Showing papers in "European Respiratory Journal in 2014"

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

Abstract: Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults. A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations. When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled” or that remains “uncontrolled” despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided. Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.

An official European Respiratory Society/American Thoracic Society Technical Standard: field walking tests in chronic respiratory disease

Abstract: Field walking tests are commonly employed to evaluate exercise capacity, assess prognosis and evaluate treatment response in chronic respiratory diseases. In recent years, there has been a wealth of new literature pertinent to the conduct of the 6-min walk test (6MWT), and a growing evidence base describing the incremental and endurance shuttle walk tests (ISWT and ESWT, respectively). The aim of this document is to describe the standard operating procedures for the 6MWT, ISWT and ESWT, which can be consistently employed by clinicians and researchers. The Technical Standard was developed by a multidisciplinary and international group of clinicians and researchers with expertise in the application of field walking tests. The procedures are underpinned by a concurrent systematic review of literature relevant to measurement properties and test conduct in adults with chronic respiratory disease. Current data confirm that the 6MWT, ISWT and ESWT are valid, reliable and responsive to change with some interventions. However, results are sensitive to small changes in methodology. It is important that two tests are conducted for the 6MWT and ISWT. This Technical Standard for field walking tests reflects current evidence regarding procedures that should be used to achieve robust results.

An official systematic review of the European Respiratory Society/American Thoracic Society: measurement properties of field walking tests in chronic respiratory disease

Abstract: This systematic review examined the measurement properties of the 6-min walk test (6MWT), incremental shuttle walk test (ISWT) and endurance shuttle walk test (ESWT) in adults with chronic respiratory disease. Studies that report the evaluation or use of the 6MWT, ISWT or ESWT were included. We searched electronic databases for studies published between January 2000 and September 2013. The 6-min walking distance (6MWD) is a reliable measure (intra-class correlation coefficients ranged from 0.82 to 0.99 in seven studies). There is a learning effect, with greater distance walked on the second test (pooled mean improvement of 26 m in 13 studies). Reliability was similar for ISWT and ESWT, with a learning effect also evident for ISWT (pooled mean improvement of 20 m in six studies). The 6MWD correlates more strongly with peak work capacity (r50.59-0.93) and physical activity (r50.40-0.85) than with respiratory function (r50.10-0.59). Methodological factors affecting 6MWD include track length, encouragement, supplemental oxygen and walking aids. Supplemental oxygen also affects ISWT and ESWT performance. Responsiveness was moderate to high for all tests, with greater responsiveness to interventions that included exercise training. The findings of this review demonstrate that the 6MWT, ISWT and ESWT are robust tests of functional exercise capacity in adults with chronic respiratory disease.

An official European Respiratory Society statement on physical activity in COPD

Abstract: This European Respiratory Society (ERS) statement provides a comprehensive overview on physical activity in patients with chronic obstructive pulmonary disease (COPD). A multidisciplinary Task Force of experts representing the ERS Scientific Group 01.02 ''Rehabilitation and Chronic Care'' determined the overall scope of this statement through consensus. Focused literature reviews were conducted in key topic areas and the final content of this Statement was agreed upon by all members. The current knowledge regarding physical activity in COPD is presented, including the definition of physical activity, the consequences of physical inactivity on lung function decline and COPD incidence, physical activity assessment, prevalence of physical inactivity in COPD, clinical correlates of physical activity, effects of physical inactivity on hospitalisations and mortality, and treatment strategies to improve physical activity in patients with COPD. This Task Force identified multiple major areas of research that need to be addressed further in the coming years. These include, but are not limited to, the disease-modifying potential of increased physical activity, and to further understand how improvements in exercise capacity, dyspnoea and self-efficacy following interventions may translate into increased physical activity. The Task Force recommends that this ERS statement should be reviewed periodically (e.g. every 5-8 years).

An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome

Abstract: Bronchiolitis obliterans syndrome (BOS) is a major complication of lung transplantation that is associated with poor survival. The International Society for Heart and Lung Transplantation, American Thoracic Society, and European Respiratory Society convened a committee of international experts to describe and/or provide recommendations for 1) the definition of BOS, 2) the risk factors for developing BOS, 3) the diagnosis of BOS, and 4) the management and prevention of BOS. A pragmatic evidence synthesis was performed to identify all unique citations related to BOS published from 1980 through to March, 2013. The expert committee discussed the available research evidence upon which the updated definition of BOS, identified risk factors and recommendations are based. The committee followed the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) approach to develop specific clinical recommendations. The term BOS should be used to describe a delayed allograft dysfunction with persistent decline in forced expiratory volume in 1 s that is not caused by other known and potentially reversible causes of post-transplant loss of lung function. The committee formulated specific recommendations about the use of systemic corticosteroids, cyclosporine, tacrolimus, azithromycin and about re-transplantation in patients with suspected and confirmed BOS. The diagnosis of BOS requires the careful exclusion of other post-transplant complications that can cause delayed lung allograft dysfunction, and several risk factors have been identified that have a significant association with the onset of BOS. Currently available therapies have not been proven to result in significant benefit in the prevention or treatment of BOS. Adequately designed and executed randomised controlled trials that properly measure and report all patient-important outcomes are needed to identify optimal therapies for established BOS and effective strategies for its prevention. Diagnosis of BOS requires careful exclusion of other complications that can cause delayed lung allograft dysfunction

