Mortality In Sickle Cell Disease Research Articles

Extreme hyperbilirubinemia: An indicator of morbidity and mortality in sickle cell disease.

BACKGROUNDSickle cell disease (SCD) is a disorder that results in increased hospitalizations and higher mortality. Advances in management have resulted in increases in life expectancy and led to increasing awareness of sickle cell hepatopathy (SCH). However, its impact in patients on the natural history and outcomes of SCD is not known. Our study aims to describe the prevalence of extreme hyperbilirubinemia (EH), one form of SCH, its effect on morbidity and mortality, and correlations between sickle cell genotype and SCH type. We hypothesize that EH is associated with higher morbidity and mortality.AIMTo investigate the effects of EH on morbidity and mortality among patients with SCD.METHODSThis retrospective cohort study was performed using a database of patients with SCD treated at Grady Memorial Hospital between May 2004 and January 2017. Patients with EH (defined as total bilirubin above 13.0 mg/dL) were identified. A control group was identified from the same database with patients with total serum bilirubin ≤ 5.0 mg/dL. Electronic medical records were used to extract demographic information, laboratory values, radiology results, current medications, need for transfusions and mortality data. Two samples T-test, chi-squared test and Fisher’s exact test were then used to compare the parameters between the two groups.RESULTSOut of the database, fifty-seven charts were found of patients with bilirubin > 13 mg/dL. Prevalence of severe SCH as defined by EH was 4.8% (57/1172). There were no demographic differences between patients with and without EH. Significant genotypic differences existed between the two groups, with hemoglobin SS SCD being much higher in the EH group (P < 0.001). Patients with severe EH had a significant elevations in alanine aminotransferase (157.0 ± 266.2 IU/L vs 19.8 ± 21.3 IU/L, P < 0.001), aspartate aminotransferase (256.5 ± 485.9 U/L vs 28.2 ± 14.7 U/L, P < 0.001) and alkaline phosphatase (218.0 ± 176.2 IU/L vs 85.9 ± 68.4 IU/L, P < 0.001). Patients with EH had significantly higher degree of end organ failure measured with quick Sequential Organ Failure Assessment scores (0.42 ± 0.68 vs 0.01 ± 0.12, P < 0.001), increased need for blood products (63% vs 5%, P < 0.001), and exchange transfusions (10.5% vs 1.3%, P = 0.022).CONCLUSIONAmong patients with SCD, elevated levels of total bilirubin are rare, but indicative of elevated morbidity, mortality, and need for blood transfusions. Large differences in sickle cell genotype also exist, but the significance of this is unknown.

Alizarin interaction with sickle hemoglobin: elucidation of their anti-sickling properties by multi-spectroscopic and molecular modeling techniques

Polymerization of hemoglobin S is a major cause of morbidity and mortality in sickle cell disease, which leads to sickling and destruction of red blood cell. Alizarin, a bioactive compound from Rubia cordifolia, is reported to be blood purifier. This study investigates the potential of alizarin as an anti-sickling agent, showing a significant decrease in the rate of polymerization, therefore inhibiting the rate of sickling with increasing concentration. Interaction studies indicated that the fluorescence intensity of sickle hemoglobin (Hb S) decreases gradually with increasing alizarin concentration. This suggests the static quenching, where binding constant and the number of binding sites were deduced at different temperatures. The negative values of Gibbs energy change (ΔG0) strongly suggest that it is entropy-driven spontaneous and exothermic reaction. Negative enthalpy (ΔH0) and positive entropy (ΔS0) stipulated that hydrogen and hydrophobic bonding forces were interfering in a hydrophobic micro-environment of β6Val leading to Hb S polymerization inhibition. In circular dichroism (CD) spectra, Hb S in the presence of alizarin shows helical structural changes leading to destabilization of Hb S polymer. These findings were also supported by molecular docking simulation studies using DOCK6 and GROMACS. So, from these findings, we may conclude that alizarin interacts with Hb S through hydrogen bonding and leading to inhibition of Hb S polymerization. Consequently, alizarin may have potential use as an anti-sickle cell medication for sickle cell disorder.Communicated by Ramaswamy H. Sarma

Electrocardiographic abnormalities in sickle cell disease patients in Kano, Northwest Nigeria

Background: Cardiovascular abnormalities are important causes of morbidity and mortality in sickle cell disease (SCD) patients. Data on electrocardiography (ECG) changes in SCD are lacking in Kano, Northwest Nigeria. This study, therefore, aimed to identify the pattern of ECG changes in steady state adult sickle cell patients. Methodology: A case–control cross-sectional study was conducted among SCD patients attending the sickle cell clinic in Murtala Muhammad Specialist Hospital, Kano. One hundred SCD patients were consecutively recruited and compared with 100 age- and sex-matched controls. All consenting participants had hemoglobin (Hb) electrophoresis and were subjected to electrocardiography. Results: The mean age of the cases is 20.98 ± 5.74 years, whereas that of the controls was 22.31 ± 3.27 years, P = 0.047. Among the cases, 57% were male, whereas in the control group, 55% were male (P = 0.443). The mean body mass index (BMI) for the cases was 18.14 ± 3.57 kg/m2, whereas that of the control was 22.74 ± 2.18 kg/m2, P Conclusion: ECG abnormalities are common in SCD patients and early identification would lead to early intervention to prevent cardiac events.

