Asmanet ARLS 6-1998 Astra Respiratory Literature Service Experts comments

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AstraZeneca Respiratory Literature Service
N°6 1998 (see other Expert comments on Asmanet)

For many years, AstraZeneca Draco laboratories have brought to the asthmolgist community an excellent "Respiratory Literature Service" (ARLS) with an alert to new references, selected summaries and comments by a group of experts. In 1997, AstraZeneca is extending this concrete service with Asmanet in order to take advantage of the Internet capabilities. The following comments have been edited ( HTML format) to smooth the reading with hypertext links to integrate the comment in the Asmanet server and the worldwide distributed library on asthma, such as : abstract of the commented paper, references as seen on Medline and others, author's e-mail ...

	Title	Authors	Journal	Reviewer
1	Effect of low-dose beclomethasone dipropionate on asthma control and airway inflammation	Fahy JV, Boushey HA	Eur Respir J 1998;11:1240-1247	Professor Duncan Geddes
2	Treatment of acute asthmatic exacerbations with an increased dose of inhaled steroid	Garrett J, Williams S, Wong C, et al	Arch Dis Child 1998;79:12-17	Professor Duncan Geddes
3	Clinical efficacy of sublingual-swallow immunotherapy: a double-blind, placebo-controlled trial of a standardised five-grass-pollen extract in rhinitis	Clavel R, Bousquet J, André C.	Allergy 1998;53:493-498	Professor Duncan Geddes
4	Effect of low-dose beclomethasone dipropionate on asthma control and airway inflammation	Fahy JV, Boushey HA	Eur Respir J 1998;11:1240-1247	Professor Philippe Godard
5	Cost-effectiveness of fluticasone and budesonide in patients with moderate asthma	Steinmetz K-O, Volmer T, Trautmann M, et al.	Clin Drug Inv 1998;16:117-123	Professor Philippe Godard
6	Montelukast, a potent leukotriene receptor antagonist, causes dose-related improvements in chronic asthma	Noonan MJ, Chervinsky P, Brandon M, et al.	Eur Respir J 1998;11:1232-1239	Professor Philippe Godard
7	Bambuterol is a more cost-effective treatment than salmeterol in asthma patients with nocturnal symptoms	Crompton GK, Brusasco V, Eivindson A, et al	Value in Health 1998;1:60	Ass. Professor Leif Rosenhall
8	Effects of orally inhaled budesonide in seasonal allergic rhinitis	Greiff L, Andersson M, Svensson C, et al	Eur Resp J 1998;11:1268-1274	Ass. Professor Leif Rosenhall
9	Randomised controlled trial of inhaled corticosteroids in patients with chronic obstructive pulmonary disease	Bourbeau J, Rouleau MY, Boucher S	Thorax 1998;53:477-482	Ass. Professor Leif Rosenhall
10	Effects of orally inhaled budesonide in seasonal allergic rhinitis	Greiff L, Andersson M, Svensson C, et al	Eur Respir J 1998;11:1268-1274	Professor John H. Toogood
11	Zafirlukast and Churg-Strauss syndrome	Katz RS, Papernik M	JAMA 1998;279:1949	Professor John H. Toogood

AstraZeneca Draco laboratories is also supporting the European Federation of Asthma and Allergy Associations which can be seen at http://www.efanet.org/

Access for abstracts to Medline through Healthgate (http://www.healthgate.com/HealthGate/MEDLINE/search.shtml ) or through HealthWorld Medline Search (http://www.healthy.net/library/search/medline.htm )

or through http://www.ncbi.nlm.nih.gov/

...

This study investigated whether improvements in asthma control produced by a relatively low dose of inhaled corticosteroid (BDP 336 m g/d) are associated with a reduction in markers of airway inflammation. In 24 adult subjects with mild to moderate asthma treated over four weeks, the active treatment provided improvement in FEV₁ , peak flow and rescue salbutamol. However, there were no significant changes in markers of inflammation other than eosinophils which remain stable in the actively treated group and rose in the placebo group so that there was a significant difference at the end of the treatment period.

This dissociation between different outcome measures in asthma treated with inhaled corticosteroids is not surprising. The lack of change in inflammatory markers may be due to an insensitive assay but may also suggest an actual biological difference. Naturally, this study leads on to the question of whether persisting inflammation without clinical symptoms actually matters. Longitudinal studies will be needed to establish whether there are long-term disadvantages from low grade asymptomatic airway inflammation and until this evidence is available it seems sensible to treat patients for symptoms rather than for biochemical markers.

Fahy JV, Boushey HA Dept of Medicine and the Cardiovascular Research Institute, University of California, San Francisco 94143, USA.

