Showing papers in "European Respiratory Journal in 2007"

Weaning from mechanical ventilation

Abstract: Weaning covers the entire process of liberating the patient from mechanical support and from the endotracheal tube. Many controversial questions remain concerning the best methods for conducting this process. An International Consensus Conference was held in April 2005 to provide recommendations regarding the management of this process. An 11-member international jury answered five pre-defined questions. 1) What is known about the epidemiology of weaning problems? 2) What is the pathophysiology of weaning failure? 3) What is the usual process of initial weaning from the ventilator? 4) Is there a role for different ventilator modes in more difficult weaning? 5) How should patients with prolonged weaning failure be managed? The main recommendations were as follows. 1) Patients should be categorised into three groups based on the difficulty and duration of the weaning process. 2) Weaning should be considered as early as possible. 3) A spontaneous breathing trial is the major diagnostic test to determine whether patients can be successfully extubated. 4) The initial trial should last 30 min and consist of either T-tube breathing or low levels of pressure support. 5) Pressure support or assist-control ventilation modes should be favoured in patients failing an initial trial/trials. 6) Noninvasive ventilation techniques should be considered in selected patients to shorten the duration of intubation but should not be routinely used as a tool for extubation failure.

From the authors

Abstract: The members of the European Respiratory Society Task Force on Exercise Testing in Clinical Practice have read with interest the letter from J.E. Cotes and J.W. Reed and are of the opinion that any response to the points raised therein should be placed in the context of the purpose of a recently published Task Force 1. As stated in the introduction of this Task Force 1: “The purpose of this document is to present recommendations on the clinical use of exercise testing in patients with cardiopulmonary disease, with particular emphasis on the evidence base for functional evaluation, prognosis and assessment of interventions. While the scope of the document is broad, consideration will focus only on those indices which have demonstrable predictive power”. The key phrase here is “evidence base”, which represents a clear departure from the objectives of the 1997 Task Force 2. In recent years, there has been an accumulating body of evidence across a broad range of chronic lung and heart diseases ( e.g. chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), pulmonary vascular disease and chronic heart failure (CHF)) from studies using cycle ergometer protocols and field tests. It is upon this collective evidence base that the Task Force has formulated its recommendations for exercise testing in clinical practice. Furthermore, the Task Force was …

An epidemiological study of pulmonary arterial hypertension

Abstract: All hospitalisations for pulmonary arterial hypertension (PAH) in the Scottish population were examined to determine the epidemiological features of PAH. These data were compared with expert data from the Scottish Pulmonary Vascular Unit (SPVU). Using the linked Scottish Morbidity Record scheme, data from all adults aged 16-65 yrs admitted with PAH (idiopathic PAH, pulmonary hypertension associated with congenital heart abnormalities and pulmonary hypertension associated with connective tissue disorders) during the period 1986-2001 were identified. These data were compared with the most recent data in the SPVU database (2005). Overall, 374 Scottish males and females aged 16-65 yrs were hospitalised with incident PAH during 1986-2001. The annual incidence of PAH was 7.1 cases per million population. On December 31, 2002, there were 165 surviving cases, giving a prevalence of PAH of 52 cases per million population. Data from the SPVU were available for 1997-2006. In 2005, the last year with a complete data set, the incidence of PAH was 7.6 cases per million population and the corresponding prevalence was 26 cases per million population. Hospitalisation data from the Scottish Morbidity Record scheme gave higher prevalences of pulmonary arterial hypertension than data from the expert centres (Scotland and France). The hospitalisation data may overestimate the true frequency of pulmonary arterial hypertension in the population, but it is also possible that the expert centres underestimate the true frequency.

Exacerbations of chronic obstructive pulmonary disease

Abstract: Exacerbations of chronic obstructive pulmonary disease are of major importance in terms of their prolonged detrimental effects on patients, the acceleration in disease progression and high healthcare costs. There is still debate about how exacerbations should be defined and graded, and their mechanisms are poorly understood. The major causal agents are either bacteria or viral infections, or a combination of the two. Noninfective causes include air pollution and pulmonary embolus but, in some patients, no cause is identified. Exacerbations represent an increase in the inflammation that is present in the stable state, with increased numbers of inflammatory cells (particularly neutrophils), cytokines, chemokines and proteases in the airways, and increased concentrations of certain cytokines and C-reactive protein in the blood. There are presently no reliable biomarkers with which to predict exacerbations. Exacerbations have a long-lasting adverse influence on health status. High doses of bronchodilators are the mainstay of treatment and systemic corticosteroids have some benefit. The routine use of antibiotics remains controversial but they are of benefit with exacerbations of a bacterial origin. Noninvasive ventilation is beneficial in preventing the need for intubation and its important complications but it is not certain whether its use in stable patients prevents exacerbations. Although important advances have been made, more effective treatments are needed in the future for prevention and treatment of exacerbations.

