Long COVID, also known as post-acute coronavirus 2019 syndrome, is characterized by
debilitating, multi-organ 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. Multi-organ, 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.