Vaso-occlusive Research Articles

Differential expression of adhesion molecules in sickle cell anemia and gut microbiome effect

Sickle cell anemia (SCA) causes a long-standing vascular inflammation state, leading to endothelial dysfunction and chronic overexpression of several adhesion molecules, which contributes to acute and constant vaso-occlusive (VOC) episodes. It has been demonstrated that hydroxyurea (HU) can reduce VOC events, organ damage, blood transfusions, and even the adhesion properties to endothelial cells of SCA subjects. Due to VOC episodes, these patients are also more susceptible to recurrent bacterial translocation and dysbiosis. Given this, our study aimed to uncover the interplay between adhesion molecules, gut microbiome, and hydroxyurea in a population of Angolan SCA children. Serum and fecal samples were obtained before and after HU treatment in 35 children. After HU, four of these adhesion molecules were significantly reduced: sE-selectin (p = 0.002), ADAMTS13 (p = 0.023), sICAM-1 (p = 0.003), and sVCAM-1 (p = 0.018). A positive correlation was observed between the number of neutrophils and sICAM-1, platelets, and sP-selectin, and also between leukocytes, sICAM-1, and sVCAM-1. Most taxa showing a significant correlation mainly belonged to the Clostridiales order. Specifically, from the Clostridium genera, the groups g19, g21, and g34 were all negatively correlated with HbF levels; g19, g21, and g24 positively correlated with leukocytes; g19 positively with neutrophils and sVCAM-1; and g34 positively with E- and P-selectin. Serratia, an opportunistic pathogen, was positively correlated with sE-selectin and sICAM-1 levels. Additionally, a negative correlation was observed between sP-selectin and Bifidobacterium. Research studies in this area could improve our understanding and contribute to finding new prognostic biomarkers to guarantee precise SCA patient stratification and predict severe complications.

Neighborhood Disadvantage Increases Risk of Adverse Clinical Events in Children with Sickle Cell Disease

Background: Hydroxyurea is the most widely used pharmacologic agent to treat patients with sickle cell disease (SCD). Hydroxyurea treatment has well established effects of inducing expression of fetal hemoglobin (HbF) and a beneficial impact on clinical outcomes such as reduced number of vaso-occlusive (VOC) events, transfusions, and hospitalizations. In non-SCD populations, living in socio-economic disadvantage is a well-established factor for poor health outcomes. However, there is a paucity of data to describe how social stressors impact children with SCD. We hypothesized that socio-economic disadvantage impacts risk of adverse clinical outcomes in pediatric SCD patients even while on hydroxyurea therapy. Methods: We performed a retrospective chart review on 121 pediatric patients with severe SCD genotypes (homozygous HbS and sickle-beta 0 thalassemia) seen at Texas Children's Hospital (TCH) between 2010-2021. All patients were treated with hydroxyurea for a minimum of five years. Adherence to hydroxyurea was assessed through lab markers including absolute neutrophil count and reticulocyte counts. Patients not adherent were excluded from analysis. We examined the incidence of all clinical events for a total of 1026 patient years, including the number of office visits, ER visits, hospitalizations, transfusions, VOC, acute chest syndrome episodes (ACS), acute splenic sequestration (ASS), and febrile illness. We collected laboratory data including absolute neutrophil count, hemoglobin level, and HbF levels for each patient per year they were on hydroxyurea. We used the area deprivation index (ADI) to determine a score of neighborhood disadvantage amongst our cohort of patients. The ADI is a factor-based index which uses 17 US Census variables including poverty, education, and employment. We used individual residential addresses during our observation period to assign a geocode specific to each individual and obtain an ADI score. The ADI scores are ranked from 1-10, with higher ADI rankings reflecting a higher level of disadvantage. Results: All individuals with SCD had a robust response to hydroxyurea within their first year of initiating the drug (>20% HbF). We stratified our cohort based on their ADI scores into low ADI (1-3; n=42); medium ADI (4-6; n=42); and high ADI groups (7-10; n=37), where high ADI is the group with highest levels of disadvantage. All three groups had a similar average duration of hydroxyurea treatment. There were no significant differences in age, sex, or reason given for starting hydroxyurea between the ADI groups. When we examined hydroxyurea response, there was no significant difference in HbF levels at 1 year (23.8 vs. 24.06 %HbF in the low vs. high ADI groups) or after 5 years (19.6 vs. 18.6 % HbF in the low and high ADI groups). Individuals with high ADI did started hydroxyurea at a younger age (2.9 years vs. 4.9 years, p=0.02). We found that any individual living in an area with higher ADI had an increased incidence of adverse clinical events. We calculated the incidence of each clinical event per 100 patient years in our 3 ADI groups and used a conditional maximum likelihood estimate of rate ratio method to compare incidences (Table 1). We found that among individuals living in an area with a higher ADI (more deprived region), there was increased frequency of ER visits, hospitalizations, transfusions, VOC, and ASS. In particular, patients with the highest ADI had a 3 and 5 times higher rate of VOC and ASS, respectively (Table 1). Discussion: While we did not observe an association between ADI and HbF expression, our results show that higher neighborhood disadvantage is associated with poorer clinical outcomes among hydroxyurea-adherent pediatric patients with SCD who maintained a robust response to the drug (>20% HbF). All individuals in our study had a similar number of routine office visits at our clinic but any patient living in an area of high ADI had significantly more ER visits and hospitalizations for VOC and ASS events. While hydroxyurea is shown to reduce hospitalizations and VOC events in pediatric sickle cell patients, we show that neighborhood disadvantage can influence clinical outcomes even among patients who respond to hydroxyurea. More analysis remains in order to better characterize this association, and to understand additional strategies that can be used to reduce clinical events in pediatric patients of lower socioeconomic status.

Neutralization of IL-1β and P-Selectin Inhibition Attenuate Organ Injury in Mice with Sickle Cell Disease

