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Children with sickle cell disease (SCD) who began hydroyxurea before age five years scored no differently on a measure of cognitive funciton than age, sex, and race-matched unaffected peers.

Neurologic complications are common in patients with sickle cell anemia (SCA), but conventional tools such as MRI and transcranial Doppler ultrasonography (TCD) do not fully assess cerebrovascular pathology. Cerebral tissue oximetry measures mixed oxygen saturation in the frontal lobes (SCT O2 ) and provides early prognostic information about tissue at risk of ischemic injury. Untreated patients with SCA have significantly lower SCT O2 than healthy controls that declines with age. Hydroxyurea is effective in preventing many SCA-related complications, but the degree to which it preserves normal neurophysiology is unclear. We analyzed participants enrolled in the Therapeutic Response Evaluation and Adherence Trial (TREAT, NCT02286154), which enrolled participants initiating hydroxyurea using individualized dosing (New Cohort) and those previously taking hydroxyurea (Old Cohort) and was designed to monitor the long-term benefits of hydroxyurea. Cerebral oximetry was performed at baseline and annually. For the New Cohort (median starting age = 12 months, n = 55), mean baseline SCT O2 was normal before starting hydroxyurea (mean 65%, 95% CI 58-72%) and significantly increased after two years (mean 72%, 95% CI 65-79%, p = 0.00001). The SCT O2 for patients receiving long-term hydroxyurea (median age = 9.6 years) was normal at study entry (mean 66%, 95% CI 58-74%) and remained stable across two years. Both cohorts had significantly higher SCT O2 than published data from predominantly untreated SCA patients. Cerebral oximetry is a non-invasive method to assess cerebrovascular pathology that complements conventional imaging. Our results indicate that hydroxyurea suggests protection against neurophysiologic changes seen in untreated SCA. This article is protected by copyright. All rights reserved.

Finally,after decades of stagnation, the therapeutic landscape for sickle cell disease (SCD) is changing with an increasing number of novel therapeutics. Hydroxyurea remains the primary disease-modifying therapy and, when started early in life with maintenance of an optimal dose, can reduce many SCD-related complications. To complement hydroxyurea, there are a growing number of pharmacologic options with additional efforts focused on the development and optimization of curative therapies. Here, we review current treatment options and provide recommendations as to how to approach the treatment of children and adolescents within this evolving therapeutic landscape to allow for full and healthy lives.

BACKGROUND Without early initiation of disease-modifying therapy, the acute and chronic complications of sickle cell anemia (SCA) begin early in childhood and progress throughout life. Hydroxyurea is a safe and effective medication that reduces or prevents most SCA-related complications. Despite recommendations to prescribe hydroxyurea for all children with SCA as young as 9 months, utilization remains low. PROCEDURE We completed a retrospective review of hydroxyurea-prescribing practices and associated clinical outcomes at our institution over a 10-year period before and after the 2014 National Heart, Lung, and Blood Institute (NHLBI) recommendations to use hydroxyurea for all children with SCA. RESULTS Hydroxyurea use more than doubled within our pediatric SCA population from 43% in 2010 to 95% in 2019. The age of hydroxyurea initiation was significantly younger during 2014-2019 compared to 2010-2013 (median 2 years vs. 6 years, p ≤ .001). With this change in clinical practice, nearly all (69/71 = 97%) children born after 2013 received disease-modifying therapy by the end of 2019, primarily hydroxyurea (93%). Concurrently, the number of SCA-related admissions significantly decreased from 67/100 patient-years in 2010 to 39/100 patient-years in 2019 (p

Introduction Diffuse liver lesions in an infant have a differential diagnosis including infantile hemangioma (IH), which is common in the first year of life, and neuroblastoma (NBL) which presents at a median age of 18 months. Results We describe the case of a 4-month-old girl with a known superficial/deep IH who presented with new axillary nodules and hepatosplenomegaly, initially suspected to reflect IH but later determined to be widely metastatic NBL. Conclusion Hepatic IH and metastatic NBL can present similarly. Clinicians must maintain a broad differential when evaluating new findings in a patient with previously diagnosed IH.

