COVID-19 and Sickle Cell Disease in the Province of Quebec: Morbidity and Mortality Rates Derived from the Provincial Registry

Abstract Introduction Approximately 1500 people live with sickle cell disease (SCD) in the province of Quebec, Canada. Public health has recognized these patients as immunocompromised. SCD patients may be at higher risk of developing severe COVID-19 infection due to their underlying pro-inflammatory and thrombogenic state, splenic dysfunction and secondary organopathies. Descriptions about disease severity and mortality rates in SCD vary widely. From the SECURE-SCD registry, Mucalo et al. recently reported a 0.3% and 4.7% mortality rate in children and adults, respectively. In the French registry, Arlet and colleagues reported a 2.4% death rate among those hospitalized with COVID-19 and SCD, not different from the general population. As a result, the COVID-19 morbidity and mortality rates among the SCD population remain uncertain. Objectives The primary objectives of our study are to describe the epidemiology, baseline characteristics and clinical outcomes of SCD patients with COVID-19 infection in the province of Quebec. In addition, we aim to identify risk factors for hospitalization and severe forms of COVID-19. Methods We built a web-based SCD-COVID-19 registry regrouping 7 adult and 4 paediatric tertiary care hospitals in the province of Quebec in June 2020. All SCD patients with a confirmed SARS-CoV-2 infection by PCR test were included in the study. We compared the prevalence of infection and hospitalization rates of SCD patients to the general population of Quebec using the epidemiological data from the INSPQ (National Institute of Public Health of Quebec) public database. We retrospectively analyzed data included between March 11, 2020 to March 1, 2021. Relative risk was calculated using bilateral association measures (exact fisher, mid-p or chi-squared tests, as appropriate) to compare the incidence of infection and hospitalization of SCD patients to the population of Quebec and to assess risk factors of hospitalization among SCD patients. Results During the first 12 months of the pandemic, 74 patients were included in the registry. The male to female ratio was 1:1.12. Median age was 23 years, ranging from 8 months to 68 years old. SS-Sbeta 0 genotypes were present in 51% of cases, while 49% were SC or Sbeta +. The majority of patients were on disease modifying therapy: 54% were on hydroxyurea and 17.5% on exchange transfusion therapy. The incidence of reported COVID-19 infection was significantly higher in SCD patients compared to the general population (4.9% vs. 3.5% p=0,002) (Table 1). Even more strikingly, SCD had rate of hospitalization 10-times greater than the general population (33.8 vs 3.2%, p<0,001). Nevertheless, the risk of admission to the intensive care unit was similar between SCD patients and the general population (24.0% vs. 24.1%, p=0.99). No death was recorded amongst SCD patients with COVID-19 compared to a death rate in the general population in Quebec of less than 70 years old of 48-78 for 100 000 infections (male-female). A history of acute chest syndrome (ACS) in the last year (OR 2.6 [1.5-4.6], p=0.04) and arterial hypertension (OR 3.3 [2.3-4.8], p=0.01) were associated with a higher risk of hospitalization (Table 2). On the other hand, there was no statistically significant association with age, sex, genotype, ABO blood group, baseline SCD therapy, or other comorbidities (chronic renal disease, obesity, pulmonary hypertension, chronic lung disease and previous admission to ICU) in our cohort. Conclusions Similar to other reports, we found that SCD patients were at much greater risk of hospitalization compared to the general population. We however found no increased risk of mortality or disease complication. This contrasts with results from other registries. A history of ACS and hypertension were associated with a higher risk of hospitalization. Whether social determinants of health could explain some of the outcome variability between different countries merit further investigation. Furthermore, we believe that registries are critical to monitor the impact of preventive measures. As vaccination is ongoing, it will be important to consider its impact on hospitalization and death rate among SCD population. Recruitment to the registry is ongoing and updated data will be presented at the meeting. Figure 1 Figure 1. Disclosures Soulieres: BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Forté: Novartis: Honoraria; Canadian Hematology Society: Research Funding; Pfizer: Research Funding.

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Alkaline Phosphatase Is Associated with Red Cell Alloimmunization in the Pulmonary Hypertension and Hypoxic Response (PUSH) Sickle Cell Disease Cohort

Blood ◽

10.1182/blood-2020-143036 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 20-20

Author(s):

Victoria Brooks ◽

Oluwalonimi Adebowale ◽

Victor R. Gordeuk ◽

Sergei Nekhai ◽

James G. Taylor

Keyword(s):

Risk Factors ◽

Alkaline Phosphatase ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Research Funding ◽

