Severe asthma: advances in current management and future therapy

Effective treatment of severe asthma is a major unmet need because patients' symptoms are not controlled on maximum treatment with inhaled therapy. Asthma symptoms can be poorly controlled because of poor adherence to controller therapy, and this might be addressed by using combination inhalers that contain a corticosteroid and long-acting β(2)-agonist as reliever therapy in addition to maintenance treatment. New bronchodilators with a longer duration of action are in development, and recent studies have demonstrated the benefit of a long-acting anticholinergic bronchodilator in addition to β(2)-agonists in patients with severe asthma. Anti-IgE therapy is beneficial in selected patients with severe asthma. Several new blockers of specific mediators, including prostaglandin D(2), IL-5, IL-9, and IL-13, are also in clinical trials and might benefit patients with subtypes of severe asthma. Several broad-spectrum anti-inflammatory therapies that target neutrophilic inflammation are in clinical development for the treatment of severe asthma, but adverse effects after oral administration might necessitate inhaled delivery. Macrolides might benefit some patients with infection by atypical bacteria, but recent results are not encouraging, although there could be an effect in patients with predominant neutrophilic asthma. Corticosteroid resistance is a major problem in patients with severe asthma, and several molecular mechanisms have been described that might lead to novel therapeutic approaches, including drugs that could reverse this resistance, such as theophylline and nortriptyline. In selected patients with severe asthma, bronchial thermoplasty might be beneficial, but thus far, clinical studies have not been encouraging. Finally, several subtypes of severe asthma are now recognized, and in the future, it will be necessary to find biomarkers that predict responses to specific forms of therapy.     

Ethnic-Specific Differences in Bronchodilator Responsiveness Among African Americans, Puerto Ricans, and Mexicans with Asthma

Socioeconomic and environmental differences do not fully explain differences in asthma prevalence, morbidity, and mortality among Puerto Ricans, African Americans, and Mexican Americans. Differences in response to albuterol may be a factor. We compared bronchodilator responsiveness between these three populations. All groups demonstrated below expected responsiveness. Puerto Ricans of all ages and African American children with moderate-to-severe asthma demonstrated the lowest responsiveness overall. Among subjects with moderate-to-severe asthma, children were even less likely than adults to show the expected bronchodilator response. We conclude that ethnic-specific differences in bronchodilator drug responsiveness exist between Mexicans, Puerto Ricans, and African Americans with asthma. This may be of importance in asthma management.     

Bronchodilator reversibility in Australian adults with chronic obstructive pulmonary disease

Abstract Background and aims: Bronchodilator reversibility (BDR) and inhaled corticosteroid (ICS) use were assessed for volunteers who responded to an advertisement requesting current or ex‐smokers who were experiencing breathlessness to attend for lung function testing. Methods: One hundred and fifty‐four volunteers responded. Forced expiratory volume (FEV₁) was measured before and after 400 µg of salbutamol. Significant BDR was assessed according to guidelines of: (i) the American Thoracic Society (≥12% plus 200 mL of baseline FEV₁ or forced vital capacity), (ii) the British ­Thoracic Society (BTS) (≥15% plus 200 mL of baseline FEV₁), (iii) the European Thoracic Society (≥10% predicted FEV₁), and (iv) the most commonly used criteria in Australia and New Zealand (≥15% of baseline FEV₁). Results: One hundred and twenty‐three subjects (33 female; 40 current smokers; median pack years 48 (range 5?144)) were suitable for analysis (i.e. had no history of asthma, demonstrable airflow limitation and a forced expiratory ratio (FER) of <70%). Twenty (16%) patients had an FEV₁ within the normal range but FER of <70%, 24 (20%) patients had mild disease (FEV₁ 60?80% predicted), 31 (24%) patients had moderate disease (FEV₁ 40?59% predicted), and 48 (39%) patients had severe disease (FEV₁ <40% predicted), according to BTS criteria. Significant BDR was evident in: (i) 58 (47%) subjects by American criteria, (ii) 26 (21%) subjects by British criteria, (iii) 19 (15%) subjects by European criteria and (iv) 36 (29%) subjects by Australasian criteria. ICS use was reported by 71 (58%) subjects overall and was weakly, but significantly, related to poorer FEV₁ (r = ?0.2; P < 0.01), and greater BDR (r = 0.3; P < 0.005). Conclusion: Chronic obstructive pulmonary disease in Australian volunteers with no history of asthma encompasses many individuals with significant BDR. Interestingly, most volunteers reported ICS use and this was related to poorer spirometry and greater BDR. However, until the underlying immuno­pathology has been determined they cannot be assumed to have ‘asthma’ or even an ‘asthmatic element’. (Intern Med J 2003; 33: 572?577)     

