Consensus definition of essential, optimal, and suggested components of a pediatric sickle cell disease center.

Sickle cell disease (SCD) requires coordinated, specialized medical care for optimal outcomes. There are no United States (US) guidelines that define a pediatric comprehensive SCD program. We report a modified Delphi consensus-seeking process to determine essential, optimal, and suggested elements of a comprehensive pediatric SCD center. Nineteen pediatric SCD specialists participated from the US. Consensus was predefined as 2/3 agreement on each element's categorization. Twenty-six elements were considered essential (required for guideline-based SCD care), 10 were optimal (recommended but not required), and five were suggested. This work lays the foundation for a formal recognition process of pediatric comprehensive SCD centers.

Development and Validation of the Patient/Caregiver Reported Hydroxyurea Evaluation of Adherence for Life (HEAL) Scale.

Introduction: Hydroxyurea reduces the incidence of vaso-occlusive episodes, stroke, and respiratory, cardiac, and renal damage in sickle cell disease by increasing fetal hemoglobin. However, because suboptimal adherence to hydroxyurea limits its effectiveness, understanding patient-specific barriers to hydroxyurea adherence could help improve adherence and health outcomes in patients with sickle cell disease. The aim of this single-site, prospective, IRB-approved study was to validate a 24-item patient- and caregiver-reported hydroxyurea treatment adherence questionnaire, the Hydroxyurea Evaluation of Adherence for Life (HEAL) scale. Methods: A sample of 24 adults with sickle cell disease and 16 caregivers of children with sickle cell disease completed the HEAL scale, and a subset of the original sample provided a second HEAL scale for test-retest reliability. HEAL scale results were validated against global adherence ratings from participants and health-care providers, records of access to pill bottles, and laboratory values for fetal hemoglobin and absolute neutrophil count. Results and Discussion: Results demonstrated excellent internal consistency for the HEAL Total score and eight (3-item) subscale scores (Dose, Remember, Plan, Cost, Understand, Effectiveness, Laboratory, and Pharmacy), as well as strong test-retest reliability for all HEAL scores except the Cost subscale. HEAL Total scores correlated significantly with validity measures, including global adherence ratings and lab values. The HEAL scale offers significant clinical potential for understanding adherence in individual sickle cell disease patients and significant research potential for characterizing adherence in persons with sickle cell disease who are treated with hydroxyurea.

No child left behind: Building a comprehensive sickle cell disease care oasis in the Lake County, Indiana care desert.

BACKGROUND: Sickle cell disease (SCD) leads to end-organ damage and shortened life expectancy. The second highest incidence of SCD in Indiana is in Lake County, but until 2017, there was no SCD expert within 65 miles. The Indiana Hemophilia and Thrombosis Center (IHTC) developed the Sickle Care coordination OutReach and Education (SCORE) program in 2017 to bring high-quality, guideline-based care to children with SCD. PROCEDURE: The St. Vincent IRB deemed this retrospective analysis of SCORE clinic care from 2017 to 2020 exempt. Data on the number of transcranial Dopplers (TCD) performed, HU dosing escalation, and vaccine rates were collected along with the number of school and home visits completed. RESULTS: Fifty-three children, adolescents, and young adults completed 288 SCORE clinic visits during the study period; over 75% completed at least three clinic visits. Mean HU dose increased significantly with SCORE clinic care. TCD screening rates increased every year starting in 2018 through 2020 when we added local care coordination. One hundred seventy-three vaccines were administered in SCORE outreach clinics. The PPSV23 vaccines had a 100% acceptance rate, and seasonal influenza had a 75.8% acceptance rate. CONCLUSION: Access to care coordination services and local hematology specialty care alleviates barriers to care and enables comprehensive SCD care delivery to children in need. Prior to the establishment of the SCORE clinic, 75% of children in Lake County were not receiving recommended stroke screening. The SCORE clinic model demonstrates feasibility and impact when delivering on the promise of high-quality care for children with SCD.

Ring the Bell for Sickle Cell: Encouraging Advocacy in an Underserved Community.

Sickle cell disease (SCD) was once a disease of childhood because of a limited life expectancy. Due to medical advances, it is now common for people with SCD to live into adulthood. Funding and resources for adults with SCD, however, remain limited. Adult patients would benefit from increased access to medical care, mental health care services, and workforce development. The Indiana Sickle Cell Consortium, a group of medical providers and community-based organizations, worked closely with people living with SCD and their family members to create a campaign advocating for state funding for programs for adults with SCD. This campaign culminated with the passage of a bill that provides $250,000 in funding for program development for adults with SCD. The bill also directs the Indiana Department of Health to carry out a needs assessment for people with SCD in Indiana. However, continued efforts are needed to reduce health disparities for people with SCD. The Indiana Sickle Cell Consortium will continue advocacy efforts in future legislative cycles and bring attention to the health inequities that affect people with SCD.

