Pediatric hematology providers' contraceptive practices for female adolescents and young adults with sickle cell disease: A national survey.

BACKGROUND: Adolescent and young adult (AYA) women with sickle cell disease (SCD) have increased pregnancy-related health risks and are prescribed potentially teratogenic medications, yet limited data are available regarding pediatric SCD provider contraceptive practices. We aimed to assess pediatric hematology providers' beliefs, practices, motivators, and barriers for providing contraceptive care to female AYAs with SCD. METHODS: Guided by the Health Belief Model (HBM), we developed a 25-question, web-based survey to assess practices. Survey links were distributed nationwide to pediatric SCD and/or general hematology providers through their publicly available emails and by request to directors of U.S.-accredited Pediatric Hematology-Oncology fellowship programs for distribution to their SCD providers. Data analysis included descriptive statistics, chi-square analysis, and logistic regression. RESULTS: Of 177 respondents, 160 surveys meeting inclusion criteria were analyzed. Most providers reported counseling (77.5%) and referring female AYA patients for contraception (90.8%), but fewer reported prescribing contraception (41.8%). Proportionally fewer trainees provided counseling compared with established providers (54% vs. 85%, p < .001), with a similar trend for prescribing (p = .05). Prescription practices did not differ significantly by provider beliefs regarding potential teratogenicity of hydroxyurea. Key motivators included patient request and disclosure of sexual activity. Key barriers included inadequate provider training, limited visit time, and perceived patient/parent interest. CONCLUSION: Provider contraceptive practices for female AYAs with SCD varied, especially by provider status. Health beliefs regarding teratogenic potential of hydroxyurea did not correlate with contraceptive practices. Clinical guidelines, provider training, and patient/parent decision-making tools may be tested to assess whether provider contraceptive practices could be improved.

The Sickle Cell Disease Functional Assessment (SCD-FA) tool: a feasibility pilot study.

BACKGROUND: The life expectancy for individuals with sickle cell disease (SCD) has greatly increased over the last 50 years. Adults with SCD experience multiple complications such as cardiopulmonary disease, strokes, and avascular necrosis that lead to limitations that geriatric populations often experience. There are no dedicated instruments to measure functional decline and functional age to determine risk of future adverse outcomes in older adults with SCD. The objective of this study was to assess the feasibility of performing the Sickle Cell Disease Functional Assessment (SCD-FA). METHODS: We enrolled 40 adults with SCD (20 younger adults aged 18-49 years as a comparison group and 20 older adults aged 50 years and older) in a single-center prospective cohort study. Participants were recruited from a comprehensive sickle cell clinic in an academic center in the southeastern United States. We included measures validated in an oncology geriatric assessment enriched with additional physical performance measures: usual gait speed, seated grip strength, Timed Up and Go, six-minute walk test, and 30-second chair stand. We also included an additional cognitive measure, which was the Montreal Cognitive Assessment, and additional patient-reported measures at the intersection of sickle cell disease and geriatrics. The primary outcome was the proportion completing the assessment. Secondary outcomes were the proportion consenting, duration of the assessment, acceptability, and adverse events. RESULTS: Eighty percent (44/55) of individuals approached consented, 91% (40/44) completed the SCD-FA in its entirety, and the median duration was 89 min (IQR 80-98). There were no identified adverse events. On the acceptability survey, 95% (38/40) reported the length as appropriate, 2.5% (1/40) reported a question as upsetting, and 5% (2/40) reported portions as difficult. Exploratory analyses of physical function showed 63% (25/40) had a slow usual gait speed (< 1.2 m/s). CONCLUSION: The SCD-FA is feasible, acceptable, and safe and physical performance tests identified functional impairments in adults with SCD. These findings will inform the next phase of the study where we will assess the validity of the SCD-FA to predict patient-important outcomes in a larger sample of adults with SCD.

