Epidemiology of Shigella infections and diarrhea in the first two years of life using culture-independent diagnostics in 8 low-resource settings

Elizabeth T. Rogawski McQuade, Fariha Shaheen, Furqan Kabir, Arjumand Rizvi, James A. Platts-Mills, Fatima Aziz, Adil Kalam, Shahida Qureshi, Sarah Elwood, Jie Liu, Aldo A. M. Lima, Gagandeep Kang, Pascal Bessong, Amidou Samie, Rashidul Haque, Estomih R. Mduma, Margaret N. Kosek, Sanjaya Shrestha, Jose Paulo Leite, Ladaporn Bodhidatta, Nicola Page, Ireen Kiwelu, Sadia Shakoor, Ali Turab, Sajid Bashir Soofi, Tahmeed Ahmed, Eric R. Houpt, Zulfiqar Bhutta, Najeeha Talat Iqbal
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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.