Severe Disease ◽

Case Control ◽

Red Cell ◽

Cell Disease ◽

History Of

Background: Blood transfusion is a common therapy for sickle cell disease (SCD). Although, highly effective, a major limitation is development of alloantibodies to minor blood group antigens on donor red cells. Alloimmunization has a prevalence of 2-5% for transfusions in the general population, but it is significantly higher in SCD. Risk factors for alloimmunization have been poorly characterized, although number of lifetime transfusions is an important risk factor. Alloimmunization has been clinically observed in children with a prevalence of about 7%. With development of each antibody, blood donor matching becomes increasingly difficult and expensive with an increased risk for transfusion reactions and diminished availability of compatible red cell units for treatment of SCD. The ability to identify risk factors for developing alloantibodies would be beneficial for clinicians. To identify markers for alloimmunization in SCD, we have analyzed children and adults who developed this complication. Methods: We analyzed The Pulmonary Hypertension and Hypoxic Response in Sickle Cell Disease (PUSH) study, which enrolled n=468 pediatric and n=59 adult SCD subjects. In both children and adults, alloimmunization cases were defined as a history of at least 1 alloantibody. Controls in both cohorts were defined as subjects with no history of alloantibodies and receipt of more than 10 lifetime red cell transfusions. All others within the study who did not meet these criteria were assigned to a third comparison group. To identify differences between cases, controls and all others, we performed univariate analyses (using ANOVA or Kruskal Wallace where appropriate) for clinical parameters and laboratories. Case control comparisons were also performed for selected variables and plasma levels for 11 cytokines. Results were further analyzed using regression modeling. Results: The overall prevalence of alloimmunization was 7.3% among children (34/468 subjects; median age 12, range 3-20 years) compared to 28.8% in adults (17/59 subjects; median age 37, range 18-73 years). When only considering those with >10 lifetime transfusions, the prevalence was considerably higher at 29.3% and 54.8% in children and adults, respectively. At the same time, 8 pediatric (23.5%) and 5 adult (29.4%) alloimmunization cases had received fewer than 10 transfusions. In a 3-way pediatric cohort comparison (cases, controls and all others), risk factors associated with alloimmunization included SS genotype, older age and markers of more severe disease (higher ferritin, WBCs, platelets and total bilirubin). Comparison of cases to controls showed alkaline phosphatase (P=0.05) was significantly lower in cases, whereas AST (P=0.02) was significantly higher even with adjustment for age. Levels of plasma cytokines MCP-1 (P=0.01) and IFNgamma (P=0.08) were lower in cases from a subset of the pediatric cohort. In adults, only 4/59 (6.8%) subjects had never received a lifetime transfusion (all non-SS). In the adult 3-way comparisons, only SS genotype and higher ferritin were associated with alloimmunization. The adult case control analysis showed higher absolute monocyte count (P=0.02), absolute eosinophil count (P=0.04) and absolute basophil count (P=0.008) in association with alloimmunization cases. In addition, alkaline phosphatase was again significantly lower among cases (P=0.02) as seen in the pediatric cohort. There were no significant differences in cytokine levels among adults. Conclusions: When considering only transfused SCD patients, the prevalence of alloimmunization is higher than 30%. As seen in prior studies, higher lifetime red cell transfusions are an important risk factor especially among adults where most patients have received transfusions. Children who develop alloantibodies appear to have laboratory markers of more severe disease, but this is not observed in adults. A novel association observed across both pediatric and adult subjects is a significantly lower serum alkaline phosphatase in those with alloantibodies. The results of this study suggest a need for improved tracking of red cell transfusion therapy in the US for SCD patients due to a high prevalence of alloimmunization. Further study is also needed to elucidate the significance of the alkaline phosphatase association. Disclosures Gordeuk: CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Novartis: Consultancy; Ironwood: Research Funding; Imara: Research Funding.

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Risk Factors for Adverse Maternal and Fetal Outcomes in Pregnant Patients with Sickle Cell Disease

Blood ◽

10.1182/blood-2021-151914 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3117-3117

Author(s):

Sherraine Della-Moretta ◽

William Marshall ◽

Rui Li ◽

Erin Cleary ◽

Philip Samuels ◽

...

Keyword(s):

Risk Factors ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Research Funding ◽

Maternal Age ◽

Acute Chest Syndrome ◽

Hypertensive Disorders Of Pregnancy ◽

Cell Disease ◽

History Of ◽

Maternal Bmi

Abstract Background Approximately 100,000 Americans are affected by sickle cell disease (SCD), an inherited hematologic disorder. In women with sickle cell disease, pregnancy is associated with increased maternal and fetal adverse outcomes (Elenga et al). However, there is a paucity of data on risk factors for adverse events in this population. This retrospective study seeks to add to the deficient repertoire of information regarding maternal and fetal outcomes in patients with sickle cell disease and their children. Methods We retrospectively evaluated pregnancy outcomes of women with SCD who had previously undergone echocardiography from the year 2000-2021. The associations between clinical variables and adverse hematologic (AHE), cardiac (ACE), obstetric (AOE) and fetal/neonatal (ANE) events were evaluated by the Generalized Linear Model (GLM). The adverse hematologic events were vaso-occlusive crisis (VOC) antepartum and postpartum, acute chest syndrome, venous thromboembolism antepartum and postpartum, and transfusion antepartum. Results We identified 43 women/59 pregnancies with a median maternal age 27 years old (interquartile range [IQR] 20), pre-pregnancy BMI 25 kg/m2 (IQR 16). Maternal sickle cell genotype was SS in 31 (72%) women/37 (63%) pregnancies, SC in 8 (18%) women/18 (31%) pregnancies, and other genotype in 4 (9%) women/4 (7%) pregnancies. Prior venous thromboembolism was present in 12 (27%) women/15 (25%) pregnancies and prior acute chest syndrome (ACS) in 33 (80%) women/41 (75%) pregnancies. In the year before pregnancy, 24 (56%) women were admitted at least once for VOC. There were no maternal deaths during pregnancy or up to 1 year postpartum. AHE (n = 171) occurred in 43 (73%) pregnancies (Figure A), with a median of 2 (range 0-13) AHE per pregnancy. AHE were more common with genotype SS, history of ACS, history of ³ 10 lifetime transfusions, admission for VOC in the year before pregnancy, tricuspid regurgitation velocity (TRV) >2.5 m/s on echocardiogram, and increased maternal age, and less common with increased hemoglobin (Figure B). ACE were rare (n = 3) (Figure A) and weakly associated with increased maternal age (Figure C). AOE (n = 37) occurred in 27 (45%) pregnancies (Figure A) and were associated with lower pre-pregnancy maternal BMI (Figure D). ANE (n = 54) occurred in 27 (46%) of pregnancies, and were associated with maternal hypertensive disorders of pregnancy (Figure E). Conclusions We found that AHE during pregnancy in women with SCD were associated with genotype SS, history of ACS, ³ 10 lifetime transfusions, admission for VOC in the year before pregnancy, higher maternal age, and inversely related to hemoglobin. In addition, AHE during pregnancy were associated with TRV >2.5 m/s on echocardiogram, which has not been previously shown in women with SCD. These data may be useful to identify women at increased risk during pregnancy. Data show that patients with sickle cell disease who have more disease-related complications including history of acute chest syndrome, frequent pain crisis, elevated TRV on echocardiogram, and lower hemoglobin are at greater risk for AHE. This suggests that disease severity is directly related to outcomes. The association between increased maternal age and ACE has been demonstrated in the past in women without SCD (DeViti et al). The same can be noted for the association of AOE with lower maternal BMI (Verma et al), and ANE being associated with maternal hypertensive disorders of pregnancy (Lugobe et al). In the future, prevention of these complications will be key. Future directions include determining the effect of disease-modifying therapy on these outcomes, though safety during pregnancy has not yet been demonstrated for more novel agents such as voxelotor and crizanlizumab. With more information on these risk factors, we hope that modification and treatment can result in better outcomes. Figure 1 Figure 1. Disclosures Desai: Pfizer: Other: Publication Fee, Research Funding; Foundation for Sickle Cell Research: Honoraria; Forma: Consultancy; Novartis: Research Funding, Speakers Bureau; Global Blood Therapeutics: Honoraria, Research Funding.

