American Journal of Respiratory and Critical Care Medicine

Rationale: The contribution by asthma to the development of fixed airflow obstruction (AO) and the nature of its effect combined with active smoking and atopy remain unclear.

Objectives: To investigate the prevalence and relative influence of lifetime asthma, active smoking, and atopy on fixed AO in middle age.

Methods: The population-based Tasmanian Longitudinal Health Study cohort born in 1961 (n = 8,583) and studied with prebronchodilator spirometry in 1968 was retraced (n = 7,312) and resurveyed (n = 5,729 responses) from 2002 to 2005. A sample enriched for asthma and chronic bronchitis underwent a further questionnaire, pre- and post-bronchodilator spirometry (n = 1,389), skin prick testing, lung volumes, and diffusing capacity measurements. Prevalence estimates were reweighted for sampling fractions. Multiple linear and logistic regression were used to assess the relevant associations.

Measurements and Main Results: Main effects and interactions between lifetime asthma, active smoking, and atopy as they relate to fixed AO were measured. The prevalence of fixed AO was 6.0% (95% confidence interval [CI], 4.5–7.5%). Its association with early-onset current clinical asthma was equivalent to a 33 pack-year history of smoking (odds ratio, 3.7; 95% CI, 1.5–9.3; P = 0.005), compared with a 24 pack-year history for late-onset current clinical asthma (odds ratio, 2.6; 95% CI, 1.03–6.5; P = 0.042). An interaction (multiplicative effect) was present between asthma and active smoking as it relates to the ratio of post-bronchodilator FEV1/FVC, but only among those with atopic sensitization.

Conclusions: Active smoking and current clinical asthma both contribute substantially to fixed AO in middle age, especially among those with atopy. The interaction between these factors provides another compelling reason for atopic individuals with current asthma who smoke to quit.

Scientific Knowledge on the Subject

People with asthma who smoke are predisposed to poorly controlled asthma and developing chronic obstructive pulmonary disease (COPD). However, the relative and combined impacts of lifetime asthma, active smoking, and atopic sensitization on adult lung function are not well defined.

What This Study Adds to the Field

This study describes a three-way interaction between the effects of asthma, active smoking, and atopy on the fixed airflow obstruction measure that is used to define COPD. This synergy, which largely affects atopic ever-smokers who have current asthma, supports a role for asthma in the development of COPD and strengthens the public health recommendation for people with asthma who smoke to quit.

Obstructive lung diseases are major global health problems, with asthma and chronic obstructive pulmonary disease (COPD) being the two main contributors. COPD that is characterized by fixed post-bronchodilator (BD) airflow obstruction (AO) is currently the fourth leading cause of death worldwide (1). Asthma is not a major cause of death, but it contributes substantially to morbidity and health care expenditure (2, 3). Prevalence estimates for asthma (4) and COPD (5, 6) have varied considerably between countries, where accurate estimates for COPD are important in anticipating its future disease burden.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has previously considered asthma to be a differential diagnosis of COPD and currently asserts that evidence for a causative role is not conclusive (7, 8). Nevertheless, physician-diagnosed asthma with current symptoms at age 22 years has been linked to reduced post-BD FEV1/FVC levels in early adulthood. This link was only seen for those whose asthma was first diagnosed after the age of 16 years or for those diagnosed with asthma earlier who used prescription medication during the previous year (9). In another asthma cohort aged 13 to 44 years and followed for 26 years, around one in six developed a reduced pre-BD FEV1 that improved by less than 9% predicted after BD use (10). Conversely, active cigarette smoking is well known for its role in the development of COPD in susceptible individuals and can predispose those with asthma to poorer symptom control (11).

Some studies have investigated the impact of two-way interactions between the effects of asthma and active smoking as well as atopy on longitudinal and cross-sectional measures of lung function. An interaction between airway hyperresponsiveness and smoking status as it relates to the decline of post-BD FEV1 has been described (12). However, this multiplicative effect was not seen when measures such as self-reported asthma and pre-BD FEV1 were used (13, 14). The European Community Respiratory Health Survey has reported an interaction between the effects of atopy and smoking on pre-BD FEV1 levels independent of asthma status (15). On the other hand, the European Community Respiratory Health Survey has also reported the effect of an interaction between atopy and current asthma on FEV1 and FEV1/FVC levels while adjusting for smoking status (16). These results raise the possibility of a three-way interaction between the effects of current asthma, smoking, and atopy on adult lung function. However, these interactions may have been confounded by preexisting reduced lung function (1719) in addition to the misclassification of “forgotten” childhood asthma (20).

We aimed first to determine the prevalence of abnormal lung function measures and phenotypes of fixed AO in a middle-aged population and, second, to investigate the relative contributions and any potential interactions between lifelong asthma, active smoking, and atopy on these measures and phenotypes, while adjusting for childhood lung function. Some of the results of these analyses have been previously reported in the form of conference abstracts (2124).

Study Design and Population

The study participants were those attending the laboratory study of the fifth decade follow-up of the Tasmanian Longitudinal Health Study (TAHS), details of which have been published elsewhere (2528). This is summarized in Figure 1. Briefly, the cohort of children born in 1961 (n = 8,583) and schooling in Tasmania in 1968 were studied with surveys and pre-BD spirometry. This cohort was retraced and resurveyed from 2002 to 2005. A sample of respondents enriched for asthma and chronic bronchitis participated in a laboratory study from 2006 to 2008, which included a questionnaire, pre- and post-BD spirometry, skin prick testing, lung volumes, and diffusing capacity measurements (see Methods E1 and Table E1 in the online supplement).

