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Key Points Severe bone marrow failure was primarily observed in early childhood in children with biallelic SBDS mutations.Absolute neutrophil counts were positively associated with age (P < .0001) in patients with biallelic SBDS mutations., Visual Abstract, Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome with leukemia predisposition. An understanding of the hematologic complications of SDS with age could guide clinical management, but data are limited for this rare disease. We conducted a cohort study of 153 subjects from 143 families with confirmed biallelic SBDS mutations enrolled on the North American Shwachman Diamond Registry or Bone Marrow Failure Registry. The SBDS c.258 + 2T>C variant was present in all but 1 patient. To evaluate the association between blood counts and age, 2146 blood counts were analyzed for 119 subjects. Absolute neutrophil counts were positively associated with age (P < .0001). Hemoglobin was also positively associated with age up to 18 years (P < .0001), but the association was negative thereafter (P = .0079). Platelet counts and marrow cellularity were negatively associated with age (P < .0001). Marrow cellularity did not correlate with blood counts. Severe marrow failure necessitating transplant developed in 8 subjects at a median age of 1.7 years (range, 0.4-39.5), with 7 of 8 requiring transplant prior to age 8 years. Twenty-six subjects (17%) developed a myeloid malignancy (16 myelodysplasia and 10 acute myeloid leukemia) at a median age of 12.3 years (range, 0.5-45.0) and 28.4 years (range, 14.4-47.3), respectively. A lymphoid malignancy developed in 1 patient at the age of 16.9 years. Hematologic complications were the major cause of mortality (17/20 deaths; 85%). These data inform surveillance of hematologic complications in SDS.

Silent cerebral infarcts and arteriopathy are common and progressive in individuals with sickle cell anemia. However, most data describing brain lesions in sickle cell anemia are cross-sectional or derive from pediatric cohorts with short follow-up. We investigated the progression of silent cerebral infarct and cerebral vessel stenosis on brain MRI and MRA, respectively, by describing the incidence of new or worsening lesions over a period of up to 25 years among young adults with sickle cell anemia and explored risk factors for progression. Forty-four adults with sickle cell anemia (HbSS or HbSβ0thalassemia), exposed to chronic transfusions ( n = 12) or hydroxyurea ( n = 32), median age 19.2 years (range 18.0–31.5), received a screening brain MRI/MRA and their results were compared with a clinical exam performed during childhood and adolescence. We used exact log-rank test to compare MRI and MRA progression among any two groups. The hazard ratio (HR) and 95% confidence interval (CI) were calculated from Cox regression analyses. Progression of MRI and MRA occurred in 12 (27%) and 4 (9%) young adults, respectively, relative to their pediatric exams. MRI progression risk was high among participants with abnormal pediatric exams (HR: 11.6, 95% CI: 2.5–54.7) and conditional or abnormal transcranial Doppler ultrasound velocities (HR: 3.9, 95% CI: 1.0–15.1). Among individuals treated with hydroxyurea, high fetal hemoglobin measured in childhood was associated with lower hazard of MRI progression (HR: 0.86, 95% CI: 0.76–0.98). MRA progression occurred more frequently among those with prior stroke (HR: 8.6, 95% CI: 1.2–64), abnormal pediatric exam ( P = 0.00084), and elevated transcranial Doppler ultrasound velocities ( P = 0.004). Brain MRI/MRA imaging in pediatrics can identify high-risk patients for CNS disease progression in young adulthood, prompting consideration for early aggressive treatments.

We previously found that neurodevelopmental deficits commonly occurred in three-year-olds with sickle cell disease (SCD), but clinical significance was uncertain because a comparison group was lacking. Our objective in the current study was to prospectively compare neurodevelopment in three-year-old children with SCD to an age-appropriate control group. The Brigance Preschool Screen II is a neurodevelopmental screening examination which can be administered in 15-20 min. SCD patients (Group 1) were compared with community controls of similar age and ethnicity enrolled in daycare/preschool (Group 2). SCD patients who were receiving hydroxycarbamide treatment were also compared (Group 3). Two hundred forty-five three-year-olds were evaluated: Group 1, 111; Group 2, 114; and Group 3, 20. The below cut-off rate on the Brigance test was higher in Group 1 (73%) than in Group 2 (61%; P = 0·04). In multivariate analysis of Group 1 patients, only lower household income and more persons living in the home were independent predictors of this. Patients with SCD and matched controls had high rates of 'failing' the Brigance test. The below cut-off rate in untreated children with SCD was associated with low household income and increased number of persons living in the home.

Children with sickle cell anaemia (SCA) and conditional transcranial Doppler (TCD) flow velocities (conditional: 170-199 cm/s; normal

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.

Background Partial splenectomy (PS) may allow preservation of splenic function in cases where splenectomy is indicated for hematologic diseases; however, the long-term outcomes are uncertain. We investigated the long-term outcomes of PS in patients with sickle cell disease (SCD). Methods A single-institution retrospective chart review was performed for children with SCD who underwent PS from 1997 to 2017. For comparison, we reviewed outcomes for patients who underwent PS for hereditary spherocytosis (HS). The primary endpoint was viability of the splenic remnant as inferred by the presence of remnant perfusion on ultrasound and/or liver spleen scan. Results Nine patients with SCD and 26 patients with HS underwent PS at a median age of 11 (IQR, 9–14) and 7.5 (IQR, 6–13) years, respectively. All underwent laparoscopic PS with three (7.9%) conversions to open. Two SCD patients were lost to long-term follow-up. The remaining seven SCD patients had initial postoperative splenic remnant perfusion demonstrated by ultrasonography. By 42 months postoperatively, however, none had a functioning splenic remnant. The median time to loss of splenic remnant was 12.6 (IQR 9.2–28.5) months. In contrast, all HS patients demonstrated robust splenic remnant blood flow with a median follow-up of 46 (IQR 37–82) months. Conclusion No patient with SCD who underwent PS had viable splenic tissue for more than 42 months, likely due to continued autoinfarction typical of patients with this disease. Therefore, we believe that PS to preserve splenic function is not indicated in patients with SCD. Level of evidence III.

