Searching Clinical Chronic Obstructive Pulmonary Disease Onset
Condition: Copd
MeSH terms: Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      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.
    

Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        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.
      
Keywords: mild COPD; early COPD; six-min walk test; computed tomography; emphysema; airway disease; peripheral muscle mass; Saint George's Respiratory Questionnaire