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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°5    (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 Effects of formoterol in apparently poorly reversible chronic obstructive pulmonary disease. Maesen-BL; Westermann-CJ; Duurkens-VA; van-den-Bosch-JM 8. Eur-Respir-J. 1999 May; 13(5): 1103- Ass. Professor Leif Rosenhall 2 Exacerbations of asthma - A descriptive study of 425 severe exacerbations Tattersfield-AE et col. Am J Resp Crit Care Med 1999; 160(2):594-9 Professor Takateru Izumi 3 Once-daily budesonide inhalation suspension for the treatment of persistent asthma in infants and young children Kemp-JP; Skoner-DP; Szefler-SJ; Walton-Bowen-K; Cruz-Rivera-M; Smith-JA Ann Allergy Astrhma Immunol  SEP 1999; 83 (3) : 231-239 Professor Estelle Simons 4 Administration of budesonide once daily by means of Turbuhaler ® to subjects with stable asthma. McFadden-ER; Casale-TB; Edwards-TB; Kemp-JP; Metzger-WJ; Nelson-HS; Storms-WW; Neidl-MJ J-Allergy- Clin-Immunol. 1999 Jul; 104(1): 46-52 Professor Duncan Geddes Ass. Professor Leif Rosenhall 5 Oral corticosteroids in patients admitted to hospital with exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial Davies-L; Angus-RM; Calverley-PM Lancet. 1999 Aug 7; 354(9177): 456-60. Professor Duncan Geddes 6 Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. RA, Lofdahl CG, Laitinen LA, Schouten JP, Postma DS, Pride NB, Ohlsson SV N Engl J Med 1999 Jun 24;340(25):1948-53 Professor Duncan Geddes 7 Inhibitory effects of azelastine hydrochloride in alcohol-induced asthma. Takao-A; Shimoda-T; Matsuse-H; Mitsuta-K; Obase-Y; Asai-S; Kohno-S Ann-Allergy Asthma Immunol. 1999 Apr; 82(4): 390-4 Professor Estelle Simons 8 Underdiagnosis and undertreatment of asthma in the elderly Enright-PL; McClelland-RL; Newman-AB; Gottlieb-DJ; Lebowitz-MD CHEST-. SEP 1999; 116 (3) : 603-613. Professor Duncan Geddes Professor Takateru Izumi 9 Incidence and prevalence of asthma among adult Finnish men and women of the Finnish Twin Cohort from 1975 to 1990, and their relation to hay fever and chronic bronchitis. Huovinen-E; Kaprio-J; Laitinen-LA; Koskenvuo-M Chest. 1999 Apr; 115(4): 928-36. Professor Philippe Godard 10 Prospective multicenter study of relapse following treatment for acute asthma among adults presenting to the emergency department Emerman-CL; Woodruff-PG; Cydulka-RK; Gibbs-MA; Pollack-CV; Camargo-CA CHEST-. APR 1999; 115 (4) : 919-927. Professor Philippe Godard Ass. Professor Leif Rosenhall 11 Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics Wenzel-SE; Schwartz-LB; Langmack-EL; Halliday-JL; Trudeau-JB; Gibbs-RL; Chu-HW Am J Resp Crit Care Med. SEP 1999; 160 (3) : 1001-1008. Professor Philippe Godard Professor Takateru Izumi 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/ ...

Ass. Professor Leif Rosenhall: It is of great interest to determine whether or not good asthma drugs also are effective in COPD. This subject has been gaining increasing interest from drug companies, doctors, and patients.

In this study, formoterol Turbuhaler® was given to 12 COPD patients who were not reversible to a short-acting b ₂-agonist and who had considerable chronic obstruction. The effect on fev₁ was modest and not clinically relevant. However, the fall in airway resistance and the diminished work of breathing were impressive.

These findings may explain why some COPD patients experience clear subjective benefits from bronchodilators, particularly the long-acting b ₂-agonists, even when effects on lung function parameters, such as PEF or fev₁ are negligible.

The clinical problem is that measuring airway resistance or work of breathing is not easy. Thus, in clinical practice, the objective determination of the benefits of formoterol in COPD remains a problem. Currently, we have to rely on the patient’s opinion, but that is not too unusual to be true.

Title (1):  Effects of formoterol in apparently poorly reversible chronic obstructive pulmonary disease. (partial abstract from http://www.healthy.net/library/search/medline.htm )

This randomized, double-blind, placebo-controlled, crossover study was designed to investigate the effects of the long-acting beta2-adrenoreceptor agonist formoterol fumarate in 12 current or ex-smokers having chronic obstructive pulmonary disease, with a mean forced expiratory volume in one second (FEV1) 47% of predicted, poorly reversible (5.1% pred) after terbutaline sulphate inhalation. After inhaling a single dose of formoterol (6 or 24 microg), or placebo via Turbuhaler, FEV1 and pulmonary function parameters measured during quiet breathing (work of breathing (WoB) and airway resistance (Raw)) were recorded over 12 h on three test days. Immediate changes in FEV1 were modest, although each dose of formoterol caused a response >12% pred within 10 min in one subject. Compared to placebo, both doses of formoterol induced a clinically and statistically relevant improvement in WoB (>25%) and Raw (>20%), which occurred within 10 min and lasted over a period of 12 h (p < or = 0.02, analysis of variance). Thus, inhaled formoterol causes long-lasting lung functional improvements in apparently poorly reversible chronic obstructive pulmonary disease. Additional lung function measurements during quiet breathing after forced expiration tests may be useful in such patients to assess beneficial effects of bronchodilators.

Professor Takateru Izumi: The management of asthma exacerbations is an important problem, not only because the patient suffers from coughing, sputum, and dyspnea, but also because of the risk of asthmatic deaths. We know that the wide use of inhaled corticosteroids can prevent exacerbations to some degree, but details on the pathogenesis of exacerbation and the appropriate management remain to be solved.