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Should Sickle Cell Disease be Among the Risk Factors for Use of Thromboprophylaxis in Adolescents and Young Adults ?

Blood ◽

10.1182/blood.v128.22.4855.4855 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4855-4855 ◽

Cited By ~ 1

Author(s):

Erin Morales ◽

Gabriela Ines Villanueva ◽

Lewis L. Hsu ◽

Nili Seleski

Keyword(s):

Risk Factors ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Research Funding ◽

Pediatric Population ◽

Multivariate Regression Analysis ◽

Central Line ◽

Cell Disease ◽

Vte Prophylaxis ◽

History Of

Abstract Introduction: As published by Naik both in single-institution and multi-institution data, adults with sickle cell disease have a baseline hypercoagulable state in addition to traditional risk factors. In pediatrics, venous thromboembolism (VTE) is often overlooked because of the low incidence in children. In addition, there is no unified consensus that supports the use of prophylaxis or screening of the pediatric population at risk. Although the incidence of VTE in the general pediatric population is low, there may be those children, including those with sickle cell disease (SCD), who would benefit from VTE prophylaxis. Objectives: Estimate the contribution of sickle cell disease to rates of VTE in adolescents and young adults, compare rates of prophylaxis in the pediatric units versus the adult units, and determine risk factors associated with VTE occurrence in a hospital serving a large population with sickle cell disease. Methods: This study was a retrospective chart review of patients aged 14-25 admitted to the Pediatric Intensive Care Unit (PICU), to the Pediatric Sickle Cell Service, and to the Medical Intensive Care Unit (MICU) between the dates of April 1, 2014 and April 30, 2015. Anyone older than age 18 admitted to the PICU or Pediatric Sickle Cell Service was considered part of pediatrics. Charts were searched manually for incidence of VTE during hospitalization, risk factors for developing VTE, history of prior VTE, use of therapeutic anticoagulation, and prophylaxis use and type. Data was analyzed using a multivariate regression analysis. Results: In the 13-month period, 251 AYA admissions (108 to the PICU and 143 to the Sickle cell Unit) and 67 MICU admissions were reviewed. 66/67 (99%) MICU patients received either chemical or mechanical prophylaxis against VTE compared to 9/251 (3.5%) children. Event rates of VTE were 3/67 (4.5%) in MICU and 2/251 (0.8%) in the Pediatric units - 1 in the Sickle Cell unit and 1 in the PICU. In the pediatric units, none of the patients receiving prophylaxis had an acute VTE and both patients with VTE were not on prophylaxis. Both adolescents had central lines in place at the time of VTE occurrence. Of the MICU events, one patient had SCD and was taking systemic anticoagulation for previous VTE but had a central line in place. The other MICU patients both had infections, one with Crohns Disease and the other with a central line placed (table 2). The multivariate regression analysis demonstrated that prior history of a VTE and prolonged LOS were positively correlated with increased risk for VTE, both with a confidence interval of 95% and a corrected critical value of 0.003 using the Bonferroni correction (table 1). Conclusion: Of the 5 VTE events in the 318 AYA hospitalizations reviewed, two (40%) were in patients with SCD (ages 17 and 24). As expected, overall VTE incidence in AYA is low in our institution, and appear to be associated with heightened inflammation and central line placement. VTE events in the pediatric unit were in patients not receiving any prophylaxis, which is not surprising when VTE prophylaxis orders were rare on the pediatric units (3.5%). In both our pediatric unit cases, prophylaxis may have prevented the VTE. A consensus protocol to identify high risk children is being implemented and refined with ongoing data collection. The data from our hospital AYA population enriched in SCD reinforces previous data from adult sickle cell populations that the magnitude of VTE risk attributable to SCD can be high. SCD probably should be among the screening criteria when deciding VTE prophylaxis in hospitalized adolescents. Disclosures Hsu: Purdue Pharma: Research Funding; Gerson Lehman Group: Consultancy; Hilton Publishing: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; Eli Lilly: Research Funding; Sancilio: Research Funding; Centers for Medicare and Medicaid Innovation: Research Funding; EMMI Solutions: Consultancy; Mast Therapeutics: Research Funding.

