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Diagnosis and management of adult asthma
Adult asthma
Diagnosis and management of adult asthma
Global Initiative for Asthma (GINA) definition Asthma is: A chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. • The chronic inflammation is associated with airway hyperresponsiveness • This leads to recurrent episodes of wheezing, breathlessness, chest tightness and coughing, particularly at night or in the early morning • These episodes are usually associated with widespread but variable airflow obstruction within the lung that is often reversible either spontaneously or with treatment
Pranab Haldar Ian D Pavord
Abstract Asthma is a disorder of the airways that is characterized by typical symptoms arising from a complex interplay between chronic inflammation and disordered airway function. Worldwide disease prevalence continues to rise steadily and the condition contributes to significant morbidity and preventable mortality. The goals of treatment in asthma are to achieve control of symptoms and to prevent exacerbations. Important non-pharmacological measures include patient education, avoidance of triggers and smoking cessation. Pharmacological management involves the stepwise titration of β-agonist bronchodilators and inhaled corticosteroids according to symptoms. Although satisfactory control of asthma is achieved in primary care for a large proportion of patients, between 5 and 10% with so-called ‘refractory asthma’ remain poorly controlled and contribute disproportionately to asthma-related morbidity and mortality. The reasons for this are complex and multifactorial, and many patients with refractory asthma require referral to specialist centres.
Keywords
asthma; eosinophilic airway corticosteroids; methacholine challenge
inflammation;
Table 1
with the variable airflow obstruction that forms the basis for asthma symptoms and a positive correlation exists between airway hyperresponsiveness and asthma severity. Chronic airway inflammation: this is most often eosinophilic and caused by abnormal Th2 immunoreactivity to various nonpathogenic stimuli (allergens). Chronic inflammation leads to structural changes in airway morphology (referred to as airway remodelling) that may be associated with accelerated lung function decline and development of fixed airflow obstruction in some patients.
inhaled
Diagnosis One of the problems facing clinicians and epidemiologists is the absence of a gold standard for defining or diagnosing asthma. Characteristic clinical features (Table 2) coupled with objective demonstration of variable airflow obstruction and/or airway hyperresponsiveness will usually provide sufficient evidence to make the diagnosis.
The present Global Initiative for Asthma (GINA) definition of asthma (Table 1) is a lengthy description of pathological, physiological and clinical features that encompass the major disease characteristics. Two of the fundamental features are airway hyperresponsiveness and chronic airway inflammation. Airway hyperresponsiveness is considered to be the cardinal pathophysiological abnormality in asthma. It can be objectively demonstrated as a 20% fall in the forced expiratory volume in 1 second (FEV1) with inhalation of histamine or methacholine at a concentration of <8 mg/ml. This represents an abnormal effector response of airway smooth muscle, characterized by heightened pharmacological sensitivity and reactivity to the bronchoconstrictor stimulus.1 The reason for this is unknown but it appears to be associated with mast cell infiltration of the bronchial smooth muscle layer implying a potentially important interaction between the two cell types.2 Airway hyperresponsiveness is associated
History Asthma symptoms are typically variable and representative of the underlying variability in airflow obstruction. This is a product of heightened diurnal variation in physiological bronchomotor tone (increased at night) and airway hyperresponsiveness to a multitude of possible trigger factors. The pattern of daytime symptoms and seasonal variations can help identify common triggers. In patients with adult-onset symptoms, the possibility of occupational asthma or an alternative diagnosis should be carefully explored. In the former, symptoms are typically worse at work but improve when off work for a period of time. An assessment of disease severity can be made from the frequency of daily symptoms, exercise limitation, nocturnal wakening and exacerbation frequency.
Pranab Haldar MA MRCP is Specialist Registrar Respiratory Medicine at the Institute for Lung Health, Glenfield Hospital, Leicester, UK. Competing interests: none declared.
Clinical examination Clinical examination is frequently normal in individuals with well-controlled symptoms. Patients with persistent symptoms may display features of obstructive airways disease, notably chest hyperexpansion and diffuse expiratory wheeze that are
Ian D Pavord DM FRCP is Consultant Physician and Honorary Professor of Medicine at the Institute for Lung Health, Glenfield Hospital, Leicester, UK. Competing interests: none declared.
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Clinical assessment for diagnosing asthma Features favouring a diagnosis of asthma History Episodic and reversible symptoms of cough, breathlessness, wheeze and chest tightness. Symptoms frequently exhibit diurnal variation, being worse at night and in the early hours of the morning
Typical triggers precipitating symptoms: • cold air • exercise • aeroallergens (house dust mite, pet allergens, pollens) • non-specific irritants (cigarette smoke, perfumes) • occupational agents Relief with a bronchodilator (if tried) History of allergy, hayfever, eczema or nasal disease Onset of symptoms in childhood or adolescence History of asthma in a first-degree relative Examination Variable wheeze heard with auscultation
Features favouring an alternative diagnosis
Atypical pattern of symptoms: • cough in the absence of wheeze or chest tightness • voice disturbance • symptoms in the absence of evidence for airflow obstruction, either clinically or with spirometry or peak flow measurement Chronic, persistent symptoms without periods of significant improvement History of recurrent chest infections requiring antibiotic therapy History of cardiac disease Significant smoking history (>20 pack years).
Evidence of marked thoracic hyperinflation Evidence of clinical features associated with an alternative diagnosis (Table 4)
Table 2
indistinguishable from COPD. Physical examination is helpful for identifying features of an alternative diagnosis.
pre-test probability for the diagnosis, response to therapy and the clinical suspicion of an alternative diagnosis (Figure 1). The list of differential diagnoses will differ between groups with and without airflow obstruction (Table 4), with diagnostic and therapeutic implications. Patients with normal spirometry – in this group, the primary differential diagnoses are non-bronchodilator, non-corticosteroid responsive conditions. For patients with asthma bronchodilator response tests are frequently negative (poorly sensitive). Where diagnostic uncertainty exists, measuring airway hyperresponsiveness is the technique of choice as it is a very sensitive test, so its absence should prompt consideration of an alternative diagnosis. Patients with obstructive spirometry – in this group, all the tests of variable airflow obstruction discussed are less specific for a diagnosis of asthma. The measurement of airway hyperresponsiveness in this setting is therefore less helpful. However, dilator response tests may aid diagnosis as larger changes in FEV1 (i.e. >400 ml) are more suggestive of asthma. In many cases it may not be possible to assign a precise diagnostic label; however, bronchodilator and steroid reversibility studies are helpful for guiding the intensity of therapy with these agents.
Measuring airflow obstruction The demonstration of obstructive spirometry in patients with a history strongly suggestive of asthma is sufficient to commence therapy. Spirometry is the preferred method for demonstrating airflow obstruction as it is less effort-dependent than peak expiratory flow (PEF). Airflow obstruction is defined as an FEV1/ forced vital capacity (FVC) ratio of less than 0.7. Measuring variability in airflow obstruction When there is diagnostic uncertainty, the measurement of variability in airflow obstruction will provide useful additional information. A number of different methods exist to measure variability (Table 3). Diurnal variation – calculated from serial PEF measurements. Dilator response tests – measured as the change (improvement) in FEV1 or PEF from baseline with either a short-acting bronchodilator (bronchodilator responsiveness) or following a therapeutic trial of corticosteroid (steroid responsiveness). Constrictor response tests – these examine aspects of hyperresponsiveness, measuring the fall in FEV1 to bronchoconstrictor stimuli, including pharmacological agents (methacholine or histamine challenge tests), exercise (suitable for suspected exerciseinduced asthma) and allergen challenge.
