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BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) encoding heat-stable enterotoxin (ST) alone or with heat-labile enterotoxin (LT) cause moderate-to-severe diarrhea (MSD) in developing country children. The Global Enteric Multicenter Study (GEMS) identified ETEC encoding ST among the top four enteropathogens. Since the GEMS objective was to provide evidence to guide development and implementation of enteric vaccines and other interventions to diminish diarrheal disease morbidity and mortality, we examined colonization factor (CF) prevalence among ETEC isolates from children age <5 years with MSD and from matched controls in four African and three Asian sites. We also assessed strength of association of specific CFs with MSD. METHODOLOGY/PRINCIPAL FINDINGS: MSD cases enrolled at healthcare facilities over three years and matched controls were tested in a standardized manner for many enteropathogens. To identify ETEC, three E. coli colonies per child were tested by polymerase chain reaction (PCR) to detect genes encoding LT, ST; confirmed ETEC were examined by PCR for major CFs (Colonization Factor Antigen I [CFA/I] or Coli Surface [CS] antigens CS1-CS6) and minor CFs (CS7, CS12, CS13, CS14, CS17, CS18, CS19, CS20, CS21, CS30). ETEC from 806 cases had a single toxin/CF profile in three tested strains per child. Major CFs, components of multiple ETEC vaccine candidates, were detected in 66.0% of LT/ST and ST-only cases and were associated with MSD versus matched controls by conditional logistic regression (p≤0.006); major CFs detected in only 25.0% of LT-only cases weren't associated with MSD. ETEC encoding exclusively CS14, identified among 19.9% of 291 ST-only and 1.5% of 259 LT/ST strains, were associated with MSD (p = 0.0011). No other minor CF exhibited prevalence ≥5% and significant association with MSD. CONCLUSIONS/SIGNIFICANCE: Major CF-based efficacious ETEC vaccines could potentially prevent up to 66% of pediatric MSD cases due to ST-encoding ETEC in developing countries; adding CS14 extends coverage to ~77%.

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BACKGROUND AND OBJECTIVES: Astroviruses are important drivers of viral gastroenteritis but remain understudied in community settings and low- and middle-income countries. We present data from 8 countries with high prevalence of diarrhea and undernutrition to describe astrovirus epidemiology and assess evidence for protective immunity among children 0 to 2 years of age. METHODS: We used 25 898 surveillance stools and 7077 diarrheal stools contributed by 2082 children for enteropathogen testing, and longitudinal statistical analysis to describe incidence, risk factors, and protective immunity. RESULTS: Thirty-five percent of children experienced astrovirus infections. Prevalence in diarrheal stools was 5.6%, and severity exceeded all enteropathogens except rotavirus. Incidence of infection and diarrhea were 2.12 and 0.88 episodes per 100 child-months, respectively. Children with astrovirus infection had 2.30 times the odds of experiencing diarrhea after adjustment for covariates (95% confidence interval [CI], 2.01-2.62; P < .001). Undernutrition was a risk factor: odds of infection and diarrhea were reduced by 10% and 13%, respectively, per increase in length-for-age z score (infection: odds ratio, 0.90 [95% CI, 0.85-0.96]; P < .001; diarrhea: odds ratio, 0.87 [95% CI, 0.79-0.96]; P = .006). Some evidence of protective immunity to infection was detected (hazard ratio, 0.84 [95% CI, 0.71-1.00], P = .052), although this was heterogeneous between sites and significant in India and Peru. CONCLUSIONS: Astrovirus is an overlooked cause of diarrhea among vulnerable children worldwide. With the evidence presented here, we highlight the need for future research as well as the potential for astrovirus to be a target for vaccine development.

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OBJECTIVES: The aim of the study was to describe changes in intestinal permeability in early childhood in diverse epidemiologic settings. METHODS: In a birth cohort study, the lactulose:mannitol (L:M) test was administered to 1980 children at 4 time points in the first 24 months of life in 8 countries. Data from the Brazil site with an incidence of diarrhea similar to that seen in the United States and no growth faltering was used as an internal study reference to derive age- and sex-specific z scores for mannitol and lactulose recoveries and the L:M ratio. RESULTS: A total of 6602 tests demonstrated mannitol recovery, lactulose recovery, and the L:M ratio were associated with country, sex, and age. There was heterogeneity in the recovery of both probes between sites with mean mannitol recovery ranging for 1.34% to 5.88%, lactulose recovery of 0.19% to 0.58%, and L:M ratios 0.10 to 0.17 in boys of 3 months of age across different sites. We observed strong sex-specific differences in both mannitol and lactulose recovery, with boys having higher recovery of both probes. Alterations in intestinal barrier function increased in most sites from 3 to 9 months of age and plateaued or diminished from 9 to 15 months of age. CONCLUSIONS: Alterations in recovery of the probes differ markedly in different epidemiologic contexts in children living in the developing world. The rate of change in the L:M-z ratio was most rapid and consistently disparate from the reference standard in the period between 6 and 9 months of age, suggesting that this is a critical period of physiologic impact of enteropathy in these populations.

