Sickle cell anaemia control mission: Implementation of a comprehensive care model in Anuppur, Madhya Pradesh.

Background & objectives Sickle cell disease (SCD) is a common genetic disorder, predominantly found in the tribal population of India. The examples of models providing comprehensive care and management to individuals with SCD in public health facilities are sparse. The Sickle Cell Anaemia Control Mission is one such model implemented by Jan Swasthya Sahyog, a non-profit organization in collaboration with the National Health Mission in the Anuppur district of Madhya Pradesh. This article aimed to identify the key learnings from this programme that can guide the public health system strengthening with respect to SCD. Methods The Sickle Cell Anemia Control Mission Programme included door to door screening for anaemia, SCD and blood group. SCD cases were included in the programme and other individuals with Anemia were referred for further care. Care for individuals with SCD included counselling, provision of hydroxyurea, regular follow up of clinical parameters and management of complications. Care for individuals with SCD was provided through monthly patient support group (PSG) meetings and regular outpatient /in-patient care at public health facilities. Quantitative data on programme design, screening and patient management collected during programme implementation were used for analysis. Results A total of 39421 persons were screened in 18 months (August 2018-March 2020). Of these 81.9 per cent persons were anaemic, 16.9 per cent had sickle cell trait and 779 (1.98%) had SCD. Eighty-six already diagnosed individuals joined the programme for care. People from all caste categories were diagnosed with SCD. Out of 865 individuals with SCD, 157 underwent regular 9-11 months follow up and showed improvement in clinical symptoms and drug compliance. Interpretation & conclusions Central India has a significant burden of anaemia and SCD. This study found that SCD is present in non-tribals as well. PSGs are an efficient way to deliver non-emergency care for chronic diseases such as SCD.

Role of endothelial dysfunction in sleep-disordered breathing in egyptian children with sickle cell disease.

BACKGROUND: Endothelial dysfunction is an integral pathophysiologic mechanism in sickle cell disease (SCD), and can lead to many complications. Sleep-disordered breathing (SDB) is a SCD complication with diverse incidence and pathophysiology. This study aimed to determine the prevalence of SDB in children with SCD and to assess its relation to endothelial dysfunction. METHODS: Sixty children with SCD and 60 healthy controls were enrolled. The levels of TNF-α, IL-6, and IL-17A were evaluated in the entire cohort using enzyme-linked immunosorbent assay (ELISA) kits. Polysomnography (PSG) was performed for all SCD patients after completion of the Pediatric Sleep Questionnaire (PSQ). RESULTS: TNF-α, IL-6, and IL-17A levels were significantly greater in children with SCD than in controls (p-values < 0.001, < 0.001, and 0.006, respectively). The PSQ revealed symptoms suggestive of SDB in 50 children with SCD (83.3%), and PSG revealed obstructive sleep apnea (OSA) in 44 children with SCD (73.3%); 22 patients had mild OSA, and 22 had moderate-to-severe OSA according to the apnea-hypopnea index (AHI). TNF-α was significantly greater in SCD children who reported heavy or loud breathing, trouble breathing or struggle to breathe, and difficulty waking up in the morning (p-values = 0.002, 0.002, and 0.031, respectively). The IL-6 levels were significantly greater in SCD children who stopped growing normally (p-value = 0.002). The levels of IL-6 and IL-17A were significantly greater in SCD children with morning headaches (p-values = 0.007 and 0.004, respectively). CONCLUSION: Children with SCD showed a high prevalence of SDB with significantly elevated levels of markers of endothelial function, highlighting the interplay of SDB and endothelial dysfunction in SCD.

Spleen Uptake in Sickle Cell Anemia on Bone Scan.

A patient who had sickle cell disease and had spleen uptake on bone scans is described, and additional causes for that finding are discussed.

Mast cell extracellular trap formation underlies vascular and neural injury and hyperalgesia in sickle cell disease.

