Moses Ngari

Childhood Malnutrition: Toward an Understanding of Infections, Inflammation, and Antimicrobials

Background Undernutrition in childhood is estimated to cause 3.1 million child deaths annually through a potentiating effect on common infectious diseases, such as pneumonia and diarrhea. In turn, overt and subclinical infections, and inflammation, especially in the gut, alter nutrient intake, absorption, secretion, diversion, catabolism, and expenditure. Objective A narrative overview of the current understanding of infections, inflammation, and antimicrobials in relation to childhood malnutrition. Methods Searches for pivotal papers were conducted using PUBMED 1966–January 2013; hand searches of the references of retrieved literature; discussions with experts; and personal experience from the field. Results Although the epidemiological evidence for increased susceptibility to life-threatening infections associated with malnutrition is strong, we are only just beginning to understand some of the mechanisms involved. Nutritional status and growth are strongly influenced by environmental enteric dysfunction (EED), which is common among children in developing countries, and by alterations in the gut microbiome. As yet, there are no proven interventions against EED. Antibiotics have long been used as growth promoters in animals. Trials of antibiotics have shown striking efficacy on mortality and on growth in children with uncomplicated severe acute malnutrition (SAM) or HIV infection. Antibiotics act directly by preventing infections and may act indirectly by reducing subclinical infections and inflammation. We describe an ongoing multicenter, randomized, placebo-controlled trial of daily cotrimoxazole prophylaxis to prevent death in children recovering from complicated SAM. Secondary outcomes include growth, frequency and etiology of infections, immune activation and function, the gut microbiome, and antimicrobial resistance. The trial is expected to be reported in mid-2014. Conclusions As well as improving nutritional intake, new case management strategies need to address infection, inflammation, and microbiota and assess health outcomes rather than only anthropometry.

Mesalazine in the initial management of severely acutely malnourished children with environmental enteric dysfunction: a pilot randomized controlled trial

BackgroundEnvironmental enteric dysfunction (EED) is an acquired syndrome of impaired gastrointestinal mucosal barrier function that is thought to play a key role in the pathogenesis of stunting in early life. It has been conceptualized as an adaptive response to excess environmental pathogen exposure. However, it is clinically similar to other inflammatory enteropathies, which result from both host and environmental triggers, and for which immunomodulation is a cornerstone of therapy.MethodsIn this pilot double-blind randomized placebo-controlled trial, 44 children with severe acute malnutrition and evidence of EED were assigned to treatment with mesalazine or placebo for 28 days during nutritional rehabilitation. Primary outcomes were safety and acceptability of the intervention.ResultsTreatment with mesalazine was safe: there was no excess of adverse events, evidence of deterioration in intestinal barrier integrity or impact on nutritional recovery. There were modest reductions in several inflammatory markers with mesalazine compared to placebo. Depression of the growth hormone - insulin-like growth factor-1 axis was evident at enrollment and associated with inflammatory activation. Increases in the former and decreases in the latter correlated with linear growth.ConclusionsIntestinal inflammation in EED is non-essential for mucosal homeostasis and is at least partly maladaptive. Further trials of gut-specific immunomodulatory therapies targeting host inflammatory activation in order to optimize the growth benefits of nutritional rehabilitation and to address stunting are warranted. Funded by The Wellcome Trust.Trial registrationRegistered at Clinicaltrials.gov NCT01841099.

Daily co-trimoxazole prophylaxis to prevent mortality in children with complicated severe acute malnutrition: a multicentre, double-blind, randomised placebo-controlled trial