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/HbSβ+ thalassaemia; n = 52 HbSS/HbSβ0 thalassaemia) and those never treated with hydroxycarbamide (n = 31 HbSC/HbSβ+ thalassaemia; n = 8 HbSS/HbSβ0 thalassaemia). Demographic distributions were similar between the groups. After adjusting for socioeconomic status, the hydroxycarbamide group had significantly higher scores on nonverbal IQ (HbSC/HbSβ thalassaemia: P = 0·036, effect size [d] = 0·65), reaction speed (HbSS/HbSβ0 thalassaemia: P = 0·002, d = 1·70), sustained attention (HbSS/HbSβ0 thalassaemia: P = 0·014, d = 1·30), working memory (HbSC/HbSβ+ thalassaemia: P = 0·034, d = 0·71) and verbal memory (HbSC/HbSβ+ thalassaemia: P = 0·038, d = 0·84) when compared to those who did not receive hydroxycarbamide. In patients with HbSS/HbSβ0 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.

Individuals with sickle cell disease (SCD) are at high risk of developing life-threatening complications, particularly acute chest syndrome (ACS) postoperatively. The perioperative factors associated with the development of ACS in children with SCD after splenectomy have not been clearly identified.We retrospectively reviewed medical records of all children who underwent splenectomy at our institution between 1997 and 2017 with the goal of identifying perioperative factors associated with postoperative ACS. Categorical and noncategorical variables were compared using Fisher's exact test and Student's two-tailed t-test, respectively.Sixty-five patients with SCD underwent splenectomy at a median of 4.0 (interquartile range [IQR] 2.0-8.0) years of age. A laparoscopic approach was used for 64 (98.5%) patients. Fifty-six (86.2%) underwent laparoscopic total splenectomy, and eight (12.3%) underwent laparoscopic partial splenectomy, of which two were converted to open. One had an open partial splenectomy (1.5%). Of the 65 patients, 10 (15.4%) developed ACS with a mean time to diagnosis of 49.0 ± 34.5 h. Children who developed ACS had a higher postoperative median pain score of 6.8 (IQR 5.1-9.1) versus 2.7 (IQR 1.6-4.2), P 0.001, higher median pain score area under the curve 111.5 (IQR 76.9-169.1) versus 47.3 (IQR 30.5-78.3), P = 0.01, and received more total morphine equivalents (median 1.4 [IQR 0.4-2.7] versus 0.5 [IQR 0.3-0.9] mg/kg, respectively; P = 0.003), compared with children who did not develop ACS.Significant postoperative pain may be an early sign of ACS that could be worsened by opioid use, supporting the investigation of nonopioid pain control options in this patient population.

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/HbSβ(0)-thalassaemia (71% HU treated) and 149 patients with HbSC/HbSβ(+)-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/HbSβ(0)-thalassaemia. Earlier initiation of HU (n = 152) in HbSS/HbSβ(0)-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.

Albuminuria predicts kidney disease progression in individuals with sickle cell anaemia (SCA); however, earlier prediction of kidney disease with introduction of reno-protective therapies prior to the onset of albuminuria may attenuate disease progression. A genetic risk score (GRS) for SCA-related nephropathy may provide an improved one-time test for early identification of high-risk patients. We utilized a GRS from a recent, large, trans-ethnic meta-analysis to identify three single nucleotide polymorphisms that associate individually and in a GRS with time to first albuminuria episode in children with SCA.

Background Immunosuppressive therapy with horse antithymocyte globulin and cyclosporine currently remains the standard therapy for children with severe aplastic anemia (SAA) who lack human leukocyte antigen (HLA)-identical sibling. The thrombopoietin receptor agonist eltrombopag has been recently approved for SAA patients 2 years and older. However, there are limited data on its safety and efficacy in pediatric cohorts. Methods We conducted a retrospective study of patients ≤18 years old consecutively diagnosed with SAA between 2000 and 2018. Patients received either standard immunosuppressive therapy (IST-Std) or IST with eltrombopag (IST-Epag). The primary outcome was the objective response (OR), including partial and complete response (CR), at 6 and 12 months after starting therapy. Results We identified 16 patients receiving IST-Std and nine IST-Epag treatment (seven of nine as upfront therapy and two of seven after previously failed IST). The OR at 6 and 12 months in IST-Std arm was 71% and 100%, with CR in 29% and 58%, respectively. Seven patients receiving upfront IST-Epag had OR at 6 and 12 months, with two of seven (29%) achieving CR at 6 and 12 months. Two patients who previously failed standard IST did not respond to eltrombopag. No significant differences were observed in both cohorts with regard to infections. One IST-Epag-treated patient developed transient grade 3 transaminitis. Finally, no changes in paroxysmal nocturnal hemoglobinuria (PNH) clone size and cytogenetic abnormalities were seen in either cohort. Conclusion The addition of eltrombopag to standard IST was well tolerated and resulted in satisfactory hematological response at 6 and 12 months in this single-institution experience. A larger cohort with longer follow-up is required to assess response durability.

Individuals with monogenic disorders can experience variable phenotypes that are influenced by genetic variation. To investigate this in sickle cell disease (SCD), we performed whole-genome sequencing (WGS) of 722 individuals with hemoglobin HbSS or HbSβ0-thalassemia from Baylor College of Medicine and from the St. Jude Children’s Research Hospital Sickle Cell Clinical Research and Intervention Program (SCCRIP) longitudinal cohort study. We developed pipelines to identify genetic variants that modulate sickle hemoglobin polymerization in red blood cells and combined these with pain-associated variants to build a polygenic score (PGS) for acute vaso-occlusive pain (VOP). Overall, we interrogated the α-thalassemia deletion −α3.7 and 133 candidate single-nucleotide polymorphisms (SNPs) across 66 genes for associations with VOP in 327 SCCRIP participants followed longitudinally over 6 years. Twenty-one SNPs in 9 loci were associated with VOP, including 3 (BCL11A, MYB, and the β-like globin gene cluster) that regulate erythrocyte fetal hemoglobin (HbF) levels and 6 (COMT, TBC1D1, KCNJ6, FAAH, NR3C1, and IL1A) that were associated previously with various pain syndromes. An unweighted PGS integrating all 21 SNPs was associated with the VOP event rate (estimate, 0.35; standard error, 0.04; P = 5.9 × 10−14) and VOP event occurrence (estimate, 0.42; standard error, 0.06; P = 4.1 × 10−13). These associations were stronger than those of any single locus. Our findings provide insights into the genetic modulation of VOP in children with SCD. More generally, we demonstrate the utility of WGS for investigating genetic contributions to the variable expression of SCD-associated morbidities.

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/HbSβ0 -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.

