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Background Diarrheal diseases are a leading cause of death for children aged Methods We used clinical and demographic data from the Global Enteric Multicenter Study (GEMS) study to build predictive models for diarrhea of Shigella etiology in children aged ≤59 months presenting with moderate to severe diarrhea in Africa and Asia. We screened variables using random forests, and assessed predictive performance with random forest regression and logistic regression using cross-validation. We used the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study to externally validate our GEMS-derived CPR. Results Of the 5011 cases analyzed, 1332 (27%) had diarrhea of Shigella etiology. Our CPR had high predictive ability (area under the receiver operating characteristic curve = 0.80 [95% confidence interval, .79–.81]) using the top 2 predictive variables, age and caregiver-reported bloody diarrhea. We show that by using our CPR to triage who receives diagnostic testing, 3 times more Shigella diarrhea cases would have been identified compared to current symptom-based guidelines, with only 27% of cases receiving a POC diagnostic test. Conclusions We demonstrate how a CPR can be used to guide use of a POC diagnostic test for diarrhea management. Using our CPR, available diagnostic capacity can be optimized to improve appropriate antibiotic use.

Diarrhea continues to be a leading cause of death for children under-five. Amongst children treated for acute diarrhea, mortality risk remains elevated during and after acute medical management. Identification of those at highest risk would enable better targeting of interventions, but available prognostic tools lack validation. We used clinical and demographic data from the Global Enteric Multicenter Study (GEMS) to build predictive models for death (in-treatment, after discharge, or either) in children aged ≤59 months presenting with moderate-to-severe diarrhea (MSD), in Africa and Asia. We screened variables using random forests, and assessed predictive performance with random forest regression and logistic regression using repeated cross-validation. We used data from the Kilifi Health and Demographic Surveillance System (KHDSS) and Kilifi County Hospital (KCH) in Kenya to externally validate our GEMS-derived clinical prognostic model (CPM). Of 8060 MSD cases, 43 (0.5%) children died in treatment and 122 (1.5% of remaining) died after discharge. MUAC at presentation, respiratory rate, age, temperature, number of days with diarrhea at presentation, number of people living in household, number of children

Background: The increasing spread of fluoroquinolone resistant enteric bacteria is a global public health concern. Children recently discharged from the hospital are at high risk of carriage of antimicrobial resistance (AMR) due to frequent exposure to antimicrobials during inpatient stays. This study aimed to determine the prevalence, correlates of ciprofloxacin non-susceptibility, and distribution of plasmid-mediated quinolone resistance (PMQR) genes in Escherichia coli (E. coli) and Klebsiella spp isolated from children under five years being discharged from two Kenyan Hospitals. Methods: E. coli and Klebsiella spp were isolated from fecal samples from children discharged from hospital and subjected to antimicrobial susceptibility testing by disc diffusion and E-test. Ciprofloxacin non-susceptible isolates were screened for seven PMQR genes using multiplex PCR. Poisson regression was used to determine the association between carriage of ciprofloxacin non-susceptible isolates and patient characteristics. Results: Of the 280 ciprofloxacin non-susceptible isolates: 188 E. coli and 92 Klebsiella spp isolates identified among 266 discharged children, 195 (68%) were ciprofloxacin-resistant (MIC ≥ 1µg/mL). Among these 195 isolates, 130 (67%) had high level ciprofloxacin minimum inhibitory concentrations (MICs) (≥32 µg/mL). Over 80% of the isolates had at least one PMQR gene identified: aac(6’)lb-cr (60%), qnrB (24%), oqxAB (22%), qnrS (16%), and qepA (6%), howeverqnrA was not identified in any isolates tested. Co-carriage of qnrB with acc(6’)-lb-cr was the most predominant accounting for 20% of all the isolates. Ceftriaxone use during hospital admission and the presence of ESBL production were significantly associated with the carriage of ciprofloxacin non-susceptible E. coli and Klebsiella spp. Conclusion: Ciprofloxacin non-susceptibility is common among E. coli and Klebsiella spp isolated from hospital discharged children in Kenya. Carriage and co-carriage of PMQR, including the newly identified qepA gene, were frequently observed. These findings suggest that children leaving the hospital may serve as an important reservoir for transmission of resistant E. coli and Klebsiella spp to the community. Enhanced surveillance for AMR determinants is critical to inform interventions to control antimicrobial-resistant bacteria.

BackgroundDiarrheal diseases are a leading cause of death for children under-5.Identification of etiology helps guide pathogen-specific therapy, but availability of diagnostic testing is often limited in low resource settings. Our goal is to develop a clinical prediction rule (CPR) to guide clinicians in identifying when to use a point-of-care diagnostic forShigellain children presenting with acute diarrhea.MethodsWe used clinical and demographic data from the Global Enteric Multicenter Study (GEMS) study to build predictive models for diarrhea ofShigellaetiology in children ≤59 months presenting with moderate-to-severe diarrhea in Africa and Asia. We screened variables using random forests, and assessed predictive performance with random forest regression and logistic regression using cross-validation. We used the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study to externally validate our GEMS-derived CPR.ResultsOf the 5011 cases analyzed, 1332 (27%) had diarrhea ofShigellaetiology. Our CPR had high predictive ability (AUC=0.80 (95% CI: 0.79, 0.81) using the top two predictive variables, age and caregiver reported bloody diarrhea. We show that by using our CPR to triage who receives diagnostic testing, 3 times moreShigelladiarrhea cases would have been identified compared to current symptom-based guidelines, with only 27% of cases receiving a point-of-care diagnostic test.ConclusionsWe demonstrate how a clinical prediction rule can be used to guide use of a point-of-care diagnostic test for diarrhea management. Using our CPR, available diagnostic capacity can be optimized to improve appropriate antibiotic use.Key pointsUsing an externally validated clinical prediction tool to triage who receives diagnostic testing, 3 times moreShigelladiarrhea cases would have been identified compared to current symptom-based guidelines, with only 27% of cases receiving a point-of-care diagnostic test.

