Sickle Cell Disease Cohort Research Articles

Predictors and Clinical Complications Associated with Antiphospholipid Antibodies in Sickle Cell Disease

Introduction. The antiphospholipid syndrome is characterized by the presence of anti-phospholipid autoantibodies (aPL) leading to a hypercoagulable state as well as an arterial, venous, and microcirculatory vasculopathy. Under several physiological and pathological situations, including the sickling of red blood cells (RBC), negatively charged phospholipids translocate from the inner to the outer surface of cell membranes leading to the potential generation of the antigenic target of aPL. We tested the following two-part hypothesis: 1) repeated exposure of the immune system of patients with sickle cell disease (SCD) to the antigenic target of aPL leads to an increased formation of aPL; and 2) the presence of aPL is associated with pregnancy and SCD-related complications. Methods. We conducted a cross-sectional study in 63 adults with SCD who had aPL testing performed during a hospital admission between August 1999 & June 2017. We compared individual aPL levels with categorical and linear variables using the Kruskal-Wallis test and linear regression analysis, respectively. The anticardiolipin (aCL) IgG and lupus anticoagulant (LA) levels were log-transformed for these analyses. An abnormal aPL was defined as any of the following: IgM or IgG anti-b2GPI >20 IU/mL, IgM or IgG aCL > 20 IU/mL, LA > 10 seconds. Clinical complications were compared by abnormal aPL status using the chi-square test. Results. The median age of the SCD cohort was 32 years (IQR, 21 - 39 years), 49 (78%) were female, 62 (98%) were African American, 5 (8%) had a diagnosis of systemic lupus erythematosus (SLE), 43 (68%) were Hgb SS genotype, 17 (27%) were on hydroxyurea, and 16 (25%) were on chronic anticoagulation therapy. SCD patients with SLE had higher median aCL IgM (6 vs. 1 IU/mL, respectively; P=0.02) and anti-b2GPI IgG (3.5 vs. 0 IU/mL, respectively; P=0.008) levels compared to those without SLE, while lower hemoglobin concentrations were associated with higher aCL IgG levels (β -0.12; P=0.07) and longer LA times (β -0.18; P=0.02). Fifteen of 63 (24%) patients with SCD had an abnormal aPL. Patients with an abnormal aPL had a lower hemoglobin concentration (Figure 1A), a higher white blood cell (WBC; 13.5 vs. 11.8 x109/L, respectively; P=0.06) count, and a lower platelet (268 vs. 340 x109/L, respectively; P=0.05) count at the time of hospitalization compared to those with a normal aPL. A lower hemoglobin concentration (odds ratio [OR], 1.9; P=0.008), a higher WBC count (OR 1.2; P=0.03), and a lower platelet count (10 platelets/µL increment: OR 1.05, P=0.06) were independently associated with the presence of an abnormal aPL by logistic regression analysis, adjusting for age, sex, and prior SLE diagnosis. Consistent with the second part of our hypothesis, several adverse outcomes trended higher in SCD patients with an abnormal aPL. An abnormal aPL was more prevalent among women with ≥ 3 miscarriages, preterm deliveries, or pre-eclampsia as well as during a hospitalization complicated by acute chest syndrome or multiorgan failure (Figure 1B). Conclusions. These data support the hypothesis that patients with SCD have a high predilection to form aPL, and that the presence of an abnormal aPL is associated with pregnancy complications and the severity of acute SCD-related complications during hospitalization. Our study is limited by its small number of patients. Further larger studies are needed to assess the mechanisms of aPL generation as well as to determine the prevalence and associated risk of abnormal aPL status in patients with SCD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Creating an automated contemporaneous cohort in sickle cell anemia to predict survival after disease-modifying therapy

AbstractThe Food and Drug Administration requires contemporaneous controls to compare clinical outcomes for participants receiving experimental gene therapy or gene editing clinical trials. However, developing a contemporaneous cohort of rare diseases requires multiple person-hours. In a single referral center for sickle cell disease, we tested the hypothesis that we could create an automated contemporaneous cohort of children and adults with sickle cell anemia (SCA) to predict mortality. Data were obtained between 1 January 2004 and 30 April 2021. We identified 419 individuals with SCA with consistent medical care defined as followed continuously for >0.5 years with no visit gaps >3.0 years. The median age was 10.2 years (IQR, 1-24 years), with a median follow-up of 7.4 years (IQR, 3.6-13.5 years) and 47 deaths. A total of 98% (274 of 277) of the children remained alive at 18 years of age, and 34.3% (94 of 274) of those children were followed into adulthood. For adults, the median age of survival was 49.3 years. Treatment groups were mutually exclusive and in a hierarchical order: hematopoietic stem cell transplant (n = 22)>regular blood transfusion for at least 2 years (n = 56)>hydroxyurea for at least 1 year (n = 243)>no disease-modifying therapy (n = 98). Compared to those receiving no disease-modifying treatment, those treated with hydroxyurea therapy had a significantly lower hazard of mortality (hazard ratio = 0.38; P = 0.016), but no statistical difference for those receiving regular blood transfusions compared to no disease-modifying therapy (hazard ratio = 0.71; P = 0.440). An automated contemporaneous SCA cohort can be generated to estimate mortality in children and adults with SCA.

Influenza Vaccination Receipt in Pediatric Patients With Cancer or Sickle Cell Disease.

