The Long-Term Impact of Subclinical Shigella Infections on Environmental Enteropathy in Children Under 2 Restricted; Files Only

Liakakos, Haley (Spring 2023)

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Shigellosis, caused by the enteric pathogen Shigella, is one of the leading causes of diarrheal death from a bacterial pathogen among children living in low- and middle-income countries (LMICs). Clinical and subclinical Shigella infections have both been associated with long-term adverse effects such as impaired linear growth. The impact from subclinical infections has been theorized to occur through the mechanisms of environmental enteropathy (EE). A prospective birth cohort study of 1,715 children living in 8 different LMICs was conducted. Over the course of 24 months, monthly non-diarrheal stool samples were collected from each child and analyzed for subclinical Shigella infections through quantitative PCR methods. EE was reflected by elevated concentrations of 3 fecal biomarkers: myeloperoxidase (MPO), neopterin (NEO), and alpha-1- antitrypsin (AAT). MPO concentrations were found to be significantly higher by 0.30 log(nm/mL) (95% CI: 0.23, 0.37) in the initial month of Shigella detection among stools with subclinical Shigella infections compared to stools without Shigella infections. After the Shigella infection, MPO concentrations declined throughout the following 6 months, and concentrations were lower after 5- and 6-months post-infection among stools within an initial infection compared to stools without an initial infection [MPO 5-month difference: -0.18 log(nm/mL) (95% CI: -0.35, -0.00); MPO 6-month difference: -0.16 log(nm/mL) (95% CI: -0.26, -0.04)]. Subclinical Shigella infections had no effect on NEO concentration levels within the initial month of Shigella detection. Post-infection, NEO concentrations were lower among stools with an initial infection compared to stools without an initial infection. Subclinical Shigella infections had no effect on AAT concentration levels until 6-months post-infection when AAT levels among stools with an initial infection were lower than stools without an initial infection [AAT difference: -0.13 log(mg/g) (95% CI: -0.24, -0.03)]. These findings, both initially and longitudinally, did not differentiate by cephalosporin, macrolide, fluoroquinolone, or any antibiotic use around time of initial infection. Enteric pathogens contribute to the vicious, prolonged cycle of EE, and Shigella is among one of the highest burden pathogens among those most at risk. Our study suggests the persistent role of Shigella on EE is not captured by these fecal biomarkers. 

Table of Contents




Aims of Primary Study

Study Population

Sample Collection

Statistical Analysis

Ethics Statement


EE Biomarker Concentrations Throughout 6 Months After Shigella Infection

Sensitivity Analysis of Age and Coinfection Covariates

Sensitivity Analysis of Children 18 Months and Younger

Differential Impact of Shigella Infections on Longitudinal EE Biomarker Concentrations by Antibiotic Treatment



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