Sickle cell disease and social determinants of health: A scoping review.

Social determinants of health (SDoH) may impact outcomes in sickle cell disease (SCD). We conducted a comprehensive literature review of five electronic databases to elucidate the relationship between SDoH and SCD, and identify gaps in the literature. Our search yielded 59 articles, which we organized into five SDoH areas: Neighborhood and Built Environment, Health and Healthcare, Social and Community Context, Education, and Economic Stability. We found that social determinants, such as access to healthcare, were inconsistently evaluated. Improved recognition and understanding of SDoH should enhance the development of programs that directly address its detrimental effects on patients with SCD.

Reading intervention targeting phonemic awareness and symbol imagery in children with sickle cell disease.

Children with sickle cell disease (SCD) frequently have diminished academic attainment and are particularly vulnerable to reading dysfunction. We explored the effectiveness of a multisensory reading intervention offered during the summer to children with SCD at our institution. Subjects with reading deficits were identified through parent report, clinical findings, or school meetings. Summer reading programs utilizing Phonemic Awareness and Symbol Imagery were provided. The Lindamood-Bell Auditory Conceptualization/Phonemic Awareness Test, Third Edition (LAC-3), and the Symbol Imagery Test were used as pre- and postintervention examinations to measure progress. Fifteen students (median age 9.4 years, range 6-14 years, eight females, all African American) received the Phonemic Awareness intervention, two times a week for 6 weeks. The subjects showed statistically significant gains in standard scores derived from the LAC-3 (mean change 7.9 points, p < .001), with associated improvements in age equivalency (AE) and grade equivalency (GE). Twenty-nine students (median age 9 years, range 6-17 years, 13 females, all African American) participated in the Symbol Imagery reading program, also two times a week for 6 weeks. These students showed significant gains in overall standard scores (mean change 9.8 points, p < .001). Although results should be interpreted with caution due to small sample sizes, we found that summer reading clinics for children with SCD improved phonological processing and symbol imagery skills, potentially leading to substantial gains in reading capability.

Enuresis and Hyperfiltration in Children With Sickle Cell Disease.

Nocturnal enuresis is a common symptom in children with sickle cell disease (SCD). Risk factors for development of enuresis are currently unknown. An early manifestation of SCD-associated kidney damage is glomerular hyperfiltration. We test the hypothesis that in a pediatric SCD cohort, individuals with hyperfiltration are more likely to have nocturnal enuresis when compared to children without hyperfiltration. To assess the relationship between nocturnal enuresis and hyperfiltration, we retrospectively evaluated children with SCD enrolled in the Evaluation of Nocturnal Enuresis and Barriers to Treatment among Pediatric Patients with SCD study and prospectively identified children who reported nocturnal enuresis and were enrolled in the longitudinal cohort study Sickle Cell Clinical Research and Intervention Program. Nocturnal enuresis occurred in 46.5% of Pediatric Patients with Sickle Cell Disease participants and was more frequent in participants with HbSS/HbSß 0 thalassemia and in male participants. We did not identify an association between hyperfiltration from 3 to 5 years of age with the later development of enuresis. Severe SCD genotypes and male sex were associated with nocturnal enuresis after age 5 years. We could not identify additional renal or hematologic predictors associated with the diagnosis of nocturnal enuresis. Future studies should incorporate nonrenal risk factors into studies that predict development of enuresis.

Nocturnal Enuresis in Sickle Cell: Sociodemographic, Medical, and Quality of Life Factors.

OBJECTIVE: Nocturnal enuresis is more prevalent in youth with sickle cell disease (SCD) compared to the general population. The purpose of this study is to estimate prevalence of nocturnal enuresis using diagnostic criteria and identify associated sociodemographic, medical, and health-related quality of life (HRQOL) factors. METHODS: Youth with SCD (N = 248; ages 6.00-17.99 years) and their caregivers completed semi-structured interviews and questionnaires. HRQOL was measured using the Pediatric Quality of Life (PedsQL) Inventory. Medical information was abstracted from medical record. We generated multivariable logistic regression models to examine associations between factors and current nocturnal enuresis and nocturnal enuresis occurring any time in the past (lifetime). RESULTS: Among participants (mean age, 11.3 ± 3.6 years; 50.8% male), 21.4% reported current nocturnal enuresis and 46% reported lifetime nocturnal enuresis. Male sex [odds ratio (OR), 2.57; p = .001], difficulty arousing from sleep (OR, 3.57; p < .001), higher school functioning HRQOL (OR, 1.02; p = .014), and higher fetal hemoglobin levels (OR, 1.03; p = .048) were associated with lifetime nocturnal enuresis. Younger age (OR, 1.16; p = .005), higher youth-reported fatigue (OR, 1.01; p = .045), difficulty arousing from sleep (OR, 4.92; p < .001), and higher lactate dehydrogenase levels (OR, 1.00; p = .042) were associated with current nocturnal enuresis. CONCLUSIONS: Nocturnal enuresis is prevalent in youth with SCD and is associated with HRQOL, diminished sleep, greater fatigue, and disease severity markers. Routine assessment of sleep behaviors and fatigue are necessary when treating patients with SCD to understand the impact of nocturnal enuresis on HRQOL.

