Acute Chest Syndrome Research Articles

Longitudinal Trends in Physical Functioning Patient-Reported Outcome Domains for Children with Sickle Cell Disease

Background: Children with sickle cell disease (SCD) often experience pain and have impaired physical functioning. Patient Reported Outcomes Measurement Information System (PROMIS) tools have previously been shown to be valid and responsive to varied states of health for children with SCD. However, there is limited understanding of the trend of patient-reported outcomes (PROs) over time and the factors associated with this trend and time-dependent changes. The objective of this study was to determine the longitudinal trends in physical functioning domains in children with SCD over a three-year time period and identify factors associated with worse PROs. Methods: Our study included a convenience sample of children with SCD recruited from a tertiary care facility during 2017 - 2020. Eligible children with SCD to self-report PROs were 8 years and older and cognitively capable. Validated PROMIS measures were used to assess fatigue, physical stress experience, strength impact and functioning/mobility over time. The PRO questionnaires were administered every 6 months (with time windows to facilitate completeness of data) for three years to obtain longitudinal data. In addition, we collected clinical data including disease management strategy (hydroxyurea use, chronic transfusion), pain medication, prior acute care use for pain (3 years at baseline and 6 months at follow-up) disease complications (overt stroke, acute chest syndrome, priapism) and other comorbidities. Generalized Estimating Equations with patients as clusters were used to determine changes in PROs over time. This model used compound symmetry covariance structure to account for correlations over time and was adjusted for age and other clinical data. Stepwise regression model was used to identify the significant variables associated with PROs. Results: We recruited 170 children with SCD into our study. Of these, 145 (85.3%) had self-report PRO data for more than one time point. The mean age of the cohort was 10.6 (SD 3.3) years, 53.1% were female. Table 1 shows the demographic and clinical characteristics of our study population. The average T-score for fatigue, physical functioning/mobility, stress experience and strength impact were 47.9, 49.1, 57.2 and 41.5 respectively. Figure 1 shows the unadjusted T-scores over time for each of the listed domains. The regression models showed there were no significant changes in scores for fatigue and physical function mobility over time. However, the stress experience [β (time in months) = -0.13 (95% CI = -0.20 - - 0.07), p-value <0.0001] and strength impact B estimate [β (time in months) = 0.13 (95% CI = 0.08 - 0.18), p-value <0.0001] improved over time. Age at enrollment was significantly associated with strength impact where older kids had a higher strength impact [β (age) = 0.49 (95% CI = 0.15 - 0.83), p = 0.005]. However, age was not associated with any of the other physical functioning domains. Disease severity at baseline, as determined by acute care use in the past three years, was significantly associated with stress experience [β (3 or more acute care visits for pain vs none) = 6.32 (95% CI = 1.71 - 10.93), p-value =.007] and fatigue [β (3 or more acute care visits for pain vs none) = 5.31 (95% CI = 0.95 - 9.66), p-value =.03]. The extent of acute care use within 6 months at follow-up time points was significantly associated with worse fatigue [β (acute care for pain within past 6 months) = 2.19 (95% CI = 0.19 - 4.20), p-value = 0.03] and physical functioning/mobility [β (acute care for pain within past 6 months)=-1.76 (95% CI = -3.24 - - 0.28), p-value = 0.02]. Conclusions: Fatigue and functioning/mobility did not change over time in children with SCD. There were slight improvements in stress experience and strength impact, but the clinical significance of these improvements is unknown. Disease severity, as measured by acute care use at baseline, was significantly associated with worse physical health across all domains.

Comorbidities of Sickle Cell Disease with Obstructive Sleep Apnea

BACKGROUND Sickle cell disease (SCD) is a devastating inherited disease process that greatly impairs quality of life and lifespan. It is a common genetic hemoglobinopathy that is vulnerable to hypoxemia due to the sickling property of red blood cells. Desaturation of the hemoglobin S (HbS) molecule leads to the polymerization of HbS, causing the blockage of microvasculature, oxidative stress, and endothelial damage. The clinical sequelae of SCD include vaso-occlusive crisis, hemolytic episodes, and end-organ damage. Obstructive sleep apnea (OSA) is a common but underdiagnosed condition associated with nocturnal hypoxemia due to intermittent upper airway closure. Repetitive episodes of hypoxemia can cause nocturnal sympathetic activation, selectively activate vascular inflammatory pathways leading to endothelial dysfunction, and can impact cardiac output to predispose patients to ischemia. The impact of this pathophysiology on SCD remains unclear and the literature reviews evaluating the relationship of SCD and OSA are scarce. METHODS We performed a retrospective analysis of the Nationwide Inpatient Sample data in adult patients (age greater than 18 years) hospitalized with SCD as the primary diagnosis in 2020 using ICD-10-CM codes. The NIS is the largest all-payer publicly accessible inpatient healthcare database in the United States. We compared the SCD cohort of 164,990 patients to another consisting of SCD with associated secondary diagnosis of OSA, which consisted of 32,998 patients. The Pearson chi-square test and Student's t test were used to assess categorical and continuous variables, respectively. RESULTS Data revealed that patients diagnosed with SCD and OSA had a statistically significant (p < 0.001) greater incidence of comorbidities compared to SCD alone. These included uncomplicated hypertension (29.8 vs 15.5%), complicated hypertension (24.5 vs 10.6%), uncomplicated diabetes mellitus (9.8 vs 3.4%), complicated diabetes mellitus (17.1 vs 5.1%), obesity (38.9 vs 9.2%), peripheral vascular disease (6.0 vs 3.2%), chronic pulmonary disease (39.7 vs 21.1%), chronic kidney disease (10.0 vs 4.1%), coronary artery disease (15.3 vs 5.1%), and heart failure (13.4 vs 5.4%). Illicit drug use was higher (8.4%) in SCD only compared to SCD with OSA (5.1%). CONCLUSION In this study, co-diagnoses of SCD and OSA revealed a greater likelihood of having other comorbidities, typically 2-3 fold. A striking finding is the increased prevalence of complicated hypertension and diabetes mellitus which are known to give way to vasculopathies, a sequela that is unfavorable in patients with SCD. Considering the clinical implications of these comorbidities and concern for overall underdiagnosis of OSA, it may prove beneficial to lower the threshold for OSA screening in patients with SCD who exhibit hypertension, diabetes, obesity, and other disease processes associated with OSA. Furthermore, should OSA screening in patients with SCD prove favorable, a prospective study evaluating outcomes, such as number of hospitalizations due to sickle cell crisis or acute chest syndrome, of patients diagnosed with OSA and subsequently treated with therapeutic measures such as nocturnal continuous positive airway pressure. Likewise, patients with established co-diagnosis of SCD and OSA should have diligent surveillance and treatment of these aforementioned comorbidities.

Comparison of Devices That Measure Sickle Red Cell Deformability

Background With the emergence of novel pharmacologic and gene-based therapies, identifying the rheological and biophysical RBC abnormalities of sickle cell disease (SCD) not captured by clinical laboratory techniques is crucial. Ektacytometry (LORRCA), the current standard to assess RBC function, does not reflect mechanical stress that RBCs experience in capillary microvasculature in the body. The device is costly, requires a nitrogen gas tank, and its use is difficult to translate outside of large-scale laboratory settings. In comparison, the Microfluidic Impedance Red Cell Assay (MIRCA) is a low-cost, portable device that mimics capillary microvasculature with micropillar arrays spaced 3-12 µm apart. Thus, MIRCA measures mechanical deformability, which is more physiologic, mimicking RBCs squeezing through microvasculature. An impedance analyzer calculates the MIRCA Occlusion Index (OI), representing the % occlusion of the chip. Here we compare the MIRCA to the LORRCA, assessing the correlations of OI and Elongation Index maximum (EI) to conventional laboratory tests and SCD related complications. Methods Peripheral blood from 53 adult (n = 28) and pediatric (n = 25) individuals (HbSS = 35, HbSB0 = 6, HbSC = 5, HbSB0 = 1, and HbAA controls = 6) were obtained under an Emory University IRB approved protocol. Patients transfused < 90 days prior were excluded. Hospitalizations / emergency department (ED) visits for pain within 12 months of sample collection were determined by chart review. Samples were collected in EDTA, stored at 4°C up to 48 hours, centrifuged at 500g, washed, and resuspended to a 20% hematocrit to run on MIRCA, an oxygen gradient ektacytometer (LORRCA), and an ADVIA hematology analyzer. Polydimethylsiloxane (PDMS) fabricated MIRCA chips were bonded to a standard glass slide with pairs of gold-sputtered electrodes adjacent to each array. Chips were prepared by perfusing ethanol, 1X phosphate-buffered saline (PBS), and 3% bovine-serum albumin (BSA) in 1X PBS via syringe pump and were incubated overnight at 4°C prior to use. Baseline impedance was taken for a 2-minute perfusion of 1X PBS, then OIs were calculated from impedance values 10 minutes after sample introduction normalized to baseline. The data was analyzed using the Mann-Whitney U test, Spearman correlation, and linear regression. OriginPro (Northampton, MA, USA) and Stata 18 (College Station, TX, USA) were used for the analyses and a p < 0.05 was considered significant. Results The correlation coefficients for OI and EI with laboratory tests (Table 1) and to each other (Figure 1) were comparable (p < 0.05). HbSS/SB0 had higher OIs than HbSC/SB+ (median = 13.7% vs 6.8%, p < 0.01) and HbAA (median = 4.6%, p < 0.01). Patients with ≥ 1 vaso-occlusive events (VOE) in the past year had higher OIs and lower EIs compared to those without a VOE (median = 15.3% vs 9.6%, p <0.01; median = 0.4 vs 0.5, p = 0.02, respectively). Patients that received acute medical care (admission or ED visit) had higher OIs and lower EIs compared to those that did not (median = 15.7% vs 9.8%, p < 0.01; median = 0.4 vs 0.5, p = 0.02, respectively). In multiple linear regression, HbSS/SB0 (p < 0.01), adults (p = 0.01), and DRBC (p < 0.01) were associated with OI while HbSS/SB0 (p = 0.01), DRBC (p < 0.01), hemoglobin % (p = 0.04), absolute neutrophil count (p = 0.02), and VOE+ (p = 0.02) were associated with EI. The models explained 55.2% and 66.8% variability of OI and EI, respectively. Lower Akaike's information criterion (AIC, 186 vs -80) and Bayesian information criterion (BIC, 192 vs -71) of the EI model suggest a higher correlation to conventional laboratory values and clinical features compared to OI; OI may possibly be a unique biomarker that both laboratory tests and LORRCA fail to fully characterize. Conclusion MIRCA OI and LORRCA EI normoxic deformability are correlated to each other, and both show statistically comparable correlations to many parameters associated with SCD severity. Both OI and EI are significantly associated with SCD outcomes like VOE and acute care. Due to lower device size, cost, and relative ease-of-use, MIRCA may be more convenient for routine clinical use and for use in low resource settings where LORRCA costs and requirements hamper implementation. As the addition of chemical hypoxia to MIRCA is now underway, future work will examine OI under hypoxia and its associations with SCD-relevant outcomes like pain events, stroke and acute chest syndrome.

