ALBERT

Description: Sickle cell disease (SCD) is a recessively inherited hemoglobin disorder; the most common and severe form is a consequence of homozygous βS mutation. High concentration of hemoglobin S damages RBC membranes, leading to hemolysis, vaso-occlusion, and inflammation, which together result in anemia, recurrent painful crises, and multiple end-organ damage (i.e. brain, kidney, lung, and bone). Anemia in SCD is multi-factorial. Causes include hemolysis, ineffective erythropoiesis, impaired iron utilization, insufficient erythropoietin responsiveness, and low oxygen affinity [Sherwood Blood 1986]. RBC transfusions are used to ameliorate symptoms and complications but indications are not clearly defined for adults. We postulate that impaired iron utilization in SCD is a consequence of complex regulation of hepcidin, the main hormone regulating circulating and systemic iron. We aim to explore correlation between hepcidin, inflammation and erythropoiesis to enhance our understanding of iron metabolism, hepcidin regulation, and pathophysiology of anemia in SCD. Ultimately this may yield more specific indications for RBC transfusion, and pave the way for novel therapeutic approaches. High hepcidin results in the sequestration of iron within macrophages and prevents further iron absorption in the gastrointestinal tract. Hepcidin expression is enhanced by iron and inflammation and suppressed by hypoxia and erythropoiesis. Distinguishing the relative contribution of these competing effects on hepcidin in SCD is complicated. For example, adult SCD patients in steady state have significantly lower hepcidin relative to heterozygous controls and do not correlate with markers of inflammation and erythropoiesis [Kroot Haematologica 2009]. In a randomized, placebo-controlled trial, inhaled steroids (mometasone) were administered to non-asthmatic SCD patients [Glassberg Am J Hematol 2017]. The results demonstrate improved pain scores and reduced hemolysis in the treated group although the mechanism of this effect is not known. In a subsequent analysis, markers of inflammation are suppressed in the treated group, correlating with macrophage activation. We thus evaluate hepcidin expression in stored serum samples from this trial of SCD patients treated with inhaled steroids or placebo. Samples before and after treatment were analyzed. Serum hepcidin quantification was performed with Hepcidin-25 ELISA kit (Intrinsic Lifesciences LLC). In addition, we evaluate if and how hepcidin levels correlate with pro-inflammatory markers measured with olink inflammation assay. Serum hepcidin concentration is not different in steroid- vs. placebo-treated SCD patients before or after treatment and no significant difference is observed in the hepcidin ratio after:before treatment between the two groups (Fig 1a). However, in the steroid group, hepcidin concentrations are increased in a higher proportion of patients although the difference does not reach statistical significance (Fig 1b). We thus hypothesize that hepcidin levels may be a marker of increased erythropoiesis relative to inflammation in SCD. Both IL-6 (Fig 2a) and IL-10 (Fig 2b), cytokines known to induce hepcidin expression during inflammation, decrease after treatment with steroids relative to placebo, and neither correlates with hepcidin concentration after treatment (Table I). Hepcidin is however inversely correlated with adenosine deaminase (ADA) and hemoglobin S and directly correlative with fibroblast growth factor 23 (FGF23), monocyte chemoattractant protein 1 (MCP1), and hemoglobin F in both placebo- and steroid-treated groups (Table I), potentially suggesting that hepcidin inversely correlates with expanded erythropoiesis. We thus use the newly available human ELISA kit for erythroferrone (ERFE) (Intrinsic Lifesciences LLC), a recently identified erythroid regulator of hepcidin [Kautz Nat Gen 2014], to evaluate correlation with hepcidin. Our results demonstrate that serum ERFE concentration decreases in steroid- (Fig 3a) but not placebo-treated SCD patients (Fig 3b), and no correlation with hepcidin is observed. Taken together, these data for the first time demonstrate a decrease in erythropoiesis and erythroid-regulation-induced hepcidin suppression in inhaled-steroid-treated SCD patients. Disclosures No relevant conflicts of interest to declare.

