ALBERT

Description: Introduction: Studies have described neuroimaging abnormalities and neurocognitive dysfunction in adults living with sickle cell anemia and no previous history of neurological impairment. At the Johns Hopkins Sickle Cell Center for Adults, we have been administering the Montreal Cognitive Assessment (MoCA) at regularly scheduled outpatient appointments as part of routine screening and clinical care. The MoCA is scored out of 30 points and consists of 28 questions grouped into seven domains of cognitive function: visual-spatial and executive, naming, attention, language, abstraction, delayed recall and orientation. While the MoCA has yet to be validated as a screening tool for cognitive impairment in adults with sickle cell disease (SCD), it has been widely used and validated in other populations to screen for mild cognitive impairment with the cutoff typically ranging from 22 to 26. The objective of this study was to describe the results of MoCA testing in a sample of adults with SCD and to explore predictors of MoCA performance using data from a retrospective chart review. Methods: A cross-sectional study was completed of the first 100 MoCAs administered to adult patients with SCD. Demographic, laboratory and clinical data were collected from each participant’s medical record up to the date that the MoCA was administered. The internal validity of each MoCA domain was analyzed using standard psychometric statistics, including a Cronbach-α score and factor analysis. Bivariate analysis was completed using Mann–Whitney U tests and Spearman Rank correlations. We identified independent predictors of MoCA performance using a multivariable robust linear regression. Age, hemoglobin and genotype were included in the multivariable analysis along with any variable found to have an association with MoCA score (p-values ≤ .10). Results: The distribution of scores is displayed in Figure 1; the mean score was 24.5 with a standard deviation of 4.1. The visual-spatial and executive function and attention domains showed strong correlation with overall test performance and demonstrated high measures of internal validity. Education, gender, weight, aspartate aminotransferase, cerebral vascular accident (CVA), chronic kidney disease (CKD) and a history of hydroxyurea therapy were associated with MoCA scores in bivariate analysis. The results of multivariable analysis are displayed in Table 1. Education was found to be a significant independent predictor of increased MoCA score, while CVA and CKD were found to be significant predictors of decreased MoCA score. When limited to the 64 participants with SS or Sβ0 Thalassemia, education and a history of hydroxyurea therapy were found to be significant independent predictors of increased score, while CKD was found to be a significant predictor of decreased score. Conclusion: A screening tool for neurocognitive dysfunction in adults with SCD is needed in order to identify those that require more definitive testing. The significant association of MoCA score with both education and CVA supports the potential validity of this measure as a screening tool in this patient population. Further validation of this tool is needed as well as an exploration into the possible relationship between improved MoCA performance and hydroxyurea use. Figure 1 Figure 1. Table 1: Multivariable Analysis Model 1: Robust Linear Regression for MoCA Score (n = 89) Independent Variables Coefficient [95% Confidence Interval] P-value Education – Completed 〉 12th Grade 3.1 1.5 4.7 .0003 Gender - Male 1.4 -0.13 2.8 .0738 Age (years) -0.043 -0.11 0.024 .2055 Genotype – SS or Sβ0 Thalassemia 1.3 -1.3 3.9 .3350 Hemoglobin (g/dL) 0.033 -0.62 0.69 .9196 Weight (lbs) 0.014 -0.0052 0.034 .1504 Aspartate Aminotransferase (Units/L) -0.035 -0.078 0.0090 .1179 CVA -3.3 -5.7 -0.90 .0079 CKD -3.1 -6.2 -0.056 .0460 Model 2: Robust Linear Regression for MoCA Score for participants with SS or Sβ0 Thalassemia (n = 64) Independent Variables Coefficient [95% Confidence Interval] P-value Education – Completed 〉 12th Grade 3.7 2.2 5.2 .0000 Gender - Male 0.95 -0.71 2.6 .2561 Age (years) -0.043 -0.13 0.046 .3363 Hemoglobin (g/dL) -0.010 -0.69 0.67 .9770 Weight (lbs) 0.0067 -0.015 0.029 .5451 Aspartate Aminotransferase (Units/L) -0.044 -0.089 0.00062 .0531 CVA -1.9 -4.7 0.92 .1832 CKD -3.4 -6.4 -0.27 .0334 History of Hydroxyurea Therapy 2.1 0.14 4.0 .0364 Disclosures Haywood: NHLBI: Research Funding. Lanzkron:NHLBI: Research Funding.

