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(Chest. 2004;126:59-65.)
© 2004 American College of Chest Physicians

Asthma as a Risk Factor for COPD in a Longitudinal Study*

Graciela E. Silva, MPH; Duane L. Sherrill, PhD; Stefano Guerra, MD, PhD, MPH and Robert A. Barbee, MD, FCCP

* From the Arizona Respiratory Center, University of Arizona, College of Medicine, Tucson, AZ.

Correspondence to: Duane L. Sherrill, PhD, Arizona Respiratory Center, University of Arizona, 1501 N Campbell Ave, PO Box 245073, Tucson, AZ 85724-5073; e-mail: duane{at}resp-sci.arizona.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: For several years, asthma and COPD have been regarded as distinct entities, with distinct clinical courses. However, despite distinctive physiologic features at the time of diagnosis, and different risk factors, the two diseases over time may develop features that are quite similar.

Study objective: To evaluate the association between physician-diagnosed asthma and the subsequent development of COPD in a cohort of 3,099 adult subjects from Tucson, AZ.

Design and methods: A prospective observational study. Participants completed up to 12 standard respiratory questionnaires and 11 spirometry lung function measurements over a period of 20 years. Survival curves (with time to development of COPD as the dependent variable) were compared between subjects with asthma and subjects without asthma at the initial survey.

Results: Subjects with active asthma (n = 192) had significantly higher hazard ratios than inactive (n = 156) or nonasthmatic subjects (n = 2751) for acquiring COPD. As compared with nonasthmatics, active asthmatics had a 10-times-higher risk for acquiring symptoms of chronic bronchitis (95% confidence interval [CI], 4.94 to 20.25), 17-times-higher risk of receiving a diagnosis of emphysema (95% CI, 8.31 to 34.83), and 12.5-times-higher risk of fulfilling COPD criteria (95% CI, 6.84 to 22.84), even after adjusting for smoking history and other potential confounders.

Conclusions: Physician-diagnosed asthma is significantly associated with an increased risk for CB, emphysema, and COPD.

Key Words: asthma • chronic bronchitis • COPD • pulmonary emphysema


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The definition of asthma includes bronchial hyperresponsiveness, airway inflammation, and the presence of airflow obstruction, which may be relieved spontaneously or with medication.1 COPD, however, is defined as a chronic and usually progressive disease characterized by airflow limitation that is not fully reversible.2 Whereas asthma is most frequently diagnosed during childhood and is associated with atopy and eosinophilic inflammation, COPD is usually diagnosed during the middle or later life and is associated with neutrophilic inflammation.3

Despite distinctive clinical physiologic features at the time of initial diagnosis, epidemiologic studies45678910111213 of asthma and COPD have shown that the two diseases over time may develop physiologic features that are quite similar. The rapid rate of decline in pulmonary function, characteristic of subjects with COPD, may be seen in asthmatic subjects as well.4567 Airway hyperresponsiveness (AHR), either to methacholine or histamine, a supportive measure of asthma diagnosis, has been documented in subjects with COPD.89 Likewise, reversibility of pulmonary obstruction in response to treatment, a hallmark of asthma, may decrease over time in some patients with moderate or severe asthma, to the point of irreversible or only partially reversible airway obstruction.10111213 The overlap in many of these signs and symptoms often makes the distinction between the two diseases obscure, making it difficult to label these subjects, especially in the elderly population.1415

The progression in severity of asthma symptoms, and the overlap of symptoms seen in some patients with asthma and COPD have lead us to theorize that asthma may be a risk factor for the subsequent development of COPD. The aim of this cohort study is to assess whether active asthma diagnosis during the initial survey is a predictor for the subsequent development of characteristics that are consistent with COPD.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Data for the present study were collected as part of the Tucson Epidemiologic Study of Airway Obstructive diseases. Subjects were selected from a random, stratified cluster sample of white, non–Mexican-American households. Details of the study design have been published previously.16 In brief, the sampling frame consisted of census blocks stratified on the basis of ethnic group, age of the head of household, and socioeconomic status based on 1970 census data. Subjects were enrolled between 1972 and 1973. There were 12 periodic follow-up surveys obtained approximately 1.5 to 2 years apart for a total of 20 years. During each survey, subjects completed standardized questionnaires assessing respiratory symptoms, pulmonary diseases, and smoking history, as well as other diseases. Spirometric and flow-volume data were obtained during each survey with a pneumotachograph using American Thoracic Society criteria,17 with the exception of survey 4. The initial participants numbered 3,805 from 1,655 households, with new enrollees added by marriage and births. The total number of participants at the end of the study was 5,261. In the present study we include 3,099 subjects who fulfill the selection criteria and who were ≥ 20 years old at their initial survey.

