Abstract
Background: COPD is often regarded as a smoker's disease. In fact, up to 50% of COPD could be attributable to other causes. Relatively little is known about COPD among nonsmokers, and this group is usually excluded from studies of COPD. Methods: In this cross-sectional case-comparison study, smokers and nonsmokers aged over 45 with COPD (post-bronchodilator FEV1 ≤ 70% predicted, FEV1/FVC ratio < 0.7) were recruited from specialist outpatient clinics and from primary care. Subjects completed a questionnaire and interview, and underwent spirometry, venesection, exhaled nitric oxide (ENO) measurement, allergen skinprick testing, formal lung function testing and high resolution CT. Results: 48 nonsmokers and 45 smokers participated. Asthma was nearly universal among nonsmokers and was the commonest identifiable cause of COPD in that group. Nonsmokers also exhibited a high prevalence of objective eosinophilic inflammation (raised ENO and eosinophil counts, positive skinprick tests). Smokers had more severe airflow obstruction, but respiratory symptom prevalences were similar between groups. Nonsmokers reported greater lifetime burdens of respiratory disease. Nonsmokers’ HRCT results showed functional small airways disease, with no significant emphysema in any subject. Previously undiagnosed bronchiectasis was common in both groups (31% and 42%). Conclusions: Asthma is a very common cause of COPD among nonsmokers. Radiological bronchiectasis is common in COPD; the clinical significance of this finding is unclear.
Introduction
Chronic obstructive pulmonary disease (COPD) is the fourth commonest cause of death worldwide (Citation1). Expenditure on COPD represents a major cost to the health care system: annual direct costs associated with the treatment of COPD are estimated at $29 billion in the United States (Citation2). The majority of COPD remains undiagnosed (Citation3, 4).
COPD has been traditionally regarded as a “smoker's disease”. However, while tobacco smoking is the commonest cause of COPD, it may account for under 50% of cases worldwide (Citation5). Approximately 10–12% of individuals with COPD have never smoked (Citation3). As nonsmokers are usually excluded from studies of COPD, little is known about causes of COPD in this group, their prognosis, or their response to treatment. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has stated that “the causes of airflow limitation in nonsmokers need further investigation” (Citation6).
Other established causes of COPD include occupational exposures (Citation7, 8), air pollution (Citation6, Citation9), antiprotease deficiency (Citation10) and asthma (Citation11–13). Although population-based studies have identified these risk factors, few detailed studies of nonsmokers with COPD exist.
Asthma prevalence is high and increasing in Western countries (Citation14). Asthma is a recognised risk factor for COPD (Citation11–13, Citation15–19). Individuals with both conditions have worse quality of life (Citation20) and may experience accelerated decline in FEV1 (Citation21–23). However, most asthmatic individuals do not develop fixed airflow obstruction (AFO), and little is known about how to identify the subset at risk of COPD.
We undertook a cross-sectional case-comparison study aiming to identifying factors associated with COPD among lifelong nonsmokers. The role of asthma as a COPD risk factor was of particular interest, as were high-resolution CT (HRCT) features in smokers versus nonsmokers.
Methods
Participants and recruitment
Adults aged over 45 years with a history of physician-diagnosed COPD were invited to participate. Subjects were predominantly recruited from respiratory outpatient clinics; some were recruited from primary care using newspaper advertisements. Similar numbers of smokers and nonsmokers were recruited. The groups were matched for age and sex.
Participants were required to have post-bronchodilator FEV1 ≤ 70% predicted and FEV1/FVC ratio < 0.7. Nonsmokers had < 5 pack-years of tobacco exposure; smokers had ≥ 10 pack-years. Subjects were excluded if they had a history of other lung diseases likely to influence lung function. Participants provided written consent. Ethical approval was obtained from the Auckland Ethics Committees (reference NTY/07/12/133).
Study procedures
Subjects attended a morning visit after fasting and withholding bronchodilators for 12 hours. Subjects completed a questionnaire prior to the visit. This was reviewed by study personnel during the visit.
