bims-sicedi 2025-06-08 papers

Br J Haematol. 2025 Jun 04.

Assessment of neurocognitive functioning in sickle cell disease and thalassaemia and the association with silent cerebral infarcts, cerebral haemodynamics and oxygen metabolism.

Liza Afzali-Hashemi, Melanie Franse, Koen P A Baas, Anouk Schrantee, Erfan Nur, John C Wood, Aart J Nederveen, Bart J Biemond, Sharon H O'Neil.

Neurocognitive impairment is a key concern in sickle cell disease (SCD) patients, affecting several factors including academic performance, employment and quality of life. While the exact causes remain unclear, correlations with silent cerebral infarcts (SCIs) and abnormal perfusion and oxygenation have been reported in paediatric SCD populations. This study aimed to examine these associations in adults with SCD, including 70 severe SCD patients (HbSS & HbSβ0-thal), 22 mild SCD patients (HbSC & HbSβ+-thal), 16 thalassaemia patients and 29 healthy controls. We assessed seven neurocognitive domains: attention, working memory, processing speed, non-verbal IQ, verbal learning, visual memory and fine motor dexterity. Additionally, we analysed relationships between neurocognitive performance, SCIs, haemodynamics and oxygen metabolism parameters, including cerebral blood flow (CBF), oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2). Our findings reveal that only processing speed was affected in SCD patients relative to norms, thalassaemia patients and controls. Fine motor dexterity was lower across all groups, possibly due to normative data not reflecting the transition from handwriting to typing. Notably, we found no correlation between neurocognitive performance, SCIs and perfusion and oxygenation parameters, suggesting that reduced processing speed may stem from other SCD-related factors, highlighting the need for further research.

Keywords: neurocognitive functioning; oxygen metabolism; sickle cell disease; thalassaemia haemodynamics

DOI: https://doi.org/10.1111/bjh.20181

bioRxiv. 2025 May 15. pii: 2025.05.12.653546. [Epub ahead of print]

Voxelotor (Oxbryta) Binds Multiple Hemoglobin Sites and Influences Protein Structure.

Michael de la Cueva Tamanaha, Esmeralda Flores Cabrera, Joshua Sargeant, Paul D Gershon, Premila P Samuel Russell, Melanie J Cocco.

Voxelotor (Oxbryta, GBT440) is a first-in-class drug, FDA-approved to treat sickle cell disease in 2019 but withdrawn from market in 2024. This drug acts as an allosteric modulator, designed to shift the equilibrium to the oxygenated R conformation. The drug was shown to both limit the accumulation of deoxygenated T-conformation sickle cell Hb fibers and increase Hb oxygen affinity. X-ray crystallography previously showed one-to-one Voxelotor binding stoichiometry for Hb, with the drug molecule bound to N-terminus of an alpha subunit. Here we use NMR spectroscopy to assess the structure of Voxelotor-bound hemoglobin in solution and mass spectrometry (MS) to determine stoichiometry and sites of binding. We find that the structure and stoichiometry of binding are far more heterogeneous than previously described. The addition of Voxelotor to R-conformation Hb induces an NMR signal found in the T-conformation of Hb. In addition, MS shows that the drug binds Hb at multiple sites, including the N-terminus of the beta subunit. The properties of Hb with Voxelotor bound at secondary sites have not been explored but should be considered at high doses. Heterogeneous binding should be assessed in other drugs of this class including GBT(021)601 currently in clinical trial.

DOI: https://doi.org/10.1101/2025.05.12.653546

Turk J Pediatr. 2025 May 05. 67(2): 186-194

Increased serum YKL-40 levels in children with sickle cell disease.

Veysi Akbey, Selma Ünal, Özlem Tezol, Bahar Taşdelen, Şenay Balcı Fidancı, Feryal Karahan.

