Clinical and nutritional correlates of bacterial diarrhoea aetiology in young children: a secondary cross-sectional analysis of the ABCD trial.

OBJECTIVE: The objective was to assess the association between nutritional and clinical characteristics and quantitative PCR (qPCR)-diagnosis of bacterial diarrhoea in a multicentre cohort of children under 2 years of age with moderate to severe diarrhoea (MSD). DESIGN: A secondary cross-sectional analysis of baseline data collected from the AntiBiotics for Children with Diarrhoea trial (NCT03130114). PATIENTS: Children with MSD (defined as >3 loose stools within 24 hours and presenting with at least one of the following: some/severe dehydration, moderate acute malnutrition (MAM) or severe stunting) enrolled in the ABCD trial and collected stool sample. STUDY PERIOD: June 2017-July 2019. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Likely bacterial aetiology of diarrhoea. Secondary outcomes included specific diarrhoea aetiology. RESULTS: A total of 6692 children with MSD had qPCR results available and 28% had likely bacterial diarrhoea aetiology. Compared with children with severe stunting, children with MAM (adjusted OR (aOR) (95% CI) 1.56 (1.18 to 2.08)), some/severe dehydration (aOR (95% CI) 1.66 (1.25 to 2.22)) or both (aOR (95% CI) 2.21 (1.61 to 3.06)), had higher odds of having likely bacterial diarrhoea aetiology. Similar trends were noted for stable toxin-enterotoxigenic Escherichia coli aetiology. Clinical correlates including fever and prolonged duration of diarrhoea were not associated with likely bacterial aetiology; children with more than six stools in the previous 24 hours had higher odds of likely bacterial diarrhoea (aOR (95% CI) 1.20 (1.05 to 1.36)) compared with those with fewer stools. CONCLUSION: The presence of MAM, dehydration or high stool frequency may be helpful in identifying children with MSD who might benefit from antibiotics.

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.

Small vulnerable newborns-big potential for impact.

Despite major achievements in child survival, the burden of neonatal mortality has remained high and even increased in some countries since 1990. Currently, most neonatal deaths are attributable to being born preterm, small for gestational age (SGA), or with low birthweight (LBW). Besides neonatal mortality, these conditions are associated with stillbirth and multiple morbidities, with short-term and long-term adverse consequences for the newborn, their families, and society, resulting in a major loss of human capital. Prevention of preterm birth, SGA, and LBW is thus critical for global child health and broader societal development. Progress has, however, been slow, largely because of the global community's failure to agree on the definition and magnitude of newborn vulnerability and best ways to address it, to frame the problem attractively, and to build a broad coalition of actors and a suitable governance structure to implement a change. We propose a new definition and a conceptual framework, bringing preterm birth, SGA, and LBW together under a broader umbrella term of the small vulnerable newborn (SVN). Adoption of the framework and the unified definition can facilitate improved problem definition and improved programming for SVN prevention. Interventions aiming at SVN prevention would result in a healthier start for live-born infants, while also reducing the number of stillbirths, improving maternal health, and contributing to a positive economic and social development in the society.

Maternal Underweight and Its Association with Composite Index of Anthropometric Failure among Children under Two Years of Age with Diarrhea in Bangladesh.

Malnutrition in women has been a long-standing public health concern, with serious effects on child survival and development. Maternal body mass index (BMI) is an important maternal nutritional indicator. There are few published studies although child anthropometric failures do not occur in isolation and identifying children with single versus several co-occurring failures can better capture cases of growth failure in combination: stunting, wasting, and underweight. In the context of multiple anthropometric failures, traditional markers used to assess children's nutritional status tend to underestimate overall undernutrition. Using the composite index of anthropometric failure (CIAF), we aimed to assess the association between maternal undernutrition and child undernutrition among children with diarrhea under the age of two and to investigate the correlates. Using 1431 mother-child dyads from the Antibiotic for Children with Diarrhea (ABCD) trial, we extracted children's data at enrollment and on day 90 and day 180 follow-ups. ABCD was a randomized, multi-country, multi-site, double-blind, placebo-controlled clinical trial. The Bangladesh site collected data from July 2017 to July 2019. The outcome variable, CIAF, allows combinations of height-for-age, height-for-weight, and weight-for-age to determine the overall prevalence of undernutrition. The generalized estimating equation was used to explore the correlates of CIAF. After adjusting all the potential covariates, maternal undernutrition status was found to be strongly associated with child undernutrition using the CIAF [aOR: 1.4 (95% CI: 1.0, 1.9), p-value = 0.043] among the children with diarrhea under 2 years old. Maternal higher education had a protective effect on CIAF [aOR: 0.7 (95% CI: 0.5, 0.9), p-value = 0.033]. Our study findings highlight the importance of an integrated approach focusing on maternal nutrition and maternal education could affect a reduction in child undernutrition based on CIAF.

