Vaso-occlusive Crisis In Sickle Cell Disease Research Articles

Cost-effectiveness of l-glutamine versus crizanlizumab for adults with sickle cell disease: model focused on reducing pain episode costs from Qatar's healthcare perspective.

Treatment options for preventing vaso-occlusive crises among sickle cell disease patients are on the rise, especially if hydroxyurea treatment has failed. This economic analysis is conducted to assess the comparative clinical effectiveness, safety, and acquisition cost of l-glutamine and crizanlizumab for older adolescents and adults (⩾16 years old) with sickle cell disease in Qatar, with an emphasis on treatment costs and acute pain crises. We conduct a decision-tree model, where we compare the clinical and economic outcomes of two novel Food and drug administration (FDA)-approved medications which are available in Qatar; l-glutamine and crizanlizumab over a time horizon of 1 year in a hypothetical cohort of adult sickle cell disease patients from a Qatar healthcare perspective. The main outcome is incremental cost per sickle cell disease-related acute pain crises averted. Model clinical parameters were derived from individual drug randomized trials, published literature, whereas cost parameters from Qatar healthcare payer system (2020-2021). A sensitivity analysis was carried out, and the study results were robust around model inputs. Costs were converted to 2020 US dollars. Study results showed that both treatment modalities' costs were the main driver of this analysis, with an average annual cost of the treatments per patient being $189,014 for crizanlizumab (5 mg/kg), $143,798 for crizanlizumab (2.5 mg/kg), and $74,323 for l-glutamine. The probability of no first-time sickle cell disease-related vaso-occlusive crises averted was 0.001/year for glutamine, 0.26/year for crizanlizumab (5 mg/kg), and 0.34/year for crizanlizumab (2.5 mg/kg). Lower dose crizanlizumab (2.5 mg/kg) dominated the higher one (5 mg/kg). The incremental cost-effectiveness ratio of crizanlizumab (2.5 mg/kg), when compared to l-glutamine was $81,265 per sickle cell disease-related vaso-occlusive crises averted. When comparing crizanlizumab (5 mg/kg) and l-glutamine, crizanlizumab (5 mg/kg) showed higher efficacy, yet the crizanlizumab incremental cost-effectiveness ratio was at $459,620 than l-glutamine. Crizanlizumab (2.5 mg/kg) may be a cost-effective intervention, yet it is not the approved dose for preventing vaso-occlusive crises in adolescents and adults with sickle cell disease. Crizanlizumab (5 mg/kg) was more cost-effective than the approved l-glutamine per sickle cell disease vaso-occlusive crisis prevented. Of note, we primarily focused on modeling acute vaso-occlusive pain, which limited our ability to consider other key outcomes in sickle cell disease.

Identifying Inflammatory and Immune Markers Associated with Vasoocclusive Crisis in Patients with Sickle Cell Disease

Background: Sickle cell disease (SCD) is an inherited disorder that can cause a range of clinical complications, featured by unpredictable and recurrent acute painful episodes associated with vasoocclusive crises (VOCs). Individuals with SCD experience frequent VOCs and require high doses of opioids for pain control. Thus far, studies on biomarkers associated with VOCs in SCD are very limited and the known markers are hardly considered as critical end points in studying VOCs in SCD. This study aimed to comprehensively analyze immune and inflammatory characteristics of patients with SCD to understand the disease-specific pathogenesis and develop targeted diagnostic and therapeutic strategies related to VOCs. Methods: The study cohort consisted of 40 patients with SCD aged 14-73 years (23 female, 58%), recruited for an ongoing clinical trial (ClinicalTrials.gov Identifier: NCT05045820). Twenty-three ethnicity-, age- and gender-matched pain-free participants were also enrolled as healthy controls (HCs) (Table 1). Multiplex immunoassays were used to profile 80 inflammatory cytokines/chemokines/growth factors and 18 autoantibodies in plasma samples from patients with SCD and the matched HCs. Peripheral blood mononuclear cells were used to profile immune cells. Statistical analysis was performed using GraphPad Prism with Mann-Whitney test, χ 2 test, and Spearman's correlation. P < 0.05 was considered statistically significant. Results: Patients with SCD exhibited significantly higher plasma levels of 34 analytes, including 12 pro-inflammatory/anti-inflammatory cytokines (IFN-γ, IL-1α, IL-2, IL-8, IL-9, IL-18, TNF-α, TNF-β, IL-4, IL-5, IL-6, and TSLP), 10 chemokines (CCL21, CCL23, Eotaxin-2, Gal-3, GRO-α, IP-10, MCP-2, MIP-1α, MIP-1β, and MIP-3α), 8 growth factors (bNGF, G-CSF, GM-CSF, HGF, IL-7, IL-20, IL-34, and LIF), 2 effectors (granzymes A and B), and 2 soluble receptors (PTX3, TREM-1). Higher activation levels of B cells, CD4 T cells, CD8 T cells, and MAIT cells were seen in patients with SCD. Autoantibody profiles were also altered in patients with SCD, with elevated levels of antibodies against SSA/Ro60, Ribosomal P, Myeloperoxidase, and PM/Scl-100. Levels of cytokines/chemokines/growth factors were correlated with time interval between blood draw and occurrence of VOCs. Four soluble factors (Eotaxin-2, GRO-α, IL-6, and LIF) were positively associated with time interval after VOCs, while two factors (IL-18 and granzyme A) showed negative associations with time interval, suggesting that the altered inflammatory mediators were associated with the occurrence of VOC events. Conclusion: Our results provide novel and comprehensive understanding of the immune and inflammatory dysregulation in patients with SCD and their relationship with occurrence of VOCs, offering insights into potential SCD-specific biomarkers for further investigation.