Asthma status and potential confounders including age, sex, smoking, IgE, and skin test reactivity were assessed at the initial survey. Smoking status was determined from answers to the following questions: "Have you ever smoked cigarettes regularly? (1) Yes, and I still smoke (current smoker); (2) Yes, but I no longer smoke (ex-smoker); or (3) No, I never smoked (never-smoker)."

Total serum IgE concentrations were measured by the paper radioimmunosorbent method (Pharmacia Diagnostics; Piscataway, NJ). The reported values represent the mean of duplicate tests. Blood for serum IgE levels was obtained initially from subjects who were at least 6 years of age.18 In the present analyses, we include levels obtained from 2,302 subjects who were ≥ 20 years old at the initial survey. A logarithm base-10 transformation of IgE values was used in the present analyses to normalize the distribution. Allergy skin tests were performed using the skin-prick test technique.19 The skin test antigens were obtained from Hollister-Stier Laboratories (Spokane, WA), and included house dust (used at a dilution of 1:10), Dematiaceae mold mix (1:100), Bermuda grass (1:20), tree mix (1:20), and weed mix (1:20). A control solution of 50% glycerine was also applied. Subjects with one or more reactions of at least 2-mm greater than that produced by the glycerin control were placed in the skin test-positive group.

Single-breath diffusing capacity of the lung for carbon monoxide (DLCO) measurements were obtained from 580 subjects during survey 7 and survey 12. The DLCO measurement technique has been previously described.20 The DS model automated system (W.E. Collins; Braintree, MA) was used during both surveys with no changes in the procedures. The washout volume was 1.0 L, except for participants with a vital capacity of < 2.0 L for whom a washout volume of 500 mL was used. The test gas was 0.3% carbon monoxide, 10% helium, and balance nitrogen. At least two DLCO maneuvers were performed. The mean DLCO value from the two that matched within 2 mL/min/mm Hg was reported. For the purpose of these analyses, DLCO measurements were normalized for age, sex, and height utilizing the prediction equations of Crapo and Morris21 in accordance with American Thoracic Society recommendations.22 The percentage of predicted value of DLCO was used in this study.

Asthma status was determined at initial survey from answers to the question: Have you ever had asthma? Subjects who answered "yes, and I still have it" were considered to have active asthma, subjects who answered "yes, but I no longer have it" were considered to have inactive asthma, and subjects who answered "no" were considered to have no asthma. Subjects with active asthma were included in the analyses only if they had seen a physician about their asthma. There were 220 subjects with active asthma; of these, 211 subjects had physician-confirmed asthma. Development of chronic bronchitis (CB), physician-diagnosed emphysema, or COPD were determined at each follow-up survey. Subjects were classified as having CB if they reported having cough and phlegm for most days for as much as 3 months of the year in at least 2 consecutive years (according to the American Thoracic Society standards),8 and had FEV1 values < 80% predicted. Subjects were classified as having physician-diagnosed emphysema if they ever reported having a physician-confirmed diagnosis of emphysema. In addition, subjects had to have FEV1 or DLCO values < 80% predicted. COPD was defined as having either CB or emphysema or both, and having either FEV1 or DLCO values < 80% predicted. All subjects included in the present study had negative findings for CB and emphysema at the initial survey. Furthermore, subjects who underwent heart or lung surgery before or at any time during the study were excluded because this may have affected their lung function. There were a total of 185 subjects excluded who had reported heart or lung surgery, including 12 from the inactive asthma and 19 from the active asthma categories. In addition, to avoid having those subjects with emphysema mask the symptoms of CB, subjects who concurrently fulfilled the criteria for CB and emphysema at any given follow-up survey were excluded from the analyses for CB. The Tucson Epidemiologic Study of Airway Obstructive Diseases was approved by the Institutional Review Board for Human Studies, and informed written consent was obtained from all subjects at the time of their enrollment into the study.