Description: Background: Sickle cell disease (SCD) affects 100,000 adults and children in the United States (USA). Painful, uncomplicated vaso-occlusive episodes (VOE) are the most common complication of SCD and the #1 reason adults with SCD seek medical attention in the ED. The NHLBI guidelines suggest encouraging oral hydration, along with analgesics, during VOE but to give intravenous (IV) fluids only if the patient cannot drink. However, there exists a clinical equipoise regarding the choice of IV fluids to use during the treatment of VOE in the ED, along with the rate or volume given. Despite lack of guidelines or evidence, the use of large IV volumes of crystalloids given over short periods of time (i.e. bolus) in the ED is common practice and we recently showed normal saline (NS) boluses in particular may be associated with inferior pain control and higher admission rates in pediatric patients with VOE (Carden etal., Am J Hem, 2019). Importantly, investigations into the use and impact these different IV fluids, including IV boluses, and how they may impact clinical outcomes among adult patients with SCD and VOE who present to the ED are lacking. Methods: We conducted a cross-sectional survey of emergency providers at the 2011 annual American College of Emergency Physicians Scientific Assembly, where ED providers from across the United States attend, regarding IV fluid practices during VOE. We specifically used a validated instrument to assess self-reported practices toward patients with SCD regarding IV fluid use, including volumes and rates, during uncomplicated VOE. Basic demographic information was obtained and providers were specifically asked: "Please indicate which type of fluids and rate of administration you give to patients with acute sickle cell pain who are not hypotensive and not severely hypovolemic". Providers responded never, rarely, frequently or always to each fluid type and rate. Results: Of 795 respondents to the survey, 722 indicated they took care of patients with SCD, 669 completely responded to the survey, and of those, 244 respondents only took care of adult patients with SCD. Demographic and experience with SCD patients, as well as preferred fluid type and rate of administration is reported in Table 1. IV fluid use during uncomplicated VOE varied among adult providers, but 83% of providers surveyed used IV fluid crystalloid boluses during VOE. Only 45% of providers recommended oral hydration during VOE among adults. Conclusions: Among adults ED providers who care for patients with SCD in the USA, wide variations in practice utilizing IV fluids are common. Despite no guidelines, IV fluid boluses are commonly given, as was seen in pediatric ED studies, and oral hydration is less commonly recommended among adult ED providers. Further investigation is needed to determine if these practices have an impact on clinical outcomes among euvolemic adult patients with SCD and VOE who present to the ED. Disclosures Carden: GBT: Honoraria; NIH: Research Funding. Tanabe:NIH: Research Funding; AHRQ: Research Funding. Glassberg:ACEP: Research Funding; NHLBI: Research Funding; Pfizer: Research Funding.

Description: Introduction: It is estimated that there are 100,000 Americans living with Sickle Cell Disease (SCD). Patients with SCD experience a number of complications that frequently require hospitalization. SCD is a prothrombotic state that is commonly complicated by venous thromboembolism (VTE) and recurrent VTE. The National Heart, Lung and Blood Institute do not include VTE as one of the complications of SCD in their latest guidelines, and the topics of prophylaxis and treatment of VTE in SCD are not discussed. There are no guidelines specifically designed for the prophylaxis or treatment of VTE in the SCD population, and traditionally management guidelines for VTE in the general population are followed. Recent information on national prevalence, mortality, length of stay, and cost for hospitalized patients with with SCD complicated by VTE is limited. Methods: We used data from the Healthcare Cost and Utilization Project's National Inpatient Sample (NIS) from 1999-2014 to examine these variables. The data on SCD from 1999-2014 was analyzed using ICD-9-CM codes for SCD (ICD-9-CM: 282.41, 282.42, 282.6, 282.60, 282.62, 282.63, 282.64, 282.68, 282.69) in the primary diagnosis field, and VTE (ICD-9-CM: 453.40, 453.41, 453.42, 453.82, 453.83, 415.11, 415.19) in the secondary diagnosis field which includes codes for venous thrombosis and pulmonary embolism. Univariate and bivariate statistical analysis was performed using the chi-square test. Multivariate analysis was performed using cox proportional hazard regression. The alpha was set at 0.05. Results: Over a 15 year period, from 1999-2014, a total of 217,791 (weighted N = 1,073,215) admissions with SCD were identified. A total of 7,898 admissions were associated with VTE. Mean age at admission of those with VTE was 27.42 (+/- 0.05) years and those without VTE was 34.00 (+/- 0.51) years. In patients with SCD and VTE, the average inpatient mortality was 3.08% (p 