Childhood growth during recovery from acute illness in Africa and South Asia: a secondary analysis of the childhood acute illness and nutrition (CHAIN) prospective cohort.

Background: Growth faltering is well-recognized during acute childhood illness and growth acceleration during convalescence, with or without nutritional therapy, may occur. However, there are limited recent data on growth after hospitalization in low- and middle-income countries. Methods: We evaluated growth following hospitalization among children aged 2-23 months in sub-Saharan Africa and South Asia. Between November 2016 and January 2019, children were recruited at hospital admission and classified as: not-wasted (NW), moderately-wasted (MW), severely-wasted (SW), or having nutritional oedema (NO). We describe earlier (discharge to 45-days) and later (45- to 180-days) changes in length-for-age [LAZ], weight-for-age [WAZ], mid-upper arm circumference [MUACZ], weight-for-length [WLZ] z-scores, and clinical, nutritional, and socioeconomic correlates. Findings: We included 2472 children who survived to 180-days post-discharge: NW, 960 (39%); MW, 572 (23%); SW, 682 (28%); and NO, 258 (10%). During 180-days, LAZ decreased in NW (-0.27 [-0.36, -0.19]) and MW (-0.23 [-0.34, -0.11]). However, all groups increased WAZ (NW, 0.21 [95% CI: 0.11, 0.32]; MW, 0.57 [0.44, 0.71]; SW, 1.0 [0.88, 1.1] and NO, 1.3 [1.1, 1.5]) with greatest gains in the first 45-days. Of children underweight (<-2 WAZ) at discharge, 66% remained underweight at 180-days. Lower WAZ post-discharge was associated with age-inappropriate nutrition, adverse caregiver characteristics, small size at birth, severe or moderate anaemia, and chronic conditions, while lower LAZ was additionally associated with household-level exposures but not with chronic medical conditions. Interpretation: Underweight and poor linear growth mostly persisted after an acute illness. Beyond short-term nutritional supplementation, improving linear growth post-discharge may require broader individual and family support. Funding: Bill & Melinda Gates FoundationOPP1131320; National Institute for Health ResearchNIHR201813.

Azithromycin for Bacterial Watery Diarrhea: A Reanalysis of the AntiBiotics for Children With Severe Diarrhea (ABCD) Trial Incorporating Molecular Diagnostics.

BACKGROUND: Bacterial pathogens cause substantial diarrhea morbidity and mortality among children living in endemic settings, yet antimicrobial treatment is only recommended for dysentery or suspected cholera. METHODS: AntiBiotics for Children with severe Diarrhea was a 7-country, placebo-controlled, double-blind efficacy trial of azithromycin in children 2-23 months of age with watery diarrhea accompanied by dehydration or malnutrition. We tested fecal samples for enteric pathogens utilizing quantitative polymerase chain reaction to identify likely and possible bacterial etiologies and employed pathogen-specific cutoffs based on genomic target quantity in previous case-control diarrhea etiology studies to identify likely and possible bacterial etiologies. RESULTS: Among 6692 children, the leading likely etiologies were rotavirus (21.1%), enterotoxigenic Escherichia coli encoding heat-stable toxin (13.3%), Shigella (12.6%), and Cryptosporidium (9.6%). More than one-quarter (1894 [28.3%]) had a likely and 1153 (17.3%) a possible bacterial etiology. Day 3 diarrhea was less common in those randomized to azithromycin versus placebo among children with a likely bacterial etiology (risk difference [RD]likely, -11.6 [95% confidence interval {CI}, -15.6 to -7.6]) and possible bacterial etiology (RDpossible, -8.7 [95% CI, -13.0 to -4.4]) but not in other children (RDunlikely, -0.3% [95% CI, -2.9% to 2.3%]). A similar association was observed for 90-day hospitalization or death (RDlikely, -3.1 [95% CI, -5.3 to -1.0]; RDpossible, -2.3 [95% CI, -4.5 to -.01]; RDunlikely, -0.6 [95% CI, -1.9 to .6]). The magnitude of risk differences was similar among specific likely bacterial etiologies, including Shigella. CONCLUSIONS: Acute watery diarrhea confirmed or presumed to be of bacterial etiology may benefit from azithromycin treatment. CLINICAL TRIALS REGISTRATION: NCT03130114.

