Asthma

Asthma is a lung disease in which there is intermittent narrowing of the bronchi (airways), causing shortness of breath, wheezing, and a cough. The illness often starts in childhood but can develop at any age. At least one child in seven suffers from asthma, and the number affected has increased dramatically in recent years. Childhood asthma may be outgrown in about half of all cases. During an asthma attack, the muscle in the walls of the airways contracts, causing narrowing. The lining of the airways also becomes swollen and inflamed, producing excess mucus that can block the smaller airways.

Types and causes of asthma

In some people, an allergic response triggers the swelling and inflammation in the airways. This allergic type of asthma tends to occur in childhood, and it may develop in association with the allergic skin condition, eczema or certain other allergic conditions such as hay fever. Susceptibility to these conditions frequently runs in families. Some substances are known to trigger attacks of allergic asthma. These include pollen, house-dust mites, mould, feathers, and dander (tiny scales) and saliva from furry animals such as cats and dogs. Rarely, certain foods, such as milk, eggs, nuts, and wheat, provoke an allergic asthmatic reaction. Some people with asthma are sensitive to  aspirin, and taking it may trigger an attack.
 
When asthma starts in adulthood, there are usually no identifiable allergic triggers. The first attack is sometimes brought on by a respiratory tract infection, stress, or anxiety. In some cases, a substance that is inhaled regularly in the work environment can result in the development of asthma in a previously healthy person. This is known as occupational asthma, and it is one of the few occupatonal lung diseases that are still increasing in incidence. There are currently about 200 substances used in the workplace that are known to trigger symptoms of asthma, including glues, resins, latex, and some chemicals, especially isocyanate chemicals used in spray painting. However, occupational asthma can be difficult to diagnose because a person may be regularly exposed to a particular trigger substance for weeks, months, or even years before the symptoms of asthma begin to appear.
 
Factors that can provoke attacks in a person with asthma include cold air, exercise, smoke, and occasionally emotional factors such as stress and anxiety. Although industrial pollution and exhaust emission from motor vehicles do not normally cause asthma, they do appear to worsen symptoms in people who already have the disorder. Pollution in the atmosphere may also trigger asthma in susceptible people.

Symptoms

Asthma attacks can vary in severity from mild breathlessness to respiratory failure. The main symptoms are wheezing, breathlessness, dry cough, and a tightness in the chest. In a severe attack, breathing becomes increasingly difficult, resulting in a low level of oxygen in the blood. This causes cyanosis (a bluish discoloration) of the face, particularly of the lips. Left untreated, such attacks can be fatal.

Treatment of asthma

There is no cure for asthma, but attacks can be prevented to a large extent if a particular allergen can be identified and consequently avoided. Treatment involves inhaled broncho-dilator drugs (sometimes known as relievers) to widen the airways, thereby relieving symptoms. When symptoms occur frequently, or are severe, inhaled corticosteroids are also prescribed. These drugs (also known as preventers) are used continuously to prevent attacks by reducing inflammation in the airways.
 
Other drug treatments include sodium cromoglicate and nedocromil sodium, both of which are useful in the prevention of exercise-induced asthma. The use of a leukotriene receptor antagonist in combination with a corticosteroid drug may enable the required dose of cortico-steroid to be reduced. Theophylline or the inhaled anticholinergic drug ipratropium bromide may also be used as bronchodilators. An asthma attack that has not responded to treatment with a bronchodilator needs immediate assessment and treatment in hospital.
 

Asthma in more detail - technical

Essentials

Asthma is a chronic inflammatory disease of the bronchial airways that is characterized pathologically by a desquamative eosinophilic bronchitis and clinically by reversible airway narrowing and increased airway responsiveness to nonspecific provocative stimuli. The condition is common, frequently disabling, and can cause death. In the Western world it now affects more than 10% of children and more than 5% of adults, and in England and Wales it is the cause of more than 100 000 hospital admissions and is the certified cause of death of 1500 to 2000 people each year.

Asthma triggers

The risk of developing asthma is increased in atopic individuals, and in asthmatics natural allergen exposure induces asthma and airway hyper-responsiveness. Viral infections, most commonly with rhinoviruses, cause 80 to 85% of exacerbations of asthma in children and 50 to 75% in adults.

Occupational asthma—agents inhaled at work can be the primary cause (induce) or can exacerbate (provoke) asthma. Such occupational asthma may be due to inhalation of irritant chemicals (‘irritant induced asthma’) or substances that induce an allergic reaction (‘hypersensitivity induced asthma’).

Drugs—some can exacerbate asthma, with β-blockers and nonsteroidal anti-inflammatory drugs (NSAIDs) being the most important.

Clinical features

History—symptoms are nonspecific, typically shortness of breath, wheezing, chest tightness and cough. They are usually variable in severity over short periods of time, but can be persistent, and are typically worse at night. Because occupational causes are potentially avoidable, all cases of asthma that have occurred or recurred in adult life should be questioned about symptomatic improvement when away from work, and, if present, enquiry made about potential causes of asthma in the workplace.

Clinical examination—outside the context of an acute exacerbation (see below), the physical signs of mild or moderate asthma may be limited to expiratory wheezes audible over the lungs. Because of the variable nature of airway narrowing some patients have normal lung sounds, but this would not be expected in those with persistent symptomatic asthma.

Diagnosis

Asthma needs to be differentiated from localized airways obstruction, other causes of generalized airways obstruction, and other causes of intermittent breathlessness.

Demonstration of airflow limitation—asthma is most typically diagnosed by the demonstration that this varies spontaneously over short periods of time, or improves after inhalation of a short acting β-agonist or, over a more prolonged period of time, use of a corticosteroid either by inhalation or by mouth. The most clinically useful measurements of airflow limitation are (1) forced expiratory volume in 1 s (FEV1), which may be expressed as a proportion of the forced vital capacity (FVC) as FEV1/FVC%, and (2) peak expiratory flow rate (PEF).

Occupational asthma—(1) in irritant-induced asthma the association of the onset of asthma with inhalation of a toxic chemical is usually clear; (2) in hypersensitivity-induced asthma the diagnosis depends on (a) exposure to a sensitizing agent at work; (b) a characteristic history of onset of asthma after an initial symptom-free period of exposure, with deterioration in symptoms during periods at work and improvements during absence from work; and (c) the results of objective investigations—lung function tests, immunological tests, and inhalation tests.

Classification—patients with asthma can be categorized, at any one time, by whether their symptoms are intermittent or persistent, and by the severity of their symptoms and underlying airway narrowing (measured by lung function tests).

Management—general aims

The aims of treating patients with intermittent or persistent asthma are to: (1) educate the patient about their disease and the objectives of its management; (2) minimize or eliminate asthma symptoms; (3) achieve best possible lung function and prevent an accelerated decline in lung function; (4) prevent exacerbations of asthma; (5) achieve these objectives with fewest drugs, keeping short-term and long-term adverse effects to a minimum.

The objectives for effective asthma control in individual patients are to: (1) allow normal daytime activities as well as the ability to enjoy physically demanding activities; (2) permit sleeping through night, without being awoken by respiratory symptoms; (3) achieve a situation where use of ‘rescue’ medication with inhaled β2 agonists is needed less than once per day; (4) achieve normal or near normal PEF and FEV1 with less than 20% variability between best and worst values; (5) to avoid drug side effects.

The ‘stepped’ approach to treatment

Education—there is clear evidence that patient education to enable adults to manage their asthma can reduce the frequency of unscheduled visits to general practitioners, hospital admissions, and time off work. The four important components of effective patient education are (1) information, (2) self-monitoring, (3) regular medical review, and (4) having a written action plan.

Avoidance of precipitants—the identification and, where feasible, the avoidance of relevant allergens at home or at work is an essential part of the management of asthma.

A ‘stepped’ approach to treatment is the basis of current guidelines for asthma management:

Step 1—mild intermittent asthma controlled by the use of an inhaled shorter-acting β2-agonist (e.g. salbutamol or terbutaline) less than once a day. Requirement for more regular treatment implies the need for regular anti-inflammatory treatment (i.e. a higher step).

Step 2—mild persistent or intermittent asthma that is of sufficient frequency to require regular anti-inflammatory treatment. Treatment with an inhaled corticosteroid should be started at a dose of beclometasone 400 µg twice daily (or equivalent) in adults and continued for at least 3 months, before reducing the dose to the minimum required to maintain good control. Short-acting β2-agonists are used as required for symptomatic relief.

Step 3—moderate persistent asthma that is not controlled by Step 1 and Step 2. The treatment of choice is the addition of a long-acting β2-agonist. If it provides benefit but asthma remains inadequately controlled, the dose of inhaled corticosteroid should be doubled. If it provides no benefit it should be discontinued and the inhaled steroid dose doubled, and if this does not provide adequate control a trial of other treatments such as a slow-release theophylline or leukotriene antagonist should be instituted.

Step 4—asthma control remains poor despite the measures recommended in Step 3. Consideration should be given to further increasing the dose of the inhaled corticosteroid to the equivalent of beclometasone 2000 μg/day or to the addition of a fourth drug, e.g. slow-release theophylline, a leukotriene antagonist, or an oral β2-agonist.

Step 5—failure to respond to combinations of Step 4 treatments requires the addition of an oral corticosteroid while continuing high-dose inhaled corticosteroid treatment.

Acute exacerbations of asthma

Asthma exacerbations are episodes of progressively worsening airway narrowing that can vary in severity from those that patients are able to manage themselves by following an agreed treatment plan, to severe attacks which at their most dramatic develop rapidly and become life threatening within minutes or hours.

Fatal or near fatal attacks—these are associated with (1) patients who have previously required hospital admission for severe asthma and who require regular oral steroid treatment; (2) failure to recognize severity of asthma by the patient; (3) failure to recognize the severity of asthma by the doctor; (4) undertreatment or inappropriate treatment, with failure to use oral corticosteroids in adequate doses early in an exacerbation probably being the single commonest remediable factor.

Clinical features—in acute severe asthma the patient is usually extremely short of breath, sitting up or leaning forward to use their accessory muscles of respiration, with impaired speech and increasingly prolonged expiration alternating with short inspiratory gasps. Tachycardia and pulsus paradoxus are often found. Airway narrowing may become sufficiently severe for no wheeze to be audible and gas exchange sufficiently impaired to cause detectable cyanosis, when the patient will be distressed, anxious, apprehensive and confused. Exhaustion ultimately leads to inadequate ventilation and a rising P CO 2, the two cardinal features that indicate the need for transfer to an intensive care unit in the event that assisted ventilation is required. A value of PEF of less than 50% of predicted or of the recent best value in an adult aged less than 50 years usually indicates severe asthma; a value of less than 33% indicates a potentially life-threatening attack.

Management—initial treatment of a severe attack of asthma should be with (1) oxygen (60% FiO 2); (2) β2-agonist—nebulized salbutamol 2.5 to 5 mg or terbutaline 5 to 10 mg driven by oxygen; (3) steroid—oral prednisolone 30 to 60 mg or intravenous hydrocortisone 200 mg. If there is a poor response to initial treatment after 15 to 30 min, then (1) continue oxygen; (2) repeat nebulized salbutamol 5 mg after 15 min; (3) add ipatropium 0.5 mg to nebulized β2-agonist; (4) give intravenous hydrocortisone 200 mg 4 hourly; (5) consider intravenous magnesium sulphate 1.2 to 2 g over 20 min.

Investigations—chest radiograph to exclude pneumothorax; arterial blood gases to assess oxygenation and ventilation; monitor serum K+ (risk of hypokalaemia with high-dose β2-agonist).

The patient in extremis—indications for transfer to intensive care and for consideration of intermittent positive-pressure ventilation (IPPV) are (1) hypoxia (PaO 2 <8 kPa) despite FiO 2 60%; (2) hypercapnoea (PaCO 2 > 6 kPa); (3) exhaustion with feeble respiration; (4) confusion or drowsiness; (5) unconsciousness; (6) respiratory arrest.

Introduction

Asthma is a chronic inflammatory disease of the bronchial airways that is characterized by a desquamative eosinophilic bronchitis. The defining clinical characteristics of asthma—reversible airway narrowing and increased airway responsive-ness to nonspecific provocative stimuli—are associated with an underlying chronic inflammatory process. Definitions of asthma which have focused on these clinical characteristics to distinguish it from diseases associated with predominantly irreversible airway narrowing have emphasized the intermittent nature of asthma rather than the persistence of the underlying inflammation, with potentially inappropriate implications for treatment.

The recognition that asthma is a chronic inflammatory disease implies that, in addition to identifying and avoiding inducing causes, such as domestic pets and occupational sensitizers, disease control is likely also to require long-term anti-inflammatory treatment. Appreciation of the inflammatory nature of asthma has also led to recognition of the associated injury and damage to the airway wall—airway remodelling—which may lead to irreversible loss of function.

Pathophysiology

Airway hyper-responsiveness: inducers and provokers

The distinguishing abnormalities of lung function in bronchial asthma are (1) reversible airway narrowing, and (2) airway hyper-responsiveness to nonspecific provocative stimuli.

Airway responsiveness describes the ease with which acute airway narrowing can be provoked by a variety of stimuli. Nonspecific provocative stimuli include exercise, inhalation of cold dry air, inhaled respiratory irritants such as sulphur dioxide, and pharmacological agents such as histamine and methacholine (Table 1). Provocation of asthma by specific allergens can induce airway hyper-responsiveness to nonspecific stimuli. Patients with hyper-responsive airways require smaller doses of such stimuli to provoke acute airway narrowing. Inhaled nonspecific provocative stimuli such as histamine or methacholine incite airway narrowing that usually resolves within minutes; exercise provokes asthma within minutes which resolves within 1 h.

The degree of airway responsiveness can be expressed as the dose or concentration of the stimulus which provokes a specified fall in forced expiratory volume in 1 s (FEV1)—commonly the dose or concentration of histamine or methacholine which provokes a 20% fall in FEV1—PD20 or PC20, histamine or methacholine.

Whereas provokers of asthma incite acute airway narrowing in individuals with hyper-responsive airways, inducers of asthma increase the magnitude of airway hyper-responsiveness and the clinical manifestations of asthma by increasing the severity of the underlying airway inflammation which can persist for days or weeks. The principal inducers of asthma are inhaled allergens, viral respiratory tract infections, and low-molecular-weight chemicals encountered at work (see Table 1).

Allergen inhalation tests are a good model of the airway response to an inducer and demonstrate the inter-relationship between airway inflammation, airway narrowing and airway hyper-responsiveness. Inhalation of an allergen by an individual allergic to it with asthma will provoke:

  • an immediate fall in FEV1 that develops within minutes and usually resolves spontaneously within 1 to 1.5 h
  • a subsequent late fall in FEV1 that develops in about 50% of cases 2 to 4 h or more after the inhalation test and persists for several hours, on occasions for days
  • an increase in airway responsiveness, usually associated with the late fall in FEV1, which is frequently of longer duration than the late FEV1 fall
Table 1  Inducers and provokers of asthma
Inducers of asthma    
Allergens   Increased airway inflammation
Viral respiratory tract infections Increased airway responsiveness
Low molecular weight chemicals   Increased severity of asthma
Provokers of asthma    
Exercise    
Cold dry air    
Respiratory irritants (e.g. sulphur dioxide) Acute transient airway narrowing in individuals with hyperresponsive airways
Histamine    
Methacholine    

The immediate fall in FEV1 is IgE dependent and due to airway smooth muscle contraction and airway wall oedema provoked by mediators, such as histamine, released from mast cells resident in the airways. It is not associated with an increase in airway responsiveness. The late fall in FEV1 is the outcome of recruitment to the airways of inflammatory cells, particularly Th2 lymphocytes and eosinophils, reducing airway calibre. It is associated with an increase in airway responsiveness (manifest as a reduction in PC20) which can persist, with associated increased diurnal variation in airway calibre, for several days after resolution of airway narrowing.

Airway inflammation

Because asthma is an inflammatory disease of the airways, markers of airway inflammation have been sought both for diagnostic purposes and as a guide to the effectiveness of treatment. Two particular indices have been investigated: sputum eosinophil count and exhaled nitric oxide (NO) concentration. An increase in sputum eosinophil count (>2% or >3% total cell count in sputum) is an indicator of reversible airway narrowing and is associated with corticosteroid responsiveness. Management of asthma with the additional intention of decreasing sputum eosinophil counts to normal has been shown to reduce the frequency of asthma exacerbations. In addition, some patients may present with cough and sputum, without evidence of reversible airway narrowing, with an increased eosinophil count in sputum, responsive to inhaled corticosteroids—chronic eosinophilic bronchitis.