Patient and Parent-Reported Outcomes Post-Treatment with Shmir-Based Lentiviral Gene Therapy for Sickle Cell Disease

Background: Sickle cell disease (SCD) is among the most common monogenic disorders and causes lifelong complications, including vaso-occlusive events (VOEs) and decreased quality of life (QOL). Gene therapy (GT) has emerged as a potential curative therapy for SCD, but its impact on patients' QOL remains underexplored. We previously reported preliminary safety and efficacy data on 6 patients who received autologous CD34+ cells transduced with the BCH-BB694 lentiviral vector (Esrick et al., NEJM, 2021). Here, we report the first results of parent- and patient-reported outcomes (PROs) for 10 patients treated with BCH-BB694 up to 24 months post-infusion. Methods: We evaluated the QOL of 10 patients with severe SCD who received GT with BCH-BB694 as part of a single-center, open-label pilot study. Assessment occurred during patients' scheduled visits for safety and efficacy monitoring at baseline and months 3, 6, 12, and 24. QOL was measured using the Pediatric Quality of Life Inventory (PedsQL) self- and parent-reported questionnaires for children < 18-years old and the self-reported 36-Item Short Form Health Survey (SF-36) for adults ≥ 18-years old. Assessed domains included: physical functioning, pain, emotional functioning, social functioning, school functioning, and general health. The percent change from baseline to post-treatment score (last observation carried forward [LOCF]) was calculated with 95% confidence intervals (CI). Clinically significant improvement was defined as a score increase ≥5%. Other laboratory and clinical data collected at study timepoints included fetal hemoglobin (HbF) measured by high-performance liquid chromatography, VOEs (including vaso-occlusive pain, priapism, and acute chest syndrome), and transfusion frequency. Results: All patients demonstrated elevated HbF levels at LOCF (mean 26.9%, range 11.7-38.2%). Of 10 patients enrolled, 1 was missing baseline data and 9 had sufficient data for analysis. Patients (n=9) were aged 8-27 years at time of BCH-BB694 infusion. Baseline self-reported total scale scores (median 69.6, interquartile range [IQR] 50.1, 77.2) were consistent with baseline PedsQL scores for patients with SCD reported in the literature (median 67.4, IQR 50.0, 83.5) (Panepinto et al., J Pediatr Hematol Oncol, 2008). Average self-reported total scale scores increased at 3 months post-treatment (mean % change from baseline [95% CI]: 21% [3.3% to 38%]) and maintained at LOCF (13% [-10% to 36%]). For the 3 patient/parent pairs, parent-reported total scale scores appeared more variable, with a mean % change from baseline of -1% (95% CI: -40% to 38%) at 3 months and -17% (95% CI: -36% to 1%) at 24 months. Clinically significant self-reported improvement occurred in 8 patients (89%) for at least 1 domain and in 5 (56%) for overall QOL. The patient without baseline data reported a maximum total scale score of 100 at 24-months. Specific domains (mean % change from baseline [95% CI]) demonstrating significant improvement included: general health (7% [-11%, 25%]), physical functioning (30% [-15%, 76%]), and emotional functioning (15% [-9%, 39%]). Excluding 1 patient who had a low HbF induction associated with a low in vivo vector copy number and increase in VOEs from baseline, this cohort demonstrated decreased numbers and/or absence of VOEs post-GT (n=8), and all patients required significantly fewer transfusions. Conclusion: At most recent study visit up to 24 months post-treatment, SCD patients who had received GT with successful HbF induction (>20% in 8 patients) reported higher QOL than baseline on average. Excluding 1 patient, this cohort demonstrated improvement in at least 1 QOL domain following GT, suggesting a positive impact of GT on QOL in this group of patients with SCD. For patients <18-years, discrepancies between parent-reports and higher self-reports warrant future investigation. Few patients (n=3) did not demonstrate overall QOL total score improvement post-GT. Follow up studies may assess whether this reflects insufficient treatment response, treatment- or pre-existing disease-related morbidity, and/or need for more specific QOL assessments. An understanding of the relationship of change in QOL with VOE and/or transfusion rates will be enriched by more patients, longer follow-up, and PRO tools designed specifically for the SCD population. Larger studies are needed to fully elucidate the impact of GT on QOL in this population.

Impact of IV Contrast Exposure during Vaso-Occlusive Crisis on Sickle Cell Disease (SCD)

Background Sickle cell disease (SCD) affects more than 100.000 Americans, that can experience vaso-occlusive crisis (VOC). It can present with signs and symptoms that overlap with pulmonary embolism (PE), e.g. pleuritic chest pain, shortness of breath, hypoxia or sinus tachycardia. Hence, it is not uncommon that patients with SCD are exposed routinely to IV contrast (IV-cx) to rule out PE with every VOC recurrence. We hypothesized that exposure to IV-cx increases blood viscosity temporarily and therefore exacerbates RBC sickling with worsening oxidative stress and VOC. Methods This was a retrospective chart review study, where we analyzed all encounters for VOC at the ED of MedStar Washington Hospital Center in between 2021-2022. We excluded those not admitted to the inpatient service and discharged from the ED, those not exposed to IV-cx to rule out PE and those without 3 other VOC admission without IV-cx exposure to compare as control. Herein, will discuss 33 patients' results. A total of 132 admissions were analyzed for 33 patients (1 with IV-cx + 3 regular admissions without IV-cx exposure), each patient serving as their own controls, acknowledging the heterogeneity of SCD VOC. For control admissions we looked at the 3 closest in time from the admission with IV-cx exposure. Severity of each VOC (with or without IV-cx exposure) was determined by the composite of lab results, clinical and treatment data for each admission, creating our own scoring system “VOC Severity Index” (Table 1). Scores were given from 0-4, >3 representing end-organ damage. Maximum score was 39. Likewise, we collected data on new PE, new DVT, therapeutic anticoagulation, basic demographics and SCD genotype not recorded in the severity index score. Results were analyzed through Graphpad Prism software. This study received IRB approval from MedStar Health Research Institute. Results 54.5% (18/33) were female, mean age was 25 (18-45), 86% were HbSS, and 100% were Black. We compared the severity index of the admission with IV-cx exposure against the mean severity index score of the 3 other VOC admissions without IV-cx exposure. VOC severity index was higher for the admission related with IV-cx exposure in 90% (30/33) patients (p= 0.0004***) (Fig 1A). CT chest with PE protocol was negative in 100% (33/33). No DVT was reported in the totality of 132 encounters. AKI was noted in 15.0% (5/33) of patients when IV-cx was used, vs 7.0% (7/99) when no IV-cx was used. Length of stay was not significantly different (p=0.436) (mean IV-cx stay: 8 days vs. mean non-IV cx stay: 7.8 days) . RBCs exchange transfusion happened in 10% of total encounters analyzed (14/132), being 42% (6/14) of the situations when IV-cx was used. Acute chest syndrome (ACS) developed in 19 admissions of 10 patients (6 female/4 male). Interestingly, 42% (8/19) of ACS happened when IV contrast had been used, and only 7/19 were managed with RBC exchange transfusion. In 1 encounter with IV-cx exposure, patient developed acute chest syndrome and ARDS requiring ECMO, (end-organ damage not reflected in our severity index score). VOC Severity Index means were similar in female vs male patients. Likewise, gender was not related to higher frequency of AKI, exchange transfusion or length of stay. Conclusions IV-cx exposure is associated with worsening in the severity of the VOC, manifested as more severe pain, and need of escalation of treatments, albeit with no increase in the LOS. Iv-cx should be avoided in SCD patients in VOC, when possible. PE should remain low in the differential in the setting of VOC, despite overlapping symptoms. Our findings are limited in the nature of retrospective chart review and small number of patients. Further analysis with prospective larger cohorts are needed for a better understanding on the role of IV-cx exposure, sickle cell renal disease and VOC.