Height, weight, blood pressure and waist circumference were recorded. Exhaled nitric oxide (ENO) concentrations were measured at a flow rate of 50 mL/second using a NIOX MINO device (Aerocrine AB, Solna, Sweden). Blood was drawn for measurement of full blood count, C-reactive protein (CRP), lipid profile, fasting glucose and alpha1 antitrypsin. Spirometry was measured according to American Thoracic Society guidelines (Citation24), using an electronic spirometer (Micro Plus CE 0120, CareFusion 232 Limited, Kent, UK) before and after inhaling 400 mcg of salbutamol. Allergen skinprick testing was performed using common aeroallergens and a positive control.
Subjects were invited to undergo formal lung function testing and HRCT. HRCT images were reviewed and scored by a radiologist (D.M.) using a modification of the Bhalla system (Citation25, 26).
Definitions
The GOLD definition of COPD was used (Citation6). Bronchodilator reversibility was defined as increases in FEV1 or FVC of at least 12% and 200 mL from baseline values (Citation27). Asthma was defined as self-reported physician diagnosis and use of inhaled medications. Dyspnoea was graded using the Medical Research Council score (Citation28).
Statistical analysis
Analysis was performed using the software package R (http://www.r-project.org). For bivariate analysis, Spearman correlation, Wilcoxon and Kruskal–Wallis tests were used for continuous variables as appropriate. For categorical variables, the chi-squared test or Fisher's exact test was used as appropriate. Logistic regression was used for multivariate analysis. The significance limit was set at 0.05.
Results
Because the groups differ in mean age, all other means and proportions are reported adjusted for age, and all subsequent comparisons use multiple logistic regression with age as an input variable.
Demographic information
The analysis included 93 subjects. Their demographic characteristics are shown in . Smokers were slightly older than nonsmokers. After adjustment for age and sex, smokers had worse AFO and higher GOLD stage (p = 0.001). The groups were well matched for sex, height and body mass index (BMI).
Table 1. Participant baseline characteristics
Asthma and allergy
Physician-diagnosed asthma was almost universal among nonsmokers with COPD (). About half of smokers reported a diagnosis of asthma. Among those with asthma, age of asthma onset was younger among nonsmokers than smokers, and duration of asthma was longer, independent of age and sex. Prevalence and degree of bronchodilator reversibility were similar between groups.
Table 2. Prevalence of asthma and allergy
Family history of asthma or allergy, and prevalences of other allergic diseases, were similar between groups. Nonsmokers had more positive skinprick tests than smokers, and were more likely to have multiple positive skinprick tests. This was also true in the asthmatic subset.
Systemic and airway eosinophilic inflammation (raised eosinophil count and ENO) were commoner among nonsmokers than smokers, independent of asthma diagnosis and despite widespread inhaled corticosteroid (ICS) use. Almost all participants were taking ICS. Nonsmokers more often reported symptomatic benefit from ICS.
Systemic inflammation
Smokers and nonsmokers showed similar evidence of non-eosinophilic systemic inflammation ().
Table 3. Systemic inflammatory markers
Family history of airways disease
Family history of airways disease was generally common, especially asthma (). Prevalences of family histories of emphysema, chronic bronchitis, COPD, asthma, or airways disease were similar between groups.
Table 4. Prevalence of family history of airways disease
Symptoms
Nonsmokers reported greater durations of all respiratory symptoms (cough, sputum, dyspnoea and wheeze), independent of age and FEV1 (). Prevalences of respiratory symptoms and recent frequency of upper or lower respiratory tract infections were similar between groups.
Table 5. Symptoms of respiratory disease
Among smokers, dyspnoea grade was higher, and severe dyspnoea was commoner, independent of FEV1 and age. Both groups were prescribed similar numbers of airways medications.
Environmental tobacco smoke
Smokers more often reported childhood domestic environmental tobacco smoke (ETS) exposure, but prevalence was high in both groups (). Smokers also reported higher lifetime burden of ETS exposure, independent of pack-years. ETS exposure was unrelated to spirometry.
Table 6. Other risk factors and environmental exposures
Occupational exposures
Exposure to occupational dusts and fumes was commoner among smokers (). Nonsmokers had lower total burdens of occupational exposure, but this was dependent on age. Occupational exposures were unrelated to spirometry.
Indoor air pollution
Prevalences of exposure to indoor air pollution for cooking or heating, and years of exposure, were similar between groups ().
Childhood respiratory infection
Nonsmokers were more likely than smokers to report frequent childhood upper respiratory tract infections (URTI) and bronchitis, independent of age and ETS exposure (). Childhood pertussis and pneumonia prevalences were similar between groups. Static lung volumes and gas transfer.
