Evaluation of Ventilation Homogeneity as a Marker of Small Airway Disease in Active Smokers

Ventilation heterogeneity is a hallmark feature of most obstructive pulmonary diseases. In particular, chronic obstructive pulmonary disease (COPD) is pathologically and physiologically characterized by small airway destruction and marked airway cellular inflammation, which result in prominent expiratory airflow limitation, air trapping, hyperinflation and abnormal gas exchange. COPD is strongly linked with the exposition to inhaled irritants, most notably tobacco smoke, and is as such a potentially preventable disease. COPD-related morbidity, mortality and social costs are high: in Canada, COPD is the main cause of hospital admission among all chronic diseases and is the fourth leading cause of death.

Diagnosis of COPD requires the objective demonstration of expiratory airflow limitation using spirometry. In the right clinical context, a post-bronchodilator forced vital capacity (FVC) / forced expiratory volume in 1 second (FEV1) ratio \<0.70 is considered indicative of the presence of COPD, and therefore pulmonary function testing is required to make the diagnosis. However, the natural history of COPD represents a slowly-progressive continuum: active smokers that do not meet the criteria for COPD are still at risk of developing the disease. In fact, when compared to healthy non-smokers, active smokers without overt COPD can already show some pathological and clinical features of the disease. Notably, they report increased levels of resting dyspnea, chronic cough, lower exercise capacity, exercise-induced dynamic hyperinflation and marked airway inflammatory cellular infiltration, while conserving normal pulmonary function test values.

These findings highlight the negative, clinically-measurable effects of tobacco smoking on pulmonary function, but also the limitations of standard pulmonary function testing in identifying the presence of early, mild airway disease and quantifying physiological limitations in these subjects. As such, there is a need for a novel, simple and reliable method of quantifying airway disease in this population.

Quantitative lung ventilation single-photon emission computed tomography (SPECT) allows an objective quantification of the regional heterogeneity of ventilation in humans. The coefficient of variation (CV) of the distribution of a radioactive tracer, inhaled during the test, allows the generation of heterogeneity maps and density curves of small elements of the lung. These variables are sensitive to the presence of COPD, asthma, air trapping and are correlated to even slight anomalies in pulmonary function testing in otherwise healthy subjects. As such, SPECT could prove useful as an early marker of airway disease in active smokers at risk of developing COPD, but its use in this context has never been formally tested.

This pilot study addresses the question of whether lung SPECT could provide clinically relevant information on airway disease in active smokers without overt lung disease on pulmonary lung function testing.


Eligibility Criteria:
For Smokers group:

Inclusion Criteria:

* Active tobacco smoking of at least 10 cigarettes/day AND total smoking history of at least 15 pack-years.
* Normal lung function testing, defined as: FVC/FEV1 ratio, FEV1 and FVC all greater than the lower limit of normal; mean forced expiratory flow at 25 to 75% of CVF (FEF25-75%) \>80% of predicted value and absence of concavity on the forced expiratory flow curve, as evaluated by a trained respirologist; total lung capacity (TLC) greater than the lower limit of normal; residual volume (RV), functional residual capacity (FRC), expiratory reserve volume (ERV), inspiratory capacity (IC) and VR/TLC ratio all \>80% predicted value and diffusion capacity of the lung for carbon monoxide (DLCO) \>80% predicted value when corrected for hemoglobin level.
* Body mass index (BMI) \<30 kg/m2

Exclusion criteria:

• Post-bronchodilator change in FEV1 and FVC of more than 6% and/or 100 ml.

For Non-smokers group:

Inclusion Criteria:

* No history of tobacco-smoking.
* Normal lung function testing, defined as: FVC/FEV1 ratio, FEV1 and FVC all greater than the lower limit of normal; mean forced expiratory flow at 25 to 75% of CVF (FEF25-75%) \>80% of predicted value and absence of concavity on the forced expiratory flow curve, as evaluated by a trained respirologist; total lung capacity (TLC) greater than the lower limit of normal; residual volume (RV), functional residual capacity (FRC), expiratory reserve volume (ERV), inspiratory capacity (IC) and VR/TLC ratio all \>80% predicted value and diffusion capacity of the lung for carbon monoxide (DLCO) \>80% predicted value when corrected for hemoglobin level.
* Body mass index (BMI) \<30 kg/m2

Exclusion criteria:

• Post-bronchodilator change in FEV1 and FVC of more than 6% and/or 100 ml.