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Identifying molecular phenotypes in sepsis: an analysis of two prospective observational cohorts and secondary analysis of two randomised controlled trials.
Sinha, Pratik; Kerchberger, V Eric; Willmore, Andrew; Chambers, Julia; Zhuo, Hanjing; Abbott, Jason; Jones, Chayse; Wickersham, Nancy; Wu, Nelson; Neyton, Lucile; Langelier, Charles R; Mick, Eran; He, June; Jauregui, Alejandra; Churpek, Matthew M; Gomez, Antonio D; Hendrickson, Carolyn M; Kangelaris, Kirsten N; Sarma, Aartik; Leligdowicz, Aleksandra; Delucchi, Kevin L; Liu, Kathleen D; Russell, James A; Matthay, Michael A; Walley, Keith R; Ware, Lorraine B; Calfee, Carolyn S.
Afiliación
  • Sinha P; 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.
  • Kerchberger VE; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Willmore A; Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
  • Chambers J; Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
  • Zhuo H; 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.
  • Abbott J; 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.
  • Jones C; 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.
  • Wickersham N; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Wu N; Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
  • Neyton L; 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.
  • Langelier CR; Division of Infectious Diseases, Department of Medicine, University of California San Francisco, San Francisco, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA.
  • Mick E; Division of Infectious Diseases, Department of Medicine, University of California San Francisco, San Francisco, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA.
  • He J; Division of Clinical and Translational Research, Division of Critical Care, Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA.
  • Jauregui A; Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
  • Churpek MM; Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
  • Gomez AD; 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.
  • Hendrickson CM; Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, CA, USA.
  • Kangelaris KN; Division of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
  • Sarma A; Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
  • Leligdowicz A; Department of Medicine, Division of Critical Care Medicine, Robarts Research Institute, University of Western Ontario, London, ON, Canada.
  • Delucchi KL; Department of Psychiatry, University of California San Francisco, San Francisco, CA, USA.
  • Liu KD; 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.
  • Russell JA; 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.
  • Matthay MA; 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.
  • Walley KR; 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.
  • Ware LB; 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.
  • Calfee CS; 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.
Lancet Respir Med ; 11(11): 965-974, 2023 Nov.
Article en En | MEDLINE | ID: mdl-37633303
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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Síndrome de Dificultad Respiratoria / Choque Séptico / Sepsis Tipo de estudio: Clinical_trials / Prognostic_studies Límite: Adult / Humans Idioma: En Revista: Lancet Respir Med Año: 2023 Tipo del documento: Article
Texto completo
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Síndrome de Dificultad Respiratoria / Choque Séptico / Sepsis Tipo de estudio: Clinical_trials / Prognostic_studies Límite: Adult / Humans Idioma: En Revista: Lancet Respir Med Año: 2023 Tipo del documento: Article