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previous  next Provided by/avec le support de :     S-221 87     Lund Sweden ARLS information : Myrna Mansson Get the paper version from your local Marketing representative. Find the address on the net at http://www.astrazeneca.com/Marketing-worldwide AstraZeneca Respiratory Literature Service N°3   1999 (see other Expert comments on Asmanet) For many years, AstraZeneca Draco laboratories have brought to the asthmologist 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 Comparison of oral bambuterol and inhaled salmeterol in patients with symptomatic asthma and using inhaled corticosteroids. Cropton GK et col. Am J Respir Crit Care Med 1999; 159:824-8 Dr. Lars Larsson 2 Benefits of high-dose i.v. immunoglobulin in patients with severe steroid-dependent asthma. Lawrence P Landwehr LP et al et al Chest 1998;114 :1349-1356 Ass. Professor Leif Rosenhall  Professor Estelle Simons 3 Increase in exhaled nitric oxide levels in patients with difficult asthma and correlation with symptoms and disease severity despite treatment with oral and inhaled corticosteroids. R G Stirling et al Thorax 1998; 53:1030 Professor Duncan Geddes Professor Philippe Godard 4 Peak flow variation in childhood asthma: correlation with symptoms, airways obstruction, and hyperresponsiveness during long term treatment with inhaled corticosteroids Brand et al Thorax 1999;54:103-107 Professor Philippe Godard 5 First treatment with inhaled corticosteroids and the prevention of admissions to hospital for asthma Blais et al Thorax 1998; 53:1025-9 Dr. Lars Larsson 6 Starting with a higher dose of inhaled corticosteroids in primary care asthma treatment. Van der Molen T et al,  Am J Respir Crit Care Med 1998;158:121-5 Professor Estelle Simons 7 Glucocorticoid insensitive asthma: a one year clinical follow up pilot study. Pascal Demoly et al Thorax 1998; 53:1063 Professor Duncan Geddes 8 Intranasal corticosteroids versus oral H1 receptor antagonists in allergic rhinitis: systematic review of randomised controlled trials. Weiner et al BMJ1998; 317:1624-9 Professor Estelle Simons Ass. Professor Leif Rosenhall 9 An inhaled steroid improves markers of airway inflammation in patients with mild asthma. A Jatakanon et al Eur Respir J 1998; 12:1084-8 Dr. Lars Larsson 10 Long-term influence of inhaled corticosteroids on bone metabolism and density. Are biological markers predictors of bone loss? Louis-Philippe Boulet et al Am J Respir Crit Care Med 1999; 159:838 Professor Duncan Geddes 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/ ...

For some years, it has been considered a truth that ß2-agonists should be used preferably via the inhaled route. This study challenges that perception and demonstrates that one tablet once a day may be as effective and as well tolerated as one inhalation twice a day. In addition, the cost of the oral treatment was, in this case, only 60% of that of the inhaled treatment.

The introduction of leukotriene antagonists has renewed the interest in oral asthma treatment, and it is obvious that for some patients this route is more suitable than the inhaled route. In these cases, bambuterol seems to be a very cost-effective alternative.

Title (1): . Comparison of oral bambuterol and inhaled salmeterol in patients with symptomatic asthma and using inhaled corticosteroids. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Salmeterol inhaled twice-daily is now being used more frequently as additional treatment in asthma insufficiently controlled by inhaled corticosteroids. We compared oral bambuterol in a dose of 20 mg taken once daily in the evening with inhaled salmeterol at 50 microgram taken twice daily in 126 asthmatic patients (60 bambuterol, 66 salmeterol) aged 18 to 74 yr who were treated for at least 4 wk with inhaled corticosteroids at a constant dose of 400 to 2,000 microgram/d or with oral corticosteroids at </= 20 mg/d. The patients were able to use a pressurized metered dose inhaler (pMDI) efficiently, and had an FEV1 of 40 to 85% of the predicted normal value. During a run-in period, patients had to show at least one nocturnal or early awakening caused by asthma symptoms that required rescue medication, and a >/= 15% overnight decrease in peak expiratory flow (PEF) on 3 of the preceding 7 d, in order to be randomized into this double-blind, double dummy, multicenter parallel group study (2-wk run-in period and 6 wk of treatment). There was no significant difference between bambuterol and salmeterol in morning change from baseline in PEF (p = 0.53). The median increases in morning PEF were 50 L/min for bambuterol and 55 L/min for salmeterol. Other variables (evening PEF, percent of overnight decrease in PEF, number of awakenings, percent of nights with an awakening, number of puffs of rescue medication, asthma symptoms during the day and night, and mean tremor score) also showed no significant difference between bambuterol and salmeterol. Both treatments, at the doses given, were well tolerated. Once-daily oral bambuterol is a convenient, effective, and less expensive alternative to twice-daily inhaled salmeterol for treating nocturnal asthma.

