4.5 Article

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

Publisher

AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00090.2020

Keywords

biomarkers; critical care; flow cytomehy; olfactomedin 4 (OLFM4); outcomes; sepsis

Funding

  1. National Heart, Lung, and Blood Institute [R37 HL51856, R01 HL134828, 1K23 HL116800, R35 HL140026]
  2. National Institutes of Health [KO8AI119134, RO1 AI113272]

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The study found that the percentage of OLFM4+ neutrophils is positively associated with mortality in sepsis patients. This may represent a novel measure of the heterogeneity of host response to 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 mu L 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.

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