The Cost and Cost-Effectiveness of an Integrated Wasting Prevention and Screening Intervention Package in Burkina Faso and Mali.

BACKGROUND: Little is known about costs and cost effectiveness of interventions that integrate wasting prevention into screening for child wasting. OBJECTIVES: This study's objective was to estimate the cost and cost-effectiveness of an intervention that integrated behavior change communication (BCC) and small-quantity lipid-based nutrient supplements (SQ-LNS) into platforms for wasting screening in Burkina Faso (a facility-based platform, where BCC was enhanced compared with standard care) and Mali (a community-based platform, with standard BCC). METHODS: Activity-based costing was used to estimate the cost per child-contact for the intervention and the comparison group, which did not receive the intervention. Costs were ascertained from accounting records, interviews, surveys, and observations. The number of child-contacts was calculated using population size estimates and average attendance rates for each service. Costs per disability-adjusted life year (DALY) averted were estimated using a Markov model populated with data from the parent trials on impact of wasting incidence and treatment coverage. RESULTS: In the intervention group in Burkina Faso, the cost per child-contact of facility-based screening was $0.85 of enhanced BCC was $4.28, and of SQ-LNS was $8.86. In Mali, the cost per child-contact of community-based screening was $0.57, standard BCC was $0.72, and SQ-LNS was $4.14. Although no SQ-LNS costs were incurred in the comparison groups (hence lower total costs), costs per child-contact for screening and BCC were higher because coverage of these services was lower. The intervention package cost $1073 per DALY averted in Burkina Faso and $747 in Mali. CONCLUSIONS: Integration of wasting prevention into screening for child wasting led to higher total costs but lower unit costs than standard screening due to increased coverage. Greater cost-effectiveness could be achieved if BCC were strengthened and led to improved caregiver health and nutrition practices and if screening triggered appropriate use of services and higher treatment coverage.

Prevalence and Correlates of Stunting among a High-Risk Population of Kenyan Children Recently Hospitalized for Acute Illnesses.

Stunting (length/height-for-age z-score < -2) is associated with significant morbidity and mortality among children under 5 years of age in sub-Saharan Africa. Children who are stunted and recently hospitalized for acute illness may be at particularly elevated risk for post-discharge mortality. In this cross-sectional analysis, we measured the prevalence of stunting at hospital discharge and identified host, caregiver, and environmental correlates of stunting among children aged 1-59 months in Western Kenya enrolled in the Toto Bora Trial. Child age- and site-adjusted prevalence ratios were estimated using Poisson regression. Of the 1,394 children included in this analysis, 23% were stunted at hospital discharge. Older children (12-23 months and 24-59 months versus 0-5 months) had a higher prevalence of stunting (adjusted prevalence ratio [aPR]: 1.58; 95% CI: 1.04-2.36 and aPR: 1.59; 95% CI: 1.08-2.34, respectively). HIV-exposed, uninfected children (aPR: 1.94; 95% CI: 1.39-2.70), children with HIV infection (aPR: 2.73; 95% CI: 1.45-5.15), and those who were never exclusively breastfed in early life (aPR 2.51; 95% CI: 1.35-4.67) were more likely to be stunted. Caregiver education (primary school or less) and unimproved sanitation (pit latrine without slab floor or open defecation) were associated with increased risk of stunting (aPR: 1.94; 95% CI: 1.54-2.44; aPR: 1.99; 95% CI: 1.20-3.31; aPR: 3.57; 95% CI: 1.77-7.21, respectively). Hospital discharge represents an important opportunity for both identifying and delivering targeted interventions for nutrition-associated poor outcomes among a high-risk population of children.

Azithromycin for the prevention of rehospitalisation and death among Kenyan children being discharged from hospital: a double-blind, placebo-controlled, randomised controlled trial.

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.

Projected impact and cost-effectiveness of community-based versus targeted azithromycin administration strategies for reducing child mortality in sub-Saharan Africa.

BACKGROUND: Trials of mass drug administration (MDA) of azithromycin (AZM) report reductions in child mortality in sub-Saharan Africa (SSA). 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 post-discharge AZM. METHODS AND FINDINGS: Models employed a payer perspective with a 1-year time horizon. Cost-effectiveness was presented as cost per 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. 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 post-discharge, and 13.5% mortality reduction per trial data, post-discharge AZM would avert ~45,000 deaths, at a cost of $2.84/DALY (95% uncertainty interval [UI]: 1.71-5.57) averted. 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), MDA to all under-5 children would avert ~267,000 deaths a cost of $14.26/DALY averted (95% UI: 8.72-27.08). 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 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.

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.

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

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.

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

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.

BACKGROUND: 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. METHODS: 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). RESULTS: 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]). CONCLUSIONS: Young age, HIV exposure, acute malnutrition and poor sanitation may increase risk of antibiotic non-susceptible enteric pathogen infections among children in Kenya.

Azithromycin to prevent post-discharge morbidity and mortality in Kenyan children: a protocol for a randomised, double-blind, placebo-controlled trial (the Toto Bora trial).

INTRODUCTION: Child mortality due to infectious diseases remains unacceptably high in much of sub-Saharan Africa. Children who are hospitalised represent an accessible population at particularly high risk of death, both during and following hospitalisation. Hospital discharge may be a critical time point at which targeted use of antibiotics could reduce morbidity and mortality in high-risk children. METHODS AND ANALYSIS: In this randomised, double-blind, placebo-controlled trial (Toto Bora Trial), 1400 children aged 1-59 months discharged from hospitals in Western Kenya, in Kisii and Homa Bay, will be randomised to either a 5-day course of azithromycin or placebo to determine whether a short course of azithromycin reduces rates of rehospitalisation and/or death in the subsequent 6-month period. The primary analysis will be modified intention-to-treat and will compare the rates of rehospitalisation or death in children treated with azithromycin or placebo using Cox proportional hazard regression. The trial will also evaluate the effect of a short course of azithromycin on enteric and nasopharyngeal infections and cause-specific morbidities. We will also identify risk factors for postdischarge morbidity and mortality and subpopulations most likely to benefit from postdischarge antibiotic use. Antibiotic resistance in Escherichia coli and Streptococcus pneumoniae among enrolled children and their primary caregivers will also be assessed, and cost-effectiveness analyses will be performed to inform policy decisions. ETHICS AND DISSEMINATION: Study procedures were reviewed and approved by the institutional review boards of the Kenya Medical Research Institute, the University of Washington and the Kenyan Pharmacy and Poisons Board. The study is being externally monitored, and a data safety and monitoring committee has been assembled to monitor patient safety and to evaluate the efficacy of the intervention. The results of this trial will be published in peer-reviewed scientific journals and presented at relevant academic conferences and to key stakeholders. TRIAL REGISTRATION NUMBER: NCT02414399.