NO concentration in exhaled breath (F ENO) is increased in patients with asthma, correlates with sputum eosinophilia, particularly in steroid-naive patients, and is reduced by treatment with inhaled corticosteroids. Unfortunately the range of F ENO in the normal population overlaps with the range in patients with asthma, and F ENO is a less good discriminator between normals and asthmatics than sputum eosinophilia. In one population-based study F ENO greater than 50 ppb was a specific (96% specificity) but insensitive (20% sensitivity) test for asthma, and to date F ENO has proved less successful than sputum eosinophilia as a biomarker to monitor the severity of asthma and its response to treatment.

Asthma triggers

Atopy and allergy

Atopy is defined as the production of specific IgE antibody to common inhalant allergens, such as grass pollen, house dust mite, and cat. Atopy may be identified by the presence of immediate skin prick test responses (or of specific IgE in serum) to extracts of common inhalant allergens and has a prevalence of some 40% in the adult population of the United Kingdom.

The risk of developing asthma as well as eczema and hay fever is increased in atopic individuals. In a random population sample in the south-western United States of America a close relationship was found at all ages between skin test responses to local inhalant allergens and the prevalence of asthma and allergic rhinitis. Similarly, in Canadian university students the prevalence of airway hyper-responsiveness to inhaled histamine correlated significantly with the degree of atopy.

In asthmatics, natural allergen exposure induces asthma and airway hyper-responsiveness. In a study of hospital admissions during seven years in Canadian cities, admission rates correlated with increases in levels of aeroallergens, including grasses, trees, weeds, and moulds, with an interaction with ozone levels. Both the severity of asthma and airway responsiveness are increased in asthmatic patients allergic to ragweed pollen during the season. Similarly, avoidance of relevant allergen exposure is associated with an improvement or resolution of asthmatic symptoms, improved lung function, and decreased airway responsiveness. Patients with asthma allergic to house dust mite have shown considerable symptomatic and objective improvement when avoiding house dust mite for several months at altitude in Davos in the Swiss Alps, also for several weeks in a London hospital. In the south-eastern United States of America asthma deaths in patients allergic to the mould Alternaria alternata increased during the months of the year when alternaria spore counts were highest.

Although there is clear evidence that in asthmatics natural exposure to allergens to which they are allergic can provoke asthma (and avoidance can improve it), the influence of allergen exposure on the development of asthma is less clear. Studies comparing populations born and living in different environments and climates, and therefore exposed to different allergens in childhood, demonstrate allergy and associated disease in relation to allergens present in the particular environment. For example, children born and living in Marseilles, on the Mediterranean coast of France (humid and at sea level, encouraging the growth of house dust mite) were compared with those in Briançon, the highest town in the French Alps (not conducive to the growth of house dust mite, but encouraging to the growth of many wind-pollinated plants). Allergy to house dust mite was found to be considerably more prevalent in Marseilles than in Briançon, whereas allergy to pollens was considerably more prevalent in Briançon than Marseilles. The prevalence of asthma was similar in both environments, although the associated allergies differed. The introduction of a new allergen into an environment can cause the development of allergy and asthma, particularly among adults. Unloading soya beans in Barcelona harbour caused ‘epidemic days’, when the number of hospital admissions with asthma increased several fold. The ‘epidemic days’ continued for 7 years before the cause was identified. Filters placed on the silos to prevent the release and dissemination of soya bean during unloading resolved the problem.

Respiratory virus infections

Acute exacerbations of asthma, commonly recognized as an increase in respiratory symptoms of sufficient severity for a patient to seek medical attention, are major causes of ill health, death, and costs, accounting for some 50% of total asthma related costs. Respiratory virus infections have long been suspected to be the major cause of exacerbations of asthma, but it is only with the development and use of the polymerase chain reaction (PCR) in controlled studies that the true proportion of virus-induced asthma exacerbations, in both children and adults, has become clear. There is now consistent evidence that 80 to 85% of exacerbations of asthma in children and 50 to 75% of exacerbations in adults are caused by viral infections, of which the great majority are attributable to rhinoviruses. Exacerbations of asthma provoked by respiratory infections are often severe, can be prolonged, and are associated with increased airway responsiveness. Peak flow measurements in schoolchildren have been shown to remain abnormal for several weeks after a respiratory tract infection.

In school children the peaks of respiratory infections and asthma admissions both occur at the start of the school year. In Canada hospital admissions for asthma in school-age children during a 13-year period consistently peaked in September during the third week after return to school after the summer vacation. Similar but lower peaks in preschool children and adults followed on average 2 and 6 days after the peak for schoolage children, suggesting these acted as the vectors of transmission to their families. Aeroallergen levels are also high in Canada during the summer months and in September during the weeks following return to school and during the peak period for asthma admissions to hospital.

A number of studies have suggested that asthma exacerbations occur particularly in atopic children infected with rhinovirus concurrently exposed to relevant allergens. In one study in the United Kingdom of children aged between 3 and 17 years the risk of admission to hospital with asthma was markedly increased in children with detectable virus infection with allergen-specific IgE and heavily exposed to the sensitizing allergen, as compared to age- and sex-matched children with stable asthma or admitted to hospital with nonrespiratory disease. Virus infection, allergen, or sensitization alone, were not associated with increased risk in this study. In another study in the United States of America of children aged between 2 and 16 years, the strongest risk factors for wheezing requiring emergency care were RT-PCR evidence of rhinovirus together with atopy or eosinophilic inflammation in nasal secretions. These observations demonstrate the importance of viral infection, particularly rhinovirus infection, in exacerbations of asthma in children and adults. In addition, in children at least, virus-induced exacerbations of asthma occur particularly in the context of exposure to a relevant allergen and eosinophilic inflammation.

Recent studies have found evidence of impaired innate immunity in airway epithelial cells in patients with asthma: interferon production is deficient, and the magnitude of deficiency is related to the severity of asthma exacerbations. There is also evidence that infection with Chlamydia pneumoniae may play a role in asthma exacerbations, with one study showing a reduction in the severity and duration of asthma exacerbations in a randomized controlled trial in those treated with the antibiotic telithromycin as compared to placebo.

Occupation

Agents inhaled at work can be the primary cause (induce) or can exacerbate (provoke) asthma. Asthma whose primary cause is an agent inhaled at work is called ‘occupational asthma’ to distinguish it from ‘work-exacerbated’ asthma. Occupational asthma can be (1) ‘irritant-induced asthma’, caused by the inhalation of an irritant chemical in toxic concentrations, also known less felicitously as reactive airways dysfunction syndrome (RADS), or (2) ‘hypersensitivity-induced asthma’, the outcome of an acquired hypersensitivity (allergic) reaction to an inhaled protein or chemical. Irritant-induced occupational asthma can follow the inhalation, in sufficient concentration, of a toxic soluble chemical such as sulphur dioxide, chlorine, or ammonia. The number of described causes of hypersensitivity-induced occupational asthma is now legion, but a relatively small number cause most cases. These include chemical sensitizers such as isocyanates, complex platinum salts, and colophony fume, and proteins such as flour, enzymes used in baking and detergent manufacture, latex. and laboratory animal urine proteins (Table 2).

It is estimated from a national reporting scheme that in the United Kingdom some 2500 new cases of occupational asthma occur each year. An American Thoracic Society systematic review found that 15% of new or relapsed cases of asthma in adult life are attributable to an occupational exposure, suggesting that about 1 in 7 cases of new or relapsed asthma in adult life are potentially preventable.

Work can exacerbate asthma in several different ways, usually as a consequence of airway hyper-responsiveness, e.g. exposure to irritant chemicals such as sulphur dioxide or dust particles, inhalation of cold air in refrigerators or outdoors, or exertion, particularly in an irritant environment. One-third of patients with asthma report worsening of their symptoms at work.

Drugs

Relatively few drugs exacerbate asthma, β-blockers and nonsteroidal anti-inflammatory drugs (NSAIDs) being the most important. Although ACE inhibitors may cause cough, and occasionally rhinitis and angio-oedema, they have not been associated with the provocation of asthma and are therefore not contraindicated in asthma.

β-Blockers

Precipitation or worsening of asthma was first reported with propanolol, but subsequently found to occur with all nonselective β-adrenoceptor antagonists. This reaction to β-blockers implies adrenergic bronchodilator tone in asthmatic airways. The severity of the airway narrowing provoked by β-blockers is not predictable, nor is it closely related to the severity of airway hyper-responsiveness. The dose provoking asthma can be low: severe asthma can be precipitated by timolol eye drops, a nonselective β-blocker used to treat glaucoma. Selective β1-antagonists, such as atenolol, acebutalol, and metoprolol, provoke less severe reactions than nonselective β-blockers such as propanolol.

Although the fall in lung function provoked by a β-blocker can be reversed by an inhaled β2-agonist, patients with asthma should avoid β-blockers—including β1-selective antagonists—because of the unpredictable and potentially serious consequences of a severe asthmatic reaction, and alternative drugs should be used for treatment of hypertension and angina.

Table 2  Selected causes of hypersensitivity-induced occupational asthma by occupational group: high- and low-molecular-mass agents
Occupation Agent(s)
High molecular mass
Baking and milling Flour (wheat, barley, rye, oat, soya), fungal α-amylase, egg proteins, milk proteins, storage mites
Research science, animal handling, laboratory work Small animal proteins (urine, dander, serum): rats, mice, guinea-pigs, ferrets etc. insect proteins: cockroach, locust, housefly, fruit fly, gypsy moth, mealworm etc. other animal proteins: latex
‘Biological’ detergent powder manufacture Detergent enzymes (protease, amylase, lipase, cellulase)
Food processing (nonbaking/milling) Linseed, green coffee bean, castor bean, tea dust, tobacco leaf, rosehip, shellfish proteins, fish proteins, milk proteins, egg proteins, cocoa proteins, proteolytic enzymes
Nursing, dentistry, other health care work Latex
Farming and other agriculture Storage mites, mealworms, spider mite, poultry mite, cow dander, cow β-lactoglobulin, pig urine, mink urine, insect larvae, poultry feathers, honeybee dust, silkworm larvae, fruit, vegetable and flower pollens, fungi, grain dust, spider mite, vine weevil
Floristry, botany Pollens, Ficus elastica, gypsophila
Low molecular mass
Spray painting Hexamethylene diisocyanate, toluene diisocyanate, dimethylethanolamine, other amines
Welding, soldering, electronic assembly Colophony fume, stainless steel welding fume, aminoethylethanolamine, cyanoacrylates, toluene diisocyanate, persulphate salts
Woodwork Hardwood dusts (western red cedar, iroko, aprican maple, mahogany, mansonia, obeche, etc.)
Chemical processing Azodicarbonamide, phthalic anhydride, trimellitic anhydride, maleic anhydride, hexavalent chromium
Plastics manufacture and processing Diphenylmethane diisocyanate, toluene diisocyanate, monomer acrylates, various amines
Food processing (nonbaking/milling) Chloramine-t, metabisulphite
Hairdressing Persulphate salts, henna
Textile/fabric work Reactive dyes, gum acacia
pharmaceutical manufacture, pharmacy Psyllium, ispaghula, methyldopa, penicillins, cephalosporins, tetracycline, sulphathiazole, spiramycin, isoniazid, piperazine, cimetidine, dichloramine, ipecacuanha, bromelain, morphine and other opiates
Nursing, dentistry, other health care work Glutaraldehyde, formaldehyde, monomer acrylates, antibiotics, psyllium, hexachlorophene, pancreatic extracts, N-acetylcysteine
Metal refining Complex platinum salts, hexavalent chromium, nickel, vanadium, furfuryl alcohol
Aspirin and nonsteroidal inflammatory drugs (NSAIDs)

Aspirin and other NSAIDs, which inhibit cyclooxygenase 1 (COX1), can provoke severe attacks of asthma in some 10% of adults with asthma, more frequently in women than men. Aspirin-induced asthma (AIA) may be part of a well-recognized association of aspirin intolerance, asthma, and rhinitis with nasal polyps (Samter’s triad) that is characterized by severe mucosal eosinophilic inflammation of the nose and airways. The onset is usually in the third or fourth decade, with chronic nasal congestion, discharge, and nasal polypi. Subsequently asthma and AIA develop, when ingestion of aspirin or an NSAID typically provokes acute severe asthma within 1 h, accompanied by profuse nasal discharge, periorbital oedema, conjunctival injection, in some cases with flushing of the head and neck and, on occasions, vomiting and diarrhoea. AIA can provoke life-threatening asthma resistant to bronchodilators: in one survey, 25% of 145 patients requiring mechanical ventilation for acute severe asthma had AIA.

Despite avoidance of aspirin and NSAIDs, severe asthma and rhinitis with nasal polyps usually persist, associated with raised blood eosinophil count and intense eosinophil infiltration of the nasal and airway mucosa. The most plausible explanation of AIA is that it occurs as a consequence of specific inhibition in respiratory cells of intracellular COX enzymes. NSAIDs with anti-COX activity provoke asthma in patients with AIA; NSAIDs which do not inhibit COX activity do not provoke asthma; the potency of NSAIDs to inhibit COX correlates with their ability to provoke asthma in AIA individuals; and cross-tolerance to NSAIDs that inhibit COX occurs after desensitization to aspirin. Cross-tolerance involving such chemically distinct moieties argues strongly against AIA being an immunological reaction.

The intense tissue eosinophilia associated with AIA is accompanied by overproduction of cysteinylleukotrienes, which are important mediators of nasal inflammation and asthma. These are continuously synthesized in AIA patients, even in the absence of aspirin ingestion, are released into nasal and bronchial secretions, and can be collected in urine, and COX inhibition is associated with their release. Aspirin provoked nasal and asthmatic reactions are attenuated by leukotriene antagonists, both cysteinyl leukotriene receptor antagonists (zafirlukast, montelukast, and pranlukast) and 5-lipoxygenase inhibitors (zileuton).

Patients with AIA should avoid all aspirin-containing products and other analgesics or anti-inflammatories that inhibit COX (Table 3). Patients with AIA can usually, although not always, take paracetamol. Selective inhibitors of COX-2, celecoxib and rofecoxib, while potentially safe in AIA are associated with an increased frequency of cardiovascular events, and rofecoxib has been withdrawn.

Tolerance to aspirin and NSAIDs can be induced in patients with AIA by the ingestion of increasing doses of aspirin over 2 to 3 days, until 400 to 650 mg aspirin can be tolerated. Daily doses of between 80 and 325 mg aspirin can maintain tolerance, allowing aspirin and other COX inhibitors to be taken safely. A dose of aspirin of 650 mg twice daily can provide improvement in asthma and particularly in nasal inflammation. One report has suggested that regular aspirin treatment after sinus surgery for polypectomy may delay recurrence of nasal polyps, on average by 6 years. However, aspirin desensitization requires daily maintenance of high-dose aspirin that may not be well tolerated. Furthermore, omission of aspirin for 2 to 3 days can result in complete loss of tolerance, in which case the initial desensitization protocol needs to be repeated. It is also not clear whether aspirin desensitization has the potential to modify the long-term course of asthma. For these reasons, aspirin desensitization has not been widely adopted.

Table 3  NSAIDs that cross-react with aspirin in respiratory reactions
Type of COX inhibitor NSAID
Inhibitors of both COX-1 and COX-2 a Piroxicam
Indomethacin
Sulindac
Tolmetin
Ibuprofen
Naproxen
Naproxen sodium
Fenoprofen
Meclofenamate
Mefenamic acid
Flurbiprofen
Difluniusal
Ketoprofen
Diclofenac
Ketoralac
Etodolac
Nabumetone
Poor inhibitors of COX-1 and COX-2 b Oxaprozin
Paracetamol (acetaminophen)
Salsalate
Selective inhibitors of COX-2 c Celecoxib
Rifecoxib (now withdrawn)

a On first exposure to the drug, cross-reactions with low provoking doses.

b A small percentage of patients with AIA cross- react with high dose of these drugs

c In theory should not cross-react.

Prevalence

Asthma is a common disease. It is frequently disabling, and—uncommonly—can cause death. In the Western world it now has an estimated prevalence of more than 10% in children and more than 5% in adults. It is the cause of more than 100 000 hospital admissions and is the certified cause of death of some 1500 to 2000 people in England and Wales each year.

