A neutrophil subset defined by intracellular olfactomedin 4 is associated with mortality in sepsis

Sepsis is a heterogeneous syndrome clinically and biologically, but biomarkers of distinct host response pathways for early prognostic information and testing targeted treatments are lacking. Olfactomedin 4 (OLFM4), a matrix glycoprotein of neutrophil-specific granules, defines a distinct neutrophil subset that may be an independent risk factor for poor outcomes in sepsis. We hypothesized that increased percentage of OLFM4⁺ neutrophils on sepsis presentation would be associated with mortality. In a single-center, prospective cohort study, we enrolled adults admitted to an academic medical center from the emergency department (ED) with suspected sepsis [identified by 2 or greater systemic inflammatory response syndrome (SIRS) criteria and antibiotic receipt] from March 2016 through December 2017, followed by sepsis adjudication according to Sepsis-3. We collected 200 µL of whole blood within 24 h of admission and stained for the neutrophil surface marker CD66b followed by intracellular staining for OLFM4 quantitated by flow cytometry. The predictors for 60-day mortality were 1) percentage of OLFM4⁺ neutrophils and 2) OLFM4⁺ neutrophils at a cut point of ≥37.6% determined by the Youden Index. Of 120 enrolled patients with suspected sepsis, 97 had sepsis and 23 had nonsepsis SIRS. The mean percentage of OLFM4⁺ neutrophils was significantly increased in both sepsis and nonsepsis SIRS patients who died (P ≤ 0.01). Among sepsis patients with elevated OLFM4⁺ (≥37.6%), 56% died, compared with 18% with OLFM4⁺ <37.6% (P = 0.001). The association between OLFM4⁺ and mortality withstood adjustment for age, sex, absolute neutrophil count, comorbidities, and standard measures of severity of illness (SOFA score, APACHE III) (P < 0.03). In summary, OLFM4⁺ neutrophil percentage is independently associated with 60-day mortality in sepsis and may represent a novel measure of the heterogeneity of host response to sepsis.