In the FACET study¹, more than 800 patients receiving the inhaled corticosteroid budesonide at different doses with or without the b ₂-agonist formoterol for the management of severe and moderate asthma were followed for 1 year. In the analysis by Tattersfield et al., definite findings of an exacerbation pathogenesis were obtained from 425 severe exacerbation episodes that occurred in this study. PEF gradually decreased for several days preceding the exacerbation, and then dropped drastically within 2 or 3 days. At the same time, symptoms were exacerbated. These changes were the same in all the drug groups, and also in the groups where formoterol was added to budesonide.

These results should be described in textbooks. Further studies investigating the effect of intervention after recognizing an exacerbation pattern are being awaited.

Reference:
Pauwels et al.., New Engl J Med. 337; 1405-1411 (1997).

Title (2) : Exacerbations of asthma - A descriptive study of 425 severe exacerbations (partial abstract from http://www.healthy.net/library/search/medline.htm )

Exacerbations of asthma - A descriptive study of 425 severe exacerbations
Tattersfield-AE; Postma-DS; Barnes-PJ; Svensson-K; Bauer-CA; O'-Byrne-PM; Lofdahl-CG; Pauwels-RA; Ullman-A
AMERICAN-JOURNAL-OF-RESPIRATORY-AND-CRITICAL-CARE-MEDICINE. AUG 1999; 160 (2) : 594-599. PY: 1999 IS: 1073-449X
The identification, prevention, and prompt treatment of exacerbations are major objectives of asthma management. We looked at change in PEF, symptoms, and use of rescue p-agonists during the 425 severe exacerbations that occurred during a 12-mo parallel group study (FACET) in which low and high doses of budesonide with and without formoterol were compared in patients with asthma. Oral corticosteroids were prescribed for severe exacerbations, the main study end point, defined as the need for a course of oral corticosteroids (n = 311) or a reduction in morning PEF of > 30% on two consecutive days. PEF, symptoms, and bronchodilator use over the 14 d before and after the exacerbation were obtained from diary cards. Exacerbations were characterized by a gradual fall in PEF over several days, followed by more rapid changes over 2 to 3 d; an increase in symptoms and rescue p-agonist use occurred in parallel, and both the severity and time course of the changes were similar in all treatment groups. Exacerbations identified by the need for oral corticosteroids were associated with more symptoms and smaller changes in PEF than those identified on the basis of PEF criteria. Female sex was the main patient characteristic associated with an increased risk of having a severe exacerbation. Exacerbations may be characterized predominantly by change in symptoms or change in PEF, but the pattern was not affected by the dose of inhaled corticosteroid or by whether the patient was taking formoterol.

Professor Estelle Simons: Traditionally, the inhaled glucocorticoid budesonide has been administered four times daily to patients of all ages. Times have changed!

In this multicentre, randomized, double-blind, placebo-controlled, parallel-group study of 359 children aged 6 months to 8 years, each dose regimen of budesonide inhalation suspension 0.25 mg, 0.5 mg, or 1.0 mg administered once daily via a Pari LC-Jet Plus™ nebulizer for 12 weeks was more effective than placebo. In a similar recent study by Baker et al.¹ conducted in 480 children aged 6 months to 8 years, budesonide inhalation suspension 0.25 mg once daily, 0.25 mg twice daily, 0.5 mg twice daily, or 1.0 mg once daily were administered. All the dosing regimens produced statistically significant improvement in various clinical measures for asthma control compared with placebo, but the lowest dose used, 0.25 mg once daily, was less effective than other doses, and only the 0.5 mg bid dose significantly improved the fev₁ when compared with placebo.

In both of these studies, safety was based on a review of adverse events and assessment of HPA-axis function after ACTH stimulation. In future studies, growth velocity should also be monitored, as if a change in growth velocity is going to occur during inhaled glucocorticoid treatment. It will likely be noted within 6-12 weeks of starting treatment^2,3 .

References:

1. Baker JW, Mellon M, Wald J, Welch M, Cruz-Rivera M, Walton-Bowen K. A multiple-dosing, placebo-controlled study of budesonide inhalation suspension given once or twice daily for treatment of persistent asthma in young children and infants. Pediatrics 1999;103:414-21.
2. Simons FER, and the Canadian Beclomethasone Dipropionate Salmeterol Xinafoate Study Group. A comparison of beclomethasone, salmeterol, and placebo in children with asthma. N Engl J Med 1997;337:1659-65.
3. Doull IJM, Freezer NJ, Holgate ST, Growth of prepubertal children with mild asthma treated with inhaled beclomethasone dipropionate. Am J Respir Crit Care Med 1995;151:1715-9.

Title (3): Once-daily budesonide inhalation suspension for the treatment of persistent asthma in infants and young children (partial abstract from http://www.healthy.net/library/search/medline.htm )

Kemp-JP; Skoner-DP; Szefler-SJ; Walton-Bowen-K; Cruz-Rivera-M; Smith-JA
ANNALS-OF-ALLERGY-ASTHMA-AND-IMMUNOLOGY. SEP 1999; 83 (3) : 231-239.
PY: 1999 IS: 1081-1206

