Clinical review

Chronic asthma

Christopher Cates, general practitioner. 

Manor View Practice, Bushey, Hertfordshire WD2 2NN

chriscates{at}emailmsn.com

	Background

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Definition Asthma is characterised by dyspnoea, cough, chest tightness, wheezing, variable airflow obstruction, and airway hyper-responsiveness. The diurnal variation of peak expiratory flow rate is increased in people with asthma. Chronic asthma is defined here as asthma requiring maintenance treatment. Asthma is classified differently in the United States and United Kingdom (box): where necessary, the text specifies the system of classification used. ^{1 2} Acute asthma is defined here as an exacerbation of underlying asthma requiring urgent or emergency treatment, and will be dealt with in a separate "Extract from Clinical Evidence."³

Incidence/prevalence Reported prevalence of asthma is increasing worldwide. About 10% of people have had an attack of asthma. ^{4 5}

Aetiology/risk factors Most people with asthma are atopic; exposure to certain stimuli initiates inflammation and structural changes in airways, causing airway hyper-responsiveness and variable airflow obstruction, which in turn cause most asthma symptoms. Stimuli include environmental allergens, occupational sensitising agents, and respiratory viral infections. ^{6 7}

Prognosis In people with mild asthma, prognosis is good and progression to severe disease is rare. However, as a group, people with asthma lose lung function faster than those without asthma, although less quickly than people without asthma who smoke.⁸ Persistent asthma can improve with treatment. However, for reasons not clearly understood, some people (possibly up to 5%) have severe disease that responds poorly to treatment. These people are most at risk of morbidity and death from asthma.

Aims To minimise or eliminate symptoms; to maximise lung function; to prevent exacerbations; to minimise the need for medication; to minimise adverse effects of treatment; and to provide enough information and support to facilitate self management of asthma.

Outcomes Symptoms (daytime and nocturnal); lung function (peak expiratory flow rate (PEFR) and forced expiratory volume in one second (FEV₁)); need for rescue medication such as inhaled ₂ agonists; variability of flow rates; activities of daily living; adverse effects of treatment.

	Methods

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Clinical Evidence update search and appraisal September 2000. Additional sources identified by experts.

Summary Randomised controlled trials (RCTs) have found that regular use of short acting inhaled ₂ agonists in people with mild intermittent asthma provides no additional clinical benefits, compared with use as needed, and may worsen asthma control.

Benefits
We found no systematic review. We found several RCTs comparing regular against as needed inhaled salbutamol. The most recent RCT (983 people with asthma in a general practice setting, 90% using regular inhaled corticosteroids) compared as needed versus regular salbutamol (400 µg four times daily).⁹ At one year, it found no significant difference between regular and as needed salbutamol in the rate of exacerbations (relative risk (RR) 0.96, 95% confidence interval 0.8 to 1.15) or in morning PEFR. Evening PEFR was significantly higher with regular salbutamol (difference 10.3 l/minute, 6.7 to 14.0), and as a consequence diurnal variation was also higher (difference 3.3%, 2.5% to 4.1%).⁹ Another RCT (255 people with mild intermittent asthma taking inhaled  agonists only) compared regular and as needed salbutamol.¹⁰ At 16 weeks, the groups did not differ significantly in symptoms, quality of life, airflow obstruction, or frequency of exacerbations. People taking regular salbutamol used more medication than those taking it as needed (total salbutamol 9.3 v 1.6 puffs/day) and experienced significantly greater variability in PEFR and responsiveness to methacholine. An earlier placebo controlled, double blind crossover trial (64 people taking inhaled or oral corticosteroids or inhaled cromoglycate if usually required, or both) found that most of the 57 people who had better control during active treatment periods did better with as needed than regular treatment (40 v 17). In addition, five of the six severe exacerbations occurred in people taking regular rather than as needed fenoterol.¹¹ Exacerbations were not prevented by inhaled corticosteroids.

