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Understanding asthma-chronic obstructive pulmonary disease overlap syndrome

Open ArchivePublished:October 08, 2015DOI:https://doi.org/10.1016/j.rmed.2015.10.004

      Highlights

      • Prevalence of ACOS varies widely (12–61%) among patients with COPD or asthma.
      • The variability is linked to differences in COPD and asthma diagnostic criteria.
      • Other factors linked to variability include age and gender of the study population.

      Abstract

      Asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS) is a loosely-defined clinical entity referring to patients who exhibit characteristics of both asthma and chronic obstructive pulmonary disease (COPD). Clinical definitions and classifications for ACOS vary widely, which impacts our understanding of prevalence, diagnosis and treatment of the condition.
      This literature review was therefore conducted to characterize the prevalence of ACOS and the effect of different disease definitions on these estimates, as this has not previously been explored. From an analysis of English language literature published from 2000 to 2014, the estimated prevalence of ACOS ranges from 12.1% to 55.2% among patients with COPD and 13.3%–61.0% among patients with asthma alone. This variability is linked to differences in COPD and asthma diagnostic criteria, disease ascertainment methods (spirometry-based versus clinical or symptom-based diagnoses and claims data), and population characteristics including age, gender and smoking.
      Understanding the reasons for differences in prevalence estimates of ACOS across the literature may help guide decision making on the most appropriate criteria for defining ACOS and aid investigators in designing future ACOS clinical studies aimed at effective treatment.

      Keywords

      Abbreviations:

      ACOS (asthma-chronic obstructive pulmonary disease overlap syndrome), BOLD (Burden of Obstructive Lung Disease), COPD (chronic obstructive pulmonary disease), COPDGene (Genetic Epidemiology of COPD), GEIRD (Gene–Environment Interactions in Respiratory Disease), GINA (Global Initiative for Asthma), GOLD (Global Initiative for Chronic Obstructive Lung Disease), FEV1 (forced expiratory volume in one second), FVC (forced vital capacity), ICD (International Classification of Disease), IHCIS (Integrated Healthcare Information Services), LLN (lower limit of normal), NC BRFSS (North Carolina Behavioral Risk Factor Surveillance System), NHANES (National Health and Nutritional Examination Survey), PEF (peak expiratory flow), PLATINO (Latin American Project for the Investigation of Lung Disease), SGRQ (Saint George's Respiratory Questionnaire), SPIROMICS (Subpopulations and intermediate outcome measures in COPD study), U-BIOPRED (Unbiased BIOmarkers in PREDiction of respiratory outcomes)

      1. Introduction

      The diagnosis and differentiation of asthma from chronic obstructive pulmonary disease (COPD) in clinical practice is relatively straightforward in the majority of cases; however, some patients exhibit characteristics of both diseases. Where uncertainty exists regarding the correct diagnosis of asthma, COPD or both, this may represent a phenotype known as asthma-COPD overlap syndrome (ACOS) [
      • Carolan B.J.
      • Sutherland E.R.
      Clinical phenotypes of chronic obstructive pulmonary disease and asthma: recent advances.
      ,
      • Kim S.R.
      • Rhee Y.K.
      Overlap between asthma and COPD: where the two diseases converge.
      ,
      • Louie S.
      • Zeki A.A.
      • Schivo M.
      • et al.
      The asthma-chronic obstructive pulmonary disease overlap syndrome: pharmacotherapeutic considerations.
      ,
      • Nakawah M.O.
      • Hawkins C.
      • Barbandi F.
      Asthma, chronic obstructive pulmonary disease (COPD), and the overlap syndrome.
      ].
      COPD is highly prevalent in the global population of older adults (40 years of age and older) and has been associated with smoking and exposure to environmental tobacco smoke or fumes [
      • Global Initiative for Chronic Obstructive Lung Disease (GOLD)
      Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease.
      ]. COPD is typically characterized by persistent airflow obstruction and chronic inflammation of the airways. Airway inflammation is also seen in asthma; however, there are distinct differences in the type of inflammatory cells seen in these two respiratory diseases. Biopsies reveal that inflammation in COPD is characterized predominantly by increases in CD8+ T-lymphocytes, neutrophils, and macrophages [
      • O'Shaughnessy T.C.
      • Ansari T.W.
      • Barnes N.C.
      • et al.
      Inflammation in bronchial biopsies of subjects with chronic bronchitis: inverse relationship of CD8+T lymphocytes with FEV1.
      ,
      • Saetta M.
      • Di Stefano A.
      • Turato G.
      • et al.
      CD8+ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease.
      ,
      • Stanescu D.
      • Sanna A.
      • Veriter C.
      • et al.
      Airways obstruction, chronic expectoration, and rapid decline of FEV1 in smokers are associated with increased levels of sputum neutrophils.
      ], although increases in eosinophils have been observed in sputum at the time of exacerbation [
      • Bafadhel M.
      • McKenna S.
      • Terry S.
      • et al.
      Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers.
      ]. In contrast, inflammation in asthma is commonly characterized by increases in CD4+ T-lymphocytes and eosinophils [
      • Fabbri L.M.
      • Romagnoli M.
      • Corbetta L.
      • et al.
      Differences in airway inflammation in patients with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease.
      ]. Airflow obstruction in COPD is defined as a post-bronchodilator measurement of forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC)<0.70 or lower limit of normal (LLN), where LLN values are identified by selecting the lowest 5% of a normally distributed population [
      • Global Initiative for Chronic Obstructive Lung Disease (GOLD)
      Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease.
      ]. Asthma is also a chronic obstructive lung disease, but in mild and moderately severe asthma, airflow obstruction responds to treatment with inhaled corticosteroids and bronchodilators and is therefore not persistent and is reversible. Reversibility refers to the reduction of airflow obstruction after bronchodilator administration and is usually measured by comparing pre- and post-bronchodilator FEV1. An FEV1/FVC ratio<0.75–0.80, and a post-bronchodilator FEV1 increase of >12% and >0.200 L over the pre-bronchodilator measurements are usually indicators of asthma [
      • Global Initiative for Asthma
      From the Global Strategy for Asthma Management and Prevention.
      ]. However, applying these definitions to differentiate between severe asthma of middle-age and COPD may lead to uncertainty owing to a number of factors. For example, many patients with COPD are responsive to albuterol (reversible) while many patients with a clinical diagnosis of asthma are not reversible on testing and studies have shown that 25–45% of patients with COPD have never smoked [
      • Behrendt C.E.
      Mild and moderate-to-severe COPD in nonsmokers: distinct demographic profiles.
      ,
      • Salvi S.S.
      • Barnes P.J.
      Chronic obstructive pulmonary disease in non-smokers.
      ]. Furthermore, since the FEV1/FVC ratio declines with age, this definition may lead to over-diagnosis of COPD in the elderly and under-diagnosis in the young to middle-aged, which may be especially relevant when considering the possible diagnosis of nonreversible asthma [
      • Global Initiative for Chronic Obstructive Lung Disease (GOLD)
      Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease.
      ]. In addition, there are some individuals with asthma who have neutrophilic inflammation that may be related to treatment with inhaled steroids [
      • Cowan D.C.
      • Cowan J.O.
      • Palmay R.
      • et al.
      Effects of steroid therapy on inflammatory cell subtypes in asthma.
      ] or that is an intrinsic part of their disease [
      • Gibson P.G.
      • Simpson J.L.
      • Saltos N.
      Heterogeneity of airway inflammation in persistent asthma : evidence of neutrophilic inflammation and increased sputum interleukin-8.
      ,
      • Jatakanon A.
      • Uasuf C.
      • Maziak W.
      • et al.
      Neutrophilic inflammation in severe persistent asthma.
      ]. Finally, the histopathological differentiation of asthma as an eosinophilic disease and COPD as a neutrophilic disease is also in question as the eosinophil is becoming an increasingly important marker of treatment response in COPD [
      • Brightling C.E.
      • McKenna S.
      • Hargadon B.
      • et al.
      Sputum eosinophilia and the short term response to inhaled mometasone in chronic obstructive pulmonary disease.
      ,
      • Leigh R.
      • Pizzichini M.M.
      • Morris M.M.
      • et al.
      Stable COPD: predicting benefit from high-dose inhaled corticosteroid treatment.
      ], which is possibly a result of a rise in the prevalence of ACOS.
      While a variety of diagnostic criteria have been proposed for identifying ACOS, a specific formal definition of ACOS has yet to be determined. The importance of identifying patients with features of ACOS is underlined by recent work that has demonstrated that patients with ACOS have more symptoms, exacerbations, hospitalizations, lower health-related quality of life, and higher mortality than patients with COPD or asthma alone [
      • Andersen H.
      • Lampela P.
      • Nevanlinna A.
      • et al.
      High hospital burden in overlap syndrome of asthma and COPD.
      ,
      • Hardin M.
      • Cho M.
      • McDonald M.L.
      • et al.
      The clinical and genetic features of COPD-asthma overlap syndrome.
      ,
      • Kauppi P.
      • Kupiainen H.
      • Lindqvist A.
      • et al.
      Overlap syndrome of asthma and COPD predicts low quality of life.
      ,
      • Menezes A.M.
      • Montes de Oca M.
      • Perez-Padilla R.
      • et al.
      Increased risk of exacerbation and hospitalization in subjects with an overlap phenotype: COPD-asthma.
      ,
      • Miravitlles M.
      • Soriano J.B.
      • Ancochea J.
      • et al.
      Characterisation of the overlap COPD-asthma phenotype. Focus on physical activity and health status.
      ,
      • Putcha N.
      • Drummond M.B.
      • Martinez C.H.
      • et al.
      Self-reported asthma is associated with worse health outcomes in COPD.
      ]. Recognizing that there is no generally agreed term or definition for ACOS, the Global Initiative for Asthma (GINA) and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recently developed guidelines to help stimulate further research, to identify and characterize ACOS [
      • Global Initiative for Chronic Obstructive Lung Disease (GOLD)
      Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease.
      ,
      • Global Initiative for Asthma
      From the Global Strategy for Asthma Management and Prevention.
      ]. Broadly, ACOS can be described as an obstructive airflow condition or a set of clinical characteristics where aspects of both asthma and COPD are present, such as FEV1/FVC<0.70 and evidence of airflow reversibility (post-bronchodilator FEV1 increase of >12% and >0.200 L). Developing diagnostic criteria for ACOS is especially difficult since the clinical presentation of asthma and COPD can appear similar with respect to symptomology and, as noted above, are sometimes challenging to differentiate [
      • Carolan B.J.
      • Sutherland E.R.
      Clinical phenotypes of chronic obstructive pulmonary disease and asthma: recent advances.
      ,
      • Zeki A.A.
      • Schivo M.
      • Chan A.
      • et al.
      The asthma-COPD overlap syndrome: a common clinical problem in the elderly.
      ]. Whether ACOS is simply the coexistence of asthma and COPD or a distinct phenotype with related fundamental pathogenic mechanisms to asthma and COPD remains to be determined. Furthermore, different studies classify ACOS as a sub-phenotype of COPD [
      • Marsh S.E.
      • Travers J.
      • Weatherall M.
      • et al.
      Proportional classifications of COPD phenotypes.
      ,
      • Izquierdo-Alonso J.L.
      • Rodriguez-Gonzalezmoro J.M.
      • de Lucas-Ramos P.
      • et al.
      Prevalence and characteristics of three clinical phenotypes of chronic obstructive pulmonary disease (COPD).
      ], whereas other studies treat ACOS as a phenotype distinct from either COPD or asthma [
      • Menezes A.M.
      • Montes de Oca M.
      • Perez-Padilla R.
      • et al.
      Increased risk of exacerbation and hospitalization in subjects with an overlap phenotype: COPD-asthma.
      ,
      • Pleasants R.A.
      • Ohar J.A.
      • Croft J.B.
      • et al.
      Chronic obstructive pulmonary disease and asthma-patient characteristics and health impairment.
      ,
      • Melbye H.
      • Drivenes E.
      • Dalbak L.G.
      • et al.
      Asthma, chronic obstructive pulmonary disease, or both? Diagnostic labeling and spirometry in primary care patients aged 40 years or more.
      ]. Proposed definitions for ACOS vary widely and include (1) patients with COPD who have any diagnosis of current or past asthma, (2) spirometric-based definitions such as patients with COPD who have consistent significant reversibility (FEV1/FVC<0.70 and a post-bronchodilator FEV1 increase of >12% and >0.200 L over the pre-bronchodilator measurement), or (3) patients with asthma who have persistent airflow obstruction [
      • Louie S.
      • Zeki A.A.
      • Schivo M.
      • et al.
      The asthma-chronic obstructive pulmonary disease overlap syndrome: pharmacotherapeutic considerations.
      ,
      • Soler-Cataluna J.J.
      • Cosio B.
      • Izquierdo J.L.
      • et al.
      Consensus document on the overlap phenotype COPD-asthma in COPD.
      ]. The absence of ACOS-specific pathological definitions and the variability of ACOS criteria across the literature present challenges for conducting studies to add to the available evidence [
      • Louie S.
      • Zeki A.A.
      • Schivo M.
      • et al.
      The asthma-chronic obstructive pulmonary disease overlap syndrome: pharmacotherapeutic considerations.
      ].

