Characterizing the modern person living with sickle cell disease (SCD) in the United States has been limited without a well-curated longitudinal registry. To address this, the Globin Research Network for Data and Discovery (GRNDaD) registry strives to collect clinical outcomes and quality of life metrics from Institutional Review Board-approved centres across the United States. Here, we examined the use of different disease-modifying therapies in (actively consented) adults and children with HgbSS and HgbS-β0 thalassaemia (SCA) from 38 sites. Of the 3169 active patients in GRNDaD, about 65% of subjects were on hydroxyurea (hydroxycarbamide; HU), and 2130 had SCA. As predicted, the absolute neutrophil counts were lower and mean corpuscular volumes were higher for patients on HU. However, there was a lower proportion of patients on HU in older age groups. In contrast, chronic RBC transfusion utilization was nearly twice as high in the 18- to 29-year-old age group than in the 11- to 17-year-old age group. For novel therapeutics, we examined use prior to voxelotor's removal from the market and prior to publication of the negative phase III trial of crizanlizumab. Voxelotor utilization in this cohort was three times that reported by claims data while crizanlizumab usage was nearly double, suggesting high-quality comprehensive sickle cell care could increase utilization of novel therapies.

BACKGROUND:Lung disease is a major cause of morbidity and mortality in children with sickle cell disease (SCD), a condition that is more common in individuals of African American descent. Spirometry is utilized in monitoring lung health. Recently, the American Thoracic Society recommended the use of race-neutral predictive equations. We aimed to evaluate how the use of race-neutral equations may affect spirometry results and interpretation in children with SCD. METHODS:This retrospective study included children aged 5-21 years with SCD followed at Arkansas Children's Hospital (01/01/2000-06/30/2023) who had completed at least one spirometry. Percent predictive (pp) and z-score values were calculated using race-adjusted and race-neutral predictive equations. Absolute and relative differences were calculated. Percent of subjects with forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) with z-score <-1.645 and pp < 80%, and FEV1/FVC z-score < -1.645 were compared. Severity of impairment based on z-score was compared. RESULTS:One hundred children completed 460 spirometries. Transitioning from race-adjusted to race-neutral equations resulted in [mean (SD)]: a decrease in ppFEV1 [-9.497% (2.8344)], FEV1 z-score [-0.723 (0.2286)], ppFVC [-10.08% (3.3440)], FVC z-score [-0.750 (0.2757)], FEV1/FVC z-score [-0.057 (0.05461)], and an increase in ppFEV1/FVC [0.2785 (0.3921)]. Transitioning from race-adjusted to race-neutral equations resulted in an increase of impairment for FVC and FEV1 and a threefold increase in subjects with abnormal values. CONCLUSIONS:Adoption of race-neutral reference equations resulted in a decrease in FEV1 and FVC values (z-scores and percent predicted) and an increase in severity of impairment.

Importance:Adverse childhood experiences (ACEs) are associated with poor health care use. In African American communities, where ACEs are more prevalent, it is critical to understand the association of ACEs with chronic illnesses, such as sickle cell disease (SCD), in children to expand trauma-informed care and improve outcomes. Objective:To examine the association between parental ACEs and health care use in pediatric patients with SCD, accounting for factors that may influence this association. Design, Setting, and Participants:This unblinded cross-sectional study was conducted from January 1, 2020, to December 31, 2023, at Arkansas Children's Hospital. Seventy-two of 77 approached caregivers (93.5%) participated. All resided within the Arkansas Children's Hospital catchment area. Exposure:Parental ACEs and resiliency were assessed using the Adverse Childhood Experiences Questionnaire (ACE-Q) and the Brief Resiliency Scale, respectively. Neighborhood deprivation was assessed using the Area Deprivation Index (ADI). Main Outcomes and Measures:Primary outcomes included number of visits to the emergency department (ED), number of missed clinic visits, and medication adherence (categorical outcomes). Independent variables included parental ACEs, parental resilience, and neighborhood ADI. Coefficients were derived from mixed regression models. Results:The final sample included 79 observations (mean [SD] patient age, 9.73 [4.88] years; 44 [55.7%] female) from 72 caregivers (6 reporting for >1 child), with 70 (88.6%) of ACE-Q respondents being mothers. The ACE risk was low in 32 caregivers (40.5%), intermediate in 33 (41.8%), and high in 14 (17.7%). Patients whose caregivers were at high risk had significantly more ED visits and admissions compared with those whose caregivers were at low risk (regression coefficient = 7.35; 95% CI, 1.77-12.94). Likewise, the number of ED visits and admissions was higher among patients whose caregivers had lower resiliency compared with those with more resilient caregivers (regression coefficient = 5.69; 95% CI, 0.13-11.26). ADI was not significantly associated with ED visits and admissions (regression coefficient = -0.02; 95% CI, -0.12 to 0.08). Parental ACEs were not significantly associated with other metrics of health care use. Conclusions and Relevance:This cross-sectional study of ACEs and resiliency in parents of children with SCD found that higher levels of parental ACE scores and lower resiliency were associated with visits to the ED. These findings support the importance of screening caregivers for ACEs and resilience to enhance trauma-informed care, particularly in marginalized populations.

