COPD: Accelerated Lung Aging

As described in the previous section on risk factors for COPD, smoking cigarettes, although not the only risk factor, is the main source of inhaled noxic particles that leads to the development of COPD.40;59 However, not all smokers develop airflow limitation; early studies demonstrated that cigarette smoking is associated with inflammation in both the large and small airways60;61 and the lung parenchyma62 in smokers with normal FEV1.

Although it is unclear why some smokers develop COPD while others do not, it is known that the inflammatory response in COPD is amplified63 and persists long after smoking cessation.64 Irreversible airflow limitation is the defining feature of COPD and is associated with “lesions that obstruct the small conducting airways, produce emphysematous destruction of the lung’s elastic recoil force, or both.”65 Importantly, the disease that occurs within the airways and the lung parenchyma are independent disease processes that may develop in tandem or in isolation. In this section I will first introduce how COPD is diagnosed using spirometry and the natural history of COPD. Finally, I will discuss the underlying disease mechanisms that are thought to be responsible for the functional lung changes.

1.4.2.1

Diagnosis and Classification of COPD

When COPD is suspected based on symptoms, such as dyspnea, chronic cough or sputum production, and/or a history of exposure to risk factors,59 airflow limitation is measured

Figure 1-9 Lung volume changes that occur with age

TCV = Thoracic Cavity Volume, VC = Vital Capacity, RV = Residual Volume. Adapted from Norris et. al. (1956).54

using spirometry and the presence of a post-bronchodilator FEV1/FVC <0.70 confirms

the diagnosis of COPD.1;59 As shown in Table 1-1, COPD severity is determined according to the GOLD criteria, which uses specific spirometric cut-points that are obtained after inhalation of a short-acting bronchodilator in order to minimize variability.59

Table 1-1 Classification of Severity of Airflow Limitation in COPD

GOLD Stage Severity Post-Bronchodilator FEV1 Criteria

GOLD Stage I Mild FEV1≥ 80% predicted

GOLD Stage II Moderate 50% ≤ FEV1 < 80% predicted

GOLD Stage III Severe 30% ≤ FEV1 < 50% predicted

GOLD Stage IV Very Severe FEV1 < 30% predicted

Adapted from the Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (Revised 2011), Global Initiative for Chronic Lung Disease1

Although this approach has been introduced due to its diagnostic simplicity and ease of use in the primary care setting, the FEV1/FVC cut off has been acknowledged to

potentially result in an over-diagnosis of COPD in the elderly,66 as well as under- diagnosis of mild or early stage COPD.67 Moreover, there is only a weak correlation between GOLD spirometric severity classification and symptom scores reflecting health- related quality of life.

1.4.2.2

Natural History of Airflow Obstruction in COPD

Figure 1-10 reproduces the landmark study by Fletcher and Peto56 that shows the different rates of lung function decline, as measured by FEV1, for healthy individuals that

have never smoked in comparison with those individuals who were current cigarette smokers that exhibit the amplified inflammatory response that is associated with the development of COPD. This study indicates that while the rate of decline of FEV1 in

smokers and to 66±4 ml/year in heavy smokers. Interestingly, this study also showed that the rate of FEV1 decline was slower in individuals that had quit smoking (32±4 ml/year),

suggesting that decline in lung function can be slowed by smoking cessation. However, as described previously, this was a cross-sectional study in men.

The more recent longitudinal Lung Health Study68;69 also evaluated smokers that were randomized into three groups: a group of smokers who received no intervention, a group of smokers who received smoking cessation intervention, and a group of smokers who received smoking cessation intervention and bronchodilator therapy, and followed the subjects over 11 years. In accordance with the findings by Fletcher and colleagues,56 this study found that men who quit smoking at the beginning of the study had a FEV1 decline

of 30 ml/year while men who continued to smoke had an accelerated declined of 66 ml/year. In contrast to the study performed by Fletcher and colleagues,56 the Lung Healthy Study also evaluated women and showed that women who quit smoking at the beginning of the study had a FEV1 decline of 22 ml/year while women who continued to

smoke declined by 54 ml/year.69 Interestingly, when decline in FEV1 was expressed as a

percentage of the predicted normal value, there were no significant differences between the sexes.69

1.4.2.3

Chronic Bronchitis

Chronic bronchitis is defined as “the presence of cough and sputum production for at least 3 months in each of two consecutive years.”1 Early work investigating chronic bronchitis attributed the mucous hypersecretion with thickening of the bronchial gland.70-

72

Reid70 reported that this thickness was related to gland hypertrophy and that there was a correlation between the amount of sputum produced and gland thickness. It was later shown that chronic bronchitis was associated with bronchial inflammation.60 Mullen and colleagues60 demonstrated that smokers with chronic bronchitis had greater inflammation of the cartilaginous airways (> 4 mm in internal diameter) than smokers without chronic bronchitis, and that there was a significant correlation between inflammation of the cartilaginous airways and mucous gland thickness. These data suggest that chronic cough and sputum production was associated with an inflammatory response due to the cigarette smoke in the cartilaginous (or central) airways. Interestingly, it has also been demonstrated that this inflammatory response persists in the central airways of smokers who had quit but continued to report mucus hypersecretion.64

