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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°4    (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 An evaluation of zafirlukast in the treatment of asthma with exploratory subset analyses. Tashkin DP, Nathan RA, Howland WC, Minkwitz MC, Simonson SG, Bonuccelli CM J Allergy Clin Immunol 1999 Feb;103(2 Pt 1):246-54 Professor Duncan Geddes 2 Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma. A randomized, controlled trial. Malmstrom K, Rodriguez-Gomez G, Guerra J, Villaran C, Pineiro A, Wei LX, Seidenberg BC, Reiss TF Ann Intern Med 1999 Mar 16;130(6):487-95 Professor Duncan Geddes 3 Congenital malformations after the use of inhaled budesonide in early pregnancy Kallen B, Rydhstroem H, Aberg A Obstet Gynecol 1999 Mar;93(3):392-5 Professor Estelle Simons 4 Comparison of the efficacy of budesonide and fluticasone propionate aqueous nasal spray for once daily treatment of perennial allergic rhinitis Day J, Carrillo T J Allergy Clin Immunol 1998 Dec;102(6 Pt 1):902-8 Professor Estelle Simons 5 Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking Pauwels RA, Lofdahl CG, Laitinen LA, Schouten JP, Postma DS, Pride NB, Ohlsson SV N Engl J Med 1999 Jun 24;340(25):1948-53 Ass. Professor Leif Rosenhall 6 Predictive factors of hospitalization for acute exacerbation in a series of 64 patients with chronic obstructive pulmonary disease. Kessler R, Faller M, Fourgaut G, Mennecier B, Weitzenblum E Am J Respir Crit Care Med 1999 Jan;159(1):158-64 Ass. Professor Takateru Izumi 7 Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Niewoehner DE, Erbland ML, Deupree RH, Collins D, Gross NJ, Light RW, Anderson P, Morgan NA N Engl J Med 1999 Jun 24;340(25):1941-7 Professor Philippe Godard Ass. Professor Leif Rosenhall 8 Nebulized lidocaine in the treatment of severe asthma in children: a pilot study Decco ML, Neeno TA, Hunt LW, O'Connell EJ, Yunginger JW, Sachs MI Ann Allergy Asthma Immunol 1999 Jan;82(1):29-32 Professor Estelle Simons 9 Differences between asthma exacerbations and poor asthma control Reddel H, Ware S, Marks G, Salome C, Jenkins C, Woolcock A Lancet 1999 Jan 30;353(9150):364-9 Professor Philippe Godard 10 Cigarette smoking and asthma symptom severity among adult asthmatics Althuis MD, Sexton M, Prybylski D J Asthma 1999 May;36(3):257-64 Ass. Professor Leif Rosenhall 11 The economic burden of asthma: direct and indirect costs in Switzerland. Szucs TD, Anderhub H, Rutishauser M Eur Respir J 1999 Feb;13(2):281-6 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/ ...

Professor Duncan Geddes: There is convincing evidence that the leukotriene antagonists are effective in the treatment of asthma, but they do not seem to have clear-cut advantages over other regular anti-inflammatory treatments such as low-dose inhaled corticosteroids. Indeed, at present, inhaled corticosteroids appear to perform somewhat better. It is therefore especially important to know whether there are some groups of patients who are particularly well suited to this form of treatment.

This subset analysis on more than a thousand patients who were entered into clinical trials failed to find any relationship between the benefit derived from zafirlukast and age, gender, racial origin, or asthma characteristics. The statistical methodology was sound, and although there was a suggestion of improved treatment response with the greater the severity of asthma, only mild to moderate patients were included, and this finding is of no real help to prescribers.

These results are at first sight disappointing since they do not help to inform or refine treatment guidelines or help individual prescribers to make decisions. However, the subsets examined were relatively crude, and the possibility of a responding subset remains. Two important areas that need further investigation are genetically determined differences in drug response and environmental differences in the causation of asthma. Future progress in these areas can confidently be expected to improve the precision of asthma-prescribing decisions.

Title (1): . An evaluation of zafirlukast in the treatment of asthma with exploratory subset analyses. (partial abstract from http://www.healthy.net/library/search/medline.htm )

University of California-Los Angeles, Department of Medicine 90095-1690, USA.