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Mortality Among Women with Sickle Cell Disease Admitted for Delivery, California 2004-2014

Blood ◽

10.1182/blood.v128.22.2332.2332 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2332-2332

Author(s):

Faith S. Raider ◽

Susan Paulukonis ◽

Ward Hagar ◽

Marsha J Treadwell ◽

Mary Hulihan

Keyword(s):

Black Women ◽

Sickle Cell Disease ◽

Maternal Mortality ◽

Sickle Cell ◽

Research Funding ◽

Mortality Rates ◽

Case Definition ◽

Cell Disease ◽

Utilization Data ◽

History Of

Abstract Maternal mortality results among women with sickle cell disease (SCD) from recent population-based studies using US hospital discharge data range from 72 (Villers, 2008) to 160 per 100,000 (Alayed, 2014). Researchers use hospital discharge or death certificate data to examine maternal death, as no national SCD surveillance system exists. We analyze California's surveillance data to describe the in-hospital maternal mortality rate among women meeting a stringent case definition for SCD, compare that rate to rates for all women and for Black women, and describe cases of SCD maternal demise. The CDC has developed the Sickle Cell Data Collection (SCDC) program to conduct state level surveillance in this disease. SCDC uses a validated case definition: confirmed SCD with known genotype (via newborn screening or clinical case reports) or three or more healthcare encounters in administrative or claims data with SCD ICD-9 codes. California SCDC collected hospitalization data for years 2004-2014 on 1,829 women with SCD. We queried hospitalization data for women ages 15-45 at time of admission for ICD-9 codes for delivery (V27.X) with disposition codes indicating death during the same admission. We used the same query for all women and for Black women to calculate comparable in-hospital maternal mortality rates. We reviewed death records for ICD-10-CM underlying cause of death (COD) codes, and prior ED and inpatient records, and describe the history of the women with SCD who died. We found 636 delivery hospitalizations among 441 of the 1,829 eligible women with SCD during the 11-year period. The maternal death rate for SCD was 629 per 100,000 (n = 4 of 636 deliveries), compared to 6 per 100,000 deliveries in the general population and 12 per 100,000 among Black women. There was an additional death (#5) among the women with SCD that occurred shortly after discharge; we include this death in the case descriptions, but not in the mortality rates. All of the women with SCD who died were Black. All births were live, singleton deliveries by cesarean surgery. Case #1: 29 years old at death with no prior pregnancies in nine years of utilization data. She had a history of eight hospitalizations for septicemia, pneumonia and Hb SS with crisis, but none during her pregnancy. There were 16 ED visits, most related to SCD crisis and pain, but none in the prior three years. COD was 'O96.0, Death from direct obstetric cause.' Case #2 was 34 years old and had seven prior years of medical history. She had no record of previous pregnancies, but had 44 prior hospital admissions and 95 ED encounters, including 12 in the year prior to her death. She had a history of venous thromboembolism, and deep phlebothrombosis was the primary diagnostic code for her final hospital admission. COD was 'D57.1 Sickle cell disease without crisis.' Case #3 was 28, with four years of prior data. There was one previous cesarean birth 2.5 years prior to her death, and a record indicating that there were one or more prior cesarean deliveries before that. She had 11 prior ED encounters, most for pain, with one in the year prior to her death; there were 46 prior hospitalizations, most for SCD crisis. Primary diagnosis was severe pre-eclampsia. COD was 'D57.1 Sickle cell disease without crisis.' Case #4 was 27, and had eight years of prior data and no prior births. She had 11 admissions, three in the months prior to her death for antepartum anemia. There were 12 prior ED encounters, three for antepartum anemia. Her death included codes for heart, liver, kidney and respiratory failure after delivery. COD was 'O96.0,' as described in Case #1. She died 11 days after delivery. Case #5 was 20, and had five years of utilization data with no prior births. Her labor was induced due to fetal distress, and she was hospitalized for six days. Records included a code for infection of the amniotic cavity. Four days after release, she was re-admitted for puerperal sepsis, suffered multi-organ failure, and died. There were 10 prior ED encounters, including four during and related to the pregnancy. COD was 'O23.5, Infections of the genital tract in pregnancy.' We found maternal mortality among women with SCD to be significantly higher than previous estimates. Statewide surveillance based on multiple data sources, and that follows individual patients over time whether or not they are seen in sickle cell disease clinics, can provide less biased information on health outcomes than analyses of single data sources or clinical sites. Disclosures Raider: Pfizer: Research Funding; Biogen: Research Funding. Paulukonis:Pfizer: Research Funding; Biogen: Research Funding.

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Clinical and Biomarker Predictors for Avascular Necrosis in Sickle Cell Disease

Blood ◽

10.1182/blood-2021-147829 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3091-3091

Author(s):

Michael Rabaza ◽

Maria Armila Ruiz ◽

Liana Posch ◽

Faiz Ahmed Hussain ◽

Franklin Njoku ◽

...

Keyword(s):

Risk Factors ◽

Sickle Cell Disease ◽

Board Of Directors ◽

Avascular Necrosis ◽

Sickle Cell ◽

Research Funding ◽

Medical Attention ◽

Cell Disease ◽

Advisory Committees ◽

Early Management

Abstract Introduction Sickle cell disease (SCD) affects 1 in 365 African Americans and approximately 25 million people world-wide. A common skeletal system complication is avascular necrosis (AVN), which can cause substantial pain and a reduced quality of life. While early management of AVN is focused on increasing range of motion with physical therapy and pain relief, there are no clear predictors for who is more likely to develop AVN and earlier institution of these preventive measure could help decrease disease progression. Vascular endothelial growth factor (VEGF) is a biomarker of endothelial injury and may indicate reduced vascular supply to the femoral or humeral head. Here we describe potential risk factors and biologic pathways for AVN in SCD, as understanding these may lead to improvements in future monitoring, early detection, and early intervention practices. Methods We investigated clinical and laboratory risk factors associated with AVN in a cohort of 435 SCD patients from our center. Blood samples, clinical, and laboratory data were collected at the time of enrollment during a clinic visit. Genotyping for alpha thalassemia was performed by PCR and the serum concentration of VEGF was measured by ELISA. AVN status was confirmed by review of the medical record and available imaging. We conducted a cross-sectional analysis comparing categorical and linear variables by AVN status using the chi-square and Kruskal-Wallis test, respectively. The independent association of the clinical and laboratory variables with AVN status was determined by logistic regression analysis. The initial model included variables with a P-value < 0.1 on univariate analysis and the final model was ascertained by stepwise forward and backward selection. Median values and interquartile range (IQR) are provided. Results The median age of the cohort was 32 (IQR, 24 - 43) years, 57% (250/435) were female, and 46% (198/435) were on hydroxyurea. AVN was observed in 34% (149/435) of SCD patients. SCD patients with AVN were older, had more frequent vaso-occlusive crises requiring medical attention, and had a higher body mass index (Table I) (P ≤ 0.002). We measured VEGF in 241 of the SCD patients with serum samples available at the time of enrolment. Serum VEGF concentrations trended higher in SCD patients with versus without AVN (420 vs. 359 pg/mL, respectively; P = 0.078). In the multivariate analysis model, AVN was independently associated with increased number of vaso-occlusive crises (OR 1.1, 95% CI: 1.0 - 1.14; P = 0.02), AST concentration (natural log OR 0.5, 95% CI: 0.2 - 0.9; P = 0.03), VEGF concentration (natural log OR 1.4, 95% CI: 1.0 - 1.9; P = 0.047), and tobacco use (OR 1.9, 95% CI: 0.9 - 3.7; P = 0.078). Discussion In conclusion, we demonstrate a high prevalence of AVN in an adult cohort of SCD patients. The presence of AVN was independently associated with a greater frequency of vaso-occlusive pain episodes, which may demonstrate a shared pathophysiology between AVN and vaso-occlusion that merits further investigation. We demonstrate that serum VEGF concentrations are higher in SCD patients with AVN and may be a clinical tool to identify those at high-risk and for earlier intervention for this complication. Figure 1 Figure 1. Disclosures Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy. Saraf: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Modifiable Cardiovascular Risk Factors in Adults with Sickle Cell Disease

