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1.  Genome-Wide Meta-Analysis of Systolic Blood Pressure in Children with Sickle Cell Disease 
PLoS ONE  2013;8(9):e74193.
In pediatric sickle cell disease (SCD) patients, it has been reported that higher systolic blood pressure (SBP) is associated with increased risk of a silent cerebral infarction (SCI). SCI is a major cause of neurologic morbidity in children with SCD, and blood pressure is a potential modulator of clinical manifestations of SCD; however, the risk factors underlying these complications are not well characterized. The aim of this study was to identify genetic variants that influence SBP in an African American population in the setting of SCD, and explore the use of SBP as an endo-phenotype for SCI. We conducted a genome-wide meta-analysis for SBP using two SCD cohorts, as well as a candidate screen based on published SBP loci. A total of 1,617 patients were analyzed, and while no SNP reached genome-wide significance (P-value<5.0x10-8), a number of suggestive candidate loci were identified. The most significant SNP, rs7952106 (P-value=8.57x10-7), was in the DRD2 locus on chromosome 11. In a gene-based association analysis, MIR4301 (micro-RNA4301), which resides in an intron of DRD2, was the most significant gene (P-value=5.2x10-5). Examining 27 of the previously reported SBP associated SNPs, 4 SNPs were nominally significant. A genetic risk score was constructed to assess the aggregated genetic effect of the published SBP variants, demonstrating a significant association (P=0.05). In addition, we also assessed whether these variants are associated with SCI, validating the use of SBP as an endo-phenotype for SCI. Three SNPs were nominally associated, and only rs2357790 (5’ CACNB2) was significant for both SBP and SCI. None of these SNPs retained significance after Bonferroni correction. Taken together, our results suggest the importance of DRD2 genetic variation in the modulation of SBP, and extend the aggregated importance of previously reported SNPs in the modulation of SBP in an African American cohort, more specifically in children with SCD.
PMCID: PMC3772989  PMID: 24058526
2.  Parent education and biologic factors influence on cognition in sickle cell anemia 
American journal of hematology  2014;89(2):162-167.
Children with sickle cell anemia have a high prevalence of silent cerebral infarcts (SCIs) that are associated with decreased full-scale intelligence quotient (FSIQ). While the educational attainment of parents is a known strong predictor of the cognitive development of children in general, the role of parental education in sickle cell anemia along with other factors that adversely affect cognitive function (anemia, cerebral infarcts) is not known. We tested the hypothesis that both the presence of SCI and parental education would impact FSIQ in children with sickle cell anemia. A multicenter, cross-sectional study was conducted in 19 US sites of the Silent Infarct Transfusion Trial among children with sickle cell anemia, age 5–15 years. All were screened for SCIs. Participants with and without SCI were administered the Wechsler Abbreviated Scale of Intelligence. A total of 150 participants (107 with and 43 without SCIs) were included in the analysis. In a multivariable linear regression model for FSIQ, the absence of college education for the head of household was associated with a decrease of 6.2 points (P=0.005); presence of SCI with a 5.2 point decrease (P=0.017); each $1000 of family income per capita with a 0.33 point increase (P=0.023); each increase of 1 year in age with a 0.96 point decrease (P=0.023); and each 1% (absolute) decrease in hemoglobin oxygen saturation with 0.75 point decrease (P=0.030). In conclusion, FSIQ in children with sickle cell anemia is best accounted for by a multivariate model that includes both biologic and socioenvironmental factors.
PMCID: PMC4310566  PMID: 24123128
3.  Silent cerebral infarction, income, and grade retention among students with sickle cell anemia 
American journal of hematology  2014;89(10):E188-E192.
Children with sickle cell anemia have a higher-than-expected prevalence of poor educational attainment. We test two key hypotheses about educational attainment among students with sickle cell anemia, as measured by grade retention and use of special education services: (1) lower household per capita income is associated with lower educational attainment; (2) the presence of a silent cerebral infarct is associated with lower educational attainment. We conducted a multicenter, cross-sectional study of cases from 22 U.S. sites included in the Silent Infarct Transfusion Trial. During screening, parents completed a questionnaire that included sociodemographic information and details of their child’s academic status. Of 835 students, 670 were evaluable; 536 had data on all covariates and were used for analysis. The students’ mean age was 9.4 years (range: 5–15) with 52.2% male; 17.5% of students were retained one grade level and 18.3% received special education services. A multiple variable logistic regression model identified that lower household per capita income (odds ratio [OR] of quartile 1 = 6.36, OR of quartile 2 = 4.7, OR of quartile 3 = 3.87; P = 0.001 for linear trend), age (OR = 1.3; P < 0.001), and male gender (OR, 2.2; P = 0.001) were associated with grade retention; silent cerebral infarct (P = 0.31) and painful episodes (P = 0.60) were not. Among students with sickle cell anemia, household per capita income is associated with grade retention, whereas the presence of a silent cerebral infarct is not. Future educational interventions will need to address both the medical and socioeconomic issues that affect students with sickle cell anemia.