Advances in the clinical management of sickle cell disease (SCD) have significantly improved the life expectancy of patients. However, aging in SCD is worryingly associated with extensive end-organ damage, including nephropathy, hepatopathy, and pulmonary alterations. Continuous vaso-occlusive (VO) and inflammatory processes in the vasculature are most likely the principal cause of such lesions, and there is little evidence, to date, that long-term hydroxyurea therapy (the standard of care for SCD) reduces organ damage in SCD adults. Inhibition of P-selectin activity, using crizanlizumab, has shown some success for reducing VO crisis frequency in SCD. Furthermore, interleukin (IL)-1β blockade, in the form of canakinumab administration, was well tolerated in young patients with SCD and associated with inflammatory marker reduction. Exploring the hypothesis that a multi-target approach could potentiate the effects of biological agents such as crizanlizumab, we recently showed that acute neutralization of inflammasome-processed cytokines potentiated the effects of anti-P-selectin on tumor necrosis factor (TNF)-α-induced VO events in SCD mice. The aim of this study was to evaluate the effects of 6 weeks (wks) of anti-IL-1β and/or anti-P-selectin (CD62P) immunotherapy on inflammatory parameters and the organ histology of SCD mice. Transgenic Berkeley SCD mice (4-mo old) received ( i.p.) either anti-IL-1β monoclonal antibody (mAb) (01BSUR IgG2a; 7.5 mg/Kg; 2x/week), and/or anti-murine CD62P (RB40.34 IgG1; 30 µg/mouse; 3x/week), or an IgG1 mAb (30 µg/mouse; 3x/week) or saline (2x/week) for 6 wks (N=4-5 for each group). Prior dosing protocols determined the optimal mAb concentrations in SCD mice (data not shown). At two days after the last mAb administration, blood samples were analyzed by flow cytometry and serum stored for biomarker analysis (ELISA/colorimetric assays). Animals were then euthanized and organs were immediately collected and processed for staining with hematoxylin & eosin or Masson's trichrome (for collagen fiber staining). Histological analysis of 4 sections from each organ was performed blindly and alterations were scored qualitatively on a scale of 0 (absent) to 3 (severe). P-selectin inhibition, but not IL-1β blockade, for 6 wks resulted in inhibition (55.4 ± 6.4% inhibition, P=0.002) of the formation of circulating neutrophil-platelet (CD45 +Ly6G +CD41 +) aggregates in SCD mice, compared to non-specific IgG1, as did the combination of both anti-P-selectin/ anti-IL-1β administration (44.4 ± 5.2% inhibition, P=0.016). In contrast, IL-1β blockade, but not P-selectin inhibition, significantly reduced the circulating levels of TNF-α, compared to the saline/IgG1 controls, after 6 wks (40.4 ± 8.9% decrease, P=0.03). No significant alterations in serum biochemical markers (aspartate/alanine aminotransferase, total/direct/indirect bilirubins) were observed following any of the immunotherapies (P>0.05). With regard to effects on organ histology (see Figure): In the liver, P-selectin inhibition reduced tissue injury, while anti- IL-1β therapy significantly reduced sinusoidal congestion, injury and fibrosis, compared to saline/IgG1-treated SCD mice. In the kidney, anti-P-selectin therapy reduced renal congestion, while anti-IL-1β therapy ameliorated fibrosis, compared to saline/IgG1-treated SCD mice. In contrast, in the lungs, anti-P-selectin therapy reduced lung congestion and cell infiltrate, and significantly reduced bronchiole injury, while IL-1β immunotherapy and P-selectin/IL-1β inhibition combination therapy abrogated bronchiole injury/ fibrosis. As such, single immunotherapies had significant effects on multiple organs in SCD mice; P-selectin inhibition abrogated pulmonary bronchiole injury and vascular congestion, possibly mediated by reduced heterocellular aggregate formation, while IL-1β neutralization protected against liver and kidney alterations, and improved lung fibrosis, in association with reduced inflammatory cytokine production. Combination treatments, however, especially in the kidney and liver, had more complex effects. We suggest that future preclinical and clinical studies should investigate the potential of anti-inflammatory/adhesion approaches (alone or in combination) for preventing damage to multiple organs, in addition to preventing VO events.

Management of fever and acute painful crises in children with sickle cell disease in emergency departments: a tertiary hospital experience.

Sickle Cell Disease (SCD) is highly prevalent in Saudi Arabia with variable demographics and access to health care facilities including emergency departments. Literature reviews for locally published articles are deficient in the in-depth evaluation of current emergency practices in managing patients with SCD. The study aims to assess the current emergency practice in managing SCD patients in tertiary hospitals. We reviewed data of 212 visits by patients with SCD over three years and assessed the current emergency department practices in managing common SCD crises, such as vaso-occlusive (VOC) and febrile episodes. Our findings revealed that 47.2%, 37.7%, and 15% of the patients presented with pain, fever, or both, respectively. The patients were triaged level III according to the Canadian triage and acuity scale system in 89% of the visits. The Median time for patients to see healthcare providers was 22 min. In the first 2 h, 86% of the patients received at least one fluid bolus and 79% of them received appropriate analgesia for pain crises. Approximately 41.5% of the patients with fever were admitted and received ceftriaxone as single intravenous antimicrobial agent. However, none of the patients had bacteremia. Only 2.4% of the patients had either urinary tract infection or osteomyelitis based on imaging. ED management is a key factor in the successful management of patients with SCD in a timely manner by providing fluids, analgesia, and antibiotics. Adopting evidence-based guidelines and avoiding unnecessary admissions are suggested in clinically well patients with fever in the era of completed vaccination, antibiotic prophylaxis, and good access to care for patients with a clear viral infection focus.

5588568 ASSOCIATION OF MANNOSE-BINDING LECTIN SERUM LEVEL AND PROMOTER GENE VARIANTS RS7096206 AND RS10031251 WITH FREQUENCY OF VASO-OCCLUSIVE EVENTS IN SICKLE CELL DISEASE PATIENTS; AN EGYPTIAN CROSS-SECTIONAL STUDY

Background: Sickle cell disease (SCD) is a genetic blood disorder involving hemoglobin alterations, in addition to endothelial adhesion, thrombosis and inflammation. Low serum Mannose-binding lectin (MBL) levels can enhance SCD-related blood vessel inflammation as well as reduction of phagocytic activity, leading to sickled erythrocyte accumulation on vessel walls and impaired ability to combat infections. This may contribute to the vaso-occlusive (VOC) episodes. Aim: This work aimed to investigate serum MBL level and MBL promoter gene variants distribution among a cohort of Egyptian SCD patients and to describe their association with VOC events frequencies in the studied patients. Methods: This cross-sectional study included 88 steady-state Egyptian SCD patients aged 6-18 years diagnosed and followed up at Pediatric Hematology Unit, Cairo University Children Hospital. Informed consent was obtained willingly from all subjects or their guardians before enrolment in the study. MBL promoter (-221) (rs7096206) X/Y and (-550) (rs10031251) H/L gene variants were studied by Polymerase Chain Reaction- Restriction Fragment Length Polymorphism (PCR-RFLP) technique. Serum MBL level was assayed by ELISA technique with values <500ng/ml considered deficient. Results: The median serum MBL level in SCD patients was 130.9 ng/ml (IQR 71.2-323.9 ng/ml). Patients with serum MBL levels <500ng/ml were significantly older, had longer disease duration and higher rate of VOCs per year, VOCs per lifetime and a higher VOC index (p= 0.039, 0.034, 0.047, 0.040 and 0.008 respectively). Levels <500ng/ml predominated in SS (89.4%) than Sβ groups (70%) (p= 0.023) and in patients with high frequency of VOCs (91.4%) (p=0.008). Serum MBL level correlated negatively with patients’ age, disease duration, hydroxyurea total treatment duration, blood transfusions per lifetime and steady-state HbS level (p= <0.001, <0.001, 0.011, 0.014, 0.031 respectively) but correlated positively with steady-state HbF level (p=0.002). MBL (-221) X/Y both alleles were more associated with (H) allele of MBL (-550) than with L allele (p=0.048), however, with no statistically significant genotype distribution between the studied variants. There was no statistically significant difference in genotype distribution or allele frequencies between MBL (-221) and MBL (-550) in SCD patients regarding serum MBL level, sickle cell type (SS and Sβ), VOCs frequencies or disease severity classes. Conclusion: Serum MBL level rather than studied MBL gene variants is more likely to contribute to the clinical outcomes of SCD; patients with lower MBL levels had a higher rate of VOC per year, per lifetime and a higher VOC index. Meanwhile, the variant genotypes and alleles of the studied MBL promotor gene variants were not associated with MBL deficiency, VOCs, infection events, and disease severity.Further studies to investigate other polymorphisms in MBL gene; MBL exon-1 (codons 52,54 and 57) are recommended. Keywords: MBL, Polymorphism, Sickle cell disease, Vaso-occlusive crises, Egypt

