Sickle Cell Anemia In sub-Saharan Africa Research Articles

Neurocognitive Improvement with Hydroxyurea Therapy in Children with Sickle Cell Anemia in Uganda: Interim Analysis at Month 18

Introduction: Cerebrovascular injury can lead to neurocognitive impairment in children with sickle cell anemia (SCA). The prospective impact of hydroxyurea therapy on neurocognitive function has not been previously reported in a large sample of children with SCA in sub-Saharan Africa. We assessed the impact of hydroxyurea therapy at the trial's18-month midpoint on neurocognitive function compared to baseline assessments and to non-SCA controls. Methods: A sample of267 children with SCA, ages 3 to 9 years, were randomly selected for screening and enrollment from eligible patients who attended the Mulago Hospital Sickle Cell Clinic (MHSCC). BRAIN SAFE II is an open label hydroxyurea treatment trial with escalation to maximal tolerated dose. Primary outcomes are stroke, stroke risk and neurocognitive assessment. Controls were aged 3 to 12 years and siblings/relatives of participants with SCA.Attention, cognition and executive function were assessed for all participants by age-appropriate neurocognitive testing. Controlsestablished test z-scores for each age. Baseline (month 0) SCA group z-scores were compared to the controls and to the SCA sample at trial month 18. Results: At trial baseline, SCA trial participants (n=267) were younger than the control group (mean age 5.1±1.7 vs. 7.1± 3.9 years, p<0.001), had lower weight-for-age ( p=0.03) and had similar socio-economic score and caregiver age and educational attainment. Participants had lower z-scores in attention (p<0.001) and neurocognitive ability (p<0.001), and in executive function ( p=0.001) in a total of 15 of 17 subtests. After 18 months of hydroxyurea therapy (mean dose 25.4mg/kg) for all active SCA participants (95.1%) (n=254), significant improvements in z-scores were seen at 18 months in attention ( p<0.001), all 4 subtests for cognitive ability ( p<0.001) and in 3 of 6 subtests of executive function ( p=0.003 to <0.001). Conclusion: After 18 months of hydroxyurea therapy reaching MTD dosing, children showed significant improvements in attention and cognition, with more modest improvements in executive function. Their scores moved closer to those from non-SCA controls in most subtests. These findings suggest that hydroxyurea therapy may play an important role in enhancing overall neurocognitive function in children with SCA. Trial procedures are ongoing to assess the effects from longer-term therapy.

Bridging the Access Gap for Comprehensive Sickle Cell Disease Management Across Sub-Saharan Africa: Learnings for Other Global Health Interventions?

Sickle cell disease (SCD) is a major unresolved global health issue, with the highest disease burden in sub-Saharan African countries; yet, SCD care has not proportionally reached patients in these regions, and the disease has received limited attention in the past. Addressing the burden of SCD in sub-Saharan Africa requires a holistic, collaborative approach to ensure solutions are both comprehensive - i.e., cover the entire continuum of care from early diagnosis to treatment - and sustainable - i.e., are co-created and co-owned with local partners and integrated into existing local systems to enable long-term independence without the need for continuous external support. We outline a set of recommendations for enhancing the provision of comprehensive healthcare for prevalent diseases in resource-constraint settings, gathered from the Novartis Africa SCD Program, that could serve as 'blueprint' for public-private partnerships to tackle global health priorities. The Novartis Africa SCD program was initiated with the aim to bridge access gaps to SCD care and provide comprehensive and innovative treatment solutions for SCD, especially in SSA where the disease burden is highest. The Program was first inaugurated in 2019 in Ghana through a public-private partnership with the Ministry of Health of the Government of Ghana, the Ghana Health Service, and the Sickle Cell Foundation of Ghana. Through engagement with these partners, as well as with support from other organizations with complementary competencies and resources, several targeted solutions were implemented to help strengthen the healthcare ecosystem to allow for comprehensive SCD management. Learnings from these interventions are highlighted as best practice consideration as a catalyst and to activate more public-private actors for this neglected global health issue. A solid understanding of the access barriers to comprehensive care has to be acquired by listening to and learning from patients, civil society, and local experts. Access barriers need to be addressed at multiple levels, i.e., by not only making medicines available and affordable, but also by strengthening healthcare systems, building capacity, and fostering local research and development. Partnerships across governmental, public, academic, non-profit, and private organizations are needed to secure political will, pool resources, gather expertise with understanding of the local context, and allow integration into all levels of existing local healthcare structures and the wider society.

Current challenges and new approaches to implementing optimal management of sickle cell disease in sub-Saharan Africa

Sickle cell disease (SCD) is the most common life-threatening monogenic disorder in the world. The disease is highly prevalent in malaria endemic areas with over 75% of patients residing in Sub-Saharan Africa (SSA). It is estimated that, without proper care, up to 90% of children with SCD will not celebrate their fifth birthday. Early identification and enrolment into comprehensive care has been shown to reduce the morbidity and mortality related with SCD complications. However, due to resource constraints, the SSA is yet to implement universal newborn screening programs for SCD. Furthermore, care for patients with SCD in the region is hampered by the shortage of qualified healthcare workers, lack of guidelines for the clinical management of SCD, limited infrastructure for inpatient and outpatient care, and limited access to blood and disease modifying drugs such as Hydroxyurea which contribute to poor clinical outcomes. Curative options such as bone marrow transplant and gene therapy are expensive and not available in many SSA countries. In addressing these challenges, various initiatives are ongoing in SSA which aim to enhance awareness on SCD, improve patient identification and retention to care, harmonize the standards of care for SCD, improve the skills of healthcare workers and conduct research on pertinent areas in SCD in the SSA context. Fortifying these measures is paramount to improving the outcomes of SCD in SSA.

