1.2: Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease, or COPD, actually covers two obstructive disorders—chronic bronchitis and emphysema.

Although chronic bronchitis and emphysema have different underlying pathologies, they frequently have the same root cause and are often found together in a patient. In brief, chronic bronchitis is associated with an increase in mucus production, while emphysema involves disruption of the lung structure.

The relative role of chronic bronchitis in COPD has diminished since the Clean Air Act reduced atmospheric sulphur dioxide, but with 90 percent of COPD caused by cigarette smoking there is still plenty of bronchitis and emphysema to treat—at enormous cost to the health system from over eight million hospitalizations a year that are mostly paid for by Medicare. The COPD patient tends to be older and poorer and will likely have comorbidities, the most common of which is hypertension. What is perhaps more disturbing is that of the most common causes of death, COPD is the only one whose incidence continues to rise.

We will now look at the underlying mechanisms of COPD. Despite the fact it is usually composed of some elements of both chronic bronchitis and emphysema, we will deal with each separately for the sake of simplicity.

Chronic Bronchitis

Chronic bronchitis is clinically defined as a persistent and productive cough that lasts for at least three months per year for two consecutive years.

Chronic bronchitis arises from chronic exposure to bronchial irritants, the most common of which is tobacco smoke. These irritants initiate the release of cytokines from airway epithelial cells and macrophages that result in a cascade of responses (summarized in figure 1.11).

Neutrophils, lymphocytes, and macrophages are attracted to the irritated airway, and their presence is maintained through increased expression of cell adhesion molecules on the airway walls. These immune cells lead to acute airway wall inflammation that narrows the airway, and if chronic, can lead to tissue damage. The cytokines released by these cells also sensitize airway irritant receptors, which exacerbates the response to future irritant exposure.

Mucus production increases, and the glands themselves may also release cytokines that further exacerbate the inflammatory response. The mucus also contributes to airway narrowing, and mucus plugs may form that completely block bronchioles.

Mesenchymal cells transition into fibroblasts as part of the inflammatory response, and their chronic presence leads to the deposition of fibrotic tissue.

Collectively these responses to the irritants result in a narrowed airway that is (1) hypersensitive, (2) fibrosed, and (3) blocked by excessive secretions.

Figure 1.11: Pathophysiology of chronic bronchitis.

Continued exposure to irritants leads to other chronic changes beyond fibrosis. With excessive stimulation, the size and number of mucus glands increases. The size of mucosal glands is used as a diagnostic test, and the Reid index describes what proportion of the submucosa is spanned by a gland—in the normal airway a normal gland spans less than 40 percent of the submucosa’s depth, but in chronic bronchitis this exceeds 50 percent (figure 1.12).

Figure 1.12: The Reid index compares the width of mucus glands to the width of the submucosal layer of airways.

In conjunction with an increased mucus production capacity, the airway has a reduced mucus clearance capability with airway remodeling, including squamous metaplasia replacing normal ciliated columnar epithelium (figure 1.13). The mucus escalator is also compromised by a decline in function of the remaining cilia with exposure to cigarette smoke.

Figure 1.13: Prolonged irritant exposure can lead to airway remodeling with loss of normal ciliated epithelium.

These changes result in an airway that produces more mucus and is less capable of removing it. The static mucus not only causes airway plugging, but can also promote infections that lead to episodic and characteristic exacerbation of COPD symptoms.

Clinical Presentation of Chronic Bronchitis

The signs and symptoms of chronic bronchitis depend on the level of airway obstruction and the consequent decline in lung function (summarized in figure 1.14).

As with many pulmonary diseases, the onset can be insidious. Small airway damage may be present but undetectable with normal spirometry, while the patient becomes accustomed to and tolerates a persistent productive cough. However, with continued irritant exposure, this initial simple bronchitis progresses.

Secretions continue to worsen and peribronchiolar fibrosis marks the onset of obstructive bronchitis that is reflected by significant expiratory airflow limitation. At this point the patient may have tolerated years of productive cough and experienced frequent chest infections related to poor mucus clearance. COPDers are particularly susceptible to Haemophilus influenza and Streptococcus pneumoniae. The sputum is abundant and capable of plugging significant numbers of airways and may be blood tinged; COPD is the most common cause of hemoptysis. Airways may demonstrate hyperreactivity and mimic an asthmatic response.

The onset of dyspnea is insidious and is usually first experienced during exertion—leading the patient to avoid exercise, which in turn leads to deconditioning and a worsening of the symptom. Lung sounds include wheezes and rales, the rales often clearing after cough.

With worsening airway flow limitation expiration becomes prolonged and may be incomplete due to airway collapse that leads to characteristic hyperinflation.

