The authors confirm that Gabriele Nicolini is an employe of the “Chiesi Farmaceutici, Parma, Italy,” one of the commercial funders of this research. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.
Reviewed the manuscript, contributed to its scientific content and approved the final version of it: RdM GP AM SA LA MB LC MF GN MGP PP MEZ IC GV. Conceived and designed the experiments: RdM. Analyzed the data: GP. Wrote the paper: RdM GP AM.
The joint distribution of asthma and chronic obstructive pulmonary disease (COPD)
A screening questionnaire on respiratory symptoms, diagnoses and risk factors was administered by mail or phone to random samples of the general Italian population aged 20–44 (n = 5163) 45–64 (n = 2167) and 65–84 (n = 1030) in the frame of the multicentre Gene Environment Interactions in Respiratory Diseases (GEIRD) study.
A physician diagnosis of asthma or COPD (emphysema/chronic bronchitis/COPD) was reported by 13% and 21% of subjects aged <65 and 65–84 years respectively. Aging was associated with a marked decrease in the prevalence of diagnosed asthma (from 8.2% to 1.6%) and with a marked increase in the prevalence of diagnosed COPD (from 3.3% to 13.3%). The prevalence of the overlap of asthma and COPD was 1.6% (1.3%–2.0%), 2.1% (1.5%–2.8%) and 4.5% (3.2%–5.9%) in the 20–44, 45–64 and 65–84 age groups. Subjects with both asthma and COPD diagnoses were more likely to have respiratory symptoms, physical impairment, and to report hospital admissions compared to asthma or COPD alone (p<0.01). Age, sex, education and smoking showed different and sometimes opposite associations with the three conditions.
Asthma and COPD are common in the general population, and they coexist in a substantial proportion of subjects. The asthma-COPD overlap syndrome represents an important clinical phenotype that deserves more medical attention and further research.
Asthma and chronic obstructive pulmonary disease (COPD) are a major public health problem because of their high and still rising prevalence, their associated morbidity, mortality and socio-economic costs
Although asthma and COPD are different diseases, differential diagnosis is sometimes difficult and may be impossible in some older patients.
The joint epidemiological distribution of asthma and COPD in the general population has not been thoroughly described. One reason is that the presence of the overlap syndrome is often an exclusion criterion in studies investigating either disease alone.
Assessing self-reported -physician-diagnosed -COPD and asthma in large representative samples of the general population is one of the simplest and most affordable methods to estimate the prevalence of these diseases.
In this study we aimed at:
determining the prevalence of the self-reported physician -diagnoses of asthma, COPD and of the asthma-COPD overlap syndrome in representative samples of young, middle-aged and elderly subjects from the general population in Italy;
assessing whether subjects with asthma, COPD and the overlap syndrome diagnoses share common risk factors, and whether these vary with age.
For these purposes the data from the Gene Environment Interaction in Respiratory Diseases (GEIRD) study were used.
GEIRD is a two-stage multicentre study started in 2007.
Centre | Age class (years) | ||
[20–44] | [45–64] | [65–84] | |
Verona | 1746 (67.7%) | 676 (70.1%) | 591 (60.1%) |
Pavia | 966 (37.1%) | 460 (54.9%) | |
Torino | 1206 (54.7%) | 502 (60.2%) | |
Sassari | 1245 (53.0%) | 529 (62.8%) | 439 (44.3%) |
Ethical approval was obtained in each centre from the appropriate institutional review board (
The GEIRD Screening Questionnaire (available on
Based on the answers to the questionnaire, a subject was considered to have a physician diagnosis of:
The self reported physician diagnosis of COPD relied on the knowledge of the terms COPD, chronic bronchitis and emphysema. These are the most widely used terms when Italian doctors give patients a diagnosis of COPD.
The questionnaire also collected information on the presence of the following respiratory symptoms/conditions: wheezing or whistling in the chest in the last 12 months, asthma attacks in the last 12 months, current use of medicines for asthma, allergic rhinitis, chronic bronchitis (cough or phlegm on most days for a minimum of 3 months a year for at least 2 successive years). The dyspnoea scale of Medical Research Council (MRC) was used as a measure of the functional limitation due to breathlessness (grade ≥3: “do you get short of breath walking with other people of your own age on level ground, or do you have to stop for short of breath when walking at own pace on level ground?”)
Gender, age, season when the questionnaire was filled in, type of contact (postal waves and telephone interview) were considered as potential confounders. Moreover, as the centres had different final response rates, the centre-specific cumulative response percentile rank to which subjects had answered was included in the analysis.
Categorical data were summarized as counts with percentages. Comparisons of variables across strata were performed by the Pearson Chi-squared test.
Age-sex adjusted prevalence rates of physician-diagnosed asthma and/or COPD were obtained through a logistic regression model with a dummy indicator of diagnosed asthma and/or COPD as dependent variables and centre, percentile rank of cumulative response, type of contact and season as covariates.
