Sickle cell disease (SCD) is an inherited red blood cell disorder with significant complications, including vaso-occlusive crisis (VOC), the most common cause of emergency department (ED) visits and hospitalizations. Pain in children with SCD is often underestimated. We evaluated the impact of a standardized institutional nurse-initiated ED SCD pain protocol, using intranasal (IN) fentanyl (INF) as the initial agent, on hospital admission rates. We conducted a preintervention/postintervention study of patients with SCD (aged 0-21 years) presenting to a quaternary pediatric ED for uncomplicated VOC pain from June 2015 to December 2019. Overall, 162 patients accounted for 471 ED visits in the preintervention period and 80 patients accounted for 162 visits in the postintervention period. After intervention, hospitalization rates (P = .0017) and inpatient length of stay (P = .0019) decreased, but median pain scores at presentation (P = .0047) and discharge (P = .1451) remained comparable. The time to initial analgesia dose significantly improved in the postintervention (P< .0001), along with the time from physician order to initial analgesia administration (P = .0005). IV and IN analgesia use rose significantly in the postintervention (odds ratio, 4.7; P< .0001), with INF being the preferred analgesic agent (61%) and a corresponding reduction in oral analgesic use (P< .0001). In an ad hoc sustainability analysis, INF use remained high and time to first dose was sustained. Implementing a standardized ED SCD pain protocol improved timeliness and consistency in analgesia administration and decreased overall hospitalization rates. This study also highlights the role of INF as an effective initial analgesic within standardized ED protocols for pediatric VOC.

Hematopoietic cell transplant (HCT) for sickle cell disease from human leukocyte antigen (HLA)-identical sibling and alternate donors is associated with excellent outcomes. HCT was implemented under restrictive eligibility and exclusion criteria because mortality was >10% in the early experience. These restrictive criteria were carried over to contemporary HCT and gene therapy (GT) clinical trials. Additionally, patients with chronic pain, stroke, psychiatric disorders, or adherence issues were excluded from GT trials. The United States Food and Drug Administration qualification of GT broadly identifies recurrent vaso-occlusive episodes (VOE) as the indication and stipulates no exclusion criteria, thus raising the question of which criteria to use in clinical GT. Excellent overall and event-free survival, improvement in health-related quality of life, amelioration of VOE, and stabilization of cerebral vasculopathy following HLA-identical sibling donor HCT and GT justify broad application of GT in patients with a history of severe VOE, with shared decision-making guided by patient preferences while acknowledging gaps in evidence.

Platelet-neutrophil ratio as a potential biomarker for stroke risk stratification in children and young adults with sickle cell anaemia in resource poor settings.

Epidemiological and comorbidity burden in transfusion-dependent patients with thalassemia and sickle cell disease in Greece.

Abstract Objectives Sickle cell disease is one of the most prevalent inherited hemoglobin disorders globally, affecting over 300,000 newborns annually, with the majority born in sub-Saharan Africa. Children with sickle cell disease are particularly vulnerable to severe bacterial infections, which are a major cause of morbidity and mortality. Among these, Salmonella species, especially non-typhoidal Salmonella, are frequently implicated and are notably associated with osteomyelitis, a serious bone infection. In this study, we performed whole genome sequencing and genomic analysis of 12 Salmonella isolates recovered from osteomyelitis cases in children with sickle cell disease in Dakar, Senegal. Methods The isolates’ identity was confirmed using a MALDI-TOF biotyper and antimicrobial susceptibility testing carried out using the disc diffusion method. Whole-genome sequencing was conducted on an Illumina platform and bioinformatic analyses carried out using open-access and custom tools. Results The isolates belonged to seven serovars, with Enteritidis and Typhimurium being the most frequent (three isolates each). Antibiotic susceptibility testing showed that 11 isolates were fully susceptible to all tested drugs, while one was an extensively drug-resistant strain previously linked to a nosocomial outbreak in a neonatal unit. Most of the isolates contained important Salmonella virulence factors including several Salmonella Pathogenicity Islands and plasmid-borne virulence genes. Conclusion These findings highlight the clinical significance of Salmonella infections in children with sickle cell disease in low-income settings and underscore the urgent need for genomic surveillance and targeted public health interventions to protect this high-risk population.

