C linical R eview
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 ob-
struction resulting from bronchospasm, edema, and mucus hy-
persecretion.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 subsid-
ing after 1 hour.2 Allergens activate airway mast cells bearing
specific IgE antibodies, leading to cell degranulation and releas-
ing 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 lu-
men.2 In late-phase asthmatic response, an influx of eosinophils
releases further inflammatory mediators. Late-phase asthmatic re-
sponse 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 hyperpla-
sia, increased mucus secretion, fibrosis with collagen deposition
in the basement membrane and submucosa, increased thickness
of smooth muscle due to muscle cell hyperplasia, and angiogen-
esis.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, de-
scribed as excess airway narrowing in response to stimuli. Depend-
ing on the degree of inflammation, the airways can close. The more
severe the asthma, the more hyperreactive the airways.5 The ulti-
mate 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 Univer-
sity of Toronto. Douglas Stewart is a clinical pharmacist with the
Haliburton Highlands Family Health Team. Contact:
douglas.stewart@hhfht.com.
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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 methacho-
line 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 pa-
tients less sensitive to their personal triggers.7
Allergic
Although particularly common in children, a significant propor-
tion of all people with asthma display an allergic component to the
disease. In patients with allergic asthma, airborne allergen expo-
sure triggers early-phase asthmatic response. Many also experience
late-phase asthmatic response, which may induce and maintain
bronchial hyperreactivity. Late-phase asthmatic response is as-
sociated 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% be-
low 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 trypt-
ase 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-sensi-
tive. The pathogenesis has not been clearly described, but it is cur-
rently accepted that cyclooxygenase inhibition plays a central role.
ASA and other nonsteroidal anti-inflammatory drugs (NSAIDs)
inhibit the cyclooxygenase (COX) enzyme, preventing metabolism
S6
of arachidonic acid to prostaglandins, and, instead, leading to ex-
cess leukotriene production. The leukotrienes promote histamine
release from mast cells, leading to inflammation and broncho-
spasm. 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 patho-
genesis, although largely unknown, has been associated with pat-
terns of endogenous cortisol secretion and circulating epineph-
rine. 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 al-
lergies, 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.
COPD
Chronic obstructive pulmonary disease (COPD) is “a disease char-
acterized by a progressive airflow limitation caused by an abnor-
mal 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. Eventu-
ally, mucous glands become enlarged and the number of goblet
cells increases, leading to mucus hypersecretion.14 The combina-
tion of altered and excessive mucus with impaired clearance of-
fers 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 re-
modelling, including collagen deposition and scar tissue forma-
tion 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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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 pro-
ductive chronic cough have been excluded.”11 In COPD patients,
chronic bronchitis is depicted by inflammation with mucus pro-
duction 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, name-
ly an imbalance in the ventilation-perfusion ratio.15 The resulting
hypoxic state induces pulmonary vasoconstriction, leading to pul-
monary 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 expira-
tory 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 centrilobu-
lar 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 patient’s well-being.
Acute exacerbations
Exacerbations may be caused by environmental irritants, bacteria
(e.g., Haemophilus influenzae, Streptococcus pneumoniae, Morax-
ella catarrhalis), or viruses (e.g., influenza, parainfluenza, corona-
and 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 experi-
ence 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 pro-
viding care to these patient populations. n
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