BACKGROUND: Consensus asthma guidelines recommend antileukotriene agents as alternative therapy to existing anti-inflammatory medications; however, the full therapeutic potential of these medications has not yet been determined. 
OBJECTIVE: The purpose of this study was to assess the efficacy and safety of the oral leukotriene receptor antagonist zafirlukast (20 mg twice daily) in subgroups of patients who have asthma with the use of integrated data from four 13-week trials. 
METHODS: The trials had comparable designs, entry criteria, and clinical assessments. Patient subgroups were characterized by demographic and baseline asthma characteristics. Analysis of covariance models were tested for overall treatment effect and for interactions between treatment and subgroup characteristics.
RESULTS: Patients with mild-to-moderate asthma (12 to 76 years old) who were treated with albuterol alone were randomized (nZ = 879; nP = 605) and included in subset analyses. Significant overall treatment effects, favoring zafirlukast, were noted for measures of daytime and nighttime symptoms, beta2 -agonist use, and pulmonary function (P <.05). A significant, quantitative, treatment-by-age interaction was noted for beta2 -agonist use (P <. 03), suggesting greater reductions in rescue medication use with increasing patient age. Compared with placebo, similar size and/or direction of response was noted with zafirlukast in the various subgroups, indicating a benefit with zafirlukast regardless of subgroup. Significant treatment-by-strata interactions (P <.05), favoring zafirlukast, were noted for various outcome measures in subgroups with the greatest amount of baseline beta2 -agonist use (>8 puffs/day) and with greater baseline peak flow variability (>/=20%) and baseline airflow obstruction (FEV1 /forced vital capacity ratio, <0.70). The overall treatment failure rate was significantly lower in the zafirlukast group compared with the placebo group (P <.003). No associations were observed between any adverse events and subgroups defined by demographic characteristics. 
CONCLUSIONS: Exploratory subset analyses showed that zafirlukast is similarly efficacious in patients with asthma who have differing demographic characteristics and degrees of subjective symptoms. Additionally, zafirlukast appears to be incrementally beneficial in patients with more moderate disease, defined by a greater requirement for as-needed rescue medication and more abnormal pulmonary function at baseline. Over 13 weeks, zafirlukast was well tolerated and demonstrated a safety profile clinically indistinguishable from placebo.

Professor Duncan Geddes: Leukotriene antagonists are better than placebo in the treatment of asthma; but comparisons with other preventer therapies have been few, and so the place of these agents in asthma guidelines and in individual prescribing remains unclear. This large study (n = 895) is therefore particularly welcome and shows an unequivocal superiority of beclomethasone 400 m g daily to montelukast 10 mg daily in almost all of the outcome measures assessed. These outcomes included the number of days with asthma exacerbations and the time to first asthma attack.

There were two additional interesting findings: first, that the response to treatment for both agents was normally distributed, thus arguing against subgroups of responders and non-responders, and secondly, that the benefit from montelukast was entirely achieved during the first day, whereas the improvement with beclomethasone increased linearly over the first 9 days and reached a plateau after about 2 weeks.

Montelukast as a once-daily tablet is easier to take than using an inhaler twice daily but the fact that montelukast does not work as well and costs more suggests that inhaled beclomethasone should remain the gold standard anti-inflammatory agent for the treatment of mild to moderate asthma. In the absence of any data to define a leukotriene antagonist responding subset of patients with asthma, the only persons for whom this treatment appears appropriate as the first-line controller therapy are those who cannot or will not use an inhaler.

Title (2) : Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma. A randomized, controlled trial. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Merck Research Laboratories, Rahway, New Jersey 07065, USA.

BACKGROUND: Oral leukotriene receptor antagonists have been shown to have efficacy in chronic asthma. 
OBJECTIVE: To compare the clinical benefit of montelukast, a once-daily oral leukotriene receptor antagonist; placebo; and inhaled beclomethasone. 
DESIGN: Randomized, double-blind, double-dummy, placebo-controlled, parallel-group, 12-week study. 
SETTING: 36 sites worldwide. 
PATIENTS: 895 patients 15 to 85 years of age with chronic asthma and an FEV1 50% to 85% of predicted. 
INTERVENTIONS: Montelukast, 10 mg once daily at bedtime; inhaled beclomethasone, 200 microg twice daily, administered with a spacer device; or placebo. 
MEASUREMENTS: Primary end points were daytime asthma symptom score and FEV1. Secondary end points were peak expiratory flow rates in the morning and evening, as-needed beta-agonist use, nocturnal awakenings, asthma-specific quality of life, and worsening asthma episodes. 
RESULTS: Over the 12-week treatment period, the average percentage change from baseline in FEV1 was 13.1% with beclomethasone, 7.4% with montelukast, and 0.7% with placebo (P < 0.001 for each active treatment compared with placebo; P < 0.01 for beclomethasone compared with montelukast). The average change from baseline in daytime symptom score was -0.62 for beclomethasone, -0.41 for montelukast, and -0.17 for placebo (P < 0.001 for each active treatment compared with placebo; P < 0.01 for beclomethasone compared with montelukast). Each agent improved peak expiratory flow rates and quality of life, reduced nocturnal awakenings and asthma attacks, increased the number of asthma-control days, and decreased the number of days with asthma exacerbations (P < 0.001 for each active treatment compared with placebo for each end point; P < 0.01 for beclomethasone compared with montelukast for each end point). Although beclomethasone had a greater mean clinical benefit than montelukast, montelukast had a faster onset of action and a greater initial effect. The two agents caused similar decreases in peripheral blood eosinophil counts (P < 0.05 for each agent compared with placebo). Both agents had tolerability profiles similar to that of placebo over the 12-week study. 
CONCLUSIONS: Although beclomethasone had a larger mean effect than montelukast, both drugs provided clinical benefit to patients with chronic asthma. This finding is consistent with the use of these agents as controller medications for chronic asthma.

