Long COVID, also known as post-acute coronavirus 2019 syndrome, is characterized by
debilitating, multiorgan symptoms beyond 3 months from the onset of acute illness, consistent
with autonomic nervous system dysfunction. Prevalence estimate of long COVID is 10 - 20% of
survivors of COVID-19, representing about 10-20 million global long-term cases. Multiorgan,
autonomic-related symptoms of long COVID, such as exhausting fatigue and post-exertional
malaise, are remarkably like post-concussion syndrome and chronic fatigue syndrome.
Post-exertional malaise, likely a cardinal symptom of long COVID, is "an exacerbation of some
or all of an individual's symptoms after physical or cognitive exertion, or orthostatic
stress", significantly impacting functional ability and quality of life. This abnormal
response to exertion is often described as "flu-like" and typically includes brain fog.
Common "long hauler" symptoms reported in our cohort of patients with long COVID (n=30) were
fatigue (>70%), symptoms of dysautonomia (80%, primarily orthostasis), "brain fog" (100%),
and new or worse mood symptoms (90%), especially anxiety. Experience from Severe Acute
Respiratory Syndrome (SARS-CoV-1) notably showed that survivors suffered chronic fatigue and
mental illnesses 4 years after acute viral illness. Rehabilitation studies in coronavirus
disease (Covid-19) have targeted sub-acute lung sequelae of Covid-19 rather than post-acute
sequalae of long COVID. This study addresses the World Health Organization's urgent call for
rehabilitation research for long COVID.

The investigators identified blunted rise in heart rate (HR), called chronotropic
intolerance, during maximal cardiopulmonary exercise testing (CPET) in 19 adults with long
COVID. Chronotropic intolerance is defined as inability to meet 80% of age-derived heart
rate, HR peak. Group HR peak mean (SD) was 69 (7.7) % predicted. This blunted rise in HR is
associated with post-exertional malaise, similar to the pattern of symptoms in
post-concussion syndrome and chronic fatigue syndrome, which share underlying autonomic
nervous system (ANS) dysfunction and impaired cerebral blood flow regulation. The
investigators identified a need for more comprehensive and precise measurement of
post-exertional malaise in long COVID. In a randomized controlled trial (RCT), the
investigators also tested a sub-symptom threshold aerobic exercise program, focused on
treating persisting symptoms of post-concussion syndrome. The investigators found this
aerobic exercise program reduced persistent symptoms of exercise intolerance, fatigue, and
dysautonomia more quickly in subjects compared with a control group of stretching exercises
(n=103).

Informed by research in post-concussion syndrome, the investigators are proposing a two-arm
randomized controlled trial (RCT) to study the feasibility of an exercise program called,
Restoring Energy with Sub-symptom Threshold Aerobic Rehabilitation Exercise (RESToRE). The
central hypothesis is that restoration of autonomic control through RESToRE will resolve
persisting symptoms of long COVID faster compared with placebo-like stretching and breathing
exercise (without rise in HR). RESToRE is an interdisciplinary, hybrid 8-week intervention
consisting of three core components: (1) home-based aerobic exercise, of 20 minutes most
days, with HR monitoring at 70-80% of the HR threshold at which symptoms increase, (2)
phone-based motivational exercise coaching, 20 minutes weekly; and (3) supervised exercise
with an exercise physiologist, twice-monthly in the clinic. Key to RESToRE's feasibility is
its telehealth component, including Apple watch and app for HR fidelity monitoring,
PhysiTrack's exercise library app, and LifeData dashboard for real-time post-exertional
malaise and remote exercise monitoring. Our long-term goal is to establish an efficacious
exercise program to speed recovery from long COVID.