Mortality In Sickle Cell Disease Research Articles

Unswitched memory B cell deficiency in children with sickle cell disease and response to pneumococcal polysaccharide vaccine.

Early mortality in sickle cell disease (SCD) is attributed to increased infections due to loss of splenic function. Marginal zone B cells are important for initial opsonization of pathogens and can be absent in spleen histopathology in SCD. The frequency of unswitched memory B cells (UMBC), the circulating correlate of marginal zone B cells, reflects the immunologic function of the spleen. We hypothesized that asplenia in SCD is associated with alterations in the peripheral blood lymphocyte population and explored whether UMBC deficiency was associated with a clinical phenotype. We analyzed B cell subsets and clinical history for 238 children with SCD and 63 controls. The median proportion of UMBCs was lower in children with SCD compared with controls (4.7% vs. 6.6%, p < .001). Naïve B cells were higher in SCD compared with controls (80.6 vs. 76.3%, respectively, p = .02). UMBC frequency declined by 3.4% per year increase in age in SCD (95% CI: 2%, 4.7%, p < .001), but not in controls. A majority of children in all cohorts had an IgM concentration in the normal range for age and there were no differences between groups (p = .13). Subjects developed titers adequate for long-term protection to fewer serotypes in the polysaccharide vaccine than controls (14.7 vs. 19.4, p < .001). In this cohort, bacteremia was rare and specific clinical complications were not associated with UMBC proportion. In summary, UMBC deficiency occurs in SCD and is associated with age. Future studies should investigate B cell subsets prospectively and identify the mechanism of B cell loss in the spleen.

Heme Scavenging by Hemopexin Attenuates Sepsis-Induced Proinflammatory Cytokines and Kidney Insuffciency in a Humanized Mouse Model of Sickle Cell Disease

Sickle cell disease (SCD) is a genetic blood disorder characterized by abnormal hemoglobin production, leading to sickle-shaped red blood cells (RBC). Alteration in RBC shape results in vasoocclusion, chronic hemolysis, and multiple organ damage. One of the severe complications of SCD is an increased susceptibility to infections, including sepsis, which can be life-threatening. Kidney injury, a common and severe complication of sepsis, contributes to the complexity and poor outcomes associated with morbidity and mortality in SCD. However, the mechanisms that underlie septic acute kidney injury (AKI) in SCD are poorly understood. Here, we examined the effects of sepsis in transgenic homozygous SCD (SS; Townes model) mice and their non-sickling (AA) counterparts. We tested the hypothesis that aggravation of inflammation and oxidative stress by free heme released during hemolysis contribute to sepsis-induced kidney insuffciency in SCD. AA and SS mice were subjected to 18 h of sham operation and cecal ligation and puncture (CLP), a pre-clinical model of polymicrobial sepsis, after which kidney function was evaluated by transdermal measurement of glomerular filtration rate (GFR). AKI biomarkers, renal oxidative stress, and cytokines levels were also investigated. We demonstrate that mid- to high-grade CLP (ligation of 60-75% of the cecum and multiple punctures with 21-gauge needles) caused 100% mortality in SS mice. Unlike AA mice (100% survival), SS mice subjected to low-grade CLP (LgCLP; ligation of &lt;45% of the cecum and a single puncture with 21-gauge needles) exhibited 40% survival. LgCLP reduced body weight but did not exacerbate splenomegaly in SS mice. Basal plasma bilirubin, heme, and ferritin were significantly higher in SS than in AA mice. In contrast to AA, LgCLP amplified the increase in plasma bilirubin, heme, and ferritin in SS mice. LgCLP also decreased GFR and increased renal oxidative stress, AKI biomarkers, and kidney-to-body weight ratio in SS mice. Luminex multiplex cytokine analysis indicated that the plasma levels of multiple pro-inflammatory cytokines were elevated in septic SS mice. Heme scavenger hemopexin (HX) diminished LgCLP-induced plasma heme increase. HX also mitigated kidney insuffciency, inflammation, and mortality in the septic SS mice. Our findings suggest that free heme contributes to septic AKI in SCD mice and that HX therapy may attenuate the harmful effect of heme in SCD during sepsis. NHLBI: R01 HL151735. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Proteomic analyses of urinary exosomes identify novel potential biomarkers for early diagnosis of sickle cell nephropathy, a sex-based study.

Sickle cell nephropathy (SCN) is a leading cause of morbidity and mortality in sickle cell disease (SCD). Early intervention is crucial for mitigating its effects. However, current diagnostic methods rely on generic tests and may not detect SCN until irreversible renal damage occurs. Therefore, specific biomarkers for early diagnosis of SCN are needed. Urinary exosomes, membrane-bound vesicles secreted by renal podocytes and epithelial cells, contain both common and cell type-specific membrane and cytosolic proteins, reflecting the physiologic and pathophysiologic states of the kidney. Using proteomics, we analyzed the proteomes of urinary exosomes from humanized SCD mice at 2months (without albuminuria) and 4months (with albuminuria) of age. Excretion of 164 proteins were significantly increased and 176 proteins was significantly decreased in the exosomes when mice developed albuminuria. Based on the relevance to SCD, chronic kidney disease and Western blot confirmation in mice, we analyzed protein abundance of heparanase, cathepsin C, α2-macroglobulin and sarcoplasmic endoplasmic Ca2+ ATPase-3 (SERCA3) in the urinary exosomes and urine of 18 SCD subjects without albuminuria and 12 subjects with albuminuria using Western blot analyses. Both male and female subjects increased or tended to increase the excretion of these proteins in their urinary exosomes upon developing albuminuria, but female subjects demonstrated stronger correlations between the excretion of these proteins and urine albumin creatinine ratio (UACR) compared to male subjects. In contrast, exosomal excretion of Tamm-Horsfall protein, β-actin and SHP-1 was independent of albuminuria. These findings provide a foundation for a time-course study to determine whether increases in the levels of these proteins precede the onset of albuminuria in patients, which will help determine the potential of these proteins as biomarkers for early detection of SCN.

Decreasing alloimmunization-specific mortality in sickle cell disease in the United States: Cost-effectiveness of a shared transfusion resource.