Sickle cell disease (SCD) is the most common inherited monogenetic disorder. Chronic and acute pain are hallmark features of SCD involving neural and vascular injury and inflammation. Mast cells reside in the vicinity of nerve fibers and vasculature, but how they influence these structures remains unknown. We therefore examined the mechanism of mast cell activation in a sickle microenvironment replete with cell-free heme and inflammation. Mast cells exposed to this environment showed an explosion of nuclear contents with the release of citrullinated histones, suggestive of mast cell extracellular trap (MCET) release. MCETs interacted directly with the vasculature and nerve fibers, a cause of vascular and neural injury in sickle cell mice. MCET formation was dependent upon peptidylarginine deiminase 4 (PAD4). Inhibition of PAD4 ameliorated vasoocclusion, chronic and acute hyperalgesia, and inflammation in sickle mice. PAD4 activation may also underlie neutrophil trap formation in SCD, thus providing a novel target to treat the sequelae of vascular and neural injury in SCD.

The role of prophylactic transfusion on the maternal and fetal outcomes in pregnant women with sickle cell disease: A systematic review and meta-analysis.

BACKGROUND: In the present review, we aimed to synthesize evidence from studies on the safety and effectiveness of prophylactic blood transfusion in pregnant women with sickle cell disease. MATERIAL AND METHODS: To gather relevant information, we conducted systematic electronic searches of databases such as SCOPUS, Medline via PubMed, Web of Science, and Cochrane Central Register of Controlled Trials. We included both retrospective and prospective studies that examined the impact of prophylactic blood transfusions during pregnancy. The collected data were analyzed using Review Manager, version 5.3. RESULTS: The review included 15 cohort studies. The overall findings indicated a preference for the prophylactic blood transfusion group over the control group across several key parameters. Specifically, the prophylactic group demonstrated lower rates of maternal mortality (odds ratio [OR] = 0.33; 95% confidence interval [CI] = 0.10-1.13; P = .08), reduced incidence of vaso-occlusive painful events (OR = 0.31; 95% CI = 0.14-0.73; P = .007), fewer pulmonary complications (OR = 0.21; 95% CI = 0.08-0.53; P = .001), decreased perinatal mortality (OR = 0.35; 95% CI = 0.17-0.75; P = .03), and lower likelihood of preterm birth (OR = 0.67; 95% CI = 0.47-0.96; P = .02). Notably, statistically significant heterogeneities were observed in the pooled effect estimates. CONCLUSION: The present meta-analysis indicated that prophylactic blood transfusion in pregnant women with sickle cell disease may improve maternal and fetal outcomes. However, substantial variations in the methodology and transfusion protocols among the included studies limited the credibility of the current evidence supporting the routine clinical use of prophylactic transfusion for SCD during pregnancy.

Respiratory management of acute chest syndrome in children with sickle cell disease.

Acute chest syndrome (ACS) is a leading cause of respiratory distress and hospitalisation in children with sickle cell disease (SCD). The aetiology is multifactorial and includes fat embolism, venous thromboembolism, alveolar hypoventilation and respiratory infections, with the latter being particularly common in children. These triggers contribute to a vicious cycle of erythrocyte sickling, adhesion to the endothelium, haemolysis, vaso-occlusion and ventilation-perfusion mismatch in the lungs, resulting in the clinical manifestations of ACS. The clinical presentation includes fever, chest pain, dyspnoea, cough, wheeze and hypoxia, accompanied by a new pulmonary infiltrate on chest radiography. Respiratory symptoms may overlap with those of acute asthma, which may be difficult to distinguish. Patients with ACS may deteriorate rapidly; thus prevention, early recognition and aggressive, multidisciplinary team management is essential. In this narrative review, we highlight the current evidence regarding the epidemiology, pathophysiology, treatment and preventative strategies for ACS, focusing on the aspects of major interest for the paediatric pulmonologist and multidisciplinary team who manage children with SCD.

Effects of GBT1118, a voxelotor analog, on bone disease in sickle cell disease mice.