      2. Aims

      ACOS may represent a sizeable portion of the clinical patient population with airflow obstruction; however, the varying ACOS definitions and diagnostic criteria make this population difficult to characterize. The aim of this literature review was to characterize the prevalence of ACOS and examine how different definitions of ACOS affect prevalence estimates, as this has not previously been explored.

      3. Search strategy

      Published studies and abstracts were identified through PubMed and Searchlight, respectively, from January 1, 2000 to February 28, 2014. Only studies written in English were retained. Relevant publications found from other references, but not identified in the original search, were added. The following key words were used to identify potentially relevant abstracts in PubMed: asthma, chronic obstructive pulmonary disease, COPD, asthma-chronic obstructive pulmonary disease, fixed airway obstruction, asthma COPD overlap, persistent airway obstruction, fixed airway obstruction risk factor, and prevalence. This search strategy produced 180 results, 71 of which were retained for further review. Thirty-one additional relevant papers identified through citations of systematically identified papers were also included in this analysis.
      The following key words were used to identify potentially relevant conference abstracts in Searchlight: asthma, atopic asthma, bronchial asthma, bronchitic asthma, chronic obstructive pulmonary disease, chronic airflow obstruction, chronic obstructive airways disease, chronic obstructive lung disease, COPD, pulmonary disease, chronic obstructive, and overlap. This search strategy produced 23 conference abstracts, 18 of which were retained for further review.
      Of all the articles retained for further assessment, 43 were considered relevant and included in this review. Studies identified but not included in the review did not contain information on ACOS prevalence. Topics of the excluded articles included dysfunctional breathing, COPD subtypes excluding ACOS, smoking, treatment/management, air trapping, and airway obstruction. Studies that estimated the population prevalence of ACOS, the prevalence of ACOS in patients with COPD, and the prevalence of ACOS in patients with asthma were summarized. Variations were identified in the study populations and in the definitions of asthma, COPD, and ACOS.

      4. Prevalence of ACOS

      Estimates of the population prevalence of ACOS ranged from 1.6% to 4.5% from studies in Italy, South Korea, Latin America, and the United States [
      • Menezes A.M.
      • Montes de Oca M.
      • Perez-Padilla R.
      • et al.
      Increased risk of exacerbation and hospitalization in subjects with an overlap phenotype: COPD-asthma.
      ,
      • Pleasants R.A.
      • Ohar J.A.
      • Croft J.B.
      • et al.
      Chronic obstructive pulmonary disease and asthma-patient characteristics and health impairment.
      ,
      • Diaz-Guzman E.
      • Khosravi M.
      • Mannino D.M.
      Asthma, chronic obstructive pulmonary disease, and mortality in the U.S. population.
      ,
      • Lee J.H.
      • Kong K.A.
      • Chung J.W.
      • et al.
      Health-related quality of life in airway diseases.
      ,
      • de Marco R.
      • Pesce G.
      • Marcon A.
      • et al.
      The coexistence of asthma and chronic obstructive pulmonary disease (COPD): prevalence and risk factors in young, middle-aged and elderly people from the general population.
      ] (Table 1, Fig. 1). Estimates of the population prevalence of ACOS varied across countries at least in part because of different COPD and asthma diagnostic criteria and different underlying distribution of risk factors, such as smoking, the age distribution in the source populations, and study samples.
      Table 1COPD, asthma, and ACOS prevalence among total populations: differences in asthma definitions, spirometric criteria, COPD definitions, and population demographics.
      Population prevalence of COPD-onlyPopulation prevalence of asthma-onlyPopulation prevalence of ACOSCOPD definitionAsthma definitionACOS definitionPopulation demographics (Age: years)Author, year

      Data source

      Study sample size
      5.3%5.3%2.7%Self-reported physician diagnosis of COPD, everSelf-reported physician diagnosed, asthma everEver self-reported physician diagnosis of asthma and COPDAge25

      General population, US

      Smokers and nonsmoker
      Diaz-Guzman et al., 2011
      • Diaz-Guzman E.
      • Khosravi M.
      • Mannino D.M.
      Asthma, chronic obstructive pulmonary disease, and mortality in the U.S. population.


      NHANES III

      n = 15,203
      11.7%1.7%1.8%FEV1/FVC<0.70Report of wheezing in the last 12 months and post-bronchodilator increase in FEV1 or FVC of 0.200 L and 12%Meeting both criteria of asthma and COPDAge>40

      Population in 5 Latin American cities

      Smokers and nonsmokers
      Menezes et al., 2014
      • Menezes A.M.
      • Montes de Oca M.
      • Perez-Padilla R.
      • et al.
      Increased risk of exacerbation and hospitalization in subjects with an overlap phenotype: COPD-asthma.


      PLATINO

      n = 5044
      10.6%8.9%2.9%FEV1/FVC<0.70Self-reported physician diagnosed asthma, everMeeting both criteria of asthma and COPDAge>40

      Population in 5 Latin American cities

      Smokers and nonsmokers

      Menezes et al., 2014
      • Menezes A.M.
      • Montes de Oca M.
      • Perez-Padilla R.
      • et al.
      Increased risk of exacerbation and hospitalization in subjects with an overlap phenotype: COPD-asthma.


      PLATINO

      n = 5044
      7.8%6.1%2.4%FEV1/FVC<0.70 and no wheezing in past yearWheezing for past year and FEV1/FVC ≥ 0.70Wheezing and FEV1/FVC<0.70Korean patient population

      Smokers and nonsmokers
      Lee et al., 2013
      • Lee J.H.
      • Kong K.A.
      • Chung J.W.
      • et al.
      Health-related quality of life in airway diseases.


      4th Korean NHANES

      n = 9369
      3.3% (2.8–3.8)
      Prevalence (95% confidence interval).
      8.2% (7.5–9)
      Prevalence (95% confidence interval).
      1.6% (1.3–2)
      Prevalence (95% confidence interval).
      Self-reported physician diagnosis of COPD, everSelf-reported physician diagnosed asthma, everEver self-reported physician diagnosis of asthma and COPDAge 20–44

      General population, ItalySmokers and nonsmokers

      Age 45–64
      de Marco et al., 2013
      • de Marco R.
      • Pesce G.
      • Marcon A.
      • et al.
      The coexistence of asthma and chronic obstructive pulmonary disease (COPD): prevalence and risk factors in young, middle-aged and elderly people from the general population.


      GEIRD

      n = 5163
      5.7% (4.7–6.7)
      Prevalence (95% confidence interval).
      4.9% (4–5.9)
      Prevalence (95% confidence interval).
      2.1% (1.5–2.8)
      Prevalence (95% confidence interval).
      Self-reported physician diagnosis of COPD, everSelf-reported physician diagnosed asthma, everEver self-reported physician diagnosis of asthma and COPDSmokers and nonsmokersde Marco et al., 2013
      • de Marco R.
      • Pesce G.
      • Marcon A.
      • et al.
      The coexistence of asthma and chronic obstructive pulmonary disease (COPD): prevalence and risk factors in young, middle-aged and elderly people from the general population.


      GEIRD

      n = 2167

      13.3% (11.1–15.5)
      Prevalence (95% confidence interval).
      2.9% (1.8–4)
      Prevalence (95% confidence interval).
      4.5% (3.2–5.9)
      Prevalence (95% confidence interval).
      Self-reported physician diagnosis of COPD, everSelf-reported physician diagnosed asthma, everEver self-reported physician diagnosis of asthma and COPDAge 65–84

      General population, Italy

      Smokers and nonsmokers
      de Marco et al., 2013
      • de Marco R.
      • Pesce G.
      • Marcon A.
      • et al.
      The coexistence of asthma and chronic obstructive pulmonary disease (COPD): prevalence and risk factors in young, middle-aged and elderly people from the general population.


