Outcomes of Children with Sickle Cell Disease Born Outside Belgium Remain Different Compared to Those Born in Belgium Despite Similar Management

Sickle cell disease (SCD) is characterised by a multitude of phenotypic expressions that are influenced by the environment and genetics. The only well-established treatments are infection prevention, hydroxyurea (HU), chronic transfusions, and hematopoietic stem-cell transplantation (HSCT). Early strategies facilitated by neonatal screening programmes improve morbidity and mortality. In the context of an increasingly multiethnic society, not all our patients benefit from early intervention. This study aims to evaluate the overall outcomes of children with SCD born in Belgium (BiB) compared to those born outside Belgium (BoB) and receiving the same treatment upon arrival in Belgium.

This cohort study is based on anonymized data extracted from the Belgian National Sickle Cell Registry (BNSCR). Prospective data were collected from the date of diagnosis (start of follow-up (FU) for BoB) until the last FU visit or death. Were included in this study: all SCD children born between 01.01.2000 and 31.12.2018, followed at the Hôpital Universitaire des Enfants Reine Fabiola till 31.12.2020 and registered in the BNSCR. Clinical and hematological data are compared between both groups.

A total of 245 patients were identified, of which 186 BiB and 59 BoB (all born in Africa). No statistically significant differences were found in terms of sex, parents' origin and genotype between the two groups. The median age at diagnosis/start FU was significantly higher in BoB-patients while the median duration of FU was not statistically different in both groups. Expressed by 100 patient-years (PY), the rate of vaso-occlusive crises (VOC) was significantly higher in BoB-patients while the rate of acute chest syndrome was not (Table 1). BoB had significantly less acute anemic episodes and a trend toward less splenic sequestration. The rate of severe infections, stroke and death was similar in both groups (Table 1). At start of FU, BoB patients had a significantly higher neutrophil count (PMN) and lower fetal hemoglobin (HbF) while other hematological parameters didn't differ from BiB

The prescribed rate of HU and the rate of HSCT was similar in both groups. However, BoB-patients were significantly older at the start of HU treatment or at the time of the HSCT (Table 1). Hematological values between BoB and BiB-patients after HU did not differ. Nevertheless, PMN and Hb levels seem to be higher in BoB-patients without reaching statistical significance (Table 2).

BoB-patients have a median delay of 2 years to access to a comprehensive care program dedicated to SCD. At the same time, this group is 1.5-fold as likely to develop a VOC during FU. No clear explanation exists, but the start of HU at an older age might have an impact with reduced HbF response at distance of the physiological switch of Hb as observed in the BoB-group. In addition, children born in Africa are submitted to a different environment with a higher inflammatory burden as suggested by their higher PMN count at diagnosis. So far, the impact of early inflammation on the long-term outcome is not known and need to be investigated. These points could not be evaluated in this study.

The BoB-group's lower rate of acute anemia and splenic sequestration is explained by the older age at start of FU as these potentially lethal complications occur in very young children and could not be recorded from birth of the BoB-group. This also raises the question of the bias presented by our BoB-patients as they don't represent the SCD population from the country they originate: 1) they survived infancy and early childhood, 2) they come from families economically privileged enough to finance the travel to Belgium.

In conclusion, the outcomes between BiB and BoB-patients remain different even though the latter benefits from the same comprehensive care. It would be interesting to explore whether a deeper understanding of the underlying physiopathology in terms of genetics, inflammation/immunity, and nutritional status, could clarify the differences observed between our groups. A longer FU of the Registry will help enhance our findings.