A pharmacokinetic-pharmacodynamic analysis of l-glutamine for the treatment of sickle cell disease: Implications for understanding the mechanism of action and evaluating response to therapy.

The mechanisms of action of l-glutamine for the treatment of sickle cell disease (SCD) are not well understood and there are no validated clinical biomarkers to assess response. We conducted a three-week, dose-ascending trial of glutamine and measured the pharmacokinetic (PK) exposure parameters, peak concentration (Cmax) and area under the curve (AUC). We used a panel of biomarkers to investigate the pharmacodynamics (PD) of glutamine and studied PK-PD relationships. There was no plasma accumulation of glutamine, glutamate, arginine or other amino acids over time, but modestly improved arginine bioavailability was observed. In standard analysis by dose levels over time, there were no measurable effects on blood counts, viscosity, ektacytometry or reactive oxygen species (ROS). In PK-PD analysis, however, higher glutamine exposure (Cmax or AUC) was associated with increased whole blood viscosity and cellular dehydration, yet also with higher haemoglobin concentration, increased haematocrit-to-viscosity ratio, decreased reticulocyte ROS, improved RBC deformability and decreased point of sickling. This novel PK-PD analysis identified biomarkers reflecting the positive and negative effects of glutamine, helping to elucidate its mechanisms of action in SCD. PK-optimized dosing to achieve glutamine exposure (AUC or Cmax) that is associated with salutary biological effects should be studied to support its therapeutic use.

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.

Return visit rates after an emergency department discharge for children with sickle cell pain episodes.

BACKGROUND: High return visit rates after hospitalization for people with sickle cell disease (SCD) have been previously established. Due to a lack of multicenter emergency department (ED) return visit rate data, the return visit rate following ED discharge for pediatric SCD pain treatment is currently unknown. PROCEDURE: A seven-site retrospective cohort study of discharged ED visits for pain by children with SCD was conducted using the Pediatric Emergency Care Applied Research Network Registry. Visits between January 2017 and November 2021 were identified using previously validated criteria. The primary outcome was the 14-day return visit rate, with 3- and 7-day rates also calculated. Modified Poisson regression was used to analyze associations for age, sex, initial hospitalization rate, and a visit during the COVID-19 pandemic with return visit rates. RESULTS: Of 2548 eligible ED visits, approximately 52% were patients less than 12 years old, 50% were female, and over 95% were non-Hispanic Black. The overall 14-day return visit rate was 29.1% (95% confidence interval [CI]: 27.4%-30.9%; site range 22.7%-31.7%); the 7- and 3-day return visit rates were 23.0% (95% CI: 21.3%-24.6%) and 16.7% (95% CI: 15.3%-18.2%), respectively. Younger children had slightly lower 14-day return visit rates (27.3% vs. 31.1%); there were no associations for site hospitalization rate, sex, and a visit occurring during the pandemic with 14-day returns. CONCLUSION: Nearly 30% of ED discharged visits after SCD pain treatment had a return visit within 14 days. Increased efforts are needed to identify causes for high ED return visit rates and ensure optimal ED and post-ED care.

Using the consolidated framework for implementation research to identify recruitment barriers and targeted strategies for a shared decision-making randomized clinical trial in pediatric sickle cell disease.

