Organ damage in Sickle Cell Disease: evolution and influence of therapies

Individuals with sickle cell disease (SCD) progressively develop chronic organ injuries that limit their life expectancy. The effect of disease-modifying and curative (hematopoietic stem cell transplantation, HSCT) therapies on organ damage progression has not been fully elucidated. Biomarkers of organ damage and treatment response are sparse in SCD. Oxygenscan is a novel physiological assay of erythrocytes’ deformability at different oxygen tensions; its parameters could serve as SCD biomarkers. The aims of this project were: to describe the prevalence of chronic damage in the mainly affected organs (brain, eye, heart, lung, kidney and liver) in a cohort of children, adolescents and young adults with SCD prospectively followed according to a standardized protocol; to analyse the effect of disease-modifying and curative therapies on the development of organ damage; to explore the role of oxygenscan parameters as biomarkers of organ damage in SCD. This is a retrospective analysis of prospectively collected real world data on organ damage in SCD patients monitored since 2007 in the Paediatric Haematology, Oncology and Stem Cell Transplant Unit of Padua University Hospital. Data was systematically gathered in a Natural History Study database. Individuals with SCD, any genotype, were enrolled at diagnosis and regularly screened for chronic organ complications according to a standardized protocol based on the guidelines of the Italian Association of Paediatric Haematology and Oncology (AIEOP). Disease-modifying and curative treatments were prescribed according to the same guidelines. The course of organ damage after HSCT was studied adopting a specific follow-up schedule. Steady-state blood samples of untreated and treated patients were prospectively collected since 2023 to measure oxygenscan parameters according to a European protocol. Our study included 242 SCD patients (186 HbSS, 15 HbSβthal0, 36 HbSC, 5 HbSβthal+). The median age at diagnosis was 2.1 years and at the last follow-up 11.3 years, with a median time of observation of 8 years. The overall follow-up of the population corresponds to 2139.9 patient-years. The prevalence of SCD-related injuries among patients with at least one evaluation was: 56.69% for brain large vessels vasculopathy at magnetic resonance angiography (MRA) and 33.99% for silent cerebral infarcts at MRI; 33.58% for retinopathy; 36.76% for lung restrictive dysfunction; 28.35% for albuminuria and 37.79% for renal ultrasound abnormalities. Data on heart and liver involvement was too heterogeneous to be analysed. The cumulative incidence of organ injuries affecting the brain, lung and kidney at different intervals from diagnosis was significantly higher in untreated patients than in those who had received at least one disease-modifying treatment before damage onset. Among the 26 patients who underwent HSCT, signs of macrovasculopathy at transcranial Doppler (TCD) ultrasound and MRA improved after transplant, while brain ischemic lesions and injuries affecting other organs remained stable. A possible correlation was detected between reduced erythrocytes’ deformability at oxygenscan and abnormalities at the ophthalmological visit and renal ultrasound evaluation. Only 2/6 patients with mixed chimerism after HSCT showed altered oxygenscan curves; one of them manifested post-transplant a new onset of mild signs of retinopathy and renal ultrasound abnormalities. A prospective cohort study with a standardized protocol for organ damage monitoring and long-term follow-up provides reliable data on early signs and evolution of chronic complications in children with SCD. Wider and earlier use of disease-modifying and curative treatments might allow prevention or delay of organ damage, with improvement of life expectancy and quality. Some oxygenscan parameters appear promising as biomarkers of SCD chronic complications and treatment response, but further investigations would be necessary to confirm these results.