ERS guidelines on the assessment of cough

Abstract: ### Cough 1) All basic scientific articles should refer to cough as a three-phase motor act. For the purposes of acoustic recordings in clinical studies, however, cough should be described as a forced expulsive manoeuvre or manoeuvres against a closed glottis that are associated with a characteristic sound or sounds. 2) All scientific articles should include a clear definition of what the authors have used as their definition of cough. ### Capsaicin and citric acid inhalation cough challenge 1) The methodology for the performance of inhalation cough challenge should be standardised so as to facilitate universal interpretation and comparison of data generated by different laboratories. 2) Comprehensive normal ranges need to be developed using the standardised methodology advocated in the present document. 3) The single-breath concentration–response method using a flow-limited dosimeter is recommended for most experimental protocols. 4) Both C2 and C5 should be recorded. 5) Since there is wide inter-individual variation, cough challenge data have no intrinsic significance, but may usefully be used to follow change in cough reflex sensitivity in an individual. ### Cough induced by inhalation of aqueous solutions 1) Aerosolised aqueous solutions represent a useful experimental tool in cough research. 2) The cough challenge with ultrasonic distilled water (fog) is difficult to standardise since it is highly dependent upon nebuliser output. 3) Consideration should be given to potential adverse events, such as bronchoconstriction and cross-infection. ### Cough monitors 1) No cough monitor is currently the gold standard. 2) Monitors should be developed that are ambulatory, are capable of being digitally processed and permit prolonged (24-h) recording. 3) There is little to commend any particular method of quantifying cough over any other. ### Assessment of quality of life of patients with chronic cough 1) Cough can have profound effects on health status, which can be assessed by cough-specific health status questionnaires. 2) Cough visual analogue scale (VAS, 0–100 mm) should be used to assess cough severity in patients with chronic cough. 3) Patients with chronic cough should be assessed with cough-specific quality-of-life questionnaires in clinical studies. ### Animal models of cough 1) The most useful animal model of cough is …

Cystic fibrosis mortality and survival in the UK: 1947–2003

Abstract: Data up to 1995 on the survival of 3-yr cohorts of patients with cystic fibrosis (CF) born in the UK in the period 1968-1992 have previously been published. The present study reports survival data up to the end of 2003 together with a 2003 population estimate. All subjects with CF born in the UK in the period 1968-1992 were identified up to 1997 by active enquiry through recognised CF clinics and other hospital consultants. Information from the death certification authorities up to the end of 2003 was added. Death certificates that could not be matched with UK Cystic Fibrosis Survey records were investigated and the data reconciled. The observed survival up to 2003 of CF patients born in 1978 was 55% for males and 49% for females. For 1988 and 1992 the data were 91 and 88%, and 97 and 96%, respectively. The estimated 2003 mid-year CF population was 8,284. The continuing improvement in survival of cystic fibrosis patients in successive cohorts means that the previous prediction of median survival of >50 yrs of age for individuals born in 2000 continues to look realistic, even in the absence of proven effective therapy aimed at correcting the basic cystic fibrosis defect.

Air pollution and development of asthma, allergy and infections in a birth cohort.

Abstract: Few studies have addressed associations between traffic-related air pollution and respiratory disease in young children. The present authors assessed the development of asthmatic/allergic symptoms and respiratory infections during the first 4 yrs of life in a birth cohort study (n = approximately 4,000). Outdoor concentrations of traffic-related air pollutants (nitrogen dioxide PM(2.5), particles with a 50% cut-off aerodynamic diameter of 2.5 mum and soot) were assigned to birthplace home addresses with a land-use regression model. They were linked by logistic regression to questionnaire data on doctor-diagnosed asthma, bronchitis, influenza and eczema and to self-reported wheeze, dry night-time cough, ear/nose/throat infections and skin rash. Total and specific immunoglobulin (Ig)E to common allergens were measured in a subgroup (n = 713). Adjusted odds ratios (95% confidence intervals) per interquartile pollution range were elevated for wheeze (1.2 (1.0-1.4) for soot), doctor-diagnosed asthma (1.3 (1.0-1.7)), ear/nose/throat infections (1.2 (1.0-1.3)) and flu/serious colds (1.2 (1.0-1.4)). No consistent associations were observed for other end-points. Positive associations between air pollution and specific sensitisation to common food allergens (1.6 (1.2-2.2) for soot), but not total IgE, were found in the subgroup with IgE measurements. Traffic-related pollution was associated with respiratory infections and some measures of asthma and allergy during the first 4 yrs of life.

Airway smooth muscle dynamics: A common pathway of airway obstruction in asthma

Abstract: Excessive airway obstruction is the cause of symptoms and abnormal lung function in asthma. As airway smooth muscle (ASM) is the effecter controlling airway calibre, it is suspected that dysfunction of ASM contributes to the pathophysiology of asthma. However, the precise role of ASM in the series of events leading to asthmatic symptoms is not clear. It is not certain whether, in asthma, there is a change in the intrinsic properties of ASM, a change in the structure and mechanical properties of the noncontractile components of the airway wall, or a change in the interdependence of the airway wall with the surrounding lung parenchyma. All these potential changes could result from acute or chronic airway inflammation and associated tissue repair and remodelling. Anti-inflammatory therapy, however, does not "cure" asthma, and airway hyperresponsiveness can persist in asthmatics, even in the absence of airway inflammation. This is perhaps because the therapy does not directly address a fundamental abnormality of asthma, that of exaggerated airway narrowing due to excessive shortening of ASM. In the present study, a central role for airway smooth muscle in the pathogenesis of airway hyperresponsiveness in asthma is explored.