Patients with sickle cell anemia (SCA) have long been discouraged from physical activity (PA). The aim of the present study was to assess the impact of increasing daily step counts on physical fitness, pain and vascular function in patients with SCA. Thirty-eight patients with SCA were recruited and equipped with a Fitbit wrist-worn accelerometer-based PA tracker for 5 weeks to objectively quantify their baseline daily step counts. Patients were then randomly assigned to one of the three groups: 1) control group: no specific information regarding PA was given for 8 weeks (N=12); 2) PA1 group: daily step counts increased by 25% of baseline for 8 weeks (N=12); 3) PA2 group: daily step counts increased by 25% for 4 weeks, then by 50% for 4 additional weeks (N = 14). Pain intensity and frequency decreased after the intervention in the PA1 and PA2 groups. In addition, patients from these two groups increased the distance walked in 6 minutes. Arterial stiffness decreased in both PA1 and PA2 groups, without any change in the autonomic nervous system activity. Several inflammatory markers slightly decreased in the PA2 group. Incubation of cultured endothelial cells with patient plasma showed a decrease in the percentage of ICAM-1 positive cells in the PA2 group. This study is the first to show that increasing daily PA by a simple way (i.e., increasing daily step count of 25-50%) for 8 weeks is sufficient to decrease pain, and improve physical condition and vascular function of patients with SCA.

Abstract Objectives Sickle Cell Disease (SCD) is a rare, inherited blood disorder causing acute and chronic complications that affect physical, psychological, and social well-being. This study examines SCD patient characteristics using a biopsychosocial model integrating biological, quality-of-life (QoL), and social factors across life stages. Methods This observational study, conducted between November 2022 and July 2024 at a tertiary care hospital in Northern Italy, included patients aged 4–25 years with confirmed SCD. Participants underwent cognitive and QoL assessments; genotype, hospital visits, treatments, and socio-demographic data were collected. Wechsler scales assessed intellectual abilities; PROMIS questionnaires measured QoL. Analyses were performed with SPSS. Results Eighty-nine patients were enrolled. Profiles showed age-related clinical, cognitive, and psychosocial variations. Around 45% reported anxiety and depression, and 50% experienced social isolation and pain interference. Adolescents and young adults (12–25 years) exhibited higher psychological vulnerability—depression, pain interference, and fatigue—than younger groups (p&amp;lt;.007). Cognitive performance was below normative means, particularly in executive functions (p=.039). Working memory and processing speed were most affected, declining with age. Significant differences emerged in Verbal Comprehension [F(3,82)=6.473, p&amp;lt;.001] and Perceptual Reasoning [F(3,82)=2.987, p=.036], with poorer outcomes in older participants. Visuospatial skills were relatively preserved but declined in young adults. Conclusions Age-specific risk patterns highlight the need for developmentally tailored, multidisciplinary care. Early detection of cognitive and emotional vulnerabilities, together with preventive strategies, may reduce long-term complications and improve QoL. However, the cross-sectional design of the study limits causal inferences. Overall, findings support holistic care models addressing medical, cognitive, psychological, and social dimensions of SCD.

