Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 May 1;49(5):748-759.
doi: 10.1097/CCM.0000000000004842.

Sepsis Subclasses: A Framework for Development and Interpretation

Kimberley M DeMerle  1 , Derek C Angus  1 , J Kenneth Baillie  2 , Emily Brant  1 , Carolyn S Calfee  3 , Joseph Carcillo  4 , Chung-Chou H Chang  1   5   6 , Robert Dickson  7 , Idris Evans  1 , Anthony C Gordon  8 , Jason Kennedy  1 , Julian C Knight  9 , Christopher J Lindsell  10 , Vincent Liu  11 , John C Marshall  12 , Adrienne G Randolph  13 , Brendon P Scicluna  14   15 , Manu Shankar-Hari  16   17 , Nathan I Shapiro  18 , Timothy E Sweeney  19 , Victor B Talisa  1   6 , Benjamin Tang  20 , B Taylor Thompson  21 , Ephraim L Tsalik  22 , Tom van der Poll  14 , Lonneke A van Vught  14 , Hector R Wong  23 , Sachin Yende  1 , Huiying Zhao  24 , Christopher W Seymour  1
Affiliations

Sepsis Subclasses: A Framework for Development and Interpretation

Kimberley M DeMerle et al. Crit Care Med. .

Abstract

Sepsis is defined as a dysregulated host response to infection that leads to life-threatening acute organ dysfunction. It afflicts approximately 50 million people worldwide annually and is often deadly, even when evidence-based guidelines are applied promptly. Many randomized trials tested therapies for sepsis over the past 2 decades, but most have not proven beneficial. This may be because sepsis is a heterogeneous syndrome, characterized by a vast set of clinical and biologic features. Combinations of these features, however, may identify previously unrecognized groups, or "subclasses" with different risks of outcome and response to a given treatment. As efforts to identify sepsis subclasses become more common, many unanswered questions and challenges arise. These include: 1) the semantic underpinning of sepsis subclasses, 2) the conceptual goal of subclasses, 3) considerations about study design, data sources, and statistical methods, 4) the role of emerging data types, and 5) how to determine whether subclasses represent "truth." We discuss these challenges and present a framework for the broader study of sepsis subclasses. This framework is intended to aid in the understanding and interpretation of sepsis subclasses, provide a mechanism for explaining subclasses generated by different methodologic approaches, and guide clinicians in how to consider subclasses in bedside care.