Background Children with sickle cell disease (SCD) are at risk for neurocognitive deficits, which can lead to effects on academic performance and later job attainment. However, screening in children at high risk for poor academic performance (PAP) in a clinic setting has been limited. The goal was to identify young children with SCD at high risk for PAP via administration of a standardized screening tool at the clinic visit. Procedure Parents of 20 patients were asked to complete the Behavior Assessment System for Children, 3rd edition (BASC-3) Parent Rating Scale. Children ages six to nine years and all SCD genotypes were included. Those patients who scored at least 1 standard deviation below the mean were considered high risk. Statistics was used to associate demographic, academic, and laboratory data with risk status (RS). Results Four of 20 patients (20%) were found to be at risk by the BASC-3. A significant association was found between those with a history of PAP and RS (P = 0.001). A trend toward association was found between baseline hemoglobin, reticulocyte count, and RS. Children not at risk had a higher hemoglobin level and lower reticulocyte count (P = 0.37 and P = 0.20, respectively). Those on hydroxyurea were significantly less likely to score as at risk (P = 0.014), whereas those with siblings may be at greater risk (P = 0.037). Conclusion(s) A parent-directed screening tool may identify children with SCD in need of additional school support. Further prospective studies are necessary to understand correlations found between hemoglobin, reticulocyte count, and hydroxyurea treatment and risk for PAP.

Objectives To describe the academic concerns and risk strata of children with sickle cell disease (SCD) as identified through a parent-directed screening tool and to compare the rates of these concerns with actual school service utilization in the clinic population. Study design We completed a retrospective review of patients with SCD referred to the school intervention program during the 2017-2018 and 2018-2019 school years because of a school-related concern raised by parents or noted by the clinical team. All parents completed the Brief School Needs Inventory (BSNI), a validated parent-response tool used to stratify academic risk. Rates of special education services, grade retention, and results from neuropsychologic testing were captured. Clinical history, the use of disease-modifying therapy, and results from laboratory and neuroimaging studies were also obtained. Descriptive statistics were performed to examine demographic information, clinical history, and BSNI results. Results In total, 137 unique patients (age range, 14 months to 19 years) completed the BSNI during the study period, for 181 events. According to BSNI risk-stratification, 45% of patients were deemed low, 36% moderate, and 19% high academic risk. Over one-half of parents were concerned about their ability to advocate for their child's needs. Despite legal qualification for a Section 504 accommodation plan, only 20% had established plans. Academic concerns were common with 31% of children reporting an individualized education program and 20% with grade retention/remediation. Conclusions Concerns for academic challenges remain high among parents of children with SCD; however, school service utilization remains disproportionately low attributable to numerous reasons.

Acute vaso-occlusive episodes (VOE) are the most common reason for presentation to the Emergency Department (ED) and inpatient admission in people living with sickle cell disease (SCD). The goal of this study was to compare the hospital admission rate for VOE from our centre's day hospital (Pediatric Ambulatory Chemotherapy and Transfusion Unit; PACT) versus the ED, and to determine which factors influence admission rate. The study included a total of 370 visits involving 140 children with SCD with a mean age of 10·9 ± 5·5 years. The timing from triage to the first analgesic was significantly different between the PACT and the ED (median, 32 vs. 70 min, P < 0·0001). The initial choice of opioid dosage adhered to our centre's guidelines 84% of the time in the PACT v. 45% in the ED for morphine (P = 0·0003) and 100% in the PACT vs. 43% (P = 0·002) for hydromorphone. The admission rate from the ED (57%) was significantly higher than that of the PACT (29%) even when accounting for differences in baseline variables (P = 0·0001). In conclusion, the odds of being admitted were 3·8 times higher if the patient was treated in the ED. Timely administration and appropriate dosing of intravenous opioids may change this outcome in the future.