      GEIRD

      n = 1030
      5.6%12.1%2.4%Self-reported physician diagnosis of COPD, everSelf-reported physician diagnosed asthma, everEver physician diagnosis of asthma and COPDAge18

      General population, North Carolina

      Smokers and nonsmokers
      Pleasants et al., 2014
      • Pleasants R.A.
      • Ohar J.A.
      • Croft J.B.
      • et al.
      Chronic obstructive pulmonary disease and asthma-patient characteristics and health impairment.


      NC BRFSS

      n = 24,073
      ACOS: asthma-COPD overlap syndrome; COPD: chronic obstructive pulmonary disease; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; GEIRD: Gene–Environment Interactions in Respiratory Disease; NC BRFSS: North Carolina Behavioral Risk Factor Surveillance System; NHANES: National Health and Nutrition Examination Survey; PLATINO: Latin American Project for the Investigation of Lung Disease.
      a Prevalence (95% confidence interval).
      Figure thumbnail gr1
      Fig. 1COPD, asthma, and ACOS prevalence among total populations (corresponding to ). ACOS: asthma-COPD overlap syndrome; COPD: chronic obstructive pulmonary disease.

      5. ACOS prevalence among patients with COPD or asthma

      On the basis of the results of the literature review, the prevalence of ACOS among patients with COPD is estimated to range from 12.1% to 55.2% (Table 2) [
      • Andersen H.
      • Lampela P.
      • Nevanlinna A.
      • et al.
      High hospital burden in overlap syndrome of asthma and COPD.
      ,
      • Hardin M.
      • Cho M.
      • McDonald M.L.
      • et al.
      The clinical and genetic features of COPD-asthma overlap syndrome.
      ,
      • Kauppi P.
      • Kupiainen H.
      • Lindqvist A.
      • et al.
      Overlap syndrome of asthma and COPD predicts low quality of life.
      ,
      • Menezes A.M.
      • Montes de Oca M.
      • Perez-Padilla R.
      • et al.
      Increased risk of exacerbation and hospitalization in subjects with an overlap phenotype: COPD-asthma.
      ,
      • Putcha N.
      • Drummond M.B.
      • Martinez C.H.
      • et al.
      Self-reported asthma is associated with worse health outcomes in COPD.
      ,
      • Izquierdo-Alonso J.L.
      • Rodriguez-Gonzalezmoro J.M.
      • de Lucas-Ramos P.
      • et al.
      Prevalence and characteristics of three clinical phenotypes of chronic obstructive pulmonary disease (COPD).
      ,
      • Marsh S.E.
      • Travers J.
      • Weatherall M.
      • et al.
      Proportional classifications of COPD phenotypes.
      ,
      • Pleasants R.A.
      • Ohar J.A.
      • Croft J.B.
      • et al.
      Chronic obstructive pulmonary disease and asthma-patient characteristics and health impairment.
      ,
      • Lee J.H.
      • Kong K.A.
      • Chung J.W.
      • et al.
      Health-related quality of life in airway diseases.
      ,
      • de Marco R.
      • Pesce G.
      • Marcon A.
      • et al.
      The coexistence of asthma and chronic obstructive pulmonary disease (COPD): prevalence and risk factors in young, middle-aged and elderly people from the general population.
      ,
      • Hardin M.
      • Silverman E.K.
      • Barr R.G.
      • et al.
      The clinical features of the overlap between COPD and asthma.
      ,
      • Wurst K.E.
      • Shukla A.
      • Muellerova H.
      • et al.
      Respiratory pharmacotherapy use in patients newly diagnosed with chronic obstructive pulmonary disease in a primary care setting in the UK: a retrospective cohort study.
      ,
      • Talamo C.
      • de Oca M.M.
      • Halbert R.
      • et al.
      Diagnostic labeling of COPD in five Latin American cities.
      ,
      • Lamprecht B.
      • McBurnie M.A.
      • Vollmer W.M.
      • et al.
      COPD in never smokers: results from the population-based burden of obstructive lung disease study.
      ,
      • Iwamoto H.
      • Gao J.
      • Koskela J.
      • et al.
      Differences in plasma and sputum biomarkers between COPD and COPD-asthma overlap.
      ,
      • Kitaguchi Y.
      • Komatsu Y.
      • Fujimoto K.
      • et al.
      Sputum eosinophilia can predict responsiveness to inhaled corticosteroid treatment in patients with overlap syndrome of COPD and asthma.
      ,
      • Blanchette C.M.
      • Broder M.
      • Ory C.
      • et al.
      Cost and utilization of COPD and asthma among insured adults in the US.
      ,
      • Shaya F.T.
      • Dongyi D.
      • Akazawa M.O.
      • et al.
      Burden of concomitant asthma and COPD in a medicaid population.
      ,
      • Rhee C.K.
      • Yoon H.K.
      • Yoo K.H.
      • et al.
      Medical utilization and cost in patients with overlap syndrome of chronic obstructive pulmonary disease and asthma.
      ] and the prevalence of ACOS among patients with asthma is estimated to range from 13.3% to 61.0% (Table 3) [
      • Andersen H.
      • Lampela P.
      • Nevanlinna A.
      • et al.
      High hospital burden in overlap syndrome of asthma and COPD.
      ,
      • Kauppi P.
      • Kupiainen H.
      • Lindqvist A.
      • et al.
      Overlap syndrome of asthma and COPD predicts low quality of life.
      ,
      • Menezes A.M.
      • Montes de Oca M.
      • Perez-Padilla R.
      • et al.
      Increased risk of exacerbation and hospitalization in subjects with an overlap phenotype: COPD-asthma.
      ,
      • Pleasants R.A.
      • Ohar J.A.
      • Croft J.B.
      • et al.
      Chronic obstructive pulmonary disease and asthma-patient characteristics and health impairment.
      ,
      • Diaz-Guzman E.
      • Khosravi M.
      • Mannino D.M.
      Asthma, chronic obstructive pulmonary disease, and mortality in the U.S. population.
      ,
      • Lee J.H.
      • Kong K.A.
      • Chung J.W.
      • et al.
      Health-related quality of life in airway diseases.
      ,
      • de Marco R.
      • Pesce G.
      • Marcon A.
      • et al.
      The coexistence of asthma and chronic obstructive pulmonary disease (COPD): prevalence and risk factors in young, middle-aged and elderly people from the general population.
      ,
      • Lamprecht B.
      • McBurnie M.A.
      • Vollmer W.M.
      • et al.
      COPD in never smokers: results from the population-based burden of obstructive lung disease study.
      ,
      • Iwamoto H.
      • Gao J.
      • Koskela J.
      • et al.
      Differences in plasma and sputum biomarkers between COPD and COPD-asthma overlap.
      ,
      • Shaya F.T.
      • Dongyi D.
      • Akazawa M.O.
      • et al.
      Burden of concomitant asthma and COPD in a medicaid population.
      ,
      • Kalberg C.
      • Sense W.
      • Knobil K.
      Fixed airway obstruction in patients with asthma: data from a large clinical trials database.
      ,
      • Banga A.
      • McCarthy K.
      • Pichurko B.M.
      Predictors of airway obstruction on spirometry among patients with bronchial asthma presenting to a tertiary care center.
      ,
      • Wagener A.H.
      • Gibeon D.
      • Yang X.
      • et al.
      Associated factors persistent airflow limitation in asthma in U-BIOPRED.
      ]. The wide variations in prevalence estimates are most likely due to the method by which ACOS cases were classified, but differences in population inclusion criteria, in the data source, and in the definitions of asthma and COPD including airflow reversibility criteria and spirometric versus clinical diagnoses can also influence the prevalence of ACOS. In general, the prevalence of COPD alone is difficult to accurately estimate due to variations in COPD diagnostic criteria, thus, identifying the ACOS population is even more complicated [
      • Chang J.
      • Mosenifar Z.
      Differentiating COPD from asthma in clinical practice.
      ].
      Table 2ACOS prevalence among patients with COPD: variation in study definition and details of general population with COPD.
      Proportion of COPD Patients with ACOSCOPD definitionAsthma definitionACOS definitionDemographics of population with COPD

      (Age: years)
      Author, year

      Data source

      Study sample size
      12.1%FEV1/FVC<0.70Self-reported physician-diagnosed before the age of 40Asthma diagnosis among patients with COPDAge40

      Spain multicenter study

      Smokers only
      Izquierdo-Alonso et al., 2013
      • Izquierdo-Alonso J.L.
      • Rodriguez-Gonzalezmoro J.M.
      • de Lucas-Ramos P.
      • et al.
      Prevalence and characteristics of three clinical phenotypes of chronic obstructive pulmonary disease (COPD).


      n = 331
      12.6%FEV1/FVC<0.70, FEV1<80% of predicted, GOLD Stage II+Self-reported physician-diagnosed before the age of 40Asthma diagnosis among patients with COPDAge 45–80

      US multicenter study

      Current and former smokers
      Hardin et al., 2014
      • Hardin M.
      • Cho M.
      • McDonald M.L.
      • et al.
      The clinical and genetic features of COPD-asthma overlap syndrome.


      COPDGene

      n = 3570
      13.0%FEV1/FVC<0.70, GOLD Stage II+Self-reported physician-diagnosed before the age of 40Asthma diagnosis among patients with COPDAge 45–80

      US multicenter study

      Current and former smokers
      Hardin et al., 2011
      • Hardin M.
      • Silverman E.K.
      • Barr R.G.
      • et al.
      The clinical features of the overlap between COPD and asthma.


      COPDGene

      n = 1059
      13.0%FEV1/FVC<0.70Report of wheezing in the last 12 months and post-bronchodilator increase in FEV1 or FVC of 0.200 L and 12%Asthma diagnosis among patients with COPDAge>40

      Population in 5 Latin American cities

      Smokers and nonsmokers
      Menezes et al., 2014
      • Menezes A.M.
      • Montes de Oca M.
      • Perez-Padilla R.
      • et al.
      Increased risk of exacerbation and hospitalization in subjects with an overlap phenotype: COPD-asthma.


      PLATINO

      n = 5044
      16.7%FEV1/FVC<0.70Self-reported physician diagnosis, currentAsthma diagnosis among patients with COPDAge 40–80

      US, multicenter

      Among smokers only
      Putcha et al., 2013
      • Putcha N.
      • Drummond M.B.
      • Martinez C.H.
      • et al.
      Self-reported asthma is associated with worse health outcomes in COPD.


