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Introduction: Sickle cell disease (SCD) is the most common hemoglobinopathy in the world and it disproportionately affects population in tropical, resource-constrained regions where there is a high prevalence of malaria. Efforts to screen for SCD have been highly prioritized in these areas despite limited resources. However, follow up after diagnosis remains a challenge. Counterintuitively, many of those diagnosed with SCD are lost to follow up after screening while others lack access to treatment that would otherwise prevent them from developing adverse health effects of SCD which is the primary reason for screening for the disease. Objectives: To determine the rate of enrollment of children with sickle cell disease into comprehensive sickle cell clinic and initiation of sickle cell treatment after screening positive for SCD. Methodology: This is a cross sectional study. Families of children aged 5 years and below who screened positive for SCD as part of a validation of point of care test between 2017 and 2018 in Homabay County Referral Hospital in Kenya were contacted by phone and an inquiry was made on their health status, clinic visits and treatment for SCD. Five attempts were made at reaching the families within a period of one week. Data were analyzed using frequency tables. Results: Seven hundred children under 5 years were screened for SCD between 2017 and 2018 at Homabay County Referral Hospital and 34 were found to have sickle cell disease by screening and confirmatory testing. The mean age at the time of testing was 24 months (range 4 to 59 months). Mean follow up time was 33 months after diagnosis(range 32-35 months). Twenty-seven participants were reachable on phone and 8 could not be traced. Out of those contacted three had died from possible infectious diseases and one had stopped attending sickle cell clinic for unclear reasons. Twenty-three children were consistent with clinic attendance and were taking folic acid, and proguanil for malaria prophylaxis. Eight had not been started on hydroxyurea because they were asymptomatic for sickle cell. Fifteen patients who had been started on hydroxyurea had already experienced at least 3 or more painful crises, hospitalizations, febrile illness, or more than 1 blood transfusions within a year. These criteria are used to initiate hydroxyurea because of limited supply. In a setting where typically more than 50% of children screened for SCD are lost to follow up, 77% of the children were traceable and of those alive 96% were enrolled to comprehensive sickle cell clinic. Preliminary results from screening with point of care test permitted intensive education of families with a child highly likely to have SCD. This likely contributed to the high proportion of children attending SCD clinic. Relocation of families and unreliable phone contacts may have contributed to cases of lost to follow up. Conclusion: While screening for SCD is crucial for timely diagnosis and prevention of life-threatening complication of SCD, establishing consistent follow-up of patients is challenging. Timely screening results and education based on these results is an effective strategy to increase SCD clinic attendance, treatment adherence, and improve outcomes in children with SCD. Disclosures Strouse: Takeda: Consultancy.

Background Over the last five decades, advancements in management of sickle cell disease (SCD) have led to more individuals living beyond the median life expectancy, which has historically been 14 years based on autopsy data in 1973, to approximately 40 to 45 years in population-based studies and 61 years in recent cohorts from comprehensive programs. Despite the increasing life expectancy for people with SCD, there is a paucity of literature on the unique experiences of older adults with SCD (age > 50). This limits providers' understanding of how to address the unique needs of older adult patients with SCD as they age. Thus, the purpose of this study was to describe experiences with aging for older adults with SCD. Methods We recruited 19 older adults with SCD (age > 50) from a single academic comprehensive SCD center in the Southeastern United States. We conducted semi-structured qualitative interviews by phone and in person. Participants were asked open-ended questions about their experiences living with SCD, aging, and surviving beyond the SCD life expectancy. Audio-recorded interviews were transcribed verbatim. The transcripts were analyzed using conventional content analysis. Results The mean age of participants was 58 years (range 50-71) and 47% (n=9) were female. The majority of participants were married or had a domestic partner (58%, n=11) and 47% (n=9) were working. Most participants had HbSS genotype (53%, n=10), 37% (n=7) had HbSC, and 11% (n=2) had HbSβ+-thalassemia. Most people reported current use of hydroxyurea (58%, n=11) and their most common chronic complications were avascular necrosis (79%, n=15), retinopathy (58%, n=11), and chronic kidney disease (47%, n=9). Participants described their experiences aging and living beyond the life expectancy for SCD, encompassed in three themes (Figure 1): Theme 1 was "challenges with SCD across the lifespan," which focused on obstacles participates described from youth to adulthood, including experiencing pain and complications of SCD, but not being diagnosed with SCD until later in their childhood or until as late as mid-life. They described multiple obstacles as an older adult with SCD, including challenges maintaining employment, limitations in physical and social activities, and additional health problems such as kidney disease, increased fatigue, and pulmonary complications. They also reported perceiving healthcare providers were not knowledgeable enough about SCD to properly care for them. Theme 2 was "knowledge and self-management of SCD improves with age," where participants described differences between being younger vs. older with SCD, including sharing lessons they learned over time about managing SCD, which made them feel more knowledgeable about how to care for themselves in their older age. They described strategies that helped prevent and manage pain crises, such as preparing for weather extremes, learning personal triggers for sickle cell crises, knowing when to rest and when to keep moving, hydration, and being proactive with their SCD care. Theme 3 was "surpassing life expectancy," where participants discussed how their expectations for their life expectancy changed throughout their lives, and how their life expectancy was influenced by their family members, healthcare providers, and personal experiences and beliefs. Participants described being told by doctors at a young age that they would not live past age 18; however, when they made it to adulthood, some participants conveyed how they stopped allowing their prognosis to influence their thinking. Instead, they chose to trust in God that they would live long. Most participants said that their faith in God and healthy lifestyle choices were the main reasons why they surpassed the life expectancy for SCD. Conclusion These findings described the experiences conveyed by older adults with SCD about living beyond their expected lifespan. These data provide direction for providers to address areas of care that are most important to this older population and inform development of interventions to increase the knowledge of providers about SCD and health self-efficacy. The information these participants shared will also provide guidance for younger adults with SCD as they navigate the aging process and implement strategies that can support successful aging with SCD. Figure 1 Figure 1. Disclosures Strouse: Takeda: Consultancy.

Introduction: Pregnancies of women with sickle cell disease (SCD) have increased risk of morbidity and mortality, with potential additional complications due to uncertain teratogenicity of hydroxyurea and the newer medications. Unintended pregnancy is common among adolescents and young adults (AYA). We aimed to assess the beliefs, practices and barriers of U.S. pediatric hematology providers related to contraception for female AYA with SCD, as little is known about this topic. Methods: We developed a 25-question, web-based survey guided by the Health Belief Model to assess pediatric SCD providers' contraceptive perspectives and practices. Most questions were adapted from published surveys assessing provider views and practices on contraception for general AYA care or patients with other chronic health conditions. The survey was distributed from December 2020-April 2021 to licensed U.S. prescribers who provided care to female SCD AYAs ages 12-21 years within the prior two years. The anonymous survey was distributed by two methods: (1) a list of 526 pediatric SCD and/or general hematology providers from the HRSA SCD Treatment Demonstration Program Regional Collaborative, cross-referenced for reminder emails to 126 providers using a list from the HRSA Regional Genetics Collaborative (https://www.hrsa.gov); (2) directors from all 74 U.S. ACGME-accredited Pediatric Hematology-Oncology fellowship programs, asking then to forward the survey to their SCD providers. Surveys with >50% completion were analyzed using descriptive statistics and chi square analyses. Results: Of 177 respondents, 160 surveys met inclusion criteria and were analyzed: 73 (45.6%) contacted by emails and 87 (54.4%) contacted via the fellowship directors (Table 1). Respondents recruited via fellowship program directors were more frequently NP/PAs (total of 30 (18.7%)), of younger age (total 103 (64.4%) and had fewer years in practice compared to those contacted directly. The majority of providers reported counseling (76.9%) and/or referring patients for contraception (90.9%), but not prescribing (41.8%). Practices regarding contraception differed by provider characteristics (Table 2). Trainees vs. established providers less frequently reported counseling about contraception (54.1% vs. 84.6%, p30% respondents) were insufficiencies in time, patient/parent willingness, formal training, knowledge/ability and/or professional guidelines. Concerns about side effects was a barrier to prescribing (34.2%), while lack of access to providers with contraceptive expertise was the most common barrier to patient referral (34.9%). Multivariate analyses are ongoing. Conclusions: To our knowledge, this is the first national report of pediatric hematology providers' beliefs and practices regarding contraception for female AYA with SCD. While providers generally felt responsible for offering counseling and referral but not prescribing, practices varied based on certain provider characteristics, beliefs and perceived barriers. Clinical guidelines, improved provider education and training, and patient/parent decision Figure 1 Figure 1. Disclosures Smith-Whitley: Global Blood Therapeutics: Current Employment. Strouse: Takeda: Consultancy.

