BMJ BR MED J BMJ : British Medical Journal 0959-8138 1468-5833 British Medical Journal 10617533 Education and Debate Should steroids be the first line treatment for asthma? For and against 1 1 2000 320 7226 47 49 Copyright © 2000, British Medical Journal 2000

Step one of the current British asthma guidelines recommends that inhaled short acting β2 agonists should be used as required. Some clinicians, including George Strube, a general practitioner from Crawley, believe that this step is unnecessary and that steroids should be introduced earlier. Michael Rudolph, a consultant physician from Ealing Hospital, defends the guidelines.

For Strube George general practitioner 33 Goffs Park Road, Crawley, West Sussex RH11 8AX GStrube@aol.com

Evidence for the inflammatory basis of asthma comes from bronchial biopsies, which show inflammation of the mucosa even in patients with mild intermittent asthma.1-1 Mucosal oedema and excess mucus production cause reduction in the lumen and obstruction to airflow. Bronchospasm occurs as the natural “foreign body” response to irritation caused by inflammation, the bronchi become hyperactive and the airflow is further reduced. Persistent inflammation may lead to structural changes in the airways, with reduction in lung function and irreversible airways obstruction.1-2

Steroids and β agonists

Steroids are the most effective anti-inflammatory drugs available. They reduce mucosal oedema and bronchial hyperreactivity thus relieving acute symptoms and preventing structural damage to the lungs. It is therefore best to give them as soon as the diagnosis of asthma has been confirmed.

β Agonists are effective bronchodilators but they have no anti-inflammatory activity and so although they offer temporary clinical improvement the underlying inflammation persists. When their effect wears off there is a return of bronchial hyperreactivity and bronchoconstriction, which may even be increased.1-3 If this is countered with further doses of bronchodilator a pattern of dependence can be established with regular use aggravating the asthma it is intended to control. This may even occur in patients already taking steroids, and the dose required for control may need to be increased. Regular use of bronchodilators should therefore be avoided and should be kept in reserve for breakthrough wheezing.

 Clinical evidence

Trials comparing the effect of inhaled steroids with β agonists showed that patients taking inhaled corticosteroids had better control of their symptoms and required fewer supplemental drugs. Bronchial hyperreactivity, as measured by tolerance to histamine, was reduced and lung function was preserved.1-4–1-6 Bronchial biopsies showed reduction in inflammatory changes.1-7

In asthmatic patients regular use of β agonists was less likely to achieve control than regular use of placebo with on demand bronchodilators.1-8 Restricting the dose of β agonists in patients taking both β agonists and inhaled steroids improved asthma control, and the dose of inhaled steroids could be reduced.1-9 This has also been found in general practice.1-10

This evidence suggests that steroids should be used as early as possible in all asthmatic patients, not only to control symptoms but also to prevent damage to the lungs from the effects of chronic inflammation. The use of β agonist bronchodilators should be kept to a minimum and reserved for emergencies.

 The present treatment of asthma

The present treatment of asthma is based on guidelines from the British Thoracic Society,1-11 which advise starting patients with “mild” asthma on β agonists alone (step 1), with steroids given only if there is poor control and too much bronchodilator is being used (step 2). β Agonists are therefore widely regarded as the treatment for asthma, with steroids as an optional extra. The evidence shows that the reverse is true but it is difficult to convince patients (and some doctors) of this in the face of the current guidelines, which support the use of β agonists as the drug of first choice. Thus many patients who should be taking inhaled corticosteroids are receiving β agonists only.1-12 Even when steroids are given the dose is often insufficient to abolish symptoms due to bronchial hyperreactivity, and most patients are taking more β agonists than is realised.1-13

Confusion over the use of drugs for asthma can lead to poor compliance. The terms “preventer” (inhaled steroids) and “reliever” (bronchodilators) may be misleading so that when symptoms become obtrusive reliance is placed on bronchodilators, and steroids are abandoned causing the vicious circle already described. This is unfortunate as steroids are the only true relievers of underlying inflammation, and reluctance to use an adequate dose early enough allows bronchial hyperreactivity to increase and an attack of acute asthma to develop.