Pain in sickle cell disease (SCD) can have a neuropathic component. This randomized phase II double-blinded placebo-controlled study evaluated the efficacy of gabapentin in reducing pain and opioid consumption (morphine-equivalent dose [MED]) during acute vaso-occlusive crisis (VOC). Of 90 patients aged 1-18 years with VOC pain, 45 were randomized to a single gabapentin dose (15 mg/kg) and 45 to placebo, in addition to standard treatment; 42 and 44 patients were evaluable in the gabapentin and placebo arms, respectively. A decrease in pain of ≥33% was reported in 68% of patients in the gabapentin arm and 60% of those in the placebo arm (one-sided

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 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.

The Coronavirus Disease 2019 pandemic, caused by the severe acute respiratory syndrome-associated coronavirus (SARS-CoV-2), is having devastating effects on every country around the world. SARS-CoV-2 can be fatal in patients with described risk factors. A question remains as to whether other immunosuppressed populations are at risk for severe complications. There is limited data on the impact of COVID-19 in young patients with bone marrow failure syndromes (BMFs). 29 institutions, from the NAPAAC consortium, reported 4 with BMFs diagnosed with SARS-CoV-2. These patients presented with relatively mild clinical courses, raising questions as to why this apparently low morbidity and mortality

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/HbSβ0 -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

Due to fear of short-term toxicities, there is nonconsensus of hydroxycarbamide dosing strategy (escalated vs fixed-dosing methods), which contributes to its suboptimal use. We performed a meta-analysis to summarize the incidence rates of toxicities associated with both dosing methods. Summarized incidence rates could not be statistically compared between dosing methods due to sparse data. Summarized neutropenia and thrombocytopenia incidence rates were slightly higher when using escalated dosing than with fixed. Summarized reticulocytopenia was comparable. Summarized hepatic and renal toxicities' incidence rates were slightly higher when using fixed doses than with escalated. We recommend diligent and transparent reporting of toxicities.

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 (p20% 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%.

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.

Laparoscopy offers many benefits to splenectomy, such as reduced incisional pain and shortened hospital duration. The purpose of this study is to evaluate procedural and outcome differences between multiport (MP) and reduced port (RP) splenectomy when utilized to treat children.An institutional review board approved retrospective analysis of all consecutive laparoscopic total splenectomies performed at a single institution between January 2010 and October 2015 was conducted. We evaluated demographics, surgical technique, instance of conversion, operative duration, estimated blood loss, need for intraoperative blood transfusion, postoperative length of stay, time to full feeds, complications, and follow-up duration.Over a 5-year period, 66 patients less than 20 years of age underwent laparoscopic total splenectomy. RP splenectomy was attempted in 14 patients. The remaining 52 were MP operations. Populations were comparable with regard to demographics. Preoperative splenic volumes (mL) were greater in the RP population (median [IQR]: 1377 [747-1508] versus 452 [242-710], P = .039). RP splenectomy demonstrated no difference compared to MP splenectomy in operative time (153 versus 138 minutes, P = .360), estimated blood loss (120 versus 154 mL, P = .634), or percent of cases requiring intraoperative blood transfusion (14 versus 23, P = .716). By the first postoperative day, 57% of RP and 17% of MP patients could be discharged (P = .005). Thirty-day readmission rates were similar, at 7% for RP and 8% for MP operations. Fever was the indication for all readmissions. Mean duration of follow-up is 28 months for MP and 13 months for RP cases.A reduced number of ports can be safely utilized for total splenectomy in pediatric patients without increasing procedural duration or need for intraoperative blood transfusion. In addition, rate of discharge on the first postoperative day was significantly higher in the RP splenectomy group.

Background: Fetal hemoglobin (HbF) is the most influential modifier of the clinical and hematologic phenotype of sickle cell disease (SCD) and is highly heritable. Low HbF is independently associated with increased white matter changes on brain imaging and poorer performance on neurocognitive measures (Ruffiuex, Child Neuropsychology, 2013). Our previous work has shown that 11 SNPs in three genes (BCL11A, MYB, and β-globin), contribute over 20% of the variance in HbF (Rampersaud, Kang. et al., 2020, under review). Clinically, these HbF-associated SNPs are associated with disease severity and frequency of pain events. However, the neurocognitive implications of these SNPs have yet to be explored. As part of a prospective longitudinal cohort study, the Sickle Cell Clinical Research and Intervention Program (SCCRIP), we evaluated the relationship between HbF-associated SNPs and neurocognitive functioning in SCD patients. Methods: We included 257 patients with SCD (69% HbSS/HbSβ0-thalassemia). The median age of participants was 13 years (range 4 - 25). We extracted genotypes for the 11 HbF-associated SNPs from whole genome sequencing data and analyzed them based on an additive genetic model. Following informed consent, patients completed a battery of gold-standard neurocognitive measures, supervised by a psychologist, assessing IQ, verbal and perceptual reasoning, working memory, processing speed, sustained attention, and executive functioning skills. HbF was the average value of measurements collected within 3 months of neurocognitive assessment, or the closest value. In univariate analyses, Kruskal-Wallis rank sum test was used to assess the associations of the 11 HbF-associated SNPs with neurocognitive measures. Linear regression was used to examine these associations adjusting for age, sickle genotype, hydroxyurea exposure, socioeconomic status (index of social vulnerability) and 5 principal components to adjust for population stratification. Benjamini and Hochberg false discovery rate (FDR) was used for multiple corrections and FDR adjusted p (pFDR) Results: One SNP in the β-globin gene, rs968857, was associated with performance on measures of IQ, verbal reasoning, working memory, and executive functioning by Kruskal-Wallis rank sum test (Figure 1) and by linear regression adjusting for covariates listed above at pFDR Conclusions: This is the first study to demonstrate a relationship between genetic modifiers of SCD and neurocognitive functioning. Beyond findings on neuroimaging and sociodemographic factors, there is little known about risk for neurocognitive deficits in SCD. The present results suggest an influence of SNP rs968857 on cognitive function, which was partially mediated by expression of HbF. rs968857, is one of four SNPs that defines almost all β-globin gene cluster haplotypes and influences HbF levels in SCD. How this SNP effects HbF and neurocognition is unknown and requires further investigation of its mechanism. The highly heritable nature of HbF may allow for future use of precision medicine. SCD patients could be stratified according to risk for neurocognitive deficits to utilize early intervention strategies, informed by genetic polymorphisms. Correlation with neuroimaging will help further elucidate the relationship between genetic modifiers and neurocognitive functioning. Future trials with larger samples are needed to validate our findings and investigate if the observed relationships differ by age or hydroxyurea treatment status. Disclosures Estepp: Daiichi Sankyo, Esperion, Global Blood Therapeutics: Consultancy; Global Blood Therapeutics, Forma Therapeutics, Pfizer, Eli Lilly and Co: Research Funding; ASH, NHLBI: Research Funding. King:Amphivena Therapeutics: Research Funding; Bioline: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novimmune: Research Funding; RiverVest: Consultancy; Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company. Hankins:Novartis: Research Funding; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; UptoDate: Consultancy; Global Blood Therapeutics: Consultancy, Research Funding; MJH Life Sciences: Consultancy, Patents & Royalties; American Society of Pediatric Hematology/Oncology: Honoraria; LINKS Incorporate Foundation: Research Funding.