Abstract Objective Neurocognitive complications in pediatric sickle cell disease (SCD)—even without overt stroke—are increasingly recognized, yet adolescents remain underrepresented in research. Adolescence is a critical window for brain maturation, particularly in regions supporting executive function, which are metabolically demanding and vulnerable to oxygen and nutrient deficits. This ongoing study aimed to characterize neurodevelopmental alterations in adolescents with SCD using comprehensive neurocognitive testing and multimodal MRI. Methods African American adolescents aged 12–17 years with severe SCD (HbSS or HbS/β⁰-thalassemia) and controls were enrolled. Stroke history was an exclusion criterion. Participants underwent a single visit including computerized neurocognitive assessment (NIH Toolbox), multimodal 3T MRI, and blood sampling. MRI protocols assessed cerebral perfusion (arterial spin labeling), brain structure (T1/T2-weighted imaging), metabolite levels (magnetic resonance spectroscopy), and white matter integrity (diffusion tensor imaging). Multivariable linear models included group and age as predictors. Results Sixteen participants (10 with SCD, 6 controls; mean age = 15.3 years; 53% female) were included. Adolescents with SCD showed significantly poorer executive function than controls (mean score: 89 vs. 109; p = 0.006). Cerebral perfusion was elevated in patients across all regions (p< 0.05). Significant group differences were observed in metabolite levels, including glutathione (difference (95% CI) = 0.07 [0.03, 0.11], p = 0.002), N-acetylaspartate (0.26 [0.04, 0.48], p = 0.025), and glycerophosphocholine (0.05 [0.01, 0.09], p = 0.015). Poorer executive function was associated with increased perfusion in the cerebrum (β = –1.60 [-2.61, -0.59], p = 0.005), cerebellum (β = -1.67 [-2.62, -0.73], p = 0.002), hippocampus (β = -0.93 [-1.75, -0.11], p = 0.029), and amygdala (β = -1.08 [-2.06, -0.10], p = 0.034). Reduced volumes of the hippocampus (β = -74.34 [-148.52, -0.17], p = 0.050), caudate (β = -68.12 [-131.54, -4.70], p = 0.037), and putamen (β = -105.99 [-193.15, -18.84], p = 0.021) were also significantly associated with executive dysfunction. Conclusion This study demonstrates that adolescents with SCD, even without stroke, show measurable disruptions in executive function that are potentially linked to altered perfusion, metabolite imbalance, and structural brain differences. These findings underscore the utility of multimodal neuroimaging in uncovering hidden neurodevelopmental vulnerabilities and support the need for targeted interventions during adolescence.

Sickle cell disease (SCD) is one of the most common genetic diseases, affecting nearly every organ, causing disability and reduced life expectancy. Newborn screening (NBS) is a successful public health initiative identifying SCD and other hemoglobinopathy disorders in infants to facilitate early treatment and management. A linked comprehensive surveillance system for SCD does not exist across programs in the United States (US), but collaborative efforts backed by agencies such as the Centers for Disease Control and Prevention and Centers for Medicare and Medicaid Services (CMS) are in place to generate population-based longitudinal public health surveillance to inform understanding of long-term outcomes.

