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Friday, March 1, 2013

Asthma: Epidemiology, Classification, Causes, Pathogenesis, Morphological changes of airway, Signs and Symptoms, Investigations, Treatment/Management, Asthma in pregnancy and Prognosis of Asthma

Asthma is a common chronic inflammatory condition of the airway which is classically characterized by:

Asthma most frequently occurs between
the ages of 3-5 years

  1. Airflow limitation which is usually reversible spontaneously or with treatment.
  2. Airway hyper-responsiveness to a wide range of stimuli which would cause no ill effects in the normal airways of nonasthmatic individuals.
  3. Inflammation of the bronchi/airway with T lymphocytes, mast cells, eosinophils with associated plasma exudation, oedema, smooth muscle hypertrophy, matrix deposition, mucus plugging and epithelial damage.

What happens during an asthma attack?
The underlying genetic basis for hyper-responsive airways is not entirely clear, although significant advances have been made in understanding the pathogenesis and environmental triggers of asthma "attack." In some cases, the attacks are triggered by exposure to an allergen to which the person has been previously sensitized, but often no trigger can be identified.

Typical symptoms of asthma include wheeze (high pitched musical sound), cough, chest tightness and dyspnoea (breathlessness) particularly at night and/or early in the morning.

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.

    Epidemiology of asthma:

    World map showing the prevalence of clinical asthma (proportion of population (%)). Data drawn from the European Community Respiratory Health Study (ECRHS) and the International Study of Asthma and Allergies in Childhood (ISAAC).

    Asthma is more common in more developed countries. There has been a significant increase in the incidence of asthma in the Western world over the past 3 decades. 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. Long-term follow-up in developing countries suggests that the disease may become more frequent as individuals adopt a more ‘westernized’ lifestyle.

    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.

    Current estimates suggest that asthma affects 300 million people world-wide and an additional 100 million persons will be diagnosed by 2025.

    Although the development, course of disease and response to treatment are influenced by genetic determinants, the rapid rise in the prevalence of asthma implies that environmental factors are critically important in terms of its expression.  


    Classification of asthma:

    Asthma is a heterogeneous disease triggered by a variety of inciting agents, there is no universally accepted classification. But the simplest classification of asthma is:
    1. Extrinsic/atopic asthma (70%) – implying a definite external cause and are due to IgE and TH2-mediated immune responses to environmental antigens
    2. Intrinsic/Non-atopic asthma (30%) – caused by non-immune stimuli such as aspirin; pulmonary infections, especially those caused by viruses; cold; psychological stress; exercise; and inhaled irritants.
    This classification is useful from the point of pathophysiology, in clinical practice it is not always possible to classify asthma.

    Extrinsic/Atopic asthma:

    This most common type of asthma usually begins in childhood. A positive family history of atopy is common, serum IgE levels are elevated and asthmatic attacks are often preceded by allergic rhinitis, urticaria, or eczema.

    The term atopy or atopic syndrome is a genetic predisposition toward developing certain allergic hypersensitivity reactions to common environmental antigens such as pollen, house dust mite, animal dander, fungi (particularly Aspergillus: allergic bronchopulmonary aspergillosis), pets such as cats and dogs, pests such as cockroaches. This term was used by clinicians at the beginning of the twentieth century to describe a group of disorders, including asthma and hayfever, that appeared:
    1. to run in families
    2. to have characteristic wheal-and-flare skin reactions to common allergens in the environment
    3. to have circulating allergen-specific IgE.
    Atopic individuals show positive skin-prick reactions to common inhalant allergens (examples given above). A skin test with the offending antigen results in an immediate wheal-and-flare reaction (a classic example of the type I IgE-mediated hypersensitivity reaction)

    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/Non atopic asthma:

    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. A positive family history is uncommon, serum IgE levels are normal, and there are no associated allergies.

    In such cases the trigger may be a viral infections of the respiratory tract (most common) or inhaled air pollutants such as sulfur dioxide, ozone, and nitrogen dioxide. These agents increase airway hyper-reactivity in both normal and asthmatic subjects. In the latter, however, the bronchial response, manifested as spasm, is much more severe and sustained.

    Non-atopic individuals may also 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.

