Determinants of linear growth faltering among children with moderate-to-severe diarrhea in the global enteric multicenter study

Background: Moderate-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.Methods: Using 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-age z-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.Results: Of 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%).Conclusion: Younger 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

High-Throughput High-Resolution Class I HLA Genotyping in East Africa

HLA, the most genetically diverse loci in the human genome, play a crucial role in host-pathogen interaction by mediating innate and adaptive cellular immune responses. A vast number of infectious diseases affect East Africa, including HIV/AIDS, malaria, and tuberculosis, but the HLA genetic diversity in this region remains incompletely described. This is a major obstacle for the design and evaluation of preventive vaccines. Available HLA typing techniques, that provide the 4-digit level resolution needed to interpret immune responses, lack sufficient throughput for large immunoepidemiological studies. Here we present a novel HLA typing assay bridging the gap between high resolution and high throughput. The assay is based on real-time PCR using sequence-specific primers (SSP) and can genotype carriers of the 49 most common East African class I HLA-A, -B, and -C alleles, at the 4-digit level. Using a validation panel of 175 samples from Kampala, Uganda, previously defined by sequence-based typing, the new assay performed with 100% sensitivity and specificity. The assay was also implemented to define the HLA genetic complexity of a previously uncharacterized Tanzanian population, demonstrating its inclusion in the major East African genetic cluster. The availability of genotyping tools with this capacity will be extremely useful in the identification of correlates of immune protection and the evaluation of candidate vaccine efficacy

Addressing adverse outcomes following acute illness among children in Sub-Saharan Africa: predicting risks and cost-effectiveness

Thesis (Ph.D.)--University of Washington, 2019Children under age 5 in sub-Saharan Africa suffer a disproportionately high burden of infections disease, and the consequences of these conditions extend beyond the period during which the child is acutely ill. Children remain at high risk of mortality in the time period following a severe infectious disease, and, in the case of diarrhea, linear growth faltering. Interventions are needed to address these adverse outcomes following acute illness, but little is known about which children are at high risk, whether antibiotics may be effective, or the relative cost-effectiveness of various antibiotic administration strategies. We identified risk and predictive factors of linear growth faltering following moderate-to-severe diarrheal disease, and evaluated whether children who were exposed to antibiotics at diarrhea presentation had lower risks of linear growth faltering than children who were unexposed. Further, we compared two methods for collected patient-level hospitalization cost data and evaluated the comparative cost-effectiveness of mass distribution of azithromycin vs targeted azithromycin strategies. Using data from the Global Enteric Multicenter Study of children 0-59 moths old in 7 low- and middle-income countries in Africa and Asia presenting with moderate-to-severe diarrhea, we used linear regression to identify clinical and sociodemographic factors associated with loss in length-for-age z-score (LAZ) in the 50-90 days following presentation with moderate-to-severe diarrhea, and poisson regression with robust standard errors to identify factors associated with severe linear growth faltering (loss of ≥ 0.5 LAZ in the study period). Young age, nutritional status (low weight-for-length z-score, or high length-for-age z-score at presentation), high socioeconomic status, and severity of disease (hospitalization, presentation with fever, comorbidities, or general danger signs) identified children at high risk of linear growth faltering. These populations may benefit from diarrhea management interventions address post-diarrhea linear growth faltering. To evaluate the effects of antibiotics during moderate-to-severe diarrhea on linear growth, we used linear regression to estimate associations between antibiotic exposure (any antibiotic given or prescribed at diarrhea presentation) and linear growth faltering, using propensity score adjustment for factors associated with likelihood of receiving antibiotics. After propensity score adjustment, children who received antibiotics lost 0.04 less LAZ than those who did not (95% confidence interval: 0.01, 0.07) and were 20% less likely to experience severe linear growth faltering (adjusted odds ratio: 0.80 [0.69, 0.94]). Antibiotic management may offer modest protection against linear growth faltering in a sub-set of high risk children, but clinical trial evidence will be needed and the benefits should be weighed against the consequences. To evaluate the completeness of medical record documentation for the purposes of costing, we collected resource utilization data on children 1-59 months old hospitalized in a public hospital in western Kenya two different ways: by direct observation and medical record abstraction. Only 38% of children had medical records that completely documented all resources that were received. Micro-costing by medical record abstraction may slightly underestimate costs, but researchers should select the data collection method that best fits the goals and budget of the project Finally, we constructed a decision tree model to estimate the cost-effectiveness of several azithromycin strategies for preventing mortality: mass drug administration (MDA) of azithromycin to children 1-59 months old, MDA to children 1-5 months old, and azithromycin administered at hospital discharge to children recently hospitalized for any infectious condition. MDA to children 1-59 months old would cost approximately $14/disability-adjusted-life-year (DALY) averted, MDA to children 1-5 months old would cost approximately$5/DALY averted, and post-discharge azithromycin would cost approximately $3/DALY averted. All azithromycin strategies would be highly cost-effective for preventing mortality, but targeting azithromycin to a high mortality population would be even more cost-effective