What drives transcranial Doppler velocity improvement in paediatric sickle cell anaemia: analysis from the Sickle Cell Clinical Research and Intervention Program (SCCRIP) longitudinal cohort study.

Children with sickle cell anaemia (SCA) and conditional transcranial Doppler (TCD) flow velocities (conditional: 170-199 cm/s; normal: <170 cm/s) have an increased risk of stroke. The Sickle Cell Clinical Research and Intervention Program (SCCRIP), a lifetime observational study, assessed the influence of haematological markers on TCD velocities. In children (≤16 years) with SCA (HbSS/HbSß0 -thalassaemia) and conditional TCD velocities (n = 32), increases in haemoglobin and in fetal haemoglobin after hydroxyurea initiation were significantly associated with decreases in TCD velocities. The benefit of pharmacological intervention to increase haemoglobin and fetal haemoglobin and normalise TCD velocities was demonstrated in this real-world dataset.

Hydroxyurea treatment and neurocognitive functioning in sickle cell disease from school age to young adulthood.

Neurocognitive impairment is common in sickle cell disease (SCD) and is associated with significant functional limitations. In a cross-sectional analysis, we examined the association between hydroxyurea (HU) treatment and neurocognitive functioning from school-age to young adulthood in individuals with SCD. A total of 215 patients with HbSS/HbSß0 -thalassaemia (71% HU treated) and 149 patients with HbSC/HbSß+ -thalassaemia (20% HU treated) completed neurocognitive measures at one of four developmental stages: school-age (age 8-9 years), early adolescence (age 12-13 years), late adolescence (age 16-17 years) and young adulthood (ages 19-24 years). For participants with multiple assessments, only the most recent evaluation was included. In multivariable analysis adjusted for social vulnerability, HU treatment and sex, older age was associated with a reduction in overall intelligence quotient (IQ) of 0·55 points per year of life [standard error (SE) = 0·18, false discovery rate adjusted P value (PFDR) = 0.01] for patients with HbSS/HbSß0 -thalassaemia. Earlier initiation of HU (n = 152) in HbSS/HbSß0 -thalassaemia was associated with higher scores on neurocognitive measures across most domains, including IQ [estimate (SE) 0·77 (0·25)/year, PFDR = 0·01], after adjusting for social vulnerability, sex and treatment duration. These results support the early use of HU to limit the detrimental neurocognitive effects of SCD, while highlighting the need for additional measures to further mitigate neurocognitive deterioration.

Cognitive performance as a predictor of healthcare transition in sickle cell disease.

Neurocognitive deficits in sickle cell disease (SCD) may impair adult care engagement. We investigated the relationship between neurocognitive functioning and socio-environmental factors with healthcare transition outcomes. Adolescents aged 15-18 years who had neurocognitive testing and completed a visit with an adult provider were included. Transition outcomes included transfer interval from paediatric to adult care and retention in adult care at 12 and 24 months. Eighty adolescents (59% male, 64% HbSS/HbSß0 -thalassaemia) were included. Mean age at adult care transfer was 18·0 (±0·3) years and transfer interval was 2·0 (±2·3) months. Higher IQ (P = 0·02; PFDR  = 0·05) and higher verbal comprehension (P = 0·008; PFDR  = 0·024) were associated with <2 and <6 month transfer intervals respectively. Better performance on measures of attention was associated with higher adult care retention at 12 and 24 months (P = 0·009; PFDR  = 0·05 and P = 0·04; PFDR  = 0·12 respectively). Transfer intervals <6 months were associated with smaller households (P = 0·02; PFDR  = 0·06) and households with fewer children (P = 0·02; PFDR  = 0·06). Having a working parent was associated with less retention in adult care at 12 and 24 months (P = 0·01; P = 0·02 respectively). Lower IQ, verbal comprehension, attention difficulties and environmental factors may negatively impact transition outcomes. Neurocognitive function should be considered in transition planning for youth with SCD.

Effects of hydroxyurea on brain function in children with sickle cell anemia.

