ALBERT

Description: Background Acute chest syndrome (ACS) is the second most frequent reason for hospitalization in children and adults with sickle cell disease (SCD) and the most common cause of death. Physicians caring for SCD patients need to be aware of the early symptoms and signs of ACS, assessment of ACS severity to guide optimal therapy, and measures to prevent ACS. Recently there is some consensus on the definition of ACS, and an ACS severity assessment tool used in multicenter clinical research (Ballas et al. for the Investigators of the Comprehensive Sickle Cell Centers. Am J Hematol 2010) has been utilized but not validated in a real-world setting. Thus, existing guidelines and policy statements for the management of children with ACS do not provide a uniform system for grading of severity and management, and the new guidelines from NHLBI for sickle cell disease management by primary care physicians does not rectify this situation [2014 NIH guidelines]. In contrast, the evidence base for role of incentive spirometry in preventing ACS (Bellet et al, NEJM 1995)and decreasing severity of ACS is strong/moderate and accordingly incentive spirometry recommendations are included in guidelines [2014 NIH guidelines, Crabtree et al. Pediatrics 2011]. As a first step toward this quality improvement initiative at our institution our objective was to assess the current knowledge of resident physicians and nursing regarding these 2 aspects of ACS: Severity assessment and Incentive spirometry. Methods This tertiary care teaching hospital admits over 20 sickle cell patients per month on the pediatric ward. Pediatric house staff learns about ACS management and prevention as part of 2 formal didactic sessions on SCD per year and bedside teaching by rotating pediatric hematology-oncology faculty, fellows, and advanced-practice nurses. Pediatric ward nurses have 1 didactic session on SCD per year. An anonymous survey consisting of ten items regarding the use of a scoring system for ACS and incentive spirometry was administered to 40 pediatric resident physicians and 20 pediatric inpatient nurses who routinely engage in care of pediatric patients hospitalized with ACS. Descriptive statistics were employed for analysis. This was followed by an education session on ACS for the group. This study was approved by the institutional IRB. Results SEVERITY SCORING: We found that 15% of resident physicians and 5% of nurses had been educated on the use of a ACS severity assessment score in past (Fig 1a), however an overwhelming 92% felt that such a scoring system would be extremely useful for assessing their patient's condition and their management (Fig 1b). Only 5% of residents and 3% of nurses had used a severity scoring system for ACS in the past to guide their management decisions (Fig 1c). This was further confirmed by testing them on a clinical vignette based on ACS and a majority of the residents and nurses (58%) answered it incorrectly (Fig 1d). INCENTIVE SPIROMETRY: An impressive 91% responded they were aware that incentive spirometry during hospitalization can decrease the severity of and improve outcomes of acute chest syndrome (Fig 2a). Greater than 88% of resident physicians thought that incentive spirometry is almost always ordered for the patients but the same proportion felt that the patients are compliant less than 50% of the time with instructions regarding use (Fig 2b and 2c). Nurses' responses were more variable on the ordering of incentive spirometry for the patients but 95% thought that less than patients were compliant less than half the time with the orders (Fig 2b and 2c). Conclusions We conclude that the knowledge of resident physicians and nurses regarding severity assessment of acute chest syndrome is extremely limited and greater efforts are needed to educate and encourage them to include this assessment in their management decisions to improve their understanding of patient condition and optimize care. In addition, we found that importance of incentive spirometry is recognized by house staff, however, the patient compliance is far below desirable and stricter reinforcement will be needed by the physicians and nurses to potentially improve outcomes for hospitalized patients with ACS. This pilot study thus identifies room for quality improvement at several different steps in the process of care for SCD. Disclosures No relevant conflicts of interest to declare.