Professor Estelle Simons: Congenital malformations are surprisingly common in newborns; approximately 2 % of infants of at least 20 weeks gestational age have a major malformation and minor anomalies with no surgical or cosmetic significance are even more common. Administration of glucocorticoids during the first trimester, and maternal asthma, per se, are not recognised human teratogens. In the United States and other countries, however, budesonide and other inhaled glucocorticoids are classified as Category C (to be prescribed only if the expected benefit to the mother exceeds the unknown risk for the foetus), because of insufficient human data and a teratogenic risk identified in animal experiments.

It is therefore reassuring that in this study (which has been published with a potentially misleading title), budesonide use in early pregnancy was not associated with a clinically significant teratogenic risk. Additional confirmation could be obtained from well-designed, prospective, observational cohort studies in which infants exposed to budesonide in utero during the first trimester, and matched non-budesonide-exposed controls, are followed to term and closely examined after birth.

1. Holmes LB, Congenital malformations. In: McMillan JA, DeAngelis CS, Feigin RD, Warshaw JB, eds. Oski’s Pediatrics, Principles and Practice. 3^rd Ed. Philadelphia: Lippincott Williams & Wilkins, 1999;136-8

Title (3): Congenital malformations after the use of inhaled budesonide in early pregnancy. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Tornblad Institute, and the Department of Obstetrics and Gynecology, University of Lund, Sweden. embryol (at) embryol.lu.se 

OBJECTIVE: To study possible teratogenic risks with the use of an inhaled glucocorticoid, budesonide, in early pregnancy. 
METHODS: Using the Swedish Medical Birth Registry, congenital malformations were studied in 2014 infants whose mothers had used inhaled budesonide for asthma in early pregnancy. The presence of congenital malformations was checked further with auxiliary registries. 
RESULTS: No increase in the general rate of congenital malformations was observed: 3.8% (95% confidence interval [CI] 2.9, 4.6) of the infants had a congenital malformation diagnosed, which is similar to the population rate (3.5%). After exposure to budesonide, four infants were born with orofacial clefts; this also is similar to the expected number (3.3). 
CONCLUSION: Even though a specific teratogenic effect of use of budesonide in early pregnancy cannot be ruled out, it is unlikely that a clinically significant teratogenic risk exists.

Professor Estelle Simons: This study was double-blind for budesonide and placebo (dispensed in identical bottles) and single-blind to the investigators (for fluticasone propionate). It demonstrated that for relieving nasal symptoms, including blockage, both the intranasal glucocorticoids were superior to placebo, and budesonide was superior to fluticasone propionate. The more rapid onset of action of budesonide compared to fluticasone propionate is of interest.

Rhinoscopy, performed at all visits, was "reassuring in all treatment groups because no clinical sign of fungal infection were seen, and purulent secretions were seen only occasionally in the fluticasone and placebo-treated groups". Objective monitoring of eosinophils and other cells in nasal secretions was not done. Blood-Tinged nasal secretions were reported in 18 % of participants treated with budesonide, 7 % of those treated with fluticasone propionate, and 2 % of those treated with placebo.

Title (4): Comparison of the efficacy of budesonide and fluticasone propionate aqueous nasal spray for once daily treatment of perennial allergic rhinitis. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Kingston General Hospital, Nuestra Senora Del Pino, Angel Guimera, Las Palmas, Grand Canary Island.

BACKGROUND: Intranasal corticosteroids, such as budesonide and fluticasone propionate, are widely prescribed in the treatment of perennial allergic rhinitis. Once daily budesonide dry powder and fluticasone propionate aqueous suspension have been found to provide similar efficacy in controlling symptoms of perennial allergic rhinitis. 
OBJECTIVE: The purpose of this study was to assess the efficacy and safety of treatment with once daily budesonide aqueous nasal spray. 
METHODS: This study involved a multicenter, blinded, randomized, parallel-group, placebo-controlled trial of adults with perrenial allergic rhinitis. Patients (n = 273) recorded daily nasal symptoms for 8 to 14 days (baseline) and 6 weeks (treatment). 
RESULTS: Budesonide decreased combined symptoms to a significantly greater extent than did fluticasone (P =.03); both treatments significantly decreased mean combined nasal symptoms scores compared with placebo. Of the 3 nasal symptoms assessed (ie, nasal blockage, runny nose, and sneezing), nasal blockage was significantly (P =. 009) more decreased with budesonide compared with fluticasone. Both treatments also significantly improved runny nose and sneezing compared with placebo. Improvement in combined nasal symptom scores of the budesonide-treated group reached statistical significance within 36 hours compared with placebo (P =.01); in those patients treated with fluticasone, significant improvement compared with placebo was first observed within 60 hours. Adverse events were mild and transient. 
CONCLUSIONS: Once daily budesonide aqueous nasal spray, 256 microgram, was significantly better in controlling the symptoms of perrenial allergic rhinitis than once daily fluticasone propionate, 200 microgram, especially nasal blockage. Both treatments were superior to placebo. Budesonide may have a faster onset of action than fluticasone.

