Children's Hospital Medical Center Research Articles

Quality Improvement Methodology Optimizes Infliximab Levels in Pediatric Patients with Inflammatory Bowel Disease.

We participated in Intermediate Improvement Science Series, a course at Cincinnati Children's Hospital Medical Center designed to catalyze change using quality improvement methodology. We implemented interventions through plan-do-study-act cycles. Our outcome measure was balanced by 2 process measures to determine what actions impacted improvement. These measures included the percentage of infusion plans revised in response to a drug level <5 μg/mL and the proportion of plans for which a follow-up drug level was ordered. We increased the percentage of infusion plans revised before the next infusion from 63% to 87% and the percentage of plans that had an appropriate drug level recheck from 61% to 83% from July 2017 to January 2018. We increased the percentage of patients with an infliximab level >5 μg/mL, and results checked in the last 12 months, from 73% to 80%. Quality improvement methodology was effective in improving provider adherence to infliximab therapeutic drug monitoring guidelines. Improvement in adherence to guidelines directly improved the percentage of patients achieving target infliximab levels at any time during infliximab therapy.

Increasing Pediatric Audiology Services via Telehealth.

Telehealth as a means to deliver health care services has been used by physicians for many years, but the use of telehealth in audiology, specifically in pediatrics, has been minimal. Barriers such as licensure, reimbursement, technology, and equipment have been cited as reasons for audiologists not participating in telehealth. However, the COVID-19 pandemic created the need for telehealth services to be widely used to safely increase access to healthcare, and emergent orders helped reduce previous barriers so that audiologists could participate in telehealth service delivery. This article details three cases where audiologists delivered telehealth services to children. These case studies demonstrate portions of the Division of Audiology Telehealth Program of the Cincinnati Children's Hospital Medical Center and how they increased access to hearing healthcare in response to the COVID-19 pandemic.

First person – Lauren Falkenberg

ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models &amp; Mechanisms, helping early-career researchers promote themselves alongside their papers. Lauren Falkenberg is first author on ‘Ccdc103 promotes myeloid cell proliferation and migration independent of motile cilia’, published in DMM. Lauren is a MD/PhD student in the lab of Joshua S. Waxman at Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA, investigating the intersection of rare disease biology, human genetics and immunology.

Variation in imaging outcomes associated with individual sonographers and radiologists in pediatric acute appendicitis: a retrospective cohort of 9271 examinations

To determine if individual sonographers and radiologists impact appendix visualization by ultrasound and utilization of computed tomography (CT) in children with suspected acute appendicitis. Appendix ultrasound examinations performed at Cincinnati Children's Hospital Medical Center on Emergency Department patients ≤ 18 years old were retrospectively identified. Examinations performed/interpreted by sonographers/radiologists with fewer than 100 examinations were excluded. Multivariable logistic regression was used to assess the effect of sonographer, radiologist, clinical variables, and system factors on imaging outcomes, including appendix visualization and subsequent CT utilization. A total of 9271 ultrasound examinations (mean [SD] patient age, 9.9 [4.2] years; 5392 [58.2%] boys) performed by 31 sonographers (mean number examinations, 299 [139]; range, 115-610) and interpreted by 31 radiologists (mean number examinations, 299 [157]; range, 101-845) were included. The mean frequency of appendix visualization per sonographer was 57.8% [8.7%] (range, 40.9-76.0%) and per radiologist was 59.5% [4.1%] (range, 51.7-66.3%). The mean rate of CT utilization per sonographer was 9.2% [2.0%] (range, 5.9-14.0%) and per radiologist was 9.2% [1.8%] (range, 3.4-12.1%). Predictors of appendix visualization by ultrasound included patient weight (p < 0.0001), sex (p = 0.0003), white blood cell count (p < 0.0001), temperature (p = 0.002), abdominal tenderness (p = 0.004), presence of appendicitis (p < 0.0001), sonographer (p < 0.0001), and radiologist (p = 0.02). Predictors of CT utilization included patient weight (p < 0.0001), white blood cell count (p < 0.0001), abdominal tenderness (p < 0.0001), rebound tenderness (p = 0.0003), and presence of appendicitis (p < 0.0001), but not sonographer or radiologist. Individual sonographers and radiologists were associated with appendix visualization by ultrasound in children with suspected acute appendicitis; neither was associated with CT utilization. • Individual sonographers and radiologistsare significantly and independently associated with appendix visualization by ultrasound in children with suspected acute appendicitis. • Frequency of appendix visualization per sonographer demonstrated significant and wide variability across 31 sonographers, ranging from 40.9 to 76.0%. • Fewer than 10% of patients with an ultrasound examination for suspected acute appendicitis underwent CT imaging within the following 24 h. Individual radiologists and sonographers were not predictive of CT utilization within 24 h.

