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Azithromycin is a promising alternative to amoxicillin in the management of uncomplicated severe acute malnutrition (SAM) as it can be administered as a single dose and has efficacy against several pathogens causing infectious disease and mortality in children under 5. In this pilot trial, we aimed to establish the feasibility of a larger randomized controlled trial and provide preliminary evidence comparing the effect of azithromycin to amoxicillin on weight gain in children with uncomplicated SAM. We enrolled children 6-59 months old with uncomplicated SAM at six healthcare centers in Burkina Faso. Participants were randomized to a single dose of azithromycin or a 7-day course of amoxicillin and followed weekly until nutritional recovery and again at 8 weeks. Apart from antibiotics, participants received standard of care, which includes ready-to-use therapeutic food. Primary feasibility outcomes included enrollment potential, refusals, and loss to follow-up. The primary clinical outcome was weight gain (g/kg/day) over 8 weeks. Outcome assessors were masked. Between June and October 2020, 312 children were screened, 301 were enrolled with zero refusals, and 282 (93.6%) completed the 8-week visit. Average weight gain was 2.5 g/kg/day (standard deviation [SD] 2.0) in the azithromycin group and 2.6 (SD 1.7) in the amoxicillin group (mean difference -0.1, 95% CI -0.5 to 0.3, P = 0.63). Fewer adverse events were reported in the azithromycin group (risk ratio 0.50, 95% CI 0.31-0.82, P = 0.006). With strong enrollment and follow-up, a fully powered trial in this setting is feasible.

Access to improved sanitation and hygiene may improve child nutritional status by reducing exposure to enteric pathogens. We evaluated this relationship as part of the Community Health with Azithromycin Trial, a community-randomized trial of azithromycin versus placebo for the prevention of child mortality in rural Burkina Faso. Before the baseline study visit, a door-to-door household survey was conducted for all households in the study area. During the baseline study census, which occurred approximately 9 months after the household survey, a mid-upper arm circumference (MUAC) measurement was obtained from each child. We evaluated the relationship between household improved latrine use compared with unimproved latrines or open defecation and MUAC in children aged 6-59 months. Among 32,172 children with household survey data and MUAC measurements, 931 (2.9%) had an MUAC less than 12.5 cm and were classified as having moderate acute malnutrition (MAM). The odds of MAM were higher in children living in households with an unimproved latrine than those with an improved latrine (adjusted odds ratio: 1.60; 95% CI: 1.11-2.31). Children in households with unimproved latrines and households that practiced open defection had approximate 0.15 cm reduced MUAC compared with those in households with an improved latrine. There was a small, but statistically significant, association between improved latrine and nutritional status in preschool children as measured by MUAC.

The Trachoma Control Program in Amhara region, Ethiopia, scaled up the surgery, antibiotics, facial cleanliness, and environmental improvement (SAFE) strategy in all districts starting in 2007. Despite these efforts, many districts still require additional years of SAFE. In 2017, four districts were selected for the assessment of antibody responses against Chlamydia trachomatis antigens and C. trachomatis infection to better understand transmission. Districts with differing endemicity were chosen, whereby one had a previous trachomatous inflammation-follicular (TF) prevalence of ≥ 30% (Andabet), one had a prevalence between 10% and 29.9% (Dera), one had a prevalence between 5% and 10% (Woreta town), and one had a previous TF prevalence of < 5% (Alefa) and had not received antibiotic intervention for 2 years. Survey teams assessed trachoma clinical signs and took conjunctival swabs and dried blood spots (DBS) to measure infection and antibody responses. Trachomatous inflammation-follicular prevalence among children aged 1-9 years was 37.0% (95% CI: 31.1-43.3) for Andabet, 14.7% (95% CI: 10.0-20.5) for Dera, and < 5% for Woreta town and Alefa. Chlamydia trachomatis infection was only detected in Andabet (11.3%). Within these districts, 2,195 children provided DBS. The prevalence of antibody responses to the antigen Pgp3 was 36.9% (95% CI: 29.0-45.6%) for Andabet, 11.3% (95% CI: 5.9-20.6%) for Dera, and < 5% for Woreta town and Alefa. Seroconversion rate for Pgp3 in Andabet was 0.094 (95% CI: 0.069-0.128) events per year. In Andabet district, where SAFE implementation has occurred for 11 years, the antibody data support the finding of persistently high levels of trachoma transmission.

