Chronic Obstructive Pulmonary Disease (COPD) : Pathophysiology, Diagnosis and Treatment

Tuesday, June 13th 2017. | Anti Aging, Disease

The National Heart, Lung, and Blood Institute (NHLBI) and World Health Organization (WHO) have proposed that chronic obstructive pulmonary disease (COPD) be defined as a disease characterized by progressive airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. The most common conditions comprising COPD are chronic bronchitis and emphysema.
Chronic bronchitis is associated with chronic or recurrent excess mucus secretion into the bronchial tree with cough that occurs on most days for at least 3 months of the year for at least 2 consecutive years when other causes of cough have been excluded.
Emphysema is defined as abnormal, permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of their walls, but without obvious fibrosis.

chronic obstructive pulmonary disease copd


PATHOPHYSIOLOGY

The most common etiology is exposure to environmental tobacco smoke, but other chronic inhalational exposures can also lead to COPD. Inhalation of noxious particles and gases stimulates the activation of neutrophils, macrophages, and CD8+ lymphocytes, which release a variety of chemical mediators, including tumor necrosis factor (TNF), interleukin-8 (IL-8), and leukotriene B4 (LTB4). These inflammatory cells and mediators lead to widespread destructive changes in the airways, pulmonary vasculature, and lung parenchyma.
Other pathophysiologic processes may include oxidative stress and an imbalance between aggressive and protective defense systems in the lungs (proteases and antiproteases). Increased oxidants generated by cigarette smoke react with and damage various proteins and lipids, leading to cell and tissue damage. Oxidants also promote inflammation directly and exacerbate the protease-antiprotease imbalance by inhibiting antiprotease activity.
The protective antiprotease 1-antitrypsin (AAT) inhibits several protease enzymes, including neutrophil elastase. In the presence of unopposed AAT activity, elastase attacks elastin, which is a major component of alveolar walls. A hereditary deficiency of AAT results in an increased risk for premature development of emphysema. In the inherited disease, there is an absolute deficiency of AAT. In emphysema resulting from cigarette-smoking, the imbalance is associated with increased protease activity or reduced activity of antiproteases. Activated inflammatory cells release several other proteases, including cathepsins and metalloproteinases (MMPs). In addition, oxidative stress reduces antiprotease (or protective) activity.
An inflammatory exudate is often present in the airways that leads to an increased number and size of goblet cells and mucus glands. Mucus secretion increases, and ciliary motility is impaired. There is a thickening of the smooth muscle and connective tissue in the airways. Chronic inflammation leads to scarring and fibrosis. Diffuse airway narrowing occurs and is more prominent in small peripheral airways.
Parenchymal changes affect the gas-exchanging units of the lungs (alveoli and pulmonary capillaries). Smoking-related disease most commonly results in centrilobular emphysema that primarily affects respiratory bronchioles. Panlobular emphysema is seen in AAT deficiency and extends to the alveolar ducts and sacs.
Vascular changes include thickening of pulmonary vessels that may lead to endothelial dysfunction of the pulmonary arteries. Later, structural changes increase pulmonary pressures, especially during exercise. In severe COPD, secondary pulmonary hypertension leads to right-sided heart failure (cor pulmonale).

CLINICAL PRESENTATION

Initial symptoms of COPD include chronic cough and sputum production; patients may have these symptoms for several years before dyspnea develops.
The physical examination is normal in most patients who present in the milder stages of COPD. When airflow limitation becomes severe, patients may have cyanosis of mucosal membranes, development of a “barrel chest” due to hyperinflation of the lungs, an increased resting respiratory rate, shallow breathing, pursing of the lips during expiration, and use of accessory respiratory muscles.
Patients experiencing a COPD exacerbation may have worsening dyspnea, increase in sputum volume, or increase in sputum purulence. Other common features of an exacerbation include chest tightness, increased need for bronchodilators, malaise, fatigue, and decreased exercise tolerance.

DIAGNOSIS

The diagnosis of COPD is based in part on the patient’s symptoms and a history of exposure to risk factors such as tobacco smoke and occupational exposures.
PULMONARY FUNCTION TESTS

Assessment of airflow limitation through spirometry is the standard for diagnosing and monitoring COPD. The forced expiratory volume after 1 second (FEV1) is generally reduced except in very mild disease. The forced vital capacity (FVC) may also be decreased. The hallmark of COPD is a reduced FEV1/FVC ratio to less than 70%.
An improvement in FEV1 of less than 12% after inhalation of a rapid-acting bronchodilator is considered to be evidence of irreversible airflow obstruction.
Peak expiratory flow measurements are not adequate for diagnosis of COPD because of low specificity and a high degree of effort dependence. However, a low peak expiratory flow is consistent with COPD.
ARTERIAL BLOOD GASES

Significant changes in arterial blood gases are not usually present until the FEV1 is less than 1 L. At this stage, hypoxemia and hypercapnia may become chronic problems. Hypoxemia usually occurs initially with exercise but develops at rest as the disease progresses.
Patients with severe COPD can have a low arterial oxygen tension (Pao2 = 45 to 60 mm Hg) and an elevated arterial carbon dioxide tension (Paco2 = 50 to 60 mm Hg). Hypoxemia results from hypoventilation (V) of lung tissue relative to perfusion (Q) of the area. The low V/Q ratio progresses over several years, resulting in a consistent decline in the Pao2.
Some patients lose the ability to increase the rate or depth or respiration in response to persistent hypoxemia. This decreased ventilatory drive may be due to abnormal peripheral or central respiratory receptor responses. This relative hypoventilation leads to hypercapnia; in this situation the central respiratory response to a chronically increased Paco2 can be blunted. Because these changes in Pao2 and Paco2 are subtle and progress over many years, the pH is usually near normal because the kidneys compensate by retaining bicarbonate.
If acute respiratory distress develops (e.g., due to pneumonia or a COPD exacerbation) the Paco2 may rise sharply resulting in an uncompensated respiratory acidosis.