Use of dual-electron probes reveals the role of ferritin as an iron depot in ex vivo erythropoiesis.

In the finely regulated process of mammalian erythropoiesis, the path of the labile iron pool into mitochondria for heme production is not well understood. Existing models for erythropoiesis do not include a central role for the ubiquitous iron storage protein ferritin; one model proposes that incoming endosomal Fe3+ bound to transferrin enters the cytoplasm through an ion transporter after reduction to Fe2+ and is taken up into mitochondria through mitoferrin-1 transporter. Here, we apply a dual three-dimensional imaging and spectroscopic technique, based on scanned electron probes, to measure Fe3+ in ex vivo human hematopoietic stem cells. After seven days in culture, we observe cells displaying a highly specialized architecture with anchored clustering of mitochondria and massive accumulation of nanoparticles containing high iron concentrations localized to lysosomal storage depots, identified as ferritin. We hypothesize that lysosomal ferritin iron depots enable continued heme production after expulsion of most of the cellular machinery.

How we coordinate care for uninsured children with nonmalignant hematologic disorders.

Providing medical care for uninsured children with nonmalignant hematologic diagnoses presents unique challenges to medical providers and multidisciplinary staff. Financial and psychosocial stressors can hinder optimal care of the uninsured child. Maximizing coverage of medical costs through patient enrollment in state and charity care programs and capitalizing upon community partnerships can help providers achieve comprehensive care for these children. Collaboration between primary care providers, subspecialists, and multidisciplinary teams can be optimized to facilitate provision of hematology care for uninsured children. We detail our experience in establishing these collaborations to improve access to subspecialty care for children with nonmalignant hematologic disorders.

Hematopoietic stem cell transplant referral patterns for children with sickle cell disease vary among pediatric hematologist/oncologists' practice focus: A Sickle Cell Transplant Advocacy and Research Alliance (STAR) study.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) provides a curative therapy for children severely affected by sickle cell disease (SCD). Rejection-free survival after matched sibling donor (MSD) HSCT is very high, but adoption of HSCT as a curative SCD therapy has been slow. In this study, we assess providers' perceptions about MSD HSCT for children with variable SCD severity, and determine the influence of provider characteristics on HSCT referrals. PROCEDURE: After our Institutional Review Board deemed the study exempt, American Society of Pediatric Hematology/Oncology Clinical Forum listserv subscribers and American Society of Hematology members who self-identified as pediatric hematologists/oncologists (PHO) were emailed a survey. Analysis was performed to describe and evaluate correlations between participant demographics (including practice focus within PHO) and likelihood of HSCT referral for each scenario. RESULTS: Spearman's rank correlation analysis did not reveal any significant relationship between demographic characteristics except practice focus and likelihood to refer to HSCT for any scenarios. Providers focused on SCD and HSCT were more likely to refer a child who had never been admitted to the hospital or had suboptimal adherence to hydroxyurea than general PHOs. A significantly higher proportion of all respondents would refer a child with ß-thalassemia major (87%) than an asymptomatic child with HbSS (47%, P < .00001) or non-HbSS variant (23%, P < .00001). CONCLUSION: PSCD and HSCT physicians are more likely to refer for MSD HSCT in almost every condition than general PHO practitioners, likely because of increased awareness of long-term effects of SCD and safety of MSD HSCT for children with SCD.

Not all red cells sickle the same: Contributions of the reticulocyte to disease pathology in sickle cell anemia.

Sickle cell anemia (SCA) is associated with morbidity and early death. While the switch from fetal to sickle hemoglobin during the first months of life results in hemolytic anemia with reticulocytosis, the role of the reticulocyte in the pathophysiology and prognosis of SCA is not well-defined. Reticulocytes have unique cytoskeletal and membrane components that allow them to be distinguished from mature sickle erythrocytes in the circulation. Reticulocytes in patients with SCA are less dense than more mature and 'sickled' erythrocytes, and have increased adhesive properties. The circulating reticulocyte number in peripheral blood may assist in predicting disease severity in SCA; characterization of patient-specific reticulocyte properties during infancy and childhood may assist in predicting therapeutic response to therapies. Here, we review the biological and clinical data regarding reticulocytes and their potential impact on SCA pathophysiology and disease severity.

Adherence to Quality of Care Indicators and Location of Sickle Cell Care Within Indiana.