Biannual mass azithromycin distribution reduces all-cause child mortality in some settings in sub-Saharan Africa; however, adverse events and short-term infectious outcomes following treatment have not been well characterized. Children aged 0-59 months were recruited in Nouna Town, Burkina Faso, and randomized 1:1 to a single directly observed oral 20 mg/kg dose of azithromycin or placebo. At 14 days after treatment, caregivers were interviewed about adverse event symptoms their child experienced since treatment and if they had sought health care for their child. All children had tympanic temperature measured at the 14-day visit. We compared adverse events and clinic visits using logistic regression models between azithromycin- and placebo-controlled children. Of 450 children enrolled, 230 were randomized to azithromycin and 220 to placebo. On average, children were aged 28 months, and 50.9% were female. Caregivers of 20% of children reported that their child experienced at least one adverse event, with no significant difference between study arms (19.9% azithromycin; 20.0% placebo, logistic regression P = 0.96). Vomiting was more often reported by caregivers of azithromycin-treated children than by those of placebo-treated children (7.2% azithromycin, 1.9% placebo, logistic regression P = 0.01). There were no significant differences in other adverse events or clinic visits. Adverse events following a single oral dose of azithromycin in preschool children were rare and mild. Azithromycin administration appears safe in this population.

Poor nutrition and hand hygiene are risk factors for acute respiratory infections (ARIs). Safe drinking water and sanitation can reduce exposure to pathogens and encourage healthy immune responses, reducing the risk of ARIs. Within a trial assessing impacts of water, sanitation, and handwashing (WASH), and nutritional interventions, we evaluated effects on ARIs. The WASH Benefits cluster-randomized trial enrolled pregnant women from Kenyan villages and evaluated health outcomes in children born to enrolled mothers 1 and 2 years after intervention delivery. Geographically adjacent clusters were block-randomized into a passive control (no promotional visits), a double-sized active control (monthly visits to measure mid-upper arm circumference), and six intervention groups: chlorinated drinking water (W), improved sanitation (S), handwashing with soap (H), combined WSH, improved nutrition (N) through counseling and lipid-based nutrient supplementation (LNS), and combined WSHN. The main outcome was the prevalence of ARI symptoms (cough, panting, wheezing, or difficulty breathing) in children younger than 3 years. Masking participants was not possible. Analyses were intention-to-treat. Between November 2012 and May 2014, 702 clusters were enrolled, including 6,960 (year 1) and 7,088 (year 2) children with ARI data. The cluster-level intra-cluster correlation coefficient for ARIs was 0.026 across both years. Water, sanitation, and handwashing interventions with behavior change messaging did not reduce ARIs. Nutrition counseling and LNS modestly reduced ARI symptoms compared with controls in year 1 [prevalence ratio (PR): 0.87, 95% confidence interval (CI): 0.77-0.99], but no effect in the combined WSHN group weakens this finding.

Acute respiratory infections cause mortality in young children. We assessed the effects of water, sanitation, hygiene (WASH) and nutritional interventions on childhood ARI. Geographic clusters of pregnant women from rural Bangladesh were randomly assigned to receive 1) chlorinated drinking water and safe storage (W); 2) upgraded sanitation (S); 3) handwashing promotion (H); 4) combined water, sanitation, and handwashing (WSH); 5) nutrition intervention including lipid-based nutrient supplements; 6) combined WSH plus nutrition (WSHN); or 7) no intervention (control). Masking of participants was not possible. Acute respiratory illness was defined as caregiver-reported persistent cough, panting, wheezing, or difficulty breathing in the past 7 days among index children, those born to enrolled women. We assessed outcomes at 12 and 24 months of intervention using intention to treat. Compared with children in the control group (ARI prevalence, P: 8.9%), caregivers of index children reported significantly lower ARI in the water (P: 6.3%, prevalence ratio (PR): 0.71; 95% CI: 0.53, 0.96), sanitation (P: 6.4%, PR: 0.75, 95% CI: 0.58, 0.96), handwashing (P: 6.4%, PR: 0.68, 95% CI: 0.50, 0.93), and the combined WSH+N arms (P: 5.9%, PR: 0.67, 95% CI: 0.50, 0.90). Those in the nutrition (P: 7.4%, PR: 0.84, 95% CI: 0.63, 1.10) or the WSH arm (P: 8.9%, PR: 0.99, 95% CI: 0.76, 1.28) reported similar ARI prevalence compared with control children. Single targeted water, sanitation, and hygiene interventions reduced reported respiratory illness in young children. There was no apparent respiratory health benefit from combining WASH interventions.

