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The vast majority of children with sickle cell anemia (SCA) live in Africa, where evidence-based guidelines for primary stroke prevention are lacking. In Kano, Nigeria, we conducted a feasibility trial to determine the acceptability of hydroxyurea therapy for primary stroke prevention in children with abnormal transcranial Doppler (TCD) measurements. Children with SCA and abnormal non-imaging TCD measurements (≥ 200 cm/s) received moderate fixed-dose hydroxyurea therapy (~20 mg/kg/day). A comparison group of children with TCD measurements < 200 cm/s was followed prospectively. Approximately 90% (337 of 375) of families agreed to be screened, while 92% (25 of 27) of those with abnormal TCD measurements, on two separate occasions, enrolled in the trial. No participant elected to withdraw from the trial. The average mean corpuscular volume increased from 85 fL at baseline to 101.3 fL at 24 months, demonstrating adherence to hydroxyurea. The comparison group consisted of 210 children, of which four developed abnormal TCD measurements, and were started on hydroxyurea. None of the monthly research visits were missed (n = total 603 visits). Two and ten deaths occurred in the treatment and comparison groups, with mortality rates of 2.69 and 1.81 per 100 patient-years, respectively (p = 0.67). Our results provide strong evidence, for high family recruitment, retention, and adherence rates, to undertake the first randomized controlled trial with hydroxyurea therapy for primary stroke prevention in children with SCA living in Africa.

Sickle cell disease (SCD) is the most common inherited hemoglobinopathy in the world, with the majority of cases in sub-Saharan Africa. Concomitant nutritional deficiencies, infections or exposure to environmental toxins exacerbate chronic anemia in children with SCD. The resulting relative anemia is associated with increased risk of strokes, poor cognitive function and impaired growth. It may also attenuate optimal response to hydroxyurea therapy, the only effective and practical treatment option for SCD in sub-Saharan Africa. This review will focus on the epidemiology, clinical sequelae, and treatment of relative anemia in children with SCD living in low and middle-income countries in sub-Saharan Africa. Areas covered: The causes and treatment of relative anemia in children with SCD in sub-Saharan Africa. The MEDLINE database was searched using medical subject headings (MeSH) and keywords for articles regarding relative anemia in children with SCD in sub-Saharan Africa. Expert commentary: Anemia due to nutritional deficiencies and infectious diseases such as helminthiasis and malaria are prevalent in sub-Saharan Africa. Their co-existence in children with SCD increases morbidity and mortality. Therefore, preventing, diagnosing and treating the underlying cause of this relative anemia will improve SCD-related outcomes in children in sub-Saharan Africa.

We wish to formally correct the above-referenced article and omit mention utilization of the Morisky medication adherence scale. The Morisky medication adherence scale was used to access study participants adherence on a monthly basis by parental recall. We did not realize that the questions were protected by copyright and required permission for utilization. For the duration of the study, the adherence tool is used as a secondary measurement of adherence, while the primary indicator included change in mean cell volume. The removal of the Morisky scale adherence data does not affect the primary outcomes of the study and does not alter the evidence of adherence, because increase in MCV was the primary measure of adherence.All the authors of the manuscript have been informed of the changes and have agreed to the publication of an erratum. We apologize for any inconvenience that this error might have caused.