Influenza causes greater morbidity in children with cancer or sickle cell disease (SCD). Literature on influenza vaccination receipt for these populations is limited in low-vaccination states. Outpatient interventions improve vaccine receipt but isolated inpatient interventions remain unstudied. We reviewed influenza vaccine receipt of children with cancer or SCD treated at Children's Healthcare of Atlanta during three influenza seasons. We implemented a clinical decision support intervention during an influenza season and compared influenza vaccine receipt preintervention and postintervention among admitted children. The oncology cohort (N=1548, 60% to 62%) and the SCD cohort (N=2549, 61% to 65%) had similar-to-higher vaccination receipt to the United States (58% to 64%, P =0.01 to 0.79) and Georgia (51% to 56%, P <0.01). The intervention did not significantly improve vaccination receipt for admitted children with cancer (40% vs. 56%, P =0.05 to 0.88) or SCD (44% vs. 56%, P =0.01). Regression modeling also found no significant increase in vaccine receipt (hematologic malignancy: 0.8 [0.73 to 0.98], solid tumor: 0.9 [0.80 to 1.90], central nervous system tumor: 0.9 [0.71 to 1.14], SCD: 0.9 [0.85 to 0.99]). Children with cancer and SCD have similar-to-greater influenza vaccination receipt compared with Georgia and the United States. An inpatient intervention did not significantly improve influenza vaccine receipt in these patient cohorts. Future studies are needed to identify alternative approaches to improving vaccine receipt in these cohorts.

THE ROLE OF HYDROXYUREA IN INCREASING PULSE OXIMETRY AMONG PATIENTS WITH SICKLE CELL DISEASE

To identify the influence of hydroxyurea (HU) on oxygen saturation levels among patients with Sickle Cell Disease (SCD). A cross-sectional study was carried out that evaluated the use of HU for at least 1 year and the oxygen saturation measured on the oximeter in patients recruited in a SCD cohort in Brazil. A total of 275 patients were evaluated and 132 were included in this study. Inclusion criteria were (i) SS genotype, (ii) age over 18 years, (iii) HU use for more than 1 year (iv) no HU use, (v) active follow-up. Patients who did not use HU were the control group. The HU group had 57 patients with a mean age of 32 (±13.38) years, 50.88% women and 49.12% men. The means of Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Heart Rate (HR) and Oxygen Saturation (SpO 2 ) in this group were, respectively, 117.95 (±15.52) mmHg, 65.39 (±11.22) mmHg, 81.40 (±14.55) bpm and 93.02 (±14.55)%. The Control group consisted of 32 patients, the mean age was 30.50 (±10.92) years, 56.25% were women and 43.75% were men. The means of SBP, DBP, HR and SpO 2 in the control were respectively 114.69 (±12.37) mmHg, 62.44 (±9.37) mmHg, 80.19 (±15.66) bpm and 90.16 (±6.16)%. The difference between SpO 2 in the groups was statistically significant (p = 0.01). In the other variables evaluated there was no statistical significance. Oxygen desaturation is common in SCD and predicts clinical severity. Hypoxemia is associated with risk of stroke, abnormal transcranial Doppler velocities, elevation of tricuspid regurgitation, diastolic dysfunction, increased incidence of vaso-occlusive crises and chest syndrome sharp. Pulse oximetry is a non-invasive method of measuring oxyhemoglobin saturation. Peripheral perfusion, external light sources, and skin color and device quality should be observed. HU is the primary therapy in SCD and is capable of increasing the production of fetal hemoglobin (HbF). Studies have shown a strong correlation between peripheral SpO 2 and HbF level, so treatments that elevate HbF should impact desaturation and be beneficial for complications associated with hypoxia. In the United Kingdom, there is already a recommendation from the HU for the treatment of chronic hypoxemia in SCD. The measurement of SpO 2 is crucial for effective management in SCD. The association between HbF and SpO 2 reaffirms the importance of interventions that are able to increase both, like the HU. This study shows that the patients under use of HU had a significantly higher SpO 2 when compared to patients without it.

ASSOCIATION OF VITAMIN D RECEPTOR (VDR) VARIANTS, HYDROXYUREA THERAPY, AND CEREBROVASCULAR DISEASE STATUS ON 25-HYDROXYVITAMIN D (25(OH)D) LEVELS IN PATIENTS WITH SICKLE CELL ANEMIA

Vitamin D, through binding to its specific receptor, vitamin D receptor (VDR), executes actions beyond calcium metabolism and impacts sickle cell anemia (SCA) pathophysiology, such as regulating inflammation, vascular tone, and thrombogenesis. Genetic polymorphisms that can potentially disturb VDR function or its levels may modify the vitamin D mechanism and have already been associated with several conditions, including stroke. Therefore, we evaluated the association of 25-hydroxyvitamin D (25(OH)D) levels with VDR gene polymorphisms, hydroxyurea (HU) therapy, and cerebrovascular disease (CVD) in an SCA cohort. 25(OH)D levels were determined using the automated microparticle chemiluminescence method in 45 non-related SCA patients (55.5% males). Genotyping for functional FokI (rs2228570) and Cdx-2 (rs11568820) VDR polymorphisms was performed with TaqMan fluorogenic probes. Nonparametric Mann-Whitney and Kruskal-Wallis tests, followed by Dunn's multiple comparisons post-test, were used to analyze continuous variables. The median 25(OH)D levels were 20.9 ng/mL (range, 10 – 37.2 ng/mL). 18 patients (40%) had vitamin D deficiency (25(OH)D < 20ng/mL), 22 (49%) had insufficient levels (25(OH)D 20 - 30 ng/mL) and 05 (11 %) had sufficient levels (25(OH)D > 30 ng/mL). No difference was observed in 25(OH)D levels according to FokI and Cdx-2 genotypes (p > 0.05). However, 25(OH)D levels were decreased in patients with CVD (p = 0.026) and patients under hydroxyurea (HU) therapy (p = 0.005). Considering patients under HU therapy, individuals with variant TT- FokI genotype had lower levels of 25(OH)D (median: 13.9 ng/mL) when compared to those with CC/CT genotypes (median: 20.2 ng/mL; p = 0.03). In the group of individuals without HU therapy, this finding was not observed (p > 0.05). Although not statistically significant, patients with CVD and TT- FokI genotype had lower levels of 25(OH)D (median: 12.3 ng/mL) when compared to individuals with CC/CT genotypes (median: 20,8 ng/mL; p = 0.075). Despite the influence of HU in 25(OH)D levels has already been addressed with conflicting results, the mechanism that might explain these associations is not yet known. Moreover, previous findings indicate that the effect of functional VDR variants can be influenced by vitamin D status. Therefore, under the influence of factors that affect vitamin D levels, the defective VDR isoform, resulting from the FokI polymorphism, possibly accentuates the 25(OH)D deficiency, contributing to an adverse outcome. In summary, 25(OH)D levels are reduced in SCA patients with CVD and those under HU therapy. Further studies are required to determine the mechanism underlying HU and 25(OH)D levels associations and the effect of vitamin D supplementations in patients with CVD in SCA, especially those under HU therapy.