Summary Background Mass drug administration of azithromycin to children in sub-Saharan Africa has been shown to improve survival in high-mortality settings. The period after hospital discharge is a time of elevated risk unaddressed by current interventions and might provide an opportunity for targeting empirical azithromycin administration. We aimed to assess the efficacy of azithromycin administered at hospital discharge on risk of death and rehospitalisation in Kenyan children younger than 5 years. Methods In this double-blind, placebo-controlled randomised trial, children were randomly assigned (1:1) to receive a 5-day course of azithromycin (oral suspension 10 mg/kg on day 1, followed by 5mg/kg per day on days 2–5) or identically appearing and tasting placebo at discharge from four hospitals in western Kenya. Children were eligible if they were aged 1–59 months at hospital discharge, weighed at least 2 kg, and had been admitted to hospital for any medical reason other than trauma, poisoning, or congenital anomaly. The primary outcome was death or rehospitalisation in the subsequent 6-month period in a modified intention-to-treat population, compared by randomisation group with Cox proportional hazards regression and Kaplan-Meier. Azithromycin resistance in Escherichia coli isolates from a random subset of children was compared by randomisation group with generalised estimating equations. This trial is registered with ClinicalTrials.gov , NCT02414399 . Findings Between June 28, 2016, and Nov 4, 2019, 1400 children were enrolled in the trial at discharge from hospital, with 703 (50·2%) randomly assigned to azithromycin and 697 (49·8%) to placebo. Among the 1398 children included in the modified intention-to-treat analysis (702 in the azithromycin group and 696 in the placebo group), the incidence of death or rehospitalisation was 20·4 per 100 child-years in the azithromycin group and 22·5 per 100 child-years in the placebo group (adjusted hazard ratio 0·91, 95·5% CI 0·64–1·29, p=0·58). Azithromycin resistance was common in commensal E coli isolates from enrolled children before randomisation (37·7% of 406 isolates) despite only 3·7% of children having received a macrolide antibiotic during the hospitalisation. Azithromycin resistance was slightly higher at 3 months after randomisation in the azithromycin group (26·9%) than in the placebo group (19·1%; adjusted prevalence ratio 1·41, 95% CI 0·95–2·09, p=0·088), with no difference observed at 6 months (1·17, 0·78–1·76, p=0·44). Interpretation We did not observe a significant benefit of a 5-day course of azithromycin delivered to children younger than 5 years at hospital discharge despite the overall high risk of mortality and rehospitalisation. These findings highlight the need for more research into mechanisms and interventions for prevention of morbidity and mortality in the post-discharge period. Funding Eunice Kennedy Shriver National Institute of Child Health & Human Development.

Background: Current guidelines for the management of childhood wasting primarily focus on the provision of therapeutic foods and the treatment of medical complications. However, many children with wasting live in food-secure households, and multiple studies have demonstrated that the etiology of wasting is complex, including social, nutritional, and biological causes. We evaluated the contribution of household food insecurity, dietary diversity, and the consumption of specific food groups to the time to recovery from wasting after hospital discharge. Methods: We conducted a secondary analysis of the Childhood Acute Illness Network (CHAIN) cohort, a multicenter prospective study conducted in six low- or lower-middle-income countries. We included children aged 6–23 months with wasting (mid-upper arm circumference [MUAC] ≤ 12.5 cm) or kwashiorkor (bipedal edema) at the time of hospital discharge. The primary outcome was time to nutritional recovery, defined as a MUAC > 12.5 cm without edema. Using Cox proportional hazards models adjusted for age, sex, study site, HIV status, duration of hospitalization, enrollment MUAC, referral to a nutritional program, caregiver education, caregiver depression, the season of enrollment, residence, and household wealth status, we evaluated the role of reported food insecurity, dietary diversity, and specific food groups prior to hospitalization on time to recovery from wasting during the 6 months of posthospital discharge. Findings: Of 1286 included children, most participants (806, 63%) came from food-insecure households, including 170 (13%) with severe food insecurity, and 664 (52%) participants had insufficient dietary diversity. The median time to recovery was 96 days (18/100 child-months (95% CI: 17.0, 19.0)). Moderate (aHR 1.17 [0.96, 1.43]) and severe food insecurity (aHR 1.14 [0.88, 1.48]), and insufficient dietary diversity (aHR 1.07 [0.91, 1.25]) were not significantly associated with time to recovery. Children who had consumed legumes and nuts prior to diagnosis had a quicker recovery than those who did not (adjusted hazard ratio (aHR): 1.21 [1.01,1.44]). Consumption of dairy products (aHR 1.13 [0.96, 1.34], p = 0.14) and meat (aHR 1.11 [0.93, 1.33]), p = 0.23) were not statistically significantly associated with time to recovery. Consumption of fruits and vegetables (aHR 0.78 [0.65,0.94]) and breastfeeding (aHR 0.84 [0.71, 0.99]) before diagnosis were associated with longer time to recovery. Conclusion: Among wasted children discharged from hospital and managed in compliance with wasting guidelines, food insecurity and dietary diversity were not major determinants of recovery.

Background Shigella is a leading cause of childhood diarrhea and target for vaccine development. Microbiologic and clinical case definitions are needed for pediatric field vaccine efficacy trials. Methods We compared characteristics of moderate to severe diarrhea (MSD) cases in the Global Enteric Multicenter Study (GEMS) between children with culture positive Shigella to those with culture-negative, quantitative polymerase chain reaction (qPCR)-attributable Shigella (defined by an ipaH gene cycle threshold, Molecular methods identified Shigella more commonly than microbiologic culture in younger and stunted children. A simplified clinical score containing dehydration, hospitalization, and diarrhea duration could be used to stratify vaccine trial endpoints by severity based on its ability to predict death.

