Biomarkers of endothelial dysfunction predict sepsis mortality in young infants: a matched case-control study

Julie Korol Wright, Kyla Hayford, Vanessa Tran, Gulam Muhammed Al Kibria, Abdullah Baqui, Ali Manajjir, Arif Mahmud, Nazma Begum, Mashuk Siddiquee, Kevin C Kain, Azadeh Farzin, Julie Korol Wright, Kyla Hayford, Vanessa Tran, Gulam Muhammed Al Kibria, Abdullah Baqui, Ali Manajjir, Arif Mahmud, Nazma Begum, Mashuk Siddiquee, Kevin C Kain, Azadeh Farzin

Abstract

Background: Reducing death due to neonatal sepsis is a global health priority, however there are limited tools to facilitate early recognition and treatment. We hypothesized that measuring circulating biomarkers of endothelial function and integrity (i.e. Angiopoietin-Tie2 axis) would identify young infants with sepsis and predict their clinical outcome.

Methods: We conducted a matched case-control (1:3) study of 98 young infants aged 0-59 days of life presenting to a referral hospital in Bangladesh with suspected sepsis. Plasma levels of Ang-1, Ang-2, sICAM-1, and sVCAM-1 concentrations were measured at admission. The primary outcome was mortality (n = 18); the secondary outcome was bacteremia (n = 10).

Results: Ang-2 concentrations at presentation were higher among infants who subsequently died of sepsis compared to survivors (aOR 2.50, p = 0.024). Compared to surviving control infants, the Ang-2:Ang-1 ratio was higher among infants who died (aOR 2.29, p = 0.016) and in infants with bacteremia (aOR 5.72, p = 0.041), and there was an increased odds of death across Ang-2:Ang-1 ratio tertiles (aOR 4.82, p = 0.013).

Conclusions: This study provides new evidence linking the Angiopoietin-Tie2 pathway with mortality and bacteremia in young infants with suspected sepsis. If validated in additional studies, markers of the angiopoietin-Tie2 axis may have clinical utility in risk stratification of infants with suspected sepsis.

Keywords: Angiopoietins; Biomarkers; Endothelial activation; Neonatal Sepsis.

Conflict of interest statement

Ethics approval and consent to participate

Ethical approval for this study was granted from the University Health Network Research Ethics Board, University of Toronto; the Johns Hopkins Bloomberg School of Public Health; the Bangladesh Institute of Child Health Ethical Review Committee; and the Sylhet MAG Osmani Medical College Ethical Review Committee. Parents or guardians of enrolled infants provided written informed consent.

Consent for publication

Not applicable.

Competing interests

K.C.K. is listed as an inventor on patents related to the use of angiopoietin markers, entitled “Angiopoietin-1 and -2 biomarkers for infectious diseases that compromise endothelial integrity” (application no. WO2009059404) and “Biomarkers for early determination of a critical or life threatening response to illness and monitoring response to treatment” (application no. CA2769433). For the remaining authors, no competing interests were declared.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Study Flow Diagram. Infants in the matched case-control analysis included all infants from the Observational Cohort Study with an outcome of death (n = 18) or culture-confirmed bacteremia (n = 10) plus control infants who were randomly selected at a 3:1 ratio after matching on birthweight and age at admission
Fig. 2
Fig. 2
Distribution of angiogenic biomarkers by mortality, bacteremia, and combined outcomes. Circulating levels of Ang-2, sICAM-1 and the Ang-2:1 ratio at admission were associated with increased risk of death and the combined outcome of death and bacteremia. Only the Ang-2:1 ratio was significantly associated with bacteremia. Ang-1 levels at admission were not associated with any of the clinical outcomes. * indicates p < 0.05 based on conditional logistic regression adjusting for relevant confounding variables: sex and lethargy for mortality outcome, sex for bacteremia outcome, and sex, lethargy and temperature for combined case outcome

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