      SPIROMICS

      n = 581
      22.8%FEV1/FVC<0.70Self-report medical-diagnosed asthma, priorAsthma diagnosis among patients with COPDAge40

      Population in 5 Latin American cities

      Smokers and nonsmokers
      Talamo et al., 2007
      • Talamo C.
      • de Oca M.M.
      • Halbert R.
      • et al.
      Diagnostic labeling of COPD in five Latin American cities.


      PLATINO

      n = 5303
      23.5%FEV1/FVC<0.70, FEV1<80% of predictedSelf-reported physician diagnosed, everAsthma diagnosis among patients with COPDAge40

      Multi-country

      Never smokers only
      Lamprecht et al. 2011
      Lamprecht et al., 2011 [37]: Of the patients with a physician diagnosis of asthma ‘ever’, 30.4% and 17.7% were considered GOLD stage II+ (FEV1/FVC<0.7 and FEV1<80% predicted) and GOLD stage I (FEV1/FVC<0.7 and FEV1≥80% predicted), respectively.
      • Lamprecht B.
      • McBurnie M.A.
      • Vollmer W.M.
      • et al.
      COPD in never smokers: results from the population-based burden of obstructive lung disease study.


      BOLD Study

      n = 4291
      23.6%FEV1/FVC<0.70 and no wheezing in past yearWheezing for past year and FEV1/FVC ≥0.70Wheezing and FEV1/FVC<0.70Korean patient population

      Smokers and nonsmokers
      Lee et al., 2013
      • Lee J.H.
      • Kong K.A.
      • Chung J.W.
      • et al.
      Health-related quality of life in airway diseases.


      4th Korean NHANES

      n = 9369
      25.0%Self-reported physician diagnosis of COPD, everSelf-reported physician diagnosed asthma, everEver self-reported physician diagnosis of asthma and COPDAge 65–84

      General population, Italy

      Smokers and nonsmokers
      de Marco et al., 2013
      • de Marco R.
      • Pesce G.
      • Marcon A.
      • et al.
      The coexistence of asthma and chronic obstructive pulmonary disease (COPD): prevalence and risk factors in young, middle-aged and elderly people from the general population.


      GEIRD

      n = 1030
      26.0%ICD-10 codes for COPD diagnoses (ICD-10:J41-J44)ICD-10 codes for asthma diagnoses (ICD-10:J45-J46)Diagnosis of both asthma and COPD based on ICD-10 codes at different timesAge>34

      Persons with a primary and/or secondary diagnosis of asthma and/or COPD based on ICD-10 codes among the entire Finnish population
      Andersen et al., 2013
      • Andersen H.
      • Lampela P.
      • Nevanlinna A.
      • et al.
      High hospital burden in overlap syndrome of asthma and COPD.


      Hospitalization records

      n = 105,122
      26.4%FEV1/FVC<0.70 or FEV1/FVC<88% of predictedPost-bronchodilator increase in FEV1 of ≥12%, a bronchodilator response of ≥15% or diurnal variation of ≥20% in PEF recording, moderate-to-severe bronchial hyperactivity, or a decrease in FEV1 of ≥15% in the exercise testDiagnosis of both asthma and COPD based on spirometric criteria134 volunteers

      Finnish patients with asthma and COPD
      Iwamoto et al., 2014
      • Iwamoto H.
      • Gao J.
      • Koskela J.
      • et al.
      Differences in plasma and sputum biomarkers between COPD and COPD-asthma overlap.


      Sample of patients from FinnCADStudy

      n = 134
      27.0%Self-reported physician diagnosis of COPD, everSelf-reported physician diagnosed asthma, everEver self-reported physician diagnosis of asthma and COPDAge 45–64

      General population, ItalySmokers and nonsmokers
      de Marco et al., 2013
      • de Marco R.
      • Pesce G.
      • Marcon A.
      • et al.
      The coexistence of asthma and chronic obstructive pulmonary disease (COPD): prevalence and risk factors in young, middle-aged and elderly people from the general population.


      GEIRD

      n = 2167
      27.0%FEV1/FVC<70% and FEV1 <80%Experience of asthmatic symptoms (i.e., wheezing, cough, and chest tightness worsening at night)Diagnosis of COPD and report of experiencing asthmatic symptomsHospital-based patient sample with stable COPD (2007–2009), JapanKitaguchi et al., 2012
      • Kitaguchi Y.
      • Komatsu Y.
      • Fujimoto K.
      • et al.
      Sputum eosinophilia can predict responsiveness to inhaled corticosteroid treatment in patients with overlap syndrome of COPD and asthma.


      n = 63
      30.2%ICD-9 codes 491, 492, and 496ICD-9 code 493Diagnosis of asthma and COPD within 12 monthsAge40

      US patients with medical and pharmacy benefits
      Blanchette et al., 2009
      • Blanchette C.M.
      • Broder M.
      • Ory C.
      • et al.
      Cost and utilization of COPD and asthma among insured adults in the US.


      US IHCIS Claims

      n = 24,935
      32.9%FEV1/FVC<0.70

      COPD Medical Codes
      Current or previous asthma diagnosisAsthma diagnosis among patients with COPDAge40

      UK patients with newly diagnosed COPD

      Smokers and nonsmokers
      Wurst et al., 2014
      • Wurst K.E.
      • Shukla A.
      • Muellerova H.
      • et al.
      Respiratory pharmacotherapy use in patients newly diagnosed with chronic obstructive pulmonary disease in a primary care setting in the UK: a retrospective cohort study.


      General practice research database

      n = 7881
      33.0%Self-reported physician diagnosis of COPD, everSelf-reported physician diagnosed asthma, everEver self-reported physician diagnosis of asthma and COPDAge 20–44

      General population, ItalySmokers and nonsmokers
      de Marco et al., 2013
      • de Marco R.
      • Pesce G.
      • Marcon A.
      • et al.
      The coexistence of asthma and chronic obstructive pulmonary disease (COPD): prevalence and risk factors in young, middle-aged and elderly people from the general population.


      GEIRD

      n = 5163
      41.4%Self-reported physician diagnosis of COPD, everSelf-reported physician diagnosed, everDiagnosis of asthma and COPD everAge18

      General population, US

      Smokers and nonsmokers
      Pleasants et al., 2014
      • Pleasants R.A.
      • Ohar J.A.
      • Croft J.B.
      • et al.
      Chronic obstructive pulmonary disease and asthma-patient characteristics and health impairment.


      NC BRFSS

      n = 24,073
      43.0%ICD-9 codes 491, 492, and 496ICD-9 code 493Diagnosis of asthma and COPD within 30 monthsAge 40–64

      US Medicaid patients
      Shaya et al., 2008
      • Shaya F.T.
      • Dongyi D.
      • Akazawa M.O.
      • et al.
      Burden of concomitant asthma and COPD in a medicaid population.


      Medicaid claims

      n = 9131
      49.0%FEV1/FVC<0.70 or FEV1/FVC<88% of predicted reference valuePost-bronchodilator increase in FEV1 of ≥12%, a bronchodilator response of ≥15% or diurnal variation of ≥20% in PEF recording, moderate to severe bronchial hyper reactivity, or a decrease in FEV1 of ≥15% in the exercise testDiagnosis of both asthma and COPD based on spirometric criteriaAge 18–75

      Finnish hospital-based population, identified from ICD-10 codes J44–J46

      Smokers and nonsmokers
      Kauppi et al., 2011
      • Kauppi P.
      • Kupiainen H.
      • Lindqvist A.
      • et al.
      Overlap syndrome of asthma and COPD predicts low quality of life.


      Medical records

      n = 1546
      54.6%ICD-10 codes J42–J44, except J430

      Use of more than one drug for COPD at least twice per year
      ICD-10 codes J45-J46

      Use of more than one drug for asthma at least twice per year
      Diagnosis of asthma and COPD within 12 monthsAge40

      Korean patient population

      Rhee et al., 2014
      • Rhee C.K.
      • Yoon H.K.
      • Yoo K.H.
      • et al.
      Medical utilization and cost in patients with overlap syndrome of chronic obstructive pulmonary disease and asthma.


      Insurance data

      n = 185,147
      55.2%FEV1/FVC<0.70Post-bronchodilator increase in FEV ≥15%, peak flow variability ≥20% during 1 week of testing, physician diagnosis of asthma in conjunction with current symptoms or inhaler use in the last 12 monthsDiagnosis of asthma within last 12 months and current COPDAge>50

      Random population based participants, New Zealand

      Smokers and nonsmokers
      Marsh et al., 2008
      • Marsh S.E.
      • Travers J.
      • Weatherall M.
      • et al.
      Proportional classifications of COPD phenotypes.


      Wellington respiratory survey subset

      n = 469
      ACOS: asthma-COPD overlap syndrome; COPD: chronic obstructive pulmonary disease; BOLD: Burden of Obstructive Lung Disease; COPDGene: Genetic Epidemiology of COPD; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; GEIRD: Gene–Environment Interactions in Respiratory Disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICD: International Classification of Diseases; IHCIS: Integrated Healthcare Information Services; NC BRFSS: North Carolina Behavioral Risk Factor Surveillance System; NHANES: National health and Nutrition Examination Study to the footnote; PEF: peak expiratory flow; PLATINO: Latin American Project for the Investigation of Lung Disease; SPIROMICS: Subpopulations and intermediate outcome measures in COPD study.
      a Lamprecht et al., 2011
      • Lamprecht B.
      • McBurnie M.A.
      • Vollmer W.M.
      • et al.
      COPD in never smokers: results from the population-based burden of obstructive lung disease study.
      : Of the patients with a physician diagnosis of asthma ‘ever’, 30.4% and 17.7% were considered GOLD stage II+ (FEV1/FVC<0.7 and FEV1<80% predicted) and GOLD stage I (FEV1/FVC<0.7 and FEV180% predicted), respectively.
      Table 3ACOS prevalence among patients with asthma: variation in study definition and details of general population of patients with asthma.
      Proportion of asthma Patients with ACOSCOPD definitionAsthma definitionACOS definitionDemographics of population with asthma

      (Age: years)
      Author, year

      Data

      Study sample size
      13.3%FEV1/FVC<0.70 and FEV1<80% predictedSelf-reported physician diagnosed, asthma everEvidence of obstruction (FEV/FVC<0.70 and FEV1<80% predicted, and ever self-reported physician diagnosis of asthma)Age25

      General Population, US

      Smokers and nonsmokers
      Diaz-Guzman et al., 2011
      • Diaz-Guzman E.
      • Khosravi M.
      • Mannino D.M.
      Asthma, chronic obstructive pulmonary disease, and mortality in the U.S. population.


