*Review* **Bronchial Asthma and Sarcopenia: An Upcoming Potential Interaction**

**Nikolaos D. Karakousis <sup>1</sup> , Ourania S. Kotsiou 2,3,\* and Konstantinos I. Gourgoulianis <sup>3</sup>**


**Abstract:** Background: Sarcopenia seems to be an emerging health issue worldwide, concerning the progressive loss of skeletal muscle mass, accompanied by adverse outcomes. Asthma is a chronic inflammatory respiratory condition that is widespread in the world, affecting approximately 8% of adults. Although data are scarce, we aim to shed light on the potential association between low muscle mass and asthma and point out any probable negative feedback on each other. Methods: We searched within the PubMed, Scopus, MEDLINE, and Google Scholar databases. Study selections: Three studies were included in our analysis. Only original studies written in English were included, while the references of the research articles were thoroughly examined for more relevant studies. Moreover, animal model studies were excluded. Results: 2% to 17% of asthmatics had sarcopenia according to the existent literature. Sarcopenic asthmatic patients seem to have reduced lung function, while their mortality risk may be increased. Furthermore, patients with asthma- chronic obstructive pulmonary disease (COPD) overlap syndrome phenotype and sarcopenia might have a higher risk of osteopenia and osteoporosis progression, leading consequently to an increased risk of fractures and disability. Conclusions: Emerging data support that pulmonologists should be aware of the sarcopenia concept and be prepared to evaluate the existence of low muscle mass in their asthmatic patients.

**Keywords:** asthma; sarcopenia; low muscle mass; inflammation; respiratory disease

#### **1. Introduction**

Worldwide, it there is an emerging interest concerning the progressive loss of skeletal muscle mass and loss of muscle function, broadly known as sarcopenia [1]. Sarcopenia prevalence in the elderly is considered quite variable, ranging from 5% to 50%, depending on different factors such as age, gender, pathological conditions, and last but not least, criteria concerning diagnosis [1]. Moreover, it is closely related to frailty syndrome, which is related to increased vulnerability [2]. Besides the aging process, low muscle mass can also be associated with pathological conditions. Among these conditions are chronic liver and kidney disease, inflammatory bowel disease, diabetic foot, and many others [2–5].

Asthma is a chronic inflammatory disorder concerning the airways [6]. It is characterized by chronic airway inflammation, which is manifested as variable airway narrowing leading to wheezes, dyspnea, and cough [7]. Asthma affected an estimated 262 million people in 2019 [1] and caused 455,000 deaths [8]. It seriously affects people's physical along with their mental health, resulting in limited physical activity and decreased quality of life (QoL) [8].

In this non-systematic review, we aim to investigate the potential interplay between these two clinical entities, even though data are limited and further studies are needed to validate this interaction.

#### *1.1. The Concept of Sarcopenia: Where We Stand?*

The combination of low muscle mass and low muscle function is characterized as sarcopenia [9,10]. Even though this term was used to describe the loss of muscle mass and physical

**Citation:** Karakousis, N.D.; Kotsiou, O.S.; Gourgoulianis, K.I. Bronchial Asthma and Sarcopenia: An Upcoming Potential Interaction. *J. Pers. Med.* **2022**, *12*, 1556. https:// doi.org/10.3390/jpm12101556

Academic Editor: Bruno Mégarbané

Received: 23 August 2022 Accepted: 16 September 2022 Published: 21 September 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

performance associated with aging, nowadays, factors harming sarcopenia progression may concern chronic diseases, an idle lifestyle, disability, and malnutrition [9,11]. It is already established that alterations in mitochondrial function, muscle fiber types, myokines, nicotinamide adenine dinucleotide (NAD+) metabolism, and gut microbiota are present in aged muscle compared to young muscle or healthy aged muscle [12]. Several age-related factors, such as neuromuscular degeneration, changes in hormone levels, chronic inflammation, and oxidative stress, are related to the development of low muscle mass [13]. On the other hand, low muscle mass might be related to pathological clinical conditions such as chronic kidney disease (CKD), chronic liver disease, respiratory disease, endocrine disorders, and others [4,14–16].

Sarcopenia is an important component of the syndrome of frailty, which is associated with increased vulnerability, a decline in the physiological reserves of several systems of the human body and augmented susceptibility to both endogenous and exogenous stressors [17,18]. Frailty syndrome has also been associated and linked to the aging population, and other pathological conditions such as postoperative complications, metabolic syndrome, cardiovascular disease, inflammation and many others [17,19,20].

In 2010, the European Working Group on Sarcopenia in Older People (EWGSOP) published a sarcopenia definition. Still, in early 2018, the Working Group carried out a new meeting (EWGSOP2) to determine an update concerning the description of this condition. In its 2018 definition, EWGSOP2 uses low muscle strength as the basic parameter of sarcopenia [21]. The updated consensus on sarcopenia uses detection of low muscle quantity and quality to confirm the sarcopenia diagnosis while it identifies poor physical performance as indicative of severe sarcopenia. Moreover, it updates the clinical algorithm used for sarcopenia case-finding, diagnosis and confirmation, and severity determination and provides clear cut-off points for measurements of variables that identify and characterize sarcopenia [21].

To monitor sarcopenia among individuals, there are specific tools. One screening tool for sarcopenia is SARC-F, which is a questionnaire consisting of five questions: Strength (S), Assistance walking (A), Rising from a chair (R), Climbing stairs (C), and Falls (F) on a scale of 0 to 2. The cutoff value recommended is ≥4 points [22,23]. In addition, tools such as grip strength and chair stand test (chair rise test), gait speed, timed-up-and-go test (TUG), 400-m walk or long-distance corridor walk (400-m walk) and short physical performance battery (SPPB) may also be of great importance to assess skeletal muscle strength and physical performance [21].

The laboratory evaluation of skeletal muscle mass, or skeletal muscle quality, can be carried out by appendicular skeletal muscle mass (ASMM) by Dual-energy X-ray absorptiometry (DXA), muscle ultrasonography, neutron activation (NAA), electrical impedance myography (EIM), whole-body skeletal muscle mass (SMM) or ASMM predicted by Bioelectrical impedance analysis (BIA) and lumbar muscle cross-sectional area by CT or MRI [21,24,25].