PubMed Disclaimer

Conflict of interest statement

Dr. DeMerle’s institution received funding from R35 GM119519-03 and T32HL007820. Dr. Calfee is supported in part by grants from the National Institutes of Health (NIH; HL140026). Dr. Carcillo is supported in part by grants from the National Institutes of Health (R01GM108618). Dr. DeMerle is supported in part by grants from the National Institutes of Health (T32HL007820). Dr. Angus received funding from Ferring Pharmaceuticals, Bristol-Myers Squibb, Bayer AG, and Alung Technologies. Drs. Angus, Brant, Carcillo, Chang, Dickson, Kennedy, Lindsell, Liu, Randolph, Thompson, Tsalik, Wong, and Seymour received support for article research from the NIH. Dr. Baillie received support for article research from Wellcome Trust/Charity Open Access Fund (COAF), and Research Councils UK. Dr. Calfee’s institution received funding from Roche/Genentech and Bayer, and she received funding from Roche/Genentech, Quark, CSL Behring, Bayer, Gen1e Life Sciences, and Vasomune. Drs. Carcillo’s and Seymour’s institutions received funding from the National Institute of General Medical Sciences. Drs. Chang’s, Lindsell’s, Liu’s, Randolph’s, Shapiro’s, and Wong’s institutions received funding from the NIH. Dr. Gordon’s institution received funding from the National Institute for Health Research (NIHR) Research Professorship (RP-2015-06-18), NIHR Imperial Biomedical Research Centre, GlaxoSmithKline, and Bristol Myers Squibb. Dr. Knight received support for article research from Wellcome Trust/COAF. Dr. Lindsell’s institution received funding from the Centers for Disease Control and Prevention (CDC), Department of Defense, Marcus Foundation, Entegrion, Endpoint Health, and bioMerieux, and he disclosed he is a coinventor on patents related to risk stratification in septic shock. Dr. Marshall received funding from AM Pharma, AKPA Pharma, and the Society of Critical Care Medicine (Critical Care Medicine Associate Editor). Dr. Randolph’s institution received funding from the CDC, and she received funding from La Jolla Pharma. Dr. Shapiro’s institution received funding from rapid pathogen screening, Baxter, and Inflammatix, and he received funding from Diagnostic Robotics. Dr. Sweeney received funding from Inflammatix. Dr. Thompson’s institution received funding from the National Heart, Lung, and Blood Institute, and he received funding from Bayer and Thetis. Dr. Tsalik disclosed that he is a founder and holds equity in Predigen; he receives salary support from the Durham VA Healthcare System and Duke University; and he has received salary support and/or grant funding (paid to his university) from the NIH, DARPA, DTRA, Karius, and Sanofi US. Dr. Wong disclosed that he and his institutions hold U.S. patents for sepsis biomarkers. Dr. Yende received funding from serving as consultant for expert testimony and he disclosed government work. Dr. Knight is supported by a Wellcome Trust Investigator Award (204969/Z/16/Z) and the NIHR Oxford Biomedical Research Centre. Dr. Lindsell was supported in part by grants from the National Institutes of Health (R35GM126943, R01HL149422), a research grant to VUMC from Endpoint Health, and is also listed as co-inventor on patents for endotyping and risk-stratification in pediatric septic shock. Dr. Liu is supported in part by grants from the National Institutes of Health (R35GM128672). Dr. Marshall is supported in part by grants from the Canadian Institutes of Health Research. Dr. Randolph is supported in part by grants from the National Institutes of Health (R21HD095228). Dr. Shankar-Hari is supported by the National Institute for Health Research Clinician Scientist Award (CS-2016-16-011). Dr. Wong is supported in part by grants from the National Institutes of Health (R35 GM126943). Dr. Sweeney is an employee of, and shareholder in, Inflammatix. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Figures

Figure 1.
Figure 1.
The ideal case in sepsis subclasses involves the integration across different compartments that is; A, (i) suggestive of biologic mechanism, (ii) prognostic of outcome, and/or (iii) predictive of treatment response. However, there are challenges in sepsis subclasses, including: uncertainty (B), missing data (C), different statistical methods (D), and different study types (E).
Figure 2.
Figure 2.
Proposed nomenclature for sepsis subclasses. RCT = randomized clinical trial, UTI = urinary tract infection.
See this image and copyright information in PMC

Comment in

  • Moving Forward With Refinement of Definitions for Sepsis.
    Abraham E. Abraham E. Crit Care Med. 2021 May 1;49(5):861-863. doi: 10.1097/CCM.0000000000004856. Crit Care Med. 2021. PMID: 33854010 No abstract available.
  • Plausibility Limits Imagination.
    Zijlstra JG, van Meurs M, Moser J. Zijlstra JG, et al. Crit Care Med. 2021 Oct 1;49(10):e1047. doi: 10.1097/CCM.0000000000005043. Crit Care Med. 2021. PMID: 34529625 No abstract available.
  • The authors reply.
    DeMerle KM, Seymour CW. DeMerle KM, et al. Crit Care Med. 2021 Oct 1;49(10):e1048. doi: 10.1097/CCM.0000000000005115. Crit Care Med. 2021. PMID: 34529626 Free PMC article. No abstract available.

References

    1. Singer M, Deutschman CS, Seymour CW, et al.: The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016; 315:801–810 - PMC - PubMed
    1. Shankar-Hari M, Phillips GS, Levy ML, et al.; Sepsis Definitions Task Force: Developing a new definition and assessing new clinical criteria for septic shock: For the third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016; 315:775–787 - PMC - PubMed
    1. Rudd KE, Johnson SC, Agesa KM, et al.: Global, regional, and national sepsis incidence and mortality, 1990-2017: Analysis for the global burden of disease study. Lancet 2020; 395:200–211 - PMC - PubMed
    1. Marshall JC: Why have clinical trials in sepsis failed? Trends Mol Med 2014; 20:195–203 - PubMed
    1. Seymour CW, Liu VX, Iwashyna TJ, et al.: Assessment of clinical criteria for sepsis: For the third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016; 315:762–774 - PMC - PubMed

Publication types