      NHANES III

      n = 15,203
      16.0%Self-reported physician diagnosis of COPD, everSelf-reported physician diagnosed asthma, everEver self-reported physician diagnosis of asthma and COPDAge 20–44

      General population, Italy

      Smokers and nonsmokers
      de Marco et al., 2013
      • de Marco R.
      • Pesce G.
      • Marcon A.
      • et al.
      The coexistence of asthma and chronic obstructive pulmonary disease (COPD): prevalence and risk factors in young, middle-aged and elderly people from the general population.


      GEIRD

      n = 5163
      17.0%FEV1/FVC<0.70 or FEV1/FVC<88% of predictedPost-bronchodilator increase in FEV1 of ≥12%, a bronchodilator response of ≥15% or diurnal variation of ≥20% in PEF recording, moderate to severe bronchial hyper reactivity, or a decrease in FEV1 of ≥15% in the exercise test.Diagnosis of both asthma and COPD based on spirometric criteriaAge 18–75

      Finnish hospital-based study population identified fromICD-10 codes J44–J46
      Kauppi et al., 2011
      • Kauppi P.
      • Kupiainen H.
      • Lindqvist A.
      • et al.
      Overlap syndrome of asthma and COPD predicts low quality of life.


      Hospital medical records

      n = 1546
      18.0%FEV1/FVC<0.70Physician diagnosis of asthmaMeeting the criteria for asthma and COPDPatients with asthma ages 18–40

      Former or nonsmokers
      Kalberg et al., 2005
      • Kalberg C.
      • Sense W.
      • Knobil K.
      Fixed airway obstruction in patients with asthma: data from a large clinical trials database.


      Clinical trials database (1998–2002)

      n = 6497
      24.9%FEV1/FVC<0.70, FEV1<80% of predictedSelf-reported physician diagnosed, everMeeting the criteria for asthma and COPDAge40

      Multi-country

      Never smokers only
      Lamprecht et al., 2011
      • Lamprecht B.
      • McBurnie M.A.
      • Vollmer W.M.
      • et al.
      COPD in never smokers: results from the population-based burden of obstructive lung disease study.


      BOLD study

      n = 4291
      27.5%Airway obstruction where FEV1/FVC ratio < predicted LLNDiagnosis of bronchial asthma between 2009 and 2011Meeting the criteria for asthma and COPDAge 18–88 years

      Sample of US patients with spirometry data
      Banga et al., 2013
      • Banga A.
      • McCarthy K.
      • Pichurko B.M.
      Predictors of airway obstruction on spirometry among patients with bronchial asthma presenting to a tertiary care center.


      Tertiary care center

      n = 1482
      27.8%Self-reported physician diagnosis of COPD, everSelf-reported physician diagnosed asthma, everEver physician diagnosis of asthma and COPDAges18

      Smokers and nonsmokers

      General population,

      North Carolina, US
      Pleasants et al., 2014
      • Pleasants R.A.
      • Ohar J.A.
      • Croft J.B.
      • et al.
      Chronic obstructive pulmonary disease and asthma-patient characteristics and health impairment.


      NC BRFSS

      n = 24,073
      28.2%FEV1/FVC<0.70and no wheezing in past yearWheezing for past year and FEV1/FVC ≥ 0.70Wheezing and FEV1/FVC<0.70Korean patient population

      Smokers and nonsmokers
      Lee JH et al., 2013
      • Lee J.H.
      • Kong K.A.
      • Chung J.W.
      • et al.
      Health-related quality of life in airway diseases.


      4th Korean NHANES

      n = 9369
      29.0%FEV1/FVC<0.70Physician diagnosis of asthmaMeeting the criteria for asthma and COPDPatients with asthma ages 40–60

      Former or nonsmokers
      Kalberg et al., 2005
      • Kalberg C.
      • Sense W.
      • Knobil K.
      Fixed airway obstruction in patients with asthma: data from a large clinical trials database.


      Clinical trials database (1998–2002)

      n = 3346
      29.8%ICD-10 codes for COPD diagnoses (ICD-10:J41-J44)ICD-10 codes for asthma diagnoses (ICD-10:J45-J46)Diagnosis of both asthma and COPD based on ICD-10 codes at different timesAge34

      Persons with a primary and/or secondary diagnosis of asthma and/or COPD based on ICD-10 codes among the entire Finnish population
      Andersen et al., 2013
      • Andersen H.
      • Lampela P.
      • Nevanlinna A.
      • et al.
      High hospital burden in overlap syndrome of asthma and COPD.


      Hospitalization records

      n = 105,122
      30.0%Self-reported physician diagnosis of COPD, everSelf-reported physician diagnosed asthma, everEver self-reported physician diagnosis of asthma and COPDAge 45–64

      General population, Italy

      Smokers and nonsmokers
      de Marco et al., 2013
      • de Marco R.
      • Pesce G.
      • Marcon A.
      • et al.
      The coexistence of asthma and chronic obstructive pulmonary disease (COPD): prevalence and risk factors in young, middle-aged and elderly people from the general population.


      GEIRD

      n = 2167
      30.4%FEV1/FVC<0.70 or FEV1/FVC<88% of predictedPost-bronchodilator increase in FEV1 of ≥12%, a bronchodilator response of ≥15% or diurnal variation of ≥20% in PEF recording, moderate-to-severe bronchial hyperactivity, or a decrease in FEV1 of ≥15% in the exercise testDiagnosis of both asthma and COPD based on spirometric criteria134 volunteers

      Finnish patients with asthma and COPD
      Iwamoto et al., 2014
      • Iwamoto H.
      • Gao J.
      • Koskela J.
      • et al.
      Differences in plasma and sputum biomarkers between COPD and COPD-asthma overlap.


      Sample of patients from FinnCADStudy

      n = 134
      43.0%FEV1/FVC<0.70Physician diagnosis of asthmaMeeting the criteria for asthma and COPDPatients with asthma age>60

      US population

      Former or nonsmokers
      Kalberg et al., 2005
      • Kalberg C.
      • Sense W.
      • Knobil K.
      Fixed airway obstruction in patients with asthma: data from a large clinical trials database.


      Clinical trials database (1998–2002)

      n = 601
      45.9%ICD-9 Codes 491, 492, and 496ICD-9 Code 493Diagnosis of asthma and COPD within 30 monthsAge 40–64

      US Medicaid patients
      Shaya et al., 2008
      • Shaya F.T.
      • Dongyi D.
      • Akazawa M.O.
      • et al.
      Burden of concomitant asthma and COPD in a medicaid population.


      Medicaid claims

      n = 9131
      46.0%Post-bronchodilator FEV1 or FEV1/FVC<75% of predicted with a TLC>75% of predictedWheezing history, FEV1/FVC<0.70 and post-bronchodilator FEV1 increase of 12%, PC20, diurnal PEF variation/tapering medMeeting criteria for asthma and COPDAverage age 55.3 (SD 11.7)

      Former or nonsmokers
      Wagener, 2013
      • Wagener A.H.
      • Gibeon D.
      • Yang X.
      • et al.
      Associated factors persistent airflow limitation in asthma in U-BIOPRED.


      U-BIOPRED study cohort

      n = 148
      51.4%FEV1/FVC<0.70Report of wheezing in the last 12 months and post-bronchodilator increase in FEV1 or FVC of 0.200 L and 12%COPD diagnosis among patients with asthmaAge>40

      Population in 5 Latin American cities

      Smokers and nonsmokers
      Menezes et al., 2014
      • Menezes A.M.
      • Montes de Oca M.
      • Perez-Padilla R.
      • et al.
      Increased risk of exacerbation and hospitalization in subjects with an overlap phenotype: COPD-asthma.


      PLATINO

      n = 5044
      61.0%Self-reported physician diagnosis of COPD, everSelf-reported physician diagnosed asthma, everEver self-reported physician diagnosis of asthma and COPDAge 65–84

      General population, Italy

      Smokers and nonsmokers
      de Marco et al., 2013
      • de Marco R.
      • Pesce G.
      • Marcon A.
      • et al.
      The coexistence of asthma and chronic obstructive pulmonary disease (COPD): prevalence and risk factors in young, middle-aged and elderly people from the general population.


      GEIRD

      n = 1030
      ACOS: asthma-COPD overlap syndrome; COPD: chronic obstructive pulmonary disease; BOLD: Burden of Obstructive Lung Disease; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; GEIRD: Gene–Environment Interactions in Respiratory Disease; ICD: International Classification of Diseases; LLN, lower limit of normal; NC BRFSS: North Carolina Behavioral Risk Factor Surveillance System; NHANES: National Health and Nutrition Examination Survey; PEF: peak expiratory flow; PLATINO: Latin American Project for the Investigation of Lung Disease; U-BIOPRED: Unbiased BIOmarkers in PREDiction of respiratory outcomes; SD: standard deviation.

      6. Spirometry-based versus clinical or symptom-based diagnoses

      In some studies an asthma diagnosis is based on spirometry-confirmed reversibility. The investigators from the Latin American Project for the Investigation of Lung Disease (PLATINO) study in Latin America noted that two different definitions of asthma resulted in varied ACOS prevalence estimates in the same population. The prevalence of ACOS based on spirometry and the presence of reversibility was estimated to be 1.8% compared with 2.9% using physician diagnosis only [
      • Menezes A.M.
      • Montes de Oca M.
      • Perez-Padilla R.
      • et al.
      Increased risk of exacerbation and hospitalization in subjects with an overlap phenotype: COPD-asthma.
      ].

