Manifestations Of Sickle Cell Disease Research Articles

Spinal Manifestation of Sickle Cell Disease. A Report On 35 Patients with Literature Review

Background: Sickle cell disease is a hereditary hemoglobinopathy affecting the spine in a wide range of pathology. Despite the several pathological involvements, some patients remain asymptomatic even with positive imaging findings. Objectives: Theme of this study is to report the various pathological disorders involving the spine of patients with sickle cell disease in Basra “south of Iraq” Patients and method: 35 Homozygous and heterozygous sickle cell patients were included in this study. 22 Males and 13 females, their age range from 6 to 69 years they were evaluated clinically, and also by laboratory imaging studies like plain radiography, computerized tomography, magnetic resonance imaging and mineral bone density “DEXA scan “ Results: 54% of the patients were homozygous, and the remaining were heterozygous, 66% of them were asymptomatic, back pain was the complaint in 60% while spine tenderness was reported in 40%, 31% had tenderness in the sacroiliac region and only 6% had neurological claudication and focal neurological deficit.  Biconcave vertebra was confirmed in 72% of the patients and mainly localized in the lumbar Spine, MRI findings of vertebral infarction were observed in 58% of the studied patients while sacroiliac joint changes appeared in 60%, 60% of those who had DEXA scan showed low mineral bone density in the lumbar spine Conclusion: Sickle cell disease involve the whole Spine in a wide range of pathological process, some show clinical symptoms, and some remain asymptomatic in spite of changes. The structural changes are more obvious in the homozygous group (55) the lumber spine is dominantly involved, disc prolapse, and neurological deficit is rare while the low mineral changes is common. We did not report a case of spondylodiscitis in this series, though it is very much expected, so routine screening of the spine in sticklers is mandatory

Is There any Relationship Between the Repeated Complications of Sickle Cell Disease and the Potential Development of Acute Leukemia?

Sickle cell disease (SCD) is a severe monogenic hereditary hemoglobinopathy that is characterized by repeated clinical and biological manifestations able to generate stress erythopoiesis. A clonal hematopoiesis involving mainly variants of TP53, DNMT3A, ASXL1, and/or TET2 may be more prevalent in patients with SCD, suggesting that mutations in these genes may lead to an increased risk of leukemia. An increased prevalence of leukemia in patients with SCD has been confirmed by an increasing number of acute myeloid leukemia cases with myelodysplastic features reported in this patient population even in the absence of disease-modifying treatments. This leads to the hypothesis of a mechanism involving multifactorial causes through the pathophysiologic manifestations of SCD, in which cells are undergoing constant hematopoietic hyperplasia, inducing genomic damage and somatic mutations.

Assessing Bone Mineral Density in Sickle Cell Disease Patients and linking it to Admission Rates: A Prospective Uni-center Study

INTRODUCTION: Sickle cell disease (SCD) is an inherited autosomal recessive disorder with bone mineral density (BMD) as a common clinical manifestation of SCD. With a prevalence of 2.6%, Saudi Arabia is among the highest incidence of SCD worldwide. The purpose of this research was to examine how SCD evolves and how it affects bone density in Saudi patients from an Eastern Province tertiary hospital. METHODS: This was an observational prospective study conducted in the tertiary care hospital among 119 SCD patients. Patients were divided into two groups: Group A – severe SCD patients requiring hospital care ≥3/year; and Group B included patients with a smooth course of SCD who did not require frequent hospitalization (<3 hospitalizations per year), with a milder course of the disease. Analysis was based on the frequency of hospitalizations with pain crises and measuring BMD. RESULTS: Of 119 patients, 73.1% had low bone density. Compared to the femur (47.9%), the spine (62.2%) had a higher prevalence of low bone density. The prevalence of low BMD did not significantly differ between the two groups (64.8 vs. 79.9%, P = 0.081). Patients with more frequent hospital visits had significantly higher Mg concentrations (2.30 vs. 0.84, P = 0.001), higher gamma-glutamyl transferase (59.44 vs. 39.49, P = 0.030), and significantly lower 25-hydroxy Vitamin D (34.82 vs. 49.48, P = 0.004). CONCLUSIONS: Patients with SCD had a generally higher prevalence of low BMD. Further research is needed to answer the proposed debate about the accuracy of DXA scanning in patients with SCD.