Distinguishing the Variances in Patient Care between Hematologists and Hospitalists for Individuals with Sickle Cell Disease Hospitalized Due to Vaso-Occlusive Crisis

Introduction: Sickle cell disease (SCD) is a chronic condition characterized by multiple vaso-occlusive complications. Patients often experience recurrent, severe pain that can be disabling and necessitate opioid treatment. Hospitalization for vaso-occlusive crisis (VOC) is a common occurrence for individuals with SCD. In recent times, the care of hospitalized SCD patients has increasingly shifted from adult hematology specialists to hospitalists. At our institution, we are yet to make this transition, with hospitalists rarely taking over the care of inpatients with SCD. Initially, recommendations to the hospitalist service were provided through informal opinions or formal consultations when requested. Hospitalists have demonstrated efficient inpatient management; however, some may have knowledge gaps and biases that can influence their interactions with SCD patients. To gain a better understanding of the differences in care practices between hematologists and hospitalists and to identify potential areas for improvement in the care of SCD patients, we conducted a formal comparison of their approaches. Methods: We performed a single-institution, retrospective review of patients with SCD hospitalized for VOC between January 1, 2014, and September 31, 2022. Results: Table 1 portrays the significant results. Conclusion: We observed significant distinctions in the care provided by hematologists and hospitalists to patients admitted for VOC in SCD. Hematologists tended to transfer fewer patients to the intensive care unit compared to hospitalists. On the other hand, hospitalists more frequently sought consultations from the pain service than hematologists. Interestingly, patients under the care of hematologists received longer hours of patient-controlled analgesia for pain management. Additionally, patients managed by hematologists exhibited higher hemoglobin levels at the time of discharge when compared to those treated by hospitalists. Notably, only 39.8% of patients had a formal hematology consult requested during their hospital stay, indicating a potential need for better collaboration between hematologists and hospitalists. This study emphasizes the importance of enhancing cooperation between these two specialties to elevate the quality of care for patients hospitalized with VOC.

Impact of IV Contrast Exposure during Vaso-Occlusive Crisis on Sickle Cell Disease (SCD)

Background Sickle cell disease (SCD) affects more than 100.000 Americans, that can experience vaso-occlusive crisis (VOC). It can present with signs and symptoms that overlap with pulmonary embolism (PE), e.g. pleuritic chest pain, shortness of breath, hypoxia or sinus tachycardia. Hence, it is not uncommon that patients with SCD are exposed routinely to IV contrast (IV-cx) to rule out PE with every VOC recurrence. We hypothesized that exposure to IV-cx increases blood viscosity temporarily and therefore exacerbates RBC sickling with worsening oxidative stress and VOC. Methods This was a retrospective chart review study, where we analyzed all encounters for VOC at the ED of MedStar Washington Hospital Center in between 2021-2022. We excluded those not admitted to the inpatient service and discharged from the ED, those not exposed to IV-cx to rule out PE and those without 3 other VOC admission without IV-cx exposure to compare as control. Herein, will discuss 33 patients' results. A total of 132 admissions were analyzed for 33 patients (1 with IV-cx + 3 regular admissions without IV-cx exposure), each patient serving as their own controls, acknowledging the heterogeneity of SCD VOC. For control admissions we looked at the 3 closest in time from the admission with IV-cx exposure. Severity of each VOC (with or without IV-cx exposure) was determined by the composite of lab results, clinical and treatment data for each admission, creating our own scoring system “VOC Severity Index” (Table 1). Scores were given from 0-4, >3 representing end-organ damage. Maximum score was 39. Likewise, we collected data on new PE, new DVT, therapeutic anticoagulation, basic demographics and SCD genotype not recorded in the severity index score. Results were analyzed through Graphpad Prism software. This study received IRB approval from MedStar Health Research Institute. Results 54.5% (18/33) were female, mean age was 25 (18-45), 86% were HbSS, and 100% were Black. We compared the severity index of the admission with IV-cx exposure against the mean severity index score of the 3 other VOC admissions without IV-cx exposure. VOC severity index was higher for the admission related with IV-cx exposure in 90% (30/33) patients (p= 0.0004***) (Fig 1A). CT chest with PE protocol was negative in 100% (33/33). No DVT was reported in the totality of 132 encounters. AKI was noted in 15.0% (5/33) of patients when IV-cx was used, vs 7.0% (7/99) when no IV-cx was used. Length of stay was not significantly different (p=0.436) (mean IV-cx stay: 8 days vs. mean non-IV cx stay: 7.8 days) . RBCs exchange transfusion happened in 10% of total encounters analyzed (14/132), being 42% (6/14) of the situations when IV-cx was used. Acute chest syndrome (ACS) developed in 19 admissions of 10 patients (6 female/4 male). Interestingly, 42% (8/19) of ACS happened when IV contrast had been used, and only 7/19 were managed with RBC exchange transfusion. In 1 encounter with IV-cx exposure, patient developed acute chest syndrome and ARDS requiring ECMO, (end-organ damage not reflected in our severity index score). VOC Severity Index means were similar in female vs male patients. Likewise, gender was not related to higher frequency of AKI, exchange transfusion or length of stay. Conclusions IV-cx exposure is associated with worsening in the severity of the VOC, manifested as more severe pain, and need of escalation of treatments, albeit with no increase in the LOS. Iv-cx should be avoided in SCD patients in VOC, when possible. PE should remain low in the differential in the setting of VOC, despite overlapping symptoms. Our findings are limited in the nature of retrospective chart review and small number of patients. Further analysis with prospective larger cohorts are needed for a better understanding on the role of IV-cx exposure, sickle cell renal disease and VOC.