We assessed the effect of GBT1118, a sickle hemoglobin polymerization inhibitor on bone loss in humanized sickle cell disease (SCD) mice. Healthy control (Ctrl) 4-months-old female and male mice were fed Vehicle-chow for 2-months, while SCD mice were fed Vehicle-chow or GBT1118-chow. By micro-CT, GBT1118 significantly increased femur metaphyseal trabecular thickness (Tb.Th) and tissue mineral density (TMD), and significantly decreased trabecular spacing in female SCD mice. In SCD male mice, there was significant reduction in epiphyseal trabecular bone volume fraction (BV/TV), Tb.Th and TMD and GBT1118 significantly increased BV/TV and TMD but not Tb.Th. A significant decrease in cortical area fraction in SCD female mice was rescued by GBT1118 but not SCD males. Markedly decreased mineralized femur trabeculae in SCD females and males was partially rescued by GBT1118. Bone histomorphometry of femurs demonstrated significantly decreased bone formation parameters and increased bone resorption parameters in SCD mice of both sex that were rescued by GBT1118. Significant alteration in bone and hypoxia related genes of SCD mice of both sexes were differentially modulated by GBT1118. We conclude that "a sickle hemoglobin polymerization inhibitor" might be efficacious in improving some parameters of SCD bone loss.

Buprenorphine: Opioid Agonist-Antagonist for Refractory Pain of Sickle Cell Disease Patients During Hematopoietic Stem Cell Transplant, Uncontrolled By Full-Agonist Opioids.

BACKGROUND: Bone marrow transplant (BMT) offers potential cure for cancer and a spectrum of otherwise incur- able diseases. The BMT process can cause multi-systemic pain in patients with sickle cell disease (SCD) refractory to high-dose opioid analgesics during BMT because of their pre-existing opioid-tolerance. Because of frequent pain resulting in hyperalgesia and chronic opioid use, SCD patients undergoing BMT often experience excruciating pain uncontrolled by exceedingly high-dose opioids with severe and intolerable adverse effects. PURPOSE/HYPOTHESIS: There is a small but growing body of literature about the successful buprenorphine effect for SCD's chronic pain management that had failed sufficient pain relief by the traditional full-agonist opioids in the outpatient setting. However, the buprenorphine use for acute inpatient pain management has not been previously researched. Pilot prospective clinical trial with buprenorphine-based pain management for acute BMT-related pain was initiated for SCD patients' pain uncontrolled by full-agonist opioids. Procedures/data/observations: Buprenorphine was started as scheduled and as-needed analgesics, supplemented by full-agonist opioids upon consultation for uncontrolled BMT-related pain of SCD patients. Patients' 24-hour opioid requirement by morphine equivalent daily doses (MEDD) were assessed at 3 time points: 1)immediately before pain escalation; 2)consultation; 3)discharge. MEDDs were compared to those of patients treated with full-agonist opioids only. Cases treated by full-agonist opioids (morphine/hydromorphone/fentanyl/methadone/oxycodone) had MEDD escalation by 1230-16300% by discharge compared to immediately before BMT-related pain escalation. Buprenorphine-supported cases had significantly smaller MEDD increase by 220-317%. CONCLUSIONS/APPLICATIONS: Our case series suggests superior pain control by adding Buprenorphine prior to opioid dose escalation during BMT for SCD. Buprenorphine may provide the advantageous effect for other patients with complex pain background and experiencing difficult pain management during BMT due to pre-existing hyperalgesia and high opioid-tolerance. The evidence for buprenorphine's analgesic effect is moderate but growing, and more randomized controlled trials comparing the buprenorphine and other standard opioids are needed.

Prevalence and associated factors of glomerular hyperfiltration among adult stable sickle cells in Kinshasa, DR Congo.

INTRODUCTION: Glomerular hyperfiltration is highly frequent, theoretically dependent on cardiac output, low systemic vascular resistance and hemolysis markers. In sickle cell disease (SCD), hyperfiltration is an extremely common phenomenon and occurred in young and early adult patients. Despite the fact that the glomerular hyperfiltration is known as the early manifestations of sickle cell nephropathy, its burden among adult sickle cell disease in sub-Saharan is poor studied. This study aimed to determine the prevalence and associated factors of hyperfiltration. METHODS: This was an analytical multicentric cross-sectional study involving stable adult sickle cell patients in Kinshasa, recruited between March and October 2023. Parameters of interest encompasses demographic, clinical, biological, echocardiographic and pulse wave measurement data. Hyperfiltration was defined using the CDK-EPI equation based on cystatin C; eGFR >130 for women and >140 ml/min/1.73m2 for men. We used multivariate logistic regression analysis to search determinants of glomerular hyperfiltration. RESULTS: Two hundred and fourty six (246) patients with SCD were enrolled. The prevalence of hyperfiltration was 20.7%. In multiple logistic regression analysis, hyperfiltration status was independently associated with age (< 25 years) [3.57 (1.78-7.49); p = 0.027)], female sex [4.36 (2.55-5.62); p = 0.031), CRP (< 6 mg/l) [0.77 (0.61-0.97); p = 0.028)], central systolic pressure (< 100 mmHg) and central diastolic pressure (< 60 mmHg) [0.86(0.74-0.98), p = 0.028)], [(0.83 (0.71-0.98); p = 0.032)]. CONCLUSION: One out of five SS adults exhibits hyperfiltration, which is associated with young age and female sex, whereas low CRP and blood pressure were negative risk factors.

