Birth Prevalence of Sickle Cell Disease and County-Level Social Vulnerability - Sickle Cell Data Collection Program, 11 States, 2016-2020.

Sickle cell disease (SCD) remains a public health priority in the United States because of its association with complex health needs, reduced life expectancy, lifelong disabilities, and high cost of care. A cross-sectional analysis was conducted to calculate the crude and race-specific birth prevalence for SCD using state newborn screening program records during 2016-2020 from 11 Sickle Cell Data Collection program states. The percentage distribution of birth mother residence within Social Vulnerability Index quartiles was derived. Among 3,305 newborns with confirmed SCD (including 57% with homozygous hemoglobin S or sickle ß-null thalassemia across 11 states, 90% of whom were Black or African American [Black], and 4% of whom were Hispanic or Latino), the crude SCD birth prevalence was 4.83 per 10,000 (one in every 2,070) live births and 28.54 per 10,000 (one in every 350) non-Hispanic Black newborns. Approximately two thirds (67%) of mothers of newborns with SCD lived in counties with high or very high levels of social vulnerability; most mothers lived in counties with high or very high levels of vulnerability for racial and ethnic minority status (89%) and housing type and transportation (64%) themes. These findings can guide public health, health care systems, and community program planning and implementation that address social determinants of health for infants with SCD. Implementation of tailored interventions, including increasing access to transportation, improving housing, and advancing equity in high vulnerability areas, could facilitate care and improve health outcomes for children with SCD.

Deciphering and disrupting PIEZO1-TMEM16F interplay in hereditary xerocytosis.

ABSTRACT: Cell-surface exposure of phosphatidylserine (PS) is essential for phagocytic clearance and blood clotting. Although a calcium-activated phospholipid scramblase (CaPLSase) has long been proposed to mediate PS exposure in red blood cells (RBCs), its identity, activation mechanism, and role in RBC biology and disease remain elusive. Here, we demonstrate that TMEM16F, the long-sought-after RBC CaPLSase, is activated by calcium influx through the mechanosensitive channel PIEZO1 in RBCs. PIEZO1-TMEM16F functional coupling is enhanced in RBCs from individuals with hereditary xerocytosis (HX), an RBC disorder caused by PIEZO1 gain-of-function channelopathy. Enhanced PIEZO1-TMEM16F coupling leads to an increased propensity to expose PS, which may serve as a key risk factor for HX clinical manifestations including anemia, splenomegaly, and postsplenectomy thrombosis. Spider toxin GsMTx-4 and antigout medication benzbromarone inhibit PIEZO1, preventing force-induced echinocytosis, hemolysis, and PS exposure in HX RBCs. Our study thus reveals an activation mechanism of TMEM16F CaPLSase and its pathophysiological function in HX, providing insights into potential treatment.

A comparison of the effect of patient-specific versus weight-based protocols to treat vaso-occlusive episodes in the emergency department.

BACKGROUND: Vaso-occlusive crises (VOCs) cause debilitating pain and are a common cause of emergency department (ED) visits, for people with sickle cell disease (SCD). Strategies for achieving optimal pain control vary widely despite evidence-based guidelines. We tested existing guidelines and hypothesized that a patient-specific pain protocol (PSP) written by their SCD provider may be more effective than weight-based (WB) dosing of parenteral opiate medication, in relieving pain. METHODS: This study was a prospective, randomized controlled trial comparing a PSP versus WB protocol for patients presenting with VOCs to six EDs. Patients were randomized to a PSP or WB protocol prior to an ED visit. The SCD provider wrote their protocol and placed it in the electronic health record for future ED visits with VOC exclusion criteria that included preexisting PSP excluding parenteral opioid analgesia or outpatient use of buprenorphine or methadone or highly suspected for COVID-19. Pain intensity scores, side effects, and safety were obtained every 30 min for up to 6 h post-ED bed placement. The primary outcome was change in pain intensity score from placement in an ED space to disposition or 6 h. RESULTS: A total of 328 subjects were randomized; 104 participants enrolled (ED visit, target n = 230) with complete data for 96 visits. The study was unable to reach the target sample size and stopped early due to the impact of COVID-19. We found no significant differences between groups in the primary outcome; patients randomized to a PSP had a shorter ED length of stay (p = 0.008), and the prevalence of side effects was low in both groups. Subjects in both groups experienced both a clinically meaningful and a statistically significant decrease in pain (27 mm on a 0- to 100-mm scale). CONCLUSIONS: We found a shorter ED length of stay for patients assigned to a PSP. Patients in both groups experienced good pain relief without significant side effects.