Hemapheresis Clinic Scheduling Quality Improvement Project

Abstract Introduction/Objective Outpatient (OP) Red blood cell exchange (RCE) therapy is used to treat patients with severe manifestations of sickle cell disease. Like any blood transfusion, a patient must have an active type and screen, drawn 24 to 72 hours prior to scheduled RCE procedure. UIH Hemapheresis clinic performs several types of apheresis procedures treating sickle cell disease, kidney transplant rejection and autoimmune disorders. Outpatient clinic staff perceived that most RCE procedures are scheduled disproportionately between Wednesday through Friday, which creates an unbalanced schedule that is lighter on Monday and Tuesday, and heavier Wednesday through Friday. The study's objective was to determine if there is a significant difference between the number of outpatient procedures scheduled on the different days of the week. If significant differences are identified, processes may be improved to schedule a more balanced OP clinic week. Potential benefits may include a more balanced patient to nursing staff ratios which can improve patient care and more efficient RBC utilization which can ease workload across multiple cross-functional departments such as nursing staff, reference labs and in-house blood bank staff. Methods/Case Report The UIH Epic Hemapheresis Clinic schedule was searched to identify how many total OP procedures, including RCE, were scheduled each day of the week between 01AUG2021 – 31JUL2022. Only OP procedures occurring in complete five-day weeks were included. Weekends and weeks having clinic closures for holidays were excluded Results (if a Case Study enter NA) Our study show that the lowest number of OP RCE (mean 1.4) and total number of OP procedures (mean 2.6) were on Monday. Wednesday is the busiest day with overall averaging 3.5 total procedures (Standard Deviation: 1.56). However, Friday is the most variable, with the largest SD for both RBCX (SD 1.4) and Total number of procedures (SD 1.7). Conclusion Contributing factors to low procedure volume on Monday are likely multifactorial. Some patients may prefer not to come to the hospital on Saturday for type and screen, while some may forget they need labs. Transportation issues are another factor. One intervention the clinic has implemented is automatic appointment call reminders. Staff encourage patients or caregivers to sign up for the EPIC MyChart app which also notifies patients of upcoming appointments. Future studies need to be conducted to address other bottlenecks within the scheduling workflow and to determine ways to optimize patient appointment adherence.

Benefit of Inpatient Pain Plan Utilization on Hospital Length of Stay in Adolescents and Young Adults with Sickle Cell Disease

Introduction Vaso-occlusive crisis (VOC) is the most common manifestation of sickle cell disease (SCD) and the most common cause for emergency department (ED) visits and hospital admissions. VOC accounts for approximately 230,000 annual admissions in children with SCD. Patients with SCD face inconsistent analgesic management, leading to high inpatient healthcare utilization and financial burden for healthcare institutions. Furthermore, patients describe their pain management as the area of their care in most need of improvement. A prospective longitudinal cohort study showed that implementation of individualized pain plans in adult patients with SCD significantly decreased the duration of VOC hospital stays by 1.2 days. A similar study in children showed no change in duration of hospital stay, however the study was limited by a small sample size. We hypothesized parallel results to the prior adult study in adolescent and young adult (AYA) SCD patients. Methods At UCSF Benioff Children's Hospital Oakland, we implemented inpatient pain plans for SCD patients with frequent VOC admissions (i.e., >1 VOC admission in the prior year or complicated VOC admission history). Pain plans are individualized and embedded into the patient's electronic health record. These plans include detailed daily analgesic recommendations with the general recommendation for discharge on day 5 of the pain plan. After IRB approval, we performed a retrospective chart review of SCD patients with individualized inpatient pain plans initiated between November 2017 and April 2022. We recorded baseline demographic information including age at pain plan initiation, SCD genotype and sex. We assessed length of inpatient hospitalization for VOC admissions in the year prior and the year after pain plan initiation for each individual patient. We also noted number of admissions secondary to VOC during this two year time period. Results Twenty-six patients with SCD and individualized pain plans were identified (Table 1). Average length of hospital stay for VOC was significantly decreased in the year after inpatient pain plan initiation (Table 2). There was a trend towards increased admissions due to VOC in the year after inpatient pain plan initiation (Table 2). Conclusions Similar to the prior adult study in SCD patients, we found significantly reduced inpatient length of hospitalization after initiation of an inpatient pain plan for AYA patients with SCD and VOC. Although there was a trend towards increased hospitalizations in the year after inpatient pain plan initiation, this was likely secondary to the average patient age with an expected increased in VOC year over year. The National Heart, Lung, and Blood Institute (NHLBI) SCD guidelines recommend an individualized prescribing and monitoring protocol be written by a SCD provider and used in patients withVOC to promote effective, timely, and safe analgesic management. We further demonstrate that individualized pain plans for AYA patients with SCD can decrease length of hospital stay due to VOC, likely secondary to more effective pain management recommendations that have been prior agreed upon by the patient/family and SCD provider. We currently are calculating morphine equivalents and hypothesize total opioid utilization will be concomitantly decreased due to this significantly decreased length of hospitalization.