Implementation of Transcranial Doppler Ultrasound Stroke Risk Screening in Urban and Rural Sickle Cell Disease Clinics in Zambia

Introduction Transcranial Doppler Ultrasound (TCD) has a long-established role in the diagnosis of sickle cell disease (SCD) related vasculopathy, paving the way for therapeutic interventions that reduce stroke risk by 92% in high-risk children. In sub-Saharan Africa (SSA), where 75% of the global burden of SCD resides and an estimated 1.03 million children are afflicted, SCD-associated stroke risk evaluation with TCD remains an urgent unmet need. Methods Through a collaborative network with Nationwide Children's Hospital in the USA, 6 health facilities including two in Zambia, had personnel and infrastructure set up to introduce Transcranial Doppler Ultrasonography clinical and research centres of excellence (TCD-COE). The SSA TCD Academy course, designed to advance the technical expertise and capability of participants to perform TCD was created. Learners completed virtually delivered didactic lectures focused on neuroanatomy, scan techniques, doppler waveform characteristics, diagnostic criteria, and clinical application in children. Thereafter, they underwent a week-long, hands-on, practical, introduction to TCD, to increase understanding of the key concepts and to develop basic TCD scanning proficiency. An electronic registry, collecting demographic, clinical and laboratory data was also set up. Ongoing mentorship occurred through real-time consultation and evaluation with feedback given directly from a TCD expert to trainees as they performed the screening. Following completion of the course, participants trained began TCD screening in existing sickle cell out-patient clinics at their institutions, namely, the University Teaching Hospitals-Children's Hospital in Lusaka, and at Chipata Central Hospital in Chipata, in Zambia. Results Trainees selected included a pediatric neurologist, a pediatrician in training, 2 nurses and 2 radiographers. They completed the TCD academy course content over 6 months’ time. To date, over a period of an additional six months, 171 children in Lusaka and 71 children in Chipata with SCD have undergone their first ever, successful TCD stroke risk screening, using a standardized protocol focused on terminal internal carotid artery and middle cerebral artery evaluation. Plans to incorporate TCD screening into routine clinical care are underway. This will require rolling out the screening from the current outpatient clinic day to additional days, to the in-lay ward, as well as to train more staff. Several factors may have facilitated the successful implementation of TCD services into the SCD clinics. The participating institutions had already established SCD clinics, with dedicated staff, therapeutic interventions, and monitoring facilities in place. A referral system was in place to allow the trained staff to interact with the physicians in charge of each SCD clinic. Additionally, the trainees had prior experience with other kinds of ultrasound performance, allowing for more rapid acquisition of the technical skill. Lastly, TCD screening for stroke risk was considered standard of care, according to the Zambian guidelines, catalyzing a notable pre-existing high awareness among the staff and affected families and a high acceptance of the service. Several challenges were also encountered. The physical space available is relatively limited, with insufficient room to set up TCD equipment and examination tables for children to rest comfortably during examinations. Additional space was provided, and the teams were able to expand to locations adjacent to clinics to overcome this obstacle. Staff often had multiples tasks, oftentimes only a single provider could be present to perform TCD examinations. Providing dedicated time and staff may offset this setback. Additionally, other days when staff were available, screening was limited based on the availability of the single machine. This obstacle was overcome with the provision of an additional TCD unit. Lastly, some families did not have financial means to return for the recommended follow up visits. Conclusions TCD screening, to determine stroke risk in children with SCD in SSA is feasible with a modest degree of investment in equipment, staff, and training.

Global perspectives on cellular therapy for children with sickle cell disease.

Low-income and middle-income countries (LMICs), primarily in sub-Saharan Africa (SSA), predominantly experience the burden of sickle cell disease (SCD). High frequency of acute and chronic complications leads to increased utilization of healthcare, which burdens fragile health systems. Mortality for children with limited healthcare access remains alarmingly high. Cellular based therapies such as allogeneic hematopoietic stem cell transplant (HSCT) are increasingly used in resource-rich settings as curative therapy for SCD. Broad access to curative therapies for SCD in SSA would dramatically alter the global impact of the disease. Currently, application of cellular based therapies in LMICs is limited by cost, personnel, and availability of HSCT-specific technologies and supportive care. Despite the challenges, HSCT for SCD is moving forward in LMICs. Highly anticipated gene modification therapies have recently proven well tolerated and feasible in clinical trials in resource-rich countries, but access remains extremely limited. Translation of curative cellular based therapies for SCD should be prioritized to LMICs where the disease burden and cost of noncurative treatments is high, and long-term quality of life is poor. Focus on thoughtful modifications of current and future therapies to meet the need in LMICs, especially in SSA, will be especially impactful.

O-01: HYDROXYUREA REDUCES THE TRANSFUSION BURDEN IN CHILDREN WITH SICKLE CELL ANEMIA IN SUB-SAHARAN AFRICA: THE REACH EXPERIENCE

Purpose: Many children with sickle cell anemia (SCA) require blood transfusions, which carry risks and utilize a scarce resource globally, particularly in Africa. Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) has documented the safety, feasibility, and benefits of hydroxyurea for children with SCA living in sub-Saharan Africa. In REACH, hydroxyurea escalated to maximum tolerated dose (MTD) significantly decreased vaso-occlusive events, malaria, and death; transfusions were decreased by ~70% over 30 months of treatment when compared to the 2-month screening period. Characterizing and investigating how hydroxyurea reduces transfusion needs in REACH could contribute to improved clinical understanding, better outcomes, a decreased transfusion burden, and preservation of the blood supply in these limited-resource settings. Materials and methods: Transfusions were recorded prospectively in the REACH REDCap database. Transfusion rates and indications were compared during screening and treatment. Risk factors for receiving a transfusion were identified using time-varying predictors and landmark analysis. Univariate relationships were assessed using the Anderson-Gill model, plus multiple regression to estimate Hazard Ratios (HR) with 95% confidence intervals (CI). Results: A total of 635 children with HbSS from Angola, Democratic Republic of Congo, Kenya, and Uganda enrolled, and 606 started hydroxyurea treatment. During screening, 48 transfusions were administered to 43 children, and during the treatment phase 405 transfusions were administered to 214 children over a mean treatment time of 5.2 ± 1.3 years. The transfusion rate was 43.3 per 100 patient-years during screening, which decreased to 22.0 per 100 patient-years during the initial fixed dose treatment period (IRR = 0.50; 95%CI = 0.35-0.74, p<0.001 compared to screening) and then decreased further to 12.1 per 100 patient-years during the dose escalation period (IRR = 0.28; 95%CI = 0.21-0.39, p<0.001 compared to screening; IRR = 0.54; 95%CI = 0.43-0.73, p<0.001 compared to fixed-dose). For every 100 children treated for one year with hydroxyurea dose escalation, there were 31.4 fewer transfusions compared to the untreated screening period (number needed to treat = 3.2). Children with palpable splenomegaly at enrollment had a higher likelihood of receiving a transfusion during the trial (HR 1.98, 95% CI 1.59 to 2.47, p<0.0001). Age, gender, alpha thalassemia trait, and G6PD deficiency were not associated with differences in transfusion rates. Conclusion: Hydroxyurea significantly reduces blood transfusion administration in children with SCA in sub-Saharan Africa, especially when escalated to MTD. Overall, this demonstrates that treating children with SCA may not only improve individual patient outcomes through reduction in anemia, transfusion burden, and transfusion-associated complications including infections, but may also to help preserve the scarce blood supply for the benefit of the larger population. For example, applying similar outcomes to the population of Uganda predicts that about 30,000 transfusions per year are administered to patients with SCA and that with universal screening and treatment that 21,600 (72%) of these could be preventable, representing ~20% of all annual transfusions administered. The fact that treating SCA patients can benefit the entire population through reducing blood transfusion utilization reframes the importance of treating this population from an individual health decision to a public health strategy. R. WARE, MD, PHD declares a conflict of interest: Consultancy, Expert: DSMB Member for Novartis and Editas clinical trials; Medical Advisor for Nova Laboratories Research support/Scientific studies: Hydroxyurea donations from Bristol Myers Squibb and Addmedica; equipment donation from Hemex Health

Reduction in seroprevalence of viral transfusion-transmitted infections in southwest Nigeria in children with sickle cell disease using an enhanced screening strategy.

