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Summary Background The phosphodiesterase-4 inhibitor roflumilast can improve lung function and prevent exacerbations in certain patients with chronic obstructive pulmonary disease (COPD). We therefore investigated whether roflumilast would reduce the frequency of exacerbations requiring corticosteroids in patients with COPD. Methods In two placebo-controlled, double-blind, multicentre trials (M2-124 and M2-125) with identical design that were done in two different populations in an outpatient setting, patients with COPD older than 40 years, with severe airflow limitation, bronchitic symptoms, and a history of exacerbations were randomly assigned to oral roflumilast (500 μg once per day) or placebo for 52 weeks. Primary endpoints were change in prebronchodilator forced expiratory volume in 1 s (FEV 1 ) and the rate of exacerbations that were moderate (glucocorticosteroid-treated) or severe. Analysis was by intention to treat. The trials are registered with ClinicalTrials.gov, number NCT00297102 for M2-124, and NCT00297115 for M2-125. Findings Patients were assigned to treatment, stratified according to smoking status and treatment with longacting β 2 agonists, and given roflumilast (n=1537) or placebo (n=1554). In both studies, the prespecified primary endpoints were achieved and were similar in magnitude. In a pooled analysis, prebronchodilator FEV 1 increased by 48 mL with roflumilast compared with placebo (p Interpretation Since different subsets of patients exist within the broad spectrum of COPD, targeted specific therapies could improve disease management. This possibility should be explored further in prospective studies. Funding Nycomed.

Asthma is a chronic disease of the airways in which inflammation of the respiratory mucosa plays a crucial role. The mechanisms responsible for the maintaining of this inflammatory response are only partially known and there is evidence that a role could be paid by chronic infection by intracellular pathogens (such as Chlamydia pneumoniae). Macrolides are antibiotics with both antimicrobial and anti-inflammatory activities and thus their use in asthmatic patients could lead to reduction of the airways inflammation and therefore improvement of symptoms and pulmonary function.To determine whether macrolides are effective in the management of patients with chronic asthma.We searched MEDLINE, EMBASE and CINAHL up to May 2001. This was also supplemented by manually searching bibliographies of previously published reviews, conference proceedings, and contacting study authors. All languages were included in the initial search.Randomised, controlled clinical trials involving both children and adult patients with chronic asthma treated with macrolides for more than 4 weeks, versus placebo.Two reviewers independently examined all identified articles. Two reviewers reviewed the full text of any potentially relevant article independently.The initial search retrieved 95 studies. Preliminary evaluation identified 20 studies that were potentially eligible. Five (357 patients) met the entry criteria. The entry criteria for the primary trials differed, but all recruited a specific subgroup of patients (eg severe oral steroid dependent, aspirin intolerant or evidence of Chlamydia pnuemoniae infection). There was a positive effect on symptoms (Standardised Mean Difference -1.25, 95% Confidence Intervals (CI) -1.80, -0.70) and markers of eosinophilic inflammation; eg sputum eosinophils Weighted Mean difference -78.5, 95%CI -90.8, -66.1). Tests of oral corticosteroid-sparing effects have not yet been performed on the newer agents such as roxithromycin and clarithromycin.Considering the small number of patients studied, there is insufficient evidence to support or to refute the use of macrolides in patients with chronic asthma. Further studies are needed in particular to clarify the potential role of macrolides in some subgroups of asthmatics such as those with evidence of chronic bacterial infection.

We measured circulating platelet factor 4 (PF4) and heparin-releasable platelet factor 4 (HR-PF4) in 13 symptomatic patients suffering from bronchial asthma and in 10 matched normal controls. Neither a difference between patients and controls, nor a correlation between platelet count and HR-PF4 was found (PF4: controls 2.1 +/- 2.9; patients 3.6 +/- 4.4 ng/ml (n.s.); HR-PF4: controls 127 +/- 49, patients 101 +/- 34 ng/ml (n.s.). Therefore, the pathogenetic role of PF4 in the mechanism of bronchial asthma, elsewhere hypothesized, cannot definitely be established.

