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Prim Care Resp J 2009;18(3):148-158
doi:10.4104/pcrj.2009.00035
The ADMIT series - Issues in Inhalation Therapy. 3) Mild persistent asthma: the case for inhaledcorticosteroid therapy Chris J Corrigan, Mark L Levy, PN Richard Dekhuijzen, Graham K Crompton,
on behalf of the ADMIT Working Group
ISSN 1471-4418 • Volume 18 • Issue 3 • September 2009 REPRINT Primary Care Respiratory Journal (2009); 18(3): 148-158 The ADMIT series - Issues in Inhalation Therapy. 3) Mild persistent asthma: the case for inhaledcorticosteroid therapy *Chris J Corrigana, Mark L Levyb, PN Richard Dekhuijzenc, Graham K Cromptond,
on behalf of the ADMIT Working Groupe
a Department of Asthma, Allergy & Respiratory Science, King's College London School of Medicine, London, UKb Senior Clinical Research Fellow, Allergy & Respiratory Research Group, Division of Community Health Sciences:GP Section, University of c Department of Pulmonary Diseases, Radboud University Nijmegen Medical Centre, The Netherlandsd Western General Hospital, Edinburgh, UKe Members of the Aerosol Drug Management Improvement Team (ADMIT): Peter J Barnes, London, UK; Mariëlle Broeders, Nijmegen, The Netherlands; Chris Corrigan, London, UK; Graham K Crompton, Edinburgh, UK; Lorenzo Corbetta, Firenze, Italy; Richard Dekhuijzen, Nijmegen, The Netherlands; Jean Christophe Dubus, Marseille, France; Thomas Hausen, Essen, Germany; Meinhard Kneussl, Vienna, Austria;Federico Lavorini, Firenze, Italy; Mark L Levy, Edinburgh, UK; Soren Pedersen, Kolding, Denmark; Antonio Ramalho de Almeida, Porto, Portugal; Joaquin Sanchis, Barcelona, Spain; Jose L. Viejo, Hospital General Yagüe de Burgos, Spain; Walter Vincken, Brussels, Belgium;Thomas Voshaar, Moers, Germany Received 28th August 2008; revised version received 6th February 2009; accepted 6th February 2009; online 10th June 2009 Abstract
Mild persistent asthma should be treated with continuous inhaled corticosteroids (ICS), which reduces exacerbations of disease, controlssymptoms and reduces bronchial mucosal inflammation. Most patients can be controlled with low dosage ICS (≤ 500 mcg/daybeclometasone or equivalent) and there is limited benefit from further escalating dosages. There is some evidence of additional benefitof early treatment in terms of better longer term control of symptoms, but not alteration of the natural history of the disease. Withdrawalof ICS therapy results in rapid relapse of symptoms. Although some studies have suggested that intermittent therapy with ICS is notdetrimental to asthma control, in the absence of any studies investigating the long term clinical, functional and pathophysiologicaldifferences between regular and intermittent therapy, the former continues to be recommended in guidelines. In patients well controlledon low/moderate dosages of ICS there is little benefit of adding any other medication and no rationale for commencing combinationtherapy routinely as first line controller therapy. There is no evidence that ICS or any other medication prevents the occurrence of asthma,and scanty evidence that the decline in lung function associated with asthma is arrested to any significant degree by ICS therapy. ICS hasvariable effects on features of airways remodelling but the long term physiological consequences of these effects, if any, are as yetunknown.
2009 General Practice Airways Group. All rights reserved.
C Corrigan et al. Prim Care Resp J 2009; 18(3): 148-158.
doi:10.4104/pcrj.2009.00035
Keywords asthma, management, primary care, inhaled corticosteroids, mild persistent asthma
Contents
Abstract. 148
Introduction. 149
ICS for asthma therapy: effects on lung function, symptoms and mortality. 149
Early intervention with ICS to prevent progression of asthma. 149
Withdrawal of ICS in stable mild/moderate persistent asthma. 150
Daily versus intermittent ICS therapy. 151
* Corresponding author: Professor Chris Corrigan, Department of Asthma, Allergy & Respiratory Science, King's College London School of Medicine, 5th Floor, Tower Wing, Guy's Hospital, London SE1 9RT, UK. Tel: +44 (0)207 188 0599 Fax: +44 (0)207 403 8640 E-mail:chris.corrigan@kcl.ac.uk www.thepcrj.orgdoi:10.4104/pcrj.2009.00035 ICS versus cysteinyl leukotriene receptor antagonist (LTRA) monotherapy for mild persistent asthma. 151ICS versus theophylline monotherapy for mild persistent asthma. 152Corticosteroid resistance. 152Beyond ICS alone: other therapeutic options. 152 (1) Addition of long-acting β2-agonist (LABA). 152(2) Addition of leukotriene receptor antagonist (LTRA). 153 Management of mild intermittent asthma. 153Does ICS therapy prevent asthma?. 154Does ICS therapy prevent lung function decline in asthma?. 154ICS and airway remodelling. 155References. 156 Introduction
the frequency and severity of exacerbations.10,13 Asthma is a clinical syndrome characterised by airway The use of ICS on a regular basis also leads to reduced inflammation, variable airway obstruction and airway mortality from asthma. Suissa and colleagues14 used hyperresponsiveness.1 Asthma severity is usually classified Canadian health data to review a population-based cohort of according to the Global Initiative for Asthma (GINA) over 30,000 patients receiving anti-asthma drugs between classification system1 or the American National Institutes of 1975 and 1991. Subjects who had died from asthma and for Health asthma education and prevention programme EPR3 whom records were complete (n=68) were matched with guideline.2 The British guideline, published by the British 2,681 control subjects within the cohort. Rate ratios for Thoracic Society/Scottish Intercollegiate Guidelines Network death from asthma were calculated after adjustment for a (BTS/SIGN)3 does not formally define asthma severity. There number of variables. The authors calculated that the death are four categories based on clinical and functional features - rate from asthma decreased by 21% with each additional mild intermittent, mild persistent, moderate persistent and canister of ICS used by the patients in the preceding year.