Alkaline Phosphatase As a Marker for Acute Complications in Sickle Cell Disease

Background: Sickle cell disease (SCD) can result in complications affecting multiple organ systems, including renal, pulmonary, and central nervous system. Alkaline phosphatases (ALP) comprise a group of isoenzymes which function to catalyze the hydrolysis of inorganic phosphate monoesters, including phosphoethanolamine, inorganic pyrophosphate, and pyridoxal-5′-phosphate. Predominantly, serum ALP is derived from the liver and bone (1). An elevation in serum ALP primarily signifies hepatobiliary disorders, wherein cholestasis and bile duct damage results in increased enzyme synthesis as a compensatory mechanism. Increased ALP levels can also be an indication of bone disease associated with increased osteoblast activity (2). ALP has been linked to the severity of the pain crisis in SCD (3), and there is also evidence that ALP is a predictor for increased mortality risk in SCD (4-6). This study aims to investigate ALP as a biomarker of SCD severity and acute organ complications (VOE). Methods: This retrospective study included 252 patients aged 18 years or older with SCD who were admitted to the University of Illinois Chicago (UIC) hospital for the management of vasoocclusive pain events (VOEs) between July 1, 2017, and June 30, 2018. The study recorded the following complications during hospitalization: acute chest syndrome, acute kidney injury, acute liver injury, thrombotic or hemorrhagic stroke, deep vein thrombosis or thromboembolism, the need for transfer to the intensive care unit, the need for exchange blood transfusion, or death during hospitalization. Data analyses were performed using the Kruskal-Wallis test, Chi-square test, linear or a stepwise ordinal logistic regression analysis. Results: The median age of this cohort was 31 years (interquartile range 26-42 years), 36% were males and 72% had hemoglobin SS/Sβ0 with 33% on hydroxyurea. In this cohort, 105 patients experienced at least one complication during at least one hospitalization(s) within the one-year study period, while 147 were hospitalized but did not experience complications during the hospitalization (Table 1). A comparison of clinical characteristics between the two cohorts revealed that patients with complications had a higher prevalence of HgbSS/Sβ0-genotype; had higher ALP, total bilirubin, and AST concentrations; Patients with complications had a greater number of hospitalizations and longer length of stay in both the median length and the total length over the study period (Table 2). In a multivariable model comparing baseline characteristics, HgbSS/Sβ0-genotype and increased ALP levels at baseline were significant predictors of complications during hospitalization, after adjusting for other variables as listed in the table (Table 3). Furthermore, in a subgroup analysis of patients with HgbSS/Sβ0-genotype, this relationship was even stronger: higher baseline ALP levels were significantly associated with acute complications during the study period (OR 7.3, 95% CI: 2.2 - 24.1, p = 0.001). Summary: Our findings suggest that SCD patients with longer hospital stay and higher numbers of admissions tend to have acute complications during hospitalization. Individuals with the HgbSS/Sbeta0 genotype and higher levels of ALP are at an increased risk of developing acute complications, which could potentially account for the increased mortality risk associated with alkaline phosphatase reported by previous literature. K. Makris, C. Mousa, E. Cavalier, Alkaline Phosphatases: Biochemistry, Functions, and Measurement. Calcif Tissue Int112, 233-242 (2023).J. Masrour Roudsari, S. Mahjoub, Quantification and comparison of bone-specific alkaline phosphatase with two methods in normal and paget's specimens. Caspian J Intern Med3, 478-483 (2012).J. I. Brody, W. N. Ryan, M. A. Haidar, Serum alkaline phosphatase isoenzymes in sickle cell anemia. JAMA232, 738-741 (1975).J. J. Feld et al., Liver injury is associated with mortality in sickle cell disease. Aliment Pharmacol Ther42, 912-921 (2015).S. A. Curtis, N. Danda, Z. Etzion, H. W. Cohen, H. H. Billett, Longitudinal Analysis of Patient Specific Predictors for Mortality in Sickle Cell Disease. PLoS One11, e0164743 (2016).V. Sachdev et al., A phenotypic risk score for predicting mortality in sickle cell disease. Br J Haematol192, 932-941 (2021).

Clinical and Epidemiological Characteristics of Patients Admitted with Acute Chest Syndrome on a National Scale and Factors Affecting Clinical Outcomes in Inpatient Setting

Introduction Acute chest syndrome (ACS) is a clinical presentation of fever, chest pain, pulmonary symptoms, and new infiltrates on lung imaging. It affects nearly 50% of patients with sickle cell disease during their lifetime and often leads to hospitalization. The mortality rate is variable ranging from 3 to 9 %. and depends on several factors. We aimed to identify the clinical and epidemiological characteristics of patients admitted with ACS on a national scale and factors affecting clinical outcomes in inpatient setting. Methods: We utilized the National Inpatient Sample (NIS) database 2019 for the purpose of this study. Using this database, we identified patients with a principle diagnosis of ACS using International Classification of Diseases (ICD-10) codes. Data on demographic characteristics such as age, sex, race, insurance type were collected. Additionally, we selected clinically significant medical comorbidities such as asthma, chronic obstructive pulmonary disease (COPD), coronary artery disease (CAD), chronic kidney disease (CKD), heart failure, hypertension, diabetes mellitus (DM), sepsis, obesity, and others. The primary endpoint of this study was to identify factors influencing all-cause mortality, while the secondary endpoint was to identify factors influencing mechanical intubation, in-patient blood transfusion, and length of stay. We used multivariate logistic regression analysis to adjust for confounders. A p value of ≤0.05 considered statistically significant. Results: Baseline Characteristics Our analysis consisted of 22,459 patients who were admitted with principal diagnosis of ACS. 49.5% were female and 50.5% were male. Mean age was 30.5 years. African American race was predominant (92%) with sickle cell Hb-SS disease (87%). Major insurance payer was Medicaid (47%) followed by Medicare (27%) and then private insurance (21%). Asthma was the most common comorbidities (24%) and majority of patient had Charlson Comorbidity Index (CCI) score of zero (55%). The details of clinical and epidemiological characteristics are shown in Table 1. Clinical outcomes and factors influencing mortality Only 0.89% patient died of ACS. Average length of stay was 6.86 days. 34% of the patient required packed red blood cell (pRBC) transfusion. 3.2% needed mechanical ventilation. In multivariate analysis, factors associated with mortality included age of patient, CCI and sepsis. Younger patient had higher odds of mortality however this was not statistically significant. There was no difference in mortality with sex, race and insurance status of the patients. Factors affecting inpatient transfusion, mechanical ventilation and length of stay Female, higher CCI score and sepsis on admission were associated with higher needs of inpatient pRBC transfusion. Within race, White (OR 3.16, CI 1.44-6.93, P <0.01) and Hispanics (OR 2.68, CI 1.59-4.51, P<0.01) had higher odds of receiving transfusion compared to African Americans (OR 1.84, CI: 1.17-2.89, P <0.01). Similarly patient with sepsis, supraventricular tachycardia had more odds of needing mechanical ventilation. Patient's insurance status was also related to increased odds of intubation. Comorbidities such as asthma and CAD were not associated with need of mechanical ventilation and in fact our study shows they had less odd of needing mechanical ventilation. Length of stay was influenced by several of epidemiological and clinical comorbidities. Females had less odds of longer length of stay compared to male (OR: 0.65, P <0.01). Comorbidities such as asthma, heart failure, CAD, DM2 and hypertension did not increase the length of stay while patients with sepsis and high CCI score had higher odds of hospitalization for extended period of time. The details are in Table 2. Conclusion We found mortality was 0.89% in patients admitted with ACS compared to 3 to 9% previously reported. Sepsis and CCI were one of the predictors for odds of having higher mortality, need of blood transfusion, mechanical ventilation and increased length of stay in patient with ACS. Female, White and Hispanic had higher odds of needing transfusion then African Americans. Comorbidities such as asthma, heart failure, CAD, DM 2 and hypertension did not increase the odds of prolonged hospital stay.