BACKGROUND: YKL-40 is a glycoprotein secreted by various cell lines during inflammation and vascular dysfunction. Sickle cell disease (SCD) also involves inflammation and endothelial dysfunction processes. Thus, we aimed to assess the levels of YKL-40 in pediatric SCD patients.
METHODS: We evaluated serum levels of YKL-40 in children with steady state SCD and those with vaso-occlusive crisis (VOC) episodes and compared them with healthy subjects.
RESULTS: Overall, 33 children with SCD and 33 healthy controls participated in this study. Serum YKL-40 concentrations of children with steady state SCD were significantly higher than the concentrations found in the healthy controls (median [Q1-Q3]: 71.0 [53.3-133.3] vs. 43.6 [37.9-69.9] ng/mL, p=0.001). Seventeen of the 33 children with SCD (51.5%) had a VOC during the one-year follow-up period. Steady state and VOC episode YKL-40 did not significantly differ in children who were experiencing VOC during the one-year follow-up (77.6 [55.2-126.8] vs. 69.7 [49.3-100.0] ng/mL, p=0.381). During VOC episodes, children with SCD had significantly higher YKL-40 levels than the healthy controls (69.7 [49.3-100.0] vs. 43.6 [37.9-69.9] ng/mL, p=0.005). YKL-40 levels at steady state and during VOC episodes did not show significant correlation (p=0.955).
CONCLUSIONS: YKL-40 may have a potential role in the inflammation component of SCD. Circulating YKL-40 levels may be used to monitor chronic inflammation in SCD patients.

Keywords: YKL-40; chitinase-3-like protein-1; endothelial dysfunction; human cartilage glycoprotein 39; inflammation; sickle cell disease

DOI: https://doi.org/10.24953/turkjpediatr.2025.4805

Br J Haematol. 2025 Jun 03.

Risk factors for immediate postpartum sickle cell disease-specific maternal morbidity.

Joanna Loh, Kevin H M Kuo, Ilinca Georgescu, Stella Wang, Ella Huszti, Nadine Shehata, A Kinga Malinowski.

Pregnant individuals with sickle cell disease (SCD) are more likely to have postpartum complications. In this retrospective single-centre study, 201 pregnancies from 145 individuals were assessed between 2000 and 2018 for the presence of a composite of immediate postpartum complications from admission during delivery to discharge, which included vaso-occlusive pain events, acute chest syndrome, infection (blood, urine, pulmonary) and/or new-onset hypoxia. Hypoxia was defined as SpO2 below 92%. An immediate postpartum complication occurred in 74 pregnancies (37%), of which 97% experienced a vaso-occlusive pain event. No immediate postpartum deaths were recorded. Pregnancies with HbSS/HbSβ0 as compared to HbSC/HbSβ+ had a higher incidence of the composite outcome (51% vs. 19%). On univariate analysis, HbSS/HbSβ0 genotype was associated with a higher likelihood of developing a postpartum complication (OR 4.49, 95%CI 2.35-8.57; p < 0.0001); however, this significance was reduced on multivariable analysis. The strongest risk factors associated with experiencing the composite outcome on multivariable analysis were hypoxia during pregnancy (OR 4.95, 95%CI 1.86-13.23; p = 0.001) and an unscheduled caesarean delivery (OR 2.67; 95%CI 1.26-5.64; p = 0.01). Future studies need to address whether correcting hypoxia and use of predictive scores to guide the need for a scheduled caesarean delivery can reduce immediate postpartum complication rates.

Keywords: postpartum; pregnancy; puerperium; risk factors; sickle cell disease

DOI: https://doi.org/10.1111/bjh.20178

BMC Public Health. 2025 Jun 04. 25(1): 2070

The economic burden and catastrophic health expenditures among children with sickle cell anaemia on households in malaria-endemic areas: insights from Uganda and Malawi.

Carol Kamya, Richard Idro, Dennis Kalibbala, Kamija S Phiri, Thandile Nkosi-Gondwe, Pamela Akun, Joanita Kirikumwino, Oddvar Kaarboe, Robberstad Bjarne.