Hemolytic, Vaso-Occlusive and Renal Complications of SCD: Report from the Central Missouri Cohort

BackgroundThe clinical phenotype and complications of sickle cell disease (SCD) are heterogeneous and disease outcomes are influenced by both genetic and non-genetic factors, including geography, socioeconomic and educational status and access to health care. These factors serve a role in the quality of life and overall survival in the SCD population. Prior studies have sought to characterize the genotype-phenotype relationship and geographic clustering of SCD with distinct clinical differences found between the African and Asian SCD subtypes. The Central Missouri SCD Cohort (MU-SCD Cohort) has a heterogeneous population of SCD patients who seek medical care from University of Missouri. The clinical characteristics and frequency of SCD-related complications in this group have not yet been defined. This is a retrospective cohort analysis of patients HbSS, HbSC, and HbS/b-thalassemia in central Missouri, ranging in age from the first through the sixth decade of life. We hypothesize that SCD patients from central Missouri, with its mix of African American, Congolese, Nigerian, Kenyan, Southeast Asian and other refugee populations, will have clinical complications distinct from the previously described North American Sickle Cell Disease series and needs further characterization.ObjectiveTo survey the SCD phenotype by evaluating complications of patients in the MU-Sickle Cell Disease Cohort.MethodsWe retrospectively reviewed clinical and laboratory data for pediatric and adult SCD patients who were treated at the University of Missouri between 2002 to 2018. Prevalence of major vaso-occlusive, hemolytic and renal complications by decade was estimated.ResultsA total of 81 patients were reviewed, with five excluded due to insufficient clinical data. The sample size for prevalence estimation was 76, 61, 30, 14 and 8 for first to fifth decade, respectively. In this cohort, 60.5% were male with average age of 21.2 years. Genotypes represented included 52.6% HbSS, 38.2% HbSC, and 7.9% HbS/b-thalassemia. A total of 94.7% of patients identified as African American. Clinical features of vaso-occlusive complications predominated in the first two decades of life. The frequency of acute chest syndrome for patients ages ≤10 years and 11-20 years of age were 23.7% and 21.3%, respectively (Table 1). Seven children (9.2%) developed overt stroke by age 10 years. Greater than one vaso-occlusive pain crisis occurred in 46% of patients in the first decade of life and thereafter declined with age (Figure 1). In contrast, the MU-SCD Cohort exhibited increasing frequency of hemolytic complications with advancing age. The peak prevalence of pulmonary hypertension occurred between the ages of 21-30 years (13.3%). In congruence, only 4% of patients aged ≤10 years were diagnosed with gallstones requiring cholecystectomy, which increased to 57.1% at age 31-40 years. Reticulocytopenia was noted in the fourth decade with further decline in the fifth decade of life (Figure 2). Renal evaluation revealed an average estimated glomerular filtration rate (eGFR) of 149.9 ± 43 in patients ≤10 years, with progressive decline to 117.3 ± 25 in SCD patients aged 41-50 years (Figure 3). The average serum creatinine demonstrated an increasing trend with advancing age. There was a prevalence of persistent proteinuria in patients older than 11 years. Disease modifying agents were assessed, in which only 21% of patients ≤10 years, 25% of patients aged 11-20 years, and 15.8% of patients aged 21-30 years received therapy with hydroxyurea (Table 1). The use of exchange transfusion or packed red blood cell (pRBC) transfusion for anemia was predominant in SCD patients aged ≤20 years.ConclusionsThis is the first report describing prevalence of SCD-related complications in the MU-SCD Cohort. We identified this population to have an increasing frequency of hemolytic complications and sickle cell nephropathy with advancing age. Onset of persistent proteinuria occurred in the second decade of life, followed by renal insufficiency or end stage renal disease in subsequent decades. As previously demonstrated in the Cooperative Study of Sickle Cell Disease and the Jamaican SCD Cohort study, renal insufficiency was a significant risk factor for early mortality. Further studies are required for identification of biomarkers and institution of early intervention strategies to prevent end-organ damage and decrease mortality in SCD. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Sickle Cell Disease and Venous Thromboembolism: Hospital Mortality, Length of Stay and Cost

Introduction:It is estimated that there are 100,000 Americans living with Sickle Cell Disease (SCD). Patients with SCD experience a number of complications that frequently require hospitalization. SCD is a prothrombotic state that is commonly complicated by venous thromboembolism (VTE) and recurrent VTE. The National Heart, Lung and Blood Institute do not include VTE as one of the complications of SCD in their latest guidelines, and the topics of prophylaxis and treatment of VTE in SCD are not discussed. There are no guidelines specifically designed for the prophylaxis or treatment of VTE in the SCD population, and traditionally management guidelines for VTE in the general population are followed. Recent information on national prevalence, mortality, length of stay, and cost for hospitalized patients with with SCD complicated by VTE is limited.Methods:We used data from the Healthcare Cost and Utilization Project's National Inpatient Sample (NIS) from 1999-2014 to examine these variables. The data on SCD from 1999-2014 was analyzed using ICD-9-CM codes for SCD (ICD-9-CM: 282.41, 282.42, 282.6, 282.60, 282.62, 282.63, 282.64, 282.68, 282.69) in the primary diagnosis field, and VTE (ICD-9-CM: 453.40, 453.41, 453.42, 453.82, 453.83, 415.11, 415.19) in the secondary diagnosis field which includes codes for venous thrombosis and pulmonary embolism. Univariate and bivariate statistical analysis was performed using the chi-square test. Multivariate analysis was performed using cox proportional hazard regression. The alpha was set at 0.05.Results:Over a 15 year period, from 1999-2014, a total of 217,791 (weighted N = 1,073,215) admissions with SCD were identified. A total of 7,898 admissions were associated with VTE. Mean age at admission of those with VTE was 27.42 (+/- 0.05) years and those without VTE was 34.00 (+/- 0.51) years. In patients with SCD and VTE, the average inpatient mortality was 3.08% (p < 0.0001) versus mortality of 0.27% in patients that did not have VTE. The hazard ratio for mortality was 4.18 (CI: 2.95-5.93) (p < 0.0001). Length of stay in the SCD with VTE group was 10.45 days (+/- 0.43) versus 5.09 days (+/- 0.02) (p < 0.0001) in SCD without VTE. Overall hospital cost was higher in those with VTE at $60,055 (+/- $1,940) versus $28,729 (+/- 232.97) (p < 0.0001) in those without VTE.Conclusions:Patients with SCD and VTE experience significant morbidity, mortality, prolonged hospitalization and increased cost associated with this complication of the disease as was observed in this study. Furthermore, patients who experience VTE are significantly younger than those who do not, with mean age of 27 versus 34. After controlling for multiple confounders like age, race, sex, income, comorbidities, the presence of VTE is associated with a significantly higher risk of mortality in SCD. Currently, there are no prophylaxis or treatment guidelines designed specifically for patients with SCD and VTE. We recommend the use of antithrombotic prophylaxis or therapy in patients with SCD be evaluated in prospective studies. DisclosuresNo relevant conflicts of interest to declare.