      7. Spirometry-defined asthma

      The variation in ACOS prevalence estimates among patients with COPD is highlighted by the reversibility criteria in patients with COPD set forth in different medical systems internationally. In a Finnish medical records cohort study, the authors stated that reversibility seen in patients with COPD is considered to be asthma, so definitions of COPD and asthma among the Finnish population will sometimes differ compared with other populations [
      • Andersen H.
      • Lampela P.
      • Nevanlinna A.
      • et al.
      High hospital burden in overlap syndrome of asthma and COPD.
      ,
      • Kauppi P.
      • Kupiainen H.
      • Lindqvist A.
      • et al.
      Overlap syndrome of asthma and COPD predicts low quality of life.
      ]. Analysis of medical records and hospitalization records in Finland estimated that between 30% and 49% of patients with COPD also have ACOS [
      • Andersen H.
      • Lampela P.
      • Nevanlinna A.
      • et al.
      High hospital burden in overlap syndrome of asthma and COPD.
      ,
      • Kauppi P.
      • Kupiainen H.
      • Lindqvist A.
      • et al.
      Overlap syndrome of asthma and COPD predicts low quality of life.
      ]; here diagnostic criteria of asthma appeared to be based on spirometric measurements, including spirometric criteria for reversibility [
      • Andersen H.
      • Lampela P.
      • Nevanlinna A.
      • et al.
      High hospital burden in overlap syndrome of asthma and COPD.
      ].
      In other countries where reversibility among patients with COPD is not necessarily regarded as asthma, it is difficult to distinguish between COPD with asthma and COPD alone with airway reversibility. If ACOS is defined on the basis of obstruction and reversibility, this phenotype may include patients with COPD who have reversibility but no other asthma features. Evidence now suggests that 12–42% of patients with COPD may demonstrate post-bronchodilator reversibility; however, reversibility may vary over time and thus it may not be a stable phenotype [
      • Calverley P.M.
      • Burge P.S.
      • Spencer S.
      • et al.
      Bronchodilator reversibility testing in chronic obstructive pulmonary disease.
      ,
      • Albert P.
      • Agusti A.
      • Edwards L.
      • et al.
      Bronchodilator responsiveness as a phenotypic characteristic of established chronic obstructive pulmonary disease.
      ].

      8. Spirometry-defined COPD

      When using spirometric criteria for COPD classification, the estimates of ACOS among patients with asthma ranged from 25.0% to 51.4% (Table 3). The diagnostic criteria for COPD also influence estimates of both overall COPD prevalence and ACOS prevalence. Marsh et al., [
      • Marsh S.E.
      • Travers J.
      • Weatherall M.
      • et al.
      Proportional classifications of COPD phenotypes.
      ] estimated an ACOS prevalence of 55.2% in patients with COPD aged 50 years and older using spirometric criteria. The authors estimated the prevalence of ACOS using two different criteria for COPD, (1) FEV1/FVC<0.70 and (2) FEV1/FVC less than the LLN [
      • Marsh S.E.
      • Travers J.
      • Weatherall M.
      • et al.
      Proportional classifications of COPD phenotypes.
      ]. They concluded that when less than the LLN criterion was used in COPD diagnosis rather than the FEV1/FVC<0.70 criterion, one-third fewer patients presented with COPD. Furthermore, Marsh et al., concluded that fewer patients with COPD also presented with the ‘asthma phenotype’ (reversibility, peak flow variability, or physician diagnosis in addition to COPD) when the LLN criterion was used instead of the FEV1/FVC<0.70 criterion [
      • Marsh S.E.
      • Travers J.
      • Weatherall M.
      • et al.
      Proportional classifications of COPD phenotypes.
      ].
      A Norwegian study compared spirometric results against physician diagnoses in 376 patients aged 40 years or older [
      • Melbye H.
      • Drivenes E.
      • Dalbak L.G.
      • et al.
      Asthma, chronic obstructive pulmonary disease, or both? Diagnostic labeling and spirometry in primary care patients aged 40 years or more.
      ]. The study reported that among patients previously diagnosed with only asthma by a physician, 17.1% could be re-diagnosed with COPD because of obstruction using spirometric criteria [
      • Melbye H.
      • Drivenes E.
      • Dalbak L.G.
      • et al.
      Asthma, chronic obstructive pulmonary disease, or both? Diagnostic labeling and spirometry in primary care patients aged 40 years or more.
      ]. Diaz-Guzman et al., reported that 13.3% of patients with asthma in the US National Health and Nutrition Examination Survey (NHANES) III had evidence of obstruction and thus may also be classified as COPD or ACOS [
      • Diaz-Guzman E.
      • Khosravi M.
      • Mannino D.M.
      Asthma, chronic obstructive pulmonary disease, and mortality in the U.S. population.
      ].

      9. Self-reported physician diagnosis

      In the Continuing to Confront COPD survey, international prevalence estimates of ACOS among patients with COPD in 12 countries ranged from 12% to 54% [
      • Landis S.H.
      • Muellerova H.
      • Mannino D.M.
      • et al.
      Continuing to confront COPD International Patient Survey: methods, COPD prevalence, and disease burden in 2012-2013.
      ]. Asthma was defined as self-reported physician diagnosis and COPD as self-reported physician diagnosis or symptom-based chronic bronchitis. The broad range of estimates highlights the differences in underlying asthma population characteristics, diagnosis practices, and healthcare systems across countries.

      10. ACOS defined in claims data

      ACOS prevalence estimates are generally higher using claims data than those using spirometric definitions or self-reported physician diagnoses. It is unknown whether the medical codes are based on reversibility criteria or other criteria including symptoms such as wheezing. An analysis of US claims data using International Classification of Disease (ICD)-9 codes estimated that 30–43% of the population over 40 years of age with a diagnosis code for COPD also had an asthma diagnosis code within 12–30 months [
      • Blanchette C.M.
      • Broder M.
      • Ory C.
      • et al.
      Cost and utilization of COPD and asthma among insured adults in the US.
      ,
      • Shaya F.T.
      • Dongyi D.
      • Akazawa M.O.
      • et al.
      Burden of concomitant asthma and COPD in a medicaid population.
      ]. Estimates from claims data depend on the duration of time allowed between COPD and asthma diagnostic codes and whether more than one asthma code is required, as some patients may receive an asthma diagnosis before their COPD diagnosis and thus could be misclassified as having both diseases. Patients with more utilizations (for any reason) also have more opportunities to receive dual diagnoses. Additionally, as was previously mentioned, it may not be clear how the physician diagnosed COPD or asthma (i.e., if spirometry was used and if reversibility was considered).

      11. Asthma definition: past versus current asthma

      Another source of variation in ACOS prevalence estimates is the definition of asthma with regard to timing of the diagnosis, for example, ‘ever’ diagnosed with asthma, ‘prior’ asthma diagnosis (usually before the age of 40), or ‘current’ asthma diagnosis. The ACOS literature lacks consensus on whether the ACOS population only includes those with the concurrence of existing asthma and clinical characteristics of COPD or if the ACOS population includes patients with COPD and a history of asthma. The GINA guidelines include both [
      • Global Initiative for Asthma
      From the Global Strategy for Asthma Management and Prevention.
      ].
      In the subpopulations and intermediate outcome measures in the COPD study (SPIROMICS), restricting asthma diagnostic criteria to a current asthma diagnosis resulted in an ACOS prevalence estimate of 16.7% among smokers over the age of 40 with COPD [
      • Putcha N.
      • Drummond M.B.
      • Martinez C.H.
      • et al.
      Self-reported asthma is associated with worse health outcomes in COPD.
      ]. A study of self-reported, physician-diagnosed asthma among smokers before the age of 40 with no current diagnosis reported a prevalence of ACOS of 12.1% among patients with COPD [
      • Izquierdo-Alonso J.L.
      • Rodriguez-Gonzalezmoro J.M.
      • de Lucas-Ramos P.
      • et al.
      Prevalence and characteristics of three clinical phenotypes of chronic obstructive pulmonary disease (COPD).
      ]. A UK study of ACOS that defined asthma as a current or former diagnosis reported a prevalence of 32.9% in smokers and nonsmokers with COPD [
      • Wurst K.E.
      • Shukla A.
      • Muellerova H.
      • et al.
      Respiratory pharmacotherapy use in patients newly diagnosed with chronic obstructive pulmonary disease in a primary care setting in the UK: a retrospective cohort study.
      ]. All three of these studies used spirometric criteria for the evaluation of COPD, and used either self-reported physician diagnosis or medical codes for asthma identification. Comparing these studies, the inclusion of current or past asthma (i.e., ‘ever’ asthma) resulted in higher estimates of ACOS prevalence than studies with asthma defined as ‘current’ asthma or as only ‘past’ asthma.
      Ford and Mannino [
      • Ford E.S.
      • Mannino D.M.
      Time trends in obesity among adults with asthma in the United States: findings from three national survey.
      ] utilized data from the US NHANES III (1988–1994) to estimate the prevalence of ‘ever’ asthma (7.8%) and ‘current’ asthma (5.2%) in people aged 20–74 years. Taken together, these estimates suggest that 67% of people to ever report asthma will currently report asthma; applying that proportion to the ACOS population prevalence estimate of 2.7% from Diaz-Guzman et al., who defined asthma as ‘ever’ reported, the prevalence of ACOS decreases to 1.8%, demonstrating the change in estimate when using ‘current’ versus ‘ever’ asthma [
      • Diaz-Guzman E.
      • Khosravi M.
      • Mannino D.M.
      Asthma, chronic obstructive pulmonary disease, and mortality in the U.S. population.
      ].