CTH1/TH2 repolarization in induction of immune tolerance to non-steroidal anti-inflammatory drugs during the management of sickle cell disease vaso-occlusive crisis

Respiratory manifestations related to the intake of non-steroidal anti-inflammatory drugs (NSAIDs) during the treatment of the painful vaso-occlusive crisis of sickle cell disease are either a type I hypersensitivity mechanism of the Gell and Coombs classification, or a pharmacological mechanism of NSAIDs. The use of NSAIDs is essential in the Abidjan school because of the absence of therapeutic alternatives in the management of the inflammatory crisis of this disease. The induction of tolerance to NSAIDs initiated by the authors has had clear clinical success. The basic biological reasons for this tolerance were evaluated in this study. A group of 11 sickle cell patients aged 12 to 39 years in whom post-NSAID respiratory manifestations disappeared for at least 6 months following a short tolerance induction protocol with ibuprofen, was assayed by ELISA for TNFα, INFg (Th1 cytokines), IL-4 (Th2 cytokine), IL-10, TGF-β (immunosuppressive cytokines) and total IgE, before induction or pre-induction (D-1) and at day one (D1), D2- 3, one month (M1), and M6 after induction. A repolarization of the Th1/Th2 balance was noted during the post induction period. The high concentration of IL-4 observed at D-1 gradually decreased in favor of the cytokines TNFα, INFg. The decrease in cytokine IL-4 with the level of total IgE was accompanied by the increase of IL-10 and TGF-β demonstrating the regulatory role of these cytokines in the control of allergic diseases. In conclusion, the induction of immuno-tolerance to NSAIDs through a short protocol is well supported by immune regulation. The medium-term effects are real, unlike the results of allergen desensitization or specific immunotherapy. However, this protocol could be used in certain circumstances such as in the case of intolerance to trimethoprim-sulfamethoxazole, used as the treatment of choice for the prevention of opportunistic diseases in people living with human immunodeficiency virus.

Emerging Therapies for the Management of Pain and Vaso-Occlusive Crises in Patients With Sickle Cell Disease: A Systematic Review of Randomized Controlled Trials.

Sickle cell disease (SCD) is an inherited disorder that impairs red blood cells (RBCs) and disrupts the delivery of oxygen to tissues. There is currently no cure. Symptoms can appear as early as six months of age and include anemia, acute episodes of pain, swelling, infections, delayed growth, and vision problems. A growing number of therapies are being investigated for reducing these episodes of pain, also known as vaso-occlusive crises (VOCs). The research literature evidence, however, currently includes far more approaches that have not shown superiority versus placebo than ones that have been proven effective. The purpose of this systematic review is to evaluate the body of randomized controlled trials (RCTs) to determine the quality of support for and against the use of a variety of current and emerging therapies for treading SCD VOCs. Several important new papers have emerged since previous systematic reviews with similar objectives were published. This review was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and focused on PubMed exclusively. Only RCTs were sought, and no other filters, except for a five-year historical timeline cut-off, were used. Of the 46 publications that were returned in response to the query, 18 were ultimately accepted as meeting the pre-established inclusion criteria. The Cochrane risk-of-bias tool was utilized as a quality assessment measure, and the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) framework was used to assess the certainty of the evidence. Among the included publications, five out of 18 featured positive results with superiority and statistical significance versus placebo for either reduction in pain score or number/duration of VOCs. The approaches featured therapies ranging from de novo molecules to currently available drugs approved for other indications to naturally occurring metabolites such as amino acids and vitamins. A single therapy, arginine, was supported for both clinical endpoints: pain score reduction and shortened VOC duration. Currently, two therapies are approved by the United States Food and Drug Administration (FDA) and are commercially available (crizanlizumab, ADAKVEO and L-glutamine, Endari). All other therapies are investigational only in nature. Several studies included measurement of biomarker endpoints as well as clinical outcomes. Generally, beneficial outcomes related to improving biomarker levels did not also translate into statistically significant reduction of pain scores or number/duration of VOCs. While measuring biomarkers may contribute to the understanding of pathophysiology, it does not appear to directly offer predictive value toward treatment success clinically. It can be concluded that there exists a specific opportunity to design, fund, and execute investigations that both compare emerging and existing therapies versus one another and compare combinational therapies versus placebo.