Lower-Dose Zinc for Childhood Diarrhea - A Randomized, Multicenter Trial.

BACKGROUND: The World Health Organization recommends 20 mg of zinc per day for 10 to 14 days for children with acute diarrhea; in previous trials, this dosage decreased diarrhea but increased vomiting. METHODS: We randomly assigned 4500 children in India and Tanzania who were 6 to 59 months of age and had acute diarrhea to receive 5 mg, 10 mg, or 20 mg of zinc sulfate for 14 days. The three primary outcomes were a diarrhea duration of more than 5 days and the number of stools (assessed in a noninferiority analysis) and the occurrence of vomiting (assessed in a superiority analysis) within 30 minutes after zinc administration. RESULTS: The percentage of children with diarrhea for more than 5 days was 6.5% in the 20-mg group, 7.7% in the 10-mg group, and 7.2% in the 5-mg group. The difference between the 20-mg and 10-mg groups was 1.2 percentage points (upper boundary of the 98.75% confidence interval [CI], 3.3), and that between the 20-mg and 5-mg groups was 0.7 percentage points (upper boundary of the 98.75% CI, 2.8), both of which were below the noninferiority margin of 4 percentage points. The mean number of diarrheal stools was 10.7 in the 20-mg group, 10.9 in the 10-mg group, and 10.8 in 5-mg group. The difference between the 20-mg and 10-mg groups was 0.3 stools (upper boundary of the 98.75% CI, 1.0), and that between the 20-mg and 5-mg groups was 0.1 stools (upper boundary of the 98.75% CI, 0.8), both of which were below the noninferiority margin (2 stools). Vomiting within 30 minutes after administration occurred in 19.3%, 15.6%, and 13.7% of the patients in the 20-mg, 10-mg, and 5-mg groups, respectively; the risk was significantly lower in the 10-mg group than in the 20-mg group (relative risk, 0.81; 97.5% CI, 0.67 to 0.96) and in the 5-mg group than in the 20-mg group (relative risk, 0.71; 97.5% CI, 0.59 to 0.86). Lower doses were also associated with less vomiting beyond 30 minutes after administration. CONCLUSIONS: Lower doses of zinc had noninferior efficacy for the treatment of diarrhea in children and were associated with less vomiting than the standard 20-mg dose. (Funded by the Bill and Melinda Gates Foundation; ZTDT ClinicalTrials.gov number, NCT03078842.).

Challenges of developing a district child welfare plan in South Africa: lessons from a community-engaged HIV/AIDS research project.

The Amajuba Child Health and Wellbeing Research Project measured the impact of orphaning due to HIV/AIDS on South African households between 2004 and 2007. Community engagement was a central component of the project and extended through 2010. We describe researcher engagement with the community to recruit participants, build local buy-in, stimulate interest in study findings, and promote integration of government social welfare services for families and children affected by HIV/AIDS. This narrative documents the experience of researchers, drawing also on project reports, public documents, and published articles, with the objective of documenting lessons learned in this collaboration between researchers from two universities and a community in South Africa during a period that spanned seven years. This experience is then analyzed within the context of an applied research, community-engagement framework.

Effect of dose reduction of supplemental zinc for childhood diarrhoea: study protocol for a double-masked, randomised controlled trial in India and Tanzania.

BACKGROUND: Diarrhoea-associated mortality and morbidity are highest in infants and young children in low-income and middle-income countries (LMICs). Zinc supplementation during acute diarrhoea has been shown to reduce the duration of illness and the risk of persistent diarrhoea. However, vomiting with zinc supplementation is a common side effect that may interfere with compliance and programmatic scale-up, and may be related to the dose prescribed. METHODS/DESIGN: The Zinc Therapeutic Dose Trial (ZTDT) is a two-centre (Tanzania and India), three-arm randomised, double-blind controlled non-inferiority trial. Children 6-59 months of age with acute diarrhoea are eligible to participate. Enrolled children (1500 per arm; 4500 total) will be randomly allocated to receive 5, 10 or 20 mg of zinc sulfate daily for 14 days and will be followed up for 60 days after enrolment. All children will receive WHO/Unicef Integrated Management of Childhood Illness standard of care (oral or intravenous rehydration and zinc as indicated and feeding advice). The primary efficacy outcomes of the trial are the percentage of subjects with diarrhoea duration >5 days, the mean total number of loose or watery stools after enrolment and the proportion of children vomiting within 30 min of zinc administration. DISCUSSION: The ZTDT trial will determine the optimal dose of therapeutic zinc supplements for treatment of acute diarrhoea in children aged 6-59 months in two LMICs. The results of the trial are likely to be generalisable to childhood acute diarrhoea in similar resource-limited settings and may influence global policy about zinc supplementation dosage during acute diarrhoea. TRIAL REGISTRATION NUMBER: NCT03078842. TRIAL STATUS: Enrolment began in January 2017 and follow-up is estimated to be completed by April 2019. As of 1 February 2019, 742 children are still contributing data to the ZTDT study.