We examined one group of 33 patients with primary Sjogren's syndrome, one group of 17 patients with secondary Sjogren's syndrome, i.e. associated with other connective tissue diseases, and one group of 14 patients with connective tissue diseases but without Sjogren's syndrome. In each patient we obtained chest radiographs and measured lung volumes, carbon monoxide diffusing capacity and airway responsiveness to methacholine. We observed no difference in chest radiograph abnormalities, in lung volumes and in carbon monoxide diffusing capacity among the three groups. However, we found a slight but significant increase of bronchial responsiveness in patients with primary and secondary Sjogren's syndrome compared with patients with connective tissue disorders but without Sjogren's syndrome. Thus PD20FEV1 methacholine was 1.07 mg (1.2) (geometric mean and GSEM) in primary Sjogren's syndrome, 0.91 mg (1.4) in secondary Sjogren's syndrome (NS), and 2.24 mg (1.09) in patients with connective tissue diseases but without Sjogren's syndrome (t = 2.59 and t = 2.8, both p less than 0.05, vs primary and secondary Sjogren's syndrome, respectively). These results show that some patients with Sjogren's syndrome have mild bronchial hyperresponsiveness, which may be related to the specific airway abnormalities of this disease.

To determine the importance of airway inflammation for late asthmatic reactions and increased airway responsiveness induced by TDI, we investigated whether late asthmatic reactions and increased responsiveness induced by TDI are associated with airway inflammation and whether steroids prevent them by modifying the inflammatory response within the airways. We measured FEV1 before and at regular intervals after exposure to TDI and performed dose-response curves to methacholine and bronchoalveolar lavage 8 hr after TDI in two subjects with previously documented late asthmatic reaction; then we repeated the same procedure a few weeks after treatment with steroids. Airway responsiveness and polymorphonuclear cells were increased in both subjects after the late asthmatic reaction; treatment with steroids prevented late asthmatic reaction and the increase in airway responsiveness and polymorphonuclear cells in bronchoalveolar lavage. These results suggest that late asthmatic reaction induced by TDI may be caused by airway inflammation.

162 subjects who had been exposed to isocyanates, who had developed symptoms during the exposure period, or in the evening or night and, therefore, had a history compatible with isocyanate-induced asthma, were studied with inhalation challenge testing to isocyanates (toluene diisocyanate and methylene diphenyl diisocyanate) and methacholine, because they were suspected of having occupational asthma. None of these subjects had symptomatic asthma before employment. The diagnosis of occupational asthma was delayed (duration of symptoms before diagnosis: 3.9 +/- 0.4 yrs). Isocyanate-asthma documented by a positive inhalation challenge to isocyanates was present in 57.4% of the subjects. A higher degree of airway responsiveness to methacholine was present in subjects with a positive isocyanate inhalation challenge compared to subjects with a negative challenge (Gmean and GESM: 0.407 (1.14) vs 0.942 (1.14) mg). The majority of the subjects complained of shortness of breath and cough. The low proportion of atopic subjects (21.5%) and of smokers (7.5%), and the high proportion of subjects with the late component in the asthmatic reaction (71%) appear to be common features in this disease.

Two workers, who developed asthmatic symptoms, were studied with inhalation provocation tests using diphenylmethane diisocyanate (MDI) and toluene diisocyanate (TDI). The subjects showed specific asthmatic reactions to MDI challenge (more than 20% fall in FEV1), and one also had an alveolar response. Alveolitis was suggested by fever, basal crackles, increased neutrophil counts in venous blood and in bronchoalveolar lavage. The asthmatic reaction to MDI challenge was associated with an increase in airway responsiveness to methacholine in both subjects. We conclude that MDI is a cause of asthma and/or hypersensitivity pneumonitis in workers exposed to diphenylmethane diisocyanate.

The dosimeter method of administering doubling cumulative doses of methacholine to measure bronchial responsiveness was standardized to control for the effects of a number of potential influencing variables. The aerodynamic mass median diameter of the challenge aerosol produced from a DeVilbiss 646 nebulizer proved to be 1.2 mu, and the mean output per inhalation 8.9 microliters. Each challenge dose comprised 5 inhalations. Cumulative doses ranged from 0.3 methacholine inhalation units (1 unit = 1 inhalation of aerosol from a 1-mg/ml solution of methacholine, i.e., 8.9 micrograms methacholine) to a possible 640 units, the maximum that was considered reasonable to avoid the risk of unacceptable systemic effects. Responsiveness was expressed as the dose provoking a 20% decline (PD20) in FEV1. Modifications in this full protocol were introduced to facilitate epidemiologic investigations. Physician assessments coupled with baseline measurements of ventilatory function allowed starting at higher dosages for persons with low probability of hyperresponsiveness, thereby shortening the time required for testing to an average of 38 min. In a validation study of 20 persons using both the full and modified protocols, no significant differences were detected between measured PD20 values (geometric means Full versus Modified, 14.83 versus 14.88; r = 0.99). The modified protocol was used to measure bronchial responsiveness in 254 workers exposed to toluene diisocyanate. It proved to be safe and acceptable. Sixty-four workers (25.2%) were found to be reactors. The frequency distribution of the PD20 values exhibited a steadily increasing trend, consistent with a unimodal distribution.