These data and a very large body of additional comparative The standard of care for patients with mild intermittent evidence quoted in all of the above guidelines1-3 have resulted and mild persistent asthma in the past was intermittent or in concordant agreement that ICS is the most effective current controller therapy for asthma in adults and children of all ages.
respectively. Whilst this is still true for mild intermittent The EPR3 guidelines2 further conclude that "studies asthmatics, current guidelines1-3 no longer recommend this demonstrate that ICS improves asthma control more effectively for the mild persistent group because of reports of increased in both children and adults than leukotriene receptor risk of death and deterioration of asthma control.4,5 Regular antagonists or any other single long-term control medication".
controller therapy in the form of inhaled corticosteroid (ICS) isnow recommended for this group of patients. Early intervention with ICS to prevent
This paper - the third in a series of reviews on various progression of asthma
inhalation therapy topics being published in this journal by In the START study, investigators looked into whether early the ADMIT working group (see the first review paper5a for intervention with ICS prevented progression of asthma in adults individual affiliations and conflict of interest declarations) - and children aged 5-11 years with newly diagnosed mild will examine aspects of the appropriateness and efficacy of persistent asthma.15 A total of 7,241 patients were treated with ICS therapy in the management of mild persistent asthma.
low-dose budesonide (400 mcg/day for adults or 200 mcg/dayfor children younger than 11) or placebo for three years. During ICS for asthma therapy: effects on lung
the first year, almost 34% of individuals in the placebo arm function, symptoms and mortality
needed rescue treatment with ICS and 4% had had at least one ICS monotherapy achieves successful control of severe asthma exacerbation. By comparison, in the budesonide mild/moderate persistent asthma in a significant proportion treated group, only 20% needed additional ICS and 2% of patients. Generally, the dose-response curve of ICS is experienced severe exacerbations. Compared with placebo, relatively flat for a number of outcome measures6 and for budesonide therapy increased lung function over the course of many patients the therapeutic benefits of high-dosage versus one year of therapy and further after three years. This study low-dosage ICS may be marginal.6-9 Nevertheless, in the suggests that early treatment with low-dose ICS decreases the majority of patients, even at low dosages, ICS rapidly risk of severe exacerbations, and improves asthma control and improves clinical symptoms and measures of lung function.10 lung function in patients with mild persistent asthma of recent The anti-inflammatory action of ICS markedly decreases onset. A cost-effectiveness analysis based on these data also airways hyperresponsiveness11,12 and in the long term reduces favoured early use of ICS.16 A second report on the START study17 presented results of 5-year follow-up of the patients. After the greater improvement in all lung function measures in the initial 3-year treatment period with placebo or ICS therapy, all patients who received early budesonide treatment. In a similar patients then went on to receive ICS treatment for two more study,21 a mixture of patients with asthma and chronic years in an open label fashion. Over the entire 5-year study obstructive pulmonary disease (COPD) were treated with ICS and period, patients taking ICS in the double-blind phase had a short-acting bronchodilator or short-acting bronchodilator alone significantly lower risk (odds ratio 61%) of a severe, asthma- for 2.5 years, and then ICS therapy was started in the patients related event compared with those taking placebo. Furthermore, not having previously received it. After a further six months of these patients overall used less additional medication. The follow-up, the improvement in FEV1 was not significantly authors concluded that early intervention with ICS in mild, different in the asthmatics having received ICS for 2.5 years as persistent asthma improves asthma control and is associated compared to those having received it for six months after a 2.5 with reduced usage of additional medications. year delay; bronchial hyperresponsiveness did, however, improve In the CAMP study,11 in which treatment with ICS, inhaled significantly more in the former group (histamine PC20 1.7 as nedocromil and placebo was compared in 1,041 children aged compared with 0.79 doubling concentrations, albeit following a 5-12 years with mild intermittent asthma over a 4-6 year period, treatment period which was 5 times longer).