Background: Inhaled glucocorticosteroids (GCS) are the most effective longterm controller medications for the treatment of persistent asthma. Currently, however, available delivery devices limit their use in young children. A nebulized formulation of budesonide has been developed to address the needs of infants and young children.Objective: To evaluate the efficacy and safety of once-daily budesonide inhalation suspension in children 6 months to 8 years old with mild persistent asthma not on inhaled GCS.Methods: Three hundred fifty-nine children were randomized to receive once-daily budesonide inhalation suspension (0.25 mg, 0.50 mg, or 1.0 mg) or placebo via a Pari LC-Jet Plus(TM) nebulizer for 12 weeks. Efficacy assessments included nighttime/daytime asthma symptoms, pulmonary function (subset of patients), rescue medication use, and treatment discontinuations. Safety was based on adverse events and assessment of HPA-axis function.Results: Demographics, baseline characteristics, asthma symptoms, and pulmonary function were similar across treatment groups. Mean nighttime/daytime asthma symptom scores were 1.19 +/- 0.63 and 1.34 +/- 0.53, respectively. Mean duration of asthma was 36.3 months and mean FEV1 was 81.3% of predicted with 27.7% reversibility.Following 12 weeks of treatment, all budesonide inhalation suspension doses produced significant improvements in nighttime/daytime symptoms (P less than or equal to.049) and significant decreases in rescue medication use (P less than or equal to.038) compared with placebo. Significant improvements (P less than or equal to.044) in FEV1, were observed in the 0.5- and 1.0-mg budesonide inhalation suspension groups. There were no differences between doses of budesonide inhalation suspension. Adverse events and basal and ACTH-stimulated cortisol levels were similar among all groups.Conclusion: Once-daily administration of budesonide inhalation suspension was well tolerated and effective for the treatment of mild persistent asthma in infants and young children not adequately controlled with bronchodilators or non-GCS antiinflammatory treatments.

Professor Duncan Geddes : This simple study establishes that patients with asthma improve on 200 ug of budesonide and that improvement can be achieved with once-daily dosing. The improvements were similar to those in other inhaled steroid studies, and once again emphasize how effective this treatment is in low dosage.

However, a number of important questions remain:

• Is there an important difference between once-daily and twice-daily dosing?
• How does the frequency of dosing interact with the total daily dose to achieve optimal asthma control?
• Is there a compliance advantage in once- as compared with twice-daily dosing?

The last 10 years have seen considerable improvements in the simplicity of inhaled corticosteroid treatment together with an overall reduction in the doses used for maintenance treatment. Nevertheless, much remains to be learned about the bottom of the dose-response curve and its interaction with timing and compliance to make treatment as simple and safe as possible.

Ass. Professor Leif Rosenhall : Inhaled corticosteroids are the most important asthma drugs, and their doses should be adjusted to the disease severity. This means that the dose varies between patients, but it also varies in time for the individual patient.

In this American study, patients with mild-to-moderate stable asthma were treated with budesonide once daily. A dose of 400 µg was not significantly superior to a dose of 200 µg, but, of course, both doses were better than placebo. About half of the patients were treated with beclomethasone given at least twice daily at in the study. These patients did not deteriorate when they switched to a once-daily budesonide dose regimen. Although the study had not been designed to compare once- and twice-daily treatments, it is fair to conclude that the once-daily regimen may be as good as the twice-daily regimen in many patients.

The discussion section of the paper is interesting to read. The authors mention that, although most patients prefer to take their medication in the morning, still some will prefer to take their inhalation in the afternoon or evening. The authors also mention that "quality of life" should be measured in all studies of mild and moderate asthmatics. Lung function measurements are not enough.

The number of exacerbations in the actively treated groups was small: 4% and 1% in the budesonide 200 m g and the budesonide 400/200 mcg group, respectively.

Nevertheless, it is interesting to know whether these exacerbations could have been prevented if the patients had increased the dose of inhaled steroids when they felt that the asthma had become worse.

Title (4): Administration of budesonide once daily by means of turbuhaler® to subjects with stable asthma. (partial abstract from http://www.healthy.net/library/search/medline.htm )

McFadden-ER; Casale-TB; Edwards-TB; Kemp-JP; Metzger-WJ; Nelson-HS; Storms-WW; Neidl-MJ
J-Allergy-Clin-Immunol. 1999 Jul; 104(1): 46-52. ISSN: 0091-6749

BACKGROUND: Optimal management of chronic, mild-to-moderate asthma with inhaled steroids may include use of the lowest possible doses, as recommended in guidelines, and a reduction in the frequency of daily administration for greater convenience. Lower doses and once daily treatment with inhaled steroids must be rigorously evaluated in controlled clinical trials. 
OBJECTIVES: The objective of this study was to assess the efficacy and safety of once daily treatment with budesonide in subjects with stable asthma. 
METHODS: Once daily budesonide was assessed in 309 adult subjects, including those who were and were not using an inhaled steroid at baseline. The subjects were stratified by inhaled steroid use and randomly assigned to one of 3 treatments: 200 microgram budesonide, 400 microgram budesonide, or placebo administered by means of Turbuhaler once daily in the morning for 6 weeks. Beyond this point, treatment was continued unchanged for another 12 weeks (maintenance) in those receiving 200 microgram budesonide once daily and placebo. In those who received 400 microgram budesonide once daily, the dose was reduced to 200 microgram once daily at week 6 and held constant for the remaining 12 weeks (400/200 microgram group). Primary efficacy endpoints were mean change from baseline in FEV1 and morning peak expiratory flow. 
RESULTS: Once daily budesonide was well tolerated and resulted in significant improvements in all efficacy endpoints, even though baselines were well stabilized. Baseline lung function was elevated with little room for improvement; however, mean increases in FEV1 during the maintenance period were 0.10 L and 0.11 L in the 200 microgram and 400/200 microgram groups, respectively, versus a decrease of -0.09 L in the placebo arm (P <.001). Results for peak expiratory flow were similar. Significant improvements in secondary endpoints, including symptoms, beta-agonist use, and quality of life, also developed with budesonide 200 and 400 microgram once daily. 
CONCLUSION: Inhaled budesonide, in doses as low as 200 microgram, may be an appropriate introductory or maintenance dose in subjects with stable, mild-to-moderate asthma.

