Effects of Inspiratory Muscle Training After Covid-19 (ReCOV)

Introduction:

Covid-19 was declared a global pandemic in March 2020 by the World Health Organization (WHO).
So far (August 2021), there are over 1 100 000 confirmed cases and over 14 000 deaths in
Sweden. 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-
acute Covid-19 syndrome (PACS) 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. Patients who have
been in hospital for Covid-19 for a long time may need specialized rehabilitation, however,
also non-hospitalized patients with mild symptoms may need specific rehabilitation to be able
to meet the complex symptoms and problems that may arise. Previous studies on the recovery
and rehabilitation after other coronavirus shows the importance to develop tailored
interventions so that these patients receive appropriate rehabilitation with a
multi-professional approach throughout the whole care chain. Some studies suggest that the
rehabilitation should be similar to pulmonary rehabilitation, but since a lot of patients
often have symptoms from different organ systems this is not yet fully investigated and needs
to be addressed from different perspectives. A study by Liu et al (2020), showed that 6 weeks
of physical exercise and respiratory muscle training improved lung function and physical
capacity compared to a control group in elderly patients after Covid-19.

At the Karolinska University Hospital there is a specialized multidisciplinary and
multi-professional approach aiming to follow up patients who have been hospitalized. However,
from mid-2020 and onwards, referrals from primary care have significantly increased. This
includes patients who have never been hospitalized but with varying symptoms from several
organs that have lasted for more than 3 months.

This study is part of a bigger research project (ReCoV) and is integrated with the clinical
follow-up and linked research project of patients who have been hospitalized or referred from
primary care

Hypothesis: The overall hypothesis of the hole research project is that physical and
physiological function, work ability and HRQoL are important factors for recovery after
Covid-19 which can be improved by individual tailored rehabilitation.

The aim of this study is to evaluate the effects of inspiratory muscle training (IMT) on
physical and psychological function, work ability and HRQoL in patients with decreased
respiratory muscle strength after Covid-19.

Methods:

To evaluate the effects of IMT, a randomized controlled trial design will be used.

Participants:

Patients with PACS above 18 years old (N=90) with 80% or less of predicted value in maximal
inspiratory pressure (MIP) are eligible for participation in the study.

Procedure:

Baseline assessment before the intervention period will be performed at an outpatient visit
at Karolinska university hospital. After baseline assessment participants will be randomized
to either an intervention group or to an active control group using random permuted blocks.
The intervention will take place at the physiotherapy outpatient clinic at the hospital or at
a primary care facility and in the participants' homes. The intervention group will perform
IMT twice daily (two sets of 30 receptions) at home during 8 weeks with a resistance of 20-50
% of MIP using an inspiratory muscle trainer (Threshold or digital advice). Follow-up of
execution and increase in intensity during IMT will be conducted weekly by the
physiotherapist. This will be combined with an 8-week physical exercise program including
aerobic, strength and mobility exercises which will be performed at the care facility and at
home at least two times a week. The active control group will perform the same physical
exercise program according to standard care.

Outcome assessment:

All measurements will be performed at baseline and after the intervention period (8 weeks).

Primary outcome is maximal inspiratory pressure (MIP) and secondary outcomes are: maximal
expiratory pressure (MEP), lung function, physical capacity (6-min walk test), Chair stand
test, physical activity, respiratory status and symptoms, health-related quality of life,
work ability, fatigue, self-reported outcome measure of physical function and voice function.

Statistical analyses:

Data will be described with mean (standard deviation), median (inter-quartile range) and
proportion and analyzed with parametric and non-parametric methods depending on data level.
All voice recordings will be assessed by a group of speech and language pathologists all
experts on voice disorders. The longitudinal group variations will be analyzed using Linear
Mixed Models that in addition to studying change at the group level also can model change on
the individual level. In addition, the method can handle dependency for repeated observations
and provide correct estimates with missing data. To detect differences of 10% in the MIP a
calculation of 36 patients in each group plus 25% drop-out in the power analyses, which lead
to 45 participants in each group.

Clinical significance:

Covid-19 has the potential to affect physical, cognitive, and psychological functions in
multiple ways and lead to a negative impact on quality of life in the long-term perspective.
Therefore, development of a rehabilitation program with specific tailored interventions will
be necessary to improve physical and psychological function, as well as health-related
quality of life and work ability.

Covid-19 is a new disease and large knowledge gaps need to be filled. Previous studies
indicate that the patients are affected at several levels and a rehabilitation period is
necessary. It is of great importance that data is collected systematically and standardized.
If significant effects occur, the possibility to generalize the results to other individuals
with Covid-19, are promising. The physical interventions may thus improve the ability to
adjust to the implications of Covid-19, which can potentially have significant health
economic effects. For example, the interventions may prolong patients' meaningful activities
of daily living and their ability to return to their previous workplaces (conduct their
professions). This project will deepen the knowledge about the effects of specialized
rehabilitation

Ethical considerations:

The project has been approved by the Swedish Ethical Review Authority. The participants will
receive verbal and written information about the study and informed consent will be obtained
from all participants.