Dual P-Selectin and Complement Inhibition with Subcutaneous IHP-102 Treatment Potently Reduces Lung Vaso-Occlusion in Sickle Cell Disease Mice

One of the most debilitating manifestations of sickle cell disease (SCD) are the excruciatingly painful vaso-occlusive episodes (VOEs), commonly referred to as “pain crises.” Vaso-occlusion, which underlies the pathomechanism of VOE, also causes downstream tissue and organ damage resulting in complications that plummet life-expectancy by more than 20 years. Current treatment options for VOE are limited and all require chronic administration, often with intolerable side-effects, and none fully prevent VOE. An acute VOE rescue therapy that could be administered in the home-setting would transform care for the more than 100,000 people in the U.S. and over 7 million worldwide who suffer from this inherited condition. IHP-102 is a novel glycan-based drug with dual anti-P-selectin and anti-complement activity. It is bioavailable by subcutaneous route of administration and could therefore be self-administered at the earliest sign of VOE. Early intervention in VOE is critical, before ischemia and tissue damage becomes irreversible. This treatment paradigm would also circumvent the wholly inadequate treatment experience that the SCD community has widely described, being treated as an opioid “drug-seeker” when engaging the healthcare system during a debilitating VOE. There are multiple pathomechanisms of VOE. P-selectin is a clinically validated therapeutic target for partially attenuating VOE, while complement has more recently been identified as an important driver of VOE, in part due to hemolysis and ischemia. While several therapeutics targeting P-selectin or complement are currently in clinical development, no therapy targets both pathomechanisms. We have previously shown that IHP-102 inhibits P-selectin mediated cell adhesion in vitro (IC50 = 0.7 µg/mL) and that intravenous administration of IHP-102 reduces lung vaso-occlusion by 75% in Townes SCD mice challenged with oxy-hemoglobin (oxy-Hb). Here, we extend these studies with subcutaneous delivery of IHP-102, achieving greater than 75% reduction in lung vaso-occlusion. This magnitude of effect is greater than that achieved in P-selectin deficient Townes SCD mice (~50% reduction), thus indicating additional activity of IHP-102 beyond P-selectin inhibition. In studies using human serum, IHP-102 inhibits complement by upstream mechanisms, including through inhibition of Factor B. Factor B is responsible for alternative pathway amplification of complement. Its fragment Bb has been found in elevated concentrations during VOE in patient serum, suggesting it plays an important role in the pathomechanism of VOE. By inhibiting Factor B, IHP-102 reduces downstream complement fragments of C3 and C5, which are widely recognized complement targets given their critical role in the complement system and promoting inflammation. The dual anti-complement and anti-P-selectin activity of IHP-102, together with its potential for home-based treatment, offers great potential to fill a major treatment gap for acute VOE. Its potent in vivo activity suggests that this dual target approach could provide robust therapeutic benefit and warrants further investigation toward clinical trials.

Reduced Intensity Haploidentical Bone Marrow Transplantation in Adults with Severe Sickle Cell Disease: BMT CTN 1507

