Establishing Sickle Cell Disease Stroke Prevention Teams in Africa is Feasible: Program Evaluation Using the RE-AIM Framework.

We used the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to evaluate a Stroke Prevention Team's readiness to prevent strokes in children with sickle cell anemia living in northern Nigeria. The NIH sponsored Stroke Prevention Trial in Nigeria included a goal of a sustainable stroke prevention program. The program's 1-year reach for transcranial Doppler screening was 14.7% (4710/32,000) of which 6.0% (281/4710) had abnormal velocities (≥200 cm/s). All participants with abnormal transcranial Doppler velocities were started on hydroxyurea (effectiveness). The leaders of all 5 hospitals agreed to adopt the program. After 1 year, program-implementation and maintenance rates were 100%, demonstrating the program's feasibility and short-term sustainability.

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 [StrokePreventioninNigeria (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.

Rate of Food Insecurity Among Households with Children with Sickle Cell Disease is Above the National Average.

OBJECTIVES: Despite studies demonstrating the negative impact of food insecurity on health in children, limited research has been done to assess the prevalence and sequelae of food insecurity in sickle cell disease (SCD). We tested the hypothesis that food insecurity is common in children with SCD and is associated with increased SCD morbidity. METHODS: Between May and November 2017, we conducted a single-center cross-sectional study using the previously validated, self-administered, US 18-item household food security survey module and the 9-item youth (12-17 years old) food security survey module during regular outpatient clinic visits. We also included the incidence of vaso-occlusive pain or acute chest syndrome requiring hospitalizations in the year before the questionnaire. RESULTS: A total of 75 caregivers and 24 children completed the surveys. The median age of the children was 10.4 years (interquartile range 5.5-15.3), 46.7% were boys. The rate of household food insecurity was 21.3% (16 of 75). Among the 24 children who completed the youth survey, 45.8% were classified as food insecure. Discordance occurred between caregivers' and children's assessment of food insecurity. A total of 81.8% (9 of 11) children reported being food insecure, whereas their caregivers reported to be food secure. The incidence for pain and acute chest syndrome in the year pre-enrollment was not different between food-secure and food-insecure children (59.3 and 43.8/100 patient-years, P = 0.54; 8.5 and 12.5/100 patient-years, P = 0.49, respectively). CONCLUSIONS: In a tertiary care medical center in Tennessee, one in five households with children with SCD were assessed as food insecure, with a substantial discordance between caregiver and child assessment of food insecurity.

Integrated psychology support and comprehensive cognitive evaluation improves access to special education services for children with sickle cell disease.

BACKGROUND: Children with sickle cell disease (SCD) are at risk for cognitive deficits. Limited data describe whether comprehensive cognitive evaluation improves education resources and whether caregivers perceive the assessment as beneficial. We tested our two hypotheses: (a) an integrated comprehensive cognitive evaluation program in children with SCD results in increased special education services allocation; and (b) caregivers will value comprehensive cognitive evaluation services provided. PROCEDURE: In a tertiary care medical facility, as part of quality improvement project, in a before-and-after evaluation between March 2011 and July 2014, we examined the impact of targeted comprehensive cognitive evaluation on change in special education services. We also evaluated the caregiver's perception regarding the utility of the provided services. RESULTS: A total of 21% (42 of 196) students (median age 11 years, range 3-18) with SCD were referred for cognitive assessment due to overt stroke (n = 11), silent stroke (n = 14), or concerns about cognitive or academic functioning without evidence of strokes (n = 17). At baseline, 45.2% received special education services and after the comprehensive cognitive evaluation 86.7% received special education services (P < 0.001). Among 33 caregivers who completed the survey, 97% reported that the assessment was helpful and 60% indicated that assessment led to beneficial changes for their children at school. CONCLUSION: Education advocacy coupled with comprehensive cognitive assessment in students with SCD improved access to special education services, and caregivers uniformly endorse this service as having added value.

Contraceptive Methods and the Impact of Menstruation on Daily Functioning in Women with Sickle Cell Disease.