    Causes of asthma:

    Asthma is a multifactorial disease, ie many factors are responsible for the development of asthma.
    The major factors involved in the development of asthma are shown in the figure below:

    Major factors responsible for the development of asthma

    1. Atopy and allergy

    2. Genetic factors:

    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.

    3. 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.

    4. Increased responsiveness of the airways of the lung (airway / bronchial hyperresponsiveness):

    Normal airway vs asthmatic airway
    Bronchial hyperresponsiveness- the tendency for airways to contract too easily and too much in response to triggers that have little or no effect in normal individuals-is integral to the diagnosis of asthma and appears to be related, although not exclusively so, to airway inflammation.

    Other factors likely to be important include the degree of airway narrowing and the influence of neurogenic mechanisms. 

    Bronchial hyperresponsiveness (BHR) is demonstrated by asking the patient to inhale gradually increasing concentrations of either histamine or methacholine (bronchial provocation tests).

    5. Occupational asthma: 

    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.

    Occupational asthma

    Low molecular weight
    (non-IgE related)

    Polyurethane varnishes
    Industrial coatings
    Spray painting
    Colophony fumes
    Electronics industry
    Wood dust


    Bleaches and dyes

    Complex metal salts, e.g.nickel, platinum, chromium

    High molecular weight
    (IgE related)

    Allergens from animals and insects
    Farmers, workers in poultry and seafood processing industry;
    laboratory workers
    Nurses, health industry
    Health workers
    Proteolytic enzymes
    Manufacture (but not use) of‘biological’ washing powdes
    Complex salts of platinum
    Metal refining
    Acid anhydrides and polyamine hardening agents
    Industrial coatings
    Table: Occupational asthma

    Occupational 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.
    The risk of developing some forms of occupational asthma increases in smokers.

    The proportion of employees developing occupational asthma depends primarily upon the level of exposure.

    Proper enclosure of industrial processes or appropriate ventilation greatly reduces the risk.

    Atopic individuals develop occupational asthma more rapidly when exposed to agents causing the development of specific IgE antibody. 

    Non-atopic individuals can also develop asthma when exposed to such agents, but after a longer period of exposure.

    6. 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.

    a. 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. 

    b. 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.

    c. 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.

    d. 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.

    e. Drugs:

    i. 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 production of 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. 

    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.

    ii. Beta-blockers. 
    The airways have a direct parasympathetic innervation that tends to produce bronchoconstriction. There is 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. 

    7. 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.

    Pathogenesis of Asthma:

    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 major etiologic factors of asthma are genetic predisposition to type I hypersensitivity ("atopy"), acute and chronic airway inflammation, and bronchial hyper-responsiveness to a variety of stimuli.

    The inflammation involves many cell types and numerous inflammatory mediators, but the role of type 2 helper T (TH2) cells may be critical to the pathogenesis of asthma.

    The classic "atopic" form of asthma is associated with an excessive TH2 reaction against environmental antigens. Cytokines produced by TH2 cells account for most of the features of asthma-IL-4 stimulates IgE production, IL-5 activates eosinophils, and IL-13 stimulates mucus production. All three of these cytokines are produced by TH2 cells.

    In addition, epithelial cells are activated to produce chemokines that promote recruitment of more TH2 cells and eosinophils, as well as other leukocytes, thus amplifying the inflammatory reaction.

    In addition to the inflammatory responses mediated by TH2 type cells, asthma is characterized by structural changes in the bronchial wall, referred to as "airway remodeling." These changes include hypertrophy of bronchial smooth muscle and deposition of subepithelial collagen.

    Until recently, airway remodeling was considered a late, secondary change of asthma; the current view suggests that it may occur over several years before initiation of symptoms.

    The etiologic basis for remodeling is not clear, although there may be an inherited predisposition associated with polymorphisms in genes that result in accelerated proliferation of bronchial smooth muscle cells and fibroblasts. One candidate gene that has emerged in recent years is ADAM33, which is expressed by the cell types implicated in airway remodeling (smooth muscle cells and fibroblasts), although there are undoubtedly other genetic factors involved in this process.

    Mast cells, part of the inflammatory infiltrate in asthma, are also thought to contribute to airway remodeling by secreting growth factors that stimulate smooth muscle proliferation.