ICS therapy was superior to placebo in terms of reducing disease These studies clearly show that ICS therapy, compared with exacerbations, systemic corticosteroid and rescue medication placebo, reduces symptoms and exacerbations in mild usage, and improving symptom scores. In a smaller study18 in intermittent asthma. They also provide some evidence to support which 44 adults with mild persistent asthma were randomised to the contention that delay in commencing regular ICS therapy receive inhaled fluticasone 500 mcg/day or placebo for 11 when this is indicated because of symptoms may result in a months, fluticasone therapy improved spirometry, airways slower and less extensive subsequent response to therapy, so hyperresponsiveness and reduced exhaled nitric oxide that ICS therapy should be commenced as soon as justified by significantly more than placebo. Although there were no such symptoms. This is certainly the line taken by major asthma significant differences in the usage of rescue medication (which guidelines and advocated by most physicians in the UK.
was in any case <2 times/week at the commencement of the However, other physicians22 have pointed out that, in the follow- study), symptoms or quality of life, fewer patients suffered mild up to the START study,17 although patients with mild intermittent exacerbations taking fluticasone compared to placebo (22% vs asthma taking placebo instead of ICS for three years showed 62%) over the duration of the study.
some evidence of delay in "catching up" after two further years Examination of bronchial biopsies of asthmatics indicates of ICS therapy compared with those taking ICS for the full five that significant inflammation is present early in the course of years, the differences were not all that great - at the end of two asthma, even in those patients having had a short duration of years their impairment, symptomatology and risk of symptoms.10 Early use of ICS suppresses airway inflammation, exacerbation were no different to those who had received ICS improves symptom control and restores pulmonary function.10,13 for five years. According to this view, delay in commencing ICS A prospective controlled study19 followed pulmonary function in in patients with symptoms that merit them is, while not 216 children during long term treatment with ICS and compared necessarily desirable, also not necessarily disadvantageous in the the findings of those with 62 children not so treated. Children who started ICS therapy more than five years following adiagnosis of asthma had significantly lower FEV1 measurements Withdrawal of ICS in stable
than those starting it within two years of the onset of asthma.
mild/moderate persistent asthma
Additionally, children treated with ICS had significantly fewer In a small study,23 19 patients with stable mild/moderate asthma hospital admissions because of exacerbations and a lower were randomised into two groups. In the first group ICS was cumulative exposure to corticosteroids in the long term. The withdrawn and in the other group ICS was continued. 90% of effect of early as opposed to delayed ICS therapy has also been patients in whom ICS was withdrawn relapsed in a mean of 1.55 studied in patients with asthma symptoms for less than a year months compared with 25% in the group in which ICS was with no previous exposure to anti-inflammatory therapy.20 Over continued. Asthma symptom scores and lung function during a 2-year period, 50 patients received budesonide at 1200 follow-up over a year were found to be lower in the group mcg/day while 50 received terbutaline 500 mcg/dose taken as where ICS was withdrawn. In a second study,24 28 children required. After this period the 37 patients remaining in the treated for one year with budesonide (200 mcg three times daily) terbutaline group were switched to budesonide and results were randomised to continue treatment or to receive a lower compared again after a further year of therapy. Patients who dose of budesonide for two months followed by placebo for switched to budesonide did improve but to a lesser degree than four months. In the withdrawal group there were eight those receiving early budesonide therapy. There was a trend for exacerbations of asthma compared with none in the group that continued therapy; in addition, lung function deteriorated and function even though neither the IMPACT nor the START studies bronchial hyperreactivity increased. Similar findings were suggested this). However, it is possible that at least some patients with mild persistent asthma may not be disadvantaged by These studies all confirm that withdrawal of ICS therapy in intermittent ICS therapy, which in any case it has been argued stable asthmatics previously deemed to require it for disease better resembles the "real life" situation in which very few control increases the risk of relapse in the fairly short term. Thus, patients in practice take controller therapy absolutely regularly at asthma guidelines1-3 agree in stressing the point that, while ICS therapy is currently the most effective therapy known forasthma, it is not curative - and if withdrawn when needed, ICS versus cysteinyl leukotriene receptor
deterioration of clinical control follows typically within weeks to antagonist (LTRA) monotherapy for mild
months. On the other hand, these studies do not obviate the persistent asthma
obligation of the physician to minimise the dosage of ICS needed Cysteinyl leukotrienes, produced by a variety of inflammatory to control symptoms in each individual patient: this might cells implicated in asthma, are powerful bronchoconstrictors and include a trial of complete withdrawal of ICS therapy in those also increase mucus secretion and oedema in the bronchial whose symptoms become intermittent or disappear.
mucosa. They amplify inflammation through their chemo-attractive effects on inflammatory cells such as eosinophils.
