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.

BACKGROUND: Sickle-cell disease increases the risk of malnutrition. Low arginine and nitric oxide bioavailability are implicated in morbidity related to sickle-cell disease. Simple interventions are required, especially in low-income settings. We aimed to test the hypotheses that: (1) supplementary arginine, citrulline, and daily chloroquine increase bioavailable arginine and flow-mediated dilatation (FMD; maximal diameter change; FMDmax%), a measure of nitric oxide-dependent endothelial function; and (2) protein energy supplementation in the form of ready-to-use supplementary food (RUSF) improves the height-for-age and body-mass index-for-age Z-scores in children with sickle-cell disease. METHODS: We performed a double-blind, random order crossover trial with two 4-month intervention periods (each followed by 4-month washout periods) in Muhimbili National Hospital in Dar-es-Salaam, Tanzania. We enrolled 119 children from the Muhimbili Sickle Cohort who were aged 8-12 years, naive to hydroxyurea, and had documented HbSS phenotype. Two formulations of RUSF (providing 500 kcal/day) were tested: basic (RUSF-b), with which children also received weekly chloroquine (150 mg or 225 mg chloroquine base, dependent on bodyweight); and vascular (RUSF-v), which was fortified with arginine and citrulline (designed to achieve mean intakes of 0·2 g/kg per day of arginine and 0·1 g/kg per day of citrulline), and with which children received daily chloroquine (maximum 3 mg chloroquine base/kg per day). Children were randomly allocated to receive either RUSF-b first or RUSF-v first and, after a washout period, were then given the other treatment. The primary outcomes in comparing the two RUSF formulations were mean plasma arginine, arginine to ornithine ratio, and arginine to asymmetric dimethylarginine ratio, and mean FMDmax%. The primary outcomes of the combined effect of both RUSF interventions were mean height-for-age Z-score and body-mass index-for-age Z-score. Analyses were done on the eligible intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01718054; and with ISRCTN74331412. FINDINGS: Between Aug 9, 2012, and Feb 26, 2014, 145 children were randomised (71 children to RUSF-v first and 74 children to RUSF-b first) and 119 children were treated, of whom 114 children yielded complete data for all reported endpoints. The ratio of arginine to ornithine (mean of individual differences -8·67%, 95% CI -19·55 to 2·20; p=0·12) and the mean FMDmax% (1·00, -0·47 to 2·47; p=0·18) did not significantly differ between the RUSF-b and RUSF-v treatments. However, the arginine to asymmetric dimethylarginine ratio was significantly increased by RUSF-v compared with RUSF-b (56·26%, 31·13 to 81·38; p<0·0001). In planned analyses that used mixed effects models to estimate the effect of each intervention compared with the participants at baseline or during washout periods, the arginine to asymmetric dimethylarginine ratio increased following both RUSF-v treatment (86%; p<0·0001) and RUSF-b treatment (40%; p<0·0001). However, FMDmax% was higher after treatment with RUSF-v (0·92; p<0·0001) but not RUSF-b (0·39; p=0·22). Following either intervention (RUSF-b and RUSF-v, pooled) body-mass index-for-age Z-score (0·091; p=0·001) and height-for-age Z-score (0·013; p=0·081) increased compared with baseline and washout timepoints. In 83 participants in the treated population, there were 71 adverse events during the intervention, of which 21 (30%) were serious, and 81 adverse events during the washout periods, of which 26 (32%) were serious (p=0·31), including one patient who died in the second washout period. INTERPRETATION: RUSF providing 500 kcal/day results in small weight gains in children with sickle-cell disease. However, even without arginine and citrulline fortification, RUSF seems to ameliorate arginine dysregulation and might improve endothelial function. Long-term studies are required to assess whether these physiological effects translate to improved clinical outcomes and better growth and development in patients with sickle-cell disease. FUNDING: Wellcome Trust.

Altered Neurophysiological Processing of Auditory Attention in Preschool Children With Sickle Cell Disease.

