The aim of this study is to determine if presence of dyspnea identifies differences in the 6-min walk test performance among smokers with normal or mild spirometric obstruction, accounting for the confounding effect of heart failure on dyspnea with stress echocardiography.

Chronic obstructive pulmonary disease (COPD) has a prolonged course before onset, following classical epidemiological principles of chronic disease and genetic predisposition. "Disease onset" may be defined as a physiologic impairment expressed by an abnormal spirometric index, but "early disease" could include clinical manifestations, such as cough, phlegm, dyspnea or exercise limitation, but normal spirometry. For the present proposal, we will use dyspnea to define a symptomatic subject, since dyspnea is the most relevant symptom all over the range of the disease. Besides, we have defined "early disease" when current or ex-smoker-adults: a) complain of dyspnea but have normal spirometry; b) complain of dyspnea and have mild bronchial obstruction; and, c) have mild bronchial obstruction without dyspnea. These subtypes are roughly similar to Global initiative for Chronic Obstructive Lung Disease (GOLD) stages 0 and 1 [1], although further characterized by the presence or absence of dyspnea. The dyspnea cut off value we have chosen to separate symptomatic from asymptomatic subjects is a modified Medical Research Council (mMRC) score ≥1, which is in line with several recent communications [2-4], but differs from the cut off recommended by GOLD (score ≥2) [5]. In addition, GOLD 0 stage [1], included in the GOLD guidelines of 2001 and currently not in use, did not comprise a dyspneic subtype, which is now included in light of new evidence pointing out at their potential relevance [6, 7].

Early disease subtypes

1. Symptomatic current or ex-smokers with normal spirometry have been reported by Woodruff et al [7] on a large sample of individuals who complain of chronic respiratory symptoms, reduced exercise tolerance, and computed tomography (CT) imaging bronchiolitis. These results are in line with previous findings of another large study from Regan et al [8] where more than 50% of symptomatic smokers with normal spirometry have respiratory-related impairment and evidence of emphysema on CT imaging. Woodruff et al [7] used the COPD Assessment Test (CAT) questionnaire to define symptoms [9] and found that cough, phlegm, dyspnea, activity limitation, and energy level were equally distributed among symptomatic smokers regardless of the presence of spirometric COPD. However, although CAT is intended to be specific for COPD [9], most of its domains may reflect concomitant respiratory (asthma and bronchiectasis) and/or nonrespiratory diseases (heart failure, ischemic heart disease, obesity, and depression) [10]. In contrast, Regan et al [8] measured seven "respiratory-related impairments" and found one or more to be present in 54% of patients. Three of these impairments could be considered rather specific of COPD, like CT percentage of emphysema >5% and gas trapping >20%, and St. George's Respiratory Questionnaire (SGRQ) total score >25. However, four impairments (chronic bronchitis, modified Medical Research Council (mMRC) dyspnea score ≥2, exacerbations and 6-min walk distance <350 m) are non-specific as they may be partly or fully explained by comorbidities like gastroesophageal reflux disease, rhinosinusitis, obesity or heart failure, among others. Actually, retrospective data suggest that patients with COPD and comorbid conditions may have greater risk for having symptoms than those without comorbidity [11, 12].
2. Non-dyspneic current or ex-smokers with mild COPD has been also described [13, 14]. It seems that in this group coexist individuals with normal lung function and 6-min walk test performance [14] and subjects with resting lung hyperinflation, reduced diffusion capacity of the lung for carbon monoxide (DLCO) and slightly increased cycle-exercise-induced dyspnoea [13].
3. Dyspneic current or ex-smokers with mild COPD have significant emphysema and airway thickness, lower DLCO, exercise-induced arterial desaturation, and reduced 6-min walking distance [14, 15]. In addition, during incremental cycle-exercise they exhibit increased ventilatory demand, lung hyperinflation and greater exertional dyspnea than smoker controls [16].