Pyruvate kinase (PK) deficiency is the most common red cell glycolytic enzyme defect causing hereditary non-spherocytic hemolytic anemia. Current treatments are mainly supportive and include red cell transfusions and splenectomy.[1][1] Regular red cell transfusions are known to result in iron

This review describes current considerations in the use of hydroxyurea for the management of sickle cell disease in the context of clinical severity. Randomized trials of hydroxyurea have generally enrolled subjects with increased severity based on frequent vaso-occlusive events. An exception was the BABY HUG study in infants which documented substantial benefit even for asymptomatic subjects. Increasing data indicate that hydroxyurea has a substantial effect on reducing mortality in both adults and children—perhaps the most compelling reason for advocating the drug’s widespread use. Although the efficacy of hydroxyurea is mediated primarily through increased erythrocyte fetal hemoglobin and much has been learned about the genomic influences on fetal hemoglobin levels in sickle cell disease, our ability to predict the fetal hemoglobin response to hydroxyurea remains limited; much more work in this area is indicated. The review is concluded with the recommendations of the 2014 NIH Evidence-Based Management of Sickle Cell Disease Expert Panel Report.

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.

Introduction Individuals with sickle cell disease (SCD) experience recurrent acute vaso-occlusive events (VOE) beginning in infancy, that can be prevented with hydroxyurea therapy (Wang W. Lancet 2011), while chronic organ dysfunction becomes evident in adolescence and progresses with age. Nutritional insufficiencies and deficiencies occur in SCD (e.g., zinc, vitamin D and B6), and are associated with greater frequency of VOE (McCaskill M. Nutrients 2018, Martyres D. PBC 2016, Schall J. J Pediatr 2004). While infants and young children (age Methods Participants were recruited from the IRB-approved longitudinal clinical cohort study, Sickle Cell Clinical Research and Intervention Program (Hankins J. PBC 2018). Home addresses were mapped to census-tract environmental data from the US Food Access Research Atlas (USDA ERS 2017). Food deserts were defined as "low income census tracts where at least 33% (minimum of 500 people/tract) of the population live >1.0 (urban area) or >10 (rural area) miles from a grocery store or a supermarket" (Food Access, USDA ERS 2019). Three main outcomes: emergency department (ED) visits, hospitalizations, and acute care utilization (ACU=ED + hospitalizations) from a VOE, were collected from birth to age 6 and analyzed as cross-sectional outcomes at age 6-years. Generalized linear models (GLM) were used to associate environmental factors as continuous and categorical variables with the outcomes adjusted for sickle genotype and hydroxyurea exposure. False discovery rate (FDR)-adjusted p-values (pFDR) were calculated to account for multiple comparisons. Environmental factors with pFDR Results 523 children with SCD, all African American, were included. The median age at last follow-up was 5.5 years (range 1- 6), 51.7% were girls (Table 1). Differences in health care utilization and hydroxyurea use were observed according to SCD genotype. A total of 33.5 % of the studied population resided in census tracts considered food deserts. The average distance to the nearest supermarket from participants' household was 2.8 miles. Except for % of children per census tract, there were no neighborhood differences by SCD genotype (Table 1). Participant neighborhoods had on average 14.7% unemployment rate, while 30.8% of individuals were under the federal poverty threshold and received Food and Nutrition Services. 7.9% of adults had a bachelors' degree. Among the tracts where the population was considered low income, 9% did not own a car, and the proportion of those living >0.5 and >1.0 miles from a supermarket was 37% and 16%, respectively. Living in a household without a vehicle and located >0.5 miles from a supermarket was associated with increased hospitalizations and ACU (Figure 1). The odds ratio (OR) of experiencing >0 hospitalizations or ACU were 1.3 (95%CI: 1.0-1.8) or 1.5 (95%CI: 1.1-2.0), for those living in a household without a vehicle and >0.5 miles from a supermarket, respectively. Living in a household with children and >1.0 mile from a supermarket was associated with high risk of experiencing >0 hospitalizations (OR: 1.5; 95%CI: 1.2-1.8) and >0 ACU (OR: 1.3; 95%CI: 1.1-1.7) (Figure 2). The accuracy of predicting a SCD-related acute event by age 6 years significantly improved when adding markers of poor food access to the predictive model (AUC increase: ≥0.06, p=0.01) (Figure 3). Conclusion Living in food deserts limits access to affordable and nutritious foods. Food deserts are associated with poor health outcomes among pre-school children with SCD. The prediction of acute care utilization in young childhood increases when food access is considered. Treatment with hydroxyurea did not mitigate the effects of reduced food access on the frequency of acute care utilization of young children with SCD. Disclosures Estepp: ASH, NHLBI: Research Funding; Daiichi Sankyo, Esperion, Global Blood Therapeutics: Consultancy; Global Blood Therapeutics, Forma Therapeutics, Pfizer, Eli Lilly and Co: Research Funding. Hankins:LINKS Incorporate Foundation: Research Funding; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; Novartis: Research Funding; UptoDate: Consultancy; MJH Life Sciences: Consultancy, Patents & Royalties; Global Blood Therapeutics: Consultancy, Research Funding; American Society of Pediatric Hematology/Oncology: Honoraria.

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 5 .007), lower indirect bilirubin (P 5 .005), and missense PKLR mutations (P 5 .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.