Data Collection Methods

Lung function tests, including pre- and post-BD spirometry, single breath diffusing capacity (DlCO), and lung volume measurements, were conducted according to the joint American Thoracic Society and European Respiratory Society criteria (2931). The predicted values for spirometry, DlCO, and lung volumes, as well as spirometry from 1968 were derived from the reference equations by Hankinson and colleagues (32), Thompson and colleagues (33), Quanjer and colleagues (34), and Stanojevic and colleagues (35), respectively. Skin prick testing to eight aeroallergens was also performed. Additional details are outlined in Methods E1 and E2.

Clinical Definitions

Early-onset asthma was defined as the presence of asthma or “wheezy breathing” reported at the 1968 and/or 1974 surveys; the parental answer was used preferentially to the answer provided by the participants in the 2004 and 2006 surveys. Late-onset asthma was defined as a participant-recalled asthma history starting after 20 years of age. Current clinical asthma was defined by asthma-related symptoms and/or healthcare access for asthma within the last 12 months. Atopy was defined by positive skin sensitivity to one or more of eight allergen extracts, where positivity equaled a wheal size greater than or equal to 3 mm larger than the negative control.

Abnormal lung function categories, such as low DlCO and high TLC, were defined using the statistical upper and lower limits of normal of nominated reference equations (2931). Fixed AO, or AO that was not fully reversible, was defined as post-BD FEV1/FVC less than the lower limit of normal, regardless of BD reversibility. Fixed small AO was defined as post-BD forced expiratory flow between 25% and 75% of the FVC (FEF25–75%) less than the lower limit of normal plus normal FVC but without fixed AO.

Statistical Analysis

Prevalence was calculated using the survey design for dataset function. Prevalence and 95% confidence intervals (CI) of the entire TAHS population was extrapolated back from the observed prevalence by reweighting the known sampling fractions derived from the 1968, 1974, and 2004 surveys.

Multiple linear and logistic regression was used to evaluate the relative and combined associations between active smoking, asthma, and atopy on lung function measures (continuous data) and phenotypes of fixed AO (categorical data), respectively. A linear relationship between pack-years and lung function was confirmed (Methods E3). Pre-BD FEV1 percent predicted at age 7 years that was expressed as a continuous variable, atopy, sampling weights, sex, current occupation, passive smoking, and family history of obstructive lung disease were included in the models as a priori confounders. Education, heating, and cooking were only retained if their inclusion changed the estimates by more than 10%.

All analyses were performed using the statistical software Stata (release 11, Stata Corporation, College Station, TX). A conventional cut-off of P < 0.05 was used to determine statistical significance.

Ethics

The study was approved by the Human Ethics Review Committees at The Universities of Melbourne, Tasmania, and New South Wales, the Alfred Hospital, and Royal Brisbane and Women’s Hospital Health Service District. Written informed consent was obtained from all participants.

Demographic, Clinical, and Lung Function Features

The clinical and lung function data of the 1,389 who participated in the laboratory study are summarized in Table 1.

TABLE 1. CLINICAL CHARACTERISTICS AND LUNG FUNCTION DATA FROM THE LABORATORY STUDY (2006–2008)*

Men (N = 709)Women (N = 680)
Age, yr44.8 (0.8)44.9 (0.8)
BMI, kg/m228 (4.3)28 (6.5)
Smoking history
 Never, n (%)302 (43)284 (42)
 Former, n (%)198 (28)203 (30)
  Pack-years, median (IQR)9.3 (2.1–19)5.5 (1.8–14)
 Current, n (%)203 (29)172 (25)
  Pack-years, median (IQR)25 (14–35)18 (8.6– 26)
Lifetime asthma, n (%)
 Never231 (33)210 (31)
 Remitted322 (45)268 (39)
 Current clinical
  Early-onset108 (15)110 (16)
  Late-onset33 (5)84 (12)
 Previous ICS use64 (9)87 (13)
  Current ICS use33 (5)54 (9)
 Family history400 (57)476 (70)
Atopy, n (%)416 (59)352 (52)
Post-BD spirometry
 n (%)685 (97)645 (95)
 FEV1, L3.9 (0.6)2.9 (0.5)
  % Predicted97 (13)98 (14)
 FVC, L5.0 (0.7)3.7 (0.5)
  % Predicted98 (12)99 (12)
 FEF25–75%, L/s3.6 (1.1)2.9 (0.9)
  % Predicted98 (29)98 (30)
 FEV1/FVC0.78 (0.07)0.79 (0.07)
  % Predicted99 (8.6)98 (8.6)
  Predicted LLN0.69 (0.002)0.71 (0.002)
FEV1 BD-reversibility
 n (%)671 (95)645 (95)
  Δ ml143 (182)104 (126)
  % Δ from baseline4.2 (6.1)4.1 (5.7)
Single breath DlCO
 n (%)570 (80)554 (81)
  mmol/min/kPa10.4 (1.8)7.9 (1.5)
  ml/min/mm Hg31.0 (5.5)23.6 (4.5)
  % Predicted104 (17)102 (18)
Lung volumes
 n (%)629 (89)592 (87)
 TLC, L7.3 (1.1)5.5 (0.8)
  % Predicted105 (13)110 (13)
 Residual volume, L2.1 (0.7)1.8 (0.5)
  % Predicted102 (33)105 (29)
 RV/TLC ratio, %28 (6.9)31 (7.2)

Definition of abbreviations: BMI = body mass index; DlCO = diffusing capacity of the lung for carbon monoxide; FEF25–75% = forced expiratory flow between 25% and 75% of the FVC; ICS = inhaled corticosteroid; IQR = interquartile range; LLN = lower limit of normal; post-BD = post-bronchodilator; RV = residual volume; SPT, skin prick tests.

