Effect of a home-based inspiratory muscle training programme on functional capacity in postdischarged patients with long COVID: the InsCOVID trial

Abstract

Background
Fatigue and exercise intolerance are the most common symptoms in patients with long COVID.

Aims
This study aimed to evaluate whether a home-based inspiratory muscle training (IMT) programme improves maximal functional capacity in patients’ long COVID after a previous admission due to SARS-CoV-2 pneumonia.

Methods
This study was a single-centre, blinded assessor, randomised controlled trial. Twenty-six patients with long COVID and a previous admission due to SARS-CoV-2 pneumonia were randomly assigned to receive either a 12-week IMT or usual care alone (NCT05279430). The physiotherapist and participants were not blinded. Patients allocated to the IMT arm were instructed to train at home twice daily using a threshold inspiratory muscle trainer and to maintain diaphragmatic breathing during the training session. The usual care arm received no intervention.The primary endpoint was the change in peak oxygen consumption (peakVO2). Secondary endpoints were changes in quality of life (QoL), ventilatory efficiency and chronotropic response during exercise (evaluated by chronotropic index-CIx- formula). We used linear mixed regression analysis for evaluating changes in primary and secondary endpoints.

Results
The mean age of the sample and time to first visit after discharge were 50.4±12.2 years and 362±105 days, respectively. A total of 11 (42.3%) were female. At baseline, the mean of peakVO2, ventilatory efficiency and CIx were 18.9±5 mL/kg/min, 29.4±5.2 and 0.64±0.19, respectively. The IMT arm improved their peakVO2 significantly compared with usual care (+Δ 4.46 mL/kg/min, 95% CI 3.10 to 5.81; p<0.001). Similar positive findings were found when evaluating changes for CIx and some QoL dimensions. We did not find significant changes in ventilatory efficiency.

Conclusion
In long COVID patients with a previous admission due to SARS-CoV-2 pneumonia, IMT was associated with marked improvement in exercise capacity and QoL.

Trial registration number
NCT05279430.

Full text

1
PalauP, etal. BMJ Open Resp Res 2022;9:e001439. doi:10.1136/bmjresp-2022-001439
To cite: PalauP, DomínguezE,
GonzalezC, etal. Effect of
a home- based inspiratory
muscle training programme
on functional capacity in
postdischarged patients with
long COVID: the InsCOVID
trial. BMJ Open Resp Res
2022;9:e001439. doi:10.1136/
bmjresp-2022-001439
►Additional supplemental
material is published online
only. To view, please visit the
journal online (http:// dx. doi.
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001439).
PP and ED contributed
equally.
Received 1 September 2022
Accepted 14 December 2022
For numbered affiliations see
end of article.
Correspondence to
Dr Patricia Palau;
patricia. palau@ uv. es
Effect of a home- based inspiratory
muscle training programme on
functional capacity in postdischarged
patients with long COVID: the
InsCOVID trial
Patricia Palau ,1 Eloy Domínguez ,2 Cruz Gonzalez,3 Elvira Bondía,3
Cristina Albiach,4 Clara Sastre,5 Maria Luz Martínez,4 Julio Núñez,1 Laura López6
Respiratory research
© Author(s) (or their
employer(s)) 2022. Re- use
permitted under CC BY- NC. No
commercial re- use. See rights
and permissions. Published by
BMJ.
ABSTRACT
Background Fatigue and exercise intolerance are the
most common symptoms in patients with long COVID.
Aims This study aimed to evaluate whether a home-
based inspiratory muscle training (IMT) programme
improves maximal functional capacity in patients’ long
COVID after a previous admission due to SARS- CoV- 2
pneumonia.
Methods This study was a single- centre, blinded
assessor, randomised controlled trial. Twenty- six patients
with long COVID and a previous admission due to SARS-
CoV- 2 pneumonia were randomly assigned to receive
either a 12- week IMT or usual care alone (NCT05279430).
The physiotherapist and participants were not blinded.