Role of peak expiratory flow Variability in PEF may be informative in the following settings: • patients with infrequent symptoms – a documented fall in PEF at the time of symptoms suggests asthma • suspected occupational asthma – serial peak flow recordings at least 4 times per day that show a significant difference between measurements at and away from work are highly predictive for the diagnosis.3
Diagnostic pathway Given the broad range of tests available, the diagnostic pathway followed will be determined by clinical factors formulating the
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Adult asthma
Overview of tests to measure variable airflow obstruction Test
Measurement
Diagnostic range
Diagnostic value
Comments
PEF variabilty
Amplitude percent best = (PEFmax−PEFmin)/PEFmax × 100
>20%
Moderate specificity but poor sensitivity. Useful in the assessment of occupational asthma (see text)
Serial measurements at least twice daily (morning and evening) for 2 or more weeks, best of 3 blows recorded each time
Bronchodilator responsiveness
% change in FEV1 from baseline after inhalation of 400 μg salbutamol
>15% (and >200 ml)
Reversibility testing with bronchodilators or steroids is appropriate in patients with obstructive spirometry at baseline
Although figures for % change are quoted, absolute improvements in FEV1 of >400 ml are more specific for a diagnosis of asthma
Steroid responsiveness
% change in FEV1 after a therapeutic trial of corticosteroids (400 μg of inhaled beclomethasone for 6–8 weeks or 30–40 mg prednisolone for 2 weeks)
>15% (and >200 ml)
Though not specific for asthma, steroid responsiveness testing is helpful to identify patients who will benefit from regular corticosteroid therapy
Steroid responsiveness may be seen in the absence of significant bronchodilator responsiveness in patients with obstructive spirometry and is associated with high levels of eosinophilic airway inflammation
Methacholine or histamine challenge test
The concentration of bronchoconstrictor agent required to induce a 20% drop in FEV1 from baseline
<8 mg/ml
The most sensitive and specific test in patients with normal spirometry
Limited availability of test in a hospital setting. Reserved for patients in whom there is diagnostic uncertainty
PEF, peak expiratory flow; FEV1, forced expiratory volume in one second.
Table 3
Exacerbations are defined as periods of poor asthma control manifest by an increase in symptoms and deterioration in lung function that are not adequately managed by the individual’s usual therapeutic regimen. They are frequently precipitated by allergen exposure or viral infections.4 Severe exacerbations lead to hospitalization and are the major cause of asthma mortality. Recent evidence suggests that the extent of underlying eosinophilic airway inflammation is associated with an increased risk of a subsequent exacerbation5 and controlling this inflammation with corticosteroid therapy significantly reduces this risk.6 Lung function decline: chronic asthma is associated with accelerated decline in lung function7 that is considered to be a function of persistent airway inflammation. Clinically important decreases in lung function may occur early in the disease, presenting a challenge for its prevention. The rate of decline in adults is more marked in those with severe disease or frequent exacerbations, and smokers.8 Although interventions preventing decline are poorly understood, it is likely that smoking cessation, early removal from occupational sensitizers and, possibly, optimal corticosteroid therapy, are effective.
Other investigations Further investigations are helpful if an alternative diagnosis or an additional diagnosis that may aggravate asthma symptoms, is suspected (Table 4).
Management of stable asthma Aims There are three major consequences of clinical importance in asthma, and management goals are directed at addressing each of these: • control of asthma symptoms • prevention of exacerbations • preservation of normal lung function. Both pharmacological and non-pharmacological measures play an important role in achieving these aims. Asthma symptoms are a cause of both physical and psychological morbidity that impact upon quality of life. Several well-validated questionnaires exist to assess the control of asthma symptoms. Of these, the Royal College of Physicians (RCP) three questions are favoured for being short and quickly implemented: • “Have you had difficulty sleeping because of your asthma symptoms (including cough)?” • “Have you had your usual asthma symptoms during the day (cough, wheeze, chest tightness or breathlessness)?” • “Has your asthma interfered with your usual activities (e.g. housework, work, school, etc)?” A positive response to any question indicates persistent symptoms.
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Pharmacotherapy in asthma Inhaled pharmacological therapies are central to asthma management. The range of available drugs may be categorized mechanistically into bronchodilators and anti-inflammatory agents. Bronchodilators Despite their diverse pharmacological properties, this group of drugs act by a common final pathway of increased intracellular 203
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Adult asthma
Diagnostic pathway in asthma Clinical assessment and spirometry
High clinical probability of asthma
Diagnosis uncertain
Diagnosis unlikely
Results of spirometry Trial of therapy* FEV1/FVC <0.7 Positive
Negative Bronchodilater reversibility testing
Positive
Normal
Negative Trial of therapy*
Positive
Negative Explore respective differential diagnosis based on spirometry (Table 4)
Review diagnostic probability
Possible asthma
Asthma unlikely
Bronchial challenge testing
Negative
Treat as asthma
Positive
Asthma likely, consider reasons for poor therapeutic response (Table 7)
*Steroid response trial
Figure 1
cyclic AMP in smooth muscle cells that inhibits contractility, leading to improvements in lung function and airway hyperresponsiveness. The primary role of bronchodilators is the relief (short acting) and prevention (long acting) of symptoms. Additionally, sustained improvements in lung function may be achieved with the regular use of long-acting bronchodilators.9
effects of corticosteroids are mediated by the direct repression of transcription factors, such as nuclear factor ĸB. The poor systemic bioavailability of inhaled corticosteroids minimizes systemic side effects, though chronic treatment with higher doses of potent steroid may be associated with mild adrenal suppression10 and stunted growth in children. Corticosteroids are efficacious suppressants of eosinophilic inflammation which is associated with clinical improvement in symptoms and exacerbation frequency. The latter is responsible for lowering asthma mortality risk.11 ICS are less effective for managing severe asthma and may not be useful to treat severe asthma exacerbations, perhaps because of more intense and distal localication of
Anti-inflammatory therapies Corticosteroids – inhaled corticosteroids (ICS) are the mainstay of asthma pharmacotherapy. They act topically in the largeand medium-sized airways, binding to glucocorticoid receptors that are expressed ubiquitously by cells. The anti-inflammatory
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Normal spirometry Dysfunctional breathing* Vocal cord dysfunction*
Gastroesophageal reflux disease* Pulmonary vascular disease Cough syndromes Rhinitis
Restrictive spirometry Cardiac failure† Pulmonary fibrosis
With airflow obstruction
COPD*
Step down if asthma controlled for 3 months
Without airflow obstruction
Bronchiectasis*† (including allergic bronchopulmonary aspergillosis) Churg–Strauss syndrome* Inhaled foreign body† Obliterative bronchiolitis Large airway stenosis Sarcoidosis†
Oral prednisolone (use lowest dose providing adequate control) Maintain high-dose inhaled steroid at 2000 mcg/day Consider other treatments to minimize the use of steroid tablets Refer patient for specialist care Consider trials of: Increase inhaled steroid up to 2000 mcg/day Addition of a fourth drug, e.g. leukotriene modifier, theophyline, β2-agonist tablet Add inhaled long-acting 2-agonist (LABA) Benefit from LABA but control still inadequate – continue LABA and increase inhaled steroid to 800 mcg/day
Step up if asthma uncontrolled consistently
Stepwise algorithm for the titration of asthma pharmacotherapy
Differential diagnosis in asthma
Add inhaled steroid 200–800 mcg/day 400 mcg is appropriate starting dose for many patients Inhaled short-acting
*These conditions may coexist with asthma and aggravate clinical symptoms. †These conditions may be associated with normal spirometry.
2-agonist
as required
Source: Scottish Intercollegiate Guidelines Network and British Thoracic Society. British guideline on the management of asthma. July 2007.