Red blood cell alloimmunization and consequent delayed hemolytic transfusion reaction (DHTR) incidence and mortality in patients with sickle cell disease (SCD) are high. A shared transfusion resource has decreased both in other countries, while in the United States cost concerns persist. We conducted a Markov cohort simulation of a birth cohort of alloimmunized patients with SCD to estimate lifetime DHTR incidence, DHTR-specific mortality, quality-adjusted life expectancy (QALE), and costs with the implementation of a shared transfusion resource to identify antibody history versus without (i.e., status quo). We conducted our analysis using a lifetime analytic time horizon and from a United States health system perspective. Implementation of shared transfusion resource projects to decrease cumulative DHTR-specific mortality by 26% for alloimmunized patients with SCD in the United States, relative to the status quo. For an average patient population of 32 000, this intervention would generate a discounted increment of 4000 QALYs at an incremental discounted cost of $0.3 billion, resulting in an incremental cost-effectiveness ratio of $75 600/QALY [95% credible interval $70 200-81 400/QALY]. The results are most sensitive to the baseline lifetime medical expenditure of patients with SCD. Alloantibody data exchange is cost-effective in 100% of 10 000 Monte Carlo simulations. The resource would theoretically need a minimum patient population of 1819 patients or cost no more than $5.29 million annually to be cost-effective. By reducing DHTR-specific mortality, a shared transfusion resource in the United States projects to be a life-saving and cost-effective intervention for patients with SCD in the United States.

Patterns of Blood Transfusion in Sickle Cell Disease Hospitalizations

Background: Transfusional iron overload causes significant morbidity and mortality in sickle cell disease (SCD). Nevertheless, red blood cell transfusions continue to be essential in its management. This study describes the transfusion patterns among SCD hospitalizations. Methods: Hospitalizations for SCD in the 2017–2018 Nationwide Readmissions Database were divided into two groups based on whether they received transfusions. Descriptive analysis was performed to compare their demographics and complications. Multivariable logistic regression was performed to determine the factors associated with transfusions. Results: Out of 109,783 hospitalizations, 28,300 were transfused, and 81,483 were not transfused. Females and older individuals were higher in the transfused category than the non-transfused category (59.49% vs. 53.52% and 28.86% vs. 21.27%, respectively; p &lt; 0.001 for both). The wealthiest population was more likely to be in the transfused category (11.27% vs. 8.34%; p &lt; 0.001). Admissions to teaching hospitals, large metropolitan hospitals, and highest-volume hospitals were higher in the non-transfused category vs. transfused category (79.89% vs. 72.17%; p &lt; 0.001, 69.26% vs. 65.35%; p 0.003 and 74.71% vs. 63.51%; p &lt; 0.001, respectively). Most admissions were transfused once, with three or more transfusions being given more in the non-teaching hospitals than the teaching hospitals (1.27% vs. 0.41%; p 0.01). Furthermore, a higher proportion of early transfusions occurred in the non-teaching hospitals (65.6% vs. 57.82% for admission days 1 and 2; p &lt; 0.001). Admission to a teaching hospital was associated with lower blood transfusion odds than a non-teaching hospital. Conclusion: A quarter of admissions for SCD receive a blood transfusion. In addition to performing more frequent and early transfusions, the odds of being transfused are higher in non-teaching hospitals.

Sickle Cell Disease Update: New Treatments and Challenging Nutritional Interventions.

Sickle cell disease (SCD), a distinctive and often overlooked illness in the 21st century, is a congenital blood disorder characterized by considerable phenotypic diversity. It comprises a group of disorders, with sickle cell anemia (SCA) being the most prevalent and serious genotype. Although there have been some systematic reviews of global data, worldwide statistics regarding SCD prevalence, morbidity, and mortality remain scarce. In developed countries with a lower number of sickle cell patients, cutting-edge technologies have led to the development of new treatments. However, in developing settings where sickle cell disease (SCD) is more prevalent, medical management, rather than a cure, still relies on the use of hydroxyurea, blood transfusions, and analgesics. This is a disease that affects red blood cells, consequently affecting most organs in diverse manners. We discuss its etiology and the advent of new technologies, but the aim of this study is to understand the various types of nutrition-related studies involving individuals suffering from SCD, particularly in Africa. The interplay of the environment, food, gut microbiota, along with their respective genomes collectively known as the gut microbiome, and host metabolism is responsible for mediating host metabolic phenotypes and modulating gut microbiota. In addition, it serves the purpose of providing essential nutrients. Moreover, it engages in direct interactions with host homeostasis and the immune system, as well as indirect interactions via metabolites. Nutrition interventions and nutritional care are mechanisms for addressing increased nutrient expenditures and are important aspects of supportive management for patients with SCD. Underprivileged areas in Sub-Saharan Africa should be accompanied by efforts to define and promote of the nutritional aspects of SCD. Their importance is key to maintaining well-being and quality of life, especially because new technologies and products remain limited, while the use of native medicinal plant resources is acknowledged.

Reversal of Cerebral Arteriopathy Post-Hematopoietic Stem Cell Transplant for Sickle Cell Disease.

Sickle cell disease (SCD) is a chronic hematologic disorder which causes progressive cerebral arteriopathy beginning in childhood. As a result, arterial ischemic stroke is a major cause of morbidity and mortality in SCD, and SCD is a leading cause of childhood stroke worldwide. Allogenic hematopoietic stem cell transplant (HSCT) may be curative for individuals with SCD. Long-term outcomes and effects are currently being studied. In this report, we describe a child with SCD who presented with arterial ischemic stroke at 6 years of age and was found to have a severe form of cerebral large vessel arteriopathy by catheter-directed angiography. The patient initially underwent revascularization surgery by indirect superficial temporal artery to middle cerebral artery bypass, and 1 year later, he underwent curative HSCT. Approximately 3 years after HSCT, repeat catheter-directed angiography revealed a striking reversal of cerebral large vessel arteriopathy. This article reveals a previously unrecognized and potentially beneficial effect of HSCT that may ameliorate cerebral large vessel arteriopathy and improve cerebrovascular health for children with SCD.

Hydroxyurea at escalated dose versus fixed low-dose hydroxyurea in adults with sickle cell disease.

Hydroxyurea reduces the frequency of vaso-occlusive complications, increases hemoglobin, and decreases mortality in sickle cell disease (SCD). Although current guidelines recommend escalation to maximum tolerated dose (MTD), the use of fixed low-dose hydroxyurea is common in low-resource countries. We conducted a systematic review and meta-analysis to evaluate the efficacy of escalated doses versus fixed low-dose of hydroxyurea in adults with SCD. Nine studies were included in the quantitative synthesis, four evaluating fixed low-dose and five evaluating escalated doses of hydroxyurea. Average daily doses of hydroxyurea in the fixed low-dose and escalated dose studies were ~10 and 22 mg/kg, respectively. There was no difference in the estimate of vaso-occlusive crisis rate between escalated and fixed low-dose studies (p = .73). The mean difference in hemoglobin from baseline to follow-up was greater for fixed low-dose than escalated dose studies (1.07 g/dL vs. 0.54 g/dL, p = .01). No difference was seen in the mean estimate of fetal hemoglobin. Despite limited eligible studies and substantial heterogeneity of effect between the studies for several outcomes, there appears to be clinical equipoise regarding the most appropriate hydroxyurea dosing regimen in adults with SCD. Controlled studies of hydroxyurea at MTD versus fixed low-dose in adults with SCD are required.

