Sickle Cell Disease Genotype Research Articles

Building Adaptive Coping and Knowledge to Improve Daily Life (Back2Life): A Pilot Feasibility Trial for Youth with Chronic Sickle Cell Pain

Introduction: Cognitive-behavioral therapy (CBT) for pain is an effective non-pharmacological treatment for chronic pain management, yet can have limited generalizability, access, and reach for underrepresented populations like youth with sickle cell disease (SCD). We aimed to conduct a single-arm proof-of-concept clinical trial to evaluate the feasibility, acceptability, and preliminary efficacy of Back2Life, an adapted, culturally congruent CBT intervention for youth with chronic SCD pain and their parents. We hypothesized that Back2Life would be feasible and acceptable as demonstrated by high levels of treatment engagement (≥80% attendance of treatment sessions) and satisfaction. We also expected clinically significant reductions in pain and pain interference and improvements in pain coping efficacy from baseline to 3-month follow-up (primary endpoint) and 6-month follow-up (maintenance endpoint). Methods: Youth receiving care at comprehensive SCD clinics at 3 tertiary care locations within a southeast children's hospital were included if they were aged 10-18 years, any SCD genotype, reported chronic pain (i.e., pain on most days per month for at least 3 months), had English fluency, and had stable disease-modifying treatments in the past 3 months. Youth were excluded if they had comorbid medical conditions typically associated with pain but unrelated to SCD, had significant cognitive or developmental limitations that would interfere with study procedures, or received ≥ 3 sessions of outpatient psychological therapy for pain management in the preceding 6 months. Patients completed assessments at baseline, post-treatment, 3-month follow-up, and 6-month follow-up. Primary outcomes included pain characteristics (i.e., intensity, frequency, burden), pain interference, and coping self-efficacy. Secondary outcomes included depressive symptoms, pain catastrophizing, and sleep quality. The Back2Life program included evidence-based CBT treatment manuals that were adapted based on qualitative feedback from patient and parent stakeholders to optimize the cultural congruence and relevance to chronic SCD pain. Back2Life was an adaptive treatment comprised of 6-10 module-based sessions delivered by a behavioral health coach via telehealth. All participants received 6 core sessions and up to 4 additional sessions were included to optimize tailored treatment components to address individual family needs. Tailored sessions targeted common co-morbidities associated with chronic pain and were identified based on findings of the baseline assessment. Families also could opt-in to tailored sessions based on interest. Descriptive statistics were conducted to evaluate feasibility and acceptability metrics as well as clinically significant changes in primary and secondary clinical outcomes. Results: Youth (n=20) were on average 15.9 years old (SD=1.6), 50% female, 100% Black or African American, and 95% Non-Hispanic/Latinx. Most (80%) had hemoglobin types HbSS or HbSβ 0. Feasibility and acceptability ratings were high, including 85% consent rate, 80% initiated study procedures, 100% treatment session completion, 93% intervention fidelity, 100% reported moderate-high treatment satisfaction, and strong qualitative feedback suggested treatment acceptance. Patients reported clinically significant changes from baseline to 6-month follow-up in pain frequency (>35% reduction), worst and typical pain intensities (>30% reduction), SCD pain burden (>30% reduction), pain interference (moderate to mild severity), and improvement in pain coping self-efficacy (see Table 1). Patients also reported changes in pain catastrophizing (high to moderate severity), depressive symptoms (mild severity to within normal limits), and no change in sleep quality. Conclusions: The Back2Life treatment program demonstrated high feasibility and acceptability, participant engagement, participant retention, and meaningful changes in patient-reported outcomes. An adapted, culturally congruent, telehealth-delivered CBT for pain intervention tailored to meet the unique needs experienced by youth with chronic SCD pain can promote increased access, reach, and health equity in SCD.

Neighborhood Disadvantage Increases Risk of Adverse Clinical Events in Children with Sickle Cell Disease

Background: Hydroxyurea is the most widely used pharmacologic agent to treat patients with sickle cell disease (SCD). Hydroxyurea treatment has well established effects of inducing expression of fetal hemoglobin (HbF) and a beneficial impact on clinical outcomes such as reduced number of vaso-occlusive (VOC) events, transfusions, and hospitalizations. In non-SCD populations, living in socio-economic disadvantage is a well-established factor for poor health outcomes. However, there is a paucity of data to describe how social stressors impact children with SCD. We hypothesized that socio-economic disadvantage impacts risk of adverse clinical outcomes in pediatric SCD patients even while on hydroxyurea therapy. Methods: We performed a retrospective chart review on 121 pediatric patients with severe SCD genotypes (homozygous HbS and sickle-beta 0 thalassemia) seen at Texas Children's Hospital (TCH) between 2010-2021. All patients were treated with hydroxyurea for a minimum of five years. Adherence to hydroxyurea was assessed through lab markers including absolute neutrophil count and reticulocyte counts. Patients not adherent were excluded from analysis. We examined the incidence of all clinical events for a total of 1026 patient years, including the number of office visits, ER visits, hospitalizations, transfusions, VOC, acute chest syndrome episodes (ACS), acute splenic sequestration (ASS), and febrile illness. We collected laboratory data including absolute neutrophil count, hemoglobin level, and HbF levels for each patient per year they were on hydroxyurea. We used the area deprivation index (ADI) to determine a score of neighborhood disadvantage amongst our cohort of patients. The ADI is a factor-based index which uses 17 US Census variables including poverty, education, and employment. We used individual residential addresses during our observation period to assign a geocode specific to each individual and obtain an ADI score. The ADI scores are ranked from 1-10, with higher ADI rankings reflecting a higher level of disadvantage. Results: All individuals with SCD had a robust response to hydroxyurea within their first year of initiating the drug (>20% HbF). We stratified our cohort based on their ADI scores into low ADI (1-3; n=42); medium ADI (4-6; n=42); and high ADI groups (7-10; n=37), where high ADI is the group with highest levels of disadvantage. All three groups had a similar average duration of hydroxyurea treatment. There were no significant differences in age, sex, or reason given for starting hydroxyurea between the ADI groups. When we examined hydroxyurea response, there was no significant difference in HbF levels at 1 year (23.8 vs. 24.06 %HbF in the low vs. high ADI groups) or after 5 years (19.6 vs. 18.6 % HbF in the low and high ADI groups). Individuals with high ADI did started hydroxyurea at a younger age (2.9 years vs. 4.9 years, p=0.02). We found that any individual living in an area with higher ADI had an increased incidence of adverse clinical events. We calculated the incidence of each clinical event per 100 patient years in our 3 ADI groups and used a conditional maximum likelihood estimate of rate ratio method to compare incidences (Table 1). We found that among individuals living in an area with a higher ADI (more deprived region), there was increased frequency of ER visits, hospitalizations, transfusions, VOC, and ASS. In particular, patients with the highest ADI had a 3 and 5 times higher rate of VOC and ASS, respectively (Table 1). Discussion: While we did not observe an association between ADI and HbF expression, our results show that higher neighborhood disadvantage is associated with poorer clinical outcomes among hydroxyurea-adherent pediatric patients with SCD who maintained a robust response to the drug (>20% HbF). All individuals in our study had a similar number of routine office visits at our clinic but any patient living in an area of high ADI had significantly more ER visits and hospitalizations for VOC and ASS events. While hydroxyurea is shown to reduce hospitalizations and VOC events in pediatric sickle cell patients, we show that neighborhood disadvantage can influence clinical outcomes even among patients who respond to hydroxyurea. More analysis remains in order to better characterize this association, and to understand additional strategies that can be used to reduce clinical events in pediatric patients of lower socioeconomic status.