Ass. Professor Leif Rosenhall : We have great problems with a small number of asthmatics that are on far too high doses of steroids. The paper by Lawrence et al. reports a beneficial treatment with high intravenous doses of immunoglobulins in 11 such patients. All 11 patients could reduce their oral steroid dose by at least 40% and similarly improve their clinical situation.

All the patients had normal serum immunoglobulin levels, and the authors are unable to explain the results. Nevertheless, this treatment is worth trying in the small group of hopeless steroid-dependent asthmatics.

Professor Estelle Simons : This is the fourth published study in which the efficacy of IVIg in steroid-dependent asthma has been assessed. In the first such study, Page et al evaluated 5 children with asthma and IgG subclass deficiency after a dose of 100-300 mg/kg IVIg monthly; they found overall improvement in asthma. Mazer and Gelfand studied 8 children with severe steroid-dependent asthma, giving a monthly dose of 2 grams/kg IVIg for one year. Clinical symptoms, frequency of exacerbations, and peak expiratory flows all improved, as did skin-test reactivity to allergens. Recently, Jakobsson et al, using 400-800 mg/kg IVIg in 9 moderately severe asthmatics not receiving chronic oral steroid therapy, found rather minimal inhaled glucocorticoid-sparing effects.

In the Landwehr study reported here, 11 adolescents and adults had their asthma therapy optimised during a two-month pretreatment observation period, before IVIg infusion every four weeks for seven months. Nine of eleven patients were able to reduce their oral steroid requirement by > 50% during treatment, and the remaining two patients reduced their requirement by 40% and 42%, respectively, with average daily steroid doses declining from 31.6 ± 0.2 mg, an 82% overall mean reduction. Despite this, the bronchodilator FEV₁ improved in 82% of the subjects, as did other pulmonary function tests, including total lung capacity. Bronchial hyperresponsiveness did not change significantly.

The adolescents had a more favorable response than the adults, perhaps reflecting greater potential for reversibility due to shorter disease duration.

Although the subjects had many stigmata of steroid toxicity at the onset of the study, including Cushingoid features, osteopenia/osteoporosis, striae, acne, cataracts, hypertension, and short stature, the authors did not comment on any change in these signs after IVIg treatment. Bone-mineral density improved in 9 of 10 subjects.

The precise mechanism of action of IVIg is unknown; however, it has been demonstrated to reduce skin-test reactivity to specific allergens and to decrease cytokine production.

References:

1. Page R, Friday G, Stillwagon P, Skoner D, Caliguiri L, Fireman P. Asthma and selective immunoglobulin subclass deficiency: improvement of asthma after immunoglobulin replacement therapy. J Clin Pharmacol 1988;112:127-31.
2. Mazer BD, Gelfand EW. An open-label study of high-dose intravenous immunoglobulin in severe childhood asthma. J Allergy Clin Immunol 1991;87:976-83.
3. Jakobsson T, Croner S, Kjellman N-IM, Pettersson A, Vassella C, Björksten B. Slight steroid-sparing effect of intravenous immunoglobulin in children and adolescents with severe bronchial asthma. Allergy 1994;49:413-20.

Title (2) : Benefits of high-dose i.v. immunoglobulin in patients with severe steroid-dependent asthma. (partial abstract from http://www.healthy.net/library/search/medline.htm )

STUDY OBJECTIVE: To determine the efficacy of IV immunoglobulin (IVIg) in severe asthma to reduce steroid requirements. DESIGN: Pre- and posttreatment measurements were analyzed using Dunnett's multiple comparison procedure. SETTING: Hospital clinical research center. PATIENTS: Eleven adolescents and adults with severe, steroid-dependent asthma enrolled over a 14-month period. INTERVENTIONS: IVIg was administered at a dose of 2 g/kg every 4 weeks for a total of seven infusions. MEASUREMENTS AND RESULTS: Steroid requirements, pulmonary function including lung volumes, symptom scores, bone densitometry, and airway reactivity monitored by methacholine challenge were followed over the course of 7 months. A significant decrease in steroid usage was achieved. Despite substantial steroid reduction, the patients demonstrated improvement in their pulmonary function and symptom scores. The responses to methacholine challenge were unaffected by IVIg treatment. CONCLUSIONS: IVIg provides a potentially important adjunctive therapy in severe asthma, reducing oral steroid requirements and steroid side effects without deterioration of lung function.

