Spleen Function and Infections in the Youngest Patients with Sickle Cell Disease in the Netherlands
Authors: Van Der Torren Cornelis R , Rook Celine H.A. , van Valderen Nimue , De Ligt Lydian A. , van Bruggen Robin , Fijnvandraat Karin 
Published: December 2024

Introduction: Young children suffering from sickle cell disease (SCD) have a high mortality from infections if not adequately treated. This vulnerability is at least partly attributable to severe infections with encapsulated bacteria which are the result of a loss of splenic function due to the disease. We hypothesized that patients with more severe disease (HbSS and HbS-beta0 thalassemia: group 1) had earlier loss of splenic function and more encapsulated bacterial infections at young age then patients with a less severe genotype (HbSC and HbS-beta+ thalassemia:group 2).
Methods: All potential bacterial infections of children with the designated genotypes born between January 1, 2014 and April 30, 2024 and treated from birth at the Amsterdam UMC in the Netherlands were retrospectively inventoried from patient files. The start of therapeutic antibiotics defined ‘potential bacterial infections’. Infections with an identified encapsulated pathogen, a focus suspicious for encapsulated pathogens, CRP &gt;80 mg/L and/or documented suspicion of bacterial origin by the treating physician were also classified as ‘suspected encapsulated bacterial infections’. After obtaining consent, rest material of regular blood checks was collected to determine splenic function by the frequency of marginal zone B-cells (CD19+CD27+IgD+) and by combining two recently described techniques assessing erythrocyte phenotype. The first method visualizes erythrocytic vacuoles using CellTrace Yellow, which are increased in patients without splenic function (Sissoko Am J Hematol 2022). The second method detects surface mannose glycans on erythrocytes, by staining with Narcissus Pseudonarcissus lectin and Galanthus nivalis agglutinin, which accumulate in patients without a spleen (Cao Br J Haematol 2022). Laboratory measures were compared to older patients with SCD and healthy blood donors.
Results: Hundred patients (mean age 4.7±3.1 years) were included for review of infections of which 52% were in group 1. Gender, co-morbidity, vaccinations, prophylactic antibiotic use and compliance did not differ between the groups. In group 1 more hydroxycarbamide was used (62 vs 13%, p=&lt;0.001) and more hospitalizations had occurred in the last year (mean 0.48 vs 0.17, p=0.03) compared to group 2. In total 128 potential bacterial infectionswere identified of which 42 classified as suspected encapsulated bacterial infections. Most infections were respiratory tract infections: 94 potential bacterial infectionsand 36 suspected encapsulated bacterial infections. No pathogens were identified by blood culture. No pneumococcal, meningococcal or haemophilus influenzae infections were identified. At age 0-5 years, group 1 tended to have more potential bacterial infections(p=0.06 for genotype in mixed ANOVA for age and genotype). suspected encapsulated bacterial infections were not statistically different between the groups, although the Kaplan Meier curve suggested the first infection to be at younger age in group 1. Blood samples of the first 13 patients have been analyzed. Higher B-cell numbers were found in the blood of these patients than in samples of older patients and blood donors, while the proportion of marginal zone B-cells was similar. The frequency of erythrocytes with vacuoles and high mannose glycans in these young patients with SCD was in between healthy donors and older patients.
Conclusion and discussion: No difference was shown in bacterial infection frequency at young age between different SCD genotypes. However, there was a trend towards more and earlier onset of bacterial infections in patients with the HbSS/HbS-beta0 genotypes. Severe infections have likely been prevented by the use of prophylactic antibiotics, consistent with the lack of detection of encapsulated bacteria. Additional inclusion of patients for splenic function analysis will allow to assess splenic function over time and correlate this to infections in both genotype groups.