Fecal Biomarkers to Characterize Intestinal Inflammation among Children with Medically Attended Diarrhea across Six Low-Resource Settings: Findings from the Enterics for Global Health (EFGH) Shigella Surveillance Study

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ABSTRACT Background Frequent enteric infections can damage the small intestine causing inflammation and malabsorption, leading to environmental enteric dysfunction. We aimed to characterize the association between intestinal inflammation and enteric pathogens among children in low- and middle-income countries (LMICs) who presented to care with diarrhea. Methodology/Principle Findings We conducted a cross-sectional analysis within the Enterics for Global Health - Shigella Surveillance Study at six LMIC sites: Bangladesh, Kenya, Malawi, Pakistan, Peru, and The Gambia. From August 2022 to July 2024, rectal swabs and whole stool samples were collected from 4,903 children with medically attended diarrhea aged 6-35 months (44.4% females, n=2178/4903; mean age: 15.4 months ± 7.4 months) and were analyzed for Shigella and four fecal inflammatory biomarkers: hemoglobin, lipocalin-2, myeloperoxidase, and calprotectin via Enzyme Linked Immunosorbent Assays. Caregivers and clinicians demonstrated moderate accuracy in identifying blood in stool compared to fecal hemoglobin (area under the curve (AUC)=0.70). Among 10 pathogens evaluated, Shigella -attributable diarrhea had the highest concentrations of calprotectin, hemoglobin, and myeloperoxidase. Shigella culture-/PCR+ episodes had intermediate levels of inflammation between culture-/PCR- and culture+ episodes. In multivariable models restricted to Shigella episodes, dysentery was positively associated and vomiting was negatively associated with biomarker concentrations, with the strongest associations observed for hemoglobin (dysentery geometric mean ratio: 14.91 μg/g (95% CI: 8.77, 25.36) and vomiting geometric mean ratio: 0.44 μg/g (95% CI: 0.24, 0.81)). Age, sex, and both acute and chronic malnutrition were not associated with inflammatory biomarker concentrations. Conclusions/Significance Hemoglobin appeared to be a more sensitive marker of blood in stool than visual observation. While Shigella was associated with heightened levels of all inflammatory biomarkers, hemoglobin was most strongly associated with Shigella , especially among attributable and culture positive episodes. The distinct clinical characteristics of Shigella were most closely associated with elevated hemoglobin concentrations, suggesting its potential utility as a point-of-care diagnostic. AUTHOR SUMMARY Diarrhea is common among children under five years of age in low- and middle-income countries (LMICs). Repeated diarrheal illnesses can damage the gut, leading to issues with growth and brain development. We examined fecal samples collected from 4,903 children with diarrhea who were enrolled in the Enterics for Global Health - Shigella Surveillance Study. We tested samples for diarrheal pathogens and measured four inflammatory biomarkers. We found that hemoglobin better identified blood in stool than visual observation of blood. Additionally, certain biomarkers (calprotectin, myeloperoxidase, and most notably hemoglobin) were higher when diarrhea was caused by bacteria such as Shigella than when diarrhea was caused by viruses. Also, we discovered that Shigella episodes identified using molecular diagnostics caused a similar illness as those identified by culture. These results support that Shigella diarrhea episodes identified by molecular diagnostics or culture are more inflammatory than other episodes of diarrhea and may require appropriate antibiotic treatment.

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