PMCID: PMC4261188  PMID: 25042018
4.  Hydroxyurea Is Associated With Lower Costs of Care of Young Children With Sickle Cell Anemia 
Pediatrics  2013;132(4):677-683.
In the BABY HUG trial, young children with sickle cell anemia randomized to receive hydroxyurea had fewer episodes of pain, hospitalization, and transfusions. With anticipated broader use of hydroxyurea in this population, we sought to estimate medical costs of care in treated versus untreated children.
The BABY HUG database was used to compare inpatient events in subjects receiving hydroxyurea with those receiving placebo. Unit costs were estimated from the 2009 MarketScan Multi-state Medicaid Database for children with sickle cell disease, aged 1 to 3 years. Inpatient costs were based on length of hospital stay, modified by the occurrence of acute chest syndrome, splenic sequestration, or transfusion. Outpatient expenses were based on the schedule required for BABY HUG and a “standard” schedule for 1- to 3-year-olds with sickle cell anemia.
There were 232 hospitalizations in the subjects receiving hydroxyurea and 324 in those on placebo; length of hospital stay was similar in the 2 groups. Estimated outpatient expenses were greater in those receiving hydroxyurea, but these were overshadowed by inpatient costs. The total estimated annual cost for those on hydroxyurea ($11 072) was 21% less than the cost of those on placebo ($13 962; P = .038).
Savings on inpatient care resulted in a significantly lower overall estimated medical care cost for young children with sickle cell anemia who were receiving hydroxyurea compared with those receiving placebo. Because cost savings are likely to increase with age, these data provide additional support for broad use of hydroxyurea treatment in this population.
PMCID: PMC4074648  PMID: 23999955
hydroxyurea; medical costs; young children; sickle cell anemia
5.  Acute chest syndrome is associated with single nucleotide polymorphism-defined beta globin cluster haplotype in children with sickle cell anaemia 
British journal of haematology  2013;163(2):268-276.
Genetic diversity at the human β-globin locus has been implicated as a modifier of sickle cell anaemia (SCA) severity. However, haplotypes defined by restriction fragment length polymorphism sites across the β-globin locus have not been consistently associated with clinical phenotypes. To define the genetic structure at the β-globin locus more thoroughly, we performed high-density single nucleotide polymorphism (SNP) mapping in 820 children who were homozygous for the sickle cell mutation (HbSS). Genotyping results revealed very high linkage disequilibrium across a large region spanning the locus control region and the HBB (β-globin gene) cluster. We identified three predominant haplotypes accounting for 96% of the βS-carrying chromosomes in this population that could be distinguished using a minimal set of common SNPs. Consistent with previous studies, fetal haemoglobin level was significantly associated with βS-haplotypes. After controlling for covariates, an association was detected between haplotype and rate of hospitalization for acute chest syndrome (ACS) (incidence rate ratio 0.51, 95% confidence interval 0.29–0.89) but not incidence rate of vaso-occlusive pain or presence of silent cerebral infarct (SCI). Our results suggest that these SNP-defined βS-haplotypes may be associated with ACS, but not pain or SCI in a study population of children with SCA.
PMCID: PMC4026174  PMID: 23952145
Sickle cell anaemia; acute chest syndrome; β-globin; genetic analysis; haplotype
6.  Validation of the Sickle Cell Disease Pain Burden Interview-Youth 
The purpose of this study was to develop and validate a brief, clinically relevant, multidimensional interview to assess pain burden among children and adolescents with sickle cell disease (SCD). The Sickle Cell Disease Pain Burden Interview-Youth (SCPBI-Y) was developed using a panel of experts, patients and caregivers. Validation was undertaken with youth with SCD, ages 7 to 21 years (N=129), recruited from four urban children’s hospitals. Youth were recruited from inpatient (N=62) and outpatient (N=67) settings. The SCPBI-Y demonstrated strong internal consistency reliability, cross-informant concordance (child-caregiver), and test-retest reliability (outpatient setting). Moderate construct validity was found with validated measures of functional ability, pain, and quality of life. The SCPBI-Y demonstrated construct validity using a contrasted group approach between youth in inpatient versus outpatient settings and by severity of SCD symptoms, suggesting that youth in inpatient settings and with higher disease severity exhibited greater pain burden. Discriminant validity was found between SCPBI-Y and mood. Our preliminary findings suggest that the SCPBI-Y is a valid and reliable multidimensional interview that can be utilized in different clinical settings to evaluate pain burden among children and adolescents with SCD.