Arthrogryposis-renal Dysfunction-cholestasis Syndrome

Background: Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare autosomal recessive disorder mostly affecting the liver, kidney, skin, as well as central nervous and musculoskeletal systems. This multisystemic disease results from mutations in the vacuolar protein sorting 33B (VPS33B) or VPS33B- interacting protein, and apical-basolateral polarity regulator (VIPAR) genes. This is a lethal disorder from which few patients can survive at the first year of their life. This syndrome exhibits a wide range of phenotypes, such as ichthyosis, hypothyroidism, agenesis of the corpus callosum, and congenital cardiovascular anomalies. Case report: Here, we present the case of a 32-day-old male neonate with respiratory distress admitted to Children's Medical Center Hospital in Tehran, Iran, in August 2019. He had ichthyosis, cholestasis with arthrogryposis as bilateral clubfeet, developmental dysplasia of the hip, and flexion contractures in upper limbs. During hospitalization, he received Shohl’s solution for metabolic acidosis, intravenous antibiotics, fat-soluble vitamins, and levothyroxine. Other presentations in our case included ichthyosis, failure to thrive, congenital heart disease, and hypothyroidism. Conclusion: Timely diagnosis, supportive care and genetic counseling should be provided for better outcome. Keywords:

Pediatric flexible airway endoscopy training during a pandemic and beyond: Bending the curve.

Flexible airway endoscopy, for diagnostic and therapeutic purposes, is a vital aspect of pediatric pulmonology practice, and has become an integral aspect of formal training in pediatric pulmonology. This article is protected by copyright. All rights reserved.

Cervicofacial Lymphangioma: Is it Time to Put Down the Scalpel?

To assess the efficacy of intralesional injection of bleomycin for treatment of pediatric lymphangiomas in head and neck region in Iranian population. This prospective study was conducted from February 2017 to March 2019. All consecutive patients presented to pediatric otolaryngology clinic in Children Medical Center Hospital in Tehran with macrocystic lymphangiomas of head neck were enrolled in this study. Informed consent was taken from parents. Bleomycin was diluted to a concentration of 1mg/ml by normal saline and a dose of 0.5mg/kg was injected into the lymphangioma. Ultrasonography was performed before and after each injection at 1, 3, 6 and 12months. Age, gender, number of injections, size of lymphangioma and complications including fever, discoloration and respiratory problems were recorded. A total of 20 patients were assessed. Mean age at first injection was 31.9months. Average reduction in size was 84%. Complete disappearance of mass was observed in 65% (13/20) of patients. Twenty-five percent (5/20) of patients had more than 50% reduction in size. Ten percent (2/20) had unsatisfactory results. Three patients developed transient erythema or swelling of injection site, but none of the patients had any respiratory problem. Intralesional injection of bleomycin is an effective modality to use as a first-line treatment of macrocystic head and neck lymphangiomas in Iranian pediatric population.

It takes a village to raise a sickle cell warrior.

