Feasibility and preliminary efficacy of the Balance Program to reduce pain-related disability in pediatric sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) pain is associated with functional impairment, and treatment is often limited to pharmacological approaches with unwanted side effects. Although behavioral interventions exist for non-SCD pain populations, interventions designed to address pain-related impairment in SCD are lacking. METHODS: Twenty youth (9-17 years) with SCD completed a four-week telemedicine pain intervention (NCT04388241). Participants and caregivers completed baseline and post-intervention PROMIS pain measures and the Treatment Evaluation Inventory-Short Form (TEI-SF). Descriptive analyses assessed feasibility and acceptability. Reliable Change Index analyses assessed for significant post-intervention changes in pain functioning. Paired t test analyses compared baseline and post-intervention opioid prescription fills. RESULTS: All participants completed at least one treatment session. Eighteen (90%) youth completed all sessions. Youth (100%) and caregivers (94%) rated the intervention as moderately or highly acceptable on the TEI-SF. Forty-seven percent of caregivers and 44% of youth reported reliably significant improvements in pain interference after the intervention (median T-score differences: 24.8 and 23.5, respectively). Sixty-five percent of caregivers (T-score improvement difference: 19.3) and 31% of youth (T-score improvement difference: 32) reported improvements in pain behaviors. There was no significant difference in opioid prescription fills pre- and post-intervention (P > 0.05). CONCLUSIONS: The Balance Program is feasible, highly acceptable, and can be delivered remotely to reduce barriers to care. Approximately half of youth and caregivers reported significant declines in pain interference following the intervention, with substantial improvements in functioning for treatment responders. Behavioral pain interventions are important adjunctive treatments to uniquely address functional impairment associated with acute and chronic pain in SCD.

The evolution of the COVID-19 pandemic in paediatric patients with sickle cell disease: From Alpha to Omicron.

We compare the impact of SARS-CoV-2 variants on healthcare utilization and clinical presentation in paediatric patients with sickle cell disease (SCD). One hundred and ninety-one unique patients with SCD and positive SARS-CoV-2 polymerase chain reactions were identified between March 2020 and January 2022. Hospitalizations, which accounted for 42% (N = 81) of cases, were highest during the Delta dominant era (48%) and lowest during Omicron (36%) (p = 0.285). The most common SCD-related complication was vaso-occlusive pain (37%, N = 71), which accounted for 51% of all hospital admissions (N = 41), and acute chest was highest in the Alpha variant era (N = 15). Overall, COVID-19 remained mild in clinical severity within most paediatric SCD patients.

Neurocognitive and emotional factors predict pain-related healthcare utilization in children with sickle cell disease.

BACKGROUND: Youth with sickle cell disease (SCD) experience increased rates of neurocognitive and emotional difficulties. Cross-sectional studies suggest neurocognitive and emotional functioning are associated with health outcomes in SCD. We investigated whether neurocognitive and emotional factors predicted future pain-related healthcare utilization in children with SCD. PROCEDURE: Total 112 youth with SCD between ages 7 and 16 years reported sociodemographics and completed measures of neurocognitive functioning and emotional well-being. The number of emergency department (ED) visits and hospitalizations for pain 1 and 3 years after enrollment were determined by chart review. RESULTS: The mean age of participants was 10.61 years (standard deviation = 2.91), with most being female (n = 65; 58%). Eighty-three (74%) participants had either HbSS or HbSß0 thalassemia. Regression analyses showed that attention significantly predicted ED visits and hospitalizations for pain at 1 and 3 years after enrollment (all p-values ≤ .017), such that poorer attention was associated with higher healthcare utilization. Lower emotional quality of life also predicted more ED visits for pain at 3 years (b = -.009, p = .013) and hospitalizations for pain at 3 years (b = -.008, p = .020). CONCLUSIONS: Neurocognitive and emotional factors are associated with subsequent healthcare use in youth with SCD. Poor attentional control might limit implementation of strategies to distract from pain or could make disease self-management behaviors more challenging. Results also highlight the potential impact of stress on pain onset, perception, and management. Clinicians should consider neurocognitive and emotional factors when developing strategies to optimize pain-related outcomes in SCD.

Clinical outcomes of children and adolescents with sickle cell disease and COVID-19 infection: A year in review at a metropolitan tertiary pediatric hospital.