Background Life expectancy for individuals with sickle cell disease (SCD) has improved significantly in the last 50 years, creating a new population of older adults with SCD; however, life expectancy of adults with SCD is still up to 30 years shorter than African Americans in the general population and much lower than whites. SCD complications cause significant morbidity, requiring patients to make complex decisions about end of life care. Yet, there is a paucity of literature on SCD advance care planning (ACP), to guide providers on how to address ACP in this population. Thus, the purpose of this study was to assess barriers and facilitators to ACP for older adults with SCD. Methods We recruited 19 older adults with SCD (age > 50) from a comprehensive SCD center in the Southeastern United States. We conducted semi-structured interviews by phone or in person. Interview questions addressed aging with SCD, living beyond SCD life expectancy, experience with health care, experience with end of life care, comfort discussing death and end of life care, presence and nature of prior ACP discussions, and preferences for future ACP discussions. Audio-recorded interviews were transcribed verbatim. The data were analyzed using conventional content analysis. Results The mean age of participants was 57 years (range 50-71) and 47% (n = 9) were female. Most participants were diagnosed with SCD several years after birth and were told that they were not expected to live past age 18. Four of 19 participants had written advanced directives. Most participants were comfortable and willing to discuss ACP and thought that SCD ACP discussions should ideally start in early adulthood. Barriers to ACP included lack of communication, inappropriate contexts for ACP discussions, lack of trust, difficulty navigating ACP documents, and spirituality (Figure 1). Lack of communication included limited to no communication from trusted healthcare providers about ACP preferences. Inappropriate contexts for ACP discussions included being approached at difficult times by unfamiliar providers, such as being asked to complete advance directives while sick in the hospital by a provider who did not know the patient well. Trust was a barrier, as several participants were concerned that being asked about ACP while sick meant providers were giving up on them; others were unsure if they could trust providers or family members to carry out their end of life wishes as written. They reported difficulty navigating ACP documents and several participants incorrectly assumed a lawyer was required to finalize ACP documents. Finally, spirituality was a barrier as some participants reported that end of life planning was inconsistent with their religious beliefs. Facilitators of ACP included discussion at the right time, provider familiarity and knowledge, presence of family, and assistance in completing ACP documents. Participants expressed a desire to have an opportunity to openly communicate their end of life wishes with their provider when they were not sick in the hospital. They preferred discussing ACP with a provider whom they had a good relationship with, was familiar with their history, and they perceived was knowledgeable about SCD. Participants identified their SCD provider, PCP, or pulmonologist as suitable providers to talk to about ACP. Most preferred their family to be present during the ACP discussion. Those that had already completed advance directives at the time of the study received assistance from someone outside the health system to do so, such as help from their church, a lawyer, or their family. Conclusion Older adults with SCD expressed a desire for communication about ACP from trusted providers who are knowledgeable about SCD and want to have ACP conversations when they are feeling well. In addition, having the patient's family present and giving them assistance may increase the patient's comfort in completing their advance directives. The lack of communication from trusted providers or communication from unfamiliar providers about ACP during hospitalizations for acute complications are major barriers to creating advance directives for older adults with SCD. Future research is needed to obtain providers' perspectives on barriers to initiating conversations about ACP with adults with SCD. We will use these results to inform development of patient-centered and culturally-sensitive interventions to improve ACP in adults with SCD. Disclosures Strouse: Takeda: Research Funding.

Background Nearly 95% of individuals with sickle cell disease (SCD) live to become adults (age ≥ 18 years). As individuals with SCD age, they acquire both SCD and age-related complications leading to functional decline. There is a growing need for stragies to improve their function and quality of life.The purpose of this study was to assess the feasibility and acceptability of a sickle cell disease functional assessment (SCD-FA) in both younger and older adults with SCD. Methods We enrolled 20 younger adults (age 18-49 years) and 20 older adults (age ≥ 50 years) in a prospective cohort study. We included measures previously validated in functional geriatric assessment for oncology patients enriched with additional physical and cognitive functional measures. We monitored physical activity for 7 days using the Actigraph wT3X-BT. The primary endpoint was the proportion of subjects who complete the assessment. Secondary endpoints were duration of the SCD-FA, proportion who completed activity monitoring and biospecimen collection, and acceptability. Results Eighty percent (44/55) of adults approached for the study consented, and 91% (40) of consented participants completed the SCD-FA. The median duration of the assessment was 89 minutes (IQR 80-98 minutes), and there were no adverse events. A comparison of characteristics of younger and older participants is shown in Table 1. The mean usual gait speed (GS) was similar between younger and older adults, 1.10 m/s and 1.14m/s, respectively (p = 0.57). Both males and females in each age group had a GS similar to non-SCD adults over the age of 80 (Table 2). There was no difference detected in GS between participants with and without avascular necrosis (AVN) (1.12 m/s vs 1.13 m/s, respectively, p = 0.89) nor between severe SCD genotypes (HbSS and HbSß0) and less severe genotypes (HbSC and HbSß+) (1.08 m/s vs 1.18 m/s, respectively, p =0.13). There was no correlation between hemoglobin and GS (ρ = 0.22, p = 0.17). Young and old exhibited similar performance on the Timed Up and Go (TUG) with a mean time of 9.2 seconds for younger adults and 10.1 seconds for older adults (p = 0.14). Younger adults walked farther on the six-minute walk test (6MWT) compared to older adults (546 meters vs 482 meters p = 0.04). There was no difference in 6MWT between participants with and without AVN (499 meters vs 537 meters, p = 0.22), and no correlation between hemoglobin and distance on 6MWT (rs = 0.20, p = 0.21). Younger adults had a better performance on the 30-second chair stand test (30sCST) with a mean of 14 (range 4-22) vs 11 (range 3-16) in older adults, p = 0.02. There was no difference in 30sCST in people with or without avascular necrosis (12 vs 14, respectively, p = 0.24). Nearly all participants (95%) completed activity monitoring (18 younger adults and 18 older adults). Younger adults wore the monitors for a mean of 8 days (range 4-12) and older adults wore it for a mean of 7 days (range 4-10). The median step count for younger adults was 9253 steps/day (IQR 6449-10546) and the median step count for older adults was 6839 steps/day (IQR 6304-8144) (p = 0.44). The majority of both younger and older adult's activity was sedentary (42-44% of weartime) or light (47-48% of weartime). On the acceptability survey, 95% (38/40) reported that the length of the assessment was appropriate and particiants even had suggestions for additional questions to add. One participant found a question upsetting, about a history of drug use. 5% (2/40) reported portions as difficult to understand. When asked about feedback on removing items from the SCD-FA, 10% (4/40) recommended removing the Montreal Cognitive Assessment due to difficulty. Conclusions The SCD-FA was feasible, acceptable, and safe in both older and younger adults with SCD. There was no difference in GS in older and younger adults with SCD. Similar to older adults with SCD, younger adults had a mean GS similar to non-SCD adults over the age of 80. Younger adults did have significantly a better performance on the 6MWT and 30sCST compared to older adults, which may suggest better aerobic endurance and lower body strength. GS is one of the most powerful predictors of morbidity and mortality in non-SCD geriatric populations but its role in SCD awaits larger longitudinal samples. In future studies we will explore the role of GS and other components of the SCD-FA in predicting patient-important outcomes and mortality. Disclosures Strouse: Takeda: Research Funding.

Von Willebrand factor (VWF) contains binding sites for platelets and for vascular collagens to facilitate clot formation at sites of injury. Although previous work has shown that VWF can bind type IV collagen (collagen 4), little characterization of this interaction has been performed. We examined the binding of VWF to collagen 4 in vitro and extended this characterization to a murine model of defective VWF-collagen 4 interactions. The interactions of VWF and collagen 4 were further studied using plasma samples from a large study of both healthy controls and subjects with different types of von Willebrand disease (VWD). Our results show that collagen 4 appears to bind VWF exclusively via the VWF A1 domain, and that specific sequence variations identified through VWF patient samples and through site-directed mutagenesis in the VWF A1 domain can decrease or abrogate this interaction. In addition, VWF-dependent platelet binding to collagen 4 under flow conditions requires an intact VWF A1 domain. We observed that decreased binding to collagen 4 was associated with select VWF A1 domain sequence variations in type 1 and type 2M VWD. This suggests an additional mechanism through which VWF variants may alter hemostasis.

