Frequency Of Vaso-occlusive Crises Research Articles

Genotypic Variations in Exercise-Induced Hemoglobin Oxygen Desaturation in Sickle Cell Disease: The Role of Hemoglobin Levels

Background: Sickle cell disease (SCD) presents abnormal hemoglobin S (HbS) and frequent vaso-occlusive crises. Previous studies reveal exercise intolerance in SCD patients. However, the role of exercise-induced hemoglobin oxygen desaturation (EIHOD) and its predictors remains unclear. This study investigates EIHOD in adult SCD patients, focusing on potential predictors, aligning with the hypothesis that EIHOD is prevalent and varies across genotypes, with hemoglobin as a predictor. Methods: A cross-sectional study was conducted on adult patients with HbSS and HbSC genotypes in a steady state at the Korle-Bu Teaching Hospital, Ghana. Clinical, hematological, and haemolytic markers were assessed. Lung function was evaluated through spirometry, and a six-minute walk test (6MWT) was performed to assess EIHOD. Logistic regression was used to identify predictors of EIHOD. We hypothesis that, EIHOD is common in SCD, varying across genotypes, with hemoglobin predicting its occurrence. Results: The prevalence of EIHOD was 41% in HbSS patients and 36.1% in HbSC patients. No significant differences were observed in age, white blood cell count, platelet count, hemolytic markers, hemoglobin levels, or lung function parameters between SCD patients with and without EIHOD. In the logistic regression model, none of the variables predicted EIHOD in HbSS patients. In HbSC patients, reduced hemoglobin was the only predictor of EIHOD (OR=0.551; 95% CI=0.315-0.964; p-value= 0.037). Discussion: The study highlights a high prevalence of EIHOD within the HbSS genotype, emphasizing the importance of hemoglobin levels as a predictor of EIHOD in SCD. Contrarily, hemolytic markers and lung function were not predictors of EIHOD across either genotype. These results suggest the potentially heightened significance of EIHOD-related complications in patients with the HbSS genotype. Conclusion: EIHOD is common in SCD, more so in HbSS. Reduced hemoglobin predicts EIHOD in HbSC. Lung function and hemolytic markers don't. Understanding the impact of EIHOD in SCD may guide interventions to improve exercise tolerance and reduce complications in this population. No Funding. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Brain network hypersensitivity underlies pain crises in sickle cell disease

Sickle cell disease (SCD) is a genetic disorder causing painful and unpredictable Vaso-occlusive crises (VOCs) through blood vessel blockages. In this study, we propose explosive synchronization (ES) as a novel approach to comprehend the hypersensitivity and occurrence of VOCs in the SCD brain network. We hypothesized that the accumulated disruptions in the brain network induced by SCD might lead to strengthened ES and hypersensitivity. We explored ES's relationship with patient reported outcome measures (PROMs) as well as VOCs by analyzing EEG data from 25 SCD patients and 18 matched controls. SCD patients exhibited lower alpha frequency than controls. SCD patients showed correlation between frequency disassortativity (FDA), an ES condition, and three important PROMs. Furthermore, stronger FDA was observed in SCD patients with a higher frequency of VOCs and EEG recording near VOC. We also conducted computational modeling on SCD brain network to study FDA's role in network sensitivity. Our model demonstrated that a stronger FDA could be linked to increased sensitivity and frequency of VOCs. This study establishes connections between SCD pain and the universal network mechanism, ES, offering a strong theoretical foundation. This understanding will aid predicting VOCs and refining pain management for SCD patients.

The Associations Between Opioid Use Disorder and Healthcare-Related Outcomes in Vaso-occlusive Crisis.

In patients who experience frequent vaso-occlusive crises (VOC), opioid dependence may be due to a need for pain control as opposed to addiction; the implications of opioid use disorder (OUD) in this population are unclear. To compare outcomes in hospitalizations for VOC in those with a history of OUD to those without a history of OUD. A retrospective assessment of hospitalizations for adults in the USA with a primary discharge diagnosis of VOC using the National Inpatient Sample database from 2016 to 2019. We also compared VOC hospitalizations to hospitalizations for all other reasons to assess differences in OUD-associated clinical factors. In total, 273,460 hospitalizations for VOC; 23,120 (8.5%) of these hospital stays involved a secondary diagnosis of OUD. Primary outcomes were length of hospital stay and cost. Mortality was a secondary outcome. Hospital length of stay was increased (mean 6.2 vs 4.9days) in patients with OUD (adjusted rate ratio = 1.24, 95% CI 1.20-1.29, p < 0.001). Mean cost was also higher in those with OUD ($9076) than those without OUD ($8020, p < 0.001). Mortality was decreased in VOC hospitalizations in those with OUD, but the difference was not statistically significant (adjusted OR = 0.64, 95% CI 0.028-1.48, p = 0.30). OUD is associated with increased length of stay and costs in patients with VOC. While there are many possible explanations, providers should consider undertreatment of pain due to addiction concerns as a potential factor; individualized pain plans to mitigate this challenge could be explored.

Avascular Bone Necrosis in Pediatric Patients with Sickle Cell Disease in Basrah, Iraq

BACKGROUND: Avascular necrosis (AVN) is regarded as a manifestation of severe sickle cell disease (SCD), with the femoral head being the most affected. OBJECTIVES: The main objectives of this study were to look for the frequency of AVN in pediatric patients with SCD, evaluate the clinical pattern and severity of AVN, and study the possible risk factors associated with AVN. MATERIALS AND METHODS: A cross-sectional study has been conducted on SCD patients, aged 6–18 years, who visited the Basrah Center for Hereditary Blood Diseases from the first of February 2021 to August 2021. Patients were screened for AVN by hip plain radiography and magnetic resonance imaging. The modified Ficat-Arlet staging system was used to classify different stages of AVN. RESULTS: The total number of screened patients was 291; 193 (66.3%) had sickle cell anemia, 71 (24.4%) with S/β0 thalassemia, 21 (7.2%) with S/β+ thalassemia, and 6 (2.1%) had S/D disease. Fifty-eight (19.9%) patients were found to have different stages of AVN; 7 (12.1%) were asymptomatic and 51 (87.9%) were symptomatic. The logistic regression analysis has revealed that frequent vaso-occlusive crises requiring hospitalization (B = 1.576, P = 0.003), acute splenic sequestration crises (B = 1.256, P = 0.003), homozygous sickle hemoglobin genotype (B = −0.208, P = 0.001), and low reticulocyte count (B = 1.452, P = 0.027) are significant variables associated with AVN. CONCLUSION: AVN was reported in a significant percentage of pediatric patients with SCD and was associated with selected indicators of disease severity. Further studies that evaluate the natural history, progress of AVN, and variations in selected variables over time like reticulocytes and the co-inheritance of α-thalassemia are important.

