Long-term Endurance Training in Sickle Cell Disease Patients: Impact on Clinical Profile, Physical Fitness, and Quality of Life.

Overview

Sickle cell disease (SCD), the most common genetic disease worldwide and in France, is an inherited haemoglobinopathy characterised by chronic haemolytic anaemia, vaso-occlusive crisis (VOC), acute pain, and multi-organ damage. Due to anaemia and multiple pulmonary, cardiac, endothelial, muscle, and metabolic dysfunctions, fatigue and poor physical capacity are common in SCD patients and constitute the primary reason for a sedentary lifestyle. However, recent findings demonstrated in the first randomised, controlled, and prospective study implementing endurance training in SCD that, when adequately calibrated, regular moderate-intensity endurance training is not only safe but also beneficial for patients (primary outcome: improvement of physical ability). This pivotal randomised, controlled, prospective study is designed to prove, on a large multicentre cohort, adult and paediatric, including patients with complications and over a longer period (one year). The objective of the study is to demonstrate the efficacy of participating in a program of regular physical activity to reduce the rate of vaso-occlusive crises requiring hospitalisation and to improve physical ability in patients with SCD.

Sickle cell disease (SCD) is an inherited haemoglobinopathy characterised by chronic haemolytic anaemia, vaso-occlusive crisis (VOC), acute pain, and multi-organ damage, making it the most common genetic disease in France. The mutation involves the substitution of glutamic acid by valine at position β6, leading to the synthesis of abnormal haemoglobin (HbS). The properties of HbS differ significantly from those of normal haemoglobin (HbA). Under deoxygenated conditions, HbS tends to polymerize, inducing deformation of the red blood cell (RBC), causing it to take on a sickle shape. This leads to a very low haemoglobin concentration and haematocrit (typically 6-8 g/dL and 25%-30%, respectively). Anaemia, coupled with arterial desaturation, results in tissue hypoxia. Furthermore, RBCs containing HbS (RBC-HbS) are less deformable and exhibit abnormal adherence properties. The reduced deformability of HbS-containing RBCs, along with the stiffening of sickle-shaped RBCs, impedes their passage through small vessels, potentially causing blockages in capillaries and obstructing microcirculation, leading to the particularly painful vaso-occlusive crisis (VOC). In patients with SCD, physical exercise has been shown to be physiologically stressful, resulting in severe exercise intolerance. Exercise limitations in SCD are related to anaemia, as walking for 5 minutes at 5 km/h leads to large elevations in heart rate (\~175 beats/min) and blood lactate concentration (6.6 ± 0.4 mmol/L) in patients. This indicates that exercise, which is relatively easy for sedentary healthy adults, is already too difficult for patients with SCD. Additionally, the first lactate threshold is around 30-35 W for women and 44-50 W for men. These extremely low values reflect the significantly reduced physical ability of patients with SCD, suggesting that even common daily tasks are challenging for them. The National Sports Health Strategy (SNSS) promotes physical activity for chronic conditions, including SCD. This project aligns with the second axis of the SNSS, which focuses on the development and use of adapted physical activity as a therapeutic treatment for SCD patients. Endurance training for trained groups involves a submaximal incremental cycling test. The total test duration is expected to range from 9 to 15 minutes. During the last 5 seconds of each step, a blood sample (7 µL) will be taken from the earlobe and immediately analysed (in less than 20 seconds using Lactate Scout+, EKF Diagnostics) to determine the blood lactate concentration (\[lactate\]b). Exercise should cease when a \[lactate\]b of 4 mmol/L is reached. This protocol will allow for the determination of exercise powers and heart rates at the first lactate threshold, at 2.5 mmol/L, and at 4 mmol/L. These values will help set the heart rates used during training/physical activity and assess the physical fitness of patients. The study will occur in four main stages: i) A screening visit ii) An initial evaluation of the patients (W0, Initial Evaluations), which includes two visits: an inclusion visit (V0) and a physical evaluation visit (V1) iii) A 52-week period (W1-W52) where the control group maintains their usual inactive lifestyle, while the trained groups engage in training and/or physical activity following a therapeutic education session (V2apa) iv) The period will be interspersed with evaluations at M6/W25 and followed by evaluations at M12/W52. These evaluations will include two visits (V3 and V4 at M6, and V5 and V6 at M12), similar to V0 and V1.