Effectiveness of 4% chlorhexidine umbilical cord care on neonatal mortality in Southern Province, Zambia (ZamCAT): a cluster-randomised controlled trial.

BACKGROUND: Chlorhexidine umbilical cord washes reduce neonatal mortality in south Asian populations with high neonatal mortality rates and predominantly home-based deliveries. No data exist for sub-Saharan African populations with lower neonatal mortality rates or mostly facility-based deliveries. We compared the effect of chlorhexidine with dry cord care on neonatal mortality rates in Zambia. METHODS: We undertook a cluster-randomised controlled trial in Southern Province, Zambia, with 90 health facility-based clusters. We enrolled women who were in their second or third trimester of pregnancy, aged at least 15 years, and who would remain in the catchment area for follow-up of 28 days post-partum. Newborn babies received clean dry cord care (control) or topical application of 10 mL of a 4% chlorhexidine solution once per day until 3 days after cord drop (intervention), according to cluster assignment. We used stratified, restricted randomisation to divide clusters into urban or two rural groups (located <40 km or ≥40 km to referral facility), and randomly assigned clusters (1:1) to use intervention (n=45) or control treatment (n=45). Sites, participants, and field monitors were aware of their study assignment. The primary outcomes were all-cause neonatal mortality within 28 days post-partum and all-cause neonatal mortality within 28 days post-partum among babies who survived the first 24 h of life. Analysis was by intention to treat. Neonatal mortality rate was compared with generalised estimating equations. This study is registered at ClinicalTrials.gov (NCT01241318). FINDINGS: From Feb 15, 2011, to Jan 30, 2013, we screened 42 356 pregnant women and enrolled 39 679 women (mean 436·2 per cluster [SD 65·3]), who had 37 856 livebirths and 723 stillbirths; 63·8% of deliveries were facility-based. Of livebirths, 18 450 (99·7%) newborn babies in the chlorhexidine group and 19 308 (99·8%) newborn babies in the dry cord care group were followed up to day 28 or death. 16 660 (90·0%) infants in the chlorhexidine group had chlorhexidine applied within 24 h of birth. We found no significant difference in neonatal mortality rate between the chlorhexidine group (15·2 deaths per 1000 livebirths) and the dry cord care group (13·6 deaths per 1000 livebirths; risk ratio [RR] 1·12, 95% CI 0·88-1·44). Eliminating day 0 deaths yielded similar findings (RR 1·12, 95% CI 0·86-1·47). INTERPRETATION: Despite substantial reductions previously reported in south Asia, chlorhexidine cord applications did not significantly reduce neonatal mortality rates in Zambia. Chlorhexidine cord applications do not seem to provide clear benefits for newborn babies in settings with predominantly facility-based deliveries and lower (<30 deaths per 1000 livebirths) neonatal mortality rates. FUNDING: Bill & Melinda Gates Foundation.

Engagement of the community, traditional leaders, and public health system in the design and implementation of a large community-based, cluster-randomized trial of umbilical cord care in Zambia.

Conducting research in areas with diverse cultures requires attention to community sensitization and involvement. The process of community engagement is described for a large community-based, cluster-randomized, controlled trial comparing daily 4% chlorhexidine umbilical cord wash to dry cord care for neonatal mortality prevention in Southern Province, Zambia. Study preparations required baseline formative ethnographic research, substantial community sensitization, and engagement with three levels of stakeholders, each necessitating different strategies. Cluster-specific birth notification systems developed with traditional leadership and community members using community-selected data collectors resulted in a post-natal home visit within 48 hours of birth in 96% of births. Of 39,679 pregnant women enrolled (93% of the target of 42,570), only 3.7% were lost to follow-up or withdrew antenatally; 0.2% live-born neonates were lost by day 28 of follow-up. Conducting this trial in close collaboration with traditional, administrative, political, and community stakeholders facilitated excellent study participation, despite structural and sociocultural challenges.