Ass. Professor Leif Rosenhall: The treatment of COPD and the prevention of the destruction of the lung tissue due to the emphysematous process are two of the main challenges for pulmonary medicine. Smoking cessation is hitherto the only effective method, but sadly enough it is very often rejected by patients.

It is very interesting and tempting to evaluate whether inhaled steroids, which are so effective in asthma, also have effects in COPD. Most clinical studies and experiences from clinicians suggest that the effect in COPD is small and that the therapy is probably not justified.

In this very large, well-performed, and probably very expensive study, a large number of COPD patients who had not stopped smoking after participating in a professional smoking-cessation programme have been treated with either placebo or budesonide 400 µg twice daily for 3 years. There was a small but statistical significant beneficial effect on FEV₁ during the first 6 months of the study. During the next 30 months, the decline in FEV₁ was the same in both groups, and obviously the inhaled steroid did not prevent the gradually developing emphysema.

The patients in this study had mild COPD, and if they stop smoking they probably will never develop severe lung obstruction. Therefore, new attempts of smoking cessation should be instituted. Inhaled steroids can be used to gain time, but can never replace smoking cessation.

Title (5): 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 )

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 Takateru Izumi: An acute exacerbation of COPD is a serious problem from three standpoints: first, it is a direct cause of death; secondly, it worsens the stability of the condition after recovery; and thirdly, it increases medical costs, such as the costs of hospitalization. Thus, the prevention of acute exacerbation is considered an important target in the management and care of COPD. Accordingly, it is necessary to identify the cause of acute exacerbations and to establish the predictive factors of acute exacerbations in COPD patients.

Several studies have been performed to identify predictive factors for the prognosis and for acute exacerbations of COPD, but all of them have been retrospective. The report by Kessler et al. is the first progressive study. It evaluated 64 COPD patients for at least 2.5 years and recorded the time to first hospitalization for exacerbation.

In this report, baseline hypercapnia and pulmonary hypertension, even at moderate stages, were shown to be independent predictors of hospitalization for acute exacerbation in patients with COPD. On the other hand, age, complications, and smoking were not found to be useful risk factors. These findings are considered to be useful for the establishment of a new classification of the stage of COPD identifying not only present conditions, but also future risks.

Title (6): Predictive factors of hospitalization for acute exacerbation in a series of 64 patients with chronic obstructive pulmonary disease.  (partial abstract from http://www.healthy.net/library/search/medline.htm )

Service de Pneumologie, Hopitaux Universitaires, Strasbourg, France.

Hospitalizations for acute exacerbation in patients with chronic obstructive pulmonary disease (COPD) have a great impact on health care expenditure. The aim of this study was to look at predictive factors of hospitalization for acute exacerbation in a group of patients with moderate to severe COPD. During the year 1994, we included 64 patients with COPD in this study. At inclusion, the patients being in a stable state, we performed a complete evaluation of their clinical, spirometric, gasometric, and pulmonary hemodynamic characteristics. All patients were followed during a period of at least 2.5 yr. We recorded the intervals free of hospitalization for exacerbation and realized an analysis of the proportional hazards not to be hospitalized using the Kaplan-Meier method. Univariate analysis using the log-rank test showed that the risk of being hospitalized was significantly increased in patients with COPD with a low body mass index (BMI <= 20 kg/m2, p = 0.015) and in patients with a limited 6-min walk distance (<= 367 m, p = 0. 045). But above all, the risk of hospitalization for acute exacerbation was significantly increased by gas exchange impairment and pulmonary hemodynamic worsening: PaO2 <= 65 mm Hg versus PaO2 > 65 mm Hg, p = 0.005; PaCO2 > 44 mm Hg versus PaCO2 <= 44 mm Hg, p = 0.005; and mean pulmonary artery pressure ( Ppa) at rest > 18 mm Hg versus Ppa <= 18 mm Hg, p = 0.0008. Neither age, nor the association of one or more comorbidities with COPD, nor the smoking habits had a significant impact on the risk of hospitalization in our study. Multivariate analysis showed that only PaCO2 and Ppa were independently related to the risk of hospitalization for acute exacerbation of COPD. We conclude that chronic hypercapnic respiratory insufficiency and pulmonary hypertension are predictive factors of hospitalization for acute exacerbation in COPD patients.