Data are expressed as mean (SD) unless otherwise indicated.

*Complete data were obtained in 1,362 (98%) for smoking, 1,366 (98%) for asthma, 1,384 (100%) for atopy, 1,273 (92%) for current ICS use. Numbers with technically acceptable lung function results are indicated in italics.

The LLN represents the fifth percentile or 1.645 SD below the predicted mean of values derived from reference equations (32).

Values were adjusted to a standard hemoglobin concentration and corrected for the presence of carboxyhemoglobin.

Nine hundred twenty-five (67%) participants reported ever having asthma, of whom 335 (36%) had current clinical asthma. Among those with current clinical asthma, 218 (65%) and 117 (35%) had early-onset and late-onset asthma, respectively. The median [interquartile range] asthma duration for the corresponding groups was 42 [39–43] years for early-onset and 14 [6.2–21] years for late-onset current clinical asthma. There was a female predominance in the late-onset group. Atopy was present in 82% of those with early-onset and 47 to 54% with late-onset current clinical asthma (Tables E2 and E3).

More than one-half (57%) of those attending were ever-smokers, and 9.5% (n = 130) had a smoking history of at least 30 pack-years. Almost one-half (48%, n = 89) of the ever-smokers with current clinical asthma were current smokers.

Technically acceptable post-BD spirometry was obtained from 1,330 (96%) participants. Of these, 131 (10%) had fixed AO, for whom the mean (SD) FEV1/FVC was 0.64 (0.06), and the mean FEV1 was 80.8 (14.2) % predicted. A total of 1,021 (73%) participants had complete lung function and skin prick test data. The majority (n = 1,148 [83%]) had valid pre-BD FEV1 values from 1968.

Reweighted Population Prevalence

The prevalence of fixed AO adjusted for the entire TAHS cohort was 6.0% (95% CI, 4.5–7.5), with no significant difference by sex (Figure 2; Table E4). When adopting the GOLD criteria definition for COPD stages II to IV that specify an FEV1 less than 80% of the predicted value (5), the prevalence for fixed AO was significantly less (1.8%; 95% CI, 0.9–2.6), again with no difference by sex.

Fixed AO Measures

We observed a two-way interaction (multiplicative effect) between the effects of active smoking and asthma on post-BD FEV1/FVC levels, but only for those with atopic sensitization (P value for three-way interaction = 0.0495) (Table 2). In other words, subjects with current clinical asthma with atopy who smoked more than the median value had reductions in post-BD FEV1/FVC levels that were greater than the individual smoking and asthma associations combined, such that the difference was attributable to the asthma–smoking interaction itself. The combined effect was additive among those without atopy.

TABLE 2. INTERACTION BETWEEN EFFECTS OF ASTHMA AND SMOKING ON POST-BRONCHODILATOR FEV1/FVC LEVELS, STRATIFIED BY ATOPY

Atopy Status (N = 1,009)
Nonatopic (N = 443)
Atopic (N = 566)
Asthma PatternActive Smoking (Pack-Years)*n (%)Post-BD FEV1/FVC % Predicted (95% CI)n (%)Post-BD FEV1/FVC % Predicted (95% CI)
No asthma<0.9197 (22)96 (92 to 100)72 (13)97 (92 to 101)
≥0.9197 (22)−1.4 (−2.3 to −0.5)64 (11)+0.4 (−0.6 to +1.4)
Remitted asthma (any age of onset)<0.9179 (18)+0.3 (−1.9 to +2.5)143 (25)−0.2 (−2.8 to +2.4)
≥0.9196 (22)−0.6 (−3.0 to +1.8)118 (21)−1.6 (−4.2 to +1.1)
Early-onset current clinical asthma<0.919 (2)−1.9 (−5.5 to +1.7)80 (14)−5.7 (−8.6 to −2.8)§
≥0.9118 (4)−4.0 (−7.6 to −0.3)47 (8)−8.4 (−12 to −5.1)§
Late-onset current clinical asthma<0.9118 (4)−1.5 (−4.3 to +1.3)21 (4)−5.4 (−8.7 to −2.1)
≥0.9129 (7)−4.0 (−6.9 to −1.1)21 (4)−8.2 (−12 to −4.1)§
Asthma–smoking interactionP = 0.187P < 0.001

Definition of abbreviations: BD = bronchodilator; CI = confidence interval.

Multivariable-adjusted model includes sampling weights, sex, current occupation, passive smoking, family history of obstructive lung disease, and the interaction term active smoking × lifelong asthma pattern stratified by atopy (n = 1,236, Table E3); plus pre-BD FEV1 percent predicted at age 7 years (n = 1,009).

*Median smoking history was 0.91 pack-years.

Values expressed as baseline % predicted (95% CI) followed by reduction in % predicted from baseline (95% CI) unless otherwise indicated.

P < 0.01.

§P < 0.001.

P < 0.05.