Financial burden for tuberculosis patients in low- and middle-income countries: a systematic review

Abstract: In order to inform the development of appropriate strategies to improve financial risk protection, we conducted a systematic literature review of the financial burden of tuberculosis (TB) faced by patients and affected families. The mean total costs ranged from $55 to $8198, with an unweighted average of $847. On average, 20% (range 0-62%) of the total cost was due to direct medical costs, 20% (0-84%) to direct non-medical costs, and 60% (16-94%) to income loss. Half of the total cost was incurred before TB treatment. On average, the total cost was equivalent to 58% (range 5-306%) of reported annual individual and 39% (4-148%) of reported household income. Cost as percentage of income was particularly high among poor people and those with multidrug-resistant TB. Commonly reported coping mechanisms included taking a loan and selling household items. The total cost of TB for patients can be catastrophic. Income loss often constitutes the largest financial risk for patients. Apart from ensuring that healthcare services are fairly financed and delivered in a way that minimises direct and indirect costs, there is a need to ensure that TB patients and affected families receive appropriate income replacement and other social protection interventions.

Xpert MTB/RIF assay for the diagnosis of extrapulmonary tuberculosis: a systematic review and meta-analysis

Abstract: Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) is endorsed for the detection of pulmonary tuberculosis (TB). We performed a systematic review and meta-analysis to assess the accuracy of Xpert for the detection of extrapulmonary TB. We searched multiple databases to October 15, 2013. We determined the accuracy of Xpert compared with culture and a composite reference standard (CRS). We grouped data by sample type and performed meta-analyses using a bivariate random-effects model. We assessed sources of heterogeneity using meta- regression for predefined covariates. We identified 18 studies involving 4461 samples. Sample processing varied greatly among the studies. Xpert sensitivity differed substantially between sample types. In lymph node tissues or aspirates, Xpert pooled sensitivity was 83.1% (95% CI 71.4-90.7%) versus culture and 81.2% (95% CI 72.4-87.7%) versus CRS. In cerebrospinal fluid, Xpert pooled sensitivity was 80.5% (95% CI 59.0-92.2%) against culture and 62.8% (95% CI 47.7-75.8%) against CRS. In pleural fluid, pooled sensitivity was 46.4% (95% CI 26.3-67.8%) against culture and 21.4% (95% CI 8.8-33.9%) against CRS. Xpert pooled specificity was consistently .98.7% against CRS across different sample types. Based on this systematic review, the World Health Organization now recommends Xpert over conventional tests for diagnosis of TB in lymph nodes and other tissues, and as the preferred initial test for diagnosis of TB meningitis.

Ageing and the epidemiology of multimorbidity

Abstract: The world's population is ageing and an important part of this demographic shift is the development of chronic illness. In short, a person who does not die of acute illnesses, such as infections, and survives with chronic illnesses is more likely to develop additional chronic illnesses. Chronic respiratory diseases are an important component of these diseases associated with ageing. This article reviews the relationship between ageing and chronic respiratory disease, and also how certain chronic diseases cluster with others, either on the basis of underlying risk factors, complication of the primary disease or other factors, such as an increased state of inflammation. While death is inevitable, disabling chronic illnesses are not. Better understanding of how individuals can age healthily without the development of multiple chronic illnesses should lead to an improved global quality of life.

Eosinophilic inflammation in COPD: prevalence and clinical characteristics

Abstract: To the Editor: Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, with patients displaying varying clinical and pathophysiological features. The identification of COPD phenotypes with distinct characteristics may allow targeted treatment strategies directed towards specific biological pathways. Eosinophilic inflammation is thought to be a characteristic feature of asthma rather than COPD. However, studies have shown that a subset of COPD patients with eosinophilic airway inflammation exists, even after the careful exclusion of patients with any features of asthma, such as β-agonist reversibility, bronchial hyperresponsiveness, atopy or a childhood history of asthma [1–4]. Interestingly, these patients exhibit the greatest response to corticosteroid treatment [1–4]. Likewise, sputum eosinophil numbers are increased in a subset of COPD exacerbations [5, 6], and titrating corticosteroid therapy according to sputum eosinophil counts reduces exacerbation rates [7]. Furthermore, there are similar increases in sputum and blood eosinophil numbers during COPD exacerbations [5]; using blood eosinophils as a surrogate maker for airway eosinophils to direct oral corticosteroid therapy for the treatment of COPD exacerbations enhances clinical recovery [8]. Taken together, these observations suggest that eosinophilic airway inflammation in COPD is a predictive biomarker of corticosteroid responsiveness during clinical stability and exacerbations. The prevalence of eosinophilic inflammation in COPD patients is unknown. We do not know whether patients with sputum or blood eosinophilia represent a stable COPD phenotype over time and, apart from corticosteroid responsiveness, little is known about the other clinical characteristics of this subset of patients. We analysed samples from the ECLIPSE (Evaluation of COPD Longitudinally to Identify …