The effects of usual or low doses of inhaled corticosteroids on airway mucosal inflammation have not yet been examined. We therefore, compared the effects of inhaled beclomethasone dipropionate (BDP) 336 microg x day(-1) on asthma control outcomes and markers of airway inflammation.
Twenty-four adult subjects with mild and moderate asthma were randomized to receive either BDP
or placebo for four weeks; then subjects entered a single blind four week placebo run-in period. We found that the BDP group had significantly greater improvements in forced expiratory volume in one second (FEV1), morning peak flow, and rescue salbutamol use than the placebo-treated group. The improvement in FEV1 largely reversed one week after treatment was stopped. The decrease in the median percentage of eosinophils in induced sputum in the BDP group from 3.8% to 3.4% was not significant, but because eosinophils increased from 8.4% to 12.7% in the placebo group, there was a significant difference between treatment groups (p=0.03). There was no significant difference between groups during treatment in the levels of eosinophil cationic protein (ECP), tryptase mucin-like glycoprotein, or fibrinogen in induced sputum. The change in FEV1 in the BDP group did not correlate significantly with the change in eosinophil percentage or ECP levels. We concluded ...

Many asthma management guidelines advise that patients should increase their dose of inhaled steroids when their asthma deteriorates. This recommendation is based on a consensus opinion rather than evidence and this trial is therefore valuable and interesting.

Twenty-eight children were studied for six months and no difference was found between increasing inhaled steroid or placebo on any measures during the 18 pairs of exacerbations that were available for analysis.

Although the trial can be criticised on the ground that it is too small to detect a significant difference, the authors provide compelling arguments that any clinically significant benefit was satisfactorily excluded. The results agree with a substantial body of data emphasising that patients taking an effective dose of inhaled steroid are on the flat part of the dose response curve. Therefore, any increase in dose during an exacerbation will provide minimal benefit so long as patients are already taking an effective dose.

Some guidelines may need to be rewritten. The study emphasises the need to re-evaluate consensus opinion in the light of evidence.

This double-blind placebo-controlled trial of sublingual-swallow immunotherapy showed a worthwhile improvement in rhinitis. Although the study was not designed to evaluate the effect of this treatment on asthma 30% of the patients happened to have seasonal asthma. Among these only one in the active treatment group had an asthma attack compared to eight in the placebo group (p<0.02).

The possibility of simple oral immunotherapy for seasonal asthma is attractive and a further trial to examine this would be welcome.

Title (3): Clinical efficacy of sublingual-swallow immunotherapy: a double-blind, placebo-controlled trial of a standardised five-grass-pollen extract in rhinitis (partial abstract from http://www.healthy.net/library/search/medline.htm )

Clavel R, Bousquet J, Andre C Groupement d'Allergologie et d'Immunologie Clinique du Rhone Moyen, Lyon, France.

Sublingual-swallow immunotherapy (SLIT) using high doses of standardized allergen extracts has been found to be effective in reducing allergic symptoms and medication needs. A double-blind, placebo-controlled study was carried out in a large number of patients to determine whether medication needs can be reduced by SLIT. Some 136 patients with grass-pollen rhinitis with or without mild asthma were studied. Patients received either placebo or SLIT with a standardized grass-pollen extract administered daily with increasing doses up to 300 IR (index of reactivity) from January to the end of July 1994. During the grass-pollen season, patients were instructed to use medications as required and to visit their doctors in case of asthma. Symptom-medications scores were assessed during the pollen season, and serum-specific IgG4 was measured before and at the end of SLIT. In the SLIT group, drug consumption dropped significantly throughout the pollen season (P < 0.02). Moreover, at the peak of the pollen season, betamethasone consumption was significantly reduced in the SLIT group (P < 0.02). Only one patient in the SLIT group had an asthma attack compared to eight patients in the placebo group (P < 0.02). IgG4 levels increased significantly in the SLIT group (P < 0.001) but without correlation with symptoms. Side-effects were comparable in both groups. This study indicates that SLIT in grass-pollen rhinitis is well tolerated, improves overall clinical symptoms, and reduces drug consumption and the need for oral corticosteroids.

This study is very exciting because of the excellent design and the good clinical and laboratory evaluations. Although the conclusions will not change our daily clinical practice, the study puts our practice in a new light.

The dose of 336 m g per day is remarkable. This dose was administered as four puffs twice daily via a beclomethasone inhaler which contained 42 m g per puff. This is a standard dose in the USA. In Europe, 300 or 400 m g per day would be used. More than 15 years ago, patients in Europe were treated in a similar way - four puffs of beclomethasone 50 m g, twice daily. Doses higher than 250 m g per day induced a clear clinical improvement.