Background: In children with sickle cell anemia (SCA), the routine use of transcranial Doppler (TCD) measurements and regular blood transfusion therapy for those with elevated velocities > 200 cm/sec, has dramatically decreased the rate of strokes. However, blood transfusion therapy for primary stroke prevention is not an option for most children in Africa. In preparation for a phase III trial of hydroxyurea therapy (20 mg/kg/day vs 10 mg/kg/day) for primary prevention of strokesin children with SCA in Africa, we conducted a single site, single-arm feasibility trial of hydroxyurea therapy for primary stroke prevention in children with SCA. Participants were between 5 and 12 years of age, attending the pediatric sickle cell disease clinic of Aminu Kano Teaching Hospital, in Kano, Nigeria. The main objectives of the feasibility trial were to determine the acceptability rate of a hydroxyurea therapy trial to families, and to obtain preliminary evidence of hydroxyurea safety in Africa. Methods: All eligible participants were screened with TCD, non-imaging technique, to determine increased stroke risk; defined as time-averaged maximum velocity (TAMV) greater than or equal to 200cm/sec in the middle cerebral artery (MCA). Families were offered moderate fixed dose hydroxyurea (~20mg/kg/day) for initially 2 years. Primary outcome measures of acceptability were based on three key components required for phase II randomized controlled trial: recruitment rate, retention rate and adherence to the study medication. To determine the expected background rate of adverse events and serious adverse events in this population, children with TCD velocities less than 200cm/sec who were not on hydroxyurea therapy were enrolled. Results: A total of 375 families were approached to be screened for elevated TCD measurements, of which 90% (330 of 375) enrolled; 8% (27 of 330) had two consecutive elevated TCD measurements; and 92% (25 of 27) participated in the trial. A total of 210 participants were identified with TCD velocities less than 200 cm, signed informed consents, and agreed to be followed prospectively in a comparison group. The median age for the trial participants and comparison group were 8 and 6.8 years, respectively. No statistically significant difference was observed in age, sex, ethnicity, height and weight of the treatment and comparison groups. The median time on therapy was 2.1 years (range: 0 to 2.8 years), and the average mean cell volume increased from 85 fl at baseline to 101.3 fl at 2 years. As per protocol, all patients were expected to attend monthly research visits and none were missed (n=total 603 visits). No participant in the treatment group dropped voluntarily from the trial, though one participant was withdrawn due to development of progressive renal failure. After follow up visits, participants in the comparison group with subsequent TCD measurements, were given the option to receive hydroxyurea therapy, and the only 2 with elevated TCD values elected to do so. No stroke occurred in the treatment group and 1 stroke occurred in the comparison group. Hospitalization rates in treatment and comparison groups were 35.1 and 48.0 per 100 patient years respectively, (p=0.06). A total of 9 deaths occurred, 1 death in the treatment group, but after participant withdrew from the trial because of progressive renal disease (1.76 per 100 patient-years) and 8 deaths in the comparison group (1·88 per 100 patient-years) p = 0.94. No participants that died received any PCV-13 vaccinations and only 2 received Hib vaccinations. At the time of death, all participants were prescribed malaria prophylaxis, and 8 of 9 participants were prescribed penicillin prophylaxis. Conclusion: In Nigeria, participants in SPIN Trial with elevated TCD measurements treated with moderate dose of hydroxyurea, showed high rates of successful recruitment, retention and adherence rates to trial medication. Importantly hydroxyurea therapy did not reveal any evidence of excessive toxicity when compared to those not treated with hydroxyurea. Our results provide strong preliminary evidence supporting the current multi-center randomized controlled trial comparing hydroxyurea therapy (20 mg/kg/day vs 10 mg/kg/day) for preventing primary strokes in children with SCA living in Nigeria (1R01NS094041-01;clinical trials.gov NCT 02560935). Disclosures No relevant conflicts of interest to declare.

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Anthropometric indices are widely used to assess the health and nutritional status of children. We tested the hypothesis that the 2007 World Health Organization (WHO) reference for assessment of malnutrition in children with sickle cell anemia (SCA) overestimates the prevalence of severe malnutrition when compared to a previously constructed SCA-specific reference. We applied the WHO and SCA-specific references to children with SCA aged 5–12 years living in northern Nigeria (Primary Prevention of Stroke in Children with SCA in sub-Saharan Africa (SPRING) trial) to determine the difference in prevalence of severe malnutrition defined as body mass index (BMI) Z-score <−3 and whether severe malnutrition was associated with lower mean hemoglobin levels or abnormal transcranial Doppler measurements (>200 cm/s). A total of 799 children were included in the final analysis (median age 8.2 years (interquartile range (IQR) 6.4–10.4)). The application of the WHO reference resulted in lower mean BMI than the SCA-specific reference (−2.3 versus −1.2; p < 0.001, respectively). The use of the WHO reference when compared to the SCA-specific reference population also resulted in a higher prevalence of severe malnutrition (28.6% vs. 6.4%; p < 0.001). The WHO reference significantly overestimates the prevalence of severe malnutrition in children with SCA when compared to an SCA-specific reference. Regardless of the reference population, severe malnutrition was not associated with lower mean hemoglobin levels or abnormal transcranial Doppler (TCD) measurements.

Summary Severe anaemia, defined as haemoglobin level < 6·0 g/dl, is an independent risk factor for death in individuals with sickle cell disease living in resource‐limited settings. We conducted a cross‐sectional study of 941 children with sickle cell anaemia, who had been defined as phenotype HbSS or HbSβ0 thalassaemia, aged five to 12 years, and were screened for enrollment into a large primary stroke prevention trial in Nigeria (SPRING; NCT02560935). The main aim of the study was to determine the prevalence and risk factors for severe anaemia. We found severe anaemia to be present in 3·9% (37 of 941) of the SPRING study participants. Severe anaemia was significantly associated with the lower educational level of the head of the household (P = 0·003), as a proxy for poverty, and a greater number of children per room in the household (P = 0·004). Body mass index was not associated with severe anaemia. The etiology of severe anaemia in children living with sickle cell anaemia in Nigeria is likely to be multifactorial with an interplay between an individual's disease severity and other socio‐economic factors related to poverty.