Patients allocated to the IMT arm were instructed to train
at home twice daily using a threshold inspiratory muscle
trainer and to maintain diaphragmatic breathing during
the training session. The usual care arm received no
intervention.
The primary endpoint was the change in peak oxygen
consumption (peakVO2). Secondary endpoints were
changes in quality of life (QoL), ventilatory efciency and
chronotropic response during exercise (evaluated by
chronotropic index- CIx- formula). We used linear mixed
regression analysis for evaluating changes in primary and
secondary endpoints.
Results The mean age of the sample and time to rst
visit after discharge were 50.4±12.2 years and 362±105
days, respectively. A total of 11 (42.3%) were female. At
baseline, the mean of peakVO2, ventilatory efciency and
CIx were 18.9±5 mL/kg/min, 29.4±5.2 and 0.64±0.19,
respectively. The IMT arm improved their peakVO2
signicantly compared with usual care (+Δ 4.46 mL/
kg/min, 95% CI 3.10 to 5.81; p<0.001). Similar positive
ndings were found when evaluating changes for CIx and
some QoL dimensions. We did not nd signicant changes
in ventilatory efciency.
Conclusion In long COVID patients with a previous
admission due to SARS- CoV- 2 pneumonia, IMT was
associated with marked improvement in exercise capacity
and QoL.
Trial registration number NCT05279430.
INTRODUCTION
The pathophysiology of long COVID condi-
tions is complex and multifactorial. Patients
with long COVID have long- lasting and heter-
ogeneous symptoms with a non- accepted
uniformed definition.1 2 The most commonly
reported symptoms among long COVID
patients are muscular weakness, fatigue and
breathlessness.1 3 Indeed, compared with
control individuals matched for age, sex and
comorbidities, patients with long COVID
showed significantly impaired exercise
capacity.4
Current clinical recommendations from
international societies5 and evidence
from supervised exercise training
programmes6–8 and unsupervised training
programmes8 9 support the beneficial effect
WHAT IS ALREADY KNOWN ON THIS TOPIC
⇒Little is known about the clinical utility of home-
based rehabilitation programmes on maximal func-
tional capacity and quality of life in patients with
long COVID, particularly in those with a previous
admission due to SARS- CoV- 2 pneumonia.
WHAT THIS STUDY ADDS
⇒Home- based inspiratory muscle training (IMT) im-
proves maximal functional capacity and quality of
life in patients with long COVID after a previous ad-
mission due to SARS- CoV- 2 pneumonia.
HOW THIS STUDY MIGHT AFFECT RESEARCH,
PRACTICE OR POLICY
⇒Home- based IMT seems to be a suitable, feasible
and effective alternative to supervised exercise
training programmes for improving exercise capaci-
ty and quality of life in patients with long COVID and
may offer an accessible physical therapy model, re-
quiring minimal infrastructure resources.
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2PalauP, etal. BMJ Open Resp Res 2022;9:e001439. doi:10.1136/bmjresp-2022-001439
Open access
of physical therapies on COVID and post- COVID- 19
conditions. Nevertheless, home- based programmes’ feasi-
bility and clinical utility on maximal functional capacity
in long COVID are small or even absent, particularly in
symptomatic postdischarged patients. Based on results
in other clinical scenarios,10–12 we hypothesised that a
home- based IMT programme might significantly improve
maximal functional capacity in long COVID patients.
Accordingly, this randomised controlled study aimed to
evaluate the effect of a 12- week home- based inspiratory
muscle training (IMT) programme on maximal func-
tional capacity and quality of life (QoL) in patients with
long COVID recovering from a SARS- CoV- 2 pneumonia
requiring hospitalisation.
METHODS
Study design
This study was a single- centre, blinded assessor,
randomised clinical trial designed to evaluate the effect
of a home- based IMT programme on maximal functional
capacity in long- term symptomatic patients (>3 months)
after hospital admission due to SARS- CoV- 2 pneumonia
(InsCOVID trial). The patients received a concealed
allocation 1:1 to either a 12- week programme of IMT
(IMT group) or usual care (UC) alone by a computer-
generated randomisation scheme. At the baseline visit,
demographic, echocardiographic and laboratory data
were collected, and baseline primary and secondary
endpoint measures were recorded for all participants. All
participants underwent these measures after 12 weeks.