Objective: Sickle cell disease (SCD) is a genetic red blood cell disorder that often leads to stroke and executive dysfunction in school-age children and adults. This study aimed to characterize the development of the neural correlates of selective attention, an early component of executive function, in preschool children with SCD. Methods: Auditory event-related potentials (ERPs) were recorded while children attended to a story stream in one ear and ignored a second story in the other ear interchangeably. In total, 12 patients (mean age = 5.5, 7 males) and 22 typically developing children (mean age = 4.4, 10 males) were included in the final analyses. Results: By 100 ms, more positive ERP amplitudes were observed for attended relative to unattended stimuli in typically developing children but not those with SCD, suggesting deficits in the ability to focus attention. Reduced attention effects were associated with lower performance intellectual quotient. Conclusion: There are deficits in early attention modulation in young children with SCD.

Subcortical and cerebellar volumetric deficits in paediatric sickle cell anaemia.

Sickle cell anaemia (SCA) is associated with silent cerebral infarction (SCI), affecting white and cortical grey matter, but there are few data on subcortical volumes. We analysed retrospective magnetic resonance imaging (MRI) data in 26 SCA patients and 20 controls, comparing mean subcortical volumes between three groups: controls, SCA with SCI (n = 13) and SCA without visible abnormality (n = 13). Specific volumetric differences were found in the hippocampus, amygdala, pallidum, caudate, putamen, thalamus, and cerebellum. This is the first study to demonstrate subcortical volume change in SCA, with the most severe volumetric deficits occurring in children with SCI seen on MRI.

The tympanic membrane displacement analyser for monitoring intracranial pressure in children.

PURPOSE: Raised intracranial pressure (ICP) is a potentially treatable cause of morbidity and mortality but tools for monitoring are invasive. We sought to investigate the utility of the tympanic membrane displacement (TMD) analyser for non-invasive measurement of ICP in children. METHODS: We made TMD observations on normal and acutely comatose children presenting to Kilifi District Hospital (KDH) at the rural coast of Kenya and on children on follow-up for idiopathic intracranial hypertension at Evelina Children's Hospital (ECH), in London, UK. RESULTS: We recruited 63 patients (median age 3.3 (inter-quartile range (IQR) 2.0-4.3) years) at KDH and 14 children (median age 10 (IQR 5-11) years) at ECH. We observed significantly higher (more negative) TMD measurements in KDH children presenting with coma compared to normal children seen at the hospital's outpatient department, in both semi-recumbent [mean -61.3 (95 % confidence interval (95 % CI) -93.5 to 29.1) nl versus mean -7.1 (95 % CI -54.0 to 68.3) nl, respectively; P = 0.03] and recumbent postures [mean -61.4 (95 % CI -93.4 to -29.3) nl, n = 59) versus mean -25.9 (95 % CI -71.4 to 123.2) nl, respectively; P = 0.03]. We also observed higher TMD measurements in ECH children with raised ICP measurements, as indicated by lumbar puncture manometry, compared to those with normal ICP, in both semi-recumbent [mean -259.3 (95 % CI -363.8 to -154.8) nl versus mean 26.7 (95 % CI -52.3 to 105.7) nl, respectively; P < 0.01] and recumbent postures [mean -137.5 (95 % CI -260.6 to -14.4) nl versus mean 96.6 (95 % CI 6.5 to 186.6) nl, respectively; P < 0.01]. CONCLUSION: The TMD analyser has a potential utility in monitoring ICP in a variety of clinical circumstances.

Mortality in sickle cell anemia in Africa: a prospective cohort study in Tanzania.