Background: COVID-19 was declared a global pandemic in March 2020. Early reports were primarily in adults, and sickle cell disease (SCD) was classified as a risk factor for severe COVID-19 disease. However, there are a limited number of primarily multi-center studies reporting on the clinical course of pediatric patients with SCD and COVID-19. Methods: We conducted an observational study of all patients with SCD diagnosed with COVID-19 at our institution between March 31, 2020, and February 12, 2021. Demographic and clinical characteristics of this group were collected by retrospective chart review. Results: A total of 55 patients were studied, including 38 children and 17 adolescents. Demographics, acute COVID-19 clinical presentation, respiratory support, laboratory findings, healthcare utilization, and SCD modifying therapies were comparable between the children and adolescents. Seventy-three percent (N = 40) of all patients required emergency department care or hospitalization. While 47% (N = 26) were hospitalized, only 5% (N = 3) of all patients required intensive care unit admission. Patients frequently had concurrent vaso-occlusive pain crisis (VOC) (N = 17, 43%) and acute chest syndrome (ACS) (N = 14, 35%). Those with ACS or an oxygen requirement had significantly higher white blood cell count, lower nadir hemoglobin, and higher D-dimers, supporting a pro-inflammatory and coagulopathic picture. Non-hospitalized patients were more likely to be on hydroxyurea than hospitalized patients (79 vs. 50%, p = 0.023). Conclusion: Children and adolescent patients with SCD and acute COVID-19 often present with ACS and VOC pain requiring hospital-level care. Hydroxyurea treatment appears to be protective. We observed no mortality despite variable morbidity.

Optimising the screening for haemoglobinopathies in pregnancy planning.

Haemoglobinopathies are among the most common inherited disorders around the world. In the United States the diagnosis of haemoglobinopathy or a carrier state is made by universal newborn screening. However, many individuals of childbearing age do not know they are a haemoglobinopathy carrier. Screening for common haemoglobinopathies is generally offered as a part of pregnancy planning so that prospective parents can be counselled regarding the risk of having a child with a haemoglobinopathy. Multiple tests exist to screen patients for presence of haemoglobinopathy carrier or disease state; however, it is crucial to order and interpret the results correctly to appropriately counsel couples. In this case series, we describe clinical scenarios where prospective parents were surprised to unexpectedly have a child with sickle cell disease, a haemoglobinopathy that causes severe clinical complications. Through these cases we demonstrate that deficiencies in testing can occur at different levels which may lead to incorrect estimation of the risk of having a child affected by a haemoglobinopathy. Consultation with a haematologist, laboratory medicine specialist, or genetic counsellor should be considered to select the appropriate test and interpret its results.

Telemedicine in sickle cell disease: Patient, parent, and provider perspectives.

INTRODUCTION: Patients with sickle cell disease (SCD) need frequent health maintenance visits and may face barriers accessing care. Telemedicine, during COVID pandemic, has provided a unique model of care to improve access; however, potential barriers and satisfaction with its use in SCD have not been fully evaluated. OBJECTIVE: To determine caregiver, patient, and healthcare provider (HCP) perspectives and satisfaction with telemedicine in healthcare delivery. METHODS: We surveyed patients with SCD, caregivers, and HCP, who participated in at least one telemedicine visit from March 2020 to June 2021, using the Telemedicine Usability Questionnaire (TUQ). We also accessed and compared the Press Ganey surveys completed by families who completed a telemedicine or in-person visit. Data were summarized using descriptive statistics. The internal reliability of TUQ was assessed using Cronbach's coefficient alpha. Press Ganey data comparing satisfaction with telemedicine versus in-person visits were analyzed by Mann-Whiney U test. RESULTS: Fifty-two patients/caregivers and 10 HCP completed the survey. Patients/caregivers rated satisfaction "excellent" in the five areas (Usefulness, Ease of use, Effectiveness, Reliability and Satisfaction). HCP rated Usefulness, Ease of use, Effectiveness, Satisfaction as "good," and Reliability as "excellent." Press Ganey scores for satisfaction with care for telemedicine and in-person visits were not statistically different (p > .05). DISCUSSION: We found high satisfaction for caregivers and patients as well as HCP in the delivery of clinical services via telemedicine for SCD. We suggest that telemedicine is a viable option for this population and may help overcome the barriers SCD families often face accessing care.