Table 4 Figure 2
airway inflammation. Oral therapy is felt to be more effective in these settings.12 Anti-leukotrienes – this class of drugs act by inhibiting different levels of the lipoxygenase pathway, which is involved in the formation of leukotrienes from arachidonic acid. Leukotrienes are important pro-inflammatory mediators in asthma that also promote bronchoconstriction. These mediators are significantly elevated in patients who have asthma with aspirin sensitivity and/or nasal polyps. In this disease subgroup, a constitutive deficiency in prostaglandin (PG) E2, an important regulator of leukotriene production, exists13 and anti-leukotrienes are thought to be particularly efficacious.14 These drugs have also shown efficacy for the management of exercise-induced asthma and are often considered for children due to a paucity of significant side effects.15
Combination inhalers of long-acting β2-agonists and ICS have been developed (Figure 2) and are commonly prescribed. They have the advantage of patient convenience, but restrict independent dose alterations of the component drugs. Identifying and treating common aggravators of symptoms There are a number of factors that may aggravate the expression of clinical symptoms in patients with asthma (Table 4). Of these, gastroesophageal reflux disease and rhinitis are amenable to pharmacotherapy. In both circumstances, the patient may report persistent cough as the presenting feature of their suboptimal asthma control. The additional diagnosis may be suspected from a careful history, although a trial of therapy is often considered in the absence of strong corroborative evidence. Although proton pump inhibitors and nasal steroids may be beneficial in individual cases, their efficacy is not proven in clinical trials.18,19
Stepwise algorithm for asthma treatment Guidelines recommend the titration of therapy for asthma in a stepwise manner, with the primary aim of satisfactorily controlling symptoms at the lowest dose of corticosteroid (Figure 2). Changes in therapy should be reviewed every three months until stability is achieved. This algorithm assumes clinical control is concomitantly associated with control of underlying airway inflammation and therefore fulfilment of all three targets of care. It is notable that step 3 of the British Thoracic Society pathway recommends the addition of a long-acting β2-agonist to low-dose corticosteroid therapy over an increase in corticosteroid dose. There is molecular evidence for a synergistic effect between the two drug classes.16 In clinical practice, the strategy achieves an improvement in symptoms and lung function and a fall in exacerbation frequency that is comparable with a dose escalation in corticosteroid alone.17
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Monitoring asthma control and guided self-management plans Self-management plans are individualized written protocols instructing patients with recommended courses of action on the basis of their asthma control that is graded and risk stratified according to peak flow (expressed as % best or % predicted) and/or symptoms (Table 5). They are attractive for being patientcentred. Both symptom-guided and peak-flow-guided plans improve asthma morbidity and reduce the frequency of hospitalizations and unscheduled doctor visits.20 Although there is little evidence that one strategy is superior, a peak-flow-based plan may be more appropriate in patients with impaired perception of airflow obstruction.21 205
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Principles of a self-management plan Monitoring asthma control Symptoms More frequent symptoms or new nocturnal symptoms requiring reliever use Effects of reliever lasting less than two hours No improvement with reliever or failing to improve with oral steroids after two days
Peak expiratory flow (% best or predicted) 60–75%
50–60% <50%
Risk stratification
Advice and recommended action
I: mild–moderate exacerbation
Increase dose of inhaled corticosteroid and continue until symptoms have settled for at least 1 week, use reliever as needed (reliever should last 3–4 hours) Contact GP and commence oral steroids
II: moderate–severe exacerbation III: acute severe exacerbation
Call for ambulance urgently
Table 5
Referral to a specialist Approximately 20% of patients with asthma are referred to a respiratory specialist in the UK. Recommendations for referral broadly fall into 3 groups: • patients with suspected occupational asthma • patients with treatment-refractory asthma, defined as those failing to achieve control despite high-dose therapy (BTS step 4 or 5). Although constituting 5–10% of the asthma population, this group account for over 60% of healthcare resource utilization for asthma in the UK. The reasons for a poor therapeutic response are multifactorial (Table 6) • patients at higher risk of asthma-related death (Table 7).22 Relative risk is additive and therefore patients with several minor risk factors, as well as patients with a single major risk factor, require referral.
Non pharmacological aspects of asthma care Patient education Appropriate patient education is essential for the provision of patient-centred care. There are several aspects to this: • identifying and avoiding asthma triggers, most importantly smoking cessation • understanding the role of different prescribed therapies, i.e. distinguishing between therapy for immediate relief from symptoms (‘relievers’) and therapy to prevent or reduce the frequency of symptoms (‘preventers’). This can help compliance with therapy, which is a considerable problem in asthma care • encouraging compliance with medication • ensuring correct inhaler technique • recording and monitoring peak flow • following a self-management plan.
Aetiology of refractory asthma Patient factors
Disease factors
Poor inhaler technique and incorrect use of inhalers Poor compliance with therapy (particularly younger patients and those with psychological disorders) Persistent exposure to sensitized allergen Occupation Pets Smoking (associated with increased symptoms, accelerated decline in lung function and impaired steroid responsiveness) Obesity (associated with increased symptoms and impaired steroid responsiveness) Coexistent psychological morbidity (both anxiety and depression can heighten perception of breathlessness leading to increased symptoms)
Coexistent aggravating disorders Dysfunctional breathing disorders Rhinosinusitis Gastro-oesophageal reflux disease Cardiac failure ABPA (associated with more intense eosinophilic airway inflammation and bronchiectasis) Churg–Strauss syndrome
True steroid-resistant asthma (this subgroup constitutes a minority of patients with refractory asthma, high doses of oral or parenteral steroid usually overcome the impaired response to conventional therapy) Absence of demonstrable eosinophilic airway inflammation (noneosinophilic asthma: patients with this condition have corticosteroid resistance and escalation of steroids is unlikely to be helpful. Best management uncertain)
Table 6
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• the development of monoclonal antibody therapies as targeted anti-inflammatory agents • novel techniques for treating airway dysfunction.
Risk factors for asthma mortality Major risk factors
Minor risk factors
Previous mechanical ventilation for asthma Previous admission to intensive care Recent hospital admission for asthma
Targeted anti-inflammatory therapy Monitoring airway inflammation – recent studies suggest eosinophilic airway inflammation is predictive of future exacerbation risk in asthma. Titrating corticosteroid therapy to suppress eosinophilic inflammation leads to a significant reduction in exacerbation frequency when compared with a clinical (symptom-based) algorithm.6 This suggests symptoms are not reliably informative of underlying eosinophilic inflammation and may not predict exacerbation risk. Measuring eosinophilic airway inflammation may provide useful additional clinical information for stratifying exacerbation risk to guide therapy in patients with refractory asthma. Reliable non-invasive techniques for clinical use are presently under development.
Asthma requiring oral steroid or theophylline for control High β2-agonist consumption Factors associated with poor compliance: lower socioeconomic class, coexistent psychopathology, history of drug abuse or alcohol dependence, adolescence
Table 7
Single inhaler therapy – Symbicort (budesonide/formoterol: AstraZeneca) is licensed for use as a single combination inhaler for relief of symptoms and maintenance of asthma control (SMART: symbicort maintenance and reliever therapy). This dual role is made possible as formoterol is a long-acting β2-agonist with a rapid onset of action, comparable to salbutamol. Thus, the frequency of inhaler use will be governed by the severity and frequency of symptoms, ensuring higher doses of corticosteroid during periods of poor control. This is appropriate if deteriorating symptoms are associated with worsening underlying airway inflammation. Studies have shown improvements in lung function, reduction in exacerbation frequency and better symptom control with this approach.26
Specialist asthma nurses are central providers of information and education for patients. Regular follow-up with an asthma nurse reinforces key messages and leads to superior asthma control.23 Smoking cessation and allergen avoidance Approximately 25% of patients with asthma smoke and this is associated with increased symptoms and accelerated lung function decline. Smoking cessation studies have shown a significant improvement in the control of symptoms and lung function within weeks of stopping.24 Allergen sensitization and exposure is common and often contributes to increased asthma symptoms. Simple measures, such as limiting contact with household pets, notably cats, should be advised. There is no evidence that more intensive and often expensive measures to lower the burden of ubiquitous allergens, e.g. house dust mite, are beneficial. Regular antihistamines may be helpful when there is a clear association between allergen exposure and deteriorating asthma control, e.g. loss of control with concomitant hayfever.