The study design was previously published.13
Study population
The eligibility of candidate patients was based on the
following inclusion criteria: (a) symptomatic adult >18
years old with a previous admission due to SARS- CoV- 2
pneumonia; (b) at least 3 months after discharge; and (c)
provide informed consent. In addition, exclusion criteria
were: (a) inability to perform a maximal baseline exercise
test; (b) structural heart disease, valve heart disease or
diastolic dysfunction estimated by two- dimensional echo-
cardiography; (c) previous ischaemic heart disease, heart
failure, myocardiopathy or myocarditis; (d) effort angina
or signs of ischemia during cardiopulmonary exercise
testing (CPET); (e) significant primary pulmonary
disease, including a history of pulmonary arterial hyper-
tension, chronic thromboembolic pulmonary disease or
chronic obstructive pulmonary disease; (f) treatment
with digitalis, calcium channel blockers, β-blocker or
ivabradine; (g) chronic kidney disease (glomerular filtra-
tion rate <60 mL/min/1.73 m2); (h) patients with pace-
makers or previous history of atrial fibrillation; (i) auto-
immune, inflammatory or active neoplastic disease; (j)
anaemia; and (k) pregnancy.
The intervention sessions were conducted by a single
physiotherapist with more than 20 years of respiratory
physiotherapy experience and no contact with the asses-
sors or the participants’ results.
Intervention
Eligibility assessment, randomisation and baseline visit
Patients who met the inclusion–exclusion criteria and
signed the informed consent form were randomised (1:1)
into two arms: (1) a home- based 12- week programme of
IMT (IMT group) or (2) UC. At the baseline visit (day 0),
a comprehensive medical history, physical examination,
anthropometry and examination tests were performed by
one pulmonologist and two cardiologists blinded to the
patients’ allocation arm. The examination tests included:
an ECG, two- dimensional transthoracic echocardiog-
raphy, CPET, QoL assessment by the European Quality
of Life 5 Dimensions 3 Level Version (EQ- 5D- 3L) ques-
tionnaire, pulmonary function test and blood samples for
a panel of baseline biomarkers. Researchers performing
the CPET and the other study procedures, excluding
physiotherapist visits, were also blinded to treatment
assignment.
Treatment intervention and physiotherapist visits
Following screening and baseline visit (day 0), patients
received the following physiotherapist visits:
1. UC arm: Patients allocated to this arm were checked
by a physiotherapist at the first visit (at day 1±3) and last
visit (at day 90±5), who measured their maximal inspi-
ratory pressure (MIP). MIP was obtained using a hand-
held respiratory mouth pressure metre (electronic
manometer- ELKA, PM15). With a nose clip, patients
were instructed to breathe through a mouthpiece only
during inspiration. Patients repeated this manoeuvre
within a 1 min interval until three technically satisfactory
and reproducible measurements were obtained (varia-
tion of −10%). The MIP values were obtained standing by
inspiration from residual volume.
Patients allocated to this arm did not receive any phys-
ical therapy.
2. IMT group arm: patients allocated to this arm were
checked by a physiotherapist at visit 1 (at day 1±3), weekly
and at the last visit (at day 90±5). MIP was measured at
each visit. Also, on visit 1 (day 1±3), a physiotherapist
instructed and educated patients to perform diaphrag-
matic breathing during the training sessions. After visit
1, the patients started home- based inspiratory training at
a resistance of 25%–30% of measured MIP, twice daily,
for 20 min each session, for 12 weeks, using a threshold
inspiratory muscle trainer (Threshold IMT, Respironics).
The physiotherapist examined the patients weekly
by checking the diary card and measuring their MIP.
The resistance was modified each session according to
25%–30% of their weekly MIP measured.
