Asmanet ARLS 1998 Astra Respiratory Literature Service Experts comments

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AstraZeneca Respiratory Literature Service
N°4 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	Duration of growth suppressive effects of regular inhaled corticosteroids	Doull IJM, Campbell MJ, Holgate ST	Arch Dis Child 1998;78:172-173	Professor Duncan Geddes
2	Prospective, double-blind, placebo-controlled, multicentre study on the effect of high-dose, intravenous immunoglobulin in children and adolescents with severe bronchial asthma.	Niggemann B, Leupold W, Schuster A, et al	Clinical and Experimental Allergy 1998;28:205-210	Professor Duncan Geddes
3	Pulmonary infiltrates, eosinophilia, and cardiomyopathy following corticosteroid withdrawal in patients with asthma receiving zafirlukast	Wechsler ME, Garpestad E, Filer SR, et al	JAMA 1998;279:455-457	Professor Duncan Geddes
4	Neuropsychological and behavioural changes in asthmatic children treated with beclomethasone diproprionate vs theophylline	Bender BG, Iklé DN, DuHamel T, et al	Pediatrics 1998;101:355-360	Professor Philippe Godard
5	Duration of growth suppressive effects of regular inhaled corticosteroids	Doull IJM, Campbell MJ, Holgate ST	Arch Dis Child 1998;78:172-173	Professor Philippe Godard
6	Short-term treatment with budesonide does not improve hyperresponsiveness to adenosine 5’-monophosphate in COPD	Rutgers SR, Koëter GH, van der MARK TW, et al	Am J Resp Crit Care Med	Professor Philippe Godard
7	Duration of growth suppressive effects of regular inhaled corticosteroids	Doull IJM, Campbell MJ, Holgate ST	Arch Dis Child 1998;78:172-173	Ass. Professor Leif Rosenhall
8	The US Lung Health Study	Buist AS	Respirology 1997;2:303-307	Ass. Professor Leif Rosenhall
9	Pulmonary infiltrates, eosinophilia and cardiomyopathy following corticosteroid withdrawal in patients with asthma receiving zafirlukast	Wechsler ME, Garpestad E, Filer SR, et al.	J Am Med Ass 1998;279:455-457	Ass. Professor Leif Rosenhall
10	Duration of growth suppressive effects of regular inhaled corticosteroids	Doull IJM, Campbell MJ, Holgate ST	Arch Dis Child 1998;78:172-173	Professor John H. Toogood
11	Bone mineral density in children with asthma receiving long-term treatment with inhaled budesonide	Agertoft L, Pedersen S	Am J Respir Crit Care Med 1998;157:178-183	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 ): direct access to the abstract whenever it's available is not possible. You have to perform a "search" using the search engine (and be exposed to the local advertiser banner which sort-of pays for the free access). You will then go through the following steps :

Select the names of the first two authors (or part of the title) and do a "copy" (ctrl C on a PC under Windows) so that you will have the search key at hand.
Click on the link in order to get the HealthGate/HealthWorld search home page.
Paste the search key (ctrl V) into the search window displayed on your screen and perform the search.

The search engine will send you back the list of papers with those two authors. HealthWorld search engine will give you related papers if you select it by the title. You will then select the link which you want if the paper is known and click on the link to get the abstract.

...

Evidence on growth suppression in children taking inhaled corticosteroids is conflicting. Some studies show no problem while others using very sensitive measures have shown short-term reductions in growth. Nonetheless, children who have taken inhaled corticosteroids for long periods seem to achieve normal adult height.

The study by Doull et al. measured the growth of 50 children for 30 weeks after starting beclomethasone dipropionate 200 m g twice daily. There was significant growth suppression during the first six weeks of treatment. However, after 18 weeks the children grew similarly to when they were not receiving treatment.

The results of this study are reassuring and emphasise that short-term changes do not necessarily predict long-term side-effects.

Author : Doull IJ; Campbell MJ; Holgate ST
Address : Department of Child Health, University Hospital of Wales, Heath Park, Cardiff.
Source : Arch Dis Child, 78(2):172-3 1998 Feb
Abstract : The growth of 50 children receiving regular inhaled corticosteroids was segregated into divisions of six weeks from the start of treatment and compared with their growth when not receiving regular corticosteroids using a random effects regression model. Growth suppression was most marked during the initial six weeks after starting treatment, with most suppression occurring during the initial 18 weeks. Thereafter the children's growth was similar to their growth when not receiving treatment. These findings have important consequences for patterns of treatment of asthma in children.