Identifying Geriatric Syndromes in Adults with Sickle Cell Disease Using the Sickle Cell Disease Functional Assessment (SCD-FA): The Sickle Cell Disease Functional Assessment Validation and Refinement (SILVR) Study

Introduction As people with sickle cell disease (SCD) age, they experience accelerated functional decline. Since historically survival for SCD has been limited to middle age, geriatric syndromes in adults with SCD remains understudied. Chronological age does not accurately represent a person's health status; thus, valid functional measures for adults with SCD are required. Geriatric assessments are commonly used to measure function in older adults in the general population. We previously demonstrated feasibility, safety, and acceptability of a geriatric assessment battery called the Sickle Cell Disease Functional Assessment (SCD-FA) in adults with SCD. The SCD-FA includes physical performance test and surveys evaluating multiple health domains. The purpose of this study was to evaluate the construct validity of the SCD-FA. Methods We enrolled younger (age 18-39) and older (age ≥ 40 years) adults with SCD in a single center prospective study. We assessed construct validity of each SCD-FA measure by determining known-group validity. Specifically, we evaluated whether the SCD-FA could distinguish between participants known to differ based on the following: age (< 40 vs ≥ 40), SCD genotype non-severe (HbSC/HbSβ +-thalassemia) vs severe (HbSS/HbSβ 0-thalassemia), and dependence in Activities of Daily Living/Instrumental Activities of Daily Living (no ADL/IADL deficit vs ≥ 1 ADL/IADL deficits). We used Student's t-tests and Wilcoxon rank sum test to gauge significant differences between groups. Results We performed the SCD-FA in 111 adults with SCD at steady state, with 93 (84%) having complete data. Most participants (58%) were female. The mean age of all participants was 44 ± 14 (range 19-82 years), with most (56%) age ≥ 40 years. The mean age for younger adults (18-39 years) was 30 ± 5.8 and 54 ± 9.3 for older adults (≥ 40 years). When evaluating SCD-FA measures by age, older adults had lower scores on PROMIS Physical Function (younger 52 ± 6.9 vs older 46 ± 8.4; p<0.001). Although there was no difference in number of falls by age, there were several participants with ≥ 1 fall (15%) or near fall (36%) in the last 6 months. Older adults had higher scores on the Social Support Survey (implying better support) (younger 69 ± 30 vs older 80 ± 20; p< 0.05). Older adults had more non-SCD comorbidities (younger 0.5 ± 0.7 vs older 1.7 ± 1.7; p<0.001), with no younger adults with ≥ 3 comorbidities vs. 33% of older adults with ≥ 3 comorbidities, more SCD conditions (younger 2.0 ± 1.5 vs older 2.7 ± 1.7; p< 0.05), and more reports of fair or poor hearing (0% younger vs 8% older; p = 0.01). Older adults took more prescribed medications (younger 3.9 ± 2.4 vs older 6.3 ± 3.9; p = 0.001) and were more likely to meet criteria for polypharmacy (defined as ≥ 5 prescribed medications) with 30% of younger adults vs 64% of older adults (Figure). Most participants (64%) had HbSS/HbSβ 0 (severe genotype) and 36% had HbSC/HbSβ + (non-severe genotype). When comparing groups by genotype, participants with severe genotypeshad a lower body mass index (severe25 ± 5.8 vs non-severe 31 ± 8.4 kg/m2; p < 0.005) and fewer non-SCD comorbidities (severe 0.75 ± 1.0 vs non-severe 1.9 ± 1.8; p< 0.005). There was no difference in physical performance, falls, psychological state, SCD conditions, and number of medications by genotypes. Of all participants, 34% reported dependence in ≥ 1 ADL/IADL. When comparing groups by ADL/IADL dependence, those who were dependent in ≥ 1 ADL/IADL had worse physical performance for all measures (gait speed, grip strength, 6-minute walk, Timed Up and Go test, and 30-Second Chair Stands). ADL/IADL dependent participants had more falls, higher PHQ-9 scores, lower MiniCog scores, more non-SCD comorbidities, and were more likely to report fair or poor vision. There was no difference in reported hearing deficits. (Table) Conclusion The SCD-FA was able to distinguish between known-groups by age and ADL/IADL dependence and identify deficits in adults with SCD such as falls, polypharmacy, comorbidities, and sensory deficits. Geriatric syndromes did increase with age in adults with SCD and were more common than in the general population (34% ADL dependent SCD participants vs 15% of middle-aged U.S. adults). Therefore, there is a need for early initiation of interventions to improve function and quality of life. We are currently adapting geriatric interventions for older adults with SCD. In future studies we will assess the predictive validity of the SCD-FA.

A Genotype Validated Bimodal Method for the Large-Scale Identification and Phenotyping of Persons with Sickle Cell Disease Using Electronic Health Record Data

Introduction Clinical trials for using hematopoietic stem cell transplant (HSCT) with gene therapies to cure sickle cell disease (SCD) began in 2019. The Food and Drug Administration (FDA) requires that 1) all gene therapy participants receive at least 15 years of ongoing surveillance and 2) their outcomes be compared to a contemporaneous cohort that did not receive gene therapy. Previously we developed an automated contemporaneous cohort of children and adults with SCD from electronic health record (EHR) data (Cronin RM et al. 2023, Blood Adv). Our work was built upon previously explored algorithms utilizing ICD codes and laboratory data to identify persons with sickle cell anemia (SCA), a severe form of SCD (Singh et al. 2018, Blood Adv). Still, our algorithm additionally classifies other predicted genotypes. However, we could not test the SCD phenotypes against the SCD genotypes due to the absence of beta-globin gene sequence data. Here we tested the hypothesis that our Vanderbilt-EHR algorithm for identifying a contemporaneous cohort at Vanderbilt can classify their predicted genotype compared to beta-globin gene sequencing, the gold standard for SCD diagnosis, in the cohort. We subsequently tested the Vanderbilt-EHR algorithm in an established cohort of children from St. Jude Children's Research Hospital that have been deeply phenotyped. Methods We applied the Vanderbilt-EHR algorithm to a cohort of 275 samples from Vanderbilt's biorepository of DNA, BioVU, linked to de-identified medical records in a data warehouse called the Synthetic Derivative. These 275 samples were previously submitted for whole genome sequencing as part of the Genetic Variation of Heart, Lung, and Kidney Disease in Sickle Cell Disease: Pre- and Post-Curative Therapies TOPMed project (HLK-SCD phs002617). The returned genotypes were validated using the hemoglobin variant database HbVar (Giardine BM et al. 2021, Nucleic Acids Res) (Table 1). We applied the hemoglobinopathy genotype classification portion of the algorithm to the Sickle Cell Clinical Research and Intervention Program (SCCRIP) cohort from St. Jude Children's Research Hospital, which includes putative genotype diagnoses derived from a comprehensive evaluation of clinical data for each member. We performed statistical analyses of the identification and classification results of the Vanderbilt cohort and the SCCRIP cohort's classification results. Results Of the 275 genotyped samples, the algorithm correctly predicted 255 SCD cases and 10 non-SCD cases. There were three cases predicted to be false positives; however, a comprehensive analysis showed that all have laboratory values indicative of SCA (high hemoglobin S levels >60%, absent or negligible hemoglobin A levels, elevated reticulocytes, and low mean corpuscular volume) suggesting that there may be a genotyping error. The remaining 7 cases were either indeterminate in the prediction or in the genotype (Table 1). Given the small number of indeterminate results, we performed a sensitivity analysis to identify the range of performance for SCD identification. The method performed very well with over 98% sensitivity and over 96% positive predictive value (PPV) (Table 2). The lower specificity and negative predictive value (NPV) could be largely attributed to the disproportionately high number of SCD cases in the dataset compared to non-SCD cases. The SCD classification algorithm performed similarly in both the VUMC and SCCRIP cohorts (Table 2). The algorithm performs best in identifying SC and SCA types of SCD with nearly 100% accuracy for SC and over 94% accuracy for SCA. Transfusions can confound the diagnosis of SCA vs. S beta thalassemia +, but the latter has a much lower prevalence consistent with our results (Table 2). Discussion and Conclusions Larger SCD cohorts will be identified using these approaches in singular EHR databases and in de-identified data warehouses that EHR companies have developed by aggregating data across multiple EHR systems (e.g., EPIC Cosmos and Cerner Real-World Data). The ongoing need for contemporaneous comparison cohorts of persons with SCD to understand outcomes related to treatment and phenotype can be greatly assisted by accurate automated approaches. The Vanderbilt-EHR algorithm is the first to comprehensively phenotype SCD and other hemoglobinopathies involving variant hemoglobin beta alleles.