Professor Duncan Geddes

Asthma can be monitored by lung function, symptoms, medication use or its effect on life and none of these measures is ideal. This study shows that while exhaled NO may add additional information it certainly does not solve the problem.

Patients with difficult asthma were found to have higher NO levels than normal controls but lower levels than steroid naïve mild asthmatics. Those requiring Prednisolone had higher levels than those whom did not. This suggests linkage to greater disease severity. However, the exhaled NO levels were only poorly correlated with symptom frequency and rescue beta-agonist use and they did not correlate at all with lung function.

This study confirms that exhaled NO does correlate in some ways with asthma activity. However, it does not establish the measurement as either more precise than existing measures or providing an additional dimension to asthma management. The measurement appears to be highly variable. While it may give valuable information about mechanisms, clinicians are yet to be convinced that it has clinical value.

Professor Philippe Godard

Although the number of patients with difficult asthma is low, having difficult asthma is a great problem. Therefore, the European Respiratory Society implemented a task force to study this problem. The conclusions will be published in the European Respiratory Journal soon.

The paper by Stirling et al. adds to our knowledge about difficult asthma. In difficult asthmatics and control subjects, Stirling et al. assessed levels of exhaled nitric oxide (NO) as a surrogate marker of inflammatory activity.

Unfortunately, at the present time there is no full consensus about the definition of difficult asthma. Stirling et al. used five criteria of which the fifth was "stable disease with no evidence of exacerbation or infection within the preceding two weeks." Chung et al. in 1994 characterised difficult asthma by uncontrolled symptoms and a failure to respond to usual "adequate treatment". The criteria stable disease (Stirling et al.) and uncontrolled symptoms (Chung et al.) seem contradictory.

In difficult asthma, it is important to check first compliance with treatment. However, a simple and good method to measure this does not exist. Stirling et al. estimated compliance by measuring serum prednisolone levels. Only 2 out of 36 patients were considered noncompliant. This seems low because at our research institute it was found that approximately 50% of the patients were noncompliant in an ongoing prospective study on difficult asthma (30 patients have been included at the present time).

Overall, the paper is of good scientific quality. Control groups were included, and the disease statuses of the patients were well defined and carefully described. NO levels correlated with symptom frequency and with b -agonist consumption. The paper showed convincingly that measuring NO might help to assess airway inflammation. However, before implementing this new tool, we need the following:

• a portable and inexpensive NO meter that can be used in an outpatient clinic
• additional evidence that adjusting steroid therapy based on results from NO measurements improves asthma control

Title (3): Increase in exhaled nitric oxide levels in patients with difficult asthma and correlation with symptoms and disease severity despite treatment with oral and inhaled corticosteroids. (partial abstract from http://www.healthy.net/library/search/medline.htm )

BACKGROUND: Patients with difficult asthma suffer chronic moderate to severe persistent asthma symptoms despite high doses of inhaled and oral corticosteroid therapy. These patients suffer a high level of treatment and disease related morbidity but little is known about the degree of airway inflammation in these patients.
 METHODS: Fifty two patients were examined to assess levels of exhaled nitric oxide (NO) as a surrogate marker of inflammatory activity in this condition. From this group, 26 patients were defined with severe symptoms and current physiological evidence of reversible airway obstruction requiring high dose inhaled (> or = 2000 micrograms beclomethasone dipropionate (BDP) equivalent) or oral steroid therapy to maintain disease control. 
RESULTS: Exhaled NO levels were higher in subjects with difficult asthma (mean 13.9 ppb, 95% CI 9.3 to 18.5) than in normal controls (7.4 ppb, 95% CI 6.9 to 7.8; p < 0.002), but lower than levels in steroid naive mild asthmatics (36.9 ppb, 95% CI 34.6 to 39.3; p < 0.001). Prednisolone treated patients had higher exhaled NO levels than patients only requiring inhaled corticosteroids (17.5 ppb, 95% CI 11.1 to 24.0 versus 7.2 ppb, 95% CI 4.6 to 9.8; p = 0.016), suggesting greater disease severity in this group. Non-compliance with prednisolone treatment was observed in 20% of patients but this did not explain the difference between the treatment groups. Exhaled NO levels were closely correlated with symptom frequency (p = 0.03) and with rescue beta agonist use (p < 0.002), but they did not correlate with lung function. 
CONCLUSIONS: Exhaled NO may serve as a useful complement to lung function and symptomatology in the assessment of patients with chronic severe asthma, and in the control and rationalisation of steroid therapy in these patients