The prevalence of asthma has markedly increased in the Western world, most obviously but not exclusively in children. Studies of disease frequency in the last half of the 20th century suggest a doubling in asthma prevalence in developed nations every 15 years. More recent evidence suggests that in some countries the increase in both children and adults has slowed or plateaued. There have been similar trends in the prevalence of specific IgE sensitization to common aeroallergens. Although in part changes in prevalence may reflect a greater awareness of and tendency to diagnose asthma, repeat cross-sectional studies of children in the United Kingdom, using identical methods of ascertainment at different time points, have shown a definite increase. A study of Aberdeen schoolchildren found the prevalence of wheeze and of diagnosed asthma had increased 2.5-fold in the 25 years between 1964 and 1989. A similar study in South Wales at two time points 15 years apart found a history of reported asthma to have doubled from 6 to 12%, and also reported similar increases of reported hay fever and eczema and of the proportion of children in whom exercise provoked asthma. A third study of the same population in 1998 found a further increase in asthma symptoms but a decrease in exercise-provoked bronchoconstriction, possibly reflecting more frequent use of effective treatments by asthmatic children.

Comparison of the prevalence of asthma in different parts of the world suggests that the high prevalence in the Western world is associated with urbanization and material prosperity, and comparisons between countries are reflected in comparisons within countries. A study of school children in Zimbabwe found asthma to be uncommon in those living in a rural area, more common in poor urban dwellers, and most common in the affluent urban dwellers, equally in black and white, in Harare. In Europe the reunification of Germany allowed comparison of the prevalence of asthma and associated conditions in cities in former East and West Germany. The prevalence of asthma, hay fever, eczema, and atopy (identified as immediate skin test responses to common inhalant allergens) was greater in school-age children living in the West German city of Munich than in the East German cities of Leipzig and Halle. Interestingly, the prevalence of atopy (particularly skin test responses to pollens) and hay fever, but not asthma, subsequently increased in children living in reunified Germany who had lived the first 5 years of their lives in Leipzig. Other intranational studies of European populations suggest stark differences in disease prevalence between urban and rural communities, even where these are geographically close.

Many explanations have been advanced to explain these observations. These include increased indoor allergen exposure (particularly house dust mite and cat), increased exposure to vehicle exhaust pollution, increased tobacco smoking by women of childbearing age, changing diet, and reduced infection rates in childhood. Of these, outdoor air pollution has until recently grabbed most public attention, although there is no substantive evidence in its support: the prevalence of asthma in urban parts of the United Kingdom is no greater (and possibly less) than in rural parts, including Skye, where measured levels of air pollutants are the lowest in United Kingdom. Similarly, there is little evidence that the increased prevalence of asthma and other atopic disease has been caused by increased indoor allergen exposure or tobacco smoking, although the increase in asthma has been paralleled by an increase in cigarette smoking by women of childbearing age. Several dietary explanations have also been advanced, including increased salt and reduced antioxidant intake.

The most plausible explanation for increased prevalence of atopy and asthma advanced to date is that it is a consequence of reduced levels of microbial exposure during childhood. The evidence is both indirect and direct, although not yet conclusive. The most consistent observation, providing indirect evidence, is of an inverse relationship between family size and/or birth order and the risk of atopy and hay fever, a pattern that is evident in populations born almost a century ago. This has been interpreted as being consistent with the age at which a child encounters microbial agents having a decisive influence on the development of atopy and associated diseases: children in large families and those with older sibs are more likely to encounter infections earlier in life, reducing their risk of becoming atopic. More directly, several studies, most of them in European populations, have shown a relationship between growing up on a farm and a reduced risk of developing atopy, hay fever, and asthma, and the effects may persist into adult life. If a farm childhood confers protection then it remains unclear which exposure(s) may be responsible; unpasteurized milk, pig farming, haymaking, and endotoxin in domestic dust have all been proposed, but none as yet confirmed.

Prognosis

Knowledge of the outcome of asthma has been hindered by the lack of a clear workable definition of asthma, which includes all cases (sensitive) and excludes noncases (specific), and by the relative paucity of longitudinal data on well-defined community cohorts including a representative group of cases of asthma and not limited to those coming to medical attention. Nonetheless there is now sufficient information to allow a reasonable view of the outcome of the disease.

The relationship between wheezing in preschool children and asthma in school-age children has been clarified by a number of overlapping studies. Wheezing and cough in children aged less than 2 to 3 years is common and typically associated with viral respiratory infections. In one study in the United States of America, wheezing episodes in children aged less than 2 years were primarily associated with respiratory syncytial virus (RSV) infection (as opposed to rhinovirus infection in children aged >2 years). The important risk factors for wheezing in children aged less than 2 to 3 years are reduced lung function at birth, prematurity or low birth weight, and maternal smoking during pregnancy, which both reduces lung function and alters the baby’s immune responses. The prognosis for such children is good, with remission in most by school age and normal lung function in adult life. ‘Wheezy bronchitis’ in preschool years does not occur more frequently in school-age children with asthma, whose risk factors are different, suggesting the two disorders are independent. The peak prevalence of asthma occurs between the ages of 5 and 10 years, and is associated with eczema in infancy and evidence of sensitization to common inhalant allergens (identified either by skin test responses or by increased total IgE).

The outcome for children who develop asthma has been the subject of several general practice and hospital-based reports, which of necessity will describe the prognosis of more severe cases. The outcome for cases identified in random population samples has been reported from Australia and the United Kingdom. The Australian study found that risk of asthma persisting at ages 21 and 28 years was associated with the frequency of wheezing at ages 7 and 14 years. Children who wheezed infrequently in childhood and adolescence were least likely to have continuing asthma as young adults: more than one-half of those with asthma before the age of 7 years that had remitted by the age of 14 years remained symptom free aged 21 years. However, less than 20% of those with persistent symptoms in childhood were symptom free in adolescence, and frequent attacks in this group continued to the age of 28 years. Some two-thirds of those without symptoms in adolescence remained free of asthma at the age of 28 years. The United Kingdom study described the incidence of wheezing from birth to age 33 years. The incidence of wheezy illness at all ages was related to a history of eczema and hay fever. One-quarter of children with a history of asthma or wheezy bronchitis by the age of 7 years continued to have symptoms when aged 33 years. Asthma developing in adult life was strongly associated with cigarette smoking and a history of hay fever.

In both the United Kingdom and Australian studies, asthma recurred in adult life after a period of remission in adolescence. More than one-half of those in the United Kingdom study who had wheezed before the age of 7 years and reported wheezing aged 33 years had been free of symptoms for 7 years between the age of 16 to 23 years. Similarly, in the Australian study wheezing had recurred in 30% of those who were free of wheezing aged 21 years. In both studies asthma recurred in some individuals with mild symptoms in childhood that were frequently not recalled, and who would otherwise have been labelled as having ‘adult-onset’ asthma.

Clinical Manifestations

The symptoms of asthma are nonspecific: shortness of breath, wheezing, chest tightness, and cough. These are manifestations of airway narrowing, which is usually variable in severity over short periods of time, but can be persistent, and of airway hyper-responsiveness. Asthma as the cause of these symptoms is suggested by the variability in their severity and distinguished by their periodicity (e.g. daily, weekly, monthly, or seasonal), their provocation by specific (e.g. allergen) and nonspecific stimuli, and their reversibility with bronchodilators or corticosteroids.

Patients with asthma can be categorized, at any one time, by whether their symptoms are intermittent or persistent, and by the severity of their symptoms and underlying airway narrowing (measured by lung function tests). It is important to appreciate that even those with mild intermittent asthma can develop severe exacerbations given an appropriate stimulus.

  • Mild intermittent asthma—symptoms less than weekly with normal or near normal lung function between episodes
  • Mild persistent asthma—symptoms more than weekly but less than daily with normal, or near normal, lung function between episodes
  • Moderate persistent asthma—daily symptoms with mild to moderate airflow limitation
  • Severe persistent asthma—daily symptoms that interfere with normal activities, frequent nocturnal waking and moderate to severe airflow limitation

It is also helpful to distinguish chronic and acute asthma: chronic asthma is asthma requiring maintenance treatment; acute asthma is an exacerbation of underlying asthma requiring additional treatment.

Symptoms

Symptoms of asthma are typically worse at night, waking the affected individual on occasion several times in the early hours of the morning and on first waking in the morning, when chest tightness may be the dominant symptom. Asthmatic symptoms may also be provoked by nonspecific stimuli such as exercise and cold air, and by specific allergens such as domestic animals, particularly cats. In patients allergic to pollens or moulds, asthmatic symptoms occur or worsen during the relevant season (in the United Kingdom tree pollen in the late spring, grass pollen in May and June, and mould spores in the late summer months). In patients with asthma induced by occupational sensitizers, symptoms characteristically increase in severity during the working week and improve when away from work on holidays of 1 week or more, if not at weekends.

Because occupational causes of asthma are potentially avoidable, all cases of asthma that have occurred or recurred in adult life should be questioned about symptomatic improvement when away from work, and if this is present enquiry should be made about potential causes of asthma in the workplace. The onset of symptoms occurs after a latent interval usually of months or years from the onset of exposure. By contrast, irritant-induced occupational asthma follows a single identifiable exposure to an irritant chemical in toxic concentrations causing irritation of eyes, nose, and airways of sufficient severity for the individual to seek medical advice within 24 h of the incident.

Respiratory viral infections that occur predominantly in the autumn and winter months are the most important precipitating causes of exacerbations of asthma. In some women asthma has a monthly periodicity, becoming increasingly severe during the days before menstruation and improving with its onset.

Although breathlessness and wheeze are often considered the most characteristic symptoms of asthma, cough can be the dominant and, on occasions, the only symptom of asthma. Nocturnal cough particularly suggests asthma, although in community studies isolated nocturnal cough has been found to be a poor predictor of asthma. ‘Cough-variant asthma’ is occasionally seen in adults in whom cough and eosinophil-rich sputum are the only manifestations of the disease.

The characteristic symptoms of asthma are manifestations of variable airway narrowing and airway hyper-responsiveness. Patients with chronic severe asthma have more persistent airway narrowing, are limited in their day-to-day activities by breathlessness, and may have less symptomatic evidence of spontaneous variability of airway narrowing, although they can be awoken by asthma at night as well as having symptoms provoked by inhalation of cold air or by laughter.

Patients with acute severe asthma are usually distressed by severe shortness of breath with wheezing, and are unable to sleep or to complete sentences in one breath because of the severity of the airway narrowing.

Signs

The physical signs of mild or moderate asthma may be limited to expiratory wheezes audible over the lungs. Because of the variable nature of the airway narrowing some patients have normal lung sounds, although expiratory wheezes are to be anticipated in patients with persistent symptomatic asthma. Patients with chronic persistent asthma can develop hyperinflated lungs.

In acute severe asthma patients are usually extremely short of breath, sitting up or leaning forward using their accessory muscles of respiration. Characteristically, with increasingly severe airway narrowing increasingly prolonged expiration alternates with short inspiratory gasps, impairing speech. Tachycardia and pulsus paradoxus (an exaggeration of the normal fall in systolic blood pressure on inspiration to >10 mmHg) often accompany acute severe asthma, but pulsus paradoxus is not a reliable indicator of severity (because it depends on respiratory effort and is therefore not seen in the patient who is exhausted, and may be near death). Airway narrowing may become sufficiently severe for no wheeze to be audible and gas exchange sufficiently impaired to cause detectable cyanosis. Patients with asthma of this severity are usually distressed, anxious, apprehensive and can be confused because of hypoxia. Exhaustion ultimately leads to inadequate ventilation and a rising P CO 2, the two cardinal features that indicate the need for transfer to an intensive care unit in the event that assisted ventilation is required.

Diagnosis

Although asthma is now defined by characteristic pathological changes in the airways, it is usually identified by its pathophysiological manifestations, variable or reversible airway narrowing and airway hyper-responsiveness. In some patients the presence of eosinophils in sputum or a raised eosinophil count in the blood can be a valuable diagnostic pointer.

Most typically, asthma is diagnosed by the demonstration of airflow limitation that varies spontaneously over short periods of time, or which reverses after inhalation of a short-acting β-agonist or, over a more prolonged period of time, use of a corticosteroid either by inhalation or by mouth. In a few patients provocation tests using exercise or pharmacological agents such as histamine or methacholine can be valuable. Inhalation tests with the specific agent may be indicated in suspected cases of occupational asthma, but inhalation tests with common inhalant allergens are rarely indicated in clinical practice.

Airflow limitation

The most clinically useful measurements of airflow limitation are (1) FEV1, which may be expressed as a proportion of the forced vital capacity (FVC) as FEV1/FVC%; and (2) peak expiratory flow rate (PEF). Both tests require the patient to provide a reproducible maximal forced expiratory manoeuvre using tested and validated equipment. FEV1 has the advantage of a visible tracing of the expelled volume of air over time that allows the observer to determine whether reproducible maximal forced expiratory manoeuvres have been made. PEF does not provide this opportunity. Peak flow meters, used to measure PEF, continue to be used more often than spirometers to measure FEV1 for home use, and they can be used regularly by patients to provide them with an assessment of their lung function and indication of the need for further treatment at an early stage. Whether abnormality of FEV1 and PEF should be expressed in absolute or proportional terms remains undecided. Expression as an absolute difference from the average value anticipated for an individual of given age, gender, and height has more physiological validity, but most lung function laboratories in United Kingdom continue to define values of FEV1 or PEF of 20% or more below the mean predicted value as abnormal.

Variability and reversibility

Serial measurements of PEF in most (although not all) patients with asthma show spontaneous variability. The most characteristic pattern is of a circadian variation with airflow limitation, most severe on waking in the morning (and during the night if awoken) and with improvement occurring during the morning after waking. A small circadian variation in PEF or FEV1 is seen in normal individuals; in asthma a difference of 20% or more between the highest and lowest values may be found.

Other patterns of variation in severity of airflow limitation may be imposed on the circadian pattern, such as falls in PEF provoked by exercise, exposure to an allergen or occupational sensitizer, which resolve after avoidance of the stimulus. While variations of 20% or more in FEV1 or PEF are commonly regarded as indicating asthma, in patients with severe airflow limitation and an FEV1 of 1 litre, 20% variability equates to 200 ml, a level of spontaneous variation observed in nonasthmatics.

The most commonly used means to identify asthma in clinical practice is an improvement in airflow limitation, identified by FEV1 or PEF, 15 to 20 min after inhalation of bronchodilator, usually a short-acting β-agonist such as salbutamol 200 µg: improvement in FEV1 or PEF of 20% or more is generally regarded as evidence of asthma. However, it is important to appreciate that the absence of a significant improvement in lung function after inhalation of bronchodilator does not exclude a diagnosis of asthma (i.e. it is a more specific than sensitive test). Rapid reversibility of airflow limitation is more readily seen in young adults with mild or moderate asthma than in more elderly patients with more severe airflow limitation. Reversibility cannot be tested in a patient whose lung function is normal at the time of testing.

Expressing changes in airflow as a proportion of baseline will exaggerate the degree of improvement in those with a low initial FEV1 or PEF. A 20% increase in FEV1 in a patient with a baseline FEV1 of 4 litres is 800 ml, but only 200 ml in a patient whose baseline FEV1 is 1 litre. Studies of short-term (20 min) variability in FEV1 in patients with airflow limitation have found that the increase in FEV1 needed to exclude natural variability with 95% confidence was 160 ml. This value did not differ significantly from the value in normal individuals, in whom an absolute increase in FEV1 of 190 ml was needed to exclude a chance increase with 95% confidence. Both in normal individuals and in those with an airflow limitation, expression of variability as an absolute difference was similar at all levels of FEV1, whereas when expressed as a percentage change, the degree of variability decreased with increasing FEV1. This means that selecting a specific percentage change in FEV1 (or PEF) to define asthma will necessarily include a greater proportion of patients with lower prebronchodilator FEV1: patients with a higher baseline FEV1 need to achieve a greater absolute increase to fulfil the defined criterion. Expression of variability as an absolute change has more biological and statistical validity: an increase of more than 200 ml in FEV1 has a probability of less than 5% of occurring by chance. However, as with expression of lung function, it is unlikely that the use of results based on absolute values, although biologically more valid, will be adopted. It should be appreciated, however, that in patients with a low FEV1a 20% increase in FEV1 may have occurred by chance, and in those with a high FEV1 an increase of more than 200 ml is unlikely to have occurred by chance.