Harms
Two case-control studies found an association between increased asthma mortality and overuse of inhaled short acting ₂ agonists. ^{12 13} The evidence does not establish causality, as overusing ₂ agonists to treat frequent symptoms may simply indicate severe uncontrolled asthma in high risk individuals. Other RCTs found that regular use of inhaled ₂ agonists was associated with transient rebound deterioration in airway hyper-responsiveness after the drug was stopped¹⁴ and increased allergen induced bronchoconstriction.¹⁵ Tremor was commonly reported, but tolerance developed with more frequent use.¹⁶

Comment
In the most recent RCT, 33% of people randomised did not complete the trial, reducing the power of the RCT to detect a significant difference between regular and as needed salbutamol.⁹

Benefits
Versus placebo: We found no systematic review. We found seven placebo controlled RCTs (1000 adults and adolescents with mild persistent asthma, using US classification; see box) evaluating low doses of inhaled budesonide,^17-20 beclomethasone, ^{21 22} and triamcinolone.^22-24 They all found significant improvement in lung function, symptoms, and short acting bronchodilator use compared with placebo. Versus 2 agonists: We found one systematic review (search date not stated, 5 small RCTs, 141 adults with mild persistent asthma using regular inhaled corticosteroids, 2 drugs to control asthma).²⁵ It found that inhaled corticosteroids significantly improved lung function (overall weighted effect size for PEFR 0.59, 0.32 to 0.84). One RCT not included in the review (103 adults with mild asthma, diagnosed within 12 months, not using oral corticosteroids) found that inhaled budesonide 1200 µg/day compared with inhaled ₂ agonists persistently and significantly improved all outcomes over two years (no confidence intervals available).²⁶

Harms
We found no published evidence that low doses of inhaled corticosteroids (<1000 µg/day of beclomethasone dipropionate or equivalent) cause important systemic effects in adults.²⁷ Although posterior subcapsular cataracts are more common in people taking oral corticosteroids,²⁸ most studies in adults provide no evidence that inhaled corticosteroids increase the risk once the confounding effect of oral corticosteroids is removed.²⁹ However, one recent population based case-control study found that, in older people, inhaled high dose beclomethasone dipropionate was associated with a slightly greater risk of nuclear cataracts (RR 1.5, 1.2 to 1.9) and posterior subcapsular cataracts (RR 1.9, 1.3 to 2.8).³⁰ We found no published reports of an increased risk of osteoporosis or fractures. Inhaled corticosteroids can cause oral candidiasis, dysphonia, and bruising, but these are troublesome in fewer than 5% of people. ^{31 32}

Comment
The results of the systematic review should be interpreted with caution as the few small RCTs included neither consistently measured PEFR at the same time of the day nor reported morning and evening PEFRs.²⁵ The case-control study on cataract formation did not allow for the confounding effect of allergy,³⁰ which is also a risk factor for cataract development.³³

Benefits
Versus placebo: We found no systematic review. We found two RCTs (506 and 217 people with moderate, persistent asthma, which was not controlled with inhaled corticosteroids 250-2000 µg/day beclomethasone or equivalent) ^{34 35} comparing regular, long acting inhaled ₂ agonists and placebo. These trials found that twice daily salmeterol or formoterol improved quality of life scores, PEFR, and FEV₁ more than placebo. Exacerbation rates were not significantly different between the two groups in either trial. Versus increased use of inhaled corticosteroids: We found one systematic review³⁶ and one additional RCT.³⁷ The review (search date 1999, 9 double blind RCTs, 3685 people with symptomatic asthma on their current dose of inhaled steroids, duration 3-6 months) compared adding salmeterol against increased use of inhaled corticosteroids (at least double the usual dose). It found that morning PEFR was significantly higher with salmeterol (3 months: weighted mean difference (WMD) in PEFR 22 l/minute, 15 to 30, P <0.001; 6 months: WMD 28 l/minute, 19 to 36). Salmeterol compared with higher dose corticosteroids significantly increased days without symptoms (WMD at 6 months: 15, 12 to 18) and nights without symptoms (WMD at 6 months: 5, 3 to 7). Salmeterol compared with higher dose corticosteroids also significantly reduced the need for rescue medication. No increase in asthma exacerbations of any severity was found in the salmeterol group.³⁶ The additional RCT (852 people taking low to moderate dose inhaled corticosteroids) found that additional twice daily formoterol plus as needed terbutaline compared with no additional treatment significantly improved symptoms and lung function and reduced exacerbations.³⁷ Exacerbations were reduced further by a fourfold increase in daily dosage of inhaled corticosteroid, and further still by combined, higher dose of budesonide plus formoterol.

