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Original Investigation
Caring for the Critically Ill Patient
May 19, 2019

Derivation, Validation, and Potential Treatment Implications of Novel Clinical Phenotypes for Sepsis

Author Affiliations
  • 1Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 2Department of Emergency Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 3Clinical Research, Investigation, and Systems Modeling of Acute Illness Center, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 4Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 5Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 6Berry Consultants, Austin, Texas
  • 7Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 8Department of Sports Medicine and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 9Department of Medicine, Infectious Disease Division, Rhode Island Hospital, Providence
  • 10Center of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
  • 11Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 12Machine Learning Department, Carnegie Mellon University, Pittsburgh, Pennsylvania
  • 13Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania
JAMA. 2019;321(20):2003-2017. doi:10.1001/jama.2019.5791
Key Points

Question  Are clinical sepsis phenotypes identifiable at hospital presentation correlated with the biomarkers of host response and clinical outcomes and relevant for understanding the heterogeneity of treatment effects?

Findings  In this retrospective analysis using data from 63 858 patients in 3 observational cohorts, 4 novel sepsis phenotypes (α, β, γ, and δ) with different demographics, laboratory values, and patterns of organ dysfunction were derived, validated, and shown to correlate with biomarkers and mortality. In the simulations using data from 3 randomized clinical trials involving 4737 patients, the outcomes related to the treatments were sensitive to changes in the distribution of these phenotypes.

Meaning  Four novel clinical phenotypes of sepsis were identified that correlated with host-response patterns and clinical outcomes and may help inform the design and interpretation of clinical trials.


Importance  Sepsis is a heterogeneous syndrome. Identification of distinct clinical phenotypes may allow more precise therapy and improve care.

Objective  To derive sepsis phenotypes from clinical data, determine their reproducibility and correlation with host-response biomarkers and clinical outcomes, and assess the potential causal relationship with results from randomized clinical trials (RCTs).

Design, Settings, and Participants  Retrospective analysis of data sets using statistical, machine learning, and simulation tools. Phenotypes were derived among 20 189 total patients (16 552 unique patients) who met Sepsis-3 criteria within 6 hours of hospital presentation at 12 Pennsylvania hospitals (2010-2012) using consensus k means clustering applied to 29 variables. Reproducibility and correlation with biological parameters and clinical outcomes were assessed in a second database (2013-2014; n = 43 086 total patients and n = 31 160 unique patients), in a prospective cohort study of sepsis due to pneumonia (n = 583), and in 3 sepsis RCTs (n = 4737).

Exposures  All clinical and laboratory variables in the electronic health record.

Main Outcomes and Measures  Derived phenotype (α, β, γ, and δ) frequency, host-response biomarkers, 28-day and 365-day mortality, and RCT simulation outputs.

Results  The derivation cohort included 20 189 patients with sepsis (mean age, 64 [SD, 17] years; 10 022 [50%] male; mean maximum 24-hour Sequential Organ Failure Assessment [SOFA] score, 3.9 [SD, 2.4]). The validation cohort included 43 086 patients (mean age, 67 [SD, 17] years; 21 993 [51%] male; mean maximum 24-hour SOFA score, 3.6 [SD, 2.0]). Of the 4 derived phenotypes, the α phenotype was the most common (n = 6625; 33%) and included patients with the lowest administration of a vasopressor; in the β phenotype (n = 5512; 27%), patients were older and had more chronic illness and renal dysfunction; in the γ phenotype (n = 5385; 27%), patients had more inflammation and pulmonary dysfunction; and in the δ phenotype (n = 2667; 13%), patients had more liver dysfunction and septic shock. Phenotype distributions were similar in the validation cohort. There were consistent differences in biomarker patterns by phenotype. In the derivation cohort, cumulative 28-day mortality was 287 deaths of 5691 unique patients (5%) for the α phenotype; 561 of 4420 (13%) for the β phenotype; 1031 of 4318 (24%) for the γ phenotype; and 897 of 2223 (40%) for the δ phenotype. Across all cohorts and trials, 28-day and 365-day mortality were highest among the δ phenotype vs the other 3 phenotypes (P < .001). In simulation models, the proportion of RCTs reporting benefit, harm, or no effect changed considerably (eg, varying the phenotype frequencies within an RCT of early goal-directed therapy changed the results from >33% chance of benefit to >60% chance of harm).

Conclusions and Relevance  In this retrospective analysis of data sets from patients with sepsis, 4 clinical phenotypes were identified that correlated with host-response patterns and clinical outcomes, and simulations suggested these phenotypes may help in understanding heterogeneity of treatment effects. Further research is needed to determine the utility of these phenotypes in clinical care and for informing trial design and interpretation.