Common data model for sickle cell disease surveillance: considerations and implications.

Objective: Population-level data on sickle cell disease (SCD) are sparse in the United States. The Centers for Disease Control and Prevention (CDC) is addressing the need for SCD surveillance through state-level Sickle Cell Data Collection Programs (SCDC). The SCDC developed a pilot common informatics infrastructure to standardize processes across states. Materials and Methods: We describe the process for establishing and maintaining the proposed common informatics infrastructure for a rare disease, starting with a common data model and identify key data elements for public health SCD reporting. Results: The proposed model is constructed to allow pooling of table shells across states for comparison. Core Surveillance Data reports are compiled based on aggregate data provided by states to CDC annually. Discussion and Conclusion: We successfully implemented a pilot SCDC common informatics infrastructure to strengthen our distributed data network and provide a blueprint for similar initiatives in other rare diseases.

Cognitive-motor dual-task interference in adults with sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) is a genetic disorder that causes physical and cognitive impairment due to hemolysis, painful vaso-occlusion episodes, joint avascular necrosis, and strokes. As individuals with SCD age and develop conditions impacting their physical and cognitive function, their ability to multitask successfully and safely may decline. Cognitive-motor dual-task interference occurs when there is deterioration in one or both tasks while dual-tasking relative to single-tasking. Dual-task assessment (DTA) is a valuable measure of physical and cognitive function; however, there is limited data on DTA in adults with SCD. RESEARCH QUESTION: Is DTA a feasible and safe method of measuring physical and cognitive function in adults with SCD? What patterns of cognitive-motor interference occur in adults with SCD? METHODS: We enrolled 40 adults with SCD (mean age 44 years, range 20-71) in a single-center prospective cohort study. We used usual gait speed as the measure of motor performance and verbal fluency (F, A, and S) as the measure of cognitive performance. We measured feasibility as the proportion of consented participants able to complete the DTA. We calculated the relative dual-task effect (DTE %) for each task and identified patterns of dual-task interference. RESULTS: Most consented participants completed the DTA (91%, 40/44) and there were no adverse events. There were 3 main dual-task interference patterns for the first trial using letter 'A': Motor Interference (53%, n = 21), Mutual Interference (23%, n = 9), and Cognitive-Priority Tradeoff (15%, n = 6). For the second trial using letter 'S', there were two main dual-task interference patterns: Cognitive-Priority Tradeoff (53%, n = 21) and Motor Interference (25%, n = 10). STATEMENT OF SIGNIFICANCE: DTA was feasible and safe in adults with SCD. We identified specific patterns of cognitive-motor interference. This study supports further evaluation of DTA as a potentially useful tool to measure physical and cognitive function in ambulatory adults with SCD.

Successful quality improvement project to increase hydroxyurea prescriptions for children with sickle cell anaemia.

Hydroxyurea (HU) is an effective but underused disease-modifying therapy for patients with sickle cell anaemia (SCA). EMBRACE SCD, a sickle cell disease treatment demonstration project, aimed to improve access to HU by increasing prescription (Rx) rates by at least 10% from baseline in children with SCA.The Model for Improvement was used as the quality improvement framework. HU Rx was assessed from clinical databases in three paediatric haematology centres. Children aged 9 months-18 years with SCA not on chronic transfusions were eligible for HU treatment. The health belief model was the conceptual framework to discuss with patients and promote HU acceptance. A visual aid showing erythrocytes under the effect of HU and the American Society of Hematology HU brochure were used as educational tools. At least 6 months after offering HU, a Barrier Assessment Questionnaire was given to assess reasons for HU acceptance and refusals. If HU was declined, the providers discussed with family again. We conducted chart audits to find missed opportunities to prescribe HU as one plan-do-study-act cycle.At initial measurement, 50.2% of 524 eligible patients had HU prescribed. During the testing and initial implementation phase, the mean performance after 10 data points was 53%. After 2 years, the mean performance was 59%, achieving an 11% increase in mean performance and a 29% increase from initial to the last measurement (64.8% HU Rx). During a 15-month period, 32.1% (N=168) of the eligible patients who were offered HU completed the barrier questionnaire with 19% (N=32) refusing HU, mostly based on not perceiving enough severity of their children's SCA or fearing side effects.Reviewing patient charts for missed opportunity of offering HU with feedback and evaluating the reasons of declining HU via a questionnaire were key components in increasing HU Rx in our population.