Clocking the Processes and Challenges of Urgent Red Blood Cell Exchange for Acute Complications of Sickle Cell Disease

Background: Red blood cell exchange transfusion (RBCX) is the therapy of choice for some acute complications of sickle cell disease (SCD), including stroke, severe acute chest syndrome and multi-organ failure. Rapid initiation of RBCX is critical to reduce morbidity and mortality in those with acute complications of SCD. A typical RBCX procedure requires anywhere from 6-10 units of packed red blood cells (RBC) and measures are taken to provide higher-fidelity RBC matches (key RHCE and KEL antigens at a minimum, ±suitable KIDD, FY, Ss profiles for the sensitized). Our recent review of urgent apheresis transfers to our tertiary-care centre, including 26 for RBCX, demonstrated that the median time per transfer was approximately 4 hours. Not yet characterized is the additional time required to start RBCX once a patient arrives. The time required to investigate antibody repertoires, and to procure sufficient quantities of blood that can bypass these specificities, is of interest in a specialty center with substantial but not unlimited investigative expertise and inventory. Methods: This was a retrospective database and chart review of all patients referred to our apheresis service for urgent RBCX for severe complications of SCD between Jan 1, 2013 to Dec 31, 2020. Time stamps for admission, blood bank, and apheresis processes were extracted from the electronic medical record and blood bank database. Categorical variables were analyzed using nonparametric tests. Results: Thirty-eight patients were included (65.8% males, 35.2% females) (Table 1). HbSS was the most common SCD genotype represented (81.6%). Most patients (71.1%) were transferred from another hospital, with the remaining patients arriving through the emergency department (26.3%) and one (2.6%) as a direct admission from clinic. ACS +/- additional complications constituted the most common indication for RBCX (78.9%). Two patients died due to complications of multi-organ failure, the remaining patients were discharged from hospital. Six patients (15.8%) had a positive antibody screen. The majority had RBC phenotype (42.1%) or genotype +/- phenotype (36.8%) on file to facilitate extended matching, and sufficient appropriate units were available in the blood bank in 82% of cases. Four (10.5%) patients required top-up transfusions prior to RBCX due to significant anemia. The median number of units issued per procedure was 9 (IQR 2). The median times from index group and screen (G&S) collection to sample accession, and from accession to result were 23 minutes (IQR 26) and 46 minutes (IQR 31), respectively (Figure 1). The median time from G&S result to RBC units issued was 348.5 minutes (IQR 479). The median total time from patient admission (or determination of RBCX indication) to RBC units issued was 569 minutes (IQR 464). A positive antibody screen, patient origin (ED vs. transfer), and the availability of sufficient RBC units in house were associated with turnaround time from accession of the index G&S sample to the issuing of RBCs (p<0.01 for all). Patients having antibodies to high prevalence antigens (e.g. anti-U) or to multiple targets (demanding unique donor profiles) had some of the longest times to initiate treatment. These constraints necessitated orders and coordinated deliveries of units from across the geographic network of the national blood provider.Discussion: These data from the largest apheresis unit in the country characterize the time invested in blood preparation for an urgent RBCX for acute SCD complications. A positive antibody screen is predictive of increased time to procedure start, reflecting delays inherent to serologic investigations, product sourcing, and serologic crossmatch times. While the precise moment of a blood request was available for a minority of patients, the G&S time stamp was used as a surrogate, thus potentially overestimating turnaround times in the blood bank. Nevertheless, the serologic demands inherent to a case present a tension between speed (treating the disease) and safety (averting immune rejection reactions).

Predicting Hemoglobin Response to Hydroxyurea and Voxelotor in Adults with Sickle Cell Disease

Background: Chronic anemia contributes to morbidity and mortality in sickle cell disease (SCD) and is associated with stroke, leg ulcers, pulmonary hypertension (PH), priapism, and chronic kidney disease (CKD). Treatment options for anemia in SCD are limited - hydroxyurea (HU) is the gold standard treatment, but hemoglobin (Hb) responses to HU in adult and pediatric cohorts appear to be modest at best. We evaluated the Hb response to HU and voxelotor in an adult SCD cohort, as well as baseline factors associated with Hb response to HU. Methods: This longitudinal study was based on retrospective chart review of patients with SCD followed in the UPMC Adult Sickle Cell Program, with drug start dates between 2007 and May 2023. Subjects with a documented start date for HU/voxelotor, a baseline Hb ≤ 3 months prior to starting drug, and a follow-up Hb at 1 or 3 months (± 2 weeks) after the start date were included. Those who self-discontinued therapy were excluded. Baseline factors were collected within ≤ 3 months of drug start date. Given the small number of subjects on voxelotor, factors associated with Hb response were evaluated in the HU group only. Baseline factors were reported using descriptive statistics and compared between Hb responders (defined as Hb increase ≥ 1 g/dL from baseline - a common outcome measure in clinical trials of anti-polymerization agents) and non-responders. Linear regression analysis was performed with change in Hb at 1 month (ΔHb) as the outcome of interest, as Hb levels at 1 and 3 months were highly correlated (r=0.905, p<0.001) and there were fewer missing values for Hb at 1 month. Variables associated with ΔHb with p<0.25 were included in a multivariable regression model. P<0.05 was considered significant, and 95% confidence intervals (CI) were reported. Results: Out of 394 subjects, 93 met eligibility criteria, including 88 starting HU and 5 starting voxelotor. One subject in the voxelotor group was on stable-dose HU. Median ages at start of HU and voxelotor were 24.5 years (range 13-57) and 45.4 years (range 22-60), respectively. Females accounted for 50/88 (56.8%) HU subjects and 4/5 (80%) voxelotor subjects. HbSS genotype made up 47/88 (53.4%) of the HU group and 4/5 (80%) of the voxelotor group. Median baseline Hb in the HU group was 9.8 g/dL, with a median increase of 0.2 g/dL and 0.3 g/dL at 1 and 3 months, respectively. In contrast, baseline Hb in the voxelotor group was 7.2 g/dL with a median increase of 1.9 g/dL and 2.1 g/dL at 1 and 3 months, respectively. Hb response was observed in 21/88 (24%) subjects in the HU group vs. 4/5 (80%) subjects in the voxelotor group. Among responders, median Hb increase was 2.2 g/dL (1 month) and 2.0 g/dL (3 months) with HU. Median baseline ferritin was 200 ng/mL in the HU group and 2413 ng/mL in the voxelotor group. In the HU group, lower baseline Hb was associated with female sex, severe SCD genotype (HbSS, HbSβ 0), and higher HbS%, WBC count, platelet count, and hemolytic markers (lactate dehydrogenase, total bilirubin, and reticulocyte count) (data not shown). Demographic/clinical variables were not associated with Hb response, except for male gender at 3 months (Table 1). Lower baseline Hb, RBC count, and hematocrit and higher MCHC, HbS%, LDH, and total bilirubin were associated with positive Hb response at 3 months. HbF% was higher in the responder groups but was not significant. In a multivariable linear regression model including age, PH, leg ulcers, CKD, baseline Hb, platelets, and total bilirubin as explanatory variables, baseline Hb was negatively associated with ΔHb (B = -0.26, CI = -0.40 to -0.12, p<0.001). History of leg ulcers was also negatively associated with ΔHb but was not significant (B = -0.94, CI = -2.01 to 0.13, p=0.083). Conclusion: Overall, Hb response to HU was much lower compared to voxelotor, though in the 24% of subjects who responded to HU, the Hb increase was comparable. Though limited by small sample size, our data revealed that patients started on voxelotor vs. HU were older, more anemic, and more iron overloaded. Subjects with lower baseline Hb had a more robust Hb response to HU. While limited by the absence of dosing and adherence data, this study provides proof of concept of using baseline characteristics to predict Hb response to SCD therapies, demonstrating the feasibility of a personalized treatment approach in SCD. In addition, our data provide real-world evidence of the effectiveness of HU vs. voxelotor for chronic anemia in SCD.

Patterns of Emergency Department Utilization of Adolescents and Young Adults Living with Sickle Cell in North Carolina