      12. Comparisons among definitions

      Differences between studies such as sample size, source population, and age inclusion criteria make it difficult to conclude that using spirometric diagnosis is solely responsible for the difference in estimates [
      • Marsh S.E.
      • Travers J.
      • Weatherall M.
      • et al.
      Proportional classifications of COPD phenotypes.
      ,
      • Pleasants R.A.
      • Ohar J.A.
      • Croft J.B.
      • et al.
      Chronic obstructive pulmonary disease and asthma-patient characteristics and health impairment.
      ]. Generally, there are four different classification schemes for defining ACOS: (1) a reported physician diagnosis of asthma and a reported physician diagnosis of COPD at any point in a patient's life, (2) a reported physician diagnosis of asthma and spirometry-defined COPD, (3) both spirometry-defined asthma and spirometry-defined COPD, and (4) ICD codes to determine both asthma and COPD diagnoses among patients. There is considerable variability in prevalence estimates of ACOS for each of the definitions in patients with COPD [
      • Andersen H.
      • Lampela P.
      • Nevanlinna A.
      • et al.
      High hospital burden in overlap syndrome of asthma and COPD.
      ,
      • Hardin M.
      • Cho M.
      • McDonald M.L.
      • et al.
      The clinical and genetic features of COPD-asthma overlap syndrome.
      ,
      • Kauppi P.
      • Kupiainen H.
      • Lindqvist A.
      • et al.
      Overlap syndrome of asthma and COPD predicts low quality of life.
      ,
      • Menezes A.M.
      • Montes de Oca M.
      • Perez-Padilla R.
      • et al.
      Increased risk of exacerbation and hospitalization in subjects with an overlap phenotype: COPD-asthma.
      ,
      • Putcha N.
      • Drummond M.B.
      • Martinez C.H.
      • et al.
      Self-reported asthma is associated with worse health outcomes in COPD.
      ,
      • Izquierdo-Alonso J.L.
      • Rodriguez-Gonzalezmoro J.M.
      • de Lucas-Ramos P.
      • et al.
      Prevalence and characteristics of three clinical phenotypes of chronic obstructive pulmonary disease (COPD).
      ,
      • Marsh S.E.
      • Travers J.
      • Weatherall M.
      • et al.
      Proportional classifications of COPD phenotypes.
      ,
      • Pleasants R.A.
      • Ohar J.A.
      • Croft J.B.
      • et al.
      Chronic obstructive pulmonary disease and asthma-patient characteristics and health impairment.
      ,
      • Lee J.H.
      • Kong K.A.
      • Chung J.W.
      • et al.
      Health-related quality of life in airway diseases.
      ,
      • de Marco R.
      • Pesce G.
      • Marcon A.
      • et al.
      The coexistence of asthma and chronic obstructive pulmonary disease (COPD): prevalence and risk factors in young, middle-aged and elderly people from the general population.
      ,
      • Hardin M.
      • Silverman E.K.
      • Barr R.G.
      • et al.
      The clinical features of the overlap between COPD and asthma.
      ,
      • Wurst K.E.
      • Shukla A.
      • Muellerova H.
      • et al.
      Respiratory pharmacotherapy use in patients newly diagnosed with chronic obstructive pulmonary disease in a primary care setting in the UK: a retrospective cohort study.
      ,
      • Talamo C.
      • de Oca M.M.
      • Halbert R.
      • et al.
      Diagnostic labeling of COPD in five Latin American cities.
      ,
      • Lamprecht B.
      • McBurnie M.A.
      • Vollmer W.M.
      • et al.
      COPD in never smokers: results from the population-based burden of obstructive lung disease study.
      ,
      • Iwamoto H.
      • Gao J.
      • Koskela J.
      • et al.
      Differences in plasma and sputum biomarkers between COPD and COPD-asthma overlap.
      ,
      • Kitaguchi Y.
      • Komatsu Y.
      • Fujimoto K.
      • et al.
      Sputum eosinophilia can predict responsiveness to inhaled corticosteroid treatment in patients with overlap syndrome of COPD and asthma.
      ,
      • Blanchette C.M.
      • Broder M.
      • Ory C.
      • et al.
      Cost and utilization of COPD and asthma among insured adults in the US.
      ,
      • Shaya F.T.
      • Dongyi D.
      • Akazawa M.O.
      • et al.
      Burden of concomitant asthma and COPD in a medicaid population.
      ,
      • Rhee C.K.
      • Yoon H.K.
      • Yoo K.H.
      • et al.
      Medical utilization and cost in patients with overlap syndrome of chronic obstructive pulmonary disease and asthma.
      ] (Fig. 2) and in patients with asthma [
      • Andersen H.
      • Lampela P.
      • Nevanlinna A.
      • et al.
      High hospital burden in overlap syndrome of asthma and COPD.
      ,
      • Kauppi P.
      • Kupiainen H.
      • Lindqvist A.
      • et al.
      Overlap syndrome of asthma and COPD predicts low quality of life.
      ,
      • Menezes A.M.
      • Montes de Oca M.
      • Perez-Padilla R.
      • et al.
      Increased risk of exacerbation and hospitalization in subjects with an overlap phenotype: COPD-asthma.
      ,
      • Pleasants R.A.
      • Ohar J.A.
      • Croft J.B.
      • et al.
      Chronic obstructive pulmonary disease and asthma-patient characteristics and health impairment.
      ,
      • Diaz-Guzman E.
      • Khosravi M.
      • Mannino D.M.
      Asthma, chronic obstructive pulmonary disease, and mortality in the U.S. population.
      ,
      • Lee J.H.
      • Kong K.A.
      • Chung J.W.
      • et al.
      Health-related quality of life in airway diseases.
      ,
      • de Marco R.
      • Pesce G.
      • Marcon A.
      • et al.
      The coexistence of asthma and chronic obstructive pulmonary disease (COPD): prevalence and risk factors in young, middle-aged and elderly people from the general population.
      ,
      • Lamprecht B.
      • McBurnie M.A.
      • Vollmer W.M.
      • et al.
      COPD in never smokers: results from the population-based burden of obstructive lung disease study.
      ,
      • Iwamoto H.
      • Gao J.
      • Koskela J.
      • et al.
      Differences in plasma and sputum biomarkers between COPD and COPD-asthma overlap.
      ,
      • Shaya F.T.
      • Dongyi D.
      • Akazawa M.O.
      • et al.
      Burden of concomitant asthma and COPD in a medicaid population.
      ,
      • Kalberg C.
      • Sense W.
      • Knobil K.
      Fixed airway obstruction in patients with asthma: data from a large clinical trials database.
      ,
      • Banga A.
      • McCarthy K.
      • Pichurko B.M.
      Predictors of airway obstruction on spirometry among patients with bronchial asthma presenting to a tertiary care center.
      ,
      • Wagener A.H.
      • Gibeon D.
      • Yang X.
      • et al.
      Associated factors persistent airflow limitation in asthma in U-BIOPRED.
      ] (Fig. 3).
      Figure thumbnail gr2
      Fig. 2ACOS prevalence among patients with COPD (corresponding to ). Asthma – Diagnosis/COPD – Spirometry: studies with a reported physician diagnosis of asthma and spirometry defined COPD; Asthma – Spirometry/COPD – Spirometry: studies with spirometry defined asthma and spirometry defined COPD; Asthma – Diagnosis/COPD – Diagnosis: studies with a reported physician diagnosis of asthma and a reported physician diagnosis of COPD at any point in a patient's life; Asthma – ICD Code/COPD – ICD Code: studies with ICD code classification for both asthma and COPD. ACOS: asthma-COPD overlap syndrome; COPD: chronic obstructive pulmonary disease; ICD, International Classification of Diseases.
      Figure thumbnail gr3
      Fig. 3ACOS prevalence among patients with asthma (corresponding to ). Asthma – Diagnosis/COPD – Spirometry: studies with a reported physician diagnosis of asthma and spirometry defined COPD; Asthma – Spirometry/COPD – Spirometry: studies with spirometry defined asthma and spirometry defined COPD; Asthma – Diagnosis/COPD – Diagnosis: studies with a reported physician diagnosis of asthma and a reported physician diagnosis of COPD at any point in a patient's life; Asthma – ICD Code/COPD – ICD Code: studies with ICD code classification for both asthma and COPD. ACOS: asthma – COPD overlap syndrome; COPD: chronic obstructive pulmonary disease; ICD, International Classification of Diseases.
      The ACOS prevalence estimate ranged from 25.0% to 41.4% when ACOS was defined as a self-report of a physician diagnosis of both asthma and COPD (1) [
      • Pleasants R.A.
      • Ohar J.A.
      • Croft J.B.
      • et al.
      Chronic obstructive pulmonary disease and asthma-patient characteristics and health impairment.
      ,
      • de Marco R.
      • Pesce G.
      • Marcon A.
      • et al.
      The coexistence of asthma and chronic obstructive pulmonary disease (COPD): prevalence and risk factors in young, middle-aged and elderly people from the general population.
      ]. When ACOS was defined as a reported physician diagnosis of asthma and spirometry-defined COPD, the ACOS prevalence estimates in patients with COPD ranged from 12.1% to 32.9% (2) [
      • Hardin M.
      • Cho M.
      • McDonald M.L.
      • et al.
      The clinical and genetic features of COPD-asthma overlap syndrome.
      ,
      • Putcha N.
      • Drummond M.B.
      • Martinez C.H.
      • et al.
      Self-reported asthma is associated with worse health outcomes in COPD.
      ,
      • Izquierdo-Alonso J.L.
      • Rodriguez-Gonzalezmoro J.M.
      • de Lucas-Ramos P.
      • et al.
      Prevalence and characteristics of three clinical phenotypes of chronic obstructive pulmonary disease (COPD).
      ,
      • Hardin M.
      • Silverman E.K.
      • Barr R.G.
      • et al.
      The clinical features of the overlap between COPD and asthma.
      ,
      • Wurst K.E.
      • Shukla A.
      • Muellerova H.
      • et al.
      Respiratory pharmacotherapy use in patients newly diagnosed with chronic obstructive pulmonary disease in a primary care setting in the UK: a retrospective cohort study.
      ,
      • Talamo C.
      • de Oca M.M.
      • Halbert R.
      • et al.
      Diagnostic labeling of COPD in five Latin American cities.
      ,
      • Lamprecht B.
      • McBurnie M.A.
      • Vollmer W.M.
      • et al.
      COPD in never smokers: results from the population-based burden of obstructive lung disease study.
      ,
      • Kitaguchi Y.
      • Komatsu Y.
      • Fujimoto K.
      • et al.
      Sputum eosinophilia can predict responsiveness to inhaled corticosteroid treatment in patients with overlap syndrome of COPD and asthma.
      ]. Prevalence estimates for ACOS in patients with COPD from varying geographic regions using spirometry-defined asthma and spirometry-defined COPD (3) produced the widest range of all subgroups at 13.0–55.2% [
      • Kauppi P.
      • Kupiainen H.
      • Lindqvist A.
      • et al.
      Overlap syndrome of asthma and COPD predicts low quality of life.
      ,
      • Menezes A.M.
      • Montes de Oca M.
      • Perez-Padilla R.
      • et al.
      Increased risk of exacerbation and hospitalization in subjects with an overlap phenotype: COPD-asthma.
      ,
      • Marsh S.E.
      • Travers J.
      • Weatherall M.
      • et al.
      Proportional classifications of COPD phenotypes.
      ,
      • Lee J.H.
      • Kong K.A.
      • Chung J.W.
      • et al.
      Health-related quality of life in airway diseases.
      ,
      • Iwamoto H.
      • Gao J.
      • Koskela J.
      • et al.
      Differences in plasma and sputum biomarkers between COPD and COPD-asthma overlap.
      ]. In studies that used ICD codes for both the COPD and asthma diagnoses (4) [
      • Andersen H.
      • Lampela P.
      • Nevanlinna A.
      • et al.
      High hospital burden in overlap syndrome of asthma and COPD.
      ,
      • Blanchette C.M.
      • Broder M.
      • Ory C.
      • et al.
      Cost and utilization of COPD and asthma among insured adults in the US.
      ,
      • Shaya F.T.
      • Dongyi D.
      • Akazawa M.O.
      • et al.
      Burden of concomitant asthma and COPD in a medicaid population.
      ,
      • Rhee C.K.
      • Yoon H.K.
      • Yoo K.H.
      • et al.
      Medical utilization and cost in patients with overlap syndrome of chronic obstructive pulmonary disease and asthma.
      ], the range of ACOS prevalence estimates in patients with COPD was generally higher than when ACOS was defined as self-reported asthma and spirometry-defined COPD (26.0–54.6% versus 12.1–32.9%, respectively, Fig. 2) [
      • Hardin M.
      • Cho M.
      • McDonald M.L.
      • et al.
      The clinical and genetic features of COPD-asthma overlap syndrome.
      ,
      • Putcha N.
      • Drummond M.B.
      • Martinez C.H.
      • et al.
      Self-reported asthma is associated with worse health outcomes in COPD.
      ,
      • Izquierdo-Alonso J.L.
      • Rodriguez-Gonzalezmoro J.M.
      • de Lucas-Ramos P.
      • et al.
      Prevalence and characteristics of three clinical phenotypes of chronic obstructive pulmonary disease (COPD).
      ,
      • Hardin M.
      • Silverman E.K.
      • Barr R.G.
      • et al.
      The clinical features of the overlap between COPD and asthma.
      ,
      • Wurst K.E.
      • Shukla A.
      • Muellerova H.
      • et al.
      Respiratory pharmacotherapy use in patients newly diagnosed with chronic obstructive pulmonary disease in a primary care setting in the UK: a retrospective cohort study.
      ,
      • Talamo C.
      • de Oca M.M.
      • Halbert R.
      • et al.
      Diagnostic labeling of COPD in five Latin American cities.
      ,
      • Lamprecht B.
      • McBurnie M.A.
      • Vollmer W.M.
      • et al.
      COPD in never smokers: results from the population-based burden of obstructive lung disease study.
      ,
      • Kitaguchi Y.
      • Komatsu Y.
      • Fujimoto K.
      • et al.
      Sputum eosinophilia can predict responsiveness to inhaled corticosteroid treatment in patients with overlap syndrome of COPD and asthma.
      ].
      The same high variability also exists when examining ACOS prevalence among patients with asthma, again, with variability depending on the asthma and COPD definitions used (Table 3, Fig. 3). When ACOS was defined by the combination of self-reported asthma and spirometry-defined COPD (2), the ACOS prevalence estimates ranged from 13.3% to 43.0% [
      • Diaz-Guzman E.
      • Khosravi M.
      • Mannino D.M.
      Asthma, chronic obstructive pulmonary disease, and mortality in the U.S. population.
      ,
      • Lamprecht B.
      • McBurnie M.A.
      • Vollmer W.M.
      • et al.
      COPD in never smokers: results from the population-based burden of obstructive lung disease study.
      ,
      • Kalberg C.
      • Sense W.
      • Knobil K.
      Fixed airway obstruction in patients with asthma: data from a large clinical trials database.
      ,
      • Banga A.
      • McCarthy K.
      • Pichurko B.M.
      Predictors of airway obstruction on spirometry among patients with bronchial asthma presenting to a tertiary care center.
      ]. When defining ACOS as a self-reported physician diagnosis of COPD and a self-reported physician asthma diagnosis (1), the ACOS prevalence estimates had a wider range (16.0–61.0%) [
      • Pleasants R.A.
      • Ohar J.A.
      • Croft J.B.
      • et al.
      Chronic obstructive pulmonary disease and asthma-patient characteristics and health impairment.
      ,
      • de Marco R.
      • Pesce G.
      • Marcon A.
      • et al.
      The coexistence of asthma and chronic obstructive pulmonary disease (COPD): prevalence and risk factors in young, middle-aged and elderly people from the general population.
      ] than the ACOS estimates using spirometric criteria for both (3) asthma and COPD (17.0–51.4%) [
      • Kauppi P.
      • Kupiainen H.
      • Lindqvist A.
      • et al.
      Overlap syndrome of asthma and COPD predicts low quality of life.
      ,
      • Menezes A.M.
      • Montes de Oca M.
      • Perez-Padilla R.
      • et al.
      Increased risk of exacerbation and hospitalization in subjects with an overlap phenotype: COPD-asthma.
      ,
      • Lee J.H.
      • Kong K.A.
      • Chung J.W.
      • et al.
      Health-related quality of life in airway diseases.
      ,
      • Iwamoto H.
      • Gao J.
      • Koskela J.
      • et al.
      Differences in plasma and sputum biomarkers between COPD and COPD-asthma overlap.
      ,
      • Wagener A.H.
      • Gibeon D.
      • Yang X.
      • et al.
      Associated factors persistent airflow limitation in asthma in U-BIOPRED.
      ]. Two disparate prevalence estimates (29.8% and 45.9%) of ACOS among patients with asthma were obtained from the studies that used ICD codes (4) [
      • Andersen H.
      • Lampela P.
      • Nevanlinna A.
      • et al.
      High hospital burden in overlap syndrome of asthma and COPD.
      ,
      • Shaya F.T.
      • Dongyi D.
      • Akazawa M.O.
      • et al.
      Burden of concomitant asthma and COPD in a medicaid population.
      ].