Pediatric Neurodevelopmental Delays in Children 0 to 5 Years of Age With Sickle Cell Disease: A Systematic Literature Review.

INTRODUCTION: Sickle cell disease (SCD) is the most common abnormal genetic blood disease that affects ∼100,000 Americans. Approximately 20% to 37% of children with sickle cell anemia have silent cerebral infarcts by the age of 14 years old. Neurocognitive deficits are identified in infants and preschool children with SCD. The purpose of this systematic literature review is to provide a comprehensive understanding of the prevalence, severity, and the associated risk factors for neurodevelopmental delays (NDDs) in children with SCD 5 years of age and younger. METHODS: Systematic search of 6 databases identified 2467 potentially relevant publications and 8 were identified through a manual search. Only 24 articles met the inclusion criteria. RESULTS: We identified an increased prevalence of NDDs (cognitive, motor, or both). Children experienced deficits with language, attention and behavior, executive functioning, school readiness and/or academic performance, and motor skills (fine and gross motor functioning). Risk factors include silent cerebral infarcts and strokes, SCD genotype (HbSS>HbSC), other biologic, and social factors. CONCLUSION: NDDs are common in children ages 0 to 5 years old with SCD. There is an opportunity to improve adherence to national guideline recommendations and early detection practices by pediatricians, hematologists, and other health care providers.

Geriatric assessment for older adults with sickle cell disease: protocol for a prospective cohort pilot study.

BACKGROUND: The life expectancy for people with sickle cell disease (SCD) has improved tremendously over the last 50 years. This population experiences hemolysis and vaso-occlusion in multiple organs that lead to complications such as cardiopulmonary disease, strokes, and avascular necrosis. These complications can limit mobility and aerobic endurance, similar to limitations that often occur in geriatric populations. These sickle-cell and age-related events lead to frequent hospitalization, which further increases the risk of functional decline. We have few tools to measure functional decline in people with SCD. The purpose of this paper is to describe a protocol to evaluate the feasibility of sickle cell disease geriatric assessment (SCD-GA). METHODS/DESIGN: We will enroll 40 adults with SCD (20 age 18-49.99 years and 20 age ≥ 50 years) in a prospective cohort study to assess the feasibility of SCD-GA. The SCD-GA includes validated measures from the oncology geriatric assessment enriched with additional physical and cognitive measures. The SCD-GA will be performed at the first study visit, at 10 to 20 days after hospitalization, and at 12 months (exit visit). With input from a multidisciplinary team of sickle cell specialists, geriatricians, and experts in physical function and physical activity, we selected assessments across 7 domains: functional status (11 measures), comorbid medical conditions (1 measure), psychological state (1 measure), social support (2 measures), weight status (2 measures), cognition (3 measures), and medications (1 measure). We will measure the proportion completing the assessment with feasibility as the primary outcome. Secondary outcomes include the proportion consenting and completing all study visits, duration of the assessment, acceptability, and adverse events. DISCUSSION: We present the protocol and rationale for selection of the measures included in SCD-GA. We also outline the methods to determine feasibility and subsequently to optimize the SCD-GA in preparation for a larger multicenter validation study of the SCD-GA.

Comparison of US Federal and Foundation Funding of Research for Sickle Cell Disease and Cystic Fibrosis and Factors Associated With Research Productivity.