Strategies in Recruitment and Retention of Patients with Sickle Cell Disease for a Single-Site Longitudinal Clinical Trial

Background Sickle cell disease (SCD) leads to vaso-occlusive crises (VOCs) and increased healthcare use, disproportionately affecting Black/African Americans. Recruiting and retaining patients with SCD in clinical trials is challenging, with &amp;lt;5% participation rates (Masese et al., 2021) due to complexity, limited awareness, and socio-economic factors (Suarez et al., 2020). Addressing these obstacles to patient recruitment is crucial for advancing SCD research. An estimated 1,695 individuals in various counties in Indiana state are affected by SCD, with 87% being of Black/African American ethnicity (Okolo et al., 2023). The limited number of comprehensive SCD care centers poses significant challenges to recruitment for our ongoing single-site longitudinal trial in Indianapolis to explore the neurobiological mechanisms underlying pain in SCD and the effectiveness of acupuncture. The study consists of 14 in-person visits in 6-8 weeks with 12-month follow-up visits (ClinicalTrials.gov Identifier: NCT05045820). To address these recruitment challenges and ensure meaningful research outcomes, strategic communication, collaboration, and outreach efforts were undertaken to recruit eligible participants and ensure retention. This work aimed to identify factors affecting participant retention rates, including demographic differences between those who completed and those who dropped out. Study Design and Method SCD participants were recruited from either local hospitals, including the Indiana University Affiliated Hospitals and local hospitals (such as Eskenazi Hospital, St. Vincent and the Indiana Hemophilia &amp; Thrombosis Center), or external organizations, such as the Martin Center SCD Initiative and community settings, such as churches and community care centers. Various media platforms and events, such as health fairs, campus center events, and church events, were employed to widen our outreach. Local events suggested by participants further reinforced the study's credibility among prospective participants. Retaining participants was achieved through robust and customized strategies throughout the study, including but not limited to 1) personalized real-time communication with the principal investigator, 2) regular check-ins to address concerns, 3) real-time appointment scheduling, rescheduling and reminding system, and 4) hybrid (remote/in-person) follow-up visits. Moreover, additional complementary strategies, such as motivational incentives, transportation vouchers, education platforms, actively listening to feedback, timely communication, and spiritual support were utilized to ensure our complete dedication to their well-being. Results We achieved high recruitment and retention rates in our study. So far, our retention rate is 87.1%. Of these, 24.19% completed the entire study, including in-person visits and the 12-month follow-up (n=15). 56.45% of participants are still actively enrolled in the study (n=35), while 12.9% have discontinued participation (n=8). Two participants were deceased. Our utilization of effective recruitment and retention strategies yielded continuous success in actively recruiting and retaining patients with SCD. Compared to the group of participants who dropped out from the study (n=8 total, female: n=2), participants who completed all scheduled study visits (n=15, female: n=12) were more likely to be female (p = 0.008, independent samples t-test) and have lower disease severity assessed by the frequency of VOCs in the preceding 12 months (p = 0.007, independent samples t-test). Participants recruited from external facilities/events yielded a significantly lower dropout rate than those recruited from local hospitals (p = 0.036, Chi-Square Tests). These results suggest the impact of gender, disease severity, and recruitment source on the retention rate. Conclusion The success of SCD clinical trials hinges on implementing personalized recruitment and retention strategies. Further efforts are necessary to explore innovative engagement methods targeting gender and disease-specific challenges while continuously forging solid partnerships with external facilities/organizations.

Acute Chest Syndrome at the Emory University Georgia Comprehensive Sickle Cell Center at Grady Health System

Background: Individuals who have sickle cell disease (SCD) are susceptible to several severe consequences, such as vasoocclusive crisis (VOC), which may further develop into acute chest syndrome (ACS), a specific type of acute lung injury. Although VOC can result in substantial morbidity, it is important to note that ACS is the primary cause of mortality among individuals with SCD. Despite the devastating consequences of ACS, no interventions exist that directly treat this complication. Consequently, when patients present with ACS, their treatment options are frequently limited to supportive care. The absence of ideal therapeutic interventions for individuals with SCD who are experiencing ACS is a significant factor in their increased rates of illness and death. A cohort of adult patients diagnosed with ACS was examined with the objective to evaluate indicators of disease severity and identify risk factors associated with recurrent ACS. Methods: The Emory University Georgia Comprehensive Sickle Cell Center, located at Grady Health System, offers a dedicated acute care unit (ACU) that operates around the clock. This unit is specifically designed to assess and manage SCD patients who present with sickle cell crises. A pilot retrospective study was undertaken to analyze 25 patients with ACS. The evaluation included the examination of admission laboratory results, demographic information, past medical history, co-morbidity, interventions for each ACS admission for each patient (refer to Table 1). Descriptive statistics were used to report frequencies or median and range (Table 2). Patient characteristics of patients with 1 ACS event versus those with recurrent ACS (&amp;gt;=2) were compared using fishers exact test or the Wilcoxon-rank-sum test. Statistical significance was set at 0.05. Analysis was completed using SAS 9.4 (Cary, NC). Results: A total of 47 ACS episodes were detected in a cohort of 25 individuals, resulting in a median of 1 ACS event per patient (range of 1 to 6). A total of 85% of the patients included in this study had homozygosity for SCD, whereas 36% of the patients were receiving hydroxyurea treatment. Chronic pain was reported in three-fourth of the cohort. Out of all the ACS events observed, only 40% necessitated red cell exchange transfusion. A correlation between a minimum hemoglobin (Hb) level of 3.3 g/dL and lactate dehydrogenase (LDH) levels over 4000 U/L was noted during ACS admission. These findings indicate the presence of intravascular hemolysis. Three individuals died to ACS. Next, we conducted a comparison between a group of 10 patients who experienced recurring ACS events, with a minimum of 2 to a maximum of 6 occurrences, and another group of 15 patients who only had a single ACS episode. The group of patients with recurrent ACS exhibits a median of 5.5 episodes of VOC that necessitate visits to the acute care unit within the year prior. In contrast, the group with a single ACS episode has a median of 1 event. There was a notable disparity in the frequency of transfusions received by patients with recurrent ACS compared to those who experienced only a single episode over the past year. Although no other variable demonstrated statistical significance, the recurrent ACS group exhibited lower levels of hemoglobin and higher levels of LDH in comparison to the group with a single ACS episode. Further examination of our patients with SCD could provide valuable insights into the potential factors that may predict ACS episodes. These factors include a patient's genetic background, the frequency of VOC, the use of hydroxyurea, evidence of hemolysis, and previous blood transfusions. Furthermore, the utilization of acute care unit by patients with SCD has had a positive effect in our cohort, on the reduction of red cell exchange transfusions and mortality rates from ACS, possibly from early identification and episodic transfusion, in comparison to similar cohorts with ACS.