Blood transfusion is an integral component in the management of children and adults with sickle cell disease (SCD). Concerns about blood safety due to the high risk of bloodborne infections in sub-Saharan Africa limits the application of this cost-effective strategy in the management of individuals with SCD. In a single-centre, retrospective, longitudinal study in southwest Nigeria, we hypothesised that the use of stringent blood donor selection, along with very sensitive enzyme-linked immunosorbent assay (ELISA) screening methods would reduce transfusion-transmitted infections (TTIs). Among 45 002 eligible blood donors at the Lagos University Teaching Hospital in Nigeria, over a 5-year review period (2015-2019), the seroprevalence rate of viral TTIs was 9.83%. The seroprevalence rates for human immunodeficiency, hepatitis B, and hepatitis C viruses were 1.37%, 6.2%, and 2.25% respectively. Among 172 children with SCD, 71% (122/172) on regular blood transfusion and 29% (50/172) who had never been transfused or had less than two transfusions per lifetime, none acquired any TTIs using our enhanced screening approach during the study period. Thus, safe blood transfusion practices can be provided for children with SCD in sub-Saharan Africa with the use of stringent donor selection protocols and fourth-generation ELISA kits for TTI screening.

Hydroxyurea Reduces the Transfusion Burden in Children with Sickle Cell Anemia: The Reach Experience

▪Introduction: Many children with sickle cell anemia (SCA) require blood transfusions, which carry risks and utilize a scarce resource globally, particularly in Africa. Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) has documented the safety, feasibility, and benefits of hydroxyurea for children with SCA living in sub-Saharan Africa. In REACH, hydroxyurea escalated to maximum tolerated dose (MTD) significantly decreased vaso-occlusive events, malaria, and death; transfusions were decreased by ~70% over 30 months of treatment when compared to the 2-month screening period. Characterizing how hydroxyurea reduces transfusion needs in REACH could contribute to improved clinical understanding and lead to better outcomes, a decreased transfusion burden, and preservation of the blood supply in these limited-resource settings.Methods: Transfusions were recorded prospectively in the REACH REDCap electronic database. Using time-varying predictors and landmark analysis, transfusions during screening and treatment were analyzed by clinical site, calendar month, age, gender, splenomegaly, hydroxyurea dose, MTD status, baseline and latest laboratory values (Hemoglobin, MCV, HbF, absolute neutrophil count, and platelets, all measured at least 30 days prior to the transfusion), alpha thalassemia trait, and G6PD deficiency. Incidence rate ratios (IRR) were calculated for treatment periods compared to screening. Univariate relationships were assessed using the Anderson-Gill model, plus multiple regression to estimate Hazard Ratios (HR) with 95% confidence intervals (CI's).Results: A total of 635 children with SCA enrolled in REACH, and 606 started hydroxyurea treatment. During screening, 48 transfusions were given to 43 children, and during the treatment phase 405 transfusions were administered to 214 children over an average treatment time of 5.2 ± 1.3 years. The transfusion rate was 43.3 per 100 patient-years during screening, which decreased to 22.0 per 100 patient-years during the initial fixed dose treatment period (IRR = 0.50; 95%CI = 0.35-0.74, p<0.001 compared to screening) and then decreased further to 12.1 per 100 patient-years during the dose escalation period (IRR = 0.28; 95%CI = 0.21-0.39, p<0.001 compared to screening; IRR = 0.54; 95%CI = 0.43-0.73, p<0.001 compared to fixed-dose). For every 100 children treated for a year with hydroxyurea during dose escalation, there were 31.4 fewer transfusions compared to the untreated screening period. Comparison of the indications for transfusion between the screening and treatment periods revealed transfusions administered for anemia decreased from a rate of 26.1 to 5.1 per 100 patient-years (p<0.001), while transfusions for malaria trended toward a decrease from 7.2 to 3.8 per 100 patient-years (p=0.08). Lower transfusion rates on hydroxyurea were associated with higher hemoglobin concentration (HR = 0.72 per 1g/dL increase; 95%CI = 0.65-0.78, p <0.0001) and higher HbF levels (HR = 0.80 per 10% increase, 95%CI = 0.69-0.92, p=0.0071). Those with palpable splenomegaly had higher transfusion rates (HR = 1.58, 95%CI = 1.22-2.03, p=0.0094). Age, gender, alpha thalassemia trait, G6PD deficiency, and neutrophil count were not associated with differences in transfusion rates.Conclusion: Hydroxyurea significantly reduces blood transfusion administration in children with SCA in sub-Saharan Africa, especially when escalated to MTD. Transfusions for the sole indication of anemia decreased significantly on hydroxyurea treatment, likely due to higher treatment-associated hemoglobin levels and decreased hemolysis, and transfusions for malaria also trended toward a decrease. Splenomegaly remains a risk factor for transfusions despite hydroxyurea treatment. Overall, increased access to and implementation of hydroxyurea treatment for children with SCA across sub-Saharan Africa may not only improve individual patient outcomes through reduction in anemia, transfusion burden, and transfusion-associated complications including infections, but may also to help preserve the scarce blood supply for the benefit of the larger population. DisclosuresAygun: Global Blood Therapeutics: Consultancy; Patient Centered Outcomes Research Institute: Research Funding; National Heart, Lung, Blood Institute: Research Funding; National Institute of Nursing Research: Research Funding; bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stuber: ASH Research Collaborative: Consultancy. Ware: Bristol Myers Squibb: Research Funding; Addmedica: Research Funding; Hemex Health: Research Funding; Nova Laboratories: Research Funding; Novartis: Other: DSMB Chair; Editas: Other: DSMB Chair.