BACKGROUND/AIMS: Recruitment is often a barrier in clinical trials that include minoritized populations, such as individuals with sickle cell disease. In the United States, the majority of people with sickle cell disease identify as Black or African American. In sickle cell disease, 57% of the United States trials that ended early did so due to low enrollment. Thus, there is a need for interventions that improve trial enrollment in this population. After lower-than-expected recruitment during the first 6 months of the Engaging Parents of Children with Sickle Cell Anemia and their Providers in Shared-Decision-Making for Hydroxyurea trial, a multi-site study for young children with sickle cell disease, we collected data to understand barriers and used the Consolidated Framework for Implementation Research to categorize them and guide the development of targeted strategies. METHODS: Study staff used screening logs and coordinator and principal investigator calls to identify recruitment barriers that were then mapped onto Consolidated Framework for Implementation Research constructs. Targeted strategies were implemented during Months 7-13. Recruitment and enrollment data were summarized before (Months 1-6) and during the implementation period (Months 7-13). RESULTS: During the first 13 months, 60 caregivers (M = 30.65 years; SD = 6.35) enrolled in the trial. Most caregivers primarily self-identified as female (n = 54, 95%) and African American or Black (n = 51, 90%). Recruitment barriers mapped onto three Consolidated Framework for Implementation Research constructs: (1) Process barriers (i.e. no identified "site champion" and poor recruitment planning at several sites); (2) Inner setting barriers (i.e. limited communication, low relative study priority at several sites); and (3) Outer setting barriers (i.e. poor patient attendance at clinic appointments). Targeted strategies to improve recruitment included (1) principal investigator site visits and retraining on recruitment procedures to address process barriers; (2) increased frequency of communication through all coordinator, site principal investigator, and individual site calls to address inner setting barriers; and (3) development and implementation of no-show procedures for clinic appointments to address outer setting barriers. After implementation of the recruitment strategies, the number of caregivers identified for pre-screening increased from 54 to 164, and enrollment more than tripled from 14 to 46 caregiver participants. CONCLUSION: Consolidated Framework for Implementation Research constructs guided the development of targeted strategies that increased enrollment. This reflective process reframes recruitment challenges as the responsibility of the research team rather than characterizing minoritized populations as "difficult" or "hard to reach." Future trials including patients with sickle cell disease and minoritized populations may benefit from this approach.

Iron status and burden of anemia in children with recessive dystrophic epidermolysis bullosa.

BACKGROUND AND OBJECTIVES: To describe the prevalence, severity, and management of anemia in a cohort of children with recessive dystrophic epidermolysis bullosa (RDEB) and to highlight the use of soluble transferrin receptor (sTfR) to diagnose iron deficiency in this chronic inflammatory state. METHODS: We studied a cohort of 114 patients with RDEB followed at a pediatric hospital-based Epidermolysis Bullosa Center from 2010 to 2020; data were prospectively tracked in a comprehensive clinical database that captured all visits, laboratory tests, iron infusions, and transfusions. The primary outcome was occurrence of anemia, which was assessed by age and sex, with and without transfusion support. Secondary outcomes included iron status using a combination of ferritin and sTfR levels, the cumulative incidence of parenteral iron therapy and transfusions, and survival. RESULTS: In RDEB, anemia begins in the first year of life and becomes more frequent and severe with age. The prevalence of iron deficiency anemia (IDA) estimated by ferritin was 33.6% (37/110), but the sTfR/log10 -ferritin ratio indicated a 1.5-fold higher true prevalence of IDA of 50.6% (41/81). 53.5% (61/114) received parenteral iron infusions, transfusions, or both. Higher ferritin was associated with earlier mortality. CONCLUSIONS: Individuals with RDEB have a high burden of anemia (IDA and anemia of inflammation) that requires frequent medical interventions. The sTfR/log10 -ferritin ratio improves the detection of iron deficiency in the context of inflammation and guides therapy.

Early hydroxyurea use is neuroprotective in children with sickle cell anemia.

Children with sickle cell disease (SCD) who began hydroyxurea before age five years scored no differently on a measure of cognitive funciton than age, sex, and race-matched unaffected peers.

An Immersive Virtual Reality Curriculum for Pediatric Hematology Clinicians on Shared Decision-making for Hydroxyurea in Sickle Cell Anemia.

Although hydroxyurea (HU) is an effective treatment for sickle cell anemia, uptake remains low. Shared decision-making (SDM) is a recommended strategy for HU initiation to elicit family preferences; however, clinicians lack SDM training. We implemented an immersive virtual reality (VR) curriculum at 8 pediatric institutions to train clinicians on SDM that included counseling virtual patients. Clinicians' self-reported confidence significantly improved following the VR simulations on all communication skills assessed, including asking open-ended questions, eliciting specific concerns, and confirming understanding (Ps≤0.01 for all). VR may be an effective method for educating clinicians to engage in SDM for HU.

Early initiation of hydroxyurea (hydroxycarbamide) using individualised, pharmacokinetics-guided dosing can produce sustained and nearly pancellular expression of fetal haemoglobin in children with sickle cell anaemia.

