Professor Amanda Wilson

Background: Theophylline and long acting beta-2 agonists are bronchodilators used for the management of persistent asthma symptoms, especially nocturnal asthma. They represent different classes of drug with differing side-effect profiles. Objectives: To assess the comparative efficacy, safety and side-effects of long-acting beta-2 agonists and theophylline in the maintenance treatment of adults and adolescents with asthma. Search strategy: We searched the Cochrane Airways Group trials register and reference lists of articles. We also contacted authors of identified RCTs for other relevant published and unpublished studies and pharmaceutical manufacturers. Most recent search: November 2006. Selection criteria: All included studies were RCTs involving adults and children with clinical evidence of asthma. These studies must have compared oral sustained release and/or dose adjusted theophylline with an inhaled long-acting beta-2 agonist. Data collection and analysis: In original review, two reviewers independently assessed trial quality and extracted data, similarly in this update two reviewers undertook this. Study authors were contacted for additional information. Main results: Thirteen studies with a total of 1344 participants met the inclusion criteria of the review. They were of varying quality. There was no significant difference between salmeterol and theophylline in FEV1 predicted (6.5%; 95% CI -0.84 to 13.83). However, salmeterol treatment led to significantly better morning PEF (mean difference 16.71 L/min, 95% CI 8.91 to 24.51) and evening PEF (mean difference 15.58 L/min, 95% CI 8.33 to 22.83). Salmeterol also reduced the use of rescue medication. Formoterol, used in two studies was reported to be as effective as theophylline. Bitolterol, used in only one study, was reported to be less effective than theophylline. Participants taking salmeterol experienced fewer adverse events than those using theophylline (Parallel studies: Relative Risk 0.44; 95% CI 0.30 to 0.63, Risk Difference -0.11; 95% CI -0.16 to -0.07, Numbers Needed to Treat (NNT) 9; 95% CI 6 to 14). Significant reductions were reported for central nervous system adverse events (Relative Risk 0.50; 95% CI 0.29 to 0.86, Risk Difference -0.07; 95% CI -0.12 to -0.02, NNT 14; 95% CI 8 to 50) and gastrointestinal adverse events (Relative Risk 0.30; 95% CI 0.17 to 0.55, Risk Difference -0.11; 95% CI -0.16 to -0.06, NNT 9; 95% CI 6 to 16). Authors' conclusions: Long-acting beta-2 agonists, particularly salmeterol, are more effective than theophylline in improving morning and evening PEF, but are not significantly different in their effect on FEV1. There is evidence of decreased daytime and nighttime short-acting beta-2 agonist requirement with salmeterol. Fewer adverse events occurred in participants using long-acting beta-2 agonists (salmeterol and formoterol) as compared to theophylline. Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Background: Allergic bronchopulmonary aspergillosis is hypersensitivity to the fungus Aspergillus fumigatus that complicates patients with asthma and cystic fibrosis. The mainstay of treatment for allergic bronchopulmonary aspergillosis remains oral corticosteroids, though this does not completely prevent exacerbations and may not prevent the decline in lung function. Objectives: The purpose of this review was to determine the efficacy of azoles in the treatment of allergic bronchopulmonary aspergillosis. Search methods: We searched the Cochrane Airways Group Asthma trials register, CENTRAL, MEDLINE and EMBASE. Searches are current as of May 2008. Selection criteria: All controlled trials that assessed the effect of azole antifungal agents compared to placebo or other standard therapy for allergic bronchopulmonary aspergillosis were reviewed. Patients with cystic fibrosis were not included. Data collection and analysis: Two reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects information was collected from the trials. Main results: Twelve trials were identified, but only three were prospective, randomised and controlled. A total of 94 participants were included. One demonstrated a reduction in immunological markers of disease activity and symptom scores using ketoconazole 400 mg daily for 12 months. There was no significant improvement in lung function. The other two examined the use of itraconazole for 16 weeks. In one there was a reduction in sputum eosinophils by 35% compared to 19% with placebo (p < 0.01). In the same trial, the number of exacerbations requiring oral corticosteroids was 0.4 per patient with itraconazole compared with 1.3 per patient with placebo (p < 0.03). Meta-analysis of data from both trials showed that itraconazole treated patients were more likely to have decline in serum IgE over 25% or more (Peto OR 3.30; 95% confidence intervals 1.30 to 8.15). Authors' conclusions: Itraconazole modifies the immunologic activation associated with allergic bronchopulmonary aspergillosis and improves clinical outcome, at least over the period of 16 weeks. Adrenal suppression with inhaled corticosteroids and itraconazole is a potential concern.