PMCID: PMC3759569  PMID: 23701707
sickle cell disease; SCD; pain; functional assessment; adolescents
7.  Partial manual exchange reduces iron accumulation during chronic red cell transfusions for sickle cell disease 
Iron overload is an inevitable consequence of chronic red cell transfusions without erythrocytapheresis or chelation therapy. The effectiveness of partial manual exchange, a technique used to slow iron loading, has not been evaluated. We evaluated all children with sickle cell disease (SCD) receiving chronic transfusion to identify chelation naïve subjects who had quantitative liver iron concentration (LIC) studies. Seventeen chelation naïve children with SCD received a median of 29 transfusions prior to first LIC determination. Serum ferritin concentrations were assessed prior to each transfusion. The mean volume of blood phlebotomized prior to each transfusion was 5.1±1.8 cc/kg, which cumulatively resulted in a calculated median 35.0 mg/kg removal of iron. Using linear regression, pretransfusion phlebotomy resulted in a statistically significant reduction in ferritin (-8.8 ng/mL of ferritin for each mg/kg of iron phlebotomized, P = 0.02). A reduction in LIC from pretransfusion phlebotomy could not be established (P =0.4). Partial manual exchanges appear to be an effective strategy for slowing the pace of iron loading in the setting of chronic transfusion for SCD.
PMCID: PMC3753792  PMID: 23887022
Sickle cell; iron loading; transfusion; iron; ferritin
8.  High Rates of Recurrent Biliary Tract Obstruction in Children with Sickle Cell Disease 
Pediatric blood & cancer  2012;60(4):650-652.
Individuals with sickle cell disease (SCD) have an increased risk of cholelithiasis from bilirubin stones. Symptomatic biliary tract disease (BTD) includes acute and chronic cholecystitis, obstruction of the common bile duct (CBD), cholangitis, and gallstone pancreatitis. Cholecystectomy is the main treatment strategy for symptomatic patients; however, the prevalence of recurrent BTD following cholecystectomy has not been systematically evaluated. We conducted a retrospective cohort study to describe the recurrence of BTD after cholecystectomy and characterize risk factors for recurrent disease.
We identified patients <22 years of age who presented to the Johns Hopkins Children Center with symptomatic BTD from July 1993 to June 2008.
We identified 56 patients with a total of 76 episodes of symptomatic BTD (median age at first event 15.9, range 4.6 to 21.5 years). Eleven of the 56 patients (19.6%) had at least one episode of recurrent symptomatic BTD (median follow-up of 5.3 years). Baseline characteristics were similar between the patients with a single episode of BTD and those with recurrent BTD.
These results demonstrate that recurrent BTD is a frequent complication of SCD (20% by age 4 years) and often presents as CBD obstruction by stone, despite cholecystectomy. In our cohort, recurrence was not associated with age at first episode, baseline total bilirubin, gender, or genotype of SCD.
PMCID: PMC3977003  PMID: 23255346
sickle cell disease; cholecystitis; cholangitis
9.  Developmental Function in Toddlers With Sickle Cell Anemia 
Pediatrics  2013;131(2):e406-e414.
Neurocognitive impairment occurs in children and adults with sickle cell anemia, but little is known about neurodevelopment in very young children. We examined the neurodevelopmental status of infants participating in the Pediatric Hydroxyurea Phase III Clinical Trial (Baby Hug) to determine relationships with age, cerebral blood flow velocity, and hemoglobin concentration.
Standardized measures of infant neurodevelopment were administered to 193 infants with hemoglobin SS or hemoglobin S-β0 thalassemia between 7 and 18 months of age at the time of their baseline evaluation. Associations between neurodevelopmental scores and age, family income, parent education, hemoglobin concentration, and transcranial Doppler velocity were examined.
Mean functioning on the baseline neurodevelopment scales was in the average range. There were no mental development scores <70 (impaired); 22 children had scores in the clinically significant range, 11 with impaired psychomotor scores and 11 with problematic behavior rating scores. Significantly poorer performance was observed with older age at baseline. Behavior rating scores were an average of 2.82 percentile points lower per month of age, with similar patterns observed with parent report using adaptive behavior scales. Parent-reported functional abilities and hemoglobin were negatively associated with higher transcranial Doppler velocities.
Whereas overall functioning was in the normal range, behavioral and adaptive function was poorer with older age, even in this very young group of children. Explanatory mechanisms for this association between poorer developmental function and older age need to be identified.
PMCID: PMC3557401  PMID: 23296434
sickle cell disease; cognitive development; transcranial Doppler; Bayley Scales; toddlers
10.  Daily changes in pain, mood and physical function in youth hospitalized for sickle cell disease pain 
Youth with sickle cell disease (SCD) are commonly hospitalized for treatment of painful vaso-occlusive episodes (VOE). However, limited data are available concerning the course of hospitalization for these children and adolescents and, in particular, whether daily changes occur in pain, emotional status and physical function.