Vaccine candidates for Shigella are approaching phase 3 clinical trials in the target population of young children living in low- and middle-income countries. Key study design decisions will need to be made to maximize the success of such trials and minimize the time to licensure and implementation. We convened an ad hoc working group to identify the key aspects of trial design that would meet the regulatory requirements to achieve the desired indication of prevention of moderate or severe shigellosis due to strains included in the vaccine. The proposed primary endpoint of pivotal Shigella vaccine trials is the efficacy of the vaccine against the first episode of acute moderate or severe diarrhea caused by the Shigella strains contained within the vaccine. Moderate or severe shigellosis could be defined by a modified Vesikari score with dysentery and molecular detection of vaccine-preventable Shigella strains. This report summarizes the rationale and current data behind these considerations, which will evolve as new data become available and after further review and consultation by global regulators and policymakers.

BackgroundNearly 150 million children under-5 years of age were stunted in 2020. We aimed to develop a clinical prediction rule (CPR) to identify children likely to experience additional stunting following acute diarrhea, to enable targeted approaches to prevent this irreversible outcome.MethodologyWe used clinical and demographic data from the Global Enteric Multicenter Study (GEMS) study to build predictive models of linear growth faltering (decrease of ≥0.5 or ≥1.0 in height-for-age z-score [HAZ] at 60 day follow-up) in children ≤59 months presenting with moderate-to-severe diarrhea (MSD), and community controls, in Africa and Asia. We screened variables using random forests, and assessed predictive performance with random forest regression and logistic regression using 5-fold cross-validation. We used the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study to A) re-derive, and B) externally validate our GEMS-derived CPR.ResultsOf 7639 children in GEMS, 1744 (22.8%) experienced severe growth faltering (≥0.5 decrease in HAZ). In MAL-ED, we analyzed 5683 diarrhea episodes from 1322 children, of which 961(16.9%) episodes experienced severe growth faltering. Top predictors of growth faltering in GEMS were: age, HAZ at enrollment, respiratory rate, temperature, and number of people living in the household. The maximum AUC was 0.75 (95% CI: 0.75, 0.75) with 20 predictors, while 2 predictors yielded an AUC of 0.71 (95% CI: 0.71, 0.72). Results were similar in the MAL-ED re-derivation. A 2-variable CPR derived from children 0-23 months in GEMS had an AUC=0.63 (95% CI 0.62, 0.65), and AUC=0.68 (95% CI: 0.63, 0.74) when externally validated in MAL-ED.ConclusionsOur findings indicate that use of prediction rules could help identify children at risk of poor outcomes after an episode of diarrheal illness.

Background:Nearly 150 million children under-5 years of age were stunted in 2020. We aimed to develop a clinical prediction rule (CPR) to identify children likely to experience additional stunting following acute diarrhea, to enable targeted approaches to prevent this irreversible outcome.Methods:We used clinical and demographic data from the Global Enteric Multicenter Study (GEMS) to build predictive models of linear growth faltering (decrease of ≥0.5 or ≥1.0 in height-for-age z-score [HAZ] at 60-day follow-up) in children ≤59 months presenting with moderate-to-severe diarrhea, and community controls, in Africa and Asia. We screened variables using random forests, and assessed predictive performance with random forest regression and logistic regression using fivefold cross-validation. We used the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study to (1) re-derive, and (2) externally validate our GEMS-derived CPR.Results:Of 7639 children in GEMS, 1744 (22.8%) experienced severe growth faltering (≥0.5 decrease in HAZ). In MAL-ED, we analyzed 5683 diarrhea episodes from 1322 children, of which 961 (16.9%) episodes experienced severe growth faltering. Top predictors of growth faltering in GEMS were: age, HAZ at enrollment, respiratory rate, temperature, and number of people living in the household. The maximum area under the curve (AUC) was 0.75 (95% confidence interval [CI]: 0.75, 0.75) with 20 predictors, while 2 predictors yielded an AUC of 0.71 (95% CI: 0.71, 0.72). Results were similar in the MAL-ED re-derivation. A 2-variable CPR derived from children 0–23 months in GEMS had an AUC = 0.63 (95% CI: 0.62, 0.65), and AUC = 0.68 (95% CI: 0.63, 0.74) when externally validated in MAL-ED.Conclusions:Our findings indicate that use of prediction rules could help identify children at risk of poor outcomes after an episode of diarrheal illness. They may also be generalizable to all children, regardless of diarrhea status.Funding:This work was supported by the National Institutes of Health under Ruth L. Kirschstein National Research Service Award NIH T32AI055434 and by the National Institute of Allergy and Infectious Diseases (R01AI135114).

Background Cytomegalovirus (CMV) viremia is associated with mortality in severely ill immunocompetent adults and hospitalized children with HIV (CWH). We measured CMV viremia in HIV-exposed and -unexposed Kenyan children aged 1–59 months discharged from hospital and determined its relationship with postdischarge mortality. Methods CMV DNA levels were measured in plasma from 1024 children (97 of which were HIV exposed uninfected [HEU], and 15 CWH). Poisson and Cox proportional hazards regression models were used to identify correlates of CMV viremia ≥ 1000 IU/mL and estimate associations with 6-month mortality, respectively. Results CMV viremia was detected in 31% of children, with levels ≥ 1000 IU/mL in 5.8%. HIV infection, age < 2 years, breastfeeding, and midupper arm circumference < 12.5 cm were associated with CMV viremia ≥ 1000 IU/mL. Among HEU children, CMV ≥ 1000 IU/mL (hazard ratio [HR] = 32.0; 95% confidence interval [CI], 2.9–354.0; P = .005) and each 1-log increase in CMV viral load (HR = 5.04; 95% CI, 1.7–14.6; P = .003) were associated with increased risk of mortality. CMV viremia was not significantly associated with mortality in HIV-unexposed children. Conclusions CMV levels at hospital postdischarge predict increased risk of 6-month mortality in Kenyan HEU children. CMV suppression may be a novel target to reduce mortality in HEU children. Clinical Trial Registration NCT02414399.

