1.1: Asthma

Asthma is a commonly occurring member of the obstructive lung disorders and is distinguished by its acute, or episodic, nature. It affects between 5 and 7 percent of the U.S. population and is characterized by a hyperresponsive airway that shows episodic bronchoconstriction, inflammation, and elevated mucous secretion.

About half of asthma arises before ten years old, and about one-third of all cases have a genetic or familial component.

There are numerous underlying mechanisms of asthma (figure 1.1), and they may not be exclusive or independent within the same patient.

• Allergic asthma: (sometimes called atopic, or extrinsic, asthma) is probably the most common and thoroughly researched.
• Cholinergic: Because airways are under neural control, asthma can also be caused by failing autonomic reflexes.
• Occupational/environmental: Inhaled environmental substances, particularly those found in certain work places, can also sensitize airway responses.
• Infection: Triggering of inflammatory responses to infection can also produce or exacerbate an asthmatic response.

We will also look at how exercise and certain pharmacological agents can produce asthma.

Allergenic asthma: Most allergic asthma is caused by the presence of an excessive amount of IgE (the hallmark antibody of an allergy). Formation of an immune complex between the antigen and the overexpressed IgE results in binding to surface receptors on mast cells and basophilic granulocytes, of which there are plenty in the lung. The IgE receptor binding results in the release of a cocktail of proinflammatory and airway-active substances. Some of these, including histamine and cytokines that attract eosinophils and neutrophils, are stored in vesicles of mast cells shown in figure 1.2. Others are produced on demand, including leukotrienes, and are derivatives of arachidonic acid (we will return to this later).

Figure 1.1: Forms and prevalence of asthma.

Figure 1.2: Example of a mast cell loaded with secretory granules.

The results of this cocktail’s release are the hallmarks of asthma:

• contraction of smooth muscle in the airway, producing bronchoconstriction;
• microvascular leaking and congestion, producing airway wall edema; and
• increased airway secretion.

The timeline from the exposure to the antigen to asthmatic response is not straightforward. A response may occur within minutes ("early response"), or hours later ("late response"). Some patients show only an early response, some only a late one, and some show both in a "dual" response. The late response may correspond to the arrival of leucocytes in response to the initial release of cytokines. It may also be due to a mild stimulus arriving later in an airway that was sensitized earlier.

Cholinergic asthma: Because it is open to the external environment, the airway has defensive, vagal reflexes (figure 1.3). An inappropriate exaggeration of some of these may lead to asthma. The basic reflex arch that ends with a cholinergic response begins with stimulation of airway irritant receptors in the epithelium. An afferent signal to the brainstem instigates an efferent signal to cause airway smooth muscle contraction and mucus secretion by glandular cells. The reflex also stimulates mast cells to release their cocktail, which includes histamine.

The released histamine stimulates the airway receptors, setting up the potential for a positive feedback loop and perpetuating the cycle of bronchoconstriction and secretion. The histamine also stimulates bronchoconstriction through its direct action on the smooth muscle as well as sensitizing the smooth muscle to further vagal stimulation. These processes are summarized in figure 1.3.

Figure 1.3: Vagal reflex of irritant airway receptors and the onset of asthma.

The cholinergic response may help produce an asthmatic response to another stimulus that normally would not have produced one (i.e., it may play a part in the hypersensitivity of the asthmatic airways). Likewise, the presence of an infection, particularly a viral infection, may place the airway in a proinflammatory state.

Neural airway control may also contribute to the high prevalence of nocturnal asthma, as during rest when the airways are predominantly under parasympathetic control. But other factors (summarized in figure 1.4) may contribute:

• Normal circadian fluctuations in epinephrine, cortisol, histamine, and other circulating factors may leave the airway more susceptible at night or the early morning.
• The normal suppression of the cough reflex may leave secretions in the airway and promote a proinflammatory state.
• The airway may also be demonstrating a late response to an exposure that happened earlier in the day.
• Being in the supine position promotes gastric reflux, which, while not necessarily causing aspiration, can induce oesphageal vagal reflexes that instigate the airway defensive reflexes we have just seen.

Exercise-induced asthma: Although exercise is associated with increased airway caliber, it can also induce asthma. Increased airway flow to meet the increased metabolic demand of exercise results in loss of fluid and heat from airway surfaces. This leaves the peribronchial fluid in a hypertonic state and causes excitation of the irritant airway receptors, which leads to release of the mast cells’ cocktail.

Figure 1.4: Factors promoting asthma at night.

Exercise-induced asthma is more prevalent in cold (i.e. dry air) where water loss will be higher, so occurs more in sports such as cross-country skiing than swimming in a warm humid environment.

Bronchoconstriction usually occurs when exercise stops—when the protective effect of sympathetic activity to the airway smooth muscles ceases.

Drug-induced asthma: There are several pharmaceutical and food products that can promote asthma, including tartrazine (a yellow food coloring) and sulfides used as food preservatives. Additionally, 10 to 20 percent of asthmatics are sensitive to aspirin.