Rapid Decline in Kidney Function in Sickle Cell Disease

Introduction:Chronic kidney disease (CKD) is common in sickle cell disease (SCD). We have recently reported on the progression of CKD in SCD and factors associated with it (Ciccone EJ et al, ASH, 2016). The purpose of this study was to evaluate the prevalence of rapid decline in kidney function, factors associated with such decline, and the association of rapid decline in kidney function with mortality in adult patients with SCD.Methods: We conducted a retrospective study of patients seen between July 2004 and December 2013 at an adult Sickle Cell Clinic. Patients had confirmed diagnoses of SCD, were at least 18 years old, and were in non-crisis state. We excluded patients with histories of HIV, hepatitis B and C, or systemic lupus erythematosus. Clinical and laboratory variables were obtained from medical records. Estimated glomerular filtration rate (eGFR) was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. Rapid decline of kidney function was defined as eGFR loss of >3.0 ml/min/1.73 m2per year during the observation period.Logistic regression was used to model the association of rapid eGFR decline with clinical and laboratory variables, adjusting for age and sex. Multivariable analysis with variable selection was performed with backward elimination from the following initial variables - hemoglobin, reticulocyte count, lactate dehydrogenase, baseline eGFR, history of stroke, hydroxyurea therapy, systolic blood pressure, use of ACE inhibitors/angiotensin receptor blockers (ACE-I/ARB) and history of diabetes. Since proteinuria measures were missing for many patients, we performed sensitivity analyses with 1) exclusion of proteinuria, 2) inclusion of only patients with available values, 3) assignment of no proteinuria to those missing values, or 4) assignment of proteinuria to those missing values. Age- and sex- adjusted Cox proportional hazards models were used to evaluate the association of the slope of eGFR (continuous variable) or rapid decline in eGFR (binary variable) with mortality. The slope of eGFR was estimated by linear regression modeling of eGFR over time. Kaplan-Meier estimates of survival probabilities for rapid and non-rapid decline groups were obtained, and the log-rank test was used to compare the survival probabilities for the two groups.Results: Three hundred and thirty-one SCD patients with at least two eGFR measurements(SS = 218, SC = 67, Sβ0= 18, Sβ+= 22, SE = 2, SD = 2, SHPFH = 2), median age of 29 years (IQR: 20 - 41 years) were evaluated and followed for a median of 4.01 years (IQR: 1.66, 7.19). Rapid decline of eGFR (>3.0 ml/min/1.73 m2per year) was noted in 103 (31.1%) patients; 80 (33.9%) with severe genotype (HbSS/HbSβ0thalassemia) and 21 (23.6%) with mild genotype (HbSC/HbSβ+thalassemia).Baseline laboratory factors significantly associated with rapid decline in eGFR were hemoglobin (p = 0.007), ferritin (p = 0.01), and baseline eGFR (p = 0.01) (Table 1). There was a trend towards an association (p = 0.06) with baseline proteinuria (at least 1+ on dipstick urinalysis). Clinical variables significantly associated with eGFR decline were history of stroke (p = 0.002) and use of ACE-I/ARB (p = 0.006). In multivariable analysis, history of stroke (estimate: 1.07, p = 0.01) and use of ACE-I/ARB (estimate: 1.15, p = 0.01) were associated with rapid eGFR decline when proteinuria was excluded from the model or proteinuria status was assigned to those with missing values. When we limited the dataset to those with available values for proteinuria, only history of stroke (estimate: 2.00, p = 0.007) was associated with rapid decline in eGFR. Finally, we observed an association of the slope of eGFR change over time with mortality (hazard ratio [HR]: 0.99, p = 0.0002). Rapid decline in eGFR was significantly associated with increased mortality compared with eGFR decline of ≤ 3 ml/min/1.73 m2per year (HR: 2.40, p = 0.005). Kaplan-Meier estimates also showed significantly lower survival probabilities for patients with rapid eGFR decline (log-rank test; p = 0.0002) (Figure 1).Conclusion:Rapid decline in eGFR is common in SCD. Use of ACE-I/ARB and history of stroke are associated with rapid decline in renal function. Rapid decline in eGFR is associated with an increased risk of death in SCD. Long-term studies are required to determine if therapies that may reduce loss of kidney function may decrease mortality in SCD. [Display omitted] DisclosuresAtaga:Pfizer: Research Funding; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Honoraria; Modus Therapeutics: Honoraria; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Pulmonary Function Abnormalities in Adults with Sickle Cell Anemia

