Rationale Sepsis is a life-threatening syndrome causing significant morbidity and mortality especially in the aging population. Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition of clonal expansion of hematopoietic stem cells harboring somatic mutations associated with increased incidence of chronic illness and all-cause mortality.

Objective Evaluate the association of pre-illness CHIP with mortality and morbidity in patients admitted to the ICU with sepsis.

Methods We performed a retrospective study using a de-identified electronic health record linked with a DNA biorepository. We identified adult patients with sepsis who had DNA collected prior to ICU admission. We tested the association between CHIP status, determined from whole-genome sequencing, and ICU mortality, organ support-free days, and long-term survival adjusting for age, sex, race and Sequential Organ Failure Assessment (SOFA) score on ICU admission.

Measurements and Main Results Pre-illness CHIP was associated with increased sepsis mortality (OR = 1.54, 95% CI 1.13 to 2.07, P = 0.005) and fewer days alive and free of organ support (−1.7 days, 95% CI −3.2 to −0.2, P = 0.028) after adjusting for age, sex, race, and SOFA score. In sepsis survivors, CHIP was also associated with increased long-term mortality after discharge (HR 1.40, 95% CI 1.01 to 1.93, P = 0.041).

Conclusions Pre-illness CHIP was independently associated with increased mortality and morbidity in critically-ill adults with sepsis. These findings suggest that CHIP is a risk factor for sepsis severity. Elucidating the mechanism underlying this association could uncover new therapeutic interventions for sepsis.

The authors have declared no competing interest.

Vanderbilt University Medical Center BioVU projects are supported by numerous sources: institutional funding, private agencies, and federal grants. These include NIH funded Shared Instrumentation Grant S10OD017985, S10RR025141, and S10OD025092; CTSA grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, R01HD074711; and additional funding sources listed at https://victr.vumc.org/biovu-funding/. The sequencing of WGS individuals from BioVU, including the 35,024 described here, has been funded by the Alliance for Genomic Discovery consisting of NashBio, Illumina and industry partners Amgen, AbbVie, AstraZeneca, Bayer, BMS, GSK, Merck Sharp & Dohme LLC, and Novo Nordisk. DNA sequencing was performed at deCODE genetics using Illumina sequencing technology. This work was also supported by National Heart, Lung, and Blood Institute (NHLBI) K01HL157755 (V.E.K.); National Institute on Aging F30AG099331 (Y.P.); funding from Arthritis Foundation (Pilot Award), the Rheumatology Research Foundation (K Bridge Award) and the Arthritis National Research Foundation (Grant #1288083) (R.W.C.); NHLBI grants HL164937 and HL158906 (L.B.W.).

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