    Morphological changes of the airway in asthma:

    The morphologic changes in asthma have been described in persons who die of prolonged severe attacks (status asthmaticus) and in mucosal biopsy specimens of persons challenged with allergens.

    In fatal cases, grossly, the lungs are overdistended because of overinflation, and there may be small areas of atelectasis. The most striking macroscopic finding is occlusion of bronchi and bronchioles by thick, tenacious mucus plugs.

    Histologically, the mucus plugs contain whorls of shed epithelium (Curschmann spirals). 
    Numerous eosinophils and Charcot-Leyden crystals (collections of crystalloids made up of eosinophil proteins) are also present. 

    The other characteristic findings of asthma, collectively called "airway remodeling" include: 
    • Thickening of the basement membrane of the bronchial epithelium. 
    • Edema and an inflammatory infiltrate in the bronchial walls, with a prominence of eosinophils and mast cells. 
    • An increase in the size of the submucosal glands.
    •  Hypertrophy of the bronchial muscle walls.
    Comparison of a normal bronchiole with that in a person with asthma. Note the accumulation of mucus in the bronchial lumen resulting from an increase in the number of mucus-secreting goblet cells in the mucosa and hypertrophy of submucosal mucous glands. In addition, there is intense chronic inflammation caused by recruitment of eosinophils, macrophages, TH2 cells and other inflammatory cells. Basement membrane underlying the mucosal epithelium is thickened, and there is hypertrophy and hyperplasia of smooth muscle cells.

    Clinical features / Signs and Symptoms of Asthma:

    Typical symptoms include recurrent episodes of wheeze, chest tightness, breathlessness and cough. Not uncommonly, asthma is mistaken for a cold or chest infection that is failing to resolve (e.g. after more than 10 days).

    Classical precipitants include exercise, particularly in cold weather, exposure to airborne allergens or pollutants, and viral upper respiratory tract infections.

    Wheeze apart, there is often little to find on examination. An inspection for nasal polyps and eczema should be performed. Rarely, a vasculitic rash may be present in Churg-Strauss syndrome.

    Patients with mild intermittent asthma are usually asymptomatic between exacerbations.

    Patients with persistent asthma report on-going breathlessness and wheeze, but variability is usually present with symptoms fluctuating over the course of one day, from day to day, or from month to month.

    Asthma characteristically displays a diurnal pattern, with symptoms and lung function being worse in the early morning. Particularly when poorly controlled, symptoms such as cough and wheeze disturb sleep and have led to the use of the term 'nocturnal asthma'. Cough may be the dominant symptom in some patients, and the lack of wheeze or breathlessness may lead to a delay in reaching the diagnosis of so-called 'cough-variant asthma'.

    Although the aetiology of asthma is often elusive, an attempt should be made to identify any agents that may contribute to the appearance or aggravation of the condition. With regard to potential allergens, particular enquiry should be made into exposure to a pet cat, guinea pig, rabbit or horse, pest infestation, or mould growth following water damage to a home or building.

    In some circumstances, the appearance of asthma is triggered by medications. For example, β-adrenoceptor antagonists (β-blockers), even when administered topically as eye drops, may induce bronchospasm, and aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) may also induce wheeze as above. The classical aspirin-sensitive patient is female and presents in middle age with asthma, rhinosinusitis and nasal polyps. Aspirin-sensitive patients may also report symptoms following alcohol (in particular white wine) and foods containing salicylates. Other medications implicated include the oral contraceptive pill, cholinergic agents and prostaglandin F2α.

    Betel nuts contain aceroline, which is structurally similar to methacholine, and can aggravate asthma.

    Some patients with asthma have a similar inflammatory response in the upper airway. Careful enquiry should be made as to a history of sinusitis, sinus headache, a blocked or runny nose, and loss of sense of smell.

    An important minority of patients develop a particularly severe form of asthma; this appears to be more common in women. Allergic triggers are less important and airway neutrophilia predominates. 

    Investigations done to diagnose asthma:

    The diagnosis of asthma is predominantly clinical and based on a characteristic history. There is no single satisfactory diagnostic test for all asthmatic patients.

    1. 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 is useful, 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.

    The carbon monoxide (CO) transfer test is normal in asthma.

    2. 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.