CLINICAL AND GENETIC FACTORS ASSOCIATED WITH OSTEONECROSIS IN BRAZILIAN SICKLE CELL DISEASE PATIENTS: CASE-CONTROL STUDY

Sickle cell disease (SCD) includes a group of hereditary disorders characterized by mutations on the gene that codes hemoglobin (Hb). Patients with SCD are vulnerable to vascular occlusion within bone tissue, which may result in complications such as medullary infarction in the diaphysis and osteonecrosis (ON), which affects the epiphysis. Both processes may result in substantial morbidity and pain for the patients. This study aims to identify factors associated with the development of ON in patients with SCD. A nested case-control study of patients with SCD from six Brazilian blood centers, participating in the Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) Brazil SCD Cohort was performed. A history of ON was abstracted from participants medical record using standardized definitions to define cases. Cases were matched to controls without ON in a 1:3 ratio matched by age, genotype and blood center using propensity score. A genome-wide association study (GWAS) was conducted to identify single nucleotide polymorphisms (SNPs) associated with ON. There were 307 ON cases in the 2793 cohort participants (prevalence 11%) who were compared to 921 controls without ON. The most common locations of ON were the proximal femur (91.2%) and proximal humerus (7.7%). Variables independently associated with ON in a multivariable model included patients with more severe sickle cell disease (SS, Sβ0, severe Sβ+ or SD genotypes, OR 1.81, 95% CI 1.11; 2.95 compared to less severe genotypes SC/SB+), higher values of hemoglobin (OR 1.25, 1.12; 1.39), hospitalization by pain crisis (OR 1.44, 1.06; 1.94), chronic transfusion treatment (OR 1.53, 1.10; 2.11), acute chest syndrome (OR 1.46, 1.06; 2.00), sepsis/bacteremia (OR 1.67, 1.03; 2.70) and osteomyelitis (OR 1.72, 1.05; 2.80). Increased indirect bilirubin and stroke were associated with a lower chance of developing ON (OR 0.81, 0.71; 0.93 for indirect bilirubin and OR 0.42, 0.24; 0.72 for stroke). The GWAS suggested an association of ON with the gene doublesex and mab-3 related transcription factor 2 (DMRT2) (p < 5 × 10−8). SCD is the most common monogenic disorder in Brazil and is associated with multisystem complications. Orthopedic complications represent 31.0% of these manifestations, with ON being the most common non-infectious joint complication. Knowing the risk factors that precede ON may help to diagnose and treat it early in order to improve the quality of life of patients. The few studies carried out in the Brazilian population on the occurrence of ON in SCD patients had small sample sizes. A higher chance of having ON was associated with patients with higher hemoglobin levels, more hospitalizations for pain crises and acute chest syndrome. Also the relationship of treatment with chronic transfusion, sepsis/bacteremia and osteomyelitis were associated with ON, which may indicate that the occurrence of this complication may be multifactorial or related to the severity of SCD. SNPs near DMRT2, a gene previously associated with skeletal disorders, rib malformation in a newborn and transition of endochondral bone formation, showed an altered risk for ON.

CLINICAL PREDICTORS OF VASO-OCCLUSIVE PAIN HOSPITALIZATION IN PATIENTS WITH SICKLE CELL DISEASE (SCD)

Vaso-occlusive painful episodes (VOE) are the most common clinical manifestation of sickle cell disease (SCD) and the primary reason for hospitalizations and emergency visits. This project aims to identify the clinical predictors of VOE hospitalization in adult participants of the Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) Brazil SCD Cohort. The REDS-III Brazil SCD Cohort enrolled participants from 2013 to 2015 who were followed until 2018. Participants were randomly selected as eligible from public blood centers in 6 cities. Medical records were reviewed to abstract clinical data including the indications for all hospitalizations that occurred from one year prior to enrollment through the end of follow up. Adult cohort participants with 3+ hospitalizations per year due to VOE (cases) were compared to controls with less frequent VOE admissions to identify predictors of frequent VOE. Of the 2793 participants enrolled in the cohort, 184 (6.7%) had 3+ VOE admissions per year (5.5% of 1330 children <18yr and 7.5% of 1453 adults). Compared to adults with <3 VOE admissions/ year, the adults with frequent VOE had higher white blood cell counts (11,566 vs. 98,659 cells/uL), platelet counts (389,500 vs 357,333 cells/uL) and lower hemoglobinF (4.4% vs 6.9%) and were more likely to have received red blood cell transfusions (80% vs. 41%) and hydroxyurea (60% vs. 49%) in the past year. Acute chest syndrome, bacteremia, and asthma were also more common in adult cases compared to controls (83% vs 61%, 16% vs 8% and 17% vs 8%, respectively). Independent predictors of 3+ VOE admissions/year in multivariable models included higher white blood cell (OR 1 [1.000-1.001], history of acute chest syndrome (OR 2.8 [1.581-5.202] and treatment with hydroxyurea (OR 1.8 [1.123-3.038]. Frequent hospitalizations due to VOE are a marker of severe SCD used to identify patients for disease modifying therapy or even curative therapies such as bone marrow transplant. Understanding the significant predictors of frequent VOE in adults may identify other surrogate markers of severe disease that can be used to target therapies for high risk individuals. In this multi institutional cohort of SCD, white blood cell count and a history of acute chest syndrome were identified as significant independent predictors of frequent VOE while the association of hydroxyurea likely reflects treatment with this disease modifying therapy for frequent pain. Individuals with high white blood cell counts and acute chest syndrome should have close follow up to be monitored frequently and considered for early and aggressive treatment of pain as well as other disease modifying therapies.

