Abstract
Environmental enteric dysfunction (EED) is an intestinal disorder common among children in low-resource settings and is associated with increased risk of growth stunting, cognitive deficits, and reduced oral vaccine immunogenicity. The Micronutrient and EED Assessment Tool (MEEDAT) is a multiplexed immunoassay that measures biomarkers previously associated with child growth faltering and/or oral vaccine immunogenicity: intestinal fatty acid-binding protein (I-FABP), soluble CD14 (sCD14), insulin-like growth factor 1 (IGF-1), and fibroblast growth factor 21 (FGF21). MEEDAT also measures systemic inflammation (α1-acid glycoprotein, C-reactive protein), ferritin, soluble transferrin receptor, retinol binding protein 4, thyroglobulin, and Plasmodium falciparum antigenemia (histidine-rich protein 2). The performance of MEEDAT was compared with commercially available enzyme-linked immunosorbent assays (ELISAs) using 300 specimens from Malian infant clinical trial participants. Regression methods were used to test if MEEDAT biomarkers were associated with seroconversion to meningococcal A conjugate vaccine (MenAV), yellow fever vaccine (YFV), and pentavalent rotavirus vaccine (PRV) after 28 days, or with growth faltering over 12 weeks. The Pearson correlations between the MEEDAT and ELISA results were 0.97, 0.86, 0.80, and 0.97 for serum I-FABP, sCD14, IGF-1, and FGF21, respectively. There were significant associations between I-FABP concentration and the probability of PRV IgG seroconversion and between IGF-1 concentration and the probability of YFV seroconversion. In multivariable models neither association remained significant, however there was a significant negative association between AGP concentration and YFV seroconversion. GLP-2 and sCD14 concentrations were significantly negatively associated with 12-week change in weight-for-age z-score and weight-for-height z-score in multivariable models. MEEDAT performed well in comparison to commercially-available ELISAs for the measurement of four analytes for EED and growth hormone resistance. Adoption of MEEDAT in low-resource settings could help accelerate the identification of interventions that prevent or treat child stunting and interventions that boost the immunogenicity of child vaccinations.
Highlights
Environmental enteric dysfunction (EED) is an intestinal disorder common among people living in low-resource settings with a high enteric-pathogen burden and poor sanitation and hygiene [1, 2]
A key challenge to identifying children with EED at highest risk of morbid sequelae is the lack of validated predictive biomarkers
The Micronutrient and EED Assessment Tool (MEEDAT) is a multiplexed immunoassay that measures biomarkers associated with child growth faltering and oral vaccine immunogenicity, and biomarkers indicative of systemic inflammation and micronutrient deficiencies
Summary
Environmental enteric dysfunction (EED) is an intestinal disorder common among people living in low-resource settings with a high enteric-pathogen burden and poor sanitation and hygiene [1, 2]. We have developed a multiplexed planar immunoassay that measures four blood-based markers that are indicative of EED and growth-hormone resistance (in addition to seven markers of systemic inflammation and micronutrient status, described below) These biomarkers include intestinal fatty acid–binding protein (I-FABP), soluble CD14 (sCD14), insulin-like growth factor 1 (IGF-1), and fibroblast growth factor 21 (FGF21). Elevated blood levels of sCD14 are a marker of monocyte activation (triggered by exposure to lipopolysaccharide) indicative of Gram-negative bacterial translocation across the intestinal epithelial barrier It has been associated with future risk of growth faltering, poor immune responses to oral immunizations (oral polio vaccine type 1 and Rotarix rotavirus vaccine) in infants, and poor cognitive test scores later in childhood [5, 11, 12]. A priori, we expect that EED would not be associated with parenteral vaccine response due to the lack of mucosal immune system involvement
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