Clinical Significance of Symptoms in Smokers with Preserved Pulmonary Function

Abstract

Background: Currently, the diagnosis of chronic obstructive pulmonary disease (COPD) requires a ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) of less than 0.70 as assessed by spirometry after bronchodilator use. However, many smokers who do not meet this definition have respiratory symptoms.

Methods: We conducted an observational study involving 2736 current or former smokers and controls who had never smoked and measured their respiratory symptoms using the COPD Assessment Test (CAT; scores range from 0 to 40, with higher scores indicating greater severity of symptoms). We examined whether current or former smokers who had preserved pulmonary function as assessed by spirometry (FEV1:FVC ≥0.70 and an FVC above the lower limit of the normal range after bronchodilator use) and had symptoms (CAT score, ≥10) had a higher risk of respiratory exacerbations than current or former smokers with preserved pulmonary function who were asymptomatic (CAT score, <10) and whether those with symptoms had different findings from the asymptomatic group with respect to the 6-minute walk distance, lung function, or high-resolution computed tomographic (HRCT) scan of the chest.

Results: Respiratory symptoms were present in 50% of current or former smokers with preserved pulmonary function. The mean (±SD) rate of respiratory exacerbations among symptomatic current or former smokers was significantly higher than the rates among asymptomatic current or former smokers and among controls who never smoked (0.27±0.67 vs. 0.08±0.31 and 0.03±0.21 events, respectively, per year; P<0.001 for both comparisons). Symptomatic current or former smokers, regardless of history of asthma, also had greater limitation of activity, slightly lower FEV1, FVC, and inspiratory capacity, and greater airway-wall thickening without emphysema according to HRCT than did asymptomatic current or former smokers. Among symptomatic current or former smokers, 42% used bronchodilators and 23% used inhaled glucocorticoids.

Conclusions: Although they do not meet the current criteria for COPD, symptomatic current or former smokers with preserved pulmonary function have exacerbations, activity limitation, and evidence of airway disease. They currently use a range of respiratory medications without any evidence base. (Funded by the National Heart, Lung, and Blood Institute and the Foundation for the National Institutes of Health; SPIROMICS ClinicalTrials.gov number, NCT01969344.).

Figure 1. Prevalence of Respiratory Symptoms, According to Study Group

Respiratory symptoms were assessed with the use of the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) in controls who had never smoked, in current or former smokers with preserved pulmonary function as assessed by spirometry (a ratio of the forced expiratory volume in 1 second to the forced vital capacity [FVC] of ≥0.70 after bronchodilator use and an FVC above the lower limit of the normal range), and in current or former smokers who had COPD symptoms of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 or 2 (indicating mild and moderate disease, respectively). Scores on the CAT, a validated eight-question health-status instrument, range from 0 to 40, with higher scores indicating a greater severity of symptoms. The red line indicates the cutoff for more severe symptoms that is used by GOLD (CAT score, ≥10). The horizontal line in the boxes represents the median, and the bottom and top of the boxes the 25th and 75th percentiles, respectively. I bars represent the upper adjacent value (75th percentile plus 1.5 times the interquartile range) and the lower adjacent value (corresponding formula below the 25th percentile), and the dots outliers. P values were adjusted with Bonferroni correction for multiple comparisons.

Figure 2. Prevalence of Symptoms and Risk of Respiratory Exacerbations, According to Study Group

Prospective respiratory exacerbations were defined as respiratory events that were treated with antibiotics or oral glucocorticoids, those associated with health care utilization (office visit, emergency department visit, or hospitalization), those that were considered to be severe exacerbations (i.e., that led to an emergency department visit or hospitalization), or any exacerbation (any of the above). T bars indicate 1 SD. Asterisks indicate a P value of less than 0.05, with Bonferroni correction for multiple comparisons, for the comparison with current or former smokers with preserved pulmonary function and a CAT score of less than 10.

Figure 3. Effect on Prospective Exacerbation Rates of Different FEV₁:FVC Cutoffs to Define Preserved Pulmonary Function

Shown are the prospective annualized exacerbations rates of any exacerbation, according to different cutoffs of the ratio of the forced expiratory volume in 1 second (FEV₁) to the FVC. The definition of preserved pulmonary function that was based on the lower limit of the normal range (LLN) for the FEV₁:FVC or that used an FEV₁:FVC cutoff of 0.65 did not significantly change the predictive value of the CAT score for any exacerbation. The definition that was based on an FEV₁:FVC cutoff of 0.75 weakened the predictive value of the CAT score for any exacerbation, although the sample size was smaller with an FEV₁:FVC cutoff of 0.75 than with a cutoff of 0.70 (577 vs. 849 persons). Asterisks indicate a P value of less than 0.05, and the dagger a P value of 0.07, with Bonferroni correction for multiple comparisons, for the comparison with current or former smokers with a FEV₁:FVC equal to or greater than the specified cutoff and a CAT score of less than 10.