Feature ArticlesSepsis Subclasses: A Framework for Development and Interpretation*DeMerle, Kimberley M. MD1; Angus, Derek C. MD, MPH1; Baillie, J. Kenneth MD, PhD2; Brant, Emily MD1; Calfee, Carolyn S. MD, MAS3; Carcillo, Joseph MD4; Chang, Chung-Chou H. PhD1,5,6; Dickson, Robert MD7; Evans, Idris MD, MSc1; Gordon, Anthony C. MD8; Kennedy, Jason MS1; Knight, Julian C. MD9; Lindsell, Christopher J. PhD10; Liu, Vincent MD, MS11; Marshall, John C. MD12; Randolph, Adrienne G. MD, MSc13; Scicluna, Brendon P. PhD14,15; Shankar-Hari, Manu MD, MSc16,17; Shapiro, Nathan I. MD18; Sweeney, Timothy E. MD, PhD19; Talisa, Victor B. PhD1,6; Tang, Benjamin MD, PhD20; Thompson, B. Taylor MD21; Tsalik, Ephraim L. MD, PhD22; van der Poll, Tom MD, PhD14; van Vught, Lonneke A. MD, PhD14; Wong, Hector R. MD23; Yende, Sachin MD, MS1; Zhao, Huiying MD24; Seymour, Christopher W. MD, MSc1Author Information 1 Department of Critical Care Medicine, The Clinical Research, Investigation, and Systems Modeling of Acute illness (CRISMA) Center, University of Pittsburgh School of Medicine, Pittsburgh, PA. 2 Anaesthesia, Critical Care, and Pain Medicine, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom. 3 Division of Pulmonary and Critical Care Medicine, University of California San Francisco, San Francisco, CA. 4 Division of Pediatric Critical Care Medicine, Department of Critical Care Medicine, Children’s Hospital of Pittsburgh, Pittsburgh, PA. 5 Department of Medicine, University of Pittsburgh, Pittsburgh, PA. 6 Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA. 7 Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan, Ann Arbor, MI. 8 Division of Anaesthetics, Pain Medicine, and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom. 9 Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. 10 Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN. 11 Kaiser Permanente Division of Research, Oakland, CA. 12 Keenan Research Centre for Biomedical Science, St Michael’s Hospital, Toronto, ON, Canada. 13 Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Boston, MA. 14 Center for Experimental and Molecular Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 15 Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 16 Guy’s and St Thomas’ NHS Foundation Trust, ICU support Offices, St Thomas’ Hospital, London, United Kingdom. 17 School of Immunology and Microbial Sciences, Kings College London, London, United Kingdom. 18 Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA. 19 Inflammatix, Burlingame, CA. 20 Department of Intensive Care Medicine, Nepean Hospital, Sydney, NSW, Australia. 21 Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA. 22 Department of Medicine, Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC. 23 Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center and Cincinnati Children’s Research Foundation, Cincinnati, OH. 24 Department of Critical Care Medicine, Peking University People’s Hospital, Beijing, China. *See also p. 861. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and social care. The funding source did not have any role in the design, conduct or interpretation of study results. Dr. Seymour helped in designing the concept. Drs. DeMerle, Angus, and Seymour helped in designing. Drs. DeMerle, Baille, Brant, Calfee, Carcillo, Chang, Dickson, Evans, Gordon, Kennedy, Knight, Lindsell, Liu, Marshall, Randolph, Scicluna, Shankar-Hari, Shapiro, Sweeney, Talis, Tang, Thompson, Tsalik, van der Poll, van Vught, Wong, Yende, Zhao, and Seymour drafted the article and critically revised the article for important intellectual content. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). 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. For information regarding this article, E-mail: [email protected] Critical Care Medicine: May 2021 - Volume 49 - Issue 5 - p 748-759 doi: 10.1097/CCM.0000000000004842 Buy SDC Metrics 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. Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.