The different clinical faces of obstructive sleep apnoea: a cluster analysis

Abstract: Although commonly observed in clinical practice, the heterogeneity of obstructive sleep apnoea (OSA) clinical presentation has not been formally characterised. This study was the first to apply cluster analysis to identify subtypes of patients with OSA who experience distinct combinations of symptoms and comorbidities. An analysis of baseline data from the Icelandic Sleep Apnoea Cohort (822 patients with newly diagnosed moderate-to-severe OSA) was performed. Three distinct clusters were identified. They were classified as the "disturbed sleep group" (cluster 1), "minimally symptomatic group" (cluster 2) and "excessive daytime sleepiness group" (cluster 3), consisting of 32.7%, 24.7% and 42.6% of the entire cohort, respectively. The probabilities of having comorbid hypertension and cardiovascular disease were highest in cluster 2 but lowest in cluster 3. The clusters did not differ significantly in terms of sex, body mass index or apnoea-hypopnoea index. Patients with OSA have different patterns of clinical presentation, which need to be communicated to both the lay public and the professional community with the goal of facilitating care-seeking and early identification of OSA. Identifying distinct clinical profiles of OSA creates a foundation for offering more personalised therapies in the future.

Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study

Abstract: Patients with severe pulmonary arterial hypertension (PAH) in New York Heart Association (NYHA) functional class (FC) III/IV have a poor prognosis, despite survival benefits being demonstrated with intravenous epoprostenol. In this pilot study, the efficacy and safety of a triple combination therapy regimen in patients with severe PAH was investigated. Data from newly diagnosed NYHA FC III/IV PAH patients (n=19) initiated on upfront triple combination therapy (intravenous epoprostenol, bosentan and sildenafil) were collected retrospectively from a prospective registry. Significant improvements in 6-min walk distance and haemodynamics were observed after 4 months' triple combination therapy in 18 patients (p<0.01); 17 patients had improved to NYHA FC I or II. One patient was not included in the month 4 assessment (due to an emergency lung transplant in month 3). At the final evaluation (mean ± sd 32 ± 19 months), all 18 patients had sustained clinical and haemodynamic improvement. Overall survival estimates for the triple combination cohort were 100% at 1, 2 and 3 years. Expected survival calculated from the French equation was 75% (95% CI 68-82%), 60% (95% CI 50-70%) and 49% (95% CI 38-60%) at 1, 2 and 3 years, respectively. This pilot study provides preliminary evidence of the long-term benefits of upfront triple combination therapy in patients with severe PAH.

A staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice

Abstract: Staphylococcus aureus secretes α-hemolysin, a pore-forming cytotoxin that contributes to the pathogenesis of pneumonia. α-hemolysin injures epithelial cells by interacting with the zinc-dependent metalloprotease ADAM10 as its receptor 5 . We show that conditional knock out mice of Adam10 in the lung epithelium are highly resistant to lethal pneumonia. Investigation of the molecular mechanism of toxin-receptor function revealed that α-hemolysin upregulates ADAM10 metalloprotease activity in alveolar epithelial cells, resulting in cleavage of the adherens junction protein E-cadherin. Cleavage causes a disruption of epithelial barrier function, contributing to the pathogenesis of acute lung injury. A specific metalloprotease inhibitor of ADAM10 prevents toxin-induced E-cadherin cleavage; similarly, E- cadherin proteolysis and barrier disruption is attenuated in ADAM10 knockout mice. The observation that Hla can usurp the metalloprotease activity of its receptor reveals a novel mechanism of pore-forming cytotoxin action in which pathologic insults are not solely the result of irreversible membrane injury, and defines inhibition of ADAM10 activity as a strategy for disease modification.

Nitrogen dioxide and mortality: review and meta-analysis of long-term studies.