Background During the last five decades the life expectancy for people living with sickle cell disease (SCD) has improved markedly, with median survival of 61 years in recent cohorts enrolled from academic centers. Older adults with SCD (defined herein as age ≥ 50 years) make up 13% of the adult population at four major academic medical health systems in North and South Carolina. As this population continues to grow, more data are needed to guide medical management appropriate to their needs, as a lifetime of vaso-occlusion often leads to functional decline and premature development of complications seen in geriatric populations. There are no validated assessment tools and interventions to improve physical function in older adults with SCD. In this study we evaluated the feasibility of a focused geriatric assessment (FGA) for older adults with SCD. Methods Twenty adults with SCD ≥ 50 years old were enrolled in a prospective cohort study. Measures previously validated in the oncology FGA were included and enriched with additional physical and cognitive functional measures. Activity monitoring was performed for 7 days using the Actigraph wT3X-BT, and biomarkers were collected at each study visit (baseline, 10-20 days after a hospitalization [for those who experienced a hospitalization during the study period] and 12-month after baseline). The primary endpoint was the proportion of subjects who complete the assessment. Secondary endpoints were duration of the FGA, proportion who completed the activity monitoring and lab collection, and acceptability. Results Twenty-one of 25 older adults approached for the study consented. Nearly all (20/21, 95%) completed the FGA. One was removed after missed study visits. The median duration of the assessment was 97 minutes (range 73-175 minutes), and there were no adverse events. The mean age was 57 years (range 50-71), 50% (10) were female, 30% (6) were on disability and 50% (10) were working. 45% (9) were former smokers but only 5% (1) were current smokers (Table). On the acceptability survey, 95% (19) reported the length of the assessment as appropriate. 10% (2) subjects reported a portion of the Montreal Cognitive Assessment (MoCA) as difficult. No subject found the questions upsetting, and 2 subjects reported that they would remove redundant questions. All subjects had a Karnofsky Performance Score of at least 80% and were able to complete activities of daily living. A third (35%) had been admitted in the last 6 months, and most (75%) had had severe pain crises at home that limited their activity. 40% (8) had > 4 severe crises at home in the last 6 months. The mean usual gait speed was 1.14 m/sec (range 0.90-1.50) (Figure). Mean Timed Up and Go (TUG) was 10.1 seconds (range 7.7-14.0). Two (10%) subjects had a TUG consistent with increased fall risk (≥ 12 seconds). Mean grip strength of the dominant hand was 39 kg (range 22-54 kg) for males and 25 kg (range 20-34 kg) for females, which is 38% and 43% lower than expected for age and gender. Mean six-minute walk (6MW) was 465m for males and 499m for females, which is 22% and 4% lower than expected for age/gender/height/weight. In the 17 subjects with heart rate recovery (HRR) recorded after 6MW, the mean HRR at 1 minute (HRR1) was 20 bpm (range 0-46). 31% of tested subjects had a HRR1 consistent with impaired HRR (12 bpm or fewer). HRR negatively correlated with age (HRR1 B=-1.1; 95% CI -0.2 - -2; p The first 12 subjects wore the activity monitor 6 days (range 4-8 days) for an average of 15 hours a day. Average activity was sedentary for 7 hours (47%), light 7.5 hours (50%), and moderate 1 hour (7%) per day. There was a median of 7070 steps/day. Conclusions We found FGA to be feasible, acceptable, and safe. The duration of the FGA in our population was 3 times longer than the FGA for oncology. One of our most remarkable findings is that the older adults with SCD in this study have a physical function similar to non-SCD adults over the age of 80. They also demonstrate impaired HRR, an independent predictor of mortality in the elderly. After completion of the 12-month follow-up assessments, we will develop a briefer assessment to be evaluated in a larger study. Future steps will be to determine if FGA can predict outcomes such as risk of hospitalization and mortality and to develop interventions to improve these outcomes. Disclosures Strouse: Global Blood Therapeutics: Consultancy.

Sickle cell disease (SCD) is an inherited hemoglobinopathy that frequently causes neurological complications, such as stroke, silent cerebral infarct (SCI) and other forms of brain injury, including loss of cognition. SCI is defined as any ischemic lesion visible on T2-weighted magnetic resonance imaging (MRI) that is not associated with a focal neurologic deficit in the same vascular distribution, and is the most commonly recognized form of brain injury in SCD. SCI is associated with decreased neurocognitive function and increased risk for new or enlarging SCI/stroke. The purpose of this study was to use mass spectrometry (MS) based proteomics to discover and validate plasma brain proteins associated with brain injury in children with SCD. The plasma samples used for the proteomics discovery analyses were from two groups: screening samples of participants in the Silent Cerebral Infarct Multi-Center Clinical Trial (SIT Trial) (n=15), and 6 age-matched, healthy non-SCD controls, three of whom had sickle cell trait. Samples from children with SCD were divided into two groups: those with SCI (n=7) and those without SCI (n=8) matched for age, hemoglobin (Hb) and white blood cell counts. To identify circulating markers of SCI, plasma proteomes were analyzed using a sequential separation approach of Hb and top abundant plasma protein depletion, followed by reverse phase separation of intact proteins, trypsin digestion and tandem MS. Neurogranin (NRGN), a small calmodulin-binding synaptic protein (PMID 9886843), was the most abundant brain-enriched protein found in the plasma of children with SCD. We developed a NRGN sandwich immunoassay for verification of MS analysis results in an independent cohort from the SIT Trial longitudinal samples. For this verification study, plasma samples from the SIT Trial and 25 normal controls were tested for NRGN levels at study entry and exit by immunoassay. The majority of the SCD samples were obtained from an ancillary study to collect longitudinal samples that started after the SIT Trial had begun. There was no overlap between the discovery and the verification group samples. The normal control samples were from 25 healthy, age and gender comparable non-SCD pediatric controls unrelated to the SIT Trial, without evidence of acute/chronic illness. From the discovery SCD group, 1172 unambiguous proteins were identified; 639 proteins were identified from normal controls, as shown in Figure 1. Twenty-five percent (289/1172) of these proteins were found solely in the SCI group. Our MS protein identification data were filtered against this list of expressed brain proteins to produce a composite list of brain proteins found in plasma from children with SCD, but not found in plasma from age, gender and race-matched healthy control children. Twenty-five plasma proteins known to be expressed in one or more cell type enriched in the human brain based on bioinformatics searches were more abundant in the SCD vs control groups, as shown in Table 1. Median NRGN levels were higher at study entry in children with SCD (0.44 ng/mL, N=98), in comparison to a healthy, non-SCD control group (0.12 ng/mL, N=25, p < 0.0001), as shown in Figure 2. Using the longitudinal samples from the SIT Trial, there were no differences in NRGN levels between the observation group and the treatment group (p=0.35) over time. There was no significant difference in median NRGN levels between the observation group and the treatment group at the initial visit (0.36 vs 0.19, p=0.069) or final visit (0.39 vs 0.52, p=0.52). Using the initial visit samples from the SIT Trial, there was no significant difference in median NRGN levels between the non-SCI (n=35) and SCI groups (n=61) (p=0.073). There was no significant correlation between NRGN levels and neuropsychological measures of executive function (rho=0.089, p=0.58) and IQ (rho=-0.081, p=0.62). Our non-biased proteomic discovery studies demonstrate that NRGN levels are increased in children with SCD, when compared to normal children. Additional studies will be necessary to determine whether NRGN levels correlate with specific forms of neurologic injury. Further validation studies of larger cohorts with a multi-analyte ELISA of these brain proteins identified in plasma (Table 1) are warranted, and could help establish possible links between brain-specific proteins and neurocognitive outcomes. Disclosures Lance: NIH: Research Funding; KKI: Research Funding. Faulcon:FDA: Employment, Other: Although the author is a FDA/CTP employee, this work was not done as part his/her official duties. This publication reflects the views of the author and should not be construed to reflect the FDA/CTP's views or policies.. Fu:GSK: Employment. Yang:ImmunArray: Patents & Royalties: ImmunArray. Strouse:Global Blood Therapeutics: Consultancy. Barron-Casella:Mast Pharmaceudicals - spouse: Consultancy; ImmunArray - spouse: Patents & Royalties. Van Eck:ImmunArray: Consultancy, Patents & Royalties. Casella:NIH: Research Funding; Mast Pharmaceuticals: Consultancy; Immunoarray Ltd.: Patents & Royalties. Everett:ImmunArray: Consultancy, Patents & Royalties.

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.

BACKGROUND: Sickle cell disease (SCD) and cystic fibrosis (CF) are rare inherited disorders of similar severity. Disparities in funding between these two diseases have been long recognized and likely contribute to limited access to care and treatments for sickle cell disease. Private investment in therapeutics for these and other orphan diseases has greatly increased in the past ten years. We hypothesized that these increased private expenditures may help correct disparities in research publications, clinical trials, and FDA approval of new therapies. METHODS: We compared funding and research output for SCD and CF between 2008-2012 versus 2013-2017. We estimated disease-specific funding using NIH Research Portfolio Online Reporting Tools and the Form 990 financial reports for foundation expenditures of multiple organizations dedicated to each disease from 2008-2016. We developed a comprehensive search strategy to identify relevant publications in PubMed and new postings of US based interventional clinical trials by disease. In addition, we reviewed FDA drug approvals and new indications for each disease from 2008-2017. RESULTS: Average annual NIH funding per affected individual was 3.4-fold greater for CF than SCD from 2008 to 2016. Between 2008-2012, private foundation funding was 161-fold greater for CF than SCD. Between 2013-2016, private funding was 971-fold greater for CF than SCD. There were 1.8 times as many PubMed publications for CF compared to SSD. There was no significant difference in PubMed publications between the two time periods. There was a significant increase in interventional clinical trials for SCD between 2013-2017, with the largest increase coming from university/philanthropic funded trials. However, CF has significantly increased FDA drug approvals of both novel compounds and novel indications. CONCLUSIONS: Although the US prevalence of SCD is three times greater than CF, the amount of federal and private foundation research funding is magnitudes greater for CF. Foundation funding for CF benefited significantly from revenue based on the successful development of targeted therapies. However, despite the significant funding difference, the number of clinical trials for SSD are comparable to CF and have increased over the past few years. Research productivity as measured by articles indexed in PubMed, and new drug approvals remain substantially higher for cystic fibrosis despite greatly increased industry investment in orphan diseases. Disclosures Strouse: Global Blood Therapeutics: Consultancy.