Monoclonal antibody therapies: a growing number of monoclonal antibodies are being developed to target key pro-inflammatory mediators of the Th2 pathway that are considered important for perpetuating inflammation in asthma. Of these, omalizumab (an IgE receptor antagonist) has received a licence for use in patients with uncontrolled allergic asthma.27 Trials exploring blocking antibodies to interleukins 4, 5 and 13 are also under way. Given their cost and specificity, it is likely that these agents will be restricted to subgroups within the refractory asthma population that display disease characteristics predicting a therapeutic response.28
Breathing retraining techniques Disordered breathing patterns such as hyperventilation frequently coexist with asthma and may contribute significantly to the clinical expression of asthma-like symptoms. The diagnosis should be suspected in patients with prominent symptoms that do not follow a predictable or episodic pattern and are out of proportion to their lung function. Physiotherapy-based breathing retraining programmes can be effective and may avoid the inappropriate escalation of pharmacotherapy.25
Bronchial thermoplasty offers a non-pharmacological approach to asthma treatment. The technique is targeted at the airway smooth muscle which is considered central to airway dysfunction in asthma. Thermal energy is applied bronchoscopically to the bronchial wall using a wired basket. This leads to disruption of smooth muscle bundles that disrupts their function. Preliminary studies report improvement in symptoms.29 Double-blind randomized clinical trials incorporating a sham bronchoscopy arm are under way to evaluate this further. ◆
Recent developments in asthma management The failure to optimize asthma control in some patients highlights deficiencies in current therapeutic modalities and strategies. There are three key areas of ongoing research that are likely to influence future asthma care, particularly in subgroups with refractory disease: • targeted anti-inflammatory therapy and non-invasive measurement of eosinophilic airway inflammation
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References 1 Lotvall J, Inman M, O’Byrne P. Measurement of airway hyperresponsiveness: new considerations. Thorax 1998; 53: 419–24.
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2 Brightling CE, Bradding P, Symon FA, Holgate ST, Wardlaw AJ, Pavord ID. Mast-cell infiltration of airway smooth muscle in asthma. N Engl J Med 2002; 346: 1699–705. 3 Newman Taylor AJ, Cullinan P, Burge PS, Nicholson P, Boyle C. BOHRF guidelines for occupational asthma. Thorax 2005; 60: 364–66. 4 Murray CS, Poletti G, Kebadze T, et al. Study of modifiable risk factors for asthma exacerbations: virus infection and allergen exposure increase the risk of asthma hospital admissions in children. Thorax 2006; 61: 376–82. 5 Deykin A, Lazarus SC, Fahy JV, et al. Sputum eosinophil counts predict asthma control after discontinuation of inhaled corticosteroids. J Allergy Clin Immunol 2005; 115: 720–27. 6 Green RH, Brightling CE, McKenna S, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 2002; 360: 1715–21. 7 Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year followup study of ventilatory function in adults with asthma. N Engl J Med 1998; 339: 1194–200. 8 Ulrik CS. Outcome of asthma: longitudinal changes in lung function. Eur Respir J 1999; 13: 904–18. 9 Johnson M. Pharmacology of long-acting beta-agonists. Ann Allergy Asthma Immunol 1995; 75: 177–79. 10 Sim D, Griffiths A, Armstrong D, Clarke C, Rodda C, Freezer N. Adrenal suppression from high-dose inhaled fluticasone propionate in children with asthma. Eur Respir J 2003; 21: 633–36. 11 Barnes PJ. Mechanisms of action of glucocorticoids in asthma. Am J Respir Crit Care Med 1996; 154(suppl 2): S21–S26. 12 Berry M, Hargadon B, Morgan A, et al. Alveolar nitric oxide in adults with asthma: evidence of distal lung inflammation in refractory asthma. Eur Respir J 2005; 25: 986–91. 13 Szczeklik A, Stevenson DD. Aspirin-induced asthma: advances in pathogenesis, diagnosis, and management. J Allergy Clin Immunol 2003; 111: 913–21. 14 Dahlen SE, Malmstrom K, Nizankowska E, et al. Improvement of aspirin-intolerant asthma by montelukast, a leukotriene antagonist: a randomized, double-blind, placebo-controlled trial. Am J Respir Crit Care Med 2002; 165: 9–14. 15 Leff JA, Busse WW, Pearlman D, et al. Montelukast, a leukotrienereceptor antagonist, for the treatment of mild asthma and exerciseinduced bronchoconstriction. N Engl J Med 1998; 339: 147–52. 16 Barnes PJ. Scientific rationale for inhaled combination therapy with long-acting {beta}2-agonists and corticosteroids. Eur Respir J 2002; 19: 182–91. 17 Pauwels RA, Lofdahl CG, Postma DS, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med 1997; 337: 1405–11. 18 Nathan RA, Yancey SW, Waitkus-Edwards K, et al. Fluticasone propionate nasal spray is superior to montelukast for allergic rhinitis while neither affects overall asthma control. Chest 2005; 128: 1910–20. 19 Littner MR, Leung FW, Ballard ED, Huang B, Samra NK. Effects of 24 weeks of lansoprazole therapy on asthma symptoms, exacerbations, quality of life, and pulmonary function in adult asthmatic patients with acid reflux symptoms. Chest 2005; 128: 1128–35. 20 Powell H, Gibson PG. Options for self-management education for adults with asthma. Cochrane Database Syst Rev 2003; (1): CD004107. 21 Kikuchi Y, Okabe S, Tamura G, et al. Chemosensitivity and perception of dyspnea in patients with a history of near-fatal asthma. N Engl J Med 1994; 330: 1329–34.
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22 Alvarez GG, Schulzer M, Jung D, Fitzgerald JM. A systematic review of risk factors associated with near-fatal and fatal asthma. Can Respir J 2005; 12: 265–70. 23 Griffiths C, Foster G, Barnes N, et al. Specialist nurse intervention to reduce unscheduled asthma care in a deprived multiethnic area: the east London randomised controlled trial for high risk asthma (ELECTRA). BMJ 2004; 328: 144. 24 Chaudhuri R, Livingston E, McMahon AD, et al. Effects of smoking cessation on lung function and airway inflammation in smokers with asthma. Am J Respir Crit Care Med 2006; 174: 127–33. 25 Cooper S, Oborne J, Newton S, et al. Effect of two breathing exercises (Buteyko and pranayama) in asthma: a randomised controlled trial. Thorax 2003; 58: 674–79. 26 Rabe KF, Pizzichini E, Stallberg B, et al. Budesonide/formoterol in a single inhaler for maintenance and relief in mild-to-moderate asthma: a randomized, double-blind trial. Chest 2006; 129: 246–56. 27 Walker S, Monteil M, Phelan K, Lasserson TJ, Walters EH. Anti-IgE for chronic asthma in adults and children. Cochrane Database Syst Rev 2006; (2): CD003559. 28 Heaney LG, Robinson DS. Severe asthma treatment: need for characterising patients. Lancet 2005; 365: 974–76. 29 Cox G, Thomson NC, Rubin AS, et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med 2007; 356: 1327–37.
Further reading British Thoracic Society and Scottish Intercollegiate Guidelines Network. British guideline on the Management of Asthma: a national clinical guideline. Revised edition July 2007. Available at: http://www.brit-thoracic.org.uk/c2/uploads/asthma_fullguideline2007.pdf (accessed 28 November 2007). Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. GINA, 2006. Available at: http://www. ginasthma.org Johnston SL, ed. Asthma. An atlas of investigation and management. Oxford: Clinical Publishing, 2007.
