Stefano Centanni

Once-daily indacaterol versus twice-daily salmeterol for COPD: a placebo-controlled comparison

Indacaterol is a novel, inhaled, once-daily, ultra-long-acting &bgr;2-agonist bronchodilator recently approved in Europe for the treatment of chronic obstructive pulmonary disease (COPD). The aim of the present study was to investigate the efficacy and safety of indacaterol compared with placebo and the twice-daily &bgr;2-agonist, salmeterol, as an active control. Patients with moderate-to-severe COPD were randomised to 6 months double-blind treatment with indacaterol (150 &mgr;g once daily), salmeterol (50 &mgr;g twice daily) or placebo. The primary efficacy end-point was trough (24 h post-dose) forced expiratory volume in 1 s (FEV1) after 12 weeks. 1,002 patients were randomised and 838 (84%) completed the study. Indacaterol increased trough FEV1 at week 12 by 170 mL over placebo (p<0.001) and by 60 mL over salmeterol (p<0.001). Both active treatments improved health status (St Georges Respiratory Questionnaire) and dyspnoea (transition dyspnoea index) compared with placebo, with differences between them favouring indacaterol. Safety profiles were similar across the treatment groups, and both indacaterol and salmeterol were well tolerated. Once-daily treatment with 150 &mgr;g indacaterol had a significant and clinically relevant bronchodilator effect over 24 h post-dose and improved health status and dyspnoea to a greater extent than twice-daily 50 &mgr;g salmeterol. Indacaterol should prove a useful additional treatment for patients with COPD.

Acute exacerbations of asthma in adults: role of Chlamydia pneumoniae infection

Respiratory infections precipitate wheezing in many asthmatic patients and may be involved in the aetiopathogenesis of asthma. Several studies have demonstrated that viral infections may provoke asthma. Bacterial infections seem to play a minor role. However, Chlamydia pneumoniae has been recently reported as a possible cause of asthma. The aim of the present study was to evaluate the role of C. pneumoniae infection in acute exacerbations of asthma in adults. Seventy four adult out-patients with a diagnosis of acute exacerbation of asthma were studied. Acute and convalescent (> or = 3 weeks) serological determination of antibodies to cytomegalovirus, respiratory syncytial virus, adenovirus, influenza A and B, parainfluenza 1 and 3, Mycoplasma pneumoniae and Legionella pneumophila were performed by means of immunofluorescence tests. C. pneumoniae specific antibodies were detected by two microimmunofluorescence tests using a specific antigen (TW-183) and a kit with three chlamydial antigens. Pharyngeal swab specimens were also obtained for C. pneumoniae identification. Samples for bacterial culture were obtained in patients with productive cough (15 out of 74 patients). Fifteen patients (20%) presented seroconversion to at least one of the studied pathogens. Seven were found to be infected by virus, six by C. pneumoniae alone, and one by M. pneumoniae. One more patient showed seroconversion to C. pneumoniae and cytomegalovirus.(ABSTRACT TRUNCATED AT 250 WORDS)

Chlamydia pneumoniae and chronic bronchitis: association with severity and bacterial clearance following treatment

Background: A study was undertaken to evaluate Chlamydia pneumoniae chronic infection, other respiratory infections, and functional impairment in patients with chronic bronchitis (stage 1) and to examine chronic C pneumoniae infection, rate of acute exacerbations of chronic bronchitis, and rate of C pneumoniae eradication following antibiotic treatment (stage 2). Methods: In the stage 1 study respiratory specimens from 42 patients with steady state chronic bronchitis were analysed for Gram staining, sputum culture, and C pneumoniae DNA detection by nested touchdown polymerase chain reaction (PCR). On the basis of the results of stage 1, a second population of 141 consecutive patients with steady state mild to moderate chronic bronchitis (FEV1 ≥50% predicted) was studied. On admission, at regular intervals, and at exacerbation all patients underwent serological testing for C pneumoniae (microimmunofluorescence) and a nested touchdown PCR to detect C pneumoniae DNA was performed on peripheral blood mononuclear cells (PBMCs). Patients were assessed over a 12 month period. Information regarding the previous 12 months was taken from medical records. Results: Chronic colonisation of the sputum with C pneumoniae was significantly associated with lower FEV1 and greater airway bacterial colonisation. On admission to the stage 2 study, 80 patients were PCR negative and 61 were PCR positive. Over the 2 years a mean (SD) of 1.43 (1.32) acute exacerbations occurred in PCR negative patients and 2.03 (1.21) in PCR positive patients (p<0.01). During the 12 month follow up period 34 PCR positive patients had acute exacerbations and were treated with azithromycin for 6 weeks. Serological evidence of acute C pneumoniae reinfection/reactivation was found in two of the 34 patients. The rate of C pneumoniae DNA clearance from blood following treatment was 29% at follow up. Conclusion: Chronic colonisation with C pneumoniae is associated with a higher rate of exacerbations of chronic bronchitis. Long term treatment is required to obtain clearance of the organism from the blood.

