Evidence map›Paper›PMID 37633303›Full record

Observational studyThe Lancet. Respiratory medicine2023

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 and 17 more

Registry-linked trialOpen access · greenAbstract readObservational Study
PubMed Full text at PMC Publisher
In one paragraph

Observational study in The Lancet. Respiratory medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT07511582 (Efficacy, Safety, and Tolerability of Methylprednisolone in Critically Ill Patients With the Hyperinflammatory Phenotype), which is not on this map. Cited by 141 papers.

0numbers the graph read from it
0cells of the map it votes in
141citing papers in PubMed
36.5field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT07511582 phase2recruitingnot on this mapstarted 2026, after this paper: background citation

Efficacy, Safety, and Tolerability of Methylprednisolone in Critically Ill Patients With the Hyperinflammatory Phenotype: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase II Trial

TypeinterventionalSponsorBin DuRan2026 to 2028Enrolled150ConditionsSepsis, Acute Respiratory Distress SyndromeArmsMethylprednisolone (MP), Placebo
3 · Its place in the literature

Who cites it

141 citing papers in PubMed, 170 citations in OpenAlex.

  1. Trial
  2. Molecular Phenotyping of Sepsis and Differential Response to Fluid Resuscitation.American journal of respiratory and critical care medicine · 2025
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81 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

27 authors at 9 institutions in 2 countries.

Pratik SinhaDivision 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.
V Eric KerchbergerDivision of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Andrew WillmoreDivision of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
Julia ChambersDepartment of Medicine, University of California San Francisco, San Francisco, CA, USA.
Hanjing ZhuoDivision 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.
Jason AbbottDivision 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.
Chayse JonesDivision 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.
Nancy WickershamDivision of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Nelson WuDivision of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
Lucile NeytonDivision 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.
Charles R LangelierDivision of Infectious Diseases, Department of Medicine, University of California San Francisco, San Francisco, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA.
Eran MickDivision of Infectious Diseases, Department of Medicine, University of California San Francisco, San Francisco, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA.
June HeDivision of Clinical and Translational Research, Division of Critical Care, Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA.
Alejandra JaureguiDivision of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
Matthew M ChurpekDepartment of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
Antonio D GomezDivision 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.
Carolyn M HendricksonZuckerberg San Francisco General Hospital and Trauma Center, San Francisco, CA, USA.
Kirsten N KangelarisDivision of Hospital Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
Aartik SarmaDivision of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
Aleksandra LeligdowiczDepartment of Medicine, Division of Critical Care Medicine, Robarts Research Institute, University of Western Ontario, London, ON, Canada.
Kevin L DelucchiDepartment of Psychiatry, University of California San Francisco, San Francisco, CA, USA.
Kathleen D LiuDivision 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.
James A RussellDivision 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.
Michael A MatthayDivision 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.
Keith R WalleyDivision 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.
Lorraine B WareDivision 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.
Carolyn S CalfeeDivision 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.
University of California, San Francisco · USUniversity of California System · USVanderbilt University Medical Center · USSt. Paul's Hospital · CAWashington University in St. Louis · USChan Zuckerberg Initiative (United States) · USSan Francisco General Hospital · USUniversity of Wisconsin–Madison · USWestern University · CA

Funding

Precision Medicine in the Acute Respiratory Distress SyndromeR35HL140026 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CALFEE, CAROLYN · 2018 to 2024
$6.8M
Precision Medicine in Sepsis with Critical IllnessR35GM142992 · NIGMS · WASHINGTON UNIVERSITY · PI Pratik Sinha · 2021 to 2026
$2.4M
Haptoglobin 2 variant and endothelial glycocalyx shedding in sepsis-induced ARDSR01HL158906 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI WARE, LORRAINE B · 2021 to 2024
$2.3M
Sepsis Early Prediction and Subphenotype Illumination Study (SEPSIS)R35GM145330 · NIGMS · UNIVERSITY OF WISCONSIN-MADISON · PI Matthew Michael Churpek · 2022 to 2026
$1.9M
Mechanisms of organ dysfunction and recovery in the Acetaminophen and Ascorbate Trial in SepsisR01HL164937 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI WARE, LORRAINE B · 2022 to 2025
$1.7M
Tissue-specific functional genomics in the acute respiratory distress syndromeK01HL157755 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI KERCHBERGER, VERN ERIC · 2021 to 2025
$845k
NHLBI NIH HHS K01 HL157755NHLBI NIH HHS R01 HL158906NHLBI NIH HHS R01 HL164937NHLBI NIH HHS R35 HL140026NIGMS NIH HHS R35 GM142992NIGMS NIH HHS R35 GM145330
6 · The paper itself

Abstract

backgroundIn 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.

methodsWe 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.

findingsA 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).

interpretationMolecular 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.

fundingUS National Institutes of Health.

Indexed as

Respiratory Distress SyndromeSepsisShock, SepticAdultBiomarkersHumansPhenotypeProspective StudiesProtein CRandomized Controlled Trials as TopicRetrospective StudiesVasoconstrictor AgentsBiomarkersProtein CVasoconstrictor Agents

Identifiers

PMID37633303
PMCPMC10841178
OpenAlexW4386102775

What OpenQuestion holds

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.