In some patients with asthma, particularly those with severe airflow limitation, inhalation of a short-acting bronchodilator does not provide significant improvement in FEV1 or PEF. In these circumstances the diagnosis of asthma and differentiation from less reversible causes of airflow limitation such as chronic bronchitis and emphysema can be made with a ‘trial’ of treatment with corticosteroids. Significant improvement in airflow limitation both implies a diagnosis of asthma and demonstrates that corticosteroids (inhaled or oral) are effective treatment. However, corticosteroids can also improve exercise tolerance by enhancing mood and outlook, and the benefit of a trial of steroids therefore has to be judged by its effect on lung function. Although there is no formally agreed protocol for a steroid trial, a generally acceptable trial would be oral prednisolone taken in a dose of 0.6 mg/kg, (e.g. 40 mg/day in a 70-kg man) for 3 weeks, with measurement of lung function made on at least two separate occasions, once before and once at the end of the trial. Symptomatic improvement with an increase in FEV1 or PEF of 20% or more during the trial is generally considered as evidence of asthma and an indication for treatment with corticosteroids, inhaled or oral.

Tests of airway hyper-responsiveness

Airway hyper-responsiveness—an exaggerated response to nonspecific provocative stimuli—is a cardinal feature of asthma. Tests of airway responsiveness to exercise and to inhaled histamine or methacholine, which can provoke acute airway narrowing in a dose-dependent fashion, can be of value in the diagnosis of asthma, particularly in patients with symptoms suggestive of asthma but in whom lung function when measured is normal or, if abnormal, shows no reversibility with inhaled bronchodilators. These tests are required in only a few patients, and each has its limitations: exercise testing can be insensitive (i.e. false negatives), and tests of airway reactivity to inhaled histamine or methacholine nonspecific (i.e. false positives), although the provocation of a 20% fall in FEV1 by histamine 4 mg/ml or less (or equivalent) occurs uncommonly in nonasthmatic patients.

In general, normal airway responsiveness to exercise, histamine, or methacholine makes a diagnosis of current asthma very unlikely, whereas an abnormal test is diagnostically less helpful.

Exercise testing

Acute airway narrowing provoked by exercise is a common feature of asthma, particularly in children. To test for exercise provoked asthma requires continuous exertion for 6 min. This is most conveniently undertaken in a lung function laboratory by running on a treadmill or exercising on a cycle ergometer, although free running is more likely to provoke an asthmatic reaction. Measurements are made of FEV1 or PEFR during 5 min before and for 30 min at intervals of 5 min after the test. A normal individual will have a less than 5% increase in FEV1 or PEFR during and a less than 10% fall after exercise. Depending on the level of baseline, patients with asthma can have a greater than 5% increase during exercise and greater than 10% fall from pretest value after exercise. Exercise is a valid and reproducible test for asthma, but particularly when undertaken by methods other than free running, can have false negatives. It has, however, proved less reliable in community studies, with a significant false-positive rate.

Airway reactivity to inhaled histamine or methacholine

Acute airway narrowing can be provoked in a dose-dependent manner by the inhalation of increasing doses of a bronchoconstrictor, of which histamine or methacholine are the most commonly used. The test as described by Cockcroft et al. consists of tidal breathing of doubling doses of histamine, with measurement of FEV1 6 min after each inhaled dose. The percentage change in FEV1 from a post-saline baseline after each concentration of inhaled (histamine) can be plotted, with the test terminated when either a 20% or greater fall in FEV1 is provoked or the maximum concentration (usually 16 or 32 mg/ml) is reached. The level of airway reactivity is usually expressed as the concentration of histamine that provokes a 20% fall in FEV1 (PC20 histamine), which can be identified by linear interpolation: the lower the PC20, the more reactive the airways. The test is usually repeatable within one doubling dose, but may not be consistent in any individual, PC20 falling for instance after exposure to allergen or occupational sensitizer.

In population studies the major determinants of airway reactivity have been atopy (in older children and young adults) and smoking in older adults (probably reflecting reduced FEV1). Airway responsiveness can be increased in atopic children with rhinitis and in healthy adults after a viral respiratory tract infection. Evidence of measurable airway reactivity is therefore not necessarily evidence of asthma. However, it is uncommon for nonasthmatic individuals to have a PC20 for histamine or methacholine of less than 8 mg/ml.

Measurement of airway reactivity to histamine or methacholine is more sensitive than exercise testing, although a less specific test for asthma. Like exercise testing its value in clinical practice is primarily in symptomatic patients with normal or near normal FEV1, without evidence of spontaneous variability or reversibility. A negative test in a symptomatic patient suggests that current asthma is unlikely to be the cause of their symptoms.

Diagnosis of occupational asthma

The diagnosis of occupational asthma should be considered in any adult who develops asthma or whose asthma has deteriorated in working life. In the case of irritant-induced asthma the association of the onset of asthma with inhalation of a toxic chemical is usually clear. The association of asthma caused by a specific hypersensitivity reaction is often less apparent, and the diagnosis is based on the following:

  • Exposure to a sensitizing agent at work
  • A characteristic history of onset of asthma after an initial symptom-free period of exposure; and deterioration in symptoms during periods at work and improvements during absence from work
  • The results of objective investigations: lung function tests, immunological tests, and inhalation tests

Lung function tests

The most commonly used criterion for diagnosing asthma—improvement in airflow limitation (FEV1 or PEF) after inhalation of bronchodilator—is often not present in cases of occupational asthma because lung function may be normal when the patient is seen away from work and, if present, does not identify a work relationship. The measure of lung function most commonly used to identify work related asthma is serial self-recorded PEF. A patient with suspected occupational asthma is asked to record their PEF at intervals of 2 to 3 h for a month from waking to sleeping, and at night if awoken, both during periods at and absences from work. The results can be summarized in a graphical display that records the best, worst, and average values for each day, allowing comparison of PEF during days at work with days away from work. The diagnostic value of the test depends on the reproducibility of the patients’ forced expiratory manoeuvres and their honesty and compliance. Concurrent treatment can influence the results, particularly when treatment is systematically increased during periods at work and reduced during absences from work, hence when possible treatment should be kept constant during the period of testing, and at a minimum any changes should be recorded.

Comparisons with the results of inhalation testing as the ‘gold standard’ have shown that serial self-recorded PEF measurements are a sensitive and specific index of work-related asthma. The major diagnostic difficulties are in patients with evidence of asthma on PEF records without a work relationship, of whom a proportion are eventually shown to have occupational asthma, the commonest reason for such ‘false-negative’ responses being insufficient time away from work for significant improvement to have occurred.

Immunological tests

The presence of specific IgE antibody, identified either by immediate skin test response to a soluble protein extract or a hapten–protein conjugate, or by immunoassay in serum, is evidence of sensitization to a specific agent. Specific IgE can be identified in most, if not all, protein causes of occupational asthma, and in a small number of low-molecular-weight chemical causes of asthma, notably complex platinum salts, acid anhydrides, and reactive dyes. No reliable immunological test has been developed for sensitivity to other important causes of asthma such as isocyanates and colophony. The diagnostic value of a positive test has been formally examined for few of the causes of occupational asthma, and in these cases has been found to be significantly associated with asthma caused by both proteins and low-molecular-weight chemicals inhaled at work.

Specific inhalation testing

The objective of an inhalation test is to expose the individual under single-blind conditions to the putative cause of their asthma in circumstances that resemble as closely as possible the conditions of exposure at work. The different test methods used depend upon the physical state of the test material, which can be water soluble (most proteins) and inhaled in solution, a volatile organic liquid inhaled as a vapour, or a dust. Any change in lung function, both in airways calibre (usually measured as FEV1 or PEF) and in airways responsiveness to inhaled histamine or methacholine (measured as PC20), is compared with results on appropriate control days. The patterns of airways response provoked by specific inhalation tests have been distinguished by their time of onset and duration. Immediate asthmatic responses occur within minutes of the test exposure and usually resolve spontaneously within 1 to 2 h. Late asthmatic responses develop 1 h or more after the test exposure and can persist for 24 to 36 h. Late asthmatic (but usually not immediate) responses are accompanied by an increase in nonspecific airways responsiveness 3 h and, less reliably, 24 h after the test inhalation. An immediate response followed by a late response has been called a dual response.

Inhalation testing allows the investigation of specific causes of asthma in individuals exposed to them. Provided that the agent being tested is not a nonspecific mucosal irritant and does not provoke an immediate asthmatic response in patients with hyper-responsive airways—such as sulphur dioxide, histamine, or exercise—the provocation of an asthmatic response by an occupational agent implies that it is a cause of asthma. This causal relationship is strengthened if the agent reproducibly provokes a late asthmatic response and increases nonspecific airways responsiveness.

There are four major indications for inhalation testing in the diagnosis of occupational asthma:

  • Where the diagnosis or cause of occupational asthma remains in doubt after other investigations, including serial PEF and immunological tests (where applicable), have been completed
  • Where the agent considered responsible for causing asthma has not previously been reliably shown to do so
  • Where an individual with occupational asthma is exposed at work to more than one potential cause, which cannot be distinguished by other means, and where such a distinction is going to be clinically and occupationally helpful
  • Where asthma is of such severity that further uncontrolled exposure at work is unjustifiable

Inhalation tests should be undertaken only for clinical purposes to provide information important for future management advice: conducting them solely for medicolegal purposes is not justified.

The diagnosis of occupational asthma requires differentiation from work-exacerbated asthma, which is incidental asthma aggravated by nonspecific provocative stimuli encountered at work such as sulphur dioxide, exercise, or cold air, also from other causes of similar respiratory symptoms, in particular chronic airflow limitation and hyperventilation.

Particular causes of occupational asthma

Occupational asthma is a prescribed disease for ‘employed earners’ and includes asthma caused by exposure to any one of a number of specified agents as well as ‘any other sensitizing agent inhaled at work’.

One condition worthy of note that should probably be considered as a form of occupational asthma is byssinosis, which in the United Kingdom most commonly occurs in cotton mill workers after 20 to 25 years of exposure to cotton dust. It is characterized by chest tightness on the first day of the working week, which usually develops 3 to 4 h after the start of a work shift and typically improves on subsequent working days despite continuing exposure. Proportion of cotton textile workers with byssinosis develop COPD, with chronic airflow limitation.

Imaging

Imaging of the chest is not commonly of diagnostic value in asthma but can be important in identifying its complications. In patients in whom asthma develops over the age of 30 years the chest radiograph is usually normal, but about one-quarter of children and one-fifth of adults show changes of hyperinflation. These changes include a low diaphragm (below the sixth intercostal space anteriorly) and an increased retrosternal space. In some children with chronic persistent asthma the length of the lung becomes greater than the width of the thorax, with the posterior ends of the ribs becoming more horizontal. A commonly observed radiographic sign in asthma is of thickened bronchial walls due to eosinophilic infiltration of the airways: these are visible on the chest radiograph as parallel lines (‘tram lines’), or as a thick-walled ring shadow when seen end on.

The complications of asthma include pneumothorax, pneumomediastinum, pulmonary collapse, and eosinophilic pneumonia. The physical signs of pneumothorax can be difficult to discern in asthmatic attack, but its detection can be life saving. Pneumomediastinum is of less clinical importance. Plugging of the airways by mucus characteristically occurs in allergic bronchopulmonary aspergillosis (ABPA), but can occur in asthmatic patients without ABPA: in both it can cause atelectasis, which is usually lobar or segmental.

ABPA causes fleeting nonsegmental areas of consolidation that are characteristically perihilar, accompanied by a moderate blood eosinophilia (1–1.5 × 109/litre). Less commonly, lobar or segmental atelectasis is caused by mucus impaction. With progression the disease characteristically causes bronchiectasis that is predominantly proximal, visible both on the chest radiograph and CT scan, and upper lobe fibrosis.

Eosinophilic pneumonia is characterized by consolidation on the chest radiograph accompanied by a raised blood eosinophil count. This can be a manifestation of several conditions, including ABPA, helminth infections, and drug reactions, as well as being of unknown cause—acute and chronic eosinophilic pneumonia. Of these, ABPA and chronic eosinophilic pneumonia (which can be a manifestation of Churg–Strauss syndrome—allergic granulomatosis, are the most common causes of eosinophilic pneumonia in patients with asthma.

Chronic eosinophilic pneumonia causes fleeting consolidation that is characteristically peripheral in distribution, either in localized areas or more widespread (the ‘photographic negative’ of pulmonary oedema). The blood eosinophil count is usually considerably more elevated than in ABPA. If seen as a manifestation of Churg–Strauss syndrome, a granulomatous vasculitis that develops in patients with rhinitis and asthma, then other features can include pleural and pericardial effusions, congestive cardiomyopathy and mononeuritis multiplex. Abnormalities on the chest radiograph include enlargement of the heart, because of pericardial or myocardial disease, and consolidation due to chronic eosinophilic pneumonia.

Differential diagnosis

Asthma needs to be differentiated from localized airways obstruction, other causes of generalized airways obstruction, and other causes of intermittent breathlessness.

Localized airways obstruction

Upper airways obstruction of the larynx or trachea causes a monophonic inspiratory wheeze (stridor) audible over the trachea, with a characteristic abnormality of the flow volume loop showing decreased inspiratory flow rate. Wheezing in a child can be caused by an inhaled foreign body (classically a peanut), which should be suspected particularly if wheeze develops suddenly in a child who is previously healthy. The chest radiograph may show the foreign body if opaque, or distal atelectasis, consolidation or air trapping on an expiratory film (which may not be possible to obtain in small children), but it can be normal and—if foreign body inhalation is suspected—bronchoscopy should be undertaken to identify and remove it or to exclude the possibility. In adults localized airway narrowing is more likely to be due to a tumour, benign or malignant, which may occasionally cause a unilateral monophonic wheeze. The tumour may be visible on the chest radiograph, but definite diagnosis will require bronchoscopy and biopsy.

Generalized airways obstruction

The main causes of generalized airways obstruction from which asthma needs to be distinguished are chronic bronchitis and emphysema (COPD), although in some cases these may coexist with asthma. Other causes such as obliterative bronchiolitis are less common. In general, chronic bronchitis and emphysema (COPD) cause breathlessness that increases slowly in severity over years and only uncommonly causes breathlessness before the age of 40 years. Nocturnal waking by respiratory symptoms is uncommon in chronic bronchitis and emphysema (COPD), although not universal in asthma. Chronic severe asthma responsive to corticosteroids, but without significant reversibility to inhaled bronchodilators, may have similar radiographic and spirometric abnormalities. In both the lungs may be hyperinflated on the chest radiograph, but in asthma—unlike emphysema—there is no associated loss of vascular markings.

Lung function tests in both asthma and emphysema can show airflow limitation with reduced FEV1, reduced FEV1/FVC ratio, and hyperinflated lungs with increased total lung capacity. However, while factor transfer (TLCO) and gas transfer coefficient (K CO) are reduced in emphysema, in asthma K CO is normal or increased.

Differentiation from chronic bronchitis can be difficult because, like asthma, there is no loss of vascular markings on the chest radiograph or reduction of K CO. Sputum (and blood) eosinophilia, if present, can suggest asthma, but differentiation in these circumstances often depends on the outcome of a trial of steroids.

In young children asthma needs to be differentiated from wheezing episodes associated with viral respiratory tract infections, and in children and adolescents from cystic fibrosis. Cystic fibrosis is suggested by a disproportionate production of (usually discoloured) sputum, weight loss, and an abnormal chest radiograph. The presence of staphylococci in sputum and the development of nasal polyps in childhood are very suggestive of cystic fibrosis. Other causes of chronic suppurative lung disease in children, such as primary ciliary dyskinesia (PCD) and severe combined immunodeficiency (SCID), may also need to be excluded.

Other causes of intermittent breathlessness

The most important causes of intermittent breathlessness from which asthma should be differentiated are left ventricular failure, pulmonary emboli, extrinsic allergic alveolitis, hyperventilation, and vocal cord dysfunction.

Left heart failure sufficient to cause breathlessness will usually be apparent on clinical examination, and the chest radiograph and echocardiogram are likely to be abnormal, as is the ECG. The heart is clinically and radiographically enlarged with the exception of pulmonary venous hypertension caused by mitral stenosis. Inspiratory crackles are usually audible at the lung bases, and jugular venous pressure may be elevated. In addition to an enlarged heart the chest radiograph may show upper lobe venous distension, Kerley ‘B’ lines and pleural effusion. Echocardiography will usually show evidence of left ventricular disease, or in the case of mitral stenosis left atrial enlargement. However, identification of the cause of breathlessness can be difficult when left heart failure is provoked by an intermittent arrhythmia.

Pulmonary embolism causes breathlessness that can occasionally be associated with wheezing. The diagnosis is suggested by associated pleuritic pain and haemoptysis. The diagnosis is usually made by imaging with a ventilation–perfusion scan or spiral CT scan. A normal ventilation–perfusion scan makes all but the smallest emboli unlikely, although interpretation can be difficult in patients with widespread ventilatory disease. A normal spiral CT scan excludes pulmonary emboli to subsegmental level. The chest radiograph and CT scan (lung windows) may show pleural-based ‘humpback’ opacities and pleural effusion.

