Asthma
"Introduction - Prevalence - Classification - Aetiology and pathogenesis"
Asthma is a common chronic inflammatory condition of the lung airways whose cause is incompletely understood. Symptoms are cough, wheeze, chest tightness and shortness of breath, often worse at night. The most frequent form has its onset in childhood between the ages of 3 and 5 years and may either worsen or improve during adolescence. Classically asthma has three characteristics:
■ airflow limitation which is usually reversible spontaneously or with treatment
■ airway hyperresponsiveness to a wide range of stimuli (see below)
■ inflammation of the bronchi with T lymphocytes, mast cells, eosinophils with associated plasma exudation, oedema, smooth muscle hypertrophy, matrix deposition, mucus plugging and epithelial damage.
In chronic asthma, inflammation may be accompanied by irreversible airflow limitation as a result of airway wall remodelling that may involve large and small airways and mucus impaction.
■ airflow limitation which is usually reversible spontaneously or with treatment
■ airway hyperresponsiveness to a wide range of stimuli (see below)
■ inflammation of the bronchi with T lymphocytes, mast cells, eosinophils with associated plasma exudation, oedema, smooth muscle hypertrophy, matrix deposition, mucus plugging and epithelial damage.
In chronic asthma, inflammation may be accompanied by irreversible airflow limitation as a result of airway wall remodelling that may involve large and small airways and mucus impaction.
Prevalence
In many countries the prevalence of asthma is increasing. This increase, with its accompanying allergy, is particularly in children and young adults where this disease may affect up to 15% of the population. There is also a geographical variation, with asthma being commoner in more developed countries. Some of the highest rates are in the UK, New Zealand and Australia, but the rates are lower in Far Eastern countries such as China and Malaysia, Africa and Central and Eastern Europe. However, long-term follow-up in developing countries suggests that the disease may become more frequent as individuals adopt a more ‘westernized’ lifestyle, but the environmental factors accounting for this remain unknown. Studies of occupational asthma suggest that a high percentage of the workforce, 15–20%, may become asthmatic if exposed to potent sensitizers. World-wide, approximately 300 million people have asthma and this is expected to rise to 400 million by 2025.
In many countries the prevalence of asthma is increasing. This increase, with its accompanying allergy, is particularly in children and young adults where this disease may affect up to 15% of the population. There is also a geographical variation, with asthma being commoner in more developed countries. Some of the highest rates are in the UK, New Zealand and Australia, but the rates are lower in Far Eastern countries such as China and Malaysia, Africa and Central and Eastern Europe. However, long-term follow-up in developing countries suggests that the disease may become more frequent as individuals adopt a more ‘westernized’ lifestyle, but the environmental factors accounting for this remain unknown. Studies of occupational asthma suggest that a high percentage of the workforce, 15–20%, may become asthmatic if exposed to potent sensitizers. World-wide, approximately 300 million people have asthma and this is expected to rise to 400 million by 2025.
Classification
Asthma is a complex disorder of the conducting airways that most simply can be classified as:
■ extrinsic – implying a definite external cause
■ intrinsic – when no causative agent can be identified.
Extrinsic asthma occurs most frequently in atopic individuals who show positive skin-prick reactions to common inhalant allergens such as dust mite, animal danders, pollens and fungi. Positive skin-prick tests to inhalant allergens are shown in 90% of children and 70% of adults with persistent asthma. Childhood asthma is often accompanied by eczema (atopic dermatitis). A frequently overlooked cause of late-onset asthma in adults is sensitization to chemicals or biological products in the workplace.
Intrinsic asthma often starts in middle age (‘late onset’). Nevertheless, many patients with adult-onset asthma show positive allergen skin tests and on close questioning give a history of respiratory symptoms compatible with childhood asthma.
Non-atopic individuals may develop asthma in middle age from extrinsic causes such as sensitization to occupational agents such as toluene diisocyanate, intolerance to nonsteroidal anti-inflammatory drugs such as aspirin or because they were given β-adrenoceptor-blocking agents for concurrent hypertension or angina that block the protective effect of endogenous adrenergic agonists. Extrinsic causes must be considered in all cases of asthma and, where possible, avoided.
Asthma is a complex disorder of the conducting airways that most simply can be classified as:
■ extrinsic – implying a definite external cause
■ intrinsic – when no causative agent can be identified.
Extrinsic asthma occurs most frequently in atopic individuals who show positive skin-prick reactions to common inhalant allergens such as dust mite, animal danders, pollens and fungi. Positive skin-prick tests to inhalant allergens are shown in 90% of children and 70% of adults with persistent asthma. Childhood asthma is often accompanied by eczema (atopic dermatitis). A frequently overlooked cause of late-onset asthma in adults is sensitization to chemicals or biological products in the workplace.
Intrinsic asthma often starts in middle age (‘late onset’). Nevertheless, many patients with adult-onset asthma show positive allergen skin tests and on close questioning give a history of respiratory symptoms compatible with childhood asthma.
Non-atopic individuals may develop asthma in middle age from extrinsic causes such as sensitization to occupational agents such as toluene diisocyanate, intolerance to nonsteroidal anti-inflammatory drugs such as aspirin or because they were given β-adrenoceptor-blocking agents for concurrent hypertension or angina that block the protective effect of endogenous adrenergic agonists. Extrinsic causes must be considered in all cases of asthma and, where possible, avoided.
Aetiology and pathogenesis
The two major factors involved in the development of asthma and many other stimuli that can precipitate attacks are shown in next figure.
Atopy and allergy
The term ‘atopy’ was used by clinicians at the beginning of the twentieth century to describe a group of disorders, including asthma and hayfever, that appeared:
The two major factors involved in the development of asthma and many other stimuli that can precipitate attacks are shown in next figure.