Home Management and Prevention of Vaso-Occlusive Crisis of Sickle Cell Disease Knowledge among Nursing Students

Sickle cell crisis, or vaso-occlusive crisis, is a painful complication of sickle cell disease that occurs in adolescents and adults, which is considered the most common reason these patients seek medical attention in an emergency room. Despite the high prevalence of sickle cell disease in the Jazan region, Saudi Arabia, there hasn’t been a study looking at nursing students’ knowledge about sickle cell disease and home management and prevention of vaso-occlusive crises associated with sickle cell disease. Most of those focused on the investigation of the public, parents of children with sickle cell disease, school students, and patients with sickle cell disease. Therefore, this study aims to assess the level of knowledge about home management and prevention of vaso-occlusive crises among Saudi nursing students at the Aldayer University College, Jazan University, Kingdom of Saudi Arabia. A descriptive cross-sectional design was used in this study that involved 167 nursing students. The study revealed that Aldayer nursing students had adequate knowledge about the home management and prevention of sickle cell disease vaso-occlusive crises.

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

Increased Susceptibility for Adverse Reactions to Ultrasound Enhancing Agents in Sickle Cell Disease

Pain-related adverse events (AEs) to ultrasound enhancing agents (UEAs) have been reported in patients with sickle cell disease (SCD). The aims of this study were to characterize the scope of these AEs in the SCD population and to investigate potential mechanisms on the basis of pathways involved in SCD vaso-occlusive crisis (VOC) and pain. The prevalence and classification of AEs were analyzed from two clinical trials in which high-dose Definity infusions were used in patients with SCD (n=55) or matched control subjects (n=43) to study muscle or myocardial microvascular perfusion. Because complement (C') activation can trigger VOC in SCD, C' activation and surface adhesion of C' proteins on lipid UEAs were studied invitro. C'-mediated UEA attachment to bone marrow immune cells was assessed using flow cytometry in a murine SCD model (Townes mice). Blood from patients receiving Definity was obtained to measure specific lysophospholipid metabolites of lipids in Definity thought to mediate SCD pain. Moderate or greater AEs, all of which were nociceptive (back or bone pain), occurred in one control subject and nine SCD subjects (2% vs 16%, P=.02). Patients with SCD who had AEs tended to have more severe manifestations of SCD. Three of the subjects with SCD had previously received Definity without complications. In patients with SCD, four AEs were classified as severe in intensity and as serious AEs on the basis of need for medical intervention. AEs were described to be similar to SCD-related pain, but there was no evidence for VOC, hemolysis, hypotension, or hypoxemia. At baseline, markers of C' activation were greater in patients with SCD than control subjects. However, after administration of lipid UEAs, SCD and control subjects were similar with regard to C' activation response, anaphylatoxin production, bone marrow microbubble retention, and production of lysophospholipids. There was a trend toward increased deposition of C3b and C3bi on lipid UEAs exposed to serum from patients with SCD. Patients with SCD are particularly susceptible to nociceptive AEs when given Definity at high doses. The mechanism for these AEs remains unclear but most are not related to the triggering of classic VOC.

P1482: PATIENTS WITH SEVERE SICKLE CELL DISEASE ON STANDARD OF CARE TREATMENT ARE VERY UNLIKELY TO BECOME VOC FREE FOR ONE YEAR: A COHORT STUDY OF MEDICAID ENROLLEES

Background: Sickle cell disease (SCD) patients have frequent vaso-occlusive crises (VOCs), which impact their quality of life, contribute to organ damage and failure, and are associated with increased mortality. An ongoing, open-label Ph3 clinical trial with CTX001, an investigational, autologous, ex vivo CRISPR/Cas-9-based gene edited therapy, in patients with severe SCD, is evaluating the proportion of patients who become VOC-free for at least 1 year after CTX001 treatment. Thus, it is important to know the proportion of patients with severe SCD on standard-of-care (SOC) who become VOC-free over time to provide context for the efficacy of CTX001 in eliminating VOCs in severe SCD. Aims: To contextualize the efficacy of CTX001 in eliminating VOCs in patients with severe SCD, we used nationwide Medicaid claims data from 2000 to 2014 to assess the proportion of patients on SOC who became VOC-free during a 1-year follow-up. The inclusion/exclusion criteria were similar to those of the Ph3 clinical trial of CTX001 in patients with severe SCD. Methods: A cohort of patients 12-35 years old with SCD was identified based on ≥1 inpatient claim or ≥2 outpatient claims for SCD after at least 2 years of continuous Medicaid enrollment. The date patients met the SCD case algorithm was defined as the cohort entry date. The 2-year period preceding the cohort entry date was defined as the baseline period. Consistent with the inclusion criteria in the CTX001 Ph3 trial, we restricted this population to severe SCD defined by ≥2 VOCs per year in each of 2 consecutive years (total of ≥4 VOCs over 2 years) at baseline. A VOC was identified using ICD diagnosis codes in hospitalization and ER visit claims for acute pain crisis, acute chest syndrome, priapism, and splenic sequestration. Additional exclusion criteria that were operationalizable using claims data included prior bone marrow transplant, moyamoya syndrome or history of stroke, low left heart function, low lung diffusing capacity (including pulmonary hypertension), advanced liver disease, decreased kidney function, significant bleeding disorder, prior malignancy or myelodysplasia, and select infections. We further restricted the cohort to patients with 1-year of continuous Medicaid enrollment (or less if any deaths) following the cohort entry. The primary outcome was the proportion of patients with 0 VOCs during a 1-year follow-up. Results: A total of 5,874 patients with severe SCD were identified [mean (SD) age: 20.5 (6.0) years, 54.4% female, 87% African Americans]. Patients had a mean of 5.1 VOCs, 4.7 ER visits and 3.6 all-cause hospitalizations per year during the 2-year baseline period. Hydroxyurea was used in 37.5%, opioid analgesics in 88.7%, and NSAIDs in 71.9%. The proportion of patients with 0 VOCs during the 1-year follow-up was 9.1% (95% CI: 8.4, 9.9). When stratified by the number of VOCs at baseline, patients with higher numbers of VOCs had a lower proportion of 0 VOCs in the 1-year follow-up (Table). Image:Summary/Conclusion: Fewer than 10% of patients with severe SCD with at least 2 VOCs per year in the prior 2 years at baseline became VOC-free for 1 year with SOC in this nationwide cohort of Medicaid enrollees. This demonstrates that patients with severe SCD are very unlikely to become VOC-free over a 1-year period and provides context for the efficacy of gene therapies in eliminating VOCs. These data also highlight the urgent need to develop effective therapies for patients with severe SCD as ~90% of patients continue to have VOCs, which are life-limiting and life-threatening events.