Use of Structured Electronic Health Records Data Elements for the Development of Computable Phenotypes to Identify Potential Adverse Events Associated with Intravenous Immunoglobulin Infusion.

INTRODUCTION: Detection of adverse reactions to drugs and biologic agents is an important component of regulatory approval and post-market safety evaluation. Real-world data, including insurance claims and electronic health records data, are increasingly used for the evaluation of potential safety outcomes; however, there are different types of data elements available within these data resources, impacting the development and performance of computable phenotypes for the identification of adverse events (AEs) associated with a given therapy. OBJECTIVE: To evaluate the utility of different types of data elements to the performance of computable phenotypes for AEs. METHODS: We used intravenous immunoglobulin (IVIG) as a model therapeutic agent and conducted a single-center, retrospective study of 3897 individuals who had at least one IVIG administration between 1 January 2014 and 31 December 2019. We identified the potential occurrence of four different AEs, including two proximal AEs (anaphylaxis and heart rate alterations) and two distal AEs (thrombosis and hemolysis). We considered three different computable phenotypes: (1) an International Classification of Disease (ICD)-based phenotype; (2) a phenotype-based on EHR-derived contextual information based on structured data elements, including laboratory values, medication administrations, or vital signs; and (3) a compound phenotype that required both an ICD code for the AE in combination with additional EHR-derived structured data elements. We evaluated the performance of each of these computable phenotypes compared with chart review-based identification of AEs, assessing the positive predictive value (PPV), specificity, and estimated sensitivity of each computable phenotype method. RESULTS: Compound computable phenotypes had a high positive predictive value for acute AEs such as anaphylaxis and bradycardia or tachycardia; however, few patients had both ICD codes and the relevant contextual data, which decreased the sensitivity of these computable phenotypes. In contrast, computable phenotypes for distal AEs (i.e., thrombotic events or hemolysis) frequently had ICD codes for these conditions in the absence of an AE due to a prior history of such events, suggesting that patient medical history of AEs negatively impacted the PPV of computable phenotypes based on ICD codes. CONCLUSIONS: These data provide evidence for the utility of different structured data elements in computable phenotypes for AEs. Such computable phenotypes can be used across different data sources for the detection of infusion-related adverse events.

Management of Older Adults with Sickle Cell Disease: Considerations for Current and Emerging Therapies.

People with sickle cell disease (SCD) are living longer than ever before, with the median survival increasing from age 14 years in 1973, beyond age 40 years in the 1990s, and as high as 61 years in recent cohorts from academic centers. Improvements in survival have been attributed to initiatives, such as newborn screening, penicillin prophylaxis, vaccination against encapsulated organisms, better detection and treatment of splenic sequestration, and improved transfusion support. There are an estimated 100,000 people living with SCD in the United States and millions of people with SCD globally. Given that the number of older adults with SCD will likely continue to increase as survival improves, better evidence on how to manage this population is needed. When managing older adults with SCD (defined herein as age ≥ 40 years), healthcare providers should consider the potential pitfalls of extrapolating evidence from existing studies on current and emerging therapies that have typically been conducted with participants at mean ages far below 40 years. Older adults with SCD have historically had little to no representation in clinical trials; therefore, more guidance is needed on how to use current and emerging therapies in this population. This article summarizes the available evidence for managing older adults with SCD and discusses potential challenges to using approved and emerging drugs in this population.

Hemorrhagic Stroke in Children and Adults With Sickle Cell Anemia: The Post-STOP Cohort.

BACKGROUND: Hemorrhagic stroke in young patients with sickle cell anemia remains poorly characterized. METHODS: The Post-STOP (Stroke Prevention Trial in Sickle Cell Anemia) retrospective study collected follow-up data on STOP and STOP II clinical trial cohorts. From January 2012 to May 2014, a team of analysts abstracted data from medical records of prior participants (all with sickle cell anemia). Two vascular neurologists reviewed data to confirm hemorrhagic strokes defined as spontaneous intracerebral, subarachnoid, or intraventricular hemorrhage. Incidence rates were calculated using survival analysis techniques Results: Follow-up data were collected from 2850 of 3835 STOP or STOP II participants. Patients (51% male) were a median of 19.1 (interquartile range, 16.6-22.6) years old at the time of last known status. The overall hemorrhagic stroke incidence rate was 63 per 100 000 person-years (95% CI, 45-87). Stratified by age, the incidence rate per 100 000 person-years was 50 (95% CI, 34-75) for children and 134 (95% CI, 74-243) for adults >18 years. Vascular abnormalities (moyamoya arteriopathy, aneurysm or cavernous malformation) were identified in 18 of 35 patients with hemorrhagic stroke. CONCLUSIONS: The incidence rate of hemorrhagic stroke in patients with sickle cell anemia increases with age. Structural vascular abnormalities such as moyamoya arteriopathy and aneurysms are common etiologies for hemorrhage and screening may be warranted.