Host and Environmental Correlates of Multi-Drug Resistance in Kenyan Children with Acute Bacterial Diarrhea

Thesis (Master's)--University of Washington, 2016-06Bacterial diarrhea results in significant morbidity and mortality in children in sub-Saharan Africa. Antibiotic treatment can be a life-saving intervention, but the emergence of antibiotic resistance limits its clinical efficacy. Data on the burden and risk factors for antibiotic resistance in enteric pathogens are needed to inform diarrhea management recommendations and resistance control interventions. Stool/rectal swab samples of children aged 6 mos - 15 yrs presenting with acute diarrhea in western Kenya were cultured for bacterial pathogens. HIV-uninfected children with identified Shigella or Salmonella species, or enteropathogenic [EPEC], enterotoxigenic [ETEC], enteroaggregative [EAEC], or enteroinvasive Escherichia coli [EIEC] were included in this substudy. Resistance to ampicillin, ceftriaxone, ciprofloxacin, cotrimoxazole, and tetracycline was determined using MicroScan Walkaway40 Plus. To evaluate correlates of multi- !3 drug resistance (MDR [resistance to ≥ 3 classes of antibiotics]), we used multivariable log- binomial regression to estimate prevalence ratios (PRs) and 95% confidence intervals (CIs). Of 292 children in the analysis, median age was 22.5 mos (interquartile range: 10.5-41.5 mos), 60.6% used pit latrines and 8.6% were HIV-exposed. Resistance to cotrimoxazole (96.2%) was most common among all pathogens, followed by ampicillin (79.1%) and tetracycline (73.0%). Phenotypic MDR was identified in 60.3% of children; and in 38.2% of Shigella, 40.0% of Salmonella, 73.0% of EPEC, 54.1% of ETEC, 76.0% of EAEC, and 72.2% of EIEC isolates. Children 6-24 mos were more likely to have MDR infections identified than those 24-59 mos (PR = 1.51 [95% CI: 1.19, 1.90]) whereas there was no difference in MDR prevalence between children in the two older age categories, >59m vs. 24-59m (PR = 1.30 [95% CI: 0.91, 1.87]). Children in households with a shared pit latrine were more likely to have MDR (aPR = 1.92 [95% CI: 1.08, 3.38]), than those with flush toilets, as were children in households that practiced open defecation (aPR = 1.91 [95% CI: 1.11, 3.30]). Children living in a household with 2 or more persons per room were 22% more likely to have an MDR pathogen than children living with fewer than 2 persons per room (PR = 1.22 [95% CI: 1.04, 1.43]). Duration of exclusive breastfeeding, malnutrition, maternal HIV, and water source were not associated with MDR infections in this study. Young children and those living in contaminated environments may be at higher risk for infection by antibiotic resistant enteric pathogens

Spatial and Temporal Variations of Microplastic Concentrations in Portland\u27s Freshwater Ecosystems

