Lung Function Decline in Children with Sickle Cell Disease Treated with Hydroxyurea

Sickle cell disease (SCD), the most common form of an inherited hematological disorder, is caused by a genetic variant that leads to the synthesis of an abnormal haemoglobin, HbS. Deoxygenated HbS tends to polymerize which results in a distortion of the red blood cell shape, causing vaso-occlusion and end-organ damage. The most severe forms of SCD are homozygous HbSS and HbSβ0 –thalassemia.

The latter is characterized by compound heterozygosity for HbS and a non-functional beta-thalassemia gene. Milder forms of SCD include compound heterozygous conditions, such as HbSC. SCD is a systemic disease, associated with episodes of acute illness and chronic solid organ damage, including SCD lung disease. Prior to therapy with hydroxycarbamide, also called hydroxyurea (HU), in SCD HbSS untreated children suffered from severe and progressive SCD lung disease with annualized declines in pulmonary function testing (PFT) similar to cystic fibrosis. Male sex was associated with a more rapid PFT decline in HbSS children not treated with HU, and HbSC genotype was associated with less lung disease compared to HbSS.

HU is a disease-modifying agent that increases HbF production, total hemoglobin concentration, as well as red blood cell survival, and has been used for SCD therapy for decades. In adults, HU therapy results in a remarkable reduction in morbidity and mortality. An earlier, preliminary study in a small pediatric cohort had suggested that HU therapy in SCD children may lead to improvement in PFT decline. However, longitudinal data on lung disease progression and risk factors associated with PFT decline in current, larger pediatric cohorts of SCD HbSS treated with HU or HbSC are lacking.

The aim of this study therefore was to quantify lung disease progression in a large cohort of SCD HbSS children treated with HU according to current guidelines, and to analyze the potential effects of sex on lung function decline in children with HbSS or HbSC.