Professor Duncan Geddes: Most patients admitted to hospital with acute exacerbations of COPD are treated with systemic corticosteroids, and this study provides good supporting evidence. Although there was no significant difference in symptoms, the fev₁ improved more rapidly, and there was a reduction in the median hospital stay of 2 days. The paper almost certainly underestimates the benefits of treatment, because 5 patients in the placebo group compared with only 1 in the active treatment group were withdrawn owing to poor clinical progress, and they subsequently received corticosteroids. No patient in the study died during the exacerbations, and any possible mortality benefit was obscured in part by the withdrawal policy above and in part because acidotic patients were excluded from the study.

The important practical messages are first that a negative steroid trial under chronic stable conditions does not predict short-term benefits during exacerbations, and secondly in the face of this evidence of benefits without side-effects, all such patients should be given systemic corticosteroids. The need of such treatment in patients with very mild exacerbations has not been established, but if in doubt, give a short-course of treatment. The patient will get better more rapidly, although the long-term outcome is the same.

Title (5): Oral corticosteroids in patients admitted to hospital with exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial (partial abstract from http://www.healthy.net/library/search/medline.htm )

Davies-L; Angus-RM; Calverley-PM
Lancet. 1999 Aug 7; 354(9177): 456-60.
ISSN: 0140-6736

BACKGROUND: The role of oral corticosteroids in treating patients with exacerbations of chronic obstructive pulmonary disease (COPD) remains contentious. We assessed in a prospective, randomised, double-blind, placebo-controlled trial the effects of oral corticosteroid therapy in patients with exacerbations of COPD requiring hospital admission. 
METHODS: We recruited patients with non-acidotic exacerbations of COPD who were randomly assigned oral prednisolone 30 mg once daily (n=29) or identical placebo (n=27) for 14 days, in addition to standard treatment with nebulised bronchodilators, antibiotics, and oxygen. We did spirometry and recorded symptom scores daily in inpatients. Time to discharge and withdrawals were noted in each group. We recalled patients at 6 weeks to repeat spirometry and collect data on subsequent exacerbations and treatment. Hospital stay was analysed by intention to treat and forced expiratory volume in 1 s (FEV1) according to protocol. 
FINDINGS: FEV1 after bronchodilation increased more rapidly and to a greater extent in the corticosteroid-treated group: percentage predicted FEV1 after bronchodilation rose from 25.7% (95% CI 21.0-30.4) to 32.2% (27.3-27.1) in the placebo group (p<0.0001) compared with 28.2% (23.5-32.9) to 41.5% (35.8-47.2) in the corticosteroid-treated group (p<0.0001). Up to day 5 of hospital stay, FEV1 after bronchodilation increased by 90 mL daily (50.8-129.2) and by 30 mL daily (10.4-49.6) in the placebo group (p=0.039). Hospital stays were shorter in the corticosteroid-treated group. Groups did not differ at 6-week follow-up. 
INTERPRETATION: These data provide evidence to support the current practice of prescribing low-dose oral corticosteroids to all patients with non-acidotic exacerbations of COPD requiring hospital admission.

Professor Duncan Geddes: Should people with COPD be treated with inhaled steroids? A large amount of time, money, and effort have been spent over the last 5 years trying to answer this simple question, and this study provides a limited set of answers. The study cannot be criticized in terms of size or methodology, but it addresses and answers only one simple question, namely, Do inhaled steroids alter the rate of decline of FEV1 in smokers? Most clinicians have more than this on their mind when deciding whether or not to prescribe inhaled steroids.

In the first place, patients consulting doctors usually have symptoms, and treatment decisions are aimed at these as well as the long-term consequences. Do patients with COPD feel better, walk further, have fewer exacerbations, and have less absenteeism from work as a result of inhaled steroids? These questions were not addressed and remain unanswered. In particular, the single-step improvement in FEV1 on the order of 100 ml was sustained, and while it may not be very important in terms of survival or the date on which symptoms develop, it may nevertheless be quite valuable in relieving symptoms among those who have them. Certainly a bronchodilator response of 100 ml is usually enjoyed by patients with severe COPD. We need therefore to know whether this single-step change is similar in patients with much worse airflow obstruction. Secondly, the patients studied were continuing to smoke, and therefore the applicability of the results to those who stopped smoking is unknown, because many persons with COPD do stop smoking as they develop symptoms. Thirdly, the delivery device and dose of inhaled steroids could be challenged. However, given the flat dose response curve for all asthma outcome measures and the efficiency of the Turbuhalerâ , this does not present an important problem.

Overall, this is one of a number of very carefully designed studies addressing the question of inhaled steroids in COPD. The authors should be congratulated on answering one of the important questions so successfully. Nevertheless, there are a number of other studies in the pipeline, and much more information is needed before prescribers can support their decisions with evidence.

Title (6): Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. european respiratory society study on chronic obstructive pulmonary disease  (partial abstract from http://www.healthy.net/library/search/medline.htm )

N Engl J Med 1999 Jun 24;340(25):1948-53
RA, Lofdahl CG, Laitinen LA, Schouten JP, Postma DS, Pride NB, Ohlsson SV
Department of Respiratory Diseases, University Hospital, Ghent, Belgium. romain.pauwels (at) rug.ac.be