L-glutamine for sickle cell disease: more than reducing redox.

Oxidative stress is a major contributor to the pathophysiology of sickle cell disease (SCD) including hemolysis and vaso-occlusive crisis (VOC). L-glutamine is a conditionally essential amino acid with important roles, including the synthesis of antioxidants, such as reduced glutathione and the cofactors NAD(H) and NADP(H), as well as nitric oxide. Given the increased levels of oxidative stress and lower (NADH):(NAD + + NADH) ratio in sickle erythrocytes that adversely affects the blood rheology compared to normal red blood cells, L-glutamine was investigated for its therapeutic potential to reduce VOC. While L-glutamine was approved by the United States (US) Food and Drug Administration to treat SCD, its impact on the redox environment in sickle erythrocytes is not fully understood. The mechanism through which L-glutamine reduces VOC in SCD is also not clear. In this paper, we will summarize the results of the Phase 3 study that led to the approval of L-glutamine for treating SCD and discuss its assumed mechanisms of action. We will examine the role of L-glutamine in health and propose how the extra-erythrocytic functions of L-glutamine might contribute to its beneficial effects in SCD.Further research into the role of L-glutamine on extra-erythrocyte functions might help the development of an improved formulation with more efficacy.

Preventive measures of vaso-occlusive crisis among sickle cell disease patients in South-Eastern Nigeria: How much do our patients know?

Background: Vaso-occlusive crisis (VOC) is a feature of sickle cell disease (SCD), an inherited medical condition which is more common in Sub-Saharan Africa especially Nigeria and is saddled with multi-systemic complications. Knowledge and practice of preventive measures of VOC by patients may reduce the risk of morbidity and mortality. Aim: The purpose of this manuscript is to determine the knowledge, attitude, and practice of the various preventive measures of VOC by patients and their relationship with their frequency of painful crisis. Materials and Methods: A cross-sectional descriptive survey was used. This study was conducted between August, 2018, and February, 2019. Participants were selected consecutively as they came for clinic consultations. Demographic characteristics and the knowledge, attitude, and practice of various preventive measures of VOC were obtained using a structured interviewer-administered questionnaire. The analysis was performed using Statistical Package for the Social Sciences software version 23.0. Descriptive and inferential statistics were used with P < 0.05 which was considered statistically significant. Ethical clearance and informed consent were obtained before the commencement of the study. Results: A total of 154 SCD patients participated in the study and were made up of 73 (47.4%) males and 81 (52.6%) females, with a male-to-female ratio of 1: 1.1. Majority of the respondents (76.6%) had good knowledge of preventive measures toward VOC in SCD. This study also found that 59 (38.3%) participants had good practice of preventive measures toward VOC while 95 (61.7%) had fair practice. Majority (68% [40/59]) of those who had good practice of preventive measures were less likely to have more than three crises in a year compared to those who do not practice good preventive measures, though not statistically significant (OR = 2.489, P = 0558) (confidence interval = 0.480 – 0.637). Conclusion: Majority of the patients have good knowledge and practice of preventive measures of VOC and this appears to have reduced the frequency of their crisis in a year. Health education for sickle cell patients is an important tool that may reduce morbidity and mortality by reducing the frequency of crisis.

