Asthma

Key Concepts
1. Asthma as an allergic inflammatory disorder
2. Mechanisms of disease
3. Clinical manifestations

Epidemiology
Australia has one of the highest prevalence rates of asthma in the
world with 10.2%. The rate has been increasing over the past 25 years, and is
the second most common self-reported illness affecting indigenous people. The
main problem with asthma is that it interferes with normal daily functions as
well as work; therefore it contributes more to morbidity than mortality. Despite
this, in 2006, 402 people in Australia died from asthma, although the death rate
has decreased by almost 70% since 1989. Most deaths related to asthma occur
in patients over 65 years.

Asthma
Asthma is an illness which has a mechanism that is not completely
understood. Classically, it is a chronic inflammatory disorder of the airways
in which many cells play a role, in particular mast cells, eosinophils and T
lymphocytes. Asthma is an extremely common syndrome (aggregation of signs
and symptoms), that is usually associated with atopy (allergies). There is no
single pathognomonic feature which defines asthma; therefore there is no
diagnostic test available to be performed. It is usually diagnosed on the basis of
clinical manifestations and the trial of therapy, which is a very unreliable
method of diagnosis.

Characteristics of Asthma
The common characteristics of asthma include: functional
abnormalities, inflammation of the airways and airway wall remodelling
(structural changes).

Functional Abnormalities
Functional abnormalities manifest in two ways: increased resistance
to airflow and airway hyper-reactivity. The increased resistance to airflow is
usually reversible, involving bronchoconstriction, airway wall oedema and
obstruction by mucus. Bronchoconstriction is the contraction of the
bronchial smooth muscle, which is an immediate effect, but not the most
important in determining the severity of the attack. Airway wall oedema occurs
when there is an excessive accumulation of fluid within the tissues causing
swelling of the walls and thus, narrowing of the lumen. Mucus production can
become problematic as the coughing cause air to be expelled, facilitating the
evaporation of the water within the mucus. If the water evaporates, the mucus
becomes dehydrated and more viscous causing the obstruction of the airways.
Airway wall oedema and mucus obstruction are the two most severe aspects of
asthma.

Airway hyper-reactivity can occur in response to a

bronchoconstrictor, where an asthmatic has a much more rigorous reaction
than non-asthmatics. It can also occur in response to non-specific irritants,
such as dust and altered gas levels. But this is not always demonstrable in
patients.

Asthma is obstructive disease.

Airway Inflammation
Airway inflammation occurs through: the recruitment of eosinophils,
accumulation and degranulation of mast cells and an accumulation of
activated T-cells and macrophages.

Airway Wall Remodelling

Airway wall remodelling occurs through several mechanisms.
o The lining of the epithelium changes due to the metaplasia and
hyperplasia of goblet cells.
Normally, bronchial glands are the sites which produce mucus
within the respiratory tract, but the proliferation of goblet cells
greatly increases the production of mucus.
o Subepithelial fibrosis where the basal membrane is subjected to an
increase in collagen deposition and is therefore thickened.
o In all asthmatics, there is increase smooth muscle via hyperplasia
and hypertrophy. This results in the same amount of stimulus as
before the growth in muscle, eliciting a greater amount of
constriction since there is a greater amount of smooth muscle.
o Increased vascularity is also a feature of airway wall remodelling,
which results in more fluid entering the airways and causing greater
obstruction.
 This is an asthmatic bronchiole with a
collapsed airway, illustrating abnormal
epithelium with lots of goblet cells.

There is a large band of smooth muscle

around the outer regions.

There is also the presence of eosinophils

intraepithelially, in the lamina propria and the adventitia.

Subepithelial fibrosis results in a thick layer of

collagen in the basal lamina.

Spirometry
Spirometry can be used to determine whether a
person has an obstructive or restrictive airway
disease. Asthma is typically an obstructive respiratory
disease. Spirometry compares the Force Expiratory Capacity in one second
(FEV1) with the Force Vital Capacity (FVC) to determine the type of respiratory
disease. FVC is the total volume of air blown out of an individual after taking a
deep breath, with a normal male being able to expel 5L of air. FEV1 is the
volume of air expired in one second. The ratio of FEV1 to FVC is then
calculated to determine the category of disease. If it is obstructive, then
bronchodilators are given to the patient. If the ratio improves, then it is
classified as asthma.

In obstructive diseases such as asthma, the total capacity of the lungs is

decreases due to mucous obstruction and the rate at which the air is expelled is
slow due to the narrower lumen of the airways. In restrictive diseases, it is only
the capacity of the lungs that is affected, thus resulting in a normal ratio of FEV 1
to FVC.
Allergic & Non-Allergic Triggers
At least two-thirds of asthma in children is caused by an allergen. Some
important allergens include: house dust mites, pollens, fungal spores, organic
and dusts. Generally, asthma spontaneously resolves in individuals.

The development of asthma in adulthood is generally due to non-

allergic triggers, such as chemicals, drugs, particulate pollution and viral
infections. Allergic asthma can be triggered by non-allergic causes.

Immunological Mechanisms of Asthma

Upon first exposure, the allergens stimulate TH2 cells to produce
leukotrienes which mediate further responses by B cells and eosinophils. The
B cells are stimulated to produce IgE antibodies, which bind to IgE receptor
proteins on the surface of mast cells. Next time the allergen is encountered,
the antigen of the allergen cross-links with the IgE Fc receptor, causing the
degranulation of the mast cells, releasing histamine and initiating the hyper-
reactive inflammatory response. There is also the stimulation of eosinophil
recruitment causing further release of granules and mediators.

The allergens are usually able to move through the tight junctions
between the epithelial cells to access the immune system.

Treatment Options
There are many approaches to treatment, but since the mechanisms
behind asthma are poorly understood, only the symptomatic components are
treated, rather than the underlying cause. Types of treatment include: anti-
inflammatory drugs (inhaled glucocorticoids, 2-agonists and leukotriene
receptor antagonists), inhibition of specific mediators in the inflammatory
process (anti-cytokine antibodies and soluble cytokine receptors) and
immunoprophylaxis and immunotherapy (native or modified allergens,
peptide epitopes and DNA vaccines).