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.

Family MUAC supported by a two-way SMS platform for identifying children with wasting: the Mama Aweza randomised controlled trial.

Background: Effective methods of preventing and identifying childhood wasting are required to achieve global child health goals. Family mid-upper arm circumference (MUAC) programs train caregivers to screen their child for wasting with MUAC tapes. We assessed the effectiveness of a two-way short message service (SMS) platform (referred to as the Maternally Administered Malnutrition Monitoring System [MAMMS]) in western Kenya. Methods: In this individual-level randomised controlled trial in two rural countries in western Kenya, children (aged 5-12 months) were randomly allocated (1:1) to receive either standard care (SOC) or MAMMS. Randomisation method was permuted-block randomisation with a block size of 10. Eligible participants were children attending maternal child health clinics in the two counties whom had a MUAC between 12.5 and 14.0 cm. The MAMMS group received two MUAC tapes and weekly SMS reminders to screen their child's MUAC. The SOC group received routine community health volunteer services and additional quarterly visits from the study team. The primary analysis used a cox proportional hazards model to compare SOC and MAMMS time-to-diagnosis of wasting (MUAC <12.5 cm) confirmed by a health professional during 6-months follow-up. Secondary outcomes were days from enrolment to treatment initiation among children with wasting, proportion of all children with wasting who were identified by the two approaches (treatment coverage), mean MUAC at treatment initiation, and duration of wasting treatment. This trial was registered on ClinicalTrials.gov, NCT03967015. Findings: Between August 1, 2019 and January 31, 2022, 1200 children were enrolled, among whom the incidence of confirmed wasting was 37% lower in the MAMMS group (hazard ratio: 0.63, 95% CI: 0.42-0.94, p = 0.022). Among children with wasting, the median number of days-to-diagnosis was similar between study groups (MAMMS: 63 days [interquartile range (IQR): 23-92], SOC: 58 days [IQR: 22-94]). Treatment coverage in the MAMMS group was 83.3% (95% CI: 39.9-100.0) while coverage in the SOC group was 55.6% (95% CI: 22.3-88.9%, p = 0.300). Treatment duration and mean MUAC at treatment initiation were similar between groups. Interpretation: Family MUAC supported by SMS was associated with a 37% reduction in wasting among young children. Empowering caregivers to monitor their child's nutritional status at home may prevent a substantial proportion of moderate wasting. Funding: Thrasher Research Foundation and Pamela and Evan Fowler.

Plasma proteomic signatures of enteric permeability among hospitalized and community children in Kenya and Pakistan.

We aimed to establish if enteric permeability was associated with similar biological processes in children recovering from hospitalization and relatively healthy children in the community. Extreme gradient boosted models predicting the lactulose-rhamnose ratio (LRR), a biomarker of enteric permeability, using 7,500 plasma proteins and 34 fecal biomarkers of enteric infection among 89 hospitalized and 60 community children aged 2-23 months were built. The R2 values were calculated in test sets. The models performed better among community children (R2: 0.27 [min-max: 0.19, 0.53]) than hospitalized children (R2: 0.07 [min-max: 0.03, 0.11]). In the community, LRR was associated with biomarkers of humoral antimicrobial and cellular lipopolysaccharide responses and inversely associated with anti-inflammatory and innate immunological responses. Among hospitalized children, the selected biomarkers had few shared functions. This suggests enteric permeability among community children was associated with a host response to pathogens, but this association was not observed among hospitalized children.

Clinical epidemiology of COVID-19 among hospitalized children in rural western Kenya.