Background Sickle cell disease (SCD) is a major chronic hematologic disorder in Saudi Arabia associated with recurrent vaso-occlusive crises (VOCs), acute pain episodes, and heavy reliance on emergency department (ED) visits. Despite improvements in survival, longitudinal data on ED utilization patterns and their determinants remain limited in the region. Therefore, the aim of this study is to assess temporal trends and predictors of ED utilization among patients with SCD across multiple tertiary centers in Saudi Arabia between 2016 and 2021. Methods This multicenter retrospective cohort study analyzed data from the National Guard Health Affairs (NGHA) electronic health record (EHR) system across five hospitals (Riyadh, Jeddah, Madinah, Dammam, and Al-Ahsa). The study included all patients with a confirmed SCD diagnosis (ICD-10 code D57) and at least one ED visit during the study period. After applying the eligibility criteria, 691 patients were included. Exposure Demographics, comorbidities, hospital region, and prescribed ED medications, including opioids, non-steroidal anti-inflammatory drugs (NSAIDs), neuropathic agents, and benzodiazepines. The primary outcome was annual ED visits per patient. Multivariable negative binomial regression estimated incidence rate ratios (IRRs) with 95% confidence intervals (CIs), adjusted for demographics, comorbidities, and clustering by hospital site. Results The cohort [mean (SD) age, 26.5 (13.6) years; 350 (50.7%) men] showed a sharp rise in ED visits from 9.2 visits in 2016 to 38.8 in 2021 (relative increase, + 76.3%; P &amp;lt; 0.001). Hospital admissions also rose from 6.3 to 13.6 ( P &amp;lt; 0.001). In 2021, the mean ED visit rate [38.83 (2) ± 10.59] exceeded the threshold for high ED utilization &amp;gt; 33. Male gender (IRR, 1.52; 95% CI, 1.28–1.81; P &amp;lt; 0.001), older age (per 10 years: IRR, 1.27; 95% CI, 1.08–1.50; P = 0.006), and asthma (IRR, 1.29; 95% CI, 1.04–1.60; P = 0.02) predicted higher ED utilization. Opioids were prescribed in 96.5% of visits, mostly for single-day use (93.5%). Conclusion ED utilization among patients with SCD from the NGHA hospitals in Saudi Arabia rose substantially between 2016 and 2021, reflecting both clinical severity and system-level care gaps. Our findings highlight the need for standardized pain protocols, comprehensive outpatient services, and Vision 2030–aligned transformations to reduce preventable ED dependence.

Sickle-cell disease (SCD) is a severe autosomal recessive disorder. At-risk couples may prevent transmission either through prenatal diagnosis with possible termination of pregnancy or preimplantation genetic testing for monogenic disease (PGT-M). Data on PGT-M outcomes in this population remain scarce. We conducted a monocentric retrospective study (2006-2021). To assess ovarian response to stimulation, each PGT-M cycle for SCD was matched with two control cycles. Sixty couples underwent at least one ovarian stimulation for PGT procedure for SCD. Eight couples (13.3%) had one affected partner (S/S or S/C) and one carrier (A/S), while 52 couples (86.7%) were both carriers (A/S). Thirty-five couples (58.3%) already had an affected child, and 17 couples (28.3%) requested PGT-M with HLA typing. Median female age at first attempt was 33years. Overall, 19 couples (31.7%) achieved at least one live birth following fresh or frozen embryo transfer. Among the 17 couples requesting HLA typing, three HLA-matched births (15.7%) and one unmatched healthy birth were achieved. None of the five women affected by SCD achieved a live birth. Ovarian response did not differ significantly between women with sickle cell trait and the controls. PGT-M is as a viable option for obtaining healthy offspring. These results bolster the argument that PGT-M serves as an alternative to prenatal diagnosis for eligible couples. Our study aims to assist geneticists, gynecologists, and hematologists in providing the necessary guidance before embarking couples on this long and often challenging journey.

Diffuse optical spectroscopies are promising non-invasive optical techniques that may provide a point-of-care tool to evaluate cerebral hemometabolic stress. This study quantifies the intra- and inter-operator reliability of a battery of cerebral hemometabolic parameters quantified with diffuse correlation spectroscopy (DCS) and frequency-domain near-infrared spectroscopy (FDNIRS) in children with sickle cell anemia. For measures of cerebral blood flow, oxygen extraction fraction, metabolic rate of oxygen, and cerebral blood volume, we found inter-operator concordance correlation coefficients (CCC) ranging from 0.45 to 0.97, intra-operator CCCs ranging from 0.81 to 0.98, and a median coefficient of variation &lt; 16%.

