Factors Affecting Balance in Chronic Obstructive Pulmonary Disease

Abstract:

Context:

Excess prevalence of balance deficit in COPD has been reported, suggesting a link between these two conditions

Aims:

Balance being affected in Chronic Obstructive Pulmonary Disease (COPD) is generally accepted. However, determining the cause of impaired balance in COPD has not been directly investigated. Thus, this study aimed at find out the underlying cause of balance deficits in COPD.

Settings and design: Case control Study

Methods and material

A total of 48 patients aged 40-65 years, with COPD, diagnosed clinically and by Spirometry were compared with 39 healthy non-COPD controls matched for age, BMI and nationality. The functional balance (Brief-Balance Evaluation Systems Test and Berg Balance Scale), respiratory muscle strength (maximal Inspiratory pressure and maximal expiratory pressure), lower limb muscle strength (repeated chair stand test), functional capacity (6-minute walk test) and BODE index were assessed in COPD cases and control group.

Statistical analysis used:

Independent t-test was used to determine between group differences for continuous variable. Correlation were assessed to determine the relationship between variables in moderate and severe COPD groups

Results: Significant difference was observed in all the components between COPD and healthy controls. A strong association was found between Brief-BES test and posterior sway with eyes open (p=0.006)

Conclusions: The findings indicate that balance is impaired in COPD which may increase the chances of falls. There is a need of future research to evaluate the role of COPD specific balance training as a comprehensive management of patients with COPD.

Key-words: COPD, Balance, Peripheral muscle strength, respiratory muscle strength, functional capacity, BODE index.

Introduction

Chronic obstructive pulmonary disease (COPD) is primarily a pulmonary disease and a leading cause of morbidity and mortality worldwide. It has an economic and social burden that is both substantial and increasing.The increasing burden of the disease will be projected as fourth leading cause of death by the year 2030. ^[1] In a previous study the overall prevalence of COPD in India is to be 4.36% where the prevalence among males and females were 5.32% and 3.41% respectively. ^[2]

Recently in past 10 years its extra-pulmonary manifestations are increasing and are recognised as contributing to the severity of the disease. Some of the extra-pulmonary manifestations are loss of weight, muscle dysfunction (respiratory and peripheral muscles) osteoporosis, cardiovascular diseases, anaemia, depression and anxiety. ^[3] Numerous factors have been identified to contribute to peripheral muscle changes including airflow obstruction, disuse, oxidative stress, hypoxia, malnutrition, systemic inflammation and medication. ^[4] To maintain postural control both in static and dynamic posture sensory, musculoskeletal and neural components should work in synchrony. Previous studies showed deficits in balance or postural control both in static and dynamic postures in COPD. ^{[5, 8, 11, 12, 13, & 14]} These studies proposed a number of mechanisms for reduced level of postural control and increased fall risk in COPD. These are decreased level of physical activity ^[6] peripheral muscle weakness ^[10] and altered trunk muscle mechanics ^[9] and Somatosensory deficits. ^[10] Many studies had reported impairment in functional balance, mobility, postural sway ^[7], functional capacity ^[11], upper and lower limb muscle strength ^[5] and static postural control ^[7] in moderate to severe COPD. ^[6] These studies suggested that balance is impaired in COPD and the factors which affect the balance should be identified so that a COPD specific   balance rehabilitation protocol would be designed. Therefore, this paper aimed to identify the relationship between balance and respiratory muscle strength, functional capacity, BODE Index, postural control and lower limb muscular strength in COPD patients as compared with age and BMI matched healthy subjects.

Methodology

The study is Case control Study in nature. The permission to conduct the study was taken from ethical committee of Indian spinal institute centre, Institute of rehabilitation sciences and National institute of tuberculosis and respiratory disease, New Delhi.