Alkaline Phosphatase As a Marker for Acute Complications in Sickle Cell Disease

Background: Sickle cell disease (SCD) can result in complications affecting multiple organ systems, including renal, pulmonary, and central nervous system. Alkaline phosphatases (ALP) comprise a group of isoenzymes which function to catalyze the hydrolysis of inorganic phosphate monoesters, including phosphoethanolamine, inorganic pyrophosphate, and pyridoxal-5′-phosphate. Predominantly, serum ALP is derived from the liver and bone (1). An elevation in serum ALP primarily signifies hepatobiliary disorders, wherein cholestasis and bile duct damage results in increased enzyme synthesis as a compensatory mechanism. Increased ALP levels can also be an indication of bone disease associated with increased osteoblast activity (2). ALP has been linked to the severity of the pain crisis in SCD (3), and there is also evidence that ALP is a predictor for increased mortality risk in SCD (4-6). This study aims to investigate ALP as a biomarker of SCD severity and acute organ complications (VOE). Methods: This retrospective study included 252 patients aged 18 years or older with SCD who were admitted to the University of Illinois Chicago (UIC) hospital for the management of vasoocclusive pain events (VOEs) between July 1, 2017, and June 30, 2018. The study recorded the following complications during hospitalization: acute chest syndrome, acute kidney injury, acute liver injury, thrombotic or hemorrhagic stroke, deep vein thrombosis or thromboembolism, the need for transfer to the intensive care unit, the need for exchange blood transfusion, or death during hospitalization. Data analyses were performed using the Kruskal-Wallis test, Chi-square test, linear or a stepwise ordinal logistic regression analysis. Results: The median age of this cohort was 31 years (interquartile range 26-42 years), 36% were males and 72% had hemoglobin SS/Sβ0 with 33% on hydroxyurea. In this cohort, 105 patients experienced at least one complication during at least one hospitalization(s) within the one-year study period, while 147 were hospitalized but did not experience complications during the hospitalization (Table 1). A comparison of clinical characteristics between the two cohorts revealed that patients with complications had a higher prevalence of HgbSS/Sβ0-genotype; had higher ALP, total bilirubin, and AST concentrations; Patients with complications had a greater number of hospitalizations and longer length of stay in both the median length and the total length over the study period (Table 2). In a multivariable model comparing baseline characteristics, HgbSS/Sβ0-genotype and increased ALP levels at baseline were significant predictors of complications during hospitalization, after adjusting for other variables as listed in the table (Table 3). Furthermore, in a subgroup analysis of patients with HgbSS/Sβ0-genotype, this relationship was even stronger: higher baseline ALP levels were significantly associated with acute complications during the study period (OR 7.3, 95% CI: 2.2 - 24.1, p = 0.001). Summary: Our findings suggest that SCD patients with longer hospital stay and higher numbers of admissions tend to have acute complications during hospitalization. Individuals with the HgbSS/Sbeta0 genotype and higher levels of ALP are at an increased risk of developing acute complications, which could potentially account for the increased mortality risk associated with alkaline phosphatase reported by previous literature. K. Makris, C. Mousa, E. Cavalier, Alkaline Phosphatases: Biochemistry, Functions, and Measurement. Calcif Tissue Int112, 233-242 (2023).J. Masrour Roudsari, S. Mahjoub, Quantification and comparison of bone-specific alkaline phosphatase with two methods in normal and paget's specimens. Caspian J Intern Med3, 478-483 (2012).J. I. Brody, W. N. Ryan, M. A. Haidar, Serum alkaline phosphatase isoenzymes in sickle cell anemia. JAMA232, 738-741 (1975).J. J. Feld et al., Liver injury is associated with mortality in sickle cell disease. Aliment Pharmacol Ther42, 912-921 (2015).S. A. Curtis, N. Danda, Z. Etzion, H. W. Cohen, H. H. Billett, Longitudinal Analysis of Patient Specific Predictors for Mortality in Sickle Cell Disease. PLoS One11, e0164743 (2016).V. Sachdev et al., A phenotypic risk score for predicting mortality in sickle cell disease. Br J Haematol192, 932-941 (2021).

Fucosyltransferase VII (FUT7) Activity in Patients with Sickle Cell Disease and Healthy Controls

Background:Sickle cell disease (SCD) is a severe monogenic disorder with a majority of the affected individuals living in Africa. Vaso-occlusion is a significant cause of morbidity and mortality in SCD, and selectin mediated intercellular adhesion is recognized as an important target for therapy. As such Anti-P-selectin agents are in clinical use to reduce the frequency of vaso-occlusive crises (VOCs) in SCD patients. Sialyl lewis x is a crucial ligand common to all members of the selectin family and the final step in the biosynthesis of sialyl lewis X antigen (fucosylation), is catalysed by Fucosyltransferase VII (FUT7). This enzyme is most expressed in leukocytes and endothelial cells. We hypothesized that FUT7 enzyme activity is abnormal in SCD patients and differs by VOC severity. We sought to measure plasma levels of FUT7 in SCD patients and healthy controls, and investigate their association with clinical and laboratory features, such as the frequency of VOCs. Methods:This wasa single centre cross-sectional analytical study at the University of Nigeria Teaching Hospital, Enugu. 38 steady state adult SCD patients and 40 HbAA age- and sex-matched healthy control subjects were enrolled. SCD patients were stratified by clinical severity into: Group A- 19 subjects with mild disease (0-1 crises and no disease complication such as stroke, chronic leg ulcers, nephropathy, or avascular necrosis in the previous year), and Group B- 19 patients with moderate to severe disease (2 or more crises in the previous year, with or without complications). We excluded patients with red cell transfusion within 4 months, on hydroxyurea, or other agents that may affect vaso-occlusive crisis frequency, and co-existing chronic disorders unrelated to SCD, such as asthma and diabetes mellitus. We performed a CBC and plasma FUT7 enzyme concentration measurements (ELISA kit, MyBiosource Inc, USA). Statistical analysis was performed with SPSS version 22.0 for Windows. A 2-tailed P value of &amp;lt;0.05 was used. Results:Our subjects were predominantly female (SCD 52.5%, HbAA 55%), with median age 28 years (range 19-46 and 19-45 for SCD and HbAA, respectively). Median frequency of VOCs in patients was 1 (range 0-5). Avascular necrosis (32.5%) was the most common complication, while stroke, acute chest syndrome, and eye disease were the least common. As expected, SCD patients had lower haemoglobin levels than HbAA (7.9±1.3g/dL vs. 12.6±1.4g/dL, P&amp;lt;0.001). Significantly higher WBC, ANC, and platelet counts were observed in SCD patients compared with HbAA controls (P&amp;lt;0.001). No significant correlations were found between FUT7 and haematocrit (r =0.06), WBC count (r = -0.08), neutrophil count (r = -0.12), and platelet count (r =0.1), with P values of 0.7, 0.6, 0.5, and 0.6, respectively. We found no difference between the median and IQR values of plasma FUT7 of SCD (2.1; 1.8-2.5) and controls (2.2; 1.8-2.8), P = 0.7. FUT7 activity was higher in SCD subjects in Group A (2.2; 1.9-2.9) than in Group B (2.0; 1.2- 2.4), with a trend towards significance P = 0.1. Discussion:In this study, FUT7 activity did not differ between SCD patients and controls. We also did not find correlations between FUT7 and blood cell counts, suggesting that plasma FUT7 activity is not increased at baseline in SCD and that the degrees of anemia or leukocytosis are not associated with changes in FUT7. Nonetheless, a mild decrease in FUT7 levels was found in more severe SCD patients and should be confirmed in a larger study. Our study did not evaluate patients in crises or who received hydroxyurea and/or other SCD-modifying therapies. Since FUT7 catalyses selectin expression, variation in its activity may be more relevant in subgroups of SCD patients on anti-selectin therapies. Future studies should be carried out in such patients to explore FUT7 activity as a marker of acute vaso-occlusion and as a modifier of response to therapy.