Extrinsic allergic alveolitis

Extrinsic allergic alveolitis (EAA) can provoke recurrent episodes of breathlessness that characteristically develop 4 to 8 h after exposure to the cause (usually mouldy hay or birds—pigeons or budgerigars). Breathlessness in EAA is usually not accompanied by wheeze but with fever, influenza-like symptoms, and a neutrophil leucocytosis. The chest radiograph often shows widespread nodular or ground-glass shadowing, the CT scan discrete areas of ground-glass opacification. Lung function tests show a proportionate reduction in FEV1 and FVC that may be accompanied by a reduced T LCO and K CO

Hyperventilation

Episodes of hyperventilation may be difficult to distinguish symptomatically from asthma, and in some cases complicate asthma, which can be very confusing. The diagnosis should be suspected in a patient who complains of breathlessness that occurs without identifiable cause (e.g. while sitting reading), may be associated with pins and needles in the fingers and dizziness (attributable to hypocapnoea), and does not disturb sleep, although hyperventilation may inhibit the onset of sleep. The symptoms complained of can often be reproduced by a short period of voluntary overbreathing: 20 deep breaths are usually sufficient. Various explanations for the tendency of some patients to hyperventilate have been suggested, but none are convincing. However, it is important to recognize that asthma is characteristically a variable condition and a diagnosis of hyperventilation should not be made solely on the basis of absent physical signs or normal lung function at the time of consultation, but on the characteristics described above.

Vocal cord dysfunction

Vocal cord dysfunction is easily misdiagnosed as asthma and may coexist with asthma. In vocal cord dysfunction wheezing is caused by adduction of the anterior two-thirds of the vocal cords, and does not occur during sleep. The diagnosis if best made by direct examination of the cords during an attack, which shows characteristic paradoxical vocal cord adduction on inspiration. Other helpful pointers include poorly reproducible spirometry and flow–volume curves (particularly during the inspiratory phase), and a disproportionate reduction in FEV1 compared to other effort-independent measures of airflow obstruction, such as specific airways conductance as determined by whole-body plethysmography. Management can be difficult, but recognition of this not uncommon condition allows high dose oral corticosteroid treatment for ‘uncontrolled asthma’ to be avoided.

Hyperventilation and vocal cord dysfunction can each occur in patients with underlying asthma, frequently in association with underlying psychosocial problems. A critical point can be to determine the relevant life events associated in time with the onset of deterioration in a patient often with previously well controlled asthma. The inciting event may have occurred several years previously, e.g. bereavement, family upheaval, etc., and require specific probing in the history. Vocal cord dysfunction is more common in women and in those engaged in health care provision.

The objectives of treatment

The objectives of treating patients with intermittent or persistent asthma are to:

  • Educate the patient about their disease and the objectives of its management
  • Minimize or eliminate asthma symptoms
  • Achieve best possible lung function and prevent an accelerated decline in lung function
  • Prevent exacerbations of asthma
  • Achieve these objectives with fewest drugs, keeping short-term and long-term adverse effects to a minimum

These objectives are most likely to be achieved by treatment that reduces airway inflammation, either by avoidance of its inducing cause or by drugs with anti-inflammatory activity. The risk of side effects of asthma treatment should be appreciated and minimized, and patients’ concerns about the potential side effects of long-term treatment recognized and relevant information provided to them.

A number of recent studies have compared the level of asthma control, particularly with regard to the frequency of exacerbations and duration of freedom from an exacerbation, in patients with asthma whose management was based on usual clinical criteria (symptom severity, lung function, and bronchodilator requirements), with management based on a measure of airway inflammation, usually sputum eosinophilia but also exhaled NO (F ENO). In general these studies have shown that using indices of airway inflammation to guide treatment reduced the frequency of exacerbations and duration of exacerbation free interval without an increase in the need for corticosteroid treatment. In one study of 74 patients with moderate or severe asthma followed up for 1 year after random allocation to management by BTS guidelines or by maintenance of sputum eosinophils to less than 3%, there were significant fewer exacerbations (35 vs 109) and hospital admissions (1 vs 6) in the group managed by maintaining sputum eosinophils lessthan 3%. In a second similar study the exacerbation frequency was reduced overall by one-half, and by two-thirds in those with moderate or severe asthma, in patients whose management was controlled on the basis of maintaining sputum eosinophils less than 2% as compared to usual clinical indices of symptoms, lung function and bronchodilator requirement. In a similar comparison study maintaining F ENO <15ppb was associated with a nonsignificant reduction in exacerbations by 50% in the year of follow-up, and a reduction by 40% in overall corticosteroid dosage as compared to a group managed on usual clinical criteria.

These studies indicate the value of using an index of airway inflammation (at present better demonstrated for sputum eosinophils than for F ENO) \ inhaled corticosteroid) of patients with moderate and severe asthma. However, these are not currently widely used in clinical practice, and if they are introduced decisions will need to be guided by them in addition to—not instead of—the current indices of symptom severity, lung function, and bronchodilator requirements.

Treatment selection

Randomized controlled trials of asthma treatments have determined the benefit of different treatment interventions in patients with asthma of varying severity. This information has provided a secure basis for deciding which treatment is likely to be most effective in individual patients, with broadening of the indications for the use of inhaled corticosteroids being of particular importance, and has informed the published guidelines for asthma management in the United Kingdom, the United States of America, and elsewhere.

The objectives for effective asthma control in individual patients are to:

  • Allow normal daytime activities (e.g. going to work or to school) as well as the ability to enjoy physically demanding activities (e.g. sport)
  • Permit sleeping through night, without being awoken by respiratory symptoms
  • Achieve a situation where use of ‘rescue’ medication with inhaled β2-agonists is needed less than once per day.
  • Achieve normal or near normal PEF and FEV1 with less than 20% variability between best and worst values.
  • Avoid drug side effects

Asthma, except where caused by a dominant and avoidable agent (e.g. a domestic pet or an occupational sensitizer) is not curable, but current treatment offers the great majority of patients the opportunity to enjoy a normal life. In most cases asthma is mild: in one community survey only 15% of patients had persistent asthma of moderate severity (Step 3 BTS Guidelines or worse—see below), but some 5% of patients have severe asthma that responds poorly to conventional treatment. These patients suffer most both from their disease and from the side effects its treatment, and are at highest risk from hospitalization and death from asthma.

Patient education

There is now clear evidence from a systematic review and additional randomized controlled trials for patient education to enable adults to manage their asthma. In comparison to usual care it has been shown that this can reduce the frequency of unscheduled visits to general practitioners, hospital admissions, and time off work. The four important components of effective patient education are:

  • Information—provision of information about asthma and its management
  • Self monitoring—regular assessment by the patient of symptoms, or peak expiratory flow rate, or both
  • Regular medical review—assessment of asthma control, severity, and treatment
  • Written action plan (Bullet list 1: an individualized written plan to allow self-management of asthma exacerbations that is informed by the severity and treatment of the patients’ asthma and includes four essential components: (1) information about when to increase treatment, (2) how to increase treatment, (3) the duration of treatment increase, and (4) when to cease self-treatment and seek medical help.

Bullet list 1 Components of written asthma plan

    • When to increase treatment
      • • Symptoms v PEF
      • • PEF % predicted vs personal best
      • • Number of action points based on % best PEF
    • How to increase treatment
      • • Increased inhaled corticosteroids
      • • Oral corticosteroid
      • • Combination
    • For how long
      • • Duration of treatment increase
    • When to call for help

    (After Gibson PG, Powell H (2004). Written action plans for asthma: an evidence based review of key components. Thorax, 59, 94–9.)

Treatments to prevent or avoid asthma

Allergen avoidance

The identification and, where feasible, the avoidance of relevant allergens at home or at work is an essential part of the management of asthma. It enables patients to recognize important causes of their asthma and take responsibility for their avoidance. Allergen avoidance should be regarded as complementary to drug treatment of asthma, with the advantage in some cases (where a single allergen is the dominant cause) of providing a cure with avoidance of the potential side effects of drugs. Complete avoidance of exposure to house dust mite, domestic pets, and occupational causes of asthma have been associated with marked improvement in respiratory symptoms, lung function, and airway hyper-responsiveness. Avoidance of exposure to the house dust mite, Dermatophagoides pteronyssinus, by spending several months in the Alps or in a hospital, has been shown to provide symptomatic and functional improvement. However, house dust mites are ubiquitous in many environments, including much of the United States of America, the United Kingdom, and Europe, and elimination of mites from the home sufficient to reduce exposure to the relevant allergens (e.g. Der p1) to concentrations that do not continue to induce airway inflammation can be difficult. The issue with house dust mite avoidance is therefore the feasibility of securing an effective intervention, and the utility of routine advice for implementation of house dust mite avoidance strategies in mite-sensitive adult asthma has been questioned following the results of a recent large randomized controlled trial of a single intervention of mite-proof bedding for 12 months, which failed to improve symptoms or PEF rates or reduce asthma medication requirements. Given that effective mite avoidance is both expensive and time-consuming, more trials involving multiple interventions are needed. Data in favour of mite avoidance is more convincing in mite-allergic asthmatic children than in adults.

Avoidance of exposure is most clearly indicated and usually most feasible when the cause of asthma is an agent inhaled at work. Removal of a pet from the home, particularly a cat, is most effective when accompanied by thorough cleaning and washing of the house to remove residual allergen, which can otherwise persist in concentrations sufficient to provoke asthma for many months.

Occupational asthma

Occupational asthma offers a rare opportunity to cure a patient of their disease. In almost all cases of hypersensitivity-induced asthma there is considerable and often complete resolution of symptoms and accompanying bronchial hyper-responsiveness once exposure to the causative agent has ceased. However, occupational asthma, whatever its cause, may become chronic and persist for several years, if not indefinitely, even after avoidance of exposure to the causative agent. The only important determinant of chronicity identified to date has been the duration of symptomatic exposure to the initiating cause after the onset of asthma: those who remain exposed to the cause are more likely to develop chronic asthma. Any improvement after avoidance of exposure seems to occur in the first 2 years, subsequently reaching a plateau. There is little evidence that pharmacological treatments affect the rate or extent of recovery.

Patients who develop ‘hypersensitivity-induced’ occupational asthma in whom a specific cause is identified should be advised to avoid further exposure to that cause. In this way the risk of developing chronic asthma and airways hyper-responsiveness is diminished, and the likelihood of significant improvement or cure is enhanced.

Avoidance of further exposure may be achieved by relocation within the same workplace, but frequently requires a change of job or occupation. This requires sensitive handling, and liaison with the occupational health service (if there is one) is essential. However, in some cases a change of job may be impossible for social or financial reasons. In the short term individuals who are unable to avoid further exposure altogether should be advised to minimize it by attention to their work practices and consideration of adequate respiratory protection, the choice of suitable protective equipment being a matter for an expert. It is probably helpful to institute treatment with an inhaled corticosteroid; antihistamines and sometimes sodium cromoglicate may also be useful, especially where there is predictable and only occasional exposure, such as in some jobs involving animal contact. However, it should be emphasized that such measures are temporary, and in the long term means should be sought to avoid exposure to the cause of asthma.

When an individual does remain exposed to the cause of their asthma, either directly or indirectly, the effectiveness of relocation or of respiratory protection needs to be monitored. This can be done conveniently by serial self-recordings of PEF to determine whether or not asthma is continuing and, if so, whether it is work related.

It is a rule of thumb that if there is one employee with occupational asthma, then there is likely to be one or more others in the same place of work. A confirmed ‘index’ diagnosis should therefore prompt a wider investigation, with detailed consideration of exposures in the workplace. In many countries employers (sometimes physicians) are required to notify new cases of occupational asthma to a central authority, instigating a formal, external inspection of the workplace with recommendations for the prevention of any further cases. These processes have had some notable success in preventing new cases of occupational asthma. Examples include asthma arising from enzymes in the detergent manufacturing industry, from latex (gloves) in health care workers, from laboratory animal proteins in the pharmaceutical industry, and from diisocyanates in a variety of settings. Other common causes of occupational asthma—in particular those associated with commercial baking—have been more intractable.

Immunotherapy

Allergen immunotherapy involves the provision of gradually increasing doses of allergen subcutaneously to promote immunological tolerance to future environmental exposures to the specific allergen. This fell into disrepute some 20 to 30 years ago because of reports of anaphylactic reactions, and in a few cases death, following allergen injection. More recent studies have demonstrated its efficacy and safety, particularly in seasonal allergic rhinitis with or without peak seasonal wheezing, where there is clear evidence of efficacy and long-term benefits that may persist for years following its discontinuation. However, subcutaneous immunotherapy should only be undertaken under direct medical observation and supervision, with immediate access to resuscitation facilities.

A recent Cochrane review has shown that allergen immunotherapy is effective in reducing asthma symptoms as compared to placebo, reducing the need for asthma medication and, where measured, improving airway hyper-responsiveness. The most consistent evidence of benefit was found for pollen and mite allergens. However, the risks of systemic side effects of treatment are increased in patients with bronchial asthma, and immunotherapy has been shown to be ineffective for asthma in patients with multiple allergies. Thus, although immunotherapy for seasonal allergic rhinitis with or without asthma is recommended in patients who fail to respond to usual medication, in view of the increased risks and less benefit, asthma remains a relative contra-indication for immunotherapy, at least in the United Kingdom. Exceptions may include asthmatics whose disease is clearly related to a single allergen (with associated elevated allergen-specific IgE), and where the allergen cannot be avoided, such as occupational exposure to cats in veterinary practitioners.

Drug treatments for asthma

The drugs primarily used to treat asthma are the progeny of cortisol and adrenaline (epinephrine): selective β2-agonists, both short and long acting, and lipid-soluble topically active inhaled corticosteroids; these drugs accounting for nearly 90% of prescriptions for asthma in the United Kingdom. Other drugs sometimes used in the treatment of asthma include sodium cromoglicate and nedocromil sodium amongst the prophylactic agents, and ipratropium bromide and theophyllines amongst the bronchodilators.

The core treatments for mild and moderately severe persistent asthma are inhaled corticosteroids and inhaled β2-agonists. Other treatments are added when these alone are not sufficient to provide control. Leukotriene receptor antagonists and 5-lipypoxygenase inhibitors have been introduced recently; their place in the treatment of asthma continues to be evaluated.

Corticosteroids

Corticosteroids are the most effective treatment for asthma. Systemic corticosteroids were introduced for the treatment of asthma in the 1950s, but their use was limited by serious unwanted side effects, which stimulated research into the development of equally effective but safer alternatives. The introduction of topically active corticosteroids—administered by inhalation and free of the systemic side effects of oral corticosteroids at therapeutically effective doses—revolutionized the treatment of asthma.

Corticosteroids suppress airway inflammation, with improvement in airway hyperresponsiveness, lung function and associated respiratory symptoms. Although their mechanism of action continues to be debated, they inhibit the formation of cytokines relevant to asthmatic inflammation, such as interleukins IL-4, IL-5, IL-13 and GM-CSF, by lymphocytes and macrophages by inhibition of transcription of cytokine genes. While suppressing inflammation they do not, however, cure the disease: to be effective they must be taken continuously.

Oral corticosteroids

Oral corticosteroids—prednisolone and prednisone—are rapidly absorbed from the gut, achieving peak plasma levels at 1–2 h. Prednisone is biologically inactive but rapidly and completely converted in the liver to the active form, prednisolone, which has a plasma half-life of around 2–3 h. Some 20% of prednisolone is inactivated in the liver by conjugation by first-pass metabolism, leaving 80% of the oral dose bioavailable. Hepatic enzyme inducers such as rifampicin, barbiturates, and phenytoin can reduce the half-life of prednisolone by 50%. To counter the consequent reduction in anti-inflammatory activity the dose of oral prednisolone should be doubled in patients concurrently receiving these treatments. Drugs, such as itraconazole, reduce the rate of metabolism of corticosteroids, both oral and inhaled, increasing its blood level for a given dose.

Oral corticosteroids effect detectable improvement in airflow limitation in patients with asthma within 6–12 h of administration. In cases of severe asthma maximum improvement can take several days, probably reflecting the time to reverse the inflammatory changes in the airways.

The early use of oral corticosteroids in the treatment of asthma was severely limited by the high risk of unwanted effects, including osteoporosis, hypertension, diabetes mellitus, cataract formation, adrenal suppression, and (in children) growth suppression. The introduction in the 1970s of inhaled corticosteroids allowed local anti-inflammatory activity without limiting systemic side effects.