Daily versus intermittent ICS therapy
Consequently, in addition to causing bronchodilatation, In the IMPACT study,26 a total of 225 adults with long-standing leukotriene receptor antagonists (LTRAs) have also been shown mild persistent asthma underwent a 10-14 day period of to have anti-inflammatory properties in asthma.29,30 Four studies "intense combined therapy" with oral prednisolone, inhaled involving both adults and children with mild persistent asthma budesonide and oral zafirlukast, and were then randomised to compared therapy with LTRA and low-dosage ICS.31-34 Both drugs receive inhaled budesonide, oral zafirlukast or daily placebo for improved most asthma outcomes, but ICS was significantly one year. In addition to this regular therapy, all patients were superior in terms of most outcomes (asthma control, lung instructed to take intermittent, short-course corticosteroid function and inflammatory biomarkers).
guided by a standard, symptom based action plan. At the end of Despite these studies, LTRAs are widely used outside the UK one year, the ICS-treated patients showed greater improvements as monotherapy for mild, persistent asthma, especially in in lung function, bronchial hyperreactivity and symptom-free children. Furthermore, guidelines are curiously ambivalent about days. There were no differences between the groups in terms of the use of LTRA as monotherapy instead of ICS in mild persistent changes in quality of life, numbers of asthma exacerbations or asthma. The GINA guideline1 states that LTRAs "may be used as post-bronchodilator FEV1. In a second study,27 patients with mild an alternative treatment for adults with mild persistent asthma" persistent asthma were treated with continuous ICS (budesonide but also that "when used alone as a controller the effects of 400 mcg/day), continuous zafirlukast (40 mg/day), or LTRA are less than those of ICS and, in patients already on ICS, intermittent courses of ICS (budesonide 1600 mcg/day) for 10 LTRA cannot substitute for this treatment without risking the loss days or systemic corticosteroid (prednisone 0.5 mg/kg/day) for of asthma control".35,36 For children, no specific comment is made five days, again according to a symptom-based action plan.
about their use as monotherapy, although it is stated that "LTRA Improvements in morning peak expiratory flow (PEF) and disease provide clinical benefit in children at all levels of severity but less exacerbation rates were similar in all three groups, despite the than that of low dose ICS".31,37 The EPR3 guidelines,2 based on fact that that the patients randomised to intermittent ICS evidence from five placebo-controlled trials,31,32,37-39 state that therapy took this for a mean of no more than 0.5 weeks/year.
"patients who have mild or moderate persistent asthma and are Furthermore, improvements in other outcome measures (pre- treated with ICS, compared to other single long term control bronchodilator FEV1, bronchial hyperresponsiveness, symptom medications, demonstrate greater improvements in pre- scores and number of symptom-free days) were better in this bronchodilator FEV1, reduced airway hyperresponsiveness, group. These studies, along with the question regarding the symptom scores, exacerbation rates and symptom frequency, as possible disadvantages of delaying regular ICS therapy in mild well as less use of supplemental SABA [short-acting β2-agonist], persistent asthma (see above) have generated calls22,28 for fewer courses of oral systemic corticosteroids, and less use of guidelines to consider the feasibility and cost effectiveness of hospitalisation" but nevertheless conclude that, in both adults intermittent ICS treatment as a possible management option in and children, LTRA monotherapy is an "alternative, not this group of patients (especially in poor or underdeveloped preferred" treatment. The BTS/SIGN guideline3 states that LTRA countries). They have not yet been incorporated into treatment therapy is "less effective" than ICS as monotherapy and suggests guidelines because of reservations about the longer term effects that LTRA might be used in children <5 years old in whom ICS of intermittent therapy (particularly accelerated decline in lung "cannot be used". Notwithstanding this, most clinicians would have to conclude from all of these studies that LTRA should be in any major guidelines, and cannot be generally used as monotherapy for mild persistent asthma only as a last recommended until further long-term studies are available.
resort when ICS cannot, for whatever reason, be used. Thereasons for the continuing popularity of LTRAs as monotherapy Corticosteroid resistance
in practice in some countries are not clearly defined but may Despite the generally favourable response of mild, persistent relate to perceived problems with giving ICS to children or using asthmatics to ICS therapy, as with all drugs there is a spectrum of response and there will be some patients who require morethan an "acceptable" dose of ICS (beclometasone or ICS versus theophylline monotherapy for equivalent ≤800 mcg/day in adults, ≤400 mcg/day in children)
mild persistent asthma
to achieve symptom control. Before coming to this conclusion Theophylline is a rather weak, non-specific inhibitor of the physician should review, and eliminate where possible, phosphodiesterase which elevates cyclic AMP concentrations external factors which may be upsetting asthma control in in airway smooth muscle and immune cells, resulting in individual patients (allergens, including food allergens in modest bronchodilatation and inhibition of inflammatory children and occupational allergens, concomitant untreated cells. Theophylline has limited effectiveness when given as rhinosinusitis, drugs such as β-blockers and non-steroidal anti- monotherapy in adult asthmatics40 but is more effective than inflammatory drugs such as aspirin). By far the commonest placebo at relieving symptoms in children.41 Several studies causes of "non-responsiveness" to therapy are, however, have shown that ICS is more effective than theophylline for poor inhaler technique and poor compliance.