Pulmonary Hypertension and Associated Risk Factors in a High Burden Sickle Cell Disease Population

▪Introduction: Chronic pulmonary complications in sickle cell disease (SCD) are major causes of morbidity and mortality, particularly among those with sickle cell anemia (SCA), and accounts for 20-30% of all sickle cell deaths (Gray et. al. J Clin Pathol 1991; Thomas et. al. BMJ 1982).These complications include abnormalities in pulmonary function, interstitial lung disease and pulmonary hypertension (PH) in its severest form. An elevated tricuspid regurgitant jet velocity (TRV) obtained via doppler echocardiography, is a validated non-invasive screening tool for possible PH and an independent risk factor for early death among patients with SCD (Gladwin et. al. N Engl J Med 2004; Mehari et. al. JAMA 2012). It has been shown that measured TRV ≥ 2.5m/s is associated with decreased survival, estimated to be 40% at 40 months (Castro et. al. Blood 2003). The prevalence of PH determined by echocardiography is between 25-30% in SCA patients (Aliyu et. al. Am J Hematol 2008).Though the burden of SCD in Sub-Saharan Africa is high, there is paucity of research into chronic lung complications, particularly pulmonary hypertension in this special population. Ghana, a West African country, has a high burden of SCD with over 16,000 babies born annually with the disease. This study therefore determined the prevalence of pulmonary hypertension and its associated risk factors.MethodsThis was a cross-sectional study involving 76 clinically stable SCA patients aged 18 years and above. A structured and pre-tested questionnaire was used to obtain socio-demographic and clinical information. The cardiopulmonary system of participants was thoroughly examined and a modified version of St George's questionnaire was used to screen and exclude those with chronic lung disease. Doppler echocardiography was used to measure TRV. The participants underwent spirometry testing, pulse oximetry measurement, and laboratory investigations including a complete blood count, free plasma hemoglobin, blood urea and creatinine.ResultsTwenty-five (32.9%) of the SCA participants had elevated TRV (≥ 2.5m/s), which was suggestive of pulmonary hypertension. Nineteen (76%) had values between 2.5m/s - 2.9m/s, representing mild pulmonary hypertension and Six (24%) had values ≥ 3.0m/s suggestive of moderate-severe pulmonary hypertension.A negative correlation between TRV and steady-state haemoglobin (Hb) was observed (R= - 0.456, p < 0.001). Those with elevated TRV had a mean Hb of 6.9g/dl compared to 8.6g/dl in those with TRV < 2.5m/s. Further analysis showed that 6 of the SCA participants with TRV ≥ 3.0m/s had a much lower mean Hb (5.8g/dl). There was also an association between TRV and blood urea level (p = 0.030), but not with serum creatinine (p < 0.088). Oxygen saturation was significantly associated with measured TRV (p < 0.001) values. The proportion of SCA with abnormal spirometry (restrictive, obstructive and mixed defects) was 70.4% but this was however not significantly associated with measured TRV values.ConclusionPulmonary hypertension occurred in about a third of the SCA participants, the presence of which was significantly associated with steady state hemoglobin, oxygen saturation and blood urea level. Early screening and identification of risk factors for PH is therefore recommended to reduce morbidity and mortality. DisclosuresNo relevant conflicts of interest to declare.

Increased prevalence of Stroke Recurrence and Stroke Related Mortality in Children with Sickle Cell Disease in Nigeria: evidence for a Secondary Stroke Prevention Trial.

Introduction- Nigeria has the highest burden of sickle cell anemia (SCA) in the world accounting for 50% of the 300,000 SCA births globally. In a recent survey conducted locally in Nigeria, Kano state was shown to have the highest number of children with SCA in Nigeria, with Kano metropolitan city alone having over 15,000 children with SCA. Stroke is one of the most devastating yet preventable complications in children with SCA. Without transcranial Doppler (TCD) screening and treatment, approximately 7 to 10% of the children with SCA will develop strokes. Among untreated children with strokes, there is at least a 50% recurrence rate after 2 years. Due to the high rate of stroke recurrence and the absence of regular blood transfusion therapy as a viable option due to availability, poor parental acceptance of blood transfusion, and cost, hydroxyurea therapy is the only viable option for the majority of children. However, the benefit and risks of hydroxyurea for secondary stroke prevention is poorly defined in Nigeria.Methodology- In preparation for a phase III trial of hydroxyurea for secondary stroke prevention in children with SCA in sub-Saharan Africa, we initiated a standard care protocol in 2014 to manage children with strokes at Aminu Kano Teaching Hospital Kano, Nigeria, to determine the prevalence of stroke among children with SCA between Jan 2014 to May 2017. Ethical approval to conduct the study was received from the ethics committee of Aminu Kano Teaching hospital in Kano, Nigeria.Result-We identified 29 children with SCA who had an initial stroke within the study period, with 7 children having >1 stroke, and a mortality rate of 6.9% (2/29). Death was unrelated to any toxicity associated with hydroxyurea. None of the children treated with hydroxyurea, had therapy held because of myelosuppression or anemia. The rate of initial stroke in the pediatric clinic population of approximately 500 children (age birth through 12 years) over a three-year period was 1.97 per 100 patient-years. The median age for the first stroke was 5.6 years (range 1.1 to 14.2 years). Children with initial strokes were followed for a total of 38.8 years and had a rate of recurrence of 18.1 events per 100 patient-years, (figure 1) significantly below the expected rate of 29 events per 100 patient years if no treatment was offered, but a significantly higher incidence rate compared to regular blood transfusion of 1.9 events per patient year. Of the patients with an initial stroke, 65.5% received an exchange transfusion and 92.6% were either already on hydroxyurea (n=1) or started on fixed dose hydroxyurea (n=24), 20 mg/kg/day, within 2 months of the stroke, as part of standard care. The median modified Rankin was 1 with a range from 0 to 6, on the gross motor function classification system score. 10 children (40.0%) had normal function and 6 (24.0%) had level III or higher. Both measurements were completed at a median of 1.6 years (IQR 1.9 years) after the initial stroke. (Table I)Conclusion-Our results provide strong evidence for the high prevalence of stroke and death following a stroke in children with SCA in Nigeria. Optimal hydroxyurea dose for secondary stroke prevention is unknown in low-resource setting. Given the prevalence of strokes in unscreened and untreated children with SCA, primary and secondary stroke prevention program are a public urgency in children with SCA living in Nigeria. We are currently conducting a randomized controlled trial for secondary prevention of strokes comparing fixed dose of 20 mg/kg/day vs 10 mg/kg/day (NCT NCT01801423). [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Systemic complications and imaging challenges of sickle cell disease in sub-saharan Africa

