Exercise in Child Health (Project REACH)

Children's Hospital of Orange County (CHOC), Children's Hospital of Los Angeles (CHLA), Lurie Children's Hospital in Chicago

This study is a cooperative investigation funded by the NIH. The project is a collaboration among three major NIH Clinical Translational Science Awardees: 1) UCI (lead site with its affiliate CHOC), 2) Northwestern University (with its affiliate Lurie Children's Hospital), and 3) USC (with its affiliate Children's Hospital of Los Angeles). There is an increasing number of children who, through medical advances, now survive diseases and conditions that were once fatal, but which remain chronic and debilitating. A major challenge to improve both the immediate and long term care and health of such children has been the gap in our understanding of how to assess the biological effects of exercise. Like otherwise healthy children, children with chronic diseases and disabilities want to be physically active. The challenge is to determine what constitutes safe and beneficial level of physical activity when the underlying disease or condition [e.g., cystic fibrosis (CF) or sickle cell disease (SCD)] imposes physiological constraints on exercise that are not present in otherwise healthy children. Current exercise testing protocols were based on studies of athletes and high performing healthy individuals and were designed to test limits of performance at very high-intensity, unphysiological, maximal effort. These approaches are not optimal for children and adolescents with disease and disability. This project (REACH-Revamping Exercise Assessment in Child Health) is designed to address this gap. Cohorts of children will be identified with two major genetic diseases (CF and SCD) and measure exercise responses annually as they progress from early puberty to mid or late puberty over a 3-4year period. In addition, in the light of the pandemic, a group of children will be added who were affected by SARS-CoV-2 and investigate their responses to exercise. SARS-CoV-2 has similar long-term symptoms than CF and SCD have. Novel approaches to assessing physiological responses to exercise using advanced data analytics will be examined in relation to metrics of habitual physical activity, circulating biomarkers of inflammation and growth, leukocyte gene expression, and the impact of the underlying CF, SCD or SARS-CoV-2 condition. The data from this study will help to develop a toolkit of innovative metrics for exercise testing that will be made available to the research and clinical community.

New, generalizable approaches are needed for measuring physical fitness and activity across a spectrum of pediatric health and disease. Exercise in children and adolescents is not merely play but is an essential component of growth and development. Children are among the most spontaneously physically active human beings. It is not surprising that participation in PA (Physical Activity) is a major determinant of health across the lifespan and health-related quality of life in both healthy children and in children with chronic diseases. Despite this essential biologic role for PA, children have not been spared the relentless reduction in levels of PA that is creating a crisis in health care in our nation and throughout the world. Recognition of the enormous morbidity and cost of physical inactivity-related diseases, such as atherosclerosis, type 2 diabetes, and osteoporosis, has spurred new policy initiatives targeting preventive medicine early in life. The concept of pediatric origins of adult health and disease is gaining scientific merit, highlighting the need to transform existing notions of how to evaluate health in a growing child. A physically inactive (even normal weight) child may have no symptoms of disease, but evidence of deterioration in vascular health may already be present. As era of population health management and precision medicine are approaching, the notion of what it means to be a healthy child must change and include robust metrics of physical fitness. Equally worrisome is that the deleterious health effects of physical inactivity and poor fitness are exacerbated in children with chronic disease and/or disabilities or with environmental-lifestyle conditions like obesity. Children with diseases or conditions previously associated with mortality during the first two decades of life (e.g., SCD, CF) are living longer due to remarkable advances in research and care, but are often unable to achieve levels of PA and fitness associated with health benefits in otherwise healthy children. Not surprisingly, the healthspan [the period of life free from serious chronic diseases and disability of children with chronic diseases is threatened not only by the underlying disease, but by the compounding effects of insufficient PA and sedentary behavior. Increasing PA and fitness is feasible, but has proven quite challenging to implement in a systematic manner. Once a pattern of physical inactivity and a sedentary lifestyle is established, a vicious cycle ensues, in which constraints on PA harm immediate health and contribute to lifelong health impairment ranging from cardiovascular and metabolic disease to osteoporosis. Exactly what constitutes ideal physical fitness in a child with a chronic condition remains unknown. Finding beneficial levels of PA in children with chronic disease or disability is challenging because the optimal range of exercise is much narrower than in a healthy child. Finally, as a result of the COVID-19 pandemic a sizable number of children are experiencing long-term effects such as fatigue, and will be included in our study. Similar to children with CF and SCD, studies of exercise and physical activity will provide insight into disease mechanisms and possible therapies.

