*2.2.1 Airflow limitation*

Diagnosis of COPD is based on the physiologic criteria of fixed obstruction in forced expiratory flow (0.7 as cutoff point for FEV1/FVC ratio); however, the use of a fixed cut point like this probably misclassifies some older patients as developing COPD (more frequent diagnosis of COPD in elderly subjects), compared with the use of a cutoff point derived from the lower limit normal (LLN) for FEV1/FVC ratio. On the other hand, the use of this fixed cutoff point for FEV1/FVC ratio results in less frequent diagnosis of COPD in younger adults, compared with that of the LLN. Since the LLN for FEV1/FVC ratio decreases with age, the accuracy of these diagnostic criteria also should be changed with age [36]. The use of the LLN affects the establishment of early diagnosis for COPD in younger adults. Criterion used in the LLN would be a more desirable parameter that increases the accuracy of diagnosis in this disease. However, those values are dependent on the reference population and are unlikely to

accurately reflect the normality of many different ethnic groups. Moreover, there are no longitudinal studies available validating the use of the LLN.

FEV1 also normally decreases with age, and FEV1 (% of the predicted value) is used as an indicator for staging of COPD. However, FEV1 is not always associated with shortness of breath, exercise tolerance, and quality of life [17, 18]. The rate of decrease is probably an important indicator of disease progression in patients with COPD. However, the rate of lung function decrease (a decline of FEV1) is not also considered for diagnosis or stage classification of this disease. In these approaches using spirometry (the physiologic criteria), first-line medications have been applied consistently in the condition that COPD is once diagnosed without much consideration of possible distinct phenotypes of COPD.

#### *2.2.2 Impaired diffusion*

Diffusing capacity derived from DLCO can estimate the potential of gas exchange of the lung [37]. DLco is frequently reduced in patients with established COPD. There is also a subset of cigarette smokers with normal spirometry (FEV1/FVC ratio > 0.7), who have a low value of DLCO. Decreased DLCO in smokers is pathologically correlated to the destruction of the pulmonary capillary bed, and a low value of DLCO in the context of a normal total lung capacity (TLC) probably indicates alveolar destruction, i.e., emphysema [37, 38] and possibly small airway disease, both of which are components of COPD [39, 40]. Clinical trials have reported a significant correlation between reduced DLCO and emphysema on CT imaging of the chest [41, 42]. Decreased DLCO has also been correlated with dynamic hyperinflation caused by the presence of severe expiratory airflow limitation derived from emphysema and small airway diseases, independent of decreases in FEV1/FVC or FEV1 [43]. Moreover, smokers with normal post-bronchodilator FEV1 but low DLCO have a higher risk of developing COPD with airflow limitation, compared with those with normal postbronchodilator FEV1 and normal DLCO [44]. Hence, DLCO measurement is useful for early diagnosis of COPD who are cigarette smokers without airflow limitation. However, this examination is not part of the GOLD criteria and is currently not used as a routine screening tool [45, 46].

#### *2.2.3 Airway trapping*

Gas trapping develops in patients with COPD from the early stages of this disease. Gas trapping results in a rise in residual volume (RV), and static hyperinflation, which is an increase in TLC, as airflow limitation worsens. Lung volume such as RV and TLC is impossible to measure by spirometry in the routine use, and these alterations are estimated by body plethysmography and helium dilution lung volume measurement. RV and TLC are probably helpful to characterize the severity of COPD; however, these are not generally used for management of this disease.

Patients with COPD show widely variable exercise capacities. It is recently considered that FEV1 was a poor predictor of exercise capacity, and that dynamic hyperinflation, which is a concomitant with decreases in inspiratory capacity (IC) and inspiratory reserve volume (IRV), is more closely related to exercise tolerance than FEV1 [47]. Dynamic hyperinflation is defined as the variable and temporary increase in end expiratory lung volume (EELV) above its baseline value, which occurs when ventilatory demand is acutely increased during exercise [48, 49]. This phenomenon results from gas trapping in the airways. This is usually measured by IC, which

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

accurately reflects changes in EELV provided that TLC remains unaltered. During exercise, in normal subjects, the tidal volume (VT) is markedly increased at the expense of both the IRV and the expiratory reserve volume. In contrast, since airflow is limited and RV is increased in patients with COPD, VT is only a little increased at the expense of their reduced IRV. Therefore, a reduction in IC causes impaired exercise tolerance in patients with this disease. IC can be measured using spirometry, but IC is currently not used as a clinical predictor of exercise capacity.