BACKGROUND: The World Health Organization has declared Sickle Cell Anemia (SCA) a public health priority. There are 300,000 births/year, over 75% in Africa, with estimates suggesting that 6 million Africans will be living with SCA if average survival reaches half the African norm. Countries such as United States of America and United Kingdom have reduced SCA mortality from 3 to 0.13 per 100 person years of observation (PYO), with interventions such as newborn screening, prevention of infections and comprehensive care, but implementation of interventions in African countries has been hindered by lack of locally appropriate information. The objective of this study was to determine the incidence and factors associated with death from SCA in Dar-es-Salaam. METHODS AND FINDINGS: A hospital-based cohort study was conducted, with prospective surveillance of 1,725 SCA patients recruited from 2004 to 2009, with 209 (12%) lost to follow up, while 86 died. The mortality rate was 1.9 (95%CI 1.5, 2.9) per 100 PYO, highest under 5-years old [7.3 (4.8-11.0)], adjusting for dates of birth and study enrollment. Independent risk factors, at enrollment to the cohort, predicting death were low hemoglobin (<5 g/dL) [3.8 (1.8-8.2); p = 0.001] and high total bilirubin (≥102 µmol/L) [1.7 (1.0-2.9); p = 0.044] as determined by logistic regression. CONCLUSIONS: Mortality in SCA in Africa is high, with the most vulnerable period being under 5-years old. This is most likely an underestimate, as this was a hospital cohort and may not have captured SCA individuals with severe disease who died in early childhood, those with mild disease who are undiagnosed or do not utilize services at health facilities. Prompt and effective treatment for anemia in SCA is recommended as it is likely to improve survival. Further research is required to determine the etiology, pathophysiology and the most appropriate strategies for management of anemia in SCA.

Stroke in Children with Sickle Cell Disease.

Children with sickle disease are at high risk for ischemic stroke and transient ischemic attacks, usually secondary to intracranial arteriopathy involving the terminal internal carotid and proximal middle cerebral and anterior cerebral arteries, which may be diagnosed using transcranial Doppler ultrasound or magnetic resonance angiography (MRA). Other central nervous system (CNS) complications include seizures and coma, which may be secondary to ischemic stroke, sinovenous thrombosis, reversible posterior leukoencephalopathy, or acute demyelination. The immediate priority after an acute CNS event is to improve cerebral oxygenation with oxygen supplementation to maintain peripheral saturation measured using pulse oximetry between 96% and 99%, and a simple transfusion of packed cells within an hour of presentation if the patient's hemoglobin is less than 10 g/dL. The patient then should have erythrocytapheresis or manual exchange to reduce the hemoglobin S percentage to below 30%. Computed tomography to exclude hemorrhage is mandatory and MR T2-weighted imaging with MRA, fat-saturated imaging of the neck (dissection), MR venography (sinovenous thrombosis), and diffusion-weighted imaging usually distinguishes between arterial ischemic stroke and the differential diagnoses. Comatose patients with widespread focal or global cerebral edema may have good functional outcome after surgical decompression. Anticoagulation may be indicated for dissection or sinovenous thrombosis and steroids for demyelination. Blood pressure should be reduced slowly if raised in patients with reversible posterior leukoencephalopathy. Seizures should be treated aggressively and electroencephalogram monitoring should be done to exclude subclinical seizures if the patient is unconscious. Hemorrhagic stroke may require craniectomy and drainage and/or management of vasospasm. Interventional neuroradiology with coils is an alternative to surgical clipping for aneurysms. For secondary prevention, regular blood transfusion to hemoglobin S of less than 30% reduces the risk of recurrent stroke from approximately 67% to approximately 10%. Hydroxyurea and phlebotomy may be used in patients who are alloimmunized. Moyamoya syndrome is a risk factor for recurrence despite prophylactic blood transfusion. Revascularization may prevent additional stroke. Bone marrow transplantation may be offered to patients with human leukocyte antigen-compatible siblings. Blood transfusion prevents stroke in patients with velocities greater than 200 cm per second on TCD; a phase III trial studying the prevention of the progression of silent infarction is being done. Emerging primary prophylaxis regimens being tested include citrulline and arginine, aspirin, and overnight oxygen supplementation. Physicians caring for children with sickle cell disease also should ensure adequate nutrition, including five servings of fruit and vegetables a day. The role of vitamin supplementation is controversial, particularly when patients must take daily penicillin prophylaxis.