Practice points • Asthma diagnosis is made on the basis of history and a demonstration of variable airflow obstruction • Bronchial provocation testing should be performed if there is diagnostic uncertainty in patients with normal spirometry • In patients with fixed airflow obstruction, it may not be possible to make a clear distinction between asthma and other related conditions. Assessment should focus more on defining best achievable lung function and symptom control • Treatment goals are targeted at controlling symptoms, preventing exacerbations and preserving normal lung function • Asthma pharmacotherapy is broadly categorized into bronchodilator and anti-inflammatory agents • 5–10% of patients have treatment-refractory asthma. Alternative or additional diagnoses should be sought in these individuals. Newer therapies and different management strategies are being developed for this small but significant subgroup
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Diagnosis and management of adult asthma
Global Initiative for Asthma (GINA) definition Asthma is: A chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. • The chronic inflammation is associated with airway hyperresponsiveness • This leads to recurrent episodes of wheezing, breathlessness, chest tightness and coughing, particularly at night or in the early morning • These episodes are usually associated with widespread but variable airflow obstruction within the lung that is often reversible either spontaneously or with treatment
Pranab Haldar Ian D Pavord
Abstract Asthma is a disorder of the airways that is characterized by typical symptoms arising from a complex interplay between chronic inflammation and disordered airway function. Worldwide disease prevalence continues to rise steadily and the condition contributes to significant morbidity and preventable mortality. The goals of treatment in asthma are to achieve control of symptoms and to prevent exacerbations. Important non-pharmacological measures include patient education, avoidance of triggers and smoking cessation. Pharmacological management involves the stepwise titration of β-agonist bronchodilators and inhaled corticosteroids according to symptoms. Although satisfactory control of asthma is achieved in primary care for a large proportion of patients, between 5 and 10% with so-called ‘refractory asthma’ remain poorly controlled and contribute disproportionately to asthma-related morbidity and mortality. The reasons for this are complex and multifactorial, and many patients with refractory asthma require referral to specialist centres.
Keywords
asthma; eosinophilic airway corticosteroids; methacholine challenge
inflammation;
Table 1
with the variable airflow obstruction that forms the basis for asthma symptoms and a positive correlation exists between airway hyperresponsiveness and asthma severity. Chronic airway inflammation: this is most often eosinophilic and caused by abnormal Th2 immunoreactivity to various nonpathogenic stimuli (allergens). Chronic inflammation leads to structural changes in airway morphology (referred to as airway remodelling) that may be associated with accelerated lung function decline and development of fixed airflow obstruction in some patients.
inhaled
Diagnosis One of the problems facing clinicians and epidemiologists is the absence of a gold standard for defining or diagnosing asthma. Characteristic clinical features (Table 2) coupled with objective demonstration of variable airflow obstruction and/or airway hyperresponsiveness will usually provide sufficient evidence to make the diagnosis.
The present Global Initiative for Asthma (GINA) definition of asthma (Table 1) is a lengthy description of pathological, physiological and clinical features that encompass the major disease characteristics. Two of the fundamental features are airway hyperresponsiveness and chronic airway inflammation. Airway hyperresponsiveness is considered to be the cardinal pathophysiological abnormality in asthma. It can be objectively demonstrated as a 20% fall in the forced expiratory volume in 1 second (FEV1) with inhalation of histamine or methacholine at a concentration of <8 mg/ml. This represents an abnormal effector response of airway smooth muscle, characterized by heightened pharmacological sensitivity and reactivity to the bronchoconstrictor stimulus.1 The reason for this is unknown but it appears to be associated with mast cell infiltration of the bronchial smooth muscle layer implying a potentially important interaction between the two cell types.2 Airway hyperresponsiveness is associated
History Asthma symptoms are typically variable and representative of the underlying variability in airflow obstruction. This is a product of heightened diurnal variation in physiological bronchomotor tone (increased at night) and airway hyperresponsiveness to a multitude of possible trigger factors. The pattern of daytime symptoms and seasonal variations can help identify common triggers. In patients with adult-onset symptoms, the possibility of occupational asthma or an alternative diagnosis should be carefully explored. In the former, symptoms are typically worse at work but improve when off work for a period of time. An assessment of disease severity can be made from the frequency of daily symptoms, exercise limitation, nocturnal wakening and exacerbation frequency.
Pranab Haldar MA MRCP is Specialist Registrar Respiratory Medicine at the Institute for Lung Health, Glenfield Hospital, Leicester, UK. Competing interests: none declared.
Clinical examination Clinical examination is frequently normal in individuals with well-controlled symptoms. Patients with persistent symptoms may display features of obstructive airways disease, notably chest hyperexpansion and diffuse expiratory wheeze that are
Ian D Pavord DM FRCP is Consultant Physician and Honorary Professor of Medicine at the Institute for Lung Health, Glenfield Hospital, Leicester, UK. Competing interests: none declared.
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Clinical assessment for diagnosing asthma Features favouring a diagnosis of asthma History Episodic and reversible symptoms of cough, breathlessness, wheeze and chest tightness. Symptoms frequently exhibit diurnal variation, being worse at night and in the early hours of the morning
Typical triggers precipitating symptoms: • cold air • exercise • aeroallergens (house dust mite, pet allergens, pollens) • non-specific irritants (cigarette smoke, perfumes) • occupational agents Relief with a bronchodilator (if tried) History of allergy, hayfever, eczema or nasal disease Onset of symptoms in childhood or adolescence History of asthma in a first-degree relative Examination Variable wheeze heard with auscultation
Features favouring an alternative diagnosis
Atypical pattern of symptoms: • cough in the absence of wheeze or chest tightness • voice disturbance • symptoms in the absence of evidence for airflow obstruction, either clinically or with spirometry or peak flow measurement Chronic, persistent symptoms without periods of significant improvement History of recurrent chest infections requiring antibiotic therapy History of cardiac disease Significant smoking history (>20 pack years).
Evidence of marked thoracic hyperinflation Evidence of clinical features associated with an alternative diagnosis (Table 4)
Table 2
indistinguishable from COPD. Physical examination is helpful for identifying features of an alternative diagnosis.
pre-test probability for the diagnosis, response to therapy and the clinical suspicion of an alternative diagnosis (Figure 1). The list of differential diagnoses will differ between groups with and without airflow obstruction (Table 4), with diagnostic and therapeutic implications. Patients with normal spirometry – in this group, the primary differential diagnoses are non-bronchodilator, non-corticosteroid responsive conditions. For patients with asthma bronchodilator response tests are frequently negative (poorly sensitive). Where diagnostic uncertainty exists, measuring airway hyperresponsiveness is the technique of choice as it is a very sensitive test, so its absence should prompt consideration of an alternative diagnosis. Patients with obstructive spirometry – in this group, all the tests of variable airflow obstruction discussed are less specific for a diagnosis of asthma. The measurement of airway hyperresponsiveness in this setting is therefore less helpful. However, dilator response tests may aid diagnosis as larger changes in FEV1 (i.e. >400 ml) are more suggestive of asthma. In many cases it may not be possible to assign a precise diagnostic label; however, bronchodilator and steroid reversibility studies are helpful for guiding the intensity of therapy with these agents.
Measuring airflow obstruction The demonstration of obstructive spirometry in patients with a history strongly suggestive of asthma is sufficient to commence therapy. Spirometry is the preferred method for demonstrating airflow obstruction as it is less effort-dependent than peak expiratory flow (PEF). Airflow obstruction is defined as an FEV1/ forced vital capacity (FVC) ratio of less than 0.7. Measuring variability in airflow obstruction When there is diagnostic uncertainty, the measurement of variability in airflow obstruction will provide useful additional information. A number of different methods exist to measure variability (Table 3). Diurnal variation – calculated from serial PEF measurements. Dilator response tests – measured as the change (improvement) in FEV1 or PEF from baseline with either a short-acting bronchodilator (bronchodilator responsiveness) or following a therapeutic trial of corticosteroid (steroid responsiveness). Constrictor response tests – these examine aspects of hyperresponsiveness, measuring the fall in FEV1 to bronchoconstrictor stimuli, including pharmacological agents (methacholine or histamine challenge tests), exercise (suitable for suspected exerciseinduced asthma) and allergen challenge.
