The clinical features of the overlap between COPD and asthma

Chronic Obstructive Pulmonary Disease (COPD) affects over 10 million Americans. In the United States, COPD is the third leading cause of death [1] and is responsible for over $15 billion in annual healthcare costs [2]. World-wide, COPD is one of the few conditions in which mortality is rising, and it is estimated to become the third leading cause of death by 2020[3, 4]. More than 40% of patients with COPD will additionally report a history of asthma, and this dual-diagnosis increases with age [5, 6].

There is increasing evidence that patients who have COPD and asthma experience more rapid disease progression than those with either disease alone. Airway hyperresponsiveness (AHR) and the diagnosis of asthma have been associated with greater decline in FEV₁ in both smokers and nonsmokers [7–9] and asthma has been recognized as a risk factor for COPD [10]. The presence of AHR in patients with COPD has been associated with an increase in COPD exacerbations and overall mortality [11], and the coexistence of asthma and COPD is associated with increased co-morbidities and health-care utilization [12, 13].

Despite these known interactions between COPD and asthma, the clinical aspects of this overlap population have not been well described. In fact, the dual-diagnosis of COPD and asthma is often an exclusion criterion for participation in studies investigating either disease alone [14]. The aim of this study was to examine the clinical, physiologic and chest CT scan features of subjects with the overlapping diagnoses of COPD and asthma in comparison to subjects with COPD alone. We hypothesized that subjects with COPD and asthma would have markers of more severe disease, including greater exacerbation frequency and worse quality of life scores. We analyzed subjects in the Genetic Epidemiology of COPD Study (COPDGene) study, a large case-control study of COPD for which asthma was not an exclusion criterion.

We examined the first 2500 subjects from the COPDGene study. Of these, 1059 subjects had COPD defined as GOLD stage 2-4. We excluded 144 subjects who did not provide information about their asthma history, leaving 915 subjects for analysis. Out of 915 COPD subjects, 119 (13%) reported a physician's diagnosis of asthma prior to the age of 40. In comparison to subjects with COPD alone, subjects with COPD and asthma were younger (61.3 vs 64.7 years old, p = 0.0001) and had fewer pack-years of smoking (43.7 vs 55.1, p < 0.0001) (Table 1). More subjects with COPD and asthma additionally reported a history of hay fever than subjects with COPD alone. There was no significant difference in gender among the groups or in current smoking status. There were more African-American COPD subjects who reported a history of asthma, and there were more subjects in this group who were frequent exacerbators in the year prior to enrollment (Figure 1). In an unadjusted analysis, more subjects with COPD and asthma were currently taking inhaled corticosteroids in comparison to those with COPD alone (p < 0.0001); however, when adjusted for FEV₁, this difference was no longer significant (Table 1). A secondary analysis performed without the use of the age restriction in the definition of asthma demonstrated consistent findings. 1026 subjects were included and 223 (21.7%) reported a history of asthma. In contrast to the restricted analysis, more women were found to additionally report a history of asthma (44% with COPD only compared to 56% with COPD and asthma, p = 0.012).