Eosinophilic airway inflammation and exacerbations of COPD: a randomised controlled trial

Abstract: Evidence suggests that eosinophilic airway inflammation is important in the pathogenesis of severe chronic obstructive pulmonary disease (COPD) exacerbations. The present authors tested the hypothesis that a management strategy that aims to reduce sputum eosinophil counts is associated with a reduction in exacerbations of COPD. A total of 82 patients with COPD were randomised into two groups. One group was treated according to traditional guidelines (British Thoracic Society (BTS) group) and the other (sputum group) was treated with the additional aim of minimising eosinophilic airway inflammation, assessed using the induced sputum eosinophil count. The primary outcome was exacerbations, which were categorised as mild, moderate or severe. The frequency of severe exacerbations per patient per year was 0.5 and 0.2 in the BTS and sputum groups, respectively (mean reduction 62%). The majority of this benefit was confined to patients with eosinophilic airway inflammation. There was no difference in the frequency of mild and moderate exacerbations. The average daily dose of inhaled or oral corticosteroids during the trial did not differ between the groups. Out of 42 patients in the sputum group, 17 required regular oral corticosteroids to minimise eosinophilic airway inflammation. A management strategy that aims to minimise eosinophilic airway inflammation, as well as symptoms, is associated with a reduction in severe exacerbations of chronic obstructive pulmonary disease.

A USA-based registry for pulmonary arterial hypertension: 1982–2006

Abstract: The aim of this study was to define the epidemiology of World Health Organization (WHO) Group I pulmonary arterial hypertension (PAH) in a large referral centre in the USA. The Pulmonary Hypertension Connection registry, initiated in 2004, evaluated all patients in a single USA practice from 1982-2006. For comparison, the authors divided the group by incident versus prevalent cohorts, aetiology and by treatment era. In total, 578 patients (77% female) aged 48+/-14 yrs were entered. Of these, 80% had class III or IV symptoms. Over time, connective tissue disease-associated PAH increased, while referrals for HIV remained low. One-third of patients were referred on calcium channel blocker therapy even though only 4.6% had an acute response to vasodilator challenge. When compared by treatment era, there were no differences in the severity of PAH. However, survival had improved over time, with a 1-yr survival of 85% in the incident cohort. In the USA, pulmonary arterial hypertension patients are still referred to tertiary centres too late. Referral of connective tissue disease is increasing, while referral of HIV remains low. Inappropriate calcium channel blocker treatment is common. Survival rates have increased but remain low suggesting that prognosis is improving but PAH is still a progressive, fatal disease.

Eosinophilic airway inflammation and exacerbations of COPD : A randomised controlled trial. Commentary

Abstract: Evidence suggests that eosinophilic airway inflammation is important in the pathogenesis of severe chronic obstructive pulmonary disease (COPD) exacerbations. The present authors tested the hypothesis that a management strategy that aims to reduce sputum eosinophil counts is associated with a reduction in exacerbations of COPD. A total of 82 patients with COPD were randomised into two groups. One group was treated according to traditional guidelines (British Thoracic Society (BTS) group) and the other (sputum group) was treated with the additional aim of minimising eosinophilic airway inflammation, assessed using the induced sputum eosinophil count. The primary outcome was exacerbations, which were categorised as mild, moderate or severe. The frequency of severe exacerbations per patient per year was 0.5 and 0.2 in the BTS and sputum groups, respectively (mean reduction 62%). The majority of this benefit was confined to patients with eosinophilic airway inflammation. There was no difference in the frequency of mild and moderate exacerbations. The average daily dose of inhaled or oral corticosteroids during the trial did not differ between the groups. Out of 42 patients in the sputum group, 17 required regular oral corticosteroids to minimise eosinophilic airway inflammation. A management strategy that aims to minimise eosinophilic airway inflammation, as well as symptoms, is associated with a reduction in severe exacerbations of chronic obstructive pulmonary disease.

Definition, epidemiology and natural history of COPD

Abstract: Chronic obstructive pulmonary disease (COPD) is the fifth cause of morbidity and mortality in the developed world and represents a substantial economic and social burden. Patients experience a progressive deterioration up to end-stage COPD, characterised by very severe airflow limitation, severely limited and declining performance status with chronic respiratory failure, advanced age, multiple comorbidities and severe systemic manifestations/complications. COPD is frequently underdiagnosed and under-treated. Today, COPD develops earlier in life and is less gender specific. Tobacco smoking is the major risk factor for COPD, followed by occupation and air pollution. Severe deficiency for alpha(1)-antitrypsin is rare; several phenotypes are being associated with elevated risk for COPD in the presence of risk factor exposure. Any patient presenting with cough, sputum production or dyspnoea should be assessed by standardised spirometry. Continued exposure to noxious agents promotes a more rapid decline in lung function and increases the risk for repeated exacerbations, eventually leading to end-stage disease. Without major efforts in prevention, there will be an increasing proportion of end-stage patients who can live longer through long-term oxygen therapy and assisted ventilation, but with elevated suffering and huge costs. Smoking prevention and smoking cessation are the most important epidemiological measurements to counteract chronic obstructive pulmonary disease epidemics.

Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease

Abstract: Aspergillus spp. cultured in specimens from the airways of chronic obstructive pulmonary disease (COPD) patients are frequently considered as a contaminant. However, growing evidence suggests that severe COPD patients are at higher risk of developing invasive pulmonary aspergillosis (IPA), although IPA incidence in this population is poorly documented. Some data report that COPD is the underlying disease in 1% of patients with IPA. Definitive diagnosis of IPA in COPD patients is often difficult as tissue samples are rarely obtained before death. Diagnosis is therefore usually based on a combination of clinical features, radiological findings (mostly thoracic computed tomography scans), microbiological results and, sometimes, serological information. Of 56 patients with IPA reported in the literature, 43 (77%) were receiving corticosteroids on admission to hospital. Breathlessness was always a feature of disease and excess wheezing was present in 79% of patients. Fever (>38 degrees C) was present in only 38.5%. Chest pain and haemoptysis were uncommon. Six out of 33 (18%) patients had tracheobronchitis observed during bronchoscopy. The median delay between symptoms and diagnosis was 8.5 days. The mortality rate was high: 53 out of 56 (95%) patients died despite invasive ventilation and antifungal treatment in 43 (77%) of them. In chronic obstructive pulmonary disease patients, invasive pulmonary aspergillosis currently carries a very poor prognosis. Outcome could perhaps be improved by more rapid diagnosis and prompt therapy with voriconazole.

Inflammatory changes, recovery and recurrence at COPD exacerbation

Abstract: Chronic obstructive pulmonary disease (COPD) exacerbations are associated with increased airway and systemic inflammation, though relationships between exacerbation recovery, recurrent exacerbation and inflammation have not been previously reported. In the present study, inflammatory changes at COPD exacerbations were related to clinical nonrecovery and recurrent exacerbations within 50 days. Serum interleukin (IL)-6, C-reactive protein (CRP), sputum IL-6 and IL-8 were measured in 73 COPD patients when stable, at exacerbation and at 7, 14 and 35 days post-exacerbation. In 23% of patients, symptoms did not recover to baseline by day 35. These patients had persistently higher levels of serum CRP during the recovery period. A total of 22% of the patients who had recurrent exacerbations within 50 days had significantly higher levels of serum CRP at day 14, compared with those without recurrences: 8.8 mg.L(-1) versus 3.4 mg.L(-1). Frequent exacerbators had a smaller reduction in systemic inflammation between exacerbation onset and day 35 compared with infrequent exacerbators. Nonrecovery of symptoms at chronic obstructive pulmonary disease exacerbation is associated with persistently heightened systemic inflammation. The time course of systemic inflammation following exacerbation is different between frequent and infrequent exacerbators. A high serum C-reactive protein concentration 14 days after an index exacerbation may be used as a predictor of recurrent exacerbations within 50 days.

Inhibition of PDGF, VEGF and FGF signalling attenuates fibrosis

Abstract: BIBF 1000 is a small molecule inhibitor targeting the receptor kinases of platelet-derived growth factor (PDGF), basic fibroblast growth factor and vascular endothelial growth factor, which have known roles in the pathogenesis of pulmonary fibrosis. The anti-fibrotic potential of BIBF 1000 was determined in a rat model of bleomycin-induced lung fibrosis and in an ex vivo fibroblast differentiation assay. Rats exposed to a single intra-tracheal injection of bleomycin were treated with BIBF 1000 starting 10 days after bleomycin administration. To gauge for anti-fibrotic activity, collagen deposition and pro-fibrotic growth factor gene expression was analysed in isolated lungs. Furthermore, the activity of BIBF 1000 was compared with imatinib mesylate (combined PDGF receptor, c-kit and c-abl kinase inhibitor) and SB-431542 (transforming growth factor (TGF)-beta receptor I kinase inhibitor) in an ex vivo TGF-beta-driven fibroblast to myofibroblast differentiation assay, performed in primary human bronchial fibroblasts. Treatment of rats with BIBF 1000 resulted in the attenuation of fibrosis as assessed by the reduction of collagen deposition and the inhibition of pro-fibrotic gene expression. In the cellular assay both SB-431542 and BIBF 1000 showed dose-dependent inhibition of TGF-beta-induced differentiation, whereas imatinib mesylate was inactive. BIBF 1000, or related small molecules with a similar kinase inhibition profile, may represent a novel therapeutic approach for the treatment of idiopathic pulmonary fibrosis.

