Introduction:

Covid-19, was in March 2020, declared a global pandemic by the World Health Organization
(WHO). In August 2021, in Sweden, over 1 100 000 cases were confirmed and over 14 000
deaths. Initially, it was suspected that Covid-19 would primarily affect the airways, but
several studies have now shown that it is a disease with multisystem manifestations. The
impact of the virus ranges from an asymptomatic infection to a severe and
life-threatening disease that can affect the cardiac, renal gastrointestinal, nervous,
endocrine, and musculoskeletal systems. Therefore, Covid-19 has the potential to affect
physical, cognitive, and psychological functions in multiple ways.

It has been clear that a significant proportion of patients with Covid-19 develop
long-term symptoms. Signs and symptoms may arise from any system in the body, often with
significant overlap, and may develop over time. The term post COVID-19 condition (defined
by WHO) is now used to describe the wide range of prolonged symptoms following the
infection. Fatigue, decreased physical and psychological function have been reported in
the initial recovery phase, but still little is known on the long-term consequences.
Previous studies on the recovery and rehabilitation after other coronavirus shows the
importance to develop tailored interventions.

A more specific syndrome that seems to occur more frequently in non-hospitalized persons
with post COVID-19 condition is the postural orthostatic tachycardia syndrome (POTS). It
is a chronic orthostatic intolerance where upright posture is associated with an
excessive increase in heart rate (HR) and associated symptoms, such as palpitation,
exercise intolerance, hypermobile joints, migraine headaches, brain-fog, sleep
disturbances, and fatigue. Symptoms can be exacerbated by simple activities of daily life
and the patients often report a low quality of life, equivalent to what patients with
severe heart failure or COPD report. Consequently, patients seem to reduce their physical
activity, which make them deconditioned and limits the activities in daily living even
more.

Nevertheless, supervised individual tailored physical exercises, is a recommended
non-pharmacological treatment of POTS. However, few studies have investigated the effect
of physical exercise in POTS, and studies of POTS and post COVID-19 condition are very
sparse. Therefore a feasibility study were performed and data found that the intervention
(individually tailored physical exercise) was feasible in terms of safety, recruitment
and compliance. Moreover the feasibility study provided optimistic results of the effects
according to the participants physical, psychological functions as to their quality of
life.

The planned RCT is part of research project (ReCOV), integrated with the clinical
follow-up at Karolinska University Hospital and linked research project of patients who
have been hospitalized or refereed to the clinic from primary care. The hypothesis is
that an individually tailored rehabilitation program will have a beneficial effect on the
ability to spend time in an upright position, as well as on HRQoL, for individuals with
POTS, post COVID-19 condition.

The overall aim of this study is to evaluate the effects of an individually tailored
exercise and its impact on time spent in upright position and health-related quality of
life (HRQoL), physical activity, physical and psychological function and work-ability in
persons with POTS, post COVID-19 condition.

Methods

Participants:

A total of 60 adult patients (>18 years) with POTS (diagnosed by a cardiologist), post
COVID-19 condition. Recruitment will take place at the outpatient clinic at Karolinska
University Hospital or in the primary care in Region Stockholm. Exclusion criteria: known
pregnancy, cancer, already ongoing individual physical exercise (specific for POTS) or
not able to perform measurements and/or intervention.

Procedure:

Prior to randomization baseline measurements will be performed. The measurements include
Active Standing (AST), Test, 6-minute Walk Test (6MWT), muscle strength with MicroFET,
measurements of pulsoximetry, pulse and blood pressure before, during and after tests,
and participant will report their symptoms with BORG CR10 and BORG RPE. To evaluate time
in upright position participants will wear two accelerometers (ActivPAL) during a week
before intervention start. Questionnaires that will be used are EQ-5D-5L, Vanderbuildt
Orthostatic Symptom Scale (VOSS), Malmö POTS Symptom Scale (MaPS), Fatigue Severeity
Scale (FSS), Mental Fatigue Scale (MFS), DePaul Symtom Questionnaire - Post-Exertion
Malaise (DSQ-PEM), Generalized Anxiety Disorder 7-item scale (GAD-7), Patient Health
Questionnaire (PHQ-9) and Insomnia Severeity Index (ISS).

Controls: Participants randomized to control will receive standard care during 16 weeks.
Standard care includes (but not restricted to) information about POTS and lifestyle
changes that may effect the symptoms, advice about what fluid intake and nutrition,
compression garments, pharmacological interventions etc.

Intervention: Participants randomized to intervention will receive standard care (same as
controls) and undergo an individually tailored physical exercise program during a period
of 16 weeks. The intervention will consist of exercises to enhance muscle strength and
endurance. The program includes progression regarding duration and position for the
exercise (starting i laying position and progression towards upright position).
Progression should be halted if post exertional malaise (PEM) or other problems occur
whitin 24h after exercise. The participants will once a week be supervised and guided
individually by a physioherapist. Participants will, on a weekly basis, complete a
training diary regarding their physical activity and training intensity in which they
report any setbacks or adverse events.

Measurements of both groups (control and intervention) will be repeated after completion
of a period of 16 weeks and longitudinal follow-up at 6 and 12 months.