A Phase II Study to Evaluate the Safety and Efficacy of Defibrotide and Changes in Plasma Biomarkers in Sickle Cell Disease-Related Acute Chest Syndrome (IND 127812)

Background: Acute Chest Syndrome (ACS) is the greatest contributor to the morbidity and mortality of Sickle Cell Disease (SCD) patients with a rate of 12.8 cases per 100 patient-years. The mortality rates of ACS are 4 times higher in adults than in children (Vichinsky et al, Blood, 1997). The root cause of ACS in SCD is related to endothelial dysfunction (Paul et al, European Journal of Hematology 2011). While existing therapies target infection, inflammation, and alveolar hypoxia, they do not address endothelial dysfunction, a major contributor to SCD associated ACS. Defibrotide is a polydisperse mixture of predominantly single stranded oligonucleotides derived from porcine intestinal mucosa. Several pre-clinical studies indicate that defibrotide primarily protects endothelium, particularly in small vessels, and reduces endothelial cell injury (Falanga et al, Leukemia, 2003) (Cairo/Cooke et al, British Journal of Haematology 2020). In a randomized phase III study, a decrease in incidence of SOS/VOD was observed in pediatric hematopoietic stem cell transplantation patients who received prophylactic defibrotide (Corbacioglu et al, Lancet, 2012). We hypothesized that Defibrotide would be safe and well tolerated in children and adolescents with SCD-associated ACS. Primary Aims: To determine the safety and efficacy of defibrotide in the treatment of patients with SCD-associated ACS. Design/Methods: Patients with SCD- (Homozygous Hemoglobin S disease, Hemoglobin SC Disease or Hemoglobin Sβ 0/+ Thalassemia) associated ACS 2 to 40 years of age were enrolled. Defibrotide, generously supplied by Jazz Pharmaceuticals, was administered at 6.25 mg/kg IV Q6H (total daily dose 25 mg/kg/day) within 24 hours of consent and continued for 7 days or until the patient was discharged from hospital (IND 127812) (NCT 03805581). All patients were treated with current standard of care, including antibiotics, analgesics, oxygen, intravenous fluids, and packed red blood cells (PRBC)/exchange transfusion. Complete blood counts and coagulation studies were performed at baseline, day 7 and day 30, while chest radiograph (CXR), CT chest angiogram (CTA), pulmonary function test, and transthoracic echocardiogram were performed at baseline and 30 days after defibrotide was first given. Blood plasma was collected from patients at baseline, day 7, day 30, and age matched SCD patients without ACS and analyzed for biomarkers of inflammation through ELISA and Luminex multiplex assays and significance was calculated using two-tailed T tests. Results: We have enrolled 20 patients (median age 9.5 years) with a gender ratio of M/F 8/12. Patients had hemoglobin SS (n=14), hemoglobin Sβ 0/+ (n=2), or hemoglobin SC (n=4). The median doses of defibrotide per patient was 18.5 (range 6-28) and the average hospital admission length was 6.1 days (range 3-13 days). There were no serious adverse events possibly, probably, or directly related to defibrotide, as judged by investigators. Two patients had a grade I/II epistaxis that did not disrupt defibrotide's course. Pulmonary infiltrate on CXR and/or CTA was the most common finding at diagnosis, detected in 18/20 study participants. Thirteen patients had fever as a presenting symptom, with an average fever duration of 2.8 days (range 1-6 days). Nine patients required O 2 supplementation, with an average duration of 4.1 days (range 2-7 days). Thirteen patients were treated with blood transfusions with a median of 1.9 units (PRBC unit was defined as 15ml/kg) transfused per patient (range, 1-5 units) and 1 patient underwent an exchange transfusion (Table 1). Soluble Intercellular Adhesion Molecule-1 (sICAM-1) was significantly elevated at the onset of ACS (p &amp;lt; 0.01) compared to control SCD plasma and was reduced by Day 30 after defibrotide treatment. Other markers of inflammation, including Angiopoetin-2 (Ang2), Interleukin-6 (IL-6), and Phospholipase A2-IIA (PLA2G2A) were elevated at baseline in patient plasma samples but were significantly decreased following defibrotide treatment (p &amp;lt; 0.05, 0.01, 0.01, respectively) (Figure 1). Conclusion: Our data suggests that defibrotide is safe and well tolerated in SCD patients with ACS. sICAM-1, Ang2, IL-6, and PLA2G2A may serve as important biomarkers in SCD associated ACS. A randomized phase II/III multi-center clinical trial will need to be conducted to further investigate efficacy of defibrotide in patients with SCD-associated ACS.