Importance: Sickle cell disease (SCD) and cystic fibrosis (CF) are severe autosomal recessive disorders associated with intermittent disease exacerbations that require hospitalizations, progressive chronic organ injury, and substantial premature mortality. Research funding is a limited resource and may contribute to health care disparities, especially for rare diseases that disproportionally affect economically disadvantaged groups. Objective: To compare disease-specific funding between SCD and CF and the association between funding and research productivity. Design, Setting, and Participants: This cross-sectional study examined federal and foundation funding, publications indexed in PubMed, clinical trials registered in ClinicalTrials.gov, and new drug approvals from January 1, 2008, to December 31, 2018, in an estimated US population of approximately 90 000 individuals with SCD and approximately 30 000 individuals with CF. Main Outcomes and Measures: Federal and foundation funding, publications indexed in PubMed, clinical trial registrations, and new drug approvals. Results: From 2008 through 2018, federal funding was greater per person with CF compared with SCD (mean [SD], $2807 [$175] vs $812 [$147]; P < .001). Foundation expenditures were greater for CF than for SCD (mean [SD], $7690 [$3974] vs $102 [$13.7]; P < .001). Significantly more research articles (mean [SD], 1594 [225] vs 926 [157]; P < .001) and US Food and Drug Administration drug approvals (4 vs 1) were found for CF compared with SCD, but the total number of clinical trials was similar (mean [SD], 27.3 [6.9] vs 23.8 [6.3]; P = .22). Conclusions and Relevance: The findings show that disparities in funding between SCD and CF may be associated with decreased research productivity and novel drug development for SCD. Increased federal and foundation funding is needed for SCD and other diseases that disproportionately affect economically disadvantaged groups to address health care disparities.

Correlates of successful transition in young adults with sickle cell disease.

The transition period from pediatric care to adult care for patients with sickle cell disease (SCD) is associated with increased mortality and morbidity. Identification of risk factors for unsuccessful transition may aid in developing strategies to improve the transition process and health outcomes in this population. We examined factors associated with unsuccessful transition from pediatric to adult care for patients with SCD at the Johns Hopkins Hospital. We found that public insurance and increased hospitalization rates were associated with poor transition to adult care. The findings provide possible areas of intervention.

Secondhand Smoke Is an Important Modifiable Risk Factor in Sickle Cell Disease: A Review of the Current Literature and Areas for Future Research.

Sickle cell disease (SCD) is an autosomal recessive hemoglobinopathy that causes significant morbidity and mortality related to chronic hemolytic anemia, vaso-occlusion, and resultant end-organ damage. Tobacco smoke exposure (TSE) through secondhand smoke exposure in people with SCD of all ages and through primary smoking in adolescents and adults is associated with significantly increased morbidity, with increased rates of emergency department visits and hospitalizations for painful vaso-occlusive crises and acute chest syndrome (ACS). Secondhand smoke is also associated with pulmonary function abnormalities in children with SCD who are already at risk for pulmonary function abnormalities on the basis of SCD. TSE is emerging as one of the few modifiable risk factors of SCD. This review discusses the current state of the evidence with respect to TSE and SCD morbidity, discusses potential mechanisms, and highlights current gaps in the evidence and future research directions.

Preventive Care Delivery to Young Children With Sickle Cell Disease.

Preventive services can reduce the morbidity of sickle cell disease (SCD) in children but are delivered unreliably. We conducted a retrospective cohort study of children aged 2 to 5 years with SCD, evaluating each child for 14 months and expecting that he/she should receive ≥75% of days covered by antibiotic prophylaxis, ≥1 influenza immunization, and ≥1 transcranial Doppler ultrasound (TCD). We used logistic regression to quantify the relationship between ambulatory generalist and hematologist visits and preventive services delivery. Of 266 children meeting the inclusion criteria, 30% consistently filled prophylactic antibiotic prescriptions. Having ≥2 generalist, non-well child care visits or ≥2 hematologist visits was associated with more reliable antibiotic prophylaxis. Forty-one percent of children received ≥1 influenza immunizations. Children with ≥2 hematologist visits were most likely to be immunized (62% vs. 35% among children without a hematologist visit). Only 25% of children received ≥1 TCD. Children most likely to receive a TCD (42%) were those with ≥2 hematologist visits. One in 20 children received all 3 preventive services. Preventive services delivery to young children with SCD was inconsistent but associated with multiple visits to ambulatory providers. Better connecting children with SCD to hematologists and strengthening preventive care delivery by generalists are both essential.