BACKGROUND: Although patients with chronic obstructive pulmonary disease (COPD) should stop smoking, some do not. In a double-blind, placebo-controlled study, we evaluated the effect of the inhaled glucocorticoid budesonide in patients with mild COPD who continued smoking. After a six-month run-in period, we randomly assigned 1277 subjects (mean age, 52 years; mean forced expiratory volume in one second [FEV1], 77 percent of the predicted value; 73 percent men) to twice-daily treatment with 400 microg of budesonide or placebo, inhaled from a dry-powder inhaler, for three years. 
RESULTS: Of the 1277 subjects, 912 (71 percent) completed the study. Among these subjects, the median decline in the FEV1 after the use of a bronchodilator over the three-year period was 140 ml in the budesonide group and 180 ml in the placebo group (P=0.05), or 4.3 percent and 5.3 percent of the predicted value, respectively. During the first six months of the study, the FEV1 improved at the rate of 17 ml per year in the budesonide group, as compared with a decline of 81 ml per year in the placebo group (P<0.001). From nine months to the end of treatment, the FEV1 declined at similar rates in the two groups (P=0.39). Ten percent of the subjects in the budesonide group and 4 percent of those in the placebo group had skin bruising (P<0.001). Newly diagnosed hypertension, bone fractures, postcapsular cataracts, myopathy, and diabetes occurred in less than 5 percent of the subjects, and the diagnoses were equally distributed between the groups. 
CONCLUSIONS: In patients with mild COPD who continue smoking, the use of inhaled budesonide is associated with a small one-time improvement in lung function but does not appreciably affect the long-term progressive decline.

Professor Estelle Simons: This small study confirms that 1-week treatment with the H₁-antagonist azelastine in the usual oral dose of 2 mg twice daily prevents alcohol-induced bronchoconstriction. The study represents an interesting contribution to our understanding of the role of histamine in alcohol-induced asthma and the potential role of H₁-receptor antagonists in the treatment of alcohol-induced asthma, a phenotype that has not received as much attention as it deserves.

In addition to its ability to produce H₁-receptor blockade, azelastine, like many H₁-receptor antagonists, has anti-allergic effects, including prevention of the release of histamine and other mediators of inflammation from human basophils and most cells by mechanisms that do not involve H₁-receptor antagonism¹. Azelastine has a half-life of 22 ± 4 hours, whereas its active metabolite desmethylazelastine has a half-life of 54 ± 15 hours. Thus, steady-state plasma concentrations are not reached for many days after administration of the first dose, and the investigators appropriately performed their investigations after 1 week of treatment. The oral formulation of azelastine is not available in many countries.

Reference
Simons FER, Antihistamines. In: Middleton E Jr, Reed CE, Ellis EF, Adkinson NF Jr, Yunginger JW, Busse WEW, eds. Allergy Principles and Practice. 5^th Ed. St. Louis: Mosby-Year Book, Inc., 1998:612-37.

Title (7): Inhibitory effects of azelastine hydrochloride in alcohol-induced asthma. (partial abstract below from http://www.healthy.net/library/search/medline.htm )

Takao-A; Shimoda-T; Matsuse-H; Mitsuta-K; Obase-Y; Asai-S; Kohno-S
Ann-Allergy-Asthma-Immunol. 1999 Apr; 82(4): 390-4.
ISSN: 1081-1206

BACKGROUND: Alcohol-induced bronchoconstriction is due to high blood concentrations of acetaldehyde, a metabolic product of ethanol, which lead to the release of histamine from basophils and mast cells. 
OBJECTIVE: We examined the inhibitory effects of azelastine hydrochloride, which inhibits histamine release and blocks H1 receptors, in alcohol-induced asthma. 
METHODS: Subjects were 13 Japanese asthmatic patients. We measured the change in FEV1 after ingestion of 30 g of pure ethanol. Blood ethanol, acetaldehyde, histamine, leukotriene C4 (LTC4), and thromboxane B2 (TXB2) concentrations were also measured. Alcohol challenge test was repeated in responders after administration of azelastine for 1 week at 4 mg/day. 
RESULTS: Of 13 asthmatic patients, five (38.5%) tested positive during an ethanol challenge test, represented by a fall more than 20% in FEV1. The responders had a high blood ethanol, and showed a rise in blood acetaldehyde and histamine concentrations, but not in LTC4 or TXB2. After azelastine treatment, there was no significant fall in FEV1 among responders. Neither the rise in blood ethanol nor blood acetaldehyde levels were blunted by treatment with azelastine, but the rise in blood histamine was blunted by this treatment. 
CONCLUSION: Our results suggest that antihistamine agents may be effective against alcohol-induced asthma by both blocking H1 receptors and inhibiting histamine release.

Professor Duncan Geddes : There are numerous studies of asthma prevalence and treatment in children and persons in middle life, but surprisingly few studies in the elderly. This large study demonstrates well that asthma is common and undertreated in the elderly, with a prevalence of 8% having definite or probable asthma and another 11% having possible asthma. A disturbing number were taking oral corticosteroids, and were thus risking side-effects, which are a particular problem in the elderly, while less than a third were taking inhaled corticosteroids in spite of experiencing quite a high number of symptoms and sleep disturbances. There has been considerable improvement in the diagnosis and treatment of asthma in children in the last 10 years, but this does not appear to have extended to older age groups, although as the study acknowledges, there may be important differences between different countries.

Respiratory specialists continue to play an important role not only in treating asthma, but also in extending the message about underdiagnosis and undertreatment to their nonspecialist colleagues.

Professor Takateru Izumi, M.D. : Many elderly persons throughout world suffer from asthmatic conditions that go on undiagnosed and untreated. Several reports have already described this problem. Of the 5968 patients who died of asthma in Japan in 1997, 4669 (78%) were over 65 years old. There is a possibility that COPD deaths were included among them, but these results strongly imply that asthma in the elderly has been undertreated.