Hydroxyurea (hydroxycarbamide) is an effective treatment for sickle cell anaemia (SCA), but clinical responses depend primarily upon the degree of fetal haemoglobin (HbF) induction and the heterogeneity of HbF expression across erythrocytes. The number and characteristics of HbF-containing cells (F-cells) are not assessed by traditional HbF measurements. Conventional hydroxyurea dosing (e.g. fixed doses or low starting doses with stepwise escalation) produces a moderate heterocellular HbF induction, but haemolysis and clinical complications continue. Robust, pancellular HbF induction is needed to minimise or fully inhibit polymerisation of sickle haemoglobin. We treated children with hydroxyurea using an individualised, pharmacokinetics-guided regimen starting at predicted maximum tolerated dose (MTD). We observed sustained HbF induction (mean >30%) for up to 6 years, which was not dependent on genetic determinants of HbF expression. Nearly 70% of patients had ≥80% F-cells (near-pancellular), and almost half had ≥90% F-cells (pancellular). The mean HbF/F-cell content was ~12 pg. Earlier age of initiation and better medication adherence were associated with high F-cell responses. In summary, early initiation of hydroxyurea using pharmacokinetics-guided starting doses at predicted MTD can achieve sustained near-pancellular or pancellular HbF expression and should be considered an achievable goal for children with SCA treated with hydroxyurea at optimal doses. Clinical trial registration number: NCT02286154 (clinicaltrials.gov).

Hydroyxurea improves cerebral oxygen saturation in children with sickle cell anemia.

Neurologic complications are common in patients with sickle cell anemia (SCA), but conventional tools such as MRI and transcranial Doppler ultrasonography (TCD) do not fully assess cerebrovascular pathology. Cerebral tissue oximetry measures mixed oxygen saturation in the frontal lobes (SCT O2 ) and provides early prognostic information about tissue at risk of ischemic injury. Untreated patients with SCA have significantly lower SCT O2 than healthy controls that declines with age. Hydroxyurea is effective in preventing many SCA-related complications, but the degree to which it preserves normal neurophysiology is unclear. We analyzed participants enrolled in the Therapeutic Response Evaluation and Adherence Trial (TREAT, NCT02286154), which enrolled participants initiating hydroxyurea using individualized dosing (new cohort) and those previously taking hydroxyurea (old cohort) and was designed to monitor the long-term benefits of hydroxyurea. Cerebral oximetry was performed at baseline and annually. For the new cohort (median starting age = 12 months, n = 55), mean baseline SCT O2 was normal before starting hydroxyurea (mean 65%, 95% CI 58-72%) and significantly increased after 2 years (mean 72%, 95% CI 65-79%, p < .001). The SCT O2 for patients receiving long-term hydroxyurea (median age = 9.6 years) was normal at study entry (mean 66%, 95% CI 58-74%) and remained stable across 2 years. Both cohorts had significantly higher SCT O2 than published data from predominantly untreated SCA patients. Cerebral oximetry is a non-invasive method to assess cerebrovascular pathology that complements conventional imaging. Our results indicate that hydroxyurea suggests protection against neurophysiologic changes seen in untreated SCA.

Implementation of near-universal hydroxyurea uptake among children with sickle cell anemia: A single-center experience.

BACKGROUND: Without early initiation of disease-modifying therapy, the acute and chronic complications of sickle cell anemia (SCA) begin early in childhood and progress throughout life. Hydroxyurea is a safe and effective medication that reduces or prevents most SCA-related complications. Despite recommendations to prescribe hydroxyurea for all children with SCA as young as 9 months, utilization remains low. PROCEDURE: We completed a retrospective review of hydroxyurea-prescribing practices and associated clinical outcomes at our institution over a 10-year period before and after the 2014 National Heart, Lung, and Blood Institute (NHLBI) recommendations to use hydroxyurea for all children with SCA. RESULTS: Hydroxyurea use more than doubled within our pediatric SCA population from 43% in 2010 to 95% in 2019. The age of hydroxyurea initiation was significantly younger during 2014-2019 compared to 2010-2013 (median 2 years vs. 6 years, p ≤ .001). With this change in clinical practice, nearly all (69/71 = 97%) children born after 2013 received disease-modifying therapy by the end of 2019, primarily hydroxyurea (93%). Concurrently, the number of SCA-related admissions significantly decreased from 67/100 patient-years in 2010 to 39/100 patient-years in 2019 (p < .001). CONCLUSION: The early and universal prescription of hydroxyurea for children with SCA is the standard of care. Here, we demonstrate that a careful and deliberate commitment to follow this guideline in clinical practice is feasible and results in measurable improvements in clinical outcomes. Our approach and improved outcomes can serve as a model for other programs to expand their hydroxyurea use for more children with SCA.