The World Health Organization (WHO) recommends tuberculosis (TB) diagnostic evaluation for children with HIV (CHIV) who have history of TB contact, poor weight gain, cough, or fever. These screening criteria were developed based on studies of symptomatic CHIV with incomplete microbiologic confirmation. We performed routine TB microbiologic evaluation of hospitalized CHIV with and without symptoms to develop a data-driven TB symptom screen.Among hospitalized antiretroviral therapy-naive Kenyan CHIV enrolled in the Pediatric Urgent Start of Highly Active Antiretroviral Therapy (PUSH) trial, we performed Xpert MTB/RIF and mycobacterial culture of respiratory and stool specimens independent of TB symptoms. We evaluated performance of WHO and other published pediatric TB screening criteria and derived optimized criteria using a combination of symptoms.Of 168 CHIV who underwent TB microbiologic evaluation, 13 (8%) had confirmed TB. WHO TB symptom screening had 100% sensitivity and 4% specificity to detect confirmed TB. Published TB screening criteria that relied on prolonged symptoms missed cases of confirmed TB (sensitivity 85%-92%). An optimized symptom screen including weight loss, cough, anorexia, or TB contact had 100% sensitivity and improved specificity (31%) compared with the WHO pediatric TB symptom screen.The WHO TB symptom screen was highly sensitive but resulted in a high proportion of hospitalized CHIV who would require TB diagnostic evaluation. Other published TB screening criteria missed CHIV with confirmed TB. Our optimized screening tool increased specificity while preserving sensitivity. Future multicenter studies are needed to improve TB screening tools for CHIV in both inpatient and outpatient settings.

Vaccine candidates for

Background Diarrhoeal infections are one of the leading causes of child’s mortality and morbidity. Vaccines against Shigella, enterotoxigenic E. coli (ETEC), norovirus and invasive non-typhoidal Salmonella are in clinical development, however, their full value in terms of short and long-term health and socio-economic burden needs to be evaluated and communicated, to rationalise investment in vaccine development, and deployment. While estimates of mortality of enteric infections exist, the long-term morbidity estimates are scarce and have not been systematically collected. Methods The World Health Organization (WHO) has convened a Burden of Enteric Diseases Morbidity Working Group (BoED MWG) who identified key workstreams needed to characterise the morbidity burden of enteric infections. The group also identified four criteria for the prioritisation of pathogens of which impact on long-term morbidity needs to be assessed. Results The BoED MWG suggested to identify and analyse the individual level data from historical datasets to estimate the impact of enteric infections and confounders on long-term morbidity, including growth faltering and cognitive impairment in children (workstream 1); to conduct a systematic review of evidence on the association of aetiology specific diarrhoea with short- and long- term impact on growth, including stunting, and possibly cognitive impairment in children, while accounting for potential confounders (workstream 2); and to conduct a systematic review of evidence on the association of aetiology specific diarrhoea with short- and long- term impact on health outcomes in adults. The experts prioritised four pathogens for this work: Campylobacter jejuni, ETEC (LT or ST), norovirus (G1 or G2), and Shigella (dysenteriae, flexneri, sonnei). Conclusions The proposed work will contribute to improving the understanding of the impact of enteric pathogens on long-term morbidity. The timing of this work is critical as all four pathogens have vaccine candidates in the clinical pipeline and decisions about investments in development, manufacturing or vaccine procurement and use are expected to be made soon.

HIV-exposed, uninfected (HEU) children are a growing population at particularly high risk of infection-related death in whom preventing diarrhea may significantly reduce under-5 morbidity and mortality in sub-Saharan Africa. A historic cohort (1999–2002) of Kenyan HEU infants followed from birth to 12 months was used. Maternal and infant morbidity were ascertained at monthly clinic visits and unscheduled sick visits. The Andersen–Gill Cox model was used to assess maternal, environmental, and infant correlates of diarrhea, moderate-to-severe diarrhea (MSD; diarrhea with dehydration, dysentery, or related hospital admission), and prolonged/persistent diarrhea (> 7 days) in infants. HIV-exposed, uninfected infants (n = 373) experienced a mean 2.09 (95% CI: 1.93, 2.25) episodes of diarrhea, 0.47 (95% CI: 0.40, 0.55) episodes of MSD, and 0.34 (95% CI: 0.29, 0.42) episodes of prolonged/persistent diarrhea in their first year. Postpartum maternal diarrhea was associated with increased risk of infant diarrhea (Hazard ratio [HR]: 2.09; 95% CI: 1.43, 3.06) and MSD (HR: 2.89; 95% CI: 1.10, 7.59). Maternal antibiotic use was a risk factor for prolonged/persistent diarrhea (HR: 1.63; 95% CI: 1.04, 2.55). Infants living in households with a pit latrine were 1.44 (95% CI: 1.19, 1.74) and 1.49 (95% CI: 1.04, 2.14) times more likely to experience diarrhea and MSD, respectively, relative to those with a flush toilet. Current exclusive breastfeeding was protective against MSD (HR: 0.30; 95% CI: 0.15, 0.58) relative to infants receiving no breast milk. Reductions in maternal diarrhea may result in substantial reductions in diarrhea morbidity among HEU children, in addition to standard diarrhea prevention interventions.