Blood ◽

10.1182/blood-2018-99-115595 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1088-1088

Author(s):

Foluso Joy Ogunsile ◽

Kerry Stewart ◽

Hang Wang ◽

Sophie Lanzkron

Keyword(s):

Risk Factors ◽

Body Composition ◽

Sickle Cell Disease ◽

Body Fat ◽

Sickle Cell ◽

Exercise Testing ◽

Research Funding ◽

Knee Extension ◽

Normative Values ◽

Cell Disease

Abstract Introduction: Body composition, cardiorespiratory fitness (CRF) and muscular strength(MusS) are important predictors of cardiovascular (CV) mortality and morbidity. Poor CRF, body composition and MusS are each associated with higher rates of musculoskeletal injury, inflammation, heart disease, and all-cause mortality. Fortunately, these parameters in the general population, are partly influenced by lifestyle habits and can improve with modifying unhealthy behaviors such as increasing activity levels. Few studies have examined fitness parameters, in particularly MusS, in adults with sickle cell disease (SCD). As cardiopulmonary disease is a leading cause of death in SCD, we sought to better characterize fitness and body composition in adults with SCD. The objective of this study is to describe modifiable CV risk factors of fitness along with other risk factors of smoking, hypertension, and cholesterol in a population of adults with SCD. Methods: Forty-six participants (ages 21-66 yrs.; 74% female; sickle cell anemia n =29, sickle variant genotype n=17) were recruited from a comprehensive adult sickle center. Non-pregnant adults in steady-state SCD disease without an absolute contraindications to exercise were eligible to participate. CRF was measured using symptom-limited exercise testing performed on a cycle ergometer following an incremental ramp protocol. Maximal oxygen uptake (VO2 max), a key measure of CRF, was calculated during exercise testing. MusS was assessed using an isokinetic dynamometer, the Biodex system 3, the gold standard to measure MusS in rehabilitative medicine. Peak isokinetic torques of knee extension and flexion were determined at 60 degrees per second, and adjusted for body weight on the Biodex system 3. A medical history, fitness assessments, anthropometric testing, and laboratory testing were completed on all SCD participants. Sixteen SCD participants had dual energy x-ray absorptiometry imaging to assess fat, lean, and bone mass. The remaining 30 SCD patients underwent isokinetic CRF and MusS testing. Lean muscle mass and body fat of participants were compared to US national guidelines, VO2max was compared to predicted norms. As there are no well-established normative values for MusS, we compared values to a cohort of 60 adults without SCD (age 21-40 yrs.; 63% female) who underwent MusS testing as a part of a separate study. For muscle strength, multivariate regression was performed to control for the effects of age, BMI, gender, and SCD status on peak torques. Results: All SCD and control participants were able to complete testing safely without any adverse events. 34.7% of SCD participants (n=16) had a smoking history with a mean pack year history of 9 years (Table 1). 18% of participants (n=10) received medical treatment for hypertension (Table 1). 64% (n=32) of participants had reduced HDL levels and 8% (n=3) had elevated triglycerides. Median (IQR) waist-hip circumference (F=0.89(0.14), M=0.93 (0.11)) and total percent body fat (F=37.7(11.5), M=22.3(11.5)) for SCD participants were higher than national normative values and 66% were classified as obese (Table 1). SCD participants had reduced mean (SD) VO2max, 16.77 (3.29) and 19.56 (7.27) ml/min/kg for females and males respectively compared with norms. In 90% of SCD participants (n=28), percent-predicted VO2max was less than normal (i.e. < 84 percent-predicted) with 4 adults having markedly reduced VO2max with a percent-predicted value less than 50%. Hemoglobin, hydroxyurea use and SCD genotype were not predictive of VO2max. Compared to controls, mean (SD) peak torque values for knee extension (82.7 Nm (19) vs 44.33 Nm (18.85), p<0.0001) and flexion ( 38.6 Nm (9.03)vs 19.19 Nm (13.2), p<0.0001) at 60 degrees were lower in SCD participants even after adjusting for age, sex, and body mass index (BMI) (Table1). Limitations: Study limitations include a small sample size, and the lack of controls matched for race, age, BMI, and hemoglobin. Conclusion: In this pilot study we show that both CRF and MusS are decreased in adults with SCD. Additionally, this cohort had a number of CV risk factors including smoking, hypertension and reduced HDL levels. As we know these are important predictors of poor CV outcomes additional research is needed to determine whether a carefully designed exercise and diet program can improve these modifiable CV risk factors and ultimately health status in adults living with SCD. Disclosures Wang: PCORI: Research Funding. Lanzkron:Pfizer: Consultancy, Research Funding; NHLBI: Research Funding; Ironwood: Research Funding; PCORI: Research Funding; GBT: Consultancy, Research Funding; Selexys: Research Funding; Prolong: Research Funding.