Apohemoglobin-Haptoglobin Complex Improves Cardiac and Pulmonary Function in Homozygous Townes (HbSS Townes) Mice

The constant ischemia-reperfusion injury and the release of hemoglobin and heme in patients with sickle cell disease (SCD) can affect the heart, lungs, and vasculature. While treatments have improved survival, cardiovascular complications are becoming more prevalent, including pulmonary hypertension and left ventricular diastolic dysfunction. Pulmonary hypertension is associated with increased mortality risk and linked to intravascular hemolysis, leg ulcers, renal insufficiency, iron overload, and liver dysfunction. Chronic anemia leads to heart chamber dilation and left ventricular mass increase, often accompanied by left ventricular diastolic dysfunction, both impacting exercise capacity. Additionally, it can cause Acute Chest Syndrome (ACS), which is characterized by inflammation and blockage of small blood vessels in the lungs. In some cases, the heart may enlarge (cardiomegaly) due to the increased workload it faces in pumping blood through narrowed or obstructed blood vessels. Sudden death is also emerging as a concern, necessitating further cardiac investigations and risk assessment for effective management. These issues are speculated to result from the high amount of hemoglobin and heme released into circulation. In this study, a synthetic protein scavenger for heme and Hb, the apohemoglobin (apoHb) was stabilized with haptoglobin (Hp) to create the apoHb-Hp complex, was used to study the cardiac and pulmonary changes in SCD mice resulting from heme and Hb. Homozygous Townes (HbSS Townes) mice (B6; 129-Hbatm1(HBA)Tow Hbbtm2(HBG1,HBB)Tow/Hbbtm3(HBG1,HBB)Tow/J) were used as the murine model of SCD, and HbAA Townes mice (homozygous for Hbatm1(HBA)Tow and Hbbtm3(HBG1,HBB)Tow) were used as the phenotypically controls. The results conclusively illustrate the benefits of using apohb-Hb, as it improves cardiac output, decreases pulmonary hypertension, and alleviates the immune response that is expected. In conclusion, our study provides strong evidence supporting the significant cardiovascular implication of heme and hemoglobin. We have demonstrated that apoHb-Hp complex effectively neutralizes these harmful activities, rendering these heme and free Hb nonreactive, leading to a marked reduction in hemolysis induced endothelial activation. These findings have important implications, suggesting that apoHb-Hp complex plays a protective role for cardiac and pulmonary cells exposed to elevated levels of heme and free Hb, a condition commonly seen in SCD. Furthermore, our study's consistency with prior research reinforces the role of apoHb-Hp complex in preventing P-selectin expression. Our SCD mouse model experiments reveal that apoHb-Hp complex effectively ameliorates vaso-occlusion, regardless of whether the vaso-occlusion was triggered by Hb or heme-independent factors like hypoxia-reoxygenation. Notably, the apoHb-Hp complex also demonstrated some efficacy, indicating that the protective effect extends beyond simple heme clearance and TLR4 signaling inhibition. While our results are promising, further experiments are required to gain a deeper understanding of the apoHb-Hp complex activity in both clearance-dependent and independent mechanisms of resolving vaso-occlusion. Overall, our research highlights the potential therapeutic value of the apoHb-Hp complex in combating the detrimental effects of Hb and heme, and offers valuable insights into its protective role in managing vaso-occlusive events associated with conditions like SCD.

Identification of Risk Factors for Sickle Cell Crisis Readmissions: A Community Center Experience

Introduction: Sickle cell disease (SCD) exerts a significant morbidity and mortality burden worldwide, with 300,000 infants being diagnosed with SCD annually. The term sickle cell crisis (SCC) encompasses several acute conditions under its umbrella, namely vaso-occlusive crisis, aplastic crisis, splenic sequestration crisis, dactylitis, and acute chest syndrome. SCC has been established to be a known cause of readmissions across the year with studies showing 17% of the population returning two to three times annually. This has resulted in a high mean length of stay for this diagnosis (5.3 days) in comparison to an index hospitalization (4.9 days), with a mean cost of $8485 per admission. Readmissions owing to SCC have relayed a significant burden of 95,445 hospitalization days and a total charge of $609 million in the US. Despite the high morbidity and financial burden it imposes, limited studies have been performed studying the risk factors for readmissions in these patients. Despite the establishment of a framework of recommendations and guidelines, there appears to be a high incidence of readmissions and discrepancies in adherence to evidence based recommendations. We performed a retrospective study to evaluate the risk factors for patients hospitalized in three community hospitals between October 2021 and August 2022. Methods: The admissions database of a community health system across three hospitals was scanned for admissions with SCC between the time period October 2021 and August 2022. ICD9 and ICD-10 codes of SCC were used. 50 patients found with the admitting diagnosis code of SCC and 103 encounters were included. After excluding patients who left against medical advice before initiation of treatment, those with the wrong diagnosis and incomplete documentation, a cohort of 47 patients with 100 encounters was attained. Patient charts were reviewed and demographic variables such as age, gender and race were studied. Readmissions and the length of stay were assessed for risk factors with the help of a chi square test. Risk factors assessed included use of pain medications (opioids with non-steroid anti-inflammatory medications versus monotherapy), use of IV Fluid Boluses, placement of Hematology consult, having an established primary care physician and the use of hydroxyurea as a home medication. Results: 87% of the patient population was African American with equal gender distribution (Males 51%; Females 49%). 59% of the patient population lay in the age group of 18-35. 49% of the patient population was noted to have readmissions within the time frame studied with 29% of the patient population having a length of stay of more than 3 days. 100% of the patients without an established primary care physician (PCP) were noted to have readmissions in comparison to 3.6% of the patients with an established PCP (p< 0.01). Length of stay was less than 3 days for 91.3% of the patients treated with the combination of opioids and NSAID's for pain in comparison to 64.9% of the patients that were not treated with this combination (p= 0.014). It was noted however, that 37% of the population was on hydroxyurea outpatient and 44% of the cases had involved hematology for the inpatient management of these patients. IV Fluid boluses and their association with length of stays in our patient population was unequivocal. 52.7% of the patients on hydroxyurea had readmissions within 30 days as opposed to 28.6% of the patients not on the drug. This was likely explained by non-compliance to the medication. No deaths were reported in this patient cohort. Conclusion: Several risk factors for readmissions in SCC patients exist in the community setting. Our findings reported that lack of close outpatient follow up is associated with higher readmission rates. In addition, we also observed that the type of medical pain management (combination vs monotherapy) played a role in length of stay with combination therapy being linked to shorter hospitalization stay. Integrated education for various medicine specialties regarding management guidelines should be instituted. In addition, maximum utilization of social work and case management for ensuring close follow ups for this patient population may further mitigate readmissions of SCC patients in the community setting.

Assessing the Impact of the Covid-19 Pandemic on Outcomes of Patient Admitted with Sickle Cell Disease

Introduction: Sickle cell disease (SCD) is an autosomal recessive hemoglobinopathy which affects millions of people worldwide. It is caused by a substitution of the glutamic acid (Glu) amino acid with valine (Val) at the sixth position of the β-globin gene, resulting in a mutated hemoglobin tetramer, HbS, in the erythrocytes of affected individuals. This morphology results in sickle-shaped red blood cells and hemolysis when deoxygenated and leads to vaso-occlusion with associated ischemia. SCD is characterized by repeated severe acute pain episodes, acute chest syndrome, and can be complicated by stroke, nephropathy, avascular necrosis, and more. Many studies have shown disparities in outcomes in racial/ethnic minorities as well as in those with lower socioeconomic status. These factors have also been linked to increased risk of COVID-19 infection and infection related mortality. In this study, we aim to explore the baseline characteristics of patients with SCD, prevalence of hospitalizations, and compare inpatient outcomes during the COVID-19 pandemic with those prior to the pandemic. Methods: Nationwide Inpatient Sample (NIS) was queried to determine adult hospitalized patients with a primary diagnosis of SCD using ICD-10 codes. They were stratified into two cohort groups based on year of admission, comparing admissions during 2016-2019 with admission during the year 2020. Primary outcomes assessed were inpatient mortality, length of stay (LOS), and total hospitalization charges. Secondary outcomes included respiratory failure, need for mechanical ventilation, cerebrovascular accident (CVA), myocardial infarction (MI), acute kidney injury (AKI), pulmonary embolism (PE), and need for blood transfusions. Multivariate linear and logistic regression analysis was performed to adjust for confounding variables. Results: A total of 456, 750 patients were hospitalized with SCD. 377, 285 were admitted between 2016-2019 and 79, 465 were admitted during 2020. Age distribution and sex were similar between the two groups. Patients admitted in the year 2020 were older and had more comorbidities when compared to patients admitted during prior years. Distribution of race, insurance type, hospital type, hospital size, hospital locations, and household income was not significantly different between the two groups. In 2020 patients admitted with SCD had greater odds of developing acute respiratory failure and PE, though the overall prevalence of these secondary outcomes were very low (3.6% and 0.80% respectively). Despite these outcomes, there was no significant difference in inpatient mortality (0.31% vs. 0.23%) for SCD patients admitted during 2020 when compared to prior years. In addition, the length of hospital stay was not significantly different in these two groups as well (5.1 vs. 4.9 days). Finally, patients admitted in 2020 incurred significantly higher hospital costs than SCD during pre-pandemic years ($42, 307 vs. $36, 087). Conclusion: SCD is the most common hemoglobinopathy in the United States. The African American population is most commonly affected by this disease. In addition, it is well known that this racial minority suffers inequities in accessing and receiving health care, which is associated with worse overall outcomes. During the COVID-19 pandemic, reduced access to hospital services combined with fear of exposure to the virus, led to a significant drop in overall access to healthcare and treatment. In this study, we found that those with SCD admitted during the COVID-19 pandemic overall had more comorbidities and more commonly had respiratory failure and pulmonary embolism, yet there was no change in inpatient mortality and LOS for these patients. Although disparities existed during the pandemic, it is fortunate that SCD itself did not serve as an additional risk factor for inpatient mortality and hospitalization duration.