Description: Primary hemorrhagic stroke is an uncommon but serious complication of sickle cell disease (SCD) with mortality from 20 to 65%. Proposed risk factors include previous ischemic stroke, aneurysms, low steady-state hemoglobin, high steady-state leukocyte count, acute chest syndrome, and transfusion. We performed a retrospective case-control study to evaluate risk factors for primary hemorrhagic stroke in adults (age 〉19 years) with SCD hospitalized at Johns Hopkins Hospital from January 1989 to June 2007. Cases had SCD and intraparenchymal (IPH), subarachnoid (SAH), or intraventricular (IVH) hemorrhage confirmed by neuroimaging or analysis of cerebrospinal fluid; traumatic subdural and epidural hemorrhages were excluded. Controls had SCD and ischemic stroke (focal neurological deficits with corresponding cerebral infarcts by neuroimaging). Both were identified by searching the hospital discharge database using ICD-9 codes for acute stroke and SCD and reviewing divisional records. We compared continuous variables by Student’s t-test and calculated odds ratios with exact methods. We identified 7 cases (mean age 31 years, range 19 – 49, 29% male) and 9 controls (mean age 37 years, range 21 – 61, 11% male). All cases had sickle cell anemia (HbSS) and 17% had a prior overt stroke; Controls had HbSS (5/9) and HbSC (4/9) and 50% had a history of overt stroke. Cases presented with impaired mental status (5/6), headache (7/7) and seizure (5/7). Controls presented with hemiparesis (7/8) and rarely seizure (1/7). Three cases had IPH involving the frontal lobe, frontal and parietal lobes, or basal ganglia. Four patients had SAH with IVH (2) and frontal IPH (1). Cerebral angiography identified aneurysms in 3 cases. One case (14%) and no controls died during the initial hospitalization. About 50% of cases (3/6) and controls (4/9) had elevated systolic blood pressure at the time of stroke. Cases had lower steady-state hemoglobin (mean ± SEM 7.4 ± 1 g/dl vs. 9.3 ± 1.1 g/dl), lower steady-state blood pressures (systolic 120 ± 7 vs. 132 ± 11 mm Hg, diastolic 72 ± 7 vs. 73 ± 5 mm Hg) and higher steady-state leukocyte counts (12,912 ± 1007/ul vs. 11,097 ± 2520/ul) than controls, but these differences were not statistically significant. Mean hemoglobin concentration at the time of stroke increased 1.3 g/dl (22%) from steady-state in cases and 0.7 g/dl (10%) in controls. Three cases had simple transfusions (1, 4, and 11 days before their primary hemorrhagic stroke) in preparation for surgery (2) and for aplastic crisis (1). No controls were transfused, but a woman with HbSS had a hemoglobin of 14.5 g/dl at the time of stroke (from excessive erythropoietin administration). In this group of adults with SCD, primary hemorrhagic stroke was associated with genotype and antecedent transfusion. Mortality was lower than that previously described and may reflect improvements in medical care or random variation within a small sample. The contribution of antecedent events and other potentially modifiable risk factors for hemorrhagic stroke in adults with SCD deserves further evaluation. Table 1: Associations with Primary Hemorrhagic Stroke Variable Odds Ratio (95% CI) P-Value NC indicates not calculated Genotype (HbSS vs. Other) NC (1.1-∝) 0.09 Seizure (at presentation) 20 (1.0–1059)