Bronchial asthma is clearly a heterogeneous condition, and phenotypes differ among patients. International workshop guidelines try to clarify diagnosis and classify disease severity using one or more parameters. In clinical practice, however, each asthmatic patient is like a puzzle, which cannot be characterised by only one or two pieces.

As explained in the introduction section of the paper, assessment of PEF has been recommended by various guidelines either in adults or in children. This is assumed to be important for monitoring disease severity. However, Brand and the Dutch CNSLD Study Group concluded from their study that PEF assessment alone is not sufficient.

The Dutch CNSLD Study Group has conducted several major studies in asthma, and results of these have been widely acknowledged.

PEF variation, symptoms, and FEV1 improved during the first 2 months of treatment with inhaled corticosteroids and then remained the same. In contrast, PD 20 histamine continued to improve throughout the whole follow-up period. Bronchial hyperreactivity might be a much better parameter for disease severity.

Regular assessment of bronchial hyperreactivity might help to improve asthma therapy.

Title (4): Peak flow variation in childhood asthma: correlation with symptoms, airways obstruction, and hyperresponsiveness during long term treatment with inhaled corticosteroids (partial abstract from http://www.healthy.net/library/search/medline.htm )

Background-Guidelines for asthma management focus on treatment with inhaled corticosteroids and on home recording of peak expiratory flow (PEF). The effect of maintenance treatment with inhaled corticosteroids on PEF variation and its relation to other parameters of disease activity were examined in 102 asthmatic children aged 7-14 years. Methods-During 20 months of treatment with inhaled salbutamol, with or without inhaled budesonide (600 mu g daily), forced expiratory volume in one second (FEV1), the dose of histamine required to provoke a fall in FEV1 of more than 20% (PD20), the percentage of symptom free days, and PEF variation were assessed bimonthly. PEF variation was computed as the lowest PEF as a percentage of the highest PEF occurring over 14 days, the usual way of expressing PEF variation in asthma selfmanagement plans. For each patient using inhaled corticosteroids within subject correlation coefficients (rho) were computed of PEF variation to the percentage of symptom free days, FEV1, and PD20.Results-PEF variation decreased significantly during the first two months of treatment with inhaled corticosteroids and then remained stable. The same pattern was observed for symptoms and FEV1. In contrast, PD20 histamine continued to improve throughout the whole follow up period. In individual patients predominantly positive associations of PEF variation with symptoms, FEV1, and PD20 were found, but the ranges of these associations were wide.
Conclusions-During treatment with inhaled corticosteroids the changes in PEF variation over time show poor concordance with changes in other parameters of asthma severity. When only PEF is monitored, clinically relevant deteriorations in symptoms, FEV1, or PD20 may be missed. This suggests that home recording of PEF alone may not be sufficient to monitor asthma severity reliably in children

The effect of a certain asthma treatment is usually only documented in subgroups of patients because clinical trials have carefully selected inclusion criteria. Most clinical trials include moderate asthmatics. The results of these trials are extrapolated to the total population of asthmatics and generalisations are made.

The important information in the paper by Blais et al. is that such generalisations are probably valid. The superiority of inhaled steroids as early treatment in asthma was shown not only in the selected subgroups, but also in a general population of asthmatics.

The main finding that treatment with inhaled corticosteroids reduces the risk for hospitalisation – while theophylline does not – is in full agreement with results from clinical trials. Surprisingly, no reduced risk of hospitalisation was seen after irregular use of inhaled steroids. This indicates that irregular treatment (probably driven by symptoms) is not sufficient to avoid exacerbations leading to hospitalisation.