The epidemiology of pediatric COVID-19 in sub-Saharan Africa and the role of fecal-oral transmission in SARS-CoV-2 are poorly understood. Among children and adolescents in Kenya, we identify correlates of COVID-19 infection, document the clinical outcomes of infection, and evaluate the prevalence and viability of SARS-CoV-2 in stool. We recruited a prospective cohort of hospitalized children aged two months to 15 years in western Kenya between March 1 and June 30 2021. Children with SARS-CoV-2 were followed monthly for 180-days after hospital discharge. Bivariable logistic regression analysis was used to identify the clinical and sociodemographics correlates of SARS-CoV-2 infection. We also calculated the prevalence of SARS-CoV-2 detection in stool of confirmed cases. Of 355 systematically tested children, 55 (15.5%) were positive and were included in the cohort. The commonest clinical features among COVID-19 cases were fever (42/55, 76%), cough (19/55, 35%), nausea and vomiting (19/55, 35%), and lethargy (19/55, 35%). There were no statistically significant difference in baseline sociodemographic and clinical characteristics between SARS-CoV-2 positive and negative participants. Among positive participants, 8/55 (14.5%, 95%CI: 5.3%-23.9%) died; seven during the inpatient period. Forty-nine children with COVID-19 had stool samples or rectal swabs available at baseline, 9 (17%) had PCR-positive stool or rectal swabs, but none had SARS-CoV-2 detected by culture. Syndromic identification of COVID-19 is particularly challenging among children as the presenting symptoms and signs mirror other common pediatric diseases. Mortality among children hospitalized with COVID-19 was high in this cohort but was comparable to mortality seen with other common illnesses in this setting. Among this small set of children with COVID-19 we detected SARS-CoV-2 DNA, but were not able to culture viable SARs-CoV-2 virus, in stool. This suggests that fecal transmission may not be a substantial risk in children recently diagnosed and hospitalized with COVID-19 infection.

Plasmid-mediated quinolone resistance genes detected in Ciprofloxacin non-susceptible Escherichia coli and Klebsiella isolated from children under five years at hospital discharge, Kenya.

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 (CIP) 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 (AST) by disc diffusion and E-test. CIP non-susceptible isolates were screened for seven PMQR genes using multiplex polymerase chain reaction (PCR). Poisson regression was used to determine the association between the carriage of CIP non-susceptible isolates and patient characteristics. RESULTS: Of the 280 CIP non-susceptible isolates: 188 E. coli and 92 Klebsiella spp isolates identified among 266 discharged children, 195 (68%) were CIP-non-susceptible with minimum inhibitory concentrations (MICs) of ≥ 1 µg/mL. Among these 195 isolates, 130 (67%) had high-level CIP MIC = ≥ 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%), however, qnrA 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 extended spectrum beta-lactamase (ESBL) production were significantly associated with the carriage of CIP non-susceptible E. coli and Klebsiella spp. CONCLUSION: CIP 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.

Considering Risks to Researchers and Staff in Low-Resource Settings during Public Health Crises: A Proposed Conceptual Model.

Human subjects research protections have historically focused on mitigating risk of harm and promoting benefits for research participants. In many low-resource settings (LRS), complex and often severe challenges in daily living, poverty, geopolitical uprisings, sociopolitical, economic, and climate crises increase the burdens of even minimal risk research. While there has been important work to explore the scope of ethical responsibilities of researchers and research teams to respond to these wider challenges and hidden burdens in global health research, less attention has been given to the ethical dilemmas and risk experienced by frontline researcher staff as they perform research-related activities in LRS. Risks such as job insecurity, moral distress, infection, or physical harm can be exacerbated during public health crises, as recently highlighted by the COVID-19 pandemic. We highlight the layers of risk research staff face in LRS and present a conceptual model to characterize drivers of this risk, with particular attention to public health crises. A framework by which funders, institutions, principal investigators, and/or research team leaders can systematically consider these additional layers of risk to researchers and frontline staff is an important and needed addition to routine research proposals and protocol review.

The Role of Food Insecurity and Dietary Diversity on Recovery from Wasting among Hospitalized Children Aged 6-23 Months in Sub-Saharan Africa and South Asia.

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.

Enteric Permeability, Systemic Inflammation, and Post-Discharge Growth Among a Cohort of Hospitalized Children in Kenya and Pakistan.