A total of 48 COPD patients aged between 45-65, and BMI matched healthy controls were randomly assigned after meeting the inclusion  criteria of diagnosed stable, moderate and severe COPD as per GOLD guidelines updated in 2016 ^[1], and those who maintained saturation at room air above 90% were included in both groups. Eligible patients were informed and provided with patient information sheet. Before baseline evaluation, a written consent was taken from the participants. If the participant presented with diagnosed pulmonary condition other than COPD or any other disease were excluded. Other exclusion criteria included were; Patient using invasive & non-invasive mechanical ventilation. ^[2] Any diagnosed visual or vestibular deficits that could affect postural control. ^[3] Any participant with dyspnoea at rest. ^[4] Cognitive impairment. Evaluation of functional balance, postural sway, respiratory muscle strength (PImax & PEmax), and lower limb muscle strength, functional activity, Pulmonary functions and BODE index was done.

Pulmonary function results were obtained through Spirometry followed by evaluation of respiratory muscle strength using pressure manometer in both COPD and controls. All subjects underwent a clinical balance performance test and test for lower limb muscle strength. Postural sway and functional capacity were measured by sway meter and six minute walk test respectively.

Clinical balance measures

Clinical balance tests included the Brief- Balance Evaluation Systems Test (Brief-BESTest) and Berg Balance Scale (BBS). The Brief-BESTest was created from 6 items of the BESTest, 1 from each section, with 2 items (single-leg stance and functional forward reach) being scored bilaterally, resulting in an 8-item test. Brief- BESTest is defined by Timed “Up & Go test, push & release laterally, closed eye standing on foam, strength of hip abductor, functional reach and one leg stance. Items are scored from 0 to 3, and the scores are summed to obtain a total score out of a possible maximum score of 24 points. Higher scores indicate better balance performance. Brief-BESTest demonstrated reliability comparable to that of the Mini-BESTest and potentially superior sensitivity while requiring half the items of the Mini-BESTest and representing all theoretically based sections of the original BESTest.12 Berg balance scale (BBS) was developed to measure balance among older people with impairment in balance function by assessing the performance of functional task. It is a valid instrument used for evaluation of the effectiveness of intervention and for quantitative descriptions of function in clinical practice and research. The BBS consisted of 14 items that are scored on an ordinal scale of 0 to 4. A score of 0 is given if the participants are unable to do the task, and a score of 4 is given if the participants are able to complete the task. The maximum total score on the test is 56. The items vary from simple mobility task to complex ones. Time taken to complete the test is 15- 20 minutes. Individuals who score 41 -56 have low fall risk; 21-40 have medium fall risk and 0 -20 have high fall risk. ^[13]

Lower limb muscle strength

The repeated chair stand test (number of sit-to-stands the subject can complete in 30 s) was used as a measure of lower body strength. ^[14]

Postural sway

Sway meter was constructed with a 40 centimetre rod attached to a belt. One end is attached to anterior superior iliac spine and other to the pen which rests on a horizontal place at the level of anterior superior iliac spine. The sway meter was placed posterior to the subject so that the vision could be excluded. Subjects were asked to stand on the paper sheet with foot prints. The distance between two feet would be around three inches. The graph sheet was placed behind the subject. The graph was levelled in such a way; the rod was maintained in horizontal position. The individuals were standing straight with their hands by their sides. Duration of each trial was 30 seconds. A starting point was marked on the graph sheet. The subjects were allowed to take rest of 5-10 second, after each trial. A total of six trials were done. The first three trials were done with eyes open and then three trials with eyes closed. Maximum duration of all trials was 6-7 minutes. Maximum deviation out of the trials was taken for analysis. ^[15]

Respiratory muscle strength testing

Maximal  inspiratory pressure ( PImax )  and  the  maximal  expiratory  pressure  ( PEmax) measures the respiratory muscle strength. The   PImax reflects the strength of the diaphragm and other inspiratory muscles, while the PEmax reflects the strength of the abdominal muscles & other expiratory muscles. ^[16]

Pulmonary functional test (PFT)