Background: Allogeneic hematopoietic stem-cell transplantation has curative potential for sickle cell disease (SCD). Event-free survival (EFS) in children with SCD is >90% after a bone marrow transplant (BMT) from a myeloablative matched sibling donor (MSD). Unfortunately, <15% of patients with SCD have MSD, and myeloablative conditioning can be prohibitively toxic in adults with SCD. Reduced intensity HLA-haploidentical BMT with post-transplant cyclophosphamide (PTCy) has been shown in small studies to expand the donor pool with encouraging results. Still, concerns about graft failure and graft-versus-host disease (GVHD) persist. We present the results of a Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1507, multi-center single-arm, phase-II, prospective clinical trial (clinicaltrials.gov #NCT03263559) of haploidentical-BMT with PTCy to estimate EFS at 2-years in adults with severe SCD. Pediatric stratum data is not included in the data presentation and will be available in 2-years. Study Design and Methods: Eligibility: SCD patients aged 15.00-45.99 years with prior stroke, recurrent ACS or pain, chronic transfusion regimen, or tricuspid valve regurgitant jet velocity (TRJV) ≥2.7 m/sec were eligible. Participants were required to have an HLA-haploidentical first-degree relative donor, willing and able to donate bone marrow. The primary objective was EFS (survival without primary or secondary graft failure or second infusion of stem cells) at 2 years after haploidentical-BMT. Secondary objectives included determining the impact on clinical and laboratory manifestations of SCD and other transplant outcomes at 2 years post haploidentical-BMT. The protocol was opened for enrollment on 10/5/2017, completed accrual on 01/6/2021, and data are current as of 8/2023. Preconditioning with hydroxyurea (HU) 30mg/kg/day (Day-70 to Day-10); Conditioning regimen included Thymoglobulin (rATG), Thiotepa, Fludarabine, Cyclophosphamide, and Total Body Irradiation (TBI). GVHD prophylaxis included PTCy, sirolimus, and mycophenolate mofetil, figure. Results: A total of 54 eligible participants enrolled from 19 sites; 42 (78%) proceeded to transplant. Amongst enrolled participants, 59.3% are male, 92.6% are Black, and 3.7% are Hispanic. 10 participants started HU but did not proceed to BMT, and 2 did not start HU or proceed to BMT. Reasons included donor issues (n=4), withdrawal of consent (n=2), insurance coverage (n=2), death (n=1), and other (n=3). 38/42 (90%) participants completed the study as planned; 2 participants withdrew consent, and 2 were lost to follow-up. The median age was 22.8 years at enrollment; 47/54 (87%) of enrolled participants had Hemoglobin SS disease, 40/54 (74.1%) had a Lansky/Karnofsky score of 90-100 at baseline, and 41/54 (75.9%) had an HLA match score of 4/8. Recurrent vaso-occlusive pain episodes (38.9%), acute chest syndrome (16.8%), and overt stroke (16.7%) were the most common indications for transplant. Only 13 (31%) participants achieved the intended 30 mg/kg/day dosing of HU preconditioning. Estimated 2-year EFS is 88% (95% CI: 73.5%, 94.8%); all except one qualifying event occurred within 12 months. The 2-year overall survival (OS) post-HU was 93.0% (95% CI: 79.8%, 97.7%), and the 2-year OS post-transplant was 95.0% (95% CI: 81.5%, 98.7%); 2 (4.8%) participants had primary graft failure, and 1 (2.4%) had secondary graft failure before day +100. The cumulative incidence of grades II-IV acute GVHD at day 100 was 26.2% (95% CI: 14.0%, 40.2%), and grades III-IV acute GVHD at day 100 was 4.8% (95% CI: 0.9%, 14.4%). There were two deaths in the first year post-BMT (1 -organ failure; 1-ARDS), none in the second year; 33 (78.6%) participants reported at least one re-admission post-BMT, mainly due to either bacterial infection (n=41) or viral reactivation (n=36), table. Conclusion: This multi-center phase-II trial of a reduced intensity haploidentical-BMT in adults with SCD shows durable donor engraftment at 2-years with low mortality. The 2-year EFS and OS are comparable to that reported after MSD myeloablative BMT. These results support haploidentical BMT with PTCy as a suitable and tolerable curative therapy for adults with SCD and severe end-organ toxicity such as stroke and pulmonary hypertension, a population typically excluded from participating in myeloablative gene therapy and gene editing trials.

Prevention of neurovascular complications in children with Sickle Cell Disease in the real-world setting: What adult medicine physicians should know

Neurovascular complications represent one of the most detrimental manifestations of Sickle Cell Disease (SCD), affecting many patients since infancy. They include overt stroke, silent cerebral infarcts and neurocognitive disorders. In fact, neurodevelopment can be impaired in children resulting in cognitive dysfunction in adults with SCD. This review is meant to resume the most recent guidelines about the prevention of SCD neurovascular complications and to highlight the open challenges in their implementation. Transcranial Doppler, Magnetic Resonance Imaging/Angiography and neurocognitive test are useful screening tools. Chronic transfusion regimen, hematopoietic stem cell transplantation and neurocognitive rehabilitation find indications in the context of primary and secondary prevention of neurovascular complications of SCD. However, international guidelines are often difficult to bring into the real world due to the lack of appropriate instruments and trained personnel. Many challenges have still to be faced to guarantee the best possible neurocognitive function to each child affected by SCD.

Response to Lisinopril in Patients with Sickle Cell Anemia and Proteinuria.