Sickle cell anemia (SCA) is an inherited red blood cell disorder that leads to hemoglobin polymerization when it deoxygenates. Lung function abnormalities are observed in up to 90% of adults with SCA (PMID: 16556694) and both the prevalence (PMID: 20644948) and rate of FEV1 decline (PMID: 18383325) are greater in SCA adults compared to the general population. Furthermore, low FEV1 is an independent predictor of early mortality in SCA (PMID: 26261241). Understanding the risk factors and mechanisms for abnormal lung function, which can impact blood oxygen and pH levels, is especially important in SCA.We evaluated the clinical, laboratory, and genetic risk factors for abnormal pulmonary function in a retrospective cohort of SCA patients. Pulmonary function test (PFT) abnormalities were categorized based on the American Thoracic Society/European Respiratory Society Guidelines. Alpha-thalassemia and BCL11A rs1427407 status were determined by PCR. Continuous and categorical variables were compared using the Kruskal-Wallis and Chi-square test, respectively, and Kaplan-Meier curves and Cox proportional hazards models were used to compare survival patterns. Median and interquartile ranges (IQR) are provided.Between 12/2004 and 12/2015, 90 SCA adult patients had PFTs performed as part of their routine medical care. The median age of the cohort was 37 years (IQR, 24-47years), 46% were male, 59% were on hydroxyurea, and 28% were cigarette smokers. Abnormal pulmonary function was observed in 56 (62%); 32 (35.6%) had obstructive, 15 (16.7%) had restrictive, and 9 (10%) had mixed lung defects. SCA patients with abnormal PFTs were more anemic (8.4 vs. 9.0g/dL, P=0.004), had higher LDH (441 vs. 306U/L, P=0.002) and urine albumin concentrations (180 vs. 29mg/g creatinine, P=0.004), and a lower hemoglobin F% (4.2% vs. 8.0%, P=0.004) compared to SCA with normal PFTs. SCA patients who inherited the BCL11A rs1427407 T allele had a lower prevalence of abnormal PFTs (G/G: 67%, G/T: 55%, T/T: 50%; P=0.2), but this was not statistically significant, and we did not observe any patterns between co-inheritance of α-thalassemia and abnormal PFTs (αα/αα: 60%, α-/αα: 64%, α-/α-: 60%; P=0.9). On logistic regression analysis, LDH (natural log OR 8.2, P=0.03) was independently associated with abnormal pulmonary function after adjusting for age, gender, and hydroxyurea use. SCA patients with abnormal pulmonary function had earlier mortality compared to those with normal pulmonary function (Figure 1) (log-rank P=0.03; age-adjusted HR 6.1, P=0.09).Next, we analyzed clinical and laboratory risk factors associated with obstructive or restrictive lung disease. Lower hemoglobin F% and a greater prevalence of tricuspid regurgitant velocity (TRJV) > 3.0m/s were associated with both restrictive and obstructive pulmonary function compared to normal pulmonary function (Table 1). In addition, lower hemoglobin concentration and higher LDH were associated with restrictive lung disease while less common treatment with hydroxyurea and higher urine albumin concentration were associated with obstructive lung disease compared to SCA patients with normal PFTs (Table 1). SCA patients with restrictive lung disease had a lower oxygen saturation, determined by pulse oximetry, compared to those with normal PFTs (P=0.02) while no difference in oxygen saturation was observed between those with obstructive versus normal PFTs (P=0.6) (Figure 2). Mortality risk was significantly increased for SCA patients with restrictive (age-adjusted HR 2.0, P=0.01) but not obstructive lung disease (age-adjusted HR 1.6, P=0.4) compared to those with normal PFTs (log rank P=0.006) (Figure 3).In conclusion, we demonstrate that increased hemolysis is associated with abnormal pulmonary function based on a lower hemoglobin concentration and lower hemoglobin F% and higher LDH. We also demonstrate that restrictive-type lung disease is associated with a lower oxygen saturation and increased mortality risk compared to those with normal PFTs. Future studies investigating the role of hemolysis in lung disease and therapies to improve pulmonary function, particularly in those with restrictive lung disease, are warranted in SCA. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The Effect of Health Care Disparities on Complications and Mortality in Sickle Cell Disease