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Outcome measurement
Cardiopulmonary exercise testing
Maximal functional capacity was evaluated using incre-
mental and symptom- limited CPET on a bicycle ergom-
eter, beginning with a workload of 10 W and increasing
gradually in a ramp protocol at 10 W increments every
1 min. We defined maximal functional capacity as when
the patient stops pedalling because of symptoms and
the respiratory exchange ratio (RER) was ≥1.1. During
exercise, patients were monitored with 12- lead ECG
and blood pressure measurements every 2 min. Gas
exchange data and cardiopulmonary variables were aver-
ages of values taken every 10 s. PeakVO2 was defined as
the highest value of VO2 during the last 20 s of exercise.
Once peakVO2 was obtained, we calculated its per cent
of predicted peakVO2 (pp- peakVO2), defined as the
percentage of predicted peakVO2 adjusted for sex, age,
exercise protocol, weight and height according to the
Wasserman/Hansen standard prediction equation for
the healthy and sedentary population. The ventilatory
efficiency was determined by measuring the slope of the
linear relationship between minute ventilation (VE) and
carbon dioxide production (VCO2) across the entire
course of the exercise (VE/VCO2 slope).
The heart rate (HR) response during CPET was eval-
uated following the chronotropic index (CIx) formu-
la=peak HR- rest HR/ [(220- age)- restHR)].14
Each subject underwent two tests (at baseline and 12
weeks).
Health-related QoL assessment
EQ- 5D- 3L instrument was used to assess the impact of
the IMT on health- related QoL.15 The EQ- 5D- 3L evalu-
ates five dimensions and uses a simple score (1–3) for
evaluating each dimension, with 11 111 representing the
best health state and 33 333 representing the worst health
state. Furthermore, the EQ- 5D- 3L instrument introduces
a visual analogue scale, which provides a self- rated health
status, with 0 representing the worst imaginable health
and 100 representing the best imaginable health.15 Each
subject underwent two tests (at baseline and 12 weeks).
Endpoints
The study’s primary endpoint was the average change
from baseline in mean peakVO2. The secondary
endpoints were: (a) absolute changes in VE/VCO2 slope,
(b) absolute changes in chronotropic response during
CPET and (c) absolute changes in different QoL dimen-
sions assessed by the EQ- 5D- 3L tool.
Statistical analysis
All statistical comparisons were made under an intention-
to- treat principle.
Descriptive analysis
Continuous variables are expressed as means (±1 SD) or
medians (IQR), and discrete variables are as percentages.
At baseline, the means, medians, and frequencies among
treatment groups were compared using the t- test,
Wilcoxon and χ2 test.
Sample size
The primary efficacy endpoint null hypothesis stated no
differences in the mean peakVO2 among the IMT group
and UC arm patients. Based on previous studies in other
clinical scenarios,10–12 IMT would be associated with a
significant increase of at least a mean peakVO2 of 3 mL/
kg/min, with an SD of ±2.5.
Assuming an allocation ratio of 1:1, 22 patients (11
patients per group) would provide 80% of power at a
significance alpha level <0.05. In addition, we assumed
15% of withdrawals or losses to follow- up. Thus, 13
patients per arm (26 patients) were estimated. The soft-
ware used for sample size calculation was GRANMO.
Inferential analyses
A linear mixed regression model (LMRM) was used to
analyse the primary and secondary continuous endpoints.
All analyses included the baseline value of the endpoint
as a covariate (mixed model within the framework of
analysis of covariance). In addition, the period effect was
tested by modelling the interaction between the treat-
ment group and the period. LMRMs are presented as
least square means with 95% CIs and p values. All anal-
yses were performed with STATA V.15.1. (Stata Statistical
Software, Release 15 (2017); StataCorp LP).
Patient and public involvement
Patients or the public were not involved in the design,
conduct, reporting or dissemination plans of our post
hoc analysis.
RESULTS
Compliance with the trial protocol
Recruitment accomplished the sample size calculation
estimated in the registered protocol. In addition, all
enrolled participants met the eligibility criteria. There-
fore, all of the outcome measures in the registered
protocol are reported.
