TY - JOUR
T1 - Uncovering heterogeneity in sepsis
T2 - a comparative analysis of subphenotypes
AU - van Amstel, Rombout B. E.
AU - Kennedy, Jason N.
AU - Scicluna, Brendon P.
AU - Bos, Lieuwe D. J.
AU - Peters-Sengers, Hessel
AU - Butler, Joe M.
AU - Cano-Gamez, Eddie
AU - Knight, Julian C.
AU - Vlaar, Alexander P. J.
AU - Cremer, Olaf L.
AU - Angus, Derek C.
AU - van der Poll, Tom
AU - Seymour, Christopher W.
AU - van Vught, Lonneke A.
AU - the MARS consortium
AU - de Beer, Friso M.
AU - Bos, Lieuwe D. J.
AU - Glas, Gerie J.
AU - Hoogendijk, Arie J.
AU - van Hooijdonk, Roosmarijn T. M.
AU - Horn, Janneke
AU - Huson, Mischa A.
AU - Schouten, Laura R. A.
AU - Schultz, Marcus J.
AU - Scicluna, Brendon P.
AU - Straat, Marleen
AU - van Vught, Lonneke A.
AU - Wieske, Luuk
AU - Wiewel, Maryse A.
AU - Witteveen, Esther
AU - Bonten, Marc J. M.
AU - Cremer, Olaf M.
AU - Ong, David S. Y.
AU - Frencken, Jos F.
AU - Klouwenberg, Peter M. C. Klein
AU - Koster‐Brouwer, Maria E.
AU - van de Groep, Kirsten
AU - Verboom, Diana M.
N1 - Funding Information: Supported by the Center for Translational Molecular Medicine ( http://www.ctmm.nl ), project MARS (grant 04I-201). Lonneke A van Vught was supported by the Netherlands Organisation for Health Research and Development ZonMW (Nederlandse Organisatie voor Wetenschappelijk Onderzoek NWO) VENI grant 09150161910033 and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Research Grant. Christopher W Seymour was funded in part by grants from the National Institutes of Health (R35GM119519, R21GM144851). The funders of the study had no role in design and conduct of the study; collection, management, analysis interpretation of the data or preparation, review, approval of the manuscript or the decision to submit. Publisher Copyright: © 2023, The Author(s).
PY - 2023/11
Y1 - 2023/11
N2 - Purpose: The heterogeneity in sepsis is held responsible, in part, for the lack of precision treatment. Many attempts to identify subtypes of sepsis patients identify those with shared underlying biology or outcomes. To date, though, there has been limited effort to determine overlap across these previously identified subtypes. We aimed to determine the concordance of critically ill patients with sepsis classified by four previously described subtype strategies. Methods: This secondary analysis of a multicenter prospective observational study included 522 critically ill patients with sepsis assigned to four previously established subtype strategies, primarily based on: (i) clinical data in the electronic health record (α, β, γ, and δ), (ii) biomarker data (hyper- and hypoinflammatory), and (iii–iv) transcriptomic data (Mars1–Mars4 and SRS1–SRS2). Concordance was studied between different subtype labels, clinical characteristics, biological host response aberrations, as well as combinations of subtypes by sepsis ensembles. Results: All four subtype labels could be adjudicated in this cohort, with the distribution of the clinical subtype varying most from the original cohort. The most common subtypes in each of the four strategies were γ (61%), which is higher compared to the original classification, hypoinflammatory (60%), Mars2 (35%), and SRS2 (54%). There was no clear relationship between any of the subtyping approaches (Cramer’s V = 0.086–0.456). Mars2 and SRS1 were most alike in terms of host response biomarkers (p = 0.079–0.424), while other subtype strategies showed no clear relationship. Patients enriched for multiple subtypes revealed that characteristics and outcomes differ dependent on the combination of subtypes made. Conclusion: Among critically ill patients with sepsis, subtype strategies using clinical, biomarker, and transcriptomic data do not identify comparable patient populations and are likely to reflect disparate clinical characteristics and underlying biology.
AB - Purpose: The heterogeneity in sepsis is held responsible, in part, for the lack of precision treatment. Many attempts to identify subtypes of sepsis patients identify those with shared underlying biology or outcomes. To date, though, there has been limited effort to determine overlap across these previously identified subtypes. We aimed to determine the concordance of critically ill patients with sepsis classified by four previously described subtype strategies. Methods: This secondary analysis of a multicenter prospective observational study included 522 critically ill patients with sepsis assigned to four previously established subtype strategies, primarily based on: (i) clinical data in the electronic health record (α, β, γ, and δ), (ii) biomarker data (hyper- and hypoinflammatory), and (iii–iv) transcriptomic data (Mars1–Mars4 and SRS1–SRS2). Concordance was studied between different subtype labels, clinical characteristics, biological host response aberrations, as well as combinations of subtypes by sepsis ensembles. Results: All four subtype labels could be adjudicated in this cohort, with the distribution of the clinical subtype varying most from the original cohort. The most common subtypes in each of the four strategies were γ (61%), which is higher compared to the original classification, hypoinflammatory (60%), Mars2 (35%), and SRS2 (54%). There was no clear relationship between any of the subtyping approaches (Cramer’s V = 0.086–0.456). Mars2 and SRS1 were most alike in terms of host response biomarkers (p = 0.079–0.424), while other subtype strategies showed no clear relationship. Patients enriched for multiple subtypes revealed that characteristics and outcomes differ dependent on the combination of subtypes made. Conclusion: Among critically ill patients with sepsis, subtype strategies using clinical, biomarker, and transcriptomic data do not identify comparable patient populations and are likely to reflect disparate clinical characteristics and underlying biology.
KW - ARDS
KW - Intensive care
KW - Phenotype
KW - Precision medicine
KW - Sepsis
UR - http://www.scopus.com/inward/record.url?scp=85174612428&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s00134-023-07239-w
DO - https://doi.org/10.1007/s00134-023-07239-w
M3 - Article
C2 - 37851064
SN - 0342-4642
VL - 49
SP - 1360
EP - 1369
JO - Intensive care medicine
JF - Intensive care medicine
IS - 11
ER -