Hypothesis

We hypothesize that dyspneic individuals notwithstanding of their spirometry results, should share some clinical, structural and physiologic abnormalities. In particular, we expect that the two dyspneic groups with and without mild COPD exhibit reduced exercise capacity, in addition to worse quality of life; lower physical activity; greater lung hyperinflation; greater emphysema and airway thickness; and reduced peripheral muscle mass, than their asymptomatic counterpart, i.e., non-dyspneic mild COPD and controls.

Study aim

This study intends to identify the three early COPD subtypes already defined using differences in exercise capacity as the primary outcome. As secondary outcomes, we will intend to separate these groups by means of differences in clinical (quality of life, physical activity), physiological (exercise testing) and structural characteristics (emphysema, airway disease, and peripheral muscle mass by CT imaging). Future analyses are planned to evaluate longitudinal deterioration in these clinical, physiological and structural characteristics. Potential influence of obesity and undiagnosed heart failure on dyspnea and thus, on exercise capacity, will be explored within the three subtypes.

Study design

The study has a cross sectional design aimed at obtaining representative samples of adults between 45 and 80 years. Two hundred and forty participants will be enrolled into four strata as already defined, i.e., dyspneic current or ex-smokers with and without mild COPD; and non-dyspneic current or ex-smokers with and without (controls) mild COPD. Study subjects will be recruited from the outpatient clinics and the pulmonary function labs at the Pontifical Catholic University of Chile Health Network by means of physician referral, advertisement in clinical areas, or self-referral at the study center. The Institutional Ethics Committee approved the study protocol and signed informed consent will be obtained from all participants.

Sample size

A sample size of at least 52 subjects per group provide enough power (80%) to detect a significant difference (95% confidence level or alpha 0.05) in the 6-min walk test among symptomatic and asymptomatic participants, based on a conservative relevant difference in walking distance of 50 meters with a common standard deviation of 110 metres. Such difference was found when comparing symptomatic and asymptomatic subjects with normal spirometry [7], but may be an underestimation in patients with mild spirometric COPD [14], where the difference between symptomatic and asymptomatic patients was 100 metres. Forestalling a participant loss rate of 20%, 60 patients will be included in each group.

Inclusion Criteria:

• Age 45 to 80 years
• Smoking history >10 pack-year
• Mild COPD subjects: Male or female individuals; post-bronchodilator forced expiratory volume in 1 s (FEV1) ≥80% of predicted normal and post-bronchodilator FEV1/forced vital capacity (FVC) ratio <0.70
• Non-COPD subjects: Male or female individuals; post-bronchodilator FEV1 ≥80% of predicted normal and post-bronchodilator FEV1/FVC ratio ≥0.70

Exclusion Criteria:

• Unable to tolerate study procedures
• Unable to walk or cycle without assistance
• Dementia or cognitive disorder, which would prevent the participant from consenting the study or completing study procedures
• Major depressive disorder
• Locomotor disease that seriously limits exercise tolerance
• Untreated symptomatic peripheral artery disease
• Body Mass Index >40 kg/m2
• Non-COPD significant pulmonary disease such as asthma; interstitial lung disease; sarcoidosis; tuberculosis; cystic fibrosis; diffuse bronchiectasis; and others
• Primary pulmonary hypertension
• Current lung cancer
• Previous lung resection
• Large thoracic metal implants that in opinion of the investigator limit CT scan analyses
• Current use of prednisone >5 mg daily
• Current use of immunosuppressive agent
• Current exposure to chemotherapy or radiation treatments that, in the opinion of the investigator could limit interpretation of pulmonary function, exercise tolerance and CT scan imaging
• Current illicit substance abuse, excluding marijuana
• Known HIV/AIDS infection
• Current extra thoracic cancer, which, in the opinion of their physicians, limits life expectancy to less than 3 years
• Recent myocardial infarction (6 months or less)
• Chronic congestive heart failure

Study subjects will be recruited from the outpatient clinics and the pulmonary function labs at the Pontifical Catholic University of Chile Health Network by means of physician referral, advertisement in clinical areas, or self-referral at the study centre.