Identifying molecular phenotypes in sepsis: an analysis of two prospective observational cohorts and secondary analysis of two randomised controlled trials

Pratik Sinha; V Eric Kerchberger; Andrew Willmore; Julia Chambers; Hanjing Zhuo; Jason Abbott; Chayse Jones; Nancy Wickersham; Nelson Wu; Lucile Neyton; Charles R Langelier; Eran Mick; June He; Alejandra Jauregui; Matthew M Churpek; Antonio D Gomez; Carolyn M Hendrickson; Kirsten N Kangelaris; Aartik Sarma; Aleksandra Leligdowicz; Kevin L Delucchi; Kathleen D Liu; James A Russell; Michael A Matthay; Keith R Walley; Lorraine B Ware; Carolyn S Calfee

doi:10.1016/S2213-2600(23)00237-0

Identifying molecular phenotypes in sepsis: an analysis of two prospective observational cohorts and secondary analysis of two randomised controlled trials

Lancet Respir Med. 2023 Nov;11(11):965-974. doi: 10.1016/S2213-2600(23)00237-0. Epub 2023 Aug 23.

Authors

Pratik Sinha¹, V Eric Kerchberger², Andrew Willmore³, Julia Chambers⁴, Hanjing Zhuo⁵, Jason Abbott⁵, Chayse Jones⁵, Nancy Wickersham², Nelson Wu³, Lucile Neyton⁵, Charles R Langelier⁶, Eran Mick⁶, June He⁷, Alejandra Jauregui³, Matthew M Churpek⁸, Antonio D Gomez⁹, Carolyn M Hendrickson¹⁰, Kirsten N Kangelaris¹¹, Aartik Sarma³, Aleksandra Leligdowicz¹², Kevin L Delucchi¹³, Kathleen D Liu¹⁴, James A Russell¹⁵, Michael A Matthay¹⁶, Keith R Walley¹⁵, Lorraine B Ware¹⁷, Carolyn S Calfee¹⁶

Affiliations

¹ Division of Clinical and Translational Research, Division of Critical Care, Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA. Electronic address: p.sinha@wustl.edu.
² Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
³ Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
⁴ Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
⁵ Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
⁶ Division of Infectious Diseases, Department of Medicine, University of California San Francisco, San Francisco, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA.
⁷ Division of Clinical and Translational Research, Division of Critical Care, Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA.
⁸ Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
⁹ Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA; Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, CA, USA.
¹⁰ Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, CA, USA.
¹¹ Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
¹² Department of Medicine, Division of Critical Care Medicine, Robarts Research Institute, University of Western Ontario, London, ON, Canada.
¹³ Department of Psychiatry, University of California San Francisco, San Francisco, CA, USA.
¹⁴ Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA; Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
¹⁵ Division of Critical Care Medicine, St Paul's Hospital, University of British Columbia, Vancouver, BC, Canada; Centre for Heart Lung Innovation, University of British Columbia, Vancouver, BC, Canada.
¹⁶ Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA; Department of Anesthesia, University of California San Francisco, San Francisco, CA, USA.
¹⁷ Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.

PMID: 37633303
PMCID: PMC10841178 (available on 2024-11-01)
DOI: 10.1016/S2213-2600(23)00237-0

Abstract

Background: In sepsis and acute respiratory distress syndrome (ARDS), heterogeneity has contributed to difficulty identifying effective pharmacotherapies. In ARDS, two molecular phenotypes (hypoinflammatory and hyperinflammatory) have consistently been identified, with divergent outcomes and treatment responses. In this study, we sought to derive molecular phenotypes in critically ill adults with sepsis, determine their overlap with previous ARDS phenotypes, and evaluate whether they respond differently to treatment in completed sepsis trials.

Methods: We used clinical data and plasma biomarkers from two prospective sepsis cohorts, the Validating Acute Lung Injury biomarkers for Diagnosis (VALID) study (N=1140) and the Early Assessment of Renal and Lung Injury (EARLI) study (N=818), in latent class analysis (LCA) to identify the optimal number of classes in each cohort independently. We used validated models trained to classify ARDS phenotypes to evaluate concordance of sepsis and ARDS phenotypes. We applied these models retrospectively to the previously published Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis and Septic Shock (PROWESS-SHOCK) trial and Vasopressin and Septic Shock Trial (VASST) to assign phenotypes and evaluate heterogeneity of treatment effect.

Findings: A two-class model best fit both VALID and EARLI (p<0·0001). In VALID, 804 (70·5%) of the 1140 patients were classified as hypoinflammatory and 336 (29·5%) as hyperinflammatory; in EARLI, 530 (64·8%) of 818 were hypoinflammatory and 288 (35·2%) hyperinflammatory. We observed higher plasma pro-inflammatory cytokines, more vasopressor use, more bacteraemia, lower protein C, and higher mortality in the hyperinflammatory than in the hypoinflammatory phenotype (p<0·0001 for all). Classifier models indicated strong concordance between sepsis phenotypes and previously identified ARDS phenotypes (area under the curve 0·87-0·96, depending on the model). Findings were similar excluding participants with both sepsis and ARDS. In PROWESS-SHOCK, 1142 (68·0%) of 1680 patients had the hypoinflammatory phenotype and 538 (32·0%) had the hyperinflammatory phenotype, and response to activated protein C differed by phenotype (p=0·0043). In VASST, phenotype proportions were similar to other cohorts; however, no treatment interaction with the type of vasopressor was observed (p=0·72).

Interpretation: Molecular phenotypes previously identified in ARDS are also identifiable in multiple sepsis cohorts and respond differently to activated protein C. Molecular phenotypes could represent a treatable trait in critical illness beyond the patient's syndromic diagnosis.

Funding: US National Institutes of Health.

Publication types

Observational Study

MeSH terms

Adult
Biomarkers
Humans
Phenotype
Prospective Studies
Protein C / therapeutic use
Randomized Controlled Trials as Topic
Respiratory Distress Syndrome*
Retrospective Studies
Sepsis* / complications
Sepsis* / diagnosis
Sepsis* / drug therapy
Shock, Septic* / diagnosis
Shock, Septic* / drug therapy
Vasoconstrictor Agents / therapeutic use

Substances

Protein C
Biomarkers
Vasoconstrictor Agents

Abstract

Publication types

MeSH terms

Substances

Grants and funding