〈 0.0001) versus mortality of 0.27% in patients that did not have VTE. The hazard ratio for mortality was 4.18 (CI: 2.95-5.93) (p 〈 0.0001). Length of stay in the SCD with VTE group was 10.45 days (+/- 0.43) versus 5.09 days (+/- 0.02) (p 〈 0.0001) in SCD without VTE. Overall hospital cost was higher in those with VTE at $60,055 (+/- $1,940) versus $28,729 (+/- 232.97) (p 〈 0.0001) in those without VTE. Conclusions: Patients with SCD and VTE experience significant morbidity, mortality, prolonged hospitalization and increased cost associated with this complication of the disease as was observed in this study. Furthermore, patients who experience VTE are significantly younger than those who do not, with mean age of 27 versus 34. After controlling for multiple confounders like age, race, sex, income, comorbidities, the presence of VTE is associated with a significantly higher risk of mortality in SCD. Currently, there are no prophylaxis or treatment guidelines designed specifically for patients with SCD and VTE. We recommend the use of antithrombotic prophylaxis or therapy in patients with SCD be evaluated in prospective studies. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Vaso-occlusive episodes are the most common complication experienced by individuals with sickle cell disease (SCD). Treatment in an emergency department (ED) is often required and significant variability in care exists. In 2014, NHLBI published evidence based recommendations suggesting treatment with either an individualized opioid dosing or standard weight-based protocol; however the supporting evidence grade was Consensus - Panel Expertise. As outlined in the results section, the aim of this project was to compare change in pain scores, patient safety and system utilization variables between patients randomized to an individualized or weight based (standard) dosing protocol for treatment of VOC from arrival to discharge in an ED setting. Methods: A randomized controlled trial was conducted in two EDs (OH and NY). Adults with SCD were eligible for inclusion and recruited during a hospitalization, clinic visit or at the end of an ED visit. Patients were randomized to treatment with an individualized opioid dosing protocol (developed by the SCD physician based on patients' prior opioid use) or standard weight based protocol. Both protocols were supported by the NHLBI recommendations for treatment of VOE (2014) to include repeat dosing. Protocols were made available on the electronic medical record for future ED visits (up to five visits/patient), should they occur. ED physicians were informed of the protocol and ordered analgesics. Research staff was notified when ED visits occurred for enrolled patients and obtained assessments of pain (0-100 cm VAS) every 30 minutes from placement in the ED to one of 3 study endpoints: 1) 6 hours; 2) decision to admit to the hospital; 3) discharge home. The unit of analysis was the ED visit rather than patient. The primary outcome was change in pain score from arrival to study endpoint. Research staff reviewed the medical record 30 days after the ED visit to determine secondary outcomes of hospital admission, re-admission and new ED visits within 72 hours, 7 and 30 days post the index ED visit. The medical record was reviewed for administration of narcan, intubation, or assisted ventilation. A hierarchical linear mixed effects model adjusting for nested patient and site effects were used to test for a difference in the mean pain change scores in the treatment arms. Generalized Linear Models adjusting for nested patient and site effects were performed to evaluate differences in the dichotomized secondary outcomes. Results: 106 patients enrolled in the study with 52 patients (sites: 25 OH, 27 NY) contributing a total of 126 ED visits over 12 months. Among the 52 patients with visits, the median number of ED visits/patient was 2.0, 58% were male, and the median age was 27 years (range: 21 to 60). No patients in either treatment arm required narcan, intubation, or assisted ventilation. Pain change: Mixed effect model adjusted mean ± standard deviation, higher positive score = greater pain reduction; *Fisher's Exact Test result due to low cell frequency. Conclusions: An individualized opioid dosing protocol resulted in a larger reduction in pain scores and lower hospital admission rate among patients with SCD treated for VOE in two EDs when compared to treatment with a weight-based opioid protocol. However, there was a tendency for more frequent ED re-visits within 72 hours, 7 and 30 days among patients in the individualized opioid dosing protocol. A pragmatic RCT with a larger and more heterogeneous sample of patients and ED settings is required to provide definitive evidence to guide treatment of VOE. Table 1. Table 1. Disclosures Tanabe: NHLBI: Research Funding. Bosworth:WestMeadVaco: Research Funding; CVS carematix: Consultancy; Improved Patient Outcomes: Research Funding; Johnson & Johnson: Consultancy, Research Funding; Genentech: Consultancy; sanofi: Honoraria, Research Funding; Pharma Foundation: Research Funding.

