BRN REVIEWS

BRN Reviews is an official journal of Barcelona Respiratory Network.

It is an online, open access, quarterly journal that publishes cutting-edge, high quality, internationally authored reviews on timely topics in respiratory medicine, with an emphasis on their translational aspects.

BRN Reviews. 14/ 2018

VOLUME 14 – NUMBER 4/ October – December

Review Articles

The Copenhagen City Heart Study Experience and its Key Contributions to Chronic Obstructive Pulmonary Disease
Peter Lange, Jørgen Vestbo

Abstract

The Copenhagen City Heart Study Experience and its Key Contributions to Chronic Obstructive Pulmonary Disease

Peter Lange, Department of Public Health, Section of Social Medicine, University of Copenhagen; Medical Department O, Respiratory Section, Herlev and Gentofte Hospital, Copenhagen University Hospital. Copenhagen, Denmark
Jørgen VestboDivision of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, The University of Manchester; Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre. Manchester, UK

Although the principal aim of the Copenhagen City Heart Study (CCHS) was to investigate risk factors for ischaemic heart disease, it already started including spirometry and a questionnaire on respiratory symptoms from its start in 1976. Longitudinal design including five examination rounds and follow-up of hospitalisations, mortality and medically treated exacerbations of chronic obstructive pulmonary disease (COPD) gave a great opportunity to study different aspects of the natural history of COPD. Since 1988, more than 100 papers on different aspects of obstructive lung diseases have been published. Among the most quoted are publications on lung function decline in asthma, trajectories leading to COPD, analyses describing positive association between physical activity and COPD, role of nutritional status for prognosis of COPD, and a nested intervention study showing no effect of an inhaled corticosteroid (ICS) on lung function decline among individuals with mild COPD. The present review describes some of these studies.

Keywords: Asthma. Chronic obstructive pulmonary disease. Epidemiology. Natural history.

Asthma-Chronic Obstructive Pulmonary Disease Overlap in Spain: Anything Special?
Borja Cosio, Luis Pérez de Llano

Abstract

Asthma-Chronic Obstructive Pulmonary Disease Overlap in Spain: Anything Special?

Borja Cosio, Department of Respiratory Medicine, Hospital Universitario Son Espases-IdISBa, Palma de Mallorca, Spain; and CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid

Luis Pérez de Llano, Department of Respiratory Medicine, Hospital Lucus Augusti, Lugo, Spain

The asthma-chronic obstructive pulmonary disease overlap (ACO) has recently attracted attention and triggered debate as evidenced by the proliferation of articles, reviews and editorials dedicated to this topic. Most of this debate is based on the lack of a consistent definition and the scarce knowledge of its underlying mechanisms. Spain has been very active in pursuing a better understanding of this topic and in developing a clearer definition to help clinicians identify and treat this condition correctly. This paper reviews the current evidence supporting its existence and the latest findings related to its mechanisms and it points out the limitations of using the classic labels to classify chronic airways diseases.

Keywords: Airway. Inflammation. Overlap.

The Clinical Relevance of Periostin in Asthma
Irene Braithwaite, Ruth Semprini, Richard Beasley

Abstract

The Clinical Relevance of Periostin in Asthma

Irene Braithwaite, Medical Research Institute of New Zealand, Wellington, New Zealand

Ruth Semprini, Medical Research Institute of New Zealand, Wellington, New Zealand

Richard Beasley, Medical Research Institute of New Zealand, Wellington, New Zealand

Periostin is a matricellular protein which is generated by airway epithelial cells in response to interleukin (IL)-4 and IL-13. Serum periostin levels have been proposed as a biomarker of type-2 inflammation with clinical utility in severe asthma. Normal reference ranges have been established in a predominant Caucasian population using the Elecsys® Periostin immunoassay. Periostin levels do not differentiate asthma from non-asthma, or mild-to-moderate asthma from severe asthma, although they are higher in adults with asthma who have raised levels of blood eosinophils and fractional exhaled nitric oxide (FeNO). Periostin status can predict response to monoclonal antibody therapy directed against IL-13 and immunoglobulin E (IgE), such that adults with severe asthma and a periostin level ≥ 50 ng/ml (designated ”periostin-high”) have a greater therapeutic response than “periostin- low” patients. The clinical relevance of these findings is uncertain, due to the similar predictive ability of the more commonly available biomarkers blood eosinophils and/or FeNO.

Keywords: Asthma. Biomarkers. Periostin. Phenotypes.

Exercise testing to evaluate therapeutic interventions in chronic respiratory diseases
Luis Puente-Maestu, William W. Stringer, Richard Casaburi

Abstract

Exercise testing to evaluate therapeutic interventions in chronic respiratory diseases

Luis Puente-Maestu, Servicio de Neumología del Hospital Universitario Gregorio Marañón, Madrid, Spain; Instituto de investigación Sanitaria Gregorio Marañón, Madrid, Spain; Facultad de Medicina de la Universidad Complutense de Madrid, Madrid, Spain

William W. Stringer, Rehabilitation Clinical Trials Center, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA; Geffen School of Medicine at UCLA. Los Angeles, CA, USA

Richard Casaburi, Rehabilitation Clinical Trials Center, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA; Geffen School of Medicine at UCLA. Los Angeles, CA, USA

From an evidence-based perspective, performance during standardised exercise testing is of considerable importance in the multidimensional evaluation of most respiratory diseases. In this review we aim to summarise the available evidence on the responsiveness of exercise tests to various pharmacological and non-pharmacological therapeutic interventions, as well as the underlying mechanisms associated with the improvements. A standard test to evaluate interventions has not yet been defined and therefore there are several available formats with different types of responsiveness to interventions. Thresholds for clinically important changes are available for several tests. The mechanism of improvement is different depending on the disease process: when moderate or severe airflow limitation is present, as in chronic obstructive pulmonary disease (COPD), the primary mechanisms are reduced ventilatory requirement and/or enhanced ventilatory capacity via reduction of dynamic hyperinflation; in pulmonary arterial hypertension the effect of treatment is typically associated to haemodynamic improvement, while in interstitial lung diseases, the amelioration of arterial oxygen desaturation seems to be the predominant physiological factor.

Keywords: Chronic obstructive pulmonary disease. Exercise physiology. Exercise testing. Interstitial lung diseases. Pulmonary arterial hypertension.

Double or Triple Therapy in Chronic Obstructive Pulmonary Disease
Mario Cazzola, Paola Rogliani, Maria G. Matera

Abstract

Double or Triple Therapy in Chronic Obstructive Pulmonary Disease

Mario Cazzola, Department of Experimental Medicine and Surgery, Chair of Respiratory Medicine, University of Rome Tor Vergata, Rome, Italy

Paola Rogliani, Department of Experimental Medicine and Surgery, Chair of Respiratory Medicine, University of Rome Tor Vergata, Rome, Italy

Maria G. Matera, Department of Experimental Medicine, Chair of Pharmacology, University of Campania Luigi Vanvitelli, Naples, Italy

Although the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy recommends triple therapy involving long-acting muscarinic antagonists (LAMAs), long-acting β2-agonists (LABAs) and inhaled corticosteroids (ICS) only for further advanced patients, particularly for those at a high risk for exacerbation (GOLD D), triple therapy is widely prescribed in real-life management of chronic obstructive pulmonary disease (COPD), even in patients with mild or moderate COPD severity, likely because physicians prefer to prescribe a full treatment to ensure the best care to their patients. While the available clinical evidence on triple therapy has greatly increased in recent years, there is still no solid evidence to indicate whether and when addition of an ICS to the LABA/LAMA combination provides additional clinical value. Therefore, a strong recommendation can still not be generated but the results of four recent pivotal triple therapy studies support the possibility that this treatment option should be considered also for GOLD B patients.

Keywords: Chronic obstructive pulmonary disease. Dual bronchodilation. Triple therapy.

Demystifying Inhaler Use in Chronic Obstructive Airways Disease
Matteo Bonini, Omar S. Usmani

Abstract

Double or Triple Therapy in Chronic Obstructive Pulmonary Disease

Mario Cazzola, Department of Experimental Medicine and Surgery, Chair of Respiratory Medicine, University of Rome Tor Vergata, Rome, Italy

Paola Rogliani, Department of Experimental Medicine and Surgery, Chair of Respiratory Medicine, University of Rome Tor Vergata, Rome, Italy

Maria G. Matera, Department of Experimental Medicine, Chair of Pharmacology, University of Campania Luigi Vanvitelli, Naples, Italy

Although the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy recommends triple therapy involving long-acting muscarinic antagonists (LAMAs), long-acting β2-agonists (LABAs) and inhaled corticosteroids (ICS) only for further advanced patients, particularly for those at a high risk for exacerbation (GOLD D), triple therapy is widely prescribed in real-life management of chronic obstructive pulmonary disease (COPD), even in patients with mild or moderate COPD severity, likely because physicians prefer to prescribe a full treatment to ensure the best care to their patients. While the available clinical evidence on triple therapy has greatly increased in recent years, there is still no solid evidence to indicate whether and when addition of an ICS to the LABA/LAMA combination provides additional clinical value. Therefore, a strong recommendation can still not be generated but the results of four recent pivotal triple therapy studies support the possibility that this treatment option should be considered also for GOLD B patients.