To characterize changes in daily pain intensity, physical function and mood over the course of hospitalization, and to determine whether specific clinical characteristics were associated with these changes.
Daily ratings of pain (0 to 10 numerical rating scale) and mood (Positive and Negative Affect Scale for Children) were completed by 25 youth (11 to 20 years of age) with SCD over a total of 152 days (mean [± SD] = 6.7±5.6 days) of hospitalization. Trained raters determined each youth’s daily physical function.
Linear mixed modelling was used to examine changes in pain, mood and physical function during hospital stay. The rate of change over the course of hospitalization was significant for reductions in pain intensity (P<0.001) and improvements in physical (motor) function (P=0.001). Positive affect over time was significantly associated with subjects’ physical function scores (B 0.24 [95% CI 0.12 to 0.35]) but not with their pain scores. In contrast, negative affect was positively associated with pain and inversely associated with physical function scores (B 1.58 [95% CI 0.23 to 2.93]).
The results of the present study demonstrated that children made daily improvements in physical function and pain over hospitalization for VOE. Mood was related to changes in pain and physical recovery. Assessment of physical function and mood during hospitalization may help guide strategies to better understand the pain experience in youth with SCD hospitalized with VOE.
PMCID: PMC3665435  PMID: 23457684
Adolescents; Functional assessment; Pain assessment; Physical functioning; Sickle cell disease; Vaso-occlusive episode
11.  Magnetic resonance angiography-defined intracranial vasculopathy is associated with silent cerebral infarcts and glucose-6-phosphate dehydrogenase mutation in children with sickle cell anaemia 
British journal of haematology  2012;159(3):352-359.
Silent cerebral infarct (SCI) is the most commonly recognized cause of neurological injury in sickle cell anaemia (SCA). We tested the hypothesis that magnetic resonance angiography (MRA)-defined vasculopathy is associated with SCI. Furthermore, we examined genetic variations in glucose-6-phosphate dehydrogenase (G6PD) and HBA (α-globin) genes to determine their association with intracranial vasculopathy in children with SCA. Magnetic resonance imaging (MRI) of the brain and MRA of the cerebral vasculature were available in 516 paediatric patients with SCA, enrolled in the Silent Infarct Transfusion (SIT) Trial. All patients were screened for G6PD mutations and HBA deletions. SCI were present in 41.5%(214 of 516) of SIT Trial children. The frequency of intracranial vasculopathy with and without SCI was 15.9% and 6.3%, respectively (p<0.001). Using a multivariate logistic regression model, only the presence of a SCI was associated with increased odds of vasculopathy (p=0.0007, odds ratio (OR) 2.84; 95% Confidence Interval (CI)=1.55-5.21). Among male patients with SCA, G6PD status was associated with vasculopathy (p=0.04, OR 2.78; 95% CI=1.04-7.42), while no significant association was noted for HBA deletions. Intracranial vasculopathy was observed in a minority of children with SCA, and when present, was associated with G6PD status in males and SCI.
PMCID: PMC3775590  PMID: 22958163
sickle cell anaemia; α-thalassaemia; glucose-6-phosphate dehydrogenase (G6PD); vasculopathy; silent cerebral infarcts
12.  Influence of Severity of Anemia on Clinical Findings in Infants with Sickle Cell Anemia: Analyses from the BABY HUG Study 
Pediatric blood & cancer  2011;59(4):675-678.
Clinical complications of sickle cell anemia begin in infancy. BABY HUG (, NCT00006400) was a NHLBI-NICHD supported randomized phase III placebo-controlled trial of hydroxyurea (HU) in infants (recruited at 9–18 months) unselected for clinical severity with sickle cell anemia. This secondary analysis of data from BABY HUG examines the influence of anemia on the incidence of sickle cell related complications, and the impact of hydroxyurea therapy in altering these events by comparing children with lower (<25th percentile) and higher (>75th percentile) hemoglobin concentrations at study entry.
Infants were categorized by: 1) age-adjusted hemoglobin quartiles as determined by higher (Hi) and lower (Lo) hemoglobin concentrations at study entry (9 to12 months old: <8.0 gm/dL and >10.0gm/dL; 12 to 18 months old: <8.1 gm/dL and >9.9gm/dL) and 2) treatment arm (hydroxyurea or placebo). Four subgroups were created: placebo (PL) LoHb (n=25), PL HiHb (n=27), hydroxyurea (HU) LoHb (n=21), and HU HiHb (n=18). The primary and secondary endpoints of BABY HUG were analyzed by subgroup.