#### *2.2.4 Small airway obstruction (less than 2 mm diameter)*

The current approach to diagnosis and staging of COPD is based on post-bronchodilator FEV1/FVC ratio, and FEV1 (% of predicted value) in spirometry, even though this disease is considered generally to begin in the small airways [50]. This area is classically recognized to be the "quiet zone" or "silent zone" because it cannot be easily assessed by means of spirometry alone [51]. The forced oscillation technique, such as impulse oscillation system (IOS) or MostGraph, was been developed to compute the respiratory system impedance that reflects the mechanical properties (resistance and reactance) of the respiratory system [52]. Higher oscillation frequencies (approximately 20 Hz) reflect large airways, and lower oscillation frequencies (<10 Hz) reflect the entire respiratory system, including the small airways. Abnormalities with low oscillation frequencies can be related to disorders in the small airways. However, the forced oscillation technique has not yet been established as clinical test to estimate the small airway function.

Although little is currently known about the clinical relevance of the small airway dysfunction, abnormalities in this area are probably correlated with magnitude of inhaled toxin exposure, severity of respiratory symptoms, response to therapy, presence of systemic inflammation. When the presence of respiratory symptoms in patients is unexplained by using routine clinical evaluation because chest CT and spirometry findings are within the normal range, these results may indicate that small airway disorders develop despite normal airflow on spirometry [53].

#### *2.2.5 Airway hyperresponsiveness*

It is classically considered that sensitivity to muscarinic activation is a hallmark of asthma, referred to as airway hyperresponsiveness (AHR). However, recent reports have demonstrated that AHR also develops in as set of COPD [12, 54–56]. Awareness of this paradigm shift is gradually increasing. To evaluate AHR, acetylcholine inhalation challenge is carried out according to the standard method of the Japanese Society of Allergy (Acetylcholine provocation test) [57], which is a modified method reported by Hargreaves and coworkers [58]. The provocation test is ended at a concentration of acetylcholine where FEV1 is reduced by more than 20% from its baseline value. Threshold values are expressed as a minimal concentration of acetylcholine that reduces FEV1 by more than 20%. AHR is generally defined as threshold values of less than 8 mg/ml of acetylcholine [56, 59]. Acetylcholine provocation test is most reliable for diagnosis of asthma because this clinical examination has great sensitivity and specificity to diagnosis of asthma [60]. Clinical reports have indicated that AHR is complicated by ~60% or ~ 94% of patients with COPD [61, 62]. Since airway narrowing occurs in COPD because of airflow limitation, exclusion criteria should be established to maintain the accuracy of this provocation test for COPD. Recently, acetylcholine provocation test was carried out for subjects who have FEV1 ≥ 70%

predicted values not only to avoid false positives but also to secure safety in this examination [63]. Moreover, the patients with COPD were enrolled in the study and do not have past history of asthma and no clinical features of asthma. As a result, AHR developed in approximate 50% of the patient with COPD excluded asthma [12].

#### **2.3 Imaging dimension**

### *2.3.1 Emphysema*

COPD, which is diagnosed in routine use of spirometry, contains both with and without emphysema. Emphysema, which can be easily detected by chest CT, occurs in a significant proportion of cigarette smokers that might not fit the COPD spirometric criteria [64]. Emphysema can be divided into with and without airflow limitation (FEV1/FVC ratio < 0.7); COPD also can be divided into with and without emphysema. Multiple different phenotypes of emphysema have been described, i.e., centrilobular, panlobular, and paraseptal phenotypes. Some differences are shown among these phenotypes. The centrilobular phenotype is associated with greater smoking history, whereas the panlobular phenotype is associated with reduced body mass index, independent of FEV1 [65]. Paraseptal emphysema is associated with fewer symptoms and less physiologic impairment. In the analysis of different emphysema patterns based on the Fleischer Society grading system, Kaplan–Meier survival curves demonstrate that patients with absent and trace emphysema have the best survival; those with moderate centrilobular emphysema have intermediate survival; and those with confluent or advanced destructive emphysema have poor survival [66]. However, little is known what determines the distribution of the emphysema. Phenotyping based on the anatomic distribution may result in important therapeutic implications that lung volume reduction surgery may be beneficial to patients with upper-lobe emphysema and low exercise capacity [67].

#### *2.3.2 Small airway*

The narrowing and loss of terminal bronchioles occur before the development of emphysema. Assessment of small airway disease is probably useful to identify COPD at an early stage [64, 68]. However, small airways are less than 2 mm in diameter [69]. Because this size falls below the resolution limit of chest CT for direct evaluation, small airways are not imaged directly using routine CT scan. For this reason, novel methods using CT have been devised to evaluate small airways diseases. Micro-CT studies, which are 3D imaging techniques utilizing X-rays to see inside an object, have demonstrated that both total bronchiolar area and the number of small conducting airways are reduced in the early stage [68]. Measures of air trapping on expiratory CT have been used to estimate functional small airway disease, including the ratio of expiratory to inspiratory mean lung density [70, 71], the expiratory to inspiratory relative volume change of voxels with attenuation between 2860 and 2950 HU, and the percentage of voxels below 2856 HU in expiration. However, these imaging techniques have their advantages and limitations. CT total airway count (TAC), which is measured as well as airway inner diameter and wall area using anatomically equivalent airways, reflects the airway-related disease changes in the "quiet" zone (small airways) [72]. A significant decrease in TAC may be observed in early stage of COPD; and that can predict a rapid decline of lung function [72]. The parametric response

