
==== Front
Am J Respir Crit Care Med
Am J Respir Crit Care Med
ajrccm
American Journal of Respiratory and Critical Care Medicine
1073-449X
1535-4970
American Thoracic Society

38843510
202405-0903ED
10.1164/rccm.202405-0903ED
Editorials
Inspiratory Muscle Training in Patients with Post–COVID-19 Condition: Considerations on Efficacy, Safety, and Patient Perception
https://orcid.org/0000-0003-4073-4001
Schreiber Annia 1 2
https://orcid.org/0000-0003-0444-8606
Gosselink Rik 3 4
1 Li Ka Shing Knowledge Institute
Unity Health Toronto (St. Michael’s Hospital)
Toronto, Ontario, Canada
2 Interdepartmental Division of Critical Care Medicine
University of Toronto
Toronto, Ontario, Canada
3 Department Rehabilitation Sciences
University of Leuven
Leuven, Belgium
4 Department of Health and Rehabilitation Sciences, Faculty of Medicine
Stellenbosch University
Cape Town, South Africa
6 6 2024
1 9 2024
6 6 2024
210 5 537539
Copyright © 2024 by the American Thoracic Society
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0. For commercial usage and reprints, please e-mail Diane Gern (dgern@thoracic.org).
==== Body
pmcMost patients, 2 years after surviving hospitalization with COVID-19, have improved physical and mental health and are able to return to their original work; however, the majority of them still have a lower health status (1). Fatigue and muscle weakness are most frequent, whereas dyspnea with a modified Medical Research Council scale score >1 is identified in 14% of patients (1). Last year, Regmi and colleagues identified, in patients with post–COVID-19 condition, diaphragm dysfunction and a correlation with exertional dyspnea (2). In his editorial accompanying this paper, Polkey suggested conducting a trial to study the effect of inspiratory muscle training (IMT) on dyspnea in these patients (3). His call is answered by Spiesshoefer and colleagues (pp. 618–628) in this issue of the Journal (4). This well-conducted study in 18 post–COVID-19 patients with exertional dyspnea and respiratory muscle weakness showed that 6 weeks of IMT at moderate intensity improves the dyspnea domain of the Chronic Respiratory Disease Questionnaire, inspiratory muscle strength (sniff nasal pressure), and endurance (time to task failure) in comparison with a sham training group.

The authors did an excellent job of identifying the specific effects of IMT on the diaphragm. Carefully conducted volitional and nonvolitional assessment of diaphragm function (twitch and sniff transdiaphragmatic pressures, diaphragm thickness, and thickening fraction) were performed. The data showed a trend toward improvement in diaphragm function in the treatment arm. However, to the authors’ disappointment, no statistically significant differences in changes of diaphragm function between the groups were observed. Obviously, inspiratory maneuvers against an external load and high inspiratory flow up to TLC provided additional stress on all the inspiratory muscles involved in overcoming the external resistance. Indeed, the present data suggest that improvement of extradiaphragmatic muscle function was probably also contributing to the improvements in overall inspiratory muscle function, as was observed after IMT in patients with chronic obstructive pulmonary disease (5), patients with diaphragm paresis (6), or patients during difficult weaning (7). This is consistent with the increase in thickness of the parasternal intercostal muscle in the intervention group of the present study, although only present at TLC, which suggests higher muscle recruitment during deep inspiration rather than an actual change in muscle structure related to training.

Importantly, IMT was also accompanied by improvements in exertional dyspnea. The relationship between respiratory muscle function/activation and dyspnea is well established (8). The authors observed an increased maximal activation of the diaphragm after IMT and related this to the observed decrease in dyspnea. Indeed, increased cortical activation after muscle training is a known neural adaptation. However, the decrease in dyspnea seems more related to less activation of the diaphragm during activities of daily life, as previously shown after IMT in patients with chronic obstructive pulmonary disease (9). This is probably also the substrate for the increased muscle endurance after IMT observed in the treatment group. Stronger muscles perform any given task at a lower percentage of maximum capacity than weaker muscles and are therefore able to sustain a given activity for longer periods (10).