Keywords: Chronic obstructive pulmonary disease. Dual bronchodilation. Triple therapy.

BRN Reviews. 13/ 2018

VOLUME 13 – NUMBER 3/ July – September 2018

Editor’s Note

New insights into chronic respiratory disorders
Robert Rodríguez-Roisin

Review Articles

Prediction Models in Chronic Obstructive Pulmonary Disease – Informing Practice and Improving Research
Milo A. Puhan, Gerben ter Riet

Abstract

Prediction Models in Chronic Obstructive Pulmonary Disease – Informing Practice and Improving Research

Milo A. Puhan, Epidemiology, Biostatistics und Prevention Institute (EBPI), University of Zurich, Zurich, Switzerland
Gerben ter Riet, Academic Medical Center, University of Amsterdam, Department of General Practice, Amsterdam, The Netherlands

Prediction models have the potential to advance personalised medicine through risk-stratified management, which optimises the benefits and harms of preventive and therapeutic interventions for individuals. Thereby, the risk that patients are either under- or over-treated can be minimised. In research, prediction models can be used to efficiently identify study subjects, to control for confounding and to study subgroup effects. In the area of chronic obstructive pulmonary disease (COPD), many prediction models have been developed to predict the risk of early death or exacerbations, the course of disease or for other outcomes. A prerequisite for their use is a careful development and external validation, which is, however, often lacking. This article describes the purposes of prediction models as well as their development and validation including novel approaches like multiple score comparison meta-analysis. It also describes research needs like the need for developing accurate and valid prediction models for exacerbations that support risk-stratified prevention of exacerbations.

Keywords: Chronic obstructive pulmonary disease. Prediction models. Prevention. Risk stratification. Treatment.

Bronchiectasis Exacerbations: Clinical Relevance and Management
M. Aurora Mendes, Amelia Shoemark, James D. Chalmers

Abstract

Bronchiectasis Exacerbations: Clinical Relevance and Management

M. Aurora Mendes, Pulmonology Department, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal

Amelia Shoemark, Scottish Centre for Respiratory Research, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland

James D. Chalmers, Scottish Centre for Respiratory Research, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland

Bronchiectasis is a clinico-radiological syndrome with variable course. Some patients are stable for years and others develop frequent exacerbations, characterised by symptoms such as increased cough and change in sputum and/or systemic features. Bacterial infections are the most frequent recognised trigger, and consequently the majority of these events are treated with systemic antibiotics. As a major cause of morbidity, mortality and healthcare related costs, exacerbations have been used as primary outcomes in clinical trials of new treatments in bronchiectasis. Furthermore, implementing prevention strategies in patients at risk of future exacerbations is a major goal of bronchiectasis management. However, evidence-based knowledge on bronchiectasis exacerbations is limited and there is no specific licensed-treatment. Further studies using the recently developed consensus-based definition are needed to clarify the unanswered questions regarding the pathophysiology, prevention and treatment of bronchiectasis exacerbations. This review summarises the existing evidence and the gaps in our knowledge of bronchiectasis exacerbations.Bronchiectasis is a clinico-radiological syndrome with variable course. Some patients are stable for years and others develop frequent exacerbations, characterised by symptoms such as increased cough and change in sputum and/or systemic features. Bacterial infections are the most frequent recognised trigger, and consequently the majority of these events are treated with systemic antibiotics. As a major cause of morbidity, mortality and healthcare related costs, exacerbations have been used as primary outcomes in clinical trials of new treatments in bronchiectasis. Furthermore, implementing prevention strategies in patients at risk of future exacerbations is a major goal of bronchiectasis management. However, evidence-based knowledge on bronchiectasis exacerbations is limited and there is no specific licensed-treatment. Further studies using the recently developed consensus-based definition are needed to clarify the unanswered questions regarding the pathophysiology, prevention and treatment of bronchiectasis exacerbations. This review summarises the existing evidence and the gaps in our knowledge of bronchiectasis exacerbations.

Keywords: Antibiotics. Bronchiectasis exacerbations. Infection.

Sleep Apnoea and Early Antecedents of Adult Disease
David Gozal

Abstract

Sleep Apnoea and Early Antecedents of Adult Disease

David Gozal, Department of Pediatrics, Section of Sleep Medicine, Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, Illinois, USA

Obstructive sleep apnoea (OSA) is a highly prevalent disorder across the life spectrum including early childhood and pregnancy. Occurrence of sleep perturbations and intermittent hypoxia that constitute major hallmarks of OSA during these favourable developmental plasticity windows may facilitate emergence of incremental risks for a variety of ageing-related disorders via a multitude of epigenetic mechanisms. In addition, OSA during late adolescence and adulthood is not immune to epigenetic changes, the latter potentially playing a role in the reversibility of OSA-associated morbidities upon implementation of therapy. Furthermore, unique epigenetic signatures may provide powerful biomarkers for precision-based medicine approaches in the framework of OSA. Taken together, the conceptual umbrellas assigning major roles to epigenetics in the context of OSA-associated phenotypic expression and longitudinal disease risk trajectories is not a farfetched idea any longer. Early adoption of these biologically relevant principles and their implementation to the upcoming future clinical trials appears inevitable if progress is to occur.

Keywords: Epigenetics. Intermittent hypoxia. Microbiome. Sleep apnoea. Sleep fragmentation.

Chronic Obstructive Pulmonary Disease and Bronchodilator Response: Does it Matter?
Donald P. Tashkin

Abstract

Chronic Obstructive Pulmonary Disease and Bronchodilator Response: Does it Matter?

Donald P. Tashkin, Emeritus Professor of Medicine, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA

A positive bronchodilator response is found in most patients with moderate-to-very-severe chronic obstructive pulmonary disease (COPD), although its presence varies over time within the same patient as well as across patients depending, in part, on the severity of the pre-bronchodilator level of airflow obstruction. Consequently, the response to a bronchodilator does not reliably distinguish COPD from asthma, although a particularly marked response suggests the presence of asthma/COPD overlap. The absence of an acute response to a bronchodilator in COPD does not preclude a favourable long-term response to maintenance bronchodilator therapy, although it may predict a reduced magnitude of the long-term response. Bronchodilator responsiveness does not appear to define a distinct phenotype of COPD or predict most clinically meaningful outcomes. However, performing spirometry after a bronchodilator may have practical utility in clinical practice as an indicator of the maximum (“ceiling”) lung function that patients are capable of attaining as a goal to attempt to achieve with pharmacotherapy.

Keywords: Asthma. Asthma/Chronic obstructive pulmonary disease. Bronchodilator response. Chronic obstructive pulmonary disease (COPD).

Current and Future Respiratory Medicine Challenges: Insights from a Barcelona Respiratory Network Foundation Retreat in Barcelona in 2017
Jordi Dorca, Álvar Agustí, Eduard Monsó

Abstract

Current and Future Respiratory Medicine Challenges: Insights from a Barcelona Respiratory Network Foundation Retreat in Barcelona in 2017

Jordi Dorca, Pneumology Service, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Barcelona (Spain). Institut de Recerca Biomèdica de Bellvitge (IDIBELL). Universitat de Barcelona; Barcelona Respiratory Network (BRN) Foundation, Barcelona, Spain

Álvar Agustí, Thorax Institute, Hospital Clínic, IDIBAPS, University of Barcelona, CIBERES, Barcelona, Spain; Barcelona Respiratory Network (BRN) Foundation, Barcelona, Spain

Eduard Monsó, Pneumology Service, Hospital Universitari Parc Taulí, Terrassa, Barcelona (Spain). Universitat Autònoma de Barcelona; Centre for Biomedical Investigation Network of Respiratory Disease (CIBERES); Barcelona Respiratory Network (BRN) Foundation, Barcelona, Spain

On a global level, respiratory diseases impose a major worldwide health burden affecting millions of people. Respiratory diseases are not only very common but present a great challenge to human health and a productive economy. Prevention, control and cure of these conditions are among the most cost-effective interventions to be taken within a healthcare system and must be a priority for researchers as well as for health authorities. Today, many novel technologies can potentially improve the diagnosis and control of numerous diseases, and the present challenge is how they can be quickly developed and implemented. This review summarises the main conclusions of a Barcelona Respiratory Network (BRN) Foundation Retreat held last year in Barcelona. The debate was structured around four distinct sections: 1) trends that impact current society; 2) foreseeable changes in the field of respiratory health; 3) challenges for the future of healthcare systems; and, 4) future biomedical research trends in respiratory medicine.