The ability to characterize the modern person living with SCD in the US has been limited by the lack of a well-curated longitudinal registry. The Globin Research Network for Data and Discovery ( GRNDaD) registry aims to overcome this challenge by collecting data from the now 53 IRB-approved centers across the US in collaboration with the National Alliance of Sickle Cell Centers (NASCC) and the HRSA-funded Sickle Cell Disease Treatment Demonstration Project Grant. Here, we describe the use of disease-modifying therapy in (actively consented) adults and children with Hgb SS/ SB 0 thalassemia (SCA) from 37 sites. Methods: Each site consents subjects and enters extensive baseline data including SCD complications and labs, subjects also complete patient-reported outcomes (PROs)-both at baseline and annually. Each subject is expected to have an annual follow-up where data is extracted from the Electronic Health Record (EHR). All data is stored in REDCap and, for this abstract, data were extracted into R on all active subjects (data entry in the last two years) who have complete minimum data collected. Median values were compared using Mann-Whitney U tests. Disease-modifying therapy (DMT) in this study comprises hydroxyurea (HU), chronic red blood cell (RBC) transfusions, crizanlizumab, L-glutamine, and voxelotor. Results: There are 2501 active patients in GRNDaD. Twenty-six percent of subjects are pediatric </= 18 years of age, 55.5% are female and 66.7% have HgbSS or HgbSB 0 thalassemia (SCA). Here, we report data on people with SCA only, whose minimum data were complete (n=1272). Table 1 shows DMT by age. 187 (21%) adults and 31 (8.5%) children were not on DMT. Figure 2 is a box plot of the absolute neutrophil count (ANC) comparing adults and children who are and are not taking HU. Adults on HU had significantly lower ANCs than those not on HU (median = 4.4 (IQR: 3.07, 6.3) v 6.6 (IQR:4.07, 8.14), p<0.001) (Figure). Similar findings were observed for children ( median = 3.5 (IQR:2.5, 5.7) Vs 8.1 (5.8, 12.8) , p =0.04) Both children and adults on HU had higher MCVs than those not on HU (median for peds: 91.5 (IQR: 85.1, 98.75) v 86 (IQR: 83.3, 86.1), p=0.05, median for adults: 96.5 (IQR: 89, 107) v 90 (IQR: 86.1, 95.1), p<0.001). We compared hemoglobin for those on and off HU, and on and off voxelotor, excluding patients on chronic transfusion therapy. There was a statistically significant difference in hemoglobin when comparing on or off of HU (median 8.9 g/dl (IQR 7.95, 9.9) v 8.2 g/dl (IQR: 7.2, 9.7, p =0.047)). There were no statistically significant differences in hemoglobin when comparing subjects on or off of voxelotor (median = 8.4 g/dl (IQR: 7.5, 9.6) vs 7.9 (IQR: 7.4, 9.8), p =0.57). In the adults, there were statistically significantly more males than females on HU, but there were no differences seen in the pediatric cohort. Examining DMT by age group, chronic RBC transfusion use doubled from the 11-17 age group to the 18-29-year age group (12% to 25%) and HU use decreased (83%-59%) over this same period. Limitations: This cohort may over-represent those on DMT as those enrolled in GRNDaD were more likely to have clinic visits. Discussion: GRNDaD has doubled the number of sites consenting subjects and entering data over the last year. The number is expected to increase again in the next 12 months, as an additional 15 sites are already IRB-approved with a goal to include all SCD centers in NASCC. This cross-sectional description of the current population of people living with SCD and treated in NASCC-recognized SCD centers in the US shows that the majority of those with SCA are receiving DMT. There is a noticeable decrease in HU use during the transition period with an increase in the use of chronic transfusion therapy. Newer DMT has had limited uptake in this cohort. The next steps will be to provide longitudinal data on this population and examine associations of DMT and important clinical outcomes including PROs.

Pupil size and reactivity have been studied to objectively measure pain utilizing pupillometry measurements. Given the challenges associated with treating vaso-occlusive pain in pediatric patients with sickle cell disease, better assessment tools are needed. The objective of this study is to establish normative values for pupil size and reactivity in pediatric patients with sickle cell disease with the hope that pupillometry can be used as a tool to objectively measure pain and response to treatment with analgesic medications. Readings were performed using a NeurOptics PLR-2000 pupillometer. Forty-four males and 38 females, all black, were studied. Their median age was 11 years (range: 2 to 21). When comparing our participants with white participants in a previously published pediatric study, there was a significant difference in maximum constriction velocity ( t =3.45, P =0.009), maximum pupil size ( t =-5.57 mm, P <0.0001), and minimum pupil size ( t =-3.24, P =0.002). There was no significant difference in pupil size and reactivity between patients with sickle cell disease and black patients without the disease when compared with the previously published study. Therefore, further investigation of pupillometry within the black population during vaso-occlusive crisis and in the "well state" is warranted in pediatric patients with sickle cell disease.