Abstract: Exposure to ambient nitrogen dioxide (NO2) has been linked to increased mortality in several epidemiological studies but the question remains of whether NO2 is directly responsible for the health effects or is only an indicator of other pollutants, including particulate matter. The aim of the present review was to provide pooled estimates of the long-term effects of NO2 on mortality, which are potentially useful for health impact assessment. We selected 23 papers, published from 2004 to 2013, evaluating the relationship between NO2 and mortality, also including an assessment of the effect of particulate matter exposure. A random-effects meta-analysis was carried out on 19 studies. The pooled effect on mortality was 1.04 (95% CI 1.02-1.06) with an increase of 10 μg · m(-3) in the annual NO2 concentration and 1.05 (95% CI 1.01-1.09) for particulate matter <2.5 μm in diameter (PM2.5) (10 μg · m(-3)). The effect on cardiovascular mortality was 1.13 (95% CI 1.09-1.18) for NO2 and 1.20 (95% CI 1.09-1.31) for PM2.5. The NO2 effect on respiratory mortality was 1.03 (95% CI 1.02-1.03) and 1.05 (95% CI 1.01-1.09) for PM2.5. Four bipollutant analyses with particulate matter and NO2 in the same models showed minimal changes in the effect estimates of NO2. There is evidence of a long-term effect of NO2 on mortality as great as that of PM2.5. An independent effect of NO2 emerged from multipollutant models.

Management of patients with multidrug-resistant/extensively drug-resistant tuberculosis in Europe: a TBNET consensus statement

Abstract: The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) substantially challenges TB control, especially in the European Region of the World Health Organization, where the highest prevalence of MDR/XDR cases is reported. The current management of patients with MDR/XDR-TB is extremely complex for medical, social and public health systems. The treatment with currently available anti-TB therapies to achieve relapse-free cure is long and undermined by a high frequency of adverse drug events, suboptimal treatment adherence, high costs and low treatment success rates. Availability of optimal management for patients with MDR/XDR-TB is limited even in the European Region. In the absence of a preventive vaccine, more effective diagnostic tools and novel therapeutic interventions the control of MDR/XDR-TB will be extremely difficult. Despite recent scientific advances in MDR/XDR-TB care, decisions for the management of patients with MDR/XDR-TB and their contacts often rely on expert opinions, rather than on clinical evidence. This document summarises the current knowledge on the prevention, diagnosis and treatment of adults and children with MDR/XDR-TB and their contacts, and provides expert consensus recommendations on questions where scientific evidence is still lacking.

Expert opinion on the cough hypersensitivity syndrome in respiratory medicine

Abstract: In 2011, a European Respiratory Society Task Force embarked on a process to determine the position and clinical relevance of the cough hypersensitivity syndrome, a disorder characterised by troublesome coughing often triggered by low levels of thermal, mechanical or chemical exposure, in the management of patients with chronic cough. A 21-component questionnaire was developed by an iterative process supported by a literature review. 44 key opinion leaders in respiratory medicine were selected and interviewed as to their opinions. There was a high degree of unanimity in the responses obtained, with all opinion leaders supporting the concept of cough hypersensitivity as a clinically useful paradigm. The classic stratification of cough into asthmatic, rhinitic and reflux-related phenotypes was supported. Significant disparity of opinion was seen in the response to two questions concerning the therapy of chronic cough. First, the role of acid suppression in reflux cough was questioned. Secondly, the opinion leaders were split as to whether a trial of oral steroids was indicated to establish a diagnosis of eosinophilic cough. The cough hypersensitivity syndrome was clearly endorsed by the opinion leaders as a valid and useful concept. They considered that support of patients with chronic cough was inadequate and the Task Force recommends that further work is urgently required in this neglected area. Cough hypersensitivity syndrome was clearly endorsed by opinion leaders as a valid and useful concept

The fibroproliferative response in acute respiratory distress syndrome: mechanisms and clinical significance

Abstract: Acute respiratory distress syndrome (ARDS) continues to be a major healthcare problem, affecting >190,000 people in the USA annually, with a mortality of 27-45%, depending on the severity of the illness and comorbidities. Despite advances in clinical care, particularly lung protective strategies of mechanical ventilation, most survivors experience impaired health-related quality of life for years after the acute illness. While most patients survive the acute illness, a subset of ARDS survivors develops a fibroproliferative response characterised by fibroblast accumulation and deposition of collagen and other extracellular matrix components in the lung. Historically, the development of severe fibroproliferative lung disease has been associated with a poor prognosis with high mortality and/or prolonged ventilator dependence. More recent studies also support a relationship between the magnitude of the fibroproliferative response and long-term health-related quality of life. The factors that determine which patients develop fibroproliferative ARDS and the cellular mechanisms responsible for this pathological response are not well understood. This article reviews our current understanding of the contribution of pulmonary dysfunction to mortality and to quality of life in survivors of ARDS, the mechanisms driving pathological fibroproliferation and potential therapeutic approaches to prevent or attenuate fibroproliferative lung disease.