Impact of sickle cell disease in shoulder arthroplasty: a matched cohort analysis

Sickle cell disease (SCD) is a genetic disorder of abnormal hemoglobin synthesis that is known to cause glenohumeral avascular necrosis (AVN). Little has been published on the use of shoulder arthroplasty (SA) for the treatment of glenohumeral AVN in SCD. We report on the clinical and radiographic results and postoperative complications following SA in the patient cohort. A retrospective review was performed identifying 17 primary SAs (9 hemiarthroplasties, 7 anatomic total SAs, and 1 reverse total SA) in patients with a confirmed diagnosis of SCD and a minimum of 2-year follow-up. This cohort was matched (1:2) according to age, sex, body mass index, type of prosthesis, and year of surgery with patients who had undergone hemiarthroplasty or total SA for osteoarthritis (OA) or reverse total SA for cuff tear arthropathy. Outcomes included the visual analog scale (VAS) for pain, American Shoulder and Elbow Surgeons score, range of motion, and strength measurements in forward elevation (FE), external rotation (ER), and internal rotation (IR). Our cohort included 9 (52.9%) men with a mean age of 43yr. The average follow-up time was 5.9yr. In patients with SCD, SA provided significant improvements in VAS pain (9.1-3.8; P<.001), FE (95°-128°; P<.001), ER (24°-38°; P<.001), IR score (3.2-5.2; P<.001), FE strength (4.2-4.8; P<.001), ER strength (4.1-4.7; P<.001), IR strength (4.1-4.7; P<.001), and American Shoulder and Elbow Surgeons scores (48.6-73.5; P<.001). When compared to the matched cohort, the SCD group demonstrated higher preoperative (9.1 vs. 3.8; P<.001) and postoperative VAS scores (3.8 vs. 1.3; P<.001). Other clinical outcomes demonstrated no significant differences. There were 5 (29%) complications, 2 (11.8%) episodes of sickle cell crisis, and 3 (18%) reoperations in the SCD cohort. When compared to the matched cohort, there were no statistical differences with respect to complications (29% vs. 12%; P=.140) or reoperations (18% vs. 12%; P=.387). SA is an effective treatment modality for glenohumeral AVN in patients with SCD. Patients may expect improvements in pain, function, motion, and strength. However, final postoperative pain relief may be less than those treated with SA without SCD. Unique perioperative management is necessary to mitigate the risk of postoperative sickle cell crises.

Incidence, kinetics, and risk factors for intra- and extracranial cerebral arteriopathies in a newborn sickle cell disease cohort early assessed by transcranial and cervical color Doppler ultrasound.

The risk of stroke in children with sickle cell disease (SCD) is detected by abnormal intracranial arterial time-averaged mean of maximum velocities (TAMVs ≥200 cm/s). Recently, extracranial internal carotid artery (eICA) arteriopathy has been reported, and a cross-sectional study showed that eICA-TAMVs ≥160 cm/s are significantly associated with eICA kinkings and stenosis. The cumulative incidence of and predictive risk factors for intracranial arteriopathy are well described in sickle cell anemia (SCA=SS/Sβ0) but are lacking for SC/Sβ+ children, as is the cumulative incidence of eICA arteriopathy. We report a prospective longitudinal cohort study including 493 children with SCD (398 SCA, 95 SC/Sβ+), all assessed by transcranial and cervical color Doppler ultrasound. Cerebral MRI/MRA data were available in 375 children with SCD and neck MRA in 365 children. eICA kinkings were defined as eICA tortuosities on neck MRA, with an internal acute angle between the two adjacent segments <90°. The median follow-up was 10.6 years. The cumulative incidence of kinkings was significantly lower in SC/Sβ+ children than in children with SCA, and no SC/Sβ+ child developed intra- or extracranial stenotic arteriopathy. The 10-year KM estimate of cumulative incidence (95% CI) for eICA-TAMVs ≥160 cm/s revealed its development in the 2nd year of life in children with SCA, reaching a plateau of 17.4% (13.2–21.6%) by about 10 years of age, while the plateau for eICA stenosis was 12.3% (8.3–16.3%). eICA assessment identified 13.5% (9.3–17.7%) patients at risk of stroke who were not detected by transcranial color Doppler ultrasound. We also show, for the first time, that in addition to a congenital origin, eICA kinkings sin patients with SCD can develop progressively with aging as a function of eICA-TAMVs, themselves related to anemia severity. Ongoing hydroxyurea treatment was significantly associated with a lower risk of abnormal intracranial arteriopathy and eICA kinkings. After adjustment with hydroxyurea, baseline low hemoglobin, high reticulocyte, and WBC counts remained independent risk factors for intracranial arteriopathy, while low hemoglobin and SEN β-haplotype number were independent risk factors for extracranial arteriopathy. The association between extracranial arteriopathy and SEN β-haplotype number suggested a genetic link between the ethnic origin and incidence of eICA kinkings. This prospective cohort study shows the importance of systematically assessing the eICA and of recording biological parameters during the 2nd year of life before any intensive therapy to predict the risk of cerebral arteriopathy and treat patients with severe baseline anemia.