Predicting Hemoglobin Response to Hydroxyurea and Voxelotor in Adults with Sickle Cell Disease

Background: Chronic anemia contributes to morbidity and mortality in sickle cell disease (SCD) and is associated with stroke, leg ulcers, pulmonary hypertension (PH), priapism, and chronic kidney disease (CKD). Treatment options for anemia in SCD are limited - hydroxyurea (HU) is the gold standard treatment, but hemoglobin (Hb) responses to HU in adult and pediatric cohorts appear to be modest at best. We evaluated the Hb response to HU and voxelotor in an adult SCD cohort, as well as baseline factors associated with Hb response to HU. Methods: This longitudinal study was based on retrospective chart review of patients with SCD followed in the UPMC Adult Sickle Cell Program, with drug start dates between 2007 and May 2023. Subjects with a documented start date for HU/voxelotor, a baseline Hb ≤ 3 months prior to starting drug, and a follow-up Hb at 1 or 3 months (± 2 weeks) after the start date were included. Those who self-discontinued therapy were excluded. Baseline factors were collected within ≤ 3 months of drug start date. Given the small number of subjects on voxelotor, factors associated with Hb response were evaluated in the HU group only. Baseline factors were reported using descriptive statistics and compared between Hb responders (defined as Hb increase ≥ 1 g/dL from baseline - a common outcome measure in clinical trials of anti-polymerization agents) and non-responders. Linear regression analysis was performed with change in Hb at 1 month (ΔHb) as the outcome of interest, as Hb levels at 1 and 3 months were highly correlated (r=0.905, p&amp;lt;0.001) and there were fewer missing values for Hb at 1 month. Variables associated with ΔHb with p&amp;lt;0.25 were included in a multivariable regression model. P&amp;lt;0.05 was considered significant, and 95% confidence intervals (CI) were reported. Results: Out of 394 subjects, 93 met eligibility criteria, including 88 starting HU and 5 starting voxelotor. One subject in the voxelotor group was on stable-dose HU. Median ages at start of HU and voxelotor were 24.5 years (range 13-57) and 45.4 years (range 22-60), respectively. Females accounted for 50/88 (56.8%) HU subjects and 4/5 (80%) voxelotor subjects. HbSS genotype made up 47/88 (53.4%) of the HU group and 4/5 (80%) of the voxelotor group. Median baseline Hb in the HU group was 9.8 g/dL, with a median increase of 0.2 g/dL and 0.3 g/dL at 1 and 3 months, respectively. In contrast, baseline Hb in the voxelotor group was 7.2 g/dL with a median increase of 1.9 g/dL and 2.1 g/dL at 1 and 3 months, respectively. Hb response was observed in 21/88 (24%) subjects in the HU group vs. 4/5 (80%) subjects in the voxelotor group. Among responders, median Hb increase was 2.2 g/dL (1 month) and 2.0 g/dL (3 months) with HU. Median baseline ferritin was 200 ng/mL in the HU group and 2413 ng/mL in the voxelotor group. In the HU group, lower baseline Hb was associated with female sex, severe SCD genotype (HbSS, HbSβ 0), and higher HbS%, WBC count, platelet count, and hemolytic markers (lactate dehydrogenase, total bilirubin, and reticulocyte count) (data not shown). Demographic/clinical variables were not associated with Hb response, except for male gender at 3 months (Table 1). Lower baseline Hb, RBC count, and hematocrit and higher MCHC, HbS%, LDH, and total bilirubin were associated with positive Hb response at 3 months. HbF% was higher in the responder groups but was not significant. In a multivariable linear regression model including age, PH, leg ulcers, CKD, baseline Hb, platelets, and total bilirubin as explanatory variables, baseline Hb was negatively associated with ΔHb (B = -0.26, CI = -0.40 to -0.12, p&amp;lt;0.001). History of leg ulcers was also negatively associated with ΔHb but was not significant (B = -0.94, CI = -2.01 to 0.13, p=0.083). Conclusion: Overall, Hb response to HU was much lower compared to voxelotor, though in the 24% of subjects who responded to HU, the Hb increase was comparable. Though limited by small sample size, our data revealed that patients started on voxelotor vs. HU were older, more anemic, and more iron overloaded. Subjects with lower baseline Hb had a more robust Hb response to HU. While limited by the absence of dosing and adherence data, this study provides proof of concept of using baseline characteristics to predict Hb response to SCD therapies, demonstrating the feasibility of a personalized treatment approach in SCD. In addition, our data provide real-world evidence of the effectiveness of HU vs. voxelotor for chronic anemia in SCD.

SNAP: Implementation of Supportive Non-Invasive Ventilation for Acute Chest Syndrome Prevention in Adults with Sickle Cell Disease

Introduction Acute chest syndrome (ACS) is the 2 nd most common cause of hospitalization and a major cause of mortality in sickle cell disease (SCD). ACS commonly occurs during a hospitalization for a vaso-occlusive crisis (VOC) when the combination of chest wall pain and intravenous opioids may lead to hypoventilation and atelectasis. Incentive spirometry may prevent ACS by encouraging patients to take deep breaths to reduce atelectasis and improve oxygenation, but requires active participation by an awake patient. Non-invasive bi-level positive airway pressure [BiPAP] provides positive pressure breaths via a mask to improve ventilation and prevent atelectasis during sleep. Hospitalized pediatric SCD patients who were at risk for ACS have used nocturnal BiPAP for ACS prevention on the Boston Medical Center (BMC) general pediatric unit since February 2017. In January 2023, BMC instituted the use of nocturnal BiPAP in hospitalized adult patients with SCD who are at high risk for ACS. Methods This is a prospective observational cohort study to examine the safety, acceptability, and tolerability of BiPAP in high-risk adult patients with SCD hospitalized with a VOC. Criteria for increased ACS risk included: 1) Oxygen saturation &amp;lt; 94% on room air at presentation; 2) History of pulmonary hypertension diagnosed by right heart catheterization; 3) Known obstructive sleep apnea (OSA) not currently treated with positive airway pressure; 4) Prior severe ACS requiring invasive or non-invasive ventilation, high-flow oxygen, and/or exchange transfusion; or 5) History of fat emboli syndrome. Exclusion criteria were: 1) OSA being treated with outpatient positive airway pressure, 2) Surgery within the last 30 days, 3) Direct admission to the intensive care unit (ICU). Manual chart extraction was used to collect patient demographic data, medical history, symptoms, vital signs, chest radiography, laboratory data, indications for BiPAP use, and acceptability and use of BiPAP. Results BiPAP was offered during 38 hospitalizations to 25 individual patients (14 (56%) female) between February and July 2023. The mean age was 35.8 years (SD 10.2); 16 (64%) were HbSS, 8 (32%) HbSC and 1 (4%) HbS-β 0. Nineteen patients (76%) were using &amp;gt;1 SCD-modifying therapy; 16 (64%) reported hydroxyurea use. ACS was present on admission in 7 hospitalizations. Patients agreed to try BiPAP in 22/38 hospitalizations (58%) and BiPAP was used for 1 night in 3 hospitalizations, 2 nights in 3 hospitalizations and more than 2 nights in 7 hospitalizations. In 9/22 hospitalizations, attempts at BiPAP use were unsuccessful. Of the 38 hospitalizations in which BiPAP was offered, 3 patients who did not use BiPAP were transferred to the ICU, 2 for ACS and 1 for ketamine infusion for pain that was refractory to high doses of opioids. Three episodes of ACS developed after admission to the hospital: 2 when BiPAP use had not been attempted and 1 when BiPAP was used for 6 days. Blood transfusions were administered during 7 hospitalizations; 5 of which BiPAP was not used. No deaths occurred during this study period. No adverse events were directly attributable to this novel use of BiPAP for ACS prevention. In the 22 encounters where BiPAP use was attempted, four patients noted difficulties with the continuous airflow and feeling suffocated, one reported lightheadedness. One patient who used BiPAP developed oral pain related to periodontal disease. Conclusion Medically stable, adult hospitalized patients with SCD and VOC were willing to try BiPAP to prevent the development of ACS. In 13/22 (59%) BiPAP was tolerated for &amp;gt;1 one night with no adverse events noted. Future directions include optimizing implementation and studying the efficacy of this intervention.