Introduction:Sickle cell disease (SCD) is a chronic and debilitating disorder that affects approximately 100,000 Americans and results in the development of significant complications, leading to high numbers of hospitalizations, healthcare cost and mortality. Despite the advent of newer therapies, the overall rate of complications has continued to rise. We aimed to study the prevalence of complications in SCD as well as its relation to differing insurance status.Methods:Patients with SCD were identified using ICD-9 codes 2826, 28260, 28261, 28262, 28263, 28264, 28268 and 28269 from the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample from 1999 to 2014. Admission with acute chest syndrome, acute myocardial infarction (AMI), avascular necrosis of the hip (AVN), end stage renal disease (ESRD), pneumococcal infections, splenic sequestration and stroke. Univariate and bivariate analyses were performed using the Chi square test. Cox proportional hazard regression was used to control for multiple confounders in calculating the hazard ratios of an event occurrence and mortality.Results:A total of 216,438 (Weighted=1,066,536) observations were identified from the years 1999 to 2014. The median age for male patients was 25 years and that for females was 27. Observing the trends from 1999 to 2014, the prevalence of acute chest syndrome increased from 1.22% to 8.82% (p=0.002), splenic sequestration from to 0.08 % to 1% (p=0.01) and AVN from 1 % to 8.8% (p=0.001). The prevalence of stroke and ESRD were unchanged over the interval studied. After controlling for confounding factors such as race, age, sex, income, comorbidities and insurance status, the hazard ratio of mortality for various complications is significantly elevated. Also, after controlling for multiple confounders, the patient's insurance status plays a significant role in the risk of developing a complication and subsequent mortality (Table 1).Discussion:The data indicates that the rate of complications from SCD have risen since 1999. With newer therapies and better understanding, the life expectancy of SCD patients has risen over time, nearly doubling from 1951 to 2018. The increased frequency of complications may be attributed to better survivorship and a rising number of older SCDs patients. However, our data also suggests that insurance status plays a significant role in the complication rate of SCD. The uninsured and patients with Medicaid have significantly increased risk of developing disease complications and resultant mortality. This could be the result of reduced access to care and health disparities due to race, socioeconomic status and insurance status. DisclosuresNo relevant conflicts of interest to declare.

Mean Platelet Volume Predicts Mortality in Sickle Cell Disease

Background: Sickle cell disease (SCD) is a life-threatening disease with varied clinical spectrum and severity leading to premature death. There is a lack of validated prognostic markers in SCD. Recent evidence suggests that inflammation and platelet adhesion plays a critical role in the pathophysiology of vaso-occlusion in SCD. Elevated Mean Platelet Volume (MPV) values are associated with a higher degree of inflammation in many disease states but its effect on sickle cell disease or its severity is unknown.Objective: To analyze the role of MPV in predicting disease severity/mortality in patients with SCD.Methodology: This is a retrospective single center study and included patients with sickle cell disease between 6 months and 60 years of age during a 10-year period (2006-2016). Demographic information, lab data and clinical information including acute chest syndrome (ACS), priapism, transfusions, sepsis, pain crisis, avascular necrosis (AVN) were collected. All laboratory data were collected in steady state with no crisis in the recent past 3 months. The disease severity score/probability of death was calculated using a validated model to predict risk of death in sickle cell disease (Sebastiani et al. Blood 2007). Spearman's correlation test was used to analyze correlation coefficient between MPV and probability of death.Results: Total no. of patients =230; Male 112 (49%); Female 118 (51%). All patients were of African-American origin. Disease severity, Hb SS - 156 (67.5%); Hb SC - 64 (27.8%) and Sickle-Beta thalassemia 11 (4.7%). MPV has a significant positive correlation with the probability of death, p < 0.001 and correlation coefficient, r=0.222. Of the total population, 78 had acute chest syndrome, 30 had AVN, 47 had recurrent pain crisis, 16 had stroke (2 -moyamoya cases), 18 had culture proven sepsis. Our population was further divided into 3 subgroups based on their age (Group 1 - 0-18 years; Group 2 - 19-40 years; group 3- above 40 years) and we found no statistical difference in the mean platelet volume across different age groups. However in pediatric population (Group 1), hydroxyurea was associated with significantly lower MPV, p=0.023 and this is independent of Hb F levels. Using linear regression model, with probability of death as a dependent variable and hydroxyurea, MPV as independent variables, MPV maintains a significant association with probability of death (p=0.003). We also found strong positive correlation of MPV with the probability of death in pediatric age group, p=0.004, r =0.405.Conclusion:MPV is an independent biomarker predicting disease severity and probability of death in patients with sickle cell disease with a strong correlation especially in pediatric age group. Although there was no statistical significance across age groups, the variation of MPV for each patient with age needs to be studied for better understanding. Hydroxyurea a known disease-ameliorating agent is associated with lower MPV values in pediatric age group. This effect is independent of the levels of fetal hemoglobin and may be due to anti-inflammatory effect of hydroxyurea or decreased platelet consumption. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Opioid Dependency Significantly Increases Complications and Mortality in Sickle Cell Disease

Introduction:According to the National Center for Health Statistics, there was a twenty-one percent increase in deaths from drug overdose in the USA, with opioids contributing to about two-thirds of these deaths. Despite nationwide efforts to reduce opioid use, narcotic pain medications are still the most frequently used method of pain control in patients with sickle cell disease (SCD). We sought to examine the burden and complications of opioid dependence in patients with SCD.Methods:The National Inpatient Sample (NIS) for the years 1999 to 2014 was queried to yield adult admissions with a primary diagnosis of sickle cell disease (ICD-9 codes: 2826, 28260, 28261, 28262, 28263, 28264, 28268, 28269) and the admissions were stratified based on the presence of opioid dependence (ICD-9 codes: 30400-30403, 30470-30473, 30550-30553). Univariate and bivariate analyses were performed using the Chi square test. Cox proportional hazard regression was used to control for multiple confounders in calculating the hazard ratios of occurrence of complications and mortality.ResultsA total of 216,438 (Weighted N=1,066,536) admissions were identified between 1999 and 2014, out of which 1.6% (N=3603) had opioid dependence. The median age of patients with opioid dependence was 26 years, compared to 31 years in patients without opioid dependence. Average cost and length of hospitalization for patients with and without opioid dependence was $29,883 & $20,638 and 6.4 days & 5.1 days, respectively. The rates of various complications and Hazard Ratio (HR) of event occurrence among patients with and without opioid dependence are depicted in Table 1. After adjusting for demographics, hospital characteristics (region, bed size, location), and baseline comorbidities, SCD patients with opioid dependence had a 50% increased risk of in-hospital mortality (H.R 1.5, 95% C.I. 1.2-1.6, p<0.001) compared to those without.Conclusions:There is a correlation between opioid dependence and SCD complications among patients hospitalized with a diagnosis of SCD. Perhaps, patients predisposed to vaso-occlusive events require more frequent use of narcotics and become opioid dependent. Alternatively, the dependence on opioids may increase the incidence of complications from sickle cell disease. Regardless, patients with opioid dependence have significantly higher in-hospital mortality. The main limitation of this study is the use of ICD codes for identifying opioid dependence. In our opinion, the abnormally low incidence of opioid dependence in our data is a poor representation of the actual population. Opioid abuse is a serious concern that has heavy financial, social and public health implications on the welfare of the community, particularly those with SCD. This study highlights the need for more effective disease modifying agents for the treatment of this chronic and debilitating disorder. DisclosuresNo relevant conflicts of interest to declare.