Title (5): First treatment with inhaled corticosteroids and the prevention of admissions to hospital for asthma  (partial abstract from http://www.healthy.net/library/search/medline.htm )

BACKGROUND: Early treatment with inhaled corticosteroids appears to improve clinical symptoms in asthma. Whether a first treatment initiated in the year following the recognition of asthma can prevent major outcomes such as admission to hospital has yet to be studied. 
METHODS: A case-control study nested within a cohort of 13,563 newly treated asthmatic subjects selected from the databases of Saskatchewan Health (1977-1993) was undertaken to investigate the effectiveness of a first treatment with inhaled corticosteroids in preventing admissions to hospital for asthma. Study subjects were aged between five and 44 years at cohort entry. First time users of inhaled corticosteroids were compared with first time users of theophylline for a maximum of 12 months of treatment. The two treatments under study were further classified into initial and subsequent therapy to minimize selection bias and confounding by indication. Odds ratios associated with hospital admissions for asthma were estimated using conditional logistic regression. Markers of asthma severity, as well as age and sex, were considered as potential confounders. 
RESULTS: Three hundred and three patients admitted to hospital with asthma were identified and 2636 matched controls were selected. subjects initially treated with regular inhaled corticosteroids were 40% less likely to be admitted to hospital for asthma than regular users of theophylline (odds ratio 0.6; 95% CI 0.4 to 1.0). The odds ratio decreased to 0.2 (95% CI 0.1 to 0.5) when inhaled corticosteroids and theophylline were given subsequently. 
CONCLUSION: The first regular treatment with inhaled corticosteroids initiated in the year following the recognition of asthma can reduce the risk of admission to hospital for asthma by up to 80% compared with regular treatment with theophylline. This is probably due, at least in part, to reducing the likelihood of a worsening in the severity of asthma.

This study, designed to investigate the effect of step-down treatment with inhaled corticosteroids during initiation of steroid treatment, was conducted in steroid-naïve asthmatic patients in 25 different general practices. The step-down treatment regimen tested was budesonide 400 µg twice daily for 4 weeks versus a control regimen of budesonide 100 µg twice daily. Both groups of patients continued on low-dose maintenance treatment with budesonide 100 µg twice daily for 2 months to maintain the induced effect of the previous treatment.

No extra benefit from the high initial dose of budesonide 400 m g twice daily was found, i.e., there appeared to be no advantage in using step-down treatment. Budesonide in a dose of 100 µg twice daily as both starting dose and maintenance dose was sufficient to control asthma in the majority of patients. The percentage of patients not reaching optimal asthma control was identical in both treatment groups.

The authors comment that further studies are needed to determine whether budesonide 100 µg twice daily is, in fact, the lowest effective dose needed for initiation of steroid treatment in steroid-naïve patients.

Title (6): Starting with a higher dose of inhaled corticosteroids in primary care asthma treatment. (partial abstract from http://www.healthy.net/library/search/medline.htm )

New British guidelines on the treatment of asthma (9) advocate starting with a higher dose of inhaled corticosteroids in newly detected asthma patients. We investigated whether initiating inhaled steroid treatment with a higher dose is clinically more effective than a lower dose in steroid naive patients with asthma. The study had a 13-wk randomized, double-blind, parallel design: 1-mo treatment with 400 microg budesonide twice a day, or 100 microg budesonide twice a day by dry powder inhaler, and follow-up treatment period of 2 mo with 200 microg budesonide once daily for all patients. Forty patients started with 400 microg budesonide twice daily, 44 with 100 microg budesonide twice daily. Mean age was 32 yr, baseline FEV1 value 84% predicted, reversibility 9% from baseline, and mean bronchodilator use 1.6 inhalations/d in the run-in period. After 4 wk of treatment with 400 microg and 100 microg budesonide twice daily mean morning peak expiratory flow (PEF) increased 27 L/min (SD 50), and 38 L/ min (SD 53), respectively (p = 0.30); mean symptom score improved from 1.1 to 0.6 and from 1.1 to 0.5. These effects were maintained in the 2 mo follow-up. This study suggests that starting inhaled corticosteroids at a higher dose is not superior to a lower dose in the treatment of newly detected asthma.

Does steroid-resistant asthma exist? This pilot study shows that glucocorticoid sensitivity varies between individuals and also varies over time within individuals. In other words, those with "steroid-resistant" asthma today may have steroid-sensitive asthma next year.

This has both clinical and mechanistic implications. In the first place, patients should not be labeled as having steroid-resistant asthma since this may deny them useful treatment some time in the future, and it also implies that they belong to a definable subgroup with consistent characteristics, which they do not. Secondly, those who search for, and find, mechanistic explanations for the condition may need to reconsider their methodology. There are many reasons why someone with asthma may not respond to steroids at a particular time, such as asthma in remission, fully treated with inhaled corticosteroids, failure to take or absorb the medication, continued exposure to an important environmental agent, psychological factors, etc. While this is only a pilot study, it seriously questions the value of the concept of steroid-resistant asthma, which should be re-evaluated.

