CLINICAL REVIEW

Pathophysiology of asthma and COPD

Kelly Sequeira, BSc; Douglas Stewart, BSc, BScPhm, RPh, CAE

Asthma
The most notable physiologic components of asthma are chronic airway inflammation, bronchial hyperreactivity, and airflow obstruction resulting from bronchospasm, edema, and mucus hypersecretion.1 Airway inflammation In asthma, inflammatory events normally occurring in response to serious infection, toxins, or other inhaled threats happen in their absence. Various triggers produce a cascade of immune-mediated events leading to chronic airway inflammation.2 Inhaled allergens cause an early-phase asthmatic response, with symptoms peaking within 15 minutes and usually subsiding after 1 hour.2 Allergens activate airway mast cells bearing specific IgE antibodies, leading to cell degranulation and releasing inflammatory mediators such as histamine and eicosanoids. These inflammatory mediators cause mucus hypersecretion and plasma leakage from blood vessels, contributing to bronchial wall edema, bronchial wall thickening, and blocking of the airway lumen.2 In late-phase asthmatic response, an influx of eosinophils releases further inflammatory mediators. Late-phase asthmatic response causes more inflammatory changes and the smooth muscle around the airways becomes hyperreactive, contracting readily in response to allergens.3 A long-term consequence of chronic airway inflammation is airway remodelling, involving epithelial and goblet cell hyperplasia, increased mucus secretion, fibrosis with collagen deposition in the basement membrane and submucosa, increased thickness of smooth muscle due to muscle cell hyperplasia, and angiogenesis.4 With bronchial walls already thickened from inflammation and airway remodelling, a small contraction of bronchial smooth muscle can lead to dramatic increases in airway resistance.2 Bronchial hyperreactivity Airway inflammation also leads to bronchial hyperreactivity, described as excess airway narrowing in response to stimuli. Depending on the degree of inflammation, the airways can close. The more severe the asthma, the more hyperreactive the airways.5 The ultimate result and significance is the degree of airflow obstruction resulting from trigger exposure.5 Kelly Sequeira is a student in the Structured Practical Experience Program at the Leslie Dan Faculty of Pharmacy at the University of Toronto. Douglas Stewart is a clinical pharmacist with the Haliburton Highlands Family Health Team. Contact: douglas.stewart@hhfht.com. Airflow obstruction Bronchospasm, edema, and mucus hypersecretion lead to airflow obstruction, but it is often reversible. Variable airflow obstruction is demonstrated by measuring forced expiratory volume (FEV1), peak expiratory flow (PEF), or hyperresponsiveness to methacholine challenge.6 Asthma triggers A variety of triggers can cause asthma exacerbations. Many patients react to multiple triggers, and many triggers are difficult to avoid. Maintaining good control with preventer medications makes patients less sensitive to their personal triggers.7 Allergic Although particularly common in children, a significant proportion of all people with asthma display an allergic component to the disease. In patients with allergic asthma, airborne allergen exposure triggers early-phase asthmatic response. Many also experience late-phase asthmatic response, which may induce and maintain bronchial hyperreactivity. Late-phase asthmatic response is associated with more airway obstruction than the early phase, and is characterized by the influx and activation of lymphocytes and other inflammatory cells that increase pro-inflammatory cytokine production.8 Exercise-induced In patients with exercise-induced asthma, vigorous exercise causes pulmonary function to increase during the first few minutes but then decrease after 6 to 8 minutes. Exercise-induced asthma is considered moderately severe if FEV1 drops more than 30% below baseline.9 It is more easily provoked in cold dry air, whereas warm humid air can blunt it. Mast cell degranulation likely plays a role, since studies show increased plasma histamine and tryptase concentrations. Some patients have a late response similar to late-phase asthmatic response and an associated secondary rise in neutrophil chemotactic factor. Exercise-induced asthma is believed to reflect the increased bronchial hyperreactivity of patients with asthma.8 ASA-induced Approximately 10% to 20% of adults with asthma are ASA-sensitive. The pathogenesis has not been clearly described, but it is currently accepted that cyclooxygenase inhibition plays a central role. ASA and other nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the cyclooxygenase (COX) enzyme, preventing metabolism
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of arachidonic acid to prostaglandins, and, instead, leading to excess leukotriene production. The leukotrienes promote histamine release from mast cells, leading to inflammation and bronchospasm. Most ASA-sensitive patients can tolerate COX-2-specific NSAIDs.10 Nocturnal Patients with nocturnal asthma exhibit significant decreases in pulmonary function between bedtime and awakening. The pathogenesis, although largely unknown, has been associated with patterns of endogenous cortisol secretion and circulating epinephrine. There is an inflammatory component that includes increased circulating histamine and activated eosinophils at night.8 Various factors may affect nocturnal worsening of asthma, including allergies, improper environmental control, gastroesophageal reflux, and sinusitis. Most experts consider nocturnal asthma a symptom of inadequately treated persistent asthma.8 Occupational Consider occupational exposure to irritants for all new cases in adults and adolescents of working age, as it accounts for 5% to 15% of adult-onset asthma.6 Two methods of confirming diagnosis are challenge testing with suspected agents and comparing PEF at and away from work.6 Eliminating exposure to the offending agent is the best treatment.