A similar asthma–smoking interaction was seen in the atopic subgroup for both post-BD FEF25–75% (P = 0.003) and post-BD FEV1 levels (P = 0.007) but not BD reversibility (P = 0.090), DlCO (P = 0.060), or TLC levels (P = 0.904).

Fixed AO Phenotypes

Fixed AO was independently associated with active smoking and current clinical asthma but not with atopy itself. Table 3 (Model 1) shows the estimate for the association between early-onset current clinical asthma and fixed AO, unadjusted for atopy and pre-BD FEV1 at age 7 years. When atopy was added to the model, this estimate was reduced by 22% and was further reduced by 14% when pre-BD FEV1 at age 7 years was added subsequently. This fully adjusted estimate for early-onset current clinical asthma was equivalent to a lifetime smoking history of 33 (95% CI, 26–40) pack-years. The association between late-onset current clinical asthma and fixed AO was equivalent to a lifetime smoking history of 24 (95% CI, 15–33) pack-years.

TABLE 3. INDEPENDENT ASSOCIATIONS BETWEEN LIFETIME ASTHMA PATTERNS, ATOPY, ACTIVE SMOKING, AND FIXED AIRFLOW OBSTRUCTION IN MIDDLE AGE

Fixed Airflow Obstruction, OR (95% CI)
Model 1 (N = 114)Model 2 (N = 113)Model 3 (N = 100)
Lifetime asthma pattern
 No asthma111
 Remitted asthma0.9 (0.4–2.0)0.8 (0.4–1.8)0.9 (0.4–2.0)
 Early-onset current clinical asthma5.5 (2.4–12)*4.3 (1.9–9.8)3.7 (1.5–9.3)
 Late-onset current clinical asthma2.7 (1.2–6.2)2.6 (1.1–5.9)2.6 (1.03–6.5)
Atopy1.7 (1.1–2.8)1.5 (0.9–2.5)
Active smoking, per 10 pack-year increments1.5 (1.3–1.8)*1.5 (1.3–1.8)*1.5 (1.3–1.7)*

Definition of abbreviations: CI = confidence interval; OR = odds ratio.

Reference group = nonatopic nonsmokers without asthma. Multivariable-adjusted models. Model 1 includes sampling weights, sex, lifetime asthma pattern, active smoking history, current passive smoking history, current occupation, and family history of obstructive lung disease, with 25, 24, 48, and 17 cases for the corresponding subgroups: no asthma, remitted asthma, early-onset current clinical asthma, and late-onset current clinical asthma, respectively. Model 2 = Model 1 plus atopy. Model 3 = Model 1 plus atopy and pre-BD FEV1 percent predicted at age 7 years. Regression totals were n = 1,049, n = 1,043, and n = 859 for Models 1–3, respectively.

*P < 0.001.

P < 0.01.

P < 0.05.

To compare the strengths of association for early-onset and late-onset current clinical asthma while taking the duration of the diseases into account, these pack-year equivalents were divided by the median asthma duration for each group. For early-onset current clinical asthma, this was equivalent to smoking 0.8 packs of cigarettes daily, in contrast to smoking 1.7 packs daily for the late-onset group. The pack-year equivalents increased when the data were reanalyzed using a cross-sectional or retrospective study design; that is, the participant-recalled asthma history from the present survey was used preferentially to the parental answer obtained from the 1968 and 1974 surveys. For those with current asthmatic symptoms who in middle age recalled a childhood asthma history, the equivalent association with fixed AO was 42 (32–52) pack-years (Table E5).

Significant relationships were seen between active smoking and fixed AO, as well as fixed AO in the presence of coexistent low DlCO or high TLC (Table 4). When using categorical data (unlike with continuous lung function data observed before), an interaction between smoking, asthma, and atopy was not present among the 10% of participants who fulfilled the formal criteria for fixed AO.

TABLE 4. ACTIVE SMOKING AND PHENOTYPES OF FIXED AIRFLOW OBSTRUCTION

Lifetime active smoking, pack-years
Regression Total, NNumber of Cases, n (% N)Median pack-years (IQR)Per 10 pack-year Increments, OR (95% CI)
Fixed airflow obstruction
Per se*859100 (12)14 (0–27)1.5 (1.3–1.7)
 Plus low DlCO51713 (3)23 (21–45)2.8 (1.5–5.1)
 Plus high TLC61324 (4)18 (0–38)1.3 (1.02–1.7)§

Definition of abbreviations: AO = airflow obstruction; CI = confidence interval; DlCO = diffusing capacity of the lung for carbon monoxide; IQR = interquartile range; OR = odds ratio.

Control definition was normal pre- and post-BD spirometry including FEF25–75% levels. The fixed AO plus low DlCO phenotype includes additional cases with fixed small AO, normal FVC, plus low DlCO.

*Derived from the multivariable-adjusted regression Model 3, from Table 3.

P < 0.001.

P = 0.001.

§P = 0.030.

This is the first longitudinal population-based study to integrate lifetime histories of active smoking and asthma, objective measures of atopic sensitization, and comprehensively documented lung function phenotypes using spirometry, DlCO, and lung volumes in middle age. The association between current clinical asthma and having fixed AO in middle age was found to be equivalent to a smoking history of 33 and 24 pack-years for early-onset and late-onset current clinical asthma, respectively. We also identified the effects of novel interactions between lifetime active smoking and asthma on multiple measures of fixed AO, but only among those with atopic sensitization.