Pulmonary hypertension in patients with pulmonary fibrosis awaiting lung transplant

Abstract: Pulmonary hypertension (PH) may complicate idiopathic pulmonary fibrosis (IPF) but the prevalence of PH in IPF remains undefined. The present authors sought to describe the prevalence of PH in IPF. The lung transplant registry for the USA (January 1995 to June 2004) was analysed and IPF patients who had undergone right heart catheterisation (RHC) were identified. PH was defined as a mean pulmonary arterial pressure ((Ppa)) > or =25 mmHg and severe PH as a (Ppa) >40 mmHg. Independent factors associated with PH were determined. Of the 3,457 persons listed, 2,525 (73.0%) had undergone RHC. PH affected 46.1% of subjects; approximately 9% had severe PH. Variables independently associated with mild-to-moderate PH were as follows: need for oxygen, pulmonary capillary wedge pressure (P(pcw)) and forced expiratory volume in one second (FEV(1)). Independent factors related to severe PH included the following: carbon dioxide tension, age, FEV(1), P(pcw), need for oxygen and ethnicity. A sensitivity analysis in subjects with P(pcw) <15 mmHg did not appreciably alter the present findings. Pulmonary hypertension is common in idiopathic pulmonary fibrosis patients awaiting lung transplant, but the elevations in mean pulmonary arterial pressure are moderate. Lung volumes alone do not explain the pulmonary hypertension. Given the prevalence of pulmonary hypertension and its relationship with surrogate markers for quality of life (e.g. activities of daily living), future trials of therapies for this may be warranted.

Severe exacerbations predict excess lung function decline in asthma

Abstract: Severe asthma exacerbations are periods of intense airway inflammation that have been hypothesised to contribute to structural changes in the airways. If so, accelerated lung function decline over time should be more prevalent in adult patients with asthma who have frequent exacerbations than those without, but to date this has not been demonstrated. A cohort study was performed in order to investigate the effect of severe exacerbations on the progression of airway obstruction in 93 nonsmoking asthmatics with moderate-to-severe disease prior to treatment with inhaled corticosteroids. Subjects were followed for > or =5 yrs (median follow-up 11 yrs). In total, 56 (60.2%) subjects experienced at least one severe exacerbation (median rate 0.10.yr(-1)). Oral corticosteroid use and more severe airway obstruction at baseline were associated with a higher exacerbation rate. Independent of these variables, asthma patients with frequent exacerbations had a significantly larger annual decline in forced expiratory volume in one second (FEV(1); median difference (95% confidence interval) 16.9 (1.5-32.2) mL.yr(-1)). Exacerbation rate significantly predicted an excess decline in FEV(1), such that one severe exacerbation per year was associated with a 30.2 mL greater annual decline in FEV(1). These data support the hypothesis that exacerbations, indicating intermittent periods of worsening airway inflammation, are associated with excess lung function decline in asthma.

Idiopathic pulmonary fibrosis: multiple causes and multiple mechanisms?

Abstract: Idiopathic pulmonary fibrosis (IPF) is a devastating condition that carries a prognosis worse than that of many cancers. A recent classification of the idiopathic interstitial pneumonias has redefined the diagnostic criteria necessary to determine a diagnosis of IPF. The present authors believe that this redefinition is incorrect, relying as it does on subtle histological differences for the definition of separate disease categories. A further issue affecting IPF research is the polarisation of views around two competing pathogenetic hypotheses. One argues for the primacy of inflammation as the trigger that initiates fibrosis, and the other proposes that fibrosis arises as a consequence of chronic epithelial injury and failure of repair due to aberrant epithelial-mesenchymal interactions. The present authors believe that this schism is hampering understanding of IPF and skewing research priorities. It is argued here, instead, that abnormalities in multiple pathways involved in wound healing and inflammation lead to the development of idiopathic pulmonary fibrosis, and it is suggested that a new rationale for clinical classification and pathogenesis may be more productive in driving the search for novel therapies in the future.

Cardiovascular and metabolic effects of CPAP in obese males with OSA

Abstract: Obstructive sleep apnoea is associated with increased blood pressure and other features of the metabolic syndrome. The aim of the present study was to determine the relative effectiveness of continuous positive airway pressure (CPAP) in modifying these outcomes. A randomised placebo-controlled blinded crossover trial comparing cardiovascular and metabolic outcomes after 6 weeks of therapeutic and sham CPAP was performed in 34 CPAP-naive patients (mean+/-SD body mass and respiratory disturbance indices were 36.1+/-7.6 and 39.7+/-13.8, respectively). Mean waking systolic and diastolic blood pressure fell by 6.7 and 4.9 mmHg, respectively, when compared with sham CPAP. No change was observed in glucose, lipids, insulin resistance or the proportion of patients with metabolic syndrome. In CPAP-compliant patients the fall in blood pressure was greater and the baroreceptor sensitivity improved significantly but no metabolic variable changed. In obese Caucasians with untreated obstructive sleep apnoea, continuous positive airways pressure can improve baroreceptor responsiveness and reduce waking blood pressure within 6 weeks, but this treatment period was insufficient to modify insulin resistance or change the metabolic profile. The mechanisms underlying this difference in the time course of blood pressure and metabolic response to continuous positive airway pressure in obstructive sleep apnoea requires further exploration.