Summary: Background: Host vulnerabilities associated with acute malnutrition could facilitate the ability of specific enteric pathogens to cause diarrhoea and associated mortality. Using data from the Global Enteric Multicenter Study, we assessed whether acute malnutrition modifies the association between common enteric pathogens and moderate-to-severe diarrhoea, and whether associations between enteric pathogens and death were modified by acute malnutrition. Methods: Children with moderate-to-severe diarrhoea and age-matched and community-matched controls were included in this post-hoc analysis if their mid-upper arm circumference had been measured and if they were older than 6 months of age. Acute malnutrition was defined as mid-upper arm circumference below 12·5 cm, capturing both severe acute malnutrition (

Diarrhoea remains one of the leading causes of childhood mortality globally. Recent epidemiological studies conducted in low-middle income countries (LMICs) identified Shigella spp. as the first and second most predominant agent of dysentery and moderate diarrhoea, respectively. Antimicrobial therapy is often necessary for Shigella infections; however, we are reaching a crisis point with efficacious antimicrobials. The rapid emergence of resistance against existing antimicrobials in Shigella spp. poses a serious global health problem. Here, aiming to identify alternative antimicrobial chemicals with activity against multi-drug resistant (MDR) Shigella, we initiated a collaborative academia-industry drug discovery project, applying high throughput phenotypic screening across broad chemical diversity. We identified several suitable compounds with antibacterial activity against Shigella. These compounds included the oral carbapenem tebipenem, which was found to be highly potent against broadly susceptible Shigella and contemporary MDR variants. Additional in vitro screening demonstrated that tebipenem had activity against a wide range of other non-Shigella enteric bacteria. Cognisant of the risk for the development of resistance against monotherapy, we identified synergistic behaviour of two different drug combinations incorporating tebipenem. The orally bioavailable prodrug (tebipenem pivoxil) effectively cleared the gut of infecting organisms when administered in physiological doses to Shigella-infected mice and gnotobiotic piglets. Our data highlight the utility of broad compound screening for tackling the emerging antimicrobial resistance crisis and shows that tebipenem pivoxil (licenced for paediatric respiratory tract infections in Japan) could be repurposed as an effective treatment for severe diarrhoea caused by MDR Shigella and other enteric pathogens in LMICs.

Background Cryptosporidium is a leading cause of diarrhea in Sub-Saharan Africa and is associated with substantial morbidity and mortality in young children. Methods We analyzed data from children aged 6–71 months presenting to 2 public hospitals in Western Kenya with acute diarrhea and their primary caregivers, including detection of Cryptosporidium by quantitative polymerase chain reaction (PCR) and immunoassay analysis in stool samples from both children and their caregivers. Associations between potential transmission sources and child/caregiver Cryptosporidium infection were evaluated using prevalence ratios (PRs). Secondary analyses evaluated host and clinical risk factors of child/caregiver Cryptosporidium infection. Results Among 243 child–caregiver pairs enrolled, 77 children (32%) and 57 caregivers (23%) had Cryptosporidium identified by either immunoassay or PCR. Twenty-six of the 243 child–caregiver pairs (11%) had concordant detection of Cryptosporidium. Cryptosporidium infection in children was associated with detection of Cryptosporidium in caregivers (adjusted PR [aPR], 1.8; 95% CI, 1.2 to 2.6; P = .002) and unprotected water source (aPR, 2.0; 95% CI, 1.3 to 3.2; P = .003). Risk factors for Cryptosporidium detection in caregivers included child Cryptosporidium infection (aPR, 2.0; 95% CI, 1.3 to 3.0; P = .002) as well as cow (aPR, 3.1; 95% CI, 1.4 to 7.0; P = .02) and other livestock ownership (aPR, 2.6; 95% CI, 1.1 to 6.3; P = .03) vs no livestock ownership. Recent diarrhea in caregivers and children was independently associated with child and caregiver Cryptosporidium infections, respectively. Conclusions Our results are consistent with the hypothesis that Cryptosporidium transmission can occur directly between child–caregiver dyads as well as through other pathways involving water and livestock. Additional research into caregivers as a source of childhood Cryptosporidium infection is warranted.

BackgroundDiarrhea in infancy can compromise linear growth and this relationship is likely influenced by diarrhea severity, number of episodes, and the timing of those episodes. HIV exposed, uninfected infants (HEU) have higher risk of growth faltering, infectious morbidity and mortality than HIV-unexposed infants and may be representative of children particularly vulnerable to diarrhea-associated linear growth faltering.Methodology/principal findingsWe utilized data from a cohort of Kenyan HEU infants followed from birth to 12 months of age. Infant length and morbidity were ascertained at monthly study visits and sick visits. Longitudinal models estimated the association between diarrhea severity and length-for-age Z-score (LAZ) in the following month, at 12 months of age, and in 6-month intervals. The 372 enrolled infants experienced an average of 2.15 episodes (range: 0-8) of diarrhea and 0.54 episodes (0-4) of moderate-to-severe diarrhea (MSD) between birth and 12 months. Surviving infants had a mean LAZ of -0.97 (standard deviation: 1.2) at 12 months. MSD was significantly associated with an average loss of 0.14 (95% Confidence Interval [CI]: -0.24, -0.05, p = 0.003) in LAZ one month after the episode. Linear growth outcomes were not predicted by cumulative episodes of diarrhea, or timing of diarrhea during infancy.Conclusions/significanceDiarrhea severity influenced the relationship between diarrhea and subsequent linear growth. HEU infants with MSD may benefit from nutritional interventions following severe diarrhea to protect against linear growth faltering.