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BACKGROUND: Most studies of the causes of diarrhoea in low-income and middle-income countries have looked at severe disease in people presenting for care, and there are few estimates of pathogen-specific diarrhoea burdens in the community. METHODS: We undertook a birth cohort study with not only intensive community surveillance for diarrhoea but also routine collection of non-diarrhoeal stools from eight sites in South America, Africa, and Asia. We enrolled children within 17 days of birth, and diarrhoeal episodes (defined as maternal report of three or more loose stools in 24 h, or one loose stool with visible blood) were identified through twice-weekly home visits by fieldworkers over a follow-up period of 24 months. Non-diarrhoeal stool specimens were also collected for surveillance for months 1-12, 15, 18, 21, and 24. Stools were analysed for a broad range of enteropathogens using culture, enzyme immunoassay, and PCR. We used the adjusted attributable fraction (AF) to estimate pathogen-specific burdens of diarrhoea. FINDINGS: Between November 26, 2009, and February 25, 2014, we tested 7318 diarrhoeal and 24 310 non-diarrhoeal stools collected from 2145 children aged 0-24 months. Pathogen detection was common in non-diarrhoeal stools but was higher with diarrhoea. Norovirus GII (AF 5·2%, 95% CI 3·0-7·1), rotavirus (4·8%, 4·5-5·0), Campylobacter spp (3·5%, 0·4-6·3), astrovirus (2·7%, 2·2-3·1), and Cryptosporidium spp (2·0%, 1·3-2·6) exhibited the highest attributable burdens of diarrhoea in the first year of life. The major pathogens associated with diarrhoea in the second year of life were Campylobacter spp (7·9%, 3·1-12·1), norovirus GII (5·4%, 2·1-7·8), rotavirus (4·9%, 4·4-5·2), astrovirus (4·2%, 3·5-4·7), and Shigella spp (4·0%, 3·6-4·3). Rotavirus had the highest AF for sites without rotavirus vaccination and the fifth highest AF for sites with the vaccination. There was substantial variation in pathogens according to geography, diarrhoea severity, and season. Bloody diarrhoea was primarily associated with Campylobacter spp and Shigella spp, fever and vomiting with rotavirus, and vomiting with norovirus GII. INTERPRETATION: There was substantial heterogeneity in pathogen-specific burdens of diarrhoea, with important determinants including age, geography, season, rotavirus vaccine usage, and symptoms. These findings suggest that although single-pathogen strategies have an important role in the reduction of the burden of severe diarrhoeal disease, the effect of such interventions on total diarrhoeal incidence at the community level might be limited.

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Newborn infections are responsible for approximately one-third of the estimated 4.0 million neonatal deaths that occur globally every year...

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OBJECTIVE: The effectiveness of Haemophilus influenzae type b (Hib) vaccine in preventing severe pneumonia in Asian children has been questioned, and many large Asian countries yet to introduce Hib conjugate vaccine in immunization programs. The primary objective of this study was to assess Hib conjugate vaccine effectiveness (VE) on radiologically-confirmed pneumonia in children born after introduction of Hib conjugate vaccine in Pakistan. STUDY DESIGN: A matched case-control study enrolled cases of radiologically-confirmed pneumonia in several hospitals serving low-income populations during 2009-2011. Cases were matched by age and season with 3 hospital and 5 neighborhood controls. Pneumonia was diagnosed using standardized World Health Organization criteria for chest radiograph interpretation. Matched OR were estimated for VE. RESULTS: A total of 1027 children with radiologically-confirmed pneumonia were enrolled; 975 cases, 2925 hospital controls, and 4875 neighborhood controls were analyzed. The coverage for 3 doses of diphtheria-tetanus-pertussis-hepatitis B-Hib conjugate vaccine was 13.7%, 18%, and 22.7% in cases, hospital controls and neighborhood controls, respectively. Estimated Hib VE for radiologically-confirmed pneumonia was 62% with 3 doses of vaccine using hospital controls and 70% using neighborhood controls. CONCLUSIONS: Hib conjugate vaccine prevented a significant fraction of radiologically-confirmed pneumonia in children in Pakistan. Maximizing impact on child survival needs improved immunization coverage.

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OBJECTIVE: Significant neurodevelopmental sequelae are known to occur after acute bacterial meningitis (ABM). This study determined the burden of such sequelae in Pakistani children aged <5 years to guide policies for Haemophilus influenzae type b (Hib) and pneumococcal vaccination. STUDY DESIGN: Cases of ABM were recruited from hospital-based surveillance and assigned to 1 of 3 etiologic groups (Hib, Streptococcus pneumoniae, or unknown etiology). Two age-matched controls were recruited for each case. Six months after enrollment, each case underwent neurologic history and examination, neurodevelopmental evaluation, and neurophysiological hearing test. Controls were assessed in parallel. RESULTS: Of 188 cases, 64 (34%) died. Mortality among subgroups were 7 (27%), 14 (28%), and 43 (39%) for Hib, Streptococcus pneumoniae, and unknown etiology, respectively. Eighty cases and 160 controls completed the assessments. Sequelae among cases included developmental delay (37%), motor deficit (31%), hearing impairment (18.5%), epilepsy (14%), and vision impairment (14%). Sequelae were higher after pneumococcal meningitis (19, 73%) compared with Hib meningitis (8, 53%). Compared with controls, cases were at significantly higher risk for all sequelae (P < .0001). CONCLUSIONS: ABM causes a substantial long-term burden of poor neurodevelopmental outcomes. Hib and pneumococcal vaccines are very effective interventions to prevent meningitis and its disabling sequelae.

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