Household dynamics and socioeconomic conditions in the context of incident adolescent orphaning in KwaZulu-Natal, South Africa.

We compared demographics, socioeconomic status, and food insecurity between households with and without recent orphans in a region of high HIV/AIDS mortality in South Africa. We recruited a cohort of 197 recent orphans and 528 non-orphans ages 9-15 and their households using stratified cluster sampling. Households were classified into three groups: orphan-only (N=50); non-orphan-only (N=377); and mixed (N=210). Between September 2004 and May 2007, households were interviewed three times regarding demographics, income and assets, and food insecurity. Baseline bivariate associations were assessed using chi-square- and t-tests. Longitudinal bivariate associations and multivariate models were tested using generalized estimating equations. At baseline, mixed households generally exhibited greater characteristics of vulnerability than orphan and non-orphan households. They were larger, had older, less educated household heads, and reported a much smaller annual per capita income. Orphan households were more likely to report a death in the previous year, and less likely to have an adult employed. These differences persisted over the study. Even non-orphan households exhibited characteristics of vulnerability, with 14% reporting a death one year before baseline, 45% of whom were prime-age adults. At baseline, a much smaller proportion of orphan households reported receiving the child support grant than the other household types, but notably, there were no differences among households in receipt of the grant by Round 3. Household food insecurity was highly prevalent: more than one in five orphan-only and mixed households reported being food insecure in the previous month. These findings suggest that the effects of HIV/AIDS only exacerbate existing high levels of poverty in the district, as virtually all households are vulnerable regardless of orphan status. Community-level programs must help families address a spectrum of needs, including food security, caregiving, and financial support, as well as better target social welfare grants and make them more accessible to vulnerable households.

Antiretroviral therapy, labor productivity, and sex: a longitudinal cohort study of tea pluckers in Kenya.

OBJECTIVE: To estimate the impact of antiretroviral therapy (ART) on labor productivity and income using detailed employment data from two large tea plantations in western Kenya for HIV-infected tea pluckers who initiated ART. DESIGN: Longitudinal study using primary data on key employment outcomes for a group of HIV-infected workers receiving antiretroviral therapy (ART) and workers in the general workforce. METHODS: We used nearest-neighbor matching methods to estimate the impacts of HIV/AIDS and ART among 237 HIV-positive pluckers on ART (index group) over a 4-year period (2 years pre-ART and post-ART) on 4 monthly employment outcomes - days plucking tea, total kilograms (kgs) harvested, total days working, and total labor income. Outcomes for the index group were compared with those for a matched reference group from the general workforce. RESULTS: We observed a rapid deterioration in all four outcomes for HIV-infected individuals in the period before ART initiation and then a rapid improvement after treatment initiation. By 18-24 months after treatment initiation, the index group harvested 8% (men) and 19% (women) less tea than reference individuals. The index group earned 6% (men) and 9% (women) less income from labor than reference individuals. Women's income would have dropped further if they had not been able to offset their decline in tea plucking by spending more time on nonplucking assignments. CONCLUSION: HIV-infected workers experienced long-term income reductions before and after initiating ART. The implications of such long-term impacts in low-income countries have not been adequately addressed.

PEPFAR's support for orphans and vulnerable children: some beneficial effects, but too little data, and programs spread thin.

Sixteen million children in developing and middle-income countries have been orphaned by HIV/AIDS, and at least another million children per year are rendered vulnerable by parental HIV/AIDS-related illness. Since 2003 the US government has provided approximately $1.6 billion to give four million of these children care and support through the President's Emergency Plan for AIDS Relief (PEPFAR). We conducted five studies to evaluate the effectiveness of PEPFAR's interventions for such children in East Africa and southern Africa. We found evidence of beneficial changes in school enrollment rates and on the psychosocial well-being of children. However, we could not demonstrate empirically the impact of most of the PEPFAR initiatives that we examined, primarily because of a lack of baseline data and clear outcome and impact indicators. We also found that many programs were spread so thin across a vulnerable population that little in the way of services actually reached beneficiaries, which raises questions about whether PEPFAR funds are sufficient, or if the program is attempting to do much with too few resources. We offer several recommendations, including better measuring the effect of programs for orphans and vulnerable children by collecting baseline data and conducting well-designed, rigorous outcome and impact evaluations.

Longitudinal evaluation of the psychosocial wellbeing of recent orphans compared with non-orphans in a school-attending cohort in KwaZulu-Natal, South Africa.