BACKGROUND: Chronic diseases such as sickle cell anaemia (SCA) often lead to catastrophic health expenditures, especially in malaria-endemic regions. There is limited evidence on the economic burden faced by households with children suffering from SCA. This study aimed to assess the household economic burden of SCA and the incidence of catastrophic health expenditures in Uganda and Malawi.
METHODS: This prospective cohort study was nested in a clinical trial comparing malaria chemoprevention regimes: weekly dihydroartemisinin-piperaquine versus monthly sulfadoxine-pyrimethamine for children aged 6 months to 15 years in Uganda and Malawi. The economic burden was evaluated using the cost of illness approach by measuring and valuing direct and indirect costs. Quantile regression models were employed to identify factors associated with these costs.
FINDINGS: The study included 723 children with an SCA (437 in Uganda and 286 in Malawi) with mean ages of 7.3 years (SD 3.9) and 8.0 years (SD 4.1), respectively. The annual median costs per household were $638.8 (IQR: $227-$2,693) in Uganda and $387.3 (IQR: $203-$694) in Malawi. The main contributors to the economic burden were direct costs in Uganda and indirect costs in Malawi. Factors such as malaria episodes, hospitalisation, hydroxyurea use, household wealth, children's age, and gender significantly influenced direct and indirect costs. The concentration indices (CI) revealed a pro-rich distribution with poorer households incurring higher direct costs in both Malawi, CI=-0.12 (SE = 0.00, P < 0.00), and Uganda, CI= -0.23 (SE = 0.02, P < 0.000). Most households in both countries experienced catastrophic health expenditures, with the highest incidence in the poorest quartile.
CONCLUSION: Households with children with SCA incur high expenditures, which are catastrophic for a substantial proportion of them. Malaria episodes, hospitalisation and wealth status significantly increase the economic burden on households. Targeted interventions are needed to alleviate this financial strain, reduce disparities and improve outcomes for vulnerable households. Enhancing access to improved treatment strategies, such as effective malaria prevention measures and the consistent availability of hydroxyurea, could help reduce the number of sick episodes and, consequently, the economic burden on households and patients.

Keywords: Africa; Catastrophic health expenditure; Cost of illness; Economic burden; Malaria-Endemic; Malawi; Sickle cell anaemia; Uganda

DOI: https://doi.org/10.1186/s12889-025-23209-x

Iran J Otorhinolaryngol. 2025 ;37(3): 123-133

Risk Factors for Sensorineural Hearing Loss in Children and Adolescents with Sickle Cell Disease.

Amos Solomon, Nurudeen Adebola Shofoluwe, Hafsat Ahmad, Abdulkadir Isa, Shuiabu Iliyasu Yunusa, Hamza Anka Manir.

Introduction: Sickle cell disease (SCD) is a major global health burden with significant clinical, social, and economic impacts. Sensorineural hearing loss (SNHL) is an underreported complication of SCD that is, primarily attributed to vaso-occlusive crises and ischemia. This condition adversely affects the quality of life, education, and social integration, particularly among children in resource-limited settings. Understanding the risk factors for SNHL is crucial for prevention, early detection, and timely intervention. This study evaluated the prevalence of SNHL in children with SCD and identified associated risk factors.
Materials and Methods: This prospective comparative study was conducted at a tertiary healthcare facility in Northwest Nigeria. A total of 250 children aged 5-16 years were enrolled, comprising 125 patients with confirmed sickle cell disease (SCD) in a steady state and 125 age- and sex-matched controls with a normal haemoglobin genotype (HbAA).
Results: Bilateral SNHL was identified in 25.6% of SCD cases, whereas no SNHL was observed in the control group. The male-to-female ratio among the affected children was 1.2:1. Multivariate logistic regression revealed significant associations between SNHL and elevated white blood cell count (Odds Ratio {OR} 1.035; 95% Confidence Interval {CI} 1.020-1.050), elevated platelet count (OR 1.209; 95% CI 1.070-1.365), poor clinic attendance (OR 28.668; 95% CI 4.879-168.458; P= < 0.001), non-compliance with SCD medications (OR 9.634; 95% CI 1.830-50.718; P = 0.008), and frequent severe sickle cell crises requiring hospitalization (OR 2.106,; 95% CI 0.019-0.598; P = 0.001).
Conclusion: This study highlights the high prevalence of SNHL in children with SCD and its association with modifiable risk factors. Routine audiological screening, consistent clinic attendance, medication adherence, and regular monitoring of haematological parameters are essential for early identification and management of SNHL. Targeted interventions can significantly improve the outcomes and reduce the burden of this debilitating complication.

Keywords: Risk factors; Sensorineural hearing loss; Sickle cell disease; Steady state

DOI: https://doi.org/10.22038/ijorl.2025.74314.3500