Nonsmokers had less hyperinflation and gas trapping than smokers, as shown by lower total lung capacity (TLC) and residual volume (RV) (). Gas transfer (DLCO) was higher among nonsmokers than smokers. These relationships were independent of age, BMI and FEV1.
Table 7. Static lung volumes and gas transfer
Radiology
HRCT scores are given in , and reveal several differences between groups. Localised bronchiectasis was common in both groups, but was commoner among smokers. In almost all cases bronchiectasis was a new finding.
Table 8. Subjective scoring of HRCT scans
Bronchial wall thickening and bronchial mucous plugging were commoner among nonsmokers (the latter was statistically nonsignificant). No nonsmokers exhibited emphysema on HRCT, whereas 31% of smokers had radiological emphysema, usually of limited extent. In contrast, regional low attenuation was much commoner among nonsmokers (86% versus 33%, p < 0.001).
Discussion
This cross-sectional study compared clinical and radiological characteristics and risk factor exposures between smokers and nonsmokers with COPD. The strongest association was with asthma. Asthma was almost universal among nonsmokers, supported by higher prevalences of atopy and eosinophilic inflammation. Bronchodilator reversibility was similar between groups. No other exposure differences existed between groups, except childhood respiratory tract infection, which was commoner among nonsmokers.
Although smokers were more severely obstructed, breathless and functionally limited, nonsmokers reported similar prevalences of respiratory symptoms and greater lifetime burdens of respiratory disease.
Asthma
Asthma was the commonest identifiable cause of COPD among nonsmoking participants. While the asthma definition used was primarily subjective, nonsmokers also exhibited more evidence of allergic inflammation (positive skinprick tests, raised ENO and eosinophil count). Their HRCT scans were devoid of emphysema, instead showing functional small airways disease, bronchial wall thickening and mucous plugging, consistent with asthma (Citation29).
The findings of the present case-comparison study agree with numerous epidemiological studies showing asthma to be an independent risk factor for fixed AFO (Citation3, Citation11–13, Citation15–19, Citation30).
Allergy, atopy and eosinophilic inflammation
Asthma is classically characterised by eosinophilic airway inflammation (ENO and sputum eosinophilia). This pattern appears to persist in COPD due to asthma (Citation31). In contrast, smoking-related COPD is marked by neutrophilic airway inflammation and minimal steroid responsiveness (Citation32, 33). Non-allergic or “neutrophilic” asthma has been suggested as a risk factor for lung function decline (Citation34, 35), either because this subgroup responds poorly to ICS, or because their disease process more closely resembles typical COPD than asthma (Citation36).
We found more eosinophilic inflammation (higher serum eosinophil count and ENO) among nonsmokers, despite near-universal ICS use, which suppresses ENO (Citation37). Nonsmokers also had more positive skinprick tests, although prevalences of atopy and allergy were comparable.
Bronchodilator reversibility
It is widely thought that bronchodilator reversibility (BDR) can distinguish COPD from asthma; indeed, testing for BDR is a recommended diagnostic step in asthma guidelines (Citation38). However, BDR is common in COPD (Citation39–41) and the post-bronchodilator percentage increase in FEV1 becomes greater as AFO worsens (Citation40).
The present study echoed these findings. BDR prevalences were similar between groups, despite smokers’ lower asthma prevalence. Smokers with asthma were not more likely to exhibit BDR.
Asthma duration
As discussed, AFO severity seems proportional to asthma duration, and childhood onset asthma confers greater risk than adult-onset disease (Citation42–44) even when asthma itself does not persist into adulthood (Citation45–48). We found that childhood asthma onset was commoner among nonsmokers with COPD, but was not associated with lower FEV1, perhaps because childhood asthma often permanently remits.
Treatment with ICS may slow the lung function decline associated with chronic asthma (Citation16, Citation49). The relationship between asthma and COPD may therefore be due to a “cohort effect,” with individuals whose asthma developed prior to widespread ICS availability having increased risk of COPD. Since ICS were not widely used to treat asthma until the 1980s, most asthmatic subjects in this study must have had long periods of “untreated” asthma, making it difficult to isolate effects of ICS on lung function. Furthermore, ICS use is widespread in smoking-related COPD, as reflected in the present study.