Description: DNA methyltransferase (DNMT1) is a validated molecular target for epigenetic therapy of non-malignant diseases (e.g., sickle cell disease, SCD) and cancer. DNMT1 can be depleted by decitabine (Dec), an FDA-approved drug, without off-target cytotoxicity, reproducibly demonstrated pre-clinically. Dec, however, has pharmacologic limitations that impede translation into clinical epigenetic therapy. For e.g., DNMT-depletion requires Dec levels to overlap with cellular S-phase entry, yet the plasma half-life of Dec is 5nM and 12 hours in vitro to

Description: Background: TranscranialDoppler ultrasound (TCD) screening for stroke risk is one of the major advances in pediatric sickle cell disease, since the landmark STOP study. TCD screening is among the measures for quality of pediatric sickle cell care proposed by expert consensus (Wang 2011, NHLBI guidelines 2014). Reeves et al 2016 shows that TCD screening rates are low but still improving (22% in 2006 -44% in 2010). To improve the quality-of-care provided to pediatric sickle cell patients at University of Illinois Hospital, we conducted chart review in 2014 to establish a baseline report of UI Hospitalsadherence to the expert care standards. At that time TCD screening rates were much lower than immunization rates. We then introduced a reminder table in the electronic medical record. 18 months since this change in EMR we re-evaluated our compliance with TCDs. Objectives: To evaluate the improvement atUIHealthpediatric sickle cell clinic compliance with annual TCD. Methods: A manual chart review of these pediatric sickle cell patients was employed to determine adherence to TCD screening standards. All patients ages 2-16yowith SCD-SS and SCD-S/Beta-0-thalassemia that were seen in pediatric sickle cell clinic and adolescent-adult transition clinics two times over 15 months from 2/1/15-5/1/16 were included in study. TCD compliance was determined if patient had TCD between 5/1/2015 through 5/31/16. 5-15 minutes per patient was spent evaluating EMR for TCD compliance Data from the 2014 previous study was also re-evaluated using the same criteria of 2 visits within 15 months of original study date and TCD within 1 year of study. Results: In this work, the charts of 91 pediatric SCD-SS and SCD-S/Beta0 patients were reviewed (ages 2-16 years; M: 34 F 28, 5 ineligible [2 on chronic transfusion, 1 high hemoglobin, 1 yearly MRI, 1 last visit before 2yo]. Lost to follow-up (Seen in clinic since 2014 but not 2 visits from 2/1/15-5/1/16): 24 The rate of TCD screening among these eligible children was 53 out of 62, or 85.5% in 2016. Comparable figures from the 2014 chart review were 17 out of 27, or 63% in 2014. Fishers exact test indicates that this was a significant improvement, p=0.05. Conclusions: We focused our quality-improvement efforts onTranscranialDoppler screening, adding a reminder table in the Electronic Medical Record then re-assessing 18 months later. The rate of TCD screening significantly improved from 63% to 85%. Although less than 100%, these compare favorably to other published TCD rates (Table). The next step is to improve clinic attendance and tracking, to reduce the rate of patients who are "lost to follow-up." To facilitate future chart reviews we have incorporated the key parameters into our "Screening & Management Table" as a component of the electronic medical record. Table Table. Disclosures Hsu: Purdue Pharma: Research Funding; Mast Therapeutics: Research Funding; Eli Lilly: Research Funding; Sancilio: Research Funding; Centers for Medicare and Medicaid Innovation: Research Funding; Pfizer: Consultancy, Research Funding; EMMI Solutions: Consultancy; Gerson Lehman Group: Consultancy; Astra Zeneca: Consultancy, Research Funding; Hilton Publishing: Consultancy, Research Funding.