Secondhand smoke is associated with more frequent hospitalizations in children with sickle cell disease.

Tobacco smoke exposure has been associated with more frequent hospitalizations in children with sickle cell disease (SCD), but previous studies have not quantified the exposure by objective methods. We enrolled 50 children and young adults with SCD in a retrospective and prospective cohort study and quantified tobacco smoke exposure by objective (salivary cotinine) and survey measures. We used a multivariable negative binomial regression model to evaluate the association between salivary cotinine and hospital admissions. Forty-five percent (22/49) of participants had significant elevation of salivary cotinine (≥ 0.5 ng/ml). The incidence risk ratio (IRR) for hospital admission for those with elevated cotinine was 3.7 (95% CI 1.8-8). Those exposed to secondhand smoke but not primary smokers (cotinine between 0.5 and 10 ng/ml) had a similarly increased risk of hospitalization [IRR 4.3 (95% CI 1.8-10)]. We show that an objective measure of tobacco smoke exposure, salivary cotinine, is strongly associated with the rate of hospital admissions in children and young adults with SCD. This association underscores the importance of screening for tobacco smoke exposure in people with SCD. Further investigation is warranted to determine the mechanisms of and to evaluate interventions to decrease tobacco smoke exposure.

Transcranial Doppler screening of Medicaid-insured children with sickle cell disease.

Transcranial Doppler screening reduces the risk of stroke in children with sickle cell disease. We tested the effect of informational letters sent to parents and doctors of Medicaid-insured children on improving screening efficiency. The letters did not improve the low baseline screening rates, suggesting the need for more aggressive outreach. Hematologist visits were correlated with increased screening rates.

Respiratory syncytial virus and seasonal influenza cause similar illnesses in children with sickle cell disease.

BACKGROUND: Respiratory syncytial virus (RSV) is a cause of acute chest syndrome (ACS) in sickle cell disease (SCD), but its clinical course and acute complications have not been well characterized. We compared RSV to seasonal influenza infections in children with SCD. PROCEDURE: We defined cases as laboratory-confirmed RSV or seasonal influenza infection in inpatients and outpatients <18 years of age with SCD from 1 September 1993 to 30 June 2011. We used Fisher's exact test to compare proportions, Student's t-test or Wilcoxon rank-sum test to compare continuous variables, and logistic regression to evaluate associations. RESULTS: We identified 64 children with RSV and 91 with seasonal influenza. Clinical symptoms, including fever, cough, and rhinorrhea were similar for RSV and influenza, as were complications, including ACS and treatments for SCD. In a multivariable logistic regression model, older age (OR 1.2 per year, 95% CI [1.02-1.5], P = 0.04), increased white blood cell count at presentation (OR 1.1 per 1,000/µl increase, 95% CI [1.03-1.3], P = 0.008), and a history of asthma (OR 7, 95% [CI 1.3-37], P = 0.03) were independently associated with increased risk of ACS in children with RSV. The hospitalization rate for children with SCD and RSV (40 per 1,000 <5 years and 63 per 1,000 <2 years) greatly exceeds the general population (3 in 1,000 <5 years). CONCLUSIONS: We conclude that RSV infection is often associated with ACS and similar in severity to influenza infection in febrile children with SCD.

Hospital-associated venous thromboembolism in children: incidence and clinical characteristics.