Impact of hydroxyurea on hospital stay &amp; analgesic utilization in sickle cell anaemia with vaso-occlusive crises

Hydroxyurea (HU) has been useful in preventing sickle cell vaso-occlusive crises (VOC). A few studies also suggest utility of HU, during acute VOC. Sickle cell anaemia (SCA) is of high prevalence in western districts of Odisha State, India, and VOC is a common presentation, despite being mostly of Arab-Indian haplotype. This study was undertaken to evaluate the impact of HU on hospital stay and analgesic utilization in acute painful VOC of SCA. Homozygous sickle cell disease (HbSS) patients were categorized as cases who were receiving low-dose HU (10 mg/kg/day) and patients who were not on HU were considered as control. Days of hospital stay, analgesic utilization and visual analogue scale (VAS) score in patients were compared with that of control. Analgesics used to control pain were tramadol hydrochloride, ketorolac and diclofenac. A total of 359 homozygous sickle cell disease (SCD) patients with VOC were studied (187 patients and 172 controls). The patient group had lesser mean days of hospital stay (1.4 days less than controls, P<0.001) and required lesser days of analgesic utilization than controls (1.18 days less than controls, P<0.001). Significant differences were observed between patients and controls concerning VAS score and amount of tramadol hydrochloride, ketorolac and diclofenac utilization (P<0.05). In this study, HU was found to have beneficial effects in acute VOC of homozygous SCD, which includes shortening the duration of hospital stay and reducing the net amount of analgesic utilization during hospitalization.

Impact of a Standardized Emergency Department Pain Protocol for Children with Sickle Cell Disease

Background/Objective: Sickle cell disease (SCD) is a common heritable red blood cell disorder that transcends the lifespan. Abnormal sickle-shaped erythrocytes interfere with blood flow in small vessels resulting in vaso-occlusion. This vaso-occlusion leads to tissue ischemia and inflammation which causes severe pain and is commonly referred to as a vaso-occlusive crisis (VOC). VOC is the most common complication seen in SCD and accounts for the majority of Emergency Department (ED) visits and hospitalizations. The primary objective of this study was to evaluate if pain management of SCD in pediatric patients at our institution was in accordance with national and institutional pain management guidelines before and after implementation of a standardized pain management algorithm.&#x0D; Methods: We retrospectively analyzed electronic medical record (EMR) data at Riley Hospital for Children between June 2015-May 2018, as well as from January 2019-December 2019 from for all pediatric patients (0-21 years old) who presented to the Riley ED with a confirmed diagnosis of SCD and uncomplicated VOC. These timeframes represented pre and post implementation of a standardized pain management algorithm, which has been described separately. The data collected included time to first dose of analgesia, type and dose of analgesia, change in pain score, length of stay in the ED, and disposition (discharge or admission). Univariate analyses were used to compare data between encounters.&#x0D; Results: Prior to implementation, 186 patients were seen for a total of 504 encounters, the majority of whom were male (59%, p&lt;0.001) and had Hb SS disease (67%, p&lt;0.001). The mean length of an ER visit was approximately 5 hours (+/-113 minutes). The median pain score at presentation was 9 (0-10 scale), with an average of 23 minutes from check in to first documented pain score. However, 19% of patients had no initial pain score documented, which occurred more often if the patient’s initial analgesic was given orally (p&lt;0.001). The mean time from ED check in to first dose of analgesia (PO, IV, IN) was 76 minutes. The mean time between pain scores and medication administration increased between subsequent doses. 70% of these encounters resulted in hospitalization, with an average LOS of 4.1 days. Analysis of data following implementation of a standardized pain management algorithm is ongoing.&#x0D; Conclusion: Acute pain episodes are the leading cause of ED visits and hospitalizations for those with SCD. Thus, to properly meet the needs of patients with SCD and improve their outcomes, there needs to be collaborative, standardized and SCD- specific clinical guidelines for ED providers to utilize. Pre-implementation of a standardized acute pain management algorithm, our institution was not meeting national guidelines for administration of analgesia and assessment of pain. Post-implementation results are currently under analysis.&#x0D; Impact and Implications: Patients with SCD experience longer wait times in the ED and significant bias and mistrust regarding pain concerns. Standardized clinical guidelines have the potential to improve care and decrease variation in care delivery. The results from our study can inform institutional and national policy makers on gaps that exist in pediatric SCD, so that research funding can be appropriately allocated.

Examining Experiences of Acute and Chronic Pain Among Individuals with Sickle Cell Disease (SCD) in Jamaica and Cameroon

Introduction: Sickle cell disease (SCD) is an autosomal recessive hemoglobinopathy that causes red blood cell sickling and blockage of blood vessels that result in painful debilitating vaso-occlusive crises (VOC). Yet, individuals with SCD face negative stereotyping and stigmatization when accessing healthcare that contribute not only to feelings of shame, anger and distrust towards providers, but also to serious complications and poor outcomes. Comparison of individuals' experiences, assessment and management of VOC across different cultural landscapes may identify intervenable targets that could improve overall care and outcomes of SCD.Methods: This is a transnational qualitative research study that examined the perceptions, treatments and socio-economic impacts of pain in participants living with SCD in Jamaica (n= 31) and Cameroon (n=50). Participants completed semi-structured interviews that were collectively examined for themes and differences in experiences with acute and chronic pain. Analysis was completed using NVivo 12.Results: Both Jamaican and Cameroonian participants reported diverse psychosocial, physical and health causes of their VOC including, strenuous physical activity, intense emotionality, unhealthy lifestyle behaviors, other health conditions and extreme weather conditions. Similarly, both had challenges communicating the severity and type of VOC pain to providers when accessing healthcare for themselves and their children. Furthermore, both reported providers' reliance on non-validated forms of pain assessment (Cameroon > Jamaica) such as behavioral cues rather than standardized numerical or visual scales that participants believed were easy-to-use and capable of improving the assessment and treatment of VOC. Jamaican participants also experienced more positive, less-discriminatory practices treating their VOC in specialized vs. unspecialized SCD public and private clinical settings. At least half of all participants reported satisfaction with overall provider treatment of VOC. Both Jamaican and Cameroonian participants primarily used non-opioid pain analgesics, daily folic acid and distraction rather than hydroxyurea to manage their acute and chronic VOC pain and thereby, presented late for treatment of unbearable pain. Participants also reported using both traditional medicine and lifestyle changes to maintain a positive mindset and decrease the occurrences of VOC. Lifestyle changes included eating a healthy diet, engaging in relaxation activities and mindfulness techniques (massages, breathing exercises, listening to music and resting). All participants were interested in learning about alternative methods of managing their VOC pain.Conclusion: The use of validated numerical and visual pain scales as well as the implementation of specialized SCD facilities in the public and private clinic settings may help eliminate communication barriers and discriminatory practices to improve overall satisfaction and treatment of VOC in SCD. DisclosuresAsnani: Aruvant Sciences: Research Funding; Avicanna Ltd.: Research Funding.