The St. Jude Children’s Research Hospital (St. Jude) comprehensive sickle cell center serves a 150 mile catchment radius around Memphis, TN, USA. Full travel expenses are provided for routine and acute care visits for sickle cell disease patients living ≥35 miles from St. Jude. We compared hospitalization rates to national estimates and assessed if driving distance was a barrier to sickle cell healthcare despite the travel reimbursement policy. We evaluated the associations between hospitalizations and routine clinic visits and distance from St. Jude using negative binomial models and we conducted bias analyses by Monte Carlo simulation. We followed 545 patients (2550 patient-years) aged ≤18 years with sickle cell disease (Hb SS only) from 2007 to 2012. The hospitalization rate per patient-year was 0.65 [95% CI (confidence interval): 0.62, 0.68), significantly lower than the national rate of 1.16 (95% CI: 1.14, 1.18). Children living 35 miles) was associated with decreased hospitalization rates, despite the travel allowances that are provided for those who live ≥35 miles from the hospital.

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.

Purpose. To evaluate a new postprocessing framework that eliminates arterial vessel signal contributions in the quantification of normalized visible venous volume (NVVV, a ratio between venous and brain volume) in susceptibility-weighted imaging (SWI) exams in patients with sickle cell disease (SCD). Materials and Methods. We conducted a retrospective study and qualitatively reviewed for hypointense arterial vessel contamination in SWI exams from 21 children with SCD. We developed a postprocessing framework using magnetic resonance angiography in combination with SWI to provide a more accurate quantification of NVVV. NVVV was calculated before and after removing arterial vessel contributions to determine the error from hypointense arterial vessels in quantifying NVVV. Results. Hypointense arterial vessel contamination was observed in 86% SWI exams and was successfully corrected by the proposed method. The contributions of hypointense arterial vessels in the original SWI were significant and accounted for approximately 33% of the NVVV [uncorrected NVVV = 0.012 ± 0.005 versus corrected NVVV = 0.008 ± 0.003 (mean ± SD), P<0.01]. Conclusion. Hypointense arterial vessel contamination occurred in the majority of SWI exams and led to a sizeable overestimation of the visible venous volume. A prospective longitudinal study is needed to evaluate if quantitation of NVVV was improved and to assess the role of NVVV as a biomarker of SCD severity or stroke risk.

BACKGROUND AND OBJECTIVE: Susceptibility to encapsulated bacteria is well known in sickle cell disease (SCD). Hydroxyurea use is common in adults and children with SCD, but little is known about hydroxyurea’s effects on immune function in SCD. Because hydroxyurea inhibits ribonucleotide reductase, causing cell cycle arrest at the G1–S interface, we postulated that hydroxyurea might delay transition from naive to memory T cells, with inhibition of immunologic maturation and vaccine responses. METHODS: T-cell subsets, naive and memory T cells, and antibody responses to pneumococcal and measles, mumps, and rubella vaccines were measured among participants in a multicenter, randomized, double-blind, placebo-controlled trial of hydroxyurea in infants and young children with SCD (BABY HUG). RESULTS: Compared with placebo, hydroxyurea treatment resulted in significantly lower total lymphocyte, CD4, and memory T-cell counts; however, these numbers were still within the range of historical healthy controls. Antibody responses to pneumococcal vaccination were not affected, but a delay in achieving protective measles antibody levels occurred in the hydroxyurea group. Antibody levels to measles, mumps, and rubella showed no differences between groups at exit, indicating that effective immunization can be achieved despite hydroxyurea use. CONCLUSIONS: Hydroxyurea does not appear to have significant deleterious effects on the immune function of infants and children with SCD. Additional assessments of lymphocyte parameters of hydroxyurea-treated children may be warranted. No changes in current immunization schedules are recommended; however, for endemic disease or epidemics, adherence to accelerated immunization schedules for the measles, mumps, and rubella vaccine should be reinforced.

Background More than 90% of children with sickle cell anemia (SCA) lose splenic function by the age of 2 yrs. Splenic function may improve with hydroxyurea, but previous studies are conflicting. We prospectively evaluated the effect of hydroxyurea on splenic filtrative function. Methods Children with SCA enrolled in the Hydroxyurea Study of Long-Term Effects (HUSTLE-NCT00305175) underwent clinical evaluations including Tc99m liver–spleen (LS) scans before hydroxyurea initiation and after 3 yrs of treatment to maximum tolerated dose (MTD). LS scans were classified as follows: no uptake

Introduction Sickle Cell Anemia (SCA) is a rare, devastating, and debilitating disease marked by the pathophysiologic features of hemolytic anemia, vaso-occlusion, and progressive end-organ damage. The most devastating complication of pediatric SCA is the development of central nervous system events such as overt stroke or silent cerebral infarcts (SCIs) which can produce significant physical and neurocognitive deficits. Transcranial Doppler ultrasonography (TCD) measures cerebral artery blood flow velocity in children with SCA. Elevated TCD velocity levels are a reliable predictor of stroke risk, and children with conditional TCD levels (defined as > 170 to < 200 cm/sec) are at increased risk of stroke compared to those with normal TCD levels (200 cm/sec), but the extent to which hemoglobin (Hb) concentration influences TCD level elevation is unknown. Using recently collected longitudinal, real world data, this study sought to quantify the impact of the rise in Hb obtained during hydroxyurea (HU) therapy on the change observed in TCD levels as an estimate for the magnitude of Hb rise that would be predicted to convert an individual from the conditional TCD level range (moderate risk of stroke) to the normal TCD level (low risk of stroke). Methods Children (age 0 g/dl, ≥0.5 g/dl, ≥1 g/dl, and ≥2 g/dl). A mixed- model repeated measures (MMRM) using longitudinal panel data were employed next to estimate the impact of Hb levels on TCD velocity, controlling for participants' demographic and clinical characteristics. Results A total of 202 children (female: 46.5%, mean age at BL TCD: 7.53 yrs) were analyzed. At BL, 33 patients (16.3%) had conditional TCD level, 162 patients (80.2%) had normal TCD level. Mean (SD) BL Hb level was 8.4 g/dl (0.97 g/dl). In cross-sectional analysis, Hb was negatively associated with corresponding TCD levels at 1 yr, 2 yrs and 4 yrs post HU (Spearman correlation coefficients: -0.20, -0.64 and -0.38, respectively, all p-values The rates of converting from conditional to normal or abnormal TCD levels was assessed for the 33 children with BL conditional TCD levels. After 1 yr of HU therapy, 87% (n=21) of 24 children with conditional TCD whose Hb increased by ≥0.5 g/dL normalized their TCD level, and this number increased to 100% (n=4) when Hb increased by ≥2 g/dL. The same analysis was repeated after 2 yrs of HU initiation and yielded similar results: increases in ≥0.5 g/dL and ≥2 g/dL were associated with 88% and 100% of conversion to normal, respectively. No patients with a conditional TCD level at BL converted to abnormal TCD after 1 and 2 yrs of HU initiation. In the MMRM models, Hb was negatively associated with TCD levels: a 1 g/dL increase in Hb was associated with a 14 cm/sec reduction in TCD level (p Conclusions In children with conditional TCD levels and elevated stroke risk prior to initiating hydroxyurea, the therapeutic rise in hemoglobin was significantly associated with a reduction in TCD levels. Importantly, the rise in hemoglobin was associated with a high likelihood of normalization of the TCD level when children had conditional TCD levels, which likely conveys a reduction in risk of stroke. Disclosures Estepp: Eli Lilly and Co: Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Esperion: Consultancy; Forma Therapeutics: Research Funding. Cong:Global Blood Therapeutics: Employment, Equity Ownership. Agodoa:Global Blood Therapeutics: Employment, Equity Ownership. Kang:MBIO: Other: St. Jude Children's Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Hankins:ASPHO: Honoraria; NHLBI: Honoraria; NHLBI: Research Funding; Bluebird Bio: Consultancy; Novartis: Research Funding; LYNKS Foundation: Research Funding; National Committee for Quality Assurance: Consultancy; Global Blood Therapeutics: Research Funding. Wang:Agios Pharmaceuticals: Consultancy; Novartis: Consultancy.