Effect of inhaled bronchodilators on inspiratory capacity and dyspnoea at rest in COPD

It has been shown that patients with chronic obstructive pulmonary disease (COPD) develop dynamic hyperinflation (DH), which contributes to dyspnoea and exercise intolerance. Formoterol, salmeterol and oxitropium have been recommended for maintenance therapy in COPD patients, but their effect on DH has only been assessed for salmeterol. The aim of the present study was to compare the acute effect of four inhaled bronchodilators (salbutamol, formoterol, salmeterol and oxitropium) and placebo on forced expiratory volume in one second, inspiratory capacity, forced vital capacity and dyspnoea in COPD patients. A cross-over, randomised, double-blind, placebo-controlled study was carried out on 20 COPD patients. Patients underwent pulmonary function testing and dyspnoea evaluation, in basal condition and 5, 15, 30, 60 and 120 min after bronchodilator or placebo administration. The results indicate that in chronic obstructive pulmonary disease patients with decreased baseline inspiratory capacity, there was a much greater increase of inspiratory capacity after bronchodilator administration, which correlated closely with the improvement of dyspnoea sensation at rest. For all bronchodilators used, inspiratory capacity reversibility should be tested at 30 min following the bronchodilator. On average, formoterol elicited the greatest increase in inspiratory capacity than the other bronchodilators used, though the difference was significant only with salmeterol and oxitropium. The potential advantage of formoterol needs to be tested in a larger patient population.

A dose-ranging study of indacaterol in obstructive airways disease, with a tiotropium comparison.

This dose-ranging study assessed the bronchodilator efficacy and tolerability of indacaterol, a novel once-daily inhaled beta2-agonist, in subjects clinically diagnosed with COPD. Comparative data with tiotropium were collected. In the double-blind, core period of the study, 635 subjects with COPD (prebronchodilator FEV(1)40% of predicted and > or =1.0L; FEV1/FVC <70%) were randomized to receive indacaterol 50, 100, 200 or 400microg or placebo via multi-dose dry powder inhaler, or indacaterol 400microg via single-dose dry powder inhaler, once daily for 7 days. After completing double-blind treatment and washout, a subset of subjects from each treatment group entered an open-label extension and received tiotropium 18microg once daily for 8 days. The primary efficacy variable was the trough bronchodilator effect: standardized area under the FEV1 curve between 22 and 24h post-dose (FEV1 AUC(22-24h)) on Day 1. Clinically relevant improvements versus placebo in FEV1 AUC(22-24h) were seen for 400 and 200microg doses on Day 1 and all doses on Day 7. All indacaterol doses significantly (P<0.05) increased FEV1 from 5min to 24h post-dose; the 400 and 200microg doses were most effective. All doses were well tolerated. Indacaterol trough FEV1 levels compared favorably with the improvement seen by Day 8 in subjects treated with tiotropium in the open-label extension. The results confirm that indacaterol has a 24-h duration of bronchodilator effect and a fast onset of action in COPD and suggest that indacaterol could be an effective once-daily inhaled beta2-agonist bronchodilator. Indacaterol demonstrated a good overall safety and tolerability profile.

Anxiety and depression in asthma.

Purpose of review There is growing awareness of the correlation between psychological factors, the course of asthma, and the outcomes of asthma treatment. However, the implications of this correlation are still poorly understood. Here, we review the role of anxiety and depression in asthma with a focus on recent literature. Recent findings Recent studies suggest an interaction between behavioral, neural, endocrine, and immune processes and suggest that psychological factors play an active role in the genesis of asthma. Notably, the role of chronic stress has been investigated, including the parental psychological state during pregnancy. There is evidence that in patients with asthma, such stress may induce hyporesponsiveness of the hypothalamus–pituitary–adrenal axis, resulting in reduced cortisol secretion. Summary Even though it is generally accepted that anxiety and depression are more common in asthmatic patients and that there is a close correlation between psychological disorders and asthma outcomes, such as poorer control of asthma symptoms, the implications and practical consequences of this link remain weak. New studies are introducing an intriguing model of the links between emotional stress, brain centers, the immune system, and the hypothalamus–pituitary–adrenal axis that is far removed from the original concept of ‘asthma nervosa’.