Keywords: Challenges. Research. Trends.

BRN Reviews. 12/ 2018

VOLUME 12 – NUMBER 2 / April – June 2018

Editor’s Note

Clinical, Mechanistic and Therapeutic Topics and Chronic Obstructive Airways Disorders
Robert Rodríguez-Roisin

Review Articles

The Challenge of Obesity and Asthma in Children and Adolescents
Erick Forno, Juan C. Celedón

Abstract

The Challenge of Obesity and Asthma in Children and Adolescents

Erick FornoDivision of Pulmonary Medicine, Allergy, and Immunology, Children’s Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Juan C. CeledónDivision of Pulmonary Medicine, Allergy, and Immunology, Children’s Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

Obesity and asthma each affect millions of people worldwide and the prevalence of both diseases has substantially risen in the last few decades. Solid epidemiological and experimental evidence strongly suggest that obesity increases asthma risk and severity, leading to growing recognition of an obese asthma phenotype. This phenotype is complex and multifactorial, differs between children and adults, and likely encompasses several sub-phenotypes. In this article, we will review the characteristics of obese asthma in children, as well as some of its underlying pathways. Furthermore, we will discuss some remaining challenges in the research, diagnosis, and management of obese asthma in children.

Keywords: Asthma. Childhood asthma. Metabolic syndrome. Obese asthma. Obesity.

Use of Biomarkers in Chronic Obstructive Pulmonary Disease: Clinical Implications
Ji-Yong Moon, Yu Ji Cho, Don D. Sin

Abstract

Use of Biomarkers in Chronic Obstructive Pulmonary Disease: Clinical Implications

Ji-Yong Moon, Centre for Heart and Lung Innovation (James Hogg Research Centre), St. Paul’s Hospital and the Institute for Heart and Lung Health, University of British Columbia, Vancouver, BC, Canada and Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea

Yu Ji Cho, Centre for Heart and Lung Innovation (James Hogg Research Centre), St. Paul’s Hospital and the Institute for Heart and Lung Health, University of British Columbia, Vancouver, BC, Canada and Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Gyeongsang National University College of Medicine, Jinju, Korea

Don D. Sin, Centre for Heart and Lung Innovation (James Hogg Research Centre), St. Paul’s Hospital and the Institute for Heart and Lung Health, University of British Columbia and of Respiratory Medicine (Department of Medicine), University of British Columbia. Vancouver, BC, Canada

Chronic obstructive pulmonary disease (COPD) is characterised by airflow limitation, which may be progressive and leads to considerable morbidity and mortality. Aside from lung function measurements, there are no biomarkers that are routinely used clinically in the care of patients with COPD. Biomarker is commonly defined as a “characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention”. Discovery and implementation of biomarkers may enhance the precision of COPD diagnosis, assessment of its risk and severity, response to therapy, and predict progression, enabling personalised health in COPD. In this review, we summarise recent advances in COPD biomarkers and discuss their clinical implications.

Keywords: Biomarkers. Chronic obstructive pulmonary disease. Personalised medicine.

Pneumonia in Patients with Chronic Obstructive Pulmonary Disease
Marcos I. Restrepo, Oriol Sibila, Antonio Anzueto

Abstract

Pneumonia in Patients with Chronic Obstructive Pulmonary Disease

Marcos I. Restrepo, South Texas Veterans Health Care System and Veterans Evidence Based Research Dissemination and Implementation Center (VERDICT) (MR), San Antonio, Texas, USA

Oriol Sibila, Department of Respiratory Medicine, Hospital de la Santa Creu i Sant Pau, and Institut d´Investigació Biomèdica Sant Pau (IBB Sant Pau), Barcelona, Spain

Antonio Anzueto, University of Texas Health Science Center at San Antonio, and South Texas Veterans Health Care System, San Antonio, Texas, USA

Chronic obstructive pulmonary disease (COPD) is a frequent comorbid condition associated with increased morbidity and mortality. Pneumonia is the most common infectious disease condition. The purpose of this review is to evaluate the impact of pneumonia in patients with COPD. We will evaluate the epidemiology and factors associated with pneumonia. We are discussing the clinical characteristics of COPD that may favour the development of infections conditions such as pneumonia. Over the last 10 years, there is an increased evidence that COPD patients treated with inhaled corticosteroids are at increased risk to develop pneumonia. We will review the available information as well as the possible mechanisms for these events. We will also discuss the impact of influenza and pneumococcal vaccination in the prevention of pneumonia in COPD patients.

Keywords: COPD. Inhaled corticosteroids. Pneumonia. Pneumonia vaccine.

Systematic Reviews on Pharmacological Treatment of Asthma and Chronic Obstructive Pulmonary Disease
Gustavo J. Rodrigo

Abstract

Systematic Reviews on Pharmacological Treatment of Asthma and Chronic Obstructive Pulmonary Disease

Gustavo J. Rodrigo, Departamento de Emergencia, Hospital Central de las Fuerzas Armadas, Montevideo, Uruguay

Typically, therapeutic decisions are made on the basis of different relevant pivotal clinical studies. However, these studies often vary in different ways, which can lead to different answers to the same question. Because it is difficult for readers to capture and evaluate all the primary studies, review articles are an important source of summarized evidence on a particular topic. Systematic reviews (SRs) condense the results of available carefully designed healthcare studies and provide a high level of evidence on the effectiveness of healthcare interventions. Thus, the aim of this article is to provide the most updated information on pharmacological treatment of the two most prevalent chronic obstructive airway diseases, bronchial asthma and chronic obstructive pulmonary disease (COPD), from fourteen SRs of randomized controlled trials (RCTs). This review analyses the strengths and weaknesses of each SR in order to evaluate its clinical applicability.

Keywords: Asthma. Chronic obstructive pulmonary disease. Meta-analysis. Systematic review.

Therapeutic Role of Tiotropium in Chronic Obstructive Airways Diseases
David M.G. Halpin

Abstract

Therapeutic Role of Tiotropium in Chronic Obstructive Airways Diseases

David M.G. Halpin, Department of Respiratory Medicine, Royal Devon and Exeter Hospital, Exeter, United Kingdom

Chronic obstructive airways disease (COPD) and asthma are major causes of morbidity around the world. This review examines the evidence on the effectiveness of tiotropium as a treatment for COPD and asthma. It discusses the role of acetylcholine in airway physiology and the effects of muscarinic antagonism on airways smooth muscle, mucous secretion and inflammation. In COPD, tiotropium increases forced expiratory volume in 1 second (FEV1) and reduces hyperinflation; it improves breathlessness, exercise capacity and health status, and it reduces exacerbation rates. Tiotropium also reduces the rate of decline in FEV1 over 4 years in patients with an FEV1 over 50% predicted. In asthma, when added to inhaled steroids alone or in combination with long-acting beta agonists, tiotropium improves lung function, improves asthma control and reduces exacerbations. These effects have been seen in children, adolescents and adults with asthma. Tiotropium is well tolerated, with a low incidence of adverse events.

Keywords: Asthma. Bronchodilator. Chronic obstructive pulmonary disease. Tiotropium.

BRN Reviews. 11/ 2018

VOLUME 11 – NUMBER 1 / January – March. 2018

Editor’s Note

Women, Small Airways, Lung Function, Imaging and Biologics, Related to Chronic Respiratory Problems …and Good News for 2018
Robert Rodríguez-Roisin

Review Articles

Women and Chronic Obstructive Pulmonary Disease
Christine Jenkins

Abstract

Women and Chronic Obstructive Pulmonary Disease

Christine JenkinsConcord Hospital Sydney, The George Institute for Global Health Sydney, Faculty of Medicine, UNSW, University of Sydney, Sydney, Australia

Around the world, chronic obstructive pulmonary disease (COPD) is affecting women more than ever before. Increased smoking rates amongst women in the last 60 years, and the continued domestic and occupational exposure of women in low-income countries to biomass fuels and smoke have greatly increased the incidence of COPD in women. COPD presents differently in men and women, and women experience a higher symptom burden, rate of exacerbations and greater risk hospitalization. Additionally, women appear to be more vulnerable to the effects of smoking and develop airways disease at lower doses than men. Despite this, women are often under-represented in clinical trials, very few analyses address sex-specific differences in response to treatment, and management is rarely tailored to the specific needs of women with COPD. This article discusses the evidence and some of the potential approaches to address the burden of COPD in women.

Keywords: COPD. Sex. Burden of disease. COPD symptoms.

Small Airways Disease and Asthma Management: Is there a Connection?
Federico Bellini, Luca Morandi, Alberto Papi

Abstract

Small Airways Disease and Asthma Management: Is there a Connection?