Using the lower limit of normal for the post-BD FEV1/FVC ratio, we estimated the prevalence of fixed AO to be 6.0%. For subjects aged in their forties and of average height, this cut-off closely approximated the FEV1/FVC ratio of less than 0.70 used by the GOLD guidelines to define COPD (8, 35). Using the GOLD definition, the prevalence of fixed AO described in the Latin American Project for the Investigation of Obstructive Lung Disease (PLATINO) study was generally higher, most likely because the PLATINO study included older individuals (6). Conversely, The Burden of Lung Disease (BOLD) Initiative reported age and sex-specific estimates for 12 international sites using the GOLD stages II to IV definition in which the FEV1 was specified to be less than 80% of the predicted value (5). Using this exact BOLD definition, our prevalence estimates were comparable with those for the 40- to 49-year-old age group in the BOLD study in most sites.

The association between childhood-onset asthma continuing into adulthood and fixed AO was reported to confer a similar risk to a smoking history equivalent to 62 pack-years by a recent cross-sectional study from New Zealand (36), whereas our estimate for that association was less, at 33 (95% CI, 26–40) pack-years. Three main reasons may explain the difference. First, our study was able to adjust for the confounding effects of atopy and childhood lung function. Second, cross-sectional studies use retrospective self-assessment of childhood asthma, and we have previously shown that adults with milder remitted disease commonly misclassify themselves to be in either the control or late-onset group (20), thereby self-selecting participants with more severe current asthma to be in the active group. Third, older participants took part in the New Zealand study, with 89% of those with COPD being older than 50 years of age.

Although our study has estimated the association between lifetime asthma and lung function in middle age, we did not have the information to determine when during the course of the asthma history the loss in lung function occurred. Our findings on the association between childhood asthma and reduced post-BD lung function in adulthood being largely related to the presence of “current clinical asthma” as opposed to remitted asthma are consistent with the Tucson Children’s Respiratory Study (9). This would imply that having asthma per se in childhood is not as important for adult lung function as the persistence of active asthma. A similar observation was seen for those with current asthma symptoms but with an asthma diagnosis after 20 years of age in our study. Although the strength of the association between late-onset current clinical asthma and fixed AO was lower than for early-onset current clinical asthma, the higher daily pack-year equivalent since age of diagnosis was consistent with other data that have shown subjects with late-onset asthma having worse lung function despite a shorter duration of disease (37).

Smokers with asthma have increased asthma symptoms compared with nonsmokers with asthma (11). This may be because smoking further increases bronchial hyperreactivity (38) and/or because it decreases the efficacy of inhaled corticosteroids (39). Consistent with this biological plausibility, we detected the effect of a two-way asthma–smoking interaction on multiple measures of fixed AO, where the combined effect of asthma and active smoking differed with the presence of atopy. This three-way interaction is a novel finding. In essence, this indicates that an atopic middle-aged smoker with current asthma who decided to quit smoking would benefit not only from ending the smoking effect but also from any future effect derived from the asthma–smoking interaction, and this might be relevant to individuals without atopy to a lesser extent (Table E3). This specific interplay between asthma, smoking, and atopy that relates to post-BD FEV1/FVC levels may in part explain the considerable variation seen in the natural course of COPD (40).

Atopy and airway hyperreactivity may be considered as host factors that are individually expressed through their interaction with specific lifetime environmental stimuli that can vary from one generation to the next (41, 42). These environmental exposures include allergens, active and passive smoking, and suppurative lung infections. In contrast to cross-sectional studies, prospective cohort studies measuring these factors at multiple appropriate time points can effectively examine the time sequence of asthma onset and lung function decline.

Reduced (pre-BD) lung function and increased bronchial hyperresponsiveness that is detected shortly after birth have been linked to the subsequent expression of clinical asthma in children (43, 44). This observation highlights the possibility of reverse causation of the association between childhood-onset asthma and adult fixed obstructive lung disease observed in our study. We were able to adjust for childhood pre-BD FEV1 levels when aged 7 years, which is relevant to subjects with asthma whose lung function levels have been shown to be largely established by the age of 6 years (17, 45, 46). However, we do not have information on post-BD FEV1 levels in childhood, which is the more relevant confounder of the association between childhood asthma and fixed AO in middle age. Thus, our study cannot provide a definitive answer to the time sequence relating childhood asthma to the development of fixed AO in later life.

However, our prospective study design has enabled a more accurate classification of early-onset and late-onset asthma than studies that used retrospective recall or self-reported history in adulthood (1316, 36). We have previously shown that young adults are frequently inaccurate when recalling their childhood asthma history, and this recall bias was particularly relevant to women (20). This may in part explain the associations between female sex, low FEV1, and new adult-onset asthma described by Antó and colleagues (47), wherein the recurrence of “forgotten childhood asthma/wheezy breathing” as a clinical disease in adulthood may have been a confounder.

Our use of DlCO and lung volume measurements provided some important findings. Almost 20% of our cases with fixed AO had coexistent low DlCO, and the combination suggests the presence of emphysema. In a population setting, the use of high-resolution computerized tomography lung density measurements, in isolation, has not been shown to be useful in detecting clinical emphysema (48), thereby supporting the need for a physiological definition in population-based studies.

There are three main strengths of our study. First, the use of sampling weights allowed the calculation of prevalence estimates of each of the lung function phenotypes for the entire TAHS population. Second, the prospective documentation of asthma from 1968, when study subjects were aged 7 years, minimized recall bias and reduced asthma misclassification (20). This also facilitated the calculation of asthma duration to determine the estimate size per year since asthma diagnosis. Third, adult smokers with asthma were by design well represented, permitting us to examine interactions between the associations of active smoking and asthma on lung function.

