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.