Introduction Despite improvements in survival and life expectancy in high-income countries, adolescent and young adults (AYAs) living with sickle cell disease (SCD) remain at significant risk for morbidity and mortality. Our previous work using group-based trajectory modeling (GTBM) has demonstrated that a subset of AYAs with SCD are at risk for significant morbidity with SCD with increased healthcare utilization, vasoocclusive pain episodes, and death, particularly after transition to adult care (Kayle et al., Pediatric Blood & Cancer, 2018). Yet, there is limited insight into which AYAs with SCD are at high risk for poor outcomes. The objective of this study was to identify patterns of emergency department (ED) utilization of AYAs with SCD in NC as individuals age, with the overarching future goal of better predicting which individuals are at highest risk. Methods The NC Hospital Discharge Data (Inpatient, Ambulatory Surgery/Outpatient and ED Databases), 2013-2020 were used. A patient with SCD was defined as a patient who had three or more visits (inpatient, ambulatory surgery, or ED visit) with International Classification of Diseases 9 or 10 codes for SCD within a 5-year period. Date of birth, sex and zip code were used to link patients across the datasets. Demographic variables including age, sex, race and ethnicity were extracted from visit level data. ED visits were defined as all ambulatory ED visits and ED visits that resulted in inpatient admissions between 2013 and 2019. Descriptive statistics were calculated to describe the sample characteristics such as sex and race. The number of ED visits per year across age 14 to 30 years were used as longitudinal variables in GTBM to identify trajectories of latent classes of ED visits. The number of latent classes was determined by model-fit indices such as BIC and entropy. Results There were 3643 participants included in this study. Participants were 95% Black or African American, 53.8% female and 46.2% male, with age ranging from 14-30 years. Our GTBM models identified three latent classes of participants (Figure 1) with similar ED utilization at age 14 years, but divergent predicted annual ED trajectories beginning around 18 years of age. Class 1, comprising 95% of the participants (n=3463) and 54% female, had minimal ED utilization throughout all the years. Class 2, comprising 4% of the participants (n=150) and 51.3% female, had a steady increase in annual ED use, peaking at 20 visits per year by at age 24 years. Class 3, comprising 0.8% of the participants (n=30) and 47% female, had more extreme ED utilization, up to 80 visits per year at age 24 years. Conclusions Using a large longitudinal dataset, we demonstrate distinct patterns of ED utilization among AYAs with SCD by age. Although ED utilization was similar between the groups at age 14 years, a small proportion (~5%) of individuals accounted for the highest ED utilization at older ages. Additionally, amongst the patients with highest ED utilization, there was a marked increase in ED utilization from age 18-24 years, highlighting the highest risk ages within the AYA population, when there is often a transition from pediatric to adult care. There were slightly more males in the highest ED utilization class, highlighting potential gender differences in ED utilization. Our next steps will be to assess which clinical and social factors predict ED utilization trajectory. Limitations in this study include the use of hospital discharge datasets, which may have limited the capture of patients with infrequent acute care visits and limited our ability to examine the role of SCD genotypes and disease-modifying therapy use on ED utilization patterns. Despite these limitations, the study identifies distinct classes of ED use among AYAs with SCD. Understanding and predicting patterns of ED utilization are critical in targeting early interventions towards individuals with the highest risk of healthcare utilization and disproportionate risk for future morbidity.

Utilization of Pharmacologic and Non-Pharmacologic Therapies for Pain in Sickle Cell Disease: A Cross-Sectional Study

Background: The sickling deformity of red blood cells in sickle cell disease (SCD) results in multisystem sequelae, including severe, acute pain from vaso-occlusive crises (VOCs) and chronic pain from central sensitization. Pain is the main cause of poor quality of life and hospital admissions among patients with SCD. While opioid therapy is an important component of treatment for acute SCD pain, it can be complicated by side effects and toxicities. In contrast, chronic SCD pain is best managed with non-pharmacologic therapies. A multimodal, multidisciplinary approach to pain management that promotes non-pharmacologic therapies can improve the quality of care for patients with SCD by addressing biopsychosocial components of the pain experience and is recommended by the American Society of Hematology (ASH). This study examines current usage of pharmacologic and non-pharmacologic therapies among Adolescents and Young Adults (AYAs) with SCD receiving care at our institution. Methods: The electronic medical record and Sickle Cell Knowledgebase, a customized data visualization platform unique to our institution, were utilized to conduct a retrospective chart review of AYAs, ages 13-21 years of age, with SCD from 2016-2021. Data collected included demographic information, diagnosis of chronic pain, emergency department (ED) visits and inpatient admissions for VOCs, as well as pharmacologic and non-pharmacologic therapies utilized in the ED, inpatient setting, and, for patients with chronic pain, in the outpatient setting. Results: The cohort included 90 AYAs with SCD (73% were 13-17 years old). The most common SCD genotypes were HbSS (n=47, 52%) and HbSC (n=32, 36%). The majority were female (n=53, 49%), Black (n=85, 94%), and non-Hispanic (n=86, 96%). There were 95 ED visits for VOC, where the patient was subsequently discharged home, and 246 admissions for VOC during the study period. There was a high frequency of opioid interventions for VOCs during the 95 extracted ED visits (81.8% in 2016, 91.7% in 2021). During VOC admissions, there was consistent use of opioids in 100% of admissions from 2016-2021 with increasing utilization of patient-controlled analgesia (7.7% in 2016, 45.1% in 2021) and subanesthetic ketamine (0% in 2016, 18.3% in 2021) each year during the study period. Compared to pharmacologic measures, non-pharmacologic therapies (i.e., healing touch, massage, art therapy, child life, music therapy, occupational therapy, physical therapy, psychology) were less utilized during VOC admissions. While healing touch and child life therapy were ordered during approximately 85% of VOC admissions, they occurred <50% of the time. All other integrative therapies were ordered between 5-55% of admissions each year and occurred <50% of the time. There was no correlation between length of hospital stay and use of integrative therapies. Seven patients with a diagnosis of chronic pain were identified. All 7 received non-pharmacologic therapies in the outpatient setting, including cognitive behavioral therapy, guided imagery, and psychology consultation. Six received either a gabapentinoid, serotonin and norepinephrine reuptake inhibitor (SNRI), or tricyclic antidepressant (TCA). Conclusion: Per the ASH SCD guidelines, non-pharmacologic therapies are recommended for SCD-related pain. In our cohort, we found that non-pharmacologic therapies occurred in <50% of VOC admissions and were underutilized for SCD-related pain in AYAs when compared to pharmacologic therapies at our institution. Though we speculate that healing touch and child life were frequently ordered as a default within our admission order set, utilization rates were still low. To better understand barriers to non-pharmacologic therapies in SCD, we are conducting qualitative interviews of patients, caregivers, and healthcare providers using the Consolidated Framework for Implementation Research (CFIR) as a theoretical model. Understanding barriers to the use of non-pharmacologic therapies will be essential to maximizing their implementation and hence maximizing pain control, improving quality of life, and increasing self-efficacy.

Patient, Caregiver, and Healthcare Provider Perspectives on Pharmacologic and Non-Pharmacologic Therapies for Pain in Sickle Cell Disease

Background: Pain is the main cause of poor quality of life among patients with sickle cell disease (SCD). While opioid therapy is the mainstay of treatment for acute SCD pain, it can be complicated by side effects and toxicities. A multimodal, multidisciplinary approach to pain management that promotes non-pharmacologic therapies can improve the quality of care for patients with SCD by addressing biopsychosocial components of the pain experience. Guided by the Consolidated Framework for Implementation Research (CFIR), this study utilized qualitative interviews with patients, caregivers, and healthcare providers at our institution to assess barriers to the use of non-pharmacologic and pharmacologic therapies for pain in SCD. Methods: Semi-structured qualitative interviews were conducted with adolescents and young adults (AYAs; ages 13-21) with SCD, caregivers of AYAs with SCD, and healthcare providers at our institution. AYAs had either a documented history of chronic pain and/or ≥1 admission/year for vaso-occlusive crises (VOCs) for at least one year from 2016-2022. After informed assent and/or consent were obtained, individual semi-structured interviews were conducted. Open-ended interview questions explored existing knowledge, perceptions, and barriers to pharmacologic and non-pharmacologic therapies for pain in SCD. Interviews proceeded until no new themes emerged in each group (i.e., thematic saturation). Interviews were analyzed using descriptive content analysis facilitated by Dedoose software. The CFIR and prior research informed a preliminary codebook, which was revised as new themes emerged. The coders independently coded transcripts and then met to discuss and resolve any discrepancies in coding. Results: Demographics: Eighteen AYAs, 17 caregivers, and 22 healthcare providers were interviewed. Of the AYAs, 61% were female, mean age was 17 years, and the most common SCD genotype was HgbSS (56%). Of the caregivers, 88% were mothers, with a mean age of 43 years. There were 15 AYA/caregiver dyads who participated. The following healthcare providers who care for patients with SCD were interviewed: physicians (31%), nurse practitioners (14%), nurses (14%), child life specialists (14%), psychologists (9%), art therapists (4.5%), healing touch providers (4.5%), physical therapists (4.5%), and social work (4.5%). Themes: Barriers to the use of non-pharmacologic therapies for pain management in SCD can broadly be grouped into two major themes: lack of knowledge about options and lack of access to non-pharmacologic options. Regarding lack of knowledge, most AYAs and caregivers endorsed a lack of knowledge about specific non-pharmacologic therapies (e.g., yoga therapy, healing touch, acupuncture), including their benefits, risks, and their abilities to reduce pain. Like AYAs and caregivers, many healthcare providers had limited knowledge about specific non-pharmacologic therapies and the evidence in support of their usage. Regarding lack of access to specific options, the majority of participants questioned the ability of patients to access non-pharmacologic options for pain management including availability of options and cost of access. Additional themes included a desire for more education about pain and pain management options. AYAs and caregivers were particularly interested in more information about yoga. Additionally, AYAs and caregivers were interested in education early in life before pain episodes occurred. Conclusions: Emerging themes among all groups include an interest in non-pharmacologic therapies for pain in SCD, but with limited knowledge on benefits, risks, options, and access to these therapies. As the American Society of Hematology (ASH) guidelines recommend non-pharmacologic therapies for sickle cell pain, it is crucial to implement these therapies into the management of pain in SCD. Education about different options paired with implementation options for ways to incorporate non-pharmacologic therapies is necessary to optimize pain control and improve quality of life. A particular focus on yoga therapy, with availability of a yoga therapist in medical settings, and organized yoga education events specific for SCD may be beneficial to engage individuals in yoga therapy with a trained yoga-therapist. As a next step, evaluation of these potential implementation strategies will occur within our health system.