The ow of participants through the study
A total of 32 patients were assessed for eligibility, of whom
26 met the inclusion criteria and agreed to participate in
the study. A detailed flow chart is presented in figure 1.
All patients allocated to the control group completed the
two physiotherapist visits. Among 13 patients assigned to
the IMT group, 12 completed all weekly physiotherapist
visits and one interrupted their weekly physiotherapist
visit for 2 weeks due to SARS- CoV- 2 reinfection.
Baseline characteristics
Patient baseline characteristics are presented in table 1.
At baseline, the mean age was 50.4±12.2 years, 42.3%
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were women, 11.5% had a history of hypertension and
the mean time to the first CPET from hospital discharge
was 362±105 days. Patients included showed a moder-
ately reduced functional capacity (mean pp- peakVO2 was
74.9±15%). There were no significant differences in clin-
ical, echocardiographic, functional tests or laboratory
data across randomisation arms.
Primary endpoint
At baseline and 3 months, all patients performed a
maximal CPET (RER>1.1).
Between-person comparisons
At 3 months, the mean of peakVO2 was higher in those
in the IMT group (22.2 mL/kg/min, 95% CI 21.3 to
23.2 vs 17.8 mL/kg/min, 95% CI 16.8 to 18.7; p<0.001
(Δ+4.46 mL/kg/min)) as shown in figure 2A. Similar
findings were found when pp- peakVO2 was analysed.
At 12 weeks, the mean of pp- peakVO2 was also higher
in patients allocated to the IMT group (89.1 %, 95%
CI 85.2 to 92.9 vs 71.1 %, 95% CI 67.2 to 74.9; p<0.001
(Δ+18.03 %)) (figure 2B).
Within-person comparisons
The precomparisons and postcomparisons within groups
showed a significant increase in mean peakVO2 values
for the IMT group (3.4 mL/kg/min, 95% CI 2.1 to 4.6,
p<0.001). Conversely, the UC group decreased in mean
peakVO2 (−1.09 mL/kg/min, 95% CI −1.8 to −0.384,
p=0.006).
Secondary endpoints
Effect of IMT on VE/VCO2 slope
VE/VCO2 slope did not significantly differ between the
IMT group versus UC at 12 weeks (Δ −1.92, 95% CI −4.69
to 0.85, p=0.165) (figure 3A).
The precomparisons and postcomparisons within
groups did not show a significant change for the IMT
group (−1.03 mL/kg/min, 95% CI –2.75 to −0.69,
p=0.214) or UC group (−0.24 mL/kg/min, 95% CI
–2.14 to 1.66, p=0.784) at 12 weeks.
Effect of IMT on HR response to maximal exercise
At 12 weeks, the mean of CIx significantly increased in
those patients allocated to the IMT group (0.75, 95% CI
0.66–0.84 vs 0.62, 95% CI= 0.53–0.71; p=0.046 (Δ+0.13))
(figure 3B).
Figure 1 Flow chart for patient’s inclusion and follow- up. IMT, inspiratory muscle training; UC, usual care.