5613480 REAL WORLD APPLICATIONS OF CLINICAL WHOLE BLOOD ADHESION (VCAM AND P-SELECTIN) BIOMARKERS IN A PEDIATRIC SCD POPULATION

Background: Vaso-occlusive (VOC) pain is the most common complication in sickle cell disease (SCD) and is associated with increased morbidity and early mortality. VOC results from intravascular sickling, and decreased red blood cell deformability with increased inflammation and adhesion in the vessel bed. Recent data has demonstrated the ability of whole blood adhesion to vascular cell adhesion molecule (VCAM) and P-selectin (Psel) to stratify individuals with SCD according to their risk of developing a self-reported VOC. Literature regarding the clinical utility of whole blood adhesion biomarkers in pediatric patients with SCD is limited. Aims: We describe our real-world application of the flow adhesion of whole blood to VCAM-1(FA-WB-VCAM) and flow adhesion of whole blood to P-selectin(FA-WB-Psel) assays in pediatric patients with SCD. Methods: This was a cross-sectional analysis of baseline flow adhesion of whole blood to VCAM-1 and flow adhesion of whole blood to P-selectin indices obtained in children (<18 y/o) and young adult patients (18-21 y/o) with SCD at Children’s National Hospital in Washington, D.C. between January 2020 and March 2022. Both FA-WB-VCAM and FA-WB-Psel were performed by the Functional Fluidic laboratory in Detroit, MI. Changes in disease severity included increased VOC pain rate (home, emergency department, or hospital management), acute chest syndrome, priapism, and nephropathy. Statistical analysis included descriptive statistics, Pearson’s correlation, and categorical analysis by t-test(GraphPad, v9, 2021). P value <0.05 was statistically significant. Results: We identified 109 unique pediatric patients with FA-WB-VCAM and FA-WB-Psel assays performed as part of the standard of care. Eighty-seven percent were children (N=95), and 13% were young adults (N=14). The median age was 11 years(IQR 7-15 years), with 47% males (N=51) and 53% females (N=58). Sixty-two percent of patients were on hydroxyurea (N=68), 4.5% on crizanlizumab (N=5), 5.5% on voxelotor (N=6), and 3% on L-glutamine (N=3). FA-WB-VCAM was similar in children vs young adults [median (IQR): 242 (142-500) cells/m2 vs. 239 (134.8-324.8) cells/m2,p=0.0856] while FA-WB-Psel was higher in the young adult population [median (IQR):32 (11-52) cells/m2 vs. 45 (20-76.5) cells/m2, p=0.8681]. Seventy-four percent of patients were HgbSS, 22% Hgb SC, 2% HgbS Beta Thalassemia Zero, 1% Hgb SBeta Thalassemia Plus, and 1% Hgb SE. Baseline FA-WB-P-Sel and FA-WB-VCAM were performed as part of our standard of care. The most common indication for testing was for baseline evaluation (N=76, 70%), followed by a change in disease severity(N=18, 16%), pre-initiation of DMT/change in DMT (N=5, 4.5%), and a combination of change in disease severity and DMT (N=8, 7%). There were FA-WB-Psel values in patients with a change in disease severity vs. without (55.8 vs. 37.28 cells/m2, p=0.036), but no difference in FA-WB-VCAM (299.7 vs. 329.2 cells/m2, p=0.729). There was an inverse correlation between FA-WB-VCAM-1 and HgbF levels (Pearson’s R = 0.483, p<0.001). Conclusions: We established preliminary mean values of FA-WB-Psel and FA-WB-VCAM adhesion indices within all SCD genotypes. FA-WB-VCAM was higher in children while FA-WB-Psel was higher in young adults. Our data represents the expected differences in HgbSS and HgbSC phenotypes. FA-WB-Psel values were most reflective of a recent change in disease severity and may represent an attractive target to monitor SCD clinical severity.

5613043 THE EVOLUTION OF THE COVID-19 PANDEMIC IN PEDIATRIC PATIENTS WITH SICKLE CELL DISEASE: FROM ALPHA TO OMICRON

Background: Approximately two years ago, COVID-19 was declared a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and through genomic surveillance, we have seen the emergence of variants of SARS-CoV-2. In the United States, over 78 million cases and >900,000 deaths attributable to COVID-19 have been reported. SCD was identified as a risk factor for severe COVID-19 disease in adults and pediatric patients. The emergence of novel SARs-CoV-2 variants has led to challenges in diagnosis, treatment, and prediction of long-term sequelae in individuals with SCD and COVID-19. Aims: We compare the overall seasonal variation of COVID-19 variants and patterns of healthcare utilization and clinical presentation over time in pediatric patients with SCD and COVID-19 at Children’s National Hospital (CNH). Methods: Our single-center, observational cohort study included 193 pediatric patients with SCD (0-21 years) with PCR-confirmed SARS-CoV-2 infection between March 31, 2020, and January 31, 2022. Per the SECURE SCD Registry definitions, clinical severity was classified as asymptomatic, mild, moderate, and severe. Results: A total of 193 unique patients with SCD and positive SARS-CoV-2 PCRs between March 2020-January 2022 were included in our registry. Most patients were female (51.8%), and the mean age was 11.2 years (SD 6.5 years). Most of the cohort resides in Maryland (N=135), and HbSS was the dominant genotype (69.4%). During the alpha dominant variant of the COVID-19 pandemic (March 2020- June 2021) there were 70 cases, followed by 40 cases during the Delta variant (July 2021- December 19, 2021), and 83 cases during the Omicron variant dominance (from December 20, 2021-January 31,2022). There were 149 patients (77%) that presented to the emergency department (ED) or were hospitalized. There were a total of 80 hospitalizations (41.5%), and a relative comparison showed that the percentage of hospitalizations was highest during the delta wave (47.5%) and lowest during the omicron wave (36.1%) (p= 0.407). ED-only utilization was highest in the era of omicron (43.4%, N=36), followed by delta (32.5%, N=13), and then alpha (30%, N=21)(p=0.197). The most common SCD-related complication was vaso-occlusive (VOC) pain (33%, N=64) which accounted for half of all hospital admissions (51%, N=41 of 80). Acute chest syndrome (ACS) was reported in 40% (N=32) of admitted patients and was highest in the alpha era (54.8%, N=17). The use of blood transfusion therapy was highest in the alpha (N=17) and delta (N=14) variants, while Remdesivir use was highest in omicron (N=15). A total of 6 patients received monoclonal antibodies (Delta, N=4; omicron, N=2). Throughout all the variants, there was a significant difference in COVID-19 clinical severity (p>0.005). Of the patients classified as asymptomatic (13%, N=25), seventy-two percent (n=18) were diagnosed during the alpha variant. Mild severity was the most prevalent (69%, N=134), with the omicron variant having the highest cases (51.5%, N=69). Severe cases were observed in all variants (6.7%, N=13) but were most prevalent during the alpha variant (46.2%, N=6). Summary - Conclusion: Interestingly, while the relative percentage of hospitalizations was lowest during the omicron wave, it saw the highest percentages of ER utilization. Overall, COVID-19 remains mild in pediatric patients with SCD, and notably, there was higher health care utilization in the omicron era.

