Suha Kadura, Ganesh Raghu
doi : 10.1183/16000617.0011-2021
European Respiratory Review 30 (160) 210011
Rheumatoid arthritis (RA) is a systemic inflammatory disorder, with the most common extra-articular manifestation of RA being lung involvement. While essentially any of the lung compartments can be affected and manifest as interstitial lung disease (ILD), pleural effusion, cricoarytenoiditis, constrictive or follicular bronchiolitis, bronchiectasis, pulmonary vasculitis, and pulmonary hypertension, RA-ILD is a leading cause of death in patients with RA and is associated with significant morbidity and mortality. In this review, we focus on the common pulmonary manifestations of RA, RA-ILD and airway disease, and discuss evolving concepts in the pathogenesis of RA-associated pulmonary fibrosis, as well as therapeutic strategies, and have revised our previous review on the topic. A rational clinical approach for the diagnosis and management of RA-ILD, as well as an approach to patients with clinical worsening in the setting of treatment with disease-modifying agents, is included. Future directions for research and areas of unmet need in the realm of RA-associated lung disease are raised.
Marc Miravitlles, Ariadna Auladell-Rispau, M?nica Monteagudo, Juan Carlos V?zquez-Niebla, Jibril Mohammed, Alexa Nu?ez, Gerard Urr?tia
doi : 10.1183/16000617.0075-2021
European Respiratory Review 30 (160) 210075
Inhaled corticosteroids (ICSs) are indicated for the prevention of exacerbations in COPD; however, a significant proportion of patients at low risk of exacerbations are treated with ICSs. We conducted a systematic review including a diversity of types of study designs and safety outcomes with the objective of describing the risk of adverse effects associated with the long-term use of ICSs in patients with COPD.
Iain R. Konigsberg, Lisa A. Maier, Ivana V. Yang
doi : 10.1183/16000617.0076-2021
European Respiratory Review 30 (160) 210076
Epigenetic modifications are emerging as important regulatory mechanisms of gene expression in lung disease, given that they are influenced by environmental exposures and genetic variants, and that they regulate immune and fibrotic processes. In this review, we introduce these concepts with a focus on the study of DNA methylation and histone modifications and discuss how they have been applied to lung disease, and how they can be applied to sarcoidosis. This information has implications for other exposure and immunologically mediated lung diseases, such as chronic beryllium disease, hypersensitivity pneumonitis, and asbestosis.
Saskia Bos, Laurens J. De Sadeleer, Arno Vanstapel, Hanne Beeckmans, Annelore Sacreas, Jonas Yserbyt, Wim A. Wuyts, Robin Vos
doi : 10.1183/16000617.0050-2021