Infants with lower hemoglobin at baseline were more likely to have a higher incidence of clinical events (acute chest syndrome, pain crisis, fever) as well as higher TCD velocities and lower neuropsychological scores at study exit. Hydroxyurea reduced the incidence of these findings.
Infants with more severe anemia are at risk for increased clinical events that may be prevented by early initiation of hydroxyurea.
PMCID: PMC3337342  PMID: 22190441
Sickle Cell Anemia; Hydroxyurea; Acute Chest Syndrome; Pain; Transcranial Doppler; Renal; Spleen
13.  Acute Silent Cerebral Ischemic Events in Children with Sickle Cell Anemia 
JAMA neurology  2013;70(1):58-65.
Irregular, sporadic episodes of ischemic brain injury are known to occur in sickle cell anemia (SCA), resulting in overt stroke and silent cerebral infarction. Ongoing ischemia in other organs is common in SCA but has never been documented in the brain.
To test the hypothesis that acute silent cerebral ischemic events (ASCIEs) are frequent and potentially transient.
Cross-sectional and cohort study of children with SCA screened by magnetic resonance imaging (MRI) of the brain for a randomized clinical trial.
Clinical trial setting in tertiary care centers.
Asymptomatic children with SCA without known stroke, neurologic injury, or epilepsy not receiving treatment with transfusions or hydroxyurea.
Main Outcome Measure
Incidence of ASCIEs calculated using single diffusion-weighted MRI scans (acute ischemic events that occurred within 10 days of the MRI).
Acute silent cerebral ischemic events were detected on 1.3% of MRIs (10 of 771) in 652 children (mean age, 10.0 years), with an incidence of 47.3 events per 100 patient-years (95% CI, 22.7–87.2). Two of 10 children with ASCIEs had follow-up MRIs of the brain; only 1 had silent cerebral infarction in the same location as the previously detected ASCIE.
Children with SCA experience ongoing (chronic, intermittent) cerebral ischemia, sometimes reversible, far more frequently than previously recognized. The brain in SCA is at constant threat of ischemia.
PMCID: PMC3677221  PMID: 23108767
14.  Prospects for Primary Stroke Prevention in Children with Sickle Cell Anaemia 
British journal of haematology  2012;157(1):14-25.
This review will focus on the strengths and limitations associated with the current standard of care for primary prevention of ischaemic strokes in children with sickle cell anaemia (SCA) - transcranial Doppler ultrasound (TCD) screening followed by regular blood transfusion therapy when TCD measurement is above a threshold defined by a randomized clinical trial (RCT). The theoretical basis for potential alternative strategies for primary prevention of neurological injury in SCA is also discussed. These strategies will include, but will not be limited to: immunizations to prevent bacterial infections, particularly in low income countries; management of elevated blood pressure; and targeted strategies to increase baseline haemoglobin levels with therapies such as hyroxycarbamide or potentially definitive haematopoietic stem cell transplant.
PMCID: PMC3400704  PMID: 22224940
Sickle cell anaemia; stroke; primary prevention; treatment; child
15.  Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: A randomized clinical trial 
Jama  2011;305(9):893-902.
Inhaled nitric oxide (NO) has shown evidence of efficacy in mouse models of sickle cell disease (SCD), case series of patients with acute chest syndrome, and 2 small placebo-controlled trials for treatment of vaso-occlusive pain crisis (VOC).
To determine whether inhaled NO gas reduces the duration of painful crisis in patients with SCD who present to the emergency room or hospital for care.
Design, Setting and Participants
Prospective, multicenter, double-blind, randomized, placebo-controlled clinical trial for up to 72 hours of inhaled NO gas versus inhaled nitrogen placebo in 150 participants presenting with VOC of SCD at 11 centers between October 5, 2004 and December 22, 2008. The primary endpoint was the time to resolution of painful crisis, defined by: 1) freedom from parenteral opioid use for 5 hours; 2) pain relief as assessed by visual analog pain scale scores ≤ 6 cm; 3) ability to walk; and 4) patient and family’s decision, with physician consensus, that the remaining pain could be managed at home.
Inhaled NO gas versus inhaled nitrogen placebo.
There was no significant change in the primary endpoint between the NO and the placebo groups, with a median time to resolution of crisis of 73.0 hours (95% CI: 46.0–91.0) and 65.5 hours (95% CI: 48.1–84.0), respectively (P=.87). There were no significant differences in secondary outcome measures, including length of hospitalization, VAS scores, cumulative opioid usage and the rate of acute chest syndrome. Inhaled NO was well tolerated with no increase in serious adverse events. Increases in venous methemoglobin concentration confirmed compliance and randomization, but did not exceed 5% in any study participant. Significant increases in plasma nitrate occurred in the treatment group, but there were no observed increases in plasma or whole blood nitrite.