Title (7): Glucocorticoid insensitive asthma: a one year clinical follow up pilot study. (partial abstract below from http://www.healthy.net/library/search/medline.htm )

BACKGROUND: Glucocorticoid resistant or insensitive asthmatic subjects are usually defined as patients whose baseline pre-bronchodilation forced expiratory volume in one second (FEV1) of less than 70-80% predicted improves significantly in response to beta 2 agonists but by less than 15% following 1-2 weeks of 40 mg prednisolone daily. Since there is little long term clinical information on these patients, a one year prospective study was performed to assess whether glucocorticoid sensitivity may vary over time. 
METHODS: Nineteen severe asthmatic subjects were studied and received 40 mg prednisolone daily for seven days. Prednisolone was given for a further seven days in glucocorticoid insensitive asthmatics and then stopped. Patients were followed up for one year and the glucocorticoid test was repeated on five patients in each group six months later. 
RESULTS: Eleven patients were classified as glucocorticoid insensitive and eight as glucocorticoid sensitive on day 7. The demographic characteristics of the patients were similar in both groups. Four glucocorticoid insensitive patients became responsive after one further week of prednisolone treatment. Six months later, four of five glucocorticoid sensitive patients and three of five previously glucocorticoid insensitive patients were glucocorticoid sensitive. 
CONCLUSIONS: Glucocorticoid sensitivity varies over time.

Professor Estelle Simons : The authors reviewed 16 randomised, controlled trials involving 2267 subjects with allergic rhinitis studied between 1966 and 1997. All the studies were double-blind, double-dummy, parallel-group, except for one crossover trial. Fifteen of the 16 studies involved seasonal allergic rhinitis and one, perennial allergic rhinitis. Nasal challenge studies, studies with non-clinical outcomes, and studies of patients with nasal polyps were not included. A variety of intranasal glucocorticoids, and aqueous and non-aqueous delivery vehicles were considered. Six studies involved intranasal beclomethasone; five, fluticasone; three, budesonide; and two, triamcinolone. Comparisons with oral antihistamines, but not with topical antihistamines or topical mast cell stabilisers, were reviewed. Seven of the 16 studies involved the antihistamine terfenadine, which is no longer used in most countries. Adequacy of double-blinding, which can be notoriously difficult with intranasal medications, was not assessed. Most outcomes were subjective, although nasal resistance was measured in two studies.

Intranasal corticosteroids produced significantly greater relief than oral antihistamines for nasal blockage, nasal discharge, sneezing, nasal itch, post-nasal drip, and total nasal symptoms, although not for nasal discomfort, nasal resistance, or eye symptoms. This is not surprising, as glucocorticoids down-regulate the entire inflammatory process in the nasal mucosa and conjunctivae, and antihistamines in the ordinary doses used would be expected to have a rather specific mechanism of action; namely, blocking the vascular and neural effects of histamine.

Although the authors did not assess the relative safety of H₁-antagonists versus intranasal glucocorticoids in their meta-analysis, in their conclusions, they imply that intranasal corticosteroids are safer than H₁-receptor antagonists. This remains to be proven in long-term studies.

Ass. Professor Leif Rosenhall : Meta-analyses of different topics are very popular and often very useful. This is a well-performed comparison between intranasal corticosteroids and oral antihistamines in 16 studies in which 2267 patients took part.

The steroids were best for relieving blockage, nasal discharge, sneezing, nasal itch, postnasal drip, and total nasal symptoms. Interestingly, there were no differences in eye symptoms, where the antihistamines would seem to be advantageous.

The compliance problems with inhaled steroids are of course not seen in clinical trials, but they should be considered when the results are translated into ordinary life.