	COPD Only	COPD and Asthma	p-value
Total Subjects	796	119	--
Race:
Non-Hispanic white	672 (84.4)	79 (66.4)	< 0.0001
African American	124 (15.6)	40 (33.6)
Gender
Male	423 (53.1)	61 (51.3)	0.77
Female	373 (46.9)	58 (48.7)
Age, years	64.7 (8.2)	61.3 (8.9)	0.0001*
Pack-years of smoking	55.1 (27.3)	43.7 (20.7)	< 0.0001*
Current smoker	270 (34.2)	46 (38.7)	0.35
BMI kg/m2	27.8 (6.0)	28.1 (6.7)	0.87*
GOLD Stage
2	408 (51.3)	61 (51.3)	0.99**
3	251 (31.5)	38 (31.9)
4	137 (17.2)	20 (16.8)
BODE Index	3.0 (2.1)	3.2 (1.9)	0.28*
SGRQ	38.6(20.5)	44.0 (21.9)	0.0075*
6MWT (ft)	1140.2 (431.9)	1158.8 (430.1)	0.78*
Severe exacerbations	140 (17.6)	39 (32.8)	0.0003
Frequent exacerbations	114 (18.0)	41 (42.7)	< 0.0001
Hay fever	204 (27.8)	65 (57.0)	< 0.0001
Inhaled corticosteroid use	387 (49.4)	80 (69.0)	0.25***
FEV1 % predicted	49.4 (18.4)	49.2 (17.5)	0.85*
FVC % predicted	76.6 (17.9)	78.3 (17.3)	0.23*
FEV1/FVC	0.48 (0.13)	0.48 (0.12)	0.62*
Presence of bronchodilator response, ATS definition	270 (36.0)	46 (41.1)	0.30
Post bronchodilator % change in FEV1	8.7 (12.1)	10.2 (12.5)	0.33*
Percent Emphysema, -950HU	15.8 (13.5)	13.7 (12.3)	0.18*
Percent gas-trapping, -856HU	42.1 (20.3)	43.1 (20.5)	0.69*
Airway wall thickness Pi10	3.78 (0.12)	3.80 (0.14)	0.34*

Values are presented as mean (SD) or N (%).

Abbreviations and definitions: COPD = chronic obstructive pulmonary disease; Hay fever = self report of a history of hay fever; BODE index = body mass index, airflow obstruction, dyspnea and exercise capacity index; SGRQ = St George's Respiratory Questionnaire; 6MWT = 6 minute walk test; Severe Exacerbations = presence of COPD exacerbation resulting in presentation to emergency room or hospital admission in year prior to presentation; Frequent exacerbations = two or more COPD exacerbations in the year prior to enrollment; FEV₁ = forced expiratory volume in 1 second; FVC = forced vital capacity; Bronchodilator response = an increase in FEV₁ of > 12% and 200 ml after administrator of bronchodilator; Pi10 = square root wall area of a hypothetical airway of 10 mm internal perimeter. Data compared using Fisher's exact test unless otherwise stated. *Wilcoxon rank sum analysis. **Chi-square analysis. ***p value adjusted for FEV₁.

In a stratified analysis in which the effect of asthma was examined separately among the subjects with moderate COPD (GOLD stage 2) and the subjects with severe and very severe COPD (GOLD stages 3 and 4), there was no significant difference in spirometry data based on asthma diagnosis. Among subjects with moderate COPD (GOLD stage 2), subjects with asthma and COPD overlap demonstrated greater percent gas-trapping on expiratory chest CT scans compared to those with COPD alone (6.4 +/- 2.2%, p = 0.003). This difference was not seen among subjects with severe COPD (-1.5 +/- 2.0%, p = 0.45). Among subjects with severe COPD there was a trend towards less percent emphysema on inspiratory CT scan in subjects with COPD and asthma compared to those with COPD alone (18.8% vs 23.0%, p = 0.05). The presence of asthma was significantly associated with an increase in respiratory exacerbations regardless of COPD severity (among the moderate group: OR 3.60 [1.72, 7.54], p = 0.007; among the severe COPD group: OR 3.55 [1.76, 7.15], p = 0.0004).

In the COPDGene Study, we demonstrate that subjects with COPD and asthma have distinct and clinically-relevant characteristics. These subjects are more likely to be younger, African-American, and have less smoking history. However their lung function is similar to that of subjects with COPD alone. Despite this, they have worse health-related quality of life and are more likely to have frequent and severe respiratory exacerbations, a marker for more severe disease overall.

This is the first study to specifically link the presence of asthma to more frequent respiratory exacerbations in subjects with COPD. Recent studies have demonstrated that the presence of frequent exacerbations appears to be a stable phenotype of COPD that exists across all levels of lung function and is identifiable by the presence of 2 or more exacerbations per year. In our study, the presence of frequent exacerbations was more common in subjects with COPD and asthma across all GOLD stages. Our findings are consistent with and extend the findings of a previous study demonstrating that patients with COPD and asthma have greater healthcare utilization related to pulmonary disease, with five times greater health care costs when compared to subjects with either disease alone [12]. These results have implications for disease management as the presence of increased COPD exacerbations has been associated with worse health-related quality of life as well as overall mortality [25, 26]. The coexistence of asthma and COPD may identify a group of patients that are more likely to include frequent exacerbators and management of these patients should be directed towards exacerbation prevention.