Inhibition of sodium-glucose cotransporter-2 improves anaemia in mice and humans with sickle cell disease, and reduces infarct size in a murine stroke model.

Sodium-glucose cotransporter-2 (SGLT-2) is expressed in the kidney and may contribute to anaemia and cardiovascular diseases. The effect of SGLT-2 inhibition on anaemia and vascular endpoints in sickle cell disease (SCD) is unknown. A murine model of SCD was studied to determine the effects of the SGLT-2 inhibitor, empagliflozin, on anaemia and stroke size. The University of Michigan's Precision Health Database was used to evaluate the effect of SGLT-2 inhibitors on anaemia in humans with SCD. SCD mice treated with daily empagliflozin for 8 weeks demonstrated increases in haemoglobin, haematocrit, erythrocyte counts, reticulocyte percentage and erythropoietin compared to vehicle-treated mice. Following photochemical-induced thrombosis of the middle cerebral artery, mice treated with empagliflozin demonstrated reduced stroke size compared to vehicle treated mice. In the electronic health records analysis, haemoglobin, haematocrit and erythrocyte counts increased in human SCD subjects treated with an SGLT-2 inhibitor. SGLT-2 inhibitor treatment of humans and mice with SCD is associated with improvement in anaemic parameters. Empagliflozin treatment is also associated with reduced stroke size in SCD mice suggesting SGLT-2 inhibitor treatment may be beneficial with regard to both anaemia and vascular complications in SCD patients.

Children and Adolescents With Sickle Cell Disease and Skull Infarction: A Systematic Review.

INTRODUCTION: Skull infarction is an uncommonly reported complication of sickle cell disease. We aimed to characterize the clinical and imaging features of skull infarction in pediatric patients with sickle cell disease. METHODS: We searched the PubMed database for case reports on skull bone infarction in pediatric patients with sickle cell disease. Out of 67 records retrieved, 15 met inclusion criteria, and a 16th case reported by the senior author was included. We extracted and analyzed clinical and imaging data. RESULTS: The most common symptom at onset was headache (88%). Bilateral skull infarction (50%) and parietal bone involvement (82%) were frequent imaging findings. Epidural hematoma developed in 65% of the cases, 30% of patients required drainage, and exchange infusion was reported in 18%. No fatal outcomes were reported. CONCLUSIONS: Skull infarction is a potentially severe complication of sickle cell disease presenting unique clinical challenges. Acute headaches should raise suspicion for this condition and may require additional investigation.

Stroke Prevention and Treatment for Youth with Sickle Cell Anemia: Current Practice and Challenges and Promises for the Future.

PURPOSE OF REVIEW: Sickle cell anemia (SCA) is an autosomal recessive inherited hemoglobinopathy that results in a high risk of stroke. SCA primarily affects an underserved minority population of children who are frequently not receiving effective, multi-disciplinary, preventative care. This article reviews primary and secondary stroke prevention and treatment for children with SCA for the general adult and pediatric neurologist, who may play an important role in providing critical neurologic evaluation and care to these children. RECENT FINDINGS: Primary stroke prevention is efficacious at reducing ischemic stroke risk, but it is not consistently implemented into clinical practice in the United States, resulting in these children remaining at high risk. Acute symptomatic stroke management requires neurology involvement and emergent transfusion to limit ischemia. Furthermore, while chronic transfusion therapy is a proven secondary preventative modality for those with prior symptomatic or silent cerebral infarcts, it carries significant burden. Newer therapies (e.g., stem cell therapies and voxelotor) deserve further study as they may hold promise in reducing stroke risk and treatment burden. Effective primary and secondary stroke prevention and treatment remain a challenge. Informing and engaging neurology providers to recognize and provide critical neurologic evaluation and treatment has potential to close care gaps.