Description: Primary hemorrhagic stroke is an uncommon but serious complication of sickle cell disease (SCD) with mortality from 20 to 65%. Proposed risk factors include previous ischemic stroke, aneurysms, low steady-state hemoglobin, high steady-state leukocyte count, acute chest syndrome, and transfusion. We performed a retrospective case-control study to evaluate risk factors for primary hemorrhagic stroke in adults (age 〉18 years) with SCD from Johns Hopkins and Barnes- Jewish Hospitals and Duke University Medical Center from January 1989 to April 2008. Cases had SCD and intraparenchymal (IPH), subarachnoid (SAH), or intraventricular (IVH) hemorrhage confirmed by neuroimaging or analysis of cerebrospinal fluid; traumatic hemorrhages and hemorrhagic conversion of ischemic strokes were excluded. Controls had SCD and ischemic stroke (focal neurological deficits with corresponding cerebral infarcts by neuroimaging). Both were identified by searching the hospital discharge database using ICD-9 codes for acute stroke and SCD and reviewing divisional records. We compared continuous variables by Student’s t-test and calculated odds ratios with exact methods. We identified 19 cases (mean age 29 years, range 18 – 66, 42% male) and 18 controls (mean age 34 years, range 19 – 61, 39% male). Most cases (14/18) had sickle cell anemia (HbSS) and 22% had a prior overt stroke; controls had HbSS (9/17), HbSB0thalassemia (1), or HbSC (7) and 41% had a history of overt stroke. Cases presented with headache (89%) and seizure (37%) and less frequently hemiparesis (27%). Controls presented with hemiparesis (78%), headache (57%), and rarely seizure (11%). Twelve cases had IPH including those with extension to the ventricles (1), subarachnoid (2) or both (2); six had SAH including ventricular extension (1). Potential causes of hemorrhagic stroke included moyamoya (4), aneurysms (3), anticoagulation (1) and ateriovenous malformation (1). Four cases (21%) and no controls died during the initial hospitalization. More cases (82%) than controls (44%, P

Description: Abstract 3221 Background: Most adult sickle cell anemia patients have received transfusion therapy. However, prospective studies evaluating the efficacy of transfusions in preventing sickle cell-related complications are lacking. The Phase II Neuropsychological Adult Sickle Cell Anemia Study is a randomized trial of chronic transfusion vs. standard of care in patients with abnormal neurocognitive function in order to determine the safety and benefits of transfusion therapy on neurocognitive function. A secondary goal of the study is to evaluate the benefit of chronic transfusion on the frequency and severity of acute sickle cell events; this is a preliminary report of this specific aim. Methods: Eligibility required normal neurological exam, WAIS III PIQ score ≤ 90, hemoglobin ≤ 9 g/dL, hemoglobin SS electrophoresis, and age between 21 and 55 years. Patients were randomly assigned to receive either standard care or transfusions. The transfusion goal was to maintain a hemoglobin of 2 g/dL rise over baseline with matched red cells for D, C/c, E/e, and Kell antigens. The protocol required simple transfusions at approximately 4 week intervals. Chelation therapy was not part of the study design. Patients underwent serial clinical and laboratory evaluations with central analysis of all clinical and transfusion events and complications. Laboratory testing of subjects in the transfusion arm included quantitative hemoglobin S/A, hemoglobin concentration, ferritin levels, and red cell antibody screening; a full hematology/chemistry panel was performed for all subjects at baseline, the study mid-point, and at the end of the study. Results: There were 20 patients in the transfusion arm (TX arm) with a mean age of 29 years vs. 16 patients in the standard care arm (SC arm) with a mean age of 30.5 years. The baseline data in the TX arm was similar to the SC arm: hemoglobin 7.8 vs. 8.0 g/dL; hematocrit 22.6% vs. 23.1%; hemoglobin F 10.5% vs. 12.5%. Thirty-five percent of patients randomized to the TX arm had a history of acute chest syndrome (ACS) vs. 31% in the SC arm; 30% of patients in the TX arm were on hydroxyurea compared to 50% in the SC arm. The TX arm patients have received an average of 5.6 transfusions (2 units per transfusion) with only one subject requiring an acute transfusion (5%); in contrast, 4 SC arm patients (25%) were transfused for acute events for a total of 7 units (average 1.8 per patient). The transfusion therapy improved the average hematologic status of patients: hemoglobin S% decreased from 85% to 32% (p=0.0003); hemoglobin and hematocrit increased from 7.6 to 9.4 g/dL (p=0.0052) and 22% to 28%, (p=0.007), respectively. Bilirubin declined from 3.6 to 2.4 mg/dL (p=0.042). In contrast, only bilirubin showed a significant decrease in the SC arm. In the TX arm, serum ferritin rose an average of 1318 to 2368 (p=.001); there was no change in liver function. There were no clinical transfusion reactions in the 120 study transfusions (360 units); however, one patient on routine screening reported a transient anti-D antibody without clinical or laboratory changes. Clinical Results: Adverse events were higher in the SC arm. Total number of adverse events in the TX arm were 23 (1.2 per person) vs. 66 in (4.1 per person) in the SC arm. There were 5 hospitalizations in the TX arm and 21 in the SC care arm, with a median number of hospitalized days per hospitalization of 5.0 and 6.0 respectively. The total number of serious events was 6 in the TX arm (0.3 per person) vs. 23 in the SC arm (1.4 per person). The total number of vaso-occlusive events in the TX arm were 14 (0.7 per person) vs. 57 (3.6 per person) in the SC arm. Acute pulmonary events occurred in 25% (4 patients) of the SC arm vs. none in the TX arm. Conclusions: This is preliminary data from the first prospective randomized study of the safety and efficacy of transfusion therapy in adults with SCD. We demonstrate the safety of transfusion therapy. Compared to standard therapy, transfusions improve or stabilize critical laboratory markers, decrease serious sickle cell anemia-related adverse events, and decrease in hospitalizations. Increase in ferritin is an expected outcome in transfused patients since chelation was not a part of this transfusion protocol. On completion of the study, the potential benefits of transfusion therapy on sickle cell disease morbidity including neurocognitive function will be reported. Disclosures: Field: Novartis Pharm: Honoraria.