With improved life expectancy of people living with sickle cell disease (SCD) as a result of modern interventions, chronic problems such as pulmonary, abdominal, cardiovascular, musculoskeletal, and obstetric challenges are more often encountered. The need for radiological examination is, therefore, growing for the early diagnosis of these complications and improved prognosis. The emphasis, therefore, should be toward safer diagnostic options such as ultrasonography, transcranial Doppler ultrasound, and echocardiography as repeated radiation is counterproductive. This review is aimed at highlighting the imaging challenges encountered in the management of SCD in sub-Saharan Africa and possible ways of mitigating them. We reviewed available electronic literature in the last 20 years, especially articles from Google Scholar and PubMed with search keywords of imaging challenges, sickle cell disease, and sub-Saharan Africa. The challenges identified in this review include lack of institutional infrastructure, poor equipment availability, weak health and imaging personnel capacity, treatment affordability, service accessibility, and poor research and training facilities. With the increasing longevity of SCD individuals in sub-Saharan Africa, imaging requirements are rising. Repeated exposure to radiation should be minimized as much as possible. Engagement of the private sector through public-private partnership in equipping health institutions with radiological equipment, as well as training of appropriate personnel for their deployment is strongly recommended to enhance care, prevent complications, and improve outcomes for SCD in sub-Saharan Africa.

Primary prevention of stroke in children with sickle cell anemia in sub-Saharan Africa: rationale and design of phase III randomized clinical trial

Strokes in children with sickle cell anemia (SCA) are associated with significant morbidity and premature death. Primary stroke prevention in children with SCA involves screening for abnormal transcranial Doppler (TCD) velocity coupled with regular blood transfusion therapy for children with abnormal velocities, for at least one year. However, in Africa, where the majority of children with SCA live, regular blood transfusions are not feasible due to inadequate supply of safe blood, cost, and the reluctance of caregivers to accept transfusion therapy for their children. We describe the Primary Prevention of Stroke in Children with Sickle Cell Disease in Nigeria Trial [ S troke Pr evention i n N i g eria (SPRING) trial, NCT02560935], a three-center double-blinded randomized controlled Phase III clinical trial to 1) determine the efficacy of moderate fixed-dose (20 mg/kg/day) versus low fixed-dose (10 mg/kg/day) hydroxyurea therapy for primary stroke prevention; 2) determine the efficacy of moderate fixed-dose hydroxyurea for decreasing the incidence of all cause-hospitalization (pain, acute chest syndrome, infection, other) compared to low fixed-dose hydroxyurea. We will test the primary hypothesis that there will be a 66% relative risk reduction of strokes in children with SCA and abnormal TCD measurements, randomly allocated, for a minimum of three years to receive moderate fixed-dose versus low fixed-dose hydroxyurea (total n = 220). The results of this trial will advance the care of children with SCA in sub-Saharan Africa, while improving research capacity for future studies to prevent strokes in children with SCA.

Optimizing Hydroxyurea Therapy with Reduced Laboratory Monitoring for Children with Sickle Cell Anemia in Sub-Saharan Africa: The Reach Experience

Introduction: Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) is an open-label study of hydroxyurea for children with sickle cell anemia (SCA) in sub-Saharan Africa (Angola, DR Congo, Kenya, and Uganda). Initial results documented the feasibility, safety, and benefits of hydroxyurea for SCA in sub-Saharan Africa but guidance for optimizing hydroxyurea therapy is needed. We describe 5 years of hydroxyurea dosing and monitoring in the largest prospective cohort of children with SCA receiving hydroxyurea to date. Methods: Children 1-10 years of age with SCA were enrolled. The hydroxyurea dose was fixed at 15-20 mg/kg/day for the first 6 months with monthly complete blood counts (CBCs) to ensure safety. From month 6-24, the dose was escalated (5 mg/kg every 8 weeks) to maximum tolerated dose (MTD), defined as mild myelosuppression with absolute neutrophil count (ANC) &amp;lt;4.0 x 109/L on 2 consecutive CBCs without hematological toxicities. CBCs were performed monthly until MTD or a stable dose was achieved, then subsequently every 3 months. Dose limiting toxicities (DLT) requiring a temporary treatment hold were defined as ANC &amp;lt;1.0 x 109/L, Hb &amp;lt;4.0 g/dL, reticulocyte count &amp;lt;80 x 109/L unless Hb &amp;gt;7.0 g/dL, or platelets &amp;lt;80 x 109/L. Known genetic modifiers of SCA, including G6PD deficiency and α-thalassemia trait, were determined for all participants. Results: A total of 606 children initiated hydroxyurea and currently 555 (92%) remain on treatment, with average treatment duration of 48 ± 12 months and a total of 2,441 patient-years of hydroxyurea treatment. Over 85% achieved MTD with an average hydroxyurea dose of 22.5 ± 5.0 mg/kg/day, ranging from 19.0 mg/kg/day in Angola to 25.4 mg/kg/day in Uganda. With dose increases over time, the most recent average dose is 23.9 ± 5.4 mg/kg/day (site range 22.9-24.6 mg/kg/day). Lab benefits have been sustained; Hb increased from 7.3 g/dL at baseline to 8.4 g/dL at MTD and remains 8.3 g/dL at Month 60. Similarly, the average HbF increased from 11% baseline to 25% at MTD and remains 23% at Month 60. The average ANC decreased from 6.8 x 109/L at baseline to 3.2 x 109/L at MTD and remains 3.5 x 109/L at Month 60. Lab toxicities are infrequent, transient, and mostly incidental. Of 19,730 CBCs obtained during the treatment phase, 421 (2.1%) in 225 participants included a DLT. The most common DLT was thrombocytopenia (33%), with only 4 platelet counts &amp;lt;20 x 109/L and no bleeding. Anemia was the second most common DLT (26%), most commonly associated with a high reticulocyte count and malarial infection, unrelated to hydroxyurea. Severe neutropenia (ANC &amp;lt;0.5 x 109/L) was rare (5 events) with no neutropenic infections. Over 2/3 of DLT events were identified incidentally during a scheduled visit when the study participant was asymptomatic, including all 5 severe neutropenic episodes. Weight-for-age and height-for-age Z-scores were not associated with higher rates of DLT during hydroxyurea treatment. Children with two-gene deletional α-thalassemia trait tolerated significantly lower hydroxyurea doses than the normal genotype (MTD dose 20.0 vs. 24.0 mg/kg/day, p &amp;lt;0.001) and had significantly different treatment responses at Month 60 including lower HbF (19.5 vs 24.3%, p &amp;lt;0.0001) and MCV (72 vs 99 fL, p&amp;lt;0.001) but higher hemoglobin (8.5 vs 8.1 g/dL, p=0.016). DLT frequency was unaffected by α-thalassemia status. Males with G6PD A- deficiency did not demonstrate significant differences in dosing, response, or toxicity. Conclusions: Hydroxyurea is safe, well-tolerated, and effective for children with SCA living in sub-Saharan Africa. Treatment responses are robust and sustained in REACH across all 4 clinical sites and unaffected by baseline Z-score. Hydroxyurea optimization requires periodic dose escalation for weight gain and titration to mild myelosuppression. Deletional α-thalassemia trait significantly influences the hydroxyurea dose and treatment responses, but the lab benefits with optimized dosing are still robust regardless of the α-globin genotype. Lab toxicities from hydroxyurea are uncommon and typically asymptomatic, suggesting that routine CBC monitoring is needed only at 3-month intervals once a stable dose is achieved, more to optimize the dose than to identify incidental toxicities. This approach to optimizing hydroxyurea therapy will allow more widespread utilization in low-resource settings with limited laboratory monitoring. Disclosures Aygun: National Heart, Lung, and Blood Institute: Research Funding; National Institute of Nursing Research: Research Funding; Patient-Centered Outsomes Research Institute: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Low- Versus Moderate-Dose Hydroxyurea for Secondary Stroke Prevention in Children with Sickle Cell Disease in Sub-Saharan Africa: Final Results of a Randomized Controlled Trial, Sprint Trial