Patterns of Nonadherence to Hydroxyurea in Pediatric Sickle Cell Disease

Background: Sickle cell disease (SCD) affects an estimated 100,000 American children and adults (CDC, 2017). Hydroxyurea is the first-line disease-modifying treatment for SCD. Daily oral hydroxyurea significantly reduces the frequency of pain and serious medical complications associated with SCD, including dactylitis and acute chest syndrome (Wang et al., 2011). However, adherence to hydroxyurea is less than optimal at 74% among pediatric patients, with 20% of children who are prescribed hydroxyurea taking less than 50% of their prescribed doses (Louiselle et al., 2016). Suboptimal hydroxyurea adherence is associated with increased risk for medical complications, diminished quality of life, and higher health care costs and utilization (e.g., Badawy et al., 2017; Thornburg et al., 2010). Factors associated with hydroxyurea nonadherence in pediatric SCD include female sex, older age, more adherence barriers (e.g., difficulty obtaining refills), lower socioeconomic status, and lower parent treatment knowledge. Purpose: This study aims to characterize trajectories of pediatric hydroxyurea adherence to identify subgroups that may be at highest risk for hydroxyurea nonadherence (e.g., sociodemographic factors), critical time periods for adherence support interventions (e.g., adolescence), and minimal adherence thresholds to optimize hydroxyurea efficacy. Methods: Retrospective chart review across two institutions (i.e., Cincinnati Children's Hospital Medical Center and Nemours Children's Hospital, Delaware) are ongoing. Participants will include patients with SCD ages 2 to 21 years who were prescribed hydroxyurea from March 2007 to February 2017. Researchers are extracting the following data from patient electronic medical records (EMRs) to estimate hydroxyurea adherence: hemoglobin F levels (HbF), mean corpuscular volume (MCV), and absolute neutrophil count (ANC). Additional clinical information will be extracted from patient EMRs including demographic information, SCD genotype, SCD complications, acute care utilization, medical and social complexity, and concomitant medication use. Descriptive statistics will be used to summarize demographic and clinical characteristics of the sample. MCV will be the primary measure of hydroxyurea adherence and Hgb F and ANC will be secondary measures. If the final sample size is sufficiently large, we will conduct group-based trajectory modeling (GBTM) to analyze patterns of hydroxyurea adherence changes over time and identify hydroxyurea adherence trajectory subgroups. Multinomial logistic regression analyses will be used to analyze potential predictors of hydroxyurea adherence trajectory subgroup membership. Results: Preliminary results revealed that as of February 2017, 88% of eligible patients (based on age) were prescribed hydroxyurea.Data from the first 30 completed chart reviews indicates that half of the sample was female (sex assigned at birth), all identified as Black or African American, all but two participants had HbSS, and the mean age 13.0 years ( SD=8.0, range=2.47 to 26.81). Average MCV across an average of 21 time points ( SD=14.2, range=5-74) was 94.3 ( SD=11.2, range=58.4-114.2). As of February 2017, 53% of individuals had MCV values at or above 100. Specifically, 60% of 5-9 year olds, 47% of 10-15 year olds, and 46% of 16+ year olds had MCV values at or above 100. Average Hgb F across an average of 21 time points ( SD=15.3, range=3-81) was 22.9 ( SD=9.3, range=2.6-44.8). As of February 2017, 50% of individuals had HbF values at or above 20.0. Specifically, 55% of 5-9 year olds, 32% of 10-15 year olds, and 55% of 16+ year olds had HbF values at or above 20.0. Average ANC (at non-ill visits) across an average of 20.0 time points ( SD=13.6, range=5-71) was 3,965 ( SD=1,227; range=1,600-6,910). As of February 2017, 31% of individuals had ANC values less than 3,000. Specifically, 20% of 5-9 year olds, 34% of 10-15 year olds, and 30% of 16+ year olds had ANC values less than 3,000. Discussion:Results from this study have the potential to help researchers and clinicians better understand patterns and correlates of hydroxyurea adherence in pediatric SCD patients that can be targeted in future interventions.

Outpatient Costs of Patients with Sickle Cell Disease with or without Hydroxyurea at an Institution in Rio De Janeiro, Brazil

Background Brazil is home to a growing population of patients with sickle cell disease (SCD) with an estimated 100,000 patients having some form of the disease. The use of hydroxyurea (HU) is known to decrease numerous complications, such as pain crises and acute chest syndrome, in SCD. In Brazil, this medication is provided by the Brazilian Ministry of Health through the National Health System. The overall cost of the drug, as well as the cost of patients with SCD visiting a large hematology clinic in Rio de Janeiro, HEMORIO, is not known. This study aimed to determine the landscape of patients visiting the hematology clinic and the cost of each visit as stratified by the use of hydroxyurea. Methodology A retrospective analysis of patients with SCD who were seen at the HEMORIO clinic between January 1, 2018, and June 30, 2018, was conducted. Patients were stratified by age, gender, genotype, and prescription use of HU. The total number of appointments attended, which included primary hematology, chronic transfusion, and other subspecialities, was computed. Absentee rates were determined and stratified as listed above. Cost per each type of appointment - outpatient clinic, transfusion visit, dressing change, and lab check - were then calculated. Finally, the cost of medications, which included HU, pain medications, and iron chelators, was calculated per patient. Data was collected from the Sash System (Hematology Service Attendance System) used in HEMORIO. The tool used for data extraction was Microsoft SQL Server 2014. Data were analyzed using the R software. All calculations converted to US dollars. Results A total of 3000 patients with SCD seen at the outpatient clinic were reviewed. 51.6% of patients were female and the mean (± standard deviation) age was 19.1 (± 14.8). 73% of patients had HbSS, 20% had HbSC, and 5% had HbS-beta thalassemia. 984 patients (32.8%) were prescribed HU. 7 patients (0.2%) died during the time of analysis. Out of 14795 appointments scheduled at the medical facility, the highest number of appointments were made in Hematology (6199, 42%) or Chronic Transfusion (2347, 14.2%). The next most common were Ophthalmology, Dentistry, or Physical Therapy (2098 combined, 14%). Patients with HbSS had the greatest number of appointments overall. 9177 (62%) were attended, making the absenteeism rate 38%. When stratified for genotype, age group, and HU use, the highest rates of absenteeism were in patients with HbSS or Sβ 0 (38%), in those aged 19-25 (45%), and in those not taking HU (41%). Patients with HbSS had a higher average outpatient visit cost of $45.88 (± $40.01) per person as compared to patients with all other genotypes ($33.10 ± $35.14 per person). The highest costs for all patients were associated with transfusion visits, with an average of $390.43 (± $299.02) per patient, followed by dressing changes at an average of $123.68 (± $109.90) per person across all genotypes. Compared to those patients not on HU, patients on HU had a statistically significant higher cost for all types of visits (p<.05), except for dressing changes (Table 1, Figure 1). Similarly, patients on HU had a higher average medication cost of $4438.08 (± $12195.34) per person compared to those not on HU at $778.14 (± $5649.32) per person. Discussion At a medical center in a middle-income country that specializes in treating SCD, patients with the HbSS/Sβ 0 genotypes had notably higher treatment costs compared to those with other genotypes. This is consistent with the fact that these patients often have a more severe form of the disease and require more outpatient visits, specialists, and transfusions. The most expensive aspect of treatment for all patients was transfusion appointments. These appointments are likely more costly because they require blood, supplies, and trained staff. Patients who received HU had higher average costs for each type of clinic visit. This is potentially because those receiving hydroxyurea have a more severe disease course, requiring more outpatient and subspecialty services. In future studies, we hope to demonstrate that these same patients have lower overall costs for inpatient and emergency visits, which would provide a net cost-saving with hydroxyurea treatment and benefit the hospital system. Given the detailed information on cost of each transfusion, medication, and intervention per patient, the Ministry of Health may be able to better allocate funds to the aid of patients with SCD in the future.