Enright et al. reported the status of underdiagnosis and undertreatment of asthma in the elderly. A total of 4581 participants over 63 years of age were selected from the Cardiovascular Health Study, an American prospective study designed to analyze the epidemiology and risk factors associated with cardiovascular disease in the elderly. The current asthma status of the selected participants were categorized into "possible", "probable", and "definite" asthma. The total percentage of patients with possible or probable asthma was 11.4% and 4.1%, respectively, and the percentage of patients with definite asthma was 3.9%. When smokers were excluded, the percentages were 10.9%, 3.7%, and 3.6%, respectively.

According to current guidelines, an inhaled corticosteroid is the first-choice drug for management of asthma. However, only 30% of the definite asthmatics received an inhaled corticosteroid. On the other hand, oral corticosteroids were used by as many as 19% of the definite asthmatics in spite of the undesirable side-effects of these drugs.

This study shows that an increased effort is needed to implement treatment according to asthma guidelines in elderly asthma patients. Moreover, clinical studies in the elderly are necessary to provide evidence-based medicine supporting the value of asthma guidelines in the elderly.

Title (8): Underdiagnosis and undertreatment of asthma in the elderly (partial abstract from http://www.healthy.net/library/search/medline.htm )

Enright-PL; McClelland-RL; Newman-AB; Gottlieb-DJ; Lebowitz-MD
CHEST-. SEP 1999; 116 (3) : 603-613. PY: 1999 IS: 0012-3692

Objective: To describe the clinical correlates of asthma in a community-based sample of elderly persons, Participants: A community sample of 4,581 persons greater than or equal to 65 years old from the Cardiovascular Health Study. Measurements: Standardized respiratory, sleep, and quality-of-life (QOL) questions, a medication inventory, spirometry, and ambulatory peak flow. Results: Four percent of the participants reported a current diagnosis of asthma (definite asthma), while another 4% reported at least one attack of wheezing accompanied by chest tightness or dyspnea during the previous 12 months (probable asthma), Smokers and those with congestive heart failure were excluded from the subsequent analyses, leaving 2,527 participants. Of those who had definite asthma, 40% were taking a sympathomimetic bronchodilator, 30% inhaled corticosteroids, 21% theophylline, and 18% oral corticosteroids; 39% were taking no asthma medications. The participants with definite or probable asthma were much more likely than the others to have a family history of asthma, childhood respiratory problems, a history of workplace exposures, dyspnea on exertion, hay fever, chronic bronchitis, nocturnal symptoms, and daytime sleepiness. They were also more likely to report poor general health, symptoms of depression, and limitation of activities of daily living. There was little difference in the morbidity and QOL of participants with recent asthma-like symptoms who had received the diagnosis of asthma versus those who had not. Conclusions: Asthma in elderly persons is associated with a lower QOL and considerable morbidity when compared with those who do not have asthma symptoms. Asthma is underdiagnosed in this group and is often associated with allergic triggers; inhaled corticosteroids are underutilized.

Professor Philippe Godard: Epidemiological studies usually focus on prevalence of diseases (cases of disease existing at a specified time). This study not only focuses on prevalence, but also analyses incidence (number of new cases developing during some specified time interval). The pattern of increase in asthma and hay fever prevalence with time was similar, but there was no increase in incidence of these diseases. Because hay fever was a strong predictor of new asthma cases and was nearly always found before asthma, the authors suggest that hay fever is a strong predisposing factor for asthma.

In 1998, von Mutius et al.¹ compared the results from two surveys performed in 1991–2 and 1995–6 that investigated the prevalence of asthma and allergic diseases in Leipzig, a city in former East Germany. This comparison showed, in contrast to the findings of Huovinen et al., an increased prevalence of atopy and rhinitis without a change for asthma. However, the prevalence of asthma and allergic diseases was significantly lower in Eastern Europe than in western countries in 1991. But by adopting a more western life style in later years, it seems likely that the observed increased prevalence of allergic diseases in Leipzig will be followed by an increased prevalence of asthma in the near future.

In this study, once again the importance of atopy and subsequent allergy in the pathogenesis of bronchial asthma is emphasized. From a pathological point of view, it is quite impossible to differentiate extrinsic (i.e., allergic) asthma and intrinsic (i.e, nonallergic) asthma² . From an epidemiological point of view, the link between atopy and asthma appears to be strong.

The ISAAC study³ informs us about the prevalence of rhinitis and asthma in countries all around the world. ISAAC Phase III is almost finished, so we will soon find out if the prevalences are, indeed, increasing. If the results are similar to this study, this would confirm the hypothesis that the prevalence of rhinitis is a marker (or a risk factor) for the prevalence of asthma. This could be of great help in disease prevention, both for populations and individuals.

References

1. Von Mutius et al. Increasing prevalence of hay fever and atopy among children in Leipzig, East Germany. The Lancet 1998; 351: 862-866.
2. Burrows et al. Association of asthma with serum IgE levels and skin-test reactivity to allergens. New Eng J Med 1989; 320: 271-277.
3. Beasley et al. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The Lancet 1998; 351: 1225-1232. ISAAC: International Study of Asthma and Allergies in Childhood

Title (9): Incidence and prevalence of asthma among adult Finnish men and women of the Finnish Twin Cohort from 1975 to 1990, and their relation to hay fever and chronic bronchitis. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Huovinen-E; Kaprio-J; Laitinen-LA; Koskenvuo-M
Chest. 1999 Apr; 115(4): 928-36. ISSN: 0012-3692