Inhaled corticosteroids

Inhaled corticosteroids are highly lipophilic and rapidly enter cells within the airways. They combine high topical potency with low systemic bioavailablilty of the swallowed dose and rapid metabolic clearance of any corticosteroid reaching the systemic circulation, conferring a high benefit:risk ratio. Although 80% to 90% of an inhaled dose from a metered dose inhaler is deposited in the oropharynx, swallowed, and absorbed, more than 80% of beclometasone, 90% of budesonide, and 99% of fluticasone is inactivated by first-pass metabolism in the liver. The 10 to 20% of the inhaled dose deposited in the airways is also absorbed from the lungs and misses first-pass metabolism, as does medication deposited in the oropharynx. For fluticasone and budesonide, devices that increase lung deposition (such as large-volume spacer and Turbohaler) therefore increase the dose available for systemic absorption.

Three inhaled corticosteroids are generally available at present: beclometasone diproprionate, budesonide, and fluticasone diproprionate. Beclometasone and budesonide are equipotent; fluticasone is twice as potent, requiring half the dose to achieve the same benefit as beclometasone and budesonide. Ciclesonide, a new inhaled corticosteroid, is of equivalent potency to beclometasone; a second new inhaled corticosteroid, mometasone, is twice as potent as budesonide.

Inhaled corticosteroids have a dose–response relationship for both efficacy and adverse effects: in general most therapeutic benefit is obtained at low to moderate doses; further increases in dosage provide small increases in benefit but a steep rise in the incidence of adverse effects.

The clinical effects and side effects of inhaled corticosteroids have been the subject of considerable clinical investigation. Systematic reviews of randomized controlled trials and additional randomized controlled trials of 393 adults and adolescents with mild, persistent asthma have shown that low-dose inhaled corticosteroids improve symptoms and lung function and reduce the need for as-needed inhaled bronchodilators as compared with placebo. In addition, a number of randomized controlled trials have shown that low-dose inhaled corticosteroids reduce the frequency of exacerbations in this group of patients. The OPTIMA trial, which compared inhaled budesonide 200 μg/day with placebo in 700 patients with mild persistent asthma who had not previously taken corticosteroids, found a significant reduction in exacerbation frequency in the budesonide group as compared to placebo (0.77 vs 0.29 exacerbations/year). The consistently shown benefits of inhaled corticosteroids in mild persistent asthma mean that these are the treatments of choice in this group of patients.

Inhaled corticosteroids are also effective in school-age children with mild and moderate persistent asthma. The START trial compared low-dose inhaled budesonide with placebo on the progression of asthma in adults and children (aged 5–11 years) with newly diagnosed mild persistent asthma as measured by time to first severe exacerbation requiring hospital treatment and decline in postbronchodilator FEV1. By 3 years the frequency of exacerbations (6% vs 3%) and need for added treatment with inhaled corticosteroids (50% vs 30%) was greater in the placebo than the budesonide group.

Local side effects of inhaled corticosteroids

The severe adverse effects of systemic steroids and the widening indications for the use of inhaled corticosteroids have led to close scrutiny of their side effects. Oropharyngeal candidiasis (thrush) and dysphonia are well recognized and dose dependent. Oropharyngeal candidiasis occurs in about 5% of patients but can be problem, particularly in older people. The risk of its development can be reduced by the use of a large volume spacer and rinsing the mouth out after each inhaled dose. Dysphonia is the commonest side effect of inhaled steroids, occurring in at least one-third of patients. It can cause particular problems for public speakers and professional singers. It is believed to be due to a myopathy of the laryngeal muscles and reverses when treatment is stopped. Inhaled corticosteroids do not cause atrophy of the airway epithelium after 10 years of treatment and are not associated with an increased risk of pulmonary infection, including tuberculosis.

Systemic side effects of inhaled corticosteroids

Concern about systemic side effects of inhaled steroids stems from the need for their regular use for prolonged periods, of several years or decades, in both adults and children. Because many patients who take inhaled corticosteroids also require oral corticosteroids, distinguishing the adverse systemic effects of inhaled corticosteroids can be difficult.

Three important risks of inhaled corticosteroids that have been the subject of recent concern are osteoporosis in adults, and growth suppression and acute adrenal failure in children at the time of intercurrent infection. Studies that have addressed these outcomes are limited by their relatively short duration as compared to the length of time for which the treatment is usually taken in routine clinical practice.

In general, systematic reviews have found that inhaled corticosteroids are associated with a reduction in bone mineral density related to cumulative dose. In addition there is evidence for an increased risk of hip fracture in older people: a population-based case–control study using the United Kingdom General Practice Research Database comparing inhaled corticosteroid use between 16 341 cases of hip fracture and 29 889 control patients matched for age (mean 79 years), sex, and general practice found that the risk of hip fracture was increased by some 25% in those who had taken inhaled corticosteroids, and by some 20% after adjustment for use of oral corticosteroids.

Both asthma and oral corticosteroids can impair growth in children. Several short-term studies in growth during a 1-year period have found evidence for growth retardation of approximately 1.5 cm/year in children taking inhaled beclometasone 400 μg/day. However, a recent prospective study of children with asthma, followed up for an average of 9.2 years, taking budesonide in a mean daily dose of 412 μg, found the children to attain their expected adult height.

Several studies have found a dose-related reduction in adrenal cortisol secretion with increasing doses of inhaled corticosteroids. In comparison to the effect of oral prednisolone, 1 mg inhaled budesonide was equivalent to between 3 and 8.7 mg prednisolone, and 1 mg fluticasone to about 8.5 mg prednisolone. A number of cases of acute adrenal failure were recently reported in patients in United Kingdom taking inhaled corticosteroids. The risk of adrenal failure is also increased in patients taking itraconazole for ABPA, which inhibits hepatic corticosteroid metabolism.

The evidence for side effects caused by inhaled corticosteroids, particularly osteoporosis and adrenal suppression, is now sufficient to imply that the lowest dose of inhaled corticosteroid that is clinically effective should be prescribed in both children and adults, and particularly in patients taking topical corticosteroids by other routes (e.g. nose or skin), and the dose tapered to the minimum necessary when symptomatic and functional improvement is achieved. However, in general current evidence indicates that inhaled corticosteroids do not cause important side effects in doses of beclometasone and budesonide of up to 400 µg/day in children and 800 µg/day in adults. The side effects that may occur at higher doses—more with beclometasone than with budesonide or fluticasone—can be reduced by the use of a spacer with metered-dose inhalers, and by rinsing the mouth after inhalation of a dry powder inhaler, which should be recommended when doses of 400 µg per day or more in children and 800 µg per day or more in adults are prescribed.

b2-Adrenoreceptor agonists

The β-agonists are sympathomimetic amines that include catecholamines, both naturally occurring (adrenaline, noradrenaline, and dopamine) and synthetic (isoprenaline), and noncatecholamines, both short acting (e.g. salbutamol and terbutaline) and long acting (salmeterol and formoterol). Catecholamines have been replaced in the treatment of asthma by β2-selective noncatecholamines. Noncatecholamines have a longer half-life than catecholamines because they are not subject to catecholamine uptake mechanisms and not broken down by catechol-O-methyl transferase (COMT). This means that the duration of bronchodilatation after inhalation of noncatecholamines is longer, salbutamol and terbutaline persisting for 3 to 6 h and salmeterol and formoterol for up to 12 h.

The actions of β-agonists in asthma are the result of stimulation of β-adrenoreceptors that are located in the airways, on airway epithelium, submucosal glands, airway and vascular smooth muscle. β-Receptors in the airways are entirely β2, with the exception of some β1 receptors on submucosal glands. β2-Agonists can influence airways function through several mechanisms: relaxation of bronchial smooth muscle by direct effect on β2 receptors; inhibition of mast cell mediator release; and enhanced mucociliary clearance.

Inhalation of a β2-agonist by a patient with asthma increases airway calibre and reduces airway hyper-responsiveness. β2-Agonists also cause tachycardia and increased cardiac output, systemic vasodilatation, and increased muscle blood flow. The tachycardia and increased cardiac output are the results of both stimulation of cardiac β adrenoreceptors and a reflex response to peripheral vasodilation. In addition, β2-agonists cause tremor and have metabolic effects, of which hypokalaemia is probably the only one of clinical importance.

Inhaled selective, short-acting β2-agonists reverse mild acute airway narrowing and are sufficient treatment, alone, for mild intermittent asthma causing occasional symptoms (Step 1 of the BTS guidelines: Table 4).

Studies in patients with asthma not taking inhaled corticosteroids comparing regular with as-needed inhaled β2-agonists have shown that regular treatment confers no benefit over as needed inhalation and can have adverse consequences. An randomized controlled trial in 255 patients with mild intermittent asthma, comparing salbutamol taken as needed with regular treatment, found no difference at 16 weeks in respiratory symptoms, airway function, or frequency of exacerbations. However, those taking regular salbutamol took more salbutamol, showed more variability in peak flow rates, and had increased airway responsiveness to inhaled methacholine. Short-acting β2-agonists should, in general, be reserved to provide reversal of acute airway narrowing, taken as-needed, and prior to exercise in patients with exercise-provoked asthma, except in cases of severe asthma not controlled with maximal doses of inhaled corticosteroids and additional long acting β2-agonist (Step 4 of the BTS guidelines), when regular inhaled short-acting β2-agonists can be added.

Table 4  Steps in the management of chronic asthma
Steps Asthma severity Treatment
Step1 Mild intermittent Short acting β2 agonist as required
Step 2 Mild persistent Low-dose ICS (BDP or BUD <800 µg/day, FP <500 µg/day, or DSG or nedocromil sodium plus short-acting β2-agonist as required.
Step 3 Moderate persistent High-dose ICS (BDP or BUD > 800 µg/day or FP > 500 µg/day OR low-dose ICS (as for Step 2) plus long acting β2-agonist OR plus slow-release theophyllines plus short-acting β2-agonist as required
Step 4 Severe persistent High-dose ICS (as for Step 3) plus regular bronchodilator, e.g. long-acting β2-agonist or slow-release theophylline or inhaled antimuscarinic or long-acting oral β2-agonists or high-dose inhaled β2-agonists
Step 5 ‘Difficult’ (not responsive to maximal inhaled treatment) Regular oral corticosteroids (in single daily dose) plus high-dose ICS and (as for Steps 3 and 4) long-acting bronchodilators (as for Step 4) and inhaled bronchodilators as required

BDP, beclomethasone; BUD, budesonide; DSG, deoxyspergualin; FP, fluticasone; ICS, inhaled corticosteroids.

Two epidemics of asthma deaths, the first in the 1960s in six countries following the introduction of isoprenaline forte, the second in the mid 1970s in New Zealand after the introduction of fenoterol, led to concerns about the safety of inhaled β-agonists. Case–control studies have also identified an association between asthma deaths and overuse of inhaled β2-agonists. However, it is difficult to distinguish cause and effect from confounding in these studies: overuse of β2-agonists to treat frequent symptoms is more likely to occur in patients with severe uncontrolled asthma who are at high risk of a fatal attack. The evidence for cause and effect in asthma epidemics is stronger: the increased death rates that followed the introduction of the particular inhaled β-agonists fell rapidly after recognition of the association and no other plausible explanation has been advanced. Isoprenaline is a nonselective β-agonist and fenoterol is less selective than salbutamol and terbutaline. Both drugs were marketed in high dose and are cardiotoxic in the presence of hypoxia, hence the two epidemics may have been due to the acute cardiac effects of β-agonists inhaled in high dose by hypoxic patients with acute severe asthma. The evidence that selective β2-agonists formulated in lower doses have a similar cardiotoxic effect and cause asthma deaths outside these epidemics is limited to associations in case–control studies, from which it is not possible to infer cause and effect. However, a small effect can be difficult to detect and, as pointed out by Tattersfield, if a fatal arrhythmia occurred in 1 in 8000 patients treated with β-agonists each year this would account for 50% of asthma deaths in patients under 65 years, but its detection would require observation of many thousands of patients.

A systematic review and additional randomized controlled trials have shown that the addition of long-acting β2-agonists (LABAs) improved respiratory symptoms and lung function with reduced requirement for ‘rescue medication’ as compared to doubling the dose of inhaled corticosteroid in patients with asthma poorly controlled by inhaled corticosteroids alone. The OPTIMA study investigated the addition of the LABA formoterol to the inhaled corticosteroid budesonide in patients with mild persistent asthma. In 700 patients with mild persistent asthma who had not previously used inhaled corticosteroids, the frequency of exacerbations was reduced in those taking budesonide 200 μg alone as compared with placebo (0.77 vs 0.29 exacerbations per patient per year). The addition of formoterol provided no further benefit in this group of patients with mild persistent asthma. In contrast, the addition of formoterol in patients with moderate persistent asthma already using inhaled corticosteroids provided significant benefit in exacerbation frequency, indicating that combination treatment is indicated in patients with moderate persistent asthma insufficiently controlled by low doses of inhaled corticosteroids.

LABAs are intended for regular use with 12-h duration of action. Of the two currently used, salmeterol has a slower onset of action than formoterol. One systematic review and a number of additional randomized controlled trials have shown that in patients with moderately severe asthma, not controlled by low-dose inhaled corticosteroids, the addition of a LABA improved symptoms and lung function and reduced the need for rescue medication as compared to increasing the dose of inhaled corticosteroid. Several randomized controlled trials have shown that the addition of a LABA to an inhaled corticosteroid improved lung function as compared to the addition of a leukotriene antagonist. However, treatment with LABAs (both salmeterol and formoterol) has been associated with an increased frequency of exacerbations of asthma requiring hospitalization, of life-threatening exacerbations in both adults and children, and of asthma-related deaths. The SMART study, which followed more than 26 000 participants for 6 months, found a fourfold increase in the risk of asthma-related deaths in those taking salmeterol, which equated to 2 asthma-related deaths per 1000 patient years of salmeterol usage. Those most at risk of asthma-related deaths were African Americans, which might reflect an increase in asthma severity in this population and a high proportion taking salmeterol without an inhaled corticosteroid. A recent meta-analysis of the results from 19 trials with 33 826 participants found, as compared to placebo, a 2.6-fold increased risk of exacerbations requiring hospitalization, a 1.7-fold increased risk of life-threatening exacerbations; the risk of asthma-related deaths was also significantly increased. Furthermore, the risk for asthma exacerbations requiring hospitalization was increased twofold in patients taking salmeterol with concomitant inhaled corticosteroids.

To put these findings into context, the addition of a LABA to low-dose inhaled corticosteroids in patients with moderately severe asthma has been shown to provide greater improvement in symptoms and lung function than doubling the dose of inhaled corticosteroid. What is clearly important is not to prescribe a LABA without a concurrent inhaled cortico steroid, not to add a LABA unnecessarily in a patient with mild asthma adequately controlled on low-dose inhaled corticosteroids, and to discontinue a LABA in those patients with moderately severe asthma in whom it is not providing benefit.

Methylxanthines

Theophylline is the pharmacologically active methylxanthine most usually employed in clinical medicine, because of its greater bronchodilator activity, less erratic absorption and longer half-life than other methylxanthines. More predictable theophylline absorption can be obtained by slow-release formulations, and the addition of ethylene diamine to theophylline (aminophylline) provides the increased solubility required for intravenous administration. Nonetheless, theophylline has a relatively narrow ‘therapeutic window’ for a safe and effective dose, with wide differences between individuals in its metabolism, which can also be adversely affected by several extrinsic factors to cause clinically important side effects (Table 5). The most common side effects are ‘caffeine-like’ anorexia, nausea, and vomiting, followed by headache and insomnia. It increases the force and rate of heart contraction and causes vasodilatation, and in toxic doses it can cause arrhythmias that may be fatal. It is also a central nervous system stimulant causing increased alertness and—in toxic doses—confusion, irritability, and fits.

Theophylline relaxes bronchial smooth muscle and, like β-agonists, is a functional antagonist that causes bronchial muscle relaxation irrespective of the constrictor stimulus. Its action was previously thought to be mediated via phosphodiesterase inhibition increasing intracellular cAMP, but the intracellular concentration of theophylline necessary to achieve this is some 20 times greater than its therapeutic plasma levels. More recently, anti-inflammatory activity in ‘sub-therapeutic’ concentrations (i.e. <10 μg/ml) has been suggested as a possible mechanism of action in asthma.