Statistical Methods
The {chi}2 test was used to compare differences in proportions between each of the asthma categories. The Student t test and analyses of variance were used to compare differences in mean values, and the score {chi}2 test for trend of odds was used to test for linear trend among the asthma categories. Independent multivariate Cox proportional hazards models were used to determine the adjusted hazard ratios (HRs) associated with each asthma category and other potential confounders at the initial survey and subsequent development of CB, emphysema, or COPD. Potential confounders included age at initial survey, sex, smoking, IgE level, and skin test. Age was centered by subtracting the mean to each subject’s age. Interaction terms between log IgE and skin test reactivity, and between log IgE and smoking were also evaluated in the model. Variables with multiple categories (> 2) ie, asthma and smoking, were entered using indicator variables. The Wald test was used to test for significant difference in linear contrast of coefficients between inactive and active asthma categories. Cox regression survival curves using time to first event of CB, emphysema, or COPD as the primary outcome and adjusting for potential confounders were compared across the asthma categories.

Some studies423 have indicated that subjects with longer duration of asthma symptoms have an increased rate of decline in lung function. Therefore, we evaluated the effect that longer asthma duration had on development of CB, emphysema, or COPD for subjects in the active asthma group. For this purpose, asthma duration was defined as the number of years with asthma prior to initial survey. This was computed by subtracting the age at which subjects reported having their first asthma attack from the subject’s age at initial survey. Asthma duration was dichotomized into subjects with ≤ 50th percentile of the distribution (≤ 22.08 years) who were considered to have short asthma duration, and those > 50th percentile (> 22.08 years) who were considered to have long asthma duration. In addition, we evaluated active asthmatics according to childhood or adulthood asthma onset. Active asthmatics were categorized on whether their asthma onset was at ≤ 14 years old (childhood asthma onset, n = 88), or at > 14 years old (adulthood asthma onset, n = 123). Statistical tests were performed using statistical software (Intercooled Stata, version 7.0 for Windows; Stata Corporation; College Station, TX). A significance level of 0.05 was used for all statistical tests.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Descriptive statistics for the selected subjects stratified by sex and by asthma status at initial survey are shown in Tables 1 , 2 . A significant difference was seen in smoking for male and female subjects. A higher percentage of current smokers and ex-smokers were men, and a higher percentage of never-smokers were women. The overall mean age at initial survey was 47 ± 19.3 years (± SD). Male subjects had a significantly lower mean age than female subjects (mean, 45 years and 48 years, respectively; p < 0.001). In addition, the mean log IgE values were also significantly different between male and female subjects, with male subjects having a higher mean value (1.57) than female subjects (1.34) [p < 0.001]. On average, female subjects died at an older age and had a longer follow-up period than did male subjects. No difference was seen between male and female subjects for skin test reactivity and mean percentage of predicted FEV1.


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  		Table 1.. Basic Descriptive Statistics for Sex and Asthma at Initial Survey*

 

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  		Table 2.. Basic Descriptive Statistics*

 
There was no significant difference in proportions between asthma categories by sex or by smoking status. However, a significant difference was seen for skin test reactivity. Inactive and active asthmatics had a higher percentage of positive skin test results than nonasthmatics. The mean values for age and log IgE were significantly higher for the active asthma group, and the mean value for FEV1 percentage of predicted was significantly lower. Active asthmatics died at a younger age and had a significantly lower mean number of years of follow-up than inactive asthmatics or nonasthmatics. The frequency distribution for the development of CB, emphysema, and COPD showed that a higher percentage of active asthmatics had the events than did inactive or nonasthmatics (Table 3 ).