Real World Applications of Clinical Whole Blood Adhesion (VCAM and P-selectin) Biomarkers in a Pediatric SCD Population

Background: Vaso-occlusive (VOC) pain is the most common complication in sickle cell disease (SCD) and is associated with increased morbidity and early mortality. VOC is the result of intravascular sickling, decreased red blood cell deformability with increased inflammation and adhesion in the vessel bed. Recent data has demonstrated the ability of whole blood adhesion to both vascular cell adhesion molecule (VCAM) and P-selectin (Psel) to stratify individuals with SCD according to their risk of developing a self-reported VOC. Literature regarding the clinical utility of whole blood adhesion biomarkers in pediatric patients with SCD is limited. We describe our real-world application of the flow adhesion of whole blood to VCAM-1 (FA-WB-VCAM) and flow adhesion of whole blood to P-selectin (FA-WB-Psel) assays in pediatric patients with SCD. Methods: This was a cross sectional analysis of baseline flow adhesion of whole blood to VCAM-1 and flow adhesion of whole blood to P-selectin indices obtained in children (<18 y/o) and young adult patients (18-21 y/o) with SCD at Children's National Hospital in Washington, D.C. between January 2020 and March 2022. Both FA-WB-VCAM and FA-WB-Psel were performed by the Functional Fluidic laboratory in Detroit, MI following overnight shipping at 4-8oC. Change in disease severity included increased VOC pain rate (home, emergency department or hospital management), acute chest syndrome, priapism, and nephropathy. Change in disease modifying therapy (DMT) included new SCD-specific pharmacologic agent or dose increases for effect (not including minor adjustments for weight gain). Statistical analysis included descriptive statistics, Pearson's correlation, and categorical analysis by t-test (GraphPad, v9, 2021). P value <0.05 was statistically significant. Results: We identified 109 unique pediatric patients with FA-WB-VCAM and FA-WB-Psel assays performed as part of the standard of care. Eighty-seven percent were children (N=95), and 13% were young adults (N=14). The median age was 11 years (IQR 7-15 years), with 47% males (N=51) and 53% females (N=58). Sixty-two percent of patients were on hydroxyurea (N=68), 4.5% on crizanlizumab (N=5), 5.5% on voxelotor (N=6), and 3% on Endari (N=3). FA-WB-VCAM was similar in children vs young adults [median (IQR): 242 (142-500) cells/m2 vs. 239 (134.8-324.8) cells/m2, p=0.0856] while FA-WB-Psel was higher in the young adult population [median (IQR): 32 (11-52) cells/m2 vs. 45 (20-76.5) cells/m2, p=0.8681]. Seventy-four percent of patients were HgbSS, 22% Hgb SC, 2% Hgb SBeta Thalassemia Zero, 1% Hgb SBeta Thalassemia Plus, and 1% Hgb SE. Baseline FA-WB-P-Sel and FA-WB-VCAM was performed as part of our standard of care. The most common indication for testing was for baseline evaluation (N=76, 70%), followed by a change in disease severity (N=18, 16%), pre-initiation of DMT/change in DMT (N=5, 4.5%), and a combination of change in disease severity and DMT (N=8, 7%). There were two patients (2%) that had an acute clinical event, including splenic sequestration and crizanlizumab-infusion related VOC. There were FA-WB-Psel values in patients with a change in disease severity vs. without (55.8 vs. 37.28 cells/m2, p=0.036) but no difference in FA-WB-VCAM (299.7 vs. 329.2 cells/m2, p=0.729). Figure 1 represents a comparison of average FA-WB-VCAM (Fig 1A)(362.4±271 vs 216.8±138 cells/m2, p<0.001) and FA-WB-PSEL (Fig 1B)(46.4±49 vs 27.83±24 cells/m2, p=0.0138) values between HgbSS (N=81) and HgbSC (N=24) genotypes. There was an inverse correlation between FA-WB-VCAM-1 and HgbF levels (Pearson's R = 0.483, p<0.001). Conclusions: We established preliminary mean values of FA-WB-Psel and FA-WB-VCAM adhesion indices within all SCD genotypes. FA-WB-VCAM was higher in children while FA-WB-Psel was higher in young adults. Our data represents the expected differences in HgbSS and HgbSC phenotypes with patients with HgbSS reflecting higher adhesion values. There was also an inverse correlation to VCAM-1 and Hgb F levels, consistent with an improvement in RBC health in response to HgbF induction. FA-WB-Psel values were most reflective of a recent change in disease severity and may represent an attractive target to monitor and predict risk of changes in SCD severity. Future studies will measure serially pre vs. post therapeutic intervention and from VOC pain hospitalization to outpatient follow-up clinic visits in pediatric SCD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P-Selectin Blockage Potentiates the Inhibiting Effects of Inflammasome Cytokine Neutralization on Leukocyte Recruitment in an In Vivo Model of Acute Sickle Cell Vaso-Occlusion

The vaso-occlusive (VO) processes that characterize sickle cell disease (SCD) pathophysiology result from a complex interplay between altered blood rheology, inflammatory mechanisms, pan-cellular activation and adhesive interactions between red blood cells, leukocytes (WBCs), platelets and the endothelium. Inhibition of the binding of the P-selectin (CD62P) adhesion molecule, expressed on activated endothelium and platelets, in the form of crizanlizumab monoclonal antibody (mAb) therapy, has demonstrated documented success for preventing VO crisis (VOC) in SCD patients (N Engl J Med (2017) 376(5):429-39), leading to marketing authorization by numerous agencies. In turn, blockade of interleukin (IL)-1β activity, in the form of canakinumab administration, was well tolerated in SCD patients and associated with inflammatory marker reduction in a multicenter phase 2a study (Blood (2022)139(17):2642-52), with in vivo studies suggesting a role for the inflammasome-processed cytokines, IL-1β and IL-18, in amplifying vaso-occlusion in SCD mice (Blood Abstract: (2021) 138 (S1):856). As targeting multiple mechanisms may enhance VOC prevention in SCD, we evaluated the combined effects of P-selectin blockage, together with IL-1β and/or IL-18 neutralization, on WBC recruitment during tumor necrosis factor-α (TNF)-induced VO processes in SCD mice. Townes mice (5-mo old) received (i.p.) either saline, anti-murine IL-1β mAb (01BSUR IgG2a; 200 µg/mouse), and/or anti-murine IL-18 (SK113AE-4 IgG1; 500 µg/mouse), and/or anti-murine CD62P (RB40.34 IgG1, BD; 30 µg/mouse), or an IgG1 antibody (iProt105125 or A110-1, BD). Previous dosing intravital microscopy (IM) protocols determined the optimal concentrations of antibodies in TNF-stimulated Townes mice (doses tested in µg/mouse; 100, 200 anti-IL-1β [N=3; 4]; 250, 500 anti-IL-18, [N=3; 4]; 10-60 anti-CD62P [N=4-7 each]; data not shown). VO-like processes were induced in mice at 30 min after anti-CD62P treatment or 21h post anti-IL1β / anti-IL-18 administrations by TNF injection (0.5μg, i.p.). At 3h after TNF, the cremaster muscles of the anesthetized mice were surgically exposed, and the rolling, adhesion and extravasation of WBCs in 6-10 venules each were observed using IM. As expected, anti-CD62P administration significantly inhibited the rolling of leukocytes along venule walls of TNF-induced SCD mice, but did not significantly affect WBC adhesion (Fig. 1A). In contrast, the administration of anti-IL-1β mAb significantly inhibited both WBC rolling and adhesion, when compared to saline (Fig 1B); likewise, IL-18 neutralization significantly reduced WBC rolling and adhesion at the venule walls, when compared to IgG1 (Fig. 1C). As previously demonstrated, the combined administration of anti-IL-1β and anti-IL-18 did not further reduce TNF-induced WBC rolling or adhesion in the microvasculature, compared to anti-IL-18 alone (Fig. 1D). Importantly, the co-administration of anti-CD62P, together with either anti-IL1β or anti-IL-18, further inhibited WBC rolling (Fig. 1B and C) and amplified the effect of IL-18 neutralization on WBC adhesion (Fig. 1C). Finally, CD62P inhibition in association with the neutralization of both IL1β and IL-18 further reduced WBC rolling in a non-significant manner and incurred a further significant decrease in the adhesion of WBCs (Fig. 1D). As regards WBC extravasation from cremaster venules, when evaluating the effect of CD62P inhibition together with either anti-IL1β or anti-IL-18, the additive effect observed was not significant (P>0.05; N=4-5); however, CD62P inhibition further reduced the extravasation of WBC in mice subjected to both IL1β and IL-18 neutralization (reduced by 71.1±8.3%, P=0.002; N=4-5). In conclusion, P-selectin blockage potentiates the inhibiting effects of IL-1β and IL-18 neutralization on TNF-induced WBC adhesion to the microvasculature of a murine model of SCD. This potentiating effect may be mediated by further inhibition of WBC rolling and tethering to the endothelium, but concurrent inhibition of platelet-mediated cellular interactions by P-selectin inhibition should not be ruled out. Given that WBC recruitment to blood vessel walls is associated with the initiation of VO processes, we suggest that the combined use of biological therapies may boost these approaches’ individual beneficial effects on SCD VOC. Financial support: Novartis Pharma AG. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Assessing the Recovery Process after a Vaso Occlusive Crisis