INTRODUCTION: Sickle cell anemia (SCA) results in numerous adverse effects on the brain, including neurocognitive dysfunction. Hydroxyurea has been utilized extensively for management of SCA, but its effects on brain function have not been established. METHODS: We examined prospectively the effects of 1 year of treatment with hydroxyurea on brain function in children with SCA (HbSS/HbSß0 -thalassemia) by baseline and exit evaluations, including comprehensive neurocognitive testing, transcranial Doppler ultrasound (TCD), and brain MRI (silent cerebral infarcts [SCI], gray matter cerebral blood flow [GM-CBF], and blood oxygen level-dependent [BOLD] signal from visual stimulation). RESULTS: Nineteen patients with SCA, mean age 12.4 years (range 7.2-17.8), were evaluated. At baseline, subjects had these mean values: full-scale IQ (FSIQ) 82.8, TCD velocity 133 cm/s, GM-CBF 64.4 ml/100 g/min, BOLD signal 2.34% increase, and frequency of SCI 47%. After 1 year of hydroxyurea, there were increases in FSIQ (+2, p = .059) and reading passage comprehension (+4, p = .033), a significant decrease in TCD velocity (-11 cm/s, p = .007), and no significant changes in GM-CBF, BOLD, or SCI frequency. Hemoglobin F (HbF) was associated with passage comprehension, hemoglobin with lower TCD velocity, and lower GM-CBF with greater working memory. Higher BOLD signal was associated with higher processing speed and lower TCD velocity with higher math fluency. DISCUSSION: Improvements in neurocognition and decreased TCD velocity following 1 year of treatment support hydroxyurea use for improving neurocognitive outcomes in SCA. Understanding the mechanisms of benefit, as indicated by relationships of neurocognitive function with HbF, hemoglobin, and CBF, requires further evaluation.

Use of Wise Device Technology to Measure Adherence to Hydroxyurea Therapy in Youth With Sickle Cell Disease.

Despite broad support for hydroxyurea (HU) therapy, suboptimal adherence is reported for youth with sickle cell disease. Valid adherence measurement is crucial to understanding the relationship between medication behavior, disease response, and patient-centered health outcomes. The current pilot study examined the feasibility of the Wise electronic device for longitudinal HU adherence measurement in a sample of 36 youths prescribed HU. The study also explored the association between HU adherence, as measured by the Wise device, with other adherence measures (ie, family report, lab values, pill count, and medication possession ratio). A measure of family-reported acceptability was also completed. Overall, results supported the feasibility of the Wise device (rate of consent=82%, device use=75%, device failure=3%) for HU adherence measurement and most families rated their experience using their device positively (favorable responses ranged from 67% to 100%). Associations between HU adherence, as measured by the Wise device, and other adherence measures were not significant. Overall, the feasibility was supported. The Wise device allows longitudinal measurement of adherence with HU from initiation as a young child (ie, with liquid formulations) through adolescence and provides a novel means of adherence measurement for both clinical and research use.

Association between hydroxycarbamide exposure and neurocognitive function in adolescents with sickle cell disease.

Patients with sickle cell disease (SCD) are at increased risk for neurocognitive impairments. While disease-modifying treatment, such as hydroxycarbamide (hydroxyurea), may decrease this risk, it has not been systematically investigated in children with SCD. We screened neurocognitive functioning in 103 adolescents with SCD (16-17 years, 50% female) and compared outcomes between patients with a history of exposure to hydroxycarbamide (n = 12 HbSC/HbSß+ thalassaemia; n = 52 HbSS/HbSß0 thalassaemia) and those never treated with hydroxycarbamide (n = 31 HbSC/HbSß+ thalassaemia; n = 8 HbSS/HbSß0 thalassaemia). Demographic distributions were similar between the groups. After adjusting for socioeconomic status, the hydroxycarbamide group had significantly higher scores on nonverbal IQ (HbSC/HbSß thalassaemia: P = 0·036, effect size [d] = 0·65), reaction speed (HbSS/HbSß0 thalassaemia: P = 0·002, d = 1·70), sustained attention (HbSS/HbSß0 thalassaemia: P = 0·014, d = 1·30), working memory (HbSC/HbSß+ thalassaemia: P = 0·034, d = 0·71) and verbal memory (HbSC/HbSß+ thalassaemia: P = 0·038, d = 0·84) when compared to those who did not receive hydroxycarbamide. In patients with HbSS/HbSß0 thalassaemia, longer treatment duration with hydroxycarbamide was associated with better verbal memory (P = 0·009) and reading (P = 0·002). Markers of hydroxycarbamide effect, including higher fetal haemoglobin (HbF), higher mean corpuscular volume (MCV) and lower white blood cell count (WBC), were associated with better verbal fluency (HbF: P = 0·014, MCV: P = 0·006, WBC: P = 0·047) and reading (MCV: P = 0·021, WBC: P = 0·037). Cognitive impairment may be mitigated by exposure to hydroxycarbamide in adolescents with SCD.