Proteinuria is a manifestation of sickle cell anemia (SCA)-related renal disease and is a risk factor of renal impairment. Angiotensin-converting enzyme (ACE) inhibitors have benefits, but their role in SCA remains undefined. This study aimed to assess the role of lisinopril, an ACE inhibitor, in reducing proteinuria in SCA patients. Thirty-five patients older than 15 years with known SCA (HbSS or HbS-β0) and a 24-h urinary protein level of 150 mg or more participated in this study. Urine was collected over 24 h to quantify proteinuria. The patients had a mean age of 28.5 ± 6.98 years. The median 24-h urinary protein before treatment was 0.3006 g and that after treatment was 0.150 g (P = 0.01). After a median follow-up of 38 months, 24-h urinary protein decreased in 27 (77%) patients and normalized in 18 (52%) patients. Urinary protein increased in 2 (6%) patients and remained stable (no change) in 6 (17%) patients. There was no significant difference in blood pressure (BP) before and after treatment. The average dose of lisinopril was 5 mg. Twenty patients were still on lisinopril at last follow-up. The reasons for stopping lisinopril included normalization of protein, noncompliance, adverse effects, and pregnancy. Lisinopril effectively reduced proteinuria in SCA patients, without significantly reducing BP. Only a few patients developed adverse effects, including coughing, dizziness, and diarrhea. It is unclear how long lisinopril should be continued and whether it can be stopped in patients with normalized urinary protein.

Crizanlizumab in sickle cell disease.

Vaso-occlusion in sickle cell disease (SCD) leads to a myriad of manifestations driving morbidity and mortality in patients with SCD. Increased leucocyte adhesion and P-selectin expression on platelets and endothelial cells is an inciting eventthat leads to obstruction of microcirculation by adhesion with rigid sickled red blood cells. Crizanlizumab is a first-in-class monoclonal antibody that inhibits P-selectin and has been shown to decrease the frequency of vaso-occlusive pain crises in patients with SCD in clinical trials. The role of crizanlizumab in other manifestations of SCD still needs further investigation.

CRISPR-Cas9 Editing of the HBG1 and HBG2 Promoters to Treat Sickle Cell Disease

BackgroundSickle cell disease is caused by a defect in the β-globin subunit of adult hemoglobin. Sickle hemoglobin polymerizes under hypoxic conditions, producing deformed red cells that hemolyze and cause vaso-occlusion that results in progressive organ damage and early death. Elevated fetal hemoglobin levels in red cells protect against complications of sickle cell disease. OTQ923, a clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9–edited CD34+ hematopoietic stem- and progenitor-cell (HSPC) product, has a targeted disruption of the HBG1 and HBG2 (γ-globin) gene promoters that increases fetal hemoglobin expression in red-cell progeny.MethodsWe performed a tiling CRISPR-Cas9 screen of the HBG1 and HBG2 promoters by electroporating CD34+ cells obtained from healthy donors with Cas9 complexed with one of 72 guide RNAs, and we assessed the fraction of fetal hemoglobin–immunostaining erythroblasts (F cells) in erythroid-differentiated progeny. The gRNA resulting in the highest level of F cells (gRNA-68) was selected for clinical development. We enrolled participants with severe sickle cell disease in a multicenter, phase 1–2 clinical study to assess the safety and adverse-effect profile of OTQ923.ResultsIn preclinical experiments, CD34+ HSPCs (obtained from healthy donors and persons with sickle cell disease) edited with CRISPR-Cas9 and gRNA-68 had sustained on-target editing with no off-target mutations and produced high levels of fetal hemoglobin after in vitro differentiation or xenotransplantation into immunodeficient mice. In the study, three participants received autologous OTQ923 after myeloablative conditioning and were followed for 6 to 18 months. At the end of the follow-up period, all the participants had engraftment and stable induction of fetal hemoglobin (fetal hemoglobin as a percentage of total hemoglobin, 19.0 to 26.8%), with fetal hemoglobin broadly distributed in red cells (F cells as a percentage of red cells, 69.7 to 87.8%). Manifestations of sickle cell disease decreased during the follow-up period.ConclusionsCRISPR-Cas9 disruption of the HBG1 and HBG2 gene promoters was an effective strategy for induction of fetal hemoglobin. Infusion of autologous OTQ923 into three participants with severe sickle cell disease resulted in sustained induction of red-cell fetal hemoglobin and clinical improvement in disease severity. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT04443907.)