The authors’ conclusion is very interesting. They reported a dissociation between the doses of inhaled corticosteroids necessary to improve clinical indices of asthma control from those needed to inhibit bronchial mucosal inflammation. This result accords with the results by Sont et al¹. They observed the persistence of airway inflammation (as assessed by bronchial biopsy) in patients who were well controlled by inhaled corticosteroids.

This work is also very interesting because of the wash-out period. Analysis of this "off effect" gives information about the kind of effect during the treatment. For example, for agents that are thought to be "disease modifying" (such as inhaled steroids) they would be expected to have a longer off-effect than simple "symptom relieving" agents (such as inhaled b ₂-agonists). In the study, the clinical benefit was lost within one week. This confirms that, even at this dose, inhaled steroids are clinically effective. Moreover, it suggests that beclomethasone may be considered as symptom relieving in addition to disease modifying. To get more insight in the symptom relieving and disease modifying characteristics of inhaled steroids, the authors recommend a long-term study (1 to 2 years) which also includes asthma exacerbations rates and an indicator of airway remodelling.

1) Sont JK, Van Krieken JH, Evertse CE, Hooijer R, Willems LN, Sterk PJ. Relationship between the inflammatory infiltrate in bronchial biopsy specimens and clinical severity of asthma in patients treated with inhaled steroids. Thorax 1996;51:496-502.

Direct and indirect costs of asthma are very high. Most of the studies evaluating costs of asthma have been conducted in the US but they are also illustrative for other countries. Therefore, a paper on this topic is important.

Being a naïve in the field of pharmacoeconomics, but being aware of its importance, I have the following comments on the paper by Steinmetz et al.:

In conclusion, pharmacoeconomic analyses are interesting but the results should be placed in the perspective of the overall costs for asthma.

In this study, chronic asthma patients were randomly assigned to one of four treatment groups (placebo, or montelukast 2 m g, 10 m g or 50 m g once daily in the evening) for a three-week treatment period. A dose-response relationship was observed for some parameters but not for all (such as FEV₁ and PEFR). The study included a short follow-up period of one week.

Administration of montelukast was associated with a decrease in peripheral eosinophils. This indicates that montelukast has some anti-inflammatory properties. However, additional studies and long-term follow-up are required in order to determine if this is important for montelukast’s clinical efficacy.

Exacerbations of asthma were also reported. While, the definition for exacerbation was clearly defined it differed from definitions used in other studies. Consensus about one definition for all clinical studies is essential in order to compare different studies.

This study demonstrates the efficacy of montelukast in chronic asthma. However, its place in daily clinical practice remains unknown. Among European countries, the positioning of the antileukotrienes is different due to differences in legislation. Nevertheless, clinico-vigilance is important for establishing the role of the antileukotrienes.

Noonan MJ, Chervinsky P, Brandon M, Zhang J, Kundu S, McBurney J, Reiss TF Allergy Associates, PC Research, Portland, Oregon, USA.
The leukotrienes are known to be important mediators of bronchial asthma. The ability of montelukast, a potent and selective CysLT1 leukotriene receptor antagonist, to cause a dose-related improvement in chronic asthma was investigated in a placebo-controlled, multicentre, parallel-group study. After a two week placebo run-in period, chronic asthmatic patients with a forced expiratory volume in one second (FEV1) 40-80% predicted with > or = 15% increase (absolute value) after beta2-agonist were randomly assigned to one of four treatment groups (placebo or montelukast 2, 10, or 50 mg once daily in the evening) for a three week, double-blind treatment period. For patient-reported end-points (daytime symptom score, use of as needed inhaled beta2 agonist, asthma-specific quality of life) and frequency of asthma exacerbations, montelukast 10 and 50 mg caused similar responses, superior to 2 mg and significantly (p<0.05; linear trend test) different from placebo. All three doses caused improvements in FEV1 and morning and evening peak expiratory flow rate (PEFR) that were significantly (p<0.05) different from placebo. Differences (least square mean) between the pooled 10 and 50 mg montelukast treatment groups and placebo were: 7.1% change from baseline in FEV1, 19.23 L x min(-1) in morning PEFR, -0.29 in daytime asthma symptom score (absolute value), and -0.82 in beta2-agonist use (puff x day(-1)). The incidence of adverse experiences was neither dose-related nor different between montelukast and placebo treatments. We conclude ...

In this abstract, Crompton et al states that bambuterol is more cost-effective than salmeterol for the treatment on nocturnal asthma.