Description: Headache and other symptoms and signs of possible CNS disease are common in children with sickle cell disease (SCD). Computerized tomography (CT) is a rapid and widely available method to image the skull and brain. However, the use of head CT to evaluate possible acute CNS complications in SCD has not been adequately addressed. We conducted a retrospective cohort study to characterize predictors of acute intracranial pathology detected by head CT. We included patients

Description: Abstract 4845 Background: Respiratory syncytial virus (RSV) has been recognized as a cause of acute chest syndrome (ACS) in children with sickle cell disease (SCD). However, the proportion of children with RSV and SCD that are admitted to hospital or develop ACS is unknown. In studies of young children without SCD, RSV has traditionally been associated with more hospitalizations in the first three years of life then influenza has. To compare the relative severity of RSV vs. seasonal influenza in children with SCD, we compared the clinical characteristics and complications associated with these infections at a single tertiary care hospital. Methods: We defined a case as laboratory-confirmed RSV infection in a patient

Description: Background: As patient-centered care advances, measurement of health-related quality of life (HRQL) has become increasingly important when assessing the impact of a disease or therapy on a child. Red blood cell transfusions are an effective preventative therapy for some acute and chronic complications in children with sickle cell disease (SCD). This study aimed to determine the impact of transfusion therapy on health-related quality of life (HRQL) outcomes of children with SCD. Procedure: Children (n = 196) who participated in the Multicenter Silent Infarct Transfusion (SIT) Trial were grouped per protocol into either those who received 18 months or more of transfusion or less than 18 months of transfusion (observation). Parents/guardians of children ages 5 to 18 years completed assessments of HRQL using the Child Health Questionnaire at baseline and at the time of study exit or neurological event, if that occurred. Results: Children (43% female) had a mean age of 9.55 years (SD= 2.59) at study enrollment, and 92% were Black. There were no differences between study groups (effectively transfused vs. observation) in regards to gender, disease severity, rates of pain and acute chest syndrome, or baseline levels of HRQL. At study exit, independent samples t-tests revealed children in the effectively transfused group had significantly higher scores than the observation group for the following HRQL domains: Physical Function (M = 12.68, SE = 3.52), t (174) = 3.61, p ≤ 0.001; Bodily Pain (M = 13.16, SE = 3.74), t (174) = 3.51, p ≤ 0.001; and Change in Health (M = 0.39, SE = 0.14), t(166) = 2.71, p=0.01. Additionally, children in the effectively transfused group scored 4.98 (SE = 1.98) points higher on Physical Summary Scores than children in the observation group, t (170) = 2.52, p= 0.01. Thus, parents report that children who received at least 18 months of transfusions had better overall physical functioning, less bodily pain, and more improved overall health than children who had fewer than 18 months of transfusions. Both groups reported changes in HRQL over time. Compared to study entry, paired samples t-tests revealed children in the observation group indicated an increase of 0.42 (SE = 0.14) points for Change in Health scores [t (77) = 3.06, p ≤ 0.001], but had a decrease of 5.95 (SE = 2.07) points for Self-Esteem at study exit, t (85) = -2.87, p = 0.01. Children in the transfusion group improved by 7.22 (SE = 3.11) points in regards to pain over the course of the study, t (78) = 2.32, p = 0.02. Additionally, these children had better overall health as exhibited by their Change in Health scores (MD = 0.93, SE = 0.14), t (72) = 6.80, p = ≤ 0.001, and General Health scores (MD = 4.13, SE = 1.83), t (77) = 2.26, p = 0.03. Further improvements over time were noted for the effectively transfused group for Physical Functioning (MD = 6.58, SE = 3.09), t (78) = 2.13, p = 0.04, and Physical Summary Scores(MD = 4.89, SE = 1.82), t (73) = 2.69, p= 0.01. Although both study groups reported improvements in Change in Health scores over the course of the study (Effectively Transfused: MD = 0.93, SE = 0.14; Observation: MD = 0.42, SE = 0.14), an estimated Least Square Means analysis revealed children in the observation group did not improve as much as children in the effectively transfused group, Difference Estimate = -0.46, p= 0.02. Conclusions: This study provides the first evidence that blood transfusion improves HRQL in children with SCD. Children in the SIT trial who received at least 18 months of chronic blood transfusion therapy felt better and had better overall HRQL than those who had less than 18 months of transfusion therapy. Disclosures Casella: Mast Therapeutics, previously Adventrix, ImmunoArray: Consultancy, Honoraria, Other, Patents & Royalties, Research Funding.