Introduction: In the United States, most children with sickle cell disease (SCD) survive into adulthood and transfer from pediatric to adult-centered care. Cognitive deficits begin during childhood and are highly prevalent among individuals with SCD, potentially affecting their functional ability to establish adult care and navigate the new adult care environment. Lack of engagement in adult care can place youth with SCD at higher risk for care discontinuity and higher disease morbidity and mortality. The relationship between cognition and transition to adult care has not been examined. We hypothesized that better performance on measures of neurocognition were associated with decreased latency in initiating adult care, greater retention in adult care, and increased utilization of adult ambulatory services. As a secondary objective, we examined the relationship of environmental outcomes to transition outcomes. Methods: We included participants enrolled in the Sickle Cell Research and Intervention Program (SCCRIP; Hankins J. et al, Pediatric Blood and Cancer 2018), a longitudinal lifetime cohort study of individuals with SCD that monitors neurocognition. Participants were included if they underwent neurocognitive screening assessment in adolescence, prior to their transfer to adult care and if they satisfied their first appointment in adult care. The neurocognitive screening battery included measures of estimated global intelligence (Wechsler Abbreviated Scales of Intelligence, 2nd Ed; WASI-2) and sustained attention (Continuous Performance Test, 2nd Ed; CPT-2). Environmental factors included the Economic Hardship Index (EHI), guardian employment status while in pediatric care, and the number of persons living in the household. Use of adult ambulatory services was measured by the number of outpatient visits per patient-year. The association between cognitive performance and the latency from pediatric to adult care, adult care retention and environmental variables was examined using the 2-sample t test if the data were normally distributed or the Wilcoxon rank-sum test otherwise. Categorical variables were analyzed with the Chi-square test or Fisher's exact test. Transition outcomes were also analyzed as continuous variables using univariate linear regression. All reported p-values are two-sided. Results: Eighty adolescents with SCD ages 15-18 years at the time of their cognitive assessment (58% male, 63% HbSS/HbSβ0-thalassemia) were included; most transferred 12 months, and 31 of the 43 (72%) remained in adult care >24 months after their first adult visit. Higher Full-Scale IQ was associated with establishing adult care ≤2 months from last pediatric visit (Table 1; Figure 1A, 1B). Belonging to families with fewer children, smaller households and a higher WASI-2 Verbal Comprehension Index were associated with establishing adult care ≤6 months from last pediatric visit. Better CPT-2 Commissions performance (less attention deficit) was associated with increased adult care retention at 12 and 24 months (Table 2; Figure 1C,1D). Having a working guardian was associated with less retention at 12 months (p=0.01), whereas having an unemployed primary guardian was associated with greater retention at 24 months (p=0.02). Further, an employed guardian was associated with greater utilization of adult ambulatory services (p=0.01). EHI was not significantly related to transition outcomes. No relationship was found between adult ambulatory services and neurocognitive assessment. Conclusion: Neurocognitive deficit (lower IQ and attention deficits) may decrease short and long-term engagement in adult care among youth with SCD as demonstrated by longer latency periods between pediatric and adult care and shorter adult care retention. Socio-economic factors may also play a role in transition outcomes but require further investigation. Investigation of disease modifying therapies that preserve cognitive function should be prioritized. Interventions that account for patients' cognitive level and their environment should be considered in the individualization of transition plans. Disclosures King: Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novimmune: Research Funding; Amphivena Therapeutics: Research Funding; Incyte: Consultancy; Tioma Therapeutics (formerly Vasculox, Inc.):: Consultancy; Cell Works: Consultancy; Bioline: Consultancy; Celgene: Consultancy; RiverVest: Consultancy; WUGEN: Equity Ownership. Wang:Agios Pharmaceuticals: Consultancy; Novartis: Consultancy. Zhao:MBIO: Other: St. Jude Children's Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Kang:MBIO: Other: St. Jude Children's Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Hankins:National Committee for Quality Assurance: Consultancy; NHLBI: Research Funding; Global Blood Therapeutics: Research Funding; Novartis: Research Funding; LYNKS Foundation: Research Funding; NHLBI: Honoraria; ASPHO: Honoraria; Bluebird Bio: Consultancy.