Professor Philippe Godard : Evidence-based medicine is an important concept and must be used as a guide for clinical practice. Is this study important enough that it can be considered to be a contribution to evidence-based medicine? Clearly yes, but to what extent?

The study was very well designed with two clear objectives. The first or principal objective was to assess the equivalence of two approaches to the treatment of COPD, i.e. systemic glucocorticoid therapy or withholding of glucocorticoids. The second objective was to assess equivalence of two periods of therapy, i.e. 2 or 8 weeks of treatment with glucocorticoids. In analogy, the end-points were classified in two orders. The primary end-point was treatment failure and secondary end-points were a change in FEV1, the length of the hospital stay, and death from any cause during the 6 months of follow-up. In my opinion, Pa_CO2 should have been included as a secondary end-point because Pa_CO2 changes can be observed in patients with no changes in FEV1. The follow-up period of 6 months is long enough to assess treatment failures. However, it would have been interesting if quality of life had been followed during this period.

Figure 2 of the paper is probably the most informative. It shows that the two glucocorticoid therapies were equivalent, and both were superior to placebo. I will inform my students about this result and use it in my practice.

Although the study is of high scientific quality, one might express some critical points of view. The first point is the starting dose of the glucocorticoids: a dose of 125 mg q.i.d for 72 hours is very high. This explains why a high proportion of the patients had adverse effects. The second critical point is the use of inhaled steroids by all patients during follow-up. The effects of inhaled steroids in COPD are not clear in terms of evidence-based medicine. The third critical point is the patient selection. Principal exclusion criteria were a diagnosis of asthma and use of systemic glucocorticoids within the preceding 30 days. These criteria are excellent from a scientific point of view, but in daily clinical practice it is often difficult to differentiate between COPD patients with an asthmatic component and purely COPD patients.

In conclusion, the study by Niewoehner et al. is outstanding and will be the starting point for other studies. The study results should be taught to students and used by all persons who want to conduct a clinical study in COPD. The clearly written paper is highly recommended reading.

Ass. Professor Leif Rosenhall : Acute exacerbations in patients with COPD are a common and troublesome situation for our hospitals and the numerous patients. The patients are usually treated with systemic steroids together with antibiotics, oxygen when needed, and bronchodilators. However, the scientific basis for the use of steroids is rather weak. In this interesting and important study, a large number of patients were treated either with placebo or systemic steroids for 2 or 8 weeks. Steroid therapy was initiated with intravenous methylprednisolone every 6 hours for 72 hours followed by oral prednisolone in decreasing doses starting with 60 mg daily. The patients were then followed for 6 months after the exacerbation. It was clearly shown that the administration of systemic steroids had a beneficial effect on the outcome of the acute exacerbation. The length of hospitalization was shortened and the treatment failures were less common. There was also a smaller risk of a new exacerbation during the 6-month follow-up period.

Interestingly, clinical outcomes were not different between patients who received a 2-week course and those who received 8 weeks of treatment.

The study is strong support for the common use of systemic steroids in acute exacerbations of COPD, but the treatment period should be short.

Title (7): Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. (partial abstract below from http://www.healthy.net/library/search/medline.htm )

Veterans Affairs Medical Center in Minneapolis, MN 55417, USA. niewo001 (at) maroon.tc.umn.edu

BACKGROUND AND METHODS: Although their clinical efficacy is unclear and they may cause serious adverse effects, systemic glucocorticoids are a standard treatment for patients hospitalized with exacerbations of chronic obstructive pulmonary disease (COPD). We conducted a double-blind, randomized trial of systemic glucocorticoids (given for two or eight weeks) or placebo in addition to other therapies, for exacerbations of COPD. Most other care was standardized over the six-month period of follow-up. The primary end point was treatment failure, defined as death from any cause or the need for intubation and mechanical ventilation, readmission to the hospital for COPD, or intensification of drug therapy. 
RESULTS: Of 1840 potential study participants at 25 Veterans Affairs medical centers, 271 were eligible for participation and were enrolled; 80 received an eight-week course of glucocorticoid therapy, 80 received a two-week course, and 111 received placebo. About half the potential participants were ineligible because they had received systemic glucocorticoids in the previous 30 days. Rates of treatment failure were significantly higher in the placebo group than in the two glucocorticoid groups combined at 30 days (33 percent vs. 23 percent, P=0.04) and at 90 days (48 percent vs. 37 percent, P=0.04). Systemic glucocorticoids (in both groups combined) were associated with a shorter initial hospital stay (8.5 days, vs. 9.7 days for placebo, P=0.03) and with a forced expiratory volume in one second that was about 0.10 liter higher than that in the placebo group by the first day after enrollment. Significant treatment benefits were no longer evident at six months. The eight-week regimen of therapy was not superior to the two-week regimen. The patients who received glucocorticoid therapy were more likely to have hyperglycemia requiring therapy than those who received placebo (15 percent vs. 4 percent, P=0.002). 
CONCLUSIONS: Treatment with systemic glucocorticoids results in moderate improvement in clinical outcomes among patients hospitalized for exacerbations of COPD. The maximal benefit is obtained during the first two weeks of therapy. Hyperglycemia of sufficient severity to warrant treatment is the most frequent complication.

