Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial.

BACKGROUND: Patients with severe asthma are at increased risk of exacerbations and lower respiratory tract infections (LRTI). Severe asthma is heterogeneous, encompassing eosinophilic and non-eosinophilic (mainly neutrophilic) phenotypes. Patients with neutropilic airway diseases may benefit from macrolides. METHODS: We performed a randomised double-blind placebo-controlled trial in subjects with exacerbation-prone severe asthma. Subjects received low-dose azithromycin (n=55) or placebo (n=54) as add-on treatment to combination therapy of inhaled corticosteroids and long-acting ß2 agonists for 6 months. The primary outcome was the rate of severe exacerbations and LRTI requiring treatment with antibiotics during the 26-week treatment phase. Secondary efficacy outcomes included lung function and scores on the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ). RESULTS: The rate of primary endpoints (PEPs) during 6 months was not significantly different between the two treatment groups: 0.75 PEPs (95% CI 0.55 to 1.01) per subject in the azithromycin group versus 0.81 PEPs (95% CI 0.61 to 1.09) in the placebo group (p=0.682). In a predefined subgroup analysis according to the inflammatory phenotype, azithromycin was associated with a significantly lower PEP rate than placebo in subjects with non-eosinophilic severe asthma (blood eosinophilia ≤200/µl): 0.44 PEPs (95% CI 0.25 to 0.78) versus 1.03 PEPs (95% CI 0.72 to 1.48) (p=0.013). Azithromycin significantly improved the AQLQ score but there were no significant between-group differences in the ACQ score or lung function. Azithromycin was well tolerated, but was associated with increased oropharyngeal carriage of macrolide-resistant streptococci. CONCLUSIONS: Azithromycin did not reduce the rate of severe exacerbations and LRTI in patients with severe asthma. However, the significant reduction in the PEP rate in azithromycin-treated patients with non-eosinophilic severe asthma warrants further study. CLINICALTRIALS.GOV NUMBER: NCT00760838.

Contribution of four common pulmonary function tests to diagnosis of patients with respiratory symptoms: a prospective cohort study.

BACKGROUND: Few studies of the diagnostic value of pulmonary function testing are available. We assessed the diagnostic contribution of four basic pulmonary function tests: spirometry, lung volume, airway resistance, and diffusing capacity. METHODS: In this prospective cohort study, we enrolled patients presenting to a pulmonologist with respiratory symptoms but no clear diagnosis from 33 hospitals in Belgium. Each patient had spirometry, lung volume, airway resistance, and diffusing capacity testing and all other tests necessary for a definitive diagnosis. Clinical history and pulmonary function data were presented to local focus groups, who established differential diagnoses and a preferred diagnosis after each test-the focus groups were masked to additional investigations. The final diagnosis was established by the attending physician on the basis of all the investigations done, and validated as the gold standard diagnosis by the local focus group. The primary outcome was a score calculated by 1/number of differential diagnoses, corrected for the accuracy of the diagnosis. Secondary outcomes were the number of differential diagnoses for patients with a correct preferred diagnosis and the proportion of preferred diagnoses that were correct. The study is registered at ClinicalTrials.gov, number NCT01297881. FINDINGS: We screened 1285 people, of whom 1023 were enrolled and 979 analysed. The primary outcome score was 0·226 after spirometry, increasing to 0·296 after measurement of lung volume, 0·373 after airway resistance test, and 0·540 after measurement of diffusing capacity (p<0·0001 for each step). The number of differential diagnoses decreased after each step (4·2, 3·4, 3·0, and 2·4; p<0·0001 for each step) and the proportion of correct preferred diagnoses increased (61%, 65%, 70%, and 77%; p<0·0001 for each step). INTERPRETATION: The increase in scores shows a progressive reduction of the number of differential diagnoses and an increased accuracy of the preferred diagnosis. Each of the four classic pulmonary function tests contributes significantly and independently to the final diagnosis in new patients with respiratory symptoms seen by pulmonologists. Thus, funding of these tests is justified in that setting. FUNDING: Belgian Society of Pneumology.

Influence of cisplatin-use, age, performance status and duration of chemotherapy on symptom control in advanced non-small cell lung cancer: detailed symptom analysis of a randomised study comparing cisplatin-vindesine to gemcitabine.

BACKGROUND: We previously reported that treatment of patients with symptomatic advanced non-small cell lung cancer with single agent Gemcitabine (GEM) resulted in a superior clinical-benefit response rate (RR) compared to cisplatin-based combination chemotherapy. We now report the detailed individual symptom control analysis, and the influence of cisplatin-use, age, performance status (PS) and duration of treatment. PATIENTS AND METHODS: Patients received either GEM (1000 mg/m(2), days 1, 8 and 15) or cisplatin (100 mg/m(2), day 1) plus Vindesine (3 mg/m(2), days 1 and 15) (PV), both every 4 weeks. Scores of 9 symptoms were listed weekly by the patient on visual analogue scales. Improvement of a symptom was defined as 2 consecutive cycles of improvement over baseline. RESULTS: Baseline symptoms in the 169 patients were well balanced between the 2 arms (84 GEM, 85 PV). Both patients with objective response and disease stabilisation had clearly better symptom control than those with disease progression. Symptom control in both arms was similar for 'disease-specific' symptoms such as cough, dyspnea, pain or haemoptysis. Compared to PV, a significantly larger number of GEM-patients had better scores for 'constitutional' items such as anorexia (P=0.007), ability to carry on with daily activities (P=0.04) and overall impression of quality-of-life (P=0.008). Symptom control was very similar in younger (<65 years) versus older (>/=65 years) patients, and only slightly better in those with a Karnofsky PS >/=80% compared to those <80%. Most of the symptom improvement occurred in the first 3 cycles, with some further symptom improvement in the following cycles in the GEM-arm only. CONCLUSIONS: Both GEM and PV yield a symptom control rate much higher than expected by the objective tumour RR. GEM is equally effective in controlling 'disease-specific' symptoms, but superior in controlling 'constitutional' symptoms. Most of the symptom control was achieved during the first 3 cycles of treatment, with some further improvement thereafter in the GEM-arm only.