Review of drug safety and efficacy of arformoterol in chronic obstructive pulmonary disease

Introduction: The global initiative for chronic obstructive lung disease guidelines recommend maintenance therapy using long-acting bronchodilators for patients with chronic obstructive pulmonary disease (COPD) who have daily symptoms. Arformoterol is the (R, R) - enantiomer of the racemic formoterol and is more potent than (R, R/ S, S) - formoterol.

Areas covered: Currently, arformoterol is one of two nebulized long-acting β-agonists on the market. It has a low incidence of cardiovascular side effects with incidence of arrhythmia and ischemia similar to placebo. β-adrenergic adverse effects are infrequent, numerically lower than formoterol, but have a quicker onset of action than salmeterol. There was no observed clinical tolerance over 12 months. arformoterol is safe in combination therapy with inhaled corticosteroids, tiotropium and rescue inhalers. A 12-month Phase IV trial found no increased risk of respiratory death or COPD exacerbation-related hospitalizations. arformoterol can potentially benefit patients with hyperinflation and low inspiratory flow rates.

Expert opinion: The introduction of the centers for medicare and medicaid services penalization for COPD readmissions may boost the appeal of long-acting bronchodilators as new discharge medications. With the advent of ultra long-acting bronchodilators, its potential as a once daily agent in isolation or combination with these new therapies needs further study.     

Aging does not affect beta-agonist responsiveness after methacholine-induced bronchoconstriction

OBJECTIVES: To assess the response to an inhaled beta-agonist alone or in combination with an anticholinergic agent after methacholine-induced bronchoconstriction in four age groups. DESIGN: Retrospective analysis. SETTING: Pulmonary function laboratory in a university-affiliated hospital. PARTICIPANTS: Seven hundred sixty-four consecutive subjects with a 20% reduction or more in forced expiratory volume during the first second (FEV1) of exhalation from total lung capacity after inhaling 189 or fewer cumulative units of methacholine were included in the analysis. INTERVENTION: The first 382 subjects received three inhalations of metaproterenol (total of 1.95 mg), and the other 382 subjects received three inhalations of albuterol and ipratropium combination (total of 309 microg of albuterol and 54 microg of ipratropium) after methacholine-induced bronchoconstriction. MEASUREMENTS: The response to bronchodilators was assessed as the postbronchodilator percentage change in FEV1 and the percentage of subjects recovering to 90% or better of baseline FEV1 after the use of bronchodilator. RESULTS: The percentage change in FEV1 postbronchodilator in the elderly was similar to that of the younger subjects. The percentage of subjects who recovered to 90% or better of their baseline FEV1 postbronchodilator was also similar in the elderly and younger age groups. Response to metaproterenol was similar to that of the albuterol/ipratropium combination in all age groups (all P>.05). CONCLUSION: Aging does not affect bronchodilator response to beta-agonist after methacholine-induced bronchoconstriction. The responsiveness to beta-agonist alone is similar to the responsiveness to the combination of beta-agonist and anticholinergic agent in all age groups.     