BackgroundModerate-to-severe diarrhea (MSD) in the first 2 years of life can impair linear growth. We sought to determine risk factors for linear growth faltering and to build a clinical prediction tool to identify children most likely to experience growth faltering following an episode of MSD.MethodsUsing data from the Global Enteric Multicenter Study of children 0–23 months old presenting with MSD in Africa and Asia, we performed log-binomial regression to determine clinical and sociodemographic factors associated with severe linear growth faltering (loss of ≥ 0.5 length-for-agez-score [LAZ]). Linear regression was used to estimate associations with ΔLAZ. A clinical prediction tool was developed using backward elimination of potential variables, and Akaike Information Criterion to select the best fit model.ResultsOf the 5902 included children, mean age was 10 months and 43.2% were female. Over the 50–90-day follow-up period, 24.2% of children had severe linear growth faltering and the mean ΔLAZ over follow-up was − 0.17 (standard deviation [SD] 0.54). After adjustment for age, baseline LAZ, and site, several factors were associated with decline in LAZ: young age, acute malnutrition, hospitalization at presentation, non-dysenteric diarrhea, unimproved sanitation, lower wealth, fever, co-morbidity, or an IMCI danger sign. Compared to children 12–23 months old, those 0–6 months were more likely to experience severe linear growth faltering (adjusted prevalence ratio [aPR] 1.97 [95% CI 1.70, 2.28]), as were children 6–12 months of age (aPR 1.72 [95% CI 1.51, 1.95]). A prediction model that included age, wasting, stunting, presentation with fever, and presentation with an IMCI danger sign had an area under the ROC (AUC) of 0.67 (95% CI 0.64, 0.69). Risk scores ranged from 0 to 37, and a cut-off of 21 maximized sensitivity (60.7%) and specificity (63.5%).ConclusionYounger age, acute malnutrition, MSD severity, and sociodemographic factors were associated with short-term linear growth deterioration following MSD. Data routinely obtained at MSD may be useful to predict children at risk for growth deterioration who would benefit from interventions.

Background Trials of mass drug administration (MDA) of azithromycin (AZM) report reductions in child mortality in sub-Saharan Africa. AZM targeted to high-risk children may preserve benefit while minimizing antibiotic exposure. We modeled the cost-effectiveness of MDA to children 1–59 months of age, MDA to children 1–5 months of age, AZM administered at hospital discharge, and the combination of MDA and postdischarge AZM. Methods Cost-effectiveness was modeled from a payer perspective with a 1-year time horizon, and was presented as cost per disability-adjusted life-year (DALY) averted and death averted, with probabilistic sensitivity analyses. The model included parameters for macrolide resistance, adverse events, hospitalization, and mortality sourced from published data. Results Assuming a base-case 1.64% mortality risk among children 1–59 months old, 3.1% among children 1–5 months old, 4.4% mortality risk postdischarge, and 13.5% mortality reduction per trial data, MDA would avert ~267 000 deaths at a cost of $14.26/DALY averted (95% uncertainty interval [UI], 8.72–27.08). MDA to only children 1–5 months old would avert ~186 000 deaths at a cost of $4.89/DALY averted (95% UI, 2.88–11.42), and postdischarge AZM would avert ~45 000 deaths, at a cost of $2.84/DALY (95% UI, 1.71–5.57) averted. Cost-effectiveness decreased with presumed diminished efficacy due to macrolide resistance. Conclusions Targeting AZM to children at highest risk of death may be an antibiotic-sparing and highly cost-effective, or even cost-saving, strategy to reduce child mortality. However, targeted AZM averts fewer absolute deaths and may not reach all children who would benefit. Any AZM administration decision must consider implications for antibiotic resistance.

Stunting remains a global health priority, particularly in sub‐Saharan Africa. Identifying determinants of linear growth in HIV‐exposed uninfected (HEU) infants can inform interventions to prevent stunting in this vulnerable population. HIV‐infected mothers and their uninfected infants were followed monthly from pregnancy to 12‐month post‐partum in Nairobi, Kenya. Mixed‐effects models estimated the change in length‐for‐age z‐score (LAZ) from birth to 12 months by environmental, maternal, and infant characteristics. Multivariable models included factors univariately associated with LAZ. Among 372 HEU infants, mean LAZ decreased from −0.54 (95% confidence interval [CI] [−0.67, −0.41]) to −1.09 (95% CI [−1.23, −0.96]) between 0 and 12 months. Declines in LAZ were associated with crowding (≥2 persons per room; adjusted difference [AD] in 0–12 month change: −0.46; 95% CI [−0.87, −0.05]), use of a pit latrine versus a flush toilet (AD: −0.29; 95% CI [−0.57, −0.02]), and early infant pneumonia (AD: −1.14; 95% CI [−1.99, −0.29]). Infants with low birthweight (

UNLABELLED SETTINGp: Among human immunodeficiency virus (HIV) infected adults living in tuberculosis (TB) endemic settings, Mycobacterium tuberculosis is a common cause of bloodstream infections. Although young children have an increased propensity for M. tuberculosis dissemination, M. tuberculosis bacteremia is infrequently described in children. OBJECTIVE To determine the prevalence of M. tuberculosis bacteremia in adult and pediatric patients and to examine sources of heterogeneity between estimates. DESIGN Systematic review and meta-analysis. RESULTS Of 1077 reviewed abstracts, 27 publications met the inclusion criteria, yielding 29 independent M. tuberculosis bacteremia prevalence estimates: 22 in adults, 6 in children, and 1 not stratified by age group. The random effects pooled M. tuberculosis bacteremia prevalence in adults was 13.5% (95%CI 10.8-16.2) and 0.4% (95%CI 0-0.9) in children (P for difference = 0.004). Restricting analyses to HIV-infected participants, pooled M. tuberculosis bacteremia prevalence from 21 adult studies was 15.5% (95%CI 12.5-18.5) and 0.8% (95%CI 0-1.8) in three pediatric studies (P = 0.001). Inclusion of pre-determined study-level confounders did not account for observed differences in M. tuberculosis bacteremia prevalence between age groups. CONCLUSION While M. tuberculosis bacteremia appears relatively common in adults, particularly those with HIV infection, bloodstream M. tuberculosis appears to be rare in children.