Description: Background: Previously our research group demonstrated that a diagnosis of asthma is associated with an increased rate of painful episodes in children with sickle cell disease (SCD); however, little is known about the temporal relationship between an asthma exacerbation and a painful episode in a child with SCD. We tested the hypothesis that respiratory symptoms either precede or occur concomitantly with painful episodes more frequently in children with SCD and asthma when compared to children without asthma. Methods: As part of standard care, a cohort study was conducted. The primary hematologist referred all children with SCD for evaluation by a pulmonologist. The definition of asthma was based on the National Heart Lung and Blood Institute’s guidelines. The primary outcome recorded was respiratory symptoms occurring up to 96 hours prior to a painful episode. Respiratory symptoms were defined as any of the following: cough wheeze tachypnea retractions, or grunting. Pain was defined as the complaint of body pain (excluding the head) requiring the administration of opioids in the hospital, clinic, or emergency department.. Cases and controls were children with and without asthma, respectively. Medical records from all hematology clinic, emergency department, and inpatient visits over a 25-month period were reviewed for painful episodes and the presence of respiratory symptoms. Results: A total of 74 children were evaluated by a hematologist and referred to pulmonologist for an asthma between 6/15/2004 and 1/31/2005. Of the eligible patients, 36 were diagnosed with asthma (mean age 9.8 years; median 9.6 years; range 2.4–19.4) and 38 were determined not to have asthma (mean age, 9.8 years; median 9.7 years; range 2.4–19.5). For children with asthma versus those without asthma, the odds ratio of having a pain episode associated with antecedent or concurrent respiratory symptoms was 4.9 (95% confidence intervals, 2.2–10.7). Conclusions: In children with both SCD and asthma, respiratory symptoms are a risk factor for subsequent painful episodes.

Description: Introduction Pregnancy in sickle cell disease (SCD) is associated with an exacerbation of SCD-related complications and an increased risk of maternal complications. The increased risk is partly due to physiologic adaptations in pregnancy, which include increased metabolic demands and a hypercoagulable state. The maternal death rate for SCD is 629 per 100,000 deliveries, compared to 12 per 100,000 deliveries in black women and 6 per 100,000 deliveries in the general population (Raider et al., 2016). Studies on maternal and perinatal outcomes of patients with SCD present inconsistent and conflicting results. Some studies have reported an increase in maternal complications such as pre-eclampsia, acute chest syndrome and thromboembolic events, while other studies have reported no significant risk in adverse maternal outcomes. The inconsistent findings reported in prior studies may be attributed to small sample sizes and single-centered sites. Our study aims to determine the prevalence and predictors of maternal morbidity among participants enrolled in the SCD Implementation Consortium (SCDIC) registry, which is the largest, most geographically diverse SCD participant sample in the United States. Methods This cross-sectional study included women enrolled in the SCDIC registry who had at least one pregnancy event. The SCDIC is composed of eight academic SCD centers across the United States and one data-coordinating center. Participants were enrolled in the SCDIC registry if they were 18 to 45 years of age and had a confirmed diagnosis of SCD. Enrolled participants completed a series of surveys that collected sociodemographic information, SCD and pregnancy history and data abstractions of participants' medical records was completed. Medical complications queried during pregnancy included: vaso-occlusive episodes, acute chest syndrome, blood transfusion requirement, preeclampsia, maternal diabetes and deep venous thrombosis. Descriptive analysis of sociodemographic, clinical and maternal characteristics was conducted. Bivariate analysis was performed using Chi-Square test, Mann-Whitney U test, t-test, and logistic regressions, as appropriate. A p-value of ≤ 0.05 was considered statistically significant for all analysis. Results The study sample included 743 women who had at least one pregnancy event, and a total of 1066 live births. Almost all women (96.3%) were African American, with a median age of 21 years (inter-quartile range of 19 to 23 years) at first birth. The majority had Hb SS SCD genotype (69.5%; 513 of the 738 with SCD genotype data). Of all reported pregnancies, participants did not use hydroxyurea during conception (78%), and pregnancy (84.5%). Only 2.7 % of the women reported using fertility drugs or assisted reproductive procedures. Seventy five percent of the pregnancies that ended in live births had maternal complications. The leading complications were vaso-occlusive episodes (61.2%), pregnancy requiring blood transfusion(s) (33.2%), preeclampsia (15.4%), deep venous thrombosis (5.6%) and acute chest syndrome (7.7%). When the pregnancies were stratified by SCD genotype, women with Hb SS had a higher occurrence of acute chest syndrome (63.4% vs. 26.7%), transfusion