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

mapping (PRM), a technique pairing inspiratory and expiratory CT, has been developed to assess small airway diseases. That images to define emphysema (PRMemph) and functional small airways disease (PRMfSAD), a measure of nonemphysematous air trapping [64, 73–76]. These techniques will allow for more accurate diagnosis of individual patients complementing standard clinical examinations to estimate COPD phenotypes. Analysis methods for CT imaging in COPD are making progress to establish novel phenotypes for development of precision medicine according to the results derived from the COPDgene study [75, 76].

Small airways disease occurs in the early stage of COPD and becomes more widespread over time as this disease progresses to more severe. Airway remodeling is observed in this peripheral area in patients with COPD, and pathological findings of that are characterized by goblet cell hyperplasia, mucous gland enlargement, peribronchiolar wall infiltration with inflammatory cells, and bronchiolar smooth muscle hypertrophy [77, 78]. The therapeutic relevance of this phenotype can include use of therapies that allow the small airways to be targeted pharmacologically [79]. However, it is not so easy to estimate accurately diagnosis and treatment outcome in the small airway disease of COPD.

#### **2.4 Endotyping dimension**

## *2.4.1 α1-Antitrypsin deficiency*

It is well known that α1-antitrypsin is a proteinase inhibitor that protects lung tissue from damage by neutrophil elastase. An imbalance between proteinases and antiproteinases causes destruction of elastin fibers, which affects the elastic recoil of the lung and brings about parenchymal destruction (emphysema). This imbalance between proteinases and antiproteinases seems to be less evident in patients with other forms of emphysema. This condition of α1-Antitrypsin deficiency is observed less than 5% of patients with COPD and presents in younger subjects compared with the rest of the COPD population [80]. Mutation of the α1-antitrypsin gene results in a much higher risk of COPD in cigarette smokers and workers exposed to environmental particules. Homozygous α1-antitrypsin deficiency occurs in 1–4.5% of patients with COPD; in contrast, the heterozygous form occurs in 17.8% of patients with COPD [81]. Previous clinical trial may provide the therapeutic relevance that intravenous augmentation with pooled human α1-antitrypsin may be beneficial to subjects with severe α1-antitrypsin deficiency [82].

#### *2.4.2 Inflammatory profiling*

It is classically considered that asthma is characterized by eosinophil inflammation in the large airways with Th2 phenotype, om the other hand, that COPD is characterized by initial macrophage, neutrophil, and CD8 lymphocyte inflammation in the small airways [83]. However, it is recently proven that eosinophil and non-TH2 related inflammation is involved not only in the large airways but also the small airways in patients with asthma; on the other hand, eosinophil inflammation is involved in the large airways in patients with COPD. Blood eosinophil counts are increased in COPD patients compared with healthy controls, even when atopic patients are removed from the analysis [84]. This paradigm shift in the approach to this disease is generally recognized. Hence, airway inflammatory profiling is not so useful for differential diagnosis between COPD and asthma since eosinophil inflammation overlaps with

these two diseases. The eosinophil count in the peripheral blood may be beneficial as a predictor of the frequency of exacerbations and response to corticosteroid in the management of COPD [85–88]. The increased blood eosinophil numbers may be a reason for increased lung eosinophil numbers observed in a subgroup of COPD patients [89, 90]. According to these reports, it has been assumed all along that blood eosinophilia is a faithful representation of tissue eosinophilia. However, this assumption has not been proven conclusively [91]. The eosinophil count in the peripheral blood does not always correspond to the eosinophil count in the lung tissue. Furthermore, high numbers of blood eosinophils are not associated with frequency of exacerbations [92]. It remains to be solved whether useful blood eosinophil counts are useful as a predictor of the management of COPD. COPD with airway eosinophilia in the tissue probably is a subgroup (phenotype) of this disease, since this phenotype has unique pulmonary and systemic manifestations and a differential response to drugs [87, 88, 93]. This phenotype of COPD probably has a good response to corticosteroids [89]; and sputum examination is probably most reliable as a clinical test to detect eosinophil inflammation in the airways, blood test is not. Blood eosinophilic phenotype was associated with PH. Eosinophilic COPD was associated with higher mPAP and PVR and increased likelihood of PH. More studies are needed to further explore this finding [94].