Professor Estelle Simons: In this innovative, uncontrolled study, lidocaine nebulized over 15-25 minutes three or four times daily, had a steroid-sparing action in 6 closely-monitored children with severe persistent asthma. Their mean age was 11 years and the mean duration of their asthma was 9.3 years. They had all been treated with oral glucocorticoids for a mean of 2.3 years and at study entry, had an average daily prednisone requirement of 37.5 mg. Five of them were able to discontinue oral glucocorticoids, yet achieve improved asthma symptom control. Bitter taste and transient oropharyngeal anaesthesia were reported after lidocaine inhalation; however, there were not serious adverse effects such as dizziness, drowsiness, visual symptoms, tremors, or seizures.

This study confirms a previous study from the Mayo Clinic in which the glucocorticoid-sparing effects of lidocaine were reported in adults ¹. The precise mechanism of action of lidocaine in asthma is unknown; however, its ability to inhibit cytokine-induced eosinophil survival, in a manner that qualitatively and quantitatively mimics the glucocorticoid inhibition of eosinophil survival, suggests further avenues of investigation.

1. Hunt LW, Swedlund HA, Gleich GJ, Effect of nebulized lidocaine on severe glucocorticoid- dependent asthma. Mayo Clin Proc 1996;71:361-8

Title (8): Nebulized lidocaine in the treatment of severe asthma in children: a pilot study. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Mayo Graduate School of Medicine, Rochester, MN, USA.

BACKGROUND: Glucocorticoids have been used to treat asthma since the 1950s; however, their adverse systemic effects have limited their duration of use and dosage. Unfortunately, many patients with severe asthma often require oral glucocorticoids in addition to inhaled glucocorticoids. Alternatives to glucocorticoids have been sought with mixed success. Recently, lidocaine has been added to the list of potent glucocorticoid sparing agents for the treatment of severe asthma. 
OBJECTIVE: We report the first group of pediatric patients with severe asthma treated with nebulized lidocaine. 
METHODS: The study was performed in an open manner with 6 severely asthmatic patients followed in the Pediatric Allergy and Immunology Section, Mayo Clinic. The only intervention was the institution of nebulized lidocaine (0.8 mg/kg/dose to 2.5 mg/kg/dose t.i.d to q.i.d). The average daily steroid requirement was followed during the administration of the nebulized lidocaine. 
RESULTS: During a mean of 11.2 months of therapy (range 7 to 16 months) 5 of the 6 patients completely discontinued their oral glucocorticoids within an average time of 3.4 months (range 1 to 7 months). 
CONCLUSIONS: After further study, lidocaine may prove to be the first non-toxic, steroid alternative to patients with severe steroid-dependent asthma.

Professor Philippe Godard: This study is extremely interesting because it touches on three issues:

1. the definition of asthma control and exacerbations
2. the role of viruses in exacerbations
3. monitoring PEF variability as a measure of asthma severity

The definitions of asthma control and exacerbation are not clear in the international literature. The study by Reddel et al. showed that both stable asthma and presumed viral exacerbations are characterized by a relatively low diurnal variability in PEFR compared with poorly controlled asthma. This implies that asthma control can be defined by a stable PEFR with no variability. However, an exacerbation cannot be defined as a period with increased PEFR variability. Therefore, the definition of asthma exacerbation remains "acute or subacute worsening of asthma" (for any reason). Unfortunately, this is an unclear definition. In a prospective clinical study with frequent assessment of diaries and PEFR recordings, presumed viral exacerbations can be clearly observed. However, in daily clinical practice, viral exacerbations are more difficult to determine for reasons as noncompliance with inhaled steroids, unscheduled visits, and unexpected intervention by other doctors.

The low PEFR variability during exacerbations is in contrast to results from studies in which exacerbations were induced by steroid reduction (1,2) or increased allergen exposure (3). The authors showed that viral-induced asthma exacerbations have a specific PEFR pattern and are accompanied by b 2 agonist resistance. Further studies are needed to understand the effects of viral infections on b 2-adrenoreceptor function. This could help to prevent some asthma deaths and to decrease the overall burden of asthma exacerbations.

