Sickle cell disease is the most common autosomal recessive disorder in the United States. Mortality in sickle cell disease is higher in those with elevated pulmonary pressures or other markers of disease severity including frequent pain, iron overload and renal insufficiency. We have enrolled 716 subjects and 115 controls in the Bethesda Sickle Cell Cohort Study, a study of the prevalence and prognosis of suspected pulmonary hypertension and other hematologic, hepatic and renal phenotypes in adults with sickle cell disease. All subjects were screened with transthoracic echocardiograms, where tricuspid regurgitant jet velocity (TRV) is used to estimate the pulmonary artery systolic pressure. Suspected cardiopulmonary disease is defined by a TRV >= 3.0 m/sec. or clinical symptoms. Subjects have been followed for up to 12 years (mean 6 years) and censored at time of death or loss to follow-up. We have analyzed Doppler echocardiographic assessments of pulmonary systolic pressure in 529 consecutive patients (mean age=33.0 years). Doppler-defined elevation of the TRV occurred in 31 percent of patients. Diastolic dysfunction was present in 18% of patients. A combination of diastolic dysfunction and TRV elevation was present in 11% of patients, and diastolic dysfunction accounted for only 10% to 20% of the variability in TR jet velocity. Diastolic dysfunction, as reflected by a low E/A ratio, was associated with mortality with a risk ratio of 3.5 (95% confidence interval 1.5 to 8.4, p<0.001), even after adjustment for TR jet velocity. The presence of both diastolic dysfunction and pulmonary hypertension conferred a risk ratio for death of 12.0 (95% confidence interval 3.8 to 38.1, p <0.001). Right heart catheterization was performed under a separate protocol in most patients with TRV >= 2.8 m/sec (based on the results of the screening echo). Based on these data, 60% of patients with sickle cell disease have elevated pulmonary artery systolic pressures (TRV >= 2.8 m/sec) and 9% have severely elevated pressures. Multiple-regression analysis identified increasing age and serum biomarkers (increased LDH, total bilirubin, and arginine/ornithine ratio) as significant independent predictors of elevation of pulmonary pressures. Fetal hemoglobin levels did not predict pulmonary artery pressure elevation nor did a history of hydroxyurea treatment. Left ventricular dysfunction was rarely observed (<2% of patients). Subjects diagnosed with pulmonary hypertension had significantly greater mortality. These studies suggest that secondary pulmonary hypertension is common in adults with sickle cell disease, appears to have no association with hydroxyurea therapy, while there are positive associations with specific biomarkers and earlier mortality. These data suggest that patients with elevated pulmonary pressures documented by right heart catheterization should have standard therapies for sickle cell disease optimized and be considered for investigational therapeutic trials. There have been 69 new subjects enrolled at the NIH during this year;10 were controls and 59 were subjects with sickle cell disease. There were no new subjects enrolled at Howard University. Total enrolled at Howard University is 131 and the total enrolled at NIH is 700. Total enrollment for all sites is 831. Subjects continue to be enrolled in this trial and referred for treatment studies available at NIH. We are conducting 2, 4, 6, 8, 10 and 12 year follow-up visits for comprehensive data collection. We also completed comprehensive survival update on all subjects enrolled to date. Our objective is to recruit at least 1000 subjects with sickle cell disease as an initial discovery cohort for exploratory genetic studies. This will allow for sufficient statistical power to preliminarily identify prognostic clinical factors and genetic modifiers. As part of this protocol, adult patients were assessed for depression and sleep disturbance using the Beck Depression Inventory II (BDI-II) and Pittsburgh Sleep Quality Index (PSQI). Depression had a prevalence of 20% in adults with sickle cell disease, while more than 70% have disrupted sleep. There was a moderate, but statistically significant, correlation between depression and sleep disturbance (p<0.001). Furthermore, pain from SCD was independently associated with depression (p=0.001) and sleep disturbance (p<0.001). These findings suggest that screening for depression and sleep disturbance are common among adults with sickle cell disease and important components of routine care. Further work is required to determine if treatment of pain, depression or sleep disturbance will improve quality of life. Vaso-occlusive pain crises resulting in hospitalization is another phenotype of sickle cell anemia, and like elevated pulmonary pressures, frequent severe pain events are another risk factor for early mortality. It is unclear if this association between frequent pain and mortality is still relevant since the institution of modern therapies. Accordingly, the epidemiology of severe acute pain crises resulting in hospitalization has been reviewed in this cohort. One quarter of subjects with sickle cell anemia are not frequently hospitalized for pain (<1 per year), and more frequent pain crises are independently associated with higher hematocrit, ferritin, and HDL cholesterol. Despite modern therapy for sickle cell anemia, more frequent pain crises remain a risk factor for early mortality. This mortality risk is independent of the previously described risk of death with an elevated TRV on echocardiogram, elevated ferritin or lower glomerular filtration rate. Thus, pain crises requiring hospital based treatment is a clinically meaningful prognostic measure along with tricuspid regurgitation, ferritin and renal function due their cumulative association with premature death. To further quantify pain in sickle cell disease, a series of experimental studies have been initiated to identify objective pain phenotypes. These studies are using neuroimaging, physiological measures and pain diaries to identify subjects with acute pain or persistent pain syndromes. These objective experimental pain measures will be tested for correlation with clinical measures of pain in sickle cell disease including annual hospitalizations and self-reports of ambulatory pain. Hydroxyurea is an important therapy known to lower mortality in sickle cell disease. Retrospective analysis of mortality in this cohort found that the most common causes of death were cardiopulmonary events, pain crises, or infections and deceased subjects had evidence of cardiopulmonary, renal, and hepatic dysfunction prior to death. While most subjects took hydroxyurea, only a percentage were prescribed a therapeutic dose. As a group, hydroxyurea did not improve organ function or survival, but, when analyzed by dose, hydroxyurea independently associated with significantly longer survival and high fetal hemoglobin responses. These results suggest sub-therapeutic doses of hydroxyurea may have limited benefit, but doses within the recommended therapeutic range appear to preserve organ function and prolong survival. Further study of the effects of hydroxyurea dose upon specific mortality risk factors may help to improve the utilization of this drug for sickle cell anemia.

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