Introduction: The neurologic changes of sickle cell anemia (SCA) are particularly devastating and include acute stroke, silent infarctions, and cerebral hypoxemia that together result in cumulative damage and significant neurocognitive deficits. Executive functioning and attention are the most commonly reported deficits with individuals with SCA scoring on average ten points lower on measures of full scale intelligence compared to matched unaffected controls, translating to poor academic achievement and later job attainment. Hydroxyurea is the standard-of-care in patients with SCA with a growing body of evidence suggesting a role in neuroprotection. However, although encouraging, until now, the only studies have involved children who began hydroxyurea in grade school, well after the onset of SCA-related neurocognitive decline. Beginning in 2014, Cincinnati Children's Hospital Medical Center (CCHMC) began treating children with SCA as young as six months with hydroxyurea; these children have had few SCA-related complications and offer a unique population to evaluate the effects of the early introduction of hydroxyurea on neurocognition. Methods: We completed a cross-sectional analysis of the neurocognitive status of our SCA population. Children at least three years old with SCA were enrolled in two cohorts: 1) children with SCA (HbSS and HbS-B 0thalassemia genotypes) who began hydroxyurea before age five years and 2) children with SCA who did not qualify for the first cohort (either on hydroxyurea or chronic transfusions (CTT)). Unaffected controls (siblings of patients with SCA or children seen in the CCHMC primary care clinic) were matched to each patient with early hydroxyurea use by age, race, and sex. All participants completed the NIH Toolbox: Cognition Battery, a shortened neuropsychological evaluation administered using a handheld tablet in the clinical setting, requiring 15-30 minutes. The mean score is 100 and standard deviation 15. We also obtained academic history, demographic variables, and laboratory values for SCA patients. Our overall objective was to compare the neurocognitive status of children with SCA who initiated hydroxyurea before age five years to an unaffected, matched sibling and community control cohort and to historically treated patients followed at the CCHMC sickle cell clinic in order to assess whether the beneficial effects of hydroxyurea extend to neuroprotection. Results: We enrolled 29 patients into the early hydroxyurea SCA group with 24 matched unaffected controls (early hydroxyurea group: mean age 7.2 +/-3.2 years, 52% female). The SCA cohort who initiated disease modifying treatment later in life included 20 patients (mean age 16 +/-5.1 years, 70% female) (Table 1). There were no differences in age, gender, patient education, maternal education, and Area Deprivation Index (ADI, a marker of socioeconomic status) between the early hydroxyurea SCA and control cohorts (Table 1). In the SCA cohort initiating treatment later in life, 5 patients received hydroxyurea, 13 were on CTT for reasons other than for stroke prophylaxis, and 2 received no therapy. The early hydroxyurea use patients and controls scored no differently on the composite cognition score (86 +/-13 versus 88 +/-12, p = 0.6), while the early hydroxyurea patients scored significantly higher than the SCA cohort treated later in life on the composite cognition (versus 77 +/-14, p = 0.03) (Table 2). On a linear regression model, age (p = 0.004) and patient years of education (p = 0.04) were significantly correlated with the composite cognition score when considering all cohorts. When limited to only patients with SCA on hydroxyurea, age (p = 0.005) and patient education (p = 0.002) remained significant, while maternal educational attainment below high school (p = 0.07), hemoglobin (p = 0.07), and fetal hemoglobin (p = 0.07) approached significance. Conclusions: Due to challenges with social determinants of health, children with SCA are already at risk for poor academic performance with early and recurrent "silent" hypoxic events further exacerbating these challenges. If started early in life and maintained through the important early years of brain development, hydroxyurea may be neuroprotective for children with SCA. These data provide further evidence to support the universal prescription of hydroxyurea beginning in the first years of life for all children with SCA. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Introduction: Sickle cell anemia (SCA) is a severe and life-threatening disorder that requires treatment to prevent short- and long-term complications and prolong life. The primary disease-modifying therapy for SCA remains hydroxyurea (HU). Due to 30 years of evidence demonstrating safety and efficacy culminating with BABY HUG, the 2014 National Heart, Lung, and Blood Institute (NHLBI) guidelines recommended offering HU to all children with the severe sickle cell genotypes (HbSS, HbS-0thalassemia) beginning at 9 months of age. Despite these recommendations, HU utilization in pediatric patients in the US remains with rates reported as low as 38-47% among the most severe genotypes as recently as 2017. Providers have identified a number of barriers to more widespread use, including the inability to identify which patients may benefit, concern for possible side effects, uncertainties regarding dose, and concerns regarding possible nonadherence. As complications begin as early as the first year of life, it is a disservice to withhold a proven therapy. Here, we describe the effective and nearly universal uptake of HU in our pediatric SCA population at Cincinnati Children's Hospital Medical Center (CCHMC). Methods: We performed an IRB-approved retrospective review to assess the hydroxyurea prescribing practices and clinical complications of patients with SCA treated at CCHMC from 2010-2019. Following the NHLBI guidelines' release in 2014, we changed the recommended age of HU initiation to be within the first year of life. Corresponding with this change, we have initiated HU for most young children with an individualized, pharmacokinetics (PK)-guided dosing strategy through both the Therapeutic Response Evaluation and Adherence Trial (TREAT, NCT03789591) and the Hydroxyurea Optimization through Precision Study (HOPS, NCT03789591). Due to the onset of symptoms for some patients before 9 months, we have offered HU initiation as early as 6 months of age since 2015. Our objective was to compare the rates of HU utilization, age of initiation, and hospitalization rate before (2010-13) and after (2014-19) the release of the NHLBI guidelines and the start of the TREAT study in 2014. Demographic and clinical data, including sickle cell genotype, prior/alternative therapy, SCA-related complications, HU dosing, and laboratory values were abstracted from each patient's electronic medical record (EMR). Patients were identified using the EMR's sickle cell registry. Results: We identified 439 patients with sickle cell disease followed at CCHMC from 2010-2019 (47% female, age range: 0-22 years); 275 had SCA (HbSS, HbS-0-thalassemia, or HbSD). The proportion of patients with SCA prescribed HU increased from 2010-19, from 35% in 2010 to 80% in 2019 with significantly more patients initiating HU during 2014-19 versus 2010-13 (average 20 versus 12 patients/yr, p = 0.0028, Figure 1A). The age of HU initiation was significantly lower during 2014-19 compared to 2010-13 (median = 2 y vs 6 y, p = 0.00028). Of 35 patients with SCA not on HU in 2019, 28 received chronic transfusions and the remaining 7 received no disease-modifying therapy with 3/7 patients not yet at the age to start HU. Ninety-six percent (53/55) of children with SCA born during 2014-19 were on treatment, including 52 on HU (median starting age = 10 months) and 1 on chronic transfusions; 45/52 (87%) were enrolled on TREAT or HOPS. With increased HU utilization during this study period, the number of admissions for sickle-related events was significantly lower in the 2014-19 group versus 2010-13 (2.8 vs 6.9 admissions/pt, p = 9.0 x 10-10) with no change in non-SCA related admissions, most commonly for fever (3.8 vs 4.0 admissions/pt, p = 0.8, Figure 1B). Conclusions: HU has become the standard of care for children with SCA, beginning at 6-9 months of age, prior to the onset of acute and chronic complications. Despite widespread concerns that HU will not be accepted by patients and national trends demonstrating low rates of utilization, we have shown that a deliberate, systematic, and preventive approach to HU is possible and results in nearly universal acceptance of HU for young patients with SCA. This has translated to excellent laboratory responses and significantly fewer SCA-related clinical complications in our population. Our approach and improved patient outcomes can serve as a model for other programs to expand their HU treatment for more children with SCA. Figure 1 Disclosures Kalfa: Agios Pharmaceuticals, Inc: Consultancy, Research Funding; Forma Therapeutics, Inc: Research Funding. Malik:Aruvant Sciences, CSL Behring: Patents & Royalties; Aruvant Sciences, Forma Therapeutics, Inc.: Consultancy.