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  		Table 3.. Frequency Distribution for Development of CB, Emphysema, and COPD by Asthma Status at Initial Survey*

 
Separate Cox proportional hazard models were used to assess the association between active and inactive asthma categories and development of subsequent CB, emphysema, or COPD. When compared to subjects with no asthma, active asthmatics were more likely to acquire CB (HR, 10; 95% confidence interval [CI], 4.94 to 20.25), emphysema (HR, 17; 95% CI, 8.31 to 34.83), and COPD (HR, 12.5; 95% CI, 6.84 to 22.84) [Table 4 ]. No association was found between inactive asthma and any of the events. Age and current smoking were also significantly associated with an increased risk of acquiring CB, emphysema, or COPD. Male subjects were more likely to acquire emphysema, but not CB or COPD. Log IgE and skin test were not significantly associated with either of the outcome variables, but were kept in the model because of possible biological associations. None of the interaction terms tested were significant. Independent tests for linear contrast of coefficients showed a significant difference between the inactive and active asthma categories separately for CB, emphysema, and COPD (p < 0.001). The Cox survival estimates are shown in Figure 1 ; after adjusting for age, sex, smoking, log IgE, and skin test reactivity, the cumulative survival is much lower for subjects in the active-asthma category compared to those in the inactive or in the no-asthma category for CB, emphysema, and COPD.


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  		Table 4.. Cox Proportional Hazards Model Predicting CB, Emphysema, and COPD by Asthma at Initial Survey and Other Independent Variables*

 


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  		Figure 1.. Cox survival estimates for CB (top), emphysema (middle), and COPD (bottom) by asthma categories at initial survey adjusted for age, sex, smoking, log IgE, and skin test. The HRs for active asthma compared to no asthma were 10.0 (95% CI, 4.94 to 20.25) for CB, 17.0 (95% CI, 8.31 to 34.83) for emphysema, and 12.5 (95% CI, 6.84 to 22.84) for COPD.

 
When analyzing the subject’s asthma duration, we found that after adjusting for age, sex, smoking, IgE, and skin test, subjects with longer asthma duration had higher risk (HR, 22.3) than those with shorter asthma duration (HR, 5.9) for acquiring emphysema when compared to nonasthmatics. This association however was not significant (p = 0.09). We saw no association between short or long asthma duration and CB or COPD. Similarly, we found no significant associations between childhood or adulthood asthma onset and risk of acquiring CB, emphysema, or COPD.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Findings from this 20-year follow-up study showed that after adjusting for age, sex, smoking, IgE, and skin test reactivity, physician-confirmed active asthma was significantly associated with subsequent development of CB, emphysema, and COPD. Active asthmatics were 10 times more likely to acquire symptoms characteristic of CB, 17 times more likely to receive a diagnosis of emphysema by a physician, and 12.5 times more likely to fulfill criteria consistent with COPD. Furthermore, the difference between active and inactive asthmatic effects was significant, suggesting that the increased risk is associated with active asthma but not inactive asthma.

Smoking has been described as the main risk factor for development of COPD.24 However, < 20% of cigarette smokers acquire COPD, suggesting that other factors convey significant additional risk. These include a rare deficiency of {alpha}1-antitrypsin25 and heavy exposure to occupational and environmental gases.2 Still, it is likely that additional factors may contribute to the development of COPD. Results from several studies45726 have suggested that asthma and AHR are important risk factors contributing to an increased rate of decline in FEV1 and thus to the development of COPD. In an 8-year follow-up study, Fletcher et al26 compared the rates of decline in FEV1 among subjects with physician-diagnosed asthma and subjects without asthma. The authors found that the rate of decline in FEV1 adjusted for smoking was significantly higher among the asthmatic subjects compared to the nonasthmatic subjects. In another study, Peat et al5 found that after 18 years of follow-up, physician-diagnosed asthmatics had a greater rate of decline in FEV1 and a lower baseline lung function than did nonasthmatic subjects. Ulrik and Lange,7 in their 5-year longitudinal study of 10,952 subjects, found that those with a new asthma diagnosis had lower initial values of lung function and an increased rate of decline in FEV1 compared to nonasthmatic subjects. Subsequent analyses from the same study showed that after 15 years of follow-up, subjects with self-reported asthma still had a greater decline in FEV1 over time than those who did not.4 These studies45726 seem to indicate that asthma may be associated with a lower baseline FEV1 and with an increased rate of decline in pulmonary function, supporting the hypothesis that asthma may be a risk factor for the development of COPD. Consistent, in a recent study6 utilizing the same population, our group reported that when the presence of comorbid COPD was not taken into account, the rate of decline in FEV1 seen in physician-confirmed asthmatics was steeper than that of nonasthmatics. However, we did not find this association to be present among asthmatics without concomitant COPD, suggesting that the progression of the disease into a nonreversible lung obstruction was the major determinant of the increased decline in lung function seen among asthmatics.