Hydroxyurea Dose Optimization Is Safe and Improves Outcomes for Children with Sickle Cell Anemia Living in Sub-Saharan Africa: The Reach Experience

Disclosures Introduction: Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) is an open-label multi-country prospective trial of hydroxyurea for children with sickle cell anemia (SCA) in sub-Saharan Africa (Angola, Democratic Republic of Congo, Kenya, and Uganda). Initial results documented the feasibility, safety, and benefits of hydroxyurea treatment with dose escalation to maximum tolerated dose (MTD), but further hydroxyurea dose optimization data are needed to assess long-term benefits and risks. We now report the REACH experience with up to 8 years of hydroxyurea treatment, describing laboratory responses, clinical outcomes, and dose-related toxicities (DLT). Methods: Children 1-10 years of age with SCA were enrolled. After screening, the hydroxyurea dose was fixed at 15-20 mg/kg/day for 6 months with monthly complete blood counts (CBC) to ensure safety. From Month 6-24, the dose was escalated (5 mg/kg every 8 weeks) to MTD, defined as mild myelosuppression with absolute neutrophil count (ANC) <4.0 x 109/L on 2 consecutive CBC. Beyond Month 24, dosing was optimized for weight gain and increased based on CBC results. With a low DLT rate using the original MTD criteria (ANC <1.0 x 109/L, Hb <4.0 g/dL, reticulocyte count <80 x 109/L unless Hb >7.0 g/dL, or platelets <80 x 109/L), dose optimization criteria were modified toward a target ANC of 3.0 x 109/L. The hydroxyurea dose was increased if ANC >3.0 x 109/L, Hb >5.0 g/dL, reticulocytes >100 x 109/L and platelets >100 x 109/L. Laboratory responses, clinical responses, and DLT rates were compared across the four dosing phases (Screening, Fixed Dose, Dose Escalation, and Dose Optimization). Results: A total of 635 children enrolled in REACH and began screening; 606 initiated hydroxyurea and currently 527 (87%) remain in the trial, with an average treatment duration of 83 months (range 76-105 months) and total of 4,199 patient-years of hydroxyurea treatment. Over 85% achieved MTD initially at an average hydroxyurea dose of 22.5 ± 5.0 mg/kg/day, ranging from 19.0 mg/kg/day in Angola to 25.4 mg/kg/day in Uganda. With dose optimization, doses have increased and the most recent average is 28.1 ± 5.1 mg/kg/day, ranging from 27.1 mg/kg/day in Congo to 28.8 mg/kg/day in Uganda. Across the four dosing phases, key laboratory responses (Hb, HbF, and ANC) have improved over time: the average Hb increased from 7.3 g/dL at baseline to 8.4 g/dL at MTD and is currently 8.7 g/dL; average HbF increased from 11% at baseline to 25% at MTD and is now 27%; and average ANC decreased from 6.8 x 109/L at baseline to 4.2 x 109/L at MTD and is currently 3.6 x 109/L. Comparing event rates per 100 patient-years between Screening to Dose Optimization, vaso-occlusive episodes decreased from 104.5 to 43.9, acute chest syndrome decreased from 9.0 to 2.1, splenic sequestration decreased from 1.8 to 0.7 and stroke decreased from 1.8 to 0.3. Transfusion rates decreased from 48.6 to 11.2, malaria from 46.8 to 19.1, non-malarial infections from 111.7 to 52.9, and death has decreased from 3.6 to 1.0 per 100 pt-years. As a composite, all sickle-related clinical events including vaso-occlusive pain, acute chest syndrome, stroke, and all serious adverse events have decreased as the dose increased (Fig 1). Lab toxicities have been infrequent and transient, with 2/3 identified incidentally during a scheduled visit without illness. Among 25,730 total CBCs obtained in REACH, only 421 (2.6%) in 225 participants had a DLT, and the incidence rate has not increased across dosing phases from Screening (0.22 events per pt-year) through Dose Optimization (0.21 events per pt-year). During COVID, 549 children had labs checked at 6-month intervals without any increase in the DLT rate or clinical events. Many DLT are unrelated to hydroxyurea including thrombocytopenia (33%) with splenomegaly, followed by anemia (26%) with malaria. Severe neutropenia (ANC <0.5 x 109/L) was very rare (5 events) with no neutropenic infections. Conclusions: Hydroxyurea is safe, well-tolerated, and effective for children in REACH. Hydroxyurea escalation to MTD with further dose optimization is associated with improved laboratory and clinical responses, but no increased toxicity. Routine CBC monitoring at 3-month intervals is sufficient and extension to longer intervals may be appropriate. Hydroxyurea dosing at 25-30 mg/kg/day is feasible and safe in sub-Saharan Africa and provides optimal treatment benefits. Aygun: GBT: Membership on an entity's Board of Directors or advisory committees; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Latham:Emmaus Medical: Research Funding. Ware:Addmedica: Research Funding; Emmaus Medical: Research Funding. Figure 1

Increased Risk for Hospitalization Associated with Short Term Particle Air Pollution Exposure for California Residents with Sickle Cell Disease

Background: Air pollution is associated with numerous adverse health outcomes in the general population such as asthma exacerbations, pneumonia, myocardial infarction, and stroke. There is a strong association between air pollution and mechanistic processes associated with oxidative stress, vasoconstriction, and inflammation, suggesting a high risk of exposure for those with sickle cell disease (SCD). A small number of published studies have explored this relationship, primarily focusing on children. Only two studies have examined air pollution in the US, both with outcomes among urban area hospitals in Atlanta, GA. None have taken place in California, which has the worst air quality, including the four most polluted cities in year-round particle pollution in the nation. Additionally, all published studies have overlooked more rural exposure areas. Recent advances in environmental exposure assessment have enabled high-resolution predictions of ambient air pollution concentrations in the whole US, making it possible to cover unmonitored suburban and rural areas that were unrepresented in the past. In addition, these high-resolution predictions are more precise surrogates of the personal exposure measures than monitored data. Particulate matter with a diameter of 2.5 microns or less (PM 2.5) is the most harmful pollutant based on current research findings. We hypothesized that short term increases in PM 2.5 exposure were associated with an increased risk for hospitalization among individuals with SCD in California. Methods: We designed a time-stratified case-crossover study to estimate the percent change in risk for hospitalization for SCD complications associated with each 1mg/m 3 increase in PM 2.5 exposure. The zip code of residence was used to spatially link each hospital admission with PM 2.5 exposure using a novel hybrid exposure model allowing for estimated exposure in areas without direct remote sensing. We used conditional logistic regressions to examine the PM 2.5 exposures at 7-day moving average and single lag days (from lag 0 to 6 days) before admission, adjusting for nonlinear confounding effects of air temperature and humidity at the same exposure window. We examined risk for all hospitalizations and specifically for vaso-occlusive pain (VOC) and acute chest syndrome (ACS). Results: From 2000-2016, among 5,835 California residents with SCD, there were 107,450 admissions for sickle cell disease complications with VOC being the most common indication (71.1%). PM 2.5 air pollution data was examined among 2,634 zip codes throughout the state. Residents with SCD were noted to be living among 1,180 zip codes. The daily burden of PM 2.5 was higher in zip codes with residents with SCD (mean 11.5 mg/m 3, standard deviation [SD] 9.0) when compared to zip codes without residents known to have SCD (mean 9.2 mg/m 3, SD 8.6, p<0.001) ( Table 1). Overall, the mean daily burden of PM 2.5 declined in the period of 2010-2016 when compared to that from 2000-2009. However, the daily mean PM 2.5 concentration remained higher in zip codes with individuals with SCD. No significant association was seen in examining the week-long exposure to PM 2.5 and increase risk in hospitalizations for any indication over the entire study period (2000-2016). However, when examining the more contemporary period of 2010-2016, we identified that each 1mg/m 3 increase in PM 2.5 was associated with 0.22% increased risk for SCD hospitalization (Confidence Interval [CI] 0.02-0.42, p=0.03) 3 days prior to admission. We observed a 0.26% increased risk for hospitalization for VOC with each 1 mg/m 3 increase in PM 2.5 exposure (CI 0.02-0.49, p=0.03) at lag day 3 (Figure 1). No effect was seen with PM 2.5 on hospitalizations for ACS during any time period. Discussion: Our study suggests that short term air pollution exposure may be a trigger for hospitalization for individuals with SCD. In particular this effect is seen in the more recent years with a lower daily average PM 2.5 burden overall, suggesting attention may be needed well below Environmental Protection Agency (EPA) thresholds. Consistent with previous studies, lag day 3 PM 2.5 exposure is associated with an increased risk for hospitalization for VOC. These results may have important implications in understanding risk factors for hospitalization for children and adults with SCD.