Introduction Strokes are a preventable cause of neurological morbidity and premature death, particularly in children with sickle cell anemia (SCA) living in low-resource countries. If untreated, 50% of children with SCA their first overt ischemic stroke will have a recurrent stroke within two years of the event. In high-income countries, ASH 2020 guidelines recommend indefinite regular blood transfusion therapy for secondary stroke prevention (Blood Adv. 2020). Unfortunately, regular blood transfusion therapy is not a feasible option for children with SCA in sub-Saharan Africa due to the high cost of monthly blood transfusion, limited blood supply, and unsafe transfusion practices. Also, children who receive regular blood transfusions will ultimately require daily iron chelation at a cost that is prohibitive to most families in low-income settings. One randomized controlled trial provided evidence that HU therapy may be an effective therapy for secondary prevention of strokes when compared to no therapy (Blood. 2012;119(17):3925-3932). In the SWiTCH trial, the incidence rate of stroke recurrence in the group randomly allocated to receive maximum tolerated dose HU therapy was significantly higher than the group randomly assigned to receive blood transfusion therapy (5.6 and 0 events per 100 person-years, respectively, but considerably lower when compared to children not treated with any treatment, approximately 28 events per 100 person-years (Niger Postgrad Med J. 2013;20(3):181-187). Given the practical limitations for regular blood transfusion therapy, we tested the hypothesis that for secondary stroke prevention among children with SCA and acute overt ischemic stroke, fixed moderated dose HU therapy (~20 mg/kg/day) results in 80% relative risk reduction when compared to fixed low-dose HU therapy (10 mg/kg/day) in a randomized controlled trial (SPRINT Trial; NCT02675790). Methodology In phase III controlled trial, partially blind d controlled trial, we randomly assigned children 1 - 16 years of age with SCA and a new-onset of ischemic stroke (within 1 month) to receive fixed moderate-dose HU therapy at 20 mg/kg/day or fixed-low dose HU therapy at 10 mg/kg/day) with a monthly follow-up for at least 36 months. The primary endpoint was a recurrence of overt stroke or transient ischemic attack. Myelosuppression was assessed with monthly CBCs. Adherence to hydroxyurea was based on an increase in MCV from baseline and monthly pill count return, as a percent of dispensed pills. Results A total of 101 children with SCA were randomly assigned to fixed low- (~10 mg/kg/day) or moderate- (~20 mg/kg/day) dose hydroxyurea. The mean age was 6.6 years; 55.4% were males, and the median follow up was 1.6 years (IQR 1.0 - 2.3). The DSMB stopped the trial early due to the futility of the primary endpoint. In the fixed low- and moderate-dose groups, the incidence rates of recurrent strokes per 100 person-years were 7.1 and 6.0, respectively, incidence rate ratio of 0.85 (95% CI: 0.20 - 3.34), p=0.999. The incidence rates of mortality per 100 person-years in the fixed low dose and moderate- fixed-dose groups were 2.38 and 3.63, respectively, with an incidence rate ratio of 1.53 (95% CI: 0.18 - 18.30), p=0.98. No participant had hydroxyurea therapy stopped because of myelosuppression. As a measure of adherence, MCV from baseline to endpoint increased 6.2 fl and 13.3 fl in the fixed low- and moderate-dose groups, respectively, p=0.025; returned pills during the trial were 3.3% and 3.5% in the fixed low- and moderate-dose groups, respectively, p= 0.76. Conclusion For secondary stroke prevention, in a randomized controlled trial in children with SCA and new onset of ischemic strokes, fixed low-dose, when compared to fixed moderate-dose hydroxyurea therapy, demonstrated no difference in the incidence rate of stroke recurrence. Fixed low-dose hydroxyurea for secondary prevention of strokes in Nigeria provided similar stroke recurrence rate, when compared to the SWiTCH Trial (Blood. 2012;119(17):3925-3932) with the maximum tolerated dose of hydroxyurea of 7.0 and 5.7 events per 100 person-years, respectively. For secondary stroke prevention, in low-income settings without access to indefinite regular blood transfusion therapy, fixed low-dose hydroxyurea of at least 10 mg/kg/day with biannual CBC is a new evidence-based strategy to prevent strokes and minimize unnecessary laboratory testing. Disclosures DeBaun: Global Blood Therapeutics (GBT): Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: fixed low and moderate dose hydroxyurea for primary stroke prevention in sickle cell

Building Capacity and Assessing Stroke Risk with Transcranial Doppler Ultrasonography in Sub-Saharan Africa: The Reach Experience