Description: Abstract 2645 RATIONALE: Pulmonary complications are of particular importance in patients with sickle cell disease (SCD) as they are commonly associated with high morbidity and mortality. Research suggests that children with both SCD and asthma have higher morbidity as measured by more frequent hospitalizations for vaso-occlusive crises and acute chest syndrome episodes, and as much as double the risk of mortality when compared to pediatric SCD patients without asthma. Therefore, the diagnosis of reactive airway disease in pediatric SCD patients is clearly a poor prognostic factor. However, it is currently not known whether there is any degree of modifiable risk associated with aggressive empirical treatment of asthma in the pediatric SCD population. Although SCD disproportionately affects people of African and Latino ancestry, there is no clear linkage of SCD with socioeconomic status. HYPOTHESIS: Low socioeconomic status, as determined by zip code distribution in the Washington Metropolitan Area, correlates with higher rates of acute pulmonary complications in pediatric SCD patients as it does in asthmatic children without SCD. Methods: A five-year retrospective chart review examined the records of 400 children randomly sampled from the 950 SCD patients seen at Children's National Medical Center in the past two years. Information extracted from the electronic medical record (Cerner PowerChart system) included hematological, pulmonary as well as demographic patient information. Patients with insufficient data because of young age or care at other hospitals were excluded. Median household incomes from 2008 were linked to zip codes in various regions of the Washington Metropolitan Area and results were then analyzed using non-parametric statistical methods. Asthma data was obtained from DC Burden of Asthma 2009 project. The Mann Whitney U test was used to test for differences in the properties between pediatric SCD patients with a diagnosis of reactive airway disease versus those without a diagnosis of reactive airway disease. Findings associated with a p-value of less than 0.05 were considered statistically significant. Results: Among the 400 pediatric SCD patients analyzed, there was a strong inverse relationship between socioeconomic status and the rate of acute chest syndrome episodes (mean number of episodes per patient per year). The rate of acute chest syndrome episodes was 0.20 for all of Washington DC (n=56), 0.15 for Prince George's County (n=147), 0.10 for Montgomery County (n=81), and 0.04 for Fairfax County (n=33), which had median household incomes of $58k, $72k, $94k, and $107k, respectively. Pediatric asthma diagnoses and need for pediatric asthma care showed similar distribution: Washington DC regions with the lowest income, such as Ward 8, had the highest rates of Emergency Department visits for asthma care. Acute chest syndrome episodes were also significantly more prevalent in children diagnosed with asthma, 18.75% of the total sample, as compared to those with no history of asthma (p 〈 0.05). Overall, pediatric SCD patients with reactive airway disease had a rate of 0.30 acute chest syndrome episodes per patient per year, while those without reactive airway disease had a rate of 0.16 episodes. The data suggest that the strongest association between asthma and sickle cell acute chest syndrome episodes for the Metropolitan Area is amongst residents of DC and Prince George's County; both of which were in the lowest range of median household incomes of the regions studied. Ward 8 had the highest disparity between the rates of acute chest syndrome episodes in patients with reactive airway disease (0.66) and those without reactive airway disease (0.16), a 4-fold difference; again, Ward 8 represents the lowest median household income in Washington DC ($26k). Discussion: Socioeconomic status as marked by geographical distribution appears to be a strong source of diversity in pulmonary complications of pediatric SCD patients in the Washington Metropolitan Area. Low-income areas have higher rates of asthma and also as much as 5-fold higher rates of sickle cell acute chest syndrome, compared to higher-income areas. Children with an asthma diagnosis had 2-fold higher rates of acute chest syndrome overall, but 4-fold higher in low income areas such as Ward 8. These data are subject to the limitations of a retrospective chart review, but the results set the stage for future prospective studies. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 2667 Background: Acute pain is the leading cause of hospitalization in both children and adults with sickle cell disease (SCD). Opioid analgesics are used for pain relief, but are associated with significant adverse effects that are bothersome to patients and may predispose to serious sickle-related pulmonary events. Evidence is limited for the most effective opioid administration strategy that maximizes analgesia and minimizes adverse effects. Patient Controlled Analgesia (PCA) has the potential advantage to allow a patient to optimize pain control without dependence on healthcare providers for administration. PCA generally consists of an opioid given by constant infusion with additional demand doses as needed; the proper dosing for each is largely unknown, particularly at high opioid doses. The SCDCRN conducted a multi-center phase III clinical trial comparing two alternative opioid PCA dosing strategies (HDLI-higher demand dose with low constant infusion or LDHI- lower demand dose and higher constant infusion). The required sample size for the trial was 278 subjects. Patients and Methods: SCD patients ≥ age 10 years hospitalized for significant pain (baseline pain VAS ≥ 4.5/10) who had received 〈 12 hours of previous analgesic therapy and provided informed consent were eligible; patients with renal/hepatic dysfunction, who received large amounts of oral opioids prior to admission, or who had evidence of acute chest syndrome were excluded. Investigators used standardized opioid dosing tables for morphine or hydromorphone, and for participants weighing ±50 kg. Opioid-related symptoms were assessed with a validated daily questionnaire; multimodal assessments of pain, physical function, and sleep were conducted by an assessor blinded to treatment assignment/dose level; because of safety concerns, individuals responsible for making dosing decisions were not blinded. The assigned PCA strategy was continued until patients were transitioned to oral analgesics. An intention to treat analysis was planned for the time to a significant (2.5 cm) improvement in average daily 10 cm pain VAS. Secondary endpoints included total opioid usage and frequency of opioid-related symptoms. Results: From January 1, 2010 to June 8, 2010, a total of 1050 patients age ≥ 10 years were hospitalized for pain; 216 were ineligible, 796 were missed for logistic/staffing issues at sites, and 38 subjects completed randomization prior to trial closure (due to inadequate time to complete enrollment prior to Network termination in March 2011). Average age of enrolled subjects was 23.9 ± 12.2 years (range 10–52 years), and 53% were female. The HDLI arm had 50% morphine and 40% pediatric subjects (10-17 years); the LDHI arm had 44% morphine and 50% pediatric subjects. Four subjects were withdrawn (1 parent permission withdrawal, 2 inadvertent withdrawals by PI, 1 ineligible). Baseline VAS was high (mean 7.5 cm HDLI, and 7.7 cm LDHI). A reduction in pain intensity during PCA treatment was observed in both treatment arms (mean difference from baseline ± SEM: 2.7 ±1.5 cm HDLI vs 2.8 ±2.0 cm LDHI; time to significant improvement 22.0 ±3.0 hours HDLI vs 22.1 ±3.8 hours LDHI), with 75% of the HDLI subjects and 79% of the LHDI experiencing a significant improvement in pain. Average length of hospitalization was 143.7 ±94.2 hours HDLI vs 102.4 ±42.6 hours LDHI. The reliability or significance of any similarities or differences noted in this descriptive analysis is limited by the small sample size. Opioid utilization in the two treatment arms is currently being analyzed. Opioid-related symptoms were well managed and similar in both treatment arms (mean daily opioid symptom severity score (1-4): 0.9 ± 0.6 HDLI vs 0.8 ± 0.6 LDHI). Four episodes of serious hypoxia, likely relate to exacerbation of pulmonary hypertension, developed in adult subjects during the study (2 HDLI, 2 LDHI). Conclusions: The premature closure of the study limits potential conclusions regarding safety and efficacy, or superiority of either treatment regimen. The data gathered will help resolve potential design issues related to the complexity of running an inpatient opiod PCA trial and help guide modification of subject selection and enrollment, optimization of opioid dosing and monitoring, and endpoint assessments. Given the clinical priority of adequate pain management and the challenges of opioid PCA therapy, completion of this trial is imperative. Supported by NHLBI. Disclosures: Dampier: Anthera Pharmaceuticals Inc:; Glycomimetics Inc:. Telen: GlycoMimetics: Consultancy, clinical trial sponsorship.

Description: Introduction: Pain is the top concern of individuals with sickle cell disease (SCD). Acute painful vaso-occlusive episodes are the leading cause of emergency department (ED) encounters and frequent hospital admissions. There are well-documented disparities for patients with SCD, including significant delays in starting therapy and under treatment of pain in the ED. An acute care observation unit (ACOU) staffed with SCD specialists can help to address these disparities. Here we study the service impact of increasing the hours of operation of a dedicated sickle cell ACOU on utilization and hospital admissions at the University of Illinois at Chicago (UIC), a regional sickle cell resource. We hypothesized that increased hours of operations will lead to decreased ED utilization and inpatient hospitalizations. Methods: The outcomes of individuals 〉16 years of age presenting with an acute painful episode to the sickle cell ACOU at UIC were assessed for the 12 months before and the 12 months after increasing the hours of operation from 9 hours/day to 15 hours/day Monday through Friday in February 2014. The