STUDY OBJECTIVES: To examine the prevalence of asthma and hay fever, and the incidence and temporal relationships of asthma, hay fever, and chronic bronchitis among adult twins during a 15-year period. 
DESIGN: Prospective cohort study. 
PARTICIPANTS: A population of 11,540 Finnish adult men and women, initially 18 to 45 years of age, who returned a health questionnaire in 1975, 1981, and 1990 as part of the Finnish Twin Cohort study. 
METHODS: Age-standardized prevalences and cumulative incidences among individuals were calculated for asthma, hay fever, and chronic bronchitis. The incidence of asthma among subjects with and without hay fever or chronic bronchitis was analyzed in the entire cohort as well as in twin pairs discordant for incident asthma. 
RESULTS: The prevalence of asthma increased slightly from 1975 (2.0% in men and 2.2% in women) to 1990 (2.9% in men and 3.1% in women). The prevalence of hay fever showed a larger increase in men and women (from 6.8% and 9.8% to 11.8% and 15.3%, respectively). Compared with figures for 1976 to 1981, no significant increase in asthma incidence occurred from 1982 to 1990, whereas the incidence of hay fever was lower during the latter period among men (incidence rate ratio, 0.7; 95% confidence interval, 0.6 to 0.9) as was the incidence of chronic bronchitis among women (incidence rate ratio, 0.7; 95% confidence interval, 0.6 to 0.9). Hay fever and chronic bronchitis were usually diagnosed before asthma. Both diseases increased the risk of asthma significantly on the basis of analyses of all individuals and of discordant twin pairs. 
CONCLUSIONS: The pattern of increase in asthma and hay fever prevalence with time was similar, and hay fever was a strong predictor of asthma. These diseases showed no significant increase in incidence.

Professor Philippe Godard : Many asthmatics have been treated for acute asthma in the emergency department (ED). After discharge, an acute asthma relapse often occurs (relapse rates from 11% over the course of 3 days up to 30% over several weeks have been reported). In this prospective multicenter study, the authors aimed to identify factors associated with relapse in the 2 weeks after ED discharge. Out of 1301 asthma patients who were discharged from the ED, 641 underwent a complete follow-up. An acute asthma relapse was defined as an urgent visit to any physician for worsening asthma symptoms.

Among the 641 patients studied with a complete follow-up, 17% reported an acute asthma relapse. Most of the relapses occurred within 6 days of the ED visit. The factors that could be associated with relapse (in a multivariate analysis) included a history of numerous ED and urgent clinic visits for asthma in the past year, use of a home nebulizer, reports of a longer duration of asthma symptoms, and of multiple asthma triggers. In this study neither PEFR nor fev₁ was significantly associated with an increased risk of relapse. The authors suggest that patients with the above-mentioned risk factors for relapse should be considered for extended treatment in either an observation unit or in an inpatient unit.

Because the factors associated with acute asthma relapse have been described previously in various other studies, the aim of this study is not very clear. Also the factors investigated in the multivariate analysis do have very low, although statistically significant, odds ratios (ranging from 1.1 to 2.2). Consequently, in daily clinical practice, decisions based on the patient’s risk factors will be difficult to evaluate. Furthermore, there is no biological evaluation of the patients, and precipitating factors that induced the acute asthma were not reported (e.g., compliance with treatment). An analysis of risks in terms of mortality would have been a valuable addition to this study. The economic impact of extended care in an observation unit has not been considered.

Ass. Professor Leif Rosenhall : This important American paper analyzed the relapse rate after treatment of acute asthma at 36 emergency departments (ED). Within 14 days, 17% of the treated patients experienced a relapse, which is an alarming figure. Interestingly, a group of patients with a history of frequent visits to the ED department were associated with a high risk for relapses.

For a European, it is also interesting to observe that the use of inhaled corticosteroids is still not common in the United States. Inhaled corticosteroid treatment did not seem to be associated with a reduced risk for relapse, but this might be because only the most severely ill patients received this treatment. Another striking finding is that overall 63% of the patients were discharged from the ED on a regimen of systemic steroids for a rather short period of therapy (median duration 5 days).

The paper, and particularly the discussion part, is interesting and important. Certainly, a high remission rate of acute asthma that needs to be treated in the ED is a sign of bad asthma management and should lead to improvements in care.

Title (10): Prospective multicenter study of relapse following treatment for acute asthma among adults presenting to the emergency department (partial abstract from http://www.healthy.net/library/search/medline.htm )

Emerman-CL; Woodruff-PG; Cydulka-RK; Gibbs-MA; Pollack-CV; Camargo-CA
CHEST-. APR 1999; 115 (4) : 919-927. PY: 1999 IS: 0012-3692

Study objective: To identify factors associated with relapse following treatment for acute asthma among adults presenting to the emergency department(ED). Design: Prospective inception cohort study performed during October 1996 to December 1996 and April 1997 to June 1997, as part of the Multicenter Asthma Research Collaboration. Setting: Thirty-six EDs in 18 states. Patients: ED patients, aged 18 to 54 years, with physician diagnosis of acute asthma. For the present analysis, we restricted the cohort to patients sent home from the ED (n = 971), then further excluded patients with comorbid respiratory conditions (n 32). This left 939 eligible subjects to have follow-up data. Interventions: None. Measurements and results: Two weeks after being sent home from the ED, patients were contacted by telephone. A relapse was defined as an urgent or unscheduled visit to any physician for worsening asthma symptoms during the 14-day follow-up period. Complete follow-up data were available for 641 patients, of whom 17% reported relapse (95% confidence interval, 14 to 20). There was no significant difference in peak expiratory flow rate (PEFR) between patients who suffered relapse and those who did not. In a multivariate logistic regression analysis (controlling for age, gender, race, and primary care provider status), patients who suffered relapse were more Likely to have a history of numerous ED (odds ratio [OD] 1.3 per 5 visits) and urgent clinic visits (OR 1.4 per 5 visits) for asthma in the past year, use a home nebulizer (OR 2.2), report multiple triggers of their asthma (OR 1.1 per trigger), and report a longer duration of symptoms (OR 2.5 for 1 to 7 days). 
Conclusion: Among patients sent home from the ED following acute asthma therapy, 17% will have a relapse and PEFR does not predict who will develop this outcome. By contrast, several historical features were associated with increased risk. Further research should focus on ways to decrease the relapse rate among these high-risk patients. The clinician may wish to consider these historical factors when making ED decisions.