Ineffective Erythropoiesis with Aging in Adults with Sickle Cell Disease

INTRODUCTION In the United States, life expectancy for adults with sickle cell disease (SCD) has improved over the last several decades and providers are now encountering increasing numbers of patients in the fourth, fifth and sixth decades. One notable feature of older SCD patients is lower ‘steady state’ hemoglobin (Hb) levels. Although it is well established that lower Hb levels are associated with increased adverse outcomes including pulmonary hypertension, stroke, cognitive decline, acute chest syndrome, frequency of vaso-occlusive crisis and shortened survival, a full understanding of the mechanisms accounting for the more prevalent and severe anemia in older SCD patients remains to be elucidated. Involved factors may include the long-term effect of chronic hemolysis, age-associated increased inflammation, progressive renal insufficiency and an age-related decline in nutritional adequacy. Despite lacking a uniform explanation for anemia applicable to individual SCD patients, it remains a management goal to optimize Hb level as possible within constraints associated with the development of secondary hemochromatosis. We postulate that the pathways to anemia in SCD patients may change with advancing age and that a better understanding of these pathways may result in a more directed intervention for the older sickle cell patient. METHODS Adult patients visiting Inova Adult Sickle Cell Center over a 6-month period (January through June 2023) with Hb levels below 9 g/dL were evaluated by a contemporary hematologic panel that included complete blood count with differential, reticulocyte count, comprehensive metabolic panel (included total bilirubin and creatinine), and lactate dehydrogenase (LDH). The reticulocyte proliferation index (RPI) was determined utilizing a readily accessible calculator (MedCalc) and a univariate regression analysis was performed for RPI against age. An RPI of &amp;lt; 2 was considered evidence for hypoproliferative anemia. RESULTS Of the 139 unique adult SCD patients visiting our clinic in this 6-month period, 60 had Hb levels equal to or below 9 g/dL. Of these, 8 patients had serum creatinine levels ≥ 1.5 mg/dL and were considered to have hypoproliferative anemia based on renal insufficiency. Among the remaining 52 patients, the mean age was 34.9 years, mean Hb was 7.49 g/dL and the mean RPI was 2.52. In patients with age ≤ 40 years, mean RPI was 2.74, compared to mean RPI of 1.61 in patients with age &amp;gt; 40 years. The mean Hb was 7.55 g/dL vs 7.21 g/dL mean total bilirubin was 3.08 mg/dL vs 2.15 mg/dL and mean LDH was 509 U/L vs 434 U/L in these two age groups (Fig 1). Regression analysis indicated that an increase in age corresponded to a reduction in RPI at 95% confidence level (Fig 2; regression coefficient: -0.04; 95% CI: -0.08 - -0.003; p-value: 0.03). CONCLUSION From the data we gathered, we conclude that despite chronic hemolysis in sickle cell disease, low RPI and ineffective erythropoiesis are evident to some extent in the majority of adult SCD patients even in the absence of renal failure and this significantly increases with age. Older patients with SCD are more likely to have ineffective erythropoiesis. We speculate that this may be evidence for age-associated bone marrow failure not unlike myelodysplasia (MDS) which occurs with increased frequency in the general population with advancing age. If future studies confirm disordered erythropoiesis, clonal hematopoiesis, or other markers of MDS, novel treatments known to be effective in patients with MDS may be examined in selected anemic SCD patients.

Addressing Chronic Anemia in Sickle Cell Disease: Characterizing Erythropoiesis-Stimulating Agent (ESA) Utilization and Practice Patterns Among Providers

Background: Chronic anemia exerts profound impacts on the morbidity, mortality, and quality of life in individuals with sickle cell disease (SCD), but therapeutic options are limited. Erythropoietin-stimulating agents (ESAs) are the standard of care for managing anemia in chronic kidney disease (CKD). However, their utilization in SCD remains ad hoc, with limited literature and no guidelines supporting the use of ESAs in SCD. To address this knowledge gap, we present preliminary findings from a survey designed to evaluate provider practices and identify factors influencing the use of ESAs in SCD. Methods: We conducted a cross-sectional web-based survey from March-July 2023 among providers taking care of patients with SCD in the United States (US) and internationally. Survey items were developed to assess provider demographic characteristics, practice environments, and provider practices around ESA use in SCD. The data was collected and managed using REDCap electronic data capture tools hosted at the University of Pittsburgh. Descriptive statistics were used to report the data. Results: The survey has been completed by 33 providers as of a cut date of July 23, 2023. Most providers were hematologists who practiced in an academic setting (23/33, 69.7%), with an equal gender distribution (Table 1). The number of patients with SCD seen annually varied, with 101-300 patients being the most common cohort size (13/33, 39.4%). In the 12 months prior to survey completion, 15/33 (45.5%) providers treated at least 1 patient with SCD with ESAs, usually outpatient (Table 2). Commonly reported barriers to outpatient ESA therapy included lack of insurance approval/coverage or cost concerns, lack of provider experience, and patient tolerability/adherence or inability to perform self-injections. Fewer respondents reported no barriers to prescribing ESAs in the outpatient setting, compared to in the acute/inpatient setting (18.2% vs. 48.5%). The most commonly reported indications for starting ESAs in the outpatient setting were chronic anemia from end-stage renal disease or CKD, reduction of blood transfusion requirement, and chronic anemia in patients refractory to approved therapies. Less commonly reported indications include severe or symptomatic anemia alone and chronic anemia in the setting of cardiopulmonary disease. Respondents reported several contraindications to starting ESAs, including a history of venous thromboembolism (VTE), malignancy, stroke, coronary artery disease, hypertension, and frequent vaso-occlusive crises. Respondents also expressed concerns about the cost/insurance coverage, efficacy, safety, patient burden, and appropriate dosing of ESAs in patients with SCD. Only 18/33 (54.5%) respondents reported ever treating outpatients with SCD with ESAs; nearly all of them used 1 st generation ESAs, and a majority used 2 nd generation ESAs. For 1 st generation ESAs, the most common starting dose was 3500-7000 units (U) (50-100 U/kg; 22.2%) or 7001-14000 U (101-200 U/kg; 22.2 %). Once weekly was the most common dosing interval (50%), followed by three times a week (TIW; 27.8%) and twice a week (16.7%). The maximum dose used was 56001-70000 U (801-1000 U/kg) TIW. For 2 nd generation ESAs, the most common starting dose was 141-210 mcg (2.1-3.0 mcg/kg) (22.2%), and administration often occurred once every 2 weeks (44.4%) or weekly (27.8%). The maximum dose used was 211-315 mcg (3.1-4.5 mcg/kg) weekly. Outpatient ESAs were most often initiated for hemoglobin (Hb) &amp;lt; 6 g/dL (8/18, 44.4%), and Hb &amp;gt; 9 g/dL was the most common treatment target (6/18, 33.3%). ESAs were often combined with hydroxyurea, voxelotor, and simple transfusions (Table 2). Conclusion: These preliminary survey results show considerable variability in how ESAs are currently being used in people with SCD. These variations in clinical practice highlight both significant ambiguity about what works in this setting and the need for further research into the optimal use of ESAs for the management of chronic anemia in SCD (ongoing clinical trial: ACHiEvE-SCD, NCT05451940). Future directions include evaluating differences in practice patterns among adult vs. pediatric and US-based vs. non-US-based providers.