Introduction Silent cerebral infarcts (SCI) and cerebral vessel stenosis are common and progressive in sickle cell anemia (SCA). Most data regarding brain lesions in SCA are cross-sectional or derive from pediatric cohorts with short follow-up not spanning the transition into adulthood. While hydroxyurea and transfusions may reduce the incidence of SCI and abnormal transcranial Doppler (TCD) in children with SCA, data on the effectiveness of these therapies in young adults are lacking. We tested the hypothesis that SCI and cerebral vessel stenosis progressed in young adults with SCA, relative to their childhood years. In addition, we explored the relationship between progression of brain vasculopathy and exposure to disease-modifying therapy. Methods We obtained brain magnetic resonance imaging (MRI) and MR angiography (MRA) in adults with SCA (HbSS or HbSβ0-thalassemia) on chronic transfusions or hydroxyurea. Participants were recruited from the IRB-approved longitudinal cohort study, Sickle Cell Clinical Research and Intervention Program (Hankins et al., PBC 2018). Participants were ages 18.0 to 32.0 at adult imaging and had at least one prior MRI/MRA between 0 and 17.9 years. Pediatric MRI/MRAs were performed for clinical indications (e.g., neurologic concern). All pediatric and adult MRI/MRAs had similar imaging protocols and were centrally reviewed by a neuroradiologist. SCIs were defined as focal T2-weighted or FLAIR hyperintensity. MRIs were considered abnormal if SCI or overt strokes were present. MRI progression was defined as new SCI or new overt strokes. Vessel stenoses were graded using a validated vasculopathy scale from 0 to 6 (Helton et al., Blood 2014). Abnormal MRA was defined as a score ≥1 and progression as any increase in the vasculopathy grading. We retrospectively ascertained childhood TCDs, treatments, overt strokes, and transient ischemic attacks (TIA, Results Forty-one young adults with SCA, all African American, median age 19.0 years, (range 18.0-31.5) were included (Table 1). All received disease-modifying therapy prior to adult MRI/MRA; median duration of hydroxyurea was 10.4 years (range, 0.3 to 20.35) and chronic transfusion was 9.2 years (range, 2.5 to 14.6). Indications for chronic transfusion were: abnormal TCD (N=6), overt stroke (N=4), recurrent vaso-occlusive events (VOE) (N=1), and chronic kidney disease (N=1). Indications for hydroxyurea were: VOE (N=27), overt stroke (N=1), and abnormal TCD (N=1). The total follow-up time from pediatric to adult brain MRI/MRA was 804 person-years, during which 2 patients had new strokes and 5 had TIAs. Progression of MRI and MRA occurred in 12 (29%) and 8 (20%) young adults, respectively, in relation to their pediatric exams (p=0.04 and p=0.01), both among hydroxyurea (Figure 1a) and transfusion (Figure 1b) groups. Both MRI and MRA progression occurred more frequently among those with prior stroke or conditional or abnormal TCD velocities, p=0.015. Controlling for age at adult imaging, exposure to hydroxyurea was associated with decreased probability of MRI progression (OR=0.05, 95%CI: 0.01~0.52, p=0.01), but not MRA (OR=0.22, 95%CI: 0.02~2.34, p=0.2). When further adjusting for transfusions, exposure to hydroxyurea was still associated with decreased probability of MRI progression (OR=0.05, 95%CI: 0.4~0.64, p=0.021) but not transfusions (OR 0.94, 95%CI: 0.16~5.39, p=0.95). Conclusion Close to a quarter of young adults with SCA treated with disease-modifying therapies for approximately a decade, experienced progression of brain lesions despite treatment with disease-modifying therapies. Among patients exposed to hydroxyurea, less progression of SCIs occurred. Overt stroke or TCD elevation in childhood increased the risk of brain lesion progression. In children with SCA, the presence of SCI and vessel stenosis in childhood should prompt consideration of alternative treatments given the evidence that brain lesions progress as they emerge into adulthood. Disclosures Kang: MBIO: Other: St. Jude Children's Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy. Estepp:Forma Therapeutics: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Eli Lilly and Co: Research Funding; Pfizer: Research Funding; Esperion: Consultancy. Ataga:Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Modus Therapeutics: Honoraria; Emmaus Life Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. King:Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novimmune: Research Funding; Cell Works: Consultancy; Bioline: Consultancy; Celgene: Consultancy; Amphivena Therapeutics: Research Funding; Tioma Therapeutics (formerly Vasculox, Inc.):: Consultancy; RiverVest: Consultancy; WUGEN: Equity Ownership. Wang:Agios Pharmaceuticals: Consultancy; Novartis: Consultancy. Hankins:NHLBI: Honoraria; ASPHO: Honoraria; Novartis: Research Funding; LYNKS Foundation: Research Funding; Bluebird Bio: Consultancy; NHLBI: Research Funding; Global Blood Therapeutics: Research Funding; National Committee for Quality Assurance: Consultancy.

Paroxysmal cold hemoglobinuria (PCH) is an autoimmune hemolytic anemia (AIHA) characterized by the presence of a Donath–Landsteiner (D-L) antibody. PCH occurs most commonly in young children and is associated with acute, often self-limited hemolytic anemia. The D-L antibody is classically a biphasic IgG anti-P autoantibody identified by the D-L test. Rare case reports confirm the existence of IgM D-L antibodies. We report the case of a 2-year-old male diagnosed with acute AIHA and found to have PCH caused by an IgA D-L antibody. The clinical course and treatment of this condition, which has not been reported previously, are described. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.

Background Randomized clinical trials in pediatric aplastic anemia (AA) are rare and data to guide standards of care are scarce. Procedure Eighteen pediatric institutions formed the North American Pediatric Aplastic Anemia Consortium to foster collaborative studies in AA. The initial goal of NAPAAC was to survey the diagnostic studies and therapies utilized in AA. Results Our survey indicates considerable variability among institutions in the diagnosis and treatment of AA. There were areas of general consensus, including the need for a bone marrow evaluation, cytogenetic and specific fluorescent in situ hybridization assays to establish diagnosis and exclude genetic etiologies with many institutions requiring results prior to initiation of immunosuppressive therapy (IST); uniform referral for hematopoietic stem cell transplantation as first line therapy if an HLA-identical sibling is identified; the use of first-line IST containing horse anti-thymocyte globulin and cyclosporine A (CSA) if an HLA-identical sibling donor is not identified; supportive care measures; and slow taper of CSA after response. Areas of controversy included the need for telomere length results prior to IST, the time after IST initiation defining a treatment failure; use of hematopoietic growth factors; the preferred rescue therapy after failure of IST; the use of specific hemoglobin and platelet levels as triggers for transfusion support; the use of prophylactic antibiotics; and follow-up monitoring after completion of treatment. Conclusions These initial survey results reflect heterogeneity in diagnosis and care amongst pediatric centers and emphasize the need to develop evidence-based diagnosis and treatment approaches in this rare disease. Pediatr Blood Cancer 2014;61:869–874. © 2013 Wiley Periodicals, Inc.