monotherapy of mild, persistent asthma. For example, in a Relative resistance to ICS therapy may also be a randomised parallel group study of 74 patients with mild consequence of particularly severe or unusual types of airways persistent asthma, patients were treated with inhaled inflammation in asthma44 or, at least in theory, structural budesonide 400 mcg/day, oral montelukast 10 mg/day or changes refractory to reversal by corticosteroids. A number of sustained-release theophylline 400 mg/day for three months.
environmental factors may affect the responsiveness of T cells The patients treated with ICS showed significantly greater and other inflammatory cells in asthma to corticosteroid improvement in lung function as compared with those treated inhibition;45 an important one is cigarette smoking, which with both alternative medications, although the changes in reduces clinical responsiveness to ICS in mild asthma46 and FEV1 and PEF did not exceed the baseline variability. Asthma symptoms and the use of rescue medication were similar in all Ultimately all patients are likely to show at least some three groups.42 Cochrane meta-analysis to determine the response to ICS therapy although in a minority the dosages efficacy of xanthines such as theophylline in the maintenance required may be relatively high. With such patients, physicians treatment of children with asthma43 demonstrated that they should weigh the problems of unwanted effects of the drugs are less effective in preventing exacerbations as compared against optimisation of quality of life, whilst minimising co- with ICS but as effective as monotherapy with regular inhaled morbidity that may compromise asthma control and encouraging short-acting β2-agonist and cromoglicate for treating mild, good inhaler technique and compliance with dosing regimens.
intermittent disease. Consequently all major guidelines, whileacknowledging the activity of theophylline, agree that it is less Beyond ICS alone: other therapeutic
effective than ICS monotherapy for mild, intermittent asthma.
In addition the EPR3 guideline2 states that theophylline is "not (1) Addition of long-acting β2-agonist (LABA)
recommended" in children 0-4 years of age owing to its In adults with mild persistent asthma insufficiently controlled with "erratic metabolism during viral infections and febrile illness" moderate dosages of ICS, all guidelines agree that adding in a and is "less desirable" in 5-11 year olds because of its "safety LABA, rather than further increases in ICS dosage, is the preferred profile" although it may be contemplated when "cost and initial course of action. Addition of a LABA to a daily regimen of adherence to inhaled medications are concerns".
ICS reduces day and night symptoms, improves lung function, In summary, these data show that early intervention with reduces rescue medication usage, reduces exacerbations, and ICS decreases the risk of severe exacerbations and improves achieves clinical control of asthma in more patients, more rapidly asthma control in mild persistent asthma of recent onset. ICS and at a lower final dosage of inhaled ICS than increased dosages therapy is superior to LTRA and xanthine therapy, at least of ICS given alone.47-53 There is a paucity of studies on the effects within the relatively short term scope of clinical trials, for of LABA in children, particularly under the age of 5 years: while control of asthma and improvement of lung function. While the BTS/SIGN guideline3 still recommends LABA as the first line intermittent, symptom-led therapy may be suitable for some add-on therapy to ICS in children over the age of 5 years, the patients with mild persistent asthma, this is not yet advocated GINA guideline1 suggests LTRA as an alternative, while the EPR3 guideline2 concludes that there is insufficient evidence at present 10 mg/day was shown to improve symptoms, reduce the use to know whether adding in a LABA or increasing ICS dosage is of rescue medication and improve lung function as compared best. All guidelines agree that LABA should never be given with placebo.57 In a second double-blind, randomised study without ICS. This follows a study54 showing a small but significant on similar patients inadequately controlled on budesonide excess of deaths in asthmatics receiving daily treatment with 800 mcg/day, addition of montelukast 10 mg/day was shown salmeterol compared with placebo added to their usual asthma to produce outcomes (improvement in symptoms, quality of therapy (13/13,176 patients taking salmeterol compared with life and lung function) equivalent to doubling the dosage of 3/13,179 patients taking placebo). The MHRA and the BTS, following a long review of the evidence, concluded that LABA A Cochrane meta-analysis comparing the addition of LABA can still be used provided they are given with ICS (the implication to LTRA in asthmatics inadequately controlled on moderate to being that masking of symptoms with LABA while avoiding ICS is high dosages of ICS suggested that LABA was superior to LTRA potentially dangerous). For this reason, combination inhalers in preventing exacerbations requiring systemic steroid therapy, containing ICS and LABA, although no more or less effective than improving lung function and reducing symptoms and the use taking the two drugs in separate inhalers, are preferable when of rescue medication.59 Thus the major guidelines recommend prescribing a LABA because they ensure that LABAs can never be LABA as a first-line add-on therapy before LTRA in adults and older children, although in infants, in whom there is a paucity Notwithstanding this evidence, it is important to note that of evidence of the effectiveness of LABA, LTRA would seem a many patients with mild, persistent asthma are adequately controlled on ICS alone. In these patients, adding in a LABA is of In conclusion, while the benefits of adding in LABA (and to no additional benefit. The BTS/SIGN guideline3 states that "in a lesser extent LTRA) in patients with asthma with good patients on ICS whose asthma is stable, no intervention has been compliance and perfect inhaler technique whose disease is not consistently shown to decrease ICS requirement in a clinically controlled with low/moderate dosages of ICS are manifest, it is significant manner compared to placebo". As an illustration of unnecessary and wasteful to use these drugs in patients whose this, the OPTIMA trial55 sought to establish whether adding a control is adequate on acceptable dosages of ICS alone.