While microplastics are a pollutant of growing concern in various environmental compartments, less is known regarding the sources and delivery pathways of microplastics in urban rivers. We investigated the relationship between microplastic concentrations and various spatiotemporal factors (e.g., land use, arterial road length, water velocity, precipitation) in two watersheds along an urban-rural gradient in the Portland metropolitan area. Samples were collected in August, September, and February and were analyzed for total microplastic count and type. Nonparametric statistics were used to evaluate potential relationships with the explanatory variables, derived at both the subwatershed and near stream scales. In August, microplastic concentrations were significantly higher than in February. August concentrations also negatively correlated with flow rate, suggesting that lower flow rates may have facilitated the accumulation of microplastics. Smaller size microplastic particles (\u3c 100 μm) were found more in August than September and February, while larger size particles were more dominant in February than the other months. Microplastic concentrations were positively related to 24-h antecedent precipitation in February. Negative correlations existed between wet season microplastic concentrations and agricultural lands at the near streamlevel. The results indicate that near stream variables may more strongly influence the presence and abundance of microplastics in Portland\u27s waterways than subwatershed-scale variables. Fragments were the most commonly observed microplastic morphology, with a dominance of gray particles and the polymer polyethylene. The findings of this study can informmanagement decisions regarding microplastic waste and identify hotspots of microplastic pollution that may benefit from remediation

Interventions to reduce post-acute consequences of diarrheal disease in children: a systematic review

Abstract Background Although acute diarrhea often leads to acute dehydration and electrolyte imbalance, children with diarrhea also suffer long term morbidity, including recurrent or prolonged diarrhea, loss of weight, and linear growth faltering. They are also at increased risk of post-acute mortality. The objective of this systematic review was to identify interventions that address these longer term consequences of diarrhea. Methods We searched Medline for randomized controlled trials (RCTs) of interventions conducted in low- and middle-income countries, published between 1980 and 2016 that included children under 15 years of age with diarrhea and follow-up of at least 7 days. Effect measures were summarized by intervention. PRISMA guidelines were followed. Results Among 314 otherwise eligible RCTs, 65% were excluded because follow-up did not extend beyond 7 days. Forty-six trials were included, the majority of which (59%) were conducted in Southeast Asia (41% in Bangladesh alone). Most studies were small, 76% included less than 200 participants. Interventions included: therapeutic zinc alone (28.3%) or in combination with vitamin A (4.3%), high protein diets (19.6%), probiotics (10.9%), lactose free diets (10.9%), oral rehydration solution (ORS) formulations (8.7%), dietary supplements (6.5%), other dietary interventions (6.5%), and antimicrobials (4.3%). Prolonged or recurrent diarrhea was the most commonly reported outcome, and was assessed in ORS, probiotic, vitamin A, and zinc trials with no consistent benefit observed. Seven trials evaluated mortality, with follow-up times ranging from 8 days to 2 years. Only a single trial found a mortality benefit (therapeutic zinc). There were mixed results for dietary interventions affecting growth and diarrhea outcomes in the post-acute period. Conclusion Despite the significant post-acute mortality and morbidity associated with diarrheal episodes, there is sparse evidence evaluating the effects of interventions to decrease these sequelae. Adequately powered trials with extended follow-up are needed to identify effective interventions to prevent post-acute diarrhea outcomes

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Identification and management of Shigella infection in children with diarrhoea: a systematic review and meta-analysis