 A new approach to the treatment of asthma

It should be clearly stated that steroids are the proper treatment for asthma and that bronchodilators must be held in reserve for emergencies. All newly diagnosed asthmatics should be given a high dose of inhaled corticosteroids,1-11 continued for 3 months, after which the dose should be gradually reduced to a point where symptoms are controlled and maximum lung function maintained with the minimum dose. Unless there is an emergency β agonists should not be given initially but kept in reserve as rescue drugs.

A satisfactory response over a few days will show the effectiveness of steroids, gain the patient's confidence, and ensure compliance. This also acts as a reversibility test to find the maximum possible peak flow rate (or forced expiratory volume in 1 second and forced vital capacity in elderly patients), which can be used as the target for future control. This procedure allows better lung function to be achieved than when gradual increments in drugs are used, as in stepped care starting with β agonists (figure).

Peak flow rate readings show how initial dose of inhaled or oral corticosteroids rapidly achieves optimum lung function in asthmatic patients. Stepped care is less likely to achieve maximum possible peak flow rate

The difficulty in assessing the severity of symptoms, in order to decide on treatment, is avoided as all patients receive inhaled corticosteroids as soon as the diagnosis of asthma is confirmed.—George Strube

 Laitinen LA Laitinen A Haahtela T Airway mucosal inflammation even in patients with newly diagnosed asthma Am Rev Respir Dis 1993 147 697 704 8442607 Redington AE Howarth PH Airway wall remodelling in asthma Thorax 1997 52 310 312 9196510 Wahedna I Wong CS Wisniewski AFZ Pavord ID Tattersfield AE Asthma control during and after cessation of regular β-agonist treatment Am Rev Respir Dis 1993 148 707 8103655 Haahtela T Järvinen M Kava T Kiviranta K Koskinen S Lehtonen K Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma N Engl J Med 1994 331 700 705 8058076 Agertoft L Pedersen S Effects of long-termtreatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children Respir Med 1994 88 373 381 8036306 Selroos O Pietinahlo A Löfroos AB Riska H Effect of early vs late intervention with inhaled corticosteroids in asthma Chest 1995 108 1228 1234 7587421 Morice A Taylor M A randomised trial of the initiation of asthma treatment Asthma Gen Pract 1999 7 7 9 Sears MR Taylor DR Print CG Lake DC Li QQ Flannery EM Regular inhaled beta-agonist treatment in bronchial asthma Lancet 1990 336 1391 1396 1978871 Sears MR Dose reduction of β-agonists in asthma Lancet 1991 338 1331 1332 1682705 Price DB Inhaler steroid prescribing over seven years in a general practice and its implications Eur Respir J 1995 8(suppl 19) 463S The British guidelines on asthma management: 1995 review and position statement Thorax 1997 52(suppl 1) 1 21S 9039230 O'Byrne P Cuddy L Taylor DW Birch S Morris J Syrotuik J Efficacy and cost benefit of inhaled corticosteroids in patients considered to have mild asthma in primary care practice Can Respir J 1996 3 169 175 Price D Ryan D Pearce L Bride F The AIR study: asthma in real life Asthma J 1999 4 74 78 Against Rudolf Michael consultant physician Department of Respiratory Medicine, Ealing Hospital NHS Trust, Southall, Middlesex UB1 3HW mrudolf@eht.org.uk

Current British asthma guidelines emphasise the importance of gaining control of asthma as soon as possible with a moderately high dose of inhaled corticosteroid and then reducing to the minimal dose needed to maintain control.2-1 In a survey designed to assess the awareness of this recommendation, 82% of general practitioners and 74% of practice nurses reported that they did now start with high doses of inhaled corticosteroids.2-2

Shortly after publication of the guidelines it was suggested that inhaled corticosteroids should be used as first line treatment for all newly diagnosed patients irrespective of disease severity and that “as required” inhaled short acting β2 agonists (step 1) should no longer be recommended as initial therapy for “mild” disease.2-3 Although the British guidelines may not distinguish as clearly as they should between “intermittent” and “mild persistent” asthma (terms used in international asthma guidelines2-4 and both of which may be interpreted as “mild” disease), inhaled corticosteroids are unquestionably recommended for all adults and schoolchildren who need to use a β agonist more than once daily. Should step 1 now be abolished and all patients with newly diagnosed asthma, however mild or intermittent the disease, be immediately commenced on high dose inhaled corticosteroids?