Clinical spectrum of pyruvate kinase deficiency: data from the Pyruvate Kinase Deficiency Natural History Study.

An international, multicenter registry was established to collect retrospective and prospective clinical data on patients with pyruvate kinase (PK) deficiency, the most common glycolytic defect causing congenital nonspherocytic hemolytic anemia. Medical history and laboratory and radiologic data were retrospectively collected at enrollment for 254 patients with molecularly confirmed PK deficiency. Perinatal complications were common, including anemia that required transfusions, hyperbilirubinemia, hydrops, and prematurity. Nearly all newborns were treated with phototherapy (93%), and many were treated with exchange transfusions (46%). Children age 5 years and younger were often transfused until splenectomy. Splenectomy (150 [59%] of 254 patients) was associated with a median increase in hemoglobin of 1.6 g/dL and a decreased transfusion burden in 90% of patients. Predictors of a response to splenectomy included higher presplenectomy hemoglobin (P = .007), lower indirect bilirubin (P = .005), and missense PKLR mutations (P = .0017). Postsplenectomy thrombosis was reported in 11% of patients. The most frequent complications included iron overload (48%) and gallstones (45%), but other complications such as aplastic crises, osteopenia/bone fragility, extramedullary hematopoiesis, postsplenectomy sepsis, pulmonary hypertension, and leg ulcers were not uncommon. Overall, 87 (34%) of 254 patients had both a splenectomy and cholecystectomy. In those who had a splenectomy without simultaneous cholecystectomy, 48% later required a cholecystectomy. Although the risk of complications increases with severity of anemia and a genotype-phenotype relationship was observed, complications were common in all patients with PK deficiency. Diagnostic testing for PK deficiency should be considered in patients with apparent congenital hemolytic anemia and close monitoring for iron overload, gallstones, and other complications is needed regardless of baseline hemoglobin. This trial was registered at www.clinicaltrials.gov as #NCT02053480.

Blood transfusion for preventing primary and secondary stroke in people with sickle cell disease.