To study the joint distribution of asthma and COPD, a four-level indicator was obtained (0: neither asthma nor COPD; 1: asthma only; 2: asthma and COPD; 3: COPD only). The association of the previous conditions with potential risk factors was studied by fitting a multinomial regression model to the data, using the four-level indicator as the dependent variable, the other potential confounders and risk factors as independent variables. The interaction of age with other independent variables in determining the joint distribution of physician diagnoses of asthma and COPD was tested by likelihood-ratio test including in the regression model an appropriate interaction term.
Statistical analyses were performed with STATA 12.1 (Stata Corp LP, College Station, TX, USA).
The response rate (
The percentage of subjects with either the doctor diagnosis of asthma or COPD (
*Adjusted for season, cumulative percentile rank of response, type of survey (postal waves/telephone) and centre.
The prevalence of the diagnosis of asthma alone almost halved (from 8.2% to 2.9%), while that of COPD alone almost doubled (from 3.3% to 13.3%) every twenty years of age (
Age class | Asthma only %(95%CI) | Asthma+COPD%(95%CI) | COPD only%(95%CI) |
8.2 (7.5–9) | 1.6 (1.3–2) | 3.3 (2.8–3.8) | |
4.9 (4–5.9) | 2.1 (1.5–2.8) | 5.7 (4.7–6.7) | |
2.9 (1.8–4) | 4.5 (3.2–5.9) | 13.3 (11.1–15.5) |
Prevalence (%) with 95% confidence interval (CI).
Among subjects who reported physician-diagnosed asthma, the percentage of the asthma-COPD overlap syndrome was 16%, 30% and 61% in the 20–44, 45–64 and 65–84 age groups, respectively. Conversely, among subjects who reported COPD the percentage of the asthma-COPD overlap syndrome was 33%, 27% and 25% in the three age group, respectively.
Respiratory symptoms, physical limitation (MRC≥3) and hospitalization were statistically significantly increased in subjects with either doctor diagnosed asthma or COPD or both (p<0.001) The risk of having respiratory symptoms or using medicines ranged from a minimum of 5-fold (wheezing) to a maximum of 200-fold (current use of anti-asthmatic drugs) with respect to subjects without a doctor diagnosis (
Respiratory symptoms or conditions | no asthma, no COPD %(95%CI) | asthma only %(95%CI) | asthma+COPD overlap %(95%CI) | COPD only %(95%CI) |
Wheezing | 9.9 (9.2–10.6) | 43.4 (39.2–47.7) | 78.7 (71.3–84.5) | 42.7 (37.6–47.9) |
Asthma attacks | 0.7 (0.5–0.9) | 38.8 (34.6–43.2) | 56.9 (48.7–64.8) | 4.4 (2.7–6.9) |
Antiasthmatic drugs | 0.3 (0.2–0.4) | 29.8 (25.8–34) | 55.4 (47–63.5) | 2 (1.1–3.8) |
Allergic rhinitis | 18.2 (17.3–19.1) | 59.2 (54.9–63.4) | 53.5 (45.5–61.3) | 23.9 (19.7–28.6) |
Cough or phlegm | 10.2 (9.5–10.9) | 23.1 (19.6–26.9) | 61.7 (53.7–69.1) | 54 (48.7–59.2) |
MRC |
3.8 (3.3–4.3) | 9.3 (7.1–12.2) | 38.8 (31.1–47.1) | 20.8 (17–25.2) |
Hospitalizations | 0.4 (0.2–0.5) | 1.1 (0.5–2.4) | 3.1 (1.4–6.7) | 2.5 (1.4–4.5) |
Adjusted for gender, age (class), season, % of answers to the questionnaire, type of survey (postal/telephone), and centre.
MRC: Medical Research Council dyspnea score.
Asthma only | Asthma+COPD | COPD only | |
1 | 1 | 1 | |
females | 0.87 (0.72–1.04) | 1.15 (0.92–1.44) | |
1 | 1 | 1 | |
[45–64] | 1.12 (0.75–1.69) | ||
[65–85] | 1.43 (0.76–2.70) | ||
1 | 1 | 1 | |
current smoker | |||
ex smoker | 0.99 (0.78–1.26) | ||
1 | 1 | 1 | |
high school | 1.26 (0.99–1.6) | ||
college/university | |||
1.00 (0.78–1.27) | 0.91 (0.55–1.50) | 1.30 (0.98–1.73) | |
1 | 1 | 1 | |
frequent | 1.00 (0.78–1.27) | 0.91 (0.55–1.50) | |
constant | 1.57 (0.98–2.50) |
Relative Risk Ratios* (RRR) with 95%CI, with subjects without diagnosed diseases as reference group. Statistically significant associations are shown in bold.
adjusted for all variables presented in this table plus design confounders (season, cumulative percentile rank of response, type of interview, GEIRD centre).