Pediatric Blood & CancerVolume 68, Issue 4 e28937 HIGHLIGHT It takes a village to raise a sickle cell warrior Alexandra Power-Hays, Corresponding Author Alexandra Power-Hays Alexandra.Power-Hays@cchmc.org orcid.org/0000-0002-5823-0218 Cancer and Blood Disorders Institute, Cincinnati Children's Hospital, Cincinnati, Ohio, USA Correspondence Alexandra Power-Hays, Cancer and Blood Disorders Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229. Email: Alexandra.Power-Hays@cchmc.orgSearch for more papers by this author Alexandra Power-Hays, Corresponding Author Alexandra Power-Hays Alexandra.Power-Hays@cchmc.org orcid.org/0000-0002-5823-0218 Cancer and Blood Disorders Institute, Cincinnati Children's Hospital, Cincinnati, Ohio, USA Correspondence Alexandra Power-Hays, Cancer and Blood Disorders Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229. Email: Alexandra.Power-Hays@cchmc.orgSearch for more papers by this author First published: 28 January 2021 https://doi.org/10.1002/pbc.28937Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume68, Issue4April 2021e28937 RelatedInformation

Overcoming barriers to establishing autopsy procurement programs in pediatric patients with central nervous system tumors: a call to develop regional centers

While autopsy-repository programs with a variety of pediatric central nervous system (CNS) tumor types are a critical resource for preclinical neuro-oncology research, few exist and there is no published guidance on how to develop one. The goal of this prospective Pediatric Brain Tumor Repository (PBTR) study was to develop such a program at Cincinnati Children's Hospital Medical Center (CCHMC) and then publish the quantitative and experiential data as a guide to support the development of similar programs. Protocols and infrastructure were established-to educate oncologists and families, establish eligibility, obtain consent, address pre- and post-autopsy logistics (e.g., patient and tissue transportation), process and authenticate tissue samples, and collect and analyze data. Of the 129 pediatric CNS tumor patients at CCHMC who died between 2013 and 2018, 109 were eligible for our study. Of these, 74% (81 of 109) were approached for PBTR donation, and 68% (55 of 81) consented. In the final year of the study, approach and consent rates were 93% and 85%, respectively. Median time from death to autopsy (postmortem interval, PMI) was 10 h (range, 1.5-30). In the outpatient setting, PMI increased with distance (from the hospice/home where the patient died to CCHMC). In all patients, PMI appeared to be lower, when consent was obtained more than 24 h before death. Procurement of autopsy specimens need not be a barrier in neuro-oncology research. Regional centers, strict timing-of-consent, patient education, and dedicated staff are all needed to minimize PMI and, thereby, increase the value of the procured tissue for an array of basic and translational research applications.

Discrepancies between F-18-FDG PET/CT findings and conventional imaging in Langerhans cell histiocytosis.

Accurate risk stratification of Langerhans cell histiocytosis (LCH) is essential as management can range from conservative in single system, low risk for central nervous system (CNS) involvement lesions to intensive chemotherapy for multisystem or high-risk disease. Additionally, being able to differentiate metabolically active from inactive lesions is essential for both prognostic reasons and to avoid potentially unnecessary treatment. A retrospective review was performed on all patients with histopathology-confirmed LCH at Cincinnati Children's Hospital Medical Center (CCHMC) between 2009 and 2019. One hundred seven positron emission tomography (PET)/computerized tomography (CT) images were included in the review. A discrepancy between PET/CT and conventional imaging occurred on 53 occasions. On 13 occasions, increased uptake was observed on PET in an area with no identifiable lesion on conventional imaging. On 40 occasions, lesions were found on conventional imaging where no increased uptake was observed on PET. On eight skeletal surveys, three other radiographs, four diagnostic CTs, five localization CTs, and one bone scan, no lesion was identified in an area with increased fluorodeoxyglucose (FDG) uptake. This occurred exclusively in bone. On nine skeletal surveys, one other radiograph, four diagnostic CTs, six localization CTs, 19 magnetic resonance imaging (MRI) scans, and one bone scan, a lesion was identified in a location without increased FDG uptake. This occurred in bone, CNS, and lungs. F-18-FDG PET/CT is vital in the evaluation of LCH lesions given its ability to detect LCH lesions not detectable on conventional imaging modalities, as well as its ability to distinguish metabolically active from inactive disease. MRI and diagnostic CT are still useful adjunctive tests for identification of CNS and lung lesions.

Building a Population Representative Pediatric Biobank: Lessons Learned From the Greater Cincinnati Childhood Cohort.