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Use of Thromboprophylaxis for Central Venous Access Devices in Patients with Sickle Cell Disease: A Survey of Canadian Providers

Blood ◽

10.1182/blood-2021-145889 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4173-4173

Author(s):

Kristine Matusiak ◽

Stephanie Forte ◽

Jameel Abdulrehman ◽

Madeleine Verhovsek ◽

Kevin H.M. Kuo

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Research Funding ◽

Central Venous Access ◽

Venous Access ◽

Cell Disease ◽

Central Venous ◽

Advisory Committees ◽

History Of

Abstract Background: Sickle cell disease (SCD) induces a chronic prothrombotic state, with a cumulative incidence of venous thromboembolism (VTE) reported to be 11% by age 40. Central venous access devices (CVAD) are commonly used for chronic transfusions and iron chelation in this patient population.The presence of a CVAD is an additional risk factor for venous thromboembolism (VTE), with a catheter related thrombosis rate of 24%. Despite this high risk of VTE, the role of thromboprophylaxis in this setting is uncertain due to a lack of high quality data. Methods: A survey was administered in March 2021 to physicians caring for adult sickle cell disease patients via the Canadian Haemoglobinopathy Association (CanHaem), covering nine SCD comprehensive care centers in Canada. One reminder email was distributed after 3 weeks to encourage participation. Questions were directed at characterizing the practice size, number of patients with CVADs, and the role of thromboprophylaxis for CVADs. Physicians were also surveyed about their willingness to enroll their SCD patients with CVADs in a randomized trial of thromboprophylaxis versus placebo. Items were generated and selected based on face and content validity. Results are reported in medians and percentages, where applicable. Results: Responses were collected from 14 physicians who care for a median of 100 (IQR 185) adult sickle cell disease patients in practices across Canada. Physicians reported approximately 5% of their patients currently require a CVAD, and physicians estimated no CVAD patients are lost to follow up. Respondents use a variety of CVADs, including port-a-caths (75%), followed by PICC lines (58%), tunneled (25%) and non-tunneled CVCs (25%) (Figure 1). Duration of venous access was reported to be <1 month (17%), 1-3 months (8%), 3-6 months (0%), 6-12 months (8%), and >12 months (67%). Fifty percent of respondents indicated they do not use thromboprophylaxis for CVADs. Responses varied with respect to choice and dose of antiplatelet or anticoagulant in cases where thromboprophylaxis is used (Figure 2). Forty-two percent of physicians indicated they were not very confident or not at all confident in choice of prophylaxis. Past history of VTE was the most cited factor influencing the choice to use thromboprophylaxis. Physicians were generally in favour of enrolling patients in an RCT using thromboprophylaxis for CVADs. The exception was that 69% answered "No" when asked about enrolling patients with a prior history of VTE who are not currently on anticoagulation. One-hundred percent of physicians agreed that an RCT would improve their confidence in decision-making around thromboprophylaxis in their patients with CVADs. Conclusions: While there is evidence for an increased risk of VTE for SCD patients with CVADs, our results suggest there remains clinical equipoise with respect to the use of thromboprophylaxis. Thromboprophylaxis options were variable when physicians chose to use them, as there is no evidence to support specific antithrombotic regimens. All physicians surveyed are supportive of an RCT to clarify this management approach, and many would enroll their patients. As a result of this survey, a Canadian multicenter pilot RCT addressing this question is currently underway. Figure 1 Figure 1. Disclosures Forte: Pfizer: Research Funding; Canadian Hematology Society: Research Funding; Novartis: Honoraria. Verhovsek: Vertex: Consultancy. Kuo: Alexion: Consultancy, Honoraria; Celgene: Consultancy; Bluebird Bio: Consultancy; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Apellis: Consultancy. OffLabel Disclosure: This survey explored the use of LMWH, direct oral anticoagulants, warfarin and ASA for prophylaxis among patients with sickle cell disease using a central venous access device.

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Increased Prevalence of Asthma Symptoms in Nigerian Children with Sickle Cell Disease Compared to Children without Sickle Cell Disease

Blood ◽

10.1182/blood.v120.21.4760.4760 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4760-4760 ◽

Cited By ~ 1

Author(s):

Najibah Aliyu Galadanci ◽

Wayne Liang ◽

Muktar Aliyu ◽

Binta Wudil Jibir ◽

Ibraheem Karaye ◽

...

Keyword(s):

Risk Factors ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Mode Of Delivery ◽