Reduction in vaso-occlusive events following stem cell transplantation in patients with sickle cell disease.

Hematopoietic stem cell transplantation (HSCT) is potentially curative for patients with sickle cell disease (SCD). Patients with stable donor engraftment after allogeneic HSCT generally do not experience SCD-related complications; however, there are no published data specifically reporting the change in vaso-occlusive events (VOE) after HSCT. Data regarding the number of VOEs requiring medical attention in the 2 years before allogeneic HSCT were compared with the number of VOEs in the 2 years (0-12 months and 12-24 months) after allogeneic HSCT in patients with SCD. One-hundred sixty-three patients with SCD underwent allogeneic HSCT between 2005 and 2019. The average age at the time of HSCT was 21 years (range, 7 months - 64 years). Most patients underwent nonmyeloablative conditioning (75% [N = 123]) and had a matched sibling donor (72% [N = 118]). The mean number of VOEs was reduced from 5.6 (range, 0-52) in the 2 years before HSCT to 0.9 (range, 0-12) in the 2 years after HSCT (P < .001). Among the post-HSCT events, VOE was more frequent during the first 12 months (0.8 [range, 0-12]) than at 12 to 24 months after HSCT (0.1 [range, 0-8) (P < .001)). In patients who had graft rejection (12%, N = 20), VOEs were reduced from 6.6 (range, 0-24) before HSCT to 1.1 (range, 0-6) and 0.8 (range, 0-8) at 0 to 12 months and 12 to 24 months after HSCT, respectively (P < .001). VOEs requiring medical care were significantly reduced after allogeneic HSCT for patients with SCD. These data will inform the development of novel autologous HSCT gene therapy approaches.

Reproductive health and knowledge among youth with sickle cell disease.

Knowledge related to reproductive health in adolescents with sickle cell disease (SCD) is not fully addressed. We evaluated reproductive health and knowledge among adolescent girls with SCD. Seventy-nine adolescents, 13-21 years of age completed a survey on reproductive health and knowledge with menarche age 13.2 (± 1.7) years. Fifty-four percent reported dysmenorrhea and 49% reported SCD pain a week before menstrual cycle. Sixty-two percent reported discussing contraception and pregnancy with medical providers. Adolescents reported late menarche, dysmenorrhea, and pain with menses. Knowledge of overall reproductive health was inadequate. There is an urgent need to improve reproductive education in this population.

Amino acid signature during sickle cell pain crisis shows significant alterations related to nitric oxide and energy metabolism.

Nitric oxide depletion secondary to arginase induced arginine deficiency has been shown to be important in the pathophysiology of vaso-occlusion in sickle cell pain crisis. Our objective of this study was to perform a comprehensive amino acid evaluation during sickle cell pain crisis. In a total of 58 subjects (29 in steady-state sickle cell disease and 29 with sickle cell pain crisis), the amino acids related to nitric oxide pathway was significantly decreased during sickle cell pain crisis compared to steady-state sickle cell disease: arginine (p = 0.001), citrulline (p = 0.012), and ornithine (p = 0.03). In addition, the amino acids related to energy metabolism was significantly decreased during a pain crisis: asparagine (p < 0.001), serine (p = 0.002), histidine (p = 0.017), alanine (p = 0.004), tyrosine (p = 0.012), methionine (p = 0.007), cystine (p = 0.016), isoleucine (p = 0.016) and lysine (p = 0.006). The amino acid related to oxidative stress were significantly higher during a sickle cell pain crisis (glutamic acid (p < 0.001). Furthermore, multivariate analysis with partial least squares-discriminant analysis (PLS-DA) showed that deficiencies of the amino acids arginine, asparagine, citrulline, methionine and alanine were the most important related to sickle cell pain crisis.

Alteration of grey matter volume is associated with pain and quality of life in children with sickle cell disease.