Socioeconomic and Inflammatory Correlates of Plasma Cortisol Among Individuals with Sickle Cell Disease

Introduction: Cortisol plays a critical role in the biological link between stress and health outcomes. It is frequently investigated in the association between socioeconomic stress and morbidity, and the hypothesized biological mechanism by which socioeconomic stress and cortisol impact health is through chronically elevated systemic inflammation. This research is relevant to individuals with sickle cell disease (SCD) for several reasons. First, up to 40% of children and adolescents with SCD are impacted by neighborhood poverty. Furthermore, individuals with SCD are faced with significant disease-related morbidities, such as chronic and acute pain, renal injury, and cerebrovascular disease that are further complicated by elevated inflammatory markers. Finally, cortisol is heavily understudied in this population, with no research investigating socioeconomic or inflammatory correlates. The purpose of this study was to investigate plasma cortisol and its association with neighborhood-level socioeconomic factors (income and poverty) and immunomodulatory cytokines (IL-6, IL-10), among individuals with SCD. Method: Plasma from individuals with SCD within Children's Hospital of Philadelphia (CHOP) and University of Pennsylvania School of Medicine (Penn Medicine) BioBanks were identified. A cortisol radioimmunoassay was used to determine plasma cortisol levels. The Olink immune response panel was used to measure plasma levels of 92 proteins involved in inflammatory pathways. Home address collected from electronic health records was used to determine neighborhood census tract geoid, which was then used to collect data on median neighborhood income and percentage of families living in poverty from the 2020 American Census Survey. Bivariate and multivariate analyses were conducted across 4 subgroups in the total sample: pediatric patients, adult patients, SCA (HbSS/HbSß 0), and other SCD genotypes (HbSC/HbSß +). Control samples (healthy and sickle cell trait; n = 22) without neighborhood information were also available for comparison. Results: Fifty-four independent outpatient samples were identified after excluding duplicates and siblings. Twenty-seven samples were from children and adolescents receiving pediatric care at CHOP (Range age = .8 to 21; Mage= 13.6, SD = 5.3; 51.9% female, 74.1% SCA) and 27 samples were from adults receiving care at Penn Medicine (Range age = 19 to 56; Mage= 35.8, SD = 10.1; 51.9% female, 51.9% SCA). There were no significant differences in cortisol levels across each subgroup ( Mpeds= 16.6, SDpeds = 6.2; Madult= 13.4, SDadult = 6.9; MSCA= 15.1, SDSCA = 7.1; MSCD= 14.9, SDSCD = 6.3). Neighborhood income and poverty did not differ across pediatric and adult patients, and income did not differ across SCD types. However, neighborhood poverty was lower among patients with SCA ( M = 13.9; SD = 11.9) relative to other SCD genotypes ( M = 21.7; SD = 13.5; p = .041). Bivariate Spearman analyses found that neighborhood variables were not correlated with cortisol or cytokines in the total sample or subgroups. Yet, multivariate analyses controlling for sex and time of blood draw showed a positive main effect for patient age ( p = .019) and a significant age by poverty interaction ( p = .041) predicting cortisol among pediatric patients. Cortisol levels were higher with age, yet the association among poverty and cortisol was strongest in younger patients. Analyses also showed a sex*poverty interaction among pediatric patients that approached significance ( p = .081), such that poverty only predicted cortisol in male patients. There were no significant differences for immunomodulatory cytokines across each SCD subgroups; however, IL-6 and IL-10 were elevated in patients with SCA relative to healthy controls ( p IL6 = .021; p IL10 = .003). Bivariate Spearman correlations showed that cortisol was positively related to IL-6 (rho [ρ]= .38, p = .027) and IL-10 (ρ= .34, p = .048) among patients with SCA. There were no additional significant bivariate or multivariate effects. Conclusion: Neighborhood factors likely have downstream effects on the biological stress response and inflammation in SCD. Further research must be conducted to elucidate concurrent and prospective associations among neighborhood socioeconomic factors, stress-related cortisol response, and inflammatory outcomes when extending this work to investigate the impact of stress on SCD morbidity and mortality.

National Long-Term Follow-up of Children with Sickle Cell Disease Diagnosed By Newborn Screening in the Netherlands: Overview of the Morbidity and Mortality

Background: Sickle cell disease (SCD) is a genetic red blood cell disorder associated with increased morbidity and mortality. Newborn screening for SCD was introduced in January 2007 in the Netherlands to enable early diagnosis and initiation of preventive measures. The objective of this study was to assess the effect of newborn screening on the morbidity and mortality of children living with SCD in the Netherlands, 16 years after its implementation. Methods: In this national cohort study all children with SCD diagnosed by newborn screening were included. Patients were followed between 1 January 2007 and 31 March 2023 until end of follow-up, death or successful stem cell transplantation. Following informed consent, data were collected from medical files on SCD genotype, treatment, mortality and development of SCD-related complications. The incidence rate of SCD-complications was presented as lifetime-event per 100 person-years for the total duration of follow-up and for the age categories: 0-4, 5-11, and 12-16 years. Results: In total, 391 out of 540 eligible patients (72%) with SCD were included in all hospitals with patients with SCD under treatment, accounting for 3047 person-years. The mean age at the end of follow-up was 7.8 years (SD±4.5). The majority of patients had SCD genotype HbSS (58%), followed by HbSC (28%). As for the mortality, five patients died during follow-up, primarily at or below the age of 2 years (4/5, 80%). In three patients, the cause of death was related to SCD, including infection (n=2; aged 1.2 and 2.0 years) and acute splenic sequestration (n=1; 2.0 years). The SCD-related complications are presented in Table 1. The most common SCD complication in this cohort was vaso-occlusive crisis (including dactylitis) with hospitalization. SCD-related complications that mainly developed within the first 4 years of life, were vaso-occlusive crisis, acute hemolytic crisis, aplastic crisis, severe infections, splenic sequestration and ischemic cerebral infarction. Acute chest syndrome occurred equally in all age categories. Other SCD-related complications developed to a lesser extent in our cohort, and at a later age in adolescence or adulthood. Conclusion: In this cohort of neonatally screened children with SCD, a substantial number of SCD-complications occurred in the first 4 years of life. This study underlines the importance of parental education and 24/7 availably, high level acute specialized clinical care for these children from birth on. Further analysis to identify risk factors at young age for a severe phenotype will be conducted, to enable more targeted interventions in a timely manner. Hopefully, this will lead to reduction of disease burden, improving the quality of life in children living with SCD in the Netherlands.