Cell Disease ◽

Parental History ◽

Nigerian Children ◽

Asthma Symptoms ◽

History Of ◽

Physician Diagnosis

Abstract Abstract 4760 Background: Nigeria has the largest population of children and adults with sickle cell disease (SCD) in the world. Approximately 150,000 children are born with SCD each year (incident cases) in Nigeria, compared to a total of approximately 100,000 children and adults living with SCD in the United States (prevalent cases). Pulmonary complications, including asthma and asthma-like symptoms are leading causes of morbidity and mortality in SCD. However, the natural history, risk factors and biological basis of asthma and SCD-associated asthma-like symptoms in SCD are poorly defined. The primary aim of this study is to determine the prevalence of asthma and asthma-like symptoms among children with and without SCD in Nigeria. In a 1:1 case-control study design, we tested the hypothesis that children with SCD would have a higher rate of asthma-like symptoms when compared to children without SCD. Methods: We enrolled 250 cases with SCD and controls, children without SCD, from patients presenting for routine medical care at the Murtala Mohammed Specialist Hospital (MMSH) in Kano, Nigeria over a 4-month period (12/2011 to 04/2012). A structured questionnaire was employed to capture participants' demographic information, medical history (including history of asthma symptoms and allergies), environmental factors (e.g., cooking, presence of animals in the home) and parental behavior (e.g., smoking). Asthma symptoms were identified based on responses to questions adapted from the American Thoracic Society Division of Lung Disease (ATS-DLD-78) questionnaire. Chi-square test of association was used for categorical variables; Wilcoxon rank-sum tests and Kruskal-Wallis U test were used for continuous and ordinal variables. Results: No differences in sex, ethnicity, or place of residence were noted between cases and controls. The average age for the cases was 5.7 years and for controls was 2.8 years (P<0.01). In both cases and controls, affirmative responses to ATS-DLD questions were unrelated to age. Cases were more likely than controls to report a history of cough that worsens with a cold (28.0% vs. 16.8%, P<0.01), cough without a cold (16.0% vs. 9.6%, P=0.03), chest congestion that worsens with a cold (8.0% vs. 1.2%, P<0.01), wheezing that worsens with a cold (19.6% vs. 6.4%, P<0.01), and wheezing without a cold (5.6% vs. 1.6%, P=0.02). Participants with SCD were more likely to have eczema (4.4% vs. 0.4%, P<0.01). Surprisingly, despite the high prevalence of asthma-like symptoms in cases when compared to controls, the prevalence of physician diagnosis of asthma was low in both groups. Only two children were reported as having asthma among cases, compared to none in the control group. No participant reported a history of wheezing attacks with shortness of breath. No difference between cases and controls existed in the distribution of risk factors for asthma, namely: mode of delivery, gestational age at delivery, parental history of asthma, maternal smoking during pregnancy, and exposure to smoking as a child. No association was observed between respiratory symptoms in either group and age, household income, household size, mode of delivery, gestational age, parental history of asthma, or use of firewood/charcoal. Subgroup analysis was performed on participants 4 years of age and older (163 cases and 96 controls). No substantial differences in the results were noted when compared to the entire cohort of 250 cases and controls (results not shown). Conclusions/Recommendation: Nigerian children with SCD have a much higher prevalence of asthma-like symptoms when compared to controls. Despite asthma symptoms being common, a diagnosis of asthma is rare in both cases and controls, suggesting under-ascertainment of an asthma diagnosis. Future work in low income countries directed towards improving co-morbid respiratory disease in children with SCD should focus on the presence of asthma-like symptoms and not a physician diagnosis of asthma. Better understanding of the biological basis for why children with SCD have a higher rate of asthma-like symptoms and atopy may lead to targeted therapy. Disclosures: No relevant conflicts of interest to declare.

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Immunophenotypes and Clinical Outcomes in Adult Patients with Sickle Cell Disease: Lymphopenia Correlates with End Organ Damage

Blood ◽

10.1182/blood-2020-142634 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 12-13

Author(s):

Stephen Zachary Peeke ◽

Qi Gao ◽

Jaeun Choi ◽

Khadijah Abdallah ◽

Ashley Buscetta ◽

...

Keyword(s):

T Cells ◽

Sickle Cell Disease ◽

Clinical Outcomes ◽

Sickle Cell ◽

Research Funding ◽

Organ Damage ◽

Cell Disease ◽

History Of ◽

Leukocyte Populations ◽

Lymphocyte Populations

Introduction: Sickle cell disease (SCD) is the most prevalent inherited hemoglobinopathy in the United States. While the primary event is polymerization of HbS under deoxygenation in red cells, the contribution of white blood cells and inflammation to SCD pathology has been increasingly recognized. Prior investigations of lymphocytes in SCD revealed varied abnormalities some of which have been shown to be corrected by hydroxyruea (HU) though not uniformly (Nickel 2015, Allali 2019). Alterations in lymphocyte subsets have previously been correlated with survival in elderly populations (Ferguson 1995) and with non-AIDS related mortality in HIV (Helleberg 2014). The aim of this study was to analyze alterations of leukocyte populations in relation to different clinical outcomes in a large set of adult patients with sickle cell disease at steady state. Methods: Patients were consented and data was obtained as part of the INSIGHTS study (NCT02156102). Only patients with HBSS/Sβ0 from whom lymphocyte subset panels had been prospectively collected were included in this analysis. Panels consisted of total CD3+ T cells, CD4+/CD8- (CD4+) and CD8+/CD4- (CD8+) T cells, CD19+ B cells and CD16/56+ NK cells; absolute neutrophil count (ANC), white blood cell count (WBC), CD4/CD8 and ANC/ALC (absolute lymphocyte count) ratios were examined as well. Patients were classified as having cardiovascular events (CVE) if they reported prior stroke, pulmonary embolism, deep vein thrombosis, myocardial infarction, arrhythmia, cardiomyopathy, coronary artery bypass or stent. Ulcer status was defined as history of, or current active cutaneous lower extremity ulcer. Also analyzed were self-reported pulmonary hypertension (pHTN), diabetes mellitus (DM), and a combined End Organ Damage Score (EODS) consisting of one point for each of the following clinical outcomes: CVA, Any Ulcer, pHTN, CAD (MI/CABG/stent), cardiomyopathy, PE/DVT, DM. Multivariate analysis was performed controlling for age, gender and active HU use and Spearman correlation coefficients were calculated using SAS software. Results: 170 patients were included in this analysis, 54.7% female, mean age of 38.7 years, 95.3% HbSS, 64.1% on active HU treatment, and 15.9% chronically transfused. Mean leukocyte counts were within reference ranges except for CD19+ cells (666 c/uL) which were double the upper limit of normal (ULN 321 c/uL) consistent with prior reports. The 40% of patients with a CVE history showed an overall decrease in their lymphocyte populations (CD3+, CD4+, CD8+, CD19+) and WBC compared to those without (Table 1). Patients with a pHTN history (15.3%) had lower total CD3+, CD8+, CD19+, ANC's and WBC's. This resulted, somewhat surprisingly, in a significantly lower ANC/ALC ratio than in those patients without pHTN. No significant correlations with organ damage outcomes were noted for CD4/CD8 ratios or NK cells. Similar to the CVE findings, increased EODS was associated with significantly lower total T lymphocytes, CD4+, CD8+, and CD19+ cells while ANC/ALC ratio was significantly increased (Tables 2 & 3). DM is very rare overall in SCD and was in our adult population (2/170) as well (Morrison 1979). It is notable that these 2 patients had significantly lower overall T and B cells and elevated ANC/ALC ratios. Compared to patients without any history of cutaneous ulcer, those with active ulcers had significantly lower total T cells (CD3+) and CD8+ cells (Table 4) while higher total WBC was seen in patients with a history of but no active ulcer compared to those without an ulcer history. Discussion: Our analysis of a large cohort of adult SCD patients at steady state revealed significant alterations in leukocyte populations in relation to a variety of clinical events. The salient finding was that B and T cell lymphocyte populations were significantly decreased in relation to clinical outcomes such as CVE and pHTN. The potential impact of this finding is highlighted by the adverse survival outcomes associated with lymphopenia seen in studies of general adult populations and in those with other medical problems such as cancer (Zidar 2019, Ray-Coquard 2009). While the interpretation of this study is limited to correlations further follow-up and study of SCD immunophenotypes may reveal important prognostic information that could enhance future care strategies. Disclosures Minniti: Bluebird bio: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CLS Bering: Consultancy; Roche: Consultancy, Research Funding; TauTona: Consultancy, Research Funding; Emmaus: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