Title (8): Intranasal corticosteroids versus oral H1 receptor antagonists in allergic rhinitis: systematic review of randomised controlled trials. (partial abstract from http://www.healthy.net/library/search/medline.htm )

OBJECTIVE: To determine whether intranasal corticosteroids are superior to oral H1 receptor antagonists (antihistamines) in the treatment of allergic rhinitis. 
DESIGN: Meta-analysis of randomised controlled trials comparing intranasal corticosteroids with oral antihistamines. 
SETTING: Randomised controlled trials conducted worldwide and published between 1966 and 1997.
SUBJECTS: 2267 subjects with allergic rhinitis in 16 randomised controlled trials. 
MAIN OUTCOME MEASURES: Nasal blockage, nasal discharge, sneezing, nasal itch, postnasal drip, nasal discomfort, total nasal symptoms, nasal resistance, and eye symptoms and global ratings. Outcomes measured on different scales were combined to determine pooled odds ratios (categorical outcomes) or standardised mean differences (continuous outcomes). Assessment of heterogeneity between studies, and subgroup analyses of eye symptoms, were undertaken. 
RESULTS: Intranasal corticosteroids produced significantly greater relief than oral antihistamines of nasal blockage (standardised mean difference 0.63, 95% confidence interval - 0.73 to - 0.53), nasal discharge (-0.5, - 0.6 to - 0.4), sneezing (- 0.49, - 0.59 to - 0.39), nasal itch (- 0.38,- 0.49 to - 0.21), postnasal drip (- 0.24,- 0.42 to - 0.06), and total nasal symptoms (- 0.42,- 0.53 to - 0.32), and global ratings gave an odds ratio for deterioration of symptoms of 0.26 (0.08 to 0.8). There were no significant differences between treatments for nasal discomfort, nasal resistance, or eye symptoms. The effects on sneezing, total nasal symptoms, and eye symptoms were significantly heterogeneous between studies. Other combined outcomes were homogeneous between studies. Subgroup analysis of the outcome of eye symptoms suggested that the duration of assessment (averaged mean score over the study period versus mean score at end of study period) might have accounted for the heterogeneity. 
CONCLUSION: The results of this systematic review, together with data on safety and cost effectiveness, support the use of intranasal corticosteroids over oral antihistamines as first line treatment for allergic rhinitis.

When is asthma severe enough to justify treatment with inhaled steroids? For clinically active physicians treating asthma, this question is important. In my opinion, this paper contains some good and some bad news.

The good news is that our old and well-tried tools to measure treatment effect seem rather sensitive also in mild asthma. In patients with apparently mild disease, 4 weeks of treatment with inhaled budesonide (800 m g bid) increased FEV₁ by 0.5 l. In addition, significant changes in bronchial responsiveness and in sputum eosinophil numbers were found.

The bad news is that the newer tools, such as NO and ECP, seem to give limited added value in the determination of treatment effects.

Title (9): An inhaled steroid improves markers of airway inflammation in patients with mild asthma. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Airway inflammation can be demonstrated in mildly asthmatic patients who are not treated with inhaled steroids. Current guidelines recommend that inhaled steroids should be introduced in mild asthmatics who use an inhaled beta2-agonist more than once daily. It was postulated that inhaled steroids can have anti-inflammatory effects in patients with even milder disease. The effect of 4 weeks of treatment with budesonide (800 microg twice daily by Turbohaler) was studied in 10 steroid-naive mildly asthmatic patients (forced expiratory volume in one second (FEV1) = 96+/-1.4% predicted) who required an inhaled beta2-agonist less than one puff daily, in a double-blind, placebo-controlled, crossover fashion. Spirometry, exhaled nitric oxide (NO), bronchial responsiveness (provocative concentration causing a 20% fall in FEV1 (PC20)), and sputum induction were performed before and after each treatment period. Following budesonide treatment, there were significant improvements in FEV1, and PC20, in association with a significant reduction in the percentage of eosinophils in induced sputum. Exhaled NO levels tended towards reduction, but the change was nonsignificant. There were also nonsignificant reductions in sputum eosinophil cationic protein and tumour necrosis factor-alpha levels. In conclusion inhaled budesonide can lead to improvements in noninvasive markers of airway inflammation, in association with a small improvement in lung function, even in mildly asthmatic patients who require an inhaled beta2-agonist less than once daily. This suggests a potential benefit of inhaled corticosteroids, even in relatively asymptomatic asthma.

Professor Duncan Geddes Two important questions, surrounding the inhaled steroid/osteoporosis risk debate, are:

1. Do inhaled corticosteroids represent a real risk of osteoporosis and therefore fractures?
2. Are there any surrogate markers which can predict those who are at risk.

This careful and detailed study shows that both of these questions remain unanswered. Bone density and bone metabolism markers were assessed over a 3-year period in two groups of asthmatic subjects. The first were taking high doses of inhaled corticosteroids (mean 983 µg per day) and the second took either no inhaled corticosteroids or less than 500 µg per day (mean 309 µg per day). Bone density was similar in both groups at the beginning and the end of the period of observation, as were serum and urinary measures of bone metabolism. The only correlation was between the decrease in bone density and mean daily dose of corticosteroid in the high-dose group, although these changes were small. Importantly, neither initial bone density nor any of the biological parameters could predict changes in bone density over the 3-year period.