Retinal microvascular alterations in sickle cell disease: a systematic review and meta-analysis of OCTA findings based on genotype and stages of retinopathy.

Clinically significant alloantibodies complicate transfusion and prenatal care, especially in individuals with genetic variants affecting high-frequency antigens. Many patients from African descent carry RHCE*ceVS alleles, which alter the expression of c (RH4), e (RH5) and hrB (RH31). However, the risk and clinical impact of alloimmunization remain uncertain. We evaluated the alloimmunization in a cohort of patients with a RHCE*ceVS genotype. We conducted a retrospective study on 48 patients with a RHCE*ceVS genotype divided into three categories: prenatal care, patients with sickle cell disease (SCD) and other or unspecified diagnosis. No anti-c, anti-e or anti-hrB were found in prenatal care patients or in patients with other or unspecified diagnosis. Among transfused patients with SCD, 50% developed an anti-e. Anti-hrB was identified in two patients, both with SCD. Warm autoantibodies were found in 58% of transfused patients with SCD, many of whom had an anti-e. The risk of developing anti-e or anti-hrB antibodies was low in patients with an RHCE*ceVS genotype, except in those with SCD. In patients with SCD, the presence of autoantibodies, recent transfusions and technical caveats complicate the assessment of clinical impact; therefore, an individualized evaluation of alloimmunization risk is recommended.

Emerging therapies in sickle cell disease (SCD) aim to restore healthy red blood cell (RBC) function, but they often yield heterogeneous cellular responses. There are no proven techniques to evaluate restored rheological functionality and heterogeneity in these RBCs. We present a biomimetic microcapillary network, high-speed imaging, and computational algorithms to analyze RBC capillary velocity profiles of the entire sample population at single-cell resolution. Using peripheral RBCs from SCD patients and healthy donors, we showed that RBC capillary transit velocity correlated with cell shape, hydrodynamic adaptability, and elongation index. Healthy RBCs exhibited a velocity distribution skewed toward higher values, whereas RBCs from individuals with SCD showed a shift toward lower velocities. SCD samples had a greater fraction of slow RBCs than healthy controls (42.1% ± 12.0% vs. 19.0% ± 4.9%, p < 0.0001). We tested mixtures of healthy and SCD RBCs to simulate heterogeneous therapeutic effects and demonstrated that the assay was sensitive to small fractions of abnormal RBCs. The slow RBC fraction emerged as a potential biomarker associated with SCD disease severity. This fraction significantly increased under hypoxia showing sensitivity to hypoxia-induced sickling. Finally, we assessed in vitro-derived RBCs and observed distinct velocity profiles for nucleated and enucleated cells. Processing methods to enrich enucleated RBCs improved the velocity profile, producing a distribution that was more comparable to that of peripheral RBCs. This platform's ability to assess individual RBCs and generate a velocity profile from a small number of cells makes it well suited for evaluating the rheological properties of in vitro-derived RBCs.

Blood transfusion remains a cornerstone in the management of sickle cell disease (SCD); however, it is frequently complicated by red cell alloimmunisation. A significant debate persists within the scientific community regarding the optimal strategy to mitigate this risk: the traditional, pragmatic approach of serologic phenotyping versus molecular genotyping, which is technically superior yet more resource-intensive. This mini-review aims to map the framework of this scientific debate and synthesize current evidence through a dual methodology. A scientometric analysis was conducted on 224 articles indexed in Scopus and Web of Science using the Bibliometrix package for R, followed by a structured narrative review of 26 selected studies. The scientometric findings confirm growing interest in this topic, identifying two distinct yet interconnected research clusters that reflect the ongoing dialectic between phenotyping and genotyping, with the latter emerging as a 'hot topic' over the past decade. The narrative synthesis highlights a predominance of evidence supporting genotyping as the most accurate approach to preventing alloimmunisation, particularly given the high prevalence of RH system variants in individuals with SCD. In contrast, cost-effectiveness analyses and implementation studies underscore substantial financial and logistical barriers that favour a more pragmatic, stepwise approach. We conclude that the future of transfusion safety in SCD does not lie in a binary choice but rather in a synergistic and stratified integration of both strategies. Implementing protocols that target genotyping for high-risk patients, while simultaneously optimising the use of extended phenotyping, represents the most promising pathway to balance safety, cost and accessibility-ultimately ensuring the best possible transfusion therapy for this vulnerable population.