Clinical relevance of airway remodelling in airway diseases

Abstract: Asthma and chronic obstructive pulmonary disease (COPD) are characterised by airflow obstruction, airway remodelling (measurable structural change) and inflammation. The present review will examine the relationship between airway remodelling in these two conditions with respect to symptoms, abnormal lung function, airway hyperresponsiveness and decline in lung function. The potential for remodelling to be a protective response will also be discussed. Asthma is associated with variable symptoms and changes in lung function and also fixed abnormalities of lung function and an increased rate of decline in lung function with age. There is a relative preservation of the relaxed airway lumen dimensions, prominent thickening of the smooth muscle layer and reduced airway distensibility. The severity of asthma is related to the degree of airway remodelling, which is most marked in cases of fatal asthma. In COPD, symptoms are persistent and predictable but also progressive and are related to fixed abnormalities of lung function. Remodelling is associated with narrowing of the airway lumen and an increased thickness of the airway wall, although not usually to the extent seen in asthma. COPD is most often due to smoking where there is also remodelling of the parenchyma that may contribute to symptoms.

Results of European post-marketing surveillance of bosentan in pulmonary hypertension.

Abstract: After the approval of bosentan for the treatment of pulmonary arterial hypertension (PAH), European authorities required the introduction of a post-marketing surveillance system (PMS) to obtain further data on its safety profile. A novel, prospective, internet-based PMS was designed, which solicited reports on elevated aminotransferases, medical reasons for bosentan discontinuation and other serious adverse events requiring hospitalisation. Data captured included demographics, PAH aetiology, baseline functional status and concomitant PAH-specific medications. Safety signals captured included death, hospitalisation, serious adverse events, unexpected adverse events and elevated aminotransferases. Within 30 months, 4,994 patients were included, representing 79% of patients receiving bosentan in Europe. In total, 4,623 patients were naive to treatment; of these, 352 had elevated aminotransferases, corresponding to a crude incidence of 7.6% and an annual rate of 10.1%. Bosentan was discontinued due to elevated aminotransferases in 150 (3.2%) bosentan-naive patients. Safety results were consistent across subgroups and aetiologies. The novel post-marketing surveillance captured targeted safety data ("potential safety signals") from the majority of patients and confirmed that the incidence and severity of elevated aminotransferase levels in clinical practice was similar to that reported in clinical trials. These data complement those from randomised controlled clinical trials and provide important additional information on the safety profile of bosentan.

Forced expiratory volume in one second: not just a lung function test but a marker of premature death from all causes

Abstract: The clinical utility of spirometric screening of asymptomatic smokers for early signs of air flow limitation has recently come under review. The current authors propose that reduced forced expiratory volume in one second (FEV(1)) is more than a measure of airflow limitation, but a marker of premature death with broad utility in assessing baseline risk of chronic obstructive pulmonary disease (COPD), lung cancer, coronary artery disease and stroke, collectively accounting for 70-80% of premature death in smokers. Reduced FEV(1) identifies undiagnosed COPD, has comparable utility to that of serum cholesterol in assessing cardiovascular risk and defines those smokers at greatest risk of lung cancer. As such, reduced FEV(1) should be considered a marker that identifies smokers at greatest need of medical intervention. Smoking cessation has been shown to attenuate FEV(1) decline and, if achieved before the age of 45-50 yrs, may not only preserve FEV(1) within normal values but substantially reduce cardiorespiratory complications of smoking. Recent findings suggest inhaled drugs (bronchodilators and corticosteroids), and possibly statins, may be effective in reducing morbidity and mortality in patients with chronic obstructive pulmonary disease. The current authors propose that spirometry has broad utility in identifying smokers who are at greatest risk of cardiorespiratory complications and greatest benefit from targeted preventive strategies, such as smoking cessation, prioritised screening and effective pharmacotherapy.

Trends in ethical and legal frameworks for the use of human biobanks.

Abstract: Numerous studies of genetic epidemiology and post-genomics in respiratory diseases rely on the use of biobanks, defined as organised biological sample collections with associated personal and clinical data. The use of biobanks is increasing and raises several ethical issues. What are the ethical trends and legal frameworks in the post-genomic era? Are there new issues in relation to the developments of techniques and new study designs? How does this affect the clinician's attitudes and relationship with the patients? The main ethical issues encountered are: informed consent; confidentiality; secondary use of samples and data over time; return of results; and data sharing. Different levels and modalities of dealing with such issues are identified and vary from legally binding measures to "soft" regulations, such as ethical recommendations by various committees or professional organisations. A further level of complexity appears with the increasing international dimension of such activities in a context in which national positions vary on those topics. There is a tension between a necessary level of diversity in ethical positions and an indispensable common pedestal of principles and procedures to manage these issues in order to foster research. Current legal and ethical trends favour the facilitation of secondary use of samples, more biobank openness, balanced with a growing attention to dialogue and public/stakeholder consultation, an increased role for research ethics committees and more sophisticated data protection and governance structures.