The clinical and genetic features of COPD-asthma overlap syndrome

Abstract: Individuals with chronic obstructive pulmonary disease (COPD) and asthma are an important but poorly characterised group. The genetic determinants of COPD and asthma overlap have not been studied. The aim of this study was to identify clinical features and genetic risk factors for COPD and asthma overlap. Subjects were current or former smoking non-Hispanic whites or African-Americans with COPD. Overlap subjects reported a history of physician-diagnosed asthma before the age of 40 years. We compared clinical and radiographic features between COPD and overlap subjects. We performed genome-wide association studies (GWAS) in the non-Hispanic whites and African-American populations, and combined these results in a meta-analysis. More females and African-Americans reported a history of asthma. Overlap subjects had more severe and more frequent respiratory exacerbations, less emphysema and greater airway wall thickness compared to subjects with COPD alone. The non-Hispanic white GWAS identified single nucleotide polymorphisms in the genes CSMD1 (rs11779254, p=1.57 × 10(-6)) and SOX5 (rs59569785, p=1.61 × 10(-6)) and the meta-analysis identified single nucleotide polymorphisms in the gene GPR65 (rs6574978, p=1.18 × 10(-7)) associated with COPD and asthma overlap. Overlap subjects have more exacerbations, less emphysema and more airway disease for any degree of lung function impairment compared to COPD alone. We identified novel genetic variants associated with this syndrome. COPD and asthma overlap is an important syndrome and may require distinct clinical management.

Factors associated with FEV1 decline in cystic fibrosis: analysis of the ECFS patient registry.

Abstract: Pulmonary insufficiency is the main cause of death in cystic fibrosis (CF). We analysed forced expiratory volume in 1 s (FEV1) data of 14,732 patients registered in the European Cystic Fibrosis Society Patient Registry (ECFSPR) database in 2007. We used linear and logistic regressions to investigate associations between FEV1 % predicted and clinical outcomes. Body mass index (BMI), chronic infection by Pseudomonas aeruginosa, pancreatic status and CF-related diabetes (CFRD) showed a statistically significant (all p<0.0001) and clinically relevant effect on FEV1 % pred after adjusting for age. Patients with a lower BMI experience a six-fold increased odds ratio (95% CI 5.0-7.3) of having severe lung disease (FEV1 <40% pred) compared to patients with normal BMI. Being chronically infected with P. aeruginosa increases the odds ratio of severe lung disease by 2.4 (95% CI 2.0-2.7), and patients with pancreatic insufficiency experience a 2.0-fold increased odds ratio (95% CI 1.6-2.5) of severe lung disease compared to pancreatic sufficient patients. Patients with CFRD have a 1.8-fold increased odds ratio (95% CI 1.6-2.2) compared to patients not affected. These potential risk factors for pulmonary disease in patients with CF are to some degree preventable or treatable. We emphasise the importance of their early identification through frequent routine tests, the implementation of infection control measures, and a timely initiation of relevant therapies.

Nutritional assessment and therapy in COPD: a European Respiratory Society statement

Abstract: Nutrition and metabolism have been the topic of extensive scientific research in chronic obstructive pulmonary disease (COPD) but clinical awareness of the impact dietary habits, nutritional status and nutritional interventions may have on COPD incidence, progression and outcome is limited. A multidisciplinary Task Force was created by the European Respiratory Society to deliver a summary of the evidence and description of current practice in nutritional assessment and therapy in COPD, and to provide directions for future research. Task Force members conducted focused reviews of the literature on relevant topics, advised by a methodologist. It is well established that nutritional status, and in particular abnormal body composition, is an important independent determinant of COPD outcome. The Task Force identified different metabolic phenotypes of COPD as a basis for nutritional risk profile assessment that is useful in clinical trial design and patient counselling. Nutritional intervention is probably effective in undernourished patients and probably most when combined with an exercise programme. Providing evidence of cost-effectiveness of nutritional intervention is required to support reimbursement and thus increase access to nutritional intervention. Overall, the evidence indicates that a well-balanced diet is beneficial to all COPD patients, not only for its potential pulmonary benefits, but also for its proven benefits in metabolic and cardiovascular risk.

Differences in content and organisational aspects of pulmonary rehabilitation programmes

Abstract: The aim was to study the overall content and organisational aspects of pulmonary rehabilitation programmes from a global perspective in order to get an initial appraisal on the degree of heterogeneity worldwide. A 12-question survey on content and organisational aspects was completed by representatives of pulmonary rehabilitation programmes that had previously participated in the European Respiratory Society (ERS) COPD Audit. Moreover, all ERS members affiliated with the ERS Rehabilitation and Chronic Care and/or Physiotherapists Scientific Groups, all members of the American Association of Cardiovascular and Pulmonary Rehabilitation, and all American Thoracic Society Pulmonary Rehabilitation Assembly members were asked to complete the survey via multiple e-mailings. The survey has been completed by representatives of 430 centres from 40 countries. The findings demonstrate large differences among pulmonary rehabilitation programmes across continents for all aspects that were surveyed, including the setting, the case mix of individuals with a chronic respiratory disease, composition of the pulmonary rehabilitation team, completion rates, methods of referral and types of reimbursement. The current findings stress the importance of future development of processes and performance metrics to monitor pulmonary rehabilitation programmes, to be able to start international benchmarking, and to provide recommendations for international standards based on evidence and best practice.