International guidelines recommend calculation of diurnal variability of PEFR for assessment of asthma severity and as an indication of a patient’s suitability for discharge from hospital. Reddel et al. have convincingly shown that some exacerbations occur without an increase in PEFR variability. Therefore, a review of published guidelines regarding the diagnosis and management of asthma exacerbations is needed.

References:

1. Gibson et al. Clin Exp Allergy 1992; 22: 525-532
2. Van Aalderen et al. Acta Paediatr Scan 1988; 77: 269-274
3. Meijer et al. Am J Resp Crit Care Med 1996; 153: 237-242

Title (9): Differences between asthma exacerbations and poor asthma control. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Institute of Respiratory Medicine at Royal Prince Alfred Hospital and the University of Sydney, Camperdown, NSW, Australia. hkr (at) mail.med.usyd.edu.au

BACKGROUND: Increased variation in peak expiratory flow (PEF) is characteristic of poorly controlled asthma, and measurement of diurnal variability of PEF has been recommended for assessment of asthma severity, including during exacerbations. We aimed to test whether asthma exacerbations had the same PEF characteristics as poor asthma control. 
METHODS: Electronic PEF records from 43 patients with initially poorly controlled asthma were examined for all exacerbations that occurred after PEF reached a plateau with inhaled corticosteroid treatment. Diurnal variability of PEF was compared during exacerbations, run-in (poor asthma control), and the period of stable asthma before each exacerbation. 
FINDINGS: Diurnal variability was 21.3% during poor asthma control and improved to 5.3% (stable asthma) with inhaled corticosteroid treatment. 40 exacerbations occurred in 26 patients over 2-16 months; 38 (95%) of exacerbations were associated with symptoms of clinical respiratory infection. During exacerbations, consecutive PEF values fell linearly over several days then improved linearly. However, diurnal variability during exacerbations (7.7%) was not significantly higher than during stable asthma (5.4%, p=0.1). PEF data were consistent with impaired response to inhaled beta2-agonist during exacerbations but not during poorly controlled asthma. 
INTERPRETATION: Asthmatics remain vulnerable to exacerbations during clinical respiratory infections, even after asthma is brought under control. Calculation of diurnal variability may fail to detect important changes in lung function. PEF variation is strikingly different during exacerbations compared with poor asthma control, suggesting differences in beta2-adrenoceptor function between these conditions.

Ass. Professor Leif Rosenhall: All asthmatics have a bronchial reactivity and are sensitive to different kinds of inhaled irritants, such as cigarette smoke. Therefore, asthmatics should not start nor continue smoking if they want to gain control over their disease. Nevertheless, many asthmatics still smoke.

The study by Althuis et al clearly shows that asthmatics who continue to smoke experience more symptoms and need more medication than those who stop smoking.

One of the main goals of asthma treatment is avoiding unnecessary inhaled irritants. When you inform your patients about this goal, the study by Althuis et al. can be quoted to emphasize that tobacco smoke is an important irritant to be avoided by asthmatics.

Title (10): Cigarette smoking and asthma symptom severity among adult asthmatics. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore 21201, USA. malthuis (at) epin.ab.umd.edu

Contrary to what would be expected, smoking habits of asthmatics do not differ from those of the general population: approximately 30% of asthmatic patients smoke cigarettes. Although the relationship between smoking and the incidence of asthma has been well explored, little attention has been paid to documenting the relationship between smoking and asthma symptoms among adults with asthma. The objective of this study was to assess the association of cigarette smoking with asthma symptom severity. The present report is of a cross-sectional study of 225 asthmatics, aged 20-54 years, from six general practice clinics in East Anglia, U.K. The outcome measures are overall asthma symptom score (range 6.3-28) and three asthma symptom domains: respiratory (range 1.3-8), daily activity interference (range 2-8), and physical activity interference (range 3-12), generated from the sum of ordinal responses to questions on asthma symptom severity. Of the sample, 27.0% were current and 22.1% were former smokers. Current smokers more frequently had bothersome asthma symptoms than nonsmokers in both unadjusted analyses and analyses controlling for age, gender, recent visits to the general practitioner for asthma, and asthma medication use (p = 0.06). Respiratory symptoms (p = 0.03) and symptoms that affect daily activities (p = 0.03) were more strongly associated with smoking than symptoms that affect physical activities (p = 0.62). Our data suggest that smoking hastens asthma progression or affects disease control. Increased frequency of symptoms may be an indicator for potential morbidity among asthmatics, especially those who smoke cigarettes. The hazards associated with smoking among asthmatics need to be more clearly emphasized by physicians and public health officials in order to convince people with asthma who smoke to stop.

Professor Philippe Godard : The number of papers about the economic burden of asthma is increasing. Apparently, governments have less and less money to spend, and therefore this topic is becoming increasingly important. However, the conclusions of these papers are always the same. The main contribution to the total costs is hospitalization. Moreover, newer, more effective drugs reduce total costs of asthma by improving asthma control. They remain cost-effective compared with older, less effective drugs, even if the newer drugs are more expensive.