OBJECTIVES: Women with sickle cell disease (SCD) are living longer as a result of advances in the care of their underlying disease. With the population growing of women living with SCD, reproductive health issues in this population have become an emphasized area of medical care. We sought to describe current patterns of contraception use, menstruation, and quality-of-life (QOL) measures in women with SCD. METHODS: Using a cross-sectional study design, we administered paper surveys at two academic medical centers to women aged 10 to 55 years with SCD to capture current contraceptive use, characteristics of menstrual cycles, and QOL metrics. RESULTS: Of the 103 women who participated, 12.7% (13/102) experienced a duration of menses >7 days (defined here as prolonged menstrual bleeding). Approximately half of women (51.5%, 53/103) used some form of contraception, with depot medroxyprogesterone acetate injections and condoms being the most common. During their last menstrual periods, women with both dysmenorrhea and prolonged menstrual bleeding (6.9%, 7/102) were more likely to experience more days of poor QOL, with more nights with sleep disturbance (P = 0.001) and more days with trouble taking care of themselves (P = 0.003), as well as being unable to do things they previously enjoyed (P = 0.001), compared with those with neither phenomenon (28.2%, 29/103). CONCLUSIONS: Dysmenorrhea and prolonged menstrual bleeding negatively affect the QOL of women with SCD. Menstrual histories and preventive measures for menstruation-related morbidity should be incorporated into routine evaluations of women with SCD.

Clustering of end-organ disease and earlier mortality in adults with sickle cell disease: A retrospective-prospective cohort study.

Chronic end-organ complications result in morbidity and mortality in adults with sickle cell disease (SCD). In a retrospective-prospective cohort of 150 adults with SCD who received standard care screening for pulmonary function abnormalities, cardiac disease, and renal assessment from January 2003 to 2016, we tested the hypothesis that clustering of end-organ disease is common and multiple organ impairment predicts mortality. Any end-organ disease occurred in 59.3% of individuals, and 24.0% developed multiple organ (>1) end-organ disease. The number of end-organs affected was associated with mortality (P ≤ .001); 8.2% (5 of 61) of individuals with no affected end-organ, 9.4% (5 of 53) of those with 1 affected organ, 20.7% (6 of 29) of those with 2 affected end-organs, and 85.7% (6 of 7) with 3 affected end-organs died over a median follow up period of 8.7 (interquartile range 3.5-11.4) years. Of the 22 individuals who died, 77.3% had evidence of any SCD-related end-organ impairment, and this was the primary or secondary cause of death in 45.0%. SCD-related chronic impairment in multiple organs, and its association with mortality, highlights the need to understand the common mechanisms underlying chronic end-organ damage in SCD, and the urgent need to develop interventions to prevent irreversible end-organ complications in SCD.

Elevated tricuspid regurgitant jet velocity, reduced forced expiratory volume in 1 second, and mortality in adults with sickle cell disease.

Cardiopulmonary disease is the leading cause of mortality in adults with sickle cell disease (SCD). Elevated tricuspid regurgitant jet velocity (TRJV) and reduced forced expiratory volume in 1 second (FEV1 ) %predicted are associated with early mortality in SCD; however their relationship and combined effect on survival is unknown. We investigated the relationship between TRJV and FEV1 %predicted, and their combined effect on mortality, in a retrospective cohort of 189 adults with SCD who underwent both pulmonary function testing and echocardiography. Nineteen (9.9%) of 189 patients died over a median follow-up of 1.4 years; cardiopulmonary disease was the major cause of death in 52.6%. FEV1 %predicted was negatively associated with TRJV (Spearman rho, -0.34, P < 0.001). Individuals with FEV1 %predicted ≤70% were more likely to have an elevated TRJV ≥2.5 m/second, compared to those with FEV1 %predicted >70% [45.8% versus 17.1%; odds ratio (OR) 4.1 (95% Confidence interval ([CI] 2.1-8.0); P = 0.001]. In a multivariable cox regression model, the combination of TRJV ≥2.5 m/second and FEV1 %predicted ≤70% predicted earlier mortality [hazard ratio (HR) 4.97 (95% CI 1.30-18.91; P = 0.019)] after adjusting for age, sex, and nephropathy. Both FEV1 %predicted ≤70% and TRJV ≥2.5 m/second were independently associated with nephropathy [OR 4.48 (95% CI 1.51-13.31); P = 0.004] and [OR 3.27 (95% CI 1.19-9.00); P = 0.017], respectively. In conclusion, pulmonary and cardiac impairment are associated with, and contribute to mortality in SCD. Therapies aimed at improving reduced FEV1 %predicted and elevated TRJV could improve survival in patients with SCD. Am. J. Hematol. 92:125-130, 2017. © 2016 Wiley Periodicals, Inc.