Role of peak expiratory flow Variability in PEF may be informative in the following settings: • patients with infrequent symptoms – a documented fall in PEF at the time of symptoms suggests asthma • suspected occupational asthma – serial peak flow recordings at least 4 times per day that show a significant difference between measurements at and away from work are highly predictive for the diagnosis.3
Diagnostic pathway Given the broad range of tests available, the diagnostic pathway followed will be determined by clinical factors formulating the
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Overview of tests to measure variable airflow obstruction Test
Measurement
Diagnostic range
Diagnostic value
Comments
PEF variabilty
Amplitude percent best = (PEFmax−PEFmin)/PEFmax × 100
>20%
Moderate specificity but poor sensitivity. Useful in the assessment of occupational asthma (see text)
Serial measurements at least twice daily (morning and evening) for 2 or more weeks, best of 3 blows recorded each time
Bronchodilator responsiveness
% change in FEV1 from baseline after inhalation of 400 μg salbutamol
>15% (and >200 ml)
Reversibility testing with bronchodilators or steroids is appropriate in patients with obstructive spirometry at baseline
Although figures for % change are quoted, absolute improvements in FEV1 of >400 ml are more specific for a diagnosis of asthma
Steroid responsiveness
% change in FEV1 after a therapeutic trial of corticosteroids (400 μg of inhaled beclomethasone for 6–8 weeks or 30–40 mg prednisolone for 2 weeks)
>15% (and >200 ml)
Though not specific for asthma, steroid responsiveness testing is helpful to identify patients who will benefit from regular corticosteroid therapy
Steroid responsiveness may be seen in the absence of significant bronchodilator responsiveness in patients with obstructive spirometry and is associated with high levels of eosinophilic airway inflammation
Methacholine or histamine challenge test
The concentration of bronchoconstrictor agent required to induce a 20% drop in FEV1 from baseline
<8 mg/ml
The most sensitive and specific test in patients with normal spirometry
Limited availability of test in a hospital setting. Reserved for patients in whom there is diagnostic uncertainty
PEF, peak expiratory flow; FEV1, forced expiratory volume in one second.
Table 3
Exacerbations are defined as periods of poor asthma control manifest by an increase in symptoms and deterioration in lung function that are not adequately managed by the individual’s usual therapeutic regimen. They are frequently precipitated by allergen exposure or viral infections.4 Severe exacerbations lead to hospitalization and are the major cause of asthma mortality. Recent evidence suggests that the extent of underlying eosinophilic airway inflammation is associated with an increased risk of a subsequent exacerbation5 and controlling this inflammation with corticosteroid therapy significantly reduces this risk.6 Lung function decline: chronic asthma is associated with accelerated decline in lung function7 that is considered to be a function of persistent airway inflammation. Clinically important decreases in lung function may occur early in the disease, presenting a challenge for its prevention. The rate of decline in adults is more marked in those with severe disease or frequent exacerbations, and smokers.8 Although interventions preventing decline are poorly understood, it is likely that smoking cessation, early removal from occupational sensitizers and, possibly, optimal corticosteroid therapy, are effective.
Other investigations Further investigations are helpful if an alternative diagnosis or an additional diagnosis that may aggravate asthma symptoms, is suspected (Table 4).
Management of stable asthma Aims There are three major consequences of clinical importance in asthma, and management goals are directed at addressing each of these: • control of asthma symptoms • prevention of exacerbations • preservation of normal lung function. Both pharmacological and non-pharmacological measures play an important role in achieving these aims. Asthma symptoms are a cause of both physical and psychological morbidity that impact upon quality of life. Several well-validated questionnaires exist to assess the control of asthma symptoms. Of these, the Royal College of Physicians (RCP) three questions are favoured for being short and quickly implemented: • “Have you had difficulty sleeping because of your asthma symptoms (including cough)?” • “Have you had your usual asthma symptoms during the day (cough, wheeze, chest tightness or breathlessness)?” • “Has your asthma interfered with your usual activities (e.g. housework, work, school, etc)?” A positive response to any question indicates persistent symptoms.
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Pharmacotherapy in asthma Inhaled pharmacological therapies are central to asthma management. The range of available drugs may be categorized mechanistically into bronchodilators and anti-inflammatory agents. Bronchodilators Despite their diverse pharmacological properties, this group of drugs act by a common final pathway of increased intracellular 203
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Diagnostic pathway in asthma Clinical assessment and spirometry
High clinical probability of asthma
Diagnosis uncertain
Diagnosis unlikely
Results of spirometry Trial of therapy* FEV1/FVC <0.7 Positive
Negative Bronchodilater reversibility testing
Positive
Normal
Negative Trial of therapy*
Positive
Negative Explore respective differential diagnosis based on spirometry (Table 4)
Review diagnostic probability
Possible asthma
Asthma unlikely
Bronchial challenge testing
Negative
Treat as asthma
Positive
Asthma likely, consider reasons for poor therapeutic response (Table 7)
*Steroid response trial
Figure 1
cyclic AMP in smooth muscle cells that inhibits contractility, leading to improvements in lung function and airway hyperresponsiveness. The primary role of bronchodilators is the relief (short acting) and prevention (long acting) of symptoms. Additionally, sustained improvements in lung function may be achieved with the regular use of long-acting bronchodilators.9
effects of corticosteroids are mediated by the direct repression of transcription factors, such as nuclear factor ĸB. The poor systemic bioavailability of inhaled corticosteroids minimizes systemic side effects, though chronic treatment with higher doses of potent steroid may be associated with mild adrenal suppression10 and stunted growth in children. Corticosteroids are efficacious suppressants of eosinophilic inflammation which is associated with clinical improvement in symptoms and exacerbation frequency. The latter is responsible for lowering asthma mortality risk.11 ICS are less effective for managing severe asthma and may not be useful to treat severe asthma exacerbations, perhaps because of more intense and distal localication of
Anti-inflammatory therapies Corticosteroids – inhaled corticosteroids (ICS) are the mainstay of asthma pharmacotherapy. They act topically in the largeand medium-sized airways, binding to glucocorticoid receptors that are expressed ubiquitously by cells. The anti-inflammatory
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Normal spirometry Dysfunctional breathing* Vocal cord dysfunction*
Gastroesophageal reflux disease* Pulmonary vascular disease Cough syndromes Rhinitis
Restrictive spirometry Cardiac failure† Pulmonary fibrosis
With airflow obstruction
COPD*
Step down if asthma controlled for 3 months
Without airflow obstruction
Bronchiectasis*† (including allergic bronchopulmonary aspergillosis) Churg–Strauss syndrome* Inhaled foreign body† Obliterative bronchiolitis Large airway stenosis Sarcoidosis†
Oral prednisolone (use lowest dose providing adequate control) Maintain high-dose inhaled steroid at 2000 mcg/day Consider other treatments to minimize the use of steroid tablets Refer patient for specialist care Consider trials of: Increase inhaled steroid up to 2000 mcg/day Addition of a fourth drug, e.g. leukotriene modifier, theophyline, β2-agonist tablet Add inhaled long-acting 2-agonist (LABA) Benefit from LABA but control still inadequate – continue LABA and increase inhaled steroid to 800 mcg/day
Step up if asthma uncontrolled consistently
Stepwise algorithm for the titration of asthma pharmacotherapy
Differential diagnosis in asthma
Add inhaled steroid 200–800 mcg/day 400 mcg is appropriate starting dose for many patients Inhaled short-acting
*These conditions may coexist with asthma and aggravate clinical symptoms. †These conditions may be associated with normal spirometry.
2-agonist
as required
Source: Scottish Intercollegiate Guidelines Network and British Thoracic Society. British guideline on the management of asthma. July 2007.