There has been considerable interest in the use of immunoglobulin for the control of difficult asthma. Initial open studies were encouraging despite a much earlier controlled trial from 1958¹ showing no benefit.

In this study by Niggeman et al., 31 children and adolescents with severe asthma received either four doses of intravenous immunoglobulin or identical doses of human serum albumin. There were no differences between the groups in symptoms, bronchial hyper-reactivity or peak flow variability. Similarly, there was no statistically significant difference in incidence of respiratory tract infections.

Negative studies of this sort are valuable both to guide treatment and also to emphasise the importance of appropriate study design in evaluating new treatments.

Title (2) : Prospective, double-blind, placebo-controlled, multicentre study on the effect of high-dose, intravenous immunoglobulin in children and adolescents with severe bronchial asthma. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Author : Niggemann B; Leupold W; Schuster A; Schuster R; v. Berg A; Gr¨ubl A; v. d. Hardt H; Eibl MM; Wahn U
Address : University of Children's Hospital, Berlin, Germany.
Source : Clin Exp Allergy, 28(2):205-10 1998 Feb
Abstract :
OBJECTIVE: In order to study the effect of high-dose, intravenous immunoglobulin (i.v.IG) in severe childhood asthma, we investigated 31 children and adolescents (15 girls, 16 boys) aged 9-22 years (median age of 14 years) suffering from severe bronchial asthma. METHODS: In a prospective, double-blind fashion, patients received either four doses of i.v.IG (1 g/kg body weight) or identical doses of intravenous human serum albumin. The first two doses were given on two consecutive days, followed by two further doses at 4 week intervals. RESULTS: There was no statistical difference in the actively treated group when compared with the placebo group in symptom-score, bronchial hyperreactivity or peak-flow-variability. There was a trend for fewer total days of upper respiratory tract infections and also symptom-scores in the i.v.IG group but these did not reach statistical significance.
CONCLUSION: Our data indicate that treatment with i.v.IG in asthmatic children did not show a significant reduction in the incidence of upper respiratory tract infections, but the patients who did have upper respiratory infections in the i.v.IG-group appear to have less protracted infections. Severity and bronchial hyperreactivity do not seem to be affected by the treatment as performed in our study.

Zafirlukast has been shown to have a weak anti-asthma effect and has been widely prescribed partly because oral medication is seen as simple and partly because of uncertainty about inhaled corticosteroid side-effects.

The paper by Wechsler et al. describes 8 adults with steroid-dependent asthma who received zafirlukast and subsequently developed a syndrome of pulmonary infiltrates, cardiomyopathy and eosinophilia consistent with the Churg-Strauss syndrome. This syndrome coincided with oral corticosteroid withdrawal.

The authors speculate that these patients had previously-undiagnosed Churg-Strauss syndrome which had been masked by steroid treatment of their asthma and which was unmasked when steroids were withdrawn. The possibility of an allergic reaction to the new drug cannot, however, be completely excluded. Similar, anecdotal reports of the syndrome appeared when systemic steroids were replaced by inhaled corticosteroids; this explanation will certainly be true for some of the cases.

The only way to exclude a genuine drug side-effect will be to monitor the frequency of this event carefully and to establish whether or not it occurs in those who have not previously received corticosteroids. Such ongoing monitoring is being pursued by the drug company concerned and the regulatory agencies.