BACKGROUND: Theophylline and long acting beta-2 agonists are bronchodilators used for the management of persistent asthma symptoms, especially nocturnal asthma. They represent different classes of drug with differing side-effect profiles. OBJECTIVES: To assess the comparative efficacy, safety and side-effects of long-acting beta-2 agonists and theophylline in the maintenance treatment of asthma. SEARCH STRATEGY: Randomised, controlled trials (RCTs) were identified using the Cochrane Airways Group register. The register was searched using the following terms: asthma and theophylline and long acting beta-agonist or formoterol or foradile or eformoterol or salmeterol or bambuterol or bitolterol. Date of last search was April 2003.Titles and abstracts were then screened to identify potentially relevant studies. The bibliography of each RCT was searched for additional RCTs. Authors of identified RCTs were contacted for other relevant published and unpublished studies. SELECTION CRITERIA: All included studies were RCTs involving adults and children with clinical evidence of asthma. These studies must have compared oral sustained release and/or dose adjusted theophylline with an inhaled long-acting beta-2 agonist. DATA COLLECTION AND ANALYSIS: Potentially relevant trials, identified by screening titles and/or abstracts, were obtained. Two reviewers independently assessed full text versions of these trials to decide whether the trial should be included in the review, and assessed its methodological quality. Where there was disagreement between reviewers, this was resolved by consensus, or reference to a third party.Data were extracted by two independent reviewers. Inter-rater reliability was assessed by simple agreement. Study authors were contacted to clarify randomisation methods, provide missing data, verify the data extracted and identify unpublished studies. Relevant pharmaceutical manufacturers were also contacted. MAIN RESULTS: Six trials originally met the inclusion criteria. Five used salmeterol and one, bitolterol. In an updated version of the review, six more trials were included. Four trials used salmeterol and two used formoterol. They were of varying quality. Salmeterol improved FEV1 significantly more than theophylline in five studies and salmeterol use was associated with significantly more symptom free nights in all the studies comparing these agents. Formoterol, used in two studies was reported to be as effective as theophylline. Bitolterol, used in only one study, was reported to be less effective than theophylline. Subjects taking salmeterol experienced fewer adverse events than those using theophylline (Parallel studies: Relative Risk 0.44; 95% CI: 0.30 to 0.63), Risk Difference -0.11 (95%CI: -0.16 to -0.07), NNT 9 (6, 14). Significant reductions were reported for central nervous system adverse events (Relative Risk 0.50; 95%Confidence Intervals 0.29, 0.86), Risk Difference -0.07(95% CI -0.12, -0.02), NNT 14(8, 50) and gastrointestinal adverse events (Relative Risk 0.30; 95%Confidence Intervals 0.17, 0.55), Risk Difference -0.11(-0.16, -0.06), NNT 9(6, 16). REVIEWER'S CONCLUSIONS: Long-acting beta-2 agonists are at least as effective than theophylline in reducing asthma symptoms including night waking and improving lung function. Fewer adverse events occurred in subjects using long-acting beta-2 agonists(salmeterol and formoterol) as compared to theophylline.

BACKGROUND: Allergic bronchopulmonary aspergillosis is hypersensitivity to the fungus Aspergillus fumigatus that complicates patients with asthma and cystic fibrosis. The mainstay of treatment for allergic bronchopulmonary aspergillosis remains oral corticosteroids, though this does not completely prevent exacerbations and may not prevent the decline in lung function. OBJECTIVES: The purpose of this review was to determine the efficacy of azoles in the treatment of allergic bronchopulmonary aspergillosis. SEARCH STRATEGY: We searched the Cochrane Airways Group Asthma trials register using the terms: (allergic bronchopulmonary aspergillosis OR aspergillosis OR allergic pulmonary aspergillosis OR allergic fungal and disease OR allergic mycotic and disease) AND (azole OR triazole OR itraconazole OR ketoconazole). Date of last search January 2003. SELECTION CRITERIA: All controlled trials that assessed the effect of azole antifungal agents compared to placebo or other standard therapy for allergic bronchopulmonary aspergillosis were reviewed. Patients with cystic fibrosis were not included. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects information was collected from the trials. MAIN RESULTS: Twelve trials were identified, but only three were prospective, randomised and controlled. A total of 94 participants were included. One demonstrated a reduction in immunological markers of disease activity and symptom scores using ketoconazole 400 mg daily for 12 months. There was no significant improvement in lung function. The other two examined the use of itraconazole for 16 weeks. In one there was a reduction in sputum eosinophils by 35% compared to 19% with placebo (p < 0.01). In the same trial, the number of exacerbations requiring oral corticosteroids was 0.4 per patient with itraconazole compared with 1.3 per patient with placebo (p < 0.03). Meta-analysis of data from both trials showed that itraconazole treated patients were more likely to have decline in serum IgE over 25% or more (Peto OR 3.30; 95% confidence intervals 1.30 to 8.15). REVIEWER'S CONCLUSIONS: Itraconazole modifies the immunologic activation associated with allergic bronchopulmonary aspergillosis and improves clinical outcome, at least over the period of 16 weeks. Adrenal suppression with inhaled corticosteroids and itraconazole is a potential concern.

