Repeated measurements of endothelin-1 precursor peptides predict the outcome in community-acquired pneumonia

Excessive activation of the endothelium is associated with adverse outcomes in patients with systemic infections. Endothelium-associated peptides, such as endothelin-1 (ET-1), correlate closely with endothelial activation, and therefore serve as surrogate biomarkers. Our aim was to investigate precursor peptides of endothelin-1 (proET1) on admission and during follow-up on days 3, 5 and 7 in a prospective cohort of 925 patients with community-acquired pneumonia.

We investigated the association of initial and follow-up proET1 and other prohormone levels with 30-day mortality and ICU admission in proportional Cox regression models with time-varying covariates adjusted for the pneumonia-severity-index (PSI), and calculated reclassification statistics.

The mortality rate and ICU admission rate were 5.4% (95% CI 3.9-6.8%) and 9.0% (95% CI 7.1-10.8%). ProET1 levels on admission and changes from baseline to day 3 were significant mortality predictors with adjusted hazard ratios of 10.5 (95% CI 2.9-38.6) and 28.4 (95% CI 7.0-115.1). Initial proET1 levels improved the PSI in reclassification statistics (net reclassification improvement of 0.29, p<0.0001) and in c-statistics (from 0.79 to 0.83, p<0.01). Changes of proET1 on day 3 improved the c-statistic of the combined model of PSI and initial proET1 from 0.80 to 0.85 (p<0.01) and reclassification tables demonstrated a significant improvement (net reclassification improvement 0.44, p<0.0001). Similar significant results were found for the risk for ICU admission.

In community-acquired pneumonia, ET-1 precursor peptides on admission and changes from baseline to day 3 were independent predictors for mortality and ICU admission, and significantly improved the PSI. If verified in intervention studies, monitoring of proET1 may be helpful for endothelium targeting therapies and for risk stratification complementary to other prohormones.