Pain is the most common symptom experienced by patients with sickle cell disease (SCD) and is associated with poor quality of life. We investigated the association between grey matter volume (GMV) and the frequency of pain crises in the preceding 12 months and SCD-specific quality of life (QOL) assessed by the PedsQLTM SCD module in 38 pediatric patients with SCD. Using voxel-based morphometry methodology, high-resolution T1 structural scans were preprocessed using SPM and further analyzed in SPSS. The whole brain multiple regression analysis identified that perigenual anterior cingulate cortex (ACC) GMV was negatively associated with the frequency of pain crises (r = -0.656, P = 0.003). A two-group t-test analysis showed that the subgroup having pain crisis/crises in the past year also showed significantly lower GMV at left supratemporal gyrus than the group without any pain crisis (p=0.024). The further 21 pain-related regions of interest (ROI) analyses identified a negative correlation between pregenual ACC (r = -0.551, P = 0.001), subgenual ACC (r = -0.540, P = 0.001) and the frequency of pain crises. Additionally, the subgroup with poorer QOL displayed significantly reduced GMV in the parahippocampus (left: P = 0.047; right: P = 0.024). The correlations between the cerebral structural alterations and the accentuated pain experience and QOL suggests a possible role of central mechanisms in SCD pain.

Spirometric Changes After Initiation of Hydroxyurea in Children With Sickle Cell Anemia.

Individuals with sickle cell disease (SCD) develop a decline in lung function over time. Hydroxyurea (HU) is the most common disease-modifying therapy used in SCD. We hypothesized that children with SCD treated with HU will have a slower decline in pulmonary function. We performed a retrospective chart review of children with HbSS and HbS-beta zero thalassemia referred to pulmonology for respiratory symptoms. We compared the spirometry results at 2 time points between children on HU (HU group) and not on HU (control group). For the HU group, these endpoints were evaluated before and after being on HU. The mean time interval between 2 spirometry studies was not significantly different between the groups (2.6±1.5 y for HU group vs. 3.0±1.8 y for the control group; P =0.33). The mean age of patients in the HU group was 9.8±3.8 years (55% male) and 10.7±4.9 years (50% male) in the control group. The spirometry data was compared within and between the groups using t test. There was a significant increase in forced vital capacity in HU group during follow-up, while children in the control group showed a decline (7.2±17.1 vs. -3.4±18.2; P <0.01). Our study suggests that HU therapy may help preserve lung function over time in children with SCD.

Low Rates of Cerebral Infarction after Hematopoietic Stem Cell Transplantation in Patients with Sickle Cell Disease at High Risk for Stroke.

Hematopoietic stem cell transplantation (HSCT) can be curative for sickle cell disease (SCD). SCD patients with cerebrovascular disease are often referred for HSCT. The objective of this study was to describe neurologic outcomes after HSCT in patients with pre-existing SCD and cerebrovascular comorbidity. Patients with SCD treated with HSCT at a single center between 1996 and 2019 were identified. Patients with cerebral ischemia and/or vasculopathy before undergoing HSCT were included. Patients with graft failure were excluded. The cohort was divided into 3 groups: symptomatic stroke, vasculopathy without symptomatic stroke, and isolated silent cerebral infarction (SCI). Magnetic resonance imaging/angiography and neurologic assessments pre- and post-HSCT were analyzed to assess outcomes. In a cohort of 44 patients, there were 25 with symptomatic infarction, 10 with vasculopathy, and 9 with isolated SCI. Post-HSCT ischemic injury (2 symptomatic strokes, 2 SCIs) was identified in 4 patients, all with previous symptomatic infarction. Within this group (n = 25), the post-HSCT incidence of subsequent symptomatic infarction was 1.6 events/100 patient-years, and SCIs occurred at a rate of 2.2 events/100 patient-years. No patient had progression of vasculopathy post-HSCT. Our data show a low incidence of new ischemic injury after successful HSCT for SCD. Patients with a history of both symptomatic stroke and vasculopathy are at greatest risk for post-HSCT ischemic injury.

Acupuncture as an Adjunctive Treatment for Pain in Hospitalized Children With Sickle Cell Disease.