Accurate and cost-effective identification of areas where co-endemic infections occur would enable public health managers to identify opportunities for implementation of integrated control programs. Dried blood spots collected during cross-sectional lymphatic filariasis surveys in coastal Kenya were used for exploratory integrated detection of IgG antibodies against antigens from several parasitic infections (Wuchereria bancrofti, Schistosoma mansoni, Plasmodium spp., Ascaris lumbricoides, and Strongyloides stercoralis) as well as for detection of responses to immunizing agents used against vaccine-preventable diseases (VPDs) (measles, diphtheria, and tetanus) using a multiplex bead assay (MBA) platform. High heterogeneity was observed in antibody responses by pathogen and antigen across the sentinel sites. Antibody seroprevalence against filarial antigens were generally higher in Ndau Island (P < 0.0001), which also had the highest prevalence of filarial antigenemia compared with other communities. Antibody responses to the Plasmodium species antigens circumsporozoite protein (CSP) and merozoite surface protein-1 (MSP-1)19 were higher in Kilifi and Kwale counties, with Jaribuni community showing higher overall mean seroprevalence (P < 0.0001). Kimorigo community in Taita-Taveta County was the only area where antibody responses against S. mansoni Sm25 recombinant antigen were detected. Seroprevalence rates to Strongyloides antigen NIE ranged between 3% and 26%, and there was high heterogeneity in immune responses against an Ascaris antigen among the study communities. Differences were observed between communities in terms of seroprevalence to VPDs. Seroprotection to tetanus was generally lower in Kwale County than in other counties. This study has demonstrated that MBA holds promise for rapid integrated monitoring of trends of infections of public health importance in endemic areas.

Diarrhea is a leading cause of death among children aged less than five years globally. Most studies of pediatric diarrhea rely on caregiver-reported stool consistency and frequency to define the disease. Research on the validity of caregiver-reported diarrhea is sparse. We collected stool samples from 2,398 children participating in two clinical trials in the Amhara region of Ethiopia. The consistency of each stool sample was graded by the child's caregiver and two trained laboratory technicians according to an illustrated stool consistency scale. We assessed the reliability of graded stool consistency among the technicians, and then compared the caregiver's grade with the technician's grade. We also tested if the illustrated stool consistency scale could improve the validity of caregiver's report. The weighted kappa measuring the agreement between the two laboratory technicians reached 0.90 after 500 stool samples were graded. The sensitivity of caregiver-reported loose or watery stool was 15.5% (95% confidence interval [CI]: 9.7, 24.2) and the specificity was 98.4% (95% CI 97.1, 99.1). With the illustrated scale, the sensitivity was 68.5% (95% CI: 58.5, 77.1) and the specificity was 86.1% (95% CI: 79.3, 90.9). The results indicate that caregiver-reported stool consistency using the terms "loose or watery" does not accurately describe stool consistency as graded by trained laboratory technicians. Given the predominance of using caregiver-reported stool consistency to define diarrheal disease, the low sensitivity identified in this study suggests that the burden of diarrheal disease may be underestimated and intervention effects could be biased. The illustrated scale is a potential low-lost tool to improve the validity of caregiver-reported stool consistency.