Dyspnoea: a multidimensional and multidisciplinary approach

Abstract: Dyspnoea is a debilitating symptom that affects quality of life, exercise tolerance and mortality in various disease conditions/states. In patients with chronic obstructive pulmonary disease (COPD), it has been shown to be a better predictor of mortality than forced expiratory volume in 1 s. In patients with heart disease it is a better predictor of mortality than angina. Dyspnoea is also associated with decreased functional status and worse psychological health in older individuals living at home. It also contributes to the low adherence to exercise training programmes in sedentary adults and in COPD patients. The mechanisms of dyspnoea are still unclear. Recent studies have emphasised the multidimensional nature of dyspnoea in the sensory-perceptual (intensity and quality), affective distress and impact domains. The perception of dyspnoea involves a complex chain of events that depend on varying cortical integration of several afferent/efferent signals and coloured by affective processing. This review, which stems from the European Respiratory Society research symposium held in Paris, France in November 2012, aims to provide state-of-the-art advances on the multidimensional and multidisciplinary aspects of dyspnoea, by addressing three different themes: 1) the neurophysiology of dyspnoea, 2) exercise and dyspnoea, and 3) the clinical impact and management of dyspnoea.

Elevated expression of the NLRP3 inflammasome in neutrophilic asthma

Abstract: Asthma is a heterogeneous inflammatory airways disorder where interleukin (IL)-1β is thought to be a key mediator, especially in the neutrophilic subtype of asthma. The generation of active IL-1β requires proteolytic cleavage typically mediated through the formation of a caspase-1-containing inflammasome. This study hypothesised that an IL-1β endotype associated with the nucleotide-binding domain, leucine-rich repeat-containing family protein (NLRP)3/apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC)/caspase-1 inflammasome is characteristic of patients with the neutrophilic subtype of asthma. Participants with asthma (n=85) and healthy controls (n=27) underwent clinical assessment, spirometry and sputum induction. Sputum was processed for differential cell count, gene expression and protein mediators. NLRP3 and caspase-1 expression was also determined by immunocytochemistry. Sputum macrophages were isolated (n=8) and gene expression of NLRP3 and IL-1β determined. There was significantly elevated gene expression of NLRP3, caspase-1, caspase-4, caspase-5 and IL-1β in participants with neutrophilic asthma. Protein levels of IL-1β were significantly higher in those with neutrophilic asthma and correlated with sputum IL-8 levels. Sputum macrophages, as well as sputum neutrophils in neutrophilic asthma, expressed NLRP3 and caspase-1 protein. NLRP3 inflammasome is upregulated in neutrophilic asthma and may regulate the inflammation process observed in this asthma phenotype through production of IL-1β.

Gas exchange and ventilation-perfusion relationships in the lung

Abstract: This review provides an overview of the relationship between ventilation/perfusion ratios and gas exchange in the lung, emphasising basic concepts and relating them to clinical scenarios. For each gas exchanging unit, the alveolar and effluent blood partial pressures of oxygen and carbon dioxide (PO2 and PCO2) are determined by the ratio of alveolar ventilation to blood flow (V'A/Q') for each unit. Shunt and low V'A/Q' regions are two examples of V'A/Q' mismatch and are the most frequent causes of hypoxaemia. Diffusion limitation, hypoventilation and low inspired PO2 cause hypoxaemia, even in the absence of V'A/Q' mismatch. In contrast to other causes, hypoxaemia due to shunt responds poorly to supplemental oxygen. Gas exchanging units with little or no blood flow (high V'A/Q' regions) result in alveolar dead space and increased wasted ventilation, i.e. less efficient carbon dioxide removal. Because of the respiratory drive to maintain a normal arterial PCO2, the most frequent result of wasted ventilation is increased minute ventilation and work of breathing, not hypercapnia. Calculations of alveolar-arterial oxygen tension difference, venous admixture and wasted ventilation provide quantitative estimates of the effect of V'A/Q' mismatch on gas exchange. The types of V'A/Q' mismatch causing impaired gas exchange vary characteristically with different lung diseases.