OBJECTIVE: To determine incidence and clinical characteristics of hospital-associated venous thromboembolism (VTE) in pediatric patients. STUDY DESIGN: A retrospective analysis of patients with hospital-associated VTE at the Johns Hopkins Hospital from 1994 to 2009 was performed. Clinical characteristics of patients aged 21 years and younger who developed VTE symptoms after 2 days of hospitalization or <90 days after hospital discharge were examined. International Classification of Diseases, Ninth Revision codes were used to categorize patients with complex chronic medical conditions and trauma. RESULTS: There were 270 episodes of hospital-associated VTE in 90,485 admissions (rate 30 per 10,000 admissions). Young adults (18-21 years) and adolescents (14-17 years) had significantly increased rates of VTE compared with children (2-9 years) (incidence rate ratio [IRR] 7.7, 95% CI 5.1-12.0; IRR 4.3, 95% CI 2.7-6.8, respectively). A central venous catheter (CVC) was present in 50% of patients, and a surgical procedure was performed in 45% of patients before VTE diagnosis. For patients without a CVC, trauma was the most common admitting diagnosis. CVC-related VTE was diagnosed most frequently in infants (<1 year old) and in patients with malignancy. Renal and cardiac diseases were associated with the highest rates of VTE (51 and 48 per 10,000, respectively). Rates were significantly higher among those with ≥ 4 medical conditions compared with those with 1 medical condition (IRR 4.0, 95% CI 1.4-8.9). CONCLUSION: Older age and multiple medical conditions were associated with increased rates of hospital-associated VTE. These data can contribute to the design of future clinical trials to prevent hospital-associated VTE in high-risk children.

Computerized physician order entry improves compliance with a manual exchange transfusion protocol in the pediatric intensive care unit.

AIM: To evaluate the use of a computerized physician order entry (CPOE) protocol on manual red blood cell (RBC) exchange transfusion in critically ill children with sickle cell disease. METHODS: We conducted a retrospective study of children with sickle cell disease who received a manual RBC exchange transfusion before (2001 to 2008, n=22) and after (2008 to 2009, n=11) implementation of a CPOE protocol. Outcomes included compliance with protocol, percentage reduction in sickle hemoglobin, and peak hemoglobin during exchange. RESULTS: Compliance with the manual exchange protocol improved after introduction of CPOE (pre-CPOE: 20 protocol violations vs. post-CPOE: 3 violations, P=0.02). Percentage reduction in sickle hemoglobin also improved (pre-CPOE: 55% vs. post-CPOE: 70%, P=0.04), whereas peak hemoglobin during RBC exchange was similar (pre-CPOE: 12.0 g/dL vs. post-CPOE: 11.5 g/dL, P=0.25). However, hemoglobin levels after the mean of 7 hours of exchange were significantly higher pre-CPOE (pre-CPOE: 11.5 g/dL vs. post-CPOE: 10.5 g/dL, P=0.006). CONCLUSIONS: Use of CPOE for manual RBC exchange transfusion in children is associated with improved protocol compliance, improved reduction of sickle hemoglobin, and better maintenance of hemoglobin levels in a goal range during prolonged exchanges.

A double-blind, randomized, multicenter phase 2 study of prasugrel versus placebo in adult patients with sickle cell disease.

BACKGROUND: Platelet activation has been implicated in the pathogenesis of sickle cell disease (SCD) suggesting antiplatelet agents may be therapeutic. To evaluate the safety of prasugrel, a thienopyridine antiplatelet agent, in adult patients with SCD, we conducted a double-blind, randomized, placebo-controlled study. METHODS: The primary endpoint, safety, was measured by hemorrhagic events requiring medical intervention. Patients were randomized to prasugrel 5 mg daily (n = 41) or placebo (n = 21) for 30 days. Platelet function by VerifyNow® P2Y12 and vasodilator-stimulated phosphoprotein assays at days 10 and 30 were significantly inhibited in prasugrel- compared with placebo-treated SCD patients. RESULTS: There were no hemorrhagic events requiring medical intervention in either study arm. Mean pain rate (percentage of days with pain) and intensity in the prasugrel arm were decreased compared with placebo. However, these decreases did not reach statistical significance. Platelet surface P-selectin and plasma soluble P-selectin, biomarkers of in vivo platelet activation, were significantly reduced in SCD patients receiving prasugrel compared with placebo. In sum, prasugrel was well tolerated and not associated with serious hemorrhagic events. CONCLUSIONS: Despite the small size and short duration of this study, there was a decrease in platelet activation biomarkers and a trend toward decreased pain.

