ASTHMA

Asthma

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.

Etiology

Precipitating factors

•        Over 250 materials encountered at the workplace, accounting for 15% of all asthma cases, give rise to occupational asthma. The causes are recognized occupational diseases in the UK, and patients in insurable employment are therefore eligible for statutory compensation provided they apply within 10 years of leaving the occupation in which the asthma developed.

•        Asthma can be due to:

■ high molecular weight compounds, e.g. flour, organic dusts and other large protein molecules involving specific IgE antibodies, or

■ low molecular weight compounds, e.g. reactive chemicals such as isocyanates and acid anhydrides that bond chemically to epithelial cells to activate them as well as provide haptens recognized by T cells.

Occupational Exposure

Non-specific factors

•        The characteristic feature of BHR in asthma means that, as well as reacting to specific antigens, the airways will also respond to a wide variety of non-specific direct and indirect stimuli.

•        Cold air and exercise

Most asthmatics wheeze after prolonged exercise. Typically, the attack does not occur while exercising but afterwards. The inhalation of cold, dry air will also precipitate an attack.

•        Exercise-induced wheeze is driven by release of histamine, prostaglandins (PGs) and leukotrienes (LTs) from mast cells as well as stimulation of neural reflexes when the epithelial lining fluid of the bronchi becomes hyperosmolar owing to drying and cooling during exercise. The phenomenon can be shown by exercise, cold air and hypertonic (e.g. saline or mannitol) provocation tests.

•         Atmospheric pollution and irritant dusts,vapours and fumes

Many patients with asthma experience worsening of symptoms on contact with tobacco smoke, car exhaust fumes, solvents, strong perfumes or high concentrations of dust in the atmosphere. Major epidemics have been recorded when large amounts of allergens are released into the air,

e.g. soybean epidemic in Barcelona.

•        Asthma exacerbations increase in both summer and winter air pollution episodes associated with climatic temperature inversions. Epidemics of the disease have occurred in the presence of high concentrations of ozone, particulates and NO2 in the summer and particulates, NO2 and SO2 in the winter.

Diet

•        Increased intakes of fresh fruit and vegetables have been shown to be protective, possibly owing to the increased intake of antioxidants or other protective molecules such as flavonoids. Genetic variation in antioxidant enzymes is associated with more severe asthma.

Emotion

•        It is well known that emotional factors may influence asthma both acutely and chronically, but there is no evidence that patients with the disease are any more psychologically disturbed than their non-asthmatic peers. An asthma attack is a frightening experience, especially when of sudden and unexpected onset. Patients at special risk of life-threatening attacks are understandably anxious.

•        Drugs

Non-steroid anti-inflammatory drugs (NSAIDs). NSAIDs, particularly aspirin and propionic acid derivatives, e.g. indometacin  and ibuprofen, have a role in the development and precipitation of asthma in approximately 5% of patients. NSAID intolerance is especially prevalent in those with both nasal polyps and asthma and is not infrequently associated with a triad of asthma, rhinitis and flushing on drug exposure. In susceptible subjects exposure to NSAIDs reveals an imbalance in the metabolism of arachidonic acid. NSAIDs inhibit arachidonic acid metabolism via the cyclo-oxygenase  (COX) pathway, preventing the synthesis of certain prostaglandins. In aspirin-intolerant asthma there is reduced productionof PGE2 which, in a sub-proportion of genetically susceptible subjects, induces the overproduction of cysteinyl leukotrienes by eosinophils, mast cells and macrophages. In such patients there is evidence for genetic polymorphisms involving the enzymes and receptors of the leukotriene generating pathway (Fig. 14.32). Interestingly, asthma in intolerant patients is not precipitated by COX-2 inhibitors, indicating that it is blockade of the COX-1 isoenzyme that is linked to impaired PGE2 production.

•        Beta-blockers. The airways have a direct parasympathetic innervation that tends to produce bronchoconstriction. Thereis no direct sympathetic innervation of the smooth muscle of the bronchi, and antagonism of parasympathetically induced bronchoconstriction is critically dependent upon circulating epinephrine (adrenaline) acting through β2-receptors on the surface of smooth muscle cells. Inhibition of this effect by β-adrenoceptor-blocking drugs such as propranolol leads to bronchoconstriction and airflow limitation, but only in asthmatic subjects. The so-called selective β1-adrenergicblocking drugs such as atenolol may still induce attacks of asthma; their use to treat hypertension or angina in asthmatic patients is best avoided.

•        Allergen-induced asthma

The experimental inhalation of allergen by atopic asthmatic individuals leads to the development of different types of reaction.