MFSD7C protects hemolysis-induced lung impairments by inhibiting ferroptosis.

Hemolysis drives susceptibility to lung injury and predicts poor outcomes in diseases, such as malaria and sickle cell disease (SCD). However, the underlying pathological mechanism remains elusive. Here, we report that major facilitator superfamily domain containing 7 C (MFSD7C) protects the lung from hemolytic-induced damage by preventing ferroptosis. Mechanistically, MFSD7C deficiency in HuLEC-5A cells leads to mitochondrial dysfunction, lipid remodeling and dysregulation of ACSL4 and GPX4, thereby enhancing lipid peroxidation and promoting ferroptosis. Furthermore, systemic administration of MFSD7C mRNA-loaded nanoparticles effectively prevents lung injury in hemolytic mice, such as HbSS-Townes mice and PHZ-challenged 7 C-/- mice. These findings present the detailed link between hemolytic complications and ferroptosis, providing potential therapeutic targets for patients with hemolytic disorders.

Uncommon Presentation of Hypersplenism in Adult Sickle Cell Disease Patients: A Rare Case Report.

BACKGROUND Hypersplenism, the rapid and premature destruction of blood cells, encompasses a triad of splenomegaly, cytopenias (anemia, leukopenia, or thrombocytopenia), and compensatory bone marrow proliferation. Secondary hypersplenism results from non-intrinsic splenic diseases, such as hemoglobinopathies. Sickle cell disease consists of a group of genotypes, where hemoglobin sickle C disease (HbSC) is the inheritance of hemoglobin S with hemoglobin C. Most homozygous genotypes undergo complete auto-splenectomy by age 6 years, whereas those with HbSC disease rarely do. We report a rare case of hypersplenism and massive splenomegaly in an adult with sickle cell disease, the HbSC genotype, requiring splenectomy. CASE REPORT A 41-year-old woman with known splenomegaly initially presented to the general surgery clinic for management of abdominal pain. She was found to have anemia, indicating cytopenia likely from hypersplenism. Consequently, she underwent splenic artery embolization, followed by an exploratory laparotomy and splenectomy, with an unremarkable postoperative course. CONCLUSIONS Acute splenic sequestration crisis can result from hypersplenism, a potentially fatal complication of sickle hemoglobinemia. The continuous cycle of sickled cell entrapment and stasis causes numerous splenic infarctions, forming splenic parenchymal scar tissue which reduces the spleen's size and functionality - the process of auto-splenectomy. Adults rarely experience these crises past adolescence, which are secondary to the scarring and atrophy from premature auto-splenectomy. Our patient's spleen measured 21.1 cm, larger than the average adult's spleen. In our case, adjunctive preoperative splenic artery embolization likely contributed to decreased intraoperative blood loss during splenectomy, mitigating the need for perioperative transfusions.

Immunization strategies for individuals with sickle cell anemia: A narrative review.

Sickle cell anemia (SCA) is a hereditary blood disorder characterized by the production of abnormal hemoglobin, leading to the formation of sickle-shaped red blood cells. These distorted cells can obstruct blood flow, causing vaso-occlusive crises and increasing the risk of severe infections due to functional asplenia and immune system dysregulation. Immunization is a crucial strategy to mitigate infection-related complications in individuals with SCA, necessitating a comprehensive and tailored vaccination approach. Current immunization guidelines for individuals with SCA recommend a combination of standard and additional vaccines to address their heightened susceptibility to infections. Key vaccines include pneumococcal conjugate (PCV13) and polysaccharide (PPSV23) vaccines, meningococcal conjugate (MenACWY) and serogroup B (MenB) vaccines, Haemophilus influenzae type b (Hib) vaccine, annual influenza vaccine, and hepatitis A and B vaccines. These vaccinations aim to provide broad protection against pathogens that pose significant risks to patients with SCA. Despite generally adequate immune responses, the variability in vaccine efficacy due to immune dysfunction necessitates booster doses and additional vaccinations. This narrative review highlights the importance of adhering to current immunization recommendations and addresses challenges such as access to care, vaccine hesitancy, and monitoring vaccination status.