Opioid Use Is NOT Associated with in-Hospital Mortality Among Patients with Sickle CELL Disease in the United States: Findings from the National Inpatient Sample

BackgroundVaso-occlusive pain crises account for the majority of hospitalizations in patients with sickle cell disease (SCD), and opioids are the mainstay of chronic pain control in SCD. However, a marked increase in opioid-related overdoses and deaths in the United States (US) - ‘the US opioid epidemic’ - has been documented since 2000. We sought to: i) examine temporal trends in hospitalization rates and in-hospital mortality rates among adults with SCD since the onset of the US opioid epidemic, and ii) compare in-hospital mortality rates for SCD with the rates of opioid prescription-related deaths in the non-SCD general population since the onset of the US opioid epidemic.MethodsWe obtained data from the National Inpatient Sample from 1998 through 2013. We identified hospitalizations for patients with sickle cell disease using discharge diagnoses (ICD-9-CM) codes 282.41, 282.42, 282.60, 282.61, 282.62, 282.63, 282.64, 282.68, and 282.69. We examined hospitalization and in-hospital mortality rates and trends for the entire sample of SCD patients, as well as by the following age groups: 0-17 years, 18-44 years, 45-64 years, and ≥65 years. We also examined in-hospital mortality hospitalization trends by U.S Census Bureau regions viz: Northeast, Midwest, South, and West. Survey weights were applied in estimating the population-based hospitalization rates. We utilized annual mid-year population figures provided by the US Census Bureau as the reference population for each year. Survey analysis and trend analyses were performed with Stata 14.2®(StataCorp, College Station, TX), and Joinpoint Regression Program 4.2.02® (National Cancer Institute), respectively.ResultsThere were 1,755,220 hospitalizations among SCD patients in the US from 1998 to 2013. Hospitalization rates for SCD patients initially declined annually by 9.9% (95% CI: 4.0, 15.5) from 39/100,000 persons in 1998 to 27/100,000 persons in 2002, but no significant temporal trends were noted from 2002 to 2013 (figure 1).However, among young adults with SCD (18-44 years), there was a significant annual increase in hospitalization rates by 3.8% (95% CI: 2.4%, 5.2) from 43/100,000 persons in 2002 to 71/100,000 persons in 2013. Elderly SCD patients (≥65 years) also had a significant annual increase in hospitalization rates by 6.5% (95% CI: 2.9%, 10.2%) from 2.7/100,000 persons in 1998 to 5.4/100,000 persons in 2013. The only region with a significant increase in SCD hospitalization rate was the South with an annual increase of 3.5% (95% CI: 0.6, 6.4) from 2001 through 2011.There was no significant increase in-hospital SCD mortality, in contrast to the 350% increase in non-SCD opioid prescription-related death rates in the US from 1999 through 2013 (figure 2).ConclusionHospitalization rates are rising among most age-groups of adults with SCD. The reasons for this finding are unclear but the rising rates may reflect the fragmentation of care for SCD in adults as well as age-related increases in pain-related comorbidities and SCD complications as SCD patients live longer. However, there has been no associated increase in-hospital SCD mortality, supporting extant data which suggest that the rate of opioid-related deaths in SCD is low, and the use of opioids for pain control may be considered relatively safe in the SCD population. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Utilising the 'Getting to Outcomes®' Framework in Community Engagement for Development and Implementation of Sickle Cell Disease Newborn Screening in Kaduna State, Nigeria.

Background: Sickle Cell Disease (SCD) has been designated by WHO as a public health problem in sub-Saharan Africa, and the development of newborn screening (NBS) is crucial to the reduction of high SCD morbidity and mortality. Strategies from the field of implementation science can be useful for supporting the translation of NBS evidence from high income countries to the unique cultural context of sub-Saharan Africa. One such strategy is community engagement at all levels of the healthcare system, and a widely-used implementation science framework, “Getting to Outcomes®” (GTO), which incorporates continuous multilevel evaluation by stakeholders about the quality of the implementation. Objectives: (1) to obtain critical information on potential barriers to NBS in the disparate ethnic groups and settings (rural and urban) in the healthcare system of Kaduna State in Nigeria; and, (2) to assist in the readiness assessment of Kaduna in the implementation of a sustainable NBS programme for SCD. Methods: Needs assessment was conducted with stakeholder focus groups for two days in Kaduna state, Nigeria, in November 2017. Results: The two-day focus group workshop had a total of 52 participants. Asking and answering the 10 GTO accountability questions provided a structured format to understand strengths and weaknesses in implementation. For example, we found a major communication gap between policy-makers and user groups. Conclusion: In a two-day community engagement workshop, stakeholders worked successfully together to address SCD issues, to engage with each other, to share knowledge, and to prepare to build NBS for SCD in the existing healthcare system.