Federico Bellini, Research Centre on Asthma and COPD, Department of Medical Sciences, University of Ferrara, Ferrara, Italy

Luca Morandi, Research Centre on Asthma and COPD, Department of Medical Sciences, University of Ferrara, Ferrara, Italy

Alberto Papi, Research Centre on Asthma and COPD, Department of Medical Sciences, University of Ferrara, Ferrara, Italy

We reviewed literature on the assessment and prevalence of small airways impairment in asthma and the relationships between small airways disease (SAD) and asthma clinical characteristics. The effects of treatments targeting small airways alterations are also discussed. We performed a PubMed search, using “asthma AND small airways” and “small airways AND treatment”. All identified works were reviewed for adequacy, including reviews, randomised clinical trials and real-life studies. We found evidence that SAD is highly prevalent in the asthma population, throughout all degrees of severity. SAD seems particularly pronounced in some specific phenotypes and in severe asthma. Further studies are needed to investigate the mechanisms of the association between SAD and clinical outcomes such as symptom control and exacerbation risk. The inhaled treatment with recently developed small particle size formulations warrants a greater drug deposition in the more peripheral district and positively affects clinical outcomes while reducing the overall drug exposure.

Keywords: Asthma. Extra fine particles. Phenotypes. Small airways.

Biologics for Chronic Obstructive Pulmonary Disease: Present and Future
Dave Singh, Ubaldo Martin

Abstract

Biologics for Chronic Obstructive Pulmonary Disease: Present and Future

Dave Singh, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK

Ubaldo Martin, AstraZeneca, Gaithersburg, MD, USA

An unmet need exists for effective treatments for patients with chronic obstructive pulmonary disease (COPD) who continue to experience exacerbations despite receiving standard-of-care treatments. Current advances for COPD are based on an evolving understanding of the molecular mechanisms of increased airway inflammation in stable-state COPD and during acute exacerbations. This review examines the current understanding of the underlying pathophysiology of COPD, discusses clinical trials of novel biologic treatments for COPD, and provides an overview of potential new targets for development of innovative therapies and biomarkers that may be used to identify appropriate patients for these novel treatments. The most promising biologic treatments at an advanced stage of development for COPD are agents targeting eosinophilia, either indirectly through anti–interleukin-5 (IL-5) or directly though anti–IL-5Rα (IL-5 receptor alpha) mechanisms. Targeting proteins involved in response to viral infection, such as IL-33, offers further potential for future advances in the development of biologics for COPD.

Keywords:Biologic therapy. Biomarkers. Chronic obstructive pulmonary disease. Inflammation.

Can the Lung be Obese? The Effects of Bariatric Surgery on Lung Function and Imaging

Abstract

Can the Lung be Obese? The Effects of Bariatric Surgery on Lung Function and Imaging

Eva Ribas, Servei d’Anestesiologia, Hospital Clínic, and Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Fundació Clínic per a la Recerca Biomédica (FCRB), Barcelona, Spain; Outcomes Research Department, Cleveland Clinic Foundation. Cleveland, OH, US

José G. Venegas, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, US

Robert Rodríguez-Roisin, Professor of Medicine, Universitat de Barcelona, IDIBAPS-CIBERES, Barcelona, Spain

Obesity is a state of low-grade chronic systemic inflammation that induces a reduction of adiponectin production with inhibition of the vasorelaxant properties of perivascular adipose tissue with underlying widespread endothelial dysfunction. This review concentrates on the main pulmonary and non-pulmonary determinants of gas exchange abnormalities, characterized by mild-to-moderate increased alveolar-arterial O2 difference, with or without mild hypoxaemia, in non-smoking morbidly obese subjects without associated relevant co-morbidities, candidates to bariatric surgery, induced by ventilation-perfusion imbalance and increased intrapulmonary shunt, including the effects of 100% oxygen breathing and those induced by postural changes. Likewise, we review lung imaging abnormalities, more specifically lung tissue volume, and their interaction with gas exchange disturbances. Finally, we address the long-term beneficial effects of bariatric surgery on all these obesity-induced lung function and imaging defects. Overall, we present a compelling evidence of lung function and imaging abnormalities underlying systemic and pulmonary inflammation in morbidly obese candidates to bariatric surgery.

Keywords:Bariatric surgery. Lung imaging. Morbid obesity. Postural changes. Pulmonary gas exchange

BRN Reviews. 10/ 2017

VOLUME 10 – NUMBER 4 / October-December 2017

Editor’s Note

More about chronic obstructive airway and pulmonary vascular disorders
Robert Rodríguez-Roisin

Review Articles

Small Airways Disease in Chronic Obstructive Pulmonary Disease: A 50 Years History
James C. Hogg, Tillie-Louise Hackett

Abstract

Small Airways Disease in Chronic Obstructive Pulmonary Disease: A 50 Years History

James C. Hogg, Centre for Heart Lung Innovation, St Pauls Hospital, University of British Columbia (UBC) and Department of Pathology and Laboratory Medicine, UBC, Vancouver, Canada
Gillie-Louise Hackett, Centre for Heart Lung Innovation, St Paul´s Hospital, University of British Columbia (UBC) and Department of Anesthesiology, Pharmacology and Therapeutics, UBC, Vancouver, Canada

Macklem and Mead provided the first direct evidence that the small conducting airways < 2 mm in diameter accounted for less than 10% of the total lower airway resistance in 1967. This seminal report was followed by Hogg, Macklem, and Thurlbeck’s 1968 report that confirmed and extended these observations by showing that the same small airways that offer so little resistance to airflow in normal human lungs become the major site of obstruction in patients with emphysema. These and other observations led Mead to postulate that these small conducting airways represent a “quiet” zone within the normal lung where disease can accumulate over many years without being noticed. This brief review revisits this hypothesis within the context of work reported in the 50 years since Macklem and Mead published their work. With special emphasis on why these small conducting airways are vulnerable to the development of disease. Keywords: Chronic obstructive pulmonary disease. Host response. Particulate matter. Small airways disease. Tertiary lymphoid organ formation.

The Impact of Emphysema on Chronic Obstructive Pulmonary Diseases
Juan Pablo de Torres, Ciro Casanova

Abstract

The Impact of Emphysema on Chronic Obstructive Pulmonary Diseases

Juan Pablo de Torres, Pulmonary Department, Clínica Universidad de Navarra, Pamplona, Spain

Ciro Casanova, Pulmonary Department, Hospital Universitario Ntra. Sra. de Candelaria, Tenerife, Spain

Emphysema is defined as an abnormal and permanent enlargement of the air spaces distal to the terminal bronchioles that is accompanied by destruction of the air space walls, with no obvious fibrosis (i.e. there is no fibrosis visible to the naked eye) and it is usually associated to tobacco smoking.
Although it is included in the pathological definition of chronic obstructive pulmonary disease (COPD), not all COPD patients have emphysema and its impact on the clinical presentation and the natural history of the disease is variable.
The present review will cover the prevalence of emphysema in COPD patients, its impact on the clinical presentation, association with comorbidities and the main outcomes of the disease: exacerbations, lung function decline and mortality. In this review, we will only evaluate the relationship of tobacco-related emphysema with COPD.

Keywords: COPD. Emphysema

Chronic Respiratory Abnormalities in the Multi-Morbid Frail Elderly
Bianca Beghé, Enrico Clini, Leonardo M. Fabbri

Abstract

Chronic Respiratory Abnormalities in the Multi-Morbid Frail Elderly

Bianca BeghéDepartment of Medical and Surgical Sciences, Section of Respiratory Diseases, University of Modena and Reggio Emilia, Modena, Italy
Enrico CliniDepartment of Medical and Surgical Sciences, Section of Respiratory Diseases, University of Modena and Reggio Emilia, Modena, Italy              Leonardo M. FabbriSahlgrenska University Hospital, Gothenburg, Sweden and Department of Medical Sciences, University of Ferrara, Ferrara, Italy

Two-thirds of people aged ≥65 years have multi-morbidity. Multi-morbidity includes both physical and mental health conditions, as anxiety and depression, that almost invariably affect patients with multiple symptomatic chronic diseases.

Management of a patient with any of the chronic diseases that are part of multi-morbidity is not just the management of that single index disease, but must include the active search and proper treatment of concomitant chronic diseases. The presence of concomitant chronic diseases should not alter the management of the index disease (e.g., chronic obstructive pulmonary disease [COPD]), and concomitant chronic diseases should be treated according to single diseases guidelines regardless of the presence of the index disease, obviously with careful consideration that this choice implies complex management, polypharmacy and potential adverse effects. Preliminary management programs suggest that a holistic integrated approach might improve quality of life and reduce hospital admissions and death in these multimorbid patients.

