Circulating hypoxia-dependent miR-210 is increased in clinical sepsis subtypes: A cohort study

Patients with community-onset sepsis can be grouped into 4 distinct subtypes (alpha, beta, gamma, and delta) based on routinely available clinical data [1]. These subtypes differ both in outcome and response to treatment, though the biologic mechanisms underlying these differences are unknown. Because ischemic end-organ damage and endothelial dysfunction may contribute to differences in sepsis [2], we hypothesize that treatment-response subtypes may be partially explained by differential activation of hypoxia-mediated pathways. Multiple studies show that circulating microRNAs (miRNAs) are candidate biomarkers for acute illness, but research in sepsis is limited [3]. As a ubiquitously expressed miRNA that regulates key downstream responses to hypoxia [4] and can be delivered to the endothelium as a biologically active molecule from the circulating bloodstream [5], miR-210 is a promising candidate to study in sepsis.

This study was approved by the University of Pittsburgh Human Research Protection Office. The data were obtained under a waiver of informed consent and with authorization under the Health Insurance Portability and Accountability Act. We used electronic health record data and plasma EDTA from adult patients meeting Sepsis-3 criteria within 6 h of presentation to a tertiary care center in southwestern Pennsylvania from 2017 to 2019. Clinical data was used to assign patients to one of four sepsis subtypes, using reproduced methods [1]. We randomly selected 20 patients from each sepsis subtype, and 20 non-septic controls for comparison from prior acute illness cohorts. We extracted circulating miRNA from plasma and quantified expression of miR-210 using qRT-PCR. Fold change (FC) was determined relative to the non-septic controls. One-way ANOVA and pairwise t-tests, with Tukey’s procedure to adjust for multiple comparisons, was used to compare fold change after log transformation. We used multivariable logistic regression to quantify the risk-adjusted association between miR-210 expression and the delta subtype. Model covariates were chosen a priori based on factors known to be associated with sepsis-specific outcomes, including age, sex, Elixhauser Comorbidity Index (range, 0–31), and presenting Sequential Organ Failure Assessment (SOFA; range, 0–24) score. Further details are provided in the Supplement.

In this prospective cohort study, circulating miR-210 was significantly increased in all subtypes of sepsis compared to control, and was further enriched in the delta sepsis subtype. After adjusting for potential confounders, including illness severity, miR-210 expression is associated with membership in the delta subtype relative to non-delta sepsis. These data suggest that activation of hypoxia-mediated pathways may contribute to different clinical subtypes of sepsis and may inform future investigation of differential treatment response.