Endobronchial ultrasound: new insight for the diagnosis of sarcoidosis

Abstract: A diagnosis of sarcoidosis should be substantiated by pathological means in order to thoroughly exclude other diseases. The role of real-time endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the diagnosis of sarcoidosis has not been reported. The purpose of the present study is to evaluate the diagnostic yield of EBUS-TBNA in demonstrating the pathological features of sarcoidosis. In total, 65 patients with suspected sarcoidosis, with enlarged hilar or mediastinal lymph nodes on computed tomography, were included in the study. Patients with a suspected or known malignancy or previously established diagnosis of sarcoidosis were excluded. Convex probe endobronchial ultrasonography integrated with a separate working channel was used for EBUS-TBNA. Surgical methods were performed in those in whom no granulomas were detected by EBUS-TBNA. Patients were followed up clinically. EBUS-TBNA was performed on a total of 77 lymph node stations in 65 patients. A final diagnosis of sarcoidosis was made for 61 (93.8%) of the patients. The remaining four patients were diagnosed as having Wegener9s granulomatosis (n = 1) or indefinite (n = 3). In patients with a final diagnosis of sarcoidosis, EBUS-TBNA demonstrated noncaseating epithelioid cell granulomas in 56 (91.8%) of the patients. No complications were reported. Endobronchial ultrasound-guided transbronchial needle aspiration proved to be a safe procedure with a high yield for the diagnoses of sarcoidosis.

Biomarkers in respiratory tract infections: diagnostic guides to antibiotic prescription, prognostic markers and mediators

Abstract: Used appropriately, biomarkers improve the assessment of respiratory tract infections and sepsis. Most prominently, circulating procalcitonin levels increase by a factor of several tens of thousands during sepsis. Using a sensitive assay, procalcitonin safely and markedly reduces antibiotic usage in respiratory tract infections and nonbacterial meningitis. Procalcitonin is the protopye of hormokine mediators. The term "hormokine" encompasses the cytokine-like behaviour of hormones during inflammation and infections. The concept is based on a ubiquitous expression of calcitonin peptides during sepsis. Adrenomedullin, another member of the calcitonin peptide superfamily, was shown to complement and improve the current prognostic assessment in lower respiratory tract infections. Other peptides share some features of hormokines, e.g. natriuretic peptide and copeptin. Hormokines are not only biomarkers of infection but are also pivotal inflammatory mediators. Like all mediators, their role during systemic infections is basically beneficial, possibly to combat invading microbes. However, at increased levels they can become harmful for their host. Multiple mechanisms of action were proposed. In several animal models the modulation and neutralisation of hormokines during infection was shown to improve survival, and thus might open new treatment options for severe infections, especially of the respiratory tract.

Haemoglobin level and its clinical impact in a cohort of patients with COPD

Abstract: Haemoglobin (Hb) abnormalities in chronic obstructive pulmonary disease (COPD) are not well characterised. The present authors investigated the prevalence and association of abnormal Hb with clinical outcomes. Analysis of a prospective cohort of stable COPD outpatients (n = 683) in a USA Veterans Administration pulmonary clinic was undertaken. Patients were classified as anaemic (Hb or =17 g.dL(-1) and > or =15 g.dL(-1) for males and females, respectively) or normal. Demographic characteristics and physiological/functional outcomes were compared between groups. Regression models adjusting for confounders examined the independent association of anaemia with clinical outcomes. Anaemia was present in 116 (17%) patients and polycythemia in 40 (6%). While the only values that differed between polycythemic and nonpolycythemic patients were mean body mass index and Hb, anaemic patients showed a significantly higher modified Medical Research Council dyspnoea scale score (2.8 versus 2.6), lower 6-min walk distance (265 versus 325 m) and shorter median survival (49 versus 74 months) than nonanaemic patients. In regression models, anaemia independently predicted dyspnoea and reduced exercise capacity. Anaemia in chronic obstructive pulmonary disease was an independent risk factor for reduced functional capacity. Polycythemia prevalence was low and had no association with worsened outcomes. Further work is required to evaluate the effect of anaemia correction on outcomes in chronic obstructive pulmonary disease.

Tuberculosis and airflow obstruction: evidence from the PLATINO study in Latin America

Abstract: The aim of the present study was to evaluate the association between history of tuberculosis and airflow obstruction. A population-based, multicentre study was carried out and included 5,571 subjects aged o40 yrs living in one of five Latin American metropolitan areas: Sao Paulo (Brazil); Montevideo (Uruguay); Mexico City (Mexico); Santiago (Chile); and Caracas (Venezuela). Subjects performed pre- and post-bronchodilator spirometry and were asked whether they had ever been diagnosed with tuberculosis by a physician. The overall prevalence of airflow obstruction (forced expiratory volume in one second/forced vital capacity post-bronchodilator ,0.7) was 30.7% among those with a history of tuberculosis, compared with 13.9% among those without a history. Males with a medical history of tuberculosis were 4.1 times more likely to present airflow obstruction than those without such a diagnosis. This remained unchanged after adjustment for confounding by age, sex, schooling, ethnicity, smoking, exposure to dust and smoke, respiratory morbidity in childhood and current morbidity. Among females, the unadjusted and adjusted odds ratios were 2.3 and 1.7, respectively. In conclusion, history of tuberculosis is associated with airflow obstruction in Latin American middle-aged and older adults.