Hydroxyurea's Impact on Erythropoiesis, Cell Death and HbF Expression in the Hudep-2 Model

Background : Sickle cell disease (SCD) is an inherited disorder caused by a mutation in the beta-globin gene, leading to the synthesis of sickle hemoglobin called HbS. Under deoxygenated conditions, HbS polymerizes and forms fibers that weakens red blood cells (RBC) resulting in hemolysis and vaso-occlusion. Recently, ineffective erythropoiesis in SCD has been reported, characterized by higher apoptosis levels during late erythropoiesis. Interestingly, fetal hemoglobin (HbF)-expressing erythroblasts during erythroid differentiation seem to be protected from the apoptosis. Hydroxyurea (HU) is the first major approved drug for SCD in US and Europe; its proven efficacy in decreasing SCD morbidity and mortality is mainly mediated by the induction of HbF expression that is well-known as a modulator of disease severity through its ability to interfere with HbS polymerization. Despite being used for decades, HU action mechanism still remains to be fully elucidated. More precisely, HU impact on RBC maturation process is poorly documented as well as its mode of action on gamma-globin gene expression. Aim : Our aim is to investigate the effect of HU on erythropoiesis kinetics, HbF induction and apoptosis. Methods : We used HUDEP-2 (Human Umbilical cord Derived Erythroid Progenitors-2) cell line as a model for erythropoiesis. Cells were differentiated in normoxia (20% oxygen) or hypoxia (5% oxygen) - to mimic bone marrow environment, and were treated or not with HU allowing the comparison of HU effect both in normoxia and hypoxia. Analysis was performed at day D1, D3, D6, D8 and D10 of differentiation using flow cytometry, microscopy (MGG staining) and High-Performance Liquid Chromatography (HPLC). Kinetics of differentiation were followed by microscopy with MGG coloration and by flow cytometry using GPA, CD49d, Band3 and HbF antibodies. Apoptosis was assessed using annexin V staining. Results : Wedid first assess HU effect on HbF expression during erythropoiesis by flow cytometry and HPLC. Both methods showed that HU induced HbF expression from D1 to D6 of differentiation and that this induction is higher when the cells are in hypoxic conditions. We also investigated the apoptotic rate during erythropoiesis. Interestingly, HU treatment does not induce apoptosis in differentiating erythroblast, but decreased proliferation rates by 2-fold change in normoxia. Hypoxic conditions also decreased proliferative rate similarly to HU in normoxia but interestingly, in hypoxic conditions, HU did not furthermore decrease cell proliferation. Then, we investigated HU effect on the differentiation kinetics. Based on the differential expression of CD49d and Band3 along the differentiation, the percentage of each stage of differentiation (proerythroblast, basophilic, polychromatic and orthochromatic) was estimated by flow cytometry in GPA + cells at D1, D3, D6, D8 and D10 of the differentiation. Figure 1 depicted flow cytometry representative results from our 4 culture conditions at D1. Our results did show that HU accelerates HUDEP-2 differentiation as soon as D1 of culture (normoxia D1 NT vs HU: ProE 53.3% vs 44%, Baso 29.9% vs 33.1%, Poly 15.2% vs 18% and Ortho 3.3% vs 3.8%) until the end of the differentiation (D8 and 10) in normoxia. This acceleration is accentuated in hypoxic conditions (Hypoxia D1 NT vs HU: ProE 34.7% vs 17.9%, Baso 42.2% vs 50.3%, Poly 17.7% vs 25.8% and Ortho 3.8% vs 4.7%) with a cumulative effect of hypoxia and HU. All the flow cytometry results were confirmed by MGG staining and quantification by microscopy. For the same day of differentiation, HU-treated HUDEP-2 are in later stages than HU-non treated cells. Conclusion : Our study is the first to investigate the impact of HU on RBC maturation - erythropoiesis. HU treatment increases HbF expression without impacting apoptosis. The treatment tends to promote erythroid differentiation by accelerating maturation processes with stronger effect in hypoxic conditions that mimic the in vivo low oxygen environment of the bone marrow, strongly suggesting that HU has other molecular targets than inducing HbF. All these results will be confirmed in CD34 + erythroid progenitors from patients with SCD. Our results give new insights on the effect of HU on erythropoiesis that would ultimately lead to a better understanding of its mechanism of action and to the identification of new therapeutical targets to counteract SCD ineffective erythropoiesis.

Characterization of Sickle Cell Disease Mortality in a National Electronic Health Record (EHR) System

