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

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          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

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          Most cited references 33

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          Evidence-based interventions for improvement of maternal and child nutrition: what can be done and at what cost?

          Maternal undernutrition contributes to 800,000 neonatal deaths annually through small for gestational age births; stunting, wasting, and micronutrient deficiencies are estimated to underlie nearly 3·1 million child deaths annually. Progress has been made with many interventions implemented at scale and the evidence for effectiveness of nutrition interventions and delivery strategies has grown since The Lancet Series on Maternal and Child Undernutrition in 2008. We did a comprehensive update of interventions to address undernutrition and micronutrient deficiencies in women and children and used standard methods to assess emerging new evidence for delivery platforms. We modelled the effect on lives saved and cost of these interventions in the 34 countries that have 90% of the world's children with stunted growth. We also examined the effect of various delivery platforms and delivery options using community health workers to engage poor populations and promote behaviour change, access and uptake of interventions. Our analysis suggests the current total of deaths in children younger than 5 years can be reduced by 15% if populations can access ten evidence-based nutrition interventions at 90% coverage. Additionally, access to and uptake of iodised salt can alleviate iodine deficiency and improve health outcomes. Accelerated gains are possible and about a fifth of the existing burden of stunting can be averted using these approaches, if access is improved in this way. The estimated total additional annual cost involved for scaling up access to these ten direct nutrition interventions in the 34 focus countries is Int$9·6 billion per year. Continued investments in nutrition-specific interventions to avert maternal and child undernutrition and micronutrient deficiencies through community engagement and delivery strategies that can reach poor segments of the population at greatest risk can make a great difference. If this improved access is linked to nutrition-sensitive approaches--ie, women's empowerment, agriculture, food systems, education, employment, social protection, and safety nets--they can greatly accelerate progress in countries with the highest burden of maternal and child undernutrition and mortality. Copyright © 2013 Elsevier Ltd. All rights reserved.
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            Beyond malaria--causes of fever in outpatient Tanzanian children.

            As the incidence of malaria diminishes, a better understanding of nonmalarial fever is important for effective management of illness in children. In this study, we explored the spectrum of causes of fever in African children. We recruited children younger than 10 years of age with a temperature of 38°C or higher at two outpatient clinics--one rural and one urban--in Tanzania. Medical histories were obtained and clinical examinations conducted by means of systematic procedures. Blood and nasopharyngeal specimens were collected to perform rapid diagnostic tests, serologic tests, culture, and molecular tests for potential pathogens causing acute fever. Final diagnoses were determined with the use of algorithms and a set of prespecified criteria. Analyses of data derived from clinical presentation and from 25,743 laboratory investigations yielded 1232 diagnoses. Of 1005 children (22.6% of whom had multiple diagnoses), 62.2% had an acute respiratory infection; 5.0% of these infections were radiologically confirmed pneumonia. A systemic bacterial, viral, or parasitic infection other than malaria or typhoid fever was found in 13.3% of children, nasopharyngeal viral infection (without respiratory symptoms or signs) in 11.9%, malaria in 10.5%, gastroenteritis in 10.3%, urinary tract infection in 5.9%, typhoid fever in 3.7%, skin or mucosal infection in 1.5%, and meningitis in 0.2%. The cause of fever was undetermined in 3.2% of the children. A total of 70.5% of the children had viral disease, 22.0% had bacterial disease, and 10.9% had parasitic disease. These results provide a description of the numerous causes of fever in African children in two representative settings. Evidence of a viral process was found more commonly than evidence of a bacterial or parasitic process. (Funded by the Swiss National Science Foundation and others.).
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              Environmental enteropathy: critical implications of a poorly understood condition.

              Environmental enteropathy (also called tropical enteropathy) is a subclinical condition caused by constant fecal-oral contamination and resulting in blunting of intestinal villi and intestinal inflammation. Although these histological changes were discovered decades ago, the clinical impact of environmental enteropathy is just starting to be recognized. The failure of nutritional interventions and oral vaccines in the developing world may be attributed to environmental enteropathy, as the intestinal absorptive and immunologic functions are significantly deranged. Here we review the existing literature and examine potential mechanisms of pathogenesis for this poorly understood condition. Copyright © 2012 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Lancet Glob Health
                Lancet Glob Health
                The Lancet. Global Health
                Elsevier Ltd
                2214-109X
                2 June 2016
                July 2016
                2 June 2016
                : 4
                : 7
                : e464-e473
                Affiliations
                [a ]Kenya Medical Research Institute (KEMRI)/Wellcome Trust Research Programme, Kilifi, Kenya
                [b ]Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
                [c ]University College, London, UK
                [d ]Imperial College, London, UK
                [e ]Mbagathi Hospital, Nairobi, Kenya
                [f ]Coast General Hospital, Mombasa, Kenya
                [g ]KEMRI Centre for Microbiology Research, Nairobi, Kenya
                Author notes
                [* ]Correspondence to: Prof James A Berkley, Kenya Medical Research Institute/Wellcome Trust Research Programme, Kilifi 80108, Kenya jberkley@ 123456kemri-wellcome.org
                Article
                S2214-109X(16)30096-1
                10.1016/S2214-109X(16)30096-1
                6132285
                27265353
                © 2016 Berkley et al. Open Access article distributed under the terms of CC BY

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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