The case for early intervention with inhaled steroids

An argument for early intervention with inhaled steroids is that airway inflammation is present in patients with mild episodic asthma2-5; a degree of irreversible airflow obstruction, due to structural changes (remodelling) in the airway wall, is correlated with the duration of asthma2-6; steroids are the most effective anti-inflammatory drugs; therefore early control of inflammation with steroids in all patients may prevent the development of these irreversible changes and subsequent progression to more severe disease. Although this argument seems plausible, the evidence quoted in its support does not withstand critical examination. None of the clinical trials2-7–2-9 referred to was actually designed to investigate the hypothesis now being proposed, and although inhaled corticosteroids undoubtedly improve lung function, control symptoms, and reduce airway inflammation, there is conflicting evidence about their ability to reverse or prevent structural changes.2-6 Early intervention with inhaled corticosteroids was discussed in a background paper to the British guidelines,2-10 with the conclusion that long term controlled trials are needed before this approach can be justified.

 The case against

Apart from obvious issues such as the expense and non-compliance with treatment, there are several cogent reasons for not prescribing steroids to all patients newly diagnosed with asthma. Although inhaled corticosteroids have several effects on mucosal inflammation2-11 and are currently regarded as the “gold standard” anti-inflammatory drug in asthma the uncomfortable fact remains that they are simply not effective in all patients. In a recent study comparing inhaled beclomethasone with zafirlukast in patients with mild to moderate asthma analysis of individual patient responses showed that 41% of patients on the steroid failed to show an improvement in peak expiratory flow of at least 5%.2-12 It seems illogical to suggest that all patients with mild asthma should be treated with inhaled corticosteroids at a time when newer, alternative treatments are becoming available,2-13 especially when the speed of onset of treatment response with leukotriene antagonists is quicker than with inhaled corticosteroids.2-14

The suggestion that all patients with asthma should immediately be started on high doses of steroids needs careful examination. Although it seems entirely logical to start with a high dose (and subsequently tail down) rather than a low dose (and increase progressively if needed), published evidence does not support this approach; starting inhaled corticosteroids at a higher dose is not superior to a lower dose in the treatment of newly detected asthma.2-15 Furthermore, there is real concern that when patients are commenced on high dose steroids for any reason the dose is not reduced once control is achieved. This has been shown well in a recent study designed to investigate the effect of montelukast in allowing tapering of steroids in patients with clinically stable asthma.2-16 Mean steroid dose was decreased by 37% before randomisation into active treatment and placebo groups and by a further 30% in those subsequently receiving placebo. Thus many patients are receiving much higher doses of steroids than clinically required, and this situation would become much worse if all patients with newly diagnosed mild asthma were routinely started on high dose treatment with inhaled corticosteroids.

The potential disadvantages of aggressive early use of inhaled corticosteroids are even more worrying in children, where there are now real concerns that asthma is overdiagnosed and overtreated.2-17 2-18 There are clearly groups of infants and young children who develop wheezing in association with viral infections yet who subsequently have normal lung function and do not develop asthma.2-19 It would seem inappropriate to treat all children who wheeze with long term inhaled corticosteroids especially in view of the continuing debate about the safety of these drugs in children. The study that is always quoted as showing effects of inhaled corticosteroids on prepubertal growth2-20 is usually criticised because the children recruited into this trial had only very mild asthma and, under current guidelines, would not be considered appropriate for steroid treatment. Yet this is now precisely the sort of “mild” disease in which early intervention with inhaled corticosteroids is being advocated.

