Prognostic accuracy of biomarkers of immune and endothelial activation in Mozambican children hospitalized with pneumonia

Abstract

Pneumonia is a leading cause of child mortality. However, currently we lack simple, objective, and accurate risk-stratification tools for pediatric pneumonia. Here we test the hypothesis that measuring biomarkers of immune and endothelial activation in children with pneumonia may facilitate the identification of those at risk of death. We recruited children <10 years old fulfilling WHO criteria for pneumonia and admitted to the Manhiça District Hospital (Mozambique) from 2010 to 2014. We measured plasma levels of IL-6, IL-8, Angpt-2, sTREM-1, sFlt-1, sTNFR1, PCT, and CRP at admission, and assessed their prognostic accuracy for in-hospital, 28-day, and 90-day mortality. Healthy community controls, within same age strata and location, were also assessed. All biomarkers were significantly elevated in 472 pneumonia cases versus 80 controls (p<0.001). IL-8, sFlt-1, and sTREM-1 were associated with in-hospital mortality (p<0.001) and showed the best discrimination with AUROCs of 0.877 (95% CI: 0.782 to 0.972), 0.832 (95% CI: 0.729 to 0.935) and 0.822 (95% CI: 0.735 to 0.908), respectively. Their performance was superior to CRP, PCT, oxygen saturation, and clinical severity scores. IL-8, sFlt-1, and sTREM-1 remained good predictors of 28-day and 90-day mortality. These findings suggest that measuring IL-8, sFlt-1, or sTREM-1 at hospital presentation can guide risk-stratification of children with pneumonia, which could enable prioritized care to improve survival and resource allocation.

Fig 1. Plasma concentrations of immune and endothelial activation biomarkers at study enrolment in healthy community controls, pneumonia cases discharged alive, and pneumonia cases who died during hospital stay.

Boxplots with median and interquartile range. Whiskers represent one and a half times the interquartile range, and outliers are plotted as individual points. Concentrations are in pg/mL, except CRP in μg/mL. p-values were computed using the Mann-Whitney U test. *p<0.05, **<0.01; ***p<0.001; ns: non-significant. Abbreviations: Angpt-2 (angiopoietin-2), CRP (C-reactive protein), IL-6 (interleukin-6), IL-8 (interleukin-8), PCT (procalcitonin), sFlt-1 (soluble fms-like tyrosine kinase-1), sTNFR1 (soluble tumor necrosis factor receptor), sTREM-1 (soluble triggering receptor expressed on myeloid cells 1).

Fig 2. AUROCs of immune and endothelial activation biomarkers and clinical parameters.

(A) IL-8, sFlt-1, sTREM-1, sTNFR1, Angpt-2, PCT, and IL-6 AUROCs for in-hospital deaths (n = 432). (B) IL-8, sFlt-1, sTREM-1, and CRP AUROCs for in-hospital deaths (n = 421). (C) IL-8, sFlt-1, and sTREM-1 AUROCs for 28-day and 90-day mortality (in-hospital & post-discharge) (n = 309). (D) IL-8 and clinical parameters AUROCs for in-hospital deaths (n = 405). Abbreviations: Angpt-2 (angiopoietin-2), AUROC (area under the receiver operating characteristic curve), CRP (C-reactive protein), IL-6 (interleukin-6), IL-8 (interleukin-8), LODS (Lambaréné Organ Dysfunction Score), PCT (procalcitonin), RISC-Malawi (Respiratory Index of Severity in Children-Malawi), sFlt-1 (soluble fms-like tyrosine kinase-1), sTNFR1 (soluble tumor necrosis factor receptor), sTREM-1 (soluble triggering receptor expressed on myeloid cells 1), WHO (World Health Organization).