Background: Biobanks can accelerate research by providing researchers with samples and data. However, hospital-based recruitment as a source for controls may create bias as who comes to the hospital may be different from the broader population.Methods: In an effort to broadly improve the quality of research studies and reduce costs and challenges associated with recruitment and sample collection, a group of diverse researchers at Cincinnati Children's Hospital Medical Center led an institution-supported initiative to create a population representative pediatric “Greater Cincinnati Childhood Cohort (GCC).” Participants completed a detailed survey, underwent a brief physician-led physical exam, and provided blood, urine, and hair samples. DNA underwent high-throughput genotyping.Results: In total, 1,020 children ages 3–18 years living in the 7 county Greater Cincinnati Metropolitan region were recruited. Racial composition of the cohort was 84% non-Hispanic white, 15% non-Hispanic black, and 2% other race or Hispanic. Participants exhibited marked demographic and disease burden differences by race. Overall, the cohort was broadly used resulting in publications, grants and patents; yet, it did not meet the needs of all potential researchers.Conclusions: Learning from both the strengths and weaknesses, we propose leveraging a community-based participatory research framework for future broad use biobanking efforts.

Sleep disordered breathing in children receiving vagus nerve stimulation therapy

ObjectiveThe effects of vagus nerve stimulation (VNS) on sleep disordered breathing (SDB) have been reported in limited case series. Detailed studies, particularly in the pediatric population, have not been performed. The primary purpose of this study is to describe clinical characteristics, polysomnographic findings, and management of children treated with VNS. MethodsA retrospective review of medical records and polysomnography data was performed in patients ages 0–20 years old receiving VNS therapy for refractory epilepsy at Cincinnati Children's Hospital Medical Center. Results22 subjects met the inclusion criteria. 50% were male. The mean age at the time of VNS insertion was 8.4 ± 4.0 years. The mean age at the first PSG was 10.6 ± 4.3 years. Common presentations to sleep clinics included snoring (77.3%), frequent nighttime awakening (68.1%), and parasomnias (63.6%). The median apnea-hypopnea index (AHI) was 4.5/hr (IQR 3.0–13.1) and the median obstructive index (OI) was 4.1/hr (1.5–12.8). Obstructive sleep apnea (OSA) was diagnosed after VNS insertion in 19 patients (86.4%), 8 of which (36.3%) had severe OSA. Six patients (27.3%) had significant hypoventilation. For management, 6 patients (27.2%) were treated with bilevel PAP, 3 patients (13.6%) with CPAP, 2 patients (9.1%) with ventilator, 4 patients (18.2%) with upper airway surgeries, and 9 patients (40.9%) received medications only. ConclusionsSDB is common in pediatric patients with medically refractory epilepsy managed with VNS who were referred to sleep medicine clinics. Both OSA and nocturnal alveolar hypoventilation are relatively common in this population. Management of SDB often involves the use of positive airway pressure therapy or upper airway surgeries. Further studies are needed to assess the prevalence, risk factors, and the effect of treatments on epilepsy control. This study highlights the need for screening of SDB prior to and following VNS implantation.

Mitochondrial genome variant m.3250T>C as a possible risk factor for mitochondrial cardiomyopathy.

The MT-TL1 gene codes for the mitochondrial leucine transfer RNA (tRNALeu(UUR) ) necessary for mitochondrial translation. Pathogenic variants in the MT-TL1 gene result in mitochondriopathy in humans. The m.3250T>C variant in the MT-TL1 gene has been previously associated with exercise intolerance and mitochondrial myopathy, yet disease classification for this variant has not been consistently reported. Molecular studies suggest the m.3250T>C variant does not alter tRNALeu(UUR) structure but may have a modest impact on aminoacylation capacity. However, functional studies are limited. Our study aimed to further define the clinical presentation, inheritance pattern, and molecular pathology of the m.3250T>C variant. Families with the m.3250T>C variant were recruited from the Mitochondrial Disease Clinic at Cincinnati Children's Hospital Medical Center and GeneDx laboratory database. Affected individuals most frequently presented with cardiac findings, exercise intolerance, and muscle weakness. Hypertrophic cardiomyopathy was the most frequent cardiac finding. Many asymptomatic individuals had homoplasmic or near homoplasmic levels of the m.3250T>C variant, suggesting the penetrance is incomplete. Patient-derived fibroblasts demonstrated lowered ATP production and increased levels of reactive oxygen species. Our results demonstrate that the m.3250T>C variant exhibits incomplete penetrance and may be a possible cause of cardiomyopathy by impacting cellular respiration in mitochondria.