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Table 1 Baseline characteristics of the patients stratied by randomisation arm
Variables All patients Training Control P value
n (%) 26 (100) 13 (50) 13 (50)
Demographic and medical history
Age, years 50.4±12.2 49.9±11.6 50.8±13.2 0.664
Women, n (%) 11 (42) 7 (54) 4 (31) 0.234
BMI, kg/m229 (26–32) 29 (26–32) 30 (27–32) 0.643
Hypertension, n (%) 3 (12) 1 (8) 2 (15) 0.536
Current smoker, n (%) 1 (4) 1 (8) 0 (0) 0.232
Prior smoker, n (%) 8 (31) 4 (31) 4 (31) 1
Length of hospital stay, days 8 (5- 15) 6 (5- 15) 8 (7- 11) 0.877
Received steroids, n (%) 25 (96) 12 (92) 13 (100) 0.232
Time to the rst CPET from discharge, days 362±105 385±97 340±105 0.638
Vital signs
Heart rate at rest, bpm 77±11 78±12 77±10 0.443
Systolic blood pressure at rest, mm Hg 117±12 116±10 118±13 0.357
Diastolic blood pressure at rest, mm Hg 61±5 63±5 60±6 0.434
Laboratory values, echocardiography parameters and pulmonary function test
Haemoglobin, g/dL 14.6±1.1 14.6±1.4 14.5±0.9 0.801
CRP, mg/L 1.6 (0.8–3.2) 1.8 (0.8–3) 1.4 (0.8–3.2) 0.939
NT- proBNP, pg/mL 28 (14–43) 30 (18–36) 26 (11–50) 0.939
LVEF, % 65.6±6.1 65.2±5.8 66.1±6.6 0.680
PASP, mm Hg* 27.7±4.7 26.8±5.9 28.7±2.9 0.105
DLCO, % 72.5±13.3 72.8±13.2 72.1±13.9 0.868
MIP, cmH2O 83 (62–105) 80 (66–101) 86 (60–110) 0.858
CPET variables
Workload, W 119.5±36 122±34.2 117.1±39 0.659
Exercise time, s 684.8±218.7 669.5±237.3 700±207 0.644
Peak heart rate, bpm 139±20 144±20 135±20 1
Chronotropic index† 0.64±0.19 0.72±0.19 0.64±0.18 0.855
Peak systolic blood pressure, mm Hg 157±20 158±20 155±20 0.918
RER 1.12 (1.1–1.16) 1.12 (1.1–1.16) 1.1 (1.1–1.15) 0.708
PeakVO2, mL/kg/min 18.9±5 18.8±5.8 18.9±4.4 0.323
pp- peakVO2, % 74.9±15 76.9±17 72.9±14 0.494
VE/VCO2 slope 29.4±5.2 28.2±4.6 30.5±5.6 0.480
Health- related QOL: EQ- 5D- 3L questionnaire
Mobility dimension 1 (1–1) 1 (1–1) 1 (1–1) 0.149
Self- care dimension 1 (1–1) 1 (1–1) 1 (1–1) 1
Usual activities dimension 1 (1–2) 1 (1–2) 1 (1–1) 0.193
Pain/discomfort dimension 1 (1–2) 1 (1–2) 1 (1–2) 1
Anxiety/depression dimension 1 (1–2) 2 (1–2) 1 (1–1) 0.098
Visual analogue scale 70 (60–80) 70 (50–80) 79 (70–87) 0.073
Continuous variables are presented as median (IQR), and categorical variables are as percentages.
*Data available in 15 patients (eight in the training arm and seven in the control arm).
†Cronotropic index formula=peak HR- rest HR/ [(220- age)- restHR)].
BMI, body mass index; CPET, cardiopulmonary exercise testing; CRP, C reactive protein; DLCO, diffusing capacity of the lungs for
carbon monoxide; LVEF, left ventricle ejection fraction; MIP, maximal inspiratory pressure; NT- proBNP, N- terminal pro b- type natriuretic
peptide; PASP, pulmonary artery systolic pressure; peakVO2, peak oxygen consumption; pp- peakVO2, percent of predicted peak oxygen
consumption, RER, respiratory exchange ratio; QoL, quality of life; VE/VCO2 slope, ventilatory efciency.
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The precomparisons and postcomparisons within
groups did not show a significant change for the IMT
group (0.06, 95% CI −0.17–0.13, p=0.122) or UC group
(−0.04, 95% CI −0.15 to 0.072, p=0.447).
Effect of IMT on health-related QoL
A significant improvement in usual activities (−0.31,
95% CI −0.54 to −0.07, p=0.013) and anxiety/depres-
sion (−0.53, 95% CI −0.67 to −0.40, p<0.001) dimensions
was found in IMT group (figure 4A,E), with no signif-
icant changes in UC. IMT resulted in a non- significant
improvement in both groups’ mobility, self- care and
pain/discomfort dimensions (figure 4B,C,D). A signif-
icant change in the patient’s self- rated health on a
vertical visual analogue scale dimension in those patients
allocated to the IMT group (21.1, 95% CI 12.9 to 29.4,
p<0.001) (figure 4F).