Table 4 Figure 2
airway inflammation. Oral therapy is felt to be more effective in these settings.12 Anti-leukotrienes – this class of drugs act by inhibiting different levels of the lipoxygenase pathway, which is involved in the formation of leukotrienes from arachidonic acid. Leukotrienes are important pro-inflammatory mediators in asthma that also promote bronchoconstriction. These mediators are significantly elevated in patients who have asthma with aspirin sensitivity and/or nasal polyps. In this disease subgroup, a constitutive deficiency in prostaglandin (PG) E2, an important regulator of leukotriene production, exists13 and anti-leukotrienes are thought to be particularly efficacious.14 These drugs have also shown efficacy for the management of exercise-induced asthma and are often considered for children due to a paucity of significant side effects.15
Combination inhalers of long-acting β2-agonists and ICS have been developed (Figure 2) and are commonly prescribed. They have the advantage of patient convenience, but restrict independent dose alterations of the component drugs. Identifying and treating common aggravators of symptoms There are a number of factors that may aggravate the expression of clinical symptoms in patients with asthma (Table 4). Of these, gastroesophageal reflux disease and rhinitis are amenable to pharmacotherapy. In both circumstances, the patient may report persistent cough as the presenting feature of their suboptimal asthma control. The additional diagnosis may be suspected from a careful history, although a trial of therapy is often considered in the absence of strong corroborative evidence. Although proton pump inhibitors and nasal steroids may be beneficial in individual cases, their efficacy is not proven in clinical trials.18,19
Stepwise algorithm for asthma treatment Guidelines recommend the titration of therapy for asthma in a stepwise manner, with the primary aim of satisfactorily controlling symptoms at the lowest dose of corticosteroid (Figure 2). Changes in therapy should be reviewed every three months until stability is achieved. This algorithm assumes clinical control is concomitantly associated with control of underlying airway inflammation and therefore fulfilment of all three targets of care. It is notable that step 3 of the British Thoracic Society pathway recommends the addition of a long-acting β2-agonist to low-dose corticosteroid therapy over an increase in corticosteroid dose. There is molecular evidence for a synergistic effect between the two drug classes.16 In clinical practice, the strategy achieves an improvement in symptoms and lung function and a fall in exacerbation frequency that is comparable with a dose escalation in corticosteroid alone.17
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Monitoring asthma control and guided self-management plans Self-management plans are individualized written protocols instructing patients with recommended courses of action on the basis of their asthma control that is graded and risk stratified according to peak flow (expressed as % best or % predicted) and/or symptoms (Table 5). They are attractive for being patientcentred. Both symptom-guided and peak-flow-guided plans improve asthma morbidity and reduce the frequency of hospitalizations and unscheduled doctor visits.20 Although there is little evidence that one strategy is superior, a peak-flow-based plan may be more appropriate in patients with impaired perception of airflow obstruction.21 205
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Principles of a self-management plan Monitoring asthma control Symptoms More frequent symptoms or new nocturnal symptoms requiring reliever use Effects of reliever lasting less than two hours No improvement with reliever or failing to improve with oral steroids after two days
Peak expiratory flow (% best or predicted) 60–75%
50–60% <50%
Risk stratification
Advice and recommended action
I: mild–moderate exacerbation
Increase dose of inhaled corticosteroid and continue until symptoms have settled for at least 1 week, use reliever as needed (reliever should last 3–4 hours) Contact GP and commence oral steroids
II: moderate–severe exacerbation III: acute severe exacerbation
Call for ambulance urgently
Table 5
Referral to a specialist Approximately 20% of patients with asthma are referred to a respiratory specialist in the UK. Recommendations for referral broadly fall into 3 groups: • patients with suspected occupational asthma • patients with treatment-refractory asthma, defined as those failing to achieve control despite high-dose therapy (BTS step 4 or 5). Although constituting 5–10% of the asthma population, this group account for over 60% of healthcare resource utilization for asthma in the UK. The reasons for a poor therapeutic response are multifactorial (Table 6) • patients at higher risk of asthma-related death (Table 7).22 Relative risk is additive and therefore patients with several minor risk factors, as well as patients with a single major risk factor, require referral.
Non pharmacological aspects of asthma care Patient education Appropriate patient education is essential for the provision of patient-centred care. There are several aspects to this: • identifying and avoiding asthma triggers, most importantly smoking cessation • understanding the role of different prescribed therapies, i.e. distinguishing between therapy for immediate relief from symptoms (‘relievers’) and therapy to prevent or reduce the frequency of symptoms (‘preventers’). This can help compliance with therapy, which is a considerable problem in asthma care • encouraging compliance with medication • ensuring correct inhaler technique • recording and monitoring peak flow • following a self-management plan.
Aetiology of refractory asthma Patient factors
Disease factors
Poor inhaler technique and incorrect use of inhalers Poor compliance with therapy (particularly younger patients and those with psychological disorders) Persistent exposure to sensitized allergen Occupation Pets Smoking (associated with increased symptoms, accelerated decline in lung function and impaired steroid responsiveness) Obesity (associated with increased symptoms and impaired steroid responsiveness) Coexistent psychological morbidity (both anxiety and depression can heighten perception of breathlessness leading to increased symptoms)
Coexistent aggravating disorders Dysfunctional breathing disorders Rhinosinusitis Gastro-oesophageal reflux disease Cardiac failure ABPA (associated with more intense eosinophilic airway inflammation and bronchiectasis) Churg–Strauss syndrome
True steroid-resistant asthma (this subgroup constitutes a minority of patients with refractory asthma, high doses of oral or parenteral steroid usually overcome the impaired response to conventional therapy) Absence of demonstrable eosinophilic airway inflammation (noneosinophilic asthma: patients with this condition have corticosteroid resistance and escalation of steroids is unlikely to be helpful. Best management uncertain)
Table 6
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• the development of monoclonal antibody therapies as targeted anti-inflammatory agents • novel techniques for treating airway dysfunction.
Risk factors for asthma mortality Major risk factors
Minor risk factors
Previous mechanical ventilation for asthma Previous admission to intensive care Recent hospital admission for asthma
Targeted anti-inflammatory therapy Monitoring airway inflammation – recent studies suggest eosinophilic airway inflammation is predictive of future exacerbation risk in asthma. Titrating corticosteroid therapy to suppress eosinophilic inflammation leads to a significant reduction in exacerbation frequency when compared with a clinical (symptom-based) algorithm.6 This suggests symptoms are not reliably informative of underlying eosinophilic inflammation and may not predict exacerbation risk. Measuring eosinophilic airway inflammation may provide useful additional clinical information for stratifying exacerbation risk to guide therapy in patients with refractory asthma. Reliable non-invasive techniques for clinical use are presently under development.
Asthma requiring oral steroid or theophylline for control High β2-agonist consumption Factors associated with poor compliance: lower socioeconomic class, coexistent psychopathology, history of drug abuse or alcohol dependence, adolescence
Table 7
Single inhaler therapy – Symbicort (budesonide/formoterol: AstraZeneca) is licensed for use as a single combination inhaler for relief of symptoms and maintenance of asthma control (SMART: symbicort maintenance and reliever therapy). This dual role is made possible as formoterol is a long-acting β2-agonist with a rapid onset of action, comparable to salbutamol. Thus, the frequency of inhaler use will be governed by the severity and frequency of symptoms, ensuring higher doses of corticosteroid during periods of poor control. This is appropriate if deteriorating symptoms are associated with worsening underlying airway inflammation. Studies have shown improvements in lung function, reduction in exacerbation frequency and better symptom control with this approach.26
Specialist asthma nurses are central providers of information and education for patients. Regular follow-up with an asthma nurse reinforces key messages and leads to superior asthma control.23 Smoking cessation and allergen avoidance Approximately 25% of patients with asthma smoke and this is associated with increased symptoms and accelerated lung function decline. Smoking cessation studies have shown a significant improvement in the control of symptoms and lung function within weeks of stopping.24 Allergen sensitization and exposure is common and often contributes to increased asthma symptoms. Simple measures, such as limiting contact with household pets, notably cats, should be advised. There is no evidence that more intensive and often expensive measures to lower the burden of ubiquitous allergens, e.g. house dust mite, are beneficial. Regular antihistamines may be helpful when there is a clear association between allergen exposure and deteriorating asthma control, e.g. loss of control with concomitant hayfever.