It is surprising to a clinician who has used both treatments, that there were no statistically significant differences between bambuterol and salmeterol regarding the effectiveness variables. The explanation may be that the power in the study is too weak. The bambuterol group had fewer nights without awakenings than the salmeterol group (69% vs 77%, respectively). If the groups had been somewhat larger the difference might have been significant.

The difference in cost for the two treatments are, of course, in favour of bambuterol. The difference might have been been smaller if a cheaper long-acting b ₂-agonist had been used, for example formoterol.

Even if we all know that asthma and rhinitis have many similarities and should be regarded as the same disease in a different organ, we tend to treat them separately.

It seems logical that proper treatment of the nose will benefit the asthma patient so he/she can easily breath. However, it was never considered important for rhinitis to treat the lower airways.

In this study patients with tree-pollen allergy were treated with orally inhaled budesonide, 600 m g bid. Compared to placebo, patients had less nasal symptoms. Increases in inflammatory markers in the nose and in the nasal secretion were significantly prevented by budesonide.

Some of these effects could be explained by a general systemic effect. However, it is known that 600 m g budesonide twice daily causes no, or minimal, systemic effects. The authors therefore suggest that the anti-inflammatory effects, particularly on eosinophils in the lower airways, affects the entire airway and therefore have a beneficial effect also in the nose.

This is an interesting paper because it shows the importance of treating the airway as an united organ. As well as it is good for the asthma that the rhinitis is well treated it is of benefit for the rhinitis that the asthma is under control. Just as it is beneficial for asthma when rhinitis is well controlled, so too is it beneficial for rhinitis when asthma is well controlled.

There is great interest in the potential benefits of inhaled corticosteroids for COPD patients.

The EUROSCOP and Isolde studies which included 900 and 751 patients, respectively, have demonstrated that inhaled steroids have an effect in COPD. The clinical relevance of this effect is at the moment evaluated and discussed.

The study by Bourbeau, however, is a smaller study. In 79 patients not responding to two weeks of 40 mg of prednisone daily, were given placebo or 1000 m g budesonide for six months. No beneficial effect was seen in the primary variable, change in FEV₁ , or in symptom variables.

The patients in this study were much sicker than the very mild cases in the EUROSCOP population and were even worse than those taking part in the Isolde study.

The study was well performed and must be compared with the other COPD studies, particularly with the Isolde study. The results contribute to the general discussion about the effects of inhaled steroids in COPD.

Bourbeau J, Rouleau MY, Boucher S McGill University Health Centre, McGill University, Montreal, Canada.
BACKGROUND: Inhaled corticosteroids are known to be beneficial for patients with asthma, but their role in treating patients with stable chronic obstructive pulmonary disease (COPD) remains controversial. A study was undertaken to determine whether inhaled corticosteroids are of functional benefit in patients who did not show improvement with a trial of oral corticosteroids. METHODS: In phase I patients with stable COPD were given a two week course of oral placebo followed by two weeks of prednisone 40 mg per day in a single blind manner to distinguish between responders and non-responders to oral corticosteroids. In phase II a double blind, randomised, parallel group trial of inhaled budesonide 1600 micrograms per day versus placebo was carried out in 79 nonresponders to oral corticosteroids. The primary outcome measure was forced expiratory volume in one second (FEV1), and secondary outcome measures were exercise capacity, dyspnoea with exertion, quality of life, peak expiration flow rate, and respiratory symptoms. RESULTS: Randomisation allocated 39 subjects to inhaled corticosteroids and 40 to placebo. There was no difference in the change in FEV1 from baseline between the treatment and placebo groups; mean difference -12 ml (95% CI -88 to 63) at three months and -4 ml (95% CI -95 to 87) at six months. The proportion of patients with a 15% or greater improvement was no higher among those receiving inhaled corticosteroids than in the placebo group at any of the follow up visits. Changes in secondary outcomes were also no different. CONCLUSIONS: Inhaled corticosteroids, even at high doses, were of no physiological or functional benefit in these patients with advanced COPD.

This study provides convincing evidence that the anti-inflammatory effect of budesonide in the airways is not limited to the site of drug deposition, but may involve more remote areas, as well.

These findings are not inconsistent with the conclusions of earlier studies which indicated that, at low dosage, the systemically absorbed bioactive fraction of inhaled budesonide or fluticasone is neither necessary for, nor contributory to, their therapeutic activity^1,2. At high doses, the possibility of a supererogatory effect from systemically absorbed drug cannot be excluded.