Introduction: Transcranial Doppler (TCD) screening data from Uganda, Tanzania, and Nigeria have documented elevated velocities in &amp;gt;20% of children with sickle cell anemia (SCA) not receiving hydroxyurea treatment. Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) has demonstrated the safety, feasibility, and benefits of hydroxyurea for children with SCA living in sub-Saharan Africa, especially when escalated to maximum tolerated dose (MTD). Whether hydroxyurea also confers protection against stroke risk in this setting remains unproven, though hydroxyurea-associated increases in hemoglobin and fetal hemoglobin, plus decreases in TCD arterial flow velocities, should lower the risk of both primary and secondary stroke. The availability of TCD equipment and appropriately trained and certified TCD examiners to perform this non-invasive and inexpensive procedure is an important limitation in low-resource settings. Methods: REACH teams in Angola, Democratic Republic of Congo, Kenya, and Uganda identified two local persons at each site to receive formal TCD training and certification from two experienced and certified super-users, one from Uganda and one from the US. Initial training included hands-on teaching at each site by the Ugandan trainer, followed by didactic teaching and hands-on examinations at a central African location with both trainers and all four REACH teams. Follow-up training included monthly web-based teaching sessions of TCD technique and discussion of centrally reviewed exams. Each local examiner had at least 30 completed examinations reviewed, critiqued, and discussed together with the trainers before becoming formally certified as a REACH TCD examiner. After certification, all REACH participants taking hydroxyurea at a stable dose were eligible for TCD using a standardized protocol with identical Sonara/tek advanced non-imaging TCD ultrasound units with 2MHz probes and version 7 software (Natus, Middleton, WI). Time-averaged maximum velocities (TAMV) were measured in the middle cerebral artery, distal internal carotid artery, and the bifurcation. The highest TAMV was recorded and categorized as normal (&amp;lt;170 cm/sec), conditional (170-199 cm/sec), or abnormal (≥200 cm/sec) and correlated with laboratory and clinical parameters. Results: Between November 2018 and March 2020, a total of 481 children in REACH received TCD screening; the average age was 9.3 ± 2.6 years, on hydroxyurea for 43 ± 8 months at an average dose of 23.5 ± 5.0 mg/kg/day with good response (Hb = 8.4 ± 1.3 g/dL, HbF = 23.9 ± 5.0%). There were 16 (3.3%) inadequate exams, defined as no vessel flow in either hemisphere; 5 inadequate exams were in children with prior stroke at hydroxyurea initiation and 1 with stroke on treatment. Of 465 adequate exams, the overall median TAMV was 128 cm/sec (IQR 25 cm/sec) with 449 normal velocities (96.6% overall, range by site 95.1-99.2%), 16 conditional velocities (3.4% overall, range by site 2.3-4.9%), and no abnormal velocities. In univariate analysis, maximum TAMV was inversely correlated with hemoglobin (r = -0.29, p&amp;lt;0.0001), age (r = -0.23, p&amp;lt;0.0001), and fetal hemoglobin (r = -0.12, p=0.027); and positively correlated with reticulocytes (r = 0.17, p&amp;lt;0.001). No gender difference was noted, but alpha thalassemia trait (2-gene deletion) was associated with significantly lower TCD velocities, while G6PD A- deficiency had no observed effects. Conclusions: Robust TCD screening capability was developed in REACH with detailed training, certification, and oversight of local personnel, most of whom had no prior experience. Compared to untreated children, very few REACH participants had elevated TAMV velocities, confirming that hydroxyurea lowers TCD velocities and reduces stroke risk for children with SCA in sub-Saharan Africa. The observed associations between TAMV and both hemoglobin and fetal hemoglobin document the importance of escalating hydroxyurea to achieve and maintain an optimized dose. In low-resource settings, TCD screening efforts by trained and certified examiners should be aligned with hydroxyurea treatment protocols that feature dose escalation, to provide a feasible and effective stroke prevention program. TCD screening of African children with SCA will allow early identification of stroke risk and optimized hydroxyurea dosing, thereby reducing morbidity and mortality in this vulnerable population. Disclosures Aygun: National Heart, Lung, and Blood Institute: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Patient-Centered Outsomes Research Institute: Research Funding; National Institute of Nursing Research: Research Funding.

Newborn Screening for Sickle Cell Disease in Tanzania: The Past, Present and Future

Sickle Cell Disease (SCD) is an inherited disorder of the Haemoglobin molecule of the red blood cells that is associated with serious complications and reduced life expectancy. Over 75% of people with SCD live in Sub-Saharan Africa (SSA), and this proportion are projected to increase to 85% by the year 2050. In Tanzania, approximately 11,000 babies are born with SCD each year, ranking 5th in the world. The high prevalence of SCD in SSA is compounded by the disproportionately higher mortality compared to that observed in the high-income countries. In Tanzania, SCD is a major contributor to under-five mortality and is estimated to account for 7% of all-cause mortality in this age group. Newborn screening (NBS) is the practice of testing babies right after delivery to ascertain whether they have diseases that are potentially lethal if not treated early. Where routinely practiced, NBS has significantly reduced morbidity and mortality associated with such diseases. The Sickle Cell Programme at Muhimbili University of Health and Allied Sciences (MUHAS) in Dar-es-salaam and Bugando Medical Center in Mwanza have both conducted pilot NBS for SCD, showing that the intervention is generally feasible and acceptable in Tanzania. The successful introduction and expansion of NBS in Tanzania will require careful planning and advocacy at community to national level.

World Health Organization's Growth Reference Overestimates the Prevalence of Severe Malnutrition in Children with Sickle Cell Anemia in Africa.

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.

Frequent Impaired Overall Neurocognitive and Executive Function in Children Ages 1-12 Years of Age with Sickle Cell Anemia in Uganda

Background: Children with sickle cell anemia (SCA) are highly susceptible to stroke, impaired neurocognitive function and other manifestations of pediatric cerebral vasculopathy. Detailed multifaceted evaluations of children with SCA in sub-Saharan Africa are limited, including neurocognitive testing. Methods: We aimed to establish the prevalence and types of neurocognitive dysfunction in a cross-sectional study in a randomly selected sample of patients with HbSS ages 1-12 years at a large SCD clinic in Kampala, Uganda. Neurocognitive function was assessed by Mullen Scales of Early Learning (ages 1-4) and Kaufman Assessment Battery for Children, 2nd edition (ages 5-12) using linguistically validated local translations (John CC, Pediatrics 2008; Bangirana P., Clin Infect Dis. 2014). The Behavioral Rating Inventory for Executive Function was used to assess executive function. Children also underwent standardized stroke examination (PedsNIHSS) and transcranial Doppler ultrasound (TCD) for measuring stroke risk by arterial velocities in pediatric SCD. Results: Experienced testers performed neurocognitive assessment in 242 participants: 100 (41%) ages of 1-4 years and 142 ages 5-12 years (58.7%). Mean age was 5.44 ±2.9 years; 51.6% were male. Mean hemoglobin was 7.3 ±1.02 g/dl; 76.5% had hemoglobin &lt;8.0 g/dl. Using established international standards, 16% were malnourished. In the older age group, more children were female, malnourished, and had a clinical evidence of a stroke. In all, 27 (11.2%) had neurocognitive dysfunction, and 63 (25.8%) with impaired executive function. In the 1-4 age group, 5 (5%) had an abnormal neurocognitive exam, with a lower average standardized Global Executive Functioning score (mean -1.70 (SD 0.78)) than in the overall neurocognitive testing. Dysfunction was more common in the group ages 5-12. Among the 5-12 age group, 22 children (15.4%) had overall neurocognitive dysfunction, with the lowest group average z-score being the standardized neurocognitive Global Executive functioning z-score (Mean -0.71, SD 0.84). In the overall sample, factors associated with neurocognitive dysfunction included age (OR 1.43, 95%CI 1.23-1.98), abnormal stroke examination (OR 6.60, 95%CI 2.14-20.4), and non-normal TCD (OR 2.90, 95%CI 1.09-7.74) (Table 1; bold font denotes significance at p&lt;0.05). These results were consistent within the age subgroups. Adjusting for sex, hemoglobin, malnutrition and stroke, age (aOR 1.50, 95%CI 1.25-1.79) and stroke (aOR 6.96, 95%CI 2.01-24.1) remained significant predictors of neurocognitive dysfunction in the entire sample. Conclusion: In children with SCA, executive function was the most common impairment. Overall, only 11% of the SCA children had impaired neurocognitive function. The major predictors of impairment were age, prior stroke and elevated TCD arterial velocity. These abnormalities were highly prevalent in the sample, and identifies significant disease-associated morbidity. Disease-modifying therapy should be assessed for improved neuropsychological function in these children. Disclosures No relevant conflicts of interest to declare.