Secondary benefit of maintaining normal transcranial Doppler velocities when using hydroxyurea for prevention of severe sickle cell anemia.

In a retrospective cohort study, we tested the hypothesis that when prescribing hydroxyurea (HU) to children with sickle cell anemia (SCA) to prevent vaso-occlusive events, there will be a secondary benefit of maintaining low transcranial Doppler (TCD) velocity, measured by imaging technique (TCDi). HU was prescribed for 90.9% (110 of 120) of children with SCA ≥5 years of age and followed for a median of 4.4 years, with 70% (n = 77) receiving at least one TCDi evaluation after starting HU. No child prescribed HU had a conditional or abnormal TCDi measurement. HU initiation for disease severity prevention decreases the prevalence of abnormal TCDi velocities.

Rapidly progressive acute chest syndrome in individuals with sickle cell anemia: a distinct acute chest syndrome phenotype.

Current definitions of acute chest syndrome (ACS) in sickle cell anemia (SCA) do not account for rapid progression of respiratory compromise. In this two-center retrospective cohort study, we tested the hypothesis that in children and adults with ACS and respiratory failure (≤24 hours after onset of respiratory symptoms) have a distinct ACS phenotype associated with multiorgan failure when compared to those with ACS that have a more subacute and protracted course. We identified 173 individuals (97 children <20 years and 76 adults ≥20 years) with SCA and at least one episode of ACS. Only one ACS episode was considered per individual. Rapidly progressive ACS occurred in 21% (n = 16) of adults, but only 2.1% (n = 2) of children. Compared to adults without rapidly progressive ACS, adults with rapidly progressive ACS more frequently developed acute kidney injury (68.8% vs. 3.3%, P < 0.001), hepatic dysfunction (75.0% vs. 15.0%, P < 0.001), altered mental status (43.8% vs. 11.7%, P < 0.001), multiorgan failure (93.8% vs. 10%, P < 0.001), and death (6.3% vs. 0%, P = 0.05). Clinical and laboratory covariates that were evaluable on the first day of respiratory symptoms were evaluated to identify predictors of rapidly progressive ACS. On multivariable analysis, decline in platelet count at presentation was the only predictor of rapidly progressive ACS [odds ratio 4.82 (95% CI 1.20-19.39), P = 0.027]. In conclusion, rapidly progressive ACS is a distinct phenotype that occurs more frequently in adults, is preceded by thrombocytopenia, and is associated with multiorgan failure. Am. J. Hematol. 91:1185-1190, 2016. © 2016 Wiley Periodicals, Inc.

Creating an automated contemporaneous cohort in sickle cell anemia to predict survival after disease-modifying therapy.

The Food and Drug Administration requires contemporaneous controls to compare clinical outcomes for participants receiving experimental gene therapy or gene editing clinical trials. However, developing a contemporaneous cohort of rare diseases requires multiple person-hours. In a single referral center for sickle cell disease, we tested the hypothesis that we could create an automated contemporaneous cohort of children and adults with sickle cell anemia (SCA) to predict mortality. Data were obtained between 1 January 2004 and 30 April 2021. We identified 419 individuals with SCA with consistent medical care defined as followed continuously for >0.5 years with no visit gaps >3.0 years. The median age was 10.2 years (IQR, 1-24 years), with a median follow-up of 7.4 years (IQR, 3.6-13.5 years) and 47 deaths. A total of 98% (274 of 277) of the children remained alive at 18 years of age, and 34.3% (94 of 274) of those children were followed into adulthood. For adults, the median age of survival was 49.3 years. Treatment groups were mutually exclusive and in a hierarchical order: hematopoietic stem cell transplant (n = 22)>regular blood transfusion for at least 2 years (n = 56)>hydroxyurea for at least 1 year (n = 243)>no disease-modifying therapy (n = 98). Compared to those receiving no disease-modifying treatment, those treated with hydroxyurea therapy had a significantly lower hazard of mortality (hazard ratio = 0.38; P = 0.016), but no statistical difference for those receiving regular blood transfusions compared to no disease-modifying therapy (hazard ratio = 0.71; P = 0.440). An automated contemporaneous SCA cohort can be generated to estimate mortality in children and adults with SCA.