BACKGROUND: Sickle cell disease is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. Sickle cell disease can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Stroke affects around 10% of children with sickle cell anaemia (HbSS). Chronic blood transfusions may reduce the risk of vaso-occlusion and stroke by diluting the proportion of sickled cells in the circulation. This is an update of a Cochrane Review first published in 2002, and last updated in 2017. OBJECTIVES: To assess risks and benefits of chronic blood transfusion regimens in people with sickle cell disease for primary and secondary stroke prevention (excluding silent cerebral infarcts). SEARCH METHODS: We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 8 October 2019. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register: 19 September 2019. SELECTION CRITERIA: Randomised controlled trials comparing red blood cell transfusions as prophylaxis for stroke in people with sickle cell disease to alternative or standard treatment. There were no restrictions by outcomes examined, language or publication status. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility and the risk of bias and extracted data. MAIN RESULTS: We included five trials (660 participants) published between 1998 and 2016. Four of these trials were terminated early. The vast majority of participants had the haemoglobin (Hb)SS form of sickle cell disease. Three trials compared regular red cell transfusions to standard care in primary prevention of stroke: two in children with no previous long-term transfusions; and one in children and adolescents on long-term transfusion. Two trials compared the drug hydroxyurea (hydroxycarbamide) and phlebotomy to long-term transfusions and iron chelation therapy: one in primary prevention (children); and one in secondary prevention (children and adolescents). The quality of the evidence was very low to moderate across different outcomes according to GRADE methodology. This was due to the trials being at a high risk of bias due to lack of blinding, indirectness and imprecise outcome estimates. Red cell transfusions versus standard care Children with no previous long-term transfusions Long-term transfusions probably reduce the incidence of clinical stroke in children with a higher risk of stroke (abnormal transcranial doppler velocities or previous history of silent cerebral infarct), risk ratio 0.12 (95% confidence interval 0.03 to 0.49) (two trials, 326 participants), moderate quality evidence. Long-term transfusions may: reduce the incidence of other sickle cell disease-related complications (acute chest syndrome, risk ratio 0.24 (95% confidence interval 0.12 to 0.48)) (two trials, 326 participants); increase quality of life (difference estimate -0.54, 95% confidence interval -0.92 to -0.17) (one trial, 166 participants); but make little or no difference to IQ scores (least square mean: 1.7, standard error 95% confidence interval -1.1 to 4.4) (one trial, 166 participants), low quality evidence. We are very uncertain whether long-term transfusions: reduce the risk of transient ischaemic attacks, Peto odds ratio 0.13 (95% confidence interval 0.01 to 2.11) (two trials, 323 participants); have any effect on all-cause mortality, no deaths reported (two trials, 326 participants); or increase the risk of alloimmunisation, risk ratio 3.16 (95% confidence interval 0.18 to 57.17) (one trial, 121 participants), very low quality evidence. Children and adolescents with previous long-term transfusions (one trial, 79 participants) We are very uncertain whether continuing long-term transfusions reduces the incidence of: stroke, risk ratio 0.22 (95% confidence interval 0.01 to 4.35); or all-cause mortality, Peto odds ratio 8.00 (95% confidence interval 0.16 to 404.12), very low quality evidence. Several review outcomes were only reported in one trial arm (sickle cell disease-related complications, alloimmunisation, transient ischaemic attacks). The trial did not report neurological impairment, or quality of life. Hydroxyurea and phlebotomy versus red cell transfusions and chelation Neither trial reported on neurological impairment, alloimmunisation, or quality of life. Primary prevention, children (one trial, 121 participants) Switching to hydroxyurea and phlebotomy may have little or no effect on liver iron concentrations, mean difference -1.80 mg Fe/g dry-weight liver (95% confidence interval -5.16 to 1.56), low quality evidence. We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: risk of stroke (no strokes); all-cause mortality (no deaths); transient ischaemic attacks, risk ratio 1.02 (95% confidence interval 0.21 to 4.84); or other sickle cell disease-related complications (acute chest syndrome, risk ratio 2.03 (95% confidence interval 0.39 to 10.69)), very low quality evidence. Secondary prevention, children and adolescents (one trial, 133 participants) Switching to hydroxyurea and phlebotomy may: increase the risk of sickle cell disease-related serious adverse events, risk ratio 3.10 (95% confidence interval 1.42 to 6.75); but have little or no effect on median liver iron concentrations (hydroxyurea, 17.3 mg Fe/g dry-weight liver (interquartile range 10.0 to 30.6)); transfusion 17.3 mg Fe/g dry-weight liver (interquartile range 8.8 to 30.7), low quality evidence. We are very uncertain whether switching to hydroxyurea and phlebotomy: increases the risk of stroke, risk ratio 14.78 (95% confidence interval 0.86 to 253.66); or has any effect on all-cause mortality, Peto odds ratio 0.98 (95% confidence interval 0.06 to 15.92); or transient ischaemic attacks, risk ratio 0.66 (95% confidence interval 0.25 to 1.74), very low quality evidence. AUTHORS' CONCLUSIONS: There is no evidence for managing adults, or children who do not have HbSS sickle cell disease. In children who are at higher risk of stroke and have not had previous long-term transfusions, there is moderate quality evidence that long-term red cell transfusions reduce the risk of stroke, and low quality evidence they also reduce the risk of other sickle cell disease-related complications. In primary and secondary prevention of stroke there is low quality evidence that switching to hydroxyurea with phlebotomy has little or no effect on the liver iron concentration. In secondary prevention of stroke there is low-quality evidence that switching to hydroxyurea with phlebotomy increases the risk of sickle cell disease-related events. All other evidence in this review is of very low quality.

Sickle Cell Clinical Research and Intervention Program (SCCRIP): A lifespan cohort study for sickle cell disease progression from the pediatric stage into adulthood.

BACKGROUND: Previous natural history studies have advanced the understanding of sickle cell disease (SCD), but generally have not included sufficient lifespan data or investigation of the role of genetics in clinical outcomes, and have often occurred before the widespread use of disease-modifying therapies, such as hydroxyurea and chronic erythrocyte transfusions. To further advance knowledge of SCD, St. Jude Children's Research Hospital established the Sickle Cell Clinical Research and Intervention Program (SCCRIP), to conduct research in a clinically evaluated cohort of individuals with SCD across their lifetime. PROCEDURES: Initiated in 2014, the SCCRIP study prospectively recruits patients diagnosed with SCD and includes retrospective and longitudinal collection of clinical, neurocognitive, geospatial, psychosocial, and health outcomes data. Biological samples are banked for future genomics and proteomics studies. The organizational structure of SCCRIP is based upon organ/system-specific working groups and is opened to the research community for partnerships. RESULTS: As of August 2017, 1,044 (92.3% of eligible) patients with SCD have enrolled in the study (860 children and 184 adults), with 11,915 person-years of observation. Population demographics included mean age at last visit of 11.3 years (range 0.7-30.1), 49.8% females, 57.7% treated with hydroxyurea, 8.5% treated with monthly transfusions, and 62.9% hemoglobin (Hb) SS or HbSB0 -thalassemia, 25.7% HbSC, 8.4% HbsB+ -Thalassemia, 1.7% HbS/HPFH, and 1.2% other. CONCLUSIONS: The SCCRIP cohort will provide a rich resource for the conduct of high impact multidisciplinary research in SCD.