In terms of limitations, the present study was designed to investigate the role of lifetime asthma and lifetime smoking on having the phenotypes of fixed AO at an age when COPD was starting to emerge, rather than addressing causation of disease. As discussed above, the progression of fixed AO, which is COPD, could not be adequately assessed due to the absence of post-BD measurements in childhood. The participation rate in our laboratory study was modest, although the 59% of invited survey respondents who underwent spirometry with 43% completing all lung function tests compares well with the Australian BOLD study, in which only 33% of those who were contacted and eligible participated (5). Our laboratory attendees, enriched for asthma and symptomatic chronic bronchitis, had similar clinical profiles regardless of completion of all lung function testing and comparable proportions of smokers to laboratory nonattendees (Table E1). Additionally, although linear regression analyzed continuous data from all participants, logistic regression analyzed categorical data that compared normal and abnormal lung function. As a result, the reduced power for the relatively small numbers of cases outside the limits of normality may have precluded the detection of some associations or interactions.

It is important to note that although inhaled corticosteroids have been proven useful in the treatment of asthma since the early 1970s, their widespread addition to oral corticosteroid use in clinical practice occurred some years later (49). Similar to other studies (10, 17), our risk estimates for the TAHS cohort born in 1961 therefore reflect, in part, a period before the widespread availability of inhaled corticosteroids. Given that the study participants were almost exclusively European in ethnicity, and the high asthma prevalence (4) and mortality rates of Australia and New Zealand by international standards (50), these factors may potentially limit the generalizability of our data to other populations.

Conclusions

This prospective cohort study has used comprehensive clinical details and lung function measurements to determine the phenotype prevalence of fixed AO in a large population-based cohort. Active smoking and early-onset and late-onset current clinical asthma were each found to contribute substantially to having fixed AO in middle age. There was no independent association between atopy and fixed AO, but we demonstrated a synergistic effect between active smoking and asthma that varied with atopic status. Evidence of this three-way interaction was manifest as an extra source of fixed AO in atopic smokers with current clinical asthma, in whom reduced post-BD FEV1/FVC levels are integral to the definition of COPD. For atopic subjects with current asthma who smoke, these findings provide another compelling reason to quit, warranting greater emphasis in public health campaigns and clinical practice guidelines.

We acknowledge the Tasmanian Longitudinal Health Study (TAHS) participants and previous investigators. We thank Mark Jenkins, Ph.D., Centre for MEGA Epidemiology, Victoria, who is a TAHS investigator but not a coauthor of this manuscript, for his assistance with obtaining funds and data collection. Furthermore, we acknowledge all the respiratory scientists who collected data in the lung function laboratories of Tasmania, Victoria, Queensland, and New South Wales; the research interviewers and data entry operators; and the organizational roles of Ms. Cathryn Wharton and Dr. Desiree Mészáros. The Archives Office of Tasmania provided data from the 1968 and 1974 TAHS questionnaires and copies of the school medical records.