To assess differences in psychosocial wellbeing between recent orphans and non-orphans, we followed a cohort of 157 school-going orphans and 480 non-orphans ages 9-15 in a context of high HIV/AIDS mortality in South Africa from 2004 to 2007. Several findings were contrary to published evidence to date, as we found no difference between orphans and non-orphans in anxiety/depression symptoms, oppositional behavior, self-esteem, or resilience. Female gender, self-reported poor health, and food insecurity were the most important predictors of children's psychosocial wellbeing. Notably, girls had greater odds of reporting anxiety/depression symptoms than boys, and scored lower on self-esteem and resilience scales. Food insecurity predicted greater anxiety/depression symptoms and lower resilience. Perceived social support was a protective factor, as it was associated with lower odds of anxiety/depression symptoms, lower oppositional scores, and greater self-esteem and resilience. Our findings suggest a need to identify and strengthen psychosocial supports for girls, and for all children in contexts of AIDS-affected and economic adversity.

Effect of training traditional birth attendants on neonatal mortality (Lufwanyama Neonatal Survival Project): randomised controlled study.

OBJECTIVE: To determine whether training traditional birth attendants to manage several common perinatal conditions could reduce neonatal mortality in the setting of a resource poor country with limited access to healthcare. DESIGN: Prospective, cluster randomised and controlled effectiveness study. SETTING: Lufwanyama, an agrarian, poorly developed district located in the Copperbelt province, Zambia. All births carried out by study birth attendants occurred at mothers' homes, in rural village settings. PARTICIPANTS: 127 traditional birth attendants and mothers and their newborns (3559 infants delivered regardless of vital status) from Lufwanyama district. INTERVENTIONS: Using an unblinded design, birth attendants were cluster randomised to intervention or control groups. The intervention had two components: training in a modified version of the neonatal resuscitation protocol, and single dose amoxicillin coupled with facilitated referral of infants to a health centre. Control birth attendants continued their existing standard of care (basic obstetric skills and use of clean delivery kits). MAIN OUTCOME MEASURES: The primary outcome was the proportion of liveborn infants who died by day 28 after birth, with rate ratios statistically adjusted for clustering. Secondary outcomes were mortality at different time points; and comparison of causes of death based on verbal autopsy data. RESULTS: Among 3497 deliveries with reliable information, mortality at day 28 after birth was 45% lower among liveborn infants delivered by intervention birth attendants than control birth attendants (rate ratio 0.55, 95% confidence interval 0.33 to 0.90). The greatest reductions in mortality were in the first 24 hours after birth: 7.8 deaths per 1000 live births for infants delivered by intervention birth attendants compared with 19.9 per 1000 for infants delivered by control birth attendants (0.40, 0.19 to 0.83). Deaths due to birth asphyxia were reduced by 63% among infants delivered by intervention birth attendants (0.37, 0.17 to 0.81) and by 81% within the first two days after birth (0.19, 0.07 to 0.52). Stillbirths and deaths from serious infection occurred at similar rates in both groups. CONCLUSIONS: Training traditional birth attendants to manage common perinatal conditions significantly reduced neonatal mortality in a rural African setting. This approach has high potential to be applied to similar settings with dispersed rural populations. Trial registration Clinicaltrials.gov NCT00518856.

Children of female sex workers and drug users: a review of vulnerability, resilience and family-centred models of care.

BACKGROUND: Injection drug users and female sex workers are two of the populations most at risk for becoming infected with HIV in countries with concentrated epidemics. Many of the adults who fall into these categories are also parents, but little is known about the vulnerabilities faced by their children, their children's sources of resilience, or programmes providing services to these often fragile families. This review synthesizes evidence from disparate sources describing the vulnerabilities and resilience of the children of female sex workers and drug users, and documents some models of care that have been put in place to assist them. REVIEW: A large literature assessing the vulnerability and resilience of children of drug users and alcoholics in developed countries was found. Research on the situation of the children of sex workers is extremely limited. Children of drug users and sex workers can face unique risks, stigma and discrimination, but both child vulnerability and resilience are associated in the drug use literature with the physical and mental health of parents and family context. Family-centred interventions have been implemented in low- and middle-income contexts, but they tend to be small, piecemeal and struggling to meet demand; they are poorly documented, and most have not been formally evaluated. We present preliminary descriptive data from an organization working with pregnant and new mothers who are drug users in Ukraine and from an organization providing services to sex workers and their families in Zambia. CONCLUSIONS: Because parents' drug use or sex work is often illegal and hidden, identifying their children can be difficult and may increase children's vulnerability and marginalization. Researchers and service providers, therefore, need to proceed with caution when attempting to reach these populations, but documentation and evaluation of current programmes should be prioritized.