Rationale: Lower airway disease is common in pediatric sickle cell disease (SCD) and is often diagnosed as asthma. This condition may be a risk factor for acute chest syndrome (ACS) and pain episodes. There are conflicting data about whether SCD-associated lower airway disease is due to allergic inflammation, as is typical in non-SCD childhood asthma. However, transgenic SCD mouse models have suggested a propensity toward allergic inflammation, and a recent study in children with SCD suggested allergic sensitization was associated with increased risk of acute chest syndrome (ACS). Allergic sensitization may be a risk factor for pulmonary inflammation and may trigger pain episodes. We hypothesized that allergic sensitization to a panel of indoor allergens would be associated with more frequent ED visits and hospitalizations for pain, ACS, and asthma symptoms in children and adolescents with SCD. Methods: Patients were recruited from two large academic children's hospitals. Ninety-nine participants with SCD ages 5-21 who were not receiving chronic exchange transfusions completed pre- and post-bronchodilator spirometry and allergy testing at a baseline visit. Allergen-specific IgE in blood was measured to Alternaria, Aspergillus, cat, cockroach, dog, dust mite (D. farinae), and mouse urine protein; we examined baseline characteristics by stratified groups (not sensitized vs. sensitized to one or more allergens) via t-tests, chi square, and Mann-Whitney U tests; we created a count variable with number of sensitizations. ED visits and hospitalizations were reviewed retrospectively two years prior to study entry. Asthma was defined as physician diagnosis in medical records plus at least one home asthma medication (albuterol or controller/preventative medication). We used negative binomial models to examine relationships between atopy [number of positive specific IgE (³0.35kU/L)] and the number of ED visits and hospitalizations, adjusting for age, sex, hydroxyurea use, and head of household (HOH) education level. FEV1 and positive bronchodilator response (³10%) were compared via multiple linear regression and multiple logistic regression. Results: Participants were 41% male, 66% HbSS or HbSb0 genotype, 52% on hydroxyurea, and 32% had a HOH with a high school education or less [Table]. Twenty-eight percent had a physician diagnosis of asthma, and 57% (N=56) were sensitized to at least one allergen. Allergic sensitization was associated with decreased risk of total ED visits1 (IRR 0.80[0.66-0.97] p=0.022), ED visits for pain (IRR 0.80[0.67-0.97] p=0.019), and fever (IRR 0.63[0.45-0.88] p=0.007), but not associated with a significant difference in ED visits for asthma or ACS. Allergic sensitization was neither associated with differences in rates of hospitalization (total, or for pain, fever, ACS, or asthma) nor with differences in FEV1 percent predicted, FEV1/FVC ratio, or positive bronchodilator response. Conclusions: In a population of children with SCD, allergic sensitization was associated with decreased risk of ED visits (total, for pain, and for fever). The mechanism for an association between atopy and a less severe phenotype of SCD is unclear. These findings point to potential differences in immunologic endotype/phenotype and add support to the hypothesis that lower airway disease in children with SCD has a different mechanism than typical childhood atopic asthma. Further investigation into the immunologic phenotypes and mechanisms of lower airway disease in children with SCD is warranted. 1All IRR presented are per allergen, adjusted for age, sex, hydroxyurea use, and HOH education level; 95% confidence interval. Disclosures Strouse: Global Blood Therapeutics: Consultancy.

Influenza causes excess morbidity in sickle cell disease (SCD). H1N1 pandemic influenza has been severe in children. To compare H1N1 with seasonal influenza in SCD (patients younger than 22), we reviewed medical records (1993-2009). We identified 123 cases of laboratory-confirmed influenza (94 seasonal, 29 H1N1). Those with seasonal influenza were younger (median 4.4 vs 8.7 years old, P = .006) and had less asthma (24% vs 56%, P = .002). Those with H1N1 influenza more often had acute chest syndrome (ACS; 34% vs 13%, P = .01) and required intensive care (17% vs 3%, P = .02), including mechanical ventilation (10% vs 0%, P = .02). In multivariate analysis, older age (odds ratio [OR] 1.1 per year, P = .04) and H1N1 influenza (OR 3.0, P = .04) were associated with ACS, and older age (OR 1.1 per year, P = .02) and prior ACS (OR 3.3 per episode in last year, P < .006) with intensive care. Influenza, especially H1N1, causes critical illness in SCD and should be prevented.

Introduction Studies of patients with ischemic stroke and silent cerebral infarcts from sickle cell anemia (SCA) have revealed abnormalities of both large and small vessels. Cerebral blood flow (CBF), a measure of the microvascular perfusion of the brain, has been recognized as a potentially sensitive and specific indicator of early cerebrovascular impairment in both children and adults with SCA. Arterial spin labeling (ASL) MRI is a non-invasive technique to acquire perfusion-weighted signal. This is typically at a single post-labeling delay (PLD) and provides only CBF measurement. The addition of multiple PLDs also permits the measurement of arterial transit time (ATT), the transit time from the labeled plane to the imaging voxels. ATT is prolonged with stenosis and/or occlusion of large vessels. In order to allow detection of both small and large vessel disease simultaneously for SCA, we employed a 4D whole-brain ASL protocol to measure CBF and ATT concurrently. Methods Experiments were performed on a 3T Philips Achieva scanner using a 32-channel head coil for reception. Seven healthy volunteers (age 36 ± 8 yrs; 3M / 4F) and 5 SCA patients with no history of stroke, recent transfusion, or renal impairment (21 ± 3 yrs; 3M / 2F) were enrolled after informed consent. The clinical laboratory performed complete blood counts on venous blood obtained the same day. The Pseudo continuous ASL (PCASL) sequence was implemented with 1000ms labeling duration and 12 PLDs (from 500 ms to 2700 ms in 200 ms intervals). A 3D acquisition scheme was employed with a field of view of 240 x 240 x 140 mm3 and acquisition resolution = 6.7 x 7.4 x 7 mm3. Total scan time was about 5 min. Fitting was performed per voxel using nonlinear-least-squares algorithm (Matlab) and maps of CBF and ATT were extracted concurrently. For each subject, five ROIs in the gray matter (frontal lobe, temporal lobe, parietal lobe, occipital lobe, and cerebellum) were manually drawn bilaterally from the corresponding anatomical image. Results Figure 1 display representative CBF and ATT maps of a participant with SCA estimated from the multi-delay PCASL scans. CBF maps (Figure 1a) were found to be uniform within the gray matter. White matter has lower CBF than gray matter and shows a longer transit time as expected. ATT maps (Figure 1b) reflected the heterogeneity between different brain regions. ATT values were about 200-400 ms shorter in the temporal lobe and medial frontal lobe, compared to the parietal/occipital lobes and cerebellum. Averaged CBF values from the five ROIs of all the subjects were calculated. For the control group (Hb = 14.1 ± 1.5 g/dL) and SCA group (Hb = 9.1 ± 2.1 g/dL), the mean CBF values were 49 ± 15 mL/100g/min vs 102 ± 23 mL/100g/min, and the mean ATT values were 1662 ± 317 ms vs 1245 ± 171 ms, respectively. Linear regression identified significant correlations between mean CBF and hemoglobin: CBF = - 9.8 Hb + 189 (r = -0.94; p < 0.001) and ATT = 81.2 Hb + 511 (r = 0.76; p = 0.004) (Figure 2). Discussion We have successfully implemented a fast and non-invasive MRI technique to measure two perfusion metrics (CBF and ATT) with a whole-brain coverage on SCA patients. It was well established only using other perfusion imaging modalities that CBF, among subjects with normal hemodynamic regulation and without neurovascular impairment, is inversely correlated with hemoglobin concentration. Conversely, a linear correlation between ATT and Hb is expected as a result of adaptive vasodilatation and lower blood viscosity. Our study's cross-subject validation of this relationship using the multi-delay PCASL method with 3D acquisition shows the potential of this technique to accurately define blood flow from both small and large vessels. This may be useful to identify people with SCA at increased risk of brain injury from silent cerebral infarct and stroke. Figure 1 Representative CBF (a) and ATT (b) maps acquired with 3D whole-brain coverage in axial, coronal and sagittal planes. Figure 1. Representative CBF (a) and ATT (b) maps acquired with 3D whole-brain coverage in axial, coronal and sagittal planes. Figure 2 Linear relationship between Hb and (a) CBF; (b) ATT. Figure 2. Linear relationship between Hb and (a) CBF; (b) ATT. Disclosures No relevant conflicts of interest to declare.