Use of Apple Watch to Acquire Baseline Wearable Biometric Data for Patients with Sickle Cell Disease and Correlations to Symptoms Such As Pain and Fatigue

Background: Sickle cell disease (SCD) is an inherited blood disorder that impacts the structure of red blood cells. The most common complication of SCD are vaso-occlusive crises (VOCs), commonly called pain crisis. Frequency and intensity of VOCs can differ among individuals. The unpredictable nature of VOCs increases risk of further complications, limits daily activities, affects mental well-being, and decreases health related quality of life. The use of mHealth and wearables for those living with SCD allows the opportunity to better understand pain and general wellbeing through real time data and analysis. Objectives: We aimed to: 1) Establish a comprehensive baseline health profile for individuals with SCD; and 2) determine potential relationships between patient reported symptoms and biometric data. Methods: Following IRB approval, patients entering the SCD clinic or the SCD Day Hospital at Duke University were approached, consented, and provided with the Nanbar Health app. Participants were instructed to make entries at least once daily and wear an Apple Watch throughout the day for 6 months. If a participant did not have Apple devices, an iOS Apple smartphone and/or Apple Watch series SE were provided. Self-reported general symptoms were recorded in the Nanbar Health app on scales from 0 (none) to 10 (most severe). General wellbeing was rated on an emoji scale, converted to 1 (worst/'frowny face') to 5 (best/'smiley face'). The biometric data from wearable collected included heart rate, step count, heart rate variability (HRV), resting heart rate (RHR), respiratory rate, and O2 saturation. For participants that had their own Apple Watch, 3 months of retroactive data was acquired. Statistical and network analysis was performed to analyze the correlations between symptoms, biometric data, and the general wellbeing of the participant. Results: Over 3 months, 18 participants were enrolled in the study. Median age of participant was 25 (IQR 21-33), 10 females, all Black/African American, and most either HgbSS (72%) or HgbSC (16%). Participants logged symptoms in the app 597 times over 93 days with a median of 0.33 entries/day/patient (IQR 0.22-0.44). The average pain score participants reported was 5.9 (SD 2.4, n=220). The three most reported symptoms, besides pain, were tiredness (22.1%), headache (5.2%), and priapism (5%). The patient-reported general feeling average was 3.3 (n=597, SD 1.6). Heart rate (n=74646), HRV (n=1277), and step count (n=1566) were the most recorded biometrics from the wearables. The average heart rate, HRV, and step count were 105.1 bpm (SD 26.8), 31.9 ms (SD 13.3), and 4100 steps/day (SD 5960), respectively. Significant expected correlations include between pain and priapism (r=0.85, p&amp;lt;0.01), aching and pain (r=0.78, p&amp;lt;0.01), and feeling bad and aching (r= -0.74, p&amp;lt;0.01). We also found feeling well correlated positively to back pain and tired correlated negatively with aching (see Table 1). Using network analysis of biometrics, RHR and HRV had a higher expected influence on patient feeling compared to the other biometrics collected. Conclusion: Baseline biometric characteristics for patients were similar to other diseases with chronic pain and as expected, pain is the most common symptom reported. Our data reflected lower HRV compared to healthy individuals and consistent with other disorders characterized by chronic pain. However, compared to other chronic pain disorders, patients with SCD appeared to have lower HRV values. There was no strong correlation (&amp;gt;0.7) between biometrics obtained by the watch and SCD patient-reported pain scores. Our study found a strong significant correlation between priapism and feeling cold. The strongest correlation was between feeling tired and feeling cold, however, tired/fatigue was also significantly correlated with priapism and feeling cold, although negatively correlated with aching. Limitations to conducting comprehensive analyses and making direct comparisons with other conditions include discrepancies in biometrics due to high variability and participant adherence. These limitations underscore the need to enroll more patients and improve patient adherence to improve the reliability of biometric data in future studies. Future efforts will compare the use of other mHealth devices besides the Apple Watch and expand to patients outside our institution.

Population Pharmacokinetic Modeling of Different Formulations of Inclacumab Using Phase 1 Data in Healthy Participants

Introduction: P-selectin is a cell adhesion molecule that contributes to vaso-occlusive crises (VOCs) in sickle cell disease (SCD). Inclacumab is a recombinant, fully human, immunoglobulin G4 monoclonal antibody that selectively binds to P-selectin to prevent binding with P-selectin glycoprotein ligand-1. Inclacumab was previously evaluated by Roche in clinical trials with healthy participants and patients with cardiovascular disease and is now being developed as a potential treatment to reduce the frequency of VOCs in individuals with SCD. Changes in the manufacturing of inclacumab have resulted in 3 formulations/drug materials: Roche v0.1, Roche v0.2, and Global Blood Therapeutics (GBT). GBT-manufactured inclacumab utilizes a similar formulation and the same cell line as Roche v0.2 (Roche v0.1 utilizes a different cell line), and analytical and nonclinical comparability between Roche v0.2 and GBT inclacumab have been demonstrated (Mihaila et al. Expert Opin Biol Ther 2022). Here we report results from a population pharmacokinetic (PopPK) model developed to compare the pharmacokinetics (PK) of different formulations using data from 4 phase 1 clinical studies in healthy participants administered Roche v0.1, Roche v0.2, or GBT inclacumab. The objectives were to develop a PopPK model to describe inclacumab PK in healthy adult participants and to quantify potential differences in inclacumab PK associated with different formulations/drug materials. Methods: A PopPK model was developed using single- and multiple-dose PK data from healthy participants who received intravenous (IV) inclacumab across 4 studies (BP21112 [Roche v0.1, single ascending dose (SAD)], BP21617 [Roche v0.1, multiple ascending dose], BP28134 [Roche v0.2, SAD], and GBT2104-111 [GBT, SAD]). Evaluable participants had ≥1 measurable postdose concentration with an associated sample time, relevant dosing information prior to each measurable concentration, and no protocol violation that could confound PK analyses. A nonlinear mixed effects model was fit to the inclacumab plasma concentration-time data using first-order conditional estimation with eta-epsilon interaction in NONMEM ® (v7.3). Model selection was based on the plausibility of parameter estimates, goodness-of-fit plots, and the objective function value. The final model was evaluated using a prediction-corrected visual predictive check (pcVPC). Results: The PopPK dataset comprised 145 healthy participants, of which 2622 inclacumab plasma concentrations (84.9%) from 143 participants were evaluable (Roche v0.1: n=68 [47.6%]; Roche v0.2: n=60 [42.0%]; GBT: n=15 [10.5%]). Median (range) age and body weight were 42 (21-63) years and 73.2 (45.8-109) kg, respectively. Nominal doses ranged from 0.03 to 40 mg/kg IV; 23.8% of participants received 3 mg/kg and 29.4% received 20 mg/kg. A 3-compartment disposition model with parallel linear clearance (CL=0.125 L/d) and nonlinear (concentration-dependent; V max=1.19 mg/d; K m=0.784 μg/mL) clearance from the central compartment described the plasma concentration-time data. The effect of drug material was incorporated a priori as relative bioavailability term F in the base model using exploratory analyses of observed exposures. Dosing of Roche v0.1 and Roche v0.2 inclacumab resulted in 23% and 2% higher exposure than GBT inclacumab, respectively. Between-subject variability was estimated for linear clearance, nonlinear clearance, and all volume parameters, and residual error was described using a proportional model (Table). Of the tested covariates, baseline body weight was a statistically significant covariate effect and was included on all linear clearance and volume terms. Model qualification by pcVPC showed good predictive performance of the final model. Conclusions: The PopPK of IV inclacumab in healthy participants was described by a 3-compartment disposition model with parallel linear and nonlinear clearances. Estimated relative exposure of Roche v0.2 and GBT-manufactured inclacumab was similar, indicating comparability in drug exposure. Understanding the relationship between exposure and dose for different formulations facilitates more accurate assessment of safety data across multiple clinical studies. These data provide support for the ongoing phase 3 clinical development in SCD using GBT-manufactured inclacumab without further clinical comparability testing.