Terminology for Retinal Findings in Sickle Cell Disease Research: A Scoping Review

To review the current sickle cell disease (SCD) literature to assess how "retinopathy" has been defined and to identify ocular outcomes that have been measured and described. A systematic scoping review of SCD literature was completed regarding ocular manifestations of SCD and vision outcomes across all medical specialties. Participants with SCD and control patients were included in our data extraction. We reviewed English-language literature from 2000 to 2021 for eligible studies by searching PubMed, Google Scholar, Embase, and the Cochrane library using terms to encompass SCD and ocular findings. Data collection included study information, patient characteristics, vision-related findings (inclusion criteria and/or study outcomes), and retinopathy characteristics (definition, when, how and by whom diagnosed). We identified 4006 unique citations and 111 were included in the analysis. Ophthalmologists were senior authors of about half (59/111; 53.2%) of the articles; most articles were published between 2016 and 2021 (71/111; 70.0%). The studies had been conducted primarily in North America (54/111; 48.6%) or Europe (23/111; 20.7%); designs were cross-sectional (51/111; 45.9%), prospective cohort (28/111; 25.2%), retrospective cohort (27/111; 24.3%), and case-control (4/111; 3.6%). Among studies reporting any retinopathy, it was commonly defined as a combination of nonproliferative sickle cell retinopathy and proliferative sickle cell retinopathy (PSR;52/87; 59.8%), infrequently as PSR only (6/87; 6.9%), or not defined at all (23/87; 26.4%). The Goldberg classification was used to grade retinopathy in almost half of the studies (41/87; 47.1%). Investigators reporting diagnostic methods used clinical fundus examination (56/111; 50.4%), OCT (24/111; 21.6%), fluorescein angiography (20/111; 18.0%), ultrawidefield fundus photographs (15/111; 13.5%), and OCT angiography (10/111; 9.0%), or did not report methods (28/111; 25.2%). There are inconsistencies in documentation of methods and outcomes in studies of SCD ophthalmic findings. Particularly concerning is the lack of documentation of ophthalmic examination methods, qualifications of examiners, and clarity and specificity of sickle cell retinopathy definitions. With the increase in SCD treatment research and novel systemic therapies available, it is important to adopt clear and consistent descriptions and rigorous data collection and reporting of ophthalmic outcomes in SCD studies. The authors have no proprietary or commercial interest in any materials discussed in this article.

Biopsychosocial Factors Associated With Pain and Pain-Related Outcomes in Adults and Children With Sickle Cell Disease: A Multivariable Analysis of the GRNDaD Multicenter Registry

Pain is the primary symptomatic manifestation of sickle cell disease (SCD), an inherited hemoglobinopathy. The characteristics that influence pain experiences and outcomes in SCD are not fully understood. The primary objective of this study was to use multivariable modeling to examine associations of biopsychosocial variables with a disease-specific measure of pain interference known as pain impact. We conducted a secondary analysis of data from the Global Research Network for Data and Discovery national SCD registry. A total of 657 children and adults with SCD were included in the analysis. This sample was 60% female with a median age of 34 (interquartile range 26–42 years) and a chronic pain prevalence of 64%. The model accounted for 58% of the variance in pain impact. Low social (P < .001) and emotional (P < .001) functioning, increasing age (P = .004), low income (P < .001), and high acute painful episodes (P = .007) were most strongly associated with high pain impact in our multivariable model. Additionally, multivariable modeling of pain severity and physical function in 2 comparable samples of registry participants revealed that increasing age and low social functioning were also strongly associated with higher pain severity and low physical functioning. Overall, the results suggest that social and emotional functioning are more strongly associated with pain impact in individuals with SCD than previously studied biological modifiers such as SCD genotype, hemoglobin, and percentage fetal hemoglobin. Future research using longitudinally collected data is needed to confirm these findings. PerspectiveThis study reveals that psychosocial (ie, social and emotional functioning) and demographic (ie, age) variables may play an important role in predicting pain and pain-related outcomes in SCD. Our findings can inform future multicenter prospective longitudinal studies aimed at identifying modifiable psychosocial predictors of adverse pain outcomes in SCD.

Multifocal osteomyelitis in a child with sickle cell disease and review of the literature regarding best diagnostic approach

Key Clinical MessageIn patients with sickle cell disease, we must be more cognizant of the possibility of multifocal osteomyelitis. Diagnosis can be challenging in this patient population as the symptoms mimic vaso‐occlusive crisis. There is no gold standard in imaging.AbstractOsteomyelitis occurs more frequently in children with sickle cell disease. Diagnosis is challenging as it mimics vaso‐occlusive crises, a common manifestation of sickle cell disease. We present a case of a 22‐month‐old girl with sickle cell disease and multifocal osteomyelitis. We review the literature on the utility of diagnostic imaging.

Ellagic Acid Exerts Dual Action to Curb the Pathophysiological Manifestations of Sickle Cell Disease and Attenuate the Hydroxyurea-Induced Myelosuppression in Berkeley Mice.