Newborn screening (NBS) follow-up programs for infants with sickle cell disease (SCD) are highly variable among states. Initiated in 2009, Sickle SAFE, the NBS follow-up program for infants with SCD in Indiana, follows infants through home visits and phone contact. The current study assessed the attainment rates for recently published quality indicators of pediatric SCD care for Sickle SAFE participants. Using retrospective data, we determined the proportion of children who received transcranial Doppler (TCD) screening, influenza, and pneumococcal vaccination and were prescribed hydroxyurea. We calculated the mean age at confirmatory testing, time to receipt of penicillin prophylaxis, and mean age when genetic counseling was offered. One hundred ninety-eight children born with SCD in Indiana between July 1, 2009 and June 30, 2017 were followed for at least 1 year. While 97.5% received at least one dose of conjugated pneumococcal vaccine, vaccination with the 23 valent pneumococcal vaccine varied by location (county) of care (Allen: 14.3%, Lake: 26.7%, St. Joseph: 40.0%, Marion: 73.3%). Overall TCD screening rate for eligible children was 53%; TCD screening rate varied widely by location of care (Lake: 25% vs. Marion: 63.8%). Similarly, hydroxyurea prescribing practices varied significantly by location of care (p < 0.001). Identified gaps in adherence to quality indicators in SCD care will serve as the basis for future quality improvement initiatives.

Characterization of natural killer cells expressing markers associated with maturity and cytotoxicity in children and young adults with sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) is increasingly recognized as a red blood cell disorder modulated by abnormally increased inflammation. We have previously shown that in patients with SCD not on a disease-modifying therapy (hydroxyurea or chronic transfusions), natural killer (NK) cell numbers are increased. In the current study, we further investigated the NK cell function to determine if there was evidence of increased activation and cytotoxicity. PROCEDURE: We conducted a cross-sectional study of 44 patients with HbSS/HbSß0 thalassemia at steady state (hydroxyurea = 13, chronic transfusion = 11, no disease-modifying therapy = 20) and 23 healthy controls. Using a fresh blood sample, NK immunophenotyping was performed as follows: NK cells (CD3- CD56+ lymphocytes) were evaluated for makers associated with activation (NKG2D, NKp30, NKp44, and CD69) and maturity (CD57, killer immunoglobulin-like receptors (KIR), and CD56dim). Degranulation and cytotoxicity assays were performed to evaluate NK cell function. RESULTS: Patients with SCD who were not on disease-modifying therapy had a higher number of NK cells with an immunophenotype associated with increased cytotoxicity (NKG2D+ , NKp30+ , CD56dim+ , and KIR+ NK cells) compared with healthy controls and patients on hydroxyurea. NK cells from SCD patients not on disease-modifying therapy demonstrated significantly increased cytotoxicity (measured by assaying NK cell killing of the K562 cell line) compared with healthy controls (P = 0.005). Notably, NK cell cytotoxicity against K562 cells in the hydroxyurea or chronic transfusion patients was not significantly different from that in healthy controls. CONCLUSION: SCD is associated with increased NK cell function as well as increased NK cell numbers, which appears to be normalized with disease-modifying therapy.

Clinical features of children, adolescents, and adults with coexisting hypermobility syndromes and von Willebrand disease.

We present five patients with coexistent von Willebrand disease (VWD) and Ehlers-Danlos syndrome and 21 with VWD and joint hypermobility. Females outnumbered males ten to three, Beighton scores were documented in 58% (15 of 26 patients), and several patients experienced moderately severe bleeding. We believe coexistent hypermobility disorder with VWD potentially affects bleeding severity and want to raise awareness among hematologists. Evaluation by geneticists is recommended because of the varying complexities observed across the disease spectrum, and the availability of new genetic tests should lead to more accurate diagnoses for the various hypermobility disorders.

Treatment Options for Sickle Cell Disease.

Sickle cell disease (SCD) complications begin with the polymerization of sickle hemoglobin (HbS). Thus, SCD therapies are focused on preventing HbS production or reducing the circulating amount of HbS. Hydroxyurea treatment has become more widespread, whereas the number of evidence-based indications for erythrocyte transfusion is small. Hematopoietic stem cell transplant is a curative option for SCD but less than 25% of patients have a suitable donor. This article focuses on supportive and preventive care improvements and the benefits of hydroxyurea. Indications for erythrocyte transfusion, hematopoietic stem cell transplant, and gene therapy trials are also summarized.

Diverse manifestations of acute sickle cell hepatopathy in pediatric patients with sickle cell disease: A case series.