Electromagnetic navigation diagnostic bronchoscopy for small peripheral lung lesions.

Abstract: The present study prospectively evaluated the diagnostic yield and safety of electromagnetic navigation-guided bronchoscopy biopsy, for small peripheral lung lesions in patients where standard techniques were nondiagnostic. The study was conducted in a tertiary medical centre on 40 consecutive patients considered unsuitable for straightforward surgery or computed tomography (CT)-guided transthoracic needle aspiration biopsy, due to comorbidities. The lung lesion diameter was mean+/-sem 23.5+/-1.5 mm and the depth from the visceral-costal pleura was 14.9+/-2 mm. Navigation was facilitated by an electromagnetic tracking system which could detect a position sensor incorporated into a flexible catheter advanced through a bronchoscope. Information obtained during bronchoscopy was superimposed on previously acquired CT data. Divergence between CT data and data obtained during bronchoscopy was calculated by the system's software as a measure of navigational accuracy. All but one of the target lesions was reached and the overall diagnostic yield was 62.5% (25-40). Diagnostic yield was significantly affected by CT-to-body divergence; yield was 77.2% when estimated divergence was

Clinical and operational value of the extensively drug-resistant tuberculosis definition.

Abstract: Currently, no information is available on the effect of resistance/susceptibility to first-line drugs different from isoniazid and rifampicin in determining the outcome of extensively drug-resistant tuberculosis (XDR-TB) patients, and whether being XDR-TB is a more accurate indicator of poor clinical outcome than being resistant to all first-line anti-tuberculosis (TB) drugs. To investigate this issue, a large series of multidrug-resistant TB (MDR-TB) and XDR-TB cases diagnosed in Estonia, Germany, Italy and the Russian Federation during the period 1999-2006 were analysed. Drug-susceptibility testing for first- and second-line anti-TB drugs, quality assurance and treatment delivery was performed according to World Health Organization recommendations in all study sites. Out of 4,583 culture-positive TB cases analysed, 361 (7.9%) were MDR and 64 (1.4%) were XDR. XDR-TB cases had a relative risk (RR) of 1.58 to have an unfavourable outcome compared with MDR-TB cases resistant to all first-line drugs (isoniazid, rifampicin ethambutol, streptomycin and, when tested, pyrazinamide), and an RR of 2.61 compared with "other" MDR-TB cases (those susceptible to at least one first-line anti-TB drug among ethambutol, pyrazinamide and streptomycin, regardless of resistance to the second-line drugs not defining XDR-TB). The emergence of extensively drug-resistant tuberculosis confirms that problems in tuberculosis management are still present in Europe. While waiting for new tools which will facilitate management of extensively drug-resistant tuberculosis, accessibility to quality diagnostic and treatment services should be urgently ensured and adequate public health policies should be rapidly implemented to prevent further development of drug resistance.

Daytime sleepiness and polysomnographic variables in sleep apnoea patients

Abstract: Excessive daytime sleepiness (EDS) is not invariably present in patients with obstructive sleep apnoea syndrome (OSAS). The aim of the present study was to investigate polysomnographic determinants of EDS in patients with OSAS. EDS was assessed using the Epworth Sleepiness Scale (ESS) and the multiple sleep latency test (MSLT). Patients showed EDS whenever the ESS score was >10 and the MSLT score 10 min. In total, 23 male patients with EDS (mean+/-sd ESS and MSLT score 17+/-3 and 4+/-1 min, respectively) and 17 without EDS (ESS and MSLT score 5+/-2 and 16+/-3 min, respectively), were studied. Both groups exhibited a similar apnoea/hypopnoea index (62+/-18 versus 60+/-20 events.h(-1)). Patients with EDS exhibited shorter sleep latency (11+/-16 versus 18+/-18 min) and greater sleep efficiency (90+/-7 versus 82+/-13%) than those without EDS. Patients with EDS showed lower oxygenation (lowest arterial oxygen saturation 69+/-12 versus 79+/-8%; mean arterial oxygen saturation 87+/-6 versus 90+/-5%). Sleep stage distribution and arousal index did not differ between the groups. Patients with obstructive sleep apnoea syndrome and excessive daytime sleepiness are characterised by shorter sleep latency, increased sleep efficiency and worse nocturnal oxygenation than those without excessive daytime sleepiness. Nocturnal hypoxaemia can be a major determinant of excessive daytime sleepiness in patients with obstructive sleep apnoea syndrome.