Figure 1-10 Lung Function Decline

Lung function declines in never-smokers during aging and declines at an accelerated rate in current smokers. However, lung function declines return to normal rates following smoking cessation. Adapted from Fletcher et. al. (1977).56

Much of this early work was performed in smokers with and without airflow limitation measured using FEV1 and therefore more recent studies have focused on evaluating

whether there is a predictive relationship between the presence of chronic cough and sputum production and the future occurrence of COPD. de Marco and colleagues73 recently evaluated a group of young subjects, aged 20-45, with normal lung function over a period of approximately 9 years. It was shown that at the baseline visit, 9% of subjects reported chronic cough and sputum production and of these subjects that reported persistent symptoms at follow-up, there was a threefold increased risk of developing COPD.73 Another study demonstrated that chronic cough and sputum production was associated with an increased decline in FEV1 and subsequent hospitalization due to

COPD.74

1.4.2.4

Small Airways Disease

Based on the study by Weibel and Gomez20 it is known that as the airway generation increases, due to the dichotomous branching pattern of the airways, the number of airways rapidly increases and therefore the total cross-sectional area increases, as shown in Figure 1-5. Although the smaller airways could be considered the major site of resistance in normal lungs based on Poiseuille’s equation that indicates that resistance in a single tube is inversely proportional to the radius of the tube to the 4th power, by inspection of the airways and according to Weibel’s data20 we must also consider the number of airways and their total cross-sectional area. Although the radius of the airways decrease as airway generation increases, the number and cross-sectional area of the airways increases.17 Since these airways are arranged in parallel, the resistances are added as reciprocals and therefore the overall resistance is very small in the small airways.

Early studies by Hogg and Macklem75 that directly measured small airway pressure using a retrograde catheter confirmed that in healthy subjects, the small airways contributed very little to the total airway resistance. However, they also demonstrated that in subjects with mild and severe emphysema, as well as subjects with bronchiectasis and bronchiolitis that there was a marked increase in the resistance of the small airways (<2 mm in diameter), while there was little or no change in total lung resistance. The authors

observed that the bronchioles were often narrowed and occluded with mucus plugging and defined these changes in the small airways as “small airways disease,” where disease changes may occur without being detected by measuring total airway resistance or by FEV1. Taken together, since the total resistance is determined largely by the more central

airways, disease may accumulate in the small airways without being detected.

It was later shown in histopathological studies that inflammation was present in the peripheral airways of smokers76 and that the most characteristic lesion in the small airways of smokers was respiratory bronchiolitis.61 However, these early reports did not perform spirometry in the smokers and therefore the subjects may or may not have had COPD. A more recent study by Hogg and colleagues77 evaluated the pathology of the small airways in relation to COPD severity, as measured by the GOLD COPD stages (Table 1).1 These authors found that although the degree to which the lumen was filled with mucous was significantly correlated with the severity of COPD, the strongest parameter associated with progression of COPD from GOLD stage 0 to GOLD stage IV was with thickening of the airway wall.77 It was also shown that the extent of inflammation was significantly correlated with COPD severity.77 Figure 1-11A shows a normal small airway of a non-smoker in comparison with a small airway filled with mucus (Figure 1-11B), a small airway with thickened airway walls and a lumen partially filled with mucus (Figure 1-11C) and a small airway with wall thickening that is thought to restrict airway caliber with lung inflation (Figure 1-11D).

1.4.2.5

Emphysema

Emphysema was first described by Laennec in 1834. He described emphysema of the lungs as “dilation of the air cells” that “may affect both lungs at the same time, one only, or a part of one or of both.”78 More recently, the National Heart, Lung, and Blood Institute defined emphysema as “a condition of the lung characterized by abnormal, permanent enlargement of airspaces distal to the terminal bronchiole, accompanied by the destruction of their walls, and without obvious fibrosis.”79 It is well known that smokers develop two distinct forms of emphysema: centrilobular and panlobular emphysema.80-82 Centrilobular emphysema results from dilation and destruction of the respiratory bronchioles, as shown in Figure 1-11E, and has been demonstrated to have a more

uneven pattern of tissue destruction, predominantly occurring in the upper lung lobes. Conversely, panlobular emphysema has a more homogenous pattern and is more likely to be associated with genetic disorders such as alpha-1 antitrypsin deficiency (Figure 1- 11F).81;82 Moreover, early studies indicated that there was a relationship between cigarette smoking and centrilobular emphysema, but not with panlobular emphysema.83 Studies in smokers and non-smokers demonstrated that inflammatory cells play a role in the parenchyma tissue destruction in smokers,62 and that this cigarette smoke-induced inflammation is amplified in subjects with emphysema versus smokers without emphysema.63

Figure 1-11 Small Airways Disease and Emphysema in COPD

A. Normal small airway. B. Small airway containing plug of mucus. C. Acutely inflamed airway with thickened wall in which the lumen is partly filled with an inflammatory exudate of mucus and cells. D. Airway surrounded by connective tissue, which appears as if it might restrict normal enlargement of the lumen and unfolding of the epithelial lining that occurs with lung inflation. E. Early lesions of centrilobular emphysema (CLE) that have destroyed central portions of several acini of a single secondary lobule. D. More even destruction of the lobule in panacinar emphysema. Reproduced with permission from Hogg (2004).65