In-Depth Immunological Typization of Children with Sickle Cell Disease: A Preliminary Insight into Its Plausible Correlation with Clinical Course and Hydroxyurea Therapy

Abstract

Sickle cell disease (SCD) is a condition of functional hypo-/a-splenism in which predisposition to bacterial infections is only a facet of a wide spectrum of immune-dysregulation disorders forming the clinical expression of a peculiar immunophenotype. The objective of this study was to perform an in-depth immunophenotypical characterization of SCD pediatric patients, looking for plausible correlations between immunological biomarkers, the impact of hydroxyurea (HU) treatment and clinical course. This was an observational case–control study including 43 patients. The cohort was divided into two main groups, SCD subjects (19/43) and controls (24/43), differing in the presence/absence of an SCD diagnosis. The SCD group was split up into HU+ (12/19) and HU− (7/19) subgroups, respectively receiving or not a concomitant HU treatment. The principal outcomes measured were differences in the immunophenotyping between SCD patients and controls through chi-squared tests, t-tests, and Pearson’s correlation analysis between clinical and immunological parameters. Leukocyte and neutrophil increase, T-cell depletion with prevalence of memory T-cell compartment, NK and B-naïve subset elevation with memory and CD21low B subset reduction, and IgG expansion, significantly distinguished the SCD HU− subgroup from controls, with naïve T cells, switched-memory B cells and IgG maintaining differences between the SCD HU+ group and controls (p-value of <0.05). The mean CD4+ central-memory T-cell% count was the single independent variable showing a positive correlation with vaso-occlusive crisis score in the SCD group (Pearson’s R = 0.039). We report preliminary data assessing plausible clinical implications of baseline and HU-related SCD immunophenotypical alterations, which need to be validated in larger samples, but potentially affecting hypo-/a-splenism immuno-chemoprophylactic recommendations.

Inflammatory status in pediatric sickle cell disease: Unravelling the role of immune cell subsets

“…Moreover, further studies may be needed to assess whether specific therapy could change the immunological profile. Recently, Giulietti et al (Giulietti et al, 2022) studied in-depth immunological alterations in SCD with many findings which were similar to the ones that we observed in SCD population (increase in WBC and neutrophils, decrease in CD3 + cells and CD4 + cells, increase in CD4 + central memory T cells), but, in addition, they observed immunological alteration probably consequent to the use of hydroxyurea. Therefore, it could be interesting to assess if recent therapies [such as Crizanlizumab (Ataga et al, 2017) or Voxelotor (Herity et al, 2021)] can lead to immunological changes as well.…”

“…There are currently few studies ( Rautonen et al, 1992 ; Balandya et al, 2016 ; Giulietti et al, 2022 ) in the literature that evaluate a large number of immune system cells in pediatric patients with SCD. This study proposes an evaluation of the immune profile in subjects with sickle cell disease in a pediatric population through a detailed analysis by flow cytometry, in order to better understand the involvement of the immune system in the pathophysiology of this disease in pediatric age.…”

Effects of hydroxyurea on fertility in male and female sickle cell disease patients. A systemic review and meta-analysis

“…Hydroxyurea (HU) remains a widely available and clinically effective therapy for SCD [9][10][11][12]. HU was initially reserved for adult patients with clinical complications, but is now recommended to all SCD patients from 9 months of age, regardless of disease severity [11,[13][14][15][16][17][18][19][20][21][22][23]. A substantial body of evidence documents the benefits of HU with acceptable short-and longterm toxicity profiles, but concerns regarding its long-term safety persist, particularly regarding fertility [24].…”