BACKGROUND The blood monocyte-to-lymphocyte ratio (MLR) is associated with active tuberculosis (TB) in adults but has not been evaluated as a TB diagnostic biomarker in HIV-infected children in whom respiratory sampling is difficult. SETTING In a cohort of HIV-infected hospitalized Kenyan children initiating antiretroviral therapy, absolute monocyte and lymphocyte counts were determined at enrollment and 4, 12, and 24 weeks thereafter. METHODS Children were classified as confirmed, unconfirmed, or unlikely pulmonary TB. Receiver operating characteristic curves of MLR cutoff values were generated to distinguish children with confirmed TB from those with unconfirmed and unlikely TB. General estimating equations were used to estimate change in the MLR over time by TB status. RESULTS Of 160 children with median age 23 months, 13 (8.1%) had confirmed TB and 67 (41.9%) had unconfirmed TB. The median MLR among children with confirmed TB {0.407 [interquartile range (IQR) 0.378-0.675]} was higher than the MLR in children with unconfirmed [0.207 (IQR 0.148-0.348), P < 0.01] or unlikely [0.212 (IQR 0.138-0.391), P = 0.01] TB. The MLR above 0.378 identified children with confirmed TB with 77% sensitivity, 78% specificity, 24% positive predictive value, and 97% negative predictive value. After TB treatment, the median MLR declined in children with confirmed TB and levels were similar to children with unlikely TB after 12 weeks. CONCLUSIONS The blood MLR distinguished HIV-infected children with confirmed TB from those with unlikely TB and declined with TB treatment. The MLR may be a useful diagnostic tool for TB in settings where respiratory-based microbiologic confirmation is inaccessible.

In children, Mycobacterium tuberculosis (M. tuberculosis) frequently disseminates systemically, presenting with nonspecific signs including fever. We determined prevalence of M. tuberculosis bacteremia among febrile children presenting to hospitals in Nyanza, Kenya (a region with high human immunodeficiency virus (HIV) and M. tuberculosis prevalence). Between March 2013 and February 2014, we enrolled children aged 6 months to 5 years presenting with fever (axillary temperature ≥ 37.5°C) and no recent antibiotic use. Blood samples were collected for bacterial and mycobacterial culture using standard methods. Among 148 children enrolled, median age was 3.1 years (interquartile range: 1.8–4.1 years); 10.3% of children were living with a household member diagnosed with M. tuberculosis in the last year. Seventeen percent of children were stunted (height-for-age z-score < −2), 18.6% wasted (weight-for-height z-score < −2), 2.7% were HIV-infected, and 14.2% were HIV-exposed uninfected. Seventeen children (11.5%) had one or more signs of tuberculosis (TB). All children had a Bacille Calmette-Guerin vaccination scar. Among 134 viable blood cultures, none (95% confidence interval: 0–2.7%) had Mycobacterium isolated. Despite exposure to household TB contacts, HIV exposure, and malnutrition, M. tuberculosis bacteremia was not detected in this pediatric febrile cohort, a finding consistent with other pediatric studies.

Despite diagnostic performance limitations, urine lipoarabinomannan (LAM) predicts death in human immunodeficiency virus (HIV)–infected adults with tuberculosis. Pediatric data are limited. Among 137 hospitalized HIV-infected children, mortality was 4.9-fold higher among those with positive LAM (127 vs 31 per 100 person-years; adjusted hazard ratio, 4.92; 95% confidence interval [CI], 1.79–13.49; P = .002). Lipoarabinomannan identifies HIV-infected children at risk for death potentially missed by respiratory sampling. Clinical Trials Registration {"type":"clinical-trial","attrs":{"text":"NCT02063880","term_id":"NCT02063880"}}NCT02063880.

Background Tuberculosis (TB) causes substantial morbidity and mortality in HIV-infected children. Sample collection and the paucibacillary nature of TB in children makes diagnosis challenging. Rapid diagnostic tools using easily obtained specimens are urgently needed. Methods Hospitalized, HIV-infected children aged 12 years or less enrolled in a randomized controlled trial (NCT02063880) comparing urgent to post-stabilization antiretroviral therapy initiation in Kenya underwent TB evaluation. At enrollment, sputum or gastric aspirates were collected for TB culture and Xpert, stool for Xpert, and urine for lipoarabinomannan (LAM). When possible, a second sputum/gastric aspirate for culture was obtained. Stool Xpert and urine LAM performance were compared to reference sputum/gastric aspirate culture. Results Among 165 HIV-infected children, median age was 24 months [interquartile range (IQR) 13-58], median CD4% was 14.3 (IQR 8.9-22.0%), and 114 (69.5%) had severe immunosuppression. Thirteen (7.9%) children had confirmed TB (positive culture and/or Xpert). Sputum/gastric aspirate Xpert, stool Xpert, and urine LAM sensitivities were 60% [95% confidence interval (CI) 26-88%], 63% (95% CI 25-92%), and 43% (95% CI 10-82%), respectively. Specificity was 98% (95% CI 94-100%) for sputum/gastric aspirate Xpert, 99% (95% CI 95-100%) for stool Xpert, and 91% (95% CI 84-95%) for urine LAM. Stool Xpert and urine LAM sensitivity increased among children with severe immunosuppression [80% (95% CI 28-100) and 60% (95% Cl 15-95%)]. Conclusion Stool Xpert had similar performance compared with sputum/gastric aspirate Xpert to detect TB. Urine LAM had lower sensitivity and specificity, but increased among children with severe immunosuppression. Stool Xpert and urine LAM can aid rapid detection of TB in HIV-infected children using easily accessible samples.

