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Pulmonary complications result in mortality in adults with sickle cell anemia (SCA). We tested the hypothesis that abnormal pulmonary function was associated with earlier death. A prospective cohort of adults with SCA, followed in the Cooperative Study for Sickle Cell Disease, was constructed using the first pulmonary function test at21 years of age. Spirometry measures: forced expiratory volume in 1 second (FEV1), forced vital capacity, and total lung capacity were categorized based on age, gender, height, and race. Pulmonary function patterns were categorized based on the American Thoracic Society guidelines using both spirometry and lung volumes. A cohort of 430 adults with SCA, mean age 32.6 ± 9.5 (range, 21.0-67.8) years at time of first pulmonary function test, and a median follow-up of 5.5 years, was evaluated. A total of 63 deaths occurred. At baseline, 47% had normal, 29% restrictive, 8% obstructive, 2% mixed, and 14% nonspecific lung function patterns. In the final multivariable model, lower FEV1 percent predicted was associated with increased hazard ratio of death (HR per % predicted 1.02; 95% confidence interval [CI] 1.00-1.04; P = .037), as was older age (HR 1.07; 95% CI 1.04-1.10; P.001), male sex (HR 2.09; 95% CI 1.20-3.65; P = .010), higher lactate dehydrogenase levels (HR per mg/dL 1.002; 95% CI 1.00-1.003; P = .015), and higher acute chest syndrome incidence rate (HR per event/year 10.4; 95% CI 3.11-34.8; P.001). Presence of obstructive (HR 1.18; 95% CI: 0.44-3.20; P = .740) and restrictive (HR 1.31; 95% CI: 0.64-2.32; P = .557) pulmonary function patterns were not associated with earlier death. Understanding the pathophysiology of a low FEV1 percent predicted in individuals with SCA is warranted, enabling early intervention for those at risk.

Treatment of patients with β-thalassemia major has improved dramatically during the past 40 years; however, the current clinical status of these patients remains poorly characterized. We performed a cross-sectional study of 342 patients in the Registry of the National Institutes of Health-sponsored Thalassemia Clinical Research Network. Evidence of hepatitis C exposure was present in 35% of tested patients, was associated with age, and had a rate of spontaneous viral clearance of 33%. Ferritin levels ranged from 147 to 11 010 ng/mL (median, 1696 ng/mL). Median hepatic iron content was 7.8 mg/g dry weight and 23% of patients had values of 15 mg/g dry weight or higher. No patients 15 years or younger and 5% of patients aged 16 to 24 years had heart disease requiring medication. Ten percent had cirrhosis on biopsy. Endocrinologic complications were common among adults. Seventy-four (22%) patients had recent implantable central venous access devices (CVADs) placed. Among 80 episodes of bacteremia in 38 patients, 90% were attributable to the CVAD. Among 330 patients who had received deferoxamine chelation therapy, 224 (68%) reported no complications. We conclude that hepatitis C, iron-related organ dysfunction, and complications of iron chelation therapy are strongly age-dependent in North American patients with β-thalassemia.

Children with sickle cell anemia (HbSS) are at high risk for neurologically overt cerebral infarcts associated with stroke and neurologically silent cerebral infarcts correlated with neuropsychometric deficit. We used complete magnetic resonance imaging (MRI) histories from 266 HbSS children, aged 6 through 19 years, who were enrolled in the Cooperative Study of Sickle Cell Disease (CSSCD) to examine silent infarct prevalence, localization, recurrence, and progression. We report a baseline prevalence of 21.8%, marginally higher than previously reported due to improved imaging technologies. Although we observed no overall sex difference in prevalence, most lesions in girls occurred before age 6, whereas boys remained at risk until age 10. Silent infarcts were significantly smaller and less likely to be found in the frontal or parietal cortex than were infarcts associated with stroke. Children with silent infarct had an increased incidence of new stroke (1.03/100 patient-years) and new or more extensive silent infarct (7.06/100 patient-years) relative to stroke incidence among all children in our cohort (0.54/100 patient-years). Both events were substantially less frequent than the risk of stroke recurrence among children not provided chronic transfusion therapy. Although chronic transfusion is known to decrease occurrence of new silent infarcts and strokes in children with elevated cerebral arterial blood flow velocity, further study is required to determine its risk-benefit ratio in children with silent infarct and normal velocities. Until safe and effective preventive strategies against infarct recurrence are discovered, MRI studies are best reserved for children with neurologic symptoms, neuropsychometric deficits, or elevated cerebral artery velocities.