Drepadom - a Homecare Protocol for Vaso-Occlusive Crisis for Sickle Cell Disease Patients

INTRODUCTION Vaso-occlusive crisis (VOC) is first cause of emergency room (ER) admissions and hospitalizations for sickle-cell disease (SCD) patients. Acute chest syndrome (ACS) is a complication that can occur during VOC and prolong hospitalization, and is the main cause of death in SCD patients. The PRESEV score (Bartolucci - eBioMed 2016), established by our team, allows physicians to evaluate the risk of developing ACS and is calculated upon arrival to the ER and has been validated by an international multicenter study in five different countries (PRESEV 2 - ASH 2020). During the Covid-19 pandemic, we set up a temporary system to monitor VOC patients at home using a telephone hotline and homecare services. The success of this system led to the establishment of DREPADOM, a home-care protocol for VOC management for patients with low risk of developing ACS, or who can be discharged early from the hospital, as standard care (DREPADOM - ASH 2021). Since 2021, Drepadom has been successfully running in seven hospitals in the Parisian region. DESCRIPTION OF SETTING Drepadom has two inclusion modes: 1/ Patients arriving at the ER for VOC with a PRESEV score ≤ 6 and not presenting any exclusion criteria; 2/ patients that are discharged early following hospitalization for VOC and/or ACS (after at least 3 days of hospitalization for patients with PRESEV > 6 upon ER arrival). The Drepadom homecare protocol is activated by a coordinator, who coordinates delivery of PO opioids and parenteral treatments, and a home oxygen concentrator, to the patients' home within four hours. Drepadom uses an online platform and mobile app (Link4Life), where the patient's medical record is shared to the homecare nurse who will perform house calls twice a day. During each visit, the nurse enters the patient's vitals into the app, which are monitored by an on-call SCD expert physician. The online platform also hosts a secure messaging service where nurses, doctors and coordinators can communicate in real-time regarding patient status and care, as well as an automatic alert system that is triggered when vitals fall outside of a predetermined range set by SCD experts. Patient safety is further ensured with a daily calls to the patient using a decision-making algorithm supervised by SCD experts, who arbitrate according to the evolution of the situation (stopping/continuing outpatient follow-up vs. rehospitalization). RESULTS Over a 30-month period we had 209 inclusions for 170 patients into DREPADOM. Of these, 105 were inclusions from the ER and 104 were early discharges (ED). SCD genotype distribution was 83.2% SS, 10.5% SC, and 5.8% S-bThalassemia and female to male ratio was 128:81. In both ER and ED groups, median age was 31 [27-40], 74% of patients were under hydroxyurea treatment and median homecare follow-up duration was 3 [2-4] days. No significant differences in population characteristics were found between the ER and ED groups. In the ER group, 96/105 patients (91.4%) were included with PRESEV ≤ 6. 9/105 (8.6%) patients were included with a PRESEV score >6 only in 2021 during the Covid-19 pandemic, when the ER was saturated. In the PRESEV ≤ 6 group, 9/96 (9.4%) patients were rehospitalized: 1 for ACS (PRESEV = 4), 4 for uncontrolled VOC pain, 2 for chest pain, 2 for fever/infection unrelated to VOC. In the PRESEV >6 group, 3/9 (33%) were hospitalized, one for ACS (PRESEV = 8), one for uncontrolled VOC pain and one for issues with veinous access. In the ED group, patients were hospitalized for a median of 4.5 [3-7] days before being discharged. 27 patients (26%) were included in a post-ACS context. 48/104 (46.2%) had a PRESEV ≤6, of which only 2/48 (4.2%) were rehospitalized for uncontrolled VOC pain. Of the 56/104 (53.8%) patients included with a PRESEV > 6, 8/56 (14.3%) were rehospitalized: 1 for ACS, 3 for uncontrolled VOC pain, 1 for chest pain, 1 for fever/infection unrelated to VOC, 1 for issues with veinous access, and 1 for morphine withdrawal symptoms. For both ER and ED groups, a total of 22/209 patients (11%) required rehospitalization (Figure 1), and no deaths or ICU were reported in either group. PERSPECTIVES Our results confirm that Drepadom is a successful and safe tool to reduce hospital stay for SCD patients.

Incidence of Maternal and Perinatal Morbidity in Sickle Cell Disease and Sickle Cell Trait Patients during Pregnancy

Background: Sickle cell disease (SCD) patients have a higher risk of maternal and neonatal morbidity during pregnancy than the general population. Pregnancy in SCD is associated with increased metabolic demands, a hypercoagulable state, endothelial dysfunction, severe anemia, and increased vaso-occlusive episodes. We designed a study to retrospectively review the clinical outcomes of pregnant patients with SCD and SCD trait to examine the incidence of maternal and perinatal morbidity and mortality. We hypothesized that SCD patients should have a higher morbidity during pregnancy and SCD trait patients should not have higher morbidity. Methods: We conducted a retrospective cohort study and reviewed 29,822 patient encounters. Pregnant patients with the SCD genotype - Hb SS, Hb S beta 0 thalassemia, Hb S beta + thalassemia and Hb SC disease, and sickle cell trait (SCD trait) - Hb AS were included. Maternal clinical outcome variables for the entire pregnancy duration were vaso-occlusive crisis (VOC), deep vein thrombosis (DVT), pulmonary embolism (PE), infections - sepsis, septic shock, asymptomatic bacteriuria, acute pyelonephritis, and urinary tract infection (UTI), cerebrovascular accident (CVA), myocardial infarction (MI) and transient ischemic attack (TIA). Clinical outcome variables for pregnancy complications were preeclampsia, gestational diabetes mellitus (GDM), and C-section rate. Clinical outcome variables for neonatal complications included preterm birth and low birth weight. ICD 9 and ICD 10 codes were used to search for the pregnancy, SCD, sickle cell trait, maternal and neonatal outcomes. Data was collected from the Health Facts Database, which contains de-identified information from electronic medical records (EMR) of hospitals in which Cerner© has a data use agreement. The categorical clinical outcome variables were analyzed using Chi-square test. Results: There were 29,822 patient encounters reviewed. Patients with SCD had higher percentages for C-section rates, CVA, preeclampsia, sepsis, septic shock, and VOC compared to those with SCD trait. C-section rates were higher in SCD patients with 76.43% versus 13.76% in SCD trait patients. CVA was higher in SCD patients with 73.78% versus 0% in SCD trait patients. Preeclampsia was higher in SCD patients with 75.92% in SCD patients versus 5.43% in SCD trait patients. Sepsis and septic shock were higher in SCD patients with 73.75% in SCD patients versus 0% in SCD trait patients. VOC was evident in SCD patients with 0.06% versus 0% in SCD trait patients. Patients with SCD trait had higher percentages for asymptomatic bacteriuria, GDM, low birth weight, preterm birth, and UTI compared to patients with SCD. Asymptomatic bacteriuria was higher in SCD trait patients with 0.25% versus 0.08 in SCD patients. GDM was higher in SCD trait patients with 3.09% versus 0% in SCD patients. Low birth weight was higher in SCD trait patients with 0.61% versus 0.17% in SCD patients. Preterm birth was higher in SCD trait patients with 0.78% versus 0.44% in SCD patients. UTI was noted in SCD trait patients with 0.02% versus 0% in SCD patients. There were no findings for DVT, PE, acute pyelonephritis, MI, and TIA in both SCD and SCD trait patients. Conclusion: Pregnant patients with SCD were more likely to have C-sections, CVA, preeclampsia, sepsis, septic shock, and VOC. Pregnant patients with SCD trait were more likely to have asymptomatic bacteriuria, GDM, low birth weight, preterm birth, and UTI. Our findings indicate that prevention and management of CVA, preeclampsia, sepsis, and septic shock is important for pregnant patients with SCD to prevent adverse maternal and neonatal outcomes. The higher rate of C-sections may have been to reduce the severity of maternal and perinatal morbidity in SCD patients. Our study has significant limitations - retrospective nature and use of ICD9 and ICD10 codes for clinical outcome variables. Certain clinical outcome variables, such as CVA, sepsis or septic shock, may have been overestimated as these diagnoses may have been recorded prior to the start of pregnancy in the EMR. Nevertheless, SCD patients have higher maternal and perinatal morbidity that needs to be addressed.