Acute exacerbation of idiopathic pulmonary fibrosis associated with air pollution exposure

Abstract: Acute exacerbations of idiopathic pulmonary fibrosis are associated with high mortality and are of unknown cause. The effect of air pollution on exacerbations of interstitial lung disease is unknown. This study aims to define the association of air pollution exposure with acute exacerbation of idiopathic pulmonary fibrosis. Patients with idiopathic pulmonary fibrosis and corresponding air pollution data were identified from a longitudinal cohort. Air pollution exposures were assigned to each patient for ozone, nitrogen dioxide, particulate matter, sulfur dioxide and carbon monoxide based on geo-coded residential addresses. Cox proportional hazards models were used to estimate the association of air pollution exposures and acute exacerbations. Acute exacerbation was significantly associated with antecedent 6-week increases in mean level, maximum level and number of exceedances above accepted standards of ozone (hazard ratio (HR) 1.57, 95% CI 1.09–2.24; HR 1.42, 95% CI 1.11–1.82; and HR 1.51, 95% CI 1.17–1.94, respectively) and nitrogen dioxide (HR 1.41, 95% CI 1.04–1.91; HR 1.27, 95% CI 1.01–1.59; and HR 1.20, 95% CI 1.10–1.31, respectively). Increased ozone and nitrogen dioxide exposure over the preceding 6 weeks was associated with an increased risk of acute exacerbation of idiopathic pulmonary fibrosis, suggesting that air pollution may contribute to the development of this clinically meaningful event. Acute exacerbation of idiopathic pulmonary fibrosis is associated with increased ozone and nitrogen dioxide exposure

Outcome of pulmonary endarterectomy in symptomatic chronic thromboembolic disease

Abstract: Chronic thromboembolic disease is characterised by persistent pulmonary thromboembolic occlusions without pulmonary hypertension. Early surgical treatment with pulmonary endarterectomy may improve symptoms and prevent disease progression. We sought to assess the outcome of pulmonary endarterectomy in symptomatic patients with chronic thromboembolic disease. Patients with symptomatic chronic thromboembolic disease and a mean pulmonary artery pressure <25 mmHg at baseline with right heart catheterisation and treated with pulmonary endarterectomy between January 2000 and July 2013 were identified. Patients were reassessed at 6 months and at 1 year following surgery. A total of 42 patients underwent surgery and the median length of stay in hospital was 11 days. There was no in-hospital mortality but complications occurred in 40% of patients. At 1 year, following surgery, 95% of the patients remained alive. There was a significant symptomatic improvement with 95% of patients in the New York Heart Association functional classes I or II at 6 months. There was a significant improvement in quality of life assessed by the Cambridge pulmonary hypertension outcome review questionnaire. In this carefully selected cohort of chronic thromboembolic disease patients, pulmonary endarterectomy resulted in significant improvement in symptoms and quality of life. Appropriate patient selection is paramount given the known surgical morbidity and mortality, and surgery should only be performed in expert centres.

Microvascular disease in chronic thromboembolic pulmonary hypertension: a role for pulmonary veins and systemic vasculature.

Abstract: Limited numbers of operated patients with chronic thromboembolic pulmonary hypertension (CTEPH) are refractory to pulmonary endarterectomy (PEA) and experience persistent pulmonary hypertension (PH). We retrospectively assessed lung histology available from nine patients with persistent PH (ineffective PEA (inPEA) group) and from eight patients transplanted for distal CTEPH inaccessible by PEA (noPEA group). Microscopically observed peculiarities were compared with the histology of a recently developed CTEPH model in piglets. Pre-interventional clinical/haemodynamic data and medical history of patients from the inPEA and noPEA groups were collected and analysed. Conspicuous remodelling of small pulmonary arteries/arterioles, septal veins and pre-septal venules, including focal capillary haemangiomatosis, as well as pronounced hypertrophy and enlargement of bronchial systemic vessels, were the predominant pattern in histology from both groups. Most findings were reproduced in our porcine CTEPH model. Ink injection experiments unmasked abundant venular involvement in so-called small vessel or microvascular disease, as well as post-capillary bronchopulmonary shunting in human and experimental CTEPH. Microvascular disease is partly due to post-capillary remodelling in human and experimental CTEPH and appears to be related to bronchial-to-pulmonary venous shunting. Further studies are needed to clinically assess the functional importance of this finding.

CFTR: cystic fibrosis and beyond

Abstract: Cystic fibrosis (CF) remains the most common fatal hereditary lung disease. The discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene 25 years ago set the stage for: 1) unravelling the molecular and cellular basis of CF lung disease; 2) the generation of animal models to study in vivo pathogenesis; and 3) the development of mutation-specific therapies that are now becoming available for a subgroup of patients with CF. This article highlights major advances in our understanding of how CFTR dysfunction causes chronic mucus obstruction, neutrophilic inflammation and bacterial infection in CF airways. Furthermore, we focus on recent breakthroughs and remaining challenges of novel therapies targeting the basic CF defect, and discuss the next steps to be taken to make disease-modifying therapies available to a larger group of patients with CF, including those carrying the most common mutation ΔF508-CFTR. Finally, we will summarise emerging evidence indicating that acquired CFTR dysfunction may be implicated in the pathogenesis of chronic obstructive pulmonary disease, suggesting that lessons learned from CF may be applicable to common airway diseases associated with mucus plugging.