Exacerbations of Churg-Strauss syndrome have been reported as a rare complication of prednisone withdrawal under the aegis of zafirlukast antileukotriene therapy for asthma¹. In this case report, Katz and Papernik describe a patient in whom similar lesions occurred without accompanying or immediately antecedent withdrawal from systemic steroid. They interpret the event as a direct adverse effect of zafirlukast.

However, other observers consider this patient to be best categorized as a forme fruste Churg-Strauss syndrome, related only indirectly to the antileukotriene drug^2,3,4. In support of such an interpretation, Wechsler and Drazen note that, in many zafirlukast-treated patients who develop this particular complication¹, the hypereosinophilia and associated lesions may recur or progress without reexposure to zafirlukast, if the oral steroid is again progressively reduced⁴.

These observations echo earlier reports of "pulmonary infiltrations with eosinophilia" complicating attempted prednisone weaning when cromolyn therapy was initially approved for use in the USA about 30 years ago. To the best of my knowledge, no proof of a causal relationship to the cromolyn treatment was ever secured⁵.

ARLS

Congrès Conçue et réalisée par: Michel Godard (at)

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Title (1) :	Effect of low-dose beclomethasone dipropionate on asthma control and airway inflammation
Authors:	Fahy JV, Boushey HA Eur Respir J 1998;11:1240-1247
Comments by:	Professor Duncan Geddes Royal Brompton Hospital London SW3 6NP, England

Title (2) :	Treatment of acute asthmatic exacerbations with an increased dose of inhaled steroid
Authors:	Garrett J, Williams S, Wong C, et al Arch Dis Child 1998;79:12-17
Comments by:	Professor Duncan Geddes Royal Brompton Hospital London SW3 6NP, England

Title (3) :	Clinical efficacy of sublingual-swallow immunotherapy: a double-blind, placebo-controlled trial of a standardised five-grass-pollen extract in rhinitis
Authors:	Clavel R, Bousquet J, André C. Allergy 1998;53:493-498
Comments by:	Professor Duncan Geddes Royal Brompton Hospital London SW3 6NP, England

Title (4) :	Effect of low-dose beclomethasone dipropionate on asthma control and airway inflammation
Authors:	Fahy JV, Boushey HA Eur Respir J 1998;11:1240-1247
Comments by: (previous comment next comment)	Professor Philippe Godard Hôpital Arnaud de Villeneuve 34059 MONTPELLIER CEDEX 1 , France

Title (5) :	Cost-effectiveness of fluticasone and budesonide in patients with moderate asthma
Authors:	Steinmetz K-O, Volmer T, Trautmann M, et al. Clin Drug Inv 1998;16:117-123
Comments by: (previous comment next comment)	Professor Philippe Godard Hôpital Arnaud de Villeneuve 34059 MONTPELLIER CEDEX 1 , France

Title (6 ) :	Montelukast, a potent leukotriene receptor antagonist, causes dose-related improvements in chronic asthma
Authors:	Noonan MJ, Chervinsky P, Brandon M, et al. Eur Respir J 1998;11:1232-1239
Comments by: (previous comment next comment)	Professor Philippe Godard Hôpital Arnaud de Villeneuve 34059 MONTPELLIER CEDEX 1 , France

Title (7) :	Bambuterol is a more cost-effective treatment than salmeterol in asthma patients with nocturnal symptoms
Authors:	Crompton GK, Brusasco V, Eivindson A, et al Value in Health 1998;1:60
Comments by:	Ass. Professor Leif Rosenhall Hudding University Hospital S-141 86 Huddinge, Sweden

Title (8) :	Effects of orally inhaled budesonide in seasonal allergic rhinitis
Authors:	Greiff L, Andersson M, Svensson C, et al Eur Resp J 1998;11:1268-1274
Comments by:	Ass. Professor Leif Rosenhall Hudding University Hospital S-141 86 Huddinge, Sweden

Title (9) :	Randomised controlled trial of inhaled corticosteroids in patients with chronic obstructive pulmonary disease
Authors:	Bourbeau J, Rouleau MY, Boucher SThorax 1998;53:477-482
Comments by:	Ass. Professor Leif Rosenhall Hudding University Hospital S-141 86 Huddinge, Sweden

Title (10) :	Effects of orally inhaled budesonide in seasonal allergic rhinitis
Authors:	Greiff L, Andersson M, Svensson C, et al Eur Respir J 1998;11:1268-1274
Comments by:	Professor John H. Toogood Victoria Hospital LONDON, Ontario N6A 4G5, Canada

Title (11) :	Zafirlukast and Churg-Strauss syndrome
Authors:	Katz RS, Papernik M JAMA 1998;279:1949
Comments by:	Professor John H. Toogood Victoria Hospital LONDON, Ontario N6A 4G5, Canada