A clinically meaningful fetal hemoglobin threshold for children with sickle cell anemia during hydroxyurea therapy.

Hydroxyurea has proven clinical benefits and is recommended to be offered to all children with sickle cell anemia (SCA), but the optimal dosing regimen remains controversial. Induction of red blood cell fetal hemoglobin (HbF) by hydroxyurea appears to be dose-dependent. However, it is unknown whether maximizing HbF% improves clinical outcomes. HUSTLE (NCT00305175) is a prospective observational study with a primary goal of describing the long-term clinical effects of hydroxyurea escalated to maximal tolerated dose (MTD) in children with SCA. In 230 children, providing 610 patient-years of follow up, the mean attained HbF% at MTD was >20% for up to 4 years of follow-up. When HbF% values were ≤20%, children had twice the odds of hospitalization for any reason (P < .0001), including vaso-occlusive pain (P < .01) and acute chest syndrome (ACS) (P < .01), and more than four times the odds of admission for fever (P < .001). Thirty day readmission rates were not affected by HbF%. Neutropenia (ANC <1000 × 106 /L) was rare (2.3% of all laboratory monitoring), transient, and benign. Therefore, attaining HbF >20% was associated with fewer hospitalizations without significant toxicity. These data support the use of hydroxyurea in children, and suggest that the preferred dosing strategy is one that targets a HbF endpoint >20%.

Clinic Attendance of Youth With Sickle Cell Disease on Hydroxyurea Treatment.

OBJECTIVE: The objective of this study is to describe rates of clinic attendance of youth with sickle cell disease prescribed hydroxyurea and examine potential demographic and medical factors related to consistent clinic attendance. METHODS: Participants included 148 youth diagnosed with sickle cell disease and prescribed hydroxyurea during a single calendar year. Clinic attendance and potential demographic and medical factors related to attendance were extracted via systematic retrospective medical chart review. RESULTS: Youth attended 90.3% of scheduled appointments and 85.1% of youth attended at least 80% of scheduled clinic appointments during the study window. Adjusting for other factors, multivariate analysis revealed families with fewer children in the household, families with private insurance, youth experiencing fever, and youth not experiencing pain during the calendar year were more likely to consistently attend clinic visits. CONCLUSIONS: Adherence to clinic appointments is critical to optimizing health outcomes for youth with sickle cell disease and integral for adequate monitoring of youth prescribed hydroxyurea, in particular. Findings may aid providers in appropriately identifying possible barriers to clinic attendance to develop attendance promotion interventions.

Blood transfusion for preventing primary and secondary stroke in people with sickle cell disease.