The COPD assessment test: a systematic review

Abstract: The COPD assessment test (CAT) is a self-administered questionnaire that measures health-related quality of life. We aimed to systematically evaluate the literature for reliability, validity, responsiveness and minimum clinically important difference (MCID) of the CAT. Multiple databases were searched for studies analysing the psychometric properties of the CAT in adults with chronic obstructive pulmonary disease. Two reviewers independently screened, selected and extracted data, and assessed methodological quality of relevant studies using the COSMIN checklist. From 792 records identified, 36 studies were included. The number of participants ranged from 45 to 6469, mean age from 56 to 73 years, and mean forced expiratory volume in 1 s from 39% to 98% predicted. Internal consistency (reliability) was 0.85-0.98, and test-retest reliability was 0.80-0.96. Convergent and longitudinal validity using Pearson's correlation coefficient were: SGRQ-C 0.69-0.82 and 0.63, CCQ 0.68-0.78 and 0.60, and mMRC 0.29-0.61 and 0.20, respectively. Scores differed with GOLD stages, exacerbation and mMRC grades. Mean scores decreased with pulmonary rehabilitation (2.2-3 units) and increased at exacerbation onset (4.7 units). Only one study with adequate methodology reported an MCID of 2 units and 3.3-3.8 units using the anchor-based approach and distribution-based approach, respectively. Most studies had fair methodological quality. We conclude that the studies support the reliability and validity of the CAT and that the tool is responsive to interventions, although the MCID remains debatable.

Right ventricular reverse remodelling after balloon pulmonary angioplasty

Abstract: Balloon pulmonary angioplasty (BPA) has been reported to improve haemodynamics and functional capacity, with an acceptable risk, in patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are not candidates for pulmonary endarterectomy. However, right ventricular (RV) function, an important predictor in CTEPH, remains to be elucidated. We aimed to examine the impact of BPA on RV remodelling and dysfunction relative to haemodynamic improvements in patients with inoperable CTEPH. 20 consecutive patients with inoperable CTEPH who underwent BPA with cardiovascular magnetic resonance before and after BPA were retrospectively studied. BPA led to significant amelioration of the mean pulmonary arterial pressure, cardiac index and pulmonary vascular resistance (PVR), without death or major complications. Furthermore, BPA significantly ameliorated right-sided heart failure symptoms and signs, and exercise capacity. Cardiovascular magnetic resonance revealed a marked improvement in RV end-diastolic and end-systolic volume index, with concomitant improvements in RV ejection fraction, mass and interventricular septal bowing after BPA. Changes in RV volumes strongly correlated with changes in cardiac index and PVR. BPA induced RV reverse remodelling and improved systolic dysfunction safely by ameliorating haemodynamics in patients with inoperable CTEPH. Evaluating RV function with cardiovascular magnetic resonance may be effective for noninvasively monitoring BPA efficacy.

Identification of intermediate-risk patients with acute symptomatic pulmonary embolism

Abstract: The identification of normotensive patients with acute pulmonary embolism (PE) at high risk of adverse PE-related clinical events (i.e. intermediate-risk group) is a major challenge. We combined individual patient data from six studies involving 2874 normotensive patients with PE. We developed a prognostic model for intermediate-risk PE based on the clinical presentation and the assessment of right ventricular dysfunction and myocardial injury. We used a composite of PE-related death, haemodynamic collapse or recurrent PE within 30 days of follow-up as the main outcome measure. The primary outcome occurred in 198 (6.9%) patients. Predictors of complications included systolic blood pressure 90-100 mmHg (adjusted odds ratio (aOR) 2.45, 95% CI 1.50-3.99), heart rate ≥ 110 beats per min (aOR 1.87, 95% CI 1.31-2.69), elevated cardiac troponin (aOR 2.49, 95% CI 1.71-3.69) and right ventricular dysfunction (aOR 2.28, 95% CI 1.58-3.29). We used these variables to construct a multidimensional seven-point risk index; the odds ratio for complications per one-point increase in the score was 1.55 (95% CI 1.43-1.68; p<0.001). The model identified three stages (I, II and III) with 30-day PE-related complication rates of 4.2%, 10.8% and 29.2%, respectively. In conclusion, a simple grading system may assist clinicians in identifying intermediate-risk PE.