Safety and adherence
There were no reports of adverse effects following or
during exposure to IMT. All patients in the IMT group
reported two daily sessions of IMT. Patients allocated
in the IMT group significantly improved the maximal
inspiratory pressure (+79.4 cmH2O, 95% CI 68.7 to 98.1,
p<0.001) at 12 weeks, with no significant change in the
UC group (+17.3cmH2O, 95% CI −2.1 to 36.7.1, p=0.075).
DISCUSSION
The main finding of the InsCOVID trial is that a
12- week home- based IMT programme in symptomatic
postdischarged patients with long COVID resulted in a
substantial improvement in physical performance and
QoL. To our knowledge, this is the first randomised
controlled study that evaluated the effect of a home-
based IMT programme on maximal functional capacity
over a middle- aged postdischarged population with long
COVID and reduced aerobic capacity.
Recent clinical practice recommendations and regu-
latory agencies have increasingly recognised patients’
symptoms and physical function as important thera-
peutic targets in long COVID.5 16–18 Among them, exer-
cise intolerance and breathlessness are cardinal clinical
features. PeakVO2 during a maximal symptom- limited
CPET is the most reliable parameter to assess maximal
functional capacity in long COVID and provides rele-
vant information about potential mechanisms of exercise
limitation among people with long COVID.19 Paradoxi-
cally, however, evidence regarding the effects of exercise-
based rehabilitation programmes on improving maximal
exercise capacity (measured as peakVO2) in long COVID
comes from observational studies and remains scarce.20 21
IMT in long COVID
Home- based IMT programmes demonstrated significant
improvement in peakVO2 in other clinical scenarios.12 22
However, regarding the long COVID setting, only a previ-
ously published randomised study evaluated the effect
of an 8- week home- based IMT programme versus UC
on reported QoL (primary endpoint), perceived dysp-
noea (secondary endpoint) and an indirect evaluation
Figure 2 Change in mean peakVO2 and pp- peakVO2.
IMT, inspiratory muscle training; peakVO2, peak oxygen
consumption; pp- peakVO2, percent predicted peak oxygen
consumption; UC, usual care.
Figure 3 Change in mean ventilatory efciency and
chronotropic index. CIx, chronotropic index; IMT, inspiratory
muscle training; UC, usual care; VE/VCO2 slope, ventilatory
efciency.
Figure 4 Change in the score of different QoL dimensions
assessed by the EQ- 5D- 3L tool. IMT, inspiratory muscle
training; QoL, quality of life; UC, usual care.
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of fitness (secondary endpoint) in a non- selected popu-
lation of outpatients with long COVID.23 The authors
reported improved perceived dyspnoea with no differ-
ences in the primary endpoint. Furthermore, although
the authors did not directly measure the maximal func-
tional capacity, they reported a significant improvement
in the trained group’s indirect measurement of peakVO2
(using a step test). Interestingly, the increase in estimated
peakVO2 was similar to the present study (Δ~+4 mL/kg/
min). Likewise, in concordance with the current study,
a home- based IMT seems to be a safe, feasible and effi-
cacious approach for improving functional capacity in
patients with long COVID.
Biological plausibility
Although it was not the aim of this study to analyse the
physiological mechanisms underlying the effects of IMT
on patients with long COVID, several potential mecha-
nisms have been postulated to explain the beneficial
effects of IMT on functional capacity: (1) decreases the
rating of perceived exertion and improves respiratory
muscle economy,24 25 improving exercise tolerance; (2)
improves ventilatory efficiency and improves breathing
patterns during exercise hyperpnoea24 26 and (3) attenu-
ates the respiratory muscle metaboreflex,24 27 which leads
to sympathetic attenuation and autonomic regulation.
Interestingly, 12- week IMT significantly improved
blunted HR response to exercise, which has been asso-
ciated with autonomic dysfunction in long COVID
patients.28 Similarly, IMT enhanced patients’ self-
reported health- related QoL or anxiety. Finally, although
VE/VCO2 decreased in patients allocated to the IMT
arm, the magnitude of this change was not significant.