•        Immediate asthma (early reaction). Airflow limitation begins within minutes of contact with the allergen, reaches its maximum in 15–20 minutes and subsides by 1 hour.

•        Dual and late-phase reactions. Following an immediate reaction many asthmatics develop a more prolonged and sustained attack of airflow limitation that responds less well to inhalation of bronchodilator drugs such as salbutamol. Isolated late-phase reactions with no preceding immediate response can occur after the inhalation of some occupational sensitizers such as isocyanates. During and up to several weeks after the exposure, the airways are hyperresponsive, which may explain persisting symptoms after allergen exposure.

The armed CD8⁺ T cells also synthesise and express IL-2 receptors and release IL-2, which stimulates the cells by autocrine action to proliferate and give rise to cytotoxic T cells. These can kill virally infected cells. IL-2 secreted by CD4⁺ cells also plays a part in stimulating CD8⁺ cells to proliferate. Note that the 'effector phase' depicted above relates to the 'protective' action of the immune response. When the response is inappropriately deployed-as in chronic inflammatory conditions such as rheumatoid arthritis-the Th1 component of the immune response is dominant and the activated macrophages (mφ) release IL-1 and tumour necrosis factor-α, which in turn trigger the release of the chemokines and inflammatory cytokines that play a major role in the pathology of the disease.

Pathogenesis

The pathogenesis of asthma is complex and not fully understood.

It involves a number of cells, mediators, nerves and vascular leakage that can be activated by several different mechanisms, of which exposure to allergens is among the most significant . The varying clinical severity and chronicity of asthma is dependent on an interplay between airway inflammation and airway wall remodelling. The inflammatory component is driven by Th2-type T lymphocytes which facilitate IgE synthesis through production of IL-4 and eosinophilic inflammation through IL-5 . However,as the disease becomes more severe and chronic and loses its sensitivity to corticosteroids, there is greater evidence of a Th1 response with release of mediators such as TNF-α and associated tissue damage, mucous metaplasia and aberrant epithelial and mesenchymal repair.

Inflammation

Several key cells are involved in the inflammatory response that characterizes all types of asthma. Mast cells . These are increased in the epithelium, smooth muscle and mucous glands in asthma and release powerful preformed and newly generated mediators that act on smooth muscle, small blood vessels, mucussecreting cells and sensory nerves, such as histamine, tryptase, PGD2 and LTC4, and its metabolites LTD4 and LTE4 (previously known as slow reacting substance of anaphylaxis, SRS-A), which cause the immediate asthmatic reaction. Mast cells are inhibited by such drugs as sodium cromoglicate and β2-agonists which might contribute to their therapeutic efficacy in preventing acute bronchoconstriction triggered by indirect challenges. Mast cells also release an array of cytokines, chemokines and growth factors that contribute to the late asthmatic response and more chronic aspects of asthma.

Eosinophils. These cells are found in large numbers in the bronchial wall and secretions of asthmatics. They are attracted to the airways by the eosinophilopoietic cytokines IL-3, IL-5 and GM-CSF as well as by chemokines which act on type 3 C-C chemokine receptors (CCR-3) (i.e. eotaxin, RANTES, MCP-1, MCP-3 and MCP-4). These mediators also prime eosinophils for enhanced mediator secretion. When activated, they release LTC4, and basic proteins such as major basic protein (MBP), eosinophil cationic protein (ECP) and peroxidase (EPX) that are toxic to epithelial cells. Both the number and activation of eosinophils are rapidly decreased by corticosteroids. Sputum eosinophilia is of diagnostic help as well as providing a biomarker of response to controller therapy.

Dendritic cells and lymphocytes. These cells are abundant in the mucous membranes of the airways and the alveoli.Dendritic cells have a role in the initial uptake and presentation of allergens to lymphocytes. T helper lymphocytes (CD4+) show evidence of activation  and the release of their cytokines plays a key part in the migration and activation of mast cells (IL-3, IL-4, IL-9 and IL-13) and eosinophils (IL-3, IL-5, GM-CSF). In addition, production of IL-4 and IL- 13 helps maintain the proallergic Th2 phenotype, favouring switching of antibody production by B lymphocytes to IgE. In mild/moderate asthma there occurs a selective upregulation of Th2 T cells with reduced evidence of the Th1 phenotype (producing gamma-interferon, TNF-α and IL-2), although additional Th1 prominence may accompany more severe disease. This polarization is mediated by dendritic cells andinvolves a combination of antigen presentation, costimulation and exposure to polarizing cytokines. The activity of both macrophages and lymphocytes is influenced by corticosteroids but not β2-adrenoceptor agonists.