The use of adjuvant therapy is an attractive approach to manage sickle cell disease (SCD) symptomatically. The present study aimed to investigate the potential of ellagic acid as an adjuvant therapy with hydroxyurea (HU), a key drug for SCD with myelosuppressive toxic effects. A panel of experiments was performed using SCD patient's blood (ex vivo) and transgenic mice model of SCD (in vivo). Ellagic acid exhibited the following beneficial pharmacological actions: (a) potent anti-sickling, polymerization inhibitory, and inherent non-hemolytic activity; (b) pronounced action to abrogate HU-induced neutropenia and to improve key hematological parameters during SCD (RBC, Hb, platelet levels); (c) considerable action to foster vascular tone (L-proline); (d) marked attenuating effect against oxidative stress (nitrotyrosine, hypoxanthine, MDA, GSH); (e) substantial inhibitory role against inflammation (analgesic activity and regulation of hemin, TNF-α, IL-1β, NF-κB/IκBα); (f) remarkable outcome of declining vaso-occlusive crisis (P-selectin, ERK1/2); (g) notable shielding deed against elevated biochemical marker for organ toxicity (creatinine); (h) noticeably prevented histopathological alterations of the spleen. Additionally, the pharmacokinetic study results of HU in the presence and absence of ellagic acid using a mouse model demonstrate that ellagic acid could be safely co-administered with HU. Overall findings suggest that ellagic acid is a promising candidate for adjuvant therapy in SCD based on its own significant ability against SCD and potentiating capability of HU action via targeting improvement at the various stages of pathophysiological complications during SCD and minimizing HU-induced toxicological manifestations.

5613458 BLOOD MICROPARTICLES: A TOOL OF EVALUATING THE EFFECT OF TRANSFUSION IN SICKLE CELL DISEASE PATIENTS

Background: Blood microparticles (MPs) are phospholipid microvesicles derived from cell membranes. Typically, they range in size from 0.1 μm to 1.0 μm and they are released upon oxidative stress, cell activation, injury or apoptosis. MPs have acquired a biological and clinical interest and are recognized as entities able to modulate many biological functions. Literature suggests that they may have a role in the pathophysiology and downstream manifestations of sickle cell disease (SCD). Aims: This present study was carried out to determine MPs profiles in patients with SCD before and after transfusion and to compare these profiles with healthy subjects. Materials: Twenty healthy donors and twelve polytransfused patients with SCD recruited from National Bone Marrow Transplant Center were recruited in this study. None of the patients was transfused for at least 3 weeks before sampling. The blood samples obtained were analyzed for circulating MPs by flow cytometry. The cellular origin was determined by a multiple labeling with specific antibodies and dyes. Results: A high level of apoptotic, platelets, and endothelial MPs with the predominance of the number of erythrocyte MPs was detected in SCD patients compared to healthy donors. This suggests that erythrocytes MPs may contribute to thrombotic risk in sickle cell patients. Moreover, after transfusion most subjects register a decreased number of different types of MPs. Conclusion: Transfusion is an effective treatment option in patients with SCD, as it seems that it decreases the abnormally elevated levels of MPs.

Neuroimaging and Cognitive Function in Sickle Cell Disease: A Systematic Review.

Sickle cell disease (SCD) is the most common inherited single-gene disease. Complications include chronic anaemia, reduced oxygen-carrying capability, and cerebral vasculopathy, resulting in silent cerebral infarction, stroke, and cognitive dysfunction with impairments in measures of executive function, attention, reasoning, language, memory, and IQ. This systematic review aims to investigate the association between neuroimaging findings and cognition in children with SCD. Searches of PubMed and Embase were conducted in March 2022. Studies were included if participants were <18 years, if original data were published in English between 1960 and 2022, if any genotype of SCD was included, and if the relationship between cognition and neuroimaging was examined. Exclusion criteria included case studies, editorials, and reviews. Quality was assessed using the Critical Appraisal Skills Programme Case Control Checklist. A total of 303 articles were retrieved; 33 met the eligibility criteria. The presence of overt or silent strokes, elevated blood flow velocities, abnormal functional connectivity, and decreased fMRI activation were associated with neuropsychological deficits in children with SCD when compared to controls. There is a critical need to address the disease manifestations of SCD early, as damage appears to begin at a young age. Most studies were cross-sectional, restricting the interpretation of the directionality of relationships. Future research employing longitudinal neuroimaging and neuropsychological assessments could improve our understanding of the cumulative consequences of SCD on the developing brain.