Protease activated receptor 1 (PAR1) is expressed by numerous cell types, including endothelial. Thrombin cleaves PAR1 at Arg41 and activates pro-inflammatory and barrier disruptive signaling. Alternatively, PAR1 is cleaved at Arg46 by activated protein C (APC) bound to endothelial protein c receptor (ECPR), inducing anti-inflammatory and barrier protective signaling. In sickle cell disease (SCD), we showed that thrombin-PAR1 signaling contributes to vascular stasis, and more recently that PAR1-R41 biased signaling enhances inflammation, whereas PAR1-R46 signaling reduces thrombo-inflammation. We hypothesized that ECPR-PAR1-R46 biased signaling protects sickle mice from thrombo-inflammation. To test this hypothesis, Townes sickle mice were treated with parmodulin (parmodulin 2 (PM2, aka ML161), or NRD-21) to promote protective, anti-inflammatory PAR1-biased signaling. We found that PM2 significantly attenuated thrombin generation, inflammation, endothelial activation, and protected sickle mice from a model of lethal acute chest syndrome. These results suggest that utilizing PM2 to block thrombin-PAR1 signaling while inducing APC-like signaling can promote cytoprotective, anti-inflammatory effects in mouse models of SCD.

Effective transition programs are essential for adolescents and young adults with sickle cell disease (SCD), yet their long-term impact remains unexplored. The St. Jude SCD Transition Program provides structured transition interventions, including disease education, personal health record (PHR) communication training, transition skills-building, academic guidance, and early adult care introduction for patients aged 12-25 . This 13-year retrospective cohort study evaluated program effectiveness on first adult visit attendance, successful adult care transfer, adult ambulatory and acute care utilization, and health-related quality of life (HRQOL). Among 638 patients, 74.5% attended their first adult visit and 40.0% successfully transferred to adult care (2 visits within the first-year post-transfer). Increased participation in nearly all transition interventions was associated with first adult visit attendance, and all interventions were associated with successful transfer. In-person SCD education and early introduction to adult care were independently associated with first adult visit attendance, while in-person SCD education and PHR training were independently associated with successful transfer. A predictive model incorporating intervention exposure and demographics yielded an area under the curve of 0.81 for attendance at the first adult visit (95% CI: 0.75-0.88; sensitivity 0.76, specificity 0.70). PHR training was associated with adult ambulatory utilization up to 3 years post-transfer and improved early adulthood HRQOL. No interventions were associated with acute care utilization. Transition interventions improving disease literacy, communication, and care transfer processes are linked to better transition outcomes and HRQOL, though sustained adult care engagement remains low. Future research is needed to promote adult care engagement.

Hereditary spherocytosis and sickle cell disease are two distinct hematologic diseases that affect the morphology of the red blood cell, causing implications related to splenic sequestration. Concurrent disease is very rare, with even fewer reported instances requiring surgical intervention. Furthermore, an individual with a third concomitant hematologic abnormality such as Factor VII deficiency, which degrades the normal clotting cascade, has not previously been reported. We describe an active-duty servicemember with known hereditary spherocytosis, sickle cell trait, and Factor VII deficiency who had recurrent worsening pain crises post-flight. The resulting hepatobiliary and splenic damage that ensued ultimately required splenectomy. These diseases in combination further enhance risks associated with splenic damage and intra-operative bleeding, with special consideration for intra-operative risk management and long-term sequala from end-organ damage. The military population exacerbates these conditions where physical exertion, high-altitude travel, and rapid geographic reassignment are considered the norm. This case of a servicemember with a unique disease triad managed successfully with surgical correction underscores the importance of individualized care planning and consideration of duty readiness.