Harms
Several studies have found that people taking regular doses of long acting inhaled ₂ agonists develop tolerance to protection against bronchoconstriction^38-40 and may develop a tremor. Short acting inhaled ₂ agonists are associated with deterioration in asthma control and increased risk of death.^11-13 Regular use of long acting inhaled ₂ agonists has not been linked to deterioration in asthma control.

Comment
We found no RCTs or other studies with sufficient power to assess the effect of regular use of long acting inhaled ₂ agonists on death rates.⁴¹

Benefits
Versus placebo: We found no systematic review. We found three RCTs (1300 adults with asthma taking ß₂ agonists alone) which compared the addition of leukotriene antagonists or placebo for 13 weeks.^42-44 The RCTs found consistently that zafirlukast (20 mg twice daily) compared with placebo significantly reduced daytime and night time asthma symptoms and use of ₂ agonists. The largest RCT (762 people) found that zafirlukast compared with placebo significantly reduced daytime symptoms, night time awakenings, and use of ₂ agonists (3.9 v 3.1 puffs per day; P<0.01).⁴² Morning FEV₁ was significantly increased in people taking zafirlukast (morning FEV₁ improved by 7% v 3%, P<0.01).⁴² Versus inhaled corticosteroids: We found one systematic review (search date 1999, 8 RCTs, >2000 adults with asthma),⁴⁵ and one subsequent RCT.⁴⁵ The review compared various leukotriene antagonists with inhaled corticosteroids for 6-12 weeks. Doses of corticosteroids were equivalent to beclomethasone 250 µg to 400 µg daily. The review found no significant difference between leukotriene antagonists and corticosteroids in the number of people with exacerbations who required systemic steroids (4 RCTs, RR 1.3, 0.9 to 1.9). However, corticosteroids compared with leukotriene antagonists significantly improved lung function (FEV₁: 3 RCTs, standardised mean difference (SMD) 0.3, 0.2 to 0.4), morning PEFR (3 RCTs, SMD 0.4, 0.2 to 0.5), quality of life (3 RCTs, WMD 0.3, 0.1 to 0.4), symptoms (3 RCTs, SMD 0.3, 0.2 to 0.4), and night awakenings (2 RCTs, WMD 0.6, 0.3 to 0.9) and reduced the need for rescue ₂ agonists (3 RCTs, SMD 0.3, 0.2 to 0.4).⁴⁵ The subsequent RCT (451 adults with asthma, previously treated with ₂ agonists alone) compared fluticasone 88 mg with zafirlukast 20 mg, both twice daily for 12 weeks.⁴⁶ The RCT found results consistent with the systematic review for exacerbations, lung function, day and night symptoms, and use of rescue ₂ agonists.

Harms
In the RCT comparing zafirlukast and placebo, the incidence of adverse effects (predominantly pharyngitis and headache) was similar in both groups (350/514 (68%) v 160/248 (65%)).⁴² The systematic review found that adverse effects were not significantly different with leukotriene antagonist compared with corticosteroids, but leukotriene antagonists significantly increased the risk of "withdrawals for any cause" (RR 1.4, 1.1 to 1.9), and "withdrawals due to adverse effects" (RR 1.9, 1.1 to 3.3).⁴⁵

Comment
The systematic review found that few RCTs providing results about specific outcomes and included few unpublished trials. The results should therefore be interpreted cautiously.

	Footnotes

   Competing interests: None declared.

This article is part of the "Asthma" topic in issue 5 of Clinical Evidence (www.clinicalevidence.org)

Clinical Evidence is published by BMJ Publishing Group. The fifth issue is available now, and Clinical Evidence will be updated and expanded every six months. Individual subscription rate, issues 5 and 6 £75/$110; institutional rate £160/$240; student rate £55/$80. For more information including how to subscribe, please visit the Clinical Evidence website at www.clinicalevidence.org

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