Impact of the 2014 NHLBI Hydroxyurea Guidelines on Cerebrovascular Events in Sickle Cell Disease

Background: Cerebrovascular disease (CVD) is a common cause of morbidity in patients with sickle cell disease (SCD). An estimated 37% of children with SCD have silent cerebral infarcts (SCI) by age 14, leading to increased stroke risk and neurocognitive impairment. In the DISPLACE trial (Kanter et al, 2021), 2.9% of patients had abnormal cerebral blood flow as measured on transcranial Doppler ultrasound (TCD). The 2014 National Heart, Lung, and Blood Institute (NHLBI) guidelines recommend hydroxyurea (HU) for all patients with SCD-SS and SCD-Sβ 0 starting at age 9 months, a significant shift from prior practice. In patients who have already developed TCD abnormalities, HU is protective against stroke and CVD progression. The real-world impact of universal early HU on the development of CVD, particularly on SCI, is not well defined . We hypothesize that the 2014 guidelines led to an increase in HU use and a reduction in the initial development of CVD. Methods: We performed a single center, retrospective cohort study investigating trends in HU prescriptions and CVD before and after the publication of the 2014 NHLBI guidelines. Patients with SCD-SS and SCD-Sβ 0 who initiated hematology care at the Children's Hospital of Philadelphia between 2009 and 2023 were identified using an institutional registry. Incident HU was defined as the first outpatient HU prescription in patients with a minimum of two orders. Incident CVD was defined as a composite outcome consisting of the first documentation of: abnormal TCD, brain magnetic resonance imaging (MRI) with silent infarct, or overt ischemic stroke. Patients with known CVD before care initiation, prematurity < 28 weeks gestational age, or non-SCD neurologic disease were excluded. For time-to-HU analysis, patients with HU prescriptions before enrollment at our center also were excluded. Patients were followed from their first hematology visit until the outcome of interest or censoring. Censoring criteria included loss to follow up, transition of care, or bone marrow transplant. All brain MRI and TCD reports were manually reviewed. Ages at HU initiation pre- and post- guideline were compared using the Wilcoxon rank-sum test . Times to 1) HU and 2) CVD were summarized using Kaplan-Meier estimators, with the guideline publication date of September 1, 2014 incorporated as a time-varying exposure. Unadjusted associations were calculated using a Cox proportional hazard regression. Results: A total of 446 patients met inclusion criteria and contributed to analyses. Median age at baseline was 2.4 months, and median duration of follow-up was 5.0 years (IQR: 2.3-8.7). Most patients (430/446, 96%) had SCD SS, and 51% were male. The proportion of patients ever prescribed HU increased with time (Fig 1), with a peak prevalence of 82% in 2022. Of 385 patients not exposed to HU at baseline, 277 (72%) were prescribed HU during study follow-up. Incident HU prescriptions significantly increased after NHLBI guideline publication (HR 3.40, CI: 2.50 to 4.63, p < 0.001) with an older age at HU initiation before (median 4.0 y, IQR 2.5-7.7) than after (median 2.9 y, IQR 1.1-5.8) publication of the guideline (p = 0.002). Over a total of 2,395 person-years of follow-up, 66 incident CVD outcomes occurred in this longitudinal cohort, corresponding to a cumulative incidence of 14.8%. These events included 53 SCI, 10 abnormal TCD, and 3 overt ischemic strokes. CVD outcome occurrence was lower after guideline publication than before (HR 0.58, CI: 0.32-1.05), though the association did not reach statistical significance (p = 0.071, Fig. 2). Discussion: After the NHLBI guideline publication, HU prescriptions increased significantly at our center.Our data suggest that the 2014 guideline-directed care may have led to a greater than 40% reduction in CVD, though this reduction was not statistically significant in our small sample size. Despite guideline recommendations and strong evidence for the role of HU in reducing pain and acute chest syndrome, few patients across the United States are prescribed HU therapy. Adherence and care continuity challenges further lessen the number of patients benefitting from HU. Evidence of efficacy of early and universal HU in CVD prevention would strengthen guideline recommendations and improve clinical care in patients with SCD. Ongoing analysis includes an expanded cohort and adjustment for clinical covariates to better examine the direct impact of early HU on CVD.

Comparison of Alloimmunization in Pregnant People with Sickle Cell Disease Receiving Chronic Versus on-Demand Transfusions: A Multinational Study

Introduction Despite exceptional maternal morbidity and mortality risk, people with sickle cell disease (SCD) lack firm indications for chronic transfusion therapy (CTT) during pregnancy. Alloimmunization may cause hemolytic transfusion reactions and can limit the safety of future blood transfusions; thus it is a rationale for restricting CTT during pregnancy. Little data quantifies this risk. The 2020 American Society of Hematology (ASH) Guidelines for SCD TransfusionSupport recommend CTT in some pregnancies, but adoption in clinical practice is unknown. This study's purpose is to use a large two-center SCD pregnancy cohort to describe alloimmunization rates in SCD pregnancies treated with CTT vs on-demand transfusion (ODT) and to determine the fraction of SCD pregnancies meeting the ASH Guideline to initiate CTT in pregnancy. Methods We reviewed SCD pregnancies delivered at Mt. Sinai Hospital, Toronto (1990-2017) and Johns Hopkins Hospital (2000-2021). We collected data on transfusions and SCD complications before and during pregnancy, delivery, and fetal outcomes. Analyses classified subjects and pregnancies as receiving CTT or ODT. We defined CTT as pregnancies treated with scheduled, prophylactic transfusions; ODT as pregnancies transfused as-needed, including no transfusions. Sinai routinely matched transfusions for Rh and K antigens while Hopkins matched Rh only. Both centers provided extended matching if an alloantibody was detected. The first analysis included singleton pregnancies to primigravida subjects. We compared new alloantibody development, SCD complications, and pregnancy outcomes in CTT vs. ODT groups and in genotype stratified groups. We used Chi-squared and Wilcoxon rank-sum tests for categorical and continuous variables; p < .05 was significant. The second analysis included all cohort pregnancies and identified which met criteria for CTT per ASH Transfusion Guidelines which advise CTT for (A) severe SCD complications before or during pregnancy here defined by acute chest syndrome (ACS) or pain requiring acute care in the year before or during pregnancy, any history of venous thromboembolism (VTE), stroke, or multi-organ failure or (B) features of high-risk pregnancy, defined by multiple gestation, pre-eclampsia, gestational hypertension, cardiac comorbidities, or preterm labor history. Results Among 145singleton, primigravida pregnancies, more received ODT than CTT (119 ODT vs 26 CTT). Among ODT subjects 46/119 received at least one transfusion during pregnancy. CTT subjects had more severe SCD than ODT subjects before pregnancy (Table 1). During pregnancy, SCD severity did not differ (Table 2). Before pregnancy, 18 subjects were alloimmunized and did not differ by treatment group (6/26 CTT vs 12/119 ODT, p=0.07). During pregnancy, six subjects developed an alloantibody and did not differ by treatment group (1/26 CTT vs 5/119 ODT, p=0.93). Half (3/6) had a history of alloimmunization before pregnancy (1 CTT vs 2 ODT, p=0.27) and three did not (0 CTT vs 3 ODT, p=0.27). All subjects with new antibodies during pregnancy and historic alloimmunization developed anti-K antibodies (1 CTT, 2 ODT) at both sites. Those without alloimmunization history developed anti-Jkantibodies (3 ODT) at Sinai. In the secondary analysis, we included 299 pregnancies to 203 subjects. Among them, 249 pregnancies (83%) met at least one ASH Guideline criteria for initiating CTT. This included all CTT pregnancies (61/61, 39 subjects) and 79% of ODT pregnancies (188/238, 164 subjects), 46% of which received at least one transfusion during pregnancy (86/188). Conclusions In this SCD pregnancy cohort, alloimmunization rates were low and did not differ between those treated with CTT versus ODT. As alloimmunization events were inconsistent with institutional matching practices, new antibody development may be attributable to transfusions from outside hospitals or pregnancy-associated alloimmunization. Antigen matching per ASH Transfusion Guidelines avoids C, E, K and Jk alloimmunization. Scheduled transfusions may reduce emergency transfusion which increases alloimmunization risk. Finally, all CTT and 79% of ODT pregnancies met ASH Guideline criteria for CTT in pregnancy, however the cohort predates ASH Guideline publication. Guideline adherence may lead to increased use of CTT during pregnancy. More discriminating tools are needed to inform CTT use in SCD pregnancy.

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.

Prevalence and Time Trends of Oral Anticoagulant Utilization in Adults with Sickle Cell Disease