DIAGNOSIS OF ACUTE RESPIRATORY FAILURE IN COPD

The diagnosis of acute respiratory failure in COPD is made on the basis of an acute drop in Pao2 of 10 to 15 mm Hg or any acute increase in Paco2 that decreases the serum pH to 7.3 or less.
Additional acute clinical manifestations include restlessness, confusion, tachycardia, diaphoresis, cyanosis, hypotension, irregular breathing, miosis, and unconsciousness.
The most common cause of acute respiratory failure in COPD is acute exacerbation of bronchitis with an increase in the volume and viscosity of sputum. This serves to worsen obstruction and further impair alveolar ventilation, resulting in worsening hypoxemia and hypercapnia. Additional causes are pneumonia, pulmonary embolism, left ventricular failure, pneumothorax, and central nervous system depressants.

DESIRED OUTCOME

The goals of therapy include smoking cessation; symptom improvement; reduction in the rate of FEV1 decline; reduction in the number of acute exacerbations; improvement in physical and psychological well-being; and reduction in mortality, hospitalizations, and days lost from work.

TREATMENT OF CHRONIC COPD

NONPHARMACOLOGIC THERAPY

Smoking cessation is the most effective strategy to reduce the risk of developing COPD and the only intervention proven to affect the long-term decline in FEV1 and slow the progression of COPD.
Pulmonary rehabilitation programs include exercise training along with smoking cessation, breathing exercises, optimal medical treatment, psychosocial support, and health education. Supplemental oxygen, nutritional support, and psychoeducational care (e.g., relaxation) are important adjuncts in a pulmonary rehabilitation program.
Annual vaccination with the inactivated intramuscular influenza vaccine is recommended. One dose of the polyvalent pneumococcal vaccine is indicated for patients at any age with COPD; revaccination is recommended for patients older than 65 years if the first vaccination was more than 5 years earlier and the patient was younger than 65 years.

PHARMACOLOGIC THERAPY

Bronchodilators are used to control symptoms; no single pharmacologic class has been proven to provide superior benefit over others, although inhaled therapy is generally preferred. Medication selection is based on likely patient adherence, individual response, and side effects. Medications can be used as needed or on a scheduled bases, and additional therapies should be added in a stepwise manner depending on response and disease severity. Clinical benefits of bronchodilators include increased exercise capacity, decreased air trapping, and relief of symptoms such as dyspnea. However, significant improvements in pulmonary function measurements such as FEV1 may not be observed.
SYMPATHOMIMETICS

Selective sympathomimetics cause relaxation of bronchial smooth muscle and bronchodilation by stimulating the enzyme adenyl cyclase to increase the formation of cyclic adenosine monophosphate (cAMP). They may also improve mucociliary clearance.
Administration via metered-dose inhaler (MDI) or dry-powder inhaler (DPI) is at least as effective as nebulization therapy and is usually favored for reasons of cost and convenience. Refer to Table 78-1 in Chapter 78 for a comparison of the available agents.
Albuterol, levalbuterol, bitolterol, pirbuterol, and terbutaline are the preferred short-acting agents because they have greater selectivity and longer duration of action than other short-acting agents (isoproterenol, metaproterenol, and isoetharine). The inhalation route is preferred to the oral and parenteral routes in terms of both efficacy and adverse effects. Short-acting agents can be used for acute relief of symptoms or on a scheduled basis to prevent or reduce symptoms. The duration of action of short-acting agonists is 4 to 6 hours.
Formoterol and salmeterol are long-acting inhaled agonists that are dosed every 12 hours on a scheduled basis and provide bronchodilation throughout the dosing interval. Their use should be considered when patients demonstrate a frequent need for short-acting agents. Neither drug is indicated for acute relief of symptoms.

ANTICHOLINERGICS

When given by inhalation, anticholinergic agents produce bronchodilation by competitively inhibiting cholinergic receptors in bronchial smooth muscle. This activity blocks acetylcholine, with the net effect being a reduction in cyclic guanosine monophosphate (cGMP), which normally acts to constrict bronchial smooth muscle.
Ipratropium bromide has a slower onset of action than short-acting β2 agonists (15 to 20 minutes vs. 5 minutes for albuterol). For this reason, it may be less suitable for as-needed use, but it is often prescribed in this manner. Ipratropium has a more prolonged bronchodilator effect than short-acting β2 agonists. Its peak effect occurs in 1.5 to 2 hours and its duration is 4 to 6 hours. The recommended dose via MDI is 2 puffs four times a day with upward titration often to 24 puffs/day. It is also available as a solution for nebulization. The most frequent patient complaints are dry mouth, nausea, and, occasionally, metallic taste. Because it is poorly absorbed systemically, anticholinergic side effects are uncommon (e.g., blurred vision, urinary retention, nausea, and tachycardia).
Tiotropium bromide is a long-acting agent that protects against cholinergic bronchoconstriction for more than 24 hours. Its onset of effect is within 30 minutes with a peak effect in 3 hours. It is delivered via the HandiHaler, a single-load, dry-powder, breath-actuated device. The recommended dose is inhalation of the contents of one capsule once daily using the HandiHaler inhalation device. Because it acts locally, tiotropium is well tolerated; the most common complaint is dry mouth. Other anticholinergic effects have also been reported.