Hydroxyurea for primary stroke prevention in children with sickle cell anaemia in Nigeria (SPRING): a double-blind, multicentre, randomised, phase 3 trial.

BACKGROUND: In high-income countries, standard care for primary stroke prevention in children with sickle cell anaemia and abnormal transcranial Doppler velocities results in a 92% relative risk reduction of strokes but mandates initial monthly blood transfusion. In Africa, where regular blood transfusion is not feasible for most children, we tested the hypothesis that initial moderate-dose compared with low-dose hydroxyurea decreases the incidence of strokes for children with abnormal transcranial Doppler velocities. METHODS: SPRING is a double-blind, parallel-group, randomised, controlled, phase 3 trial of children aged 5-12 years with sickle cell anaemia with abnormal transcranial Doppler velocities conducted at three teaching hospitals in Nigeria. For randomisation, we used a permuted block allocation scheme with block sizes of four, stratified by sex and site. Allocation was concealed from all but the pharmacists and statisticians. Participants were assigned in a 1:1 ratio to low-dose (10 mg/kg per day) or moderate-dose (20 mg/kg per day) oral hydroxyurea taken once daily with monthly clinical evaluation and laboratory monitoring. The primary outcome was initial stroke or transient ischaemic attack, centrally adjudicated. The secondary outcome was all-cause hospitalisation. We used the intention-to-treat population for data analysis. The trial was stopped early for futility after a planned minimum follow-up of 3·0 years to follow-up for participants. This trial was registered with ClinicalTrials.gov, number NCT02560935. FINDINGS: Between Aug 2, 2016, and June 14, 2018, 220 participants (median age 7·2 years [IQR 5·5-8·9]; 114 [52%] female) were randomly allocated and followed for a median of 2·4 years (IQR 2·0-2·8). All participants were Nigerian and were from the following ethnic groups: 179 (82%) people were Hausa, 25 (11%) were Fulani, and 16 (7%) identified as another ethnicity. In the low-dose hydroxyurea group, three (3%) of 109 participants had strokes, with an incidence rate of 1·19 per 100 person-years and in the moderate-dose hydroxyurea group five (5%) of 111 had strokes with an incidence rate of 1·92 per 100 person-years (incidence rate ratio 0·62 [95% CI 0·10-3·20], p=0·77). The incidence rate ratio of hospitalisation for any reason was 1·71 (95% CI 1·15-2·57, p=0·0071), with higher incidence rates per 100 person-years in the low-dose group versus the moderate-dose group (27·43 vs 16·08). No participant had hydroxyurea treatment stopped for myelosuppression. INTERPRETATION: Compared with low-dose hydroxyurea therapy, participants treated with moderate-dose hydroxyurea had no difference in the stroke incidence rate. However, secondary analyses suggest that the moderate-dose group could lower incidence rates for all-cause hospitalisations. These findings provide an evidence-based guideline for the use of low-dose hydroxyurea therapy for children with sickle cell anaemia at risk of stroke. FUNDING: National Institute of Neurological Disorders and Stroke.

Capacity Building for Primary Stroke Prevention Teams in Children Living With Sickle Cell Anemia in Africa.