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Higher Prevalence of Autoimmune Diseases in Patients with Sickle Cell Disease

Blood ◽

10.1182/blood-2021-148387 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 982-982

Author(s):

Man Wai Tang ◽

Erfan Nur ◽

Charlotte F.J. Van Tuijn ◽

Bart J. Biemond

Keyword(s):

Sickle Cell Disease ◽

General Population ◽

Autoimmune Diseases ◽

Chronic Inflammation ◽

Sickle Cell ◽

Research Funding ◽

Patient Characteristics ◽

Organ Damage ◽

Cell Disease ◽

Inflammatory State

Abstract Introduction Sickle cell disease (SCD) affects millions of people throughout the world. This is caused by a mutation in the hemoglobin gene resulting in abnormal red blood cells. Patients with SCD are in a state of chronic inflammation that is driven by ongoing hemolysis and ischemia-reperfusion injury due to recurrent vaso-occlusions.(1) It is also known that infections occur more frequently in patients with SCD. Abundant literature support the role of infections, interacting with the immune system as the so-called second hit in the cascade towards development of autoimmune diseases.(2) The chronic inflammation together with genetic predisposition and environmental factors can potentially lead to an auto-inflammatory state and/or disease. Recently, a study has shown a prevalence of autoimmune diseases (AID) of 1,3% in SCD patients between 7 and 17 years of age, although not compared to the general population.(3) Our hypothesis is that due to the chronic inflammation the prevalence of autoimmune diseases in adult patients with SCD are much higher compared to the general population. The aim of the study was to evaluate the proportion of patients with and without an AID. Methods Between 2004 and 2021, patients with SCD aged above 18 were seen at the outpatient clinic at the Amsterdam University Medical Center in Amsterdam. We performed a retrospective study in adult SCD patients to assess the prevalence of AID in SCD. AID was defined as: disease with the presence of autoantibodies and/or auto-reactive lymphocytes becoming involved in inflammation, which develop pathological autoimmunity and finally leads to tissue damage. We have selected 35 most common autoimmune diseases. A total of 338 patients with SCD were eligible and included in the study. The patient characteristics were summarized in Table 1. The previously reported prevalence of the AID in the African-American population was used to compare the prevalence in our study cohort. In addition, risk factors for AID and relation with organ damage was analyzed. Results AID was diagnosed in 36/338 patients with SCD. The prevalence of AID in this cohort is 10,7% compared to 4.7% in the general population (see table 2). There was no difference in patient characteristics (age, sex, genotype) between the SCD patients with or without AID. The BMI was higher in the group of patients with autoimmune diseases, although not statistically significant. In patients with SCD, the most frequent (>1%) diagnosed AID were: sudden deafness (1.8%), hyper- and hypothyroidism (3%) and sarcoidosis (1.2%). With respect to organ damage, a significantly high rate of retinopathy was observed in SCD patients with AID as compared to SCD patients without AID (53% and 29% respectively, p=0.005). Furthermore, a trend towards more frequently microalbuminuria was found in SCD patients with AID 14/36 (39%) as compared to patients without AID 69/302 (23%). Conclusions This study showed for the first time a higher prevalence of autoimmune diseases in adult patients with SCD compared to previous reported in the general population. In patients with AID, a trend towards more microalbuminuria and significantly higher rate of retinopathy were observed. These findings support the hypothesis that the chronic inflammatory state in SCD patients may be related to the development of AID. Further research is needed to find strategies to target the chronic inflammatory state in order to prevent the development of AID. References 1. Nader E, Romana M, Connes P. The Red Blood Cell-Inflammation Vicious Circle in Sickle Cell Disease. Front Immunol. 2020;11:454. 2. Ercolini AM, Miller SD. The role of infections in autoimmune disease. Clin Exp Immunol. 2009;155(1):1-15. 3. Li-Thiao-Te V, Uettwiller F, Quartier P, Lacaille F, Bader-Meunier B, Brousse V, et al. Coexistent sickle-cell anemia and autoimmune disease in eight children: pitfalls and challenges. Pediatr Rheumatol Online J. 2018;16(1):5. Figure 1 Figure 1. Disclosures Nur: Celgene: Speakers Bureau; Roche: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Biemond: Global Blood Therapeutics: Honoraria, Research Funding, Speakers Bureau; Sanquin: Research Funding; CSL Behring: Honoraria; Novo Nordisk: Honoraria; Celgene: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau.

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