Background: Sickle cell disease (SCD) is an inherited red blood cell disorder, caused by a genetic mutation in the β-hemoglobin chain. SCD is associated with chronic activation of coagulation and an increased risk of venous thromboembolism (VTE). Although the American Society of Hematology guidelines recommend indefinite anticoagulation for unprovoked or recurrent provoked VTE, no guidance is given regarding choice of anticoagulant due to a paucity of data. Existing evidence on the use of anticoagulants in patients with SCD has been mostly focused on oral anticoagulants, was limited by small sample sizes, and did not clearly demonstrate the temporal utilization patterns. Real-world evidence on oral anticoagulant use in SCD from large population-based studies is largely lacking. This study examined the prevalence and time trends of oral anticoagulant utilization in patients with SCD in the United States (US). Methods: This retrospective, repeated cross-sectional study analyzed the Cerner Health Facts® database from January 1, 2011, to December 31, 2016, which captures longitudinal electronic medical records (EMR) of patient data from participating facilities in the US. To be included, patients were required to (1) have ≥ 1 inpatient or emergency department encounters with SCD, or 2 outpatient encounters that were 30 days apart in a calendar year from 2012 to 2016, (2) have ≥ 1 prescription records on the encounters with SCD, (3) aged ≥ 18 years at index, and (4) have ≥ 1 encounter with SCD in a year prior to the index. For patients with multiple encounters with SCD in the calendar year, we randomly selected one encounter with SCD and defined it as the index. In this design, a patient contributed only one observation per year but may contribute to multiple years of observations if meeting the selection criterion. The outcome was the use of anticoagulants, defined as any prescription drug encounter for an oral anticoagulant (Vitamin K antagonist [VKA]: warfarin; direct oral anticoagulants [DOACs]: apixaban, rivaroxaban, dabigatran, edoxaban) within a grace period of 7 days discharged from the index. The independent variable was each calendar year measured as dummy variables. Covariates were measured during the 12-month baseline period prior to the index, which included patient demographics, comorbidities and complications of SCD, and facility characteristics. Time trends on the proportions of eligible patients with anticoagulant use against the calendar years of the SCD diagnosis were plotted, and the significance on the crude trend was examined using Cochran-Armitage trend test. In the main analysis, a modified Poisson regression by using generalized estimating equations (GEEs) estimated the adjusted prevalence ratios (APRs) for the trends and covariates associated with any anticoagulant utilization. In subgroup analysis, we estimated the APRs of covariates for the use of DOACs versus VKA. Results: The cohort included 8,824 adult patients with SCD in 182 facilities using automated Cerner EMR system for the years 2012 to 2016. Prescription rates of all oral anticoagulants gradually increased from 2012 to 2014; the rates of VKA prescriptions substantially dropped from 11.1/1000 to 4.1/1000 persons between 2014 and 2016, whereas prescription rates of DOACs increased significantly from 12.0/1000 to 29.1/1000. Prevalence of VTE was stable at approximately 6.2/1000 to 7.5/1000 between 2012 and 2016. Prescription rates of DOACs were lower in patients with (versus without) VTE (6.1/1000 vs 7.3/1000), while a reversed prescription pattern was observed for VKA (VTE [yes vs no]: 4.4/1000 vs 1.8/1000). Controlling for covariates, our main analysis demonstrated that patients with a diagnosis of acute chest syndrome, pulmonary hypertension, and depression were 1.51, 2.30, and 1.57 times more likely to have oral anticoagulant prescription, respectively (all p <0.05). Subgroup analysis showed that having a diagnosis of VTE was associated with a decreased likelihood of DOACs prescription relative to VKA (APR= 0.75, 95%CI: 0.62-0.91). Conclusion: Prescription of oral anticoagulants in adults with SCD has significantly increased from 2012 to 2016 and the increase was dominated by DOACs. The treatment paradox of a lower relative rate of DOACs utilization versus VKA in adults with SCD requires more study to understand the reasons and additional clinical outcomes associated with the utilization patterns.

Differing Definitions of Vaso-Occlusion in Clinical Studies of Sickle Cell Disease Can Result in Differing Outcomes

Background: Frequent episodes of vaso-occlusion are the hallmark of sickle cell disease (SCD), but the definition of what constitutes a vaso-occlusive episode is not consistently applied across clinical trials, creating challenges in evaluating and comparing efficacy results among different therapies. Here, we compare vaso-occlusion endpoint definitions from clinical trials for various therapies, including genetic therapies, and use clinical trial data to demonstrate the potential for outcomes differences based on differing definitions of vaso-occlusive episodes. Methods: We reviewed completed and ongoing clinical trials and published articles using endpoints assessing the reduction or elimination of vaso-occlusive crisis/events, including trials of (i) exagamglogene autotemcel (exa-cel, CRISPR/Cas-9 based genome editing treatment), (ii) lovotibeglogene autotemcel (lovo-cel, gene addition therapy), (iii) L-glutamine, (iv) voxelotor, (v) hydroxyurea (HU) and (vi) crizanlizumab. Outcomes related to vaso-occlusion were compared across variables including care setting, care duration, treatments, and complications. Data from the CLIMB SCD-121 trial of exa-cel in patients aged 12 to 35 years with severe SCD (data cut as of 10 Feb 2023) were evaluated using different published definitions of vaso-occlusion. Results: The most substantial differences in vaso-occlusion endpoint definitions were associated with frequency and duration of visits to medical facilities for acute pain and inclusion of specific SCD specific complications. Definitions of vaso-occlusions for acute pain related events differed across studies. The definitions of severe vaso-occlusive crises for exa-cel (severe VOC; exa-cel), sickle cell pain-related crises (SCPC; crizanlizumab and L-glutamine), and VOC (VOC; voxelotor) include events with medical facility visits of any duration (severe VOC and SCPC) or medical records of a patient being seen or contacting a physician within 1 business day of an event (VOC), whereas the definition of severe vaso-occlusive events (severe VOE; lovo-cel) requires a ≥ 24-hour hospital or emergency room (ER) observation unit visit or ≥2 visits to a day unit or ER over 72 hours. Vaso-occlusion definition for HU (painful crisis) required a facility visit of ≥4 hours duration. All endpoints include acute chest syndrome and priapism; however, the definition of severe VOE requires ≥4 visits to a medical facility for priapism to meet criterion, while others require only a single visit. The exa-cel phase 3 trial in SCD employs a broad and inclusive definition for severe VOC which counts each individual medical facility visit, regardless of frequency or duration of hospitalization. Based on this, 19 out of 20 patients (95%) met the primary endpoint of freedom from severe VOCs for at least 12 consecutive months (95% CI, 75.1%, 99.9%; P<0.0001). However, when the primary endpoint was analyzed using the severe VOE definition, all patients (20/20; 100.0%) were free from severe VOEs for at least 12 consecutive months (95% CI: 83.2%, 100.0%; P<0.0001). Conclusions: Requirements for health care facility visits in the definitions of severe VOC (exa-cel), VOC, and SCPC were more broadly inclusive and include events that would not be counted in the definitions of severe VOE (lovo-cel) or painful crisis. Clinically, support for this observation comes from our analysis of exa-cel SCD pivotal clinical trial data using these different definitions, which showed the number of patients free from vaso-occlusive episodes changed depending on the definition of vaso-occlusion employed. These results show differences in vaso-occlusion definitions have the potential to impact assessments of treatment efficacy across different SCD therapies.

Evaluating the Effectiveness of COVID-19 Vaccines in Adults with Sickle Cell Disease during the Omicron Period of COVID-19 Pandemic

BACKGROUND: The Omicron variant, one of the variants causing the coronavirus disease of 2019 (COVID-19), was first identified in November 2021 and became the predominant variant in 2022. Although causing less severe disease, this variant and its subvariants have been associated with increased transmissibility and limited protection despite vaccination and prior infection (PMID: 35622357). Individuals with sickle cell disease (SCD) are particularly at greater risk of severe illness and death (PMID: 35060794). As more people with SCD are getting vaccinated and restrictions are being lifted during the Omicron period of the pandemic, the impact on this group has yet to be extensively studied. The study aims to determine the effectiveness of COVID-19 vaccination during this period among individuals with SCD. Additionally, the study aims to examine various factors that can influence the likelihood of COVID-19 infection and severity among SCD individuals. METHODS: This multicenter retrospective study was conducted at three hospital centers in Michigan. A total of 101 SCD adult patients (age ≥ 18 years old) who had emergency and inpatient encounters from January 1 to December 31, 2022, were included in the study. Electronic medical records were reviewed to gather patient data such as demographics, details of COVID-19 infection, underlying comorbidities, and other clinical information, while the immunization registry in Michigan was used to obtain COVID-19 vaccination status. Multivariable regression analysis was conducted to determine the clinical correlation between COVID-19 vaccination status and infection and to examine various factors influencing COVID-19 severity. Statistical analyses were performed using SPSS version 28.0 statistical software, and a p-value of <0.05 was considered statistically significant. RESULTS: Of the 101 adults with SCD included in the study, 97 % were Black, with a mean age of 40 years. The majority had the hemoglobin SC (54%) or SS (35%) genotype. 42 individuals with SCD and confirmed COVID-19 were identified. The most reported chief complaints in the emergency rooms at the time of COVID-19 diagnosis were myalgia and chest pain. Interestingly, individuals with SCD and a history of acute chest syndrome were over 3 times more likely to have a COVID-19 infection diagnosis than those without a history of acute chest syndrome (OR=3.68, 95% CI=1.47-9.17). This was likely due to a significant overlap between the symptoms of acute chest syndrome and COVID-19 warranting emergency care visits. 47.5 % of the individuals with SCD were vaccinated by December 2022. Among these, 12.5% were partially vaccinated, 50% were fully vaccinated, and 37.5% had a booster. COVID-19 infection was significantly higher among the nonvaccinated compared to vaccinated individuals (55% vs. 27%, p=0.01). The mean interval days from the latest dose of COVID-19 vaccination to COVID-19 infection was 297.9 ± 160.5 days. The study found that COVID-19 vaccination lowered the infection risk among SCD individuals by over 70% if they have received at least one dose of the vaccine (OR=0.27, 95% CI=0.10-0.77). There was also a significant difference in preventing COVID-19 infection among the different vaccination subgroups of partial, full, and booster (33% vs. 25% vs. 28%, p=0.045).The results of the multivariable logistic regression analysis showed that none of the factors, such as obesity, pre-existing cardiac history, pulmonary history, renal disease, stroke, or transient ischemic attack, were found to be significantly associated with COVID-19 severity in this sample population. CONCLUSION: Receiving at least one dose of the COVID-19 vaccine can offer protection among individuals with SCD, even with the emergence of Omicron and its subvariants during the COVID-19 pandemic. Additionally, it is crucial that individuals with SCD remain vigilant and seek medical care if they experience chest pain, as this could be the only symptom of COVID-19 among this population.