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Metabolomic Profiles Associated with Mortality of Children with Complicated Severe Malnutrition: A Nested Case-Control Study

ABSTRACT: Abstract Objectives Children hospitalized with complicated severe malnutrition (CSM) have unacceptably high mortality rates despite receiving standard nutritional and medical treatment. The underlying pathology of the poor prognosis is not well understood. Growing evidence indicates presence of metabolic dysfunction in CSM. Yet, it is unclear whether and how metabolic dysfunction contributes the poor prognosis. This study aimed to identify metabolic signatures and pathways associated with CSM mortality. Methods A case-control study was performed on CSM patients enrolled to a multicenter (one Malawi and two Kenya hospitals) randomized control trial (NCT02246296). A total of 90 death cases and 90 discharged controls that were propensity score matched by age, HIV and mid-upper arm circumferences were included in the study. Targeted metabolomics was performed on their serum samples collected at admission and on day 3 of hospitalization. In particular, 206 metabolites, including amino acids, acylcarnitines, lipids and organic acids were quantified by LC-MS/MS. Results Discriminant analysis (PLS-DA) showed that metabolomic signatures at admission could differentiate cases from controls, with a cross-validated classification error rate of 21.8%. An increase of homovanillic, isobutyric and propionic acids, and decrease of lipids lysoPC a C18:2, lysoPC a C20:4, PC ae C42:2, SM C26:0, and SM C26:1 were the top 8 significant features characterizing the admission metabolomes of cases. Notably, cases with higher levels of isobutyrate, a microbial fermentation product, had significantly shorter survival time, implying a role of gut integrity in mortality. Pathway analysis revealed that metabolites of the tricarboxylic acid (TCA) cycle pathway differentiated cases from controls. Analysis of day 3 samples showed metabolic differences in response to treatment, especially in the recovery rate of lipids, between cases and controls. Conclusions CSM non-survivors have metabolomes distinct from survivors indicating perturbations in mitochondrial function and nutrition utilization. Perturbed metabolites identified shed light on biological mechanisms of mortality and may serve as targets of nutritional or therapeutic interventions to improve CSM survival. Funding Sources Bill and Melinda Gates Foundation, Thrasher Research Fund, and RESTRACOMP Graduate Scholarship.

SUBMITTER: Wen B

PROVIDER: S-EPMC7258544 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Project description:BackgroundChildren 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 aeruginosa bacteraemia.InterpretationDaily 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.FundingWellcome Trust, UK.

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Metabolomic Profiles Associated with Mortality of Children with Complicated Severe Malnutrition: A Nested Case-Control Study

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