Microbiological water quality is usually assessed by the identification of Escherichia coli (E. coli), a fecal indicator. The hydrogen sulfide (H2S) test is an inexpensive, easy-to-use, and portable alternative field-based water quality test. Our study evaluated the H2S test's effectiveness as a water quality indicator for diarrhea risk. Field workers collected stored drinking water samples for H2S analysis and detection of E. coli by membrane filtration and measured caregiver-reported diarrhea among children < 5 years in the same households 1 month later. We assessed the association between the H2S test (incubated for 24 hours and 48 hours) and diarrhea prevalence, with 2-day and 7-day symptom recall periods (N = 1,348). We determined the sensitivity, specificity, and positive and negative predictive value (PPV, NPV) of the H2S test compared with E. coli (N = 525). Controlling for potentially confounding covariates, H2S-positive water (at 24 or 48 hours) was not associated with 2-day diarrhea prevalence (24-hour prevalence ratio [PR] = 1.03, 95% confidence interval [CI]: 0.63-1.69; 48-hour PR = 0.89, 95% CI: 0.58-1.38) or 7-day diarrhea prevalence (24-hour PR = 1.17, 95% CI: 0.76-1.78; 48-hour PR = 1.21, 95% CI: 0.81-1.80). The sensitivity, PPV, and NPV of the H2S test was significantly higher when the H2S test was incubated for 48 versus 24 hours whereas specificity showed the opposite trend. H2S test sensitivity, PPV, and NPV increased with increasing E. coli levels, consistent with previous evidence that the H2S test is a useful water quality tool in high-contamination settings. However, our results suggest that the H2S test is not an effective indicator for waterborne diarrhea.

Accurately assessing the microbiological safety of water sources is essential to reduce waterborne fecal exposures and track progress toward global targets of safe water access. Sanitary inspections are a recommended tool to assess water safety. We collected 1,684 water samples from 902 shallow tubewells in rural Bangladesh and conducted sanitary surveys to assess whether sanitary risk scores could predict water quality, as measured by Escherichia coli. We detected E. coli in 41% of tubewells, mostly at low concentrations. Based on sanitary scores, 31% of wells were low risk, 45% medium risk, and 25% high or very high risk. Older wells had higher risk scores. Escherichia coli levels were higher in wells where the platform was cracked or broken (Δlog10 = 0.09, 0.00-0.18) or undercut by erosion (Δlog10 = 0.13, 0.01-0.24). However, the positive predictive value of these risk factors for E. coli presence was low (< 50%). Latrine presence within 10 m was not associated with water quality during the wet season but was associated with less frequent E. coli detection during the dry season (relative risk = 0.72, 0.59-0.88). Sanitary scores were not associated with E. coli presence or concentration. These findings indicate that observed characteristics of a tubewell, as measured by sanitary inspections in their current form, do not sufficiently characterize microbiological water quality, as measured by E. coli. Assessments of local groundwater and geological conditions and improved water quality indicators may reveal more clear relationships. Our findings also suggest that the dominant contamination route for shallow groundwater sources is short-circuiting at the wellhead rather than subsurface transport.

Poor sanitation could pose greater risk for enteric pathogen transmission at higher human population densities because of greater potential for pathogens to infect new hosts through environmentally mediated and person-to-person transmission. We hypothesized that incidence and prevalence of diarrhea, enteric protozoans, and soil-transmitted helminth infections would be higher in high-population-density areas compared with low-population-density areas, and that poor sanitation would pose greater risk for these enteric infections at high density compared with low density. We tested our hypotheses using 6 years of clinic-based diarrhea surveillance (2007-2013) including 4,360 geolocated diarrhea cases tested for 13 pathogens and a 2010 cross-sectional survey that measured environmental exposures from 204 households (920 people) and tested 701 stool specimens for enteric parasites. We found that population density was not a key determinant of enteric infection nor a strong effect modifier of risk posed by poor household sanitation in this setting.