    3. Histamine or methacholine bronchial provocation test:

    This test indicates the presence of airway 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. 

    4. 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.

    Exhaled nitric oxide (NO), a measure of airway inflammation and an index of corticosteroid response, is used in children as a test for the efficacy of corticosteroids.

    5. 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.

    6. 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. 

    7. 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.

    8. 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.

    Treatment/Management of Asthma:

    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.
    Whenever possible, patients should be encouraged to take responsibility for managing their own disease. Time should be taken to encourage an understanding of the nature of the condition, the relationship between symptoms and inflammation, the importance of key symptoms such as nocturnal waking, the different types of medication, and, if appropriate, the use of PEF to guide management decisions.

    A variety of tools/questionnaires have been validated to assist in assessing asthma control. Written action plans may be helpful in developing self-management skills.

    Avoidance of aggravating factors:

    This is particularly important in the management of occupational asthma, but may also be relevant to atopic patients where removing or reducing exposure to relevant antigens, e.g. a pet animal, may effect improvement.

    House dust mite exposure may be minimised by replacing carpets with floorboards and using mite-impermeable bedding, although improvements in asthma control following such measures have been difficult to demonstrate.

     Many patients are sensitised to several ubiquitous aeroallergens, making avoidance strategies largely impractical.

    Measures to reduce fungal exposure and eliminate cockroaches may be applicable in specific circumstances, and medications known to precipitate or aggravate asthma should be avoided.

    Smoking cessation is particularly important, as smoking not only encourages sensitisation but also induces a relative corticosteroid resistance in the airway. 

    A stepwise approach to the management of asthma:

    Drugs used to treat asthma

    Step 1: Occasional use of inhaled short-acting β2-adrenoreceptor agonist bronchodilators

    For patients with mild intermittent asthma (symptoms less than once a week for 3 months and fewer than two nocturnal episodes/month), it is usually sufficient to prescribe an inhaled short-acting β2-agonist (salbutamol or terbutaline), to be used on an as-required basis. 

    However, many patients (and their physicians) underestimate the severity of asthma and these patients require careful supervision.

    A history of a severe exacerbation should lead to a step up in treatment.

    A variety of different inhaled devices are available and choice should be guided by patient preference and competence in using the device. The metered-dose inhaler remains the most widely prescribed.

    How to use the inhaler

    Step 2: Introduction of regular 'preventer' therapy: 

    Regular anti-inflammatory therapy (preferably inhaled corticosteroids (ICS) such as beclometasone, budesonide, fluticasone or ciclesonide) should be started in addition to inhaled β2-agonists taken on an as-required basis in any patient who:
    • has experienced an exacerbation of asthma in the last 2 years
    • uses inhaled β2-agonists three times a week or more
    • reports symptoms three times a week or more
    • is awakened by asthma one night per week.  
    For adults, a reasonable starting dose is 400 μg beclometasone dipropionate (BDP) or equivalent per day, although higher doses may be required in smokers. Alternative but much less effective preventive agents include chromones, leukotriene receptor antagonists, and theophyllines.

    Step: Add-on therapy

    If a patient remains poorly controlled despite regular use of ICS, a thorough review should be undertaken focusing on adherence, inhaler technique and on-going exposure to modifiable aggravating factors.

    A further increase in the dose of ICS may benefit some patients, but in general, add-on therapy should be considered in adults taking 800 μg/day BDP (or equivalent).

    Long-acting β2-agonists (LABAs), such as salmeterol and formoterol, with a duration of action of at least 12 hours, represent the first choice of add-on therapy. They have consistently been demonstrated to improve asthma control and reduce the frequency and severity of exacerbations when compared to increasing the dose of ICS alone.

    Fixed combination inhalers of ICS and LABAs have been developed; these are more convenient, increase compliance, and prevent patients using a LABA as monotherapy (which may be accompanied by an increased risk of life-threatening attacks or asthma death).

    The onset of action of formoterol is similar to that of salbutamol, such that, in carefully selected patients, a fixed combination of budesonide and formoterol may be contemplated for use as both rescue and maintenance therapy.

    Oral leukotriene receptor antagonists (e.g. montelukast 10 mg daily) are generally less effective than LABA as add-on therapy but may facilitate a reduction in the dose of ICS and control exacerbations.