Among patients with SCD hospitalized with VOC, the use of inhaled NO compared with placebo did not improve time to crisis resolution.
PMCID: PMC3403835  PMID: 21364138
Nitric oxide; sickle cell disease; vaso-occlusive pain crisis; acute chest syndrome
16.  Elevation of IgE in children with sickle cell disease is associated with doctor diagnosis of asthma and increased morbidity 
A doctor diagnosis of asthma is associated with increased morbidity (pain and acute chest syndrome, ACS) among children with sickle cell disease (SCD). An association between IgE levels and asthma and morbidity has not been investigated in children with SCD.
We tested the hypothesis that elevated total and allergen-specific IgE levels are associated with asthma and SCD morbidity in children with SCD.
A cross-sectional study of children with SCD who participated in the Silent Cerebral Infarct Trial was conducted. Logistic regression and negative binomial regression were used to investigate potential associations of total and allergen-specific IgE levels with asthma diagnosis and SCD morbidity, both confirmed by medical record review. Elevation of total IgE was defined as age- and sex-adjusted IgE exceeding 90th percentile compared to a non-atopic reference population. IgE antibody positivity to Altermaria alternata (mold), Blatella germanica (cockroach), and Dermatophagoides pteronyssinus (dust mite) was assessed by ImmunoCAP analysis.
Children with SCD (140 asthmatics, 381 non-asthmatics) were evaluated. Elevations in total IgE (p = 0.04) and IgE antibody specific for Altermaria alternata (p = 0.0003), Blatella germanica (p = 0.008), and Dermatophagoides pteronyssinus (p = 0.01) were associated with asthma. ACS (p = 0.048) but not pain (p = 0.20) was associated with total IgE, but neither were associated with specific IgE levels.
Significantly increased levels of total and allergen-specific IgE levels are associated with asthma in SCD. High IgE levels are a risk factor for ACS and not pain rates.
PMCID: PMC3105194  PMID: 21388662
Total IgE; allergen-specific IgE; asthma risk indicator; acute chest syndrome; pain; sickle cell disease; hemoglobinopathies
17.  A Genome-Wide Association Study of Total Bilirubin and Cholelithiasis Risk in Sickle Cell Anemia 
PLoS ONE  2012;7(4):e34741.
Serum bilirubin levels have been associated with polymorphisms in the UGT1A1 promoter in normal populations and in patients with hemolytic anemias, including sickle cell anemia. When hemolysis occurs circulating heme increases, leading to elevated bilirubin levels and an increased incidence of cholelithiasis. We performed the first genome-wide association study (GWAS) of bilirubin levels and cholelithiasis risk in a discovery cohort of 1,117 sickle cell anemia patients. We found 15 single nucleotide polymorphisms (SNPs) associated with total bilirubin levels at the genome-wide significance level (p value <5×10−8). SNPs in UGT1A1, UGT1A3, UGT1A6, UGT1A8 and UGT1A10, different isoforms within the UGT1A locus, were identified (most significant rs887829, p = 9.08×10−25). All of these associations were validated in 4 independent sets of sickle cell anemia patients. We tested the association of the 15 SNPs with cholelithiasis in the discovery cohort and found a significant association (most significant p value 1.15×10−4). These results confirm that the UGT1A region is the major regulator of bilirubin metabolism in African Americans with sickle cell anemia, similar to what is observed in other ethnicities.
PMCID: PMC3338756  PMID: 22558097
18.  Plasma Glial Fibrillary Acidic Protein Levels in a Child with Sickle Cell Disease and Stroke 
Acta Haematologica  2010;125(3):103-106.
A 12-year-old boy with HbSS sickle cell disease (SCD) was admitted with an acute febrile illness and developed overt stroke 3 days later. Plasma glial fibrillary acidic protein levels were elevated, as compared to pediatric controls, 32 h prior to the clinical diagnosis of stroke, peaked immediately prior to the exchange transfusion, and remained elevated 1 year later despite chronic transfusion therapy. Stroke in SCD can occur in the setting of acute illness, and a biomarker that could predict the onset and triage ill children to therapeutic intervention more quickly would be useful.
PMCID: PMC3202928  PMID: 21099215
Chronic transfusion; Glial fibrillary acidic protein; Sickle cell; Stroke
19.  Burden of Influenza-related Hospitalizations among Children with Sickle Cell Disease 
Pediatrics  2010;125(2):234-243.
Children with sickle cell disease (SCD) are considered a high-risk population for complications from influenza infection, despite minimal published data characterizing the burden of influenza in this population. Our objectives were to: 1) estimate the rate of influenza-related hospitalizations (IRH) among children with SCD, 2) compare this rate to rates for children with cystic fibrosis (CF) and with neither SCD nor CF, and 3) explore mechanisms underlying these potentially preventable hospitalizations.