Keywords: Chronic bronchitis. Cigarette smoking. Emphysema. Frailty. Inactivity.

Lung Cancer Management: where are we in 2017?
Giorgio Scagliotti, Paolo Bironzo, Antoni Rosell

Abstract

Lung Cancer Management: where are we in 2017?

Giorgio ScagliottiDepartment of Clinical and Biological Sciences, S. Luigi Gonzaga Hospital, University of Torino, Orbassano, Torino, Italy
Paolo BironzoDepartment of Clinical and Biological Sciences, S. Luigi Gonzaga Hospital, University of Torino, Orbassano, Torino, Italy
Antoni RosellRespiratory Medicine Department, Hospital Universitar i de Bellvitge, Universitat de Barcelona, CIBERES, IDIBELL, Barcelona, Spain

Lung cancer remains the most common cancer and most common cause of death from cancer worldwide. Continuous advancements are taking place in this field. The year 2016 has brought many progresses; especially relevant are the new TNM Classification of Malignant Tumours (TNM) classification and the growing number of genomically-defined subpopulations in the road to developing personalized therapies. The state of the art in the management of lung cancer in 2016 is presented here.

Keywords: Bronchoscopy targeted chemotherapy. Immunotherapy. Lung cancer. Situation, Background, Assessment, Recommendation (SBAR). Screening thoracic surgery.

Chronic Obstructive Pulmonary Disease: Lessons from the Important Treatment Trials
Peter M. Calverley, Paul P. Walker

Abstract

Chronic Obstructive Pulmonary Disease: Lessons from the Important Treatment Trials

Peter M. CalverleyUniversity of Liverpool, and University Hospital Aintree, Liverpool, United Kingdom
Paul P. WalkerUniversity of Liverpool, and University Hospital Aintree, Liverpool, United Kingdom

Since 1999, clinical trials have more precisely defined the impact of various treatments on important patient-centred outcomes, allowing the development of treatment guidelines and leading to personalised treatment. The use of larger populations, seen in the Toward a Revolution in COPD Health (TORCH), Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) and The Study to Understand Mortality and Morbidity (SUMMIT) trials, has allowed hypotheses to be answered clearly albeit not always positively. Notwithstanding, each study has provided important information, often through secondary outcomes, which have been prospectively tested in other trials. Nearly two decades on, we are clearer as to the role of lung volume reduction procedures, who should and shouldn’t be prescribed inhaled steroids and long-acting bronchodilators and in what combinations, and who may benefit from roflumilast. Unexpected findings such as pneumonia risk from inhaled steroids and use of eosinophil count to direct their use have an important clinical impact now and in the future.

Keywords: Chronic obstructive pulmonary disease. Clinical trial. Therapeutics. Statistics.

Non Invasive Ventilation in Acute Hypercapnic Respiratory Failure
Mark W. Elliott

Abstract

Non Invasive Ventilation in Acute Hypercapnic Respiratory Failure

Mark W. Elliott, Department of Respiratory Medicine, Sleep and Non-invasive Ventilation Service, St James s University Hospital, Leeds, United Kingdom

This article reviews the use of non invasive ventilation (NIV) in the management of acute hypercapnic respiratory failure (AHRF). Most of the evidence and experience comes from treating acute exacerbations of chronic obstructive pulmonary disease (AECOPD) but this has been extrapolated to other conditions. Patient selection, contraindications, how to monitor and recognise when NIV is failing and what the options are then, are discussed. There are differences in criteria for initiation of NIV and the way that it is applied in patients with neuromuscular disease, chest wall disorders and obesity. The importance of staff experience and training as well as the need for regular audit are stressed. Finally, there is some horizon scanning about what may be next in the management of AHRF.

Keywords: COPD. Hypercapnia. Neuromuscular disorders. Non invasive ventilation. Obesity. Respiratory failure.

BRN Reviews. 09/ 2017

VOLUME 9 – NUMBER 3 / July – September

Editor’s Note

More about chronic obstructive airway and pulmonary vascular disorders
Robert Rodríguez-Roisin

Review Articles

Global Initiative for Chronic Obstructive Lung Disease (GOLD) Revisions 2001-2017: Historical and Critical Perspective
Claus Vogelmeier, Gerard J. Criner, Fernando J. Martinez

Abstract

Global Initiative for Chronic Obstructive Lung Disease (GOLD) Revisions 2001-2017: Historical and Critical Perspective

Claus Vogelmeier Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Centre Giessen and Marburg, Philipps-Universität Marburg, Member of the German Centre for Lung Research (DZL), Marburg, Germany
Gerard J. Criner Temple Lung Center, Temple University School of Medicine, Philadelphia, USA
Fernando J. Martinez Division of Pulmonary and Critical Care Medicine, and Department of Genetic Medicine, Weill Cornell Medicine, New York, NY, USA

In 2001, the first Global Initiative for Chronic Obstructive Lung Disease (GOLD) document was published with the goal to improve the diagnosis, prevention and treatment of chronic obstructive pulmonary disease (COPD). Since then, three major revisions (GOLD 2007, 2011 and 2017) have been released. In this review, we describe the basic principles of the first document and how it has evolved over time. Initially, assessment was based exclusively on the level of airflow limitation. Nowadays, airflow limitation, respiratory symptom load and exacerbation history are taken into account. Bronchodilators have always been first-line. However, the indication for inhaled corticosteroids (ICS) has evolved over time. Non-pharmacological therapies are now considered to be of equal importance. In the latest version, interventional methods, palliative care, and end-of-life strategies have been added. The prevention and adequate treatment of exacerbations are highlighted and an expanded discussion of comorbidities has been added.

Keywords: Assessment. Chronic obstructive pulmonary disease (COPD). Definition. Prevention. Treatment.

The Debate About the Use of Long-Acting Inhaled ß-agonists in Asthma
Paul M. O’Byrne

Abstract

The Debate About the Use of Long-Acting Inhaled ß-agonists in Asthma

Paul M. O’ByrneFirestone Institute for Respiratory Health, St. Joseph´s Healthcare and the Department of Medicine, Michael G DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada

Long-acting inhaled β2-agonists (LABAs) have been available for the treatment of asthma for almost 30 years; there is, however, concern about their safety with regular use. There is widespread agreement that LABA should not be used as monotherapy by asthmatic patients, because, while they are very effective in providing symptom relief, they have no inherent anti-inflammatory properties, and may increase the risk of asthma mortality. When used together with inhaled corticosteroids (ICS), ideally in the same inhaler, ICS/ LABA combinations have been shown to improve asthma control and reduce risk of asthma exacerbations. Concerns about the risks of severe asthma related events, such as hospitalization, intubation or death, associated with the use of ICS/LABA combinations have been allayed by the results of several recent large randomized safety trials conducted both in adults and children.

Keywords: Asthma. Efficacy. Long-acting inhaled β2-agonists. Mortality. Safety. Treatment..

Bronchiectasis in Chronic Obstructive Airway Disease: More than a Comorbidity?
Miguel Ángel Martínez-García, María José Selma Ferrer, Enrique Zaldívar Olmeda

Abstract

Bronchiectasis in Chronic Obstructive Airway Disease: More than a Comorbidity?

Miguel Ángel Martínez-GarcíaPneumology Department, Hospital Universitario y Politécnico la Fe, Valencia, Spain
María José Selma FerrerPneumology Department, Hospital Universitario y Politécnico la Fe, Valencia, Spain
Enrique Zaldívar OlmedaPneumology Department, Hospital Universitario y Politécnico la Fe, Valencia, Spain

Beyond the bronchial dilatations associated with age, several studies have documented a higher prevalence of bronchiectasis in patients with severe asthma or chronic obstructive pulmonary disease (COPD). Perhaps COPD or asthmatic patients with bronchiectasis represent a clinical phenotype characterised by greater clinical and functional severity, a higher number of exacerbations and, in the case of COPD, greater colonisation by potentially pathogenic microorganisms and probably a poor prognosis. Although international guidelines recommend that the two diseases are treated separately when they coexist, patients with COPD or asthma associated with bronchiectasis may benefit from specific treatments, such as long-term antibiotics, physiotherapy or macrolides. It is biologically plausible that severe asthma, and especially severe COPD, are related to de novo bronchiectasis, but no study has yet demonstrated any cause-effect relationship. Early diagnosis and treatment of bronchiectasis in COPD and asthma could be crucial to improve their prognosis. This relationship poses an interesting scientific challenge for the future.

Keywords: Alpha-1 antitrypsin deficiency. Asthma. Bronchiectasis. COPD. Emphysema.