    Oral theophyllines may be considered in some patients but their unpredictable metabolism, propensity for drug interactions and prominent side-effect profile limit their widespread use.

    Step 4: Poor control on moderate dose of inhaled steroid and add-on therapy: addition of a fourth drug

    In adults, the dose of ICS may be increased to 2000 μg BDP/budesonide (or equivalent) daily. A nasal corticosteroid preparation should be used in patients with prominent upper airway symptoms. Oral therapy with leukotriene receptor antagonists, theophyllines or a slow-release β2-agonist may be considered. If the trial of add-on therapy is ineffective, it should be discontinued. Oral itraconazole should be contemplated in patients with allergic bronchopulmonary aspergillosis (ABPA).

    Step 5: Continuous or frequent use of oral steroids

    At this stage prednisolone therapy (usually administered as a single daily dose in the morning) should be prescribed in the lowest amount necessary to control symptoms. Patients on long-term oral corticosteroids (> 3 months) or receiving more than three or four courses per year will be at risk of systemic side-effects.

    Osteoporosis can be prevented in this group of patients by using bisphosphonates. Steroid-sparing therapies such as methotrexate, ciclosporin or oral gold may be considered. New therapies, such as omalizumab, a monoclonal antibody directed against IgE, may prove helpful in atopic patients.

    Step-down therapy:

    Once asthma control is established, the dose of inhaled (or oral) corticosteroid should be titrated to the lowest dose at which effective control of asthma is maintained. Decreasing the dose of ICS by around 25-50% every 3 months is a reasonable strategy for most patients.

    Management of asthma in pregnancy:

    Asthma may complicate pregnancy
    • Unpredictable clinical course: one-third worsen, one-third remain stable and one-third improve.
    • Labour and delivery: 90% have no symptoms.
    • Safety data: good for β2-agonists, inhaled steroids, theophyllines, oral prednisolone, and chromones.
    • Oral leukotriene receptor antagonists: no evidence that these harm the fetus and they should not be stopped in women who have previously demonstrated significant improvement in asthma control prior to pregnancy.
    • Steroids: women on maintenance prednisolone > 7.5 mg/day should receive hydrocortisone 100 mg 6-8-hourly during labour.
    • Prostaglandin F2α: may induce bronchospasm and should be used with extreme caution.
    • Breastfeeding: use medications as normal.
    • Uncontrolled asthma represents the greatest danger to the fetus: Associated with maternal (hyperemesis, hypertension, pre-eclampsia, vaginal haemorrhage, complicated labour) and fetal (intrauterine growth restriction and low birth weight, preterm birth, increased perinatal mortality, neonatal hypoxia) complications. 

    Management of catastrophic sudden severe (brittle) asthma:

    This is an unusual variant of asthma in which patients are at risk from sudden death in spite of the fact that their asthma may be well controlled between attacks. Severe life-threatening attacks may occur within hours or even minutes.

    Such patients require a carefully worked out management plan agreed by respiratory physician, primary care physician and patient, and require:
    • emergency supplies of medications at home, in the car and at work
    • oxygen and resuscitation equipment at home and at work
    • nebulized β2-adrenoceptor agonists at home and at work; inhaled long-acting β2-agonists with a corticosteroid can be very effective
    • self-injectable epinephrine (adrenaline): two Epipens of 0.3 mg epinephrine at home, at work and to be carried by the patient at all times
    • prednisolone 60 mg
    • Medic Alert bracelet. 
    On developing wheeze, the patient should attend the nearest hospital immediately. Direct admission to intensive care may be required.

    Prognosis of asthma:

    The outcome from acute severe asthma is generally good. Death is fortunately rare but a considerable number of deaths occur in young people and many are preventable.

    Although asthma often improves in children as they reach their teens, the disease frequently returns in the second, third and fourth decades. 

    In the past the data indicating a natural decrease in asthma through teenage years have led to childhood asthma being treated as an episodic disorder. However, airway inflammation is present continuously from an early age and usually persists even if the symptoms resolve. Moreover, airways remodelling accelerates the process of decline in lung function over time. This has led to a reappraisal of the treatment strategy for asthma, mandating the early use of controller drugs and environmental measures from the time asthma is first diagnosed.

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