Author : Wechsler ME; Garpestad E; Flier SR; Kocher O; Weiland DA; Polito AJ; Klinek MM; Bigby TD; Wong GA; Helmers RA; Drazen JM
Address : Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Source : JAMA, 279(6):455-7 1998 Feb 11
Abstract :
CONTEXT: Zafirlukast is a potent leukotriene antagonist that recently was approved for the treatment of asthma. As use of this drug increases, adverse events that occur at low frequency or in populations not studied in premarketing clinical trials may become evident. OBJECTIVE: To describe a clinical syndrome associated with zafirlukast therapy. DESIGN: Case series. PATIENTS: Eight adults (7 women and 1 man) with steroid-dependent asthma who received zafirlukast. MAIN OUTCOME MEASURES: Development of a clinical syndrome characterized by pulmonary infiltrates, cardiomyopathy, and eosinophilia following the withdrawal of corticosteroid treatment. RESULTS: The clinical syndrome developed while patients were receiving zafirlukast from 3 days to 4 months and from 3 days to 3 months after corticosteroid withdrawal. All 8 patients developed leukocytosis (range, 14.5-27.6 x 10(9)/L) with eosinophilia (range, 0.19-0.71). Six patients had fever (temperature >38.5 degrees C), 7 had muscle pain, 6 had sinusitis, and 6 had biopsy evidence of eosinophilic tissue infiltration. The clinical syndrome improved with discontinuation of zafirlukast treatment and reinitiation of corticosteroid treatment or addition of cyclophosphamide treatment. COMMENT: Development of pulmonary infiltrates, cardiomyopathy, and eosinophilia may have occurred independent of zafirlukast use or may have resulted from an allergic response to this medication. We suspect that these patients may have had a primary eosinophilic infiltrative disorder that had been clinically recognized as asthma, was quelled by steroid treatment, and was unmasked following corticosteroid withdrawal facilitated by zafirlukast.

The study by Bender et al. shows that neither inhaled BDP nor theophylline causes major changes in behaviour or cognition in children aged 6-17. This result has been obtained from a well conducted, one-year, double-blind study.

These very interesting results highlight the concept of evidence based medicine. In daily clinical practice, both patients and doctors worry about the possible deleterious effects of theophylline on behaviour and cognition. The results of this study reassure us that our worries are unfounded.

Additionally, this study demonstrates a positive effect of theophylline on asthma control. Both theophylline and inhaled BDP were well tolerated.

While these authors did not find any subgroup of patients unable to tolerate theophylline, the side-effects of this drug must always be kept in mind. When psychological side-effects are suspected, the authors suggest referral to a mental health professional. This strategy might prove more effective than careful discussion with parents and child because parental perceptions are often influenced by erroneous information or beliefs about chronic illness. Identifying the misconceptions which influence the parents can be a difficult part of treatment for the clinician. Medicine is really an art which tries to be a science.

Author : Bender BG; Ikl´e DN; DuHamel T; Tinkelman D
Address : Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206, USA.
Source : Pediatrics, 101(3 Pt 1):355-60 1998 Mar
Abstract :
OBJECTIVE: Results from previous investigations that examined the psychological side effects of theophylline have been inconsistent, and none have reported about inhaled corticosteroids. The objective of this study was to assess the relative psychological side effects of theophylline and beclomethasone in asthmatic children. METHODS: This was a multicenter, randomized, double-blind, parallel-groups study in which 102 asthmatic patients were assigned to one of two treatments: beclomethasone three times daily or theophylline twice daily. At baseline, 1 month, and 1 year, parents completed standardized behavioral questionnaires while the children received psychometric testing of attention and concentration, memory and learning, and problem-solving. RESULTS: Although power was sufficient to detect meaningful mean score changes, no consistent differential treatment effects were observed. Two significant treatment-by-period interactions were discordant, with one suggesting slightly better attention in the theophylline group, whereas the other indicated a small advantage in attention scores in the beclomethasone group. Numerous significant period effects revealed that behavior and cognitive test performance improved over the 1-year period, regardless of treatment, and confirmed a well established practice effect resulting from repeated administrations of such tests. CONCLUSIONS: Neither theophylline nor beclomethasone should be avoided out of concern for significant psychological side effects...

The study by Doull et al. was published in 1995 in the Am. J. Respir. Crit. Care Med.¹. In this recent publication, they report a new statistical analysis of the original data. This a new method allows the analysis of complex longitudinal data (such as growth) over several months. During the control period, when the children did not receive beclomethasone dipropionate (BDP), growth was 0.140 mm/week. Compared to this control period, growth was significantly decreased during weeks 0-6. In week 19-24 and 25-30 of the treatment period, the children’s growth was similar to their growth when not receiving treatment (see Figure 1).

Figure 1: Growth measured over the previous period of 6 weeks, expressed in mm/week. P-values refer to comparison with period when no inhaled BDP was used. Data derived from Table 1 in the original publication.

It seems that the growth suppressive effect of inhaled BDP has its greatest effect at the start of the treatment. The authors mention the possibility that such results may be due to non-compliance.

The authors suggest that the growth suppressive effects of inhaled steroids are mediated via action on osteoblasts, which changes over time. Further data is required to support this suggestion.