Background Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) classically presents with diarrhea. Absence of diarrheal prodrome increases suspicion for atypical HUS (aHUS). Inability to obtain a fecal specimen for culture or culture-independent testing limits the ability to differentiate STEC-HUS and aHUS. Case-diagnosis/treatment Our patient presented with abdominal pain and constipation, and evaluation of pallor led to a diagnosis of HUS. There was a complete absence of diarrhea during the disease course. Lack of fecal specimen for several days delayed testing for STEC. Treatment for atypical HUS was initiated with complement-blockade therapy. PCR-testing for Shiga toxin from fecal specimen later returned positive. Alternative complement-pathway testing did not identify a causative genetic variant or anti-Factor H antibody. A diagnosis of STEC-HUS was assigned, and complement-blockade therapy was stopped. Conclusion Diagnosis of aHUS remains a diagnosis of exclusion, whereby other causes of HUS are eliminated with reasonable certainty. Exclusion of STEC is necessary and relies on testing availability and recognition of testing limitations. Diarrhea-negative STEC-HUS remains a minority of cases, and future research is needed to explore the clinical characteristics of these patients.

Purpose: Patients with sickle cell anemia can have long term neurocognitive deficits throughout their lifespan. The purpose of this study is to conduct neuropsychiatric evaluations and brain imaging to determine if individuals who have higher risk of falling behind in education can be identified, emphasize the importance of addressing educational needs of these patients, and identify patients who are at risk of developing further complications. Methods: IRB approved retrospective study of patients with Hemoglobin SS disease, who underwent Stanford-Binet Intelligence testing and Woodcock Johnson Achievement. All patients who underwent cognitive testing and also received a transcranial doppler ultrasound or magnetic resonance imaging between were included. All patients were referred to neuropsychiatric testing due to poor school performance. Results: 33 patients were included who underwent neuropsychiatric testing. These students were referred due to poor school performance. Of those, 15 patients had additional imaging studies. All patients were identified with hemoglobin SS disease. All patients were African American. The median age was 9 with an age range of 6 to 16 with a median grade was 4. This sample included 12 females and 3 males. 73% (11 of 15 individuals) were identified with below average full scale intelligence quotient. Of these, 46% (6 of 11) had measurable changes in MRI or transcranial doppler results. 5 of them had measurable changes in transcranial doppler and changes in their MRI, while 1 patient had a normal transcranial doppler, but showed changes in their MRI. On average, the maximum mean velocity was 164 cm/s and was higher than the patients with normal intelligence quotient scores at 148cm/s. The remaining 5 individuals also had below average full scale intelligence quotient without any findings on imaging. All 11 individuals also had below average scores in academic application, academic fluency, and academic skills. On average these patients were 3 years behind on reading, 2 years behind on math, and 2 years behind writing. Only one of these patients had an individualized education plan with extra assistance for education. 7 of the 11 patients with below average full scale intelligence quotients were on hydroxyurea and 2 of the 4 patients with average scores used hydroxyurea. The average hemoglobin level in the group that performed below average was 9.5 and 8.9 in the group that performed average. While, all patients who had average scores on the stanford-binet test did not have any abnormal transcranial dopplers and they all had delays in math, reading, and writing. Conclusion: Below average intelligence and delays in academic performance may be an indicator of patients at risk of developing further complications such as stroke.The full extent to this relationship is unclear. Further research is needed to determine the relationship between intelligence, academic performance and changes in imaging. Earlier detection of these patients can prevent further complications, develop individual treatment plans, and target closer monitoring. A multidisciplinary approach to treating patients with sickle cell disease should include neuropsychiatric evaluations, an assessment of academic achievement, and the opportunity for additional support in school to fully address the needs of this population.

BackgroundBoth simple transfusion (ST) of packed red blood cells and automated red cell exchange (RCE) are used in the treatment of acute chest syndrome (ACS). We report our experience using each of these modalities for the treatment of ACS.MethodsRetrospective chart review of patients with ACS treated with ST only (51 episodes, ST group) or RCE performed either at diagnosis (U-RCE group, 15 episodes) or after ST (ST+RCE group, 15 episodes).ResultsThe mean clinical respiratory score (CRS) at diagnosis was significantly higher in the U-RCE group than in the ST group, but there were no significant differences among the other groups. The CRS and WBC each decreased significantly after simple transfusion in the ST group and after RCE in the U-RCE group, but both the CRS and WBC increased significantly, and the mean platelet count fell significantly, after simple transfusion in the ST+RCE group. Only patients in the ST+RCE group required mechanical ventilation. There were no significant differences in length of stay (LOS) or total hospital charges among any of the groups, probably due to the small sample size.ConclusionsWe conclude that the CRS identifies the patients who are most severely affected with ACS, and that upfront RCE is a safe and effective treatment for these patients. Additional work is needed to develop a method to predict which of the apparently less severely affected patients will fail to improve after simple transfusion and should receive upfront RCE. Pediatr Blood Cancer 2013;60:1952-1956. (c) 2013 Wiley Periodicals, Inc.

