Lessons from the North: CanCOLD, Exercise, and Chronic Obstructive Pulmonary Disease

Canadians have contributed immeasurably to our understanding of chronic obstructive pulmonary disease (COPD). From identifying the importance of small airway disease in COPD (1) and developing the first definition of a COPD exacerbation (2), to the description of eosinophilic bronchitis using induced sputum (3), Canadian researchers have led the way. A further example comes from the pioneering work of the Kingston, Ontario, group on exercise physiology in COPD. They were the first to recognize the importance of dynamic hyperinflation of the lungs in moderate to severe COPD with its consequences for neural drive and dyspnea and subsequently showed how inhaled bronchodilators modulated this problem (4). However, changes in end-expiratory lung volume during exercise are less dramatic in those with more preserved lung mechanics. In the last decade, attention has focused on the effects of increased physiological dead space as a source of ventilatory inefficiency and increased ventilatory demand during exercise. The Kingston group showed that the dead space–to-VT ratio is closely related to the _ VE per liter of _ VCO2 calculated during an incremental workload exercise test (5), and this relates to the intensity of reported breathlessness. By contrast, this mechanism does not seem to explain the breathlessness reported by some smokers without evidence of airflow obstruction, where subtle mechanical abnormalities within the lungs may be more important (6). These conclusions derive from careful physiological studies of relatively few individuals, and how generalizable these findings are remains uncertain. Fortunately, another Canadian innovation, CanCOLD (the Canadian study of Chronic Obstructive Lung Disease), can help answer this question. CanCOLD is a large, representative population sample of Canadians more than 40 years old who completed an extensive battery of tests, includingMedical Research Council Breathlessness and COPDAssessment Test scoring, measurements of resting and exercise physiology, and quantitative computed tomography (CT) scanning (7). It has already contributed important insights into the loss of small airways early in the natural history of COPD (8) and the role of elevated blood eosinophil counts in accelerating disease progression (9). In this issue of the Journal, Phillips and colleagues (pp. 1391–1402) report, in considerable detail, the results from 1,250 individuals drawn from nine contributing centers and separated into four discrete groups: 445 never-smokers (mean FEV1 97% predicted), 381 ever-smokers (mean FEV1 100% predicted, 21% still smoking), 284 Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) grade 1 (mean FEV1 95% predicted, 19% still smoking), and 200 GOLD 2–4 (mean FEV1 65% predicted, 32% still smoking, and mostly GOLD grade 2 COPD) (10). The authors wished to determine whether a high nadir _ VE/ _ VCO2 was associated with greater breathlessness and worse exercise tolerance in a general population, which lung function and imaging variables were most closely related to the nadir _ VE/ _ VCO2, and whether smokers without airflow obstruction differed in their nadir _ VE/ _ VCO2 from never-smokers without obstruction. The nadir _ VE/ _ VCO2 was categorized as abnormal if it fell outside the values identified in a healthy population of older people (11). The groups were well matched for age and bodymass index, although the ever-smokers contained proportionately more women, and the FEV1/FVC in the never-smokers clearly included some patients with airflow obstruction despite a normal FEV1, whichmay explain some of the subsequent findings. There was a clear gradient in tobacco exposure across the groups, with ever-smokers reporting fewer pack-years than subjects with obstruction. As anticipated from the resting lung function, the people with GOLD-defined airflow obstruction and a smoking history achieved significantly lower peak work rate than the “healthy” neverand ever-smokers. The nadir _ VE/ _ VCO2 was highest in GOLD 2–4 subjects but did not differ in the other three groups. However, 12%, 13%, 23%, and 26% of neverand ever-smokers, GOLD 1, or GOLD 2–4 subjects had nadir _ VE/ _ VCO2 values above the upper limit of normal. These individuals consistently hadmore breathlessness and lower peak oxygen consumption than those with more efficient ventilation, irrespective of the group. High nadir values were associatedmost strongly with the KCO, whereas other statistically significant associations with mid-expiratory flows and CT-based variables were much weaker. Occult pulmonary vascular pathologymight explain the impaired exercise performance of some GOLD grade 1 subjects in whom the KCO was reduced. However, other pathologies might be present, not least occult cardiovascular disease and abnormal gas mixing with relatively preserved lungmechanics. Inevitably, there are limitations to consider, even in a comprehensive report such as this one. Crucially, much of the evidence for the importance of the nadir _ VE/ _ VCO2 is dependent on the stability of the classification of normality. It would be reassuring to see that individuals who were abnormal remained so at subsequent visits. Likewise, it would help to know that those in the GOLD 1 group remained in that group over time. This is a concern, as CanCOLD has already highlighted the risk of diagnostic reclassification over time (12). Thankfully, CanCOLD participants return for retesting, and it should be possible to address both these issues. Why people without obstruction exhibit inefficient ventilation is unclear, raising issues about the utility of the normative data. Whether this ventilatory inefficiency is because of subject selection or perhaps different degrees of dysanapsis within the airways, itself a risk factor for future COPD, merits further study (13). The lack of CT correlation is surprising, as This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0. For commercial usage and reprints, please e-mail Diane Gern (dgern@thoracic.org).