outcomes of SCD patients presenting to the ED during the 12-month period following expanding hours in the ACOU were also assessed. The main outcome measures were ACOU and ED utilization and hospital admission rates. Results: There were 344 encounters in the sickle cell ACOU in the 12 months before expansion of service hours compared to 796 in the 12 months after expanding the hours, an increase of 131%. This represents 0.15 patients treated per hour before increasing the hours versus 0.2 per hour after increasing the hours. Seventy-two percent of the patients treated at the sickle cell ACOU were discharged home in the 12 months prior to expanding hours versus 75% after. During the comparative 12-month period following expansion of hours in the ACOU, there were 1074 encounters for SCD acute painful episodes in our ED, representing 0.12 patients treated per hour of operation. Only 35% of SCD patients treated in the ED for an acute painful episode were discharged home. Conclusion: The sickle cell ACOU at UIC more than doubled its patient volume following the expansion of operation from 9 to 15 hours/day during weekdays. Based on the hours of operation, during a comparative 12-month period the sickle cell ACOU treated twice as many SCD patients with an acute painful compared to the ED while discharging rather than hospitalizing twice as often. These observations suggest that allocating resources to a dedicated sickle cell ACOU can decrease ED utilization and subsequent inpatient hospitalizations. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 1017 In sickle cell disease, patients are predisposed to renal dysfunction and eventual renal failure as they reach adulthood. Many advances have been made within the field of sickle cell anemia, yet to this day sickle cell nephropathy remains an important cause of mortality in adult patients. Previous studies have determined that proteinuria and hematuria are two useful markers of sickle cell nephropathy. Currently, the best marker for detecting early renal dysfunction is proteinuria on urine dipstick due to its ease of use and efficiency. Our goal in this study is to determine the age at which the first signs of renal dysfunction appear. Pediatric patients with sickle cell disease were selected for a retrospective chart review to determine age of onset for renal abnormalities. The sickle cell pediatric roster was used from the Children's Hospital University of Illinois to study a total of 175 patients within the age range of 0–31 years. Urinalysis was captured at patient's baseline when available and possible risk factors for glomerular dysfunction were studied. Factors such as urine protein and blood on dipstick were recorded and proteinuria was further quantified by using the urine protein to creatinine ratio. Blood on dipstick was further analyzed by red blood cells on microscopic urinalysis. Patients with positive urine for blood on dipstick with

Description: Introduction: Chronic hemolysis occurs in sickle cell anemia as a result of recurrent sickling and other abnormalities of the red blood cells including eryptosis. Exuberant reticulocytosis is anticipated to partially compensate for the resultant anemia. Sickle cell anemia patients may also have aplastic crisis, bone marrow (BM) infarction and erythropoietin deficiency which could lead to reticulocytopenia despite the anemia. High degree of reticulocytosis among asymptomatic infants with sickle cell anemia has been associated with an increased risk of death or stroke during childhood. Assessment of BM function in sickle cell anemia is important due to potential complications associated with both under-activity and hyperactivity. This study aimed at evaluating the erythropoietic function of the BM in steady state sickle cell anemia using corrected reticulocyte counts. Methods: This study was carried out at the hematology clinic in the University College Hospital, Ibadan. HbSS patients in steady state were recruited from the hematology clinic. Local ethical committee approval was obtained and all participants gave written informed consent. Patients with M. tuberculosis, Hepatitis B, HIV and P. falciparum infection were excluded. Peripheral blood samples were analyzed using Sysmex Ki-X21 for complete blood count (CBC) and standard point of care for serum electrolytes and liver function tests. The glomerular filtration rates were calculated using the Cockcroft-Gault formula. Reticulocyte counts were determined manually using fresh samples from K2 EDTA bottles and methylene blue stain. Two drops of stain were mixed with two to four volumes of anticoagulated blood and incubated at 37ºC for 15 minutes. Afterwards, the cells were re-suspended and blood films were made. Corrected reticulocyte count and reticulocyte production index were calculated. Participants were categorized according to corrected reticulocyte counts of greater than or less than 2.5%. Univariate and multivariate analyses were performed to determine variables associated with corrected reticulocyte count