Summary: Background: Shigella infections are a leading cause of diarrhoeal death among children in low-income and middle-income countries. WHO guidelines reserve antibiotics for treating children with dysentery. Reliance on dysentery for identification and management of Shigella infection might miss an opportunity to reduce Shigella-associated morbidity and mortality. We aimed to systematically review and evaluate Shigella-associated and dysentery-associated mortality, the diagnostic value of dysentery for the identification of Shigella infection, and the efficacy of antibiotics for children with Shigella or dysentery, or both. Methods: We did three systematic reviews (for mortality, diagnostic value, and antibiotic treatment of Shigella and dysentery), and meta-analyses where appropriate, of studies in resource-limited settings. We searched MEDLINE, Embase, and LILACS database for studies published before Jan 1, 2017, in English, French, and Spanish. We included studies of human beings with diarrhoea and accepted all study-specific definitions of dysentery. For the mortality and diagnostic value searches, we excluded studies that did not include an effect estimate or data necessary to calculate this estimate. The search for treatment included only randomised controlled trials that were done after Jan 1, 1980, and assessed antibiotics in children (aged <18 years) with dysentery or laboratory-confirmed Shigella. We extracted or calculated odds ratios (ORs) and 95% CIs for relative mortality and did random-effects meta-analysis to arrive at pooled ORs. We calculated 95% CIs assuming a binomial distribution and did random-effects meta-regression of log-transformed sensitivity and specificity estimates for diagnostic value. We assessed the heterogeneity of papers included in these meta-analyses using the I2 statistic and evaluated publication bias using funnel plots. This review is registered with PROSPERO (CRD42017063896). Findings: 3649 papers were identified and 60 studies were included for analyses: 13 for mortality, 27 for diagnostic value, and 20 for treatment. Shigella infection was associated with mortality (pooled OR 2·8, 95% CI 1·6–4·8; p=0·000) whereas dysentery was not associated with mortality (1·3, 0·7–2·3; p=0·37). Between 1977 and 2016, dysentery identified 1·9–85·9% of confirmed Shigella infections, with sensitivity decreasing over time (p=0·04). Ten (50%) of 20 included antibiotic trials were among children with dysentery, none were placebo-controlled, and two (10%) evaluated antibiotics no longer recommended for acute infectious diarrhoea. Ciprofloxacin showed superior microbiological, but not clinical, effectiveness compared with pivmecillinam, and no superior microbiological and clinical effectiveness compared with gatifloxacin. Substantial heterogeneity was reported for meta-analyses of the Shigella-associated mortality studies (I2=78·3%) and dysentery-associated mortality studies (I2=73·2%). Too few mortality studies were identified to meaningfully test for publication bias. No evidence of publication bias was found in this analysis of studies of diagnostic value. Interpretation: Current WHO guidelines appear to manage dysentery effectively, but might miss opportunities to reduce mortality among children infected with Shigella who present without bloody stool. Further studies should quantify potential decreases in mortality and morbidity associated with antibiotic therapy for children with non-dysenteric Shigella infection. Funding: Bill & Melinda Gates Foundation and the Center for AIDS Research International Core

Correlates of multi-drug non-susceptibility in enteric bacteria isolated from Kenyan children with acute diarrhea.

Reduced antimicrobial susceptibility threatens treatment efficacy in sub-Saharan Africa, where data on the burden and correlates of antibiotic resistance among enteric pathogens are limited.Fecal samples from children aged 6 mos-15 yrs presenting with acute diarrhea in western Kenya were cultured for bacterial pathogens. HIV-uninfected children with identified Shigella or Salmonella species or pathogenic Escherichia coli (EPEC, ETEC, EAEC or EIEC) were included in this cross-sectional sub-study. Non-susceptibility to ampicillin, ceftriaxone, ciprofloxacin, cotrimoxazole, and tetracycline was determined using MicroScan Walkaway40 Plus. Multivariable log-binomial regression was used to identify correlates of multi-drug non-susceptibility (MDNS, non-susceptibility to ≥ 3 of these antibiotics).Of 292 included children, median age was 22.5 mos. MDNS was identified in 62.5% of 318 isolates. Non-susceptibility to cotrimoxazole (92.8%), ampicillin (81.3%), and tetracycline (75.0%) was common. Young age (6-24 mos vs. 24-59 mos adjusted prevalence ratio [aPR] = 1.519 [95% confidence interval: 1.19, 1.91]), maternal HIV (aPR = 1.29 [1.01, 1.66]); and acute malnutrition (aPR = 1.28 [1.06, 1.55]) were associated with higher prevalence of MDNS, as were open defecation (aPR = 2.25 [1.13, 4.50]), household crowding (aPR = 1.29 [1.08, 1.53]) and infrequent caregiver hand-washing (aPR = 1.50 [1.15, 1.95]).Young age, HIV exposure, acute malnutrition and poor sanitation may increase risk of antibiotic non-susceptible enteric pathogen infections among children in Kenya