Two main reasons may partially explain this last fact.
The first, and most likely reason, is the short follow- up,
which may underestimate potential benefits that can take
longer to emerge. Second, considering that the sample
size was calculated for the primary endpoint, some of the
negative results in secondary outcome measures could be
explained by insufficient statistical power (type II error).
Clinical implications
Home- based IMT is a simple, low- cost and safe interven-
tion that could be implemented after a short physiother-
apeutic training period. According to present findings,
home- based IMT is a suitable, feasible and effective
alternative for improving exercise capacity and QoL in
patients with long COVID and may offer an accessible
physical therapy model, requiring minimal infrastructure
resources.
Study limitations
Several limitations need to be acknowledged. First, as a
single- centre study, the generalisability of our results to
other populations may be limited. Second, this study has
the inherent limitations of being a trial with a relatively
small number of participants. As such, we cannot discard
that the trial findings on secondary endpoints may be
due to low statistical power (type II error). Third, we
have exclusively evaluated patients with long COVID
after hospital admission due to SARS- CoV- 2 pneumonia.
Therefore, whether home- based IMT improves short-
term maximal exercise capacity in patients with other
post- COVID- 19 conditions remains elusive. Finally, with
the current data, we cannot unravel the biological mech-
anism behind these findings.
CONCLUSIONS
Among postdischarged patients with long COVID and
reduced aerobic capacity, home- based IMT resulted in a
significant improvement in exercise capacity and QoL.
However, further studies must confirm these results and
elucidate the underlying pathophysiological mechanisms
responsible for these benefits.
Author afliations
1Cardiology Department, Hospital Clinico Universitario de Valencia, INCLIVA,
Universitat de Valencia, Valencia, Spain
2Cardiology Department. Hospital Clínico Universitario de Valencia, Universitat
Jaume I, Castellón, Spain
3Pneumology Department, Hospital Clínico Universitario de Valencia, Hospital
Clinico Universitario, Valencia, Spain
4Cardiology Department, Hospital Clínico Universitario de Valencia, Hospital
Clínico Universitario, Valencia, Spain
5Cardiology Department. Hospital Clínico Universitario de Valencia. Universitat
de València, INCLIVA, Valencia, Spain
6Physiotherapy Department, Universitat de Valencia, Valencia, Spain
Contributors Conceptualisation and design: PP, ED, CG and LL. Acquisition,
analysis or interpretation of data for the work: all authors. Drafting protocol
manuscript: all authors. A critical review of protocol manuscript: all authors.
Guarantor: PP
Funding This work was supported in part by a grant from Sociedad Española de
Cardiología, Investigación Clínica en Cardiología, Grant SEC 2021.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in
the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Consent obtained directly from patient(s)
Ethics approval This study involves human participants and was approved by
Comité Ético de Investigación Clínica (CEIC) del Hospital Clínico Universitario de
Valencia. This study was registered at http://clinicaltrials.gov (NCT05279430).
Participants gave informed consent to participate in the study before taking part.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request.
Supplemental material This content has been supplied by the author(s). It has
not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been
peer- reviewed. Any opinions or recommendations discussed are solely those
of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
responsibility arising from any reliance placed on the content. Where the content
includes any translated material, BMJ does not warrant the accuracy and reliability
of the translations (including but not limited to local regulations, clinical guidelines,
terminology, drug names and drug dosages), and is not responsible for any error
and/or omissions arising from translation and adaptation or otherwise.
Open access This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY- NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non- commercially,
and license their derivative works on different terms, provided the original work is
properly cited, appropriate credit is given, any changes made indicated, and the
use is non- commercial. See:http://creativecommons.org/licenses/by-nc/4.0/.
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8PalauP, etal. BMJ Open Resp Res 2022;9:e001439. doi:10.1136/bmjresp-2022-001439
Open access
ORCID iDs
PatriciaPalau http://orcid.org/0000-0001-5040-0924
EloyDomínguez http://orcid.org/0000-0001-7583-8818
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