Four innovations: A robust integrated behavioral health program in pediatric primary care.

The increase in behavioral health problems presenting in pediatric primary care (PPC) has led to a greater focus on the prevention and treatment of mental health concerns. As a result, care has shifted from colocation to integrated PPC models. However, the literature provides limited guidance on the development and implementation of integrated PPC models that aim to transform both PPC and the larger health care system. We developed an integrated behavioral health (IBH) approach modeled with fidelity to the Integrated Practice Assessment Tool to fully integrate behavioral health into PPC. Over the 4 years since the application of our model, we have been successful in the development of an integration process and model for practice transformation of an urban PPC center and the spread and scale of IBH services to 2 additional clinics. Four elements combine to make our integrated behavioral health program novel: (a) clear mission and vision, (b) provision of universal prevention services, (c) continuous quality improvement, and (d) emphasis on practice and systems transformation. Trends in practice and scholarly inquiry indicate the need for robust pediatric IBH models, with a clear mission and vision; articulation of how research informs the development and implementation of the model; and infrastructure to meaningfully examine the model's impact. Cognizant of these needs, Cincinnati Children's Hospital Medical Center developed an IBH program. We provide key learnings for IBH program development, PPC transformation, and innovative systems redesign. We describe these elements and make recommendations for future research and practice. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Author's Response.

New England College of Optometry, Boston, MA [email protected] Department of Ophthalmology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH

An international telemedicine program for diagnosis of genetic disorders: Partnership of pediatrician and geneticist.

There is a shortage of genetics providers worldwide and access is limited to large academic centers. Telemedicine programs can facilitate access to genetic services to patients living in remote locations. The goal of this study was to improve access to genetic services in the Dominican Republic by creating a partnership model between a pediatrician and geneticist. This approach has been used within the United States but not in the setting of two different countries, healthcare system, and cultures. Patients were referred to the Centro de Obstetricia y Ginecologia program if a syndromic or genetic etiology was suspected by their local provider. Pediatrician first evaluated all patients prior to telemedicine appointment to review family and medical history. All genetic visits were scheduled within 2 weeks of referral in collaboration with telehealth program at Cincinnati Children's Hospital Medical Center. A total of 66 individuals were evaluated during a period of 5 years. Fifty-seven individuals underwent genetic studies, and a molecular diagnosis was made in 39 individuals. Exome sequencing was the most common first line test when differential diagnosis was broad (n = 40). The most common inheritance was autosomal recessive in 15 individuals, followed by 13 individuals with autosomal dominant disorders, 7 individuals X-linked disorders, and 4 individuals with chromosomal abnormalities. This study provides data to support utility of geneticist and pediatrician partnership to provide outreach telemedicine diagnostics and management services for rare diseases in an international setting.

Investigating the Diagnostic Value of Ultrasound in Determining the Opposite Inguinal Hernia in Children with Unilateral Inguinal Hernia Diagnosis

Objective: This study was conducted to evaluate and compare the results of ultrasound and clinical examination in the diagnosis of inguinal hernia in children and also to evaluate the benefits and complications of ultrasound in these children. Study Design: This study, was performed by a cross-sectional method in Children's Medical Center Hospital during 2013-2014 years and follow up was done until July 2020 with the help of a questionnaire from 70 children who had been referred due to unilateral inguinal hernia symptoms. All 70 children underwent Ultrasonographic evaluation and the results of the ultrasound were compared with the initial clinical examination and then with surgery and follow up. Results: In 95.7% of cases, uni or bilateral inguinal hernia was correctly diagnosed by ultrasound. Ultrasound revealed 13.4% of cases were bilateral and 86.6% were unilateral, all of which were confirmed by surgery. In 17.1% of cases, although they were referred with the chief complaint and clinical examination of unilateral inguinal hernia, Bilateral diagnosis was made for them during the ultrasound, and during the surgery, 75% of them were confirmed to have bilateral inguinal hernia. Conclusion: Ultrasound is effective in diagnosing the opposite side of the hernia in cases with unilateral hernia.