BACKGROUND: Nigeria has the highest proportion of children with sickle cell anemia (SCA) globally; an estimated 150,000 infants with SCA are born annually. Primary stroke prevention in children with SCA must include Nigeria. We describe capacity-building strategies in conjunction with two National Institutes of Health-funded primary stroke prevention trials (a feasibility trial and phase III randomized controlled trial) with initial hydroxyurea treatment for children with SCA and abnormal transcranial Doppler (TCD) velocities in Nigeria. We anticipated challenges to conducting clinical trials in a low-resource setting with a local team that had not previously been involved in clinical research and sought a sustainable strategy for primary stroke prevention. METHODS: This is a descriptive, prospective study of challenges, solutions, and research teams in two trials that enrolled a total of 679 children with SCA. RESULTS: As part of the capacity-building component of the trials, over eight years, 23 research personnel (physicians, nurses, research coordinators, a statistician, and a pharmacist) completed a one-month research governance and ethics training program at Vanderbilt University Medical Center, USA. A lead research coordinator for each site completed the Society of Clinical Research Professionals certification. TCD machines were donated; radiologists and nonradiologists were trained and certified to perform TCD. A scalable E-prescription was implemented to track hydroxyurea treatment. We worked with regional government officials to support ongoing TCD-based screening and funding for hydroxyurea for children with SCA at a high risk of stroke. CONCLUSIONS: Our trials and capacity building demonstrate a sustainable strategy to initiate and maintain pediatric SCA primary stroke prevention programs in Africa.

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.

Acute Vaso-Occlusive Pain is Temporally Associated with the Onset of Menstruation in Women with Sickle Cell Disease.

BACKGROUND: Acute vaso-occlusive pain episodes in sickle cell disease (SCD) are associated with increased rates of hospitalization and early mortality. Despite the observation that women have higher rates of acute vaso-occlusive pain episodes than men, sex-specific risk factors for acute vaso-occlusive pain have not been identified. We tested the hypothesis that acute vaso-occlusive pain is temporally associated with the onset of menstruation in women with SCD. METHODS: Initially, using a cross-sectional study design, we administered questionnaires, including validated measures of SCD pain frequency and severity within the last 30 days, as well as menstrual symptoms in a discovery group (n = 103). We then confirmed our findings by administering the same questionnaires online in a replication group (n = 118). A validated questionnaire was used to define dysmenorrhea. RESULTS: In the initial discovery group, 28% (29 of 103) reported acute vaso-occlusive pain episodes temporally associated with menstruation, and 72% (74 of 103) did not. Of the 29 reporting acute vaso-occlusive pain associated with menstruation, 90% (26) and 10% (3) did and did not meet criteria for dysmenorrhea, respectively. In the replication group, 36% (43 of 118) reported acute vaso-occlusive pain temporally associated with menstruation. Of the 43 reporting acute vaso-occlusive pain associated with menstruation, 60% (26) and 40% (17) did and did not meet criteria for dysmenorrhea, respectively. CONCLUSIONS: In both the discovery and replication groups, we demonstrate that acute vaso-occlusive pain is temporally associated with the onset of menstruation that women with SCD can distinguish from dysmenorrhea.

Fertility challenges for women with sickle cell disease.

INTRODUCTION: Sickle cell disease (SCD) represents one of the most common monogenic blood disorders worldwide, with an incidence of over 300,000 newborns affected per year. Reproductive challenges for men and women with SCD have been previously reviewed; however, evidence-based strategies to prevent and manage infertility and increase fecundity are lacking in women with SCD, which is one of the most important factors for quality of life. Areas covered: This review article summarizes the known risk factors for infertility, low fecundity, and premature menopause related to SCD. Expert commentary: Women with SCD have unique risk factors that may impact their ability to conceive, including chronic inflammation, oxidative stress, transfusion-related hemochromatosis, and ovarian sickling, causing ischemia and reperfusion injury to the ovary. Contraception is strongly recommended while on hydroxyurea therapy during reproductive years and discontinuing hydroxyurea for family planning and during pregnancy based on teratogenicity in animal studies. Hematopoietic stem cell transplantation (HSCT), the only curative therapy, sometimes involves conditioning regimens containing alkylating agents and total body irradiation that contribute to infertility and premature ovarian failure. Prior to HSCT or gene therapy, we strongly recommend referral to a reproductive endocrinologist to discuss fertility preservation and surrogacy options for all women with SCD.