This adds to the accumulating information that inhaled corticosteroids can have an effect on bone metabolism and bone mineral density but that the effect is extremely small, and whether this influences fracture rate is unknown. At present no metabolic markers can be used to identify patients at risk, and so the simple message must be to ensure that patients are treated with the lowest effective dose of inhaled corticosteroid. Given the flat dose response curve, it is difficult to understand why so many patients are still receiving such high doses.

Professor Philippe Godard: Boulet et al. performed a study to answer the question whether initial bone density or biological markers of bone metabolism can predict changes in bone mass. Although the authors had to give a negative answer, the paper is very interesting.

The rationale of the study has been well explained. Up to now, a predictor of bone loss is lacking. However, a marker that will predict who is at higher risk of bone loss after long-term therapy with corticosteroids is important, because that might allow preventive measures. Currently, the effects of ICS (inhaled corticosteroid) on bone metabolism and bone density are unclear. Boulet et al. give a good overview of the literature regarding this matter. Low doses of inhaled ICS seem to minimally influence bone metabolism, but the long-term effects of higher doses are to be further documented. Generally, daily doses equivalent to > 800 m g of beclomethasone were found to exert some influence on markers of bone metabolism. On the other hand, bone density seems unaffected by low doses of inhaled ICS, whereas the influence of high doses is uncertain.

The most important finding is that ICS do not induce a clinically significant reduction in bone density at doses of approximately 1000 m g/day over a period of 3 years. This is in line with the data by Wisniewski et al. as discussed in the paper. Wisniewski et al. also found no significant differences in mean bone density between subjects who were and were not on ICS. However, on multivariate analysis, cumulative ICS dose was associated with a small reduction in posterior-anterior and lateral lumbar spine bone mineral density in women.

When reading the Boulet study from another point of view, it is interesting to note the following:

• The severity of asthma remained constant during the 3 years; 80% of the patients kept a constant dose of ICS.
• Asthma was well controlled because the number of exacerbations, which was assessed by the need of oral steroid treatment was low.
• The prebronchodilator FEV1 in the high-dose steroid group was as low as 69% of predicted. After b 2-agonist inhalation, FEV₁ increased to 80% of predicted. This suggests that adding a long-acting b 2 agonist as maintenance therapy will benefit these patients.

In summary, the risk for a reduction in bone density by ICS is acceptable, and at this time there is no predictor of bone loss. This information should be explained to the patients.

Title (10): Long-term influence of inhaled corticosteroids on bone metabolism and density. Are biological markers predictors of bone loss? (partial abstract from http://www.healthy.net/library/search/medline.htm )

Long-term effects of high doses of inhaled corticosteroids (ICS) on bone density and metabolism are still uncertain. Fifty-one patients (37 male, 14 female) using beclomethasone or budesonide at a daily dose > 800 microgram/d (high-dose group [Group HD] mean: 983 microgram/d [prescribed dose x estimated compliance]) or no or < 500 microgram/d (control group [Group C] mean: 309 microgram/d) for more than 5 yr were enrolled in this study. Each had, 3 yr ago and at this last evaluation, a clinical evaluation and measurements of expiratory flows and of bone density and bone metabolism markers. Lumbar spine bone density (last visit) was similar in the two groups with respective values of 0.94 +/- 0.03 (HD) and 0.96 +/- 0.03 g/cm2 (C) (p > 0.05). T and Z scores were -1.21 +/- 0.19 and -0.70 +/- 0.18 (HD), -0.95 +/- 0.25 and -0.47 +/- 0.21 (C) respectively (p > 0.05). A correlation was found between the decrease in bone density and the mean daily dose of corticosteroid in Group HD although these changes were quite small, mean bone density being unchanged over the 3-yr period. Serum and urinary parameters were similar in the two groups. Furthermore, neither initial bone density nor any of the biological parameters could predict changes in bone density over a period of 3 yr. In conclusion, bone density was similar in both study groups and not significantly different over a 3-yr period. Neither initial bone density nor biological markers of bone metabolism helped to predict changes in bone mass.

. ARLS   Congrès Conçue et réalisée par: Michel Godard (at) Top
Date de création: 1er Mars 1996 -Dernière mise à jour: 16/05/00
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