Pre-illness Clonal Hematopoiesis of Indeterminate Potential is Associated with Increased Morbidity and Mortality in Sepsis

Purpose: Sepsis is a life-threatening syndrome causing significant morbidity and mortality, especially in older adults. Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition linked to chronic illness and all-cause mortality. Here, we evaluated 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. Results: The cohort comprised 220 patients with pre-illness CHIP and 3,010 patients without. 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. Uncovering the mechanism behind this link could lead to new treatments for sepsis, especially for the aging population.