We sought to determine the genetic and phenotypic antimicrobial resistance (AMR) profiles of commensal Klebsiella spp. circulating in Kenya by testing human stool isolates of 87 K. pneumoniae and three K. oxytoca collected at eight locations. Over one-third of the isolates were resistant to ≥3 categories of antimicrobials and were considered multidrug-resistant (MDR). We then compared the resistance phenotype to the presence/absence of 238 AMR genes determined by a broad-spectrum microarray and PCR. Forty-six genes/gene families were identified conferring resistance to β-lactams (ampC/blaDHA, blaCMY/LAT, blaLEN-1, blaOKP-A/OKP-B1, blaOXA-1-like family, blaOXY-1, blaSHV, blaTEM, blaCTX-M-1 and blaCTX-M-2 families), aminoglycosides (aac(3)-III, aac(6)-Ib, aad(A1/A2), aad(A4), aph(AI), aph3/str(A), aph6/str(B), and rmtB), macrolides (mac(A), mac(B), mph(A)/mph(K)), tetracyclines (tet(A), tet(B), tet(D), tet(G)), ansamycins (arr), phenicols (catA1/cat4, floR, cmlA, cmr), fluoroquinolones (qnrS), quaternary amines (qacEΔ1), streptothricin (sat2), sulfonamides (sul1, sul2, sul3), and diaminopyrimidines (dfrA1, dfrA5, dfrA7, dfrA8, dfrA12, dfrA13/21/22/23 family, dfrA14, dfrA15, dfrA16, dfrA17). This is the first profile of genes conferring resistance to multiple categories of antimicrobial agents in western and central Kenya. The large number and wide variety of resistance genes detected suggest the presence of significant selective pressure. The presence of five or more resistance determinants in almost two-thirds of the isolates points to the need for more effective, targeted public health policies and infection control/prevention measures.

HIV infection is an established risk for diarrhoeal severity, less is known about specific enteric pathogens associated with HIV status. We determined associations of selected enteric pathogens with HIV infection and HIV exposure among Kenyan children.A cross-sectional study among 6 months to 15 year olds presenting to two Western Kenya District hospitals with acute diarrhoea between 2011 and 2013.Stool was tested using standard bacterial culture and microscopy for ova and parasites. HIV status was obtained from children and mothers. Enteric pathogen prevalence was compared between HIV-infected and HIV-uninfected children and between HIV-exposed uninfected (HEU) and HIV-unexposed. Unadjusted and adjusted prevalence ratios for selected pathogens by HIV status were estimated using relative risk (RR) regression. Age, site, income, household crowding, water source/treatment, anthropometrics, cotrimoxazole use and breastfeeding history were accounted for in multivariable models.Among 1076 children, median age was 22 months (interquartile range: 11-42 months), 56 (5.2%) were HIV-infected and 105 (11.3%) of 926 HIV-uninfected children in whom maternal HIV status was obtained were HIV-exposed. The following organisms were most frequently isolated from stool: enteroaggregative Escherichia coli (13.3%), Giardia species (spp.) (11.1%), Campylobacter spp. (6.3%), enteropathogenic E. coli (EPEC) (6.1%) and Cryptosporidium spp. (3.7%). Accounting for age, HIV-infection was associated with typical EPEC infection (prevalence ratio 3.70, P = 0.002) while HIV-exposure was associated with Cryptosporidium among HIV-uninfected children (prevalence ratio 2.81, P = 0.005).EPEC and Cryptosporidium infections were more common in HIV-infected and HIV-exposed children, respectively. This could explain the increased mortality attributed to these pathogens in other studies. Interventions targeting EPEC and Cryptosporidium may reduce morbidity and mortality in high HIV-prevalence settings.

Summary Background Optimum management of childhood diarrhoea in low-resource settings has been hampered by insufficient data on aetiology, burden, and associated clinical characteristics. We used quantitative diagnostic methods to reassess and refine estimates of diarrhoea aetiology from the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study. Methods We re-analysed stool specimens from the multisite MAL-ED cohort study of children aged 0–2 years done at eight locations (Dhaka, Bangladesh; Vellore, India; Bhaktapur, Nepal; Naushero Feroze, Pakistan; Venda, South Africa; Haydom, Tanzania; Fortaleza, Brazil; and Loreto, Peru), which included active surveillance for diarrhoea and routine non-diarrhoeal stool collection. We used quantitative PCR to test for 29 enteropathogens, calculated population-level pathogen-specific attributable burdens, derived stringent quantitative cutoffs to identify aetiology for individual episodes, and created aetiology prediction scores using clinical characteristics. Findings We analysed 6625 diarrhoeal and 30 968 non-diarrhoeal surveillance stools from 1715 children. Overall, 64·9% of diarrhoea episodes (95% CI 62·6–71·2) could be attributed to an aetiology by quantitative PCR compared with 32·8% (30·8–38·7) using the original study microbiology. Viral diarrhoea (36·4% of overall incidence, 95% CI 33·6–39·5) was more common than bacterial (25·0%, 23·4–28·4) and parasitic diarrhoea (3·5%, 3·0–5·2). Ten pathogens accounted for 95·7% of attributable diarrhoea: Shigella (26·1 attributable episodes per 100 child-years, 95% CI 23·8–29·9), sapovirus (22·8, 18·9–27·5), rotavirus (20·7, 18·8–23·0), adenovirus 40/41 (19·0, 16·8–23·0), enterotoxigenic Escherichia coli (18·8, 16·5–23·8), norovirus (15·4, 13·5–20·1), astrovirus (15·0, 12·0–19·5), Campylobacter jejuni or C coli (12·1, 8·5–17·2), Cryptosporidium (5·8, 4·3–8·3), and typical enteropathogenic E coli (5·4, 2·8–9·3). 86·2% of the attributable incidence for Shigella was non-dysenteric. A prediction score for shigellosis was more accurate (sensitivity 50·4% [95% CI 46·7–54·1], specificity 84·0% [83·0–84·9]) than current guidelines, which recommend treatment only of bloody diarrhoea to cover Shigella (sensitivity 14·5% [95% CI 12·1–17·3], specificity 96·5% [96·0–97·0]). Interpretation Quantitative molecular diagnostics improved estimates of pathogen-specific burdens of childhood diarrhoea in the community setting. Viral causes predominated, including a substantial burden of sapovirus; however, Shigella had the highest overall burden with a high incidence in the second year of life. These data could improve the management of diarrhoea in these low-resource settings. Funding Bill & Melinda Gates Foundation.