SWI is a powerful tool for imaging of the cerebral venous system. The SWI venous contrast is affected by blood flow, which may be altered in sickle cell disease. In this study, we characterized SWI venous contrast in patients with sickle cell disease and healthy control participants and examined the relationships among SWI venous contrast, and hematologic variables in the group with sickle cell disease.A retrospective review of MR imaging and hematologic variables from 21 patients with sickle cell disease and age- and sex-matched healthy control participants was performed. A Frangi vesselness filter was used to quantify the attenuation of visible veins from the SWI. The normalized visible venous volume was calculated for quantitative analysis of venous vessel conspicuity.The normalized visible venous volume was significantly lower in the group with sickle cell disease vs the control group (P.001). Normalized visible venous volume was not associated with hemoglobin, percent hemoglobin F, percent hemoglobin S, absolute reticulocyte count, or white blood cell count. A hypointense arterial signal on SWI was observed in 18 of the 21 patients with sickle cell disease and none of the 21 healthy control participants.This study demonstrates the variable and significantly lower normalized visible venous volume in patients with sickle cell disease compared with healthy control participants. Decreased venous contrast in sickle cell disease may reflect abnormal cerebral blood flow, volume, velocity, or oxygenation. Quantitative analysis of SWI contrast may be useful for investigation of cerebrovascular pathology in patients with sickle cell disease, and as a tool to monitor therapies. However, future studies are needed to elucidate physiologic mechanisms of decreased venous conspicuity in sickle cell disease.

Human rhinovirus (HRV), human coronavirus (hCoV), human bocavirus (hBoV), and human metapneumovirus (hMPV) infections in children with sickle cell disease have not been well studied.Nasopharyngeal wash specimens were prospectively collected from 60 children with sickle cell disease and acute respiratory illness, over a 1-year period. Samples were tested with multiplexed-PCR, using an automated system for nine respiratory viruses, Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Bordetella pertussis. Clinical characteristics and distribution of respiratory viruses in patients with and without acute chest syndrome (ACS) were evaluated.A respiratory virus was detected in 47 (78%) patients. Nine (15%) patients had ACS; a respiratory virus was detected in all of them. The demographic characteristics of patients with and without ACS were similar. HRV was the most common virus, detected in 29 of 47 (62%) patients. Logistic regression showed no association between ACS and detection of HRV, hCoV, hBoV, hMPV, and other respiratory pathogens. Co-infection with at least one additional respiratory virus was seen in 14 (30%) infected patients, and was not significantly higher in patients with ACS (P = 0.10). Co-infections with more than two respiratory viruses were seen in seven patients, all in patients without ACS. Bacterial pathogens were not detected.HRV was the most common virus detected in children with sickle cell disease and acute respiratory illness, and was not associated with increased morbidity. Larger prospective studies with asymptomatic controls are needed to study the association of these emerging respiratory viruses with ACS in children with sickle cell disease.

Elevated foetal haemoglobin (HbF) levels are protective against some manifestations of sickle cell anaemia but the impact on retinopathy is unknown. We report on 123 children with HbSS, 10.6% of whom developed retinopathy. Independent of hydroxycarbamide, children with a HbF

BACKGROUND: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.METHODS: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.RESULTS:Mean functioning on the baseline neurodevelopment scales was in the average range. There were no mental development scores CONCLUSIONS: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.

To investigate the concordance of blood count indices measured locally and at a central laboratory.In a multi-center clinical trial of hydroxyurea therapy in infants with sickle cell anemia (BABY HUG), the concordance between blood count indices measured locally and at a central laboratory was investigated.Local laboratory measurements of neutrophil and monocyte counts were significantly higher (44% and 37%, respectively) compared to the central measurements (p0.0001), and mean corpuscular volume (MCV) was higher centrally.Overnight shipping with processing delay causes spurious reductions in absolute neutrophil count (ANC) and absolute monocyte count (AMC) that may result in incorrect monitoring decisions in multicenter clinical trials.

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 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 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.

After postoperative deaths in children who were prescribed codeine, several pediatric hospitals have removed it from their formularies. These deaths were attributed to atypical cytochrome P450 2D6 (CYP2D6) pharmacogenetics, which is also implicated in poor analgesic response. Because codeine is often prescribed to patients with sickle cell disease and is now the only Schedule III opioid analgesic in the United States, we implemented a precision medicine approach to safely maintain codeine as an option for pain control. Here we describe the implementation of pharmacogenetics-based codeine prescribing that accounts for CYP2D6 metabolizer status. Clinical decision support was implemented within the electronic health record to guide prescribing of codeine with the goal of preventing its use after tonsillectomy or adenoidectomy and in CYP2D6 ultra-rapid and poor metabolizer (high-risk) genotypes. As of June 2015, CYP2D6 genotype results had been reported for 2468 unique patients. Of the 830 patients with sickle cell disease, 621 (75%) had a CYP2D6 genotype result; 7.1% were ultra-rapid or possible ultra-rapid metabolizers, and 1.4% were poor metabolizers. Interruptive alerts recommended against codeine for patients with high-risk CYP2D6 status. None of the patients with an ultra-rapid or poor metabolizer genotype were prescribed codeine. Using genetics to tailor analgesic prescribing retained an important therapeutic option by limiting codeine use to patients who could safely receive and benefit from it. Our efforts represent an evidence-based, innovative medication safety strategy to prevent adverse drug events, which is a model for the use of pharmacogenetics to optimize drug therapy in specialized pediatric populations.

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.

The Pediatric Hydroxyurea Phase 3 Clinical Trial (BABY HUG) was a phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial of hydroxyurea in infants (beginning at 9-18 months of age) with sickle cell anemia. An important secondary objective of this study was to compare clinical events between the hydroxyurea and placebo groups. One hundred and ninety-three subjects were randomized to hydroxyurea (20 mg/kg/d) or placebo; there were 374 patient-years of on-study observation. Hydroxyurea was associated with statistically significantly lower rates of initial and recurrent episodes of pain, dactylitis, acute chest syndrome, and hospitalization; even infants who were asymptomatic at enrollment had less dactylitis as well as fewer hospitalizations and transfusions if treated with hydroxyurea. Despite expected mild myelosuppression, hydroxyurea was not associated with an increased risk of bacteremia or serious infection. These data provide important safety and efficacy information for clinicians considering hydroxyurea therapy for very young children with sickle cell anemia. This clinical trial is registered with the National Institutes of Health (NCT00006400, www.clinicaltrials.gov).