Monoclonal antibody therapies: a growing number of monoclonal antibodies are being developed to target key pro-inflammatory mediators of the Th2 pathway that are considered important for perpetuating inflammation in asthma. Of these, omalizumab (an IgE receptor antagonist) has received a licence for use in patients with uncontrolled allergic asthma.27 Trials exploring blocking antibodies to interleukins 4, 5 and 13 are also under way. Given their cost and specificity, it is likely that these agents will be restricted to subgroups within the refractory asthma population that display disease characteristics predicting a therapeutic response.28
Breathing retraining techniques Disordered breathing patterns such as hyperventilation frequently coexist with asthma and may contribute significantly to the clinical expression of asthma-like symptoms. The diagnosis should be suspected in patients with prominent symptoms that do not follow a predictable or episodic pattern and are out of proportion to their lung function. Physiotherapy-based breathing retraining programmes can be effective and may avoid the inappropriate escalation of pharmacotherapy.25
Bronchial thermoplasty offers a non-pharmacological approach to asthma treatment. The technique is targeted at the airway smooth muscle which is considered central to airway dysfunction in asthma. Thermal energy is applied bronchoscopically to the bronchial wall using a wired basket. This leads to disruption of smooth muscle bundles that disrupts their function. Preliminary studies report improvement in symptoms.29 Double-blind randomized clinical trials incorporating a sham bronchoscopy arm are under way to evaluate this further. ◆
Recent developments in asthma management The failure to optimize asthma control in some patients highlights deficiencies in current therapeutic modalities and strategies. There are three key areas of ongoing research that are likely to influence future asthma care, particularly in subgroups with refractory disease: • targeted anti-inflammatory therapy and non-invasive measurement of eosinophilic airway inflammation
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References 1 Lotvall J, Inman M, O’Byrne P. Measurement of airway hyperresponsiveness: new considerations. Thorax 1998; 53: 419–24.
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2 Brightling CE, Bradding P, Symon FA, Holgate ST, Wardlaw AJ, Pavord ID. Mast-cell infiltration of airway smooth muscle in asthma. N Engl J Med 2002; 346: 1699–705. 3 Newman Taylor AJ, Cullinan P, Burge PS, Nicholson P, Boyle C. BOHRF guidelines for occupational asthma. Thorax 2005; 60: 364–66. 4 Murray CS, Poletti G, Kebadze T, et al. Study of modifiable risk factors for asthma exacerbations: virus infection and allergen exposure increase the risk of asthma hospital admissions in children. Thorax 2006; 61: 376–82. 5 Deykin A, Lazarus SC, Fahy JV, et al. Sputum eosinophil counts predict asthma control after discontinuation of inhaled corticosteroids. J Allergy Clin Immunol 2005; 115: 720–27. 6 Green RH, Brightling CE, McKenna S, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 2002; 360: 1715–21. 7 Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year followup study of ventilatory function in adults with asthma. N Engl J Med 1998; 339: 1194–200. 8 Ulrik CS. Outcome of asthma: longitudinal changes in lung function. Eur Respir J 1999; 13: 904–18. 9 Johnson M. Pharmacology of long-acting beta-agonists. Ann Allergy Asthma Immunol 1995; 75: 177–79. 10 Sim D, Griffiths A, Armstrong D, Clarke C, Rodda C, Freezer N. Adrenal suppression from high-dose inhaled fluticasone propionate in children with asthma. Eur Respir J 2003; 21: 633–36. 11 Barnes PJ. Mechanisms of action of glucocorticoids in asthma. Am J Respir Crit Care Med 1996; 154(suppl 2): S21–S26. 12 Berry M, Hargadon B, Morgan A, et al. Alveolar nitric oxide in adults with asthma: evidence of distal lung inflammation in refractory asthma. Eur Respir J 2005; 25: 986–91. 13 Szczeklik A, Stevenson DD. Aspirin-induced asthma: advances in pathogenesis, diagnosis, and management. J Allergy Clin Immunol 2003; 111: 913–21. 14 Dahlen SE, Malmstrom K, Nizankowska E, et al. Improvement of aspirin-intolerant asthma by montelukast, a leukotriene antagonist: a randomized, double-blind, placebo-controlled trial. Am J Respir Crit Care Med 2002; 165: 9–14. 15 Leff JA, Busse WW, Pearlman D, et al. Montelukast, a leukotrienereceptor antagonist, for the treatment of mild asthma and exerciseinduced bronchoconstriction. N Engl J Med 1998; 339: 147–52. 16 Barnes PJ. Scientific rationale for inhaled combination therapy with long-acting {beta}2-agonists and corticosteroids. Eur Respir J 2002; 19: 182–91. 17 Pauwels RA, Lofdahl CG, Postma DS, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med 1997; 337: 1405–11. 18 Nathan RA, Yancey SW, Waitkus-Edwards K, et al. Fluticasone propionate nasal spray is superior to montelukast for allergic rhinitis while neither affects overall asthma control. Chest 2005; 128: 1910–20. 19 Littner MR, Leung FW, Ballard ED, Huang B, Samra NK. Effects of 24 weeks of lansoprazole therapy on asthma symptoms, exacerbations, quality of life, and pulmonary function in adult asthmatic patients with acid reflux symptoms. Chest 2005; 128: 1128–35. 20 Powell H, Gibson PG. Options for self-management education for adults with asthma. Cochrane Database Syst Rev 2003; (1): CD004107. 21 Kikuchi Y, Okabe S, Tamura G, et al. Chemosensitivity and perception of dyspnea in patients with a history of near-fatal asthma. N Engl J Med 1994; 330: 1329–34.
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22 Alvarez GG, Schulzer M, Jung D, Fitzgerald JM. A systematic review of risk factors associated with near-fatal and fatal asthma. Can Respir J 2005; 12: 265–70. 23 Griffiths C, Foster G, Barnes N, et al. Specialist nurse intervention to reduce unscheduled asthma care in a deprived multiethnic area: the east London randomised controlled trial for high risk asthma (ELECTRA). BMJ 2004; 328: 144. 24 Chaudhuri R, Livingston E, McMahon AD, et al. Effects of smoking cessation on lung function and airway inflammation in smokers with asthma. Am J Respir Crit Care Med 2006; 174: 127–33. 25 Cooper S, Oborne J, Newton S, et al. Effect of two breathing exercises (Buteyko and pranayama) in asthma: a randomised controlled trial. Thorax 2003; 58: 674–79. 26 Rabe KF, Pizzichini E, Stallberg B, et al. Budesonide/formoterol in a single inhaler for maintenance and relief in mild-to-moderate asthma: a randomized, double-blind trial. Chest 2006; 129: 246–56. 27 Walker S, Monteil M, Phelan K, Lasserson TJ, Walters EH. Anti-IgE for chronic asthma in adults and children. Cochrane Database Syst Rev 2006; (2): CD003559. 28 Heaney LG, Robinson DS. Severe asthma treatment: need for characterising patients. Lancet 2005; 365: 974–76. 29 Cox G, Thomson NC, Rubin AS, et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med 2007; 356: 1327–37.
Further reading British Thoracic Society and Scottish Intercollegiate Guidelines Network. British guideline on the Management of Asthma: a national clinical guideline. Revised edition July 2007. Available at: http://www.brit-thoracic.org.uk/c2/uploads/asthma_fullguideline2007.pdf (accessed 28 November 2007). Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. GINA, 2006. Available at: http://www. ginasthma.org Johnston SL, ed. Asthma. An atlas of investigation and management. Oxford: Clinical Publishing, 2007.
Practice points • Asthma diagnosis is made on the basis of history and a demonstration of variable airflow obstruction • Bronchial provocation testing should be performed if there is diagnostic uncertainty in patients with normal spirometry • In patients with fixed airflow obstruction, it may not be possible to make a clear distinction between asthma and other related conditions. Assessment should focus more on defining best achievable lung function and symptom control • Treatment goals are targeted at controlling symptoms, preventing exacerbations and preserving normal lung function • Asthma pharmacotherapy is broadly categorized into bronchodilator and anti-inflammatory agents • 5–10% of patients have treatment-refractory asthma. Alternative or additional diagnoses should be sought in these individuals. Newer therapies and different management strategies are being developed for this small but significant subgroup
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