BACKROUND: Sickle cell disease is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. Sickle cell disease can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Stroke affects around 10% of children with sickle cell anaemia (HbSS). Chronic blood transfusions may reduce the risk of vaso-occlusion and stroke by diluting the proportion of sickled cells in the circulation.This is an update of a Cochrane Review first published in 2002, and last updated in 2013. OBJECTIVES: To assess risks and benefits of chronic blood transfusion regimens in people with sickle cell disease for primary and secondary stroke prevention (excluding silent cerebral infarcts). SEARCH METHODS: We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 04 April 2016.We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register: 25 April 2016. SELECTION CRITERIA: Randomised controlled trials comparing red blood cell transfusions as prophylaxis for stroke in people with sickle cell disease to alternative or standard treatment. There were no restrictions by outcomes examined, language or publication status. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility and the risk of bias and extracted data. MAIN RESULTS: We included five trials (660 participants) published between 1998 and 2016. Four of these trials were terminated early. The vast majority of participants had the haemoglobin (Hb)SS form of sickle cell disease.Three trials compared regular red cell transfusions to standard care in primary prevention of stroke: two in children with no previous long-term transfusions; and one in children and adolescents on long-term transfusion.Two trials compared the drug hydroxyurea (hydroxycarbamide) and phlebotomy to long-term transfusions and iron chelation therapy: one in primary prevention (children); and one in secondary prevention (children and adolescents).The quality of the evidence was very low to moderate across different outcomes according to GRADE methodology. This was due to the trials being at a high risk of bias due to lack of blinding, indirectness and imprecise outcome estimates. Red cell transfusions versus standard care Children with no previous long-term transfusionsLong-term transfusions probably reduce the incidence of clinical stroke in children with a higher risk of stroke (abnormal transcranial doppler velocities or previous history of silent cerebral infarct), risk ratio 0.12 (95% confidence interval 0.03 to 0.49) (two trials, 326 participants), moderate quality evidence.Long-term transfusions may: reduce the incidence of other sickle cell disease-related complications (acute chest syndrome, risk ratio 0.24 (95% confidence interval 0.12 to 0.48)) (two trials, 326 participants); increase quality of life (difference estimate -0.54, 95% confidence interval -0.92 to -0.17) (one trial, 166 participants); but make little or no difference to IQ scores (least square mean: 1.7, standard error 95% confidence interval -1.1 to 4.4) (one trial, 166 participants), low quality evidence.We are very uncertain whether long-term transfusions: reduce the risk of transient ischaemic attacks, Peto odds ratio 0.13 (95% confidence interval 0.01 to 2.11) (two trials, 323 participants); have any effect on all-cause mortality, no deaths reported (two trials, 326 participants); or increase the risk of alloimmunisation, risk ratio 3.16 (95% confidence interval 0.18 to 57.17) (one trial, 121 participants), very low quality evidence. Children and adolescents with previous long-term transfusions (one trial, 79 participants)We are very uncertain whether continuing long-term transfusions reduces the incidence of: stroke, risk ratio 0.22 (95% confidence interval 0.01 to 4.35); or all-cause mortality, Peto odds ratio 8.00 (95% confidence interval 0.16 to 404.12), very low quality evidence.Several review outcomes were only reported in one trial arm (sickle cell disease-related complications, alloimmunisation, transient ischaemic attacks).The trial did not report neurological impairment, or quality of life. Hydroxyurea and phlebotomy versus red cell transfusions and chelationNeither trial reported on neurological impairment, alloimmunisation, or quality of life. Primary prevention, children (one trial, 121 participants)Switching to hydroxyurea and phlebotomy may have little or no effect on liver iron concentrations, mean difference -1.80 mg Fe/g dry-weight liver (95% confidence interval -5.16 to 1.56), low quality evidence.We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: risk of stroke (no strokes); all-cause mortality (no deaths); transient ischaemic attacks, risk ratio 1.02 (95% confidence interval 0.21 to 4.84); or other sickle cell disease-related complications (acute chest syndrome, risk ratio 2.03 (95% confidence interval 0.39 to 10.69)), very low quality evidence. Secondary prevention, children and adolescents (one trial, 133 participants)Switching to hydroxyurea and phlebotomy may: increase the risk of sickle cell disease-related serious adverse events, risk ratio 3.10 (95% confidence interval 1.42 to 6.75); but have little or no effect on median liver iron concentrations (hydroxyurea, 17.3 mg Fe/g dry-weight liver (interquartile range 10.0 to 30.6)); transfusion 17.3 mg Fe/g dry-weight liver (interquartile range 8.8 to 30.7), low quality evidence.We are very uncertain whether switching to hydroxyurea and phlebotomy: increases the risk of stroke, risk ratio 14.78 (95% confidence interval 0.86 to 253.66); or has any effect on all-cause mortality, Peto odds ratio 0.98 (95% confidence interval 0.06 to 15.92); or transient ischaemic attacks, risk ratio 0.66 (95% confidence interval 0.25 to 1.74), very low quality evidence. AUTHORS' CONCLUSIONS: There is no evidence for managing adults, or children who do not have HbSS sickle cell disease.In children who are at higher risk of stroke and have not had previous long-term transfusions, there is moderate quality evidence that long-term red cell transfusions reduce the risk of stroke, and low quality evidence they also reduce the risk of other sickle cell disease-related complications.In primary and secondary prevention of stroke there is low quality evidence that switching to hydroxyurea with phlebotomy has little or no effect on the liver iron concentration.In secondary prevention of stroke there is low-quality evidence that switching to hydroxyurea with phlebotomy increases the risk of sickle cell disease-related events.All other evidence in this review is of very low quality.

Hydroxycarbamide treatment and brain MRI/MRA findings in children with sickle cell anaemia.