Other risk factors
Frequent childhood respiratory tract infection may predict low lung function (Citation18, Citation46, Citation50, 51) and COPD (Citation3) in adulthood. In our study, childhood respiratory infection was common in both groups, but nonsmokers reported more childhood bronchitis and pneumonia. It is unclear whether these infections cause COPD, or whether they are simply markers of lifelong respiratory illness.
ETS exposure, a “probable” cause of COPD (Citation5), was more extensive in smokers than nonsmokers, throughout their lifespan. However, any effect of ETS on COPD risk among smokers is presumably dwarfed by the effects of their own smoking.
Clinical presentation of COPD in nonsmokers
COPD in nonsmokers causes a symptom burden comparable to smoking-related COPD, though the field has been little studied. In the BOLD survey, COPD was associated with more respiratory symptoms among nonsmokers than smokers (Citation3). Nonsmokers with COPD often report longer durations of respiratory disease, and hence greater lifetime disease burdens.
In our study, although nonsmokers were younger and less severely obstructed than smokers, they reported similar prevalences of respiratory symptoms, and greater durations of those symptoms, presumably due to the younger age of airways disease onset.
Radiology
Fixed AFO in asthma is probably caused by small airways narrowing and plugging rather than emphysema (Citation52). In HRCT studies, asthmatic subjects have less parenchymal disease (Citation53) and lower emphysema scores (Citation31, Citation54–56) than smokers. Gas transfer (DLCO) is better preserved in asthma than smoking-related COPD (Citation31, Citation53). These findings were replicated in our study: HRCT findings among nonsmokers were typical of asthma, and emphysema was absent.
We found high prevalences of bronchiectasis in both groups. Multiple lobes were usually affected, but the degree of bronchial dilatation was never severe. This finding is not unexpected in COPD, where bronchiectasis is a common CT finding, with prevalences of 27–50% reported (Citation57–59). However bronchiectasis is much less well described in asthma. The existing literature suggests it is common there as well, with reported prevalences of 20–40% (Citation60–63) (similar to our results), and similar risk factors to those for bronchiectasis in COPD (Citation60, Citation62). An allergic phenotype appears protective, though subjects with mild allergic asthma have a substantial bronchiectasis prevalence (Citation60, Citation63).
In our study, there was a weakly positive association between bronchiectasis and age, possibly explaining its greater prevalence among smokers. No other risk factors for bronchiectasis were evident.
Limitations
Asthma was defined by physician diagnosis, which can be inaccurate (Citation64–66). However, the high prevalence among nonsmokers of other allergic disease, eosinophilic inflammation, benefit from ICS, and typical CT findings of asthma, all suggest that asthma was truly common in this group.
Nonsmokers are less likely than smokers to undergo spirometry. Perhaps the nonsmokers in this study were referred to respiratory clinics because of unusually severe respiratory symptoms, and thus may not accurately represent the clinical presentations of most nonsmokers with COPD.
Conclusion
Despite accounting for many patients with COPD, nonsmokers with this disease have been little studied. We conducted a cross-sectional case-comparison study and correctly predicted that asthma would be the commonest identifiable risk factor among nonsmokers. This association was supported by objective evidence including CT findings and elevated markers of eosinophilic inflammation. No other risk factors for COPD in nonsmokers were identified. Our results underline the need for more research on COPD development in asthma.
Undiagnosed bronchiectasis was common in both groups. The association between COPD, asthma, and this underdiagnosed disease should be more widely appreciated, and its causes elucidated. Our results complement existing knowledge of COPD in nonsmokers. Given the high proportion of COPD that is not caused by smoking, and given that the symptom burden of nonsmokers matches smoking-related COPD, investigators must include these patients in clinical trials. Finally, nonsmokers with asthma and fixed AFO seldom receive a COPD diagnosis, and current asthma guidelines depict the two conditions as unrelated (Citation38). A more unified approach to the two conditions is needed.
Declaration of Interest Statement
This research was funded by a grant from the New Zealand Health Research Council. The authors report no conflicts of interest. The authors are responsible for the content and writing of this paper.
Acknowledgments
This paper is dedicated to Professor Peter Black, who died in January 2010 before the publication of this research. Peter played a central role in designing the present study. His death was a great loss to us, to his patients, and to the research community.
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