We analyzed hospitalizations from 4 states (California, Florida, Maryland, New York) across 2 influenza seasons (2003/4 and 2004/5) from the Healthcare Cost and Utilization Project State Inpatient Databases. We included hospitalizations with a discharge diagnosis code for influenza in a child less than 18 years of age. Using census data and disease prevalence estimates to calculate denominators, we compared rates of IRH among children with SCD, CF, and neither.
There were 7,896 pediatric influenza-related hospitalizations during the 2 influenza seasons. Of these, 159 (2.0%) included a co-occurring diagnosis of SCD. Annual rates of IRH were 112 and 2.0 per 10,000 children with and without SCD, respectively, across both seasons. Children with SCD were hospitalized with influenza at 56 times the rate of children without SCD (95% CI: 48–65). Children with SCD had approximately double the risk of IRH compared to children with CF (RR = 2.1 [1.5 – 2.9]). IRH among children with SCD were not longer, more costly or more severe than IRH among children without SCD, were rarely nosocomial, and co-occurred with a diagnosis of asthma in 14% of cases.
Influenza-related hospitalizations are substantially more common among children with SCD than those without, supporting the potential importance of vigorous influenza vaccination efforts targeting children with SCD.
PMCID: PMC3283164  PMID: 20100764
Sickle cell disease; influenza; surveillance; hospitalization
20.  A multicenter randomised controlled trial of hydroxyurea (hydroxycarbamide) in very young children with sickle cell anaemia 
Lancet  2011;377(9778):1663-1672.
Sickle cell anaemia (SCA) is associated with significant morbidity from acute complications and organ dysfunction beginning in the first year of life. In the first multicenter randomised double-blinded trial in very young children with SCA, the impact of hydroxyurea (hydroxycarbamide) therapy on organ dysfunction, clinical complications, and laboratory findings, and its toxicity, were examined.
Eligible subjects had HbSS or Sβ0thalassaemia, were age 9–18 months at randomisation, and were not selected for clinical severity. Subjects received liquid hydroxyurea, 20 mg/kg/day, or placebo for two years. Primary study endpoints were splenic function (qualitative uptake on 99Tc spleen scan) and renal function (glomerular filtration rate by 99mTc-DTPA clearance). Additional evaluations included: blood counts, HbF, chemistry profiles, spleen function biomarkers, urine osmolality, neurodevelopment, transcranial Doppler ultrasonography, growth, and mutagenicity. Study visits occurred every two to four weeks.
Ninety-six subjects received hydroxyurea and 97 placebo; 86% completed the study. Significant differences were not seen for the primary endpoints, but suggestive benefit was noted in quantitative measures of spleen function. Hydroxyurea significantly decreased pain and dactylitis with trends for decreased acute chest syndrome, hospitalisation and transfusion. Hydroxyurea increased haemoglobin and HbF and decreased WBC count. Toxicity was limited to mild-moderate neutropaenia.
Although hydroxyurea treatment did not reduce splenic and renal dysfunction assessed by primary endpoint measures, it resulted in major clinical benefit because of diminished acute complications, favorable haematologic results, and a lack of unexpected toxicities. Based on the safety and efficacy data from this trial, hydroxyurea can now be considered for all very young children with SCA.
PMCID: PMC3133619  PMID: 21571150
21.  Incidental Findings on Brain Magnetic Resonance Imaging of Children with Sickle Cell Disease 
Pediatrics  2010;126(1):53-61.
Incidental findings identified by MRI of the brain have been reported in up to18% of healthy adults, with clinically significant neuropathology in 0.5-2%. There are two smaller series of incidental findings on MRI of the brain in children. We describe the prevalence and range of incidental intracranial abnormalities identified by MRI of the brain in a large group of children screened for a clinical trial.
We included 953 children between 5 and 14 years of age screened with MRI of the brain for the Silent Infarct Transfusion Trial. All have sickle cell anemia or sickle β-null thalassemia. MRIs were interpreted by 3 neuroradiologists. MRIs reported to have any abnormality were re-reviewed by 2 study neuroradiologists. Incidental findings were classified into 4 categories: no referral, routine, urgent, and immediate referral recommended. Cerebral infarcts and vascular lesions were not considered incidental and were excluded.
We identified 63 children (6.6%, 95% CI: 5.1 to 8.4%) with 68 incidental intracranial MRI findings. Findings were classified as urgent in 6 children (0.6%), routine in 25 children (2.6%), and no referral required in 32 children (3.4%). No children required immediate referral. Two children with urgent findings underwent surgery in the next 6 months.
In this large cohort of children, incidental intracranial findings were identified in 6.6%, with potentially serious or urgent findings in 0.6%. These data should assist pediatricians and researchers in planning for and counseling families when unexpected, incidental findings are encountered on MRI of the brain.