Contribution of ADAMTS13‐independent VWF regulation in sickle cell disease

BackgroundVon Willebrand factor (VWF) is elevated in sickle cell disease (SCD) and contributes to vaso‐occlusion through its thrombogenic properties. VWF is regulated by ADAMTS13, a plasma protease that cleaves VWF into less bioactive multimers. Independent investigations have shown VWF to be elevated in SCD, whereas measurements of ADAMTS13 have been variable. ObjectivesWe assessed ADAMTS13 activity using multiple activity assays and measured levels of alternative VWF‐cleaving proteases in SCD. Methods/ PatientsPlasma samples were collected from adult patients with SCD (n = 20) at a single institution when presenting for routine red cell exchange transfusion therapy. ADAMTS13 activity was measured by FRETS‐VWF73, Technozym ADAMTS‐13 Activity ELISA kit and a full‐length VWF digestion reaction. Alternative VWF‐cleaving proteases were identified by ELISA. A cell culture model was used to study the impact of SCD stimuli on endothelial ADAMTS13 and alternative VWF‐cleaving proteases. ResultsADAMTS13 activity was found to be moderately deficient across the SCD cohort as assessed by activity assays using a VWF A2 domain peptide substrate. However, SCD plasma showed preserved ability to digest full‐length VWF, suggesting assay‐discrepant results. Neutrophil and endothelial‐derived proteases were found to be elevated in SCD plasma. Matrix metalloproteinase 9 specifically showed preferential cleavage of full‐length VWF. Upregulation of alternative VWF‐cleaving proteases occurred in endothelial cells exposed to SCD stimuli such as heme and hypoxia. ConclusionsThis is the first demonstration of accessory plasma enzymes contributing to the regulation of VWF in a specific disease state and may have implications for assessing the VWF/ADAMTS13 axis in other settings.

Sickle cell disease and the incidence and etiology of preterm birth

Medically indicated delivery can be defined as delivery owing to intervention for maternal or fetal well-being-most commonly because of preeclampsia or nonreassuring fetal status. Among the general population of the United States, approximately two-thirds of preterm deliveries are because of spontaneous labor and/or premature rupture of membranes, whereas the remaining one-third are medically indicated. Despite the increased risk of preterm birth among women with sickle cell disease, the specific etiologies have not been described in the medical literature. Without an understanding of the etiologies of preterm birth in women with sickle cell disease, it is difficult to develop preventative strategies. This study aimed to estimate the incidence and etiologies of preterm births (spontaneous vs medically indicated) in women with sickle cell disease. This was a retrospective, institutional review board-exempt cohort study of deliveries at >20 weeks' gestation in women with sickle cell disease at Duke University Hospital (2013-2020). We screened pregnancy-linked hospitalizations with International Classification of Diseases-9/10 codes for sickle cell disease (n=373). We excluded cases of pregnancy with <20 weeks' gestation, multiple gestation, or unproven sickle cell disease. We limited inclusion to deliveries within Duke (n=66). We compared the proportion of preterm birth cases between the sickle cell disease cohort and the overall Duke population (n=18,365), and the proportion of spontaneous vs medically indicated preterm births between the sickle cell disease cohort and a racially matched US population. Of the 66 pregnancies, 65 occurred in patients who self-described as Black (98.5%). There were 60.6% (n=40) term and 39.4% (n=26) preterm births vs 85.9% term (n=15,771) and 14.1% preterm (n=2594) births in the Duke population as a whole. The sickle cell disease cohort was nearly 3 times more likely to deliver preterm than the Duke cohort (risk ratio, 2.79; 95% confidence interval, 2.06-3.77; P<.001). Among the 26 preterm births in the sickle cell disease cohort, 30.8% (n=8) were spontaneous and 69.2% (n=18) were medically indicated. In the US Black population comparison cohort, 65.4% (n=392,984) of preterm births were spontaneous and 34.6% (n=207,614) were medically indicated. The sickle cell disease cohort had 2 times the risk of medically indicated preterm birth compared with the US population cohort (risk ratio, 2.00; 95% confidence interval, 1.55-2.59; P<.001). Maternal sickle cell disease confers nearly triple the risk of preterm birth, which is twice as likely to be medically indicated.

P-020: IMPLICATIONS OF SOCIOECONOMIC DISTRESS ON NUTRITIONAL STATUS AND KIDNEY FUNCTION IN PEOPLE WITH SICKLE CELL ANEMIA

Purpose: Sickle cell anemia (SCA) is characterized by a myriad of acute and chronic complications. These complications negatively impact the ability to achieve educational and occupational goals making this group a particularly vulnerable population to socioeconomic challenges (PMID 30540112). In the general population, indices of socioeconomic distress are associated with poor nutrition and kidney disease risk (PMID 25573510). The association of socioeconomic distress with nutritional status and kidney function in people with SCA is unknown. Materials and methods: We conducted a cross-sectional study to describe the burden of socioeconomic distress and its impact on nutritional status and kidney function in an SCA cohort (n=332) treated at an urban academic institution. The distressed community index (DCI), a composite of socioeconomic indicators that estimate the economic well-being of a community, was determined for each individual using the following website: https://eig.org/dci/interactive-map. A higher DCI score indicates a more distressed community. The associations of DCI with measures of nutritional status (serum albumin, body mass index [BMI], vitamin D 25-OH) and kidney function (estimated glomerular filtration rate [eGFR]; albuminuria; serum bicarbonate, potassium, and erythropoietin levels), were determined using linear or logistic regression. The analyses were adjusted for age, sex, and hydroxyurea use for nutritional status as well as for APOL1 G1 and G2 risk status for kidney function. The beta coefficients provided are based on increments of 10 for DCI. Median and interquartile ranges (IQR) are provided. Results: The median age of the cohort was 31 years (IQR, 24 – 41 years), 55% were female, and 53% were on hydroxyurea therapy. The median DCI in this cohort was 87 (IQR, 61 – 96) with 61% of SCA patients living in a distressed tier (DCI≥ 80) and only 5% living in a prosperous tier (DCI< 20). The DCI tiers for SCA patients trended towards more socioeconomically distressed communities compared to the general African American population (P=0.1) (Figure 1A). A higher DCI, reflecting an increase in socioeconomic distress, was associated with a trend for a lower odds ratio (OR) of being on hydroxyurea therapy (OR 0.93, 95% CI: 0.86 – 1.01; P=0.08). An increasing DCI was significantly associated with lower serum albumin (β= -0.02; P=0.016) (Figure 1B), BMI (β= -0.01; P=0.045), and vitamin D 25-OH levels (β= -0.7; P=0.001) (Figure 1C). A higher DCI was associated with a trend for a lower eGFR (β= -0.6; P=0.09) (Figure 1D) while no association was observed with urine albumin concentration (P=0.8). Lower serum bicarbonate (β= -0.1; P=0.02) and lower erythropoietin (β= -0.9; P=0.1) levels, but not serum potassium concentration (P=0.9), were also associated with higher DCI. Conclusion: In conclusion, we demonstrate that a high proportion of patients with SCA treated at an urban academic institution live in distressed socioeconomic communities. Furthermore, higher distressed community indices are associated with lower measures of nutritional status and with some markers of impaired kidney function. Future studies investigating the effects of socioeconomic distress on access to healthy foods and kidney disease risk may guide public health strategies to improve health disparities in the SCA population.Figure 1. The authors do not declare any conflict of interest