Summary Background Children with complicated severe acute malnutrition (SAM) have a greatly increased risk of mortality from infections while in hospital and after discharge. In HIV-infected children, mortality and admission to hospital are prevented by daily co-trimoxazole prophylaxis, despite locally reported bacterial resistance to co-trimoxazole. We aimed to assess the efficacy of daily co-trimoxazole prophylaxis on survival in children without HIV being treated for complicated SAM. Methods We did a multicentre, double-blind, randomised, placebo-controlled study in four hospitals in Kenya (two rural hospitals in Kilifi and Malindi, and two urban hospitals in Mombasa and Nairobi) with children aged 60 days to 59 months without HIV admitted to hospital and diagnosed with SAM. We randomly assigned eligible participants (1:1) to 6 months of either daily oral co-trimoxazole prophylaxis (given as water-dispersible tablets; 120 mg per day for age <6 months, 240 mg per day for age 6 months to 5 years) or matching placebo. Assignment was done with computer-generated randomisation in permuted blocks of 20, stratified by centre and age younger or older than 6 months. Treatment allocation was concealed in opaque, sealed envelopes and patients, their families, and all trial staff were masked to treatment assignment. Children were given recommended medical care and feeding, and followed up for 12 months. The primary endpoint was mortality, assessed each month for the first 6 months, then every 2 months for the second 6 months. Secondary endpoints were nutritional recovery, readmission to hospital, and illness episodes treated as an outpatient. Analysis was by intention to treat. This trial was registered at ClinicalTrials.gov, number NCT00934492. Findings Between Nov 20, 2009, and March 14, 2013, we recruited and assigned 1778 eligible children to treatment (887 to co-trimoxazole prophylaxis and 891 to placebo). Median age was 11 months (IQR 7–16 months), 306 (17%) were younger than 6 months, 300 (17%) had oedematous malnutrition (kwashiorkor), and 1221 (69%) were stunted (length-for-age Z score <–2). During 1527 child-years of observation, 122 (14%) of 887 children in the co-trimoxazole group died, compared with 135 (15%) of 891 in the placebo group (unadjusted hazard ratio [HR] 0·90, 95% CI 0·71–1·16, p=0·429; 16·0 vs 17·7 events per 100 child-years observed (CYO); difference −1·7 events per 100 CYO, 95% CI −5·8 to 2·4]). In the first 6 months of the study (while participants received study medication), 63 suspected grade 3 or 4 associated adverse events were recorded among 57 (3%) children; 31 (2%) in the co-trimoxazole group and 32 (2%) in the placebo group (incidence rate ratio 0·98, 95% CI 0·58–1·65). The most common adverse events of these grades were urticarial rash (grade 3, equally common in both groups), neutropenia (grade 4, more common in the co-trimoxazole group), and anaemia (both grades equally common in both groups). One child in the placebo group had fatal toxic epidermal necrolysis with concurrent Pseudomonas aeruginosa bacteraemia. Interpretation Daily co-trimoxazole prophylaxis did not reduce mortality in children with complicated SAM without HIV. Other strategies need to be tested in clinical trials to reduce deaths in this population. Funding Wellcome Trust, UK

Diagnostic performance of visible severe wasting for identifying severe acute malnutrition in children admitted to hospital in Kenya

OBJECTIVE To determine the diagnostic value of visible severe wasting in identifying severe acute malnutrition at two public hospitals in Kenya. METHODS This was a cross-sectional study of children aged 6 to 59.9 months admitted to one rural and one urban hospital. On admission, mid-upper arm circumference (MUAC), weight and height were measured and the presence of visible severe wasting was assessed. The diagnostic performance of visible severe wasting was evaluated against anthropometric criteria. FINDINGS Of 11,166 children admitted, 563 (5%) had kwashiorkor and 1406 (12.5%) were severely wasted (MUAC < 11.5 cm). The combined sensitivity and specificity of visible severe wasting at the two hospitals, as assessed against a MUAC < 11.5 cm, were 54% (95% confidence interval, CI: 51-56) and 96% (95% CI: 96-97), respectively; at one hospital, its sensitivity and specificity against a weight-for-height z-score below -3 were 44.7% (95% CI: 42-48) and 96.5% (95% CI: 96-97), respectively. Severely wasted children who were correctly identified by visible severe wasting were consistently older, more severely wasted, more often having kwashiorkor, more often positive to the human immunodeficiency virus, ill for a longer period and at greater risk of death. Visible severe wasting had lower sensitivity for determining the risk of death than the anthropometric measures. There was no evidence to support measuring both MUAC and weight-for-height z-score. CONCLUSION Visible severe wasting failed to detect approximately half of the children admitted to hospital with severe acute malnutrition diagnosed anthropometrically. Routine screening by MUAC is quick, simple and inexpensive and should be part of the standard assessment of all paediatric hospital admissions in the study setting.

