Ready-to-use food supplement, with or without arginine and citrulline, with daily chloroquine in Tanzanian children with sickle-cell disease: a double-blind, random order crossover trial
journal contributionposted on 18.01.2018 by Sharon E. Cox, Elizabeth A. Ellins, Alphonce I. Marealle, Charles R. Newton, Deogratias Soka, Philip Sasi, Gian Luca Di Tanna, Will Johnson, Julie Makani, A.M. Prentice, Julian P. Halcox, Fenella J. Kirkham
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Background: Sickle cell disease increases malnutrition risk. Low arginine and nitric oxide [NO] bioavailability are implicated in sickle-related morbidity. Simple interventions are required, especially in low-income settings. We aimed to test the hypotheses: (1) supplementary arginine, citrulline and daily chloroquine increases bioavailable arginine and flow-mediated-dilatation (FMDmax%; a measure of NO-dependent endothelial function), and (2); protein energy supplementation in the form of ready-to-use supplementary-food (RUSF) improves nutritional status in children with sickle cell disease. Methods: A random-order, double-blind, cross-over trial with two four-month intervention periods (each followed by four-months wash-out) was conducted in Dar-es-Salaam, Tanzania. 119 children aged 8-12 years, naïve to hydroxyurea, were enrolled from the Muhimbili National Hospital Sickle Cohort. The random order sequence and allocation codes were generated centrally. Two formulations of RUSF (500kcal/day) were tested: ‘basic’ with weekly chloroquine (150/225mg base, depending on weight) (RUSF-b) and ‘vascular’ (RUSF-v) fortified with arginine, citrulline designed to achieve mean intakes of 0.2g/0.1g/kg/day and daily chloroquine (max 3mg base/kg/day). The primary outcomes of the comparison of the 2 RUSF formulations were mean FMDmax%, mean plasma arginine to ornithine ratio and mean plasma arginine to asymmetric-di-methylated-arginine (ADMA) ratio. The primary outcomes of the combined effect of both RUSF interventions were mean height and body mass index for age z-scores with analysis by intention to treat. Trial registration: ISRCTN74331412 Findings: 114/119 children had complete data for all reported endpoints. There was no treatment effect of RUSF-v compared to RUSF-b on the ratio of arginine to ornithine (mean within individual difference -0.09, 95% CI -0.03/0.2, p=0.12), or on FMDmax% (-1.00 95% CI -2.47/0.47, p=0.18) but the arginine:ADMA ratio was significantly increased (-0.56, 95% CI -0.81/-0.31, P<0.001). In planned analyses using random effects models to estimate the effect of each intervention compared to baseline/washout, the arginine:ADMA ratio increased following both RUSF-v or RUSF-b (+86%, p<0.001; +41%, p<0.001). Similarly, FMDmax% was higher after 2 RUSF-v (+0.92, p<0.001) but not after RUSF-b intervention (+0.39, p=0.22). Adjusted for covariates, effect estimates for FMDmax% increased: RUSF-v (+1.19, p<0.001) and RUSF-b (+0.93, p=0.008). Following either intervention (RUSF-b and RUSF-v pooled) compared to baseline/wash-outs, body-mass-index-z-score (+0.091, P=0.001) and height-for-age-z-score (+0.013, P=0.081) increased. There were 71 and 81 adverse events of which 21 and 26 were serious during intervention and washout (P=0.31) in 83 participants, 1 of whom died in the 2nd washout period. Interpretation: RUSF providing 500kcal/day results in small weight gains in children with sickle cell disease. However, RUSF even without arginine and citrulline fortification improves arginine dysregulation and may improve endothelial function. Long-term studies are required to assess if these physiological effects translate to improved clinical outcomes and better growth and development in sickle cell disease.
This work was supported by the Wellcome Trust.
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