Background: Vaso-occlusive pain episodes (VOE) are the most common complication and reason for hospital admission in individuals with Sickle Cell Anemia (SCA). Recently our team demonstrated that in adults with SCA followed prospectively for approximately 5 years, a lower baseline Forced Expiratory Volume in 1 second percent predicted (FEV1%), which is associated with earlier mortality, but evidence of obstructive or restrictive lung function patterns is not (Blood 2015, in press). Based on the evidence that abnormal pulmonary function is associated with earlier mortality, we tested the hypothesis that baseline pulmonary function patterns were associated with SCA-related morbidity, including VOE and acute chest syndrome (ACS) events. Procedure: A prospective cohort of adults with SCA followed in the Cooperative Study for Sickle Cell Disease (CSSCD) was constructed based on a planned secondary analysis. Data from the first PFT record at age 21 and older were used for this study. Percent predicted values were determined for each participant based on their age, gender, height, and race for FEV1 and the ratio of FEV1 to forced vital capacity (FEV1/FVC) using the Global Lung Function 2012 equations (Eur Respir J, 2012; 40(6): 1324-1343). Assessment of lower airway obstruction was based on % predicted FEV1/FVC. Percent predicted total lung capacity (TLC), a measure of restrictive lung disease, was determined using published equations and corrected based on race. All PFT evaluations were checked for quality. Negative binomial regression models were used to determine the association between future VOE, ACS events, and spirometry measurements after adjusting for age, sex, hemoglobin, and fetal hemoglobin levels. Results : A total of 430 adults with SCA were evaluated. Ages of the study participants ranged from 21.7-66.4 years with a median age of 32.6 years at the time of first PFT and median follow-up was 5.5 years. Only FEV1/FVC% predicted as a continuous covariate was a significant predictor of future VOE. Lower FEV1/FVC% predicted was associated with higher future pain event rates with a rate ratio of 1.022 (95% CI 1.002 - 1.042; p=0.028). For every 10% decrease in FEV1/FVC% predicted there is a 23% increase in the rate ratio. TLC% predicted did not predict future VOE (p=0.762). FEV1/FVC% predicted or TLC% predicted did not predict future ACS events (p=0.618 and p=0.430 respectively). When FEV1/FVC% predicted and TLC% predicted < 5th percentile were used in the regression equation instead of continuous values, neither abnormal lung function parameter was associated with an increased incidence of VOE or ACS events. Conclusions: For the first time, we have demonstrated that spirometry evaluation with FEV1/FVC% predicted, as a measure of lower airway obstruction, identifies a group of adults with SCA at increased risk for future vaso-occlusive pain episode. Table 1. Covariate Rate Ratio (95% CI) P Age at PFT* -.112 (.850, .941) .000 Male 1.032 (.581, 1.836) .914 Average Fetal Hemoglobin .985 (.894, 1.085) .754 Average Hemoglobin .954 (.763, 1.193) .682 Negative FEV1/FVC percent predicted** .022 (1.002, 1.042) .028 Final Negative Binomial Regression model for vaso-occlusive pain episodes after lung function testing (N= 430) *PFT is Pulmonary Function Test ** Negative FEV1/FVC percent is reverse-coded so that lower values are associated with rate ratios above 1. Disclosures No relevant conflicts of interest to declare.