Radiological Findings By Magnetic Resonance (MRI) and Arteriography (MRA) Brain Imaging Compared to Neurological, Stroke and TCD Assessment in Children with Sickle Cell Anemia in Uganda

Background: Children with sickle cell anemia (SCA) are highly susceptible to stroke and other manifestations of pediatric cerebral vasculopathy. Detailed evaluations of children with SCA in sub-Saharan Africa are limited, especially magnetic resonance imaging and angiography (MRI/MRA). In a sample of Ugandan children receiving care at the Mulago Hospital sickle cell clinic in Kampala and were not on disease-modifying therapy, we examined the range of MR imaging findings, and how those findings correlated with standardized demographic, clinical, neurological and neurocognitive assessments. Methods: From within a larger sample of 265 participants with HbSS ages 1-12 years not taking disease-modifying therapy and enrolled in the BRAIN SAFE study, a sub-sample of 81 underwent non-contrast MRI/MRA on a 1.5 Telsa scanner. Participants also underwent 3 standardized assessments: neurocognitive testing by experienced testers using the Mullen Scales of Early Learning (for ages 1-4 years) or Kaufman Assessment Battery for Children, 2nd edition (for ages 5-12) (abnormal z-score of -2 or lower), stroke examination (PedsNIHSS) and transcranial Doppler ultrasound (TCD) using criteria for pediatric SCA. Participants undergoing MRI/MRA intentionally included 29 without any abnormal findings. MRI scans included T1- and T2- weighted images, T2 FLAIR and MRA three-dimensional time-of-flight technique. MR scans were interpreted by clinical and research methods, the latter per SWiTCH protocol (Helton, Blood 2014). Adjudication of differing reads was performed by a blinded third neuroradiologist. Results: A total of 81 children with SCA were examined by MRI/MRA. Mean age was 6.48 ± 2.75 years; 50.6% were male. Mean hemoglobin was 7.26±0.90 g/dl; 75% had hemoglobin &lt;8.0. In all, 16.7% were malnourished using standard international measures established by age and sex. Infarcts and/or arterial stenoses on MRI/MRA were detected in 42 (52%), including 13 (25%) with no other abnormalities detected. There were 35 children (43.2%) who had medium or large infarcts seen; an additional 16 (19.8%) had 1-2 small infarcts. Four had moya moya. Of the 29 children categorized as normal on each of the 3 other tests, 14 (48.3%) had one or more medium or large infarct(s) on MRI, and 3 (10.3%) had 1-2 small infarcts (Figure 1). The proportion of children with malnutrition was higher among those with an abnormal MRI compared to those with a normal MRI, whereas no children with a small infarct was malnourished (29.4% vs. 10.7% vs. 0% p=0.019). A higher proportion of participants with stroke by exam had medium or large infarct(s) compared to participants with normal or small infarct (28.6% vs. 10% vs. 6.3%; p=0.061). Stroke on exam was associated with medium or large infarct(s) compared to normal or small infarct (unadjusted OR 4.2; 95% CI 1.19-14.8), and remained after adjusting for age and hemoglobin (OR 3.90 95%CI 1.10-13.9). The proportion of abnormal psychological testing was higher in the small infarct group than in the group with larger infarct(s) or the normal group (37.5% vs. 28.6% vs. 17.2%; p=0.307). Conclusion: High prevalence of pediatric cerebral vasculopathy was found on MR scanning. Despite clinical evidence suggesting abnormal neuropsychological testing or a prior stroke, not all of the children who had clinical evidence of neurological disorders had MRI evidence of a stroke. Additionally, a number with no evidence of stroke had infarct(s) on MRI, so-called "silent stroke." The strongest predictors of an abnormal MRI reading included having a detectable stroke or an abnormal TCD. MR imaging is a critical aspect of evaluating cerebral vasculopathy in this patient population, and will be an important measure when prospectively assessing impact in a treatment trial. Disclosures No relevant conflicts of interest to declare.

Red Blood Cell Alloimmunization in Transfused Patients With Sickle Cell Disease in Sub-Saharan Africa; a Systematic Review and Meta-Analysis.

Sickle cell disease (SCD) is the most common monogenic disorder in sub-Saharan Africa (SSA). Blood transfusion to increase the oxygen carrying capacity of blood is vital in the management of many patients with SCD. However, red blood cell (RBC) alloimmunization is a major challenge to transfusions in these patients. Commonly in SSA, pretransfusion tests only involve ABO D grouping and compatibility without RBC antibody testing. Data on the frequency of RBC alloimmunization in patients with SCD in SSA are limited. We performed a systematic review and meta-analysis on available data on alloimmunization in transfused patients with SCD to determine the published prevalence of RBC alloimmunization in SCD patients in SSA. Six databases were systematically searched to identify relevant studies, without year or language restrictions. In all, 249 articles were identified and 15 met our selection criteria. The overall proportion of alloimmunization was 7.4 (95% confidence interval: 5.1-10.0) per 100 transfused patients. Antibodies against E, D, C, and K antigens accounted for almost half of antibody specificities, and antibodies to low- and high-frequency antigens were also common and represented almost 30% (20% to low-frequency antigens and 9% to high-frequency antigens) of specificities. Heterogeneity between studies was moderate, and meta-analysis found region of Africa as the major contributor to the heterogeneity. We also observed inconsistencies across studies in reporting of factors that may influence alloimmunization. This review provides an overview of the extent of the alloimmunization problem in SSA and provides a baseline against which to compare the effect of any interventions to reduce the alloimmunization risk.