Cigarette Smoke Exposure Alters Bacterial-Host Interactions in the Respiratory Tract to Promote Disease
Pamela Shen, Martin R. Stämpfli

Abstract

Cigarette Smoke Exposure Alters Bacterial-Host Interactions in the Respiratory Tract to Promote Disease

Pamela ShenMedical Sciences Graduate Program, McMaster University, Hamilton, Ontario, Canada and Department of Microbiology, New York University, New York, NY, USA
Martin R. StämpfliDepartment of Pathology and Molecular Medicine, McMaster Immunology Research Centre, and Department of Medicine, Firestone Institute for Respiratory Health at St. Joseph´s Healthcare, McMaster University, Hamilton, Ontario, Canada

Epidemiological studies clearly show an increased incidence of respiratory infections and community-acquired pneumonia (CAP) in smokers. Cigarette smoking is also a significant risk factor for invasive pneumococcal diseases (IPDs), leading to meningitis and sepsis. Moreover, the natural course of chronic obstructive pulmonary disease, a spectrum of lung disorders found predominantly in smokers, is punctuated by periods of disease exacerbation caused most frequently by microbial infections. Overall, these infectious episodes contribute to decreased quality of life and mortality, and place a large burden on healthcare systems. In this article, we review how cigarette smoke affects bacterial-host interactions in the upper and lower respiratory tract. We show that smoking affects multiple facets of bacterial-host interactions and postulate that these changes predispose to infection, as smokers fail to control colonizing bacteria in the upper respiratory tract (URT). Hence, we propose that targeting nasal bacterial colonization offers a novel therapeutic avenue to prevent subsequent disease pathogenesis.

Keywords: Bacterial colonization. Infection. Inflammation. Smoking. Upper respiratory tract (URT)..

The Liver-Lung Vascular Connection
Michael J. Krowka

Abstract

The Liver-Lung Vascular Connection

Michael J. KrowkaDivision of Pulmonary and Critical Care, Transplant Research Center, Mayo Clinic, Rochester MN, USA

Since the 1950’s and 1960’s it is well known that liver dysfunction can induce two distinct lung vascular disorders. We commonly refer to these disorders as hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH). This concise review is intended to update the clinician on the current understanding and management of HPS and POPH that has evolved over the last 10 years. Each disorder is discussed in 5 parts: 1) diagnostic criteria/screening/clinical presentation; 2) pathophysiology; 3) epidemiology/natural history; 4) medical management; and 5) implications for liver transplant (LT). A summary table is provided to compare these clinically significant pulmonary vascular disorders.

Keywords: Hepatopulmonary syndrome. Liver transplant (LT). Portopulmonary hypertension (POPH).

BRN Reviews. 08/ 2017

VOLUME 8 – NUMBER 2 / April – June

Editor’s Note

Chronic Respiratory Diseases, Lung Microbiome and Imaging Novelties
Robert Rodríguez-Roisin

Review Articles

Differential Features of COPD in China
Fuqiang Wen, Yongchun Shen

Abstract

Differential Features of COPD in China

Fuqiang Wen, Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University and Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, Chengdu, China
Yongchun Shen, Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University and Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China, Chengdu, China

Chronic obstructive pulmonary disease (COPD), characterized by persistent airflow limitation, is a public health problem worldwide. It is a major chronic disease in China, which has the largest population of elderly and smokers in the world, as well as the largest number of COPD patients. The occurrence of COPD is linked to multiple risk factors, including smoking, use of biomass fuel, and air pollution. COPD has a major negative effect on the quality of life, including limitations on the work ability. It increases mortality and leads to a significant use of health-care resources. Much progress has already been made in the prevention and treatment of COPD in China, but early diagnosis using spirometry should become more widespread, and general COPD knowledge among clinicians needs to be improved. This review summarizes the clinical characteristics of COPD in China, as well as current concepts for COPD diagnosis and treatment, and future actions to improve disease management in the country.

Keywords: Burden. China. Chronic obstructive pulmonary disease. Incidence. Mortality.

Idiopathic Pulmonary Fibrosis: What Is the Best Treatment?
Xiaoping Wu, Robert J. Kaner, Fernando J. Martinez

Abstract

Idiopathic Pulmonary Fibrosis: What Is the Best Treatment?

Xiaoping WuDivision of Pulmonary and Critical Care Medicine, Weill Cornell Medicine, New York, NY, USA
Robert J. KanerDivision of Pulmonary and Critical Care Medicine, and Department of Genetic Medicine, Weill Cornell Medicine, New York, NY, USA
Fernando J. MartinezDivision of Pulmonary and Critical Care Medicine, and Department of Genetic Medicine, Weill Cornell Medicine, New York, NY, USA

Idiopathic pulmonary fibrosis (IPF) is a disease of chronic progressive interstitial pneumonia limited to the lungs. There is growing interest in this disorder as its incidence has increased over time in most countries around the world. This is likely related to an aging population, increased awareness of the disease, and increasingly sensitive imaging technology. Considerable energy has been devoted to creating an improved understanding of its pathogenesis and developing novel therapies. Although dozens of drugs have been studied for the treatment of IPF, only two, pirfenidone and nintedanib, are currently recommended by international guidelines to slow the disease progression. We review the drugs that have been evaluated as IPF therapy over the past three decades, including the currently recommended pirfenidone and nintedanib, note ongoing clinical trials and provide insights into future directions.

Keywords: Combination therapy. Diopathic pulmonary fibrosis. Nintedanib. Pirfenidone. Precision medicine.

Microbiome in Chronic Lung Diseases
Manoj J. Mammen, Sanjay Sethi

Abstract

Microbiome in Chronic Lung Diseases

Manoj J. MammenDivision of Pulmonary, Critical Care, and Sleep Medicine and Department of Biomedical Informatics, Jacobs School of Medicine, University at Buffalo, State University of New York, NY, USA
Sanjay SethiDivision of Pulmonary, Critical Care, and Sleep Medicine, Jacobs School of Medicine, University at Buffalo, State University of New York, and Veterans Affairs Western New York Healthcare System, Buffalo, NY, USA

Newer genetic sequencing methods confirm the presence of a lung microbiome in healthy individuals. Microbiome imbalances can contribute to disease as they disrupt normal micro-environmental stimuli for the human host. Recent studies in chronic lung disease suggest that imbalances of the lung microbiome are associated with disease pathogenesis. The most common changes in the microbiome in chronic lung diseases are a decrease in diversity and the predominance by Proteobacteria. Additional changes in the lung microbiome have been described in various diseases when the clinical state changes from stable lung disease to respiratory exacerbation. Understanding the impact of the microbiome with robust and innovative tools on chronic lung disease pathogenesis, progression and exacerbation may ultimately lead to microbiome directed therapies.

Keywords: Asthma. Chronic obstructive pulmonary disease. Cystic fibrosis. Metagenome. Microbiota.

New Lung Imaging Findings in Chronic Respiratory Diseases
Samuel Y. Ash, George R. Washko

Abstract

New Lung Imaging Findings in Chronic Respiratory Diseases

Samuel Y. AshDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA
George R. WashkoDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

Rapid advances in image analysis technology have revealed new insights into chronic respiratory disease. In the approximately one hundred years since the first medical use of X-rays, visual, or qualitative, analysis of images acquired using traditional radiography as well as computed tomography and other modalities like magnetic resonance imaging have dramatically altered how we diagnose and care for patients with lung diseases. More recently, utilizing ever increasing computational power, the quantitative analysis of medical imaging, especially computed tomography, has further enhanced our understanding of chronic respiratory diseases. Herein we summarize some of the recent findings in the medical imaging of lung diseases, emphasizing quantitative analysis in particular.

Keywords: Computer assisted. Image processing. Lung diseases. Multidetector computed tomography.

Pulmonary Hypertension and the Heart: a Complex Interaction
Robert Naeije

Abstract

Pulmonary Hypertension and the Heart: a Complex Interaction

Robert NaeijeDepartment of Cardiology, Erasme University Hospital, ULB, Brussels, Belgium

Pulmonary hypertension primarily affects the heart by increasing right ventricular (RV) afterload. The initial response of the RV is an increased contractility soon followed by hypertrophy, with little or no increase in dimensions. When this “homeometric” adaptation fails, in case of rapid and/or severe increase in pulmonary artery pressure, the RV also uses a “heterometric” adaptation at the price of increased dimensions, higher filling pressures, systemic congestion and decreased exercise capacity. Dilatation of the RV impairs left ventricular (LV) filling. This diastolic interaction eventually alters systolic interaction, or contribution of LV contraction to the strength of RV contraction, which further deteriorates RV function. Too high or low lung volumes may increase pulmonary vascular resistance. Excessive decrease in pleural pressures be a cause of LV failure and worsening of pulmonary hypertension by upstream transmission of filling pressures. The complexity of heart-lung interactions in pulmonary hypertension needs understanding to optimize treatment strategies.

Keywords: Functional residual capacity. Heart-lung interactions. Pleural pressure. Pulmonary hypertension. Right ventricle. Ventricular interdependence.

