Histidine-Rich Glycoprotein As a Prognostic Biomarker for Sepsis: A Multicenter Prospective Observational Cohort Study

Abstract

Background: Various biomarkers were used for sepsis; however, only a few become the standard. We reported that plasma histidine-rich glycoprotein (HRG) levels decreased in septic mice. Moreover, our clinical study on patients with systemic inflammatory response syndrome (SIRS) demonstrated that HRG levels in septic patients were lower than those in noninfective SIRS patients, and HRG could be a biomarker for sepsis within the SIRS population. In this study, we focused on septic patients and assessed the differences in HRG levels between the non-survivors and survivors. Methods: We studied intensive care unit (ICU) patients newly diagnosed with sepsis. Blood samples were collected within 24 h of ICU admission, and HRG levels were determined using an enzyme-linked immunosorbent assay. Findings: Ninety-nine septic patients from 11 institutes were included. HRG levels were significantly lower in non-survivors (n = 16) than in survivors (n = 83) (median, 15·1 [IQR, 12·7-16·6] vs. 30·6 [22·1-39·6] µg/ml; p < 0·01). Survival analysis revealed that the Harrell C-index (predictive power) for HRG was 0·90. Furthermore, when patients were divided into four subgroups according to quartiles of HRG level, the lowest HRG subgroup represented a significantly higher mortality. Interpretation: The initial HRG levels were found to be lower in non-survivors than in survivors. Decreased and classified HRG levels were also found to predict patient mortality. These results suggested that HRG could be a novel prognostic biomarker for sepsis. Trial Registration: UMIN Clinical Trials Registry (UMI17651). Funding Statement: This work was supported by grants from Japan Agency for Medical Research and Development (AMED) (AMED 15lk0201014h0003; AMED 18im0210109h0002), and from Secom Science and Technology Foundation to MN. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: This was a multicenter, prospective, and observational investigation approved by the Institutional Review Board of the Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, and of each institution.