LABA (formoterol) to ICS (budesonide) in mild and moderatepersistent asthmatics would reduce exacerbations. Both children Management of mild intermittent asthma
(older than 12 years) and adults were included as long as post There are many fewer data addressing the optimal treatment for bronchodilator FEV1 was >80% of the predicated value. The patients with mild intermittent asthma since they remain prevalence of severe asthma exacerbations was reduced and relatively well and have very infrequent symptoms. Current symptom scores improved in the mild persistent asthmatics guidelines recommend intermittent short-acting bronchodilator treated with budesonide as compared with a placebo-treated for this group of patients. The SOMA study60 compared as- group over a year of therapy. The combination of budesonide needed use of LABA with as-needed use of LABA/ICS and formoterol did not provide any additional benefit in this combination therapy as the only medication in a group of group. In contrast, in the group with moderate persistent patients with mild intermittent asthma. The frequency of asthma using ICS at the beginning of the study, a significant asthma-free days was similar in the two groups; however, reduction in asthma exacerbations was seen when formoterol compared with the LABA-only group, significantly fewer patients was added to budesonide. These findings emphasise the fact in the ICS/LABA-treated group needed more than four puffs of that patients with mild, persistent asthma well controlled on ICS "as required" short-acting reliever on any day. The results of this alone do not need anything else. Similarly, in a Cochrane meta- study cannot be extrapolated to all patients with mild analysis,56 the effects of initiating therapy with ICS alone as intermittent asthma, since the patients were selected on the compared with ICS and LABA were compared in steroid-naïve basis of having high exhaled nitric oxide (thought to be a adults and children with mild persistent asthma. The addition of biomarker of active airways inflammation). Furthermore, the LABA to ICS did not significantly reduce the rate of situation has been coloured by anxiety about prescribing LABA exacerbations or use of rescue medications as compared with in the absence of ICS (see above). The long-term implications of patients treated with ICS alone. Consequently, physicians should this particular treatment strategy in terms of benefit/risk are not be tempted to use combination therapy too hastily.
therefore unknown. Similarly, there is a paucity of evidence (2) Addition of leukotriene receptor antagonist (LTRA)
examining the benefit/risk implications of long-term ICS therapy Several studies have suggested that LTRA are sparing of ICS.
in patients with mild intermittent asthma. Current evidence- For example, in a double blind controlled study of asthmatics based guidelines suggest the use of intermittent short-acting still symptomatic despite taking moderate to high dosages of bronchodilators for this patient group, and at present there is budesonide (400-1600 mcg/day), the addition of montelukast insufficient evidence to overturn this conclusion.
Does ICS therapy prevent asthma?
Most children with wheeze presenting before the age of 2 Studies of whether ICS therapy prevents asthma, at least in years become asymptomatic by mid-childhood and do not need children, are potentially confounded by the fact that at least half treatment. Symptoms present from birth, severe upper of pre-school wheezing children will stop wheezing by the time respiratory tract disease, persistent moist cough, excessive they start school.61 Indeed, there is some debate as to whether vomiting, dysphagia, stridor, abnormal voice or cry, focal signs in any pre-school wheezy children should ever be treated with ICS.62 the chest, finger clubbing and failure to thrive all lower the In the PAC study,63 infants (aged 1 month to 3 years) of probability of asthma and suggest an alternative diagnosis. Lung mothers with asthma were treated with ICS (budesonide 400 function testing adds little information in children under the age mcg/day) or placebo using a metered-dose inhaler and spacer of 5 years. For children in whom the probability of asthma is device starting on day 3 of any wheezy episode and continued considered high, a trial of ICS therapy for 2-3 months followed for two weeks. Children discontinued the trial if they developed by reassessment is indicated. A good symptomatic response persistent wheezing (more than five episodes lasting three days strongly supports the diagnosis, whereas a poor response is very within a 6-month period, or daily symptoms for more than four much against it. For children in whom the probability of asthma weeks). Two hundred and ninety-four children, mean age 10.7 is considered to be lower, a period of watchful waiting is months, were randomised. Intermittent ICS therapy had no reasonable along with possible further investigation for unusual effect on the progression from intermittent to persistent wheeze, symptoms or signs. Physicians should be mindful of the which was observed in 24% of the ICS treated group and 21% importance of not missing, but nevertheless firmly making, a diagnosis of asthma before committing a child to long term In the IFWIN study,64 206 older children aged 6 months to 5 therapy, and can be reassured that in this situation delay in years with at least one atopic parent were given ICS (fluticasone commencing ICS therapy does not appear to alter the risk of the 100 mcg twice daily) or placebo after one prolonged (>1 month) episode of wheezing or two physician-confirmed wheezyepisodes. The dosage was adjusted every three months to the Does ICS therapy prevent lung function
minimum required to control symptoms. At the age of 5 years decline in asthma?