Effect of Poloxamer 188 vs Placebo on Painful Vaso-Occlusive Episodes in Children and Adults With Sickle Cell Disease: A Randomized Clinical Trial.

Importance: Although effective agents are available to prevent painful vaso-occlusive episodes of sickle cell disease (SCD), there are no disease-modifying therapies for ongoing painful vaso-occlusive episodes; treatment remains supportive. A previous phase 3 trial of poloxamer 188 reported shortened duration of painful vaso-occlusive episodes in SCD, particularly in children and participants treated with hydroxyurea. Objective: To reassess the efficacy of poloxamer 188 for vaso-occlusive episodes. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled, multicenter, international trial conducted from May 2013 to February 2016 that included 66 hospitals in 12 countries and 60 cities; 388 individuals with SCD (hemoglobin SS, SC, S-ß0 thalassemia, or S-ß+ thalassemia disease) aged 4 to 65 years with acute moderate to severe pain typical of painful vaso-occlusive episodes requiring hospitalization were included. Interventions: A 1-hour 100-mg/kg loading dose of poloxamer 188 intravenously followed by a 12-hour to 48-hour 30-mg/kg/h continuous infusion (n = 194) or placebo (n = 194). Main Outcomes and Measures: Time in hours from randomization to the last dose of parenteral opioids among all participants and among those younger than 16 years as a separate subgroup. Results: Of 437 participants assessed for eligibility, 388 were randomized (mean age, 15.2 years; 176 [45.4%] female), the primary outcome was available for 384 (99.0%), 15-day follow-up contacts were available for 357 (92.0%), and 30-day follow-up contacts were available for 368 (94.8%). There was no significant difference between the groups for the mean time to last dose of parenteral opioids (81.8 h for the poloxamer 188 group vs 77.8 h for the placebo group; difference, 4.0 h [95% CI, -7.8 to 15.7]; geometric mean ratio, 1.2 [95% CI, 1.0-1.5]; P = .09). Based on a significant interaction of age and treatment (P = .01), there was a treatment difference in time from randomization to last administration of parenteral opioids for participants younger than 16 years (88.7 h in the poloxamer 188 group vs 71.9 h in the placebo group; difference, 16.8 h [95% CI, 1.7-32.0]; geometric mean ratio, 1.4 [95% CI, 1.1-1.8]; P = .008). Adverse events that were more common in the poloxamer 188 group than the placebo group included hyperbilirubinemia (12.7% vs 5.2%); those more common in the placebo group included hypoxia (12.0% vs 5.3%). Conclusions and Relevance: Among children and adults with SCD, poloxamer 188 did not significantly shorten time to last dose of parenteral opioids during vaso-occlusive episodes. These findings do not support the use of poloxamer 188 for vaso-occlusive episodes. Trial Registration: ClinicalTrials.gov Identifier: NCT01737814.

l-Glutamine for sickle cell anemia: more questions than answers.

In 2017, the Food and Drug Administration approved 2 medications for sickle cell anemia (SCA): hydroxyurea for children and l-glutamine for children and adults. The approval of hydroxyurea was long overdue, but the approval of l-glutamine was a surprise to many. Any effective new treatment for SCA is a welcome advance, but there are few published studies of l-glutamine as a specific treatment for SCA. Accordingly, there are many unanswered questions about its efficacy, safety, and role in current therapy.

Disease Self-Efficacy and Health-Related Quality of Life in Adolescents With Sickle Cell Disease.

Adolescents and young adults (AYA) with sickle cell disease (SCD) are at risk for poor health-related quality of life (HRQOL). Research suggests that vulnerability factors (eg, disease severity) and self-management resources (eg, disease self-efficacy) jointly impact health outcomes, including HRQOL; however, this has not been studied among AYA with SCD. This study examined the relationship between disease self-efficacy, HRQOL, and disease severity in AYA with SCD. HRQOL was positively correlated with disease self-efficacy and negatively correlated with disease severity. Disease self-efficacy and severity accounted for 35% of variance in HRQOL. Findings support the impact of disease self-efficacy on HRQOL.

Non-transfusion-dependent ß-Thalassemia Because of a Single ß-Thalassemia Mutation and Coinherited α-Globin Gene Triplication: Need for Increased Awareness to Prevent Incorrect and Delayed Diagnosis.