Opoid Use Disorder and Vaso-Occlusive Crisis Outcomes: A Retrospective Assesement

Introduction Concerns by providers for addiction can lead to under-treatment of pain in patients with sickle cell disease presenting with vaso-occlusive crisis. In patients who experience frequent vaso-occlusive crises, opioid dependence may be due to the need for pain control as opposed to addiction and the clinical meaning of a diagnosis of opioid use disorder and its impact on outcomes in this population is not known. Methods We retrospectively assessed hospitalizations in the United States for vaso-occlusive crisis in adult patients afflicted with Sickle cell disease from 2016-2019 using the National Inpatient Sample database. Outcomes were compared between those with and without a diagnosis of opioid use disorder using linear and logistical regression. Results In total, there were 273,460 hospitalizations for vaso-occlusive crisis, 23,120 (8.5%) of which involved a secondary diagnosis of opioid use disorder. Black Race was associated with opioid use disorder, but age, sex and income were not. After adjusting for confounders, hospital length of stay was increased in patients with opioid use disorder by 1.23 days (95% CI: 1.02 to 1.45, p&amp;lt;0.001) and total hospital charges were increased by $5,566 (95% CI: 3,863 to 7,269, p&amp;lt;0.001) (Table 1). Mortality was decreased in vaso-occulsive crisis hospitalizations in those with opioid use disorder, but the difference was not significant (OR=0.58, 95% CI: 0.026-1.33, p=0.199). Conclusion Opioid use disorder is associated with an increased length of stay and cost in patients with vaso-occlusive crisis. Providers should consider under-treatment of pain as a potential diagnosis when addiction concerns are present and individualized pain plans should be explored.

Vitamin D Deficiency and Avascular Necrosis in Patients with Sickle Cell Disease: A Retrospective Cohort Study

Introduction Sickle cell disease (SCD) is an inherited hemoglobinopathy with complex systemic involvement. Avascular necrosis (AVN) is a devastating complication among patients with SCD. Vitamin D deficiency (VDD) is commonly found in SCD patients, but there is limited research on the potential role of VDD as a risk factor for AVN in SCD patients. This study aimed to assess the association between VDD and AVN and determine the patterns, risk factors, diagnosis, and treatment of AVN in SCD patients. Methods We conducted a retrospective cohort study of consecutive SCD patients diagnosed with VDD from January 2020 to December 2022 at Prince Sultan Medical Military City (PSMMC) in Riyadh, Saudi Arabia. Patients meeting the following criteria were included: (1) adults and children with confirmed SCD through hemoglobin electrophoresis and (2) tested for VDD. Patients who underwent bone marrow transplant were excluded. The main outcome measured was the occurrence of AVN. VDD was diagnosed in patients with 25-hydroxyvitamin D levels below 30 nmol/L. Magnetic resonance imaging was used to stage and confirm AVN diagnosis. Associations were assessed using the chi-square test, and logistic regression was performed to control for confounding. Results The study included 711 eligible SCD patients, with 271 (38%) being children. VDD affected 301 out of 711 patients (42.3%). Among these, 212 (70.4%) were adults (&amp;gt;18 years old). VDD was observed in 32.2% of children and 48.1% of adults. Of the total cohort, 127 (17.9%) patients experienced AVN, including 18 children. Among patients with VDD, 89 developed AVN, while VDD affected 212 patients without AVN. The time between VDD diagnosis and AVN presentation ranged from 3 to 12 months. Male patients accounted for 52% of AVN cases. The average age at AVN diagnosis was 30.9 ± 11 years. The most common clinical presentation of AVN was chronic joint pain in over 95% of patients. Other presentations included limping in 3.9% of patients and limited joint movement in one patient. Affected joints included the hip (86%), shoulder (16.5%), knee (4.7%), and sacroiliac joint (0.7%). Bilateral joint involvement was present in 50.4% of AVN patients. The majority of patients (76.4%) were diagnosed with advanced stage AVN (III/IV). Treatment of patients with AVN included joint replacement in 44 (34.6%) patients, while the remaining 83 patients managed with conservative therapy such as pain control and physiotherapy. Patients with a history of VDD were significantly associated with a higher risk of AVN (p &amp;lt; 0.001), as seen in Table 1. Multivariate logistic regression showed SCD patients with VDD had 9.79 times the odds of AVN compared to SCD patients without VDD (OR 9.79; 95% CI: 5.25-18.26). Other statistically significant risk factors for AVN included frequent vaso-occlusive crises (three or more episodes per year), older age, history of acute chest syndrome, and low hemoglobin F levels. Conclusion AVN is a significant cause of morbidity in our SCD cohort, with most patients having advanced AVN disease. VDD is an independent risk factor for AVN in patients with SCD. Well-designed randomized trials are needed to determine the effect of vitamin D supplementation in reducing AVN in children and adults with SCD.

Identifying Inflammatory and Immune Markers Associated with Vasoocclusive Crisis in Patients with Sickle Cell Disease

Background: Sickle cell disease (SCD) is an inherited disorder that can cause a range of clinical complications, featured by unpredictable and recurrent acute painful episodes associated with vasoocclusive crises (VOCs). Individuals with SCD experience frequent VOCs and require high doses of opioids for pain control. Thus far, studies on biomarkers associated with VOCs in SCD are very limited and the known markers are hardly considered as critical end points in studying VOCs in SCD. This study aimed to comprehensively analyze immune and inflammatory characteristics of patients with SCD to understand the disease-specific pathogenesis and develop targeted diagnostic and therapeutic strategies related to VOCs. Methods: The study cohort consisted of 40 patients with SCD aged 14-73 years (23 female, 58%), recruited for an ongoing clinical trial (ClinicalTrials.gov Identifier: NCT05045820). Twenty-three ethnicity-, age- and gender-matched pain-free participants were also enrolled as healthy controls (HCs) (Table 1). Multiplex immunoassays were used to profile 80 inflammatory cytokines/chemokines/growth factors and 18 autoantibodies in plasma samples from patients with SCD and the matched HCs. Peripheral blood mononuclear cells were used to profile immune cells. Statistical analysis was performed using GraphPad Prism with Mann-Whitney test, χ 2 test, and Spearman's correlation. P &amp;lt; 0.05 was considered statistically significant. Results: Patients with SCD exhibited significantly higher plasma levels of 34 analytes, including 12 pro-inflammatory/anti-inflammatory cytokines (IFN-γ, IL-1α, IL-2, IL-8, IL-9, IL-18, TNF-α, TNF-β, IL-4, IL-5, IL-6, and TSLP), 10 chemokines (CCL21, CCL23, Eotaxin-2, Gal-3, GRO-α, IP-10, MCP-2, MIP-1α, MIP-1β, and MIP-3α), 8 growth factors (bNGF, G-CSF, GM-CSF, HGF, IL-7, IL-20, IL-34, and LIF), 2 effectors (granzymes A and B), and 2 soluble receptors (PTX3, TREM-1). Higher activation levels of B cells, CD4 T cells, CD8 T cells, and MAIT cells were seen in patients with SCD. Autoantibody profiles were also altered in patients with SCD, with elevated levels of antibodies against SSA/Ro60, Ribosomal P, Myeloperoxidase, and PM/Scl-100. Levels of cytokines/chemokines/growth factors were correlated with time interval between blood draw and occurrence of VOCs. Four soluble factors (Eotaxin-2, GRO-α, IL-6, and LIF) were positively associated with time interval after VOCs, while two factors (IL-18 and granzyme A) showed negative associations with time interval, suggesting that the altered inflammatory mediators were associated with the occurrence of VOC events. Conclusion: Our results provide novel and comprehensive understanding of the immune and inflammatory dysregulation in patients with SCD and their relationship with occurrence of VOCs, offering insights into potential SCD-specific biomarkers for further investigation.

