Sickle cell disease is the most common genetic disorder in the United States. Mortality is higher in those with elevated pulmonary pressures, frequent pain, iron overload and renal insufficiency. I have enrolled 795 subjects and 125 controls in the Bethesda Sickle Cell Cohort Study, a study of the prevalence and prognosis of suspected cardiopulmonary disease and other hematologic, hepatic and renal phenotypes in adults with sickle cell disease. All subjects were screened by transthoracic echocardiogram, where tricuspid regurgitant jet velocity (TRV) is used to estimate the pulmonary artery systolic pressure. Subjects have been followed for up to 13 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 533 consecutive patients with no exclusions (mean age=33.0 years). Doppler-defined elevation of the TRV occurred in 31 percent (Gladwin and Machado, NEJM 365: 1646-47). Diastolic dysfunction was present in 18%. 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 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). Because these analyses were performed years ago, a new effort is underway to determine the prevalence of left sided disease (including valvular disease, atrial enlargement, systolic dysfunction, diastolic dysfunction, ventricular hypertrophy and ventricular geometry) in 795 subjects. A current survival analysis is being incorporated into this new study. Subjects with an elevated tricuspid regugitant jet velocity have higher mortality. We are now examining sub-groups of subjects with end organ damage who appear to have increased risk for an elevated tricuspid regurgitant jet velocity, including analysis of physiologically relevant biomarkers. Specifically, chronic kidney disease and a CKD biomarker appear to be associated with some of the SCD cardiovascular phenotypes defined by echocardiography. There have been 41 new subjects enrolled at the NIH during the past year; 5 were controls and 36 with sickle cell disease. There were no new enrollments at Howard University. Total enrolled at Howard University is 131 and the total enrolled at NIH is 789. Total enrollment is 920. 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, the first such analysis in 4 years. 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. 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 central pain leads to these comorbid conditions as in other diseases of chronic pain. Vaso-occlusive pain crises resulting in hospitalization is another phenotype of sickle cell anemia which is a 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 quantify pain, a series of experimental studies have been initiated to identify objective phenotypes. Neuroimaging, physiological measures and diaries are used to identify subjects with acute or persistent pain. A prospective study of 13 static and dynamic quantitative sensory tests has been performed on 30 adults with sickle cell anemia and 30 matched controls. Static thermal testing showed hyperalgesia to cold pain and tolerance thresholds with sickle cell. More prominent sensitivity was observed with random order heat pulses and temporal summation pulses at the heat pain threshold. Sickle cell subjects also had hyperalgesia to mechanical pressure pain, but not pressure tolerance or light tactile stimuli. However, pinprick temporal summation probes showed highly significant hyperalgesia associated with lower fetal hemoglobin in a multivariable model. Finally, sickle cell subjects tolerated ischemic pain less than normal volunteers. In addition, pilot functional MRI neuroimaging studies were performed in adolescents with SCD at a local childrens hospital with intramural funding. Resting state functional connectivity was compared between high pain and low pain groups using seed based and independent component analysis. The high pain group displayed excess connectivity between pro-nociceptive structures. Not surprisingly, fetal hemoglobin was higher in those with low pain, and importantly fetal hemoglobin was also associated with greater connectivity to anti-nociceptive structures. Together, the sensory testing and neuroimaging findings support the role of central mechanisms in SCD pain. Both studies also suggest that fetal hemoglobin levels may modulate central pain in sickle cell. The ischemic pain test suggests that improved tissue oxygenation and microvascular blood flow are other means by which pain might be treated in sickle cell disease. 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 was 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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