BACKGROUND AND OBJECTIVE: In the Silent Cerebral Infarct Trial (SIT), regular blood transfusion therapy significantly reduced the incidence of recurrent cerebral infarctions in children with sickle cell anemia (SCA). As a follow-up analysis of the SIT Trial, we compared healthcare utilization, as measured by adverse events, hospitalizations and costs in regularly transfused children (transfusion group) to those who were not transfused (observation group). <>METHODS: In this multi-center trial, we randomly allocated 196 children aged 5-15 years with SCA and prior history of silent cerebral infarcts (SCI) to receive monthly blood transfusion or observation for at least 36 months or until a study endpoint was reached. The number of and reasons for hospitalizations were recorded at each site. The transfusion group was determined by a protocol approach, with all patients receiving regular transfusions over a period of at least 6 months included, irrespective of the original group assignment in the SIT study. Estimated costs per day of hospitalization were determined using data obtained from the 14 SIT institutions which contributed administrative data to the Pediatric Health Information System (PHIS) database maintained by the Children's Hospital Association. Inpatient costs were based on length of hospital stay, modified by the occurrence of categories of adverse events in the following non-overlapping hierarchy: acute chest syndrome, vaso-occlusive pain crisis, fever/infection, exchange transfusion, surgery and asthma. Outpatient expenses not related to transfusion or iron chelation were considered equivalent for transfused patients and controls for the purposes of this study and were not included in the costing model. Chelation and blood transfusion costs were based on a child that weighed 30 kg and received 20 mg/kg/day of deferoxamine or deferasirox. Follow-up occurred from time of random allocation to primary endpoint (overt stroke or new or progression of SCI) or exit MRI, whichever came first. The SIT Trial is registered at www.clinicaltrials.gov (NCT00072761). <> <>RESULTS: A total of 90 and 106 patients comprised the final transfusion and observation groups, respectively. Fifteen of the patients originally randomly allocated to the transfusion group crossed over to the observation group by either never receiving blood transfusion (N=9) or receiving less than 6 months of regular blood transfusion (N=6) and were counted as not being effectively transfused (i.e., part of the observation group). The mean follow up for individuals who did or did not receive blood transfusion therapy was 3.04 and 3.01 years, respectively. The average age of all participants at randomization was 10.0 years, with 43.4% males. There were 144 hospitalizations in the transfusion group and 269 in the observation group; average length of hospital stay was 2.5±1.8 days vs. 3.4±2.2 days for transfused and observation groups, respectively (p CONCLUSIONS: Children with SCA and silent cerebral infarcts receiving regular blood transfusions have a 54% relative reduction in hospitalization cost when compared to children with SCA; however their outpatient costs of monthly prophylactic blood transfusions are high and heavily dependent upon the type of blood transfusion therapy and choice of chelation therapy. Table Table. Disclosures McCavit: Novartis: Speakers Bureau; Pfizer: Consultancy, Research Funding. King:HRSA: Research Funding; NIH - NHLBI: Research Funding; NIH - BMTCTN: Research Funding. Strouse:NHLBI: Research Funding; HRSA: Consultancy; Maryland Dept of Health and Mental Hygiene: Research Funding; HRSA: Research Funding. Casella:Johns Hopkins: Patents & Royalties; Mast Therapeutics: Research Funding; ImmunArray: Patents & Royalties.

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.

Introduction: Sickle cell disease (SCD) is linked to high healthcare utilization, with a small subpopulation of patients accounting for a disproportionate share of healthcare use. Examination of the high utilizer population shows an association with avascular necrosis (AVN). To develop interventions to mitigate hospital utilization, we aimed to clarify this relationship. By comparing utilization rates and the clinical characteristics of SCD patients with and without AVN, our goals were to test the hypothesis that AVN would serve as an independent risk factor for utilization, and identify characteristics of those with AVN that predict higher hospital utilization. Methods: We reviewed medical records at the Johns Hopkins Sickle Cell Center for Adults to identify a sample of 87 SCD (all genotypes) patients that had been diagnosed with symptomatic AVN (femoral or humeral head) who were then individually sex- and age-matched (±5 years as of 1/31/2014) with 87 SCD patients without a symptomatic AVN diagnosis. All patients were ≥18 years old. Positive AVN diagnosis was confirmed through clinical documentation and radiographic imaging. For those with AVN, baseline was defined as the date of AVN diagnosis, and if unknown, the date of established care. For those without AVN, baseline was defined as the date of established care. All patients had ≥2 years of follow up; years without encounters were excluded. From baseline to 1/31/2014 or date of death, we collected data on the frequency of hospitalizations and acute visits to the emergency department (ED) and Sickle Cell Infusion Center (SCIC). Additionally, we recorded steady-state outpatient laboratory and clinical markers associated with AVN and/or high hospital utilization. Utilization rates per patient were calculated as ED and SCIC visits (acute care) per year of follow up and admissions per year of follow up. Student's t-tests, Wilcoxon signed-rank tests, and Mantel-Haenszel pooled odds ratios were used for bivariate analyses. Variables from significant bivariate tests (p≤0.05) and traditional AVN comorbidities were then used in a median regression risk factor model for acute care and inpatient utilization. Results: The sample was 59.7% female, with a mean match age of 41 years (24 – 71 years, as of 1/31/2014). The study included 1,381 follow up years, with a median of 7 years per patient (IQR: 5 – 10 years). Patients with SS (HbSS or HbSβ0-thalassemia) constituted 72.4% of the sample, and had a lower mean match age of 39 years compared to 45 years for patients with variant genotypes (p=0.0059). The mean age at AVN diagnosis was also lower for SS patients than for those with variant genotypes. Genotype and follow-up period distributions were comparable for both cohorts. In bivariate analysis, the AVN cohort had significantly greater rates of acute visits and admissions (Figure 1). Additionally, history of high utilization (≥4 hospital visits/yr), acute chest syndrome (ACS), pneumonia (PNA), and hydroxyurea therapy were all significantly associated with a greater prevalence of AVN (Table 1). Of note, we did not find meaningful differences in laboratory values between cohorts. In a regression model controlling for comorbidities and genotype, AVN, ACS, and PNA were independently associated with a greater number of acute visits and admissions per year (Table 2). Conclusion: AVN is an independent risk factor for acute care utilization in patients with SCD. Because this is a potentially modifiable risk factor, further investigation of AVN in SCD is urgently needed. Hospital utilization increases with disease severity, and accordingly, treating or preventing complications such as AVN may have a great impact. Figure 1 Figure 1. Disclosures Haywood: NHLBI: Research Funding. Lanzkron:NHLBI: Research Funding.

Introduction: Stroke is a leading cause of death in adults with sickle cell disease (SCD), although little is known about the underlying pathophysiology or associated risk factors. A patent foramen ovale (PFO) or other intracardiac shunts are associated with ischemic stroke in children with SCD and young adults without SCD. PFOs are relatively common, with a prevalence of about 24% in the general population. Importantly, PFOs can be closed using a minimally invasive procedure, which could potentially prevent embolic strokes in individuals with SCD at risk for stroke. We therefore designed an epidemiological study to determine the prevalence of PFOs in adults with SCD and stroke. Methods: To identify SCD patients with stroke who had evidence for a PFO by echocardiagraph, we retrospectively reviewed charts from the Johns Hopkins Hospital. All adult patients (>18 years old) with the diagnosis of stroke followed in our Sickle Cell Program were included. PFO was diagnosed by conventional echocardiogram, color Doppler studies, and contrast studies with agitated saline (10 mls) through a peripheral IV or central venous catheter with and without a Valsalva maneuver (2 times each) to increase the sensitivity of detecting intracardiac shunting. The presence of bubbles in the left atrium, either spontaneously or after Valsalva, within five cardiac cycles was noted. PFOs or other intracardiac shunts were graded by the appearance of bubbles in the left atrium, including: Grade 1 (mild shunt with 1-10 bubbles), Grade 2 (moderate shunt with 10-25 bubbles and a distinct portion filling the left atrium), and Grade 3 (substantial shunt with >25 bubbles and complete filling of the left atrium). Brain MRI/MRAs were classified by stroke subtype and severity of cerebral vasculopathy. Age at the time of the study and stroke, gender, hemoglobinopathy, presence of a peripheral deep venous thrombosis (DVT), and evidence for other stroke risk factors (moyamoya or cerebral aneurysms) were ascertained by chart review. The study was approved by the IRB at our institution. Results: From this group of 65 adult patients with a sickling hemoglobinopathy (hemoglobin SS, SC, or S beta thalassemia) and stroke, we identified 15 patients who underwent an evaluation for a PFO or other intracardiac shunt (Table 1). The prevalence of PFO or other intracardiac shunt in these adults with SCD and a history of stroke was 40% (6/15). Of these 6 patients with SCD, PFO and stroke, 1 had hemoglobin SC and 5 had hemoglobin SS. Three of the PFOs were Grade 1 and 3 were Grade 3. Three patients with PFO and stroke also had a DVT at the time of the stroke; 3 patients with PFO and stroke also had Moyamoya. Conclusions: The high prevalence of PFOs in adults with SCD and stroke compared to the prevalence of PFOs in the general population suggest that PFOs could be a risk factor for stroke in this population. These findings also underscore the urgent need for further research to establish the role of PFOs in stroke in adults with SCD because PFOs can be closed with a minimally invasive procedure. Disclosures Naik: NHLBI: Research Funding.