Altered ventricular longitudinal strain in children with sickle cell disease: Role of TGF-β and IL-18.

Cardiovascular involvement in sickle cell disease (SCD) has a great impact on patients' morbidity and mortality. Recently, interleukin-18 (IL-18) and transforming growth factor beta (TGF-β) were suggested as potential biomarkers for sickle cell cardiomyopathy. Global longitudinal strain (GLS) is a reliable early parameter for estimation of deformed myocardium. This study evaluated the role of TGF-β and IL-18 as risk indicators of altered strain in patients with SCD. Forty children with SCD (age >5years) and 40 healthy children as controls, matched in age and sex, were enrolled in the study. All participants were subjected to clinical examination, complete blood count, serum ferritin, TGF-β, IL-18, and assessment of cardiac function by echocardiography. TGF-β, IL-18, and lactic acid dehydrogenase (LDH) were significantly higher among cases (mean age: 10.6±3.5years) when compared to controls (p<.001), at cutoff values 41.7ng/mL, 128.9pg/mL, and 340 unit, respectively. The LS of free wall of RV (FW-RV) was significantly lower among cases when compared to controls (-23.55%±5.55% vs. -28.73%±2.43%, p<.001). Free wall longitudinal strain of the right ventricle (FWLS-RV) was significantly correlated to IL-18 and LDH (p<.001), while GLS-RV was significantly correlated to TGF-β. The GLS-LV was correlated to frequency of vaso-occlusive crises (VOCs) per year (p<.001). Diastolic function, E/A of LV, and RV were negatively correlated to the hemoglobin and serum ferritin levels. The TGF-β, IL-18, and LDH along with frequent VOCs are correlated to altered LS, especially the right ventricle, and could serve as risk indicators for subclinical cardiomyopathy in children with SCD.

Alterations of Cerebral Metabolites Are Associated with Frequency of Vasoocclusive Crises and Pain Sensitivity in Patients with Sickle Cell Disease

Purpose Sickle cell disease (SCD) is an inherited hemolytic disorder complicated by acute and chronic pain. Acute vasoocclusive crises (VOCs) associated with SCD are extremely painful episodes that are recurrent, unpredictable, and frequently require hospitalization and opioids for pain control. Changes in brain metabolites were identified in other chronic pain populations but haven't been well studied in SCD. Our ongoing trial (ClinicalTrials.gov Identifier: NCT05045820) aims to evaluate the characteristics of brain metabolites in SCD and understand the relationship between the altered cerebral metabolite(s) and clinical pain in patients with SCD. Materials and Methods Metabolite measurements from a single voxel (size: 2×3×3 cm 3) located within the posterior insula cortex (PIC) were acquired from 26 patients with SCD (31.9 ± 13.9 years, 14-73; 14 females) and 19 healthy controls (HCs) (37.9 ± 16.4 years, 17-62; 10 females) with PRESS (TR/TE = 3000/25 ms, Averages =128) and MEGA-PRESS (TR/TE = 3000/68 ms, Averages =256) sequences using a Siemens Prisma 3T scanner. Written consent was obtained from each participant before scanning. LCModel was used for PRESS analysis to obtain concentration values of glutamine + glutamate (Glx), total creatine (tCr), N-acetylaspartate (NAA), total choline (tCho), and myoinositol (MI). Gannet was used for processing MEGA-PRESS data to estimate GABA+. Ratios of each metabolite to tCr were also quantified. Tissue correction for cerebrospinal fluid was performed for each voxel using the tissue composition estimated from SPM12. The Cramer-Rao Lower Bounds of each metabolite analyzed with LCModel was less than 20%. The frequency of VOCs in the preceding 12 months was recorded for each participant. A moderate pressure pain stimuli (using a 0-100 scale with “0” representing “no pain” and “100” representing “most intense pain imaginable”, pain rating at 40-60 abbreviated as P40 is considered as moderate pain) was delivered via a pressure cuff to the gastrocnemius area of the non-dominant leg using a validated MR-compatible air compressor to induce a tonic pressure pain for 8 min right before MRS scan. Higher pressure intensity (mmHg) of P40 indicated higher pain tolerance and lower pain sensitivity. Correlation between the brain metabolites and pain-related outcomes was studied. Results Due to the large range of age in the SCD group, the brain metabolite profile was compared between 17 SCD patients and 17 ethnicity-, age- and gender-matched HCs. The concentration of Glx (p =0.012) and ratio of Glx to tCr (p =0.034) in PIC were significantly higher in patients with SCD compared to HCs (Figure 1). Within the SCD patient group, there was a significant positive correlation between frequency of VOCs in the preceding 12 months and Glx/tCr (r= 0.39, p=0.047, Spearman's), a significant negative correlation between P40 and Glx (r= -0.46, p=0.019, Spearman's). There were no group differences in any other metabolites. Conclusion We find increased Glx in the PIC in patients with SCD. Previous studies have also found increased Glx and/ or Glx/tCr in the PIC as well as other brain regions including the amygdala, the posterior cingulate, the ventral lateral prefrontal cortex and the anterior insula in fibromyolgia. The PIC is thought to be involved in discriminative activities of sensory pain, which suggests that Glx in PIC is related to pain processing in patients with SCD. Glx/tCr was correlated with frequency of VOCs in patients with SCD, indicating that the SCD patients with higher level of Glx/tCr had more VOCs in the preceding 12 months. In addition, the SCD patients with higher level of Glx had lower pressure intensity of P40, suggesting that elevated Glx in the PIC was related to higher pain sensitivity. Our preliminary data provide the first evidence of a link between alterations in excitatory neurotransmitter levels in the PIC in patients with SCD and indicates new information of potential brain markers for pain in SCD, which may guide treatment. Clinical Relevance Statement: Treatment of pain in SCD remains very challenging in part due to a lack of understanding of the underlying mechanisms and pathophysiology of pain. Brain excitatory neurotransmitters and their relationship with pain have been largely unexplored in SCD. These findings indicate that the relationship between clinical outcomes and excitatory brain neurotransmitters may be a potential objective outcome measure in SCD.