COPD and bronchial asthma! How many papers have been published trying to understand and treat these diseases? There is a lot of confusion in the diagnose, the understanding of pathophysiology and treatment. In fact there is no problem with each end of the spectrum; these diseases are different. However, there is important overlap and the distinction is sometimes difficult.

As usual, the phenotype of the patients has to be better assessed in order to better know the genetic component. In the near future, the selection of patients will include the description of the genotype and results will be more clear-cut.

In the current study, 44 smokers with impaired FEV₁ were included. The selection criteria were numerous and well chosen. But looking at individual results it is very difficult to see evidence of modification. Statistical analysis are absolutely necessary to demonstrate an effect of budesonide as compared to placebo.

This kind of study asks also the question about responders and non responders. This will need assessment in the future, in term of definition a priori, evaluation and understanding. This topic has not been evaluated in this paper but it probably exists COPD patients who will benefit from inhaled steroids and others who will not.

Author : Rutgers SR; Ko¨eter GH; van der Mark TW; Postma DS
Address : Department of Pulmonology, University Hospital Groningen, The Netherlands.
Source : Am J Respir Crit Care Med, 157(3 Pt 1):880-6 1998 Mar
Abstract : The role of inhaled corticosteroids in the treatment of chronic obstructive pulmonary disease (COPD) is unclear. We investigated the effects of budesonide on airway hyperresponsiveness (AHR) to methacholine (MCh) and adenosine 5'-monophosphate (AMP), to which we hypothesized the existence of greater sensitivity. Additionally, we studied the effects of budesonide on terfenadine and ipratropium bromide and on serum levels of interleukin-8 (IL-8) and histamine. Forty-four hyperresponsive smokers with moderate to severe COPD participated in the study. MCh and AMP challenges were given on three study days, after pretreatment with single doses of ipratropium bromide, terfenadine, or placebo. Thereafter, subjects were randomized to 6 wk treatment with either 1,600 microg budesonide or placebo, and the same three study days were repeated. Budesonide, as compared with placebo, did not significantly change PC20AMP, PC20MCh, or FEV1 after placebo pretreatment. Budesonide increased PC20MCh after ipratropium bromide pretreatment, from 5.05 to 10.20 mg/ml (p = 0.036). Budesonide decreased serum IL-8 from 9.2 +/- 3.7 to 6.2 +/- 2.1 pg/ml (p < 0.001). We conclude that AMP did not elicit greater sensitivity than MCh in assessing short-term effects of budesonide on AHR in smokers with COPD. We suggest that long-term treatment with inhaled corticosteroids might be beneficial, by reducing neutrophil load in the airways and improving the action of anticholinergic drugs.

This study by Doull et al. is one of many reports showing that inhaled steroids, even in accepted doses, may have some systemic effects.

It was found that growth suppression by inhaled beclomethasone diproprionate was most marked during the initial six weeks of treatment. The results are convincing. Therefore, systemic effects, such as initial growth suppression, must be taken into account when inhaled steroid therapy is considered.

Inhaled steroids are very important for the treatment of asthma. However, they gain a bad reputation when they are given at too high doses for too long, or when they are prescribed for diseases for which the drugs are not intended. For the successful treatment of asthma, proper dosing of inhaled steroids is necessary.

The US Lung Health Study is an enormously important study which will be of great interest for all people involved in lung medicine and public health.

Almost 6,000 patients with very mild COPD were followed prospectively for 5 years and had regular lung function measurements. The participants were randomised to three intervention groups. The two groups with an active but quite realistic smoking cessation program had significantly better results than the third group which was not involved in a smoking cessation program. The success of smoking cessation in the invention groups was as high as 35-40%. Besides an immediate effect on FEV₁ during the first year after cessation, the annual decline of lung function was less than in those who continued to smoke. Adding continuous bronchodilator therapy, ipratropium bromide, did not add any further beneficial effect.

Another important finding was that many patients had an increased sensitivity to methacholine which was accompanied by a steeper decline in lung function.

In comparison with EUROSCOP, the huge European COPD-study, the US study achieved better results regarding smoking cessation. Additionally, the US study found that the effect of smoking cessation on decline in lung function was better than treatment with inhaled corticosteroids. These differing results might be explained by the different populations of both studies. For example, patients with increased methacholine sensitivity would probably not have been included in the European COPD study.