there was no difference between the groups in the proportion of The natural history of lung function is that it increases during children with current wheeze, physician-diagnosed asthma or childhood, reaches a peak during early adulthood (25-35 years) and then slowly declines with age. The evidence is that children In the PEAK study,65 285 2-4 year olds considered at risk of who wheeze persistently at the age of 6 (many of whom will go asthma were randomly assigned to receive ICS (fluticasone on to develop chronic asthma) have impaired lung function propionate 88 mcg twice daily) or placebo using a metered dose which was nevertheless normal at birth.66 In contrast, children inhaler and spacer for two years. They were then followed for a under 2 years of age who wheeze with colds (most of whom do further observational year. During this year there were no not go on to develop asthma) have diminished lung function in significant differences between the groups in terms of symptom- infancy which tends to improve (though not always completely) free days or exacerbations of wheeze.
by the age of 6 years.66 There are few studies which have All of these studies, although directed at slightly different followed lung function in asthmatics over protracted periods of patient populations (all of them children) and with slightly time, but one such study suggested that middle aged asthmatics different criteria for "risk of asthma", seem to lead to the same with significant airways obstruction already had reduced lung conclusion, namely that ICS therapy does not prevent asthma.
function at the age of 10 years.67 Taken together, these studies They also underline the difficulty with diagnosing asthma and could be interpreted as showing that children who are going to distinguishing it from virus-induced wheezing in this age group.
develop chronic asthma start off in life with normal lung function The BTS/SIGN guideline3 states that suggestive symptoms which deteriorates during childhood and never recovers. Several (wheeze, cough, difficulty breathing, chest tightness), particularly studies68,69 have shown that lung function in adult asthmatics if frequent and recurrent, worse at night and early in the (and most particularly the degree of reversibility of airways morning, triggered by stimuli such as exercise, emotion and obstruction as measured by post-bronchodilator FEV1) declines allergen exposure, and occurring apart from colds, increase the substantially faster compared with non-asthmatics.
probability of a diagnosis of asthma in children, as does audible Consequently there is interest in blocking this early decline in wheeze on chest auscultation and a personal or family history of lung function in asthmatics, in the hope that it will bring long- atopic disease (eczema, allergic rhinitis, food allergy, asthma). On lived symptomatic benefit with less treatment.
the other hand symptoms only with colds, isolated cough and The first study to suggest that ICS may inhibit lung function normal chest examination and spirometry during symptoms decline in asthma was directed primarily towards effects of ICS on child growth.19 It was noticed that the annual increase in pulmonary function in a group of child asthmatics was structural changes seen in the airways of asthmatics which significantly accelerated after commencing budesonide as comprises epithelial damage, deposition of structural proteins compared with the run-in period, and also as compared with a below the reticular basement membrane (subepithelial fibrosis), group of untreated controls. The extent of the improvement with bronchial smooth muscle hypertrophy and hyperplasia, budesonide was noted to depend on how long the budesonide hyperplasia of mucous glands, and increased mucosal vascularity.
treatment was started after the onset of asthma symptoms.
The reason for the interest in these features is that they have In the CAMP study,11 children aged 5-12 years with been postulated to contribute to the accelerated decline in lung mild/moderate asthma were treated from 4-6 years with function and irreversibility of airways obstruction associated with budesonide 200 mcg twice daily and compared with a group asthma. At present there are problems with this interpretational treated with placebo and taking reliever medication and scenario. Although intuitively these changes might be surmised prednisolone only when needed. There was no significant to contribute to irreversible changes in airway function, there is difference in the change in lung function (post-bronchodilator as yet little or no direct evidence that they actually do so. They are FEV1) in each group. As compared with the children assigned to widely assumed to be brought about by mediators released by placebo, however, those treated with budesonide showed a inflammatory cells. Whilst it is true that certain cytokines, such as significantly smaller decline in pre-bronchodilator FEV1/FVC ratio transforming growth factor beta (TGF-β) and interleukins such as and improved airways hyperresponsiveness, suggesting that their IL-11 and IL-17 can cause bronchial mucosal fibroblasts to secrete asthma was better controlled but their overall lung function no fibrotic proteins such as collagen, while others such as IL-13 can promote mucous gland hypertrophy in cultured bronchial In addition, the three studies in pre-school wheezy children epithelial cells, there are still many doubts about the cause and described above63-65 all examined changes in lung function as effect relationship between inflammation and remodelling, not additional outcome measures. None of these studies least because it is so difficult to characterise the natural histories demonstrated any significant difference in changes in lung of the two phenomena. Of the few studies in children, some function in children treated with ICS as compared with placebo have reported that severe asthma is associated with airways therapy using various techniques of measurement.