Diagnostic criteria for severe acute malnutrition among infants aged under 6 mo

Background: There is an increasing recognition of malnutrition among infants under 6 mo of age (U6M). Current diagnosis criteria use weight-for-length z scores (WLZs), but the 2006 WHO standards exclude infants shorter than 45 cm. In older children, midupper arm circumference (MUAC) predicts mortality better than does WLZ. Outcomes may also be influenced by exposure to HIV and size or gestational age at birth. Diagnostic thresholds for WLZ, MUAC, and other indexes have not been fully evaluated against mortality risk among U6M infants. Objective: The aim was to determine the association of anthropometric indexes with risks of inpatient and postdischarge mortality among U6M infants recruited at the time of hospitalization. Design: We analyzed data from a cohort of U6M infants admitted to Kilifi County Hospital (2007–2013), Kenya. The primary outcomes were inpatient death and death during follow-up over 1 y after discharge. We calculated adjusted RRs for inpatient mortality and HRs for postdischarge mortality for different anthropometric measures and thresholds. Discriminatory value was assessed by using receiver operating characteristic curves. Results: A total of 2882 infants were admitted: 140 (4.9%) died in the hospital and 1405 infants were followed up after discharge. Of these, 75 (5.3%) died within 1 y during 1318 child-years of observation. MUAC and weight-for-age z score (WAZ) predicted inpatient and postdischarge mortality better than did WLZ (P < 0.0001). A single MUAC threshold of <11.0 cm performed similarly to MUAC thresholds that varied with age (all P > 0.05) and performed better than WLZ <−3 for both inpatient and postdischarge mortality (both P < 0.001). Reported small size at birth did not reduce the risk of death associated with anthropometric indexes. Conclusions: U6M infants at the highest risk of death are best targeted by using MUAC or WAZ. Further research into the effectiveness of potential interventions is required.

Lymphoedema management to prevent acute dermatolymphangioadenitis in podoconiosis in northern Ethiopia (GoLBeT): a pragmatic randomised controlled trial

Summary Background Podoconiosis (also known as endemic, non-filarial elephantiasis) affects about 4 million subsistence farmers in tropical Africa. Poor awareness of the condition and inadequate evidence for the efficacy of treatment mean that no government in an endemic country yet offers lymphoedema management for patients with podoconiosis. Among patients with filarial lymphoedema, trials suggest that limb care is effective in reducing the most disabling sequelae: episodes of acute dermatolymphangioadenitis. We aimed to test the hypothesis that a simple, inexpensive lymphoedema management package would reduce the incidence of acute dermatolymphangioadenitis in adult patients with podoconiosis in northern Ethiopia. Methods We did a pragmatic randomised controlled trial at health posts and health centres in 18 sub-districts of Aneded woreda (district) in Amhara, northern Ethiopia. Participants were adults aged 18 years and older, had a diagnosis of at least stage 2 podoconiosis (persistent lymphoedema) and a negative antigen test for filariasis, and intended to remain within Aneded woreda for the duration of the trial. Patients were randomly assigned (1:1) to either receive a package containing instructions for foot hygiene, skin care, bandaging, exercises, and use of socks and shoes, with support by lay Community Podoconiosis Agents at monthly meetings (intervention group) or to receive no intervention (control group). Participants were aware of their group assignment, but researchers doing all analyses were masked to treatment group. The primary outcome was incidence of acute dermatolymphangioadenitis episodes in the total period of observation of each participant, measured by use of validated patient self-reported pictorial diaries. This trial was registered with the International Standard Randomised Controlled Trials Number Register, number ISRCTN67805210. Findings Between Dec 1, 2014, and June 30, 2015, 1339 patients were screened, and 696 patients were enrolled and randomly allocated to treatment groups. We allocated 350 patients to the intervention group and 346 patients to the control group. 321 (92%) patients from the intervention group and 329 (95%) patients from the control group provided follow-up results at 12 months. During the 12 months of follow-up, 16 550 new episodes of acute dermatolymphangioadenitis occurred during 765·2 person-years. The incidence of acute dermatolymphangioadenitis was 19·4 episodes per person-year (95% CI 18·9–19·9) in the intervention group and 23·9 episodes per person-year (23·4–24·4) in the control group. The ratio of incidence rate in the intervention group to that of the control group was 0·81 (0·74 to 0·89; p<0·0001), with a rate difference of −4·5 (−5·1 to −3·8) episodes per person-year. No serious adverse events related to the intervention were reported. Interpretation A simple, inexpensive package of lymphoedema self-care is effective in reducing the frequency and duration of acute dermatolymphangioadenitis. We recommend its implementation by the governments of endemic countries. Funding Joint Global Health Trials scheme (from the Wellcome Trust, the UK Medical Research Council, and UK Aid).