Background: A key component of many asthma management guidelines is the recommendation for patient education and regular medical review. A number of controlled trials have been conducted to measure the effectiveness of asthma education programmes. These programmes improve patient knowledge, but their impact on health outcomes is less well established. At its simplest level, education is limited to the transfer of information about asthma, its causes and its treatment. This review focused on the effects of limited asthma education. Objectives: The objective of this review was to assess the effects of limited (i.e. information only) asthma education on health outcomes in adults with asthma. Search methods: We searched the Cochrane Airways Group trials register and reference lists of articles. Selection criteria: Randomised and controlled trials of individual asthma education involving information transfer only in adults over 16 years of age. Data collection and analysis: Trial quality was assessed and two reviewers extracted data independently. Study authors were contacted for missing information. Main results: Twelve trials were included. They were of variable quality. Limited asthma education did not reduce hospitalisation for asthma (weighted mean difference -0.03 average hospitalisations per person per year, 95% confidence interval -0.09 to 0.03). There was no significant effect on doctor visits, lung function and medication use. The effects on asthma symptoms were variable. There was no reduction in days lost from normal activity, but in two studies, perceived asthma symptoms did improve after limited asthma education (odds ratio 0.44, 95% confidence interval 0.26 to 0.74). In one study, limited asthma education was associated with reduced emergency department visits (reduction of -2.76 average visits per person per year, 95% confidence interval -4.34 to 1.18). Authors' conclusions: Use of limited asthma education as it has been practiced does not appear to improve health outcomes in adults with asthma although perceived symptoms may improve. Provision of information in the emergency department may be effective, but this needs to be confirmed.

BACKGROUND: A key component of many asthma management guidelines is the recommendation for patient education and regular medical review. A number of controlled trials have been conducted to measure the effectiveness of asthma education programmes. These programmes improve patient knowledge, but their impact on health outcomes is less well established. At its simplest level, education is limited to the transfer of information about asthma, its causes and its treatment. This review focused on the effects of limited asthma education. OBJECTIVES: The objective of this review was to assess the effects of limited (i.e. information only) asthma education on health outcomes in adults with asthma. SEARCH STRATEGY: We searched the Cochrane Airways Group trials register and reference lists of articles. SELECTION CRITERIA: Randomised and controlled trials of individual asthma education involving information transfer only in adults over 16 years of age. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and data were extracted independently by two reviewers. Study authors were contacted for missing information. MAIN RESULTS: Eleven trials were included. They were of variable quality. Limited asthma education did not reduce hospitalisation for asthma (weighted mean difference -0.03 average hospitalisations per person per year, 95% confidence interval -0.09 to 0.03). There was no effect on doctor visits, lung function and medication use. The effects on asthma symptoms were variable. There was no reduction in days lost from normal activity, but perceived asthma symptoms did improve after limited asthma education (odds ratio 0.40, 95% confidence interval 0.18 to 0.86). In one study, limited asthma education was associated with reduced emergency department visits (weighted mean difference -2.76 average visits per person per year, 95% confidence interval -4.34 to 1.18). REVIEWER'S CONCLUSIONS: Use of limited asthma education as it has been practiced does not appear to improve health outcomes in adults with asthma. However the use of information in the emergency department may be effective, but this needs to be confirmed.

