate immune activation coupled with increased glycolysis (associated with Hyperinflammatory phenotype), (2) hepatic dysfunction and immune dysfunction paired with impaired fatty acid beta-oxidation (associated with Hyperinflammatory phenotype), (3) interferon program suppression coupled with altered mitochondrial respiration (associated with Hyperinflammatory phenotype), and (4) redox impairment and cell proliferation pathways (not associated with inflammatory phenotype). These signatures persisted through Day 2 of trial enrollment. Within-phenotype analysis revealed distinct mortality-associated pathways in each group. All molecular signatures were validated in the independent EARLI cohort.

CONCLUSIONS. Inflammatory phenotypes of ARDS reflect distinct underlying biological processes with both phenotype-specific and phenotype-independent pathways influencing patient outcomes, all characterized by mitochondrial dysfunction. These findings suggest potential therapeutic targets for precise treatment strategies in critical illness.

FUNDING. This work is the result of NIH funding.

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