Is Severity Score Associated With Indication for Hematopoietic Stem Cell Transplantation in Individuals With Sickle Cell Anemia?

Manifestations of sickle cell disease (SCD) begin early in childhood and cause morbidity and decreased life expectancy. Hematopoietic stem cell transplantation (HSCT) is curative but associated with risk of mortality attributable to the transplant. This risk should be counterbalanced with SCD morbidity and mortality. A severity score using a Bayesian network model was previously validated to predict the risk of death in adult individuals with SCD. The objective of this study is to calculate the severity scores of participants in a multicenter cohort of Brazilians with SCD, using a previously published Bayesian network-derived score, associated with risk of death and then compare the severity scores between participants with and without an indication for HSCT as defined by the Brazilian Ministry of Health (MoH) criteria. This is an observational, retrospective study. We analyzed 2063 individuals with sickle cell anemia from the Recipient Epidemiology and Donor Evaluation Study-III Brazil SCD cohort and applied a Bayesian network-derived score to compare candidates and non-candidates for HSCT according to the Brazilian MoH transplant criteria. Classical statistical methods were used to analyze data and make comparisons. We compared severity scores between cohort members with (n=431) and without (n=1632) HSCT indications according to Brazilian MoH. Scores were not different in adult participants with ≥1 HSCT indication when compared to those with no indication (mean 0.342 versus 0.292; median 0.194 versus 0.183, P=.354) and receiver operating characteristic curves did not demonstrate an obvious threshold to differentiate participants with or without HSCT indications. Severity score may predict risk of death but does not differentiate HSCT candidates. Current indications should be evaluated to ensure that patients with more severe disease who might benefit from HSCT are appropriately identified.

PB2219: A REAL-WORLD EXPERIENCE WITH HEALTHCARE RESOURCE UTILIZATION PATTERNS AND RELATED COSTS IN PATIENTS WITH SICKLE CELL DISEASE IN NORTH LEBANON

Background: Sickle cell disease (SCD) remains associated with high healthcare resource utilization (HRU), despite a reduction in morbidity and mortality associated with the use of disease-modifying therapies, mostly because of vaso-occlusive crises (VOC). In Lebanon, there are limited national estimates on HRU, cost of medical care, and treatment expenditures for patients with SCD. A better understanding of these estimates may provide new perspectives to improve access to high-quality cost-effective health care services. Aims: Aim of our study is to evaluate patterns of HRU and related cost in a cohort of patients with SCD receiving care in a Comprehensive SCD referral center at NINI hospital in North Lebanon. Methods: An observational, non-interventional, retrospective study of 136 patients (54.4% females) with confirmed diagnosis of SCD was conducted in North Lebanon. Data on HRU, including ED visits, ambulatory visits, and hospitalizations, was collected in a patient health information (PHI)-anonymized format from patients’ paper and electronic medical files, as well as hospital and ED files, from May 1, 2018 to April 30, 2020. Uncomplicated VOCs were defined as pain crises, whereas complicated VOCs were defined as acute chest syndrome, acute splenic sequestration, acute hepatic sequestration or priapism. The annual rate of HRU visits was calculated as a ratio of the total number of visits to the total number of years of follow-up across all patients. Based on the available data, the average yearly cost was determined as the ratio of the total cost of these visits to the total number of years of follow-up. Results: The median age of patients in this study was 10.8 years (IQR 5.3 to 19.6 years) at the time of investigation. Majority of patients were diagnosed with SS (72.1%) and Sβ0 (21.3%) genotype across all age groups. The most prevalent SCD-related complications were pain crisis (90.4%), fever (43.4%), acute chest syndrome (33.1%), and acute splenic sequestration (22.8%). Most of hospitalizations, ICU visits, and ED visits in adult patients (age >16 years) were due to uncomplicated VOCs. The average annual costs of HRU were 8,270,920 Lebanese pounds (LBP) amounting to 5,514 USD (per patient per year) of which 92.1% was for hospitalizations, 4% for ED visits and 3.9% for ambulatory visits. Uncomplicated VOCs had the highest annual costs for ED, ICU and hospitalizations. Costs related to medications, diagnostics, non-hematologist medical consults, uncompensated care and lost productivity are not included in this analysis. Analgesics, folic acid and hydroxyurea were the most commonly prescribed drugs across all age categories, with hydroxyurea being prescribed to 84% of patients. Image:Summary/Conclusion: SCD and associated complications resulted in significant acute HRU, according to this real world study. VOCs continues to be most important factor for resource use, ICU admission and costs, with hospitalizations accounting for majority of annual costs. Despite the high HRU rate in this relatively young SCD cohort, the cost of HRU in a comprehensive setting with effective outpatient management as that in North Lebanon appears affordable for the health care system. However when additional SCD related and non SCD related costs of care are factored in, the economic burden of SCD care is likely to be far higher than the figures presented here.