Real-World Experience of Individuals with Sickle Cell Disease Treated with Voxelotor: Initial Report from the Multicenter, Prospective Prospect Study

Introduction: Sickle cell disease (SCD) is an inherited blood disorder in which sickle hemoglobin (HbS) polymerization results in red blood cell sickling, which in turn leads to chronic hemolytic anemia, unpredictable pain episodes, and recurrent vaso-occlusive crises (VOCs). Hemolysis and low hemoglobin (Hb) are associated with organ damage, increased morbidity, and early mortality. Voxelotor, a first-in-class HbS polymerization inhibitor, is approved in the US for the treatment of patients with SCD aged ≥4 years and in Europe for the treatment of hemolytic anemia due to SCD in patients aged ≥12 years. In the phase 3, randomized, controlled HOPE (NCT03036813) and the phase 2, open-label HOPE-KIDS 1 (NCT02850406) trials, patients treated with once daily oral voxelotor experienced increased Hb levels and reductions in markers of hemolysis at Week 24 compared with baseline. Here we report the first efficacy and safety data from patients with SCD enrolled in the prospective PROSPECT registry who received voxelotor in a real-world setting. Methods: PROSPECT (NCT04930445) is a post-marketing, open-label, observational, prospective patient registry of patients with SCD (aged ≥4 years) in the US. Eligible participants are being treated with voxelotor as prescribed by their physician as part of their usual care. Participants are treated and evaluated per standard of care and at the physician's discretion. Treatment, including interruptions and restarting treatment, continue at the discretion of the treating physician. Patients receive any additional medications or transfusions as determined and prescribed by their physician. Follow-up duration is 5 years after the first dose of voxelotor therapy. Study data are collected from patient medical records and secondary data sources and entered in case report forms via an electronic data capture system. Results: At data cutoff (May 30, 2023), 85 patients were enrolled at 5 sites. The mean (SD) age was 33.2 (15.3) years, 51.8% of patients were female, and most (92.9%) were Black or African American. Overall, 72.9% of patients were genotype HbSS, 62.4% were taking concurrent hydroxyurea, and mean (SD) Hb at baseline was 7.7 (1.53) g/dL. The mean (SD) duration of treatment, excluding gaps, was 47.0 (12.35) weeks. At the data cutoff, 76 patients (89.4%) continued voxelotor treatment; 7 patients (8.2%) never started voxelotor, and 2 patients (2.4%) discontinued treatment because of adverse events (AEs).The initial prescribed daily doses of voxelotor were 1500 mg (84.7%), 1000 mg (8.2%), 900 mg (4.7%), or 500 mg (2.4%). The most common reasons for prescribing voxelotor were to reduce either anemia (74.1%), frequency of VOCs (15.3%), pain (14.1%), or the frequency of blood transfusion (9.4%); multiple reasons could be selected. In 66 patients with recorded baseline and posttreatment Hb values, the observed mean (SD) peak posttreatment Hb value was 9.0 (1.75) g/dL, representing a mean (SD) increase from baseline of 1.3 (1.25) g/dL. The range of peak Hb change from baseline was −1.4 to 4.6 g/dL and 52/66 patients (78.8%) had a positive Hb response (Figure). Reductions in markers of hemolysis were also observed following voxelotor treatment, with nadir mean (SD) decreases from baseline of −23.9% (55.92%) in reticulocyte percentage (n=54), −1.8 (2.36) mg/dL in total bilirubin (n=61), and −1.6 (1.95) mg/dL in indirect bilirubin (n=38). AEs of special interest reported in &amp;gt;3% of patients included diarrhea, headache, nausea, abdominal pain, and rash (Table); most of these AEs were mild or moderate in severity. Conclusions: PROSPECT is the first prospective patient registry of voxelotor, with the potential to follow up to 1000 participants for up to 5 years and enable long-term, robust data collection of real-world care patterns that could inform how best to incorporate voxelotor into the treatment paradigm of patients with SCD. In this initial cohort of participants enrolled to date, following voxelotor treatment for a mean duration of 47.0 weeks, the mean peak increase from baseline in Hb was 1.3 g/dL, and associated reductions in markers of hemolysis were observed. Safety data were consistent with the phase 3 HOPE and HOPE-KIDS 1 trials. Overall, these initial findings provide support for the real-world safety, tolerability, and effectiveness of voxelotor treatment in individuals with SCD. While enrollment is ongoing, updated data will be regularly reported.

Fucosyltransferase VII (FUT7) Activity in Patients with Sickle Cell Disease and Healthy Controls

Background:Sickle cell disease (SCD) is a severe monogenic disorder with a majority of the affected individuals living in Africa. Vaso-occlusion is a significant cause of morbidity and mortality in SCD, and selectin mediated intercellular adhesion is recognized as an important target for therapy. As such Anti-P-selectin agents are in clinical use to reduce the frequency of vaso-occlusive crises (VOCs) in SCD patients. Sialyl lewis x is a crucial ligand common to all members of the selectin family and the final step in the biosynthesis of sialyl lewis X antigen (fucosylation), is catalysed by Fucosyltransferase VII (FUT7). This enzyme is most expressed in leukocytes and endothelial cells. We hypothesized that FUT7 enzyme activity is abnormal in SCD patients and differs by VOC severity. We sought to measure plasma levels of FUT7 in SCD patients and healthy controls, and investigate their association with clinical and laboratory features, such as the frequency of VOCs. Methods:This wasa single centre cross-sectional analytical study at the University of Nigeria Teaching Hospital, Enugu. 38 steady state adult SCD patients and 40 HbAA age- and sex-matched healthy control subjects were enrolled. SCD patients were stratified by clinical severity into: Group A- 19 subjects with mild disease (0-1 crises and no disease complication such as stroke, chronic leg ulcers, nephropathy, or avascular necrosis in the previous year), and Group B- 19 patients with moderate to severe disease (2 or more crises in the previous year, with or without complications). We excluded patients with red cell transfusion within 4 months, on hydroxyurea, or other agents that may affect vaso-occlusive crisis frequency, and co-existing chronic disorders unrelated to SCD, such as asthma and diabetes mellitus. We performed a CBC and plasma FUT7 enzyme concentration measurements (ELISA kit, MyBiosource Inc, USA). Statistical analysis was performed with SPSS version 22.0 for Windows. A 2-tailed P value of &amp;lt;0.05 was used. Results:Our subjects were predominantly female (SCD 52.5%, HbAA 55%), with median age 28 years (range 19-46 and 19-45 for SCD and HbAA, respectively). Median frequency of VOCs in patients was 1 (range 0-5). Avascular necrosis (32.5%) was the most common complication, while stroke, acute chest syndrome, and eye disease were the least common. As expected, SCD patients had lower haemoglobin levels than HbAA (7.9±1.3g/dL vs. 12.6±1.4g/dL, P&amp;lt;0.001). Significantly higher WBC, ANC, and platelet counts were observed in SCD patients compared with HbAA controls (P&amp;lt;0.001). No significant correlations were found between FUT7 and haematocrit (r =0.06), WBC count (r = -0.08), neutrophil count (r = -0.12), and platelet count (r =0.1), with P values of 0.7, 0.6, 0.5, and 0.6, respectively. We found no difference between the median and IQR values of plasma FUT7 of SCD (2.1; 1.8-2.5) and controls (2.2; 1.8-2.8), P = 0.7. FUT7 activity was higher in SCD subjects in Group A (2.2; 1.9-2.9) than in Group B (2.0; 1.2- 2.4), with a trend towards significance P = 0.1. Discussion:In this study, FUT7 activity did not differ between SCD patients and controls. We also did not find correlations between FUT7 and blood cell counts, suggesting that plasma FUT7 activity is not increased at baseline in SCD and that the degrees of anemia or leukocytosis are not associated with changes in FUT7. Nonetheless, a mild decrease in FUT7 levels was found in more severe SCD patients and should be confirmed in a larger study. Our study did not evaluate patients in crises or who received hydroxyurea and/or other SCD-modifying therapies. Since FUT7 catalyses selectin expression, variation in its activity may be more relevant in subgroups of SCD patients on anti-selectin therapies. Future studies should be carried out in such patients to explore FUT7 activity as a marker of acute vaso-occlusion and as a modifier of response to therapy.