A growth reference for mid upper arm circumference for age among school age children and adolescents, and validation for mortality: growth curve construction and longitudinal cohort study

Objectives To construct growth curves for mid-upper-arm circumference (MUAC)-for-age z score for 5-19 year olds that accord with the World Health Organization growth standards, and to evaluate their discriminatory performance for subsequent mortality. Design Growth curve construction and longitudinal cohort study. Setting United States and international growth data, and cohorts in Kenya, Uganda, and Zimbabwe. Participants The Health Examination Survey (HES)/National Health and Nutrition Examination Survey (NHANES) US population datasets (age 5-25 years), which were used to construct the 2007 WHO growth reference for body mass index in this age group, were merged with an imputed dataset matching the distribution of the WHO 2006 growth standards age 2-6 years. Validation data were from 685 HIV infected children aged 5-17 years participating in the Antiretroviral Research for Watoto (ARROW) trial in Uganda and Zimbabwe; and 1741 children aged 5-13 years discharged from a rural Kenyan hospital (3.8% HIV infected). Both cohorts were followed-up for survival during one year. Main outcome measures Concordance with WHO 2006 growth standards at age 60 months and survival during one year according to MUAC-for-age and body mass index-for-age z scores. Results The new growth curves transitioned smoothly with WHO growth standards at age 5 years. MUAC-for-age z scores of −2 to −3 and less than−3, compared with −2 or more, was associated with hazard ratios for death within one year of 3.63 (95% confidence interval 0.90 to 14.7; P=0.07) and 11.1 (3.40 to 36.0; P<0.001), respectively, among ARROW trial participants; and 2.22 (1.01 to 4.9; P=0.04) and 5.15 (2.49 to 10.7; P<0.001), respectively, among Kenyan children after discharge from hospital. The AUCs for MUAC-for-age and body mass index-for-age z scores for discriminating subsequent mortality were 0.81 (95% confidence interval 0.70 to 0.92) and 0.75 (0.63 to 0.86) in the ARROW trial (absolute difference 0.06, 95% confidence interval −0.032 to 0.16; P=0.2) and 0.73 (0.65 to 0.80) and 0.58 (0.49 to 0.67), respectively, in Kenya (absolute difference in AUC 0.15, 0.07 to 0.23; P=0.0002). Conclusions The MUAC-for-age z score is at least as effective as the body mass index-for-age z score for assessing mortality risks associated with undernutrition among African school aged children and adolescents. MUAC can provide simplified screening and diagnosis within nutrition and HIV programmes, and in research.