Likewise, several cross-sectional studies272829 have reported associations between AHR to methacholine or histamine and impaired pulmonary function. Although it has been debated whether AHR preceded or was a result of airway obstruction, results from some prospective studies suggest that AHR influences the decline in pulmonary function. O’Connor et al30 evaluated the association between AHR and the rate of decline in FEV1 in a cohort of 912 randomly selected middle-aged men. They found that after 3 years of follow-up and after adjusting for potential confounders, AHR was a significant predictor of the rate of decline in FEV1. In a 4-year prospective study31 of 324 elderly subjects, allergy (defined by positive skin test result and elevated IgE) and AHR were independently associated with an accelerated decline in FEV1 particularly in former and current smokers. Similarly, Rijcken et al32 evaluated the association between AHR and the decline in FEV1 in a random population of 1,619 subjects ≥ 25 years of age. They found that after 25 years of follow-up and after adjusting for possible confounders, subjects with increased AHR had a greater mean yearly decline in FEV1 compared to normal responders. Results from these studies seem to indicate that AHR, which is a strong asthma-related phenotype, may be a contributing risk factor for COPD, although it should be acknowledged that the nature of these associations remains unknown.

It has been hypothesized that asthma and COPD share a common background,33 the differentiation into one disease or the other being modulated by environmental (exposure to allergens, respiratory infections, and smoking) and host factors (AHR, atopy, and genetic predisposition). Although this hypothesis is still unresolved, it has been suggested that the airway inflammation and airflow obstruction seen in asthmatics with increased AHR may lead to a subsequent lung remodeling due to airway wall thickening and subepithelial fibrosis.34 This remodeling could result in irreversible airflow obstruction, supporting the hypothesis that AHR is a determinant in the development of COPD. However, from the present study, it is difficult to determine whether the association seen between active asthmatics and COPD is due to an increased development in severity of asthma symptoms or whether these subjects acquired additional comorbid lung diseases.

We acknowledge that our data do not include airway responsiveness or reversibility measurements, and therefore we could not corroborate the asthma or COPD diagnoses. Therefore, it is possible that some subjects with chronic asthma may have been classified as having CB. However, the likelihood of this happening is minimal in view of the rather pure cough and sputum criteria used for a CB diagnosis, without reference to wheezing or shortness of breath, common in asthma criteria. Furthermore, information on DLCO was available, and this objective parameter was included in the working definition of emphysema and COPD, which yielded very strong associations with active asthma.

In conclusion, results from the present study show a significant association between an active asthma diagnosis at initial survey and the subsequent development of signs and symptoms consistent with COPD. The mechanism by which asthma may have contributed to this development is still unresolved.


   Acknowledgements
 
The authors thank Mr. Seumas Rogan for his support in generating the graphs.


   Footnotes
 
Abbreviations: AHR = airway hyperresponsiveness; CB = chronic bronchitis; CI = confidence interval; DLCO = single-breath diffusing capacity of the lung for carbon monoxide; HR = hazard ratio

Ms. Silva was supported in part by National Institutes of Health fellowship grant No. HL10506-02.

Received for publication September 3, 2003. Accepted for publication February 4, 2004.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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