The Impact of Socio-Economic Determinants of Health on PedsQL and Pain Outcomes Among Individuals with Sickle Cell Disease

Background: Pain in sickle cell disease (SCD) is the most visible symptom in patients. Many recent studies have shown that socio-economic status such as low income, educational achievement or even less affluent neighborhoods may contribute to the pain experience, with those of lower socioeconomic status (SES) reporting both acute and chronic pain more frequently. Furthermore, living in a less affluent area was associated with frequent use of analgesics after adjustment for pain intensity. The relationships between SES variables, pain-related anxiety, frequency of vaso-occlusive crises and/or acute care utilization have been explored; nevertheless, the relationship between SES and quality of life pain-related measures (pain hurt, pain interference, etc.) has yet to be reported. Methods: The St. Jude Children's Research Hospital Sickle Cell Clinical Research and Intervention Program (SCCRIP) is an observation cohort study of clinical outcomes in patients with SCD. Patients enrolled in SCCRIP were retrospectively evaluated based on various SES measurements. Household SES was evaluated using the Barratt Simplified Measure of Social Status (BSMSS), a composite index of parent education and occupation. The Social Vulnerability Index (SVI) was used to classify individuals based on social vulnerabilities at the neighborhood level. The area deprivation index (ADI) ranks neighborhood in a region of interest based on social risk factors that may predispose individuals to worse clinical outcomes Quality of life measures, Pain Hurt, Pain Impact, and Pain Management/Control, were extracted from the PedsQL SCD Module. High scores on the SVI and ADI are associated with low SES and high scores on the PedsQL indicate better SCD related quality of life (QoL) with lower burden and impact of pain on function. Multivariate linear regression models were used to evaluate the associations of SES with QoL pain-related outcomes, based on a stepwise model selection strategy, with potential covariates including age, gender, disease-modifying therapy (e.g., Hydroxyurea and chronic transfusions), hemoglobin, hemoglobin F (HbF)%, and each SES variable. Results: 944 patients between the ages of 5-61 (Mean=13.75, Standard Deviation=7.57) years diagnosed with SCD completed PedsQL testing and were assessed for SVI and ADI. Multivariate models demonstrated that patients with lower SVI (i.e., higher neighborhood SES) at the neighborhood level displayed higher scores with regards to Pain Hurt (est=-7.44, standard error (SE)=2.84, p=0.01), Pain Impact (est=-9.56, SE=3.18, p=0.003) and Pain Management/Control (est=-9.35, SE=3.81, p=0.01). Similar relationships were observed for patients with lower ADI. Additionally, there was a significant association between pain impact and BSMSS (est=0.20, SE=0.10, p=0.04), suggesting that individuals with higher BSMSS (higher household SES) also had higher pain impact scores (better quality of life). Conclusions: This study demonstrated that neighborhood and household SES have an impact on pain experience in youth with SCD. Patients with increased social vulnerability and area deprivation experienced lower health-related quality of life-related to SCD pain. Increased household SES was associated with greater SCD pain impact independent of the effects of patient age, gender, SCD therapy, and HbF. Our study suggests that social determinants of health, such as SES, play a role in pain experience and QOL related to SCD pain and should be explored further.

The Burden of Sickle Cell Disease on Children and Their Caregivers: Caregiver Reports of Children's Health-Related Quality of Life and School Experiences, Caregiver Burden, and Their Association with Frequency of Vaso-Occlusive Crises.

Children with sickle cell disease (SCD) experience a multiplex of disease-related symptoms and complications, including vaso-occlusive crises (VOCs), episodes characterized by extreme pain. A cross-sectional observational survey examined the health-related quality of life (HRQoL) and school experiences of children with SCD 2 months-11 years, burden experienced by their caregivers, and associations between these outcomes and VOC frequency. Caregivers (N=167) of children with SCD in the US completed the Infant-Toddler Quality of Life-Short Form 47 (ITQoL-SF47) for children 2 months-4 years, the Child Health Questionnaire-Parent Form 50 (CHQ-PF50) and PROMIS Pain Interference and Sleep Disturbance Parent Proxy short forms for children 5-11 years, and a study-specific survey of school experiences. Children with SCD 2 months-4 years had lower ITQoL-SF47 scores (ie, worse HRQoL, p<0.001) than a normative sample of children; across domains, differences ranged from 18.73-45.03 points and exceeded minimal important difference (MID) thresholds. Except for the behavior domain, children with SCD 5-11 years had lower scores on all CHQ-PF50 domains than the normative sample (p<0.001); differences ranged from 6.78-36.37 points and exceeded MID thresholds. Children with more frequent VOCs had lower HRQoL and worse school experiences than children with less frequent VOCs (p<0.05, except for behavior domains). The largest differences based on VOC frequency were observed for overall health and bodily pain/discomfort among children 2 months-4 years (differences=40.88 and 32.50 points, respectively), and bodily pain and role/social limitations due to physical health among children 5-11 years (differences=38.99 and 37.80, respectively). Caregivers of children with more frequent VOCs experienced greater burden than caregivers of children with less frequent VOCs, though specific areas of impact (eg, caregiver emotions, time) differed across child age groups. VOC frequency is negatively associated with HRQoL, highlighting the burden experienced by children with SCD and their caregivers.

Associated Factors of Cholelithiasis among Younger Children with Sickle Cell Disease at the National Reference Center for Sickle Cell Disease in Brazzaville, Congo.

Chronic hemolysis predisposes sickle cell patients to the development of gallstones. Their frequency increases with age, but they may appear early in young children. In the absence of management, they expose the patient to complications that can hinder the quality of life and sometimes even death. This survey aimed to identify the associated factors of the occurrence of cholelithiasis. It was a case-control study carried out between January 2017 and June 2022 at the National Reference Center for Sickle Cell Disease (SCD) "Antoinette Sassou N'guesso" in Brazzaville. It concerned 37 children with cholelithiasis. Sociodemographic (socioeconomic status and diet) and clinical (body mass index, frequency of vasoocclusive crises and hospitalization for vasoocclusive crises, number of blood transfusion, and chronic complications) as well as hematological examination (type of SCD and blood count in the intercritical period) and hydroxyurea treatment were compared with those of 74 children with no clinical and radiographic signs of cholelithiasis. The chi-squared statistical test and the odds ratio were used for the comparison (p < 0.05). The average age was 9.70 ± 1.73 years. The 10-12 age group was the most represented (22 cases or 59.45%), followed by 7- to 9-year-olds (12 cases or 32.43%). Three children (8.10%) were 6 years old. The sex ratio was 0.68 vs. 1.38. Factors associated with cholelithiasis were low socioeconomic status (83.78% vs. 45.95%; IC 95% 1.46-3.89; p ≤ 0.001), a higher number of blood transfusions (5.54 ± 1.22 vs. 2.46 ± 1.13; IC 95% 1.55-6.70; p ≤ 0.001), and irregular systematic monitoring (5.54 ± 1.22 vs. 2.46 ± 1.13; IC 95% 1.55-6.70; p ≤ 0.001). A national strategy to facilitate access to care for patients living with sickle cell disease is imperative. Moreover, emphasis should be placed on the prevention and early management of acute complications of SCD.