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September 28, 2025Open Access

Higher aged neutrophils and differential inflammatory profiles in sickle cell disease patients on chronic transfusion therapy versus those on hydroxyurea

KTKatrina TerrignoChildren's Hospital at Montefiore ZFZachary FlamholzAlbert Einstein College of Medicine AMAakash Mahant MahantAlbert Einstein College of Medicine

Key Points

Patients treated with hydroxyurea had significantly lower aged neutrophils compared to those on chronic transfusion therapy.
Hydroxyurea use was linked to lower levels of several inflammatory cytokines, indicating its potential to reduce inflammation.
Analysis included aged neutrophils and gut microbial diversity, with no significant differences in cell adhesion markers between groups.
The findings support the potential of hydroxyurea to improve immune responses in patients undergoing chronic transfusion therapy.

Abstract

Background Sickle cell disease (SCD) is characterized by a point mutation in the β globin molecule, causing the sickling of red blood cells, and leading to hemolytic anemia, pain, and end-organ damage. Hydroxyurea (HU) is a cornerstone of SCD patient treatment, while chronic transfusions (CT) are used as part of treatment for more severe SCD. Increases in aged neutrophils and inflammation have been linked to more severe SCD and contribute to vaso-occlusive crises. The current study was designed to test the hypothesis that HU reduces inflammation and aged neutrophils. Study design We compared clinical characteristics, aged neutrophils, levels of select cytokines, chemokines, and cell adhesion molecules in the blood and the Shannon diversity index (SDI) and ratio of Firmicutes/Bacteroides (F:B) in stool samples from pediatric SCD patients treated with HU (n=40) versus CT (n=14). Results Patients in the HU group had significantly lower total and aged neutrophils ( p 0.0001) compared to the CT group and also had lower levels of several chemokines including CXCL10 (IP-10), CCL2 (MCP-1) and CCL4 (MIP-1β) as well as IFN-γ and IL10. Conversely, HU was associated with higher levels of IL-1α, IL-6 and IL-8. There were no significant differences in cell adhesion markers or in markers of gut microbial dysbiosis between treatment groups. In a multivariable linear regression model, only being on CT was associated with increased number of aged neutrophils (p0.001) whereas being on CT and having a lower SDI were associated with higher total neutrophil count. Discussion Lower numbers of total and aged neutrophils and lower levels of several cytokines and chemokines in the HU group highlight the drug’s potential to modulate leukocyte activation and recruitment. These findings suggest that adding or maintaining HU therapy in SCD patients undergoing CT could potentially enhance immunologic regulation and warrants further study.

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