Oxidative stress and associated clinical manifestations in malaria and sickle cell (HbSS) comorbidity.

In Ghana, uncomplicated malaria and sickle cell disease (SCD) is common, hence comorbidity is not farfetched. However, the extent of oxidative stress and the array of clinical manifestations in this comorbidity (presence of both malaria and SCD) has not been fully explored. This study highlights the impact of uncomplicated malaria on SCD. The level of isoprostane, 8-iso-prostaglandin F2α (8-iso-PGF2α) was used to assess oxidative stress while plasma biochemistry and urinalysis was used to assess renal function. Hematological profiling was also done to assess the impact of comorbidity on the hematological cell lines. Of the 411 study participants with malaria, 45 (11%) had SCD. Mean body temperature was significantly higher in comorbidity compared to malaria and SCD cohorts, while a lower parasite density range was obtained in comorbidity compared to malaria cohorts. Furthermore, in comorbidity, the 8-iso-PGF2α oxidative stress biomarker was significantly elevated in all ages, parasite density ranges and gender groups. Comorbidity affected both leukocytic and erythrocytic cell lines with significant eosinophilia and monocytosis coexisting with erythrocytic parameters consistent with severe anemia. Biochemically, while plasma creatinine and bilirubin were significantly elevated in comorbidity, spot urinary creatinine was significantly reduced. Additionally, urine samples in the comorbid state were slightly acidic and hypersthenuric with significant hematuria, proteinuria, and bilirubinemia. Finally, 80% or more malaria-SCD presented with chills, fever, anorexia, headache, joint pains, lethargy, and vomiting. In conclusion, malaria could induce vaso-occlusive crisis in sickle cell disease, therefore, prompt management will alleviate the severity of this comorbidity.

HUMAN STUDY COMT and DRD3 haplotype-associated pain intensity and acute care utilization in adult sickle cell disease.

A previous exploratory analysis of a COMT gene single-nucleotide polymorphism (SNP) and a DRD3 SNP by our group suggested possible contributions to pain-related acute care utilization in people with sickle cell disease (SCD). Our aim was to extend the analysis to gene-spanning haplotypes of COMT SNPs and DRD3 SNPs to investigate possible associations with pain intensity and pain-related acute care utilization in an SCD cohort. Genotyping was conducted, and clinical data were collected, including self-reported pain intensity using PAINReportIt® (average of current pain and least and worst in past 24 hours, average pain intensity [API]) and medical record-extracted, pain-related acute care utilization data of 130 adults with SCD. Haplotype blocks were identified based on linkage disequilibria (COMT = 7 haploblocks; DRD3 = 8 haploblocks). Regression analyses were tested for association between haplotypes and API and utilization, yielding several significant findings. For COMT block 1 (rs2075507, rs4646310, rs737865), the A-G-G haplotype was associated with higher API compared to the reference A-G-A (p = 0.02), whereas the A-A-A haplotype was associated with higher utilization (p = 0.02). For DRD3 block 2 (rs9817063, rs2134655, rs963468, and rs3773679), relative to reference T-C-G-C, the T-T-G-C haplotype was associated with higher utilization (p = 0.01). For DRD3 block 4 (rs167770, rs324029, and rs324023), the A-G-T haplotype was associated with higher API (p = 0.04) and utilization (p < 0.001) relative to reference G-A-T, whereas the A-A-T haplotype was associated with higher utilization (p = 0.01). We found COMT and DRD3 haplotypes associated with pain-related SCD features, suggesting that in future studies more emphasis be placed on cis effects of SNP alleles in evaluating genetic contributions to SCD pain and acute care utilization for pain.

Enuresis and Hyperfiltration in Children With Sickle Cell Disease.

Nocturnal enuresis is a common symptom in children with sickle cell disease (SCD). Risk factors for development of enuresis are currently unknown. An early manifestation of SCD-associated kidney damage is glomerular hyperfiltration. We test the hypothesis that in a pediatric SCD cohort, individuals with hyperfiltration are more likely to have nocturnal enuresis when compared to children without hyperfiltration. To assess the relationship between nocturnal enuresis and hyperfiltration, we retrospectively evaluated children with SCD enrolled in the Evaluation of Nocturnal Enuresis and Barriers to Treatment among Pediatric Patients with SCD study and prospectively identified children who reported nocturnal enuresis and were enrolled in the longitudinal cohort study Sickle Cell Clinical Research and Intervention Program. Nocturnal enuresis occurred in 46.5% of Pediatric Patients with Sickle Cell Disease participants and was more frequent in participants with HbSS/HbSβ 0 thalassemia and in male participants. We did not identify an association between hyperfiltration from 3 to 5 years of age with the later development of enuresis. Severe SCD genotypes and male sex were associated with nocturnal enuresis after age 5 years. We could not identify additional renal or hematologic predictors associated with the diagnosis of nocturnal enuresis. Future studies should incorporate nonrenal risk factors into studies that predict development of enuresis.