Introduction People with sickle cell disease (SCD) have a greatly increased risk of silent cerebral infarct (SCI) and ischemic and hemorrhagic stroke compared with the general population. A prospective cohort study of pediatric patients with SCD after first stroke demonstrated recurrent brain injury (SCI and stroke) in 45% of the participants (median follow-up of 5.5 years) despite regular transfusions to maintain a hemoglobin S concentration less than 30%. The rate of recurrent brain injury in adults with SCD with a history of stroke has not been described. Methods This retrospective cohort study identified patients with SCD treated at Johns Hopkins Hospital who were at least 15 years old with a history of ischemic or hemorrhagic stroke and at least 2 MRIs of the brain available for interpretation. Two neuroradiologists interpreted and completed a data extraction form for each MRI and, when available, MR angiography. The form included the type of lesion, the number of lesions, the progression of the lesion from previous MRIs, and the presence or absence of cerebral vasculopathy by vessel. Clinical and demographic data were extracted from paper and electronic medical records. All data were entered into Microsoft Access and verified for accuracy. We used Stata Intercooled 12®to calculate descriptive statistics and rates and 95% confidence intervals by exact methods. Results We identified 24 patients (50% male) with a median age of 20 years (IQR 13, 24) at the baseline imaging and 23 (IQR 21, 30) at the time of the most recent imaging. Twenty had sickle cell anemia (HbSS) and 4 had hemoglobin SC disease. At baseline, 23 (96%) had evidence of cerebral ischemic lesions with a median of 8 (IQR 4, 10) lesions and 4 (16%) had global atrophy. Two participants had acute intraparenchymal hemorrhage and one prior hemorrhage with hemosiderin deposition in the brain parenchyma. Of the 20 with interpretable MR angiography, 15 (75%) had cerebral vasculopathy. Median follow-up was 3.3 years (IQR 1.9, 8.7) with a median of 2.5 MRIs obtained during follow-up (IQR 1.5, 4). We identified recurrent ischemic brain injury in 13 (54%) of participants with 17 new SCIs (3 also had enlargement of existing lesions) and 5 overt strokes. The rate of recurrent brain injury was 18 per hundred person-years (95% CI 12, 28). The rate was lower (15 per 100 person-years) in those with cerebral vasculopathy compared with those without cerebral vasculopathy (40 per 100 person-years), but this difference was not statistically significant (p=0.12). The rate of new SCI was 14 (95% CI 8.3, 23) and the rate of recurrent ischemic stroke was 4.2 per 100 person-years (95% CI 1.4, 9.8). No participants had new hemorrhagic strokes. Discussion People with SCD and a history of stroke have high rates of recurrent brain ischemia as adolescents and adults. The proportion in this study with recurrent ischemic events was similar to that seen in children and adolescents despite a substantially shorter period of follow-up. This may be secondary to differences in the treatment of adults with SCD and stroke (perhaps lower rates of chronic transfusion therapy), ascertainment bias (adolescents and adults with concerning symptoms for recurrent stroke may be more likely to have follow-up MRIs of the brain), or a continued high rate of recurrent ischemia in this population. Given the high rate of ischemia, regular screening for brain injury should be considered in adults with SCD and a history of stroke. Disclosures No relevant conflicts of interest to declare.

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][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 Sβ 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][2] Figure 1 | 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 Sβ 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 Sβ 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 | Table 1: Multivariable Analysis Disclosures Haywood: NHLBI: Research Funding. Lanzkron: NHLBI: Research Funding. [1]: #F1 [2]: pending:yes

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 Conclusions While perceptions of race and disease-based discrimination were correlated with each other, they exhibited different relationships with clinical factors like ED utilization and chronic pain. Perceived disease-based, but not race-based, discrimination was found to be associated with a greater burden of chronic pain among patients with SCD independent of potential confounders like ED utilization. While the true causal directionality of this relationship is currently unclear, our findings do support greater use of a biopsychosocial approach to mitigating the burden of SCD pain. Efforts to identify the various mechanisms through which perceived discrimination is associated with the burden of pain are essential in order to develop targeted interventions that could improve the pain experience of persons with SCD. * Test for trend significant at p Disclosures: Haywood: NIH: Research Funding. Lanzkron:GlycoMimetics, Inc: Research Funding; NIH: Research Funding. Strouse:NIH: Research Funding; Doris Duke Charitable Foundation: Research Funding; Masimo Corporation: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Bediako:NIH: Research Funding. Haythornthwaite:NIH: Research Funding. Beach:NIH: Research Funding.

Abstract 2058 Background: Healthcare professionals caring for patients with sickle cell disease (SCD) anxiously await the release in late 2012 of evidence-based guidelines for primary care physicians. These guidelines are anticipated to include a number of recommendations for health care strategies designed to improve outcomes for SCD patients. As these guidelines become widely disseminated, the evaluation of patient adherence to recommended preventative care will be an essential component of efforts to monitor the quality of health and health care for the SCD population. Unfortunately, there is a dearth of baseline information regarding current levels of SCD patient adherence to recommended therapies. The objective of our study was to describe current levels of self-reported adherence to recommended therapies among a large sample of adults with SCD. Methods: We used data collected as part of a large cohort study of sickle cell patient experiences with care to describe sickle cell patient's self-reported adherence to a number of currently recommended preventative care behaviors. We also examined the association of different levels of adherence with self-reported levels of acute emergency department (ED) and inpatient hospital utilization over the prior 12 months. Results: 292 individuals completed baseline study questionnaires and had completed chart abstractions. The average age of participants was 34.5 (95% CI 33.1–36.), 97% were black or African American and 54% were female. 70% had either SS or SB0thal (sickle cell anemia-SCA), 21% were SC and 9% had Sb+thal. Of the 252 respondents who provided info on income, 50% reported an annual income less than $30k/yr. Those with SCA were significantly younger than those with other genotypes (33 yrs v 37 yrs p=0.02). 91% of patients reported seeing a sickle provider every year, while 73% reported seeing a primary care provider once a year. 45% of patients reported seeing a dentist in the prior year, 58% of all patients reported seeing an eye doctor in the last year. However among the 24% of patients with documented retinopathy, only 65% had seen an eye doctor in the prior year. 82% of patients had received both an influenza vaccine in the prior year and a pneumococcal vaccine within 5 years. Those with low income were less likely to report seeing a SCD provider in the prior 12 months than those with higher incomes (87% v 94% p=0.049). A significant majority of patients (88%) reported high levels (i.e. a self-report of often/very often) of adherence to taking medications as prescribed. 79% reported high-levels of adherence to keeping their clinic appointments. 87% reported high-levels of adherence in following their doctor's directions. In bivariate analyses examining those preventative care behaviors with a significant impact on outcomes, we found that those patients reporting high-levels of adherence to their medical appointments reported fewer ED visits (p=0.015) and fewer inpatient hospitalizations (p=0.005) over the prior 12 months than those with lower levels of adherence. High self-reported levels of compliance with doctor's instructions was associated with fewer ED visits, but not fewer inpatient visits, over the same 12-month period. There was no bivariate correlation between seeing a sickle cell provider or primary care provider annually with outcomes, though this may be due to the overall high levels of adherence to these behaviors that we observed in our sample. In ordinal logistic regression analyses controlling for age, education, and poverty levels, high self-reported levels of compliance with doctor's instructions exhibited an independent association with lower levels of ED visits (OR = 0.44, 95%CI [0.21, 0.90]). Conclusions: We report relatively high levels of self-reported adherence to some, but not all, recommended preventative care behaviors among a sample of adults with SCD. The relatively low levels of adherence to dental and eye care recommendations should be noted as areas of focus for future interventions. Relationships between providers and SCD patients are notoriously rife with conflict. The association of high levels of compliance with doctor's instructions with lower levels of acute care utilization observed here suggests a need to identify the specific factors and mechanisms within provider-SCD patient relationships that successfully lead to improved clinical outcomes. Disclosures: Lanzkron: Hemaquest: Membership on an entity's Board of Directors or advisory committees; NHLBI: Research Funding. Haywood:NHLBI: Research Funding. Strouse:NHLBI: Research Funding. Beach:NHLBI, NIMH: Research Funding; Merck: Speakers Bureau.