That improved asthma control results in the reduction of total asthma costs has been clearly demonstrated in Sweden as early as 1988. Use of budesonide decreased the duration of hospitalization, which was associated with a 55% reduction in the mean cost of medical treatment (1).

Other studies have shown that the severity of asthma is an important factor determining costs associated with asthma. A small percentage of severely ill patients account for a high proportion of the total costs. The study by Szucs et al. did not address this issue. However, it would have been interesting to analyse whether or not the newer asthma drugs reduce total asthma costs because they especially treat severe asthma more effectively.

The great difficulty with this kind of health-economic studies is to relate the cost data to the distribution of asthma severity, i.e. are drugs which are cost-effective in severe asthma also cost-effective in mild asthma? Current health economic and epidemiological studies have not addressed this question yet.

Reference:
1. Ädelroth and Thompson. Lancet 1988, Feb 27, p. 476

Professor Takateru Izumi, M.D. : Asthma affects roughly 7% of the population in Switzerland, and is a major health care cost factor in that country. According to this report, the annual direct cost and indirect medical cost per asthma patient in 1997 were CHF 1778 (USD1085) and CH F 1019 (USD622), respectively. The total direct and indirect expenditures in the country were CHF 762 million (USD  465 million) and CHF 490 million (USD 299 million), which adds up to an estimated total of nearly 1252 million (USD 764 million). For the treatment of asthma patients, the direct medical expenditures approached 61% of this total.

The number of asthma patients and the medical expenditures for asthma are increasing in many countries around the world. In all of these countries, reducing or at least retaining medical costs become increasingly important. Therefore, factors that contribute to increased medical costs are being analyzed.

In Japan during 17 years, from 1979 to 1996, the number of asthma patients increased 3.07 fold, reaching a total of 1,146 million (0.9% of the population). Although the proportion of asthma patients within the total population is much smaller in Japan than in Switzerland, the total direct medical cost in 1996 was 436 billion yen (USD 3573 million) annually, and the cost per patient was 380454 yen (USD 3118), i.e. almost triple the cost in Switzerland. The percentage of the total cost that went to medication was similar in the two countries, i.e. 43.1% in Japan and 41.3% in Switzerland. However, because a smaller proportion of the population is affected in Japan, the annual direct medical cost for asthma paid per capita is 3488 yen (USD 29), which is half the cost in Switzerland (CHF 107/USD 65). Indirect medical costs have never been evaluated in Japan.

There are several reports on the medical costs of asthma in western industrial countries, but most of them focus on direct medical costs and give few detailed descriptions of the indirect costs. Szucs et al. describe a method for evaluating both direct and indirect medical costs. While the study is interesting and useful as a reference for calculating medical costs of asthma in other regions and countries, it should be noted that several medical costs were not included in the paper. For example, ambulance services and the costs of patients' travel were not taken into account because in the study medical records were used, which do not include this information. Loss of work was included as an indirect cost, but loss of school days was not, and this may be a controversial omission.

Because the analysis in this report was done retrospectively, the estimated cost may have been lower than the actual cost. Asthma is a serious disease not only from a medical care but also a medical cost standpoint. Therefore, in future progressive studies, it is important to carefully define both direct and indirect medical costs.

Title (11): The economic burden of asthma: direct and indirect costs in Switzerland. (partial abstract from http://www.healthy.net/library/search/medline.htm )

Centre for Pharmacoeconomics, University of Milan, Italy.

Asthma mortality increased in Switzerland between 1980 and 1994. This study aimed to assess the economic burden of asthma in this country. Chart reviews were conducted for the last five patients seen for asthma in physician practices in 1996 and 1997. Direct expenditures and indirect costs for asthma-related morbidity were determined. A total of 589 patient charts were completely analysed, including 117 children's charts, obtained from 120 office-based physicians. The annual direct medical costs were CHF 1,778 and the mean annual indirect costs were CHF 1,019 per patient for all patients. The total estimated cost of asthma in Switzerland in 1997 was nearly CHF 1,252 million. Direct medical expenditures approached CHF 762 million, or 61% of the total. In 1997, the indirect costs for asthma were estimated to have exceeded CHF 490 million. Of these costs CHF 123 million (25%) was associated with morbidity and nearly CHF 368 million (75%) was associated with looking after asthmatic patients who had to be cared for at home. This study provides evidence that asthma is a major healthcare cost factor in Switzerland, amounting to approximately CHF 1,200 million per year. The data suggest that cost savings can be achieved by improving primary care for asthma in an ambulatory setting.

. ARLS   Congrès Conçue et réalisée par: Michel Godard (at) Top
Date de création: 1er Mars 1996 -Dernière mise à jour: 19/06/00
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