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

Abstract

SummaryBackgroundChildren 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.MethodsWe 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.FindingsBetween 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 ...

Phenotype is sustained during hospital readmissions following treatment for complicated severe malnutrition among Kenyan children: A retrospective cohort study

“…Children with cSAM were actively linked to therapeutic and supplementary feeding programmes upon hospital discharge. Missing follow‐up visits and needing to be traced by a fieldworker making a home visit was associated with readmission (with any condition, not just complicated SAM) and death, as previously published (Berkley et al, ; Ngari et al, a).…”

“…The goal of SAM treatment also includes the reduction of susceptibility to life‐threatening infections, restoration of a healthy body composition, and improvement in neurocognitive status (Ngari et al, a). However, children with SAM remain at risk of developing severe illness and/or infections after treatment of clinical complications and discharged from hospital (Berkley et al, ; Chisti et al, ; Kerac et al, ; Ngari et al, a). A study by Kerac et al () that followed 1,024 children 1 year post‐discharge reported 5% hospital readmissions but 42% deaths, whereas Khanum et al () reported 1.2% emergency hospital readmissions.…”

“…These studies however only captured one readmission event per child. Accounting for multiple hospital readmissions, a previous report recorded 616 nonfatal admissions to hospital and 3,266 nonfatal episodes of illness post‐discharge among 1,778 children in the original randomised trial (Berkley et al, ). A secondary analysis of this data focusing on life‐threatening events reported 823 life‐threatening events (257 fatal and 566 nonfatal events) among 612 children after discharge from the hospital (Ngari et al, a), including a high rate of events in those who had recovered their nutritional status.…”

“…We evaluated readmissions with cSAM among children who were discharged after index hospitalisation with cSAM using data from a multicentre randomised controlled trial with active follow‐up for 1 year after discharge (Berkley et al, ) to determine whether there was an association between a child's phenotype at index admission and the phenotype at readmission. Findings on association between the index admission and readmission phenotypes were validated using data from a longer term clinical and demographic surveillance at one site in Kenya (Scott et al, ).…”

Mechanisms of cross-talk between the diet, the intestinal microbiome, and the undernourished host

“…106 Second, among 1778 children who had recovered from severe acute undernutrition in one of four Kenyan hospitals, six months of oral co-trimoxazole (120 mg/day if <6 months of age; 240 mg/day if >6 months) had no effect on mortality during the 12-month study period. 107 It is possible that the beneficial effect on growth observed in the Malawian trial resulted from microbiota restructuring. However, the cohort of 64 undernourished Bangladeshi children studied by Subramanian et al exhibited only a transient restoration of gut microbiota maturity that was lost four months after inpatient treatment.…”