Abstract 2127 Introduction: Activation of the hemostatic cascade and platelet activation in particular, has been implicated in the pathogenesis of sickle cell disease (SCD). Prasugrel is a third generation thienopyridine antiplatelet agent, an oral P2Y12 ADP receptor antagonist that is FDA-approved for use in patients with acute coronary syndromes undergoing percutaneous coronary revascularization. We evaluated serial biomarkers of hemostatic activation from a trial of prasugrel in adult patients with SCD. Methods: This was a multicenter, randomized, double-blind phase 2 adaptive study design with a 2:1 prasugrel:placebo ratio. Study drug, prasugrel 5 mg or placebo, was given once daily for 30 days. The primary endpoint was safety as measured by hemorrhagic events requiring medical attention. Samples for biomarkers were collected prior to initiation of study drug, on day 10 ± 2, and on day 30 ± 3. Multi-color fluorescent activated cell sorting and monoclonal antibodies were used to determine platelet P-selectin expression, platelet-monocyte aggregates (PMA), and platelet-neutrophil aggregates (PNA) using previously published protocols. Soluble P-selectin (sP-selectin), soluble CD40 ligand (sCD40L), thromboxane B2 (serum TXB2), and prothrombin fragment F1.2 (F1.2) were determined using standard enzyme-linked immunoassays. Statistical comparison between prasugrel and placebo was performed using a mixed model with treatment, baseline measurement, genotype of SCD, visit and the interaction between visit and treatment as fixed effects and subjects as a random effect. Results: Forty-one patients were randomized to prasugrel 5 mg and 21 to placebo. Mean age was 32 years; 48% were female; 60% HbSS, 5% HbS/b0thalassemia, 10% HbS/b+thalassemia, and 24% HbSC (1 patient was found not to have SCD but to only have b-thalassemia trait). Eighteen patients in the prasugrel and 9 in the placebo arm were on hydroxyurea prior to study drug. Results are shown in the Figure. Compared to placebo, platelet P-selectin (unstimulated), sP-selectin, and sCD40L all achieved or approached significantly lower values in the prasugrel group on day 10 and 30, as did ADP-stimulated platelet P-selectin values (data not shown). TXB2 was significantly lower on day 10 but not on day 30 (Fig. 1), as were PMA/PNA unstimulated, and PMA/PNA in response to ADP ex vivo. F1.2 levels were not different between the groups at either day 10 or 30 (data not shown). Conclusions: As would be predicted by the mechanism of action, prasugrel resulted in decreased cellular and soluble biomarkers of platelet activation. There was no effect on coagulation as assessed by F1.2, a marker of thrombin generation. Clinical results reported elsewhere suggest a decrease in pain rate. Prasugrel 5 mg po daily clearly decreases markers of platelet activation in adult SCD patients. These biomarkers can be incorporated in future studies of prasugrel in SCD to correlate with clinical outcomes. Disclosures: Wun: Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Off Label Use: This abstract discusses prasugrel treatment in patients with sickle cell disease. Please see USPI for most up-to-date information. Knupp:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. McMahon:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Strouse:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Zhou:Eli Lilly and Company: Employment, Equity Ownership. Heath:Eli Lilly and Company: Employment, Equity Ownership. Nwachuku:Daiichi Sankyo, Inc.: Employment, Equity Ownership. Jakubowski:Eli Lilly and Company: Employment, Equity Ownership. Winters:Eli Lilly and Company: Employment, Equity Ownership. Riesmeyer:Eli Lilly and Company: Employment, Equity Ownership.

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.

Abstract 259 Objectives: Silent cerebral infarction (SCI) occurs in approximately 27% of children with sickle cell disease (SCD) by age 6 years, and is associated with decreased neurocognitive function and a 14-fold increased risk of progression to overt stroke. While several clinical parameters, such as increased white blood cell (WBC) and platelet counts and decreased hemoglobin (Hb) or hematocrit, have been reported in the literature to be associated with SCI, to date no validated biomarkers exist to predict SCI in patients with SCD. Furthermore, recent unpublished data from the Silent Infarct Transfusion (SIT) Trial has identified systolic blood pressure and total hemoglobin as risk factors. The aim of this study was to identify candidate biomarker plasma proteins that correlate with SCI in patients with SCD. Methods: We used a proteomic discovery approach involving three sequential separation steps to compare the plasma proteomes of 15 children with SCD (7 with SCI and 8 without SCI), aged 5–15 years. Baseline steady-state plasma samples were obtained from the SIT Trial Biologic Repository and matched for age, Hb and WBC. Plasma samples were Hb depleted in the first dimension, separated using immunoaffinity depletion and reverse phase liquid chromatography fractionation, and then trypsin-digested for characterization using label-free quantification on a LTQ-Orbitrap (Thermo) mass spectrometer. The resulting MS/MS data were analyzed using PASS (Integrated Analysis, Bethesda, MD) with X! Tandem searches (www.thegpm.org; version 2008.12.01) of the International Protein Index peptide database (human, 3.19). We measured candidate proteins in a validation cohort of 116 children with SCD (n=65 SCI, 51 non-SCI) and 24 age-matched, healthy African American control subjects using enzyme-linked immunosorbent assays (thrombospondin 1 [TSP1], L-selectin, RandD Systems, Minneapolis, MN) and immunoassays (E- and P-selectin, Mesoscale Discovery, Maryland). All samples were run in duplicate according to the manufacturers' protocols. Statistical differences in biomarker plasma concentrations between groups were compared by the Mann-Whitney U test. Results: TSP1 (5 peptides) and L-selectin (3 peptides) were among 335 proteins that showed differential detection between the SCI and non-SCI groups based on the spectral counts. TSP1 is an extracellular matrix glycoprotein that is involved with platelet aggregation, inhibition of neovascularization and tumorigenesis and has been shown to promote the adherence of sickle erythrocytes to the vascular endothelium. L-selectin is an adhesion molecule that mediates leukocyte interaction with the vascular endothelium. In a validation cohort of 116 children with SCD (n=65 SCI, 51 non-SCI) and 24 age matched, healthy African American control subjects, TSP1 and L-selectin were both significantly increased in SCI vs. non-SCI groups (median 8.5 vs. 6.2 μ g/ml for TSP1, P =0.03; 1.5 vs. 1.4 μ g/ml for L-selectin, P =0.03). As expected, neither TSP nor L-selectin were elevated in the age-matched normal controls (median=4.6 μ g/ml for TSP1, P =0.10, 1.2 μ g/ml for L-selectin, P =0.10). The specificity of the L-selectin results was verified by demonstrating that E-selectin and P-selectin were not increased in the SCI group. TSP1 was correlated with baseline oxygen saturation in both the SCI and non-SCI groups (r=-0.51, and r=-0.35, P Conclusions: TSP1 and L-selectin may represent the first two plasma biomarkers of SCI in children with SCD. Although further studies are needed, these and other potential biomarkers may provide insight into the pathophysiology of SCI, and may fill an important clinical need in identifying children with SCD who are at risk for SCI. Disclosures: No relevant conflicts of interest to declare.

264 Background: Admission for influenza is more than 50 times more frequent in children with sickle cell disease (SCD) than in the general population. H1N1 influenza, a novel influenza A virus of swine origin, began circulating in the United States in the spring of 2009 and has now been detected in over 170 countries. H1N1 influenza has been reported to cause more severe illness in children and young adults than seasonal influenza. To compare the relative severity of H1N1 influenza vs. seasonal influenza A and B in young persons with SCD, we compared the clinical characteristics and complications associated with these infections in patients seen at our tertiary care hospital. Methods: We defined a case as laboratory-confirmed influenza infection with influenza A or B in a patient aged 0–21 years with SCD who was evaluated at Johns Hopkins Hospital from 1 September 1993 to 31 July 2009. Through July 2006, we searched the discharge and billing databases for Johns Hopkins Hospital to identify those with SCD and laboratory testing for respiratory infections. Thereafter, we prospectively identified cases through divisional records. We confirmed the diagnosis of influenza by review of microbiology results in each patient's paper and/or electronic medical record. All respiratory samples positive for influenza A after 1 May 2009 were tested for pandemic H1N1 at the Maryland Department of Health and Mental Hygiene using a real-time reverse transcription polymerase chain reaction assay. We used Fisher's exact test to compare proportions, Student's t-test or Wilcoxon rank-sum test to compare continuous variables, and logistic regression to evaluate associations. Results: We identified 99 patients with SCD and influenza (64 seasonal influenza A, 25 seasonal influenza B, and 10 pandemic influenza A) during the study period ([Figure][1]). Eighteen patients had pandemic (10) or seasonal (8) influenza during the 2008 – 2009 season and July of 2009. Clinical symptoms, such as reported fever (90%), cough (93%), and rhinorrhea (79%), were similar. However, those with pandemic influenza were more likely to have acute chest syndrome and to require intensive care and ventilator support ([Table][2]). In a multivariable logistic regression model, older age (OR 1.2 per year, 95% CI 1.04 –1.3, P=.004) and pandemic influenza vs. seasonal influenza (OR 11, 95% CI 1.3 –88, P=0.025) were associated with increased risk of intensive care. ![Figure:][3] Figure: Patients with Seasonal Influenza A and B or Pandemic Influenza and Sickle Cell Disease by Influenza Season: Johns Hopkins Hospital 1994–2009 | Variable | Seasonal Influenza (n=89) | Pandemic Influenza (n=10) | P-value | |:-------------------------------------:| ------------------------- | ------------------------- | ------- | | Age (years, median and IQR) | 4.3 (1.8, 11) | 7.5 (2.2, 17) | 0.10 | | Male sex (%) | 61% | 50% | 0.52 | | HbSS vs. other SCD (%) | 86% | 70% | 0.30 | | Acute chest syndrome | 13% | 40% | 0.049 | | Hospitalized | 91% | 90% | 1 | | Length of Stay (days, median and IQR) | 2 (1, 3) | 3 (2, 5) | 0.07 | | RBC Transfusion | 13% | 30% | 0.16 | | Intensive care | 2% | 20% | 0.05 | | Mechanical ventilation | 0% | 20% | 0.009 | * IQR indicates interquartile range; HbSS, sickle cell anemia; RBC, red blood cells; Table: Characteristics of Patients with Seasonal Influenza A and B or Pandemic Influenza and Sickle Cell Disease (SCD), Johns Hopkins Hospital 1993–2009 Discussion: We found pandemic influenza to be associated with a greater risk of life-threatening complications than seasonal influenza in young patients with SCD, including an estimated 3-fold increased risk of acute chest syndrome and a 9-fold increased risk of need for intensive care. Older age may also be a risk factor for more severe disease, but could also reflect referral bias (with only the sickest adolescents and young adults being referred for tertiary pediatric care). We conclude that vaccination against pandemic influenza, in addition to seasonal influenza, will be essential for children and young adults with SCD and others in their households. The influenza season was defined as for 1995 (7/1/95–6/30/96) for each year. Disclosures: Casella: Boehringer Ingelheim: Consultancy, Honoraria; Cytrex: Research Funding; Ikaria: Research Funding. [1]: #F1 [2]: #T1 [3]: pending:yes