The thalassemias are genetically complex and usually autosomal recessive. We describe 5 unrelated individuals with non-transfusion-dependent ß-thalassemia (NTDT), some with apparently dominant transmission, because of a single ß-thalassemia mutation coinherited with a triplicated α-globin locus. Each had an initial, incorrect diagnosis of ß-thalassemia trait. The correct diagnosis of NTDT was made at a mean of 7 years of age. Despite reports of this compound genotype causing NTDT, it remains unfamiliar to many clinicians. To increase awareness, we highlight its varied and sometimes subtle clinical and laboratory features and the need for comprehensive genetic testing for timely and correct diagnosis.

Association between diffuse myocardial fibrosis and diastolic dysfunction in sickle cell anemia.

Sickle cell anemia (SCA)-related cardiomyopathy is characterized by diastolic dysfunction and hyperdynamic features. Diastolic dysfunction portends early mortality in SCA. Diastolic dysfunction is associated with microscopic myocardial fibrosis in SCA mice, but the cause of diastolic dysfunction in humans with SCA is unknown. We used cardiac magnetic resonance measurements of extracellular volume fraction (ECV) to discover and quantify diffuse myocardial fibrosis in 25 individuals with SCA (mean age, 23 ± 13 years) and determine the association between diffuse myocardial fibrosis and diastolic dysfunction. ECV was calculated from pre- and post-gadolinium T1 measurements of blood and myocardium, and diastolic function was assessed by echocardiography. ECV was markedly increased in all participants compared with controls (0.44 ± 0.08 vs 0.26 ± 0.02, P < .0001), indicating the presence of diffuse myocardial fibrosis. Seventeen patients (71%) had diastolic abnormalities, and 7 patients (29%) met the definition of diastolic dysfunction. Participants with diastolic dysfunction had higher ECV (0.49 ± 0.07 vs 0.37 ± 0.04, P = .01) and N-terminal pro-brain natriuretic peptide (NT-proBNP; 191 ± 261 vs 33 ± 33 pg/mL, P = .04) but lower hemoglobin (8.4 ± 0.3 vs 10.9 ± 1.4 g/dL, P = .004) compared with participants with normal diastolic function. Participants with the highest ECV values (≥0.40) were more likely to have diastolic dysfunction (P = .003) and increased left atrial volume (57 ± 11 vs 46 ± 12 mL/m2, P = .04) compared with those with ECV <0.4. ECV correlated with hemoglobin (r = -0.46, P = .03) and NT-proBNP (r = 0.62, P = .001). In conclusion, diffuse myocardial fibrosis, determined by ECV, is a common and previously underappreciated feature of SCA that is associated with diastolic dysfunction, anemia, and high NT-proBNP. Diffuse myocardial fibrosis is a novel mechanism that appears to underlie diastolic dysfunction in SCA.

Point-of-care screening for sickle cell disease in low-resource settings: A multi-center evaluation of HemoTypeSC, a novel rapid test.

Sickle cell disease (SCD) is a common, life-threatening genetic disorder that is best managed when diagnosed early by newborn screening. However, SCD is most prevalent in low-resource regions of the world where newborn screening is rare and diagnosis at the point-of-care is challenging. In many such regions, the majority of affected children die, undiagnosed, before the age of 5 years. A rapid and affordable point-of-care test for SCD is needed. The diagnostic accuracy of HemoTypeSC, a point-of-care immunoassay, for SCD was evaluated in individuals who had SCD, hemoglobin C disease, the related carrier (trait) states, or a normal hemoglobin phenotype. Children and adults participated in low-, medium- and high-resource environments (Ghana [n = 383], Martinique [n = 46], and USA [n = 158]). Paired blood specimens were obtained for HemoTypeSC and a reference diagnostic assay. HemoTypeSC testing was performed at the site of blood collection, and the reference test was performed in a laboratory at each site. In 587 participants, across all study sites, HemoTypeSC had an overall sensitivity of 99.5% and specificity of 99.9% across all hemoglobin phenotypes. The test had 100% sensitivity and specificity for sickle cell anemia. Sensitivity and specificity for detection of normal and trait states were >99%. HemoTypeSC is an inexpensive (<$2 per test), accurate, and rapid point-of-care test that can be used in resource-limited regions with a high prevalence of SCD to provide timely diagnosis and support newborn screening programs.