Abstract
Culture-independent diagnostics have revealed a larger burden of Shigella among children in low-resource settings than previously recognized. We further characterized the epidemiology of Shigella in the first two years of life in a multisite birth cohort. We tested 41,405 diarrheal and monthly non-diarrheal stools from 1,715 children for Shigella by quantitative PCR. To assess risk factors, clinical factors related to age and culture positivity, and associations with inflammatory biomarkers, we used log-binomial regression with generalized estimating equations. The prevalence of Shigella varied from 4.9%-17.8% in non-diarrheal stools across sites, and the incidence of Shigella-attributable diarrhea was 31.8 cases (95% CI: 29.6, 34.2) per 100 child-years. The sensitivity of culture compared to qPCR was 6.6% and increased to 27.8% in Shigella-attributable dysentery. Shigella diarrhea episodes were more likely to be severe and less likely to be culture positive in younger children. Older age (RR: 1.75, 95% CI: 1.70, 1.81 per 6-month increase in age), unimproved sanitation (RR: 1.15, 95% CI: 1.03, 1.29), low maternal education (<10 years, RR: 1.14, 95% CI: 1.03, 1.26), initiating complementary foods before 3 months (RR: 1.10, 95% CI: 1.01, 1.20), and malnutrition (RR: 0.91, 95% CI: 0.88, 0.95 per unit increase in weight-for-age z-score) were risk factors for Shigella. There was a linear dose-response between Shigella quantity and myeloperoxidase concentrations. The burden of Shigella varied widely across sites, but uniformly increased through the second year of life and was associated with intestinal inflammation. Culture missed most clinically relevant cases of severe diarrhea and dysentery.
Highlights
Shigella is the second leading cause of diarrhea morbidity and mortality among children in low and middle-income countries, accounting for approximately 60,000 deaths in 2016 [1]
We characterized the epidemiology of Shigella using highly sensitive diagnostic methods in 41,405 diarrheal and monthly non-diarrheal stools from the first two years of life in a multisite birth cohort
The prevalence of Shigella varied from 4.9%-17.8% across sites, and the incidence of Shigella-attributable diarrhea was 31.8 cases per 100 child-years
Summary
Shigella is the second leading cause of diarrhea morbidity and mortality among children in low and middle-income countries, accounting for approximately 60,000 deaths in 2016 [1]. Shigella is strongly associated with dysentery; correspondingly, the WHO guidelines recommend treatment of all pediatric cases of dysentery with ciprofloxacin or azithromycin for presumed Shigella infection [3]. The majority of Shigella burden was associated with watery diarrhea, not dysentery [5]. A recent meta-analysis showed that the proportion of Shigella infections that present with dysentery has been decreasing, and that Shigella infections overall had a stronger association with mortality than Shigellaassociated cases of dysentery [7]. WHO treatment guidelines do not currently recommend treatment for the majority of Shigella infections that may be associated with adverse outcomes, such that there may be missed treatment opportunities. Increasing rates of fluoroquinolone and macrolide resistance have highlighted the need for novel interventions, and increased the urgency of the development of a Shigella vaccine [10], which may offer a more sustainable solution
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