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AsthmaCOPD OverlapClinical Relevance of Genomic Signatures of Type 2 Inflammation in COPD Asthma-COPD Overlap Syndrome (ACOS) In the spectrum of chronic airway diseases, asthma and COPD are by far the most frequent. Although they have clear differences, some manifestations of both may coexist, in a given patient, and this has been called ACOS. Some authors have defined the ACOS as symptoms of increased variability of airflow in association with an incompletely reversible airflow obstruction.

Non-proportional Venn diagram showing the number of overlapping conditions in patients with asthma, emphysema and chronic bronchitis

P G Gibson, and J L Simpson Thorax 2009;64:728-735Non-proportional Venn diagram showing the number of overlapping conditions in patients with asthma, emphysema and chronic bronchitis (reproduced with permission from the American Journal of Respiratory and Critical Care Medicine). COPD, chronic obstructive pulmonary disease.DefinitionsLouie et al. defined ACOS as one of the two clinical phenotypes: asthma with partially reversible airflow obstruction, with or without emphysema or reduced carbon monoxide diffusing capacity (DLCO) to less than 80% predicted, and COPD with emphysema accompanied by reversible or partially reversible airflow obstruction, with or without environmental allergies or reduced DCLO. GINA described the ACOS as persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD.ACOS may correspond to the description of an asthmatic smoker who has developed chronic airflow obstruction; however, the previous history of asthma is occasionally not known, and the lack of specific biomarkers makes the diagnosis of ACOS difficult

Epidemiology Soriano et al . showed that the frequency of ACOS increases with advancing age, with an estimated prevalence of 50% in patients aged 80 years or older. Marco et al . , in general Italian population. They showed, through a screening questionnaire, that prevalence of asthma-COPD overlap was 1.6%, 2.1% and 4.5% in the 20-44, 45-64, 65- 84 age groups, respectively

Percentage of adults (by gender) with airflow obstruction who have an overlap syndrome with increasing age.

P G Gibson, and J L Simpson Thorax 2009;64:728-735Percentage of adults (by gender) with airflow obstruction who have an overlap syndrome with increasing age. Males are shown in the black bars and females in the white bars. Data from Soriano et al.4Clinical & Physiological Characteristics

Importance to identify patients with ACOS? ACOS patients have more frequent exacerbations compared with patients with COPDThey also have more respiratory symptoms such as dyspnoea and wheezing (but not more cough and sputum) and reduced physical activity compared with COPD alone. ACOS patients have a lower self-rated health and more impaired health-related quality of life compared with COPD and particularly with non-exacerbators with COPD. ACOS patients consume from 2 to 6-fold more healthcare resources than those used by asthma or COPD patients

Importance to identify patients with ACOS? Canadian guidelines for COPD(2007) recognized that patients with ACOS may require a different treatment and early introduction of ICS could be justified. This specific and differential treatment justifies the efforts to identify the subgroup of patients with ACOS from the large population of patients with COPD.After recognizing that response to ICS in COPD is poor, and that the use of long-term ICS at high doses is associated with an increased risk of adverse effects, there is a growing interest in identifying COPD patients who may respond to ICS.Characterization and better definition of ACOS may help to identify a subgroup of patients with COPD that respond to ICS in contrast to most of the patients with COPD that present a predominantly neutrophilic inflammation which is resistant to ICS. PathologyInammation in COPD is typically thought to be driven by Th1 immune responses such as enhanced production of interferon- by CD8+ cells, neutrophil chemokine IL-8, leukotriene B4, IL-1, and tumor necrosis factor-Asthma- associated inammatory pathways (e.g.,eosinophilia and Th2 inammation) appear to underlie disease in some patients.In asthmatics, there is a predominance of Th2 cytokines, including interleukin (IL)-4, IL-5, and IL-13, and upregulation of chemokines, including regulated on activation, normal T-cell expressed and secreted (RANTES), eotaxins, and monocyte chemoattractant protein-1

Simplified scheme of three different types of chronic airway inflammation in patients with asthma. In allergic eosinophilic asthma, Th2 lymphocytes and mast cells drive eosinophilic airway inflammation in an allergen-specific, IgE-dependent manner. In nonallergic eosinophilic asthma, innate lymphocytes such as natural killer T cells (NKT cells) and innate lymphoid cells type 2 (ILC2) might contribute to airway eosinophilia via the production of IL-5. The mechanisms underlying neutrophilic asthma need to be elucidated, but the IL-17 pathway and CXCL8 have been associated with airway neutrophilia. GM-CSF = granulocyte/macrophage colony-stimulating factor; ICS = inhaled corticosteroids; LABA = long-acting 2-agonist; MHC = major histocompatibility complex; TCR = T cell receptor; TSLP = thymic stromal lymphopoietin12

In contrast, Th1-dominated responses such as enhanced production of interferon- by CD8+ cells have been documented in COPD patients. Additionally, the main inflammatorymediators involved in the pathogenesis of tissue inflammation in COPD are the neutrophil chemokine IL-8, leukotriene B4, IL-1, and tumor necrosis factor-13It has been demonstrated that asthma, active smoking and atopy interact in the development of fixed airflow obstruction. There is a synergy that affects atopic never-smokers with asthmatic patients who will develop COPD with particular inflammatory and clinical characteristics.In obstructive pulmonary diseases and in overlap syndrome, we can notice the remodeling phenomenon. Remodeling consists of: mucosal edema, inflammation, mucus hypersecretion, formation of mucus plugs, hypertrophy and hyperplasia of the airway smooth muscle.