How air pollution influences clinical management of respiratory diseases. A case-crossover study in Milan

BackgroundEnvironmental pollution is a known risk factor for multiple diseases and furthermore increases rate of hospitalisations. We investigated the correlation between emergency room admissions (ERAs) of the general population for respiratory diseases and the environmental pollutant levels in Milan, a metropolis in northern Italy.MethodsWe collected data from 45770 ERAs for respiratory diseases. A time-stratified case-crossover design was used to investigate the association between air pollution levels and ERAs for acute respiratory conditions. The effects of air pollutants were investigated at lag 0 to lag 5, lag 0–2 and lag 3–5 in both single and multi-pollutant models, adjusted for daily weather variables.ResultsAn increase in ozone (O3) levels at lag 3–5 was associated with a 78% increase in the number of ERAs for asthma, especially during the warm season. Exposure to carbon monoxide (CO) proved to be a risk factor for pneumonia at lag 0–2 and in the warm season increased the risk of ERA by 66%. A significant association was found between ERAs for COPD exacerbation and levels of sulphur dioxide (SO2), CO, nitrate dioxide (NO2), and particulate matter (PM10 and PM2.5). The multipollutant model that includes all pollutants showed a significant association between CO (26%) and ERA for upper respiratory tract diseases at lag 0–2. For chronic obstructive pulmonary disease (COPD) exacerbations, only CO (OR 1.19) showed a significant association.ConclusionsExposure to environmental pollution, even at typical low levels, can increase the risk of ERA for acute respiratory diseases and exacerbation of obstructive lung diseases in the general population.

Can lung ultrasound replace chest radiography for the diagnosis of pneumonia in hospitalized children

Background: Lung ultrasound is a non-radiating accurate alternative tool to chest X-ray (CXR) in the diagnosis of community-acquired pneumonia (CAP) in adults. Objectives: The aim of our study was to define the accuracy of ultrasound in the diagnosis of CAP in children. Methods: 107 consecutive children with suspected CAP underwent clinical examination, blood sample analysis, CXR and lung ultrasound on admission to the Pediatric Department of the San Paolo Hospital. The diagnosis of pneumonia was made by an independent committee of physicians on the basis of the overall clinical and CXR data. Results: The diagnosis of CAP was confirmed by the committee in 81 patients (76%). Ultrasound and CXR were performed in all patients. Ultrasound had a sensitivity of 94% and specificity of 96%, while CXR showed a sensitivity of 82% and a specificity of 94%. In patients with CAP, ultrasound revealed subpleural consolidations with air bronchogram in 70 cases and focal B-lines in 6. A parapneumonic pleural effusion was detected in 17 patients by ultrasound, while only 11 of them could be detected by CXR. Conclusions: In our series, lung ultrasound was highly accurate for the diagnosis of CAP in hospitalized children. These results provide the rationale for a multicenter study in children.

effects of pulmonary rehabilitation on exercise capacity in patients with COPD: A number needed to treat study

Background Pulmonary rehabilitation (PR) is recognized as an evidence-based treatment in improving dyspnea and quality of life in patients with COPD. We evaluated the number needed to treat (NNT) to achieve an increase in physical capacity, as defined by a significant improvement in the six-minute walk test (6MWT) in patients with COPD undergoing PR. Methods The study enrolled 284 patients aged 41 to 86 years (mean age 69.4 years) divided into two groups: a study group (222 patients) undergoing a PR program, and a control group (62 patients) treated only with drugs. The study group included patients with COPD divided in four subgroups according to GOLD stages. Results In the study group, 142 out of 222 patients (64%) had an increase of at least 54 m in the 6MWT following PR versus 8 out of 62 patients (13%) in the control group after the same time interval. The NNT in the overall study group was 2; the same NNT was obtained in GOLD stages 2, 3, and 4, but was 8 in stage 1. Conclusions PR is highly effective in improving the exercise capacity of patients with COPD, as demonstrated by a valuable NNT, with better results in patients with a more severe disease.

Optimization of ventilator setting by flow and pressure waveforms analysis during noninvasive ventilation for acute exacerbations of COPD: a multicentric randomized controlled trial

IntroductionThe analysis of flow and pressure waveforms generated by ventilators can be useful in the optimization of patient-ventilator interactions, notably in chronic obstructive pulmonary disease (COPD) patients. To date, however, a real clinical benefit of this approach has not been proven.MethodsThe aim of the present randomized, multi-centric, controlled study was to compare optimized ventilation, driven by the analysis of flow and pressure waveforms, to standard ventilation (same physician, same initial ventilator setting, same time spent at the bedside while the ventilator screen was obscured with numerical data always available). The primary aim was the rate of pH normalization at two hours, while secondary aims were changes in PaCO2, respiratory rate and the patients tolerance to ventilation (all parameters evaluated at baseline, 30, 120, 360 minutes and 24 hours after the beginning of ventilation). Seventy patients (35 for each group) with acute exacerbation of COPD were enrolled.ResultsOptimized ventilation led to a more rapid normalization of pH at two hours (51 vs. 26% of patients), to a significant improvement of the patients tolerance to ventilation at two hours, and to a higher decrease of PaCO2 at two and six hours. Optimized ventilation induced physicians to use higher levels of external positive end-expiratory pressure, more sensitive inspiratory triggers and a faster speed of pressurization.ConclusionsThe analysis of the waveforms generated by ventilators has a significant positive effect on physiological and patient-centered outcomes during acute exacerbation of COPD. The acquisition of specific skills in this field should be encouraged.Trial registrationClinicalTrials.gov NCT01291303.