Newborn Screening and Clinical Profile of Children With Sickle Cell Disease in a Tribal Area of Gujarat

To present the result of newborn sickle cell disease (SCD) screening and clinical profile of SCD newborns in a tribal area of Gujarat. We screened all newborns of sickle cell trait (SCT) and SCD mothers for SCD using high-performance liquid chromatography (HPLC) within two days of birth at a secondary care hospital in a tribal area in Gujarat from 2014 to 2019. Newborns with SCD were registered under an information technology based platform for hospital-based comprehensive care. Neonates were followed prospectively every 3 months. If they missed the clinic visit, a medical counsellor visited them at home to collect the required information. Out of 2492 newborns screened, 87 (3.5%) were diagnosed with SCD. Among the 67 newborns screened for alpha-thalassemia deletion, 64 (95.4%) of babies had alpha-thalassemia deletion. We recorded total 554 clinic visits over the period of 221.5 person-years. The rates of acute febrile illness, painful crisis, hospitalization and severe anemia were 42.9, 14.9, 14.9 and 4.5 per 100 person-year, respectively. Two deaths were recorded, and 5 babies (5.7%) had severe SCD. We found a high prevalence of alpha thalassemia deletion among newborn SCD cohort in tribal area of Gujarat, and 70% babies had atleast one clinical complication on follow-up.

P127: HEALTHCARE RESOURCE UTILIZATION PATTERNS AND RELATED COSTS IN PATIENTS WITH SICKLE CELL DISEASE IN NORTH LEBANON- A REAL-WORLD EXPERIENCE

Background: Despite a reduction in morbidity and mortality associated with the use of disease modifying therapies, sickle cell disease (SCD) remains associated with high healthcare resource utilization (HRU), primarily attributed to vaso-occlusive crisis (VOC). (1, 2) There are limited national estimates on HRU, cost of medical care, and treatment expenditures for patients with SCD in Lebanon. A better understanding of these estimates may provide new perspectives to improve access to high-quality cost-effective health care services. Aims: We aimed to evaluate patterns of HRU and related cost in a cohort of patients with SCD receiving care in a Comprehensive SCD referral center at NINI hospital in North Lebanon. Methods: A retrospective non-interventional observational study was conducted among 136 patients (54.4% females) with confirmed diagnosis of SCD in North Lebanon. Data on HRU including emergency department (ED) visits, ambulatory visits and hospitalizations collected in a patient health information (PHI)-anonymized format during the period 01 May2018 - 30 Apr 2020 were obtained from patients’ paper and electronic medical files, as well as hospital and ED files. Uncomplicated VOCs were defined as pain crises, whereas complicated VOCs were defined as acute chest syndrome, acute splenic sequestration, acute hepatic sequestration or priapism. The annual rate of HRU visits was calculated as a ratio of the total number of visits to the total number of years of follow-up across all patients. The average annual cost was similarly calculated as the ratio of total cost of these visits to the total number of years of follow-up, based on available data. Results: In the present study, the median age of patients at the time of study was 10.8 years (IQR 5.3 to 19.6 years). Majority of patients were diagnosed with SS (72.1%) and Sβ0 (21.3%) genotype across all age groups. Pain crisis (90.4%), fever (43.4%), acute chest syndrome (33.1%), and acute splenic sequestration (22.8%) were the most common SCD-related complications. The annual rate of HRU visits (per patient) was 5.7. Uncomplicated VOCs led to majority of hospitalizations, ICU and ED visits in adult patients (age >16 years). The average annual costs of HRU were 8,270,920 Lebanese pounds (LBP) amounting to 5,514 USD (per patient per year) of which 92.1% was for hospitalizations, 4% for ED visits and 3.9% for ambulatory visits. Annual costs for ED, ICU and hospitalizations were highest for uncomplicated VOC. Costs related to medications, diagnostics, non-hematologist medical consults, uncompensated care and lost productivity are not included in this analysis. Analgesics, folic acid and hydroxyurea were the most frequently administered medications across all age groups with 84% of patients being treated with hydroxyurea. Conclusion: This real world study reveals that SCD and its related complications resulted in significant acute HRU. VOCs remain the primary factor for resource use, ICU admission and costs with the largest proportion of annual cost being attributed to hospitalizations. Despite the high HRU rate in this relatively young SCD cohort, the cost of HRU in a comprehensive setting with effective outpatient management as that in North Lebanon appears affordable for the health care system. However when additional SCD related and non SCD related costs of care are included, the economic burden of SCD care is likely to be significantly higher than the figures reported.

The role of immature granulocyte percentage in predicting acute chest syndrome and the severity of the vaso-occlusive crisis in sickle cell disease.

Sickle cell disease (SCD) is an inflammatory disease that can result in both chronic and acute inflammation. Immature granulocytes (IG) are not-yet-mature white blood cells that can be easily detected in complete blood count (CBC) tests. In recent studies it has been suggested that IG may play a role in determining the prognosis of inflammatory diseases. The aim of our study was to investigate the role of IG percentage on predicting acute chest syndrome (ACS) and the severity of vaso-occlusive crisis (VOC) in patients with SCD. The study cohort consisted of 49 SCD patients admitted to the emergency department for VOC. If symptoms did not regress despite appropriate treatment including hydration and analgesia, they were hospitalized. Patients whose symptoms regressed were discharged from the emergency department within 24 hours. Blood samples, including CBC and C-reactive protein (CRP), a marker of inflammation, were taken within the first hour of admission. Steady state laboratory parameters from the previous visit in the last three months were collected from patient files. The mean age was 18±4 (range 8-25) years. Most were hospitalized (41/49; 83.7%) and 8 of 49 were discharged from the emergency department after their treatment for VOC. ACS developed in 13 of 49 (26.5%). White blood cell, neutrophil and nucleated red blood cell counts, percentage of IG (IG%) and CRP levels were significantly increased in patients with VOC. IG% of patients with ACS was significantly higher than patients without ACS. However, ROC analysis showed that IG% was not associated with the development of ACS or hospitalization for VOC. Despite a small SCD cohort, the significant increase in the IG% in patients with VOC compared to their baseline values has suggested a role for IG% in predicting VOC. Although IG% was higher in ACS, its utility in predicting ACS was poor.