Introduction: Adults with sickle cell disease (SCD) suffer from vaso-occlusive pain episodes (VOEs) for which they often receive care in infusion clinics (ICs). Typically, 80% of patients treated for VOE are discharged home but it is not clear how long it takes to recover to baseline functioning after an acute visit.1 Recent clinical trials have struggled to identify practical and useful outcomes for novel therapies that decrease the length of VOE or pain during hospitalization. As many patients with VOE are seen and treated in an IC and discharged home, identifying potential endpoints for novel therapies in this site of care are needed. The purpose of this study was to measure time to recovery for two weeks post an IC visit for management of VOE and to identify patient characteristics that predict a return visit for pain management within that time period. Methods: A convenience sample of adults with SCD (≥18YO) were consented to and enrolled into this IRB-approved study during a visit to the IC for VOE. Medical records of all subjects were reviewed to collect data on the number of acute visits, hospitalizations, use of disease-modifying therapies, use of pain medications, baseline laboratory data, and comorbidities. Data was collected on the date VOE pain started, pain scores before and after treatment, and analgesic management. Baseline surveys were collected on the day of the visit and patients were sent follow-up surveys after discharge electronically through REDCap on post-discharge days 2,4,6,8,10,12,14. Participants were asked to rate their pain on a 0-10 Visual Analog Scale. The PROMIS pain interference and Fatigue scales were used to assess pain impact and the Subjective Opioid Withdrawal Scale (SOWS) was used to assess for signs of opioid withdrawal. Return to baseline functioning was estimated by asking participants at each contact post-visit to rate their current level of functioning in activities of daily living on a scale of 0-100, with 100 being their baseline level of function. A similar scale was used to measure the resolution of pain, with the anchor being "back to your usual, non-crisis, level of daily pain." Subjects were encouraged to complete surveys through text message reminders and were compensated with a fifty-dollar gift card if all surveys were completed. Cox proportional hazards modeling was used to examine predictors of time to a return acute care visit within 14 days of the index visit. Results: Table 1 shows the characteristics of the 48 patients enrolled in the study. Despite multiple text/email reminders, few patients completed all the surveys (8/48). Thirty-two out of 48 people completed initial surveys. Of the 17 patients who completed a day 2 or later SOWS score 7 had moderate or severe withdrawal symptoms and of those 3 had a return visit within 14 days while 5/10 of those with mild scores had a return visit. Nineteen out of 48 patients returned for treatment within 14 days. Controlling for pain at discharge, sex, and genotype only the number of acute visits in the six months prior to the index visit was associated with a return visit in 14 days (HR 1.31, 95% CI: 1.13 1.53). The figure shows the probability of a return visit over time by genotype. The median number of visits the entire cohort had in the six months prior to the index visit was 4.5 (IQR: 2,10) however, in those patients that returned for treatment within 14 days the median number of visits in the last six months was 8 (IQR: 5,11). Conclusions: In this study of patients' experience post an acute visit for pain management at an IC, we identified that the number of acute visits in the six months prior to the index visit predicted a return visit within 14 days. It was challenging for patients to complete surveys after their acute visits suggesting that this was not a feasible way to collect these important patient-reported outcomes. With almost 40% of patients returning for an acute care visit within 14 days, decreasing the percentage of patients with return visits may be a potential outcome for trials of novel therapies to treat VOE in the IC setting. 1. Lanzkron S, Carroll CP, Hill P, David M, Paul N, Haywood C, Jr. Impact of a dedicated infusion clinic for acute management of adults with sickle cell pain crisis. Am J Hematol. 2015;90(5):376-380. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

TREATMENT OF SICKLE CELL ANEMIA

Sickle cell disease (SCD) is an inherited disorder prevalent in many areas of the world including Africa, Middle East and parts of India. It is characterized by repetitive episodes of vaso- occlusive (VOC) process, leading to recurrent painful episodes, hemolytic anemia and predisposition to infection. Although VOC is a leading manifestation of SCD, and seen in about 90% of all patients with SCD, however organ specific complications such as acute chest syndrome, stroke, splenic sequestration, and many skeletal complications are also seen. Better understanding of pathophysiology of the disease as well as worldwide interest in the disease has allowed more progress on treatment and prevention of these complications and development of more focused pharmacological therapies. Hemoglobin polymerization is a primary triggering event in the pathophysiology of the disease, resulting in vascular injury and leading to the process of sickling. This usually ignite an intense inflammatory process/ tissue ischemia and increased adhesions. This understanding of the pathophysiology has allowed scientist to develop drugs (three FDA approved within the last few years), that interfere with these processes such as Voxelotor & Hydroxyurea (interfere with polymerization and enhance HbF production), L-glutamine and Omega 3 (interfere with inflammatory process and oxidative stress) and Crizanluzimab and Tinzaparin (works by inhibiting adhesion molecules). Others studies looking at similar and other pathways are ongoing, including drugs that improve adenosine triphosphate (ATP) levels and reducing 2,3-diphosphoglycerate (2,3-DPG) levels. The availability of these therapeutic interventions, will allow patients and physicians the freedom to have patient specific therapeutic interventions including development of combinations protocols. SCD is very complex and this meant that drug with multi-faceted action such as Hydroxyurea will remain with us for some time. Further progress also made in the area of bone marrow transplant (including alternative donor pool) and gene therapy /gene editing, with recently published data is very encouraging. Although the prognosis of patients with SCD has improved, due to introduction of vaccination, use of antibiotics prophylaxis and blood transfusions, however still patients are dying prematurely and further work is needed on understanding disease and its manifestation.

The ektacytometric elongation Index (EI) of erythrocytes, validation of a prognostic, rheological biomarker for patients with sickle cell disease.