Critically ill patients are exposed to important pharmacokinetic alteration that can lead to under- or over-exposure. In addition, children and neonates undergo physical growth and organ maturation that alter drug pharmacokinetics, especially children with sickle cell disease who frequently experience organ dysfunctions. The aim of the study was to describe cefotaxime and desacetyl-cefotaxime pharmacokinetics and optimize dosing regimens in this population. We performed a pharmacokinetic analysis of cefotaxime and its metabolite desacetyl-cefotaxime via a population approach. Trough concentrations and steady-state concentrations were then simulated using several doses and were compared to pharmacological targets: 100% fT > 4 × MIC and Cτ or CSS < 60 mg/L. A total of 797 cefotaxime and desacetyl-cefotaxime observations were collected from 242 children and neonates, including 50 with sickle cell disease (SCD). Cefotaxime data was best described by a two-compartment model with first-order absorption and elimination. A supplemental compartment was linked to the cefotaxime central compartment to describe desacetyl-cefotaxime pharmacokinetics. Allometric scaling with bodyweight, eGFR and Sickle cell status turned out to be significant in the model. Post-menstrual age was used to describe organ maturation functions for neonates. Simulations showed that probability of attaining targets was systematically better through continuous perfusion. Doses were suggested up to 300 mg/kg/day according to covariates. We identified bodyweight, SCD status and eGFR as significant covariate that influence cefotaxime PK. Continuous infusion was the most performant way to achieve the pharmacological target in critically ill children and neonates, making a first necessary step towards individualized prescription in this fragile population.

Due to the multisystemic nature of sickle cell disease (SCD), complications can occur together and thus discerning costs associated with individual complications requires a methodology that can estimate the costs of a given complication while accounting for the presence of other complications. In this study, we aimed to estimate period-based incremental costs associated with specific chronic complications in patients with SCD in England while accounting for multimorbidity. All-cause primary and secondary care healthcare resource utilisation (HCRU) was obtained for a retrospective cohort of patients with SCD using Clinical Practice Research Datalink (CPRD) Aurum linked to Hospital Episode Statistics (HES) datasets. Annualised HCRU and costs were calculated, dividing patient-level events by patient-level time (in years) to obtain per person per year estimates. A series of generalised linear models were used with adjustment for demographic factors and proportion of follow-up time with each complication to estimate the costs associated with 10 chronic SCD-related complications of interest. For these costs, annual equivalent costs can be obtained by dividing by the median follow-up time of 4.74 years. Patients with a diagnosis of SCD, with or without complications, in CPRD or HES with at least 12 months follow-up. Period-based all-cause direct healthcare costs. Of the 1271 patients with SCD included in the study, 49.9% (n=634) had at least one complication and of these 41.3% (n=262) had two or more complications either at baseline or during follow-up. Patients with complications had higher all-cause healthcare costs compared with patients without complications (mean (SD) annualised cost £16 058 (£21 488) vs £4399 (£6635)). Patients with complications had four times the number of annualised inpatient admissions (6.1 vs 1.5 admissions) and more than double the number of annualised bed days in hospital (8.3 vs 3.8 days) over a median 4.74 years of follow-up. Of the complications evaluated, end-stage renal disease had the highest estimated incremental cost of £252 083 (95% CI £214 478 to £283 745) over 4.74 years; this is in addition to the £18 547 period-based cost among patients with SCD without complications. Osteonecrosis was the most common complication with an estimated incremental cost of £27 399 (95% CI £6417 to £43 319) over the same period. Estimating the cost of complications, while accounting for multimorbidity, is essential to determine the true direct cost of SCD. The modelling method presented in our study provides period-based estimates of cost and hospital admissions for individual complications in patients with SCD, accounting for multimorbidity. This approach can be used and extended to other diseases with multisystemic complications to estimate the direct HCRU and costs of individual complications.

The Pediatric Clinician's Approach to the Diagnosis and Management of Nocturnal Enuresis, Hypertension, and Albuminuria in Children with Sickle Cell Disease.