Spirometry was done to evaluate pulmonary function testing. In order to determine whether the patient has lung problem or not, PFT is performed which measures lung capacities. For spirometry, forced vital capacity (FVC) was measured by having the patient, after inspiring maximally, expire as forcefully and rapidly as possible into a Spirometer for a minimum of 6 seconds. After 3 acceptable FVC manoeuvres have been obtained, the manoeuvre with largest sum of FVC and forced expiratory volume at 1 s (FEV1) was selected for interpretation. ^[17]

Functional capacity

The six minute walk test is being simple, valid, self-paced test to assess the sub maximal level of functional capacity and is better tolerated & more representative of activity  of daily living. It require 30 meter corridor for its implementation. Patients are instructed to rest 10 minutes before the test. Variables such as age, height, weight blood pressure, heart rate, respiratory rate, Sp02, dyspnea and fatigue are measured before the test start, immediately after the test and after 5 minutes. ^[18]

BODE Index

BODE Index consists of four components that includes body mass index (BMI), degree of air flow obstruction as measured by FEV1(O),  dyspnea measured by MRC dyspnea scale (D) and exercise capacity measured by six minute walk distance (E). These variables are incorporated into a multidimensional scale ranged from 0 (least risk) to 10 (Highest risk). ^[19]

Statistical analysis

Statistical package SPSS version 20, Microsoft Excel 2007 was used to analyze the data where mean and standard deviation was derived. Independent sample t-tests were used to determine between group differences for continuous variables. Pearson’s coefficient of correlation was used to determine the relationship between variables in COPD, moderate and severe group. A probability level, P < 0.05 was used as the criterion for statistical significance.

Results

Baseline characteristics of the both group are provided in Table 5.1. Results from the clinical balance tests, functional capacity, respiratory muscle strength, postural sway, lower limb muscle strength and BODE index in COPD and controls are shown in Table 5.2. Lower Brief-BESTest and BBS score, reduced six minute walk distance, respiratory muscle strength, lower limb muscle strength and BODE index were evident in COPD as compared to controls (all p= 0.01). There was no difference between groups in all components of postural sway except lateral sway with eye closed (p= 0.01). A similar significant difference was observed in Brief-BESTest and BBS scores between COPD and controls when divided on the basis of age and severity (p< 0.05).

Table 5.1:- Demographic details of COPD and Control group.

* Level of significance < 0.05

5.1:- Results from the clinical balance tests, functional capacity, respiratory muscle strength, postural sway, lower limb muscle strength and BODE index are shown in table 5.2. Among COPD, lower Brief-BESTest and BBS scores, reduced six minute walk distance, respiratory muscle strength, lower limb muscle strength and increased BODE index were significant compared to the controls (all p= 0.01). There was no difference between groups in all components of postural sway except lateral sway with eye closed (p= 0.01)

Table 5.2 Comparison between COPD and Control group regarding various parameters

* Level of significance < 0.05

Results from the sub-components of Brief-BESTest are shown in table 5.3. Among COPD biomechanical constraints, Stability limits, Transitions, Reactive postural responses, Sensory orientation and Stability of gait were significantly lower compared to the controls (all p< 0.01).

Comparison between Moderate COPD and Control group

Results from the clinical balance tests, functional capacity, respiratory muscle strength, postural sway, lower limb muscle strength and BODE index are shown in table 5.6. Among moderate COPD, Lower Brief-BESTest and BBS score, reduced six minute walk distance, respiratory muscle strength, lower limb muscle strength and increased BODE index were significant compared to the controls (all p= 0.01). There was no difference between groups in all components of postural sway except lateral sway with eye closed (p= 0.01)

Table 5.6 Comparison between Moderate COPD and Control group

* Level of significance < 0.05

Comparison between Severe COPD and Control group

Results from the clinical balance tests, functional capacity, respiratory muscle strength, postural sway, lower limb muscle strength and BODE index are shown in table 5.7. Among severe COPD, Lower Brief-BESTest and BBS score, reduced six minute walk distance, respiratory muscle strength, lower limb muscle strength and increased BODE index were significant compared tothe controls (all p= 0.01). There was no difference between groups in all components of postural sway except lateral sway with eye closed (p= 0.01)