The Impact of Same Day Infusion Treatment Protocols for Uncomplicated Vaso-Occlusive Crises within an Embedded Sickle Cell Care Model

Background: Infusion Center (IC) based care of uncomplicated sickle cell disease (SCD) vaso occlusive crises (VOCs) is very effective and results in better outcomes. At low volume sickle cell programs, it is challenging to acquire resources for a dedicated infusion program. Our goal was to create an embedded infusion program within our cancer center infusion services utilizing existing resources to improve the quality of care for our SCD patients.Methods: A multi-disciplinary team consisting of a Nurse Case Manager, Advanced Practice Provider, MD, IC scheduler and IC charge nurse was assembled. An agreement was made between the SCD team and IC leadership that at least one time slot would be made available for a SCD VOC visit every day. A workflow was created and all team members were educated regarding the workflow. Visit numbers for IC visits, emergency department (ED) and inpatient (IP) hospitalizations were collected from the EMR and compared for pre IC development (Jan 1, 2017- Dec 31, 2018) and post IC (January 1, 2019 - Dec 31, 2020).Results: Between 2017-2020, 182 patients with SCD were seen in the emergency room and 163 patients in our outpatient clinics. After the institution of an IC based care plan in January 2019, IC visit volume increased (270 visits pre IC vs.1076 visits post IC). ED treat and release (not requiring admissions) visits decreased from 373 visits pre IC to 286 visits post IC. The number of inpatient admissions did not change significantly during this time frame. However, the percentage of admissions from the ED increased (43% pre IC to 50% post IC), indicating a higher complexity of patients seeking care from the ED. 10 of 35 patients who used the IC in 2020 had no acute visits (ED or IP) in 2020, while these individual patients had a total of 37 ED visits in the pre IC timeframe, of which 20 were inpatient admissions with a total length of stay of 137 days and 17 treat and release episodes at the ED.Conclusions: Our project successfully utilized existing infusion based resources to facilitate outpatient management of acute uncomplicated SCD VOCs. This project presents an effective strategy that can be utilized by smaller volume sickle cell programs who do not have a stand alone infusion program to improve the quality of care for their SCD patients. DisclosuresGopal: Pharming: Consultancy; GBT: Consultancy; Alexion: Speakers Bureau; Rigel Pharmaceuticals: Other: Clinical Trial, Research Funding.

Which adults with sickle cell disease need an evaluation for pulmonary embolism?

Individuals living with sickle cell disease (SCD) are at an increased risk of venous thrombo-embolism (VTE) including pulmonary embolisms (PEs). There is a high mortality associated with PE in individuals with SCD. It can be difficult to diagnose PE since presenting symptoms of PE often mimic those of other forms of vaso-occlusive crisis in SCD. Currently, there are no validated models for predicting PEs in patients with sickle cell disease, which often leads to frequent CT scans and exposure to harmful radiation and intravenous contrast. The aim of this study was to evaluate different host variables and potential clinical biomarkers of patients with SCD including those used in the Wells score to assess predictability for PE in order to create a more accurate diagnostic algorithm to predict PE. A retrospective chart review was performed on 349 patients with SCD who underwent testing for a PE with a CT scan of the chest. Forward and backward stepwise model selection was performed to obtain a parsimonious model of the predictors of PEs. The incidence of PE in this population was 9·7%. Of the factors evaluated for this study, the Wells score was the only one with clinical significance. A Wells score greater than 4 had a sensitivity and specificity of 72·5% and 70·1%, respectively, and a score greater than 6 had a sensitivity and specificity of 50% and 87%, respectively. The Wells score is an acceptable clinical tool which may prove useful in individuals with SCD to predict who is most likely to have a PE and therefore should undergo a CT scan. A prospective study is needed to further confirm these findings.

The Association between Adenotonsillectomy and Frequency of Vaso-Occlusive Crises in Patients with Sickle Cell Disease.