Background: Sickle cell anemia (SCA) is a life threatening monogenic disorder associated with early death. Platt et al. reported median ages of death (42 years males; 48 years females) from the Cooperative Study of Sickle Cell Disease (CSSCD). Forced expiratory volume in one second (FEV1) on pulmonary function testing (PFT), is commonly used to monitor disease severity in individuals with asthma, cystic fibrosis (CF) and chronic obstructive pulmonary disease. FEV1 (% predicted) has been shown to predict mortality in the general population, but no PFT result has predicted earlier death in SCA. We tested the hypothesis that abnormal pulmonary function was associated with earlier death. Methods: A prospective cohort study using the CSSCD data was constructed. We evaluated a total of 430 participants from the CSSCD study who had evaluable PFT, using data from the first PFT at age 21 years and older, and reviewed centrally for quality. Predicted values were determined for each subject based on age, gender, height, and race for FEV1, forced vital capacity (FVC), and the FEV1/FVC ratio using the Global Lung Function 2012 equations. Abnormal results for FEV1, FEV1/FVC, and FVC were determined by comparison to their lower limits of normal. Predicted values for total lung capacity (TLC) were obtained utilizing the prediction equations published, and adjusted by 12% to account for the effect of race on these values; a value Results: Median age was 31.4 years at time of first PFT and median follow-up was 5.5 years. In the cohort, 47% had normal, 29% restrictive, 8% obstructive, 2% mixed, and 14% non-specific pulmonary function patterns. There were no differences in SCA severity between groups (PFT vs no PFT). During follow-up, 63 (15%) participants died. Those who died had significantly higher WBC, lower hemoglobin levels, and lower FEV1% predicted, but not lower FEV1/FVC ratio. Pulmonary function patterns were not associated with earlier death- obstructive (p= 0.97), restrictive (p=0.41), and non-specific (p= 0.609). In the final multi-variable model, lower FEV1% predicted is associated with increased hazard of death [HR per %-predicted 1.02 (95% CI 1.00 – 1.04; p =0.037)], as did older age [HR 1.07 (95% CI 1.04-1.10; p Conclusion: For the first time, we have demonstrated that spirometry evaluation with FEV1% predicted identifies adults with sickle cell anemia who have increased hazard of death. Routine spirometry testing should become standard care in individuals with SCA, enabling early intervention for those at risk. Table: Final Cox Regression Model for death after lung function testing with reduced set of covariates (N=404) Covariate B Hazard Ratio (95% CI) P Age at PFT# 0.07 1.07 (1.04, 1.10) # PFT = Pulmonary function test ** FEV1% is reverse-coded so that lower values are associated with hazard ratios above 1. Figure: Kaplan-Meier survival curves stratified by FEV1 above and below 70% predicted in 430 adults with sickle cell anemia followed for a median of 5.5 years (p = 0.002; Log rank test). Figure:. Kaplan-Meier survival curves stratified by FEV1 above and below 70% predicted in 430 adults with sickle cell anemia followed for a median of 5.5 years (p = 0.002; Log rank test). Disclosures No relevant conflicts of interest to declare.

Background: The Thalassemia Clinical Research Network previously reported a high prevalence of low bone mass in thalassemia (thal) despite current treatment practices. Currently we report the association of vertebral compression fractures (frs) and vertebral (vert) growth disturbances with bone pain, bone mass, bone turnover and therapies in thal. Methods: Vert frs (T10-L4) were assessed by morphometry. Vert compression frs by quantitative assessment (Fr-qt) were defined as anterior or mid-vert hts at least 25% shorter than posterior hts or average vert ht at least 25% shorter than hts of adjacent vert. Frs by qualitative assessment (Fr-ql) and growth plate (GP) abnormalities were determined. Bone mineral density by DXA and bone turnover markers were measured. Results: 353 thal pts were studied 64% beta-thal major (beta-TM) 12% beta-thal Intermedia 11% E/beta-thal 11% HbH 1% alpha thal 1% stem cell transplant pts, mean age 23 (SD 12 yrs, range 6 – 75 yrs). General bone pain and back pain were self-reported for the 30 days prior to morphometry by 34% and 26% pts, respectively. Fr-qt occurred in 41 (12%) and Fr-ql in 9 (2.5%), while only 7 pts (2%) had a history of vertebral fr and prevalence did not differ by type of thal or gender. Fr-qt and Fr-ql prevalence increased with age (Fr-qt p < 0.1; Fr-ql p < 0.001). After controlling for age, lumbar DXA Z or T scores were negatively associated with frs (odds ratio for 1-SD increase: Fr-qt 0.670, 95% CI 0.488 to 0.921, p = 0.01; Fr-ql 0.303, 95% CI 0.125 to 0.730, p < 0.01). Hypertransfusion, yrs or onset of chelation, serum transferrin receptor or ferritin did not correlate with frs after controlling for age. Decreased ht Z score (p < 0.01) and growth hormone deficiency (GHD) (p = 0.01) were associated with higher risk for Fr-qt after correcting for age. Hypogonadism was also associated with Fr-qt but not after correction for age (odds ratio 1.916, 95% CI 0.927 to 3.959 p = 0.08). Presence of Fr-ql but not Fr-qt was correlated with generalized bone and back pain specifically (Fr-ql vs. back pain odds ratio 11.05, 95% CI 2.035 to 110.2, p = 0.001). GP abnormalities were present in 30 pts (9%), including 7 (2%) who also had Fr-qt. Prevalence of GP did not differ by gender but was more common in beta-TM pts (13%), E-beta thal (5%) and among all others (0%) (p=0.04). In beta-TM pts, lumbar DXA Z or T scores (p < 0.01), ht Z scores (p < 0.001) and age that chelation was started (p < 0.01) were all negatively associated with GP abnormalities after controlling for age. Hypogonadism (p = 0.001) and GHD (p = 0.04) were positively associated with GP abnormalities after controlling for age. Presence of GP was not correlated with either general bone pain or back pain specifically. Conclusions: Morphometry identified vert abnormalities in 18% of thal pts. These included moderate to severe vert wedging or GP disturbances. A subgroup of pts (2.5%) also had vert compression frs by radiologic assessment. Morphometry vert lesions were associated with low bone mass. Back pain was strongly correlated with radiologic frs but not with other lesions seen by morphometry.