OBJECTIVES: To determine whether gut permeability is associated with post-discharge growth and systemic inflammation among hospitalized children in low- and middle-income countries. METHODS: Children aged 2-23 months being discharged from Civil Hospital Karachi (Pakistan) and Migori County Referral Hospital (Kenya) underwent lactulose-rhamnose ratio (LRR) permeability testing and were compared to age-matched children from their home communities. Linear mixed effect models estimated the associations between LRR among discharged children with change in length-for-age (LAZ) and weight-for-age z score (WAZ) at 45, 90, and 180 days after discharge. Linear regression tested if relationships between LRR, systemic inflammation [C-reative protein (CRP), Cluster of Differentiation 14 (CD14), Tumour Necrosis Factor Alpha (TNFα), Interleukin-6 (IL-6)], and enterocyte damage [Intestinal Fatty-Acid Binding protein (I-FABP)] differed between the hospitalized and community groups. RESULTS: One hundred thirty-seven hospitalized and 84 community participants were included. The hospitalized group had higher log-LRR [0.43, 95% confidence interval (CI): 0.15-0.71, P = 0.003] than the community children. Adjustment for weight-for-length z score at discharge attenuated this association (0.31, 95% CI: 0.00-0.62, P = 0.049). LRR was not associated with changes in WAZ or LAZ in the post-discharge period. Associations between LRR and CRP (interaction P = 0.036), TNFα ( P = 0.017), CD14 ( P = 0.078), and IL-6 ( P = 0.243) differed between community and hospitalized groups. LRR was associated with TNFα ( P = 0.004) and approached significance with CD14 ( P = 0.078) and IL-6 ( P = 0.062) in community children, but there was no evidence of these associations among hospitalized children. CONCLUSIONS: Although increased enteric permeability is more prevalent among children being discharged from hospital compared to children in the community, it does not appear to be an important determinant of systemic inflammation or post-discharge growth among hospitalized children.

Antimicrobial resistance including Extended Spectrum Beta Lactamases (ESBL) among E. coli isolated from kenyan children at hospital discharge.

BACKGROUND: Children who have been discharged from hospital in sub-Saharan Africa remain at substantial risk of mortality in the post-discharge period. Antimicrobial resistance (AMR) may be an important factor. We sought to determine the prevalence and risk factors associated with AMR in commensal Escherichia coli (E. coli) from Kenyan children at the time of discharge. METHODOLOGY/PRINCIPLE FINDINGS: Fecal samples were collected from 406 children aged 1-59 months in western Kenya at the time of discharge from hospital and cultured for E. coli. Susceptibility to ampicillin, ceftriaxone, cefotaxime, ceftazidime, cefoxitin, imipenem, ciprofloxacin, gentamicin, combined amoxicillin/clavulanic acid, trimethoprim-sulfamethoxazole, azithromycin, and chloramphenicol was determined by disc diffusion according to guidelines from the Clinical and Laboratory Standards Institute (CLSI). Poisson regression was used to determine associations between participant characteristics and the presence of extended-spectrum beta-lactamases (ESBL) producing E. coli. Non-susceptibility to ampicillin (95%), gentamicin (44%), ceftriaxone (46%), and the presence of ESBL (44%) was high. Receipt of antibiotics during the hospitalization was associated with the presence of ESBL (aPR = 2.23; 95% CI: 1.29-3.83) as was being hospitalized within the prior year (aPR = 1.32 [1.07-1.69]). Open defecation (aPR = 2.02; 95% CI: 1.39-2.94), having a toilet shared with other households (aPR = 1.49; 95% CI: 1.17-1.89), and being female (aPR = 1.42; 95% CI: 1.15-1.76) were associated with carriage of ESBL E. coli. CONCLUSIONS/SIGNIFICANCE: AMR is common among isolates of E. coli from children at hospital discharge in Kenya, including nearly half having detectable ESBL.

Effect of 3 Days of Oral Azithromycin on Young Children With Acute Diarrhea in Low-Resource Settings: A Randomized Clinical Trial.