BACKGROUND: A key component of many asthma management guidelines is the recommendation for patient education and regular medical review. A number of controlled trials have been conducted to measure the effectiveness of asthma education programmes. These programmes improve patient knowledge, but their impact on health outcomes is less well established. This review was conducted to examine the strength of evidence supporting Step 6 of the Australian Asthma Management Plan: "Educate and Review Regularly"; to test whether health outcomes are influenced by education and self-management programmes. OBJECTIVES: The objective of this review was to assess the effects of asthma self-management programmes, when coupled with regular health practitioner review, on health outcomes in adults with asthma. SEARCH STRATEGY: We searched the Cochrane Airways Group trials register and reference lists of articles. SELECTION CRITERIA: Randomised trials of self-management education in adults over 16 years of age with asthma. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and data were extracted independently by two reviewers. Study authors were contacted for confirmation. MAIN RESULTS: Twenty-five trials were included. Self-management education was compared with usual care in 22 studies. Self-management education reduced hospitalisations (odds ratio 0.57, 95% confidence interval 0.38 to 0.88); emergency room visits (odds ratio 0.71, 95% confidence interval (0.57 to 0.90); unscheduled visits to the doctor (odds ratio 0.57, 95% confidence interval 0.40 to 0.82); days off work or school (odds ratio 0.55, 95% confidence interval 0.38 to 0. 79); and nocturnal asthma (odds ratio 0.53, 95% confidence interval 0.39 to 0.72). Measures of lung function were little changed. Self-management programmes that involved a written action plan showed a greater reduction in hospitalisation than those that did not (odds ratio 0.35, 95% confidence interval 0.18 to 0.68). People who managed their asthma by self-adjustment of their medications using an individualised written plan had better lung function than those whose medications were adjusted by a doctor. REVIEWER'S CONCLUSIONS: Training in asthma self-management which involves self-monitoring by either peak expiratory flow or symptoms, coupled with regular medical review and a written action plan appears to improve health outcomes for adults with asthma. Training programmes which enable people to adjust their medication using a written action plan appear to be more effective than other forms of asthma self-management.

Both theophylline and long-acting ß 2-agonists are recommended as effective treatment for nocturnal asthma in Australian Asthma Management Plan. This review sought to assess the comparative efficacy and safety of long-acting s-agonists and theophylline in the maintenance treatment of asthma. Methods: The Cochrane Airways Group Clinical Trials Register was searched for relevant studies and randomised controlled trials (RCTs) reporting more than one asthma outcome were included. Interventions were defined as inhaled long-acting ß 2-agonists: salmeterol; eformoterol; bambuterol or bitolterol versus ingested sustained-release and/or doseadjusted theophylline. Data on methodological quality, study characteristics, interventions and outcomes were extracted by two independent reviewers and agreement was assessed. Results: Theophylline versus a long-acting ß 2-agonist was reviewed in 6 RCTs of varying quality conducted over a period of 8 years. There was a trend for salmeterol to improve FEV1 more than theophylline (3 studies). More symptom free nights also tended to occur with salmeterol. Bitolterol (1 study) was less efficacious than theophylline. Subjects taking salmeterol experienced fewer adverse events than those using theophylline (RR 0.37;95%CI 0.23,0.60). Significant reductions were reported for central nervous system adverse events (RR 0.54;95%CI 0.31,0.93) and gastrointestinal adverse events (RR 0.29;95%CI 0.14, 0.60). Conclusions: Salmeterol may be more effective than theophylline in reducing asthma symptoms, including night waking and the need for rescue medication. More adverse events occurred in patients using theophylline when compared to salmeterol.

In mild asthma there is typically an infiltrate with eosinophils, which improves with corticosteroid therapy. Asthma can persist despite high dose inhaled corticosteroid therapy (ICS). Aim: The aim of this study was to establish the characteristics of airway inflammation in asthma, which persists despite high dose inhaled corticosteroids. Method: Adults (n=73) with asthma and persistent symptoms who were taking =1000g ICS underwent hypertonic saline challenge and sputum induction. Sputum was dispersed using dithiothreitol and assayed for total cell count, cellular differential, supernatant eosinophil cationic protein (ECP ng/mL), myeloperoxidase (MPO ng/mL) and interleukin-8 (IL-8 ng/mL). Subjects were categorised into 4 groups based upon the presence or absence of airway hyperresponsiveness (AHR) and increased sputum eosinophils (E; being >5%). Results: Subjects with eosinophilic AHR (EAR n=16) had 22% E, compared to those with noneosinophilic AHR (NEAR, n=40) who had 1.5% E. Those with asthma in remission (normal AHR and E; n=14) had 1.2% E. Neutrophil % was similar in all 3 groups (p>0.05). ECP was highest in the EAR positive group (7572) compared with NEAR (2834) and remission (504; p = 0.001). MPO was elevated in NEAR (275) and EAR (253) compared with remission (189; p = 0.05). IL-8 levels were highest in NEAR (86.2) compared to EAR (36.5) and remission (12.9; p = 0.03). Conclusion: Asthma which remains symptomatic despite high dose ICS consists of 2 different inflammatory patterns. While some have typical eosinophil inflammation, the most common pattern is cellular (neutrophil and eosinophil) activation, with suppressed eosinophil counts. This may be mediated by IL-8 secretion. There is heterogeneity of airway inflammation in symptomatic asthma.