Silent cerebral infarction (SCI) is the most common neurological abnormality among children with sickle cell anaemia (SCA). The effect of hydroxycarbamide (also termed hydroxyurea) on the development and progression of SCI is unclear. We evaluated brain magnetic resonance imaging/angiography (MRI/MRA) in children with SCA receiving long-term hydroxycarbamide therapy. Fifty participants (median 9·4 years, range 1·1-17·3) enrolled in the Hydroxyurea Study of Long-Term Effects (HUSTLE; NCT00305175) underwent brain MRI/MRA and laboratory evaluations before hydroxycarbamide initiation and after 3 and 6 years of treatment to maximum tolerated dose. SCI and vascular stenosis were evaluated. At baseline, 3 and 6 years, SCI were present in 19/50 (38%), 20/49 (41%), and 7/17 (41%), respectively. At 3 years, one child developed a SCI lesion, and another progressed (single lesion to multiple). Lower haemoglobin (Hb) (80 g/l vs. 86 g/l, P = 0·049), fetal Hb (5·0% vs. 10·4%, P < 0·001) and oxygen saturation (97% vs. 98%, P = 0·027) before hydroxycarbamide initiation were associated with SCI. No patients had vascular stenosis identified on MRA, transient ischaemic attack or stroke. Our data indicate that children receiving hydroxycarbamide over a 3- to 6-year period have a low rate of new or worsening cerebrovascular disease. Further studies are needed to confirm that hydroxycarbamide can prevent the onset and progression of SCI.

Birth Prevalence of Sickle Cell Trait and Sickle Cell Disease in Shelby County, TN.

BACKGROUND: Accurate quantification of the regional burden of sickle cell disease (SCD) is vital to allocating health-related resources. Shelby County, TN, which includes the city of Memphis and the regional pediatric SCD treatment center at St. Jude Children's Research Hospital, is home to a large population of African Americans. PROCEDURE: We postulated that the regional birth prevalence of SCD in Shelby County, TN, would differ from national rates. Using data from 2002 to 2012, we estimated the birth prevalence of SCD and sickle cell trait (SCT) in Shelby County and evaluated the distribution of SCD cases by ZIP code of residence with geographic information systems (GIS). RESULTS: The prevalence of SCD in African Americans was 1/287 (95% confidence interval [CI]: 1/323, 1/256) live births, significantly higher than the nationally reported 1/350 -1/500. The prevalence of SCT in African Americans was 1/14.7 (95% CI: 1/15.0, 1/14.3) live births, significantly lower than the nationally reported 1/12. We found that 48% of the SCD cases resided in only six of the 37 residential ZIP codes, and using GIS mapping there were two clusters composed of two and four adjacent urban ZIP codes. SCT cases were also centered predominantly in the same two clusters, but slightly more dispersed. CONCLUSIONS: Recent Shelby County birth prevalence estimates differ substantially from national estimates with higher SCD and lower SCT than expected. Preliminary evidence suggests substantial clustering in two small geographic urban areas within Shelby County that may provide target areas for educational and outreach services.

Addressing challenges of clinical trials in acute pain: The Pain Management of Vaso-occlusive Crisis in Children and Young Adults with Sickle Cell Disease Study.

BACKGROUND/AIMS: Neuropathic pain is a known component of vaso-occlusive pain in sickle cell disease; however, drugs targeting neuropathic pain have not been studied in this population. Trials of acute pain are complicated by the need to obtain consent, to randomize participants expeditiously while optimally treating pain. We describe the challenges in designing and implementing the Pain Management of Vaso-occlusive Crisis in Children and Young Adults with Sickle Cell Disease Study (NCT01954927), a phase II, randomized, double-blind, placebo-controlled trial to determine the effect of gabapentin for vaso-occlusive crisis. METHODS: In the Pain Management of Vaso-occlusive Crisis in Children and Young Adults with Sickle Cell Disease Study, we aim to assess the analgesic effect of gabapentin during vaso-occlusive crisis. Difficulties we identified included avoiding delay of notification of study staff of potential participants which we resolved by automated notification. Concern for rapid randomization and drug dispensation was addressed through careful planning with an investigational pharmacy and a single liquid formulation. We considered obtaining consent during well-visits to avoid the time constraints with acute presentations, but the large number of patients and limited duration that consent is valid made this impractical. RESULTS: In all, 79% of caregivers/children approached have agreed to participate. The trial is currently active, and enrollment is at 45.8% of that targeted (76 of 166) and expected to continue for two more years. Maintaining staff availability after-hours remains problematic, with 8% of screened patients missed for lack of available staff. LESSONS LEARNED: Lessons learned in designing a trial to expedite procedures in the acute pain setting include (1) building study evaluations upon a standard-of-care backbone; (2) implementing a simple study design to facilitate consent and data capture; (3) assuring ample, well-trained study staff; and (4) utilizing technology to automate procedures whenever possible. CONCLUSION: This study design has circumvented many of the logistical barriers usually associated with acute pain trials and may serve as a prototype for future studies.