requirement (70.8% vs. 21%) and preeclampsia (66.7% vs 22.4%). In the univariate logistic regressions, multiparous women, with a history of adverse maternal outcomes in a previous pregnancy, had higher odds of vaso-occlusive episodes (OR: 3.42; 95% CI: 2.42-4.94) acute chest syndrome (OR:4.99; 95% CI:2.56- 9.48), transfusion requirement (OR:3.86; 95% CI:2.64- 5.69), and pre-eclampsia (OR:3.36; 95% CI:2.05-5.45). Conclusion In this large multicenter registry, we found pregnant women with SCD have significant maternal complications. Early antenatal care by healthcare providers knowledgeable about risk factors for adverse maternal outcomes in SCD is essential improve maternal and fetal outcomes and reduce the maternal death rate for SCD. Disclosures Hankins: Novartis: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; MJH Life Sciences: Consultancy, Patents & Royalties; UptoDate: Consultancy; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; LINKS Incorporate Foundation: Research Funding; American Society of Pediatric Hematology/Oncology: Honoraria. Treadwell:Global Blood Therapeutics: Consultancy; UpToDate: Honoraria. King:Amphivena Therapeutics: Research Funding; Bioline: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novimmune: Research Funding; RiverVest: Consultancy; Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company. Gordeuk:CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Imara: Research Funding; Ironwood: Research Funding; Novartis: Consultancy. Kanter:SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; GLG: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; Medscape: Honoraria; Guidepoint Global: Honoraria; bluebird bio, inc: Consultancy, Honoraria; Sanofi: Consultancy. Glassberg:Pfizer: Research Funding; Global Blood Therapeutics: Consultancy; Eli Lilly and Company: Research Funding. Shah:Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; CSL Behring: Consultancy; Bluebird Bio: Consultancy; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau.

Description: Introduction Sickle cell disease (SCD) is the most common inherited blood disorders in the United States. The disease predominantly affects African Americans with 1 out of every 365 individuals born with SCD. The disease is characterized by vascular inflammation and vaso-occlusion leading to numerous complications and multi-organ dysfunction. Previous studies have shown women with SCD tend to outlive their male counterparts. Other than the increased life expectancy, sex-based clinical outcome differences in SCD remain largely unknown. To better characterize sex-based differences in SCD, we assessed sociodemographic characteristics, pain, treatment characteristics, laboratory measures and complications among males and females currently enrolled in the Sickle Cell Disease Implementation Consortium (SCDIC) registry. Methods The SCDIC consists of eight academic and comprehensive SCD centers, and one data-coordinating center that received funding from the National Heart Lung and Blood Institute to improve outcomes for individuals with SCD. Participants were eligible for the enrollment in the SCDIC registry if they were 15 to 45 years of age and had a confirmed diagnosis of SCD. Participants were excluded if they had sickle cell trait or had a successful bone marrow transplant. Enrolled participants completed surveys. Data were also abstracted from the participants' medical records. Data were entered into a REDCap database and analyzed using SAS version 9.4 (SAS Institute; Cary, NC). Categorical variables were presented as frequencies and percentages, continuous variables were presented as medians and interquartile ranges (IQR) or means and standard deviations. Categorical variables were analyzed using Chi-Square or Fisher exact tests when appropriate. Continuous variables were compared using the Mann-Whitney U test or independent sample t-tests depending on the distribution. A two-sided p-value less than 0.05 was deemed significant. Results A total of 2,124 participants were included in the study. The mean (SD) age of our participants was 27.8 (7.9) years. Almost all (95.6%) were Africa American, female (56%) and had hemoglobin SS (68.2%) SCD genotype. More males (55.4 % vs. 44.6%, p

Description: Introduction Sex-based clinical outcome differences in sickle cell disease (SCD) remain largely unknown despite evidence that female sex is associated with an increased lifespan. To better characterize sex-based differences in SCD, we assessed pain, treatment characteristics, laboratory measures and complications among males and females currently enrolled in the Sickle Cell Disease Implementation Consortium (SCDIC) registry. Methods The SCDIC consists of eight comprehensive SCD centers and one data coordinating center that received funding from the National Heart Lung and Blood Institute to improve outcomes for individuals with SCD. Eligibility criteria included: 15 to 45 years of age and a confirmed diagnosis of SCD. Self-report surveys were completed and data were also abstracted from the participants’ medical records. Results A total of 2,124 participants were included (mean age: 27.8 years; 56% female). The majority had hemoglobin SS SCD genotype. Females had worse reports of pain severity (mean (SD) T-score 51.6 (9.6) vs 49.3 (10), p