1. World Health Organization. The top 10 causes of death. Fact sheet n°310. The 10 leading causes of death by broad income group. 2008 [updated 2011 Jun; accessed 2012 Jul 25]. Available from: www.who.int/mediacentre/factsheets/fs310/en/index.html
2. Morbidity and Mortality: 2009 Chart Book on Cardiovascular, Lung and Blood Diseases. National Institutes of Health National Heart, Lung and Blood Institute. Bethesda, MD: US Department of Health and Human Services, Public Health Service; 2009.
3. Australian Institute of Health and Welfare. Asthma, chronic obstructive pulmonary disease and other respiratory diseases in Australia. Cat. no. ACM 20. Canberra: AIHW; 2010.
4. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet 1998;351:12251232.
5. Buist AS, McBurnie MA, Vollmer WM, Gillespie S, Burney P, Mannino DM, Menezes AM, Sullivan SD, Lee TA, Weiss KB, et al.. International variation in the prevalence of COPD (the BOLD study): a population-based prevalence study. Lancet 2007;370:741750.
6. Menezes AM, Perez-Padilla R, Jardim JR, Muiño A, Lopez MV, Valdivia G, Montes de Oca M, Talamo C, Hallal PC, Victora CG. Chronic obstructive pulmonary disease in five Latin American cities (the PLATINO study): a prevalence study. Lancet 2005;366:18751881.
7. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease [revised 2011; accessed 2012 Mar 14]. Available from: http://www.goldcopd.org/uploads/users/files/GOLD_Report_2011_Jan21.pdf
8. Global Initiative for Chronic Obstructive Lung Disease (GOLD). At-a-glance outpatient management reference for chronic obstructive pulmonary disease (COPD). Based on the global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: revised 2011 [accessed 2012 Sep 13]. Available from: http://www.goldcopd.org/uploads/users/files/GOLD_AtAGlance_2011_Jan18.pdf
9. Stern DA, Morgan WJ, Halonen M, Wright AL, Martinez FD. Wheezing and bronchial hyper-responsiveness in early childhood as predictors of newly diagnosed asthma in early adulthood: a longitudinal birth-cohort study. Lancet 2008;372:10581064.
10. Vonk JM, Jongepier H, Panhuysen CI, Schouten JP, Bleecker ER, Postma DS. Risk factors associated with the presence of irreversible airflow limitation and reduced transfer coefficient in patients with asthma after 26 years of follow up. Thorax 2003;58:322327.
11. Thomson NC, Chaudhuri R. Asthma in smokers: challenges and opportunities. Curr Opin Pulm Med 2009;15:3945.
12. Tashkin DP, Altose MD, Connett JE, Kanner RE, Lee WW, Wise RA. Methacholine reactivity predicts changes in lung function over time in smokers with early chronic obstructive pulmonary disease. The Lung Health Study Research Group. Am J Respir Crit Care Med 1996;153:18021811.
13. Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med 1998;339:11941200.
14. James AL, Palmer LJ, Kicic E, Maxwell PS, Lagan SE, Ryan GF, Musk AW. Decline in lung function in the Busselton Health Study: the effects of asthma and cigarette smoking. Am J Respir Crit Care Med 2005;171:109114.
15. Sunyer J, Soriano J, Antó JM, Burgos F, Pereira A, Payo F, Martinez-Moratalla J, Ramos J. Sensitization to individual allergens as risk factors for lower FEV1 in young adults. European Community Respiratory Health Survey. Int J Epidemiol 2000;29:125130.
16. Jaén A, Sunyer J, Basagaña X, Chinn S, Zock JP, Antó JM, Burney P. Specific sensitization to common allergens and pulmonary function in the European Community Respiratory Health Survey. Clin Exp Allergy 2002;32:17131719.
17. Phelan PD, Robertson CF, Olinsky A. The Melbourne Asthma Study: 1964–1999. J Allergy Clin Immunol 2002;109:189194.
18. Stern DA, Morgan WJ, Wright AL, Guerra S, Martinez FD. Poor airway function in early infancy and lung function by age 22 years: a non-selective longitudinal cohort study. Lancet 2007;370:758764.
19. Kalhan R, Arynchyn A, Colangelo LA, Dransfield MT, Gerald LB, Smith LJ. Lung function in young adults predicts airflow obstruction 20 years later. Am J Med 2010;123:468.e1–7.
20. Burgess JA, Walters EH, Byrnes GB, Wharton C, Jenkins MA, Abramson MJ, Hopper JL, Dharmage SC. Who remembers whether they had asthma as children? J Asthma 2006;43:727730.
21. Perret JL, Walters EH, Matheson MC, Gurrin LC, Burgess JA, Morrison S, Thomas PS, Marrone J, McDonald CF, Wood-Baker R, et al.. The prevalence of emphysema is significantly less than chronic obstructive pulmonary disease [abstract]. Respirology 2012;17:TO104.
22. Perret JL, Dharmage SC, Matheson MC, Gurrin LC, Burgess JA, McDonald CF, Morrison S, Thomas PS, Marrone J, Wood-Baker R, et al.. Interactions are present between active smoking and asthma on risk of large and small airways obstruction [abstract]. Respirology 2012;17:TO103.
23. Perret JL, Walters EH, Matheson MC, Marrone J, Mészáros D, McDonald CF, Thomas PS, Abramson MJ, Johns DP, Dharmage SC. Females have lower diffusing capacity than males, with and without correction for alveolar volume [abstract]. Respirology 2011;16:TP158.
24. Perret JL, Dharmage SC, Matheson MC, Marrone J, Mészáros D, McDonald CF, Thomas PS, Johns DP, Abramson MJ, Walters EH. Spirometry alone misses some abnormal lung function phenotypes in adults [abstract]. Respirology 2011;16:TP157.
25. Gibson HB, Silverstone H, Gandevia B, Hall GJ. Respiratory disorders in seven-year-old children in Tasmania. Aims, methods and administration of the survey. Med J Aust 1969;2:201205.
26. Giles GG, Lickiss N, Gibson HB, Shaw K. Respiratory symptoms in Tasmanian adolescents: a follow up of the 1961 birth cohort. Aust N Z J Med 1984;14:631637.
27. Jenkins MA, Hopper JL, Bowes G, Carlin JB, Flander LB, Giles GG. Factors in childhood as predictors of asthma in adult life. BMJ 1994;309:9093.
28. Wharton C, Dharmage S, Jenkins M, Dite G, Hopper J, Giles G, Abramson M, Walters EH. Tracing 8,600 participants 36 years after recruitment at age seven for the Tasmanian Asthma Study. Aust N Z J Public Health 2006;30:105110.
29. Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F, Casaburi R, Crapo R, Enright P, van der Grinten CP, et al.. Standardisation of the measurement of lung volumes. Eur Respir J 2005;26:511522.
30. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, et al.. Standardisation of spirometry. Eur Respir J 2005;26:319338.
31. Macintyre N, Crapo RO, Viegi G, Johnson DC, van der Grinten CP, Brusasco V, Burgos F, Casaburi R, Coates A, Enright P, et al.. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J 2005;26:720735.
32. Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general US population. Am J Respir Crit Care Med 1999;159:179187.
33. Thompson BR, Johns DP, Bailey M, Raven J, Walters EH, Abramson MJ. Prediction equations for single breath diffusing capacity (Tlco) in a middle aged caucasian population. Thorax 2008;63:889893.
34. Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J Suppl 1993;16:540.
35. Stanojevic S, Wade A, Stocks J, Hankinson J, Coates AL, Pan H, Rosenthal M, Corey M, Lebecque P, Cole TJ. Reference ranges for spirometry across all ages: a new approach. Am J Respir Crit Care Med 2008;177:253260.
36. Shirtcliffe P, Marsh S, Travers J, Weatherall M, Beasley R. Childhood asthma and GOLD-defined chronic obstructive pulmonary disease. Intern Med J 2012;42:8388.
37. Miranda C, Busacker A, Balzar S, Trudeau J, Wenzel SE. Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation. J Allergy Clin Immunol 2004;113:101108.
38. Chinn S, Jarvis D, Luczynska CM, Ackermann-Liebrich U, Anto JM, Cerveri I, de Marco R, Gislason T, Heinrich J, Janson C, et al.. An increase in bronchial responsiveness is associated with continuing or restarting smoking. Am J Respir Crit Care Med 2005;172:956961.
39. Lazarus SC, Chinchilli VM, Rollings NJ, Boushey HA, Cherniack R, Craig TJ, Deykin A, DiMango E, Fish JE, Ford JG, et al.. Smoking affects response to inhaled corticosteroids or leukotriene receptor antagonists in asthma. Am J Respir Crit Care Med 2007;175:783790.
40. Vestbo J, Edwards LD, Scanlon PD, Yates JC, Agusti A, Bakke P, Calverley PM, Celli B, Coxson HO, Crim C, et al.. Changes in forced expiratory volume in 1 second over time in COPD. N Engl J Med 2011;365:11841192.
41. Postma DS, Kerkhof M, Boezen HM, Koppelman GH. Asthma and chronic obstructive pulmonary disease: common genes, common environments? Am J Respir Crit Care Med 2011;183:15881594.
42. Orie NG. The Dutch hypothesis. Chest 2000;117:299S.
43. Håland G, Carlsen KC, Sandvik L, Devulapalli CS, Munthe-Kaas MC, Pettersen M, Carlsen KH. Reduced lung function at birth and the risk of asthma at 10 years of age. N Engl J Med 2006;355:16821689.
44. Bisgaard H, Jensen SM, Bonnelykke K. Interaction between asthma and lung function growth in early life. Am J Respir Crit Care Med 2012;185:11831189.
45. Morgan WJ, Stern DA, Sherrill DL, Guerra S, Holberg CJ, Guilbert TW, Taussig LM, Wright AL, Martinez FD. Outcome of asthma and wheezing in the first 6 years of life: follow-up through adolescence. Am J Respir Crit Care Med 2005;172:12531258.
46. Horak E, Lanigan A, Roberts M, Welsh L, Wilson J, Carlin JB, Olinsky A, Robertson CF. Longitudinal study of childhood wheezy bronchitis and asthma: outcome at age 42. BMJ 2003;326:422423.
47. Antó JM, Sunyer J, Basagaña X, Garcia-Esteban R, Cerveri I, de Marco R, Heinrich J, Janson C, Jarvis D, Kogevinas M, et al.. Risk factors of new-onset asthma in adults: a population-based international cohort study. Allergy 2010;65:10211030.
48. Marsh S, Aldington S, Williams MV, Nowitz MR, Kingzett-Taylor A, Weatherall M, Shirtcliffe PM, McNaughton AA, Pritchard A, Beasley R. Utility of lung density measurements in the diagnosis of emphysema. Respir Med 2007;101:15121520.
49. Chu EK, Drazen JM. Asthma: one hundred years of treatment and onward. Am J Respir Crit Care Med 2005;171:12021208.
50. Australian Centre for Asthma Monitoring. Asthma in Australia 2008. AIHW Asthma series no. 3. Cat. no. ACM 14. Canberra: AIHW; 2008.
Correspondence and requests for reprints should be addressed to Jennifer L. Perret, M.D., Centre for Molecular, Environmental, Genetic, and Analytical (MEGA) Epidemiology, Melbourne School of Population Health, The University of Melbourne, Level 3, 207 Bouverie Street, Carlton, Victoria 3053, Australia. E-mail:

Supported by the National Health and Medical Research Council of Australia grant 299901; Clifford Craig Medical Research Trust of Tasmania; Victorian, Queensland, and Tasmanian Asthma Foundations; and the Australian Lung Foundation.

Author Contributions: Study concept and design: S.C.D., E.H.W., M.J.A., D.P.J., G.G.G., J.L.H. Acquisition of data: S.C.D., R.W.-B., E.H.W., M.J.A., M.C.M., P.S.T., I.F., J.M., S.M., J.M., D.P.J., J.A.B. Analysis and interpretation of data: J.L.P., S.C.D., C.F.M., L.C.G., M.J.A., E.H.W. Drafting of the manuscript: J.L.P., S.C.D., M.J.A., E.H.W. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: J.L.P., S.C.D. Obtained funding: S.C.D., E.H.W., J.M., S.M., M.J.A., D.P.J., J.L.H. Administrative, technical, and material support: S.C.D. Study supervision: S.C.D., E.H.W., M.C.M., D.P.J., M.J.A.

J.L.P. and S.C.D. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

The funding agencies had no direct role in the conduct of the study, the collection, management, statistical analysis, and interpretation of the data, preparation, or approval of the manuscript.

This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org

Originally Published in Press as DOI: 10.1164/rccm.201205-0788OC on November 15, 2012

Author disclosures are available with the text of this article at www.atsjournals.org.

Related

No related items
American Journal of Respiratory and Critical Care Medicine
187
1

Click to see any corrections or updates and to confirm this is the authentic version of record