Table 5.7 Comparison between Severe COPD and Control group

* Level of significance < 0.05

In COPD

There was a positive correlation found between Brief-BESTest and FVC% predicted (r= 0.286, p= 0.49).Brief-BESTest was also found to be negatively correlated with anterior sway with eyes open (r= -0.347, p= 0.016) and posterior sway with eyes open (r= -0.306, p= 0.035). There exists a large positive correlation between BBS and Brief-BESTest (r= 0.631, p= 0.01). Anterior sway with eyes open was observed to be positively correlated with age (r= 0.367, p= 0.010). Posterior sway with eyes open showed a negative correlation with PEmax (r= -0.294, p= 0.042). Lateral sway with eyes open showed positive correlation with FVC % predicted (r= 0.319, p= 0.027) and negative correlation with FEV1/FVC ratio observed (r= -0.295, p= 0.042). A significant negative correlation was observed between six minute walk distance and age (r=-0.361, p= 0.012) and there also exists a significant positive correlation between six minute walk distance and FEV1/FVC ratio observed (r= 0.325, p= 0.024). Lower limb muscle strength was observed to be positively correlated with PImax (r= 0.512, p= 0.01) and PEmax (r= 0.514, p= 0.01)

In Moderate COPD

A significantly large positive correlation was observed between Brief-BESTest and PEmax (r= 0.472, p= 0.017). BBS showed a significant positive correlation with Brief-BESTest (r= 0.568, p= 0.003). Six minute walk distance showed a negative correlation with age (r= -0.430, p= 0.032) and significantly large positive correlation with PImax (r= 0.488, p= 0.013), PEmax (r= 0.556, p= 0.004) and lower limb muscle strength (r= 0.664, p= 0.01). Lower limb muscle strength was observed to be positively correlated with PImax (r= 0.571, p= 0.003) and PEmax (r= 0.728, p= 0.001). A significant negative correlation was observed between PImax and age (r= -0.464, p= 0.020) and positive correlation was observed between PImax and BMI (r= 0.518, p= .008).

In Severe COPD

Brief-BESTest showed a significant negative correlation with anterior sway with eyes open (r= -0.569, p= 0.005). Anterior sway with eyes open showed a positive correlation with age (r= 0.430, p= 0.040). Lateral sway with eyes open was observed to be negatively correlated with FEV1/FVC ratio observed (r= -0.579, p= 0.004). A significant positive correlation was observed between lateral sway with eyes closed and BMI (r= 0.429, p= 0.041). Six minute walk distance was observed to be positively correlated with MEF50 % predicted (r= 0.462, p= 0.027 and lower limb muscle strength (r= 0.561, p= 0.005). Brief- BESTest which is a dependent variable showed a strong association with Posterior sway with eyes open (p= 0.006) followed by Anterior sway with eyes open (p= 0.009) and FVC % predicted (p=0.025). Thus, posterior sway with eyes open contributes maximum to disturbance in balance in COPD.

Discussion

This study was an attempt to find out the relationship between balance, pulmonary functions, functional capacity and postural sway and factors affecting balance in chronic obstructive pulmonary disease. Balance deficits are recognised as an important physical and functional limitation in COPD. Very few studies were conducted to recognise the mechanism of disturbed balance in COPD and there is a dearth of information regarding the components which are responsible for affecting the control of balance.

Balance in COPD vs. Controls

The novel finding of this study was a significant difference in Brief-BESTest and BBS score between COPD and controls (Table 6.2), which was consistent with the results of previous studies which used clinical balance measures ^{[8,20,21,22,23]}. Balance was also affected when groups were further divided on the basis of age and severity of disease. A similar significant difference was observed in Brief-BESTest and BBS scores between COPD and controls when divided on the basis of age and severity.