A Retrospective Study Evaluating the Association of Qualitative and Quantitative Aspects of Vaso-Occlusive Crises (VOC) with Length of Hospital Stay in Children with Sickle Cell Disease Hospitalized for a VOC

Background: Children with sickle cell disease (SCD) are at risk for developing a vaso-occlusive pain crisis (VOC) due to sickled red blood cells causing turbulent blood flow and obstruction within the vasculature, leading to local tissue infarcts and subsequently pain. A VOC can often be managed with analgesics and supportive care either at home or in the emergency room. However, sometimes the pain is not adequately controlled in those settings, so children require hospitalization for further management of their VOC. There exists a high degree of variability in length of hospital stay (LOS) among children who are admitted for VOCs. The purpose of this study is to determine which factors are associated with decreased or increased length of hospital stay (LOS). By identifying these factors, it will allow for a more targeted approach to VOC management with the goal of improving overall pain and reducing LOS. Methods: This 3 year (2019 - 2022) retrospective cohort study includes 88 patients (5 years to 27 years of age) with sickle cell disease (HbSS, HbSB0, HbSB+, HbSC) who were hospitalized for VOC management. Several variables were analyzed to determine if they correlated with LOS. These variables included SCD genotype, age, sex, pain scores, average hemoglobin and reticulocyte levels during hospitalization, pain medication dosage and frequency, blood transfusions and complications during hospitalization. The statistical analysis of these variables was conducted across all VOCs of all patients. Results: There were 289 hospital admissions for VOCs with a mean of 3.55 hospital admissions per patient among the 88 patients with SCD during study duration. LOS for these VOC hospital admissions ranged from 1 day to 10 days with an overall mean of 3.81 days per hospital admission. LOS was independently highest in females (mean LOS = 4.123 days, F (1, 287) = 6.415, p = .012) and patients who developed acute chest syndrome (mean LOS = 6.333 days, F (9, 277) = 4.771, p < .001). LOS positively correlated with pain scores (r 2 = .272, p = .002), number of blood transfusions (r 2 = .229, p < .001) and total units of blood transfused during admission (r 2 = .230, p < .001) and negatively correlated with morphine frequency (r 2 = -.125, p = .042) and average hemoglobin during admission (r 2 = -.142, p = .016). SCD genotype, age, reticulocyte levels and medication dosage were not found to have a statistically significant association with LOS. Conclusion: Our study showed that factors such as higher average pain scores, number of blood transfusions, total units of blood transfused, females and acute chest syndrome were associated with longer LOS. Other factors such as more frequent morphine administration and higher average hemoglobin levels were associated with shorter LOS. While this study provides initial insight into some of the factors that are associated with LOS in children with SCD admitted for a VOC, further studies are warranted to determine if these factors can be used to risk stratify patients in terms of severity of VOC and thereby better optimize and individualize their pain management.

Primary Analysis of Spartan: A Phase 2 Trial to Assess the Efficacy and Safety of Crizanlizumab in Patients with Sickle Cell Disease Related Priapism

Introduction: Priapism is a painful, sustained penile erection that occurs in 35% of adult men with sickle cell disease (SCD) and may result from the underlying mechanism of vaso-occlusion. To date, there is no effective disease-modifying drug proven to treat priapism. Crizanlizumab is a monoclonal antibody that binds and blocks P-selectin, a key mechanistic component of vascular endothelial adhesion. Based on the results of the SUSTAIN trial, crizanlizumab was approved by the FDA to reduce the frequency of vaso-occlusive crises in patients with SCD aged ≥16 years. In this primary analysis of the Phase 2 SPARTAN trial (NCT03938454), we evaluated the efficacy and safety of crizanlizumab after 26 weeks of treatment in patients with SCD-related priapism. Methods: The SPARTAN trial included male patients aged ≥12 years with all SCD genotypes who experienced ≥4 priapic episodes lasting ≥60 min over the 14-week period preceding screening. Eligible patients also experienced ≥3 priapic episodes during the subsequent 12-week screening period with ≥1 event occurring within 4 weeks prior to the first treatment. After enrollment priapic events were documented through electronic self-reporting tools and validated patient-reported outcomes surveys for 26 weeks and included start/end date, sleep status, duration, non-pharmacological treatment, triggers, emergency department visit, and pain intensity during the screening period. Baseline priapic events were collected for each patient during the 12-week screening period. Patients received crizanlizumab 5.0 mg/kg IV infusion on week 1, week 3, and every 4 weeks thereafter. The primary endpoint was percent reduction from adjusted baseline period in priapic events by 26 weeks. Percent reduction from baseline in priapic events was tested using a one-sided Wilcoxon's Sign Rank test. Hodges-Lehmann estimate of median percent reduction in priapic events (with 95% CIs) was also reported. Results: Data cutoff was March 28, 2023. Of the 36 patients enrolled, 26 (72.2%) were between 18 and 40 years, and the median (range) age was 29 (14-58) years. Most patients were HbSS genotype (n=29, [80.6%]) and more than half were on hydroxyurea (n=21, [58.3%]). Patient-reported history prior to crizanlizumab treatment revealed that more than half of patients experienced priapism daily or every other day (n=21, [58.3%]) and most reported a duration of 1 to 5 h (n=33, [91.7%]). The most common patient-reported emotions at the start of the study were frustration and exhaustion, reported by ≈50% of patients. The median (IQR) baseline number of priapic events adjusted for 26 weeks per patient was 42 (13-73) events ( Table). All patients experienced events lasting 1 to ≤4 h, although some also experienced severe events lasting >4 to 6 h (n=19, [52.8%]) and >6 to ≤12 h (n=11, [30.6%]). In one case, 38 days of screening period baseline data was not reported, resulting in a strong outlier that affected the results ( Patient 1, Figure). Thirty-six patients received ≥1 dose of crizanlizumab, with a median cumulative dose of 35.0 mg/kg over 26 weeks; 5 patients each missed 1 infusion and 1 patient missed 2 infusions. The Hodges-Lehmann estimate of median percent reduction from baseline in priapic events per patient was 46.0% (95% CI: 23.5%-65.4%; P=.068). Twenty-eight patients (77.8%) reported a reduction from baseline in priapic events ( Figure). A subgroup analysis revealed a trend towards a larger percent reduction in events for patients with ≥22 baseline events, possibly indicating that patients with severe disease benefitted more from treatment. The most frequent treatment-emergent adverse event (TEAE) was headache (16.7%). No patients discontinued crizanlizumab prematurely and only one patient withdrew consent by week 26. Conclusions: Primary analyses from the SPARTAN trial showed that patients with SCD-related priapism treated with crizanlizumab over 26 weeks experienced approximately half as many priapic events compared with baseline. There was a trend towards a more significant reduction in frequency of episodes in patients with severe disease. Crizanlizumab was safe and well tolerated, with observed TEAEs consistent with the safety profile seen in other clinical trials. Final analyses of the SPARTAN trial will provide data over 52 weeks and may provide further support for the role of crizanlizumab in reducing frequency of priapic events.