BRN Reviews. 07 / 2017

VOLUME 7 – NUMBER 1 / January – March

Editor’s Note

What the First Issue of 2017 BRN Reviews Features…
Robert Rodríguez-Roisin

Review Articles

The PLATINO Study: Contributions to COPD Knowledge
Maria Montes de Oca, Maria Victorina Lopez-Varela

Abstract

The PLATINO Study: Contributions to COPD Knowledge

Maria Montes de Oca, Department of Pneumonology, Hospital Universitario de Caracas, Facultad de Medicina, Universidad Central de Venezuela, Caracas, Venezuela
Maria Victorina Lopez-Varela Faculty of Medicine, Universidad de la República, Hospital Maciel, Montevideo, Uruguay

The PLATINO study was a large survey in Latin America, originally aimed to describe the epidemiology of chronic obstructive pulmonary disease (COPD). A baseline, cross-sectional, population-based survey was conducted in five major cities: São Paulo (Brazil), Santiago (Chile), Mexico City (Mexico), Montevideo (Uruguay), and Caracas (Venezuela). A follow-up study was completed five to nine years later in three of five original centres. This review provides information from the Spanish acronym: Latin American Project for Research in Pulmonary Obstruction (PLATINO Study) on COPD epidemiology in the region (prevalence, accurate/inaccurate diagnosis, and treatment). Available data on disease risk factors, clinical patterns, follow-up prevalence, and diagnosis stability over time, as well as mortality, are also presented.

Keywords: Asthma-COPD Overlap Syndrome (ACOS). COPD. Epidemiology. PLATINO study.

Aging and Chronic Respiratory Diseases: Novel Mechanisms
Jacobo Sellares, Mauricio Rojas

Abstract

Aging and Chronic Respiratory Diseases: Novel Mechanisms

Jacobo SellaresDivision of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, and The Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, University of Pittsburgh Medical Center, Pittsburgh, PA, USA and Servei de Pneumologia, Hospital Clínic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain
Mauricio RojasDivision of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, and The Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

Aging is a progressive loss of physiological integrity leading to impaired function and increased vulnerability to death. Research into the mechanisms of aging could contribute to a better understanding of many chronic diseases. Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are chronic respiratory diseases associated with aging due to the fact that “accelerated” aging of the lung has been proposed as an important mechanism in both diseases. Many of the hallmarks that have been described in aging are also present in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Telomere attrition, loss of proteostasis, mitochondrial dysfunction, cellular senescence, and stem cell exhaustion are all mechanisms of aging present in both diseases. In this review we will examine the underlying mechanisms that link aging with idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease.

Keywords: Aging. Cellular senescence. COPD. IPF.

Concurrence of Chronic Obstructive Pulmonary Disease and Sleep Apnoea: The Other Overlap Syndrome
José M. Marin

Abstract

Aging and Chronic Respiratory Diseases: Novel Mechanisms

José M. MarinHospital Universitario Miguel Servet, IISAragón and CIBER Enfermedades Respiratorias, Zaragoza, Spain

Obstructive sleep apnoea and chronic obstructive pulmonary disease (COPD), each a prevalent and clinically important condition in adults, carry numerous common risk factors, including obesity and smoking. It is estimated that the coexistence of obstructive sleep apnoea and COPD, the COPD/obstructive sleep apnoea overlap syndrome, affects more than 1% of the general population. The presence of such overlap, when obstructive sleep apnoea is untreated, carries a risk of more adverse diurnal and nocturnal physiological and clinical outcomes, including greater sleep fragmentation, more severe nocturnal hypoxaemia, and increased overall mortality than is documented for COPD alone and obstructive sleep apnoea alone. Effective identification and treatment of the comorbid obstructive sleep apnoea and the other features of sleep-disordered breathing in the COPD/obstructive sleep apnoea overlap syndrome improve overall clinical outcomes in the condition.

Keywords: Chronic obstructive pulmonary disease. Obstructive sleep apnoea. Overlap syndrome.

Beneficial Effects of Continuous Positive Airway Pressure Treatment in Obstructive Sleep Apnoea: The Evidence
Maria R. Bonsignore, Oreste Marrone, Walter T. McNicholas

Abstract

Beneficial Effects of Continuous Positive Airway Pressure Treatment in Obstructive Sleep Apnoea: The Evidence

Maria R. BonsignoreBiomedical Department of Internal and Specialist Medicine DiBiMIS, University of Palermo, Palermo, Italy and Institute of Biomedicine and Molecular Immunology IBIM, National Research Council CNR, Palermo, Italy
Oreste Marrone Institute of Biomedicine and Molecular Immunology IBIM, National Research Council CNR, Palermo, Italy
Walter T. McNicholasDepartment of Respiratory and Sleep Medicine, St Vincents University Hospital, Dublin, Ireland

Several meta-analyses have been published on the effects of obstructive sleep apnoea treatment with continuous positive airway pressure. However, an updated, evidence-based summary on the effects of continuous positive airway pressure on outcomes should help clinicians and researchers to navigate through the existing literature, since a PubMed search using the keywords continuous positive airway pressure (CPAP), “obstructive sleep apnea” and “meta-analysis” retrieved over 100 papers (July 2016). The aim of this review is to provide updated evidence-based information on the effects of continuous positive airway pressure on mortality, cardio-metabolic outcomes, inflammatory markers, sleepiness, car accidents, cognitive dysfunction, and quality of life in obstructive sleep apnoea. Recent randomised controlled trials and longitudinal studies not yet included in meta-analyses will also be discussed. Overall, evidence exists for positive effects of continuous positive airway pressure treatment on mortality, systemic hypertension, daytime sleepiness and car accidents, and quality of life. Positive effects on cognitive dysfunction, cardiovascular outcomes, and metabolic and inflammatory variables are still uncertain and require further study.

Keywords: Chronic obstructive pulmonary disease. Obstructive sleep apnoea. Overlap syndrome.

Alterations in Nutritional Status and Body Composition in COPD Patients
Joaquim Gea, Cristina Estirado, Esther Barreiro

Abstract

Alterations in Nutritional Status and Body Composition in COPD Patients

Joaquim GeaRespiratory Medicine Department, Hospital del Mar IMIM, DCEXS, Universitat Pompeu Fabra, CIBERES, ISCIII, Barcelona, Spain
Cristina Estirado Respiratory Medicine Department, Hospital del Mar IMIM, DCEXS, Universitat Pompeu Fabra, CIBERES, ISCIII, Barcelona, Spain
Esther BarreiroRespiratory Medicine Department, Hospital del Mar IMIM, DCEXS, Universitat Pompeu Fabra, CIBERES, ISCIII, Barcelona, Spain

This review focuses on nutritional abnormalities, one of the most prominent extra pulmonary manifestations occurring in chronic obstructive pulmonary disease (COPD). Diagnosis is usually made by either anthropometry or determination of body composition. Deficiencies in nutritional status, such as body weight and muscle mass loss, are the result of an interaction of several factors, including the imbalance between energy supply and requirements, tobacco, low physical activity, and systemic inflammation. These factors essentially determine the predominance of protein breakdown over synthesis. The loss of body weight and lean mass leads to muscle dysfunction and exercise limitation, also having a negative impact on exacerbations and mortality. Therapies include changes in lifestyle and nutritional supplements. Anabolic drugs may be administered in some cases. Obesity is also very prevalent in COPD patients, being associated with cardiovascular and metabolic comorbidities. Although, paradoxically, moderate obesity appears to reduce mortality, healthy lifestyle habits are recommended to avoid morbid obesity.

Keywords: Diet. Exercise. Low body weight. Muscle dysfunction. Nutrition. Obesity. Protein.

BRN Reviews. 06 / 2016

VOLUME 6 – NUMBER 4 / October – December

Editor’s Note

Where BRN Reviews is One and a Half Years After its Launch…
Robert Rodríguez-Roisin

Abstract

Where BRN Reviews is One and a Half Years After its Launch…

Robert Rodríguez-Roisin, Professor of Medicine, Universitat de Barcelona, IDIBAPS-CIBERES, Barcelona, Spain

With this current issue, BRN Reviews has completed, as an independent academic publication, six issues of the Journal since its launch in July 2015. Over the past one and a half years, we have published a number of reviews written by world class experts and have developed an agenda for future production. We still are amazed by the willingness of our authors whose expertise in a number of respiratory medicine areas is acknowledged worldwide, so we are well poised to make further contributions to the ever-growing body of medical publications. Once again we want to underline our immense gratitude for their willingness to collaborate, including the efforts of the reviewers, who all have made possible this important achievement by BRN Reviews.