Table 5  Factors influencing the half-life of theophylline
Increase half-life Decrease half-life
Liver disease Cigarette smoking
Heart failure Alcohol
Virus infection  
Drugs
Cimetidine Rifampicin
Erythromycin Barbiturates
Clarithromycin Phenytoin
Ciprofloxacin Carbamazepine
Oral contraceptives  

Theophylline is metabolized to inactive products by cytochrome P450-dependent pathways in the liver. The variation between individuals is large and the half-life for theophylline can vary between 4 and 24 h. This may in part reflect the wide range of exogenous factors that influence hepatic metabolism of the drug. The half-life of theophylline is increased by several drugs—cimetidine (but not ranitidine), erythromycin, ciprofloxacin, and oral contraceptives—and decreased by rifampicin, barbiturates, and carbamazepine (see Table 5).

Bronchodilatation increases linearly with increase in serum theophylline concentration. Toxic effects show a similar linear relationship, but at higher concentrations, although there are considerable differences between individuals in the serum concentration at which side effects occur. Serum concentrations of between 10 and 20 µg/ml combine substantial bronchodilatation with a low risk of side effects. Safe, effective theophylline treatment requires monitoring of plasma concentration at the start of treatment to ensure a concentration within the therapeutic window, and subsequently to ensure its maintenance. This can be measured by immunoassay: in patients on regular, twice daily, maintenance treatment the difference between peak and trough levels is usually between 5 and 10 µg/ml, although greater in smokers, who may require three times daily treatment.

Theophyllines are now most commonly used as an additional treatment in patients whose asthma is inadequately controlled by inhaled corticosteroids. Comparison in a randomized controlled trial of budesonide 400 µg twice daily and theophylline (250 or 375 mg twice daily) with budesonide 800 µg twice daily for 3 months in 62 patients, whose asthma was not controlled by the lower dose of inhaled steroid, found the combination of low-dose inhaled corticosteroid and theophylline provided the greater improvement in lung function, peak flow variability, and β2-agonist use. In those receiving it, median theophylline concentration was 8.7 µg/ml, and the additive effect was similar to that provided by inhaled salmeterol, suggesting that oral theophylline at doses lower than the conventional therapeutic dose can be an appropriate alternative to the addition of inhaled salmeterol where this does not provide adequate control at Stage 3 of the BTS guidelines.

Sodium cromoglicate

Sodium cromoglicate is a bischromone that has prophylactic but not bronchodilator activity in asthma. Originally available as a dry powder (mixed with lactose), it is now also formulated as a metered-dose inhaler and as a nebulizer solution. In inhalation tests it inhibits asthmatic reactions provoked by inhaled allergen, by exercise, and by other provocative stimuli including sulphur dioxide and adenosine, although it is less effective in a dose of 20 mg than salbutamol 200 µg in preventing asthma provoked by exercise. The major benefit of sodium cromoglicate is its safety, but it is less effective than inhaled corticosteroids and its use is now generally reserved for children with mild asthma, taken immediately prior to exercise to prevent exercise-induced asthma.

Nedocromil sodium

Nedocromil sodium has a similar activity profile to sodium cromoglicate. It is available as a metered-dose inhaler, needing to be taken four times a day. Its activity is equivalent to low-dose inhaled corticosteroid and it can be used either in place of inhaled corticosteroid or to reduce the dose of inhaled corticosteroid. Both sodium cromoglicate and nedocromil sodium are alternatives to inhaled corticosteroids in Step 2 of the BTS guidelines and may be tried when inhaled corticosteroids cause unacceptable hoarseness of the voice, as can occur occasionally.

Antileukotrienes

Antileukotrienes are new classes of anti-inflammatory drugs that inhibit leukotriene synthesis (5-lipoxygenase inhibitors) or antagonize leukotriene receptors (leukotriene receptor antagonists). The 5-lipoxygenase inhibitor zileuton inhibits the conversion of arachidonic acid into 5-hydroperoxyeicosatetraenoic acid (5-HPETE) prior to its transformation into cysteinyl-leukotriene A4. The leukotriene receptor antagonists (montelukast, pranlukast, and zafirlukast) block the receptors for the cysteinyl-leukotrienes C4, D4, and E4.

Anti-leukotrienes are used in the treatment of asthma as either single or combined therapy with inhaled corticosteroids. In general, systematic reviews of their efficacy as single therapy suggest they are safe but less effective than inhaled corticosteroids in preventing asthma exacerbations. Beclometasone 400 μg/day and fluticasone 200 μg/day are superior in efficacy to montelukast 10 mg/day and zafirlukast 20 mg twice daily. However, in patients whose asthma is not sufficiently controlled with beclometasone 400–800 μg/day (or equivalent) the addition of a leukotriene antagonist in usual doses has been found to provide some improvement in asthma control, but although the addition of a leukotriene antagonist may be an alternative to doubling the dose of inhaled corticosteroids, in adults with moderate persistent asthma both are less effective than the addition of a long-acting β2-agonist in improving asthma control.

Antileukotrienes are generally safe at usual licensed doses, but increasing the licensed dose two- to fourfold—although associated with increased efficacy—is not recommended because of the two- to fourfold increased risk of abnormal liver function tests. Churg–Strauss syndrome has now been reported with all marketed antileukotrienes, with one systematic review identifying 22 cases in patients taking antileukotrienes, but the total number of patients taking antileukotrienes in whom these cases occurred was not stated.

The 'stepped' approach to the treatment of asthma

The purpose of treatment of asthma varies in different patients, from the reversal of occasional mild symptoms to the restoration of normal life in a patient with severe disabling ill health. Treatment needs vary greatly between different patients, which is reflected in the ‘stepped’ approach to treatment that is the basis of current guidelines for asthma management, including the British Thoracic Society (BTS) and Scottish Intercollegiate Guidelines Network (SIGN) guidelines that are regularly updated. In the stepped approach, asthma severity is defined by the treatment step needed to achieve and maintain good control (see Table 4).

Inhaled corticosteroids form the mainstay of maintenance treatment for most patients, the initial dose being that considered on clinical grounds the dose most likely to control the disease. Inhaled β2-agonists are used primarily for symptomatic relief. There is good evidence that regular treatment with short-acting β2-agonists alone is less effective than regular inhaled corticosteroids and provides less good control of asthma, both symptomatically and of lung function.

Steps 1 to 5 of the BTS guidelines identify the treatment requirements for asthma of increasing severity (see Table 4). Failure to achieve treatment targets at any step implies the need to increase treatment to a step that provides good control.

  • Step 1—patients with mild intermittent asthma whose asthma is controlled by the use of an inhaled shorter-acting β2-agonist (e.g. salbutamol or terbutaline) less than once a day. Requirement for more regular treatment implies the need for regular anti-inflammatory treatment (i.e. a higher step).
  • Step 2—patients with mild persistent or intermittent asthma that is of sufficient frequency to require regular anti-inflammatory treatment. Inhaled corticosteroids are the most effective and commonly used anti-inflammatory drugs. Treatment with an inhaled corticosteroid should be started at a dose of beclometasone 400 µg twice daily (or equivalent) in adults and 200 μg twice daily in children. This dose should be continued for at least 3 months, the period when most benefit of the inhaled steroid is obtained, before reducing the dose to the minimum required to maintain good control. This can be achieved by reducing the dose by 25 to 50% every 1 to 3 months. Short-acting β2-agonists are used as required for symptomatic relief.
  • Step 3—patients with moderate persistent asthma whose disease, despite adherence to treatment and correct inhaler technique, is not controlled. The treatment of choice is the addition of a LABA, which should be continued if it provides good asthma control. If it provides benefit, but asthma remains inadequately controlled, the dose of inhaled corticosteroid should be doubled (e.g. beclometasone 400 to 800 μg/day). If the LABA provides no benefit, then it should be discontinued and the inhaled steroid dose doubled, and if this does not provide adequate control a trial of other treatments such as a slow-release theophylline or leukotriene antagonist should be instituted.
  • Step 4—if asthma control remains poor despite the measures recommended in Step 3, consideration should be given to increasing further the dose of the inhaled corticosteroid to the equivalent of beclometasone 2000 μg/day, or to the addition of a fourth drug, e.g. slow-release theophylline, a leukotriene antagonist, or an oral β2-agonist.
  • Step 5—patients who fail to respond to these combinations of Step 4 treatments will require the addition of an oral corticosteroid while continuing high-dose inhaled corticosteroid treatment. The dose of oral corticosteroid should be the lowest to provide adequate control, which is an important decision that should be made in consultation with a respiratory physician. Patients who require oral corticosteroids for longer than 3 months or need frequent courses of oral corticosteroids are at risk of systemic side effects including hypertension, diabetes mellitus, and osteoporosis. A long-acting bisphosphonate should be prescribed for those taking oral corticosteroids for more than 3 months, with their bone mineral density monitored regularly. Children should have their growth monitored and eyes regularly examined for cataracts. There is no reliable evidence for a steroid-sparing effect in the treatment of asthma for immunosuppressants such as methotrexate and gold, and inconsistent evidence for ciclosporin.

Most cases of asthma in the community are mild—Steps 1 and 2 of the BTS guidelines; ‘difficult’ asthma, requiring treatment equivalent to Step 5, constitutes less than 5% of cases. A community study of five large general practices in South Nottinghamshire, England (a population of 38 865) found a prevalence of asthma of 9%, with a peak of 17% in 10 to 14-year-olds, falling to less than 6% in adults aged more than 70 years. Most patients with diagnosed asthma were either not receiving treatment (8%) or receiving treatment equivalent to Steps 1 and 2 (76%); 11% were on Step 3 and some 5% on Steps 4 and 5. The authors endeavoured to assess the effectiveness of asthma treatment in this population by measuring the proportion of patients who during a 1-year period required oral corticosteroid courses or were prescribed 10 or more short acting β2-agonist inhalers: 12.5% patients not taking them regularly had been prescribed one or more courses of oral corticosteroids, 1.6% on three or more occasions; 13.6% patients had been prescribed 10 or more short-acting β2-agonist inhalers; both outcomes were increasingly more frequent in patients on Steps 3 or higher of the BTS guidelines. However, because only a few patients (15%) were in these categories, more than one-half of the patients who required either oral corticosteroids or 10 or more β2-agonist inhalers were on Steps 1 or 2, indicating continuing significant morbidity among some cases of asthma receiving either low dose or no anti-inflammatory treatment.

Difficult asthma

Difficult asthma is asthma that is not controlled by maximum doses of inhaled treatment, including inhaled corticosteroids in doses of beclometasone of up to 2000 µg/day (or equivalent) with additional treatment such as long-acting β2-agonists. It is uncommon, probably less than 5% of asthmatics, but important. The severity of disease and associated disability is considerable: the risks of near fatal and fatal asthma are high, and the adverse consequences of treatment are severe and worthwhile only if these are demonstrably effective.

Bullet list 2 Difficult asthma—why is it failing to respond?

1 Does patient have asthma?
  • Is there evidence of significant response to bronchodilators/steroids?
  • Have other relatively common causes of similar symptoms been excluded?
    • • COPD (irreversible airflow limitation)
    • • Localized obstruction
    • • Left heart failure
    • • Pulmonary thromboembolic disease
    • • Vocal cord dysfunction
  • Have other relatively uncommon causes of similar symptoms been excluded?
    • • Vasculitis—Churg–Strauss syndrome
2 Is prescribed treatment reaching the airways?
  • Is patient taking the treatment (inhaled and oral)
  • Is inhaler technique satisfactory?
3 Are there any unrecognized provoking factors?
  • Domestic allergens—particularly cats
  • Occupational agents
  • Drugs—e.g. aspirin, NSAIDs, β-blockers
  • Upper airway disease—rhinitis/sinusitis
  • Gastro-oesophageal reflux
4 Does the patient have a particular type of difficult asthma?
  • Unstable asthma:
    • • Nocturnal asthma
    • • Premenstrual asthma
    • • Brittle asthma—type I, type II
  • Corticosteroid-dependent asthma
  • Corticosteroid-resistant asthma
5 Are there significant psychological and social factors?

Failure to respond to maximal inhaled treatment can result from several causes (Bullet list 2). It is clearly important to confirm the diagnosis of asthma and ensure the patient is taking the asthma treatment prescribed: misdiagnosis and poor compliance with medication represent a significant proportion of patients with ‘difficult asthma’. The conditions most easily mistaken for asthma were considered earlier in this chapter (see ‘Differential diagnosis’). Demonstration of spontaneous variability or reversibility of airflow limitation is important to avoid treatment of irreversible airflow limitation, due either to localized obstruction or to chronic obstructive pulmonary disease (COPD) with ever-increasing doses of oral corticosteroids. Assessment of reversibility may require a formal steroid trial of oral prednisolone 30–40 mg taken each morning for 1 month to determine whether this provides significant improvement in airway function.

Having confirmed the diagnosis of asthma, it is important to ensure good inhaler technique and adherence to prescribed treatment, failure to take treatment properly being a common reason for failure to respond. This may reflect lack of understanding that preventive treatment needs to be taken regularly and not ‘as needed’, or poor inhaler technique. Patients may take preventive treatment irregularly because, unlike short-acting β2-agonists, it does not provide immediate symptomatic relief. Others may be inappropriately concerned about potential side effects or resent the need to take regular inhaled treatment. In patients taking oral corticosteroids blood eosinophil count is markedly reduced and often reported as 0. Failure to take prednisone can be confirmed by demonstrating its absence in serum. A blood eosinophil count above 0.3 × 109/litre in a patient prescribed oral steroid suggests that this drug is not to being taken regularly, or alternatively that another disease—particularly Churg–Strauss syndrome—may accompany the asthma.

One study, using a computerized timing device in a dry powder inhaler, found only 18% of patients took inhaled steroids as prescribed. However, in routine clinical practice adherence to inhaled treatment is difficult to monitor. Poor treatment adherence may be suspected as a cause of difficult asthma in patients whose asthma improves when treatment, although unchanged, is supervised. Patient understanding of the effectiveness of regular treatment may also be reinforced by this means.

Unidentified provoking factors include allergens, commonly domestic pets (in particular cats), whose allergens can be present in sufficient concentrations to cause asthma for several months after the animals have left the home. Sensitizing agents encountered at work can also cause asthma that is poorly controlled by inhaled treatment. Early identification and avoidance of the cause is important to minimize the risk of development of chronic asthma. Aspirin, NSAIDs, and β-blockers can also be important provoking factors.

Rhinitis commonly accompanies asthma, and its treatment can be associated with improvement in asthma and airway hyper-responsiveness. The explanation for this association is unclear but may be a consequence of inflammatory mediators in postnasal drip increasing airway responsiveness and provoking cough. Similarly, gastro-oesophageal reflux can provoke cough and worsen asthma, and a trial with a proton pump inhibitor such as omeprazole should be instituted when this is suspected to an exacerbating factor, although objective improvement in asthma with such treatment is uncommon.

Uncommonly asthma may be a manifestation of systemic disease, particularly a systemic vasculitis—Churg–Strauss syndrome—when asthma, which can be difficult to control, is accompanied by a high blood eosinophil count (usually >1.5 × 109/litre). Other manifestations include eosinophilic pneumonia, pleural and pericardial effusions, and mononeuritis multiplex. Effective treatment requires high dose oral corticosteroids and in some cases other immunosuppressant treatment.

Nocturnal asthma can persist in some patients despite treatment with inhaled corticosteroids that provides good daytime control. This may be improved by the addition of a long-acting β2-agonist or slow-release theophylline.

Premenstrual deterioration of asthma is not uncommon, and in some women can be severe and unresponsive to corticosteroid treatment. Characteristically symptoms increase and PEF falls 2 to 5 days before the menstrual period, improving with the onset of menstruation that coincides with the fall in progesterone secretion and increase in oestrogen:progesterone ratio. Some patients are improved by treatment with intramuscular, but not oral, progestogen during the week before menstruation. Patients with severe premenstrual exacerbations can require hospital admission, in some cases ventilation, and may only be improved by surgical removal of the ovaries. There is also now the option of inducing a short-term chemical menopause with GnRH analogues prior to surgery.

Brittle asthma is characterized by widely varying peak flow rates uncontrolled by maximum inhaled treatment. Two patterns have been distinguished: type I, where there is persistent chaotic daily variability in peak flow (usually >40% diurnal variation in PEF> 50% of time), and type II, where there are sporadic sudden falls in PEF against a background of usually well-controlled asthma with normal or near normal lung function.

Treatment of brittle asthma of both types is difficult. Type I brittle asthma, not responding to inhaled long-acting β2-agonists or regular nebulized β2-agonists, can be improved by subcutaneous terbutaline administered via an insulin infusion pump, usually in a dose of between 3 and 12 mg in 24 h. Treatment is limited by side effects, of which the most important is muscle cramp associated with increased levels of serum creatinine kinase. Type II brittle asthma requires immediately available treatment for what can be catastrophic falls in peak flow. The speed of onset of attacks requires immediately injected bronchodilator. Such patients should have preloaded adrenaline syringes (e.g. Epi-pen) available at all times and wear a medical ID bracelet (e.g. MedicAlert). Potential provoking factors, such as foods, should be sought and avoided.