The objective of this study is to examine the treatment of exacerbations of chronic obstructive airways disease (COAD) in the hospital and in the community setting using a retrospective study of patients admitted to a major teaching hospital combined with a general practice chart audit. The admission records for 248 admissions from 128 patients were reviewed. Most patients (70%) had visited their GP within 2 weeks of admission, antibiotics were prescribed for 30% of the exacerbations while 51% were treated with ingested corticosteroids. During hospitalization, features of infection were present in 64% (n = 159) of exacerbations and 79% (n = 196) received antibiotics. Patients were also treated with nebulized bronchodilators, oxygen and corticosteroids (82%). The median length of stay was 10 days (range 0-55). There was a high readmission rate (70%) at 1 year for exacerbation of COAD during the study period. Exacerbations of COAD frequently demonstrated the clinical features of infection. Treatment in general practice was less intensive than in hospital, and there is a need to reconcile these differences with studies of early therapy with antibiotics and corticosteroids. Although corticosteroids were used less often in general practice, the literature in this area is not conclusive and the evidence supporting guideline recommendations is not explicit. There are opportunities to examine the role of early therapy and early discharge programmes to minimize the cost burden from exacerbations of COAD.

Asthma is accompanied by the accumulation of potentially damaging eosinophils within inflamed airways. How eosinophils may be removed from the airways is not clear. The phagocytic removal of eosinophils in vitro requires that they undergo apoptosis, a form of cell death. We postulated that eosinophil apoptosis may occur in vivo, promoting the removal of airway eosinophils and the resolution of inflammation in asthma. We examined eosinophil apoptosis in sputum samples obtained from 11 subjects during an asthma exacerbation and 2 wk after corticosteroid treatment of the exacerbation. Airway function improved following corticosteroid treatment, and eosinophilic inflammation subsided, with significant decreases occurring in the number of airway eosinophils and the percentage of activated eosinophils. The proportion of apoptotic airway eosinophils increased significantly following corticosteroid treatment, and eosinophil products were apparent within macrophages. Our findings indicate that eosinophil apoptosis is clinically relevant in asthma. Apoptosis may represent a mechanism that promotes the resolution of eosinophilic inflammation in asthma. Comments. Apoptosis, a programmed form of cell death appears to be an important mechanism responsible for the removal of airway eosinophils in the resolution of acute asthma. This is the first report of apoptosis of airway eosinophils.

National asthma management guidelines have improved awareness of the rising morbidity and mortality from asthma but have not been widely implemented at a local level. This paper describes the use of continuous quality improvement techniques to facilitate the implementation of asthma management guidelines within a tertiary hospital setting. A baseline audit demonstrated satisfactory emergency assessment and treatment, but identified poor compliance with the patient education aspects of the asthma management plan. An evaluation of the literature demonstrated that programs combining asthma education and management were effective when directed towards adults with a recent severe asthma exacerbation. An asthma education and management service was developed to address these deficits. A repeat audit was conducted which identified improvements in asthma control and management skills for patients attending the education program, together with reductions in asthma re-admission rates for patients referred to the service. Ongoing quality assessments will target nonattenders to the service and the maintenance of asthma skills. An area Asthma Health Outcomes Council was formed to address the issues of asthma management throughout the area health service.

We investigated the role of endogenous prostaglandins and NO in the blood flow response of skin microcirculation in vivo. Test agents were injected intradermally in anesthetized rabbits and changes in skin blood flow measured with a laser-Doppler flow probe. Skin blood flow increased 75% at 7.33, 6.77, 11.63, 10.30, 10.55, 8.20, and <7 -log mol/site with acetylcholine, ATP, bradykinin, prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), NO gas in solution, and nitroprusside respectively. Co-injection of indomethacin (3 x 10-9 mol/site) or N(G)-nitro-L-arginine methyl ester (L-NAME; 10-7 mol/site) with either acetylcholine or bradykinin abolished the effects. This suggests a link between NO and prostaglandin release. Arachidonic acid increased blood flow, which was inhibited by indomethacin, L-NAME, or the PGD2-receptor antagonist BW-A868C. Blood flow responses to either intradermal acetylcholine or bradykinin, but not to NO in solution, were abolished by co-injection with BW-A868C. PGD2-mediated vasodilation was abolished by L-NAME or BW-A868C, but not by indomethacin. There was no evidence of a link between NO and prostaglandin release in precontracted rabbit aortic rings in vitro. The results suggest that, in the microcirculation of rabbit skin, acetylcholine- and bradykinin-mediated vasodilation involve the arachidonic acid-PGD2-NO pathway.