National Long-Term Follow-up of Children with Sickle Cell Disease Diagnosed By Newborn Screening in the Netherlands: Overview of the Morbidity and Mortality

Background: Sickle cell disease (SCD) is a genetic red blood cell disorder associated with increased morbidity and mortality. Newborn screening for SCD was introduced in January 2007 in the Netherlands to enable early diagnosis and initiation of preventive measures. The objective of this study was to assess the effect of newborn screening on the morbidity and mortality of children living with SCD in the Netherlands, 16 years after its implementation. Methods: In this national cohort study all children with SCD diagnosed by newborn screening were included. Patients were followed between 1 January 2007 and 31 March 2023 until end of follow-up, death or successful stem cell transplantation. Following informed consent, data were collected from medical files on SCD genotype, treatment, mortality and development of SCD-related complications. The incidence rate of SCD-complications was presented as lifetime-event per 100 person-years for the total duration of follow-up and for the age categories: 0-4, 5-11, and 12-16 years. Results: In total, 391 out of 540 eligible patients (72%) with SCD were included in all hospitals with patients with SCD under treatment, accounting for 3047 person-years. The mean age at the end of follow-up was 7.8 years (SD±4.5). The majority of patients had SCD genotype HbSS (58%), followed by HbSC (28%). As for the mortality, five patients died during follow-up, primarily at or below the age of 2 years (4/5, 80%). In three patients, the cause of death was related to SCD, including infection (n=2; aged 1.2 and 2.0 years) and acute splenic sequestration (n=1; 2.0 years). The SCD-related complications are presented in Table 1. The most common SCD complication in this cohort was vaso-occlusive crisis (including dactylitis) with hospitalization. SCD-related complications that mainly developed within the first 4 years of life, were vaso-occlusive crisis, acute hemolytic crisis, aplastic crisis, severe infections, splenic sequestration and ischemic cerebral infarction. Acute chest syndrome occurred equally in all age categories. Other SCD-related complications developed to a lesser extent in our cohort, and at a later age in adolescence or adulthood. Conclusion: In this cohort of neonatally screened children with SCD, a substantial number of SCD-complications occurred in the first 4 years of life. This study underlines the importance of parental education and 24/7 availably, high level acute specialized clinical care for these children from birth on. Further analysis to identify risk factors at young age for a severe phenotype will be conducted, to enable more targeted interventions in a timely manner. Hopefully, this will lead to reduction of disease burden, improving the quality of life in children living with SCD in the Netherlands.

Radchip: A Laminin-Lined Red Blood Cell (RBC) Adhesion Device for Functional Characterization and Clinical Evaluation of Sickle RBCs at Steady-State

Sickle cell disease (SCD) is a genetic disorder caused by a point mutation in the beta-globin gene producing an abnormal hemoglobin (HbS) which, under deoxygenation, polymerizes and causes severe distortion of the red blood cell (RBC). RBCs may be dehydrated, poorly deformable and highly adhesive to the endothelium, with abnormal adhesion being of primary interest to this study. Recently, several new disease modifying drugs have been FDA approved, with more in development. These novel agents target specific aspects of SCD pathophysiology, including adhesion. Changes induced by such therapies are not always detectable by common conventional lab instruments. LORRCA (oxygen-gradient ektacytometry) is the gold-standard for deformability measurement; it has been well described both analytically and clinically in SCD. Adhesion and deformability have a dynamic, yet complementary relationship that we explore here. While these may behave in an interdependent manner, each determinant must be considered independently. There is a growing demand for innovative tools to evaluate rheological properties under physiological conditions, particularly microfluidic devices. However, many current devices are limited in their clinical utility due to, choice of ligand, complexity of design, or reliance on endothelial cell culture (typically HUVEC cells) which are difficult to use, vary with passage number, and do not represent adult SCD endothelium. We developed a Red blood cell Adhesion Chip (RAdChip) to model RBC to endothelial adhesion using laminin, a physiologically relevant ligand, to easily, effectively, and reproducibly measure RBC adhesion. Here, we describe our analytic and clinical validation of our device. Peripheral blood samples were collected in EDTA from individuals with SCD and healthy controls under an IRB approved protocol. RBCs were extracted via centrifugation, washed and resuspended in PBS to a 0.5% HCT. Microfluidic devices were fabricated using polydimethylsiloxane (PDMS). A 5ug/ml solution of recombinant laminin was applied to each channel, then blocked with 1% bovine serum albumin (BSA). Resuspended RBCs were introduced to the device through tubing connected to the inlet port. Harvard Apparatus syringe pumps were used to perfuse samples and wash channels at ~1dyne/cm 2. Adhesion was visualized with a Keyence inverted bright-field microscope at 20x (Itasca, IL). Adhered cells were counted within a 1.8mm 2 region of interest (Roi) using the iCLOTS automated cell quantification software (Fay et al, Nat comm accepted 7/2023). We measured adhesion index via RAdChip for common SCD genotypes: HbSS/SB0: (median (x͂) =756; range (r): 154-1889; n=26) HbSC/SB+ : (x͂ =299; r=: 114-731; n=11 ) HbAA: (x͂) =13; r= 5-90; n=7). RBC adhesion values were independent of age (p=0.65) and gender (p=0.63). An increase of 0.1 unit in EImin and EImax decreases RBC adhesion by 214 and 268 cells/mm 2, respectively. A 1mmHg increase in PoS increased adhesion by 19.5 cells/mm 2. sRBC adhesion had a significant positive association with vaso-occlusive events (VOE) (p=0.005), absolute neutrophil count (ANC) (p=0.005), and EImax (p<0.001). Notably, analytical validation of RAdChip produced a mean CV of 0.13 ± 0.94. RAdChip adds a key component of functional RBC evaluation that conventional lab equipment does not measure. We have analytically validated our device, demonstrating an excellent coefficient of variability. 44 patient samples, each examined in triplicate produced a mean CV of 0.13. We have demonstrated clinical validity of our device by establishing correlations with known markers of severity and pain event frequency. RBC adhesion values increase as the number of VOE events increase, reaffirming the belief that adhesion is a principal element in the multistep VOE cascade. In like manner, improvements in deformability are associated with decreased RBC adhesion, strengthening the interdependent nature of VOE molecular events. Recognizing the dynamic nature of SCD, it is necessary to explore sickle erythrocyte adhesion longitudinally to investigate changes before, during, and after VOE occurrences. Continued and increased integration of adhesion measurements with RAdChip and other rheology devices into routine SCD care may be helpful in assessing disease severity, identifying need for additional disease modifying agents, and assist with second line agent selection and monitoring.

Analysis of Volatile Organic Compounds in Exhaled Air in Patients with Sickle Cell Disease during Vaso-Occlusive Episodes

Background: Sickle cell disease (SCD) is an inherited red blood cell disorder characterized by hemolytic anemia, inflammation and vaso-occlusion. Due to the process of vaso-occlusion patients with SCD experience unpredictable and painful vaso-occlusive episodes (VOE), causing stress and disruption of daily life. To date, we lack adequate markers to predict the development of a VOE before it occurs. In other conditions such as asthma, exhaled air analyses have shown to be of diagnostic value and may predict exacerbations. In the human body, metabolic processes generate volatile organic compounds, that are first released into the blood, and then exhaled by the lungs. As a result, exhaled air consists of several volatile, organic compounds that may reflect pathophysiological disease processes. As we presently lack urgently needed biomarkers to predict VOEs, the aim of this study was to identify distinctive volatile organic compounds in exhaled air (eVOC) during VOE in patients with SCD, that may serve as predictors of VOE when detected in low quantities as a VOE is evolving. Methods: In this longitudinal, observational single center cohort study, patients with SCD aged 6 years or older were eligible if they were hospitalized for a VOE at Amsterdam University Medical Centers between October 2021 and March 2023. Following informed consent, an exhaled air sample was taken during hospitalization, and one at least 4 weeks after discharge from the hospital (steady state). Clinical data were collected from medical files including demographics, medical history, medication use and laboratory values during steady state, and during hospitalization for VOE. Patients were instructed not to eat, drink or take medication orally 2 hours prior to the measurements. Exhaled air samples were collected in Nalophan bags, and the eVOCs were transferred to stainless steel thermal desorption tubes filled with Tenax GR for analysis by gas chromatography-mass spectrometry. The Wilcoxon signed-rank test was used to test for differences in eVOCs between VOE and steady state. Significantly different eVOCs were tentatively identified by linking raw chromatograms to corresponding metabolites based on NIST-library matching. The significance level was set to 0.05. All analyses were performed using R Studio (version 1.3.1093) software. Results: In total, 25 patients with SCD were included in this study, providing 71 exhaled air samples. The mean age at inclusion was 25.7 years (SD ±10.2). The majority of the participants had SCD genotype HbSS (60%). At time of exhaled air measurement during hospitalization, participants had symptoms for the median number of 1 day (IQR 0.5-3), and the median pain score was 6 out of 10 (IQR 3-7). A total of 58 different fragments could be identified between VOE and steady state (Wilcoxon rank p< 0.05), representing 26 unique eVOCs. The majority of these eVOCs were alkanes, alkenes, and esters. A representing compound for each chemical group is shown in Figure 1. In the majority of the patients, cyclohexane,1,2,4-trimethyl and propanoic acid, ethyl ester were upregulated during VOE, while 1-propene, 2-methyl- was downregulated. Conclusion: This pilot study identified 26 compounds in exhaled air that differentiated VOE from steady state in patients with SCD. Thus, analysis of exhaled air could serve as a promising, non-invasive and patient-friendly biomarker to predict VOE in SCD. Further identification of the discriminative compounds in exhaled air could provide valuable insights into the metabolic processes during VOE.