In a very few patients asthma is only controlled with continuous oral corticosteroids, often in high doses, reduction in dose being followed by worsening of asthma. The term ‘corticosteroid-dependent asthma’ has been used for such patients. They differ from corticosteroid-resistant asthma in their response to oral corticosteroids, patients with corticosteroid-resistant asthma showing no response to oral corticosteroids even in high dose, although they do show spontaneous variability of peak flow and reversibility with inhaled bronchodilators. Corticosteroid-resistant asthma is very uncommon, estimated at between 1 in 1000 and 1 in 10 000 patients, and it probably forms the end of a spectrum of resistance to the anti-inflammatory activity of corticosteroids to which corticosteroid-dependent asthma also belongs. Treatment of corticosteroid-resistant asthma is difficult, but should include stopping oral corticosteroids—which still cause side effects—and relying on other forms of treatment, including long-acting β2-agonists.

Several treatments including methotrexate, gold, and ciclosporin have been evaluated in the treatment of asthma. In general these have not provided robust evidence of benefit in patients with severe asthma. In addition, two monoclonal antibodies—anti TNFα (etanercept) and anti IgE (omalizumab)—have been shown to provide benefit in patients with severe asthma in early trials. Their possible place in the treatment of these 2 agents is still being evaluated.

Acute exacerbations of asthma

Asthma exacerbations are episodes of progressively worsening airway narrowing associated with increasing shortness of breath, cough, wheezing, and chest tightness, or some combination of these. They can vary in severity from episodes in which patients are able to manage themselves by following an agreed treatment plan, to severe and potentially life-threatening episodes that require medical attention and hospital admission. Severe attacks can vary in their speed of onset from deterioration over days to episodes that progress rapidly and can become life threatening within minutes or hours. In about one-half of cases of fatal asthma the attack lasted more than 24 h, in one-quarter less than 1 h.

Fatal or near fatal attacks of asthma are associated with:

  • Patients who have previously required hospital admission for severe asthma and who require regular oral steroid treatment
  • Failure to recognize severity of asthma by the patient: those with long-standing asthma can become accustomed to their symptoms and not appreciate an important increase in their severity that may persist for days or weeks, sometimes associated with psychosocial problems and poor adherence to treatment
  • Failure to recognize the severity of asthma by the doctor, the risk of which can be minimized by making appropriate objective measurements of respiratory, heart, and peak flow rates to assess severity
  • Undertreatment or inappropriate treatment: failure to use oral corticosteroids in adequate doses early in an exacerbation is probably the single commonest remediable factor; the use of sedatives or anxiolytics to reduce the anxiety or agitation that can often accompany acute severe asthma is absolutely contraindicated

Many of these problems can be overcome by improved patient understanding, allowing them to have control over their illness supported by a jointly agreed management plan.

Moderate exacerbations

Exacerbations of asthma with increased symptoms, both during the daytime and at night, frequently follow a viral infection or allergen exposure in allergic individuals (or both), or a reduction in anti-inflammatory treatment. The increase in symptoms, associated with deterioration in peak flow, is often treated adequately by the patient increasing the frequency of inhaled short-acting bronchodilators, doubling the dose of inhaled steroids, or taking a short course of oral steroids. Several studies have shown that early treatment with oral corticosteroids taken at the start of an acute exacerbation reduces the need for hospital admission, the frequency of relapse, and the need for β2-agonists. One recent overview of 7 randomized controlled trials in 320 patients found that systemic corticosteroids, taken at the onset of an acute exacerbation, reduced hospital admissions in both children and adults by 65% in the first week compared with placebo, an effect maintained for 21 days. No difference was observed between the use of oral and intramuscular corticosteroids. Oral corticosteroids continued for a short period after hospital discharge reduce the risk of early relapse, which occurs in some 10 to 15% of patients following discharge after emergency treatment. A Cochrane review of seven trials comparing oral corticosteroid treatment with placebo following discharge found a two-thirds reduction in relapse rate in those taking oral corticosteroids and a reduced need for β2-agonists at 1 and at 3 weeks after discharge.

Severe exacerbations

Acute severe asthma is a potentially life-threatening increase in the severity of asthma that can develop over minutes, hours, or days, and which has often failed to respond to conventional inhaled bronchodilator treatment. It is usually the outcome of airways increasingly narrowed by the consequences of chronic inflammation to cause increasing resistance to airflow identified as a reduction in PEF and FEV1, hyperinflated lungs, ventilation–perfusion inequality, and hypoxia, which is the most serious consequence of severe asthma. Initially these stimulate alveolar hyperventilation with a reduction in P CO 2, but—with increasing airway narrowing and exhaustion—arterial pO2 continues to fall while arterial P CO 2 rises to normal, and subsequently increases steeply with the development of alveolar hypoventilation. In general, P CO 2 rises into the normal range when FEV1 is some 25% and PEF 30% of predicted normal values.

The clinical features of importance in identifying acute severe asthma and assessing its severity are shown in Bullet list 3. Patients are usually extremely breathless and unable to complete sentences in one breath. A rapid respiratory rate and heart rate are good markers of severity of asthma and hypoxia. Although anxiety and increased use of β2-agonists can increase heart rate, a rapid heart rate should not be ignored by attributing it to these factors. An objective measure of airflow should be obtained because the severity of limitation is difficult to assess clinically. Although PEF is an effort-dependent measurement it is usually possible to obtain a reading from patients with severe asthma: a value of less than 50% of predicted or of the recent best value in an adult aged less than 50 years usually indicates severe asthma; a value of less than 33% indicates a potentially life-threatening attack.

Arterial blood gas analysis should be made in adults seen in hospital as an important guide to the severity of asthma; children can often be managed safely by measurement of SaO 2 alone. Most patients admitted to hospital with acute severe asthma are hypoxic, of whom about one-third will have P O 2 <8 kPa (60 mmHg). P CO 2 is reduced in patients with moderately severe asthma, but with increasingly severe airways obstruction and fatigue P CO 2 falls and subsequently rises in parallel with a falling P O 2. A normal P CO 2 in a hypoxic patient with acute severe asthma indicates impending hypoventilation, with a rapidly increasing P CO 2, falling P O 2, acidosis, narcosis, and death.

Bullet list 3  Acute severe asthma: assessment of severity

Features of acute severe asthma
  • Unable to complete sentences in one breath
  • Respiration rate >25 breaths/min
  • Pulse rate >110 beats/min
  • Peak expiratory flow rate <50% predicted or best
Life-threatening features
  • PEF <33% predicted or best
  • Silent chest
  • Bradycardia or hypotension
  • Exhaustion, confusion, or coma
Markers of life-threatening attack
  • Normal (5–6 kPa or 36–44 mmHg) or high P CO 2
  • Severe hypoxia: P O 2 <8 kPa (60 mmHg)
  • Low pH or high [H+]

Management

The aims of the treatment of acute severe asthma are to reverse the hypoxia, airflow limitation and airway inflammation with oxygen, bronchodilators, and corticosteroids (Bullet list 4).

Oxygen

Oxygen relieves the hypoxia present in most patients with acute severe asthma. High concentrations of inspired oxygen are safe in patients with asthma, and certainly in those aged less than 50 years; a high PaCO 2 in acute severe asthma reflects fatigue and the severity of airways obstruction and is not a contraindication for a high concentration of inspired oxygen. Oxygen can be administered by nasal cannulae or by face mask in high concentrations (usually FiO 2 between 40 and 60%). The aim is to increase SaO 2 to above 92% or PaO 2 to above 9 kPa (80 mmHg).

Bronchodilators

The purpose of bronchodilator treatment in acute severe asthma is to reverse the airway narrowing due to smooth muscle contraction, before the onset of the anti-inflammatory action of corticosteroids that usually takes 6 to 12 h from administration.

Bullet list 4  Treatment of acute severe asthma

Initial treatment
  • Oxygen (60% FiO 2)
  • Nebulized salbutamol 2.5–5 mg or terbutaline 5–10 mg (driven by oxygen via nebulizer)
  • Oral prednisolone 30–60 mg or intravenous hydrocortisone 200 mg

If poor response to initial treatment after 15–30 min

  • Continue oxygen
  • Repeat nebulized salbutamol 5 mg after 15 min
  • Add ipatropium 0.5 mg to nebulized β-agonist
  • Intravenous hydrocortisone 200 mg 4 hourly
  • Consider intravenous magnesium sulphate 1.2–2 g over 20 min
  • Investigations:
    • • Chest radiograph to exclude pneumothorax
    • • Monitor serum K+ (risk of hypokalaemia with high-dose β-agonist)
  • Consider intravenous salbutamol (see text)
  • Consider intravenous aminophylline (see text)
If poor response within 1 h
  • Admit to intensive care for possible intubation and ventilation

Inhaled bronchodilators

Inhaled high-dose β2-agonists (salbutamol, terbutaline) administered by spacer or nebulizer are used as initial treatment. The benefit of a nebulizer is that it allows inhalation of bronchodilator to be driven by a high flow of oxygen, which can be important in severe and life-threatening asthma as β2-agonists may increase ventilation–perfusion inequality and consequent arterial hypoxia, hence β2-agonists should not be administered without oxygen to those who are hypoxic. Nebulized salbutamol (5 mg) or terbutaline (10 mg) driven by 6 litres/min oxygen can be given safely by trained ambulance crews during transfer to hospital. However, nebulizers are inefficient and widely variable in their performance, which has led to the suggestion that large volume spacers be used as alternative delivery systems. In adults and children with severe but not life-threatening asthma, inhalation of β2-agonist by nebulizer has not been found to provide additional bronchodilatation as compared to inhalation of a metered dose inhaler via a spacer, and the latter is associated with fewer side effects. However, it should be appreciated that the studies on which these observations are based are of patients with moderately severe asthma who did not require hospital admission. Spacers do not easily allow concurrent administration of oxygen and require patient cooperation, which can be difficult in severely breathless patients.

Intravenous bronchodilators

The intravenous bronchodilators used in clinical practice are β2-agonists and theophylline. The theoretical advantage of giving β2-agonists intravenously rather than by inhalation is access to peripheral airways so narrowed that they cannot be reached by inhalation, although inhaled salbutamol is rapidly absorbed from the lungs, reaching a peak concentration within 10 min of inhalation. The major disadvantage of intravenous β2 agonists, in comparison to inhalation, is the greater frequency of systemic side effects. However, the key clinical question is whether intravenous β2-agonists provide additional improvement in bronchodilator response to inhaled β2-agonists and corticosteroids. In adults with acute asthma, intravenous salbutamol 12 µg/min taken 4 hourly after an initial dose of nebulized salbutamol 5 mg and intravenous hydrocortisone provided greater bronchodilation as compared to three further doses of nebulized salbutamol given during 2 h, although the patients receiving intravenous salbutamol had a greater increase in heart rate. Similarly, in a study of children with acute severe asthma, the addition of salbutamol (15 µg/kg) in a 10-min infusion to nebulized salbutamol and intravenous hydrocortisone was associated with a reduced period of need for inhaled salbutamol, a decreased requirement for oxygen, and earlier discharge from the Emergency Department.

The use of intravenous aminophylline in the treatment of asthma has decreased with the recognition that it does not provide additional benefit to repeated or continuous nebulized β2-agonist bronchodilators in the initial hours of emergency treatment. This, together with its narrow therapeutic window, need for drug monitoring, and interactions with other drugs, has led to its replacement as first-line bronchodilator treatment of asthma by inhaled β2-agonists. However, it is recommended as additional therapy for patients not responding to initial treatment with inhaled β2-agonists and corticosteroids and as initial treatment in the very severely ill patient with a normal or high P CO 2. In patients who have not been taking theophylline prior to admission, a loading dose of 5 mg/kg body weight over 20 min should be followed by a maintenance dose of 0.5 mg/kg body weight per hour until a serum level of 10 to 20 µg/litre is obtained. The loading dose should be omitted in those currently taking theophyllines, in whom the serum concentration should be measured. The infusion rate should be decreased in patients with liver or heart failure, or in those taking cimetidine, macrolide antibiotics (erythromycin, clarithromycin) or ciprofloxacin. Toxic side effects are increasingly common in patients whose serum level exceeds 25 µg/litre, ranging from gastrointestinal symptoms to fits and cardiac arrhythmias.

Antimuscarinics

The purpose of antimuscarinic treatment is to reverse airway narrowing caused by increased vagal tone that is not responsive to high-dose inhaled β2 agonists. Several studies have suggested the addition of a nebulized antimuscarinic provides additional benefit in the treatment of acute severe asthma, both in children and in adults. A Cochrane review in children found that multiple doses of ipatropium bromide in addition to a β2-agonist significantly increased FEV1 and reduced the risk of hospital admission in comparison to a β2-agonist alone in moderate and severe exacerbations of asthma. A Cochrane review of similar combination therapy in adults found consistent evidence for similar improvements in FEV1 and reduction in hospital admissions. Systematic reviews have confirmed the benefits of using inhaled ipatropium bromide in combination with a β2-agonist in the treatment of patients with moderate to severe acute asthma.

Magnesium

Systematic reviews have shown that intravenous magnesium sulphate is a safe and effective treatment in patients with exacerbations of severe asthma. A Cochrane review found that in severe asthma the addition of magnesium sulphate to a β2-agonist and intravenous corticosteroids improved lung function and reduced the need for hospitalization, without causing adverse effects.

Corticosteroids

Systemic corticosteroids are given in acute severe asthma to reverse the underlying airway inflammation, such anti-inflammatory action requiring 6 to 12 h from administration for demonstrable bronchodilatation to occur. Within 1 h of their administration, steroids may also reverse β2 receptor desensitization induced by regular β2 inhalation.

The value of corticosteroid treatment in acute severe asthma was first demonstrated in a randomized controlled trial in 1956 and has since been generally accepted. Corticosteroids are usually given by intravenous administration, but other than in life-threatening asthma and in patients vomiting or unable to swallow, there is no demonstrable advantage of intravenous over oral administration. When indicated, intravenous doses initially of 200 mg hydrocortisone 4 to 6 hourly can be followed by oral prednisolone in a dose of 40 to 60 mg/day. The duration of treatment with oral prednisolone will depend on the severity of and rate of recovery from the acute episode. In general, oral prednisolone should be continued until resolution of the acute episode with return to usual daytime activities, resolution of nocturnal symptoms, and PEF within 80% of the patient’s predicted or best values. Short courses of oral corticosteroids (taken for <2 weeks) do not need to be tapered provided patients are taking an appropriate dose of inhaled corticosteroid. Although some studies in patients with relatively mild exacerbations of asthma (PEF >60% predicted or best) have suggested that high-dose inhaled steroids are an effective alternative to oral corticosteroids, these results should not to extrapolated to acute severe asthma where the recommended guideline is that all patients should be given systemic corticosteroid treatment.

Bullet list 5  Acute severe asthma

Indications for intensive care
  • Hypoxia (PaO 2 <8 kPa) despite FiO 2 60%
  • Hypercapnoea (PaCO 2 > 6 kPa)
  • Exhaustion with feeble respiration
  • Confusion or drowsiness
  • Unconsciousness
  • Respiratory arrest
Indications for intermittent positive-pressure ventilation (IPPV)
  • Hypoxia (PaO 2 <8 kPa) despite 60% FiO 2
  • Increasing hypercapnoea
  • Drowsiness or unconsciousness
  • Respiratory arrest

Intensive care and intermittent positive pressure ventilation

Most attacks of acute severe asthma respond to treatment with high inspired oxygen, systemic corticosteroids and inhaled β2-agonists. However, this treatment is insufficient in a few cases, which require intensive care and—on occasion—intermittent positive-pressure ventilation (IPPV). This need arises in two particular situations: patients who have a catastrophic hyperacute attack, and those whose asthma progressively increases in severity despite maximal bronchodilator and corticosteroid treatment. The indications for intensive care and IPPV are given in Bullet list 5. Patients with increasing drowsiness or who lose consciousness with hypoxia and worsening hypercapnoea require IPPV, as do those who suffer a respiratory arrest. However, because of the high inflation pressures needed to overcome the high airway resistance and hyperinflated lungs and chest wall, IPPV in acute severe asthma can be difficult and hazardous. High inflation pressures can cause barotrauma with pneumomediastinum and, on occasion, pneumothorax. In addition, up to one-third of patients develop clinically significant hypotension, requiring inotropic support.

 

Further reading  

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