CONTEXT: Acute episodes of pain associated with sickle cell disease (SCD) account for over 100,000 hospitalizations and expenses of nearly one billion dollars annually in the U.S. New treatment approaches are needed as the current opioid based therapy is often inadequate in controlling pain, resulting in prolonged inpatient stays, and high rates of readmission. OBJECTIVES: To evaluate acceptability of acupuncture as an adjunctive therapy and explore the impact of acupuncture on pain related outcomes in a population of youth with SCD hospitalized for management of acute pain. METHODS: This IRB approved single center study recruited youth with SCD (9-20 years) who were hospitalized for management of acute pain into either the acupuncture group or controls. Both groups also received standard pain management therapies. RESULTS: Participants in the acupuncture (n = 19) and control (n = 10) group were comparable in clinical characteristics. Acupuncture had an acceptability rate of over 66% and was tolerated well without any side effects. Acupuncture was associated with reduction in pain scores (6.84-5.51; P < 0.0001). Acupuncture group demonstrated a trend toward lower length of stay and readmission rates, but these were not statistically significant. Opioid use was not different between the groups. Treatment Evaluation Inventory survey showed high rates of satisfaction with acupuncture. CONCLUSION: Acupuncture was broadly accepted and well-tolerated in our study population. Acupuncture treatment was associated with a statistically significant and clinically meaningful reduction in pain scores immediately following the treatments, and a trend towards a reduction in length of stay and readmission for pain.

Screening for new red blood cell alloantibodies after transfusion in patients with sickle cell disease.

BACKGROUND: Patients with sickle cell disease (SCD) are frequent recipients of red blood cell (RBC) transfusions and are at risk for RBC alloimmunization. RBC alloimmunization is diagnosed by identifying RBC alloantibodies as part of pre-transfusion testing, but this testing fails to detect alloantibodies that have evanesced. It may be beneficial to screen for new RBC alloantibody development after transfusion before possible antibody evanescence. STUDY DESIGN AND METHODS: Our institution started a new initiative for episodically transfused patients with SCD to obtain at least one antibody screen 2-6 months after transfusion as part of their clinical care. A database was created to prospectively track all transfused patients for 1 year and their post-transfusion antibody screen results. Patients received prophylactically CEK-matched RBC units. RESULTS: During the study year, 138 patients with SCD received a total of 242 RBC transfusions. Patients with a history of an RBC alloantibody (n = 13, 9.4%) had previously received more RBC units than non alloimmunized patients (median 11 vs. 2 RBC units, p = .0002). A total of 337 post-transfusion antibody screens were obtained in 127 patients (92.0%) with 110 patients (79.7%) having at least one antibody screen 2-6 months post-transfusion. With this prospective testing, two new RBC alloantibodies (anti-C and -M) were identified in two patients. CONCLUSION: It is feasible to test for new RBC alloantibody development in most episodically transfused patients with SCD as part of their routine care. The yield of this screening appears low with CEK matching, but it could still provide important information for individual patients.

Integrative holistic approaches for children, adolescents, and young adults with sickle cell disease: A single center experience.

CONTEXT: Painful vaso-occlusive crises (VOCs) associated with sickle cell disease (SCD) are the most common cause of morbidity, hospitalizations, and poor quality of life. Additional symptoms such as sleep disturbances, fatigue, and stress are also common. Non-traditional approaches are often used by families, but concerns remain that patients may forgo standard of care effective therapies in favor of dangerous unproven alternatives. OBJECTIVES: To describe a single center experience related to a multidisciplinary integrative medicine clinic within the division of hematology dedicated to children and young adults with SCD. METHODS: The Sickle Cell Integrative Clinic at Children's National Hospital services patients with SCD. The main goal of this clinic is to provide access to non-pharmacologic interventions, and to manage patients' symptoms in a holistic manner along with standard of care management of SCD. This IRB approved study evaluated experiences of both patients and parents who attended this clinic. RESULTS: Thirty-seven unique patients attended this clinic over 2 years and 31 participated in the study. After attending the SCD integrative clinic, the majority of patients reported integrative therapies to be an acceptable way of treating pain and believed these to be effective. Overall, the vast majority (88 %) of patients reported having a positive experience with the therapies offered in the clinic. None of the patients experienced any adverse events related to integrative therapies provided in the clinic. CONCLUSION: Our experience suggests that encouraging conversations and offering safe and potentially effective integrative therapies alongside conventional SCD therapies under medical guidance allows patients to have an open discussion about their beliefs and treatment goals, improves patient satisfaction and can improve outcomes.

The CYB5R3c .350C>G and G6PD A alleles modify severity of anemia in malaria and sickle cell disease.