Validation of the measurement of erythrocyte deformability as a useful prognostic, rheological biomarker for patients with sickle cell disease (SCD). The degree of reduced deformability was based on the value of the maximum elongation index (EImax ) of the deformability curve of an osmotic gradient ektacytometer. The performance of this technique was analytically and clinically validated by analysing 200normal subjects and 100patients with well-documented thalassemia's and Hb variants in relation to their clinical condition. In this study, we show that EImax is a reproducible parameter with a small inter-individual coefficient of (Biological) variation (CV)=1.6% and a small intra-individual CV=3.5%. We demonstrate that loss of deformability correlates with the clinical condition and the various mutations underlying sickle cell disease and thalassemia. For SCD patients, a strongly reduced EImax with a cut-off =0.360 is a signal for future vaso-occlusive (VOC) events requiring hospitalisation with a specificity=85%, sensitivity=80%, PPV=81% and NPV=84% based on a ROC curve (AUC=0.89). This study validated the clinical utility of EImax as a prognostic marker for future clinical problems in individual high-risk SCD patients. In addition, EImax may help to achieve an adequate personal transfusion policy for an optimal blood flow in anaemic patients with SCD.

Cost analysis of acute care resource utilization among individuals with sickle cell disease in a middle-income country

BackgroundThe costs associated with the treatment of sickle cell disease (SCD) are understudied in low and middle-income countries (LMIC). We evaluated the cost of treating SCD-related acute complications and the potential cost-savings of hydroxyurea in a specialized hematology center in Brazil.MethodsThe costs (US dollars) of emergency department (ED) and hospitalizations from SCD-related complications between 01.01.2018 and 06.30.2018 were ascertained using absorption and micro-costing approaches. The reasons for acute hospital visits were grouped as: 1) vaso-occlusive (VOC) pain, 2) infection, 3) anemia exacerbation, and 4) chronic organ damage complications. Hydroxyurea adherence was estimated by medication possession ratio (MPR) during the study period.ResultsIn total, 1144 patients, median age 17 years (range 0–70), 903 (78.9%) with HbSS/HbSβ0-thalassemia, 441 (38.5%) prescribed hydroxyurea, visited the ED, of whom 381 (33%) were admitted. VOC accounted for 64% of all ED visits and 60% of all admissions. Anemia exacerbation was the most expensive reason for ED visit ($321.87/visit), while chronic organ damage carried the highest admission cost ($2176.40/visit). Compared with other genotypes, individuals with HbSS/HbSβ0-thalassemia were admitted more often (79% versus 21%, p < 0.0001), and their admission costs were higher ($1677.18 versus $1224.47/visit, p = 0.0001). Antibiotics and analgesics accounted for 43% and 42% of the total ED costs, respectively, while housing accounted for 46% of the total admission costs. Costs of ED visits not resulting in admissions were lower among HbSS/HbSβ0-thalassemia individuals with hydroxyurea MPR ≥65% compared with visits by patients with MPR <65% ($98.16/visit versus $182.46/visit, p = 0.0007). No difference in admission costs were observed relative to hydroxyurea use.DiscussionIn a LMIC hematology-specialized center, VOCs accounted for most acute visits from patients with SCD, but costs were highest due to anemia exacerbation. Analgesics, antibiotics, and housing drove most expenses. Hydroxyurea may reduce ED costs among individuals with HbSS/HbSβ0-thalassemia but is dependent on adherence level.

Serum Visfatin Level in Sickle/β Thalassemia in Correlation with Frequency of Vaso Occlusion Crises

Background: Hemoglobinopathies are the most common heritable disorders of erythrocytes, with sickle cell diseases (SCDs) and thalassemia being the most common. SCDs are characterized by the presence of sickle hemoglobin within red blood cell (RBC) as a result of point mutation (β6glu→val). SCDs include sickle cell anemia, hemoglobin C disease (HbSC), and sickle/β thalassemia. The latter is caused by coinheritance of two different mutations in β globin gene, one from each parent: one for sickle hemoglobin and the other for β thalassemia. Vaso occlusion is a key feature of this disease that occurs due to a series of interactions leading to painful crisis. Visfatin is a pro-inflammatory adipocytokine that contributes to vaso occlusive crises (VOC) through its role in the inflammatory process. Visfatin can directly promote endothelial dysfunction and stimulates vascular smooth muscle cells proliferation. Objectives: The primary aim of this study was to assess serum visfatin level in sickle/β thalassemia patients and evaluate the possible association between serum visfatin level in sickle/β thalassemia patients and the frequency of VOC, serum ferritin level, complete blood count (CBC) and high-performance liquid chromatography (HPLC) parameters. The secondary aim of this study was to compare the findings in two centers (Al-Karama Teaching Hospital, in Baghdad and Babylon Teaching Hospital for Maternity and Children, in Babylon). Materials and Methods: This was a cross-sectional study conducted from December 2018 until the end of August 2019 and included 77 individuals. Among them, 57 were sickle/β thalassemia patients (Group I): 28 from Al-Karama Teaching Hospital (Group IA) and 29 from Babylon Teaching Hospital for Maternity and Children (Group IB). The remaining 20 individuals act as a healthy control group (Group II). Clinical data were gathered, with collection of 5 mL of peripheral blood in order to examine CBC, C-reactive protein (CRP), serum ferritin, and serum visfatin. Results: Mean age was (13.14 ± 5.40) years. Males formed (59.74%), whereas females formed the remaining (40.26%). The mean number of annual frequency of VOC events was (3.05 ± 0.95) with no significant difference between the two subgroups. White blood cells count was significantly higher among cases compared to controls (P = 0.004). Hemoglobin was significantly lower among cases compared to controls (P &lt; 0.001). Also, hemoglobin was significantly higher in cases of group IA compared to group IB with P = 0.022. Similarly, hemoglobin A2 (HbA2) was significantly higher in cases of group IA compared to group IB with P = 0.013. Serum ferritin was markedly higher among cases compared to controls with P &lt; 0.001. Serum visfatin was significantly higher among cases compared to controls with P &lt; 0.001. No significant difference was observed between the two subgroups regarding serum ferritin and visfatin.There was positive correlation between visfatin and annual frequency of VOC (r = 0.821, P &lt; 0.001), moderate negative correlation between visfatin and HbA (r = –0.46, P &lt; 0.001), moderate positive correlation between visfatin and HbS (r = 0.54 and P &lt; 0.001), and strong positive correlation between visfatin and ferritin among cases group (r = 0.60 and P &lt; 0.001) but not in control group. Conclusions: Serum visfatin level is significantly higher among patients with sickle/β thalassemia compared to healthy individuals with positive correlation exists between visfatin level and the annual frequency of VOC, ferritin level, and HbS; negative correlation with HbA, among those patients with sickle/β thalassemia. Hemoglobin level and HbA2 percentage significantly higher among Al-Karama hospital patients compared with those in Babylon hospital.