Can we safely provide exercise training in patients with post–COVID-19 condition? Over the last several years, numerous studies have reported disabling signs and symptoms after physical and/or cognitive exertion in post–COVID-19 patients, a condition known as “postexertional malaise” (11). Appelman and colleagues indeed showed that high-intensity (maximal) cycling exercise in post–COVID-19 condition patients with postexertional malaise was accompanied by limb muscle abnormalities, which included alteration in mitochondrial activity, signs of muscle damage, and inflammatory response (12). These findings might support the National Institute for Health and Care Excellence advice to discourage graded exercise as part of the treatment of these patients (13). However, it is now well accepted that the inflammatory response, in the context of exercise-induced muscle damage, is crucial for functional recovery and muscle regeneration (14). Moreover, there is evidence that a first bout of exercise training, generating initial muscle damage, will lead to muscle adaptations characterized by less susceptibility to further exercise-induced muscle damage, attenuated delayed-onset muscle soreness, and faster recovery (known as the “repeated-bout effect”), a process that seems to be at least partially mediated by the inflammatory response itself (15). Therefore, morphological abnormalities observed immediately after exercise are not necessarily in contrast with long-lasting muscle adaptations and long-term increase in muscle strength; they may represent instead different temporal muscle responses to the same (acute vs. protracted) stimulus.

Meaningful changes in muscle strength and gradual restoration of muscle function in weakened muscles require a certain amount and intensity of load, below which no change in strength or reversal of dysfunction is observed (i.e., a load of 10% of maximal capacity, which was used for the control training group in the Spiesshoefer and colleagues paper [4]). We can speculate that a similar phenomenon occurs during mechanical ventilation. Here, an excessive ventilatory support, providing too little load for the muscle, can lead to or perpetuate muscle atrophy and weakness (16). On the other hand, still experimental, findings suggest that insufficient ventilator assistance, resulting in too much load for the muscle, could also be injurious and contribute to muscle dysfunction (17). Probably, in training respiratory muscles, as well as in supporting them with mechanical ventilation, the secret lies in balance (the Aristotelian mesótes: μεσóτης): the level of load that will generate just the “right” amount of inspiratory effort for each patient, neither too little nor too much.

In this regard, a maximal incremental ramp exercise test, as applied by Appelman and colleagues (12), is probably extremely different, both in terms of injurious and training effects and in terms of strength training at moderate intensity (IMT resistance set at 40–50% of individual sniff nasal inspiratory pressure as applied in the present study) (4). In fact, in the present study, no adverse events were reported, which likely contributed to the excellent compliance with the scheduled training sessions (85–90%). The study has shown that well-controlled, individually tailored respiratory muscle training is effective in reducing dyspnea in this patient population. These findings further support the idea that advising against rehabilitation because of reported exercise intolerance and dyspnea in post–COVID-19 condition is likely not the best option. Symptoms will not resolve spontaneously, and respiratory muscle strength will not consistently improve on its own (as evidenced by observations in the patients of this study over the 2 yr preceding enrollment and in the sham training group). On the contrary, physical inactivity will only perpetuate (if not worsen) physical deconditioning. Indeed, patients with post–COVID-19 condition have been found to exhibit reduced stroke volume and left ventricular diameter, together with an increased resting heart rate, signs that are plausibly indicative of reduced degrees of physical fitness (18). Cautious, individualized, and symptom-titrated exercise (considering specifically postexertional malaise) is, at this point, probably the most advisable approach to prevent further muscle deconditioning and promote functional capacity in patients with post–COVID-19 condition (19).