Introduction Sickle cell disease (SCD) is a chronic condition with significant morbidity in children and early adult mortality. Identifying high-risk SCD populations has been challenging due to limited population cohorts of children and adults. Understanding the clinical course of SCD in both children and adults is crucial for informed treatment decisions around disease-modifying therapy vs. curative and transformative therapies. Recent use of Medicaid, Medicare, and private insurer claims datasets has helped define high-risk populations and estimate mortality, but they have limitations in clinical record depth. In contrast, electronic health record (EHR)-based datasets offer a better option for assessing the impact of disease-modifying therapy and allow comprehensive mortality risk prediction analyses, using high-dimensional laboratory data. Objective Previously, using the data warehouse at a single institution (Vanderbilt University School of Medicine) with data collected over 18 years, members of our team developed a contemporaneous cohort of children and adults with SCD. To do this our team developed a dual-approach algorithm that combined patients categorically selected by diagnosis using ICD-10 (International Classification of Diseases -10) codes and by laboratory data including hemoglobin fractionation values. The team estimated the median survival in adults with SCD and predicted mortality risk based on disease-modifying therapy and insurance status. We expanded this work by testing the hypothesis that we can first apply the laboratory portion of the Vanderbilt algorithm to identify children and adults with SCD living in the United States from the national Cerner Learning Health Network (Cerner LHN) EHR dataset. Methods The Cerner LHN is a nationwide dataset comprised of 88 million patients from over 74 hospital systems across 37 states (as of September 17, 2021). We used data from the Cerner LHN collected between 8/26/2002 and 12/13/2022 for our analysis. We extracted laboratory data elements required for the Vanderbilt algorithm including hemoglobin fractionation data with HbS values as well as total hemoglobin timepoints and blood transfusion time frames. The results of the laboratory portion of the Vanderbilt algorithm predict genotype of sickle cell disease in the following categories: SCA (HbSS or HbSB 0 ), SC (Hb SC), HbSBeta + and HbSE. There were 5,827 patients identified with these laboratory components necessary for the algorithm. We applied an updated python script that detailed the logic from the Vanderbilt algorithm on the 5,827 patients and we identified 3,248 children and adults with SCD. Patients were then evaluated for demographics and hospital systems coverage within the Cerner LHN. Results Black/African Americans made up 2947 patients (90.7%) of the SCD cohort. There were 1325 (54%) male and 1150 (46.5%) female patients with SCA within the phenotyped cohort. Patients with SCA were collected from 44.6% of the Cerner LHN health systems. Conclusions The population was 90.7% Black/African American as expected in patients carrying a diagnosis of SCD. This contemporaneous national cohort represents 44.6% of the health systems within the Cerner LHN which denoted wide-reaching patient sampling. These findings show that the laboratory portion of the Vanderbilt SCD algorithm can, in an automated fashion, establish a phenotyped SCD cohort of children and adults in a national EHR system. We plan to power the total number by adding the ICD-10 portion of the algorithm and estimating mortality in the final cohort. Further, we will validate combined algorithm by chart review.

Rhabdomyolysis aggravates renal iron accumulation and acute kidney injury in a humanized mouse model of sickle cell disease

Individuals with sickle cell disease (SCD) are at greater risk of rhabdomyolysis, a potentially life-threatening condition resulting from the breakdown of skeletal muscle fibers. Acute kidney injury (AKI) is one of the most severe complications of rhabdomyolysis. Chronic kidney and cardiovascular disease, which account for SCD mortality, are long-term consequences of AKI. Although SCD elevates the risks of rhabdomyolysis-induced sudden death, the mechanisms that underlie rhabdomyolysis-induced AKI in SCD are unclear. In the present study, we show that, unlike their control non-sickling (AA) counterparts, transgenic homozygous SCD (SS; Townes model) mice exhibited 100% mortality 8–24 h after intramuscular glycerol injection. Five hours after glycerol injection, SS mice showed a more significant increase in myoglobinuria and plasma creatine kinase levels than AA mice. Basal plasma heme and kidney tissue iron levels were significantly higher in SS than in AA mice. In contrast to AA, glycerol-induced rhabdomyolysis aggravated these parameters in SS mice. Rhabdomyolysis also amplified oxidative stress in SS compared to AA mice. Glycerol-treated SS mice exhibited worse renal function, exemplified by a reduction in GFR with a corresponding increase in plasma and urinary biomarkers of early AKI and renal tubular damage. The free radical scavenger and Fenton chemistry inhibitor, TEMPOL, ameliorated rhabdomyolysis-induced AKI in the SS mice. These findings demonstrate that oxidative stress driven by renal iron accumulation amplifies rhabdomyolysis-induced AKI in SCD mice.

Infection and Potential Challenge of Childhood Mortality in Sickle Cell Disease: A Comprehensive Review of the Literature from a Global Perspective

Sickle cell disease (SCD) is a complex genetic disorder associated with multiple clinical manifestations, including increased susceptibility to bacterial and viral infections. This review article presents a comprehensive analysis of the current literature obtained from various online databases focusing on the relationship between SCD and infections caused by specific pathogens, such as pneumonia- and influenza-causing pathogens, Escherichia coli, Staphylococcus aureus, parvovirus, and hepatitis viruses. We discuss the underlying mechanisms that contribute to the increased susceptibility of individuals with SCD to these infections, primarily related to the pathophysiology of variant hemoglobin (HbSS) and its impact on vascular occlusion, hemolysis, functional asplenia, and immune deficiency. Moreover, we highlight the significant burden of infections on SCD patients, particularly children under five years of age, where they are the leading cause of morbidity and mortality. Additionally, we address the challenges faced in attempts for reducing the global mortality rate associated with SCD, particularly in low-income countries, where factors such as increased pathogen exposure, co-morbidities like malnutrition, lower vaccination rates, and limited healthcare facilities contribute to the high disease burden. This review emphasizes the need for targeted interventions, improved healthcare access, vaccination programs, and infection prevention strategies to alleviate the impact of infections on individuals with SCD and reduce the global mortality rates associated with the disease.

Systematic Literature Review Shows Gaps in Data on Global Prevalence and Birth Prevalence of Sickle Cell Disease and Sickle Cell Trait: Call for Action to Scale Up and Harmonize Data Collection.

Sickle cell disease (SCD) is an inherited monogenic disorder with high prevalence throughout sub-Saharan Africa, the Mediterranean basin, the Middle East, and India. Sources of SCD epidemiology remain scarce and fragmented. A systematic literature review (SLR) to identify peer-reviewed studies on SCD epidemiology was performed, with a search of bibliographic databases and key conference proceedings from 1 January 2010 to 25 March 2022 (congress abstracts after 2018). The SLR followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Meta-analyses, using a binomial normal random-effects model, were performed to estimate global and regional prevalence and birth prevalence. Of 1770 journal articles and 468 abstracts screened, 115 publications met the inclusion criteria. Prevalence was highest in Africa (~800/100,000), followed by the Middle East (~200/100,000) and India (~100/100,000), in contrast to ~30/100,000 in Europe. Birth prevalence was highest in Africa (~1000/100,000) and lowest in North America (~50/100,000) and Europe (~30/100,000). This SLR confirmed that sub-Saharan and North-East Africa, India, the Middle East, and the Caribbean islands are global SCD hotspots. Publications including mortality data were sparse, and no conclusions could be drawn about mortality. The identified data were limited due to gaps in the published literature for large parts of the world population; the inconsistent reporting of SCD genotypes, diagnostic criteria, and settings; and a sparsity of peer-reviewed publications from countries with assumed high prevalence. This SLR demonstrated a lack of systematic knowledge and a need to provide uniform data collection on SCD prevalence and mortality.