The hepatic complications of sickle cell disease (SCD) are associated with increased morbidity and mortality in adults; children usually survive but may suffer significant sequelae. Few diagnostic tools differentiate the various hepatic manifestations of SCD. Why patients exhibit one hepatic pathology versus another is unclear. We report four pediatric patients with hemoglobin SS disease with diverse manifestations of acute hepatic involvement including acute sickle hepatic crisis, hepatic sequestration, sickle cell intrahepatic cholestasis, and a non-SCD cause of hepatopathy in a patient with viral hepatitis. These complications require a systematic approach to extensive evaluation and coordinated multidisciplinary care.

Access to hematopoietic stem cell transplant for patients with sickle cell anemia.

Hematopoietic stem cell transplantation (HSCT) is a curative therapy for patients with phenotypically severe sickle cell anemia, and survival rates following matched-sibling HSCT are very high. However, despite cure rates much higher than HSCT for malignant diseases, the field has been slow to adopt this treatment modality for sickle cell anemia. This article explores some of the social forces that may contribute to this dichotomy.

Early initiation of inhaled corticosteroids does not decrease acute chest syndrome morbidity in pediatric patients with sickle cell disease.

Acute chest syndrome (ACS) is a leading cause of mortality in patients with sickle cell disease (SCD). Systemic corticosteroids decrease ACS severity, but the risk of readmission for vaso-occlusive crises (VOC) has limited their use. The efficacy of inhaled corticosteroids (ICS) as a safer alternative is currently unknown. An observational, historic cohort study compared patients with SCD with ACS who received ICS at admission (ICS) to those who did not (non-ICS). Outcome measures included rates of transfusion, oxygen requirement, BiPAP initiation, PICU transfer, intubation, readmission, hospital cost, and length of stay. One hundred twenty patients with SCD (55 non-ICS, 65 ICS) were included. A significantly higher proportion of the non-ICS group had bilateral infiltrates, but fewer had asthma. More children in the ICS group had BiPAP initiated, however transfer to the PICU, intubation, transfusion rates, oxygen requirement, hospital cost, length of stay, and readmission rates did not differ between groups. Regression analysis did not reveal any differences in outcomes, nor were outcomes changed when patients were separated based on the presence or absence of asthma. In this observational cohort study, ICS did not demonstrate a significant reduction in ACS morbidity, though ICS use should be studied in a prospective manner.

A systematic review of the literature for severity predictors in children with sickle cell anemia.

All patients with HbSS (SCA) share the same genetic mutation but the clinical phenotype is variable and difficult to predict early in life. A reliable severity predictor would be invaluable toward directing therapeutic decisions in those patients at highest risk of SCA complications. A search of PubMed, Cochrane Clinical Trials Register, and Scopus was performed to determine which SCA severity predictors have been validated in pediatric patients. The full text of 94 of the 590 references identified was reviewed based on the title/abstract. Fifty-four articles were included in the analysis. Alpha globin gene number was the most commonly studied severity predictor, followed by fetal hemoglobin (HbF) and reticulocyte count. Alpha thalassemia trait was protective against overt stroke and abnormal transcranial Doppler (TCD) in all but one study, but not frequency of painful crisis or silent cerebral infarct. Two thirds of the HbF studies reported beneficial effects with increasing HbF levels; however, increased HbF levels were not associated with lower hospitalization or stroke rates in others. The ability to predict SCA complications was mixed for all variables, except TCD and absolute reticulocyte count. More reliable predictors are urgently needed to guide therapeutic decisions in children with SCA.

Pediatric sickle cell disease: past successes and future challenges.

Once a fatal disease of childhood, more than 95% of patients born today with sickle cell disease (SCD) in developed countries are expected to survive into adulthood, largely because of improvements in supportive and preventive care (newborn screening, penicillin prophylaxis, transcranial Doppler (TCD) screening). Hydroxyurea (HU) therapy, the only oral medication currently available to prevent SCD complications, has become more widespread over the past 20 y. The NHLBI recommends that HU be offered to all patients with HbSS beginning at 9 mo of age, and the recently published Abnormal TCD with Transfusions Changing to HU (TWiTCH) trial has shown HU as an acceptable alternative to transfusion therapy for patients at high risk of stroke. While hematopoietic stem cell transplant (HSCT) is a curative option for SCD, less than 25% of patients have a suitable donor. Alternative stem cell sources from unrelated donors and haplo-identical donors are currently under investigation as are gene therapy trials. This review will focus on early efforts to elucidate SCD pathophysiology as well as supportive and preventive care improvements. Findings from recent multi-center studies (Silent Infarct Transfusion (SIT) Trial and TWiTCH) will be summarized. Finally, HSCT trials and gene therapy will be reviewed.