remodelling70,71 whereas others72 suggest that remodelling In the START trial,15 which involved over 7,000 patients with changes predispose to, but pre-date, clinical asthma. Such studies mild intermittent asthma not previously treated with regular cast doubt upon the tenet that remodelling is caused by inhaled ICS who were randomised to receive ICS therapy or inflammation and in turn contributes to asthma symptoms and placebo for three years, post-bronchodilator FEV1 had declined physiology. In both children and adults, remodelling changes significantly less in the patients treated with ICS as compared with have been linked to asthma severity but not always those treated with placebo, although the difference was extremely longevity,70,71,73 suggesting that they are not necessarily small. In the follow-up phase of this study,17 when all patients cumulative, and possibly reversible with time.
were treated with ICS for a further two years, post-bronchodilator Boulet and colleagues74 examined bronchial biopsies in 32 FEV1 had declined by a small (mean 2.22%) but equivalent degree adult asthmatics, 16 of whom had been recently diagnosed with in all patients, irrespective of whether or not they had received ICS asthma and 16 of whom had long-standing asthma, both before in the randomised, double-blind phase. In the IMPACT study,26 in and after eight weeks of therapy with inhaled fluticasone which 225 adults with mild persistent asthma were randomised to propionate 1000 mcg daily. Baseline sub-epithelial collagen receive twice daily budesonide (200 mcg), zafirlukast (20 mg) or deposition was similar in both groups and this did not alter placebo, there were no significant differences in post- significantly following the high dose ICS therapy. However, a bronchodilator FEV1 after a year of therapy between the groups.
second study75 did show significant reduction in the thickness of Consequently it must be concluded that, whilst ICS therapy the sub-epithelial reticular layer in a group of asthmatics whose is very effective in mild persistent asthma for controlling ICS dosages were increased according to their degree of symptoms and improving lung function, there is no clear bronchial hyperresponsiveness as compared to a comparison evidence that it prevents the early lung function decline which is group where dosages were adjusted to standard asthma surmised to herald further deterioration later in life. It is perhaps worth noting that these studies - at the population level, and in With regard to mediators of remodelling, one study76 showed relatively small numbers of patients - are unlikely to unearth a no effect of systemic corticosteroid therapy on the expression of possible subgroup of asthmatics whose lung function TGF-β, considered a key remodelling cytokine, in airway biopsies deterioration is slowed by ICS therapy.
of moderate to severe asthmatics. It was noted, however, thatexpression of IL-11 and IL-17 was markedly reduced. In vitro, IL- ICS and airway remodelling
17 stimulates fibroblasts to produce IL-6 and IL-11, both of which Airway remodelling is the collective term used to describe are pro-fibrotic.77 These effects are therefore variable and it is not possible to form an overall impression from these studies of the College London School of Medicine, London, UK net effects of ICS therapy on airways remodelling.
Graham K Crompton. Western General Hospital, Edinburgh, Scotland, UKLorenzo Corbetta. Università degli Studi di Firenze, Unità Funzionale di Medicina Orsida and colleagues78 demonstrated significantly increased vascularity of the lamina propria in steroid-naïve asthmatics Richard Dekhuijzen. Radboud University Medical Centre, Nijmegen, Netherlands, compared with normal controls and asthmatics taking ICS.
Jean Christophe Dubus. Unité de Medicine Infantile, Marseille, FranceThomas Hausen. General Practice, Grafenstrasse 62, Essen, Germany Similarly, Feltis and colleagues79 showed that treatment of Meinhard Kneußl. Wilhelminenspital, Vienna, Austria asthmatics with ICS for three months significantly reduced the Federico Lavorini. Università degli Studi di Firenze Unità Funzionale di Medicina cross-sectional area of vessels in bronchial biopsy specimens as Respiratoria, ItalyMark L Levy. University of Edinburgh, Division of Community Health Sciences: GP compared with a placebo-treated group. The expression of vascular endothelial growth factor was also reduced in the Søren Pedersen. Paediatric Research Unit, Kolding Hospital, University of Southern biopsies but not within the lumen of the airways.
In summary, it would appear that there is a degree of Antonio Ramalho de Almeida. Pr. General Humberto Delgado 267, Porto, PortugalJoaquin Sanchis. Departament de Pneumologia, Hospital de la Santa Creu i Sant reversibility in at least some of the processes involved in airways Pau, Universitat Autónoma de Barcelona, Barcelona, Spain remodelling with ICS, although the effects are complex and Jose L. Viejo. Hospital General Yagüe de Burgos, Spain interpretation is confounded by lack of knowledge of the natural Walter Vincken. Academisch Ziekenhuis VUB, Dienst Pneumologie, Brussels, BelgiumThomas Voshaar. Krankenhaus Bethanien, Moers, Germany history of these processes and understanding of theircontribution to symptoms and airways physiology in chronic References
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