The most common form of neurologic injury in sickle cell anemia (SCA) is silent cerebral infarction (SCI). In the Silent Cerebral Infarct Multi-Center Clinical Trial, we sought to identify risk factors associated with SCI. In this cross-sectional study, we evaluated the clinical history and baseline laboratory values and performed magnetic resonance imaging of the brain in participants with SCA (HbSS or HbSβ° thalassemia) between the ages of 5 and 15 years with no history of overt stroke or seizures. Neuroradiology and neurology committees adjudicated the presence of SCI. SCIs were diagnosed in 30.8% (251 of 814) participants who completed all evaluations and had valid data on all prespecified demographic and clinical covariates. The mean age of the participants was 9.1 years, with 413 males (50.7%). In a multivariable logistic regression analysis, lower baseline hemoglobin concentration (P < .001), higher baseline systolic blood pressure (P = .018), and male sex (P = .030) were statistically significantly associated with an increased risk of an SCI. Hemoglobin concentration and systolic blood pressure are risk factors for SCI in children with SCA and may be therapeutic targets for decreasing the risk of SCI. This study is registered at www.clinicaltrials.gov as #NCT00072761.

Abstract 4765 Introduction: Therapy for acute chest syndrome (ACS) in our hospital includes IV hydration, pain control, antibiotic therapy, incentive spirometry, and an inhaled bronchodilator in patients who are wheezing or who have a history of asthma. Patients also receive red blood cells as either a simple transfusion (ST) or an exchange transfusion using automated erythrocytapheresis (RCE). Here we present clinical and laboratory data from patients with ACS who were treated with RCE and compare these results to a contemporaneous control group of patients with ACS who were treated with ST. Methods: This was a retrospective study of all patients who presented to Arkansas Children9s Hospital from 1996 through 2010 for the treatment of newly diagnosed ACS. Episodes of ACS were separated into a control group who were treated with ST and a RCE group. Patients were referred to the apheresis service by the treating hematologist for RCE when they presented with severe ACS and impending respiratory failure (n=20) or when they failed to improve, or deteriorated, following ST (n=29). Summary statistics were described as mean ± standard deviation for continuous data and frequency and percentage for categorical data. Because there were patients with multiple episodes, repeated measures analyses were performed to evaluate the clinical differences between the RCE and ST episodes. Results: We identified a total of 81 patients who were diagnosed with a total of 119 episodes of ACS. The average age at presentation was 8.5 years (range 5 months to 20 years), 64% were male, and 78% had SS disease. Twelve patients (accounting for 11 episodes each in the RCE and ST groups) had a previous history of asthma and 23 patients had multiple episodes of ACS (median 2, range 2–6). Episodes treated with RCE were significantly more likely to present with tachypnea, retractions, nasal flaring, and decreased air movement but episodes treated with ST were significantly more likely to present with cough and wheezing, even though a previous history of asthma was not more common in the ST group than in the RCE group. The RCE group spent significantly more time on oxygen, eight episodes required BiPAP, and 3 episodes required mechanical ventilation but no ST episodes required either BiPAP or mechanical ventilation. The median WBC at diagnosis was significantly higher in the RCE group but there were no significant differences in hemoglobin level or platelet count between the groups. As expected, blood product utilization was significantly higher in the RCE group. There were no procedural or catheter-related complications in the RCE group. Mean length of stay was not significantly longer in the RCE group but total hospital costs were significantly higher as expected in the RCE group due to the expense of RCE and the need for ICU care, BiPAP, and mechanical ventilation. There were no deaths from ACS during the study period. Additional variables that were studied but did not differ significantly between the groups included fever, sites of pain, vomiting, grunting, accessory muscle use, crackles, decreased breath sounds, color, oxygen saturation, chest radiograph findings, initial hemoglobin and platelet count, and post-treatment blood counts. Discussion: We found that children treated with RCE were sicker than those treated with ST, as determined by tachypnea, retractions, nasal flaring, decreased air movement, duration of oxygen therapy, need for BiPAP, and need for mechanical ventilation. We also found that children with ACS who present with cough and wheezing are significantly less likely to require RCE. We conclude that RCE is an effective therapy for sicker patients with ACS but that further work is required to develop a predictive scoring system to discriminate prospectively between children with ACS who will benefit from RCE and those who can be treated successfully with ST. Disclosures: No relevant conflicts of interest to declare.

is silent cerebral infarction (SCI). In the Silent Cerebral Infarct Multi-Center Clinical Trial, sought to identify risk factors we evaluated the baseline laboratory and performed magnetic resonance of the brain with (HbSS thalassemia) no of Neuroradiology