Sickle cell disease (SCD) typically manifests in early childhood as attacks of pain known as vaso-occlusive crises. Infection and hypoxemia have been linked with these recurrent episodes and with prolonged hospitalization in SCD patients. However, adenoids and tonsils as sources of infection and causes of hypoxemia have not been adequately investigated in association with vaso-occlusive crises in SCD. To assess the association between adenotonsillectomy and frequency of vaso-occlusive crisis in SCD patients who underwent this procedure at our Hospital, and between adenotonsillectomy and frequency of blood transfusions and emergency department and intensive care unit admissions. We used medical record data to conduct a retrospective review of SCD patients who underwent adenoidectomy and/or tonsillectomy between 2005 and 2017. Eligible subjects were assessed for frequency of vaso-occlusive crises, blood transfusions, and emergency department and intensive care unit admissions. Using the Wilcoxon signed rank test, we compared the frequencies of each outcome preoperatively and 1, 3, 5, and 10years postoperatively. Of 524 records reviewed, 40 eligible patients were included in the study. Minimal reduction was observed in the frequency of vaso-occlusive crisis episodes within 1 and 3years after adenotonsillectomy (p = 0.337 and p = 0.549, respectively). Although the 5- and 10-year postoperative vaso-occlusive crisis frequency tended to be higher than that in the preoperative period, none of the results reached statistical significance. The number of emergency department admissions showed a statistically significant increase 3years postoperatively compared with that in the preoperative period (P = 0.043). There were no statistically significant differences in perioperative blood transfusion frequency or number of intensive care unit admissions in any period. Adenotonsillectomy in SCD patients does not seem to be related to the frequency of vaso-occlusive crises, blood transfusions, or emergency department or intensive care unit admissions. Prospective studies with larger sample sizes are recommended to further evaluate these findings.

Absence of exaggerated pharmacology by recombinant ADAMTS13 in the rat and monkey.

Insufficiency of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin motif repeats-13) is the cause of thrombotic thrombocytopenic purpura (TTP) and contributes in microangiopathy in sickle cell disease (SCD). Recombinant ADAMTS13 effectively cleaves prothrombotic ultra-large von Willebrand factor (VWF) multimers. It is being tested as replacement therapy for TTP, and at supra-physiologic concentrations, for moderating vaso-occlusive crisis in SCD. Deficiencies of VWF, or concomitant treatment with antithrombotic drugs, could pose risks for increased bleeds in these patient populations. The purpose of the experiments was to evaluate the potential of exaggerated pharmacology and temporary bleeding risks associated with rADAMTS13 administration. We utilized safety studies in monkey and tested the effects of administering maximum-feasible doses of rADAMTS13 on nonclinical safety and spontaneous or aggressive bleeds in the rat model. Evaluation of pharmacokinetics, toxicity profiles, and challenge in a tail-tip bleeding model show that treatment with rADAMTS13 did not increase bleeding tendency, either alone, or in combination with enoxaparin or acetylsalicylic-acid. These novel findings demonstrate absence of rADAMTS13 exaggerated pharmacology without spontaneous or aggravated bleeds even at supra-physiologic (>100-fold) plasma concentrations.

System Level Informatics to Improve Triage Practices for Sickle Cell Disease Vaso-Occlusive Crisis: A Cluster Randomized Controlled Trial

BackgroundNational Heart Lung and Blood Institute guidelines for the treatment of vaso-occlusive crisis among people with sickle cell disease in the emergency department recommend assigning an emergency severity index of 2 at triage. However, patients with sickle cell disease often do not receive guideline-concordant care at triage. To address this gap, a decision support tool was developed, in the form of a text banner on the triage page in the electronic health record system, visible to triage nurses. MethodsA prospective quality improvement initiative was designed where the emergency severity index clinical decision support tool was deployed to a stratified random sample of emergency department triage nurses to receive the banner (n = 24) or not to receive the banner (n = 27), reminding them to assign the patient to emergency severity index category 2. The acceptability of the emergency severity index clinical decision support tool was evaluated with the Ottawa Acceptability of Decision Rules Instrument. Descriptive and bivariate (chi-square test) statistics were used to characterize the study's primary outcome, proportion of visits assigned an emergency severity index of 2 or higher. A generalized linear mixed model with clustering at the level of the triage nurse was performed to test the association between the banner intervention and triage practices. ResultsA total of 384 ED visits were included for analysis. Before study initiation, the percentage of sickle cell disease patients’ visits with the proper emergency severity index assignment at triage was 37.04%. After initiation, the proportion of sickle cell disease patients’ visits with an emergency severity index of 2 or higher triaged by nurses in the intervention group was markedly higher in the intervention group than in the control group (64.95% vs 35.05%; χ2 = 8.79, P ≤ .003). Accounting for clustering by nurse, the odds ratio for proper triage emergency severity index assignment was 3.22 (95% confidence interval 1.17–8.85; P ≤ .02) for the intervention versus control. Surveyed triage nurses reported the emergency severity index clinical decision support tool to be moderately acceptable (nurses’ mean Ottawa Acceptability of Decision Rules Instrument scores ranged from 4.13 to 4.90 on the 6-point scale; n = 11). There were no differences in ED experience outcomes including time to first analgesic or length of stay between the control and intervention groups. ConclusionSubstantial improvements in triage guideline concordance were achieved and sustained without direct nursing education.