Cardiopulmonary Exercise Test (CPET) will be performed to measure cardiorespiratory responses in healthy controls. Exercise will consist of up to 8, 2 minutes bouts of constant work rate cycle ergometry with 1 minute resting intervals between each exercise bout. A subgroup of children will be asked to allow the investigators to obtain blood samples during the exercise session. The following procedures will occur: The child will be in a fasted state. An IV will be placed into the child's arm. Blood sampling will be taken at 4 time points; baseline, and the end of exercise, and at 30 and 60 minutes post exercise.

Cardiopulmonary Exercise Test (CPET) will be performed to measure cardiorespiratory responses in children with a documented history of SARS CoV-2 Infection. Exercise will consist of up to 8, 2 minutes bouts of constant work rate cycle ergometry with 1 minute resting intervals between each exercise bout. A subgroup of children will be asked to allow the investigators to obtain blood samples during the exercise session. The following procedures will occur: The child will be in a fasted state. An IV will be placed into the child's arm. Blood sampling will be taken at 4 time points; baseline, and the end of exercise, and at 30 and 60 minutes post exercise.

Cardiopulmonary Exercise Test (CPET) will be performed to measure cardiorespiratory responses in children with Children With Sickle Cell Disease (SCD). Exercise will consist of up to 8, 2 minutes bouts of constant work rate cycle ergometry with 1 minute resting intervals between each exercise bout. A subgroup of children will be asked to allow the investigators to obtain blood samples during the exercise session. The following procedures will occur: The child will be in a fasted state. An IV will be placed into the child's arm. Blood sampling will be taken at 4 time points; baseline, and the end of exercise, and at 30 and 60 minutes post exercise.

Cardiopulmonary Exercise Test (CPET) will be performed to measure cardiorespiratory responses in children with Children With Cystic Fibrosis (CF). Exercise will consist of up to 8, 2 minutes bouts of constant work rate cycle ergometry with 1 minute resting intervals between each exercise bout. A subgroup of children will be asked to allow the investigators to obtain blood samples during the exercise session. The following procedures will occur: The child will be in a fasted state. An IV will be placed into the child's arm. Blood sampling will be taken at 4 time points; baseline, and the end of exercise, and at 30 and 60 minutes post exercise.

Cardiopulmonary Exercise Testing (CPET) will be used with Multiple Brief Exercise Bouts (MBEB) in order to obtain the necessary data to yield information on the study outcome variables

Inclusion Criteria: Sickle Cell Disease Tanner 1-5, corresponding approximately to ages 10-17 y/o SCD diagnosis including all relevant genotypes Determined to be in relatively good health as a patient with SCD with no complications from SCD that would render participation the study unadvisable No evidence of other disease or disability that would impair participation in PA Physician permission to perform CPET BMI within the average range for age and condition Cystic Fibrosis Confirmed diagnosis of CF based on either two CF-causing mutations and/or a sweat chloride concentration of > 60 mmol/l after a positive newborn screening test or on two separate occasions Tanner 1-5 corresponding approximately to ages 10-17 y/o as documented by a licensed independent provider at screening, or by a validated self-assessment tool Determined to be in relatively good health as a patient with CF with no complications from CF that would render participation the study unadvisable as determined by a physician. Examples include history of submassive or massive hemoptysis or moderate to severe pulmonary hypertension. BMI in the average range for age and condition No evidence of other disease or disability that would impair participation in PA Comparison (Healthy control) Tanner 1-5 corresponding approximately to ages 10-17 y/o Determined to be in good health by pre-participation history and physical examination performed by primary care providers or PERC staff BMI and PA participation (by history) in the average range for age No evidence of disease or disability that would impair participation in PA Comparison (SARS-CoV-2) Tanner 1-5 corresponding approximately to ages 10-17 y/o Documented SARS-CoV-2 infection Capable of doing exercise as determined by primary care providers or PERC a medical officer Exclusion Criteria: Sickle Cell Disease Treatment for substance or alcohol abuse Requiring chronic monthly transfusions Other conditions that preclude exercise such as neuromotor disease, heart disease, or any other condition that would prevent a child from participating in PA Cystic Fibrosis Treatment for substance or alcohol abuse Other conditions that preclude exercise (such as neuromotor disease, heart disease, or any other condition that would prevent a child from participating in PA) FEV1 < 40% predicted based on Global Lung Index equations Current infection with Burkholderia cenocepacia or Mycobacterium abscessus Comparison (Healthy control) Treatment for substance or alcohol abuse or chronic medication use • Determination by PERC staff of unsuitability for exercise Comparison (SARS-CoV-2) Treatment for substance or alcohol abuse or chronic medication use • Determination by PERC staff of unsuitability for exercise

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