Description: Introduction: As published by Naik both in single-institution and multi-institution data, adults with sickle cell disease have a baseline hypercoagulable state in addition to traditional risk factors. In pediatrics, venous thromboembolism (VTE) is often overlooked because of the low incidence in children. In addition, there is no unified consensus that supports the use of prophylaxis or screening of the pediatric population at risk. Although the incidence of VTE in the general pediatric population is low, there may be those children, including those with sickle cell disease (SCD), who would benefit from VTE prophylaxis. Objectives: Estimate the contribution of sickle cell disease to rates of VTE in adolescents and young adults, compare rates of prophylaxis in the pediatric units versus the adult units, and determine risk factors associated with VTE occurrence in a hospital serving a large population with sickle cell disease. Methods: This study was a retrospective chart review of patients aged 14-25 admitted to the Pediatric Intensive Care Unit (PICU), to the Pediatric Sickle Cell Service, and to the Medical Intensive Care Unit (MICU) between the dates of April 1, 2014 and April 30, 2015. Anyone older than age 18 admitted to the PICU or Pediatric Sickle Cell Service was considered part of pediatrics. Charts were searched manually for incidence of VTE during hospitalization, risk factors for developing VTE, history of prior VTE, use of therapeutic anticoagulation, and prophylaxis use and type. Data was analyzed using a multivariate regression analysis. Results: In the 13-month period, 251 AYA admissions (108 to the PICU and 143 to the Sickle cell Unit) and 67 MICU admissions were reviewed. 66/67 (99%) MICU patients received either chemical or mechanical prophylaxis against VTE compared to 9/251 (3.5%) children. Event rates of VTE were 3/67 (4.5%) in MICU and 2/251 (0.8%) in the Pediatric units - 1 in the Sickle Cell unit and 1 in the PICU. In the pediatric units, none of the patients receiving prophylaxis had an acute VTE and both patients with VTE were not on prophylaxis. Both adolescents had central lines in place at the time of VTE occurrence. Of the MICU events, one patient had SCD and was taking systemic anticoagulation for previous VTE but had a central line in place. The other MICU patients both had infections, one with Crohns Disease and the other with a central line placed (table 2). The multivariate regression analysis demonstrated that prior history of a VTE and prolonged LOS were positively correlated with increased risk for VTE, both with a confidence interval of 95% and a corrected critical value of 0.003 using the Bonferroni correction (table 1). Conclusion: Of the 5 VTE events in the 318 AYA hospitalizations reviewed, two (40%) were in patients with SCD (ages 17 and 24). As expected, overall VTE incidence in AYA is low in our institution, and appear to be associated with heightened inflammation and central line placement. VTE events in the pediatric unit were in patients not receiving any prophylaxis, which is not surprising when VTE prophylaxis orders were rare on the pediatric units (3.5%). In both our pediatric unit cases, prophylaxis may have prevented the VTE. A consensus protocol to identify high risk children is being implemented and refined with ongoing data collection. The data from our hospital AYA population enriched in SCD reinforces previous data from adult sickle cell populations that the magnitude of VTE risk attributable to SCD can be high. SCD probably should be among the screening criteria when deciding VTE prophylaxis in hospitalized adolescents. Disclosures Hsu: Purdue Pharma: Research Funding; Gerson Lehman Group: Consultancy; Hilton Publishing: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; Eli Lilly: Research Funding; Sancilio: Research Funding; Centers for Medicare and Medicaid Innovation: Research Funding; EMMI Solutions: Consultancy; Mast Therapeutics: Research Funding.

Description: Abstract 4693 Time to first dose (TTFD) of pain medication is one of the important measures of quality care in sickle cell disease (SCD), according to a new expert consensus (Wang et al., 2011). It is well documented that treatment of pain crises in an acute care center with immediate and aggressive treatment can dramatically reduce admission rates for pain (Benjamin, Swinson, & Nagel., 2000; AHRQ, 2012). The University of Illinois Hospital & Health Sciences System Comprehensive Sickle Cell Center is one of the largest in the United States. The volume of acute medical care is very high in this urban hospital with an enrollment of approximately 750 patients, pediatric and adult. For fiscal year 2012 clinic volume for pediatrics and adults was 2566, in-patient volume was 886 and adult ED visits for pain were 867. To improve medical treatment, outcomes and satisfaction of sickle cell patients, the University Of Illinois Hospital & Health Sciences System Comprehensive Sickle Cell Center opened its Acute Care Center (ACC) in 2009. One measure of the ACC's effectiveness is the TTFD of analgesic from patient's arrival to the ACC. Using the American Pain Society as a resource a target of 90% of patients' TTFD