Review Articles

Long-Acting Inhaled Bronchodilators: The Mainstay of COPD Management
Peter J. Barnes

Abstract

Long-Acting Inhaled Bronchodilators: The Mainstay of COPD Management

Peter J. Barnes National Heart & Lung Institute, Imperial College, London, UK

Long-acting bronchodilators are the most effective treatments currently available for managing patients with COPD.
Long-acting muscarinic antagonists and β2-agonists are equally effective in producing bronchodilation, reducing symptoms, improving quality of life, and preventing exacerbations and are well tolerated. They probably work mainly by relaxing smooth muscle of peripheral airways to reduce gas trapping. Although both drug classes have non-bronchodilator effects that might be beneficial, this has not been clearly established in COPD patients. Remarkably, long-acting β2-agonists and long-acting muscarinic antagonists have additive bronchodilator effects, although this has not always translated into greater clinical benefit. Nevertheless, long-acting β2-agonist/long-acting muscarinic antagonist fixed-dose combinations are more effective than the single components and inhaled-corticosteroid/long-acting β2-agonist combinations. Although there is some rationale for triple therapy with long-acting β2-agonist/long-acting muscarinic antagonist/inhaled-corticosteroid, it remains to be shown that this would be more effective than long-acting β2-agonist/long-acting muscarinic antagonist combinations, although may be indicated for COPD patients with frequent exacerbations and with overlapping features with asthma, including increased blood eosinophils. It is unlikely that new classes of bronchodilators will be developed for COPD and what is needed is effective and safe anti-inflammatory treatments.

Keywords: Long-Acting Inhaled Bronchodilators, β2-agonists, COPD patients

Which Are The Most Relevant Comorbidities In COPD?
Miguel Divo, Carlos Cabrera

Abstract

Which Are The Most Relevant Comorbidities In COPD?

Miguel DivoPulmonary and Critical Care Division, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts, USA
Carlos CabreraPulmonary Department, Hospital Universitario de Gran Canaria Dr Negrin, Las Palmas de Gran Canarias, Spain

The world’s population is aging. A person who does not die of acute illnesses will likely develop more than one non-communicable disease, a phenomenon known as multimorbidity.
COPD is the third leading cause of death worldwide and is defined by airflow limitation, but its clinical manifestations are variable and influenced by comorbidities. Comorbidity burden can be measured by the number of coexisting diseases, by their prevalence, and by the impact on outcomes.
There are limitations when traditional epidemiology methods are applied to study the complex interactions amongst many diseases as the relevance of some diseases may mistakenly omitted. We present in this review the results from the most influential COPD comorbidity studies, highlighting those that have provided the most relevant information,
and then we present a novel perspective derived from network analysis, which helps interpret the complex interplay among comorbidities.

Keywords: Chronic obstructive pulmonary disease, multimorbidity, comorbidity studies

Practising Personalized Medicine in Asthma
Gareth Hynes, Rahul Shrimanker, Ian D. Pavord

Abstract

Practising Personalized Medicine in Asthma

Gareth HynesRespiratory Medicine Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
Rahul ShrimankerRespiratory Medicine Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK
Ian D. PavordRespiratory Medicine Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK

Asthma is a common and, in many cases, serious condition. After rapid improvement in outcomes following the introduction of the first guidelines in 1990, progress in this area has stalled. Current treatments follow a “one size fits all” approach without acknowledgement of the many different underlying disease mechanisms that drive the morbidity of asthma. Personalized medicine allows us to instead direct treatments at these specific causal mechanisms, targeting the exact pathology present in each patient. We believe that with this approach not only will we improve patient outcomes, we will also open the door to novel areas of research and drug discovery. In this article we describe where we are presently with the move towards personalized medicine in asthma, firstly explaining why we believe our current approach is insufficient, and secondly outlining in practical terms how physicians can adopt this novel approach when treating patients with asthma in clinics today.

Keywords: Asthma, morbidity of asthma, personalized medicine

Phenotyping Asthma and COPD
Peter Gibson, Vanessa M. McDonald

Abstract

Phenotyping Asthma and COPD

Peter GibsonNational Health and Medical Research Council Centre of Excellence in Severe Asthma, University of Newcastle; Priority Research Centre for Healthy Lungs, University of Newcastle; Hunter Medical Research Institute; Department of Respiratory and Sleep Medicine, John Hunter Hospital; Newcastle, Australia
Vanessa M. McDonaldNational Health and Medical Research Council Centre of Excellence in Severe Asthma, University of Newcastle; Priority Research Centre for Healthy Lungs, University of Newcastle; Hunter Medical Research Institute; Department of Respiratory and Sleep Medicine, John Hunter Hospital; Newcastle, Australia

Clinical management of asthma and COPD is complex, largely because of the marked heterogeneity observed in these conditions. Phenotyping is a new approach that can assist clinicians. This review seeks to describe an approach to clinical and inflammatory/molecular phenotyping of asthma and COPD. Clinical phenotypes can be considered in the key domain areas of comorbidity, airway, and risk factors. Evidence-based therapy can be linked to each of the components of these airway disease phenotypes. The concept can be extended to identify disease endotypes, where a pathogenic mechanism is linked to a specific treatment, and biomarkers are used to identify endotypes. Eosinophilic inflammation is perhaps the best characterized endotype of airway disease. Molecular endotypes are now also being identified using transcriptomic approaches. Phenotyping asthma and COPD represents a new and potentially effective approach to the management of these heterogeneous airway diseases.

Keywords:Clinical management of Asthma, phenotyping, comorbidity, pathogenic mechanism

Community-Acquired Pneumonia 2000-2015: What is New?
Catia Cilloniz, Antoni Torres

Abstract

Community-Acquired Pneumonia 2000-2015: What is New?

Catia CillonizDepartment of Pneumology, Institut Clinic del Tórax, Hospital Clinic of Barcelona, Institut de Investigacions Biomèdiques August Pi i Sunyer IDIBAPS, University of Barcelona, Ciber de Enfermedades Respiratorias (Ciberes), Barcelona, Spain
Antoni TorresDepartment of Pneumology, Institut Clinic del Tórax, Hospital Clinic of Barcelona, Institut de Investigacions Biomèdiques August Pi i Sunyer IDIBAPS, University of Barcelona, Ciber de Enfermedades Respiratorias (Ciberes), Barcelona, Spain

Despite the development of new diagnostic tests, new antimicrobial agents, and the implementation of international guidelines in recent decades, community-acquired pneumonia still has high morbidity and mortality worldwide and is associated with moderate health costs. Streptococcus pneumoniae is still the most frequent pathogen related to microbial aetiology of community-acquired pneumonia, although almost 50% of cases of pneumonia still have no microbiological diagnosis.
However, the development of molecular techniques such as real-time polymerase chain reaction in the past five years has revealed respiratory viruses to be major causative agents in community-acquired pneumonia. With the explosion of information from the many studies focusing on community-acquired pneumonia epidemiology, microbial aetiology and management in the last 15 years, the introduction of predictive tools, and advances in the pathophysiology of the disease, management of community-acquired pneumonia has also improved over this time due to
the implementation of international guidelines proposed by different scientific associations. This review focuses on the new data in the management of community-acquired pneumonia.

Keywords:community-acquired pneumonia, Streptococcus pneumonia, microbial aetiology

Exercise Testing in Chronic Respiratory Diseases: Basics and Clinical Implications
Dennis O’Donnell, Nicolle J. Domnik, J. Alberto Neder

Abstract

Exercise Testing in Chronic Respiratory Diseases: Basics and Clinical Implications

Dennis O’DonnellDivision of Respiratory Medicine, Department of Medicine, Queens University, Kingston, Ontario, Canada
Nicolle J. DomniklDivision of Respiratory Medicine, Department of Medicine, Queens University, Kingston, Ontario, Canada
J. Alberto NederDivision of Respiratory Medicine, Department of Medicine, Queens University, Kingston, Ontario, Canada

Dyspnoea and exercise intolerance are common symptoms experienced by patients with various chronic lung diseases. Cardiopulmonary exercise testing provides a unique opportunity to objectively evaluate the respiratory system’s ability to respond to the metabolic stress of exercise. Although widely underutilized, cardiopulmonary exercise testing can help to unravel the underlying mechanisms of exercise intolerance in a given individual. We propose a simple, ordered approach that measures symptom intensity, metabolic and ventilatory control parameters, and dynamic respiratory mechanics during a standardized incremental test to tolerance. The aim of this concise review is to examine exercise pathophysiology in chronic obstructive pulmonary disease and interstitial lung disease. We demonstrate striking similarities in the physiological responses to exercise across these pathologically distinct conditions and provide evidence to support common underlying mechanisms of exertional dyspnoea and reduced exercise capacity. Finally, we discuss the clinical implications of these new advances in exercise pathophysiology in the context of targeted therapeutic manipulation.

Keywords: Dyspnoea, Cardiopulmonary exercise, test to tolerance

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