Originally Published in Press as DOI: 10.1164/rccm.202405-0903ED on June 6, 2024

Author disclosures are available with the text of this article at www.atsjournals.org.
==== Refs
References

1. Huang L Li X Gu X Zhang H Ren L Guo L et al. Health outcomes in people 2 years after surviving hospitalisation with COVID-19: a longitudinal cohort study Lancet Respir Med 2022 10 863 876 35568052
2. Regmi B Friedrich J Jörn B Senol M Giannoni A Boentert M et al. Diaphragm muscle weakness might explain exertional dyspnea 15 months after hospitalization for COVID-19 Am J Respir Crit Care Med 2023 207 1012 1021 36596223
3. Polkey MI Diaphragm dysfunction as a contributor to breathlessness after COVID-19 infection Am J Respir Crit Care Med 2023 207 964 965 36790374
4. Spiesshoefer J Regmi B Senol M Jörn B Gorol O Elfeturi M et al. Potential diaphragm muscle weakness-related dyspnea persists two years after COVID-19 and could be improved by inspiratory muscle training: results of an observational and an interventional trial Am J Respir Crit Care Med 2024 210 618 628 38763165
5. Ramirez-Sarmiento A Orozco-Levi M Guell R Barreiro E Hernandez N Mota S et al. Inspiratory muscle training in patients with chronic obstructive pulmonary disease: structural adaptation and physiologic outcomes Am J Respir Crit Care Med 2002 166 1491 1497 12406842
6. Schaeffer MR Louvaris Z Rodrigues A Poddighe D Gayan-Ramirez G Gojevic T et al. Effects of inspiratory muscle training on exertional breathlessness in patients with unilateral diaphragm dysfunction: a randomised trial ERJ Open Res 2023 9 00300-2023 37868146
7. Van Hollebeke M Poddighe D Clerckx B Muller J Hermans G Gosselink R et al. High-intensity inspiratory muscle training improves scalene and sternocleidomastoid muscle oxygenation parameters in patients with weaning difficulties: a randomized controlled trial Front Physiol 2022 13 786575 35222072
8. Laveneziana P Albuquerque A Aliverti A Babb T Barreiro E Dres M et al. ERS statement on respiratory muscle testing at rest and during exercise Eur Respir J 2019 53 1801214 30956204
9. Langer D Ciavaglia C Faisal A Webb KA Neder JA Gosselink R et al. Inspiratory muscle training reduces diaphragm activation and dyspnea during exercise in COPD J Appl Physiol (1985) 2018 125 381 392 29543134
10. McConnell AK Caine MP Sharpe GR Inspiratory muscle fatigue following running to volitional fatigue: the influence of baseline strength Int J Sports Med 1997 18 169 173 9187969
11. Davis HE McCorkell L Vogel JM Topol EJ Long COVID: major findings, mechanisms and recommendations Nat Rev Microbiol 2023 21 133 146 36639608
12. Appelman B Charlton BT Goulding RP Kerkhoff TJ Breedveld EA Noort W et al. Muscle abnormalities worsen after post-exertional malaise in long COVID Nat Commun 2024 15 17 38177128
13. Torjesen I NICE advises against using graded exercise therapy for patients recovering from covid-19 BMJ 2020 370 m2912 32694164
14. Wackerhage H Schoenfeld BJ Hamilton DL Lehti M Hulmi JJ Stimuli and sensors that initiate skeletal muscle hypertrophy following resistance exercise J Appl Physiol (1985) 2019 126 30 43 30335577
15. Zourdos MC Henning PC Jo E Khamoui AV Lee SR Park YM et al. Repeated bout effect in muscle-specific exercise variations J Strength Cond Res 2015 29 2270 2276 25647658
16. Goligher EC Fan E Herridge MS Murray A Vorona S Brace D et al. Evolution of diaphragm thickness during mechanical ventilation. Impact of inspiratory effort Am J Respir Crit Care Med 2015 192 1080 1088 26167730
17. Reid WD Belcastro AN Time course of diaphragm injury and calpain activity during resistive loading Am J Respir Crit Care Med 2000 162 1801 1806 11069816
18. Tryfonos A Pourhamidi K Jörnåker G Engvall M Eriksson L Elhallos S et al. Functional limitations and exercise intolerance in patients with post-COVID condition: a randomized crossover clinical trial JAMA Netw Open 2024 7 e244386 38573638
19. Gloeckl R Zwick RH Fürlinger U Schneeberger T Leitl D Jarosch I et al. Practical recommendations for exercise training in patients with long COVID with or without post-exertional malaise: a best practice proposal Sports Med Open 2024 10 47 38658496
