Abstract
Biomarkers can prognosticate outcome and enable risk-stratification. In severe infection, focusing on multiple markers reflecting pathophysiological mechanisms of organ injury could enhance management and pathway-directed therapeutics. Limited data exist on the performance of multiplex biomarker platforms. Our goal was to compare endothelial and immune activation biomarkers in severe pediatric infections using two multiplex platforms. Frozen plasma from 410 children presenting to the Jinja Regional Hospital in Uganda with suspected infection was used to measure biomarkers of endothelial (Angiopoietin-2, sFlt-1, sVCAM-1, sICAM-1) and immune (IL-6, IP-10, sTNFR-1, CHI3L1) activation. Two multiplex platforms (Luminex®, EllaTM) based on monoclonal antibody sandwich immunoassays using biotin-streptavidin conjugate chemistry were selected with reagents from R&D Systems. The two platforms differed in ease and time of completion, number of samples per assay, and dynamic concentration range. Intra-assay variability assessed using a coefficient of variation (CV%) was 2.2–3.4 for Luminex® and 1.2–2.9 for EllaTM. Correlations for biomarker concentrations within dynamic range of both platforms were best for IL-6 (ρ = 0.96, p<0.0001), IP-10 (ρ = 0.94, p<0.0001) and sFlt-1 (ρ = 0.94, p<0.0001). Agreement between concentrations obtained by both methods assessed by the Bland-Altman test varied, with best agreement for CHI3L1. Our data suggest that biomarkers of endothelial and immune activation can be readily measured with multiplex platforms. Luminex® and EllaTM produced reliable results with excellent CV% values. The EllaTM platform was more automated and completed in 75 minutes, potentially compatible with near-patient use. Trends in concentrations obtained by these methods were highly correlated, although absolute values varied, suggesting caution is required when comparing data from different multiplex platforms.
Highlights
The search for novel biological markers to predict response to therapies, prognosticate outcome, or assist in patient enrollment in clinical therapeutic trials is quickly evolving [1]
The main goal of this study was to use reagents prepared by a single manufacturer (R&D Systems) to compare concentrations of previously identified biomarkers of endothelial and immune activation in patients with severe infection measured by two different multiplex platforms
The Luminex1 and EllaTM platforms differed in ease of assay performance, number of samples analyzed per run, and time to perform each assay
Summary
The search for novel biological markers to predict response to therapies, prognosticate outcome, or assist in patient enrollment in clinical therapeutic trials is quickly evolving [1]. Emphasizing markers of pathophysiological pathways involved in severe infections and focusing on multiplex platforms with near-patient or point-of-care potential, could accelerate the development of precision medicine tools for lifethreatening infections [4, 5]. Multiple markers of inflammation have been identified and among these interleukin 6 (IL-6) [16], interferon-gammainducible protein-10 (IP-10, CXCL10) [17], chitinase-3-like-1 protein (CHI3L1) [18] and soluble tumor necrosis factor receptor-1 (sTNFR-1) [15, 19] have been correlated with severity of illness and clinical outcome in sepsis as well as other critical care illnesses such as the acute respiratory distress syndrome, usually caused by severe infection [20, 21]
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