Lymphangioleiomyomatosis Association with Underlying Genotype in Patients with Tuberous Sclerosis Complex.

Rationale: Lymphangioleiomyomatosis (LAM) is a female-predominant lung disease caused by mutations in the tuberous sclerosis complex (TSC) genes TSC1 and TSC2.Objectives: To examine the association between TSC mutation subtypes and the prevalence of LAM in women with TSC.Methods: Adult women seen at the Cincinnati Children's Hospital Medical Center's TSC clinic were stratified into the following three groups: those with TSC1 mutation, those with TSC2 mutation, and those with no mutation identified (NMI). Individual TSC manifestations were ascertained by blinded review of chest computed tomographic scans (LAM, multifocal micronodular pneumocyte hyperplasia, and sclerotic bone lesions) and chart review (all other manifestations). The association between mutation status and TSC manifestations was assessed by the Wilcoxon rank-sum test.Results: Our cohort consisted of 55 TSC women, including 30/55 (55%) with TSC2, 12/55 (22%) with TSC1, and 13/55 (23%) with NMI. Twenty-three women (42%) had characteristic cysts consistent with LAM, of whom 16 had TSC2 mutations and seven had NMI. The prevalence of LAM was higher in women with TSC2 mutations compared with women with TSC1 mutations (16/29 [55%] vs. 0/12; P = 0.003). Similarly, renal angiomyolipomas were more common in women with TSC2 mutations compared with women with TSC1 mutations (29/30 [97%] vs. 6/12 [50%]; P = 0.01). There was no association between TSC mutation subtype and the presence of multifocal micronodular pneumocyte hyperplasia, sclerotic bone lesions, and skin or brain involvement. Serum VEGF-D (vascular endothelial growth factor-D) concentrations (median [95% confidence interval]) tended to be higher in patients harboring TSC2 mutations compared with patients with TSC1 mutations (725 pg/ml [612-1,317] vs. 331 pg/ml [284-406]; P = 0.03) and in patients with LAM compared with patients without LAM (725 pg/ml [563-1,609] vs. 429 pg/ml [357-773]; P = 0.02).Conclusions: LAM and angiomyolipomas are more common in women with TSC harboring TSC2 mutations compared with women with TSC1 mutations. Serum VEGF-D is a useful biomarker to suggest the presence of LAM in women with TSC.

Features of Menstruation and Menstruation Management in Individuals with Rett Syndrome.

To describe features of menstruation, menstrual-related symptoms, and menstrual management in females with Rett syndrome (RTT) to help develop a clinical approach to these parameters in RTT. Retrospective cross-sectional chart review and prospective survey. Cincinnati Children's Hospital Medical Center, Rett Syndrome and Related Spectrum Disorders Clinic. Females with RTT (12-55years of age) and their caregivers. Descriptive data on features of menstruation and menstrual-related symptoms in individuals with Rett syndrome; prevalence, types, reason for use/discontinuation, and efficacy of hormonal treatment in females with RTT. Age at menarche, menstrual cycle length, and menstrual period length in females with RTT are comparable to those in typically developing females and females with other neurodevelopmental disabilities. Dysmenorrhea and emotional lability are common menstrual cycle-related changes among females with RTT; 22.1% of participants also reported catamenial seizures. Oral progestin, combined oral contraceptive pill, and depot-medroxyprogesterone acetate (DMPA) were effectively used to suppress or regulate menstruation and to manage menstrual-related symptoms. Characteristics of menstruation in females with RTT are comparable to those of typically developing females, with the exception of increase in catamenial seizure activity. Hormonal treatments are used for management of menstruation, dysmenorrhea, and seizures. Choice of hormonal treatment is influenced by bone health and immobility in females with RTT.

Increased Hydroxyurea Prescribing Practices over Ten Years with Improved Clinical Outcomes in Children with Sickle Cell Anemia: A Single Center's Experience

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 &amp; Royalties; Aruvant Sciences, Forma Therapeutics, Inc.: Consultancy.