Chronic bronchitis Chronic bronchitis is chronic productive cough for 3 months in each of 2 successive years in a patient in whom other causes of productive chronic cough have been excluded.11 In COPD patients, chronic bronchitis is depicted by inflammation with mucus production and narrowing of the central airways. These airways have increased mucus production, impaired mucociliary clearance, and increased connective tissue deposition.16 Airway obstruction leads to gas exchange abnormalities, namely an imbalance in the ventilation-perfusion ratio.15 The resulting hypoxic state induces pulmonary vasoconstriction, leading to pulmonary hypertension. Over time, this may cause right ventricular hypertrophy and right-sided cardiac failure (cor pulmonale).15 Emphysema Emphysema is permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis.11 The acinus is the specific unit of the lung affected, and its destruction reduces maximum expiratory flow by decreasing the elastic recoil force available to drive air out of the lungs.6 When emphysema is caused by inhaled irritants, acinar damage is usually confined to the proximal portion of the acinus, including terminal bronchioles. This is termed centrilobular emphysema.16 Another type is panacinar emphysema, which usually affects the entire acinus and is seen in people with a genetic deficiency of alpha1-antitrypsin.16 Systemic complications Patients with COPD exhibit several systemic features that may impact their overall health or comorbid conditions. Cachexia and skeletal muscle wasting are often seen in patients with severe COPD. They also tend to have osteoporosis, depression, chronic anemia, and increased risk of cardiovascular disease.15 Increased levels of C-reactive protein, free radicals, and tumour necrosis factor alpha may all play a role in these systemic complications,17 which contribute to the decline of the patients well-being. Acute exacerbations Exacerbations may be caused by environmental irritants, bacteria (e.g., Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis), or viruses (e.g., influenza, parainfluenza, coronaand rhinoviruses).17-19 Exacerbations are often marked by increases in neutrophils, eosinophils, and inflammatory mediators. Patients have hyperinflation and air trapping with reduced expiratory flow, leading to dyspnea and hypoxemia.15 Many patients experience frequent exacerbations, which contribute to their declining pulmonary function. For this reason, minimizing exacerbations should be an area of focus for health care providers. Pharmacists can have a major impact in terms of improving the quality of life of patients affected by asthma and COPD. An understanding of pathophysiology is an essential first step in providing care to these patient populations. n

COPD
Chronic obstructive pulmonary disease (COPD) is a disease characterized by a progressive airflow limitation caused by an abnormal inflammatory reaction to the chronic inhalation of particles.11 The pathophysiology is mainly characterized by inflammation throughout the central and peripheral airways, lung parenchyma, and pulmonary vasculature.12 Smoking is the usual cause.13 In the central airways, inflammation caused by the activation of sensory nerve endings by inhaled irritants results in increased mucus production and impaired mucociliary clearance. Eventually, mucous glands become enlarged and the number of goblet cells increases, leading to mucus hypersecretion.14 The combination of altered and excessive mucus with impaired clearance offers an excellent growth medium for bacteria in the bronchi, which worsens airway damage. Recurrent viral and bacterial respiratory tract infections lead to a loss of ciliated cells, which further impairs mucus clearance and increases exacerbation risk.14 Repeated cycles of inflammation and repair lead to structural narrowing of the airways. The repair process leads to airway remodelling, including collagen deposition and scar tissue formation in the airway wall that narrows the airway lumen and leads to airway obstruction.14 Obstruction causes progressive trapping of air during expiration and leads to hyperinflation. This reduces the inspiratory capacity, resulting in dyspnea and decreased exercise tolerance.15 Elastic recoil is diminished and the driving force for expiratory flow is decreased, in turn impairing the airway support structure and ultimately leading to difficulty in keeping the airways open during expiration. Chronic bronchitis and emphysema are often present in COPD patients.
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References
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