Newborn screening for sickle cell disease in Butembo and Beni: a pilot experience in a highland region of the Democratic Republic of Congo.

sickle cell disease is an inherited autosomal recessive hemoglobin disorder resulting in acute and chronic systemic complications. Despite the high burden of sickle cell disease in the Democratic Republic of the Congo, limited data on disease prevalence is available and systematic screening is not offered to newborns. This study aimed to provide neonatal prevalence and associated factors to the phenotypic manifestation of sickle cell disease in an eastern region of the Democratic Republic of the Congo. the study was conducted from 20th April 2021 to 20th January 2022 in the cities of Beni and Butembo, involving live full-term newborns whose parents consented to participate. Blood was taken with heel pricks and analyzed using the point-of-care diagnostic tool HemoTypeSC™. We used Fisher´s exact test to compare frequencies between groups. P-value <0.05 was considered statistically significant. Results: of the 1195 newborns screened, 1122 (93.9%) were tested as having hemoglobin AA, 71 (5.9%) hemoglobin AS, 2 (0.2%) hemoglobin SS and none hemoglobin C. The mother´s ethnicity was significantly associated with the phenotypic expression of sickle cell disease. sickle cell disease prevalence is lower in Butembo and Beni than in other regions of the Democratic Republic of the Congo. However, it remains an alarming public health issue. Systematic newborn screening, parent/patient education and early management programs constitute an urgent need to be addressed by decision-makers.

Asthma in Children with Sickle Cell Disease

Sickle Cell Disease is a life-threatening hereditary blood disorder which affects millions of people worldwide. Pulmonary complications are important causes of morbidity and mortality in patients with sickle cell disease. Asthma is a recognised comorbidity of sickle cell disease and may occur in between 15 and 28% of children with sickle cell disease. It has been associated with increased episodes of acute chest syndrome and all cause mortality. Obstructive lung disease, however, is common in children with sickle cell disease, independent of an asthma diagnosis. This review explores the pathophysiology, diagnosis and therapeutic opportunities for asthma in sickle cell disease patients. The diagnostic challenges and inconsistencies in current clinical approaches are highlighted. Convergence of inflammatory pathways in sickle cell disease and asthma occurs, but there is also a heightened level of inflammation unique to sickle cell disease. Thus, wheezing may not be due to asthma but be a manifestation of sickle cell disease per se and the result of the increased pulmonary vascular volume. As a consequence, anti-asthma therapy may not be appropriate for all wheezy children with sickle cell disease and commencing treatment on the basis of a physician’s diagnosis alone is inappropriate. Data from paediatric cohorts suggest use of spirometry, aeroallergen sensitisation tests, impulse oscillometry and dedicated interdisciplinary pulmonary clinics could improve diagnosis accuracy. Corticosteroids and bronchodilators are well-established treatments for asthma; observational studies suggest they may provide benefit for some children with sickle cell disease, but therapies such as hydroxyurea may improve respiratory outcomes in others. It is, therefore, essential children are thoroughly investigated and followed-up and a personalised approach taken to their care. Prospective randomised studies are required to establish the effectiveness of asthma therapies in children with sickle cell disease.

Correlation between skeletal manifestations of sickle cell disease (SCD) and transcranial doppler imaging velocities

Context: Sickle cell disease (SCD), a genetic disorder, is a debilitating illness. Among the different complications of SCD, cerebrovascular complication results in stroke in pediatric population. The cause of stroke in those patients is attributed to vasculopathy, stenosis, or vaso-occlusion of distal internal carotid arteries. Another body system that is commonly affected is the musculoskeletal system. Both skeletal manifestations and vasculopathy in Circle of Willis in SCD are known consequences of the same underlying pathology. Aim: This study was conducted to assess the correlation between osseous findings and vasculopathy of Circle of Willis. Settings and Design: It was a chart review study conducted during December 2021 to January 2022. Children suffering from SCD were the study population. Materials and Methods: The sampling was done by using convenience purposive sampling technique. The data were collected as observations using picture archiving and communication system and then entered Excel spreadsheet. Statistical Analysis Used: The data were analyzed using SPSS, Version 28. The descriptive statistics including frequencies and percentages for the skeletal manifestations and transcranial Doppler imaging (TCDI) readings were calculated. To assess the association between skeletal manifestations and TCDI, a Chi-square test of independence was performed. Results: The findings showed that abnormal TCDI readings exhibited higher frequency on abnormal skeletal manifestations as compared to normal TCDI readings. Conclusion: The study showed that an osseous manifestation of disease was associated with vasculopathy of Circle of Willis vasculature. Therefore, osseous manifestations of SCD can be associated with the chance of stroke among the children since it is associated with the vasculopathy of Circle of Willis.