Recommendations for exercise prescription currently do not exist for individuals with sickle cell anemia (SCA) despite the known impact that SCA-related complications has on physical functioning and fitness. A major barrier to increasing physical activity in SCA is the concern that the well-described inflammatory effects of exercise could precipitate or exacerbate complications such as vaso-occlusive pain or airway bronchoconstriction (i.e. exercise-induced asthma). Although the investigator's preliminary data suggest that increasing physical activity may be beneficial rather than harmful in children with SCA, the pro-inflammatory effects associated with repeated bouts of moderate to vigorous exercise remain poorly understood in this population. The long term goal is to address the safety and health impact of regular exercise in children with SCA. This proposal would help establish the safety of moderate to vigorous intensity exercise in children with SCA and importantly, will inform the design of future clinical trials focused on exercise training as a transformative strategy to improve fitness and overall well-being in this population.

The investigator's plan to evaluate the effect of acute exercise and exercise intensity on circulating systemic pro-inflammatory mediators and airway bronchoconstriction in SCA. The investigators hypothesize that regular exercise at moderate to vigorous intensity is safe for children with SCA and do not precipitate SCA-related symptoms. In this multicenter study, 70 non-asthmatic children with SCA and 70 controls without SCA will first undergo a maximal cardiopulmonary exercise test (CPET), then be randomized to an exercise challenge by controlled intensity interval training (CIIT) at either moderate or vigorous intensity (8 exercise bouts at 50% or 70% peak workload, respectively). The Investigator's Aims are to: 1) Determine the influence of exercise intensity on the acute inflammatory response to exercise, defined by an increase in soluble vascular cell adhesion molecule (VCAM) and other adhesion molecules, and 2) Define the effect of moderate to vigorous exercise on forced expiratory volume in 1 second (FEV1) and acute bronchoconstriction in children with SCA. The investigators will also explore exercise- induced changes in gene and microRNA expression in peripheral blood mononuclear cells, tissue oxygenation during exercise by near infrared spectroscopy as well as the role of hyperventilation in bronchoconstriction using eucapnic voluntary hyperventilation testing in a subset of participants.

Inclusion Criteria:

• Provide signed and dated informed consent form
• Willing to comply with all study procedures and be available for the duration of the study
• Male or female, aged 10 years to 21 years old
• Diagnosis of hemoglobin SS or S/Beta0 thalassemia confirmed by hemoglobin electrophoresis

Exclusion Criteria:

• Inability to perform CPET due to physical limitation (e.g. severe hip osteonecrosis or stroke)
• Enrollment on chronic transfusion program
• History of exercise-induced arrhythmia or syncope
• Diagnosis of asthma, defined as physician diagnosis or use of daily asthma medications
• Known exercise-induced bronchoconstriction, defined as physician diagnosis by exercise challenge test
• History of any cardiac diagnosis precluding exercise testing, unless cleared by a cardiologist
• Anything that would place the individual at increased risk or preclude the individual's full compliance with or completion of the study

This study will plan to enroll a total of 70 non-asthmatic subjects with SCA and 70 controls without SCA across all sites. Male or female, aged 10 years to 21 years old. Diagnosis of hemoglobin SS or S/Beta0 thalassemia confirmed by hemoglobin electrophoresis.

Children and young adults on hydroxyurea are eligible but must be at steady state at time of enrollment, defined as stable dosing for at least 2 months, without anticipated changes in dose during study participation.

Race and age-matched controls without SCA or sickle cell trait will be recruited among friends, relatives, siblings or individuals from similar communities to minimize confounding socio-demographic variables that may impact baseline fitness. Controls will be required to be 10 through 21 years of age.