Recall that some of the on-demand components of the mast cell’s cocktail were derived from arachidonic acid. There are two pertinent pathways in which arachidonic acid is used: the lipoxygenase pathway and the cyclooxygenase pathway (figure 1.5). The first leads to the production of leukotrienes, which are potent bronchoconstrictors. The second leads to the production of prostaglandins and thromboxane. Normally the distribution of arachidonic acid down these pathways is balanced to meet demand. However, NSAIDS such as aspirin are COX 2 inhibitors and block the cyclooxygenase route, leaving more substrate for the lipoxygenase pathway and production of leukotrienes (figure 1.5) with their bronchoconstrictive effect.

Figure 1.5: NSAIDS, including aspirin, shift metabolism of arachidonic acid toward bronchoconstrictive leukotrienes.

Environmental/occupational asthma: As the airway is open to the environment, it is susceptible to inhaled substances that can cause sensitization; there are over two hundred substances known to cause asthma, both organic and inorganic. Some common ones are listed below.

Chemical	Occurrence
Isocyanates	Polyurethane, plastics, varnish, spray paints
Trimellitic anhydride	Epoxy resins
Organic dust	Plants, grains, animal products

Table 1.1: Some of the most common environmental causes of asthma. Taking a pulmonary history should include asking about potential environmental exposures.

Determining whether airway hypersensitivity is due to environmental factors is complicated by widely varying latency periods. Short latency periods can be as brief as twenty-four hours and are associated with vapor or smoke exposure that does not cause an immunological response. Longer latency periods that may last years are more commonly associated with an immunological response to large particles that act like antigens.

The situation is further confused by occupation-related responses, which often cause the airway to become more sensitive to some of the other causes of asthma covered here. This makes the role of an environmental factor more difficult to determine.

Pathophysiology of Asthma

With numerous and maybe concurrent mechanisms, what does asthma look like in the airway? The normal lumen of the airway has a relatively lower resistance, as depicted in panel A of figure 1.6, but in mild asthma the lumen is narrowed (thereby raising resistance to airflow) through swelling of the airway wall, contraction of airway smooth muscle, and blockage (or plugging) of the airway by increased mucus secretion (figure 1.6B). This worsens in more severe asthma until the lumen can be extremely narrow (figure 1.6C) or even completely blocked.

Figure 1.6: Illustrations of normal (A), mildly asthmatic (B), and severely asthmatic (C) airways.

Other characteristics of asthma include the presence of eosinophillic that infiltrate into the airway walls. The eosinophil enzymes also leave a telltale sign: Charcot–Leyden crystals, as shown in the circled area of figure 1.7A.

Figure 1.7: Histological signs of asthma: A = Charcot–Leyden crystals, B = Curshman’s spirals.

The sputum of the asthmatic may also contain Curshman’s spirals (figure 1.7B), which are casts of small bronchioles consisting of mucus and shed epithelial cells. However, Curshman’s spirals are not exclusive to asthma.

With persistent asthma the airway undergoes remodeling (figure 1.8), with thickening of the airway wall and basement membrane, enlarged submucosal glands, and hypertrophy and hyperplasia of airway smooth muscle.

Figure 1.8: Components of airway remodeling in persistent asthma. The epithelium in asthma shows mucous hyperplasia and hypersecretion (gray), and significant basement membrane thickening. Smooth muscle volume is also increased in asthma.

Clinical Presentation of Asthma

One useful diagnostic element of asthma is its episodic or acute behavior. However, as patients may be asymptomatic between attacks, the severity of asthma can be difficult to determine without performing bronchial challenge tests.

The characteristic signs of asthma progress and vary with declining FEV₁ (summarized in figure 1.9). Most attacks start with mild wheezing and coughing, which progress with the severity of attack. The location and form of sensations vary between patients, but most asthmatics complain of chest tightness. This sensation is more commonly reported by asthmatics than other pulmonary patients, so it is a useful diagnostic sign.

Figure 1.9: The progression of an asthma "attack."

As airway resistance increases, the accessory muscles are deployed to maintain sufficient airflow through the narrowing airways, and the patient experiences an increased effort to breathe. Increased expiratory efforts produce dynamic airway collapse and lead to hyperinflation. Further decreases in airway caliber result in insufficient alveolar ventilation and deranged blood gases. The sensation reported at this point is air hunger. Once the patient is severely bronchoconstricted, delivery of inhaled therapies is much more difficult, and mechanical ventilation to support the respiratory muscles becomes complicated. Other signs present during a severe attack are raised heart (tachycardia) and breathing (tachypnea) rates as well as a paradoxical pulse (i.e., a rise in blood pressure during expiration).

Figure 1.9: Components of airway remodeling in persistent asthma. The epithelium in asthma shows mucous hyperplasia and hypersecretion (gray), and significant basement membrane thickening. Smooth muscle volume is also increased in asthma.

The typical chest x-ray of an asthmatic (figure 1.10) shows hyperlucent lung fields, evidence of hyperinflation and peribronchial infiltrate, and perhaps areas of atelectasis. However, the chest x-ray is not particularly effective at distinguishing asthma from some other obstructive disorders.

Figure 1.10: Typical chest x-ray of an asthmatic patient showing hyperlucent fields and hyperinflation. Notice the flattened diaphragm and the number of ribs that are visible; more than six anterior ribs or ten posterior ribs being visible is indicative of hyperinflation.