Abstract 16794: Early Detection of Myocardial Fibrosis by Electrocardiographic Abnormalities in Sickle Cell Patients

Introduction: Advances in screening and treatment of sickle cell disease (SCD) continue to increase life expectancy of this population. As a result, mortality from cardiopulmonary causes has become the most prevalent cause of death. While the specific etiology of cardiac death remains unclear, multiple studies have shown that diastolic dysfunction and prolonged QT are associated with early mortality in SCD. Recently, the physiopathology of a novel cardiomyopathy with both restrictive and hyperdynamic features was described in the SCD population. In addition, a high incidence of repolarization nonspecific abnormalities has been reported in SCD patients. Although these serve as surrogates for repolarization heterogeneity, because of difficulty in reproducibility and measurability they are rarely considered of clinical significance. Hypothesis: Repolarization abnormalities are the earliest manifestation of microvascular changes and fibrosis in the myocardium of SCD patients. Methods: We performed a retrospective electrocardiographic and echocardiographic analysis of 88 patients from our SCD clinic. We used commercially available QT guard plus (QTgp) software to analyze repolarization heterogeneity parameters, and performed echocardiographic measurements of previously validated diastolic markers. In addition, data from 77 individuals - matched demographically with our SCD population- with structurally normal hearts and with normal ECGs was analyzed with QTgp. Results: Our statistical analysis showed correlation between Left ventricular mass index (LVMI), and mitral E/a ratio with T wave morphology changes (T peak, T offset, t wave morphology dispersion, and QRST vector) (table 1). In addition we found that T wave morphology was significatively different between our healthy controls and our SCD population (table 2). Conclusion: T wave morphology changes could be used as an early marker of diastolic dysfunction and increased LVM in the SCD population.

Exercise capacity and clinical outcomes in adults followed in the Cooperative Study of Sickle Cell Disease (CSSCD).

To determine the factors associated with exercise capacity in adults with sickle cell disease (SCD) and its relationship to hospitalizations and mortality. A total of 223 participants in the Cooperative Study of Sickle Cell Disease (CSSCD) (64% female, 70% hemoglobin SS/Sβ0 thalassemia, mean age 43.3±7.5years) underwent maximal exercise testing using a treadmill protocol with a mean duration of 11.6±5.2minutes. Female sex (β=-3.34, 95% CI [-1.80, -4.88], P<0.001), older age (β=-0.14, 95% CI [-0.24, -0.04], P=0.005), higher body mass index (β=-0.23, 95% CI [-0.37, -0.10]; P=0.001), and lower hemoglobin (β=0.56, 95% CI [0.08, 1.04], P=0.02) were independently associated with lower fitness, while there was a trend with abnormal pulmonary function testing (β=-1.42, 95% CI [-2.92, 0.07]; P=0.06). Lower percent-predicted forced expiratory volume in 1second (FEV1 ) was independently associated with lower fitness (β=0.08, 95% CI [0.03, 0.13], P=0.001). Genotype and hospitalization rates for pain and acute chest syndrome (ACS) prior to testing were not associated with exercise capacity. Baseline exercise capacity predicted neither future pain or ACS nor survival in our cohort. Adults with SCD tolerated maximal exercise testing. Prospective studies are needed to further evaluate the impact of regular exercise and improved fitness on clinical outcomes and mortality in SCD.

Augmented NRF2 activation protects adult sickle mice from lethal acute chest syndrome.

Acute chest syndrome (ACS) mortality in sickle cell disease (SCD) rises sharply in young adult patients and mechanism-based prophylaxis is lacking. In SCD, haem oxygenase-1 (HO-1) declines with age and ACS is associated with low HO-1. To test if enhanced HO-1 can reduce ACS mortality, young SCD mice were treated with D3T (3H-1,2-dithiole-3-thione), an activator of nuclear-factor erythroid 2 like 2, which controls HO-1 expression, for 3months. Following haem-induced ACS, all vehicle-treated mice succumbed to severe lung injury, while D3T-treated mice had significantly improved survival. Blocking HO-1 activity abrogated the D3T effect. Thus HO-1 may be targeted to reduce ACS severity in adult patients.

Diastolic dysfunction is associated with exercise impairment in patients with sickle cell anemia.

Left ventricular diastolic dysfunction (DD) is an independent risk factor for mortality in sickle cell anemia (SCA) and is associated with increased extracellular volume (ECV) on cardiac MRI (CMR). Exercise impairment is common in SCA, but its causes and prognostic value are not well understood. To study the effects of DD and ECV on cardiopulmonary exercise test (CPET) in patients with SCA. As part of a prospective study to characterize the cardiomyopathy of SCA (NCT02410811), 20 children and adults with SCA underwent CMR, echocardiography, and cycle ergometer CPET (age range 8-43years). Maximum exercise was reached in 18 patients and 17 (94%) had reduced exercise capacity (%predicted VO2 less than 80%). Six patients had DD and none had systolic dysfunction. Patients with DD had lower exercise capacity compared to patients with normal diastolic function (%predicted VO2 48.2±9.1%vs. 61.2±11.7%; P=0.01). The z-score of left ventricular lateral E/e' ratio, which is a marker of DD, was negatively associated with %predicted VO2 (r=-0.61, P=0.01). All patients with moderate-to-severe exercise impairment (%predicted VO2 <60%) had lateral E/e' z-score>2. In a multivariate analysis, lateral E/e' z-score was independently associated with %predicted VO2 (P=0.02). All participants had elevated ECV but the degree of elevation was not associated with exercise parameters. Left ventricular DD is associated with decreased exercise capacity in SCA. Interventions to prevent or delay DD could improve exercise capacity, quality of life, and long-term outcomes in SCA.

