Fatigability in Long COVID-19

The overall goal of this project is to advance the understanding of underlying mechanisms impacting performance fatigability and perceived fatigability in Veterans with post-COVID-19 fatigue and explore the safety and feasibility of a home-based "minimal-dose" resistance exercise program in this population. The central hypothesis is that declines in force capacity, skeletal muscle oxygen extraction, and affective responses to physical activity offer potential mechanisms through which fatigability is increased in Veterans with post-COVID-19 fatigue. Moreover, home-based resistance exercise delivered remotely may provide a safe and feasibility treatment option for targeting neuromuscular and neurobehavioral factors influencing fatigability severity in this population.

The clinical case definition of post-COVID-19 condition (also referred to as Long COVID) as defined by the World Health Organization (WHO) includes individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms and that last for at least 2 months and cannot be explained by an alternative diagnosis. Fatigue represents one of the most frequently reported symptoms in individuals experiencing post-COVID-19 (i.e., post-COVID-19 fatigue; PCF).Fatigue is shown to persist for months after SARS-CoV-2 infection, negatively impacting activities of daily living. For the purposes of this SPiRE proposal, fatigue is operationally defined as a state characteristic encompassing a subjective lack of physical and/or mental energy that is perceived by the individual to interfere with usual or desired activities.

Increased fatigability is a possible complication following SARS-CoV-2 infection due to the presence of both neuromuscular and neurobiological consequences. Skeletal muscle alterations including reduced force capacity, fiber atrophy, mitochondria and metabolic dysfunction, and capillary impairments have been observed in patients following SARS-CoV-2 infection. Autopsy reports of patients who died after SARS-CoV-2 infection found evidence of skeletal muscle atrophy of type 2 fibers, necrotizing myopathy, and myositis. Similarly, using nerve conduction studies, patients with long-term COVID-19 were found to have signs of myopathy, even those who were not hospitalized. Evidence from cardiopulmonary exercise testing in patients diagnosed with COVID-19 has revealed impaired skeletal muscle oxygen extraction, as opposed to central limitations (i.e., cardiac output), as a determinant of exercise intolerance. In addition to neuromuscular complications, SARS-CoV-2 infection has also been shown to be associated with psychiatric sequelae. Collectively, these findings underscore neuromuscular as well as neurobiological consequences of SARS-CoV-2 as potential independent or co-occurring mechanisms by which increased fatigability occurs and persists.

Despite widespread calls for the importance of rehabilitation in individuals recovering from SARS-CoV-2 infection, little progress has been made regarding the potential benefits of physical exercise on fatigue and fatigability in this population. Moreover, concerns have been raised about the applicability of physical exercise in patients recovering from SARS-CoV-2 infection. For example, while the health and functional benefits of exercise are vast and widely known, in certain patient populations exertion is shown to exacerbate symptom severity. Some individuals with PCF may report experiencing worsening of symptoms after physical or mental exertion. Home-based exercise may offer an appealing option for those individuals concerned about attending community fitness facilities. Home-based exercise is shown to produced moderate effects on muscle strength and balance. Presently, the exact dosing of home-based exercise to elicit positive outcomes in fatigability is unknown. Minimal-dose resistance exercise has been proposed as a potential strategy for improving neuromuscular characteristics and physical function. Minimal-dose resistance exercise uses little to no equipment with exercises performed at lower workloads. The investigators aim to adapt the "minimal-dose" resistance exercise paradigm to a remote home-based resistance exercise program for Veterans with PCF to determine its implications for reducing fatigability and improving neuromuscular and neurobiological factors. Minimal-dose resistance exercise for the proposed application is defined as a single, weekly body-weight exercise session.

Eligibility Criteria:
Inclusion Criteria:

* ambulatory patients (with or without a gait aid)
* 50 years of age or older
* with a confirmed diagnosis of COVID-19 by polymerase chain reaction (PCR) test, antibody test or clinical diagnosis
* the symptom of fatigue reported greater than 12-weeks post-infection (reporting fatigue: yes/no)
* receiving care at the DC VAMC
* the ability to speak and read English, and orientation to person, place, and time

  * the comparison group will include ambulatory patients (with or without a gait aid)
  * 50 years of age or older
  * with a confirmed diagnosis of COVID-19 by PCR test, antibody test or clinical diagnosis
  * without the symptom of fatigue reported greater than 12-weeks post-infection
  * receiving care at the DC VAMC
  * the ability to speak and read English, and orientation to person, place, and time

Exclusion Criteria:

* \<50 years of age without a confirmed diagnosis of COVID-19 by PCR test
* antibody test or clinical diagnosis or with a confirmed diagnosis of COVID-19 of \<12-weeks
* non-ambulatory individuals
* Veterans who do not use the DC VAMC as their main site for care
* body mass index 40 kg/m2
* diagnosis of psychiatric disorder(s)
* any medically uncontrolled cardiovascular
* musculoskeletal disease, or other conditions that, in the opinion of the principal investigator, could make participation in the study unsafe
* any orthopedic or joint pain which would prevent the participant from safely engaging in the study protocol
* additionally, individuals with plans to relocate from the DC metro area within one year will not be eligible for the intervention portion of the study