Many more results and experiences from the US Lung Health Study are still to be published. However, this report makes it clear that:

Author : Buist AS
Address : Pulmonary and Critical Care Medicine, Oregon Health Sciences University, Portland, United States of America.
Source : Respirology, 2(4):303-7 1997 Dec
Abstract : The US Lung Health Study was a randomized clinical trial carried out in 10 clinical centres in the United States of America and Canada that enrolled 5887 male and female smokers age 35-60 years with early chronic obstructive pulmonary disease (COPD). Its purpose was to determine whether a programme incorporating smoking intervention and use of an inhaled bronchodilator (ipratropium bromide) can slow the rate of decline in the forced expiratory volume in one second (FEV1) in middle aged smokers with early COPD. Participants were randomized with equal probability into three groups: (i) smoking intervention plus bronchodilator; (ii) smoking intervention plus placebo; or (iii) no intervention. The primary outcome was rate of change and cumulative change in FEV1 over a 5 year period. The primary finding was that the use of the bronchodilator did not influence the long-term decline in FEV1. However, the aggressive smoking intervention programme significantly reduced the age-related decline in FEV1.

The development of Churg-Strauss syndrome in patients treated with one of the new antileukotrienes, zafirlukast, has evoked great interest. The paper by Wechsler et al. is a thorough report of eight cases.

The authors suggest that Churg-Strauss syndrome was caused by withdrawal of long-term systemic steroid treatment, thereby unmasking the dangerous syndrome. This suggestion seems probable since similar problems appeared 25 years ago when inhaled steroids were introduced in Sweden, also allowing withdrawal of long-term systemic steroid treatment.

The reason why zafirlukast, but none of the other antileukotrienes is associated with this syndrome was not explained in the article. It may be due to the fact that this drug was the first to be used in the US, where many more asthmatics are steroid-dependent than in Europe.

This post-hoc analysis of previously published data¹ demonstrated that the weekly growth rate of asthmatic children fell by 50% during the first six weeks after initiating regular beclomethasone treatment (0.4 mg/day), and thereafter reverted to normal despite continuation of the beclomethasone. No catch-up growth was observed during a four month observation period after cessation of the beclomethasone¹.

However, studies of the height attained at maturity by asthmatic children treated with low dose inhaled or oral steroid, indicate the initial loss in growth may eventually be fully offset at or before maturity^2,3.

The growth inhibiting potential of high dose inhaled steroid, used regularly or intermittently, remains to be determined.

This cross-sectional survey found no evidence that budesonide therapy (mean dose 0.5 mg/day for an average of 4,5 years) reduces bone mineral density. This accords with the results of other cross-sectional^1,2 or prospective³ studies in children. No data are available for children treated with high doses of inhaled steroid, presumably because such doses are rarely used.

In adults, the most unequivocal evidence that inhaled steroid treatment may actually reduce bone density, relates to the use of budesonide or beclomethasone at dosages exceeding 1 mg/day^4,5. At lower doses, the group mean bone density Z-scores did not differ significantly from normal⁵.

Author : Agertoft L; Pedersen S
Address : Department of Pediatrics, Kolding Hospital, Denmark.
Source : Am J Respir Crit Care Med, 157(1):178-83 1998 Jan
Abstract : The aim of our study was to assess the effects of long-term treatment with inhaled budesonide (BUD) on total body bone mineral density (BMD), total body bone mineral capacity (BMC), total bone calcium (TBC), and body composition in children with asthma. Dual energy X-ray absorptiometry (DEXA scan) was performed in 157 asthmatic children treated with inhaled BUD at a mean daily dose of 504 microg (range, 189 to 1,322 microg) for 3 to 6 yr (mean, 4.5 yr). Measurements were compared with those of 111 age-matched children also suffering from asthma but who had never been treated with exogenous corticosteroids for more than 14 d (control group). There were no statistically significant differences between the two groups in BMD (BUD = 0.915 g/cm2, controls = 0.917 g/cm2), BMC (BUD = 1,378 g, controls = 1,367 g), TBC (BUD = 524 g, controls = 519 g), or body composition (lean body weight = 27,600 g [BUD] and 26,923 g [control], % body fat = 20.1% [BUD] and 20.3% [control]). Furthermore, there was no correlation between any of these parameters and duration of treatment, accumulated or current dose of budesonide. Three to six years of treatment with inhaled budesonide at an average daily dose of 504 microg has no adverse effect on total BMD, total BMC, TBC, or body composition in children with chronic asthma.