Description: Introduction Perceived discrimination due to race or ethnicity has been associated with a greater burden of pain among minority groups.  Patients with sickle cell disease (SCD), who in the U.S. are comprised primarily of individuals from racial and ethnic minority groups, are known to experience behaviors from others that may be construed as discriminatory.  Nevertheless, the association of these problematic interpersonal experiences with the burden of chronic pain in SCD is unknown. Methods We conducted a cross-sectional analysis of data collected at baseline of the Improving Patient Outcomes with Respect and Trust Study (IMPORT), which is a federally funded prospective cohort study of SCD patient (age 15+) experiences of care (n = 291).  We sought to examine the association between patient perceptions of discrimination and their reports of chronic SCD pain.  Perceived discrimination from healthcare providers thought to be due to the patient's race/ethnicity (i.e., race-based), or status as having SCD (i.e, disease-based) was measured using subscales adapted from the Interpersonal Processes of Care Survey.  Using descriptive, bivariate, and multivariable analytic techniques, discrimination scores were examined for their association with self-reported chronic pain both unadjusted, and adjusted for the following potential confounders: patient age, sex, type of SCD, self-reported ED utilization for vaso-occlusive crisis, depression symptoms, the patient's perceived severity of their SCD, and the presence or absence of avascular necrosis. Results Patients in the cohort reported higher levels of race-based discrimination compared to other reports of African Americans using the same instrument.  The cohort reported an even higher level of perceived disease-based discrimination than race-based discrimination.  Race-based discrimination exhibited significant, positive associations with disease-based discrimination (r = 0.51, p

Description: The most common form of neurologic injury in sickle cell anemia (SCA) is silent cerebral infarction (SCI). In the Silent Cerebral Infarct Multi-Center Clinical Trial, we sought to identify risk factors associated with SCI. In this cross-sectional study, we evaluated the clinical history and baseline laboratory values and performed magnetic resonance imaging of the brain in participants with SCA (HbSS or HbSβ° thalassemia) between the ages of 5 and 15 years with no history of overt stroke or seizures. Neuroradiology and neurology committees adjudicated the presence of SCI. SCIs were diagnosed in 30.8% (251 of 814) participants who completed all evaluations and had valid data on all prespecified demographic and clinical covariates. The mean age of the participants was 9.1 years, with 413 males (50.7%). In a multivariable logistic regression analysis, lower baseline hemoglobin concentration (P 〈 .001), higher baseline systolic blood pressure (P = .018), and male sex (P = .030) were statistically significantly associated with an increased risk of an SCI. Hemoglobin concentration and systolic blood pressure are risk factors for SCI in children with SCA and may be therapeutic targets for decreasing the risk of SCI. This study is registered at www.clinicaltrials.gov as #NCT00072761.