Biomarker signatures of sickle cell disease severity

Identifying sickle cell disease patients at high risk of complications could lead to personalized treatment and better prognosis but despite many advances prediction of the clinical course of these patients remains elusive. We propose a system-type approach to discover profiles of multiple, common biomarkers that correlate with morbidity and mortality in sickle cell disease. We used cluster analysis to discover 17 signatures of 17 common circulating biomarkers in 2320 participants of the Cooperative Study of Sickle Cell Disease, and evaluated the association of these signatures with risk for stroke, pain, leg ulceration, acute chest syndrome, avascular necrosis, seizure, death, and trend of fetal hemoglobin and hemolysis using longitudinally collected data. The analysis shows that some of the signatures are associated with reduced risk for complications, while others are associated with increased risk for complications. We also show that these signatures repeat in two more contemporary studies of sickle cell disease and correlate with recently discovered biomarkers of pulmonary vascular disease. With replication and further study, these biomarker signatures could become an important and affordable precision medicine tool to aid treatment and management of the disease.

Transient receptor potential polymorphism and haplotype associate with crisis pain in sickle cell disease.

Episodes of acute pain crisis contribute to considerable morbidity and mortality in sickle cell disease (SCD). Incomprehensive understanding of the underlying pain heterogeneity results in inadequate pain management. The transient receptor potential (TRP) family of voltage-gated ion channels acts as sensory transducers of diverse noxious stimuli. We performed an association study of polymorphisms in candidate genesTRPV1 and TRPA1with pain in SCD patients. Utilization rate, in other words, number of emergency department/acute care center admissions over 12months as a result of pain crisis,served as a marker for acute pain. We identified that rs920829 (incident rate ratio=1.44, p=0.027additive; IRR=1.68, p=0.008 recessive models of negative binomial regression) and the CGAGG haplotype of TRPA1 (odds ratio=0.218, p=0.009) were significantly associated with utilization rate, suggesting that TRPA1 gene polymorphisms may influence acute pain crisis in SCD.

White Paper: Pathways to Progress in Newborn Screening for Sickle Cell Disease in Sub-Saharan Africa.

Sickle Cell Disease (SCD) is among the most common single-gene diseases in the world but evidence-based comprehensive health care has not been implemented where the highest prevalence of SCD occurs, in sub-Saharan Africa (SSA). It represents an urgent health burden, both in terms of mortality and morbidity with an estimated mortality of 8–16% in children under 5 years in SSA. Addressing the high mortality of SCD in SSA and for effective management of SCD, newborn screening (NBS) should be incorporated with prevention of infections (including pneumococcal septicaemia and malaria), parental education and support at all levels of healthcare provision to enable timely recognition. The NBS working group of the Africa Sickle Cell Research Network (AfroSickleNet) collaboration surveyed current projects in NBS in SSA, and current conditions that hinder more widespread implementation of NBS for SCD. Solutions based on new point-of-care testing technology to disseminate education, and implementation science approaches that leverage existing resources are proposed.

Apolipoprotein L1 Genetic Variants Are Associated with Evidence of Early Kidney Injury in Sickle Cell Disease

▪Background and Objectives: Apolipoprotein L1 (APOL1) renal risk variants prevalent in African-ancestry populations are associated with chronic kidney disease (CKD). CKD is a major cause of morbidity and mortality in sickle cell disease (SCD) in adults; yet the prevalence and significance of APOL1 renal-risk variants in this population remains unknown. Our objective was to determine expression of biomarkers of early kidney disease in African American youth with SCD, based on their APOL1 genotype.Methods:We enrolled65 African American subjects between 5 to 21 years of age with SCD (Hb SS or Hb S β0 thalassemia). Blood and concurrent urine samples were collected. Allenrolled subjects underwent APOL1 genotyping by PCR analysis of DNA extracted from whole blood. Presence of two renal-risk variants qualified for APOL1 High Risk (HR) genotype, while presence of zero or one copy of renal-risk variants qualified for APOL1 Low Risk (LR) genotype.Results: APOL1 HR genotype was expressed by 22% of our subjects; this is comparable to 23% prevalence of APOL1 HR genotype in African American adults with CKD (AASK study). Both groups were similar with respect to distribution of age, BMI z-scores, renal function and urine osmolality. Hyperfiltration was noted in both groups based on low serum creatinine for age, and elevated eGFR based on creatinine clearance. However, median urine albumin excretion rate was significantly higher in HR group vs. LR group.Conclusions: Preliminary data in this cohort of 65 children and adolescents with SCD detected greater urine albumin excretion rate in the presence of APOL1 HR genotype. Screening SCD youth for heightened CKD risk may be an avenue to initiate targeted preventive interventions to preserve renal function and reduce progression of kidney disease.Acknowledgment: Research reported in this publication was supported by the National Institute Of General Medical Sciences of the National Institutes of Health under Award Number P20GM109021; National Kidney Foundation Young Investigator Grant and DE-CTR-ACCEL grant number U54-GM104941 (PI: Binder-Macleod). [Display omitted] DisclosuresNo relevant conflicts of interest to declare.