A Resident-Led Quality Improvement Initiative to Optimize Care for Children and Young Adults with Sickle Cell Disease Vaso-Occlusive Pain with Intranasal Fentanyl in the Emergency Department

Background:Sickle cell disease (SCD) is an inherited blood condition that predisposes affected patients to severe vaso-occlusive (VOC) pain events. The NHLBI (last revised in 2014) and ASH guidelines (last revised 2020) recommend a door-to-first dose should be within 60 minutes vs. 30 minutes from registration, and reassessment and re-administration of medications should be every 30 minutes. Non-IV routes of administration, i.e. intranasal (IN) can facilitate rapid analgesic treatment. Recent studies have shown IN Fentanyl as an effective pharmacological strategy to treat vaso-occlusive pain episodes.Methods:This resident-led Quality Improvement specific aim was to reduce the meantime from check-in to first analgesic delivery to SCD patients with VOC presenting to the Pediatric Emergency Department (PED) by at least 20% during 12 months and to improve the overall care of SCD VOC in accordance to best practices.PDSA cycle methodology was utilized to identify root causes, countermeasures, and key drivers (Figure 1A). We implemented a SCD VOC clinical pathway for PED providers to utilize our enhanced and updated version of an electronic order set named “PED Sickle Cell Crisis Power Plan” that includes IN Fentanyl as first-line therapy for SCD VOC. IRB approval was obtained.PED nursing staff was trained to administer IN Fentanyl with a nasal mucosa atomizer. Exclusion criteria of patients with SCD with other ICD-10 diagnosis codes, i.e pain not associated with VOC. The main indicators were assessment-to-dose time; registration-to-discharge time; first dose-to-discharge time, and rate of VOC admissions. Data was collected by discrete-time stamps and statistically analyzed using Excel 365. The analysis compared baseline with initial PDSA cycles from December 2019 to February 2020, and from September 2020 to March 2021.Results:From September 2020 to February 2021, a total of 54 encounters for SCD VOC qualified clinically to receive IN Fentanyl. A total of 49 of these encounters received this medication, while 5 refused its administration.Patient demographics: Male-to-female ratio was 53% and 47%, respectively. The majority of the patients seen were adolescents (63% with ages between 12-21 years). African-American participants represented 88% and non-Hispanics 84%.After our interventions, 94% of encounters have documented pain reassessment in their electronic medical records. IN Fentanyl was first introduced in the PED in September 2020, and became the first medication to be administered in 94% of the encounters. The average length of stay in the PED was 269 minutes (4 hrs. with 29 minutes).The SCD VOC Clinical Pathway was used in 90% of the encounters and the SCD VOC Power Plan was used in 80% of them. From the total of encounters, 59% required admission to the floor for further pain management strategies.As shown in the control chart (Figure 1.B), the meantime from check-in to first analgesic delivery to patients with VOC presenting to the PED was reduced to under 40 minutes by February 2021.After the implementation of IN Fentanyl, there is an overall improvement of the waiting time for administration of medications of more than 70 minutes (from 138 min down to 67 minutes). Most importantly, 37% (18/49) of SCD VOC events were discharged after successful VOC pain management in the PED.Discussion:PED staff surveys demonstrated a lack of familiarity with current VOC guidelines and a standardized pathway. Medication refusal of IN Fentanyl was found to be related mostly to patient preference, poor knowledge about side effects, and parental fear for oversedation before our interventions.Conclusion:A multi-disciplinary team was formed to assist health care providers in the ED to deliver optimal care to patients with SCD based on the current evidence-based SCD VOC clinical pathway and efficient pharmacological intervention with IN Fentanyl.Standardized procedures to treat and reassess pain for SCD VOC patients in the PED resulted in check-in to first-dose time reduction by 47%. There was a consistent improvement in Length of Stay in the PED, which decreased more than 60 minutes (from 5 hrs. 21 min. to 4 hrs. 29 min).There is a significant improvement of quality in the care of VOC including 1. Pain scoring system. 2. Documented pain reassessment. 3. Use of a multidisciplinary reviewed protocol that includes PED SCD VOC clinical pathway, and an updated order set power plan with IN Fentanyl as the first line. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Quality of Life in Children, Adolescents and Young Adults with Sickle Cell Disease and Their Caregivers during Standard of Care and after Bone Marrow Transplantation: A Single Center Report

▪BackgroundIn spite of the improvements in clinical care of children with Sickle Cell Disease (SCD), painful vaso-occlusive (VOC) crises, recurrent admissions and long hospital stays contribute to the disruption of the social and school life of children and adolescents with SCD causing a poor QoL.Limited information is available regarding QoL of children, adolescents and young adults with SCD and their caregivers during standard of care and after bone marrow transplantation in Italy even though Italian patients participating in international meetings or global surveys highlighted the importance to improve QoL (Strunk C. BMC Proc. 2020, Osunkwo I. Am J Hematol. 2021). Moreover, no mention is given to QoL in the current AIEOP Recommendations for the Management of Children with SCD in Italy. The availability of new treatment options for SCD highlights the need to improve QoL evaluation before and after treatments.Our Center decided, therefore, to include QoL evaluation as part of comprehensive care for patients with SCD. This study has the following aims: to describe the QoL of children, adolescents and young adults with SCD undergoing standard care or after disease curative treatments (bone marrow transplantation) and the QoL of their caregivers; to evaluate the correlation of QoL with clinical-haematological and therapeutic variables.MethodsHealth Related QoL was examined with the Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaires in Italian: Parent Proxy Profile-49 v2.0, Pediatric Profile-49 v2.0 and 57 Profile v2.1, exploring 8 domains: Pain, Fatigue, Anxiety, Depression, Physical Abilities, Peer Relations, Sleep Disorders, Pain Interference. An English version was available for English speaking parents.Patients and caregivers accessing the SCD Clinic starting May 2021 were given the paper version of the questionnaires; due to the COVID pandemic and the limited access to the SCD Outpatient Clinic, a link to a Google online version of the questionnaires was provided to all teenagers and young adults, through their mobile devices. .PROMIS Scores were standardized through the Health Measures Scoring Service (healthmeasures.net). For the descriptive analysis, the T-score was obtained, for each patient and for each PROMIS domain (symptom or function), classifying impairment in each domain as normal, mild, moderate, or severe. The Student T Test for comparisons of the means among samples and the Wilcoxon Test for the sum of ranks were used in the statistical analysis of normal and non-normal continuous variables. For the correlation analysis between continuous variables of which at least one is not normal, the Spearman Correlation Test was used. The values with p<0.05 were considered statistically significant.ResultsAll patients and parents approached accepted to perform the questionnaire. The study involved 18 caregivers and 50 patients (25% F, mean age 16.4 years, 74% HbSS, 76% from Africa): 41 undergoing standard care (7 no therapy, 34 Hydroxyurea or chronic transfusion) and 9 who received HSCT. 37 patients (74%) and 8 parents (44%) completed the online Google version of the questionnaire. The standard of care patients displayed mild to severe symptoms in various domains (Figure 1A); in the transplant population there was impairment in QoL, with less severe impairment in most of the domains, especially in the pain domains, than what was in the standard of care group. (Figure 1B).Anxiety levels and depressive symptoms were greatest between the ages of 14-26, compared to younger ages (p 0.018).Parents do not have the same perception of the disease as their children: they appeared to overestimate the domain of pain and fatigue and underestimate anxiety and depression (p <0.001). Sleep quality was impaired in both affected and HSCT patients.The number of hospital admissions in the previous year correlated with worse QoL (p 0.04), while the number of painful VOC showed a tendency towards significance (p 0.07); there was no difference with the other domains. Updated results will be presented.ConclusionsOur data show the feasibility of evaluating QoL during routine visits and also remotely. Impairment of QoL is already present in a subgroup of young patients. Even after HSCT, QoL is not optimal but personal, social, and economic reasons need to be taken into account to adequately interpret the results. Longitudinal assessment to look at QoL will be important. [Display omitted] DisclosuresBiffi: BlueBirdBio: Consultancy, Other: Advisory Board. Colombatti: Global Blood Therapeutics: Consultancy; BlueBirdBio: Consultancy; NovoNordisk: Consultancy; Novartis: Consultancy; Forma Therapeutics: Consultancy; Addmedica: Consultancy; Global Blood Therapeutics: Research Funding; BlueBirdBio: Research Funding.