BHR In patients with COPD, increased reversibility is one of the key differential aspects of individuals with ACOS.Bronchial hyper-responsiveness (BHR) is common in asthma, especially in patients with active symptoms, but BHR is frequently asymptomatic and has shown to be a risk factor for developing COPD. BHR can be demonstrated in up to two thirds of COPD patients, and in patients with established asthma or COPD, more severe BHR is associated with more severe symptoms and a more rapid decline in forced expiratory volume in the first second (FEV1).

Sputum eosinophiliaAnother diagnostic feature of ACOS in COPD is the presence of sputum eosinophilia. Inflammation in asthma patients is considered to be mainly eosinophilic and mediated by CD4 T lymphocytes, whereas in COPD, it is neutrophillic and driven by CD8. In a study that compared stable COPD patients with concomitant asthma with the remaining COPD patients, peripheral and sputum eosinophil counts were significantly higher in the first group. Since sputum eosinophilia is not routinely performed in clinical practice, indirect markers of this type of inflammation have been investigated Inflammatory BiomarkersChou et al. demonstrated higher levels of exhaled nitric oxide (eNO) in patients with COPD and eosinophilic airway inflammation (> 3% eosinophils in induced sputum), with a cut-off of 23.5 ppb of eNO, having a sensitivity of 62.1% and a specificity of 70.5% for the identification of eosinophilic inflammation.Iwamoto et al. [19&& ] investigated four potential biomarkers in COPD [surfactant protein A (SP-A), soluble receptor for advanced glycation end products (sRAGE), myeloperoxidases (MPOs) and neutrophil gelatinase associated lipocalin (NGAL)]. Compared with asthma patients, sputum MPO and plasma SP-A were significantly elevated in ACOS, whereas only sputum NGAL was significantly increased compared to COPD.Genetic analysis of the COPD gene cohort identified single-nucleotide polymorphisms in the GPR65 gene associated with ACOS in a population of smokers or ex-smokers with COPD.Why does overlap happen?Potentially important common risk factors for overlapping asthma and COPD include increasing age, smoking, BHR, inflammation, remodeling and exacerbationsDutch hypothesis tries to answer the question, stating that asthma and BHR predispose to COPD later in life and that asthma, COPD, chronic bronchitis, and emphysema are different expressions of a single airway disease. Furthermore, the presence of these expressions is influenced by host and environmental factors

19HypothesisThere are partially overlapping airway gene expression changes in asthma and COPD, which reect shared processes that contribute to airow obstruction. Signatures of airway epithelial gene expression alterations in asthma are up- regulated in COPD, and can identify a COPD subgroup with a clinical phenotype more similar to asthma

Asthma Gene Signatures2 endotypes of asthma are dened by their degree of Th2 inammation using airway epithelial expression levels of three IL-13inducible genes:periostin (POSTN)chloride channel Ca21- activated 1 (CLCA1)serine peptidase inhibitor B2 (SERPINB2) The asthma subgroup with the Th2- high endotype had higher IL-5 and IL-13 expression levelsincreased serum total IgE levels greater blood and lung eosinophiliaincreased airway hyperresponsivenessbetter lung function (FEV1) response to ICS

Periostin derived from this signature predicted the response of subjects with asthma to omalizumab and to an antiIL- 13 monoclonal antibody, lebrikizumab.

21Compared airway cell gene expression in asthma to that of two established COPD cohorts using gene set enrichment analysis (GSEA)Studied the association of Th2 gene signatures with lung function in these cohorts. Determined whether a Th2 signature (T2S) score is associated with asthma-associated pathological features and ICS responsiveness in a previously published RCT of patients with COPD with no history of asthma.

Subjects and Sample PreparationAsthma datasetasthma and control subjects.Gene expression microarray and quantitative PCR data from large airway epithelial brushings were previously obtained from steroid-naive subjects with mild to moderate asthma (n = 62) and control subjects without asthma (n = 43) in a cross-sectional study design Bronchial biopsies were obtained in a subset (n= 61) Subjects with asthma were divided into Th2-high and -low subgroups (n = 40 and 22, respectively) using a validated standardized mean expression level of POSTN, SERPINB2, and CLCA1 (three gene mean [TGM]).

Subjects were included in the asthma group if they had a prior physician diagnosis of asthmaasthma symptoms confirmed by a study physicianairway hyperresponsiveness defined by a decrease in FEV1 of 20% or greater following inhalation of 16mg/mL).Exclusion criteria for all subjects included: a history of smoking (>10 pack-years total or any smoking in the past year)upper respiratory tract infection in the past 4 weekscurrent use of salmeterol, astemizole, nedocromil sodium, sodium chromoglycate, E2 methylxanthines, montelukast, or zafirlukast. Asthmatics and non-asthmatics were similar in age and sex

Bronchial airway epithelium COPD (BAEC) datasetRNA was isolated from bronchial epithelial brushings obtained from sixth- to eighth- generation bronchi in former and current smokers with a range of lung function (n = 87 with COPD and 151 without). COPD was defined spirometrically by FEV1/FVC 0.7 and FEV1