Background: Acute chest syndrome (ACS) is one of the leading causes of premature death among people with sickle cell anemia (SCA). Children with SCA and asthma have an increased risk of ACS (Boyd et al, Pediatric Pulmonology, 2004). The Cooperative Study of Sickle Cell Disease (CSSCD) has previously reported the median age at death to be approximately 45 years, 42 years for males and 48 years for females (Platt et al, New England Journal of Medicine, 1994). The objective of this study is to determine if asthma in patients with SCA is associated with mortality. Methods: The cohort was comprised of African American participants with SCA anemia enrolled in the CSSCD from birth to 66 years of age who were followed beyond five years and were evaluated for asthma. Patients who died before age 5 years were not included in the cohort. Asthma was classified by physician diagnosis, documentation of an acute asthma event, and/or record of use of prescribed asthma medication. Mortality was determined for patients with and without asthma. Cox regression analysis included the following established risk factors for death (Platt et al, 1994): covariates age, white blood cell count level, renal failure, hemoglobin F level, seizure, and acute chest syndrome. Results: A total of 1963 African American individuals with SCA were classifiable for asthma, enrolled in the study and followed for a total of 18,496 patient-years. The average age at study entry was 13.9 years, and the mean length of follow-up was 9.4 years. A total of 138 individuals (7.0%) had asthma; 70% were classified by a physician diagnosis, 10% by documentation of an acute asthma event, and 20% by record of using a prescribed asthma medication. Individuals with asthma had a median lifespan of 52.5 years in comparison to 64.3 years and over a two-fold higher risk of mortality after controlling for age, white blood cell count, renal failure, hemoglobin F level, seizure, and acute chest syndrome rate (hazard ratio 2.36 by Cox regression, 95% CI 1.21 to 4.62, p=0.01). Conclusion: Asthma was associated with a significant increase in the risk of all-cause mortality among patients with SCA who lived to 5 years of age. In addition to previously identified risk factors, asthma is an independent predictor of mortality.

Introduction: The development of alloantibodies and/or autoantibodies, complicates red blood cell (RBC) crossmatching, shortens red cell survival, delays provision of safe transfusion and may accelerate tissue iron loading. Little is known about the incidence of alloimmunization or its inciting factors, essential data for strategies to provide optimal transfusion. Aim: To determine the frequency of RBC allo- and autoantibodies in patients with thalassemia major (TM) who are regularly transfused and whether there is an association of RBC antibodies and age at initiation of transfusion, duration of regular transfusion, splenectomy status, transfusion of leukoreduced blood or ethnicity. Methods: We utilized a cross-sectional registry of the Thalassemia Clinical Research Network (TCRN), an NHLBI-funded consortium of patients with thalassemia followed in Canada and the United States, for data on allo- and autoantibodies, splenectomy status, ethnicity and compared rates before and after 1990, when the first leukoreduction filters were introduced. Results: 502 of the 836 subjects enrolled in the TCRN registry had been regularly transfused and reported allo- and autoimmunization status. Allo- and autoantibodies were reported in 104 (21%) and 46 (9.2%) subjects, respectively. Presence of both were reported in 26 (5.2%) individuals. The rate of alloimmunization was higher among individuals who initiated transfusions prior to 1990 (27%) versus those who initiated transfusion after that date (12.5%, p Conclusions: RBC allo- and autoimmunization continue to develop in chronically transfused thalassemia patients although the availability of leukoreduced RBC may have resulted in the lower immunization rate observed in younger patients. The risk for RBC immunization that splenectomy imparts is concerning and deserves closer analysis.

