Articles
Long-term prognosis of asthma, chronic obstructive pulmonary disease, and asthma-chronic obstructive pulmonary disease overlap in the Copenhagen City Heart study: a prospective population-based analysis

https://doi.org/10.1016/S2213-2600(16)00098-9Get rights and content

Summary

Background

Long-term prognosis of patients with characteristics of both chronic obstructive pulmonary disease (COPD) and asthma, named asthma-COPD overlap, is poorly described. We investigated the long-term prognosis of individuals with different types of chronic airway disease, with a special focus on individuals with asthma-COPD overlap.

Methods

We assigned participants from the Copenhagen City Heart Study into six subgroups: healthy never-smokers, ever-smokers without asthma and COPD, those with asthma with low cumulated smoking exposure and no airflow limitation, those with COPD, those with asthma-COPD overlap with asthma onset before the age of 40 years, and those with asthma-COPD overlap with asthma onset after the age of 40 years. We defined asthma-COPD overlap as current self-reported asthma and a postbronchodilatatory forced expiratory volume in 1 s (FEV1) to forced vital capacity ratio of less than 0·7, without any restrictions regarding smoking. We investigated the course of FEV1 decline for 18 years and risk of admission to hospital due to exacerbations or pneumonias and respiratory and all-cause mortality for 22 years. We analysed FEV1 decline in the six groups using a linear mixed-effects model.

Findings

We included 8382 participants from the Copenhagen City Heart Study in our study: 2199 never-smokers, 5435 ever-smokers, 158 with asthma, 320 with COPD, 68 with asthma-COPD overlap with early-onset asthma, and 202 with asthma-COPD overlap with late-onset asthma. The multivariable-adjusted decline in FEV1 in asthma-COPD overlap with early-onset asthma was 27·3 mL (standard error 5·0) per year, which did not differ significantly from the decline of 20·9 mL (1·2) per year in healthy never-smokers (p=0·19). FEV1 decline in individuals with asthma-COPD overlap with late-onset asthma was 49·6 mL (3·0) per year, higher than the decline in asthma-COPD overlap with early-onset asthma (p=0·0001), the decline of 39·5 mL (2·5) per year in COPD (p=0·003), and the decline in healthy never-smokers (p<0·0001). Hazard ratios for hospital admissions due to exacerbations of asthma or COPD were 39·48 (95% CI 25·93–60·11) in asthma-COPD overlap with early-onset asthma, 83·47 (61·67–112·98) in asthma-COPD overlap with late-onset asthma, 23·80 (17·43–33·50) in COPD, and 14·74 (10·06–21·59) in asthma compared with never-smokers without lung disease (all p<0·0001). Life expectancy was 9·3 years (5·4–13·1) shorter in participants with asthma-COPD overlap with early-onset asthma, 12·8 years (11·1–14·6) shorter in those with asthma-COPD overlap with late-onset asthma, 10·1 years (8·6–11·5) shorter in those with COPD (all p<0·0001), and 3·3 years (1·0–5·5) shorter in those with asthma (p=0·004) than in healthy never-smokers.

Interpretation

Prognosis of individuals with asthma-COPD overlap is poor and seems to be affected by the age of recognition of asthma, being worst in those with late asthma onset (after 40 years of age). Such patients should be followed up closely to prevent fast lung function decline and exacerbations.

Funding

Capital Region of Copenhagen, Danish Heart Foundation, Danish Lung Foundation, Velux Foundation, AstraZeneca.

Introduction

Diagnostic labelling and phenotyping of chronic airway diseases has been intensely discussed for many decades.1, 2 Initially, this debate focused on the question as to whether asthma and chronic obstructive pulmonary disease (COPD) should be considered the same or two different diseases.3, 4 During the past decade, various studies5, 6 have documented substantial heterogeneity among patients with both asthma and COPD, and various different phenotypes and endotypes within these disease entities have been proposed. Additionally, there has been an increased focus on individuals who show characteristics of both asthma and COPD.7, 8 Authors of literature reviews9, 10, 11, 12 indicate that asthma-COPD overlap is present in approximately 20% of patients with asthma or COPD and is associated with increased morbidity and a high risk of exacerbations. Yet, the long-term prognosis of individuals with overlapping features of both asthma and COPD, including the course of forced expiratory volume in 1 s (FEV1) and survival, is poorly described.

