The Boundaries of Mild Chronic Obstructive Pulmonary Disease: Searching Clinical COPD Onset

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.