Historically fractures and bone pain have been frequent problems in Thalassemia. Recently a cross-sectional observational study conducted by the North American Thalassemia Clinical Research Network (TCRN) found a high prevalence of low bone mass among the various Thalassemia syndromes. In addition, the prevalence of fractures and bone pain with contributing factors were determined and reported below. The study population consisted of 369 patients: 65% had Thalassemia Major (TM), 12% Thalassemia Intermedia (TI), 12% Beta E (βE), 5% hemoglobin H (HbH), 5% hemoglobin H/Constant Spring (HbH/CS) and 1% Homozygous alpha (Hα). A 35% prevalence of fractures which increased with age was identified (6–10 yrs: 1.1/100 pt-yrs; 11–19 yrs: 1.2/100 pt-yrs; 20+ yrs: 2.1/100 pt-yrs). Fractures occurred more frequently in males vs. females (40% vs. 31%), and among patients with Beta Thal (TM: 40%, TI: 49%, βE: 19%, HbH: 11%, HbH/CS: 5%, Hα: 0%) even after controlling for differences in age distribution. Prevalence of fractures increased with decreasing bone mass (AP spine Z or T scores measured by DXA) and increasing weight Z scores but was not associated with height or BMI Z scores. Prevalence of fractures was higher among patients treated for hypogonadism (59% vs. 26%) or hypothyroidism (65% vs. 32%) after controlling for age and gender. Traumatic fractures were most commonly reported (91%). Increased physical activity was associated with fractures among children ≤11y but not among other age groups. Rates of traumatic fractures among Beta Thal were higher than among other diagnosis (2.3/100 pt-yrs vs. 0.8/100 pt-yrs) after controlling for age. Rates of non-traumatic fractures among Beta Thal were elevated but not significantly higher than among other diagnosis (0.23/100 pt-yrs vs. 0.07/100 pt-yrs). 34% of patients reported bone pain during the 30 days prior to enrollment. Of those, 17% used prescription pain medications and an additional 36% used over-the-counter analgesics. The prevalence of bone pain increased with age, was higher in females (males: 28%, females: 40%), was higher in TM and Hα (TM: 40%, TI: 16%, βE: 19%, HbH: 37%, HbH/CS: 35%, Hα: 67%) and did not correlate with bone mass, height, weight and BMI Z scores or any reported endocrinopathies. In summary, fractures continue to occur frequently despite current treatment practices, especially among the older patients with Beta Thal. Bone pain remains a frequent complaint among the Thalassemia syndrome subjects.

Low bone mass is emerging as a frequent and debilitating morbidity in Thalassemia (thal). The TCRN conducted a cross-sectional observational study to determine the prevalence and factors contributing to bone disease among North American thal patients (pts). Spinal (L1-L4) Bone Mineral Density (BMD) Z- and T-score measurements by DXA (Hologic 4500 and Delphi models) were read centrally. Each subject’s weight, height, hematologic, endocrine and genetic parameters, iron chelation and transfusion regimens, dietary calcium intake, history of fractures and bone pain, self-reported physical activity and bone turnover markers were assessed. BMD was measured in 302 pts: 207 Thal Major (TM), 37 Thal Intermedia (TI), 35 Beta E, 7 Hemoglobin H disease (HbH), 2 homozygous alpha (α) and 14 HbH/Constant Spring (HbH/CS). Among all diagnostic groups, the prevalence of low bone mass (LBM; Z/T -1) was 52%, 27% and 21%, respectively. LBM prevalence was 55% in TM, 53% in TI, 51% in Beta E, 0% in HbH, 50% in α and 43% in HbH/CS. RBM prevalence was 26% in TM, 22% in TI, 31% in Beta E, 71% in HbH, 50% in α and 29% in HbH/CS. Pt groups aged: 6–11 yrs, 11–20 yrs, 20+ yrs had Z/T-scores mean±SD[n] were: −1.32±0.82[51], −1.73±1.08[77] and −2.43±1.14[174], respectively. Z/T-scores were significantly lower among older pts (p