Remodelling

•        A characteristic feature of chronic asthma is an alteration of structure and functions of the formed elements of the airways. Together, these structural changes interact with inflammatory cells and mediators to cause the characteristic features of the disease. Deposition of matrix proteins, swelling and cellular infiltration cause an expansion of the submucosa beneath the epithelium so that for a given degree of smooth muscle shortening there is excess airway narrowing. Swelling outside the smooth muscle layer spreads the retractile forces exerted by the surrounding alveoli over a greater surface area so that the airways close more easily. Several factors contribute to these changes.

•        The epithelium. In asthma the epithelium of the conducting airways is stressed and damaged with loss of ciliated columnar cells on to the lumen. Metaplasia occurs with a resultant increase in the number and activity of mucus-secreting goblet cells. The epithelium is a major source of mediators, cytokines and growth factors that serve to enhance inflammation and promote tissue remodelling .

•        Damageand activation of the epithelium make it more vulnerable to infection by common respiratory viruses, e.g. rhinovirus, coronavirus, and to the effects of air pollutants. Increased production of nitric oxide (NO), due to the increased expression of inducible NO synthase, is a feature of epithelial damage and activation and the measurement of exhaled NO is proving useful as a non-invasive test of continuing inflammation.

•        Epithelial basement membrane: A pathognomonic feature of asthma is the deposition of repair collagens (types I, III and V) and proteoglycans in the lamina reticularis beneath the basement membrane. This, along with the deposition of other matrix proteins such as laminin, tenascin and fibronectin, causes the appearance of a thickened basement membraneobserved by light microscopy in asthma. This collagen deposition reflects activation of an underlying sheath of fibroblasts that transform into contractile myofibroblasts whichalso have an increased capacity to secrete matrix. Aberrant signalling between the epithelium and underlying myofibroblasts is thought to be the principal cause of airway wall remodelling, since the cells are prolific producers of a range of tissue growth factors such as epidermal growth factor (EGF), transforming growth factor (TGF) -α and -β, connective tissue-derived growth factor (CTGF), platelet-derived growth factor (PDGF), endothelin (ET), insulin-like growth factors (IGF), nerve growth factors and vascular endothelial growth factors

•        The same interaction between epithelium and mesenchymal tissues is central to branching morphogenesis in the developing fetal lung. It has been suggested that these mechanisms are reactivated in asthma, but instead of causing airway growth and branching, they lead to thickening of the airway wall. Increased deposition of collagens, proteoglycans and matrix proteins creates a microenvironment conducive to ongoing inflammation since these complex molecules also possess cell-signalling functions, which aid cell movement, prolong inflammatory cell survival and prime them for mediator secretion.

•        Smooth muscle. A prominent feature of asthma is hyperplasia of the helical bands of airway smooth muscle. In addition to increasing in amount, the smooth muscle alters in function to contract more easily and stay contracted because of a change in actin–myosin cross-link cycling. These changes allow the asthmatic airways to contract too much and too easily at the least provocation. Asthmatic smooth muscle also secretes a wide range of cytokines, chemokines and growth factors that help sustain the chronic inflammatory response. ADAM33, the newly described asthma gene, may be involved in driving increased airway smooth muscle and other features of remodelling through increased availability of growth factors.

•        Nerves. Neural reflexes, both central and peripheral, contribute to the irritability of asthmatic airways. Central reflexes involve stimulation of nerve endings in the epithelium and submucosa with transmission of impulses via the spinal cord and brain back down to the airways where release of acetylcholine from nerve endings stimulates M3 receptors on smooth muscle causing contraction. Local neural reflexes involve antidromic neurotransmission and the release of a variety of neuropeptides. Some of these are smooth muscle contractants (substance P, neurokinin A), some are vasoconstrictors (e.g. calcitonin gene-related peptide, CGRP) and some vasodilators (e.g. neuropeptide Y, vasoactive intestinal polypeptide). The polymorphism in the neuropeptide S receptor (GPR 154) is associated with asthma susceptibility. Bradykinin generated by tissue and serum proteolytic enzymes (including mast cell tryptase and tissue kallikrein) is also a potent stimulus of local neural reflexes involving (nonmyelinated) nerve fibres.

Structure of Bronchi 

Phases of Asthma

Clinical Presentation

•        The principal symptoms of asthma are wheezing attacks and episodic shortness of breath. Symptoms are usually worst during the night, this being a particularly good marker of uncontrolled disease. Cough is a frequent symptom that sometimes predominates, especially in children in whom nocturnal cough can be a presenting feature. There exists great variation in the frequency and duration of the attacks.