吸入支气管扩张剂对重度COPD稳定期IC变化的意义

目的:探讨对重度慢性阻塞性肺疾病(COPD)稳定期患者吸入支气管扩张剂后检测深吸气量(IC)的临床意义。方法:对入选的50例重度慢性阻塞性肺疾病(COPD)稳定期患者,吸入沙丁胺醇前后,肺功能检测1 s用力呼气量(FEV1)、用力肺活量(FVC)、IC,测量6 min行走距离(6MWD)指标,比较用药前后各变量的变化及肺功能IC与6MWD的相关性。结果:用药后IC较用药前比较增加(P<0.05),6MWD用药后较用药前有提高(P<0.05)。回归分析显示IC的变化(△IC)与6MWD的变化(△6MWD)相关性较强(P<0.05,r=0.792 6)。结论:重度COPD稳定期患者吸入支气管扩张剂治疗前后IC的变化与运动耐力的变化相关性强,IC的测定较FEV1更能评价COPD患者的疗效。     

Correlation of IgE antibody titer to Aspergillus fumigatus with decreased lung function in cystic fibrosis

Obstructive pulmonary disease is a typical feature of cystic fibrosis (CF) and is often associated with bronchial hyperreactivity. Positive skin-test reactions to Aspergillus fumigatus antigens are frequently seen even in nonatopic patients with CF. Full-fledged allergic bronchopulmonary aspergillosis (ABPA) has been estimated to occur in 10% of patients with CF. The relationship between lung function and presence of IgE antibodies to Aspergillus antigens in patients without ABPA is not clear. In 148 outpatients with CF (aged 6-34 years) specific immunoglobulin E (IgE) to Aspergillus fumigatus antigens, basic lung-function parameters, and bronchial response to salbutamol were measured. Multiple regression was performed for age, weight as percentile for actual height (indicating general condition), and Aspergillus RAST. Aspergillus IgE was present in 46% of patients; 19% had RAST class 3 or 4. Independent negative correlations of Aspergillus RAST with FEV1, FEF50%, FEF25%, RV, Chrispin Norman score, and sRaw (P less than 0.05) were found. Bronchodilator sensitivity did not correlate significantly with age and weight percentile. However, Aspergillus RAST did correlate significantly with bronchodilator response measured by sRaw (P less than 0.05). High titers of Aspergillus RAST might serve as a selective criterion for patients to be included in future studies evaluating broncholytic or antiphlogistic therapies.     

Nasal versus oronasal raised volume forced expirations in infants--a real physiologic challenge

Raised volume rapid thoracoabdominal compression (RTC) generates forced expiration (FE) in infants typically from an airway opening pressure of 30 cm H(2)O (V(30)). We hypothesized that the higher nasal than pulmonary airway resistance limits forced expiratory flows (FEF(%)) during (nasal) FE(n), which an opened mouth, (oronasal) FE(o), would resolve. Measurements were performed during a brief post-hyperventilation apnea on 12 healthy infants aged 6.9-104 weeks. In two infants, forced expiratory (FEFV) flow volume (FV) curves were generated using a facemask that covered the nose and a closed mouth, then again with a larger mask with the mouth opened. In other infants (n = 10), the mouth closed spontaneously during FE. Oronasal passive expiration from V(30) generated either the inspiratory capacity (IC) or by activating RTC before end-expiration, the slow vital capacity ((j) SVC). Peak flow (PF), FEF(25), FEF(50), FEF(25-75), FEV(0.4), and FEV(0.5) were lower via FE(n) than FE(o) (P < 0.05), but the ratio of expired volume at PF and forced vital capacity (FVC) as percent was higher (P < 0.05). FEF(75), FEF(85), FEF(90), FVC as well as the applied jacket pressures were not different (P > 0.05). FEFV curves generated via FE(o) exhibited higher PF than FV curves of IC (P < 0.05); PF of those produced via FE(n) were not different from FV curves of IC (P > 0.05) but lower than those of (j) SVC (P < 0.05). In conclusion, the higher nasal than pulmonary airways resistance unequivocally affects the FEFV curves by consistently reducing PF and decreases mid-expiratory flows. A monitored slightly opened mouth and a gentle anterior jaw thrust are physiologically integral for raised volume RTC in order to maximize the oral and minimize nasal airways contribution to FE so that flow limitation would be in the pulmonary not nasal airways.