Interventions concerning sarcopenia are also critical to prevent its progression and adverse outcomes. Among these interventions are dietary supplementation, exercise interventions, and combined diet and exercise interventions or lifestyle interventions [26].

Both aerobic and resistance training seem to increase muscle strength and improve physical function in general [13]. Specifically, in the early 1990s, a series of studies established the role of Progressive Resistance Exercise Training (PRT) in increasing muscle size, muscle strength, and functional capacity in the elderly. At the same time, in 2009, a Cochrane review on 121 trials concluded that PRT could be imperative to improve physical performance along with muscle strength, including gait speed and getting up from a chair. PRT should be considered a first-line treatment strategy for managing and preventing sarcopenia and its adverse outcomes, but trained therapists and special equipment are required for its implementation [13].

It is already well-established that malnutrition is related to the pathogenesis of low muscle mass, specifically in frail and vulnerable elderly patients [13,18,27,28]. Interventions concerning nutrition may include increased protein, vitamin D supplementation, creatine monohydrate, antioxidants, omega-3 fatty acids, and other nutritional strategies, but all these are under consideration [13,18,29].

#### *1.2. Bronchial Asthma: A Respiratory Key Competitor*

Bronchial asthma is a medical condition that may have detrimental effects, while its prevalence globally has demonstrated a rapid increase during the last century [30,31]. It is a common clinical condition due to chronic inflammation of the lower respiratory tract, whilst due to the fact that it is a quite heterogenic clinical condition, it is often underdiagnosed, despite the fact that its clinical manifestation is already well-established and there are already valid and quite effective treatment strategies in order to confront this medical issue [32].

The risk factors concerning the bronchial asthma are already validated and it seems that gene-environment interactions have a pivotal role [32,33]. As has already been proven, genetics and heritability have an important role in bronchial asthma development along with epigenetic variation, whilst respiratory infections, particularly viral, are associated with environmental exposures, tobacco smoke, pollutants, ozone, atopic conditions, chemical exposures and effects of the microbiome, stress and metabolites [32–35].

The pathophysiology of this clinical issue is closely linked to the inflammation of the lower airway. This is most likely to derive from the combination of environmental exposures, genetic profile of its individual and probably alterations in the microbiome and metabolites [32,36]. It is well-established that the most frequent type of inflammation in asthmatic patients is the type 2 inflammation which can be associated with eosinophilic disorders, allergic diseases and parasite infections [32,37]. In addition, type 2 inflammation in asthmatic individuals can be characterized by increased IL-33 and thymic stromal lymphopoietin, increased OX40L expression and lymph node migration affecting lymphocyte maturation, metaplasia and increased mucin stores, increased TH2 bias with downregulation of Treg cells, along with increased IL-4, IL-5 and IL-13, increased IgE-producing plasma cells, IL-5–mediated accumulation and increased IgE binding and mediator storage [32,37]. All these alterations, which happen in the lower airways may lead to a remodeling status of the lung tissue in asthmatic subjects, in the mucosa and submucosa, including epithelial hyperplasia and metaplasia of goblet cells along with increased mucus production, smooth muscle hypertrophy, collagen deposition and larger mucous glands leading to airways remodeling and narrowing and increased mucous production [32,38,39]. Moreover, it is of great importance to point out, that in individuals with asthma, chest wall geometry is modified, shortening the inspiratory muscles and as a result the ability of these muscles to generate tension is quite reduced [40].

There are four essential symptoms concerning individuals living with bronchial asthma. Among these symptoms are: wheezing, coughing, shortness of breath / dyspnea and chest tightness [32,41], whilst the differential diagnosis includes medical conditions such as reactive airway disease, bronchopulmonary dysplasia, bronchiolitis and chronic obstructive pulmonary disease (COPD) [32,42].

Bronchial asthma classification concerns intermittent or persistent asthma, ranging from mild to severe, while certain asthmatic patients may have intermittent to persistent asthma [6]. Moreover, another classification concerning specific types of asthma causes and manifestations such as non-allergic, allergic, aspirin-exacerbated respiratory disease, occupational, potentially fatal, exercise-induced, and cough variant asthma [6].

Asthma management remains still quite intriguing, with acute asthma being a medical emergency that could be fatal [43]. In addition, it is well-known that asthma severity is characterized by the presence of exacerbations [43]. The four fundamental components of asthma management include patient education, monitoring and recording of symptoms and lung function, control of triggering factors and conditions that fuel comorbidity, requiring pharmacologic treatment administration [44–46].

Asthma treatment strategy is associated with the administration of inhaled corticosteroids (ICS), which have the ability to reduce asthma exacerbations and generally ameliorate the disease control [46]. In addition, in individuals living with this chronic

respiratory disease, poorly controlled asthma and a history of prior asthma exacerbations, the combined administration of ICS and long-acting β-agonists (LABA), such as budesonide and formoterol, can lead to a significant reduction of asthma exacerbations compared to ICS administration alone, whilst the prescription of ICS/LABA combinations, both for maintenance and symptom relief, has demonstrated reduction concerning asthma exacerbations [46,47]. Regarding other treatment strategies, leukotriene antagonists seem to reduce exacerbations both in children and adults, while montelukast reduced asthma exacerbations to RV infections among children, even if adding montelukast to inhaled budesonide was as effective as doubling the dose of inhaled budesonide [46]. Last but not least, the administration of anticholinergic drugs, such as tiotropium, reduces the frequency of asthma exacerbations and is approved by Food and Drug Administration (FDA) for long-term, maintenance treatment for individuals 6 years of age and older with persistent asthma, uncontrolled with ICS along with the use of one or more drugs against bronchial asthma [46,48].

It is important to underline that, in severe conditions of bronchial asthma, there is availability of biologic therapies in the form of anti-IgE (omalizumab) and anti-IL5 therapies (mepolizumab and reslizumab) [49].

Asthma and obesity, both of which are considered global health issues, tend to increase in parallel indicating a potential link between these two conditions [50,51]. There is a debate whether body mass index (BMI) status is associated with asthma control, i.e., the persistence and intensity of symptoms of asthma. [50,51].

#### *1.3. Literature Review Organization*

In this non-systematic review article, the current literature was retrieved using the PubMed, Scopus, MEDLINE, and Google Scholar databases from the date of the idea's inception concerning this review from July 1975 until August 2022. We have searched for the following terms: "sarcopenia and asthma" OR "sarcopenia and bronchial asthma" OR "low muscle mass and asthma" OR "low muscle mass and bronchial asthma". Only original studies written in English were included, while the references of the research articles were thoroughly examined for relevant studies. Animal model studies were excluded. In this study, we tried to highlight the existing literature concerning the interaction between these two entities (Table 1).


**Table 1.** The interplay between sarcopenia and bronchial asthma.

Abbreviations: ACO, Asthma—COPD overlap, COPD, chronic obstructive pulmonary disease; DXA, Dual-energy X-ray overlap.

#### *1.4. Sarcopenia and Bronchial Asthma: The Intriguing Interplay*

The association between sarcopenia and bronchial asthma seems to have been under medical investigation in recent years. Researchers worldwide tried to investigate the potential impact of these two entities on each other. Still, there is enough scientific space for a further and more thorough investigation.

Won et al. tried to investigate the association between sarcopenia and asthma in the elderly, mainly concerning asthma control and lung function [52]. The groups under investigation were divided and analyzed related to muscle mass, asthma, and physical activity. They have demonstrated that sarcopenic asthma had a younger onset and reduced physical activity than non-sarcopenic asthma, whilst asthma control was not associated with physical activity and low muscles mass [52]. Moreover, using multivariate logistic regression analyses, they further pointed out that sarcopenic asthma was associated with airway obstruction (FEV1 < 60%), older age, male gender, and lower body mass index (BMI), compared with non-sarcopenic asthma [52]. Their conclusions highlighted that intense physical activity and sarcopenia might contribute to reduced lung function in elderly asthmatics [52].

Benz et al. focused on investigating the association between sarcopenia, higher systemic immune-inflammation index (SII), COPD or asthma, and all-cause mortality in a large-scale population-based setting, taking under serious consideration that SII and sarcopenia are associated with higher morbidity in patients with COPD or asthma [53]. 4482 participants, aged > 55 years, with 57.3% being female, from the population-based Rotterdam Study were included. Asthma and COPD patients were diagnosed based on spirometry and clinical examination [53]. They defined sarcopenia according to the updated EWGSOP2 criteria while handgrip strength was obtained from the non-dominant hand using a hydraulic dynamometer, and appendicular lean mass was measured by DXA [53]. Independent of the presence of sarcopenia, COPD or asthma participants had a higher risk of all-cause mortality (HR: 2.13, 95% CI 1.46–3.12 and HR: 1.70, 95% CI 1.32–2.18 for those with and without sarcopenia, respectively, while higher SII levels increased mortality risk even in people without sarcopenia, COPD or asthma [53]. In conclusion, they pointed out that middle-aged and older people with COPD, higher SII levels, or sarcopenia had an independently increased mortality risk. At the same time, they recommended that sarcopenia and SII assessment in everyday medical practice could be predictors of worse progress in the elderly with COPD or asthma [53].

Lee et al. investigated the association between sarcopenia and bone mineral density (BMD) (which is related to osteopenia and osteoporosis) in asthma-COPD overlap (ACO), based on the existing hypothesis that sarcopenia and decreased BMD are common in the elderly and are significant comorbidities concerning obstructive airway disease (OAD) [54]. A total of 947 subjects were included in the study: 89 had asthma, 748 had COPD, and 110 ACO underwent qualified spirometry and DXA. This comparative study demonstrated that the sarcopenia group had higher risks of developing osteopenia, osteoporosis, and low BMD than the non-sarcopenia group in the ACO phenotype (OR: 6.620, 95% CI 1.129–38.828; OR: 9.611, 95% CI 1.133–81.544; and OR: 6.935, 95% CI 1.194–40.272, respectively), while in the asthma phenotype, the sarcopenia group showed no increased risk in comparison with the non-sarcopenia group [54]. They have concluded that in the ACO phenotype, individuals with sarcopenia had a higher prevalence rate and higher risks of osteopenia and osteoporosis than those without sarcopenia among all OAD phenotypes [54]. Osteoporosis is a significant factor in fractures and, as a result, disability, mortality, and morbidity [55,56]. It is already well established that the cost of osteoporosis adverse outcomes carries a significant economic burden concerning all countries, globally [57].

Figure 1 summarizes the explain the relationship between bronchial asthma and sarcopenia.

Independent of the presence of sarcopenia, COPD or asthma participants had a higher risk of all-cause mortality (HR: 2.13, 95% CI 1.46–3.12 and HR: 1.70, 95% CI 1.32–2.18 for those with and without sarcopenia, respectively, while higher SII levels increased mortality risk even in people without sarcopenia, COPD or asthma [53]. In conclusion, they pointed out that middle-aged and older people with COPD, higher SII levels, or sarcopenia had an independently increased mortality risk. At the same time, they recommended that sarcopenia and SII assessment in everyday medical practice could be predictors of

Lee et al. investigated the association between sarcopenia and bone mineral density (BMD) (which is related to osteopenia and osteoporosis) in asthma-COPD overlap (ACO), based on the existing hypothesis that sarcopenia and decreased BMD are common in the elderly and are significant comorbidities concerning obstructive airway disease (OAD) [54]. A total of 947 subjects were included in the study: 89 had asthma, 748 had COPD, and 110 ACO underwent qualified spirometry and DXA. This comparative study demonstrated that the sarcopenia group had higher risks of developing osteopenia, osteoporosis, and low BMD than the non-sarcopenia group in the ACO phenotype (OR: 6.620, 95% CI 1.129–38.828; OR: 9.611, 95% CI 1.133–81.544; and OR: 6.935, 95% CI 1.194–40.272, respectively), while in the asthma phenotype, the sarcopenia group showed no increased risk in comparison with the non-sarcopenia group [54]. They have concluded that in the ACO phenotype, individuals with sarcopenia had a higher prevalence rate and higher risks of osteopenia and osteoporosis than those without sarcopenia among all OAD phenotypes [54]. Osteoporosis is a significant factor in fractures and, as a result, disability, mortality, and morbidity [55,56]. It is already well established that the cost of osteoporosis adverse outcomes carries a significant economic burden concerning all countries, globally [57].

Figure 1 summarizes the explain the relationship between bronchial asthma and sar-

worse progress in the elderly with COPD or asthma [53].

**Figure 1.** The relationship between bronchial asthma and sarcopenia. **Figure 1.** The relationship between bronchial asthma and sarcopenia.

#### **2. Discussion 2. Discussion**

copenia.

This non-systematic review aims to demonstrate and highlight the potential interplay between bronchial asthma and low muscle mass, known as sarcopenia. These two entities play a pivotal role in respiratory and muscle health, respectively, while they are already linked to many other pathological conditions and adverse outcomes that could deteriorate the QoL among individuals. However, the existing literature is still scarce but quite prom-This non-systematic review aims to demonstrate and highlight the potential interplay between bronchial asthma and low muscle mass, known as sarcopenia. These two entities play a pivotal role in respiratory and muscle health, respectively, while they are already linked to many other pathological conditions and adverse outcomes that could deteriorate the QoL among individuals. However, the existing literature is still scarce but quite promising.

ising. Certain limitations are related to this medical issue. These limitations are associated with the currently small number of studies investigating this intriguing interplay, while the number of patients participating in them is relatively limited.

Nevertheless, it seems that it would be intriguing if further studies could include and investigate a more significant number of patients living with bronchial asthma, not only older but also of younger age, and evaluate the existence or not of a low muscle state by muscle mass assessment. In addition, it is important to study the effect of currently used treatment against asthma in sarcopenic individuals living with asthma and whether these agents could positively impact muscle mass, apart from their chronic respiratory disease.

Another interesting approach concerning this medical topic and the potential interplay between these entities could be the development of specific indexes that could evaluate the prognosis of bronchial asthma among asthmatic sarcopenic patients, probably relying on their clinical image, along with laboratory parameters concerning both muscle mass and respiratory activity.

In addition, using specific biomarkers that could assess sarcopenia phenotype in asthmatic subjects might be of great importance. It has already been analyzed the association with plasma biomarkers such as glycoprotein Dickkopf-3 (Dkk-3), c-terminal agrin fragment-22 (CAF22), and microRNAs miR-21, miR-134a, miR-133 and miR-206 with handgrip strength (HGS) and appendicular skeletal mass index (ASMI) in male, 54–73-year-old individuals with COPD, bronchial asthma or pulmonary tuberculosis and it has been demonstrated a modest-to-significant increase in the plasma markers of oxidative stress, inflammation and muscle damage, which had varying degrees of correlations with Dkk-3, CAF22 and selected micro RNAs (miRs) in these respiratory diseases [58]. This could imply that these biomarkers could be significant and valuable tools to evaluate the phenotype of sarcopenia among older patients with diseases concerning their respiratory system [58].

Last but not least, it would be appealing if an interventional protocol could be established for sarcopenic individuals with bronchial asthma. This specific protocol could

include a multimodal approach in which nutrition, exercise, and respiratory rehabilitation programs could beneficially coexist and positively affect the muscle mass, along with the asthmatic exacerbations. Ameliorating these conditions could have an upside effect on these individuals and improve their QoL.

### **3. Conclusions and Future Perspectives**

Sarcopenic patients living with a chronic respiratory disease, such as bronchial asthma, may have reduced lung function, while their mortality risk may increase. In addition, individuals with asthma-COPD overlap syndrome phenotype and low muscle mass may have a higher risk of osteopenia and osteoporosis progression, leading consequently to an increased risk of fractures, immobilization, and disability. Pulmonologists should be aware of the sarcopenia clinical condition and be prepared to evaluate low muscle mass in bronchial asthma patients using the existing screening tools for sarcopenia. Moreover, physicians who examine sarcopenic patients with bronchial asthma should be able to appropriately collaborate with specialists who deal with nutrition and exercise, giving their patients a multimodal approach concerning these entities' interplay and the optimum treatment.

**Author Contributions:** Conceptualization, N.D.K. and O.S.K.; investigation, N.D.K. and O.S.K.; writing—original draft preparation, N.D.K.; writing—review and editing, N.D.K. and O.S.K.; visualization, N.D.K.; supervision, O.S.K. and K.I.G. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Informed Consent Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


## *Article* **Evaluating Virtual and Inpatient Pulmonary Rehabilitation Programs for Patients with COPD**

**Paula Irina Barata <sup>1</sup> , Alexandru Florian Crisan <sup>1</sup> , Adelina Maritescu <sup>1</sup> , Rodica Anamaria Negrean 2,\*, Ovidiu Rosca 3,4, Felix Bratosin <sup>4</sup> , Cosmin Citu <sup>5</sup> and Cristian Oancea <sup>1</sup>**


**Abstract:** Chronic obstructive pulmonary disease (COPD) is an increasingly frequent disorder that is likely to become the third leading cause of morbidity worldwide. It significantly degrades the quality of life of patients affected and poses a significant financial burden to the healthcare systems providing treatment and rehabilitation. Consequently, our study's purpose was to compare conventional inpatient pulmonary rehabilitation (PR) with virtual (online) PR using a mobile phone application. During a three-month period, two groups of patients followed the research protocol by participating in a pulmonary rehabilitation program administered and supervised by a physical therapist five times per week. A number of respiratory variables were examined before and after the test. At the end of the study period, a total of 72 patients completed the rehabilitation in the inpatient group, respectively 58 in the online group. It was observed that post-test comparison between patients undergoing the traditional and online rehabilitation methods did not show any significant differences. However, the calculated mean differences between pre-test and post-test results were significantly higher in favor of the virtual method. The most significant variations were encountered in maximal inspiratory pressure (MIP) (6.6% vs. 8.5%, *p*-value < 0.001), 6-min walking test (6MWT) (6.7% vs. 9.4%, *p*-value < 0.001), and COPD assessment test (CAT) values (4.8 vs. 6.2, *p*-value < 0.001), respectively. However, the maximal expiratory pressure (MEP) variation was significantly higher in patients undergoing the traditional rehabilitation method, from an average of 4.1% to 3.2% (*p*-value < 0.001). In this preliminary study, the online pulmonary rehabilitation program proved non-inferiority to the traditional method, with significantly better results in several measurements. Additional studies using larger cohorts of patients and longer exposure to the online rehabilitation program are required to validate these findings.

**Keywords:** COPD; pulmonary rehabilitation; digitalization of healthcare; respiratory disease

### **1. Introduction**

Chronic obstructive pulmonary disease (COPD) is a major cause of chronic morbidity and mortality in the world and is the third leading cause of global disability-adjusted life-years (DALY) [1]. COPD is a progressive respiratory disease that leads to physical inactivity, worsening dyspnoea, muscle deconditioning, and reduced quality of life [2,3].

Although there have been remarkable advances in pharmacological treatments, a large proportion of patients remain symptomatic. Pulmonary rehabilitation (PR) has been recognized as an important, standard treatment for people with COPD aimed at reducing

**Citation:** Barata, P.I.; Crisan, A.F.; Maritescu, A.; Negrean, R.A.; Rosca, O.; Bratosin, F.; Citu, C.; Oancea, C. Evaluating Virtual and Inpatient Pulmonary Rehabilitation Programs for Patients with COPD. *J. Pers. Med.* **2022**, *12*, 1764. https://doi.org/ 10.3390/jpm12111764

Academic Editors: Ioannis Pantazopoulos and Ourania S. Kotsiou

Received: 10 October 2022 Accepted: 24 October 2022 Published: 25 October 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

the burden of symptoms by increasing exercise tolerance and improving self-management. The provision of PR is mandated by the National Institute for Health and Care Excellence (NICE) as a key pillar of integrated care [3].

There is level 1 evidence that PR improves dyspnoea, exercise capacity, and quality of life, regardless of disease severity [4]. Despite these findings, 5% of people who would benefit from PR undertake it [5] with a low referral (<15%) [6], high non-attendance (up to 50%), and poor completion rates (up to 30%) [7].

Moreover, approximately 50% of patients with severe and very severe COPD declined to participate in these programs, and between 30–50% dropped out before completion [8]. The barriers to the uptake of a PR program include lack of transportation, perceived benefits of PR, disruption of the usual routine, the timing of programs, lack of rehabilitation centers, and shortage of qualified health professionals [7].

Since 2015, the American Thoracic Society (ATS) and European Respiratory Society (ERS) have recommended investigating alternative approaches to PR in an attempt to increase uptake and make PR available to more patients [9]. Home-based models of PR have been proposed to increase the availability and accessibility of PR programs to patients [10], moreover during the COVID-19 pandemic to facilitate social distancing. Although telerehabilitation has existed for many years, this model's clinical efficacy is still unclear. Therefore, the objective of our study was to compare traditional inpatient PR with online PR through a mobile phone application.

#### **2. Materials and Methods**

#### *2.1. Study Design*

The patients were recruited from the Pneumocontrol application database. These were the patients who, during the SARS-CoV-2 pandemic, accessed the application for pulmonary rehabilitation information. The patients were randomly selected, and two groups were formed. The first group was the inpatient group that received a conventional pulmonary rehabilitation program, and the second group was the online group that performed PR through the application. The study was conducted over a period of three months, from January 2022 to April 2022.

All the patients were informed of the research, and informed consent was obtained before the beginning of the study. The research respected the Declaration of Helsinki regarding ethical principles for research regarding the safety of human subjects. The study design and contract forms were approved by the Ethics Committee of the "Victor Babes" Hospital (nr.3209 5 April 2022).

Both groups had to perform one pulmonary rehabilitation program conducted and supervised by a physical therapist five times a week. The duration of the program was 21 days. At the beginning and at the end of the program, all patients performed: lung volumes, maximal inspiratory and expiratory pressure (MIP/MEP), 6-min walking test, COPD assessment test (CAT), Borg scale, and modified Medical Research Council test (mMRC).

Patients in the online group were explained how to use the application, exercise with the POWERbreathe device, and how to increase weight through the sessions.

#### *2.2. Patients*

Over a period of three months, we included patients with stable COPD that were classified according to the ATS/ERS criteria for the severity of airway obstruction [11]. Inclusion criteria: age > 45 years, will participate, no exacerbation in the last three months, no prior rehabilitation in the last three months, former smoking history, non-smoking status, owning a mobile smartphone, able to use a smartphone, stationary bicycle at home (for the online group), owning a pulse oximeter.

Exclusion criteria: exacerbation in the last three months, other comorbidities that could interfere with their current health status, use of medication that could affect exercise response, active smoking status, musculoskeletal conditions that could impair exercise, an impaired vision that could affect the use of the mobile application, not having a stationary bicycle at home, a cognitive impairment that could affect the understanding of the exercises. After applying the inclusion and exclusion criteria, there were 72 patients in the inpatient group and 58 patients in the online group.

#### *2.3. Lung Volumes and Respiratory Strength*

The lung volumes and respiratory muscle strength were determined using the Smart PFY UI device (medical equipment Europe GmbH). The patients were seated in an upright position with the feet flat on the ground and performed three maximal expirations. The best value was recorded. The inclusion criteria for the patients were according to the ATS/ERS guideline using the refined ABCD assessment tool [11,12]. To determine respiratory muscle strength, three assessments were recorded, and the best value was used. All the maneuvers were performed according to standard procedures [13].

We used the same device as for spirometry but adapted with a shutter module. To determine maximal inspiratory pressure, the patients were instructed to expire to residual volume followed by a maximum inspiration against a resistance applied by the module. Three expirations were performed, and the best values was recorded. Maximal expiratory pressure was assessed by instructing the patient to breathe into total lung capacity, followed by a forced expiration against the module.

#### *2.4. Physical Capacity, Disease Impact, and Dyspnea*

Physical capacity was assessed using the 6-min walking distance test (6MWD), in which the patient had to cover as much distance as possible in the predicted time. To perform the 6MWD we used the ERS/ATS recording form, the BORG scale, pulse-oximeter and a stopwatch. The test was performed on a 30 m long corridor according to the ATS guidelines [14].

The global impact of COPD on the patient was evaluated using the COPD assessment test (CAT questionnaire). The questionnaire consists of 8 questions on a numerical scale from 0 to 5 for each question. Higher scores denote a more severe impact of COPD on a patient's life [15].

We assessed dyspnoea with the Borg breathlessness scale, which rates the difficulty of breathing. It rates the breathing on a scale from 0 to 10, where 0 means "breathing causes no difficulty" and 10, where "breathing is maximal". We also used this scale to determine the effort level during training sessions [16].

Dyspnoea was also evaluated using the modified Medical Research Council scale (mMRC), which assesses the degree of baseline functional disability due to dyspnoea. It rates dyspnoea on a scale from 0-"dyspnoea only with strenuous exercise" to 4-"too dyspneic to leave the house or breathless when dressing" [17].

#### *2.5. Intervention*

Inpatient pulmonary rehabilitation was performed with a physical therapist in the hospital. Home monitoring and training exercises were performed online through the Pneumocontrol application. The feasibility of the application was demonstrated in previous studies [18,19]. Patients were given basic instructions on how to use the online application after making sure the internet connection was working, and a brief test was performed before first use in live session with one of the researchers involved in the study. The training sessions lasted 45–60 min and included diaphragmatic breathing, pursed lips breathing, and strength and endurance training for both upper and lower extremities, according to the recommendation of the American Thoracic Society [20].

Each training session was composed of: (a) warm-up: duration 5–10 min—sitting, standing warm-up exercises, different breathing techniques; (b) endurance training: duration 20–30 min—stationary bicycle, Borg between 5–7, exercise performed continuous or intervals; strength/resistance training: duration 20–30 min—50–80% of 1 RM, 10–15 repetitions, three sets; cool-down: duration 5–10 min—stretching, different breathing techniques.

Respiratory muscle training was performed once per day before the training session with the POWERbreathe MEDIC device. Patients had to inhale through a variable-diameter orifice. The smaller the orifice, the greater the load achieved. Thirty breaths had to be performed per session at a level that was determined for each patient.

All the exercises were performed respecting basic physical education principles. Patients started with light and simple exercises, and as they progressed, the exercises became more complex. All training sessions were individualized according to the patients' possibilities, scores, and symptoms obtained from the questionnaire in the application.

### *2.6. Statistical Analysis*

Microsoft Excel and IBM SPSS (Armonk, NY, USA: IBM Corp.) were the programs used for statistical analysis. The presentation of continuous variables included the use of the mean and standard deviation (SD) if the variable followed a Gaussian distribution (Kolmogorov–Smirnov test). In order to determine the difference between the normally distributed variables, the Student's *t*-test was used in order to provide an estimate of the *p*-value. The Chi-square and Fisher's tests were carried out to investigate the proportional differences. A Mann–Whitney U-test was performed for the mMRC scale to compare the mean ranks. It was decided that a *p*-value of 0.05 was significant for statistical analysis.

#### **3. Results**

#### *3.1. Comparison of Pre-Test and Post-Test Results in the Inpatient Setting*

The current study enrolled a total of 72 patients in the inpatient setting and 58 in the online setting. The variables of interest from both study groups were measured before and after the intervention. As presented in Table 1, the average patient age in the inpatient setting was 64.9 years, while most of them were men (75.0%), with an average BMI of 25.4 kg/m<sup>2</sup> . Regarding pulmonary parameters, the predicted FVC value was 4.1 L, with no significant difference in actual and (%) values. Similarly, the FEV1 predicted value was 3.0 L, with no significant difference in actual and (%) values. The MIP (%) and MEP (%) comparison between pre- and post-test results showed a difference from 53.8% to 60.8% (*p*-value = 0.006), respectively, from 72.8% to 76.9% (*p*-value = 0.038), the difference between these measurements being statistically significant, as observed in Figure 1. The CAT measurement was 19.5 before intervention and 14.7 after intervention (*p*-value ≤ 0.001). Lastly, the mMRC results also showed a statistically significant decrease from a mean rank of 45.25 pre-test to 27.75 post-test (*p*-value ≤ 0.001).

#### *3.2. Comparison of Pre-Test and Post-Test Results in the Online Setting*

As described in Table 2, the average patient age in the inpatient setting was 64.3 years, while most of them were men (72.4%), with an average BMI of 25.7 kg/m<sup>2</sup> . Regarding pulmonary parameters, the predicted FVC value was 4.1 L, with no significant difference in actual and (%) values. Similarly, the predicted FEV1 value was 3.0 L, with no significant difference in actual and (%) values. The MIP (%) and MEP (%) comparison between preand post-test results showed a difference from 53.7% to 62.2% (*p*-value = 0.004), respectively, from an average of 70.9% to 74.1% (*p*-value = 0.145), as seen in Figure 2. The 6MWT levels were statistically significantly different between the pre-test and post-test measurement (342.9 vs. 387.2, *p*-value = 0.006). The CAT measurement was 20.1 before intervention and 13.9 after intervention (*p*-value < 0.001). Lastly, the mMRC results showed a statistically significant decrease from a mean rank of 39.48 pre-test to 19.52 post-test (*p*-value = 0.004).

#### *3.3. Comparison of Pre-Test Results between Inpatients and Online Participants*

The pre-test comparison between inpatients and online participants presented in Table 3 identified no statistically significant differences between the two study groups, providing an excellent basis for the post-test analysis by removing any suspicion that future changes might be caused by initial differences between groups. The actual FVC value in the inpatient group before intervention was 2.9 L compared with 3.0 L in the

online group (*p*-value = 0.105). Similarly, the actual FEV1 value was 1.3 L in the inpatient group, compared with 1.4 L in the online group (*p*-value = 0.066). The comparison of mMRC pre-test results between patients in the inpatient and online settings did not show significant differences in mean ranks (33.71 vs. 32.12, *p*-value = 0.696).


**Table 1.** Comparison of pre-test and post-test results in the inpatient setting. *J. Pers. Med.* **2022**, *12*, 1764 5 of 12

\* Data reported as mean ± SD and calculated using Student's *t*-test; \*\* Data reported as n (%), and calculated using Chi-square test; SD—standard deviation; BMI—body mass index; FVC—forced vital capacity; FEV1—forced expiratory volume in the first second; MIP—maximal inspiratory pressure; MEP—maximal expiratory pressure; 6MWT—6-min walking test; CAT—COPD assessment test; mMRC—modified Medical Research Council scale. calculated using Chi-square test; SD—standard deviation; BMI—body mass index; FVC—forced vital capacity; FEV1—forced expiratory volume in the first second; MIP—maximal inspiratory pressure; MEP—maximal expiratory pressure; 6MWT—6-min walking test; CAT—COPD assessment test; mMRC—modified Medical Research Council scale.

**Figure 1.** Comparison of pre-test and post-test results in the inpatient setting. **Figure 1.** Comparison of pre-test and post-test results in the inpatient setting.

#### *3.2. Comparison of Pre-Test and Post-Test Results in the Online Setting 3.4. Comparison in Post-Test Results between Inpatients and Online Participants*

As described in Table 2, the average patient age in the inpatient setting was 64.3 years, while most of them were men (72.4%), with an average BMI of 25.7 kg/m2. Regarding pulmonary parameters, the predicted FVC value was 4.1 L, with no significant difference in actual and (%) values. Similarly, the predicted FEV1 value was 3.0 L, with no significant difference in actual and (%) values. The MIP (%) and MEP (%) comparison Comparable to the pre-test measurements, the post-test measurements presented in Table 4 discovered statistically significant differences between inpatient and online participants with regard to the actual FVC and FEV1 levels. The FVC in the inpatient group was 2.9 L compared with 3.1 L (*p*-value = 0.004), and the actual FEV1 in the inpatient group was 1.2 L compared with 1.4 L (*p*-value = 0.010), respectively. The comparison

between pre- and post-test results showed a difference from 53.7% to 62.2% (*p*-value = 0.004), respectively, from an average of 70.9% to 74.1% (*p*-value = 0.145), as seen in Figure

post-test measurement (342.9 vs. 387.2, *p*-value = 0.006). The CAT measurement was 20.1 before intervention and 13.9 after intervention (*p*-value < 0.001). Lastly, the mMRC results showed a statistically significant decrease from a mean rank of 39.48 pre-test to 19.52

post-test (*p*-value = 0.004).

of mMRC pre-test results between patients in the inpatient and online settings did not show significant differences in mean ranks (35.33 vs. 30.10, *p*-value = 0.222). Although the actual measured post-test results between patients undergoing the traditional and online rehabilitation methods did not show many significant differences, the calculated mean differences between pre-test and post-test results were significantly higher in favor of the online method, as seen in Table 5. Therefore, the most significant variations were encountered in MIP (6.6% vs. 8.5%, *p*-value < 0.001), 6MWT (6.7% vs. 9.4%, *p*-value < 0.001), CAT values (4.8 vs. 6.2, *p*-value < 0.001), respectively. However, the MEP (%) variation was significantly higher in patients undergoing the traditional rehabilitation method (4.1% vs. 3.2%, *p*-value < 0.001). *J. Pers. Med.* **2022**, *12*, 1764 6 of 12 **Table 2.** Comparison of pre-test and post-test in the online setting. **Variables \* Pre-Test (n = 58) Post-Test (n = 58)** *p***-Value**  Age, years (mean ± SD) 64.3 ± 4.3 64.3 ± 4.3 - Sex (men) \*\* 42 (72.4%) 42 (72.4%) -


**Table 2.** Comparison of pre-test and post-test in the online setting. BMI, kg/m2 (mean ± SD) 25.7 ± 2.5 25.7 ± 2.5 -

\* Data reported as mean ± SD and calculated using Student's *t*-test; \*\* Data reported as n (%) and calculated using Chi-square test; SD—standard deviation; BMI—body mass index; FVC—forced vital capacity; FEV1—forced expiratory volume in the first second; MIP—maximal inspiratory pressure; MEP—maximal expiratory pressure; 6MWT—6-min walking test; CAT—COPD assessment test; mMRC—modified Medical Research Council scale. calculated using Chi-square test; SD—standard deviation; BMI—body mass index; FVC—forced vital capacity; FEV1—forced expiratory volume in the first second; MIP—maximal inspiratory pressure; MEP—maximal expiratory pressure; 6MWT—6-min walking test; CAT—COPD assessment test; mMRC—modified Medical Research Council scale.

**Figure 2.** Comparison of pre-test and post-test results in the online setting. **Figure 2.** Comparison of pre-test and post-test results in the online setting.

*3.3. Comparison of Pre-Test Results between Inpatients and Online Participants* 

The pre-test comparison between inpatients and online participants presented in Table 3 identified no statistically significant differences between the two study groups,

future changes might be caused by initial differences between groups. The actual FVC value in the inpatient group before intervention was 2.9 L compared with 3.0 L in the


**Table 3.** Comparison of pre-test results between inpatients and online participants.

\* Data reported as mean ± SD and calculated using Student's *t*-test; \*\* Data reported as n (%), and calculated using Chi-square test; SD—standard deviation; BMI—body mass index; FVC—forced vital capacity; FEV1—forced expiratory volume in the first second; MIP—maximal inspiratory pressure; MEP—maximal expiratory pressure; 6MWT—6-min walking test; CAT—COPD assessment test; mMRC—modified Medical Research Council scale.

**Table 4.** Comparison of post-test results between inpatients and online participants.


\* Data reported as mean ± SD and calculated using Student's *t*-test; \*\* Data reported as n (%), and calculated using Chi-square test; SD—standard deviation; BMI—body mass index; FVC—forced vital capacity; FEV1—forced expiratory volume in the first second; MIP—maximal inspiratory pressure; MEP—maximal expiratory pressure; 6MWT—6-min walking test; CAT—COPD assessment test; mMRC—modified Medical Research Council scale.


**Table 5.** Comparison of mean differences in rehabilitation results between inpatients and online participants.

\* Data reported as mean ± SD and calculated using Student's *t*-test; SD—standard deviation; BMI—body mass index; FVC—forced vital capacity; FEV1—forced expiratory volume in the first second; MIP—maximal inspiratory pressure; MEP—maximal expiratory pressure; 6MWT—6-min walking test; CAT—COPD assessment test; mMRC—modified Medical Research Council scale.

#### **4. Discussion**

#### *4.1. Important Findings*

The lockdown during the COVID-19 pandemic had a major effect on patients with respiratory diseases, who were no longer able to access respiratory rehabilitation services with the same ease [21]. Moreover, due to the imposed governmental restrictions, the level of physical activity of these patients also suffered, since everyone was advised to stay at home. Considering these conditions, respiratory rehabilitation programs had no other option but to move to the online environment or to different mobile phone platforms.

Digitalized respiratory rehabilitation performed online or through various platforms is not new, having its birth in 2008, when Liu et al. tried using the mobile phone to provide exercises that improve walking exercise [22]. The same objective was followed by the current study in order to compare respiratory rehabilitation in hospitalized patients with online respiratory rehabilitation using a mobile phone application.

When we compared each group separately, we noticed that all patients showed significant improvements in all studied parameters. When comparing both groups, we observed that there were no significant differences after 21 days of pulmonary rehabilitation. Our findings support the results of other studies and the hypothesis that there is no difference between these two approaches to delivering pulmonary rehabilitation and that both can improve outcomes, in association with smoking cessation [23].

Compared to other studies that used online rehabilitation [22,24], interactive webbased applications [25], supervised telerehabilitation [26], and home-based telerehabilitation using video conference, we used an application on a mobile phone. The feasibility and utility of this application were previously demonstrated in other studies [18,19].

To our knowledge, this is the first study that, besides the conventional PR exercises, also used a medical exercise device for inspiratory muscle training (IMT) online through a mobile phone application.

In a study that used the same device for IMT, Langer et al. were the first to demonstrate that IMT with the POWERbreathe device reduced the proportion of inspiratory neural drive to the diaphragm. This has a favorable consequence for respiratory sensation and exercises tolerance, even in severe respiratory mechanical loading and tidal volume constraints [27].

The majority of the studies from the literature have a 6–12 weeks pulmonary rehabilitation design. In our country, the National Health System pays for only three weeks of hospitalized pulmonary rehabilitation. This is a major limitation on the patients and physical therapists who have to adapt to this reduced timeline.

In a study that compared online versus face-to-face PR, Bourne et al. demonstrated that online PR through a platform is non-inferior to traditional care [24]. His study duration was six weeks, and the most significant improvements were observed in the 6MWD and CAT scores. The authors exceeded the minimal important difference (MID) for the 6MWD, which is 25 m, and reduced the CAT score by 3.4 points [28]. Compared to his study, we also exceeded the MID for the 6MWD but reduced the CAT score by 4.5 points. One explanation for our findings could be that our patients used the IMT device, which reduces dyspnoea and chest tightness.

Tsai et al. also found a clinically relevant effect on 6MWD from his supervised pulmonary rehabilitation program when compared with no intervention [29]. By contrast, in a study of 22 weeks, Hansen et al. found that neither conventional PR nor supervised pulmonary telerehabilitation improved 6MWD above the MID. Explanations for his findings are that his patients had lower FEV1, higher symptom burden, and more exacerbations [25].

Regarding the CAT score, Hansen et al. observed that the score was statistically different at the end of the intervention, with a greater symptom reduction difference of −1.6 points in the supervised pulmonary telerehabilitation group but did not exceed the MID [25]. The minimal important difference for the CAT score is −2 points [30].

In another study, Chaplin et al. compared the effect of unsupervised web-based individual exercise and education with conventional PR and found comparable betweengroup effects on walking tests [25].

An interesting finding of Chaplin et al. is that although the time spent in moderateintensity physical activity was greater in the web-based group compared to the conventional PR group, this did not translate into an increase in the total amount of moderate to vigorously physical activity. The author suggests that a more supervised approach is needed to achieve longer bouts of physical activity at the level of 3 ≥ METs [25].

In comparison to this, Loeckx et al., using a smartphone-based physical activity tele coaching approach, observed that patients requiring more contact from health care professionals experienced less physical activity benefits [31].

Compared to Loeckx's study [32], we observed that the online group had a better improvement in their 6MWD and CAT scores compared to the inpatient group. One explanation for our findings could be that the online group could leave their homes and perform their daily living activities, thus being more active and social.

#### *4.2. Strengths and Limitations*

One of the current study's strengths is that we used online IMT training using an application and thus had a better chance to improve the studied outcomes. A limitation of our study is the small number of patients and reduced days of pulmonary rehabilitation and the fact that the patients that used the application had to be connected online. Another important limitation is that we included patients who had a stationary bicycle at home for endurance training in the online PR group. Considering this factor, it would have been interesting to see what the evolution would have been for these patients if they could not perform endurance training. In the future, for those who want to perform online pulmonary rehabilitation, a pulse-oximeter, smartphone, and POWERbreathe device should be provided.

#### **5. Conclusions**

In conclusion, online pulmonary rehabilitation using a mobile phone application was not inferior to traditional inpatient pulmonary rehabilitation. As expected, improvements in all outcomes were found when comparing pre-test and post-test results of each of the two tests. In a direct comparison of pre-test and post-test variations, the online rehabilitation method showed better results regarding MIP (%), 6MWD (%), and CAT scores. However, the MEP (%) variation was significantly higher in patients undergoing the traditional rehabilitation method. Further studies are needed to demonstrate the utility and feasibility of mobile phone applications for pulmonary rehabilitation in patients with COPD.

**Author Contributions:** Conceptualization, P.I.B. and A.F.C.; methodology, C.O. and C.C.; software, F.B. and R.A.N.; validation, F.B. and R.A.N.; formal analysis, F.B. and C.C.; investigation, P.I.B. and A.F.C.; resources, C.O. and A.F.C.; data curation, A.M.; writing—original draft preparation, P.I.B. and A.F.C.; writing—review and editing, A.M. and O.R.; visualization, C.C. and F.B.; supervision, A.F.C. and C.O.; project administration, P.I.B. and C.O. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of the "Victor Babes" Hospital of Infectious Disease and Pneumophtisiology (nr.3209 5 April 2022).

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the study.

**Data Availability Statement:** The data presented in this study are available on request from the corresponding author.

**Conflicts of Interest:** The authors declare no conflict of interest.

### **References**

