Physiology of Long COVID-19 and the Impact of Cardiopulmonary Rehabilitation on Quality-of-Life and Functional Capacity

Physiological Underpinnings of Post-Acute Sequelae of SARS CoV-2 ("Long COVID") and Impact of Cardiopulmonary Rehabilitation on Quality-of-Life and Functional Capacity

The primary objectives of this study are to determine whether exercise training is an effective strategy for treatment of Long COVID and characterize the cardiorespiratory and autonomic physiology in these patients to precisely characterize mechanisms contributing to this syndrome.

Abnormalities observed among Long COVID patients are consistent with cardiac deconditioning. The Long COVID syndrome has been attributed to dysautonomia and/or postural orthostatic tachycardia syndrome (POTS) based largely on anecdotal experience and observations of positional tachycardia among affected individuals. However, it has been emphasized that data are clearly lacking to implicate dysautonomia alone as the cause of Long COVID. Alternatively, cardiac deconditioning leads to a constellation of symptoms, including exercise intolerance, brain fog/cognitive impairments, tachycardia and orthostatic intolerance, all of which are reported among reported among patients with Long COVID. Multiple studies have demonstrated that cardiac deconditioning may occur with as little as 20 hours of bedrest. Exercise training improves cardiorespiratory performance among patients suffering from cardiac deconditioning. Exercise training improves HR regulation and cardiovascular function during submaximal and peak exercise, and improves overall exercise capacity particularly among individuals with cardiac deconditioning following bedrest (e.g. Dallas bedrest studies) and among individuals with postural orthostatic tachycardia syndrome. Our preliminary data demonstrate a significant improvement/resolution in Long-COVID symptoms following a twelve-week exercise training program in a community setting. During the height of the COVID pandemic, the investigators developed an exercise protocol that has been used in the clinical setting to assist with management of patients suffering from Long COVID. This protocol involves recumbent/semi-recumbent exercise - specifically, rowing or cycling on a recumbent ergometer.

This proposal involves a clinical trial involving a two-aim initiative whereby participants with Long COVID will be randomized to a 12-week period of exercise training v. usual care ("controls") with baseline and follow-up assessments in order to: 1) Determine whether exercise training is an effective treatment strategy for management of Long COVID (Aim 1); and 2) Characterize cardiovascular/autonomic physiology among patients with Long COVID (Aim 2). In a third aim, healthy individuals will undergo a hemodynamic assessment afterbefore and after 24 hours of bedrest. The hemodynamic assessment will be identical to participants with Long COVID.

There will be a baseline assessment (Visit1) for all participants. After the baseline assessment, participants will be randomized in a 1:1 fashion to either undergo an exercise training program (exercise group) or usual care (control group) with no intervention. After completion of the exercise training program, the exercise group will return for a follow-up assessment (Visit2) that will be identical to the baseline (Visit 1) assessment. Participants in the control group will return for a follow-up (Visit 2) assessment, after which time they will crossover to complete the exercise training program. After completion of the exercise training program, these participants will return for a follow-up assessment (Visit 3). So, participants in the exercise group will complete two visits; participants in the control group will complete three visits.

Each assessment (Visits 1,2 and 3) is identical and includes a baseline resting assessment, watching heart rate and blood pressure while laying flat, as well as a tilt table test, a 10-minute stand, and an exercise test. Participants also complete a questionnaire asking about quality-of-life. The visit lasts about 2-2.5 hours.

The exercise training program is about twelve weeks long. Participants are provided exercise equipment at home, to complete the program. The program involves recumbent exercise (e.g. rowing machine, or recumbent cycling) and starts off with low duration, low intensity exercise, and gradually increases in duration and intensity over time.

Inclusion Criteria:

• Adults ≥18 years with documented history of COVID-19 infection and symptoms consistent with Long COVID lasting >12 weeks after diagnosis.

Exclusion Criteria:

• History of cardiovascular/pulmonary disease prior to infection
• COVID-related myocardial injury such as evidence of myocarditis
• Deep vein thrombosis/pulmonary embolism following COVID-19 infection
• Exercise intolerance resulting from conditions that are not related to cardiorespiratory or autonomic factors (e.g. osteoarthritis or other musculoskeletal diseases);
• Dependency of supplemental oxygen following COVID infection due to cardiovascular and/or pulmonary complications following acute COVID infection