Mortality after Inpatient Treatment for Severe Pneumonia in Children: a Cohort Study

Abstract Background Although pneumonia is a leading cause of inpatient mortality, deaths may also occur after discharge from hospital. However, prior studies have been small, in selected groups or did not fully evaluate risk factors, particularly malnutrition and HIV. We determined 1‐year post‐discharge mortality and risk factors among children diagnosed with severe pneumonia. Methods A cohort study of children aged 1–59 months admitted to Kilifi County Hospital with severe pneumonia (2007–12). The primary outcome was death <1 year after discharge, determined through Kilifi Health and Demographic Surveillance System (KHDSS) quarterly census rounds. Results Of 4184 children (median age 9 months) admitted with severe pneumonia, 1041 (25%) had severe acute malnutrition (SAM), 267 (6.4%) had a positive HIV antibody test, and 364 (8.7%) died in hospital. After discharge, 2279 KHDSS‐resident children were followed up; 70 (3.1%) died during 2163 child‐years: 32 (95% confidence interval (CI) 26, 41) deaths per 1000 child years. Post‐discharge mortality was greater after admission for severe pneumonia than for other diagnoses, hazard ratio 2.5 (95% CI 1.2, 5.3). Malnutrition, HIV status, age and prolonged hospitalisation, but not signs of pneumonia severity, were associated with post‐discharge mortality. Fifty‐two per cent (95% CI 37%, 63%) of post‐discharge deaths were attributable to low mid‐upper arm circumference and 11% (95% CI 3.3%, 18%) to a positive HIV test. Conclusions Admission with severe pneumonia is an important marker of vulnerability. Risk stratification and better understanding of the mechanisms underlying post‐discharge mortality, especially for undernourished children, are needed to reduce mortality after treatment for pneumonia.

Experience of using an open source clinical trials data management software system in Kenya

BackgroundClinical trials data management (CTDM) remains one of the many challenges in running state of the art trials in resource-poor settings since most trials do not allocate, or have available, sufficient resources for CTDM and because of poor internet connectivity. Open-source software like OpenClinica could be a solution in such scenarios.FindingsIn 2007, the KEMRI-Wellcome Trust Research Programme (KWTRP) adopted OpenClinica (OC) community edition, an open-source software system and we share our experience and lessons learnt since its adoption. We have used OC in three different modes; direct remote data entry from sites through Global System for Mobile Communications (GSM) modems, a centralized data centre approach where all data from paper records were entered at a central location and an off-line approach where data entry was done from a copy of database hosted on a field-site server laptop, then data uploaded to a centralized server later. We have used OC in eleven trials/studies with a cumulative number of participants in excess of 6000. These include large and complex trials, with multiple sites recruiting in different regions of East Africa. In the process, we have developed substantial local capacity through hands-on training and mentorship, which we have now begun to share with other institutions in the region.ConclusionsOur experience demonstrates that an open source data management system to manage trials’ data can be utilized to international industry standards in resource-poor countries.

Children concurrently wasted and stunted: A meta‐analysis of prevalence data of children 6–59 months from 84 countries

Abstract Children can be stunted and wasted at the same time. Having both deficits greatly elevates risk of mortality. The analysis aimed to estimate the prevalence and burden of children aged 6–59 months concurrently wasted and stunted. Data from demographic and health survey and Multi‐indicator Cluster Surveys datasets from 84 countries were analysed. Overall prevalence for being wasted, stunted, and concurrently wasted and stunted among children 6 to 59 months was calculated. A pooled prevalence of concurrence was estimated and reported by gender, age, United Nations regions, and contextual categories. Burden was calculated using population figures from the global joint estimates database. The pooled prevalence of concurrence in the 84 countries was 3.0%, 95% CI [2.97, 3.06], ranging from 0% to 8.0%. Nine countries reported a concurrence prevalence greater than 5%. The estimated burden was 5,963,940 children. Prevalence of concurrence was highest in the 12‐ to 24‐month age group 4.2%, 95% CI [4.1, 4.3], and was significantly higher among boys 3.54%, 95% CI [3.47, 3.61], compared to girls; 2.46%, 95% CI [2.41, 2.52]. Fragile and conflict‐affected states reported significantly higher concurrence 3.6%, 95% CI [3.5, 3.6], than those defined as stable 2.24%, 95% CI [2.18, 2.30]. This analysis represents the first multiple country estimation of the prevalence and burden of children concurrently wasted and stunted. Given the high risk of mortality associated with concurrence, the findings indicate a need to report on this condition as well as investigate whether these children are being reached through existing programmes.