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Observational Study
. 2019 Apr 23;5(10):e127623.
doi: 10.1172/jci.insight.127623.

Biomarkers of endothelial activation/dysfunction distinguish sub-groups of Ugandan patients with sepsis and differing mortality risks

Danielle V Clark  1 , Patrick Banura  2 , Karen Bandeen-Roche  3 , W Conrad Liles  4 , Kevin C Kain  5 , W Michael Scheld  6 , William J Moss  3 , Shevin T Jacob  7
Affiliations
Observational Study

Biomarkers of endothelial activation/dysfunction distinguish sub-groups of Ugandan patients with sepsis and differing mortality risks

Danielle V Clark et al. JCI Insight. .

Abstract

Background: Sepsis is a complex clinical syndrome with substantial heterogeneity. We sought to identify patterns of serum biomarkers of endothelial activation and dysfunction in individuals with sepsis and evaluate subgroup-specific differences in mortality.

Methods: Adult patients with sepsis (n=426) were consecutively recruited from two hospitals in Uganda. Clinical information was collected and serum concentrations of eleven biomarkers involved in the endothelial response to infection were measured in samples from 315 patients. Latent variable models were fit to evaluate whether the endothelial response to sepsis consists of one unified biological process or multiple processes and to identify subgroups of patients with distinct host-response profiles. Differences in survival at day 28 were evaluated using Kaplan-Meier survival curves.

Results: We identified three patient subgroups characterized by unique host endothelial response profiles. Patients fitting Profile 2 had significantly worse survival (log-rank p<0.001). Four latent factors (Factor 1-4) were identified, each potentially representing distinct biological processes for the endothelial response to sepsis: Factor 1 (CHI3L1, sTREM1, sFLT1); Factor 2 (ANGPT1, PF4, VEGF); Factor 3 (CXCL10, VWF, sICAM1); and Factor 4 (ANGPT2, sTEK).

Conclusion: Patient profiles based on patterns of circulating biomarkers of endothelial responses may provide a clinically meaningful way to categorize patients into homogeneous subgroups and may identify patients with a high risk of mortality. Profile 2 may represent dysfunction of the endothelial response to infection.

Funding: Primary funding: Investigator-Initiated Award provided by Pfizer, Inc (WMS, STJ). Additional support: Canadian Institutes of Health Research (CIHR) Foundation grant (KCK; FDN-148439) and the Canada Research Chair program (KCK).

Keywords: Clinical Trials; Clinical practice; Infectious disease.

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Conflict of interest statement

Conflict of interest: KCK and WCL are inventors on patents related to the use of angiopoietin markers, entitled “Angiopoietin-1 and -2 biomarkers for infectious diseases that compromise endothelial integrity” (application WO2009059404) and “Biomarkers for early determination of a critical or life threatening response to illness and monitoring response to treatment” (application CA2769433).

Figures

Figure 1
Figure 1. Flow diagram.
The full cohort consisted of 426 subjects. The subjects were removed from the analysis if the clinical outcome was missing (n = 5), or if data were missing on biomarker values (n = 106).
Figure 2
Figure 2. Kaplan-Meier survival curves by endothelial response profile.
Patients fitting profile 2 died significantly sooner than patients fitting profile 1 or profile 3 (log-rank P < 0.001).
Figure 3
Figure 3. Heatmap of standardized mean biomarker concentrations by patient profile.
The 3 patient profiles have distinct biomarker patterns. Patients in profile 1 have below-average biomarker concentrations of all 11 biomarkers, particularly biomarkers belonging to factor 2. Patients in profile 2 have above-average concentrations of all biomarkers except those in factor 2. Profile 3 was characterized by elevated concentrations of biomarkers in factor 2, and below-average biomarker concentrations of the other biomarkers.
See this image and copyright information in PMC

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