      13. Differences in ACOS prevalence estimates due to age of the study cohort

      As ACOS is more prevalent in the population over 40 years of age and has a relatively low prevalence in younger age groups, the age of the study population can affect the estimated ACOS prevalence. For example, in a study from Finland 0.4% of patients with ACOS were ≤40 years of age and 78.2% of patients with ACOS were over the age of 55 years [
      • Kauppi P.
      • Kupiainen H.
      • Lindqvist A.
      • et al.
      Overlap syndrome of asthma and COPD predicts low quality of life.
      ]. In a second study performed in Italy, 1.6% of patients aged 20–44 and 2.1% of patients aged 45–64 years had ACOS, compared with 4.5% of patients aged 65–84 years [
      • de Marco R.
      • Pesce G.
      • Marcon A.
      • et al.
      The coexistence of asthma and chronic obstructive pulmonary disease (COPD): prevalence and risk factors in young, middle-aged and elderly people from the general population.
      ]. Thus, inclusion of younger patients in a study can reduce the estimated ACOS prevalence.

      14. Differences in estimates due to inclusion of smoking

      Despite differences in COPD definitions across studies (SPIROMICS, Genetic Epidemiology of COPD [COPDGene] and Burden of Obstructive Lung Disease [BOLD]), smoking seems to be associated with an increase in ACOS prevalence estimates. The COPDGene and SPIROMICS studies examined the ACOS prevalence among smokers with COPD and found the prevalence of ACOS to be 12.6% and 16.7%, respectively [
      • Hardin M.
      • Cho M.
      • McDonald M.L.
      • et al.
      The clinical and genetic features of COPD-asthma overlap syndrome.
      ,
      • Putcha N.
      • Drummond M.B.
      • Martinez C.H.
      • et al.
      Self-reported asthma is associated with worse health outcomes in COPD.
      ]. However, studies estimating the prevalence of ACOS in nonsmokers are limited. Nonsmokers and never smokers with COPD may represent an important component of the ACOS population and provide information on ACOS population characteristics and risk factors. Nonsmokers (fewer than 10 pack-years) who cannot achieve adequate asthma control may often represent a portion of patients with ACOS, as they are likely to have undiagnosed COPD symptoms [
      • Louie S.
      • Zeki A.A.
      • Schivo M.
      • et al.
      The asthma-chronic obstructive pulmonary disease overlap syndrome: pharmacotherapeutic considerations.
      ,
      • Bateman E.D.
      • Feldman C.
      • O'Brien J.
      • et al.
      Guideline for the management of chronic obstructive pulmonary disease (COPD): 2004 revision.
      ]. Furthermore, COPD among never smokers is often under-diagnosed, in part because there is little understanding of the risk factors of COPD among never smokers [
      • Salvi S.S.
      • Barnes P.J.
      Chronic obstructive pulmonary disease in non-smokers.
      ].

      15. Target populations for future research

      In order to understand the phenotypes better of asthma, COPD, and ACOS, future studies should place emphasis on nonsmokers with COPD and assess whether ACOS should be defined as COPD with a history of asthma, COPD concurrent with asthma, or both. It would also be clinically important to determine if smokers who receive an early diagnosis of asthma (before the age of 35 years) have a greater risk of developing COPD than nonsmokers with an early diagnosis of asthma. Furthermore, development of distinct phenotypes and biomarkers should be prioritized not only to improve the diagnosis and definition of ACOS, but also to understand the pathogenesis of ACOS. Patients may have identical physiology in terms of FEV1/FVC ratios and reversibility, but these patients may have very different underlying pathology or different treatment responses to medication. In order to make progress in the treatment and prevention of ACOS, we need to move from an emphasis on using physiology to predict treatment responses to understanding the underlying pathology of the disease. Additionally, comprehensive therapeutic interventions for patients with ACOS need to be established.

      16. Conclusions

      Efforts to estimate the prevalence of ACOS on the basis of physiologic measures, such as FEV1, FEV1/FVC ratio and degree of reversibility, are misleading because these criteria do not always clearly separate asthma and COPD, and therefore, do not help in defining the ACOS population. We recommend that at a minimum, future investigations on ACOS include a detailed smoking history, the basis of the diagnosis of asthma, the degree of reversibility and whether this was measured on or off treatment so that a uniform dataset is available to provide a basis for comparison of results among studies and guide decision making on the most appropriate criteria for defining ACOS.

      Role of the funding source

      The work presented here, including the conduct of the literature review and analysis, was supported by GSK.

      Author contributions

      All authors contributed to the writing of the paper and participated in the review and interpretation of the data. All authors read and approved the final manuscript.

      Conflict of interest

      KW was an employee of GSK at the time the study was performed.
      SP and NB are employees of GSK and own stocks/shares in GSK.
      KK-R and GB hold graduate research assistant positions at The University of North Carolina.

      Acknowledgments

      Editorial support (provided by Joann Hettasch, PhD, and Natasha Thomas, PhD, Fishawack Indicia Ltd) was funded by GSK.

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