Professor Philippe Godard  : Various guidelines distinguish the severity of asthma as "intermittent", "mild persistent", "moderate persistent", and "severe persistent". Severe persistent asthma is a heterogeneous disease that has not been well studied. It can be subdivided into "severe", "very severe", or "difficult asthma"¹. Wenzel et al. are deeply involved in this research field. In this paper, they evaluate the hypothesis that severe asthma can be divided pathologically into two inflammatory groups based on the presence or absence of eosinophils.

Wenzel et al.. provide a thorough description of clinical characteristics of severe asthmatics. However, the study may be criticized on several points:

• It would have been helpful if a definition of "severe refractory asthmatics" had been provided. Also, it is important to know how well the asthma of these patients was controlled.
• The definitions of severe, moderate, and mild asthma did not follow the current guidelines (they were based on asthma treatment and disease history during 1 year before inclusion).
• Two important concepts are missing: viz., the concept of asthma control and the concept of compliance with the treatment. These are crucial for understanding the
• pathologic processes. For example, severe asthmatics with relatively high eosinophil levels (eosinophil(+) asthmatics) could in fact be totally noncompliant, and that would explain the eosinophil levels.

Based on this study, the authors put forward some valuable suggestions concerning asthma treatment. Multiple studies evaluating possible "steroid-sparing" drugs have been performed in severe asthmatics with mixed and marginal results. The authors suggest that these marginal results are due to similar treatment approaches to different pathologies. Unfortunately, current clinical and functional tools to evaluate severe asthma are not precise enough for a good characterization.

In addition to the suggestion of Wenzel et al., I would like to recommend the following:

• Measuring compliance is the first step in studying severe asthmatics who are not well-controlled.
• When evaluating new "steroid-sparing" drugs in severe asthma, one must take into account its heterogeneous pathology.
• The role of Neutrophils in severe asthma is intriguing and should be clarified. This may contribute to the development new anti-inflammatory drugs.

Reference
Difficult/therapy-resistant asthma – The need for an integrated approach to define clinical phenotypes, evaluate risk factors, understand pathophysiology and find novel therapies J Eur Respir J13: 1198-1208 (1999).

Professor Takateru Izumi, M.D. : Remarkable progress has been achieved in the management of asthma with inhaled corticosteroids. However, treatment with inhaled corticosteroids has not solved the problems of all asthma patients. A small percentage of severe asthmatics are corticosteroid-resistant, and the problem of how to manage these patients is slowly being resolved.

Several facts are known about the mechanism leading to refractory asthma. There are more neutrophils than eosinophils in the tissues, the binding affinity of the glucocorticoid receptor changes, and the suppression of transcription-factor binding is altered. There is also the possibility of fibrosed or "remodeled" changes in the airways.

This report by Wenzel et al. showing two pathological types of severe asthma with distinct physiological and clinical characteristics is very interesting. In the report, asthmatics were divided into an eosinophil(+) and an eosinophil(-) severe asthmatic subtype according to the presence or absence of this cell type in the tissues. It was found that each asthmatic subtype exhibited distinct physiological and clinical characteristics.

This report is the first one to divide severe asthmatics into two groups and define their characteristics clearly. Given the distinct characteristics of these subtypes, they may require different therapeutic management. Further studies on the management and treatment of severe asthma subtypes are being awaited.

Title (11): Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics (partial abstract from http://www.healthy.net/library/search/medline.htm )

Wenzel-SE; Schwartz-LB; Langmack-EL; Halliday-JL; Trudeau-JB; Gibbs-RL; Chu-HW
AMERICAN-JOURNAL-OF-RESPIRATORY-AND-CRITICAL-CARE-MEDICINE. SEP 1999; 160 (3) : 1001-1008. PY: 1999  IS: 1073-449X

The mechanisms associated with the development of severe, corticosteroid (CS)-dependent asthma are poorly understood, but likely heterogeneous. it was hypothesized that severe asthma could be divided pathologically into two inflammatory groups based on the presence or absence of eosinophils, and that the inflammatory subtype would be associated with distinct structural, physiologic, and clinical characteristics. Thirty-four severe, refractory CS-dependent asthmatics were evaluated with endobronchial biopsy, pulmonary function, allergy testing, and clinical history. Milder asthmatic and normal control subjects were also evaluated. Tissue cell types and subbasement membrane (SBM) thickness were evaluated immunohistochemically. Fourteen severe asthmatics [eosinophil (-)] had nearly absent eosinophils (< 2 SD from the normal mean). The remaining 20 severe asthmatics were categorized as eosinophil (+). Eosinophil (+) severe asthmatics had associated increases (p < 0.05) in lymphocytes (CD3+, CD4+, CD8+), mast cells, and macrophages. Neutrophils were increased in severe asthmatics and not different between the groups. The SBM was significantly thicker in eosinophil (+) severe asthmatics than eosinophil (-) severe asthmatics and correlated with eosinophil numbers (r = 0.50). Despite the absence of eosinophils and the thinner SBM, the FEV, was marginally lower in eosinophil (-) asthmatics (p = 0.05) with no difference in bronchodilator response. The eosinophil (+) group (with a thicker SBM) had more intubations than the eosinophil (-) group (p = 0.0004). Interestingly, this group also had a decreased FVC/slow vital capacity (SVC). These results suggest that two distinct pathologic, physiologic, and clinical subtypes of severe asthma exist, with implications for further research and treatment.

. ARLS   Congrès Conçue et réalisée par: Michel Godard (at) Top
Date de création: 1er Mars 1996 -Dernière mise à jour: 19/08/00
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