This study is one of the first large studies to describe the chest CT scan findings in subjects with both COPD and asthma. These subjects demonstrated more gas-trapping on expiratory chest CT scans compared to subjects with COPD alone. This is consistent with prior CT imaging studies demonstrating an increase in gas-trapping among subjects with asthma and may reflect an increase in small airway disease in this group [27]. There was no difference in emphysema or airway wall thickness between COPD subjects with and without asthma. When we restricted our analysis to subjects with moderate COPD, who may be expected to have the most variability in degree of emphysema, we did not see a difference in the percentage of emphysema between those subjects with COPD and those with COPD and asthma. Taken as a whole, these findings could suggest that airway inflammation rather than parenchymal destruction plays a greater role in the decrease in pulmonary function in subjects with COPD and asthma.

We additionally demonstrate a greater portion of subjects with asthma in the African-American population. These findings would suggest that clinicians should be more vigilant to screen for lung function decline in African-American patients with asthma, and similarly should be alert for an asthmatic component to African American subjects with COPD. This latter suggestion is supported by our multivariate analysis for clinical predictors of the diagnosis of asthma, in which we found that African-Americans with COPD were twice as likely to have asthma compared to white subjects with COPD. These findings could reflect a bias towards defining lung function decline in African American populations as asthma in comparison to COPD. These findings could also reflect the greater prevalence of asthma in this population [28]. Although prior studies have demonstrated that clinicians are less likely to diagnose COPD in women than in men [29], when examining subjects with a history of asthma diagnosed before age 40, we did not see a greater percentage of female subjects with asthma in addition to COPD. Of interest, when we examined our study population without the age restriction, we did see more women than men reporting a history of asthma.

Our study has several limitations. This is a cross-sectional study and therefore we are not able to address how COPD and asthma interact to produce this more severe disease phenotype. This would require a cohort analysis with decades of follow-up time, a potentially expensive and prolonged investigation. We were limited by our definition of asthma which included those subjects with a self report of a physician diagnosis of asthma. Self-report of physician diagnosis of asthma has been used previously in many large trials, and the percentage of subjects with asthma in COPDGene was similar to other large cohorts of subjects with COPD. More objective methods to diagnose asthma may be limited in subjects with COPD. Methacholine challenge testing in COPD subjects with FEV1 < 70% predicted has limited safety experience and can often be positive in the absence of asthma [30]. Based on self-report of physician diagnosis of asthma, we were able to identify a unique clinical phenotype among subjects with COPD. In addition, subjects with asthma demonstrated a greater incidence of atopy with more frequent occurrence of hay fever. The absence of a difference in bronchodilator responsiveness between subjects with and without asthma may reflect the overlapping nature of these diseases. Alternatively, one potential explanation is that subjects were not required to withhold their regular bronchodilator medication before spirometry testing. In order to further clarify the nature of respiratory disease between our two study populations, we examined pre-study respiratory medication use. Although in an unadjusted analysis we demonstrated that subjects with a history of asthma were more likely to be using inhaled corticosteroids, this difference did not remain significant when adjusted for FEV₁. As inhaled corticosteroids are often used in the treatment of moderate to severe COPD as well as asthma, examining a history of this medication use may not be helpful in distinguishing subjects with asthma. We limited our inclusion to subjects diagnosed with asthma before the age of 40 in order to identify subjects whose asthma diagnosis preceded their COPD diagnosis and to exclude subjects who might have other respiratory diseases confused with asthma.

In conclusion, we demonstrate that subjects with COPD and asthma demonstrate unique clinical features including an increase in respiratory exacerbations. These findings have implications for disease management and treatment. Improved monitoring and prevention of exacerbations in patients with COPD and asthma may improve quality of life and potentially survival.

Dr. Silverman has received grant support and consulting fees from GlaxoSmithKline for studies of COPD genetics and has received honoraria and consulting fees from AstraZeneca. None of the other authors has reported conflicts of interest.