6 Subjective Sleep Measures and Neurocognitive Outcomes in Pediatric Sickle Cell Disease

Objective:Youth with sickle cell disease (SCD) are at increased risk of neurocognitive difficulties with and without neurological complications. Research has identified disease-related, socioeconomic, and sociodemographic risk factors as independently having significant associations with brain physiology for youth with SCD. Notably, sleep has a profound effect on youth’s neurocognitive abilities including learning, executive function, memory, attention, and processing speed. Furthermore, youth with SCD are at an increased risk for poor sleep measured by self-report questionnaires and by polysomnography (PSG). Within the SCD literature, only a few studies have examined the relationship between sleep and cognition. Of these, the majority examined individuals with SCD and comorbid sleep disorder diagnoses. The aim of this study is to identify associations between subjective sleep measures and neurocognitive outcomes in youth with SCD.Participants and Methods:This study investigated a cohort of 24 youth with SCD (ages 9-16, 11 males, 13 females; HbSS [63%], HbSB+ [8%], HbSC [21%], HbSB0 [8%]) who received sleep questionnaires and a neuropsychological evaluation. Exclusion criteria included a history of neurological disorder (e.g., overt stroke, seizures, or moyamoya disease) or prescribed psychotropic medication. Sleep questionnaires measuring sleep disturbance (e.g., sleep onset, sleep continuity, and sleep quality) and sleep-related impairments (e.g., daytime sleepiness, sleepiness interference with concentration, and difficulty with activities of daily living skills) were collected. Executive function, working memory, processing speed, and verbal comprehension measures were assessed. Demographics and disease-related risk factors were analyzed individually from medical records.Results:All analyses were controlled for age, the time between neuropsychological testing and sleep questionnaires, SCD genotype, and sex. Partial correlations were conducted to explore associations with neurocognitive outcomes. Verbal comprehension was significantly correlated with sleep disturbance (r= -.673, p=.001). Multiple linear regressions revealed that sleep disturbance significantly predicts verbal comprehension (ß= -.572, p=.003). Specifically, verbal comprehension decreased by 4.4 standard points for every one-point increase in sleep disturbance. Additionally, total sleep problems significantly predicted working memory (ß=-.414, p=.044) and processing speed (ß= -.411, p= .046). Specifically, working memory decreased by 3.5 standard points while processing speed decreased by 3.3 standard points for every one-point increase in total sleep problems reported. Sleep parameters did not significantly predict executive function.Conclusions:Results support the association between poor sleep and neurocognitive difficulty in youth with SCD. Three of the participants in this study received a PSG, which further demonstrates the importance of the current findings. This study serves to identify potential risk factors for neurocognitive deficits and provides potential methods for identifying youth with SCD who may need to be referred for a PSG assessment. Research should replicate these findings with increased sample sizes including utilizing PSG and investigating neurobiological effects. Findings may inform future screening tools, treatment approaches, and advanced cognitive initiatives and resources for this population.

Use of consumer wearables to monitor and predict pain in patients with sickle cell disease.

In sickle cell disease (SCD), unpredictable episodes of acute severe pain, known as vaso-occlusive crises (VOC), disrupt school, work activities and family life and ultimately lead to multiple hospitalizations. The ability to predict VOCs would allow a timely and adequate intervention. The first step towards this ultimate goal is to use patient-friendly and accessible technology to collect relevant data that helps infer a patient's pain experience during VOC. This study aims to: (1) determine the feasibility of remotely monitoring with a consumer wearable during hospitalization for VOC and up to 30 days after discharge, and (2) evaluate the accuracy of pain prediction using machine learning models based on physiological parameters measured by a consumer wearable. Patients with SCD (≥18 years) who were admitted for a vaso-occlusive crisis were enrolled at a single academic center. Participants were instructed to report daily pain scores (0-10) in a mobile app (Nanbar) and to continuously wear an Apple Watch up to 30 days after discharge. Data included heart rate (in rest, average and variability) and step count. Demographics, SCD genotype, and details of hospitalization including pain scores reported to nurses, were extracted from electronic medical records. Physiological data from the wearable were associated with pain scores to fit 3 different machine learning classification models. The performance of the machine learning models was evaluated using: accuracy, F1, root-mean-square error and area under the receiver-operating curve. Between April and June 2022, 19 patients (74% HbSS genotype) were included in this study and followed for a median time of 28 days [IQR 22-34], yielding a dataset of 2,395 pain data points. Ten participants were enrolled while hospitalized for VOC. The metrics of the best performing model, the random forest model, were micro-averaged accuracy of 92%, micro-averaged F1-score of 0.63, root-mean-square error of 1.1, and area under the receiving operating characteristic curve of 0.9. Our random forest model accurately predicts high pain scores during admission for VOC and after discharge. The Apple Watch was a feasible method to collect physiologic data and provided accuracy in prediction of pain scores.

Evaluation of a prophylactic transfusion program on obstetric outcomes in pregnant women with sickle cell disease: A single centre retrospective cohort study

ObjectiveTo evaluate the effects of a prophylactic transfusion program (TP) on obstetric and perinatal outcomes in pregnant women with sickle cell disease (SCD). MethodsThis retrospective cohort study included all singleton pregnancies among women with SCD in a French university tertiary care center between 1 January 2004 and 31 December 2017. The TP group included patients selected according to the French guidelines who received regular red blood cell transfusions during pregnancy until delivery. The factors associated with TP indication [year of birth, SCD genotype, history of acute chest syndrome and delayed hemolysis transfusion reaction (DHTR) risk score] were taken into account in a propensity score. A composite obstetric adverse outcome was defined associating birth before 34 gestational weeks and/or pre-eclampsia and/or small for gestational age and/or abruption and/or stillbirth and/or maternal death and/or neonatal death. ResultsIn total, 246 pregnancies in 173 patients were analyzed. Twenty-two pregnancies with a history of DHTR were excluded. A higher frequency of TP was found before 2013 [119/148 (80.4%) vs 38/76 (50%); p < 0.001]. Rates of preterm birth before 34 gestational weeks (5.6% vs 19.7%; p = 0.001), vaso-occlusive crisis (36.5% vs. 61.8%; p < 0.001), and acute chest syndrome (6.1% vs. 14.5%; p = 0.04) during pregnancy were decreased significantly in the TP group. Among the groups with and without composite obstetric adverse outcomes, the frequency of TP was 52.6% and 74.7%, respectively [odds ratio (OR) 0.30, 95% confidence interval (CI) 0.09–1.02]. The multivariate analysis shows that the TP was associated with a significant reduction in the risk of composite obstetric adverse outcomes (OR 0.28, 95% CI 0.08–0.97; p = 0.04). ConclusionA red blood cell TP may have an independent protective effect on maternal and perinatal adverse outcomes during pregnancy in women with SCD.

Systematic Literature Review Shows Gaps in Data on Global Prevalence and Birth Prevalence of Sickle Cell Disease and Sickle Cell Trait: Call for Action to Scale Up and Harmonize Data Collection.

Sickle cell disease (SCD) is an inherited monogenic disorder with high prevalence throughout sub-Saharan Africa, the Mediterranean basin, the Middle East, and India. Sources of SCD epidemiology remain scarce and fragmented. A systematic literature review (SLR) to identify peer-reviewed studies on SCD epidemiology was performed, with a search of bibliographic databases and key conference proceedings from 1 January 2010 to 25 March 2022 (congress abstracts after 2018). The SLR followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Meta-analyses, using a binomial normal random-effects model, were performed to estimate global and regional prevalence and birth prevalence. Of 1770 journal articles and 468 abstracts screened, 115 publications met the inclusion criteria. Prevalence was highest in Africa (~800/100,000), followed by the Middle East (~200/100,000) and India (~100/100,000), in contrast to ~30/100,000 in Europe. Birth prevalence was highest in Africa (~1000/100,000) and lowest in North America (~50/100,000) and Europe (~30/100,000). This SLR confirmed that sub-Saharan and North-East Africa, India, the Middle East, and the Caribbean islands are global SCD hotspots. Publications including mortality data were sparse, and no conclusions could be drawn about mortality. The identified data were limited due to gaps in the published literature for large parts of the world population; the inconsistent reporting of SCD genotypes, diagnostic criteria, and settings; and a sparsity of peer-reviewed publications from countries with assumed high prevalence. This SLR demonstrated a lack of systematic knowledge and a need to provide uniform data collection on SCD prevalence and mortality.