Women were more likely to have the asthma-COPD overlap syndrome compared to men (RR = 1.63; 95%CI: 1.15–2.31). The risk of reporting a diagnosis of asthma only was significantly higher in young (p = 0.001) and highly educated people (p = .002), while the opposite held true for COPD, with or without asthma (
Smoking was significantly associated with both asthma and COPD. Ex-smokers were at a lower risk compared to current smokers, but they had a significantly higher risk of COPD (RR = 1.56; 95%CI:1.16–2.08) and of the COPD-asthma overlap syndrome (RR = 1.56; 95%CI: 1.04–2.35) with respect to non-smokers. Higher levels of heavy traffic near home were significantly associated with a greater risk of having diagnosed COPD. Age did not modify the associations of these risk factors with the diagnoses of asthma, COPD or both.
The main findings of this analysis are:
About 1 out of 8 subjects <65 yrs old and 1 out of 5 subjects aged 65 or more yrs reported a physician diagnosis of asthma or COPD. Aging was associated with a marked decrease in the prevalence of asthma and with a marked increase in the prevalence of COPD. However, the percentage of subjects reporting either diagnosed asthma or COPD or both was almost constant until 65 years of age;
The prevalence of the self-reported physician-diagnosed asthma-COPD “overlap syndrome” in Italy ranged from 1.6% in the 20–44 age class to 4.5% in the 65–84 age class. Subjects with the overlap syndrome had a statistically significantly higher frequency of respiratory symptoms, functional limitation and hospitalization with respect to subjects with the diagnosis of asthma or COPD alone;
Age, sex, education and active smoking showed different and sometimes opposite associations with asthma, COPD and the overlap syndrome. Age did not modify the associations of the previous factors with respiratory diseases.
There is a paucity of knowledge on the prevalence of asthma in the elderly,
Our study is one of the few that reports the prevalence of both diseases in people aged from 20 to 84 years. It documents that asthma and COPD are major health problems, affecting about 13% of adults and 20% of the elderly. As people got older, the prevalence of asthma decreased (from 8.2% to 2.9%), while the prevalence COPD increased (from 3.3% to 13.3%). However, the prevalence of asthma and COPD remained non negligible even at the extremes of the age range. It is likely that this age-related pattern of asthma and COPD reflects both the true pattern of disease prevalence and the differential doctor’s diagnostic propensity according to the age of their patients (diagnostic bias).
Our estimates of the prevalence of asthma in Italy based on the self-reported doctor diagnosis are in line with those recently obtained on adult representative national samples, by using both an internationally validated questionnaire and the diagnosis of asthma made by Italian General Practitioners.
At variance, the prevalence estimates of COPD may change considerably according to the diagnostic tools used. In general, epidemiological studies based on physician diagnoses reported lower prevalence estimates than those relying on spirometry,
It is well known that some patients suffer from both asthma and COPD, and that they represent an important clinical population with peculiar characteristics.
These data point out that the asthma-COPD overlap syndrome affects many subjects and becomes more prevalent with advancing age. Furthermore, in agreement with previous studies,
Asthma-COPD overlap syndrome can develop when there is an accelerated decline in lung function, or incomplete lung growth, or both.
Our findings show that the risk factor profiles of subjects with the diagnosis of asthma, COPD and asthma-COPD overlap syndrome are different, even if they share some common patterns. Women had a higher susceptibility for the asthma-COPD overlap syndrome (OR:1.63; 95%CI: 1.15–2.31) than men, while gender was not associated with either the prevalence of asthma or COPD alone. Accordingly, the higher prevalence of adult asthma reported in women could be at least partially due to their increased susceptibility to the overlap syndrome
In agreement with a previous practice-based study performed by the Italian College of General Practitioners,
Although it is recognised that active and passive smoking are the major risk factors for COPD,
Differently from some studies,
In agreement with a large body of epidemiological evidence,
As previously reported,
In summary, the heterogeneity of the associations of the studied risk factors across the different respiratory diseases shown in our analysis seems to suggest that asthma, COPD and the asthma-COPD overlap syndrome could represent different phenotypes.
To our knowledge, this study provides the first large scale estimate of the joint distribution of asthma and COPD in general population. It has a number of limitations. Firstly, it was not possible to assess if and how asthma and COPD interact in the pathogenesis of the overlap-syndrome and which of the two occurred first, because of the cross-sectional design of the study. Then, our definitions of asthma and COPD were based on self-reported physician-diagnoses of the disease, and did not rely on lung function tests. As such, there might be an issue of recall bias. However, these definitions have been widely used in large international surveys,
The overall response rate was quite good with an average of over 50% in all age groups. The main outlier was the centre of Pavia, with a significantly lower response rate in the 20–44 age group. However, the distribution of asthma and COPD in the centre of Pavia was similar to those obtained in the other centers (data not reported), suggesting that the low response rate in this centre did not bias our results.
Asthma and COPD affect more than one out of eight of adults aged 20 years or older. The coexistence of both diseases is present in a substantial proportion of subjects and increases with advancing age. Subjects with the asthma-COPD overlap syndrome seem to be a specific phenotype that has more respiratory symptoms, more physical impairment, consume more medical resources and have a peculiar pattern of risk factors compared to asthma or COPD alone. Improvements in monitoring, in the treatment and in the research on the asthma-COPD overlap syndrome are necessary.
Dr Pierpaolo Marchetti is acknowledged for his contribute in database management of the GEIRD Study.