Mucus plugging and airway closure leads to areas of V/Q abnormalities through the lung, and localized areas of hypoxia can lead to pulmonary vasoconstriction. When significant regions of the lung are vasoconstricted, pulmonary vascular resistance can rise enough to induce right-sided heart failure.

Figure 1.14: The pathophysiological and clinical events as chronic bronchitis progresses.

With continued progression of the disease, blood gases become deranged as insufficient alveolar ventilation is achieved. As the disease approaches its end stage, the patient experiences dyspnea at rest until respiratory failure occurs and the patient is hypoxemic and hypercarbic.

Emphysema

Emphysema, a possible second component to COPD, involves permanent enlargement of airspaces distal to the terminal bronchioles and destruction of alveolar walls, as is evident in figure 1.15.

Figure 1.15: Histological comparison of normal (left) and emphysematous (right) lung tissue.

The pattern of airspace destruction varies with underlying cause and revolves around the acinus (figure 1.16), the functional unit of the lung comprised of the terminal airways and the alveoli that collectively make up the respiratory zone of the lung. In its broadest classification, emphysema can take on either a centriacinar or panacinar distribution (figure 1.16). In centriacinar emphysema, the respiratory duct is affected while the distal alveoli are mostly unaffected. This is more commonly found in the upper lung fields and associated with smoking and the concurrent presence of chronic bronchitis.

This pathology slide in figure 1.15 illustrates this pattern of tissue destruction with isolated areas of damage, surrounded by relatively normal alveolar structure.

Panacinar emphysema, as the name suggests, involves the entire acinus (figure 1.16), and the alveolar structure is more involved creating large airspaces that occur throughout the lung. This is evident in the pathology slide in figure 1.16 that shows much more uniform damage than the centriacinar example. Panacinar emphysema is much less common and is the pattern of destruction associated with alpha-1 antitrypsin deficiency, which we will deal with in a moment.

Figure 1.16: Characteristic patterns of emphysema.

So having seen the morphology of emphysema, we will look at how this damage occurs.

Pathophysiology of Emphysema

The normal structure of alveoli and respiratory ducts consists of type 1 and type 2 pneumocytes with elastic fibers that contribute to the structure’s mechanical behavior. Emphysema involves the loss of these parenchymal fibers.

The presence of irritants, such as cigarette smoke, causes oxidization and the dysfunction of antiprotease enzymes. Without their inhibitory action, the activity of proteases increases and causes the destruction of local tissue. One of these proteases is elastase, whose elevated activity leads to irreparable loss of parenchymal fibers.

Elastase is also released by neutrophils and macrophages that arrive in response to the inflammatory cascade caused by the inhaled smoke. This causes further destruction of elastin fibers.

The pathogenesis of emphysema (figure 1.17) might be summarized as an imbalance between the activities of antiproteases and proteases. Antiproteases are suppressed, and proteases are elevated.

Figure 1.17: Pathological process of emphysema.

The emphysema in about 1 percent of COPD patients is caused by a genetic lack of alpha-1 anti-trypsin. Even without tobacco use, these patients have an antiprotease/protease imbalance that results in loss of elastin and collagen and produces the panacinar emphysema shown previously (figure 1.16). If an alpha1-anti-trypsin patient does smoke, this imbalance is worsened and emphysema may develop by their late twenties.

The loss of the elastic tissue and alveolar structure produces several pathophysiological changes in lung mechanics and function that result in typical clinical signs.

Clinical Presentation of Emphysema

Lung recoil is the opposing force to the chest wall’s tendency to spring outward. The loss of elastin reduces lung recoil and the chest wall can move outward, producing a characteristic "barrel-chest" (figure 1.18).

The lack of recoil also means that passive expiration is ineffective and active expiration must be employed. The positive pleural pressure associated with active expiration enhances dynamic airway collapse that leads to gas trapping and characteristic hyperinflation (figure 1.18). To prevent this, the emphysema patient may adopt pursed lip breathing to maintain airway pressure during expiration that props open the airways.

The hyperinflation and nonuniform tissue damage can lead to a heterogenous distribution of ventilation and V/Q abnormalities that diminish gas exchange. Gas exchange will also be diminished by the enlargement of airspaces, reducing available surface area (figure 1.18).

The deterioration of gas exchange and lung mechanics worsens as more lung becomes involved, and the stage of the disease, and any concurrent chronic bronchitis, is classified by the level of airway flow limitation (e.g., FEV₁/FVC).

Figure 1.18: The pathophysiological events that lead to the clinical signs of emphysema.

It might also be worth noting here that COPD can produce or be associated with a number of comorbidities; we have already mentioned hypertension, but pulmonary artery disease, coronary heart disease, heart failure, lung cancer, and malnutrition may contribute to a low quality of life that is typically associated with COPD. This in turn may contribute to the high incidence of anxiety disorders and depression experienced by COPD patients.