Importance: World Health Organization (WHO) guidelines do not recommend routine antibiotic use for children with acute watery diarrhea. However, recent studies suggest that a significant proportion of such episodes have a bacterial cause and are associated with mortality and growth impairment, especially among children at high risk of diarrhea-associated mortality. Expanding antibiotic use among dehydrated or undernourished children may reduce diarrhea-associated mortality and improve growth. Objective: To determine whether the addition of azithromycin to standard case management of acute nonbloody watery diarrhea for children aged 2 to 23 months who are dehydrated or undernourished could reduce mortality and improve linear growth. Design, Setting, and Participants: The Antibiotics for Children with Diarrhea (ABCD) trial was a multicountry, randomized, double-blind, clinical trial among 8266 high-risk children aged 2 to 23 months presenting with acute nonbloody diarrhea. Participants were recruited between July 1, 2017, and July 10, 2019, from 36 outpatient hospital departments or community health centers in a mixture of urban and rural settings in Bangladesh, India, Kenya, Malawi, Mali, Pakistan, and Tanzania. Each participant was followed up for 180 days. Primary analysis included all randomized participants by intention to treat. Interventions: Enrolled children were randomly assigned to receive either oral azithromycin, 10 mg/kg, or placebo once daily for 3 days in addition to standard WHO case management protocols for the management of acute watery diarrhea. Main Outcomes and Measures: Primary outcomes included all-cause mortality up to 180 days after enrollment and linear growth faltering 90 days after enrollment. Results: A total of 8266 children (4463 boys [54.0%]; mean [SD] age, 11.6 [5.3] months) were randomized. A total of 20 of 4133 children in the azithromycin group (0.5%) and 28 of 4135 children in the placebo group (0.7%) died (relative risk, 0.72; 95% CI, 0.40-1.27). The mean (SD) change in length-for-age z scores 90 days after enrollment was -0.16 (0.59) in the azithromycin group and -0.19 (0.60) in the placebo group (risk difference, 0.03; 95% CI, 0.01-0.06). Overall mortality was much lower than anticipated, and the trial was stopped for futility at the prespecified interim analysis. Conclusions and Relevance: The study did not detect a survival benefit for children from the addition of azithromycin to standard WHO case management of acute watery diarrhea in low-resource settings. There was a small reduction in linear growth faltering in the azithromycin group, although the magnitude of this effect was not likely to be clinically significant. In low-resource settings, expansion of antibiotic use is not warranted. Adherence to current WHO case management protocols for watery diarrhea remains appropriate and should be encouraged. Trial Registration: ClinicalTrials.gov Identifier: NCT03130114.

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.

Prevalence and Correlates of Cryptosporidium Infections in Kenyan Children With Diarrhea and Their Primary Caregivers.

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.

Impact of a two-way short message service (SMS) to support maternally administered childhood mid-upper arm circumference monitoring and expand malnutrition screening in Kenya: the Mama Aweza trial protocol.

INTRODUCTION: Over 52 million children under 5 years of age become wasted each year, but only 17% of these children receive treatment. Novel methods to identify and deliver treatment to malnourished children are necessary to achieve the sustainable development goals target for child health. Mobile health (mHealth) programmes may provide an opportunity to rapidly identify malnourished children in the community and link them to care. METHODS AND ANALYSIS: This randomised controlled trial will recruit 1200 children aged 6-12 months at routine vaccine appointments in Migori and Homa Bay Counties, Kenya. Caregiver-infant dyads will be randomised to either a maternally administered malnutrition monitoring system (MAMMS) or standard of care (SOC). Study staff will train all caregivers to measure their child's mid-upper arm circumference (MUAC). Caregivers in the MAMMS arm will be given two colour coded and graduated insertion MUAC tapes and be enrolled in a mHealth system that sends weekly short message service (SMS) messages prompting caregivers to measure and report their child's MUAC by SMS. Caregivers in the SOC arm will receive routine monitoring by community health volunteers coupled with a quarterly visit from study staff to ensure adequate screening coverage. The primary outcome is identification of childhood malnutrition, defined as MUAC <12.5 cm, in the MAMMS arm compared with the SOC arm. Secondary outcomes will assess the accuracy of maternal versus health worker MUAC measurements and determinants of acute malnutrition among children 6-18 months of age. Finally, we will explore the acceptability, fidelity and feasibility of implementing the MAMMS within existing nutrition programmes. ETHICS AND DISSEMINATION: The study was approved by review boards at the University of Washington and the Kenya Medical Research Institute. A data and safety monitoring board has been convened, and the results of the trial will be published in peer-reviewed scientific journals, presented at appropriate conferences and to key stakeholders. TRIAL REGISTRATION NUMBER: NCT03967015; Pre-results.