Assessment of Health-Related Quality of Life in Adults Hospitalized with Sickle Cell Disease Vaso-Occlusive Crisis

Background: Sickle cell disease (SCD) is a chronic condition characterized by painful vaso-occlusive (VOC) episodes which lead to poor health-related quality of life (HRQL) and premature mortality. As curative treatment with hematopoietic stem cell transplant is only an option for a minority of adult patients, current treatments are palliative with focus on pain management. Clinically, pain assessment is commonly performed by the Numeric Rating Scale (NRS), where patients rate the intensity of pain from 0 (no pain)-10 (worst imaginable pain). However, the incorporation of HRQL through the use of newer patient-reported outcome measures (PROs) into the assessment of pain and the care of patients with SCD is evolving. As these newer measures were developed in ambulatory populations, to date, they have not been studied among adults with SCD hospitalized for painful VOC.Objective: To describe the VOC pain experience and its effect on HRQL in hospitalized adults with SCD, using two PRO measures, the Patient-Reported Outcomes Measurement Information system (PROMIS) Global Health and the Adult Sickle Cell Quality of Life Measurement System (ASCQ-Me).Methods: Adults with SCD hospitalized at a US-based academic medical center with VOC were eligible. Following study enrollment at hospital admission (T1), participants completed the ASCQ-Me Pain Episode assessment, which yields a Frequency score (range 0-11) and Severity score (range 0-22), where higher scores reflect worse disease over the prior year. Participants also complete PROMIS Global and ASCQ-Me at T1. Seven days after hospital discharge (T2), participants again completed PROMIS Global and ASCQ-Me questionnaires. These measures yield scores in domains of global physical and mental health, and SCD-related domains of emotional, social functioning, pain, stiffness, and sleep impact, respectfully. Standardized domain scores have a mean of 50 (SD=10) where higher scores indicate better functioning. Changes of 3 points (0.3 SD) are considered clinically meaningful. We calculated means and standard deviations for the NRS and domain scores at T1 and T2. One sample t-tests were used to compare domain change scores from Admission to Discharge+7, restricted to respondents with complete follow-up.Results: We report preliminary results from our larger inception cohort. To date, 28 of 29 eligible patients consented and completed T1 assessments (97%). 18 also completed T2 assessments. Of the 10 participants who did not complete T2 assessments, 50% were readmitted within 1 week and 20% within one month; the remainder (n=3) were non-respondents at T2.The mean age was 30.6 years (SD 9.9) with 57% females and 71% self-identified as black, non-Hispanic. The remainder was Hispanic. The most common genotype was HbSS (57%). T1 mean ASCQ-Me Pain Episode Frequency score was 9 (SD 2.2, range 4-11) and Severity score was 18 (SD 3.1, range 8-22), reflecting recurrent and prolonged painful VOC episodes over the prior year.At hospital admission, 66% of patients had 4 or more pain crises in the last 12 months. The mean score for the most severe pain during the last pain attack was 8.8 (SD = 1.4) on a scale from 0-10. The most recent pain crisis for 66% of patients lasted at least 1 week; 26% reported crisis lasting longer than 2 weeks.The table presents mean domain scores at each assessment period and the change scores. All domain scores on ASCQ-Me and PROMIS Global were well below population norms. There was statistically significant and clinically meaningful improvement in pain intensity and the domains of physical health, emotional impact and sleep impact by 7 days after discharge (p<0.05).Conclusions: Administering both general and disease-specific PROs at the point-of-care is feasible and informative. Among this cohort of hospitalized patients with VOC, baseline ASCQ-Me Pain Episode scores reflect recurrent and prolonged painful VOC episodes over the prior year. All ASCQ-Me domain and PROMIS Global scores were well below population norms, indicating substantial suffering from the multidimensional impact of the VOC pain experience both upon admission and following discharge. Despite the intensity of the patients' condition, we demonstrate successful enrollment (97%) and data collection on admission. 64% data completeness at T2 indicates some degree of non-ignorable missing data, which will be addressed in final data analysis. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Polycythemia Vera Complicated by Portal Vein Thrombosis and Budd-Chiari Syndrome:

Polycythemia vera is a medical condition characterized by raised hematocrit. Owing to increased viscosity, the blood flow in the vessels become sluggish leading to the clinical features of polycythemia such as headache, blurring of vision, red skin, dizziness, raised blood pressure, itching and more serious medical events like vaso occlusion, thrombosis and strokes. In this case report, polycythemia vera presenting unusually with heamatemesis, melena and abdominal distension. Physical examination of this case revealed massive ascites with dilated veins around the umbilicus. The diagnosis of polycythemia vera complicated by Budd Chiari Syndrome and Portal Vein Thrombosis was made. Patients with polycythemia vera are at risk of vaso occlusive sequelea like portal vein thrombosis and Budd chiari syndrome

Evaluation of immunological role of Interferon gamma, Interleukin-10 and CD4+ T lymphocytes in pediatric patients with sickle cell disease

Sickle cell disease (SCD) is a chronic inflammatory disease associated with increased levels of multiple cytokines as interferon gamma (IFN-γ) during vaso-occlusive (VOC) crisis and steady state. Therefore, we aimed to explore theimmunological role of serum IFN-γ, interleukin-10 (IL-10) and CD4+ T lymphocytes in children with SCD at steady state and VOC. This study was conducted on 30 children with SCD (15 at steady state and 15 in VOC) and 30 healthy children as controls. Detailed history, complete physical, clinical examination and laboratory investigations as: complete blood count, serum ferritin, IFN-γ, IL-10 and CD4+ T lymphocytes for all patients were recorded. Results: Significant increase in serum IFN-γ in patients with SCD during VOC compared with patients at steady state and controls (P<0.001). Significant increase in serum IL-10 in patients with SCD at steady state compared with those during VOC and controls (P=0.008 and P=0.04 respectively). CD4 +T lymphocyte decreased in patients with SCD during VOC compared with those at steady state and controls (P<0.001). There was a significant positive correlation between serum IFN-ɣ and number of crisis per year (r=0.648, P=0.0001). Serum IFN-γ was increased in patients with history of frequent crisis per year (P=0.001) and decreased in patients under hydroxyurea therapy (P<0.001). IFN-γ was increased in SCD patients. Increased IFN-γ production in SCD suggesting that functionally activated natural killer cells reflecting a host immunological mechanism leading to antigen antibody activation in SCD. Serum IL-10 increased in SCD patients at steady state. CD4 +T lymphocyte decreased in patients during VOC.

PRO51 Cost Effectiveness of Crizanlizumab Compared to Hydroxyurea for Minimizing the Frequency of Vaso-Occlusive (VOC) PAIN Episodes in Patients with Sickle CELL Disease SCD from a Payer Perspective

PRO51 Cost Effectiveness of Crizanlizumab Compared to Hydroxyurea for Minimizing the Frequency of Vaso-Occlusive (VOC) PAIN Episodes in Patients with Sickle CELL Disease SCD from a Payer Perspective