Genetic modifiers of anemia in Plasmodium falciparum infection and sickle cell disease (SCD) are not fully known. Both conditions are associated with oxidative stress, hemolysis and anemia. The CYB5R3 gene encodes cytochrome b5 reductase 3, which converts methemoglobin to hemoglobin through oxidation of NADH. CYB5R3c.350C > G encoding CYB5R3T117S , the most frequent recognized African-specific polymorphism, does not have known functional significance, but its high allele frequency (23% in African Americans) suggests a selection advantage. Glucose-6-phosphate dehydrogenase (G6PD) is essential for protection from oxidants; its African-polymorphic X-linked A+ and A- alleles, and other variants with reduced activity, coincide with endemic malaria distribution, suggesting protection from lethal infection. We examined the association of CYB5R3c.350C > G with severe anemia (hemoglobin <5 g/dL) in the context of G6PD A+ and A- status among 165 Zambian children with malaria. CYB5R3c.350C > G offered protection against severe malarial anemia in children without G6PD deficiency (G6PD wild type or A+/A- heterozygotes) (odds ratio 0.29, P = .022) but not in G6PD A+ or A- hemizygotes/homozygotes. We also examined the relationship of CYB5R3c.350C > G with hemoglobin concentration among 267 children and 321 adults and adolescents with SCD in the US and UK and found higher hemoglobin in SCD patients without G6PD deficiency (ß = 0.29, P = .022 children; ß = 0.33, P = .004 adults). Functional studies in SCD erythrocytes revealed mildly lower activity of native CYB5R3T117S compared to wildtype CYB5R3 and higher NADH/NAD+ ratios. In conclusion, CYB5R3c.350C > G appears to ameliorate anemia severity in malaria and SCD patients without G6PD deficiency, possibly accounting for CYB5R3c.350C > G selection and its high prevalence.

The vaso-occlusive pain crisis in sickle cell disease: Definition, pathophysiology, and management.

Early diagnosis, treatment, and prevention of a vaso-occlusive crisis (VOC) are critical to the management of patients with sickle cell disease. It is essential to differentiate between VOC-associated pain and chronic pain, hyperalgesia, neuropathy, and neuropathic pain. The pathophysiology of VOCs includes polymerization of abnormal sickle hemoglobin, inflammation, and adhesion. Hydroxyurea, L-glutamine, crizanlizumab, and voxelotor have been approved by the US Food and Drug Administration for reducing the frequency of VOCs; the European Medicines Agency has approved only hydroxyurea. Other novel treatments are in late-stage clinical development in both the United States and the European Union. The development of agents for prevention and treatment of VOCs should be driven by our understanding of its pathophysiology.

Tricuspid regurgitation velocity and other biomarkers of mortality in children, adolescents and young adults with sickle cell disease in the United States: The PUSH study.

In the US, mortality in sickle cell disease (SCD) increases after age 18-20 years. Biomarkers of mortality risk can identify patients who need intensive follow-up and early or novel interventions. We prospectively enrolled 510 SCD patients aged 3-20 years into an observational study in 2006-2010 and followed 497 patients for a median of 88 months (range 1-105). We hypothesized that elevated pulmonary artery systolic pressure as reflected in tricuspid regurgitation velocity (TRV) would be associated with mortality. Estimated survival to 18 years was 99% and to 25 years, 94%. Causes of death were known in seven of 10 patients: stroke in four (hemorrhagic two, infarctive one, unspecified one), multiorgan failure one, parvovirus B19 infection one, sudden death one. Baseline TRV ≥2.7 m/second (>2 SD above the mean in age-matched and gender-matched non-SCD controls) was observed in 20.0% of patients who died vs 4.6% of those who survived (P = .012 by the log rank test for equality of survival). The baseline variable most strongly associated with an elevated TRV was a high hemolytic rate. Additional biomarkers associated with mortality were ferritin ≥2000 µg/L (observed in 60% of patients who died vs 7.8% of survivors, P < .001), forced expiratory volume in 1 minute to forced vital capacity ratio (FEV1/FVC) <0.80 (71.4% of patients who died vs 18.8% of survivors, P < .001), and neutrophil count ≥10x109 /L (30.0% of patients who died vs 7.9% of survivors, P = .018). In SCD children, adolescents and young adults, steady-state elevations of TRV, ferritin and neutrophils and a low FEV1/FVC ratio may be biomarkers associated with increased risk of death.