High rates of recurrent biliary tract obstruction in children with sickle cell disease.

BACKGROUND: Individuals with sickle cell disease (SCD) have an increased risk of cholelithiasis from bilirubin stones. Symptomatic biliary tract disease (BTD) includes acute and chronic cholecystitis, obstruction of the common bile duct (CBD), cholangitis, and gallstone pancreatitis. Cholecystectomy is the main treatment strategy for symptomatic patients; however, the prevalence of recurrent BTD following cholecystectomy has not been systematically evaluated. We conducted a retrospective cohort study to describe the recurrence of BTD after cholecystectomy and characterize risk factors for recurrent disease. PROCEDURE: We identified patients <22 years of age who presented to the Johns Hopkins Children Center with symptomatic BTD from July 1993 to June 2008. RESULTS: We identified 56 patients with a total of 76 episodes of symptomatic BTD (median age at first event 15.9, range 4.6-21.5 years). Eleven of the 56 patients (19.6%) had at least one episode of recurrent symptomatic BTD (median follow-up of 5.3 years). Baseline characteristics were similar between the patients with a single episode of BTD and those with recurrent BTD. CONCLUSIONS: These results demonstrate that recurrent BTD is a frequent complication of SCD (20% by age 4 years) and often presents as CBD obstruction by stone, despite cholecystectomy. In our cohort, recurrence was not associated with age at first episode, baseline total bilirubin, gender, or genotype of SCD.

Comparison of the use and results of sentinel lymph node biopsy in children and young adults with melanoma.

BACKGROUND: Data on sentinel lymph node (SLN) biopsy in children with melanoma are limited. In this study, the authors compared the factors associated with SLN biopsy use and metastases in pediatric and young adult patients with melanoma. METHODS: The 2008 Surveillance, Epidemiology, and End Results (SEER) databases were used to examine melanoma cases from 2003 to 2008. Data extracted include age, sex, race, stage, tumor thickness, ulceration, lymph node status, surgical treatment, and survival. Logistic regression models were used for adjusted analyses. RESULTS: In total, 717 children (age <20 years) and 1368 young adults (age 20-24 years) were identified who were diagnosed with melanoma. Factors that were associated with SLN biopsy use included tumor ulceration (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.4-4.3) and greater thickness (OR, 17; 95% CI, 12-24 for >1 mm vs ≤1 mm), but not younger age (OR, 1.3; 95% CI, 0.94-1.8) in adjusted analyses. SLN metastasis was correlated with ulceration (OR, 3.0; 95% CI, 1.6-5.8), increased thickness (OR, 6.8; 95% CI, 3.1-15 for 2.01-4.0 mm vs ≤1 mm), and for the interaction between age <20 years and thickness 1.01 to 2.00 mm (OR, 6.5; 95% CI, 1.7-25) in adjusted analyses. Children with nonulcerated melanomas that measured 1.01 to 2.00 mm in thickness were significantly more likely to have SLN metastases than young adults (24% vs 4%; P < .001). CONCLUSIONS: Thickness and ulceration were strong predictors of both the use of SLN biopsy and positive SLN biopsy results in children and young adults with melanoma. Compared with young adults, children were more likely to have SLN metastases despite having similar rates of SLN biopsy use.

Hydroxyurea for the treatment of sickle cell disease: efficacy, barriers, toxicity, and management in children.

Hydroxyurea is the only approved medication in the United States for the treatment of sickle cell anemia (HbSS) and is widely used in children despite an indication limited to adults. We review the evidence of efficacy and safety in children with reference to pivotal adult studies. This evidence and expert opinion form the basis for recommended guidelines for the use of hydroxyurea in children including indications, dosing, therapeutic and safety monitoring, and interventions to improve adherence. However, there are substantial gaps in our knowledge to be addressed by on-going and planned studies in children.