Standardization of coding definitions for sickle cell disease complications: A systematic literature review.

PURPOSE: Sickle cell disease (SCD) affects all organ systems and is characterized by numerous acute and chronic complications and comorbidities. Standardized codes are needed for complications/comorbidities used in real-world evidence (RWE) studies that rely on administrative and medical coding. This systematic literature review was conducted to produce a comprehensive list of complications/comorbidities associated with SCD, along with their diagnosis codes used in RWE studies. METHODS: A search in MEDLINE and Embase identified studies published from 2016 to 2023. Studies were included if they were conducted in US SCD populations and reported complications/comorbidities and respective International Classification of Diseases, Clinical Modification (ICD-CM) codes. All identified complications/comorbidities and codes were reviewed by a certified medical coding expert and hematologist. RESULTS: Of 1851 identified studies, 39 studies were included. The most reported complications/comorbidities were stroke, acute chest syndrome, pulmonary embolism, venous thromboembolism, and vaso-occlusive crisis. Most of the studies used ICD-9-CM codes (n = 21), while some studies used ICD-10-CM codes (n = 3) or both (n = 15), depending on the study period. Most codes reported in literature were heterogeneous across complications/comorbidities. The medical coding expert and hematologist recommended modifications for several conditions. CONCLUSION: While many studies we identified did not report their codes and were excluded from this review, the studies with codes exhibited diverse coding definitions. By providing a standardized set of diagnosis codes that were reported by studies and reviewed by a coding expert and hematologist, our review can serve as a foundation for accurately identifying complications/comorbidities in future research, and may reduce heterogeneity, enhance transparency, and improve reproducibility. Future efforts focused on validating these code lists are needed.

Detection of Subclinical Cardiac Dysfunction in Patients With Sickle Cell Disease Using Speckle-Tracking Echocardiography.

Sickle cell disease (SCD) is characterized by chronic anemia and recurrent ischemia-reperfusion episodes, which can lead to high-output heart failure. The impact of SCD on cardiac structure and function remains underinvestigated. We conducted a single-institution retrospective analysis of clinical and echocardiographic data from patients with hemoglobin SS SCD (SCD-SS) between January 2016 and June 2022. Patients with known heart failure, left ventricular (LV) ejection fraction <50%, moderate or severe valvular heart disease, congenital heart disease, established coronary artery disease, diabetes mellitus, hypertension, or coexistent lung disease were excluded. Compared with healthy controls (n = 28), patients with SCD-SS (n = 66) had a significantly higher left atrial (LA) volume index (35.7 vs 23.9 ml/m², p <0.001) and average E/e' (7.4 vs 6.5, p = 0.003) but lower average e' (12.3 vs 13.6 cm/s, p = 0.047) and LA reservoir strain (32.9% vs 42.4%, p <0.001). Patients with SCD-SS had higher LV end-diastolic (132.5 vs 104.1 ml, p <0.001) and LV end-systolic volumes (51.0 vs 43.8 ml, p = 0.017) with reduced LV global longitudinal strain (17.6% vs 20.0%, p <0.001). In addition, patients with SCD-SS showed reduced right ventricular (RV) global longitudinal strain (19.7% vs 22.8%, p <0.001) in the setting of normal RV tricuspid annular plane systolic excursion. Maximal systolic tricuspid regurgitation velocity (231 vs 202 cm/s, p <0.001) and right atrial area (16.6 vs 12.8 cm², p <0.001) were statistically greater in SCD-SS. Hemoglobin and hematocrit negatively correlated with LA volume index, average E/e', LV end-diastolic and LV end-systolic volumes. In conclusion, patients with SCD-SS had notable differences in cardiac chamber size and impaired LV, RV, and LA strain compared with healthy controls. Further investigations are needed to assess the impact of these variables on SCD clinical course and prognosis.