259 Background: Cerebral infarct is a frequent complication in children and adults with sickle cell disease (SCD). About 10% of children with sickle cell anemia (HbSS) will have an overt stroke by 18 years of age and another 22% will have “silent” cerebral infarcts by 14 years of age. There is a second peak in the incidence of overt ischemic stroke in adults with SCD. Both silent and overt stroke can be accompanied by cognitive impairment and thereby increased risk of academic failure. Several laboratory parameters have been associated with these complications, including low hematocrit or hemoglobin, high white blood cell count (WBC), and high platelet count, while lactate dehydrogenase (LDH) and apolipoprotein A1 have been associated with pulmonary vasculopathy in adults with SCD. Elevated C-reactive protein (CRP) and the ratio of apolipoprotein B/A1 are associated with increased stroke risk in the general population. We hypothesized that these and other biomarkers might also be important in children with silent cerebral infarction. Methods: We prospectively measured potential biomarkers, including complete blood count, reticulocytes, fetal hemoglobin (HbF), LDH, CRP, and apolipoprotein A1 and B in 73 children with HbSS and 3 with sickle-β0-thalassemia (HbSβ), in addition to performing brain magnetic resonance imaging (MRI), in a single center ancillary study of the Silent Infarct Transfusion Trial. MRIs were interpreted for the presence or absence of silent cerebral infarcts (FLAIR hyperintensities ≥3 mm in diameter seen in at least two imaging planes without corresponding symptoms or signs of stroke). Groups were compared by Student's t-test or Wilcoxon rank-sum test and associations evaluated by univariate and multivariate logistic regression. Results: Twenty-seven participants (35.5%, 1 with HbSβ) had silent cerebral infarcts (age 8.9 ± 2.4 years, 59% male) and 49 (65.2%) had normal brain MRIs (age 8.7 ± 2.1, 53% male). The group with SCD and silent cerebral infarcts had significantly lower hemoglobin concentration and apolipoprotein A1 (P=0.01 for both) than children with SCD without silent cerebral infarcts. Apolipoprotein B and the ratio of apolipoprotein B to A1 were similar between groups. By univariate logistic regression, both apolipoprotein A1 [Odds ratio (OR) 0.95 per mg/dl increase, P

Abstract 2579 Poster Board II-556 Silent cerebral infarction (SCI) is part of a spectrum of cerebrovascular disease, occurs in approximately 22% of children with sickle cell disease (SCD) and is associated with decreased cognitive function. While several plasma biomarkers have been shown to be elevated in acute stroke, to our knowledge none have been evaluated in SCD or SCI. The aim of this study was to develop a reliable pipeline to identify low abundance plasma proteins that correlate with SCI in patients with SCD. We used a proteomic discovery approach involving three sequential separation steps in order to compare the plasma proteomes in a discovery set of 15 children with SCD (7 children with SCI and 8 children without SCI). Baseline steady state plasma samples obtained from the Silent Infarct Transfusion (SIT) Trial Biologic Repository were matched for age and WBC. In the first dimension, hemoglobin was depleted with nickel-nitrilotriacetic acid (Ni-NTA). Subsequently, second dimension separation and enrichment was achieved by immunoaffinity depletion of the 12 most abundant proteins (ProteomeLab IgY-12 LC10) followed by third dimension separation by reverse phase liquid chromatography fractionation (RPLC) using a C18 column and a linear acetonitrile gradient. Collected fractions were subjected to tryptic digestion and analyzed using label-free quantification on a LTQ-Orbitrap (Thermo) mass spectrometer. The MS/MS data were analyzed using the Proteomics Analyzer Software System (PASS) version 4.0.10 (Integrated Analysis Inc, Bethesda, MD) with X! Tandem searches (www.thegpm.org; version 2008.12.01) using the human IPI database. Identified proteins were compared to databases of brain specific and brain enriched proteins to identify candidate biomarker proteins for SCI. After hemoglobin depletion, 71% of total protein was removed. On average, protein recovery after the LC-12 column was 4% of the total Ni-NTA depleted protein. Of the 9800 proteins that were identified in the plasma proteome of children with SCD, 23 were brain specific proteins. Evaluation of the relative abundance by spectral counts (SC) revealed 3 brain-related proteins that were over-represented in patients with SCI: microtubule-associated protein tau (a neurofibrillary tangle protein implicated in Alzheimer disease, frontotemporal dementia and parkinsonism), neuroligin-3 (a neuronal cell surface protein proposed to be involved in cell-cell-interactions via binding to beta-neurexins and implicated in autism and Asperger syndrome), and nucleosome-remodeling factor subunit BPTF (a histone-binding component of nucleosome-remodeling factor that is abundantly expressed in the fetal brain and re-expressed in neurodegenerative diseases). Reticulon-4, a potent neurite growth inhibitor involved in the restriction of axonal regeneration after injury, was under-represented in patients with SCI. After depletion of hemoglobin and other high abundant proteins, we were able to develop a database of plasma proteins in children with SCD and to identify brain specific proteins as potential surrogate markers of brain injury. These markers may be implicated in the pathophysiology of SCI. Although validation studies are necessary to determine the relevance of these candidate biomarkers in SCI and SCD, our methodology appears to be a practical approach to proteomic discovery in patients with hemolytic anemia. Disclosures: Casella: Boehringer Ingelheim: Honoraria, Research Funding, Travel funding.

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 Table 1: Associations with Primary Hemorrhagic Stroke Variable Odds Ratio (95% CI) P-value Genotype (HbSS vs. other) 3 (0.6 – 17) NS Moyamoya 5 (0.4 – 260) NS Transfusion in the last 14 days 13 (1.3 – 630)

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)

Most studies of survival in sickle cell disease (SCD) include only patients followed at referral centers. We used the public set of the California Patient Discharge Databases (1998–2005) to compare in-hospital mortality and charges by patient characteristics. We included discharges with any diagnostic code for SCD (282.41–2, 282.60–69). We used the Charlson index (adapted for administrative data) to adjust for comorbid conditions. Hospital charges were adjusted to 1998 levels. Statistical methods included ANOVA, Wilcoxon rank-sum, and multivariate linear and logistic regression. We identified 57,887 admissions for SCD and 376 in-hospital deaths (0.65%) from 1998–2005. The mean age of death was 40 years (95% CI 38–42) for sickle cell anemia (HbSS) and 48.3 years (95% CI 44.1–52.5, p Table 1: Odds Ratio for In-Hospital Death Based on Multivariate Logistic Regression Variable Odds Ratio (95% CI) P-Value NS indicates not significant Charlson Index=1 3.3 (2.4–4.6)

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 Table 1: Sensitivity and Specificity of Clinical Findings for Acute Intracranial Pathology Variable Sensitivity Specificity GCS

Acute chest syndrome (ACS) is a cause of frequent hospitalization and death in patients with sickle cell disease (SCD). Therapies commonly used include antibiotics, inhaled B-agonists, oxygen, high-dose dexamethasone and transfusions. Although corticosteroids appear to speed resolution of ACS, the frequency of rebound vasoocclusive crises has not been adequately assessed. We conducted a retrospective cohort study to characterize risk factors for readmission after ACS. We included patients Patient Characteristics by Treatment Supportive N=64 Corticosteroids N=20 Transfusion N=23 Corticosteroids and Transfusion N=19 P-value Age 13±6 11±4 13±5 9±3

Background: Intracranial hemorrhage (ICH) is an uncommon, but devastating, complication of sickle cell disease (SCD) with mortality from 30 to 65%. Most reported cases are in adults; little is known about children. Proposed risk factors include previous ischemic stroke, aneurysms, low steady-state hemoglobin, high steady-state leukocyte count, acute chest syndrome, and hypertransfusion. Methods: Retrospective case-control study designed to characterize and evaluate risk factors for ICH among children with SCD age < 19 years hospitalized at Johns Hopkins Children’s Center from January 1979 to March 2004. Cases had SCD and ICH (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 the Division of Pediatric Hematology’s records. ACS was defined as a new pulmonary infiltrate and two of the following: chest or rib pain, dyspnea, fever, tachypnea, grunting, nasal flaring, or retractions. Blood pressure was adjusted for age, sex, and hemoglobin genotype. Results: We identified 7 cases (mean age=11.2 years, range 2 to 16 years) and 9 controls (mean age 6.2 years, range 2 to 8 years). As expected, cases were significantly older than controls (p Conclusions: In this group of children with SCD, ICH was associated with antecedent events including transfusion and possibly corticosteroids. Mortality was similar to that of adults with SCD and ICH. Limitations of this study include the small sample size and the retrospective design. The contribution of antecedent events to ICH in children with SCD deserves further evaluation. Odds Ratios of Intracranial Hemorrhage For Events in the Last 14 Days Event Odds Ratio (95% CI) P-value Transfusion 48 (1.8-2469)