Asthma is an inflammator disorder of the airways. Patients suffer from episodes of cough, wheezing, chest tightness and/or dyspnoea (breath-lessness), which are often worse at night or early in the morning. Asthma can be usefully define as 'a chronic inflammator disorder characterized by increased responsiveness of the bronchi to various innocuous stimuli, manifested by widespread and variable airway narrowing that varies in severity either spontaneously or with treatment'. The major characteristics of asthma are (Fig. 24a):
· Narrowing of the airways and impeded airfl w, commonly reversible spontaneously or following treatment.
· Non-specifi airway hyperresponsiveness to a range of normally innocuous stimuli (e.g. cold air, irritants and pollutants) and airway spasmogens leading to bronchoconstriction (Fig. 24b).
· Increased mucosal inflammatio and recruitment of inﬂammatory cells (eosinophils, mast cells, neutrophils, T lymphocytes) to the airways.
There is also hypersecretion of mucus, which can lead to block age of airways with mucus plugs, and swelling of mucosa due to inflammation-associate vascular leak and consequent oedema of the airway wall, all of which further limit airflow. Damage to the epithelium (epithelial shedding) is reflecte by whorls of epithelial cells (Curschmann's spirals) in the mucus, which also contains eosinophil cell membranes (Charcot-Leyden crystals). In chronic asthma remodelling of the airway wall structure occurs, including increased bronchial smooth muscle content. This causes irreversible narrowing of the airways and limits the effectiveness of bronchodilators.
Asthma is increasing in prevalence, particularly in the Western world, where more than 5% of the population may be symptomatic and receiving treatment. There has been a concomitant increase in mortality, despite improved treatment. In the UK, one in seven of the population has allergic disease and over 9 million people will have wheezed in the last year. The number of teenagers with asthma has nearly doubled over the last 12 years. Asthma is least common in the Far East and most common in the UK, Australia and New Zealand. There is some correlation with Westernized lifestyles, including living conditions that favour house dust mites and atmospheric pollution. Many factors can precipitate an asthma attack or worsen symptoms, including exposure to specifix antigens, tobacco smoke and exhaust fumes, and emotional stress. Exercise (exercised-induced asthma) and inhalation of cold air often precipitate wheezing in asthmatics, probably via drying and cooling of the bronchial epithelium, and is common in children. Certain viral infections (rhinovirus, parainfluenza respiratory syncy- tial virus) are associated with asthma attacks. There may also be a genetic component to asthma. Importantly, 20% of the working population may be susceptible to occupational asthma due to their working environment (Chapter 33).
Asthma can be classifie as extrinsic, having a definit external cause, and intrinsic, where no external cause can be identified Extrinsic asthma commonly occurs as a result of an allergic response, with development of IgE antibodies to specifi antigens (allergic or atopic asthma) and tends to start in childhood with symptoms becoming less severe with age; approximately 80% of asthmatics are atopic. Intrinsic asthma generally appears in adults and is IgE-independent.
Individuals who readily produce IgE to common antigens are prone to allergic asthma. Major antigens include proteins in fecal pellets from house dust mite (Dermatophagoids pteronyssinus; DerP)-the most common cause of asthma worldwide-grass and tree pollen, dander (skin f akes) from domestic pets and fungal spores (Fig. 24c). Genetic factors, atmospheric pollution and maternal smoking in pregnancy all predispose to raised IgE levels and later development of asthma and airway hyperresponsiveness.
Inhalation of allergens by atopic individuals initiates an immediate response (bronchoconstriction) that usually subsides within 2 hours (Fig. 24d); this is reversible with bronchodilators such as β2-adrenoceptor agonists (Chapter 25). This is often followed 3-12 hours later by a late-phase response with bronchoconstriction, airway inflammatio and oedema, and hyperresponsiveness (Fig. 24d), which is less susceptible to bronchodilators. Some materials (e.g. iso-cyanates) cause only an isolated late phase. The increased hyper-responsiveness may promote recurrent asthma attacks over several days.
The immediate response is an example of type I hypersensitivity. It is caused by antigen/IgE-induced mast cell degranulation and release of histamine, prostaglandin D2 (PgD2) and leukotriene C4 and D4 (LTC4, LTD4); these cause bronchoconstriction, increased mucus production and vascular leak (Fig. 24e). The late phase (an example of type IV or cell-based hypersensitivity) is primarily due to inflamma tion. Mast cells and, in particular, activated TH2 lymphocytes release cytokines (cellular mediators) that attract eosinophils and neutrophils to the area. TH2 lymphocytes are a specifi type of TH cell that are also activated by antigen presenting cells (see Chapter 18), but unlike TH1 cells release cytokines such as IL-5 which recruit eosinophils. Asthma is therefore sometimes described as a TH2-driven disease, and may involve an imbalance between TH1 and TH2 lymphocytes.
Consequently, eosinophils are present in large numbers in asthmatic bronchi, and release leukotrienes, platelet-activating factor (PAF), ma- jor basic protein (MBP) and eosinophil cationic protein (ECP). MBP and ECP contribute to epithelial cell damage, causing increased permeability to allergens, release of cytokines that attract more eosinophils (Fig. 24e), and exposure of C-fibr sensory nerve endings which release proinflammator tachykinins. Asthmatic smooth muscle also produces cytokines. Important cytokines involved in asthma include IL-5, IL- 13, eotaxin, RANTES and granulocyte macrophage colony-stimulating factor (GM-CSF).
Aspirin and other non-steroidal anti-inflammator drugs (NSAIDs) promote asthmatic attacks in 5% of asthmatics. They inhibit the cyclooxygenase (COX) pathway that synthesizes prostaglandins and shift arachidonic acid metabolism from COX towards the lipoxygenase pathway and production of LTC4 and LTD4. Aspirin-induced asthma is partially reversed by antileukotriene therapy (Chapter 25).
The bronchi have little sympathetic innervation, but circulating epinephrine (adrenaline) acting via β2-adrenoceptors on smooth muscle causes bronchodilatation. Consequently β-adrenoceptor antagonists can cause bronchoconstriction in asthmatics. This may even occur with nominally β -selective drugs, and their use for cardiovascular disease should be avoided in asthmatics.