The intracellular parasites Babesia microti and Babesia duncani can be transmitted by blood transfusion and cause severe life-threatening hemolytic anemia in high-risk patients, including those with sickle cell disease. The rarity of the diagnosis, as well as its similar clinical presentation to delayed hemolytic transfusion reaction, may lead to a delay in diagnosis, as well as inappropriate treatment with steroids or other immunosuppressive agents. The morbidity caused by this disease in especially vulnerable populations justifies the need for a universal blood-screening program in endemic areas.

Introduction: Neurocognitive deficits are a well-known complication in patients with sickle cell disease (SCD) and are often associated with overt stroke and silent infarctions. However, cognitive deficits may be seen in patients even without apparent MRI findings as compared to non-affected controls. Studies have also shown the impact of socioeconomic status and parental education on school retention and cognition in patients with SCD. More specifically, rates of retention and special education service use through either an Individualized Education Plan (IEP, providing specialized education services) or 504 Plan (providing accommodations due to physical disability/medical diagnosis) are reported as high as 40%. However, these historical data have been limited to primarily adolescent patients. Thus, a more thorough analysis is needed to better determine the prevalence and types of academic challenges among children with sickle cell disease, particularly younger ages. Methods: The Cincinnati Children's Hospital Medical Center's Comprehensive Sickle Cell Clinic includes a school intervention program. This program includes 1-2 full time school teachers who engage directly with patients, parents, and school staff to ensure the provision of adequate school-based services and to address specific challenges or concerns. Children with SCD are referred to the school interventionist by the clinical team (including both medical and psychosocial providers) for any school-related concern. The interventionist completes the Brief School Needs Inventory (BSNI), a thirty-item tool that determines a patient's educational risk based on academic and psychosocial history and parental responses. The BSNI provides a numeric score from 0-20 and a categorical risk of 1 (low risk) to 3 (high risk). In this retrospective review, the BSNI for all patients with SCD completed during the 2018-2019 school year were reviewed. The prevalence of the receipt of special education services (SES), grade retention, neuropsychological testing, and number of school absences were captured. Basic demographic and disease-related data, including zip code, patients' disease history, use of disease-modifying therapy, and any notable brain MRI findings were also recorded. Median household income was extrapolated from the zip codes based on 2017 US Census Bureau reporting (the most recently published year). Results: A total of 78 patients (58 HbSS, 17 HbSC, 3 HbS/β+-thalassemia) completed the BSNI for the 2018-19 academic year; an additional 15 children were also referred but did not complete the evaluation. Nearly all (95%) of patients with HbSS were receiving disease-modifying therapy (hydroxyurea or transfusions); 41% of patients with MRIs showed abnormal findings. Median age was 9 years (range 14 months - 19 years, preschool - post-secondary education). Nineteen percent of patients lived in a zip code with a median household income below the federal poverty level ($25,750). The mean BSNI score was 7.6±5.5; 27 patients were deemed low risk, 32 moderate risk, and 19 high academic risk by the BSNI (Table 1). A majority (50%) of parents responded with concerns both with obtaining support/accommodations for their child and explaining their child's medical needs to the school. Of 59 recorded, 24% of patients had had at least 16 absences in the prior year. Despite the diagnosis of SCD for all patients, only 21% had established 504 medical plans. Academic concerns were common with 20% of referred children reporting an IEP, 14% of patients with a history of grade retention, and an additional 10% with concerns for possible retention. Conclusion: The prevalence of academic difficulties and challenges is high amongst patients with SCD even in the elementary to middle school years, with rates of grade retention ~20% as compared to the national average of Disclosures No relevant conflicts of interest to declare.