We used a prospective, longitudinal cohort enrolled as part of a program evaluation to assess the relationship between drinking water microbiological quality and child diarrhea. We included 50 villages across rural Bangladesh. Within each village field-workers enrolled a systematic random sample of 10 households with a child under the age of 3 years. Community monitors visited households monthly and recorded whether children under the age of 5 years had diarrhea in the preceding 2 days. Every 3 months, a research assistant visited the household and requested a water sample from the source or container used to provide drinking water to the child. Laboratory technicians measured the concentration of Escherichia coli in the water samples using membrane filtration. Of drinking water samples, 59% (2,273/3,833) were contaminated with E. coli. Of 12,192 monthly follow-up visits over 2 years, mothers reported that their child had diarrhea in the preceding 2 days in 1,156 (9.5%) visits. In a multivariable general linear model, the log10 of E. coli contamination of the preceding drinking water sample was associated with an increased prevalence of child diarrhea (prevalence ratio = 1.14, 95% CI = 1.05, 1.23). These data provide further evidence of the health benefits of improved microbiological quality of drinking water.

In preparation for a larger trial, the Water, Sanitation, and Hygiene (WASH) Benefits pilot study enrolled 72 villages and 499 subjects in two closely related randomized trials of WASH interventions in rural western Kenya. Intervention households received hardware and promotion for one of the following: water treatment, sanitation and latrine improvements, handwashing with soap, or the combination of all three. Interventions were clustered by village. A follow-up survey was conducted 4 months after intervention delivery to assess uptake. Intervention households were significantly more likely than controls to have chlorinated stored water (36-60 percentage point increases), covers over latrine drop holes (55-75 percentage point increases), less stool visible on latrine floors (16-47 percentage point reductions), and a place for handwashing (71-85 percentage point increases) with soap available (49-66 percentage point increases). The high uptake in all arms shows that combined interventions can achieve high short-term adoption rates if well-designed.

Discreet collection of spot check observations to measure household hygiene conditions is a common measurement technique in epidemiologic studies of hygiene in low-income countries. The objective of this study was to determine whether the collection of spot check observations in longitudinal studies could itself induce reactivity (i.e., change participant behavior). We analyzed data from a 12-month prospective cohort study in rural Tamil Nadu, India that was conducted in the absence of any hygiene or toilet promotion activities. Our data included hygiene and toilet spot checks from 10,427 household visits. We found substantial evidence of participant reactivity to spot check observations of hygiene practices that were easy to modify on short notice. For example, soap observed at the household's primary handwashing location increased from 49% at enrollment to 81% by the fourth visit and remained at or above 77% for the remainder of the study.

In this large-scale longitudinal study conducted in rural Southern India, we compared a presence/absence hydrogen sulfide (H2S) test with quantitative assays for total coliforms and Escherichia coli as measures of water quality, health risk, and water supply vulnerability to microbial contamination. None of the three indicators showed a significant association with child diarrhea. The presence of H2S in a water sample was associated with higher levels of total coliform species that may have included E. coli but that were not restricted to E. coli. In addition, we observed a strong relationship between the percent positive H2S test results and total coliform levels among water source samples (R(2) = 0.87). The consistent relationships between H2S and total coliform levels indicate that presence/absence of H2S tests provide a cost-effective option for assessing both the vulnerability of water supplies to microbial contamination and the results of water quality management and risk mitigation efforts.

We assessed the relationship of fecal environmental contamination and environmental enteropathy. We compared markers of environmental enteropathy, parasite burden, and growth in 119 Bangladeshi children (≤ 48 months of age) across rural Bangladesh living in different levels of household environmental cleanliness defined by objective indicators of water quality and sanitary and hand-washing infrastructure. Adjusted for potential confounding characteristics, children from clean households had 0.54 SDs (95% confidence interval [CI] = 0.06, 1.01) higher height-for-age z scores (HAZs), 0.32 SDs (95% CI = -0.72, 0.08) lower lactulose:mannitol (L:M) ratios in urine, and 0.24 SDs (95% CI = -0.63, 0.16) lower immunoglobulin G endotoxin core antibody (IgG EndoCAb) titers than children from contaminated households. After adjusting for age and sex, a 1-unit increase in the ln L:M was associated with a 0.33 SDs decrease in HAZ (95% CI = -0.62, -0.05). These results are consistent with the hypothesis that environmental contamination causes growth faltering mediated through environmental enteropathy.