**2. COPD pheotypes**

Multiple disease characteristics have been termed COPD phenotypes up until now; and individual patients with COPD can be grouped by phenotypes (phenotypic grouping). These groupings are proposed to determine clusters of patients with common characteristics that relate to clinically meaningful outcomes such as symptoms, exacerbations, response to therapy, and rate of disease progression, or death (stratified medicine) [10, 13]. This more focused definition allows for classifications of patients to distinct prognostic and therapeutic subgroups for both clinical and research purposes as a heterogeneous disease in COPD. The earliest phenotypic classification of COPD was separated into two groups based on physical examination, the "Pink Puffers" and the "Blue Bloaters" [14]. Airflow limitation detected by the routine use of spirometry is insufficient to distinguish COPD from asthma and other airway diseases (chronic bronchitis, pan bronchiolitis, bronchiectasis, etc.). It is especially difficult to distinguish between COPD and asthma. More than 50 years ago, Dutch hypothesis argued that bronchodilator responsiveness was an overlapping feature shared by various forms of obstructive lung diseases, including asthma [15]. In contrast, the British hypothesis argued that bronchodilator responsiveness in patients with COPD was due to concomitant asthma [16]. Hence, multivariable approaches to deal with diseases probably provide relevant information that can characterize different subtypes of COPD. Multiple dimensions for COPD assessment can include clinical, physiologic, imaging, and endotyping dimensions (**Figure 1**) [9]. Data from each dimension support the relevance of specific variables to diagnosis and prognosis for COPD. However, very few and limited combinations of these variables and dimensions have been studied and validated. Therefore, various classification systems for COPD have established taking into phenotypes and endotypes to allow categorization of patients in meaningful methods.

#### **2.1 Clinical dimension**

#### *2.1.1 Symptoms*

Symptoms (dyspnea, cough, sputum production) and signs (wheezing, prologued exhalation) overlap between COPD and other airway diseases, but with a decline in body mass index (BMI), very little overlap between COPD and asthma. The GOLD Report initially stated a classification system based on reduction in FEV1 [1]. However, FEV1 is no clearly associated with symptom severity, functional status, and prognosis [17, 18]. Symptom severity has been shown to be better predictor of mortality than FEV1 alone in patients with COPD [19]. Health questionnaires such as COPD Assessment Test (CAT) scores and St George Respiratory Questionnaire (SGRQ ) scores have been used to understand the relationship between symptoms and quality of life [20]. As an approach includes more variables, a multidimensional grading system including body mass index (BMI), obstruction in the airway (FEV1), dyspnea, and exercise ability (BODE index) has shown to be better than FEV1 alone in predicting mortality in patients with COPD [21].

#### **Figure 1.**

*A Schema of multiple dimensions for assessment of COPD phenotypes. Squares represent dimensions, which is consist of clinical, physiology, imaging CT, and endotypes; and enclose variables with defined or possible relevance to diagnosis, prognosis, or potential therapy in patients with COPD. Illustrated based on ref. [1, 9].*

#### *2.1.2 Exacerbations*

COPD exacerbations perhaps result in rapid decrease of lung function (FEV1), deterioration of quality of life, and escalation of healthcare cost [22]. Clinical studies have demonstrated that severe COPD exacerbations are associated with a high mortality [23], and that COPD exacerbations are independent risk factor for morbidity in the disease [24]. Frequent exacerbators are a group of subjects with two or more exacerbations per year [25]. Although recent data suggest that the frequent exacerbator phenotype is quite infrequent in a large cohort study, this phenotype seems to be quite stable over time because the best predictor for exacerbations is history of prior exacerbations [26]. In the recent GOLD Report, the stage of COPD is classified by percentage predicted FEV1 (Grades I–IV), and separately dyspnea severity and exacerbation history are incorporated into a 2 × 2 grid to form four groups A – D [1]. This assessment approach will guide more precise treatment for individualized patient with COPD. However, this classification is insufficient to seize accurately the heterogeneity of COPD.

During a COPD exacerbation, bacteria, viruses, or both are detected from lower airway secretions in two-thirds of patients, and bacterial/viral coinfection is present in one-fourth [27]. *Hemophilus influenzae, Streptococcus pneumoniae,* and *Moraxella catarrhalis* are isolated as the most common bacterial pathogens during COPD exacerbations. Acquisition of a new bacterial strain precedes exacerbations [28]. Rhino virus is most frequently associated with exacerbations [29], whereas coronavirus, parainfluenza, adenovirus, and influenza virus are less prevalent.

#### *2.1.3 Smoking*

Cigarette smokers have a higher prevalence of respiratory symptoms, and impaired lung function, a greater annual rate of decline in FEV1, and a greater rate of COPD mortality than non-smokers [1]. As shown in the SPIROMICS cohort,

### *New Perspectives in Pharmacological Therapy for COPD: Phenotype Classification and… DOI: http://dx.doi.org/10.5772/intechopen.106949*

respiratory symptoms are present in half of cigarette smokers with preserved lung function. When compared with asymptomatic cigarette smokers, these symptomatic smokers have greater limitation of physical activity, lung function abnormalities (although still within the limits considered as normal), and evidence of airway wall thickening on CT imaging of the chest [30]. Importantly, cigarette smokers with preserved lung function and respiratory symptoms have higher rates of exacerbations than asymptomatic cigarette smokers.

## *2.1.4 Comorbidity*

Patients with COPD have a high prevalence not only of other pulmonary disease (lung cancer, pulmonary hypertension, pulmonary fibrosis, etc.) but also extrapulmonary diseases (cardiovascular diseases, diabetes mellitus, hyperlipidemia, etc.) [31]. This is very important because approximately two-thirds of patients with COPD die from these other diseases, and comorbidities have a significant effect on prognosis or mortality [32, 33]. Recent investigations using network analysis of comorbidities in patients with COPD demonstrate that the presence of hubs of comorbid conditions is highly associated with this disease beyond lung cancer and cardiovascular disease (COPD comorbidity network). Prognosis of patients with COPD is most likely affected by larger number of multiple interlinked morbidities, and their clustering pattern suggests common pathobiological pathways [34].

Combined pulmonary fibrosis and emphysema (CPFE), which is defined by CT imaging of the chest, is closely associated to a history of cigarette smoking. CPFE is characterized by exertional dyspnea, emphysema in the upper lobe, and fibrosis in the lower lobe of the lungs. Patients with CPFE have preserved lung volume (total lung capacity, forced vital capacity) and severely diminished carbon monoxide diffusion capacity of the lung (DLco), moreover, have high prevalence of pulmonary hypertension, and poor prognosis [35]. Survival rate in CPFE is worse than that expected for emphysema without fibrosis; in contrast, survival rate in CPFE is better than that in usual interstitial pneumonia diagnosed by pathological findings. It is still unknown whether the therapy for COPD or pulmonary fibrosis/usual interstitial pneumonia is effective for CPFE. Corticosteroids do not have significant benefit to patients with CPFE.

#### **2.2 Physiological dimension**