PMCID: PMC3153884  PMID: 20547639
Incidental Findings; MRI-Magnetic resonance imaging; Brain imaging; Children; Sickle Cell Disease
Lancet  1988;1(8583):435-438.
A child with homozygous protein C deficiency was treated at age 20 months by orthotopic hepatic transplantation. Postoperatively there was complete reconstitution of protein C activity and resolution of the thrombotic condition.
PMCID: PMC3091362  PMID: 2893866
23.  Transcranial Doppler Ultrasonography (TCD) in Infants with Sickle Cell Anemia: Baseline Data from the BABY HUG Trial 
Pediatric blood & cancer  2010;54(2):256-259.
Transcranial Doppler ultrasonography (TCD) is used to predict stroke risk in children with sickle cell anemia (SCA), but has not been adequately studied in children under age 2 years.
TCD was performed on infants with SCA enrolled in the BABY HUG trial. Subjects were 7–17 months of age (mean 12.6 months). TCD examinations were successfully performed in 94% of subjects (n=192).
No patient had an abnormal TCD as defined in the older child (time averaged maximum mean velocity ≥ 200cm/sec) and only 4 subjects (2%) had velocities in the conditional range (170–199cm/sec). TCD velocities were inversely related to hemoglobin concentration and directly related to increasing age.
Determination of whether the TCD values in this very young cohort of infants with SCA can be used to predict stroke risk later in childhood will require analysis of exit TCD’s and long-term follow-up, which is ongoing. ( number, NCT00006400)
PMCID: PMC2794994  PMID: 19813252
Transcranial Doppler Ultrasonography; TCD; sickle cell anemia; stroke; infant
24.  The Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG): Challenges of Study Design 
Pediatric blood & cancer  2010;54(2):250-255.
Evidence of the laboratory benefits of hydroxyurea and its clinical efficacy in reducing acute vaso-occlusive events in adults and children with sickle cell anemia has accumulated for more than 15 years. A definitive clinical trial showing that hydroxyurea can also prevent organ damage might support widespread use of the drug at an early age. BABY HUG is a randomized, double-blind placebo-controlled trial to test whether treating young children ages 9 to 17 months at entry with a liquid preparation of hydroxyurea (20 mg/kg/day for two years) can decrease organ damage in the kidneys and spleen by at least 50%. Creation of BABY HUG entailed unique challenges and opportunities. Although protection of brain function might be considered a more compelling endpoint, preservation of spleen and renal function has clinical relevance, and significant treatment effects might be discernable within the mandated sample size of two hundred. Concerns about unanticipated severe toxicity and burdensome testing and monitoring requirements were addressed in part by an internal Feasibility and Safety Pilot Study, the successful completion of which was required prior to enrolling a larger number of children on the protocol. Concerns over recruitment of potentially vulnerable subjects were allayed by inclusion of a research subject advocate, or ombudsman. Finally, maintenance of blinding of research personnel was aided by inclusion of an unblinded primary endpoint person, charged with transmitting endpoint data and monitoring blood work locally for toxicity. ( number,NCT00006400)
PMCID: PMC2795081  PMID: 19731330
hydroxyurea; clinical trial; infants; sickle cell
25.  The Excess Burden of Stroke in Hospitalized Adults with Sickle Cell Disease 
American journal of hematology  2009;84(9):548-552.
To compare the relative rates and risk factors associated with stroke in adults vs. children with sickle cell disease (SCD) in the U.S. over the last decade.
We identified incident strokes in patients with SCD using ICD-9 codes for acute stroke and SCD and the California Patient Discharge Databases. We estimated SCD prevalence by using the incidence of SCD at birth with adjustment for early mortality from SCD.
We identified 255 acute strokes (70 primary hemorrhagic and 185 ischemic) among 69,586 hospitalizations for SCD-related complications from 1998–2007. The rate of stroke in children [<18 years old (310/100,000 person-years)] was similar to young adults [18 to 34 years old (360/100,000 person-years)], but much higher in middle-aged [35 to 64 years old (1160/100,000 person-years)] and elderly adults [≥65 years old (4700/100,000 person-years)]. Stroke was associated with hypertension in children and hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation, and renal disease in adults. Most acute strokes (75%) and in-hospital deaths from stroke (91%) occurred in adults.
Our results suggest that the rate of stroke in SCD peaks in older adults and is 3-fold higher than rates previously reported in African-Americans of similar age (35 to 64 years) without SCD. Stroke in SCD is associated with several known adult risk factors for ischemic and hemorrhagic stroke. Studies for the primary and secondary prevention of stroke in adults with SCD are urgently needed.
PMCID: PMC2737603  PMID: 19623672
Stroke; sickle cell disease; epidemiology; transfusion

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