Research in context

Evidence before this study

Before doing this study, we searched PubMed for clinical and epidemiological articles published in English between Jan 1, 2000, and March 1, 2015, using the following medical subject heading terms: “asthma-COPD overlap”, “asthma-COPD overlap syndrome”, “longitudinal”, “lung function”, and “mortality”. We excluded case reports and identified one study reporting a lower 4 year decline of forced expiratory volume in 1 s (FEV1) in individuals with asthma-chronic obstructive pulmonary disease (COPD) overlap than in those with COPD. When we did a new search for articles published in English between Jan 1, 2000, and Dec 15, 2015, using the same search terms, we identified one additional study describing FEV1 decline and hospital admissions due to exacerbations in young adults with asthma-COPD overlap during a 10 year observation. In this study, individuals with asthma-COPD overlap had a similar lung function decline but more hospital admissions than did participants with asthma.

Added value of this study

Our study takes advantage of a very long observation period (18–22 years). We differentiate between individuals with asthma-COPD overlap with early onset of asthma (before age of 40 years) and asthma-COPD overlap with late onset of asthma (aged 40 years or older at asthma onset). We show that decline of FEV1 is much faster in those with asthma-COPD with late-onset asthma, even exceeding the FEV1 decline among participants with COPD without asthma. In general, participants with asthma-COPD overlap had a high risk of hospital admissions. The subgroup with late-onset asthma also had very high mortality, from both all causes and respiratory diseases.

Implications of all the available evidence

The results show that in the long term, individuals with asthma-COPD overlap show considerable heterogeneity in lung function, hospital admissions, and survival, depending on the age when asthma manifests itself. In particular, the group with asthma-COPD overlap and late onset of asthma is susceptible and has a very poor prognosis according to lung function decline, hospital admissions, and survival.

In this study, we investigated the long-term prognosis of individuals with different types of chronic airway disease, with a special focus on individuals with asthma-COPD overlap. As the asthma-COPD overlap group is likely to be heterogeneous, we used a novel approach by distinguishing between participants with onset of asthma before the age of 40 years (asthma-COPD overlap stemming from asthma) and those with onset of asthma after this age (asthma-COPD overlap that is most likely to evolve from COPD), which is in line with the concept introduced by Postma and Rabe.12 These authors suggest that asthma-COPD overlap might develop in individuals who initially had asthma, but also in those with COPD caused by smoking, and that these two conditions cannot be easily distinguished by their phenotype, although the inflammatory mechanisms behind the pathological changes in the airways might differ. We used data from the Copenhagen City Heart Study,13, 14 an ongoing longitudinal study of the general population in Copenhagen, Denmark, where the participants have been followed up for FEV1, admissions to hospital, and survival for many years.

Section snippets

Study design and participants

All individuals included in this study participated in the Copenhagen City Heart Study.13, 14 Recruitment of participants and the methods are presented in detail in the appendix. We obtained written informed consent from all participants, and the study was approved by institutional review boards and Danish ethics committees (KF100.2039/91). We defined the subgroups of individuals with different types of obstructive lung disease on the basis of the third examination of the Copenhagen City Heart

Results

A flowchart showing the 8382 participants with sufficient data from the Copenhagen City Heart Study included in this study is shown in figure 1, with their distribution into the six groups and their characteristics shown in table 1. Among the 10 135 participants in the 1991–94 examination, we excluded two (<1%) as they were no longer living in Denmark and could not be followed up. In 499 (5%) participants, spirometry data were not available; 945 (9%) did not have sufficient data for

Discussion

The major new finding of this study is that the long-term prognosis of patients sharing characteristics of both asthma and COPD is affected by the age of recognition of asthma. Our data suggest that individuals with asthma-COPD overlap with onset of asthma before the age of 40 years have a significantly less rapid decline of FEV1 and a better survival than do those whose asthma manifests itself after this age. Still, both groups with asthma-COPD overlap have more severe exacerbations than do

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