Atopy and allergy
The term ‘atopy’ was used by clinicians at the beginning of the twentieth century to describe a group of disorders, including asthma and hayfever, that appeared:
 |
| Causes and triggers of asthma. RSV, respiratory syncytial virus; NSAIDs, non-steroidal antiinflammatory drugs. |
■ to run in families
■ to have characteristic wealing skin reactions to common allergens in the environment
■ to have circulating allergen-specific IgE.
Allergen-specific IgE is present in 30–40% of the UK population, and there is a link between serum IgE levels and both the prevalence of asthma and airway hyperresponsiveness. Genetic and environmental factors affect serum IgE levels.
Genetic
Genes, in combination with environmental factors, may turn out to play a key role in the development of asthma.
■ Genes controlling the production of the cytokines IL-3, IL-4, IL-5, IL-9, IL-13 and GM-CSF – which in turn affect mast and eosinophil cell development and longevity as well as IgE production – are present in a cluster on chromosome 5q31–33 (the IL-4 gene cluster).
■ Polymorphic variation in proteins along the IL-4/-13 signalling pathway is strongly associated with allergy and asthma.
■ Novel asthma genes identified by positional cloning from whole genome scans are the PHF11 locus on chromosome 2 (that includes genes SETDB2 and RCBTB1) and transcription factors, which are implicated in IgE synthesis and associated more with atopy than asthma.
■ ADAM 33 (a disintegrin and metalloproteinase) on chromosome 20p13 is more strongly associated with airway hyperresponsiveness and tissue remodelling.
■ Other recently discovered genes associated with asthma are those that encode neuropeptide S receptor (GPRA or GPR154) on chromosome 7p15, HLA-G on chromosome 6p21, dipeptidyl peptidase 10 on chromosome 2q14 and most recently on chromosome 17q21 ORMDL3, a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum.
Environmental factors
Early childhood exposure to allergens and maternal smoking has a major influence on IgE production. Much current interest focuses on the role of intestinal bacteria and childhood infections in shaping the immune system in early life. It has been suggested that growing up in a relatively ‘clean’ environment may predispose towards an IgE response to allergens (the ‘hygiene hypothesis’). Conversely, growing up in a ‘dirtier’ environment may allow the immune system to avoid developing allergic responses. Components of bacteria (e.g. lipopolysaccharide endotoxin; immunostimulatory CpG DNA sequences; flagellin), viruses (e.g. SS- and DS-RNA) and fungi (e.g. chiton, a cell wall component) are able to stimulate up to 10 different toll-like receptors (TLRs) expressed on immune and epithelial cells to direct the immune and inflammatory response away from the allergic (Th2) towards protective (Th1 and Treg) pathways. Th1 immunity is associated with antimicrobial protective immunity whereas regulatory T cells are strongly implicated in tolerance to allergens. Thus early life exposure to inhaled and ingested products of microorganisms, as occurs in livestock farming communities and developing countries, may be critical in helping shape the subsequent risk of a child becoming allergic and/or developing asthma.
The allergens involved in asthma are similar to those in rhinitis although pollen exposure causes hay fever to a greater extent than asthma. Allergens from the faecal particles of the house-dust mite are associated with most cases of asthma world-wide. Cockroach allergy has been implicated in asthma in US inner-city children, while allergens from furry pets (especially cats) are increasingly common causes. The fungal spores from Aspergillus fumigatus give rise to a complex series of lung disorders, including asthma. Many allergens, including those from Aspergillus, have intrinsic biological properties, e.g. proteolytic enzymes that facilitate their passage through the airway epithelium to increase their sensitizing capacity.
Chitins are cross-linked polysaccharides found in the exoskeleton of insects and cockroaches, fungi and in the eggs of helminths. They can be inhaled into the airways. Chitinase-family proteins may play a role in the pathogenesis of asthma as the levels in the lungs and the serum are high in asthma and correlate with disease activity.
Increased responsiveness of the airways of
the lung (airway hyperresponsiveness)
Bronchial hyperresponsiveness (BHR) is demonstrated by asking the patient to inhale gradually increasing concentrations of either histamine or methacholine (bronchial provocation tests). This induces transient airflow limitation in susceptible individuals (approximately 20% of the population); the dose of the agonist (provocation dose, PD) necessary to produce a 20% fall in FEV1 is known as the PD20 FEV1 (or provocation concentration PC20 FEV1). Patients with clinical symptoms of asthma respond to very low doses of methacholine, i.e. they have a low PD20 FEV1 (< 11 μmol). Exercise testing or inhalation of cold dry air, mannitol or hypertonic saline are other methods to assess BHR, but all of these involve the stimulus first releasing endogenous mediators such as histamine, prostaglandins and leukotrienes into the airways to cause the bronchoconstriction (indirect BHR). Measures of indirect BHR correlate more closely with symptoms and diurnal peak expiratory flow rate (PEFR) variation than PC20 histamine or methacholine and both are useful in diagnosing asthma if there is doubt and in guiding controller treatment.
Some patients also react to methacholine but at higher doses and include those with:
■ attacks of asthma only on extreme exertion, e.g. winter sports enthusiasts
■ wheezing or prolonged periods of coughing following a viral infection
■ seasonal wheeze during the pollen season
■ allergic rhinitis, but not complaining of any lower respiratory symptoms until specifically questioned
■ some subjects with no respiratory symptoms.
Although the degree of hyperresponsiveness can itself be influenced by allergic mechanisms, its pathogenesis and mode of inheritance involve a combination of airway inflammation and tissue remodelling.
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