Conclusion

The enormous benefits of treatment with inhaled corticosteroids in asthma are not disputed, and the recommended use of short acting inhaled β2 agonists only for “as required” symptom relief is acknowledged in British and international guidelines.2-1 2-4 The hypothesis that even earlier intervention with inhaled corticosteroids will prevent airway remodelling and the progressive decline in lung function is at present unproved, and it would be premature to abolish step 1 of the guidelines. If it is indeed true that “beta-agonists are widely regarded as the treatment for asthma with steroids as an optional extra,” then it is not the guidelines that need altering but the misunderstanding of them.2-21—Michael Rudolf

The British guidelines on asthma management: 1995 review and position statement Thorax 1997 52 Suppl 1 1 21S 9039230 Partridge MR Harrison BDW Rudolf M Bellamy D Silverman M The British asthma guidelines—their production, dissemination and implementation Respir Med 1998 92 1046 1052 9893774 Strube G Should steroids be first choice for asthma? Thorax 1998 53 328 9741382 National Heart, Lung and Blood Institute Guidelines for the diagnosis and management of asthma. Expert panel report 2. 1997 Bethesda, MD National Institutes of Health NIH publication No 97-4051. Laitinen LA Laitinen A Haahtela T Airway mucosal inflammation even in patients with newly diagnosed asthma Am Rev Respir Dis 1993 147 697 704 8442607 Redington AE Howarth PH Airway wall remodelling in asthma Thorax 1997 52 310 312 9196510 Haahtela T Järvinen M Kava T Kiviranta K Koskinen S Lehtonen K Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma N Engl J Med 1994 331 700 705 8058076 Agertoft L Pedersen S Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children Respir Med 1994 88 373 381 8036306 Selroos O Pietinalho A Löfroos AB Riska H Effects of early vs late intervention with inhaled corticosteroids in asthma Chest 1995 108 1228 1234 7587421 Barnes PJ Inhaled glucocorticoids: new developments relevant to updating of the asthma management guidelines Respir Med 1996 90 379 384 8796227 O'Byrne PM Postma DS The many faces of airway inflammation: asthma and chronic obstructive pulmonary disease Am J Respir Crit Care Med 1999 159 41 66S Laitinen LA Naya IP Binks S Harris A Comparative efficacy of zafirlukast and low dose steroids in asthmatics on prn beta2-agonists Eur Respir J 1997 10(suppl 25) 419 20S Drazen JM Israel E O'Byrne PM Treatment of asthma with drugs modifying the leukotriene pathway N Engl J Med 1999 340 197 206 9895400 Lipworth BJ Leukotriene-receptor antagonists Lancet 1999 353 57 62 10023966 Van der Molen T Jong BM Mulder HH Postma DS Starting with a higher dose of inhaled corticosteroids in primary care asthma treatment Am J Respir Crit Care Med 1998 158 121 125 9655717 Löfdahl CG Reiss TF Leff JA Israel E Noonan MJ Finn AF Randomised, placebo controlled trial of effect of a leukotriene receptor antagonist, montelukast, on tapering inhaled corticosteroids in asthmatic patients BMJ 1999 319 87 90 10398629 Williams J Not childhood asthma: avoiding the over-diagnosis that may result from a heightened awareness of asthma Asthma J 1998 3 24 26 Pedersen S Warner JO Price JF Early use of inhaled steroids in children with asthma Clin Exp Allergy 1997 27 995 1006 . (Debate.) 9678829 Martinez FD Wright AL Taussig LM Holberg CJ Halonen M Morgan WJ Asthma and wheezing in the first six years of life N Engl J Med 1995 332 133 138 7800004 Doull IJM Freezer NJ Holgate ST Growth of prepubertal children with mild asthma treated with inhaled beclomethasone dipropionate Am J Respir Crit Care Med 1995 151 1715 1719 7767512 Doerschug KC Peterson MW Dayton CS Kline JN Asthma guidelines: an assessment of physician understanding and practice Am J Respir Crit Care Med 1999 159 1735 1741 10351911