ARLS

Congrès Conçue et réalisée par: Michel Godard (at)

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Date de création: 1er Mars 1996 -Dernière mise à jour: 17/06/99Le secret des correspondances transmises sur le réseau Internet n'est pas garanti. Toute personne citée dispose d'un droit d'accès, de modification, de rectification et de suppression des données le concernant (art. 34 de laloi "Informatique et Libertés"n° 78-17 du 6 janvier 1978). Pour l'éxercer adressez-vous àMichel Godard (at)

Title (1) :	Duration of growth suppressive effects of regular inhaled corticosteroids
Authors:	Doull IJM, Campbell MJ, Holgate ST Arch Dis Child 1998;78:172-173
Comments by:	Professor Duncan Geddes Royal Brompton Hospital London SW3 6NP, England

Title (2) :	Prospective, double-blind, placebo-controlled, multicentre study on the effect of high-dose, intravenous immunoglobulin in children and adolescents with severe bronchial asthma.
Authors:	Niggemann B, Leupold W, Schuster A, et al Clinical and Experimental Allergy 1998;28:205-210
Comments by:	Professor Duncan Geddes Royal Brompton Hospital London SW3 6NP, England

Title (3) :	Pulmonary infiltrates, eosinophilia, and cardiomyopathy following corticosteroid withdrawal in patients with asthma receiving zafirlukast
Authors:	Wechsler ME, Garpestad E, Filer SR, et al JAMA 1998;279:455-457
Comments by:	Professor Duncan Geddes Royal Brompton Hospital London SW3 6NP, England

Title (4) :	Neuropsychological and behavioural changes in asthmatic children treated with beclomethasone diproprionate vs theophylline
Authors:	Bender BG, Iklé DN, DuHamel T, et al Pediatrics 1998;101:355-360
Comments by: (previous comment next comment)	Professor Philippe Godard Hôpital Arnaud de Villeneuve 34059 MONTPELLIER CEDEX 1 , France

Title (5) :	Duration of growth suppressive effects of regular inhaled corticosteroids
Authors:	Doull IJM, Campbell MJ, Holgate ST Arch Dis Child 1998;78:172-173
Comments by: (previous comment next comment)	Professor Philippe Godard Hôpital Arnaud de Villeneuve 34059 MONTPELLIER CEDEX 1 , France

Title (6 ) :	Short-term treatment with budesonide does not improve hyperresponsiveness to adenosine 5’-monophosphate in COPD
Authors:	Rutgers SR, Koëter GH, van der MARK TW, et al Am J Resp Crit Care Med
Comments by: (previous comment next comment)	Professor Philippe Godard Hôpital Arnaud de Villeneuve 34059 MONTPELLIER CEDEX 1 , France

Title (7) :	Duration of growth suppressive effects of regular inhaled corticosteroids
Authors:	Doull IJM, Campbell MJ, Holgate ST Arch Dis Child 1998;78:172-173
Comments by:	Ass. Professor Leif Rosenhall Hudding University Hospital S-141 86 Huddinge, Sweden

Title (8) :	The US Lung Health Study
Authors:	Buist AS Respirology 1997;2:303-307
Comments by:	Ass. Professor Leif Rosenhall Hudding University Hospital S-141 86 Huddinge, Sweden

Title (9) :	Pulmonary infiltrates, eosinophilia and cardiomyopathy following corticosteroid withdrawal in patients with asthma receiving zafirlukast
Authors:	Wechsler ME, Garpestad E, Filer SR, et al. J Am Med Ass 1998;279:455-457
Comments by:	Ass. Professor Leif Rosenhall Hudding University Hospital S-141 86 Huddinge, Sweden

Title (10) :	Duration of growth suppressive effects of regular inhaled corticosteroids
Authors:	Doull IJM, Campbell MJ, Holgate ST Arch Dis Child 1998;78:172-173
Comments by:	Professor John H. Toogood Victoria Hospital LONDON, Ontario N6A 4G5, Canada

Title (11) :	Bone mineral density in children with asthma receiving long-term treatment with inhaled budesonide
Authors:	Agertoft L, Pedersen S Am J Respir Crit Care Med 1998;157:178-183
Comments by:	Professor John H. Toogood Victoria Hospital LONDON, Ontario N6A 4G5, Canada