•        Some patients have only one or two attacks a year that last for a few hours, whilst others have attacks lasting for weeks.

•        Some patients have chronic symptoms that persist, on top of which there are fluctuations. Attacks may be precipitated by a wide range of triggers .

•        Asthma is a major cause of impaired quality of life with impact on work and recreational, as well as physical activities, and emotions.

Investigations

•        There is no single satisfactory diagnostic test for all asthmatic patients.

•        Lung function tests

Peak expiratory flow rate (PEFR) measurements on waking, prior to taking a bronchodilator and before bed after a bronchodilator, are particularly useful in demonstrating the variable airflow limitation that characterizes the disease. The diurnal variation in PEFR is a good measure of asthma activity and is of help in the longer-term assessment of the patient’s disease and its response to treatment. To assess possible occupational asthma, peak flows need to be measured for at least 2 weeks at work and 2 weeks off work.

Spirometry

•        especially in assessing reversibility. Asthma can be diagnosed by demonstrating a greater than 15% improvement in FEV1 or PEFR following the inhalation of a bronchodilator. However, this degree of response may not be present if the asthma is in remission or in severe chronic asthma when little reversibility can be demonstrated or if the patient is already being treated with long-acting bronchodilators.

•        Exercise tests

•        These have been widely used in the diagnosis of asthma in children. Ideally, the child should run for 6 minutes on a treadmill at a workload sufficient to increase the heart rate above 160 beats per minute. Alternative methods use cold air challenge, isocapnoeic hyperventilation (forced overbreathing with artificially maintained Paco2) or aerosol challenge with hypertonic solutions. A negative test does not automatically rule out asthma.

•        Histamine or methacholine bronchial provocation test

•        This test indicates the presence of airwa hyperresponsiveness, a feature found in most asthmatics, and can be particularly useful in investigating those patients whose main symptom is cough. The test should not be performed on individuals who have poor lung function (FEV1 < 1.5 L) or a history of ‘brittle’ asthma. In children, controlled exercise testing as a measure of BHR is often easier to perform.

•        Trial of corticosteroids

•        All patients who present with severe airflow limitation should undergo a formal trial of corticosteroids. Prednisolone 30 mg orally should be given daily for 2 weeks with lung function measured before and immediately after the course.

•        A substantial improvement in FEV1 (> 15%) confirms the presence of a reversible element and indicates that the administration of inhaled steroids will prove beneficial to the patient. If the trial is for 2 weeks or less, the oral corticosteroid can be withdrawn without tailing off the dose, and should be replaced by inhaled corticosteroids in those who have responded.

•        Blood and sputum tests

Patients with asthma may have an increase in the number of eosinophils in peripheral blood (> 0.4 × 109/L). The presence of large numbers of eosinophils in the sputum is a more useful diagnostic tool.

•        Chest X-ray

•        There are no diagnostic features of asthma on the chest Xray, although overinflation is characteristic during an acute episode or in chronic severe disease. A chest X-ray may be helpful in excluding a pneumothorax, which can occur as a complication, or in detecting the pulmonary shadows associated with allergic bronchopulmonary aspergillosis.

Skin tests

•        Skin-prick tests (SPT) should be performed in all cases of asthma to help identify allergic causes. Measurement of allergen-specific IgE in the serum is also helpful if SPT facilities are not available, if the patient is taking antihistamines or if a wide range of allergens are being investigated. Asthma frequently occurs in conjunction with other atopic disorders, especially rhinitis.

•        Allergen provocation tests

Allergen challenge is not required in the clinical investigation of patients, except in cases of suspected occupational asthma. Another controversial exception is the investigation of food allergy causing asthma. This diagnosis can be difficult, although many patients are concerned about the possibility. In the absence of any obvious allergy, e.g. peanut or milk, if the patient has asthma without any other systemic features, then food allergy is most unlikely to be the cause. Open food challenges are unreliable and if the diagnosis is seriously entertained, blind oral challenges with the food disguised in opaque gelatine capsules are necessary to confirm or refute a causative link . There is much speculation about food intolerance (as opposed to allergy) and asthma including the role of food additives, which occasionally can precipitate severe attacks.
Management

The aims of treatment are to:

■ abolish symptoms

■ restore normal or best possible lung function

■ reduce the risk of severe attacks

■ enable normal growth to occur in children

■ minimize absence from school or employment.

This involves:

■ patient and family education about asthma

■ patient and family participation in treatment

■ avoidance of identified causes where possible

■ use of the lowest effective doses of convenient medications to minimize short-term and long-term side-effects.

                                    S.Ali Basha....