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.

"Death is as Much Part of Life as Living": Attitudes and Experiences Preparing for Death from Older Adults with Sickle Cell Disease.

The life-limiting and unpredictable nature of sickle cell disease (SCD) is well-established, yet there is limited literature on end-of-life planning. The purpose of this study was to describe perspectives about preparing for death for older adults with SCD. We enrolled 19 older adults with SCD (age ≥ 50 years) into this qualitative descriptive study. Theme 1 was "anticipation of early death," with sub-themes: (a) informed of early death and (b) making plans for death. Theme 2 was "near death experiences." Theme 3 was "differences in level of comfort with death" with subthemes: (a) death as a part of life and (b) differences in level of comfort discussing death. Theme 4 was "influence of spirituality" with subthemes: (a) God controls the timing of death and (b) belief in the afterlife. These results will inform interventions to improve the quality of patient-provider communication to provide goal-concordant end-of-life care for adults with SCD.

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.

Proteomic discovery in sickle cell disease: Elevated neurogranin levels in children with sickle cell disease.

PURPOSE: Sickle cell disease (SCD) is an inherited hemoglobinopathy that causes stroke and silent cerebral infarct (SCI). Our aim was to identify markers of brain injury in SCD. EXPERIMENTAL DESIGN: Plasma proteomes were analyzed using a sequential separation approach of hemoglobin (Hb) and top abundant plasma protein depletion, followed by reverse phase separation of intact proteins, trypsin digestion, and tandem mass spectrometry. We compared plasma proteomes of children with SCD with and without SCI in the Silent Cerebral Infarct Multi-Center Clinical Trial (SIT Trial) to age-matched, healthy non-SCD controls. RESULTS: From the SCD group, 1172 proteins were identified. Twenty-five percent (289/1172) were solely in the SCI group. Twenty-five proteins with enriched expression in the human brain were identified in the SCD group. Neurogranin (NRGN) was the most abundant brain-enriched protein in plasma of children with SCD. Using a NRGN sandwich immunoassay and SIT Trial samples, median NRGN levels were higher at study entry in children with SCD (0.28 ng/mL, N = 100) compared to control participants (0.12 ng/mL, N = 25, p < 0.0004). CONCLUSIONS AND CLINICAL RELEVANCE: NRGN levels are elevated in children with SCD. NRGN and other brain-enriched plasma proteins identified in plasma of children with SCD may provide biochemical evidence of neurological injury.

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.

Trial design of comparing patient-specific versus weight-based protocols to treat vaso-occlusive episodes in sickle cell disease (COMPARE-VOE).

OBJECTIVES: Painful vaso-occlusive episodes (VOE) are the most common reason for emergency department (ED) visits experienced by patients with sickle cell disease (SCD). The National Heart, Lung and Blood Institute (NHLBI) evidence-based recommendations for VOE treatment are based primarily on expert opinion. In this randomized controlled trial (RCT), we will compare changes in pain scores between patients randomized to a patient-specific analgesic protocol versus those randomized to a weight-based analgesic protocol, as recommended by the NHLBI guidelines. METHODS: We report the rationale and design of a multi-site, phase III, single-blinded, RCT to be conducted in six EDs in the United States. Eligible participants will be randomized after providing consent, anticipating 50% of those randomized would have an ED visit during the enrollment period. A total of 230 participants with one VOE ED visit provides sufficient power to detect a clinically significant difference in pain score reductions of 14 between groups with 0.05 type I error. Uniquely, this trial randomizes participants in a larger population than the study population, given the impossibility of consenting and randomizing participants during emergencies. The primary endpoint is the change in pain scores in the ED from time of placement in treatment area to time of disposition (hospitalization, discharged home, or assigned to observation status) or a maximum treatment duration of 6 hours. Additional outcomes include hospitalizations and ED visits seven days post enrollment, side effects, and safety assessments. CONCLUSIONS: The COMPARE-VOE study design will provide high-level evidence to support the NHLBI VOE treatment guidelines.

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.