Numerous studies have shown similar decline in BBS score ^{[8, 11, 20, 24, 25, 26]} and balance evaluation system test (BESTest) ^{[20, 21]} scores in COPD. Other functional balance measures such as community balance and mobility scale ^[6] ,short physical performance battery (SPPB) ^[5,22,23,27] activity specific balance confidence scale (ABC scale) ^[8,28] Timed up and go (TUG) test ^{[8,24,25,26,28]} Single leg stance time ^[22,23,26] functional reach test ^[22] reported deterioration in balance in COPD. The functional balance may be affected by reduced exercise capacity and lower extremities muscular weakness. ^{[10, 11, 21, 22]}

Postural sway in COPD vs. Controls 

Another finding of this study was a significant difference in lateral sway with eyes closed between COPD and controls measured by sway meter in Table 6.2. The result of this study was similar to study conducted by Chang et al. ^[7] and Smith et al. ^{[9, 29]} on COPD where sway was measured using sway meter and force plate respectively. One study reported increased antero-posterior sway measured by force plate ^[30] unlike the results of current study. The study explained the contribution of weakness of inspiratory muscle to impaired trunk stability in COPD and  reported the weaker the inspiratory muscle, the greater the COPD show reliance on ankle  strategy which make them more prone for antero-posterior postural instability specifically on  uneven surface. Thus, due to this respiratory muscle weakness, COPD develop impaired proprioceptive postural control. ^[30]

Physical activity in COPD vs. Controls

One more finding of this study reported that COPD demonstrate reduced six minute walk distance and lower limb muscle strength when compared to controls in Table 6.2. Many previously conducted studies which used six minute walk test ^{[5,7,11,24,27]} , timed up and go test ^[6,8] , fast-gait speed test ^[6] , daily steps ^[23] and moderate to vigorous physical activity ^[10,23] and physical activity scale for the elderly ^[21] to measure functional capacity and dynamometer ^{[5,10,11,21,27]} , 30-seconds chair stand test ^[20] to measure lower extremity strength support this finding. COPD report the sensation of leg fatigue which limits the exercise and this impairment of exercise capacity in COPD is because of peripheral skeletal muscle dysfunction. ^[4] Dyspnoea causing mobility limitation predispose to lower limb muscle weakness. Other factors are reduced mitochondria in the muscles, systemic inflammation, corticosteroid therapy, decreased anabolic hormone level and hypoxia. Deterioration in peripheral muscle performance is demonstrated by reduced muscle mass, fibre type profile, capillarity, strength and endurance.

Pulmonary activity in COPD vs. Controls

Respiratory muscle strength (PImax and PEmax) and BODE index were found to be significantly different between COPD and controls in Table 6.2. The result of this study was similar to research done on COPD where only PImax was reduced and was evaluated by using electronic pressure transducer. ^[30] Weaker inspiratory muscles are multi-factorial in origin and can be explained by the consequences of abnormal dynamic hyperinflation, increased respiratory load or defective gas exchange which ultimately results in abnormal respiratory biomechanics. These limitations are more pronounced with advanced age, age-related decline in respiratory function and effects of physical deconditioning due to disease process.

Both moderate and severe COPD reported significant differences with controls when compared for the mentioned measures. Severity of the disease have impact on balance measures, postural sway, functional capacity and pulmonary functions in moderate and severe, as severe reported low means values of all the measures than moderate.

Relationship between factors affecting balance in COPD

In this study anterior sway with eye open (r= -0.347) and posterior sway with eye open (r= -0.306) were observed to be associated with balance measure in COPD. Degree of airways obstruction (r= -0.295) was the only factor observed which results in increase lateral sway. Six minute walk distance was found to be dependent on age (r= -0.361) and degree of airways obstruction (r= 0.325). Although there was no association between six minute walk distance and lower limb muscle strength, but there was a significant large mean difference between COPD and controls in this study and it was observed in previous study that poor functional capacity and balance impairment is one of the important predictors of falls in older adults.8 Also there was no correlation found between balance measure and lower limb muscle in strength in COPD but lower limb muscular weakness almost always increases the chances of impairment of balance. One of the studies reported a positive correlation between functional balance and lower limb muscle strength. ^[22]