Impact of Childhood Nutritional Status on Pathogen Prevalence and Severity of Acute Diarrhea.

Children with acute and chronic malnutrition are at increased risk of morbidity and mortality following a diarrheal episode. To compare diarrheal disease severity and pathogen prevalence among children with and without acute and chronic malnutrition, we conducted a cross-sectional study of human immunodeficiency virus-uninfected Kenyan children aged 6-59 months, who presented with acute diarrhea. Children underwent clinical and anthropometric assessments and provided stool for bacterial and protozoal pathogen detection. Clinical and microbiological features were compared using log binomial regression among children with and without wasting (mid-upper arm circumference ≤ 125 mm) or stunting (height-for-age z score ≤ -2). Among 1,363 children, 7.0% were wasted and 16.9% were stunted. After adjustment for potential confounders, children with wasting were more likely than nonwasted children to present with at least one Integrated Management of Childhood Illness danger sign (adjusted prevalence ratio [aPR]: 1.3, 95% confidence interval [CI]: 1.0 to 1.5, P = 0.05), severe dehydration (aPR: 2.4, 95% CI: 1.5 to 3.8, P < 0.01), and enteroaggregative Escherichia coli recovered from their stool (aPR: 1.8, 1.1-2.8, P = 0.02). There were no differences in the prevalence of other pathogens by wasting status after confounder adjustment. Stunting was not associated with clinical severity or the presence of specific pathogens. Wasted children with diarrhea presented with more severe disease than children without malnutrition which may be explained by a delay in care-seeking or diminished immune response to infection. Combating social determinants and host risk factors associated with severe disease, rather than specific pathogens, may reduce the disparities in poor diarrhea-associated outcomes experienced by malnourished children.

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.

Low Bacteremia Prevalence Among Febrile Children in Areas of Differing Malaria Transmission in Rural Kenya: A Cross-Sectional Study.

BACKGROUND: With malaria declining, other causes of fever may account for a substantial portion of severe childhood illness in sub-Saharan Africa. We determined prevalence, etiologies, and correlates of bacteremia among children in Western Kenya. METHODS: In a cross-sectional study, febrile children aged 6 months to 15 years presenting to Kisii (low malaria endemicity) and Homabay (high malaria endemicity) Hospitals were enrolled and screened for malaria, human immunodeficiency virus (HIV) infection and bacteremia. Correlates of bacteremia were evaluated using logistic regression. RESULTS: Among 1476 children enrolled, 48 (3.3%) had bacteremia (23 of 734, 3.1% in Kisii and 25 of 734, 3.4% in Homabay). Salmonella spp (19 typhi and 21 nontyphoidal salmonella) accounted for 83% (40 of 48) of isolates. The distribution of Salmonella spp was similar between sites. Bacteremia was associated with incomplete vaccination (adjusted odds ratio [aOR] = 2.1; 95% confidence interval [CI], 1.1-4.1), before treatment with antimalarials (aOR = 2.7; 95% CI, 1.4-4.1), having sought care elsewhere (aOR = 2.2; 95% CI, 1.2-4.0) and lower education of caregiver (aOR = 2.5; 95% CI, 1.1-4.8). Nontyphoidal salmonella bacteremia was associated with HIV (aOR = 6.8; 95% CI, 1.1-35.1) and anemia (hemoglobin <8 g/dL) (aOR = 5.2; 95% CI, 1.4-18.9). CONCLUSIONS: Bacteremia was relatively uncommon, but children with HIV, anemia, incomplete vaccination, and/or persistent fever despite malaria treatment may have higher risk and may benefit from targeted bacterial culture and/or empiric antibiotic therapy.

Mycobacterium tuberculosis Bacteremia Among Acutely Febrile Children in Western Kenya.

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.