The results of this study in moderate group reported an association between balance and respiratory muscle strength (r= 0.472). This observation explained that weaker respiratory muscles particularly inspiratory muscle contributes to impaired trunk stability which results in increased reliance on ankle strategy and ultimately postural instability. ^[30] Six minute walk distance in moderates were dependent on age (r=-0.430) and it was found that six minute walk distance was strongly associated with lower limb muscle strength (r= 0.664). Brief-BESTest showed similar but greater association with anterior sway with eyes open (r= -0.569) in severe group compared to COPD group. Similar, result was observed in severe in which lateral sway with eyes open show more reliance on degree of airway obstruction (r= -0.579) than COPD group. Six minute walk distance in severe group was found to be associated with lower limb muscle strength (r= 0.561).

Conclusion

Impairments in balance constitute an important and modifiable secondary impairment in patients with COPD- related to an increased risk of falling. It has been noted when compared with age, BMI matched control subjects, and individuals with COPD have reduced performance in all subcomponents of balance. These deficiencies in balance are associated with poor functional capacity levels and lower extremity muscle weakness. Given the association between impaired balance and an increased risk of falls in COPD, a detailed balance evaluation should be offered to at-risk individuals. There is a clear need for future research to evaluate the role of COPD specific balance training as part of the comprehensive management of patients with COPD.

Limitations of study

Clinical measure was used for assessing balance & lower limb strength in COPD as well as in controls. For measuring postural sway other objective methods can be used like force plate, posturography or Sensory Organization Test which is more specific.
References:

1. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease, 2016.
2. Chronic obstructive pulmonary disease (COPD). World Health Organization. 2017.
3. Vijayan V.K. Chronic obstructive pulmonary disease. Indian J Med Res.2013.137: 251-269.
4. Parasuramalu BG, Huliraj N, Kumar SP, Masthi NR, Babu CS. Prevalence of chronic obstructive pulmonary disease and its association with tobacco smoking and environmental tobacco smoke exposure among rural population. Indian journal of public health. 2014 Jan 1; 58(1):45.
5. Eisner MD, et al. COPD as a systemic disease: impact on physical functional limitations. The American journal of medicine. 2008 Sep 30; 121(9):789-96.
6. Smith C. COPD is a systemic disease-the extrapulmonary manifestations. SA Journal of CPD. 2009 Apr 1; 27(4):159-61.
7. Skeletal Muscle Dysfunction in Chronic Obstructive Pulmonary Disease. American Journal of Respiratory and Critical Care Medicine. 1999; 159:S2-S40.
8. Butcher SJ, Meshke JM, and Sheppard MS. Reductions in functional balance, coordination, and mobility measures among patients with stable chronic obstructive pulmonary disease. Journal of Cardiopulmonary Rehabilitation and Prevention. 2004 Jul 1; 24(4):274-80.
9. Pollock AS, Durward BR, Rowe PJ, Paul JP. What is balance? Clinical rehabilitation. 2000 Aug; 14(4):402-6.
10. Cook S. Motor control theory and practical applications. 1st ed.; 1995.
11. Chang AT, Seale H, Walsh J, Brauer SG. Static balance is affected following an exercise task in chronic obstructive pulmonary disease. Journal of cardiopulmonary rehabilitation and prevention. 2008 Mar 1; 28(2):142-5.
12. Beauchamp MK, Hill K, Goldstein RS, Janaudis-Ferreira T, Brooks D. Impairments in balance discriminate fallers from non-fallers in COPD. Respiratory medicine. 2009 Dec 31; 103(12):1885-91.
13. Smith MD, Chang AT, Seale HE, Walsh JR, Hodges PW. Balance is impaired in people with chronic obstructive pulmonary disease. Gait & posture. 2010 Apr 30; 31(4):456-60.
14. Roig M, Eng JJ, MacIntyre DL, Road JD, Reid WD. Postural control is impaired in people with COPD: an observational study. Physiotherapy Canada. 2011 Oct; 63(4):423-31.
15. Roig M, Eng JJ, Road JD, Reid WD. Falls in patients with chronic obstructive pulmonary disease: a call for further research. Respiratory medicine. 2009 Sep 30; 103(9):1257-69.
16. Eisner MD, Iribarren C, Blanc PD, Yelin EH, Ackerson L, Byl N, Omachi TA, Sidney S, Katz PP. Development of disability in chronic obstructive pulmonary disease: beyond lung function. Thorax. 2011 Feb 1; 66(2):108-14.
17. Mkacher W, Mekki M, Tabka Z, Trabelsi Y. Effect of 6 Months of Balance Training During Pulmonary Rehabilitation in Patients With COPD. Journal of cardiopulmonary rehabilitation and prevention. 2015 May 1; 35(3):207-13.
18. Tudorache E, Oancea C, Avram C, Fira-Mladinescu O, Petrescu L, Timar B. Balance impairment and systemic inflammation in chronic obstructive pulmonary disease. International journal of chronic obstructive pulmonary disease. 2015; 10:1847.
19. Beauchamp MK, Janaudis-Ferreira T, Parreira V, Romano JM, Woon L, Goldstein RS, Brooks D. A randomized controlled trial of balance training during pulmonary rehabilitation for individuals with COPD. CHEST Journal. 2013 Dec 1; 144(6):1803-10.
20. Singh P, Mitra S, Kumar L, S.M. Divya. Prevalence of balance deficits in COPD. Physiotherapy and Occupational therapy journal. 2014. 7(2): 61-68.
21. Beauchamp MK, Sibley KM, Lakhani B, Romano J, Mathur S, Goldstein RS, Brooks D. Impairments in systems underlying control of balance in COPD. CHEST Journal. 2012 Jun 1; 141(6):1496-503.
22. Vogelmeier CF,et al. Global Strategy for the diadnosis, Management and Prevention of Chronic Obstructive Lung Disease 2017 Report. Respirology. 2017 Apr 1; 22(3):575-601.
23. Silva GE, Sherrill DL, Guerra S, Barbee RA. Asthma as a risk factor for COPD in a longitudinal study. Chest Journal. 2004 Jul 1; 126(1):59-65.
24. Vonk JM, Jongepier H, Panhuysen CI, Schouten JP, Bleecker ER, Postma DS. Risk factors associated with the presence of irreversible airflow limitation and reduced transfer coefficient in patients with asthma after 26 years of follow up. Thorax. 2003 Apr 1; 58(4):322-7.
25. De Marco R, et al. Risk factors for chronic obstructive pulmonary disease in a European cohort of young adults. American journal of respiratory and critical care medicine. 2011 Apr 1; 183(7):891-7.
26. Shujaat A, Minkin R, Eden E. Pulmonary hypertension and chronic cor pulmonale in COPD. International journal of chronic obstructive pulmonary disease. 2007 Sep; 2(3):273-82.
27. Kim HC, Mofarrahi M, Hussain SN. Skeletal muscle dysfunction in patients with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2008 Dec; 3(4):637-58.
28. Maltais F, et al. An official American Thoracic Society/European Respiratory Society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease. American journal of respiratory and critical care medicine. 2014 May 1; 189(9):e15-62.
29. Bhosle P, Krishna G. et al. Functional Balance in Chronic Obstructive Pulmonary Disease: A Case Control Study. International Journal of Health Sciences and Research. 2012 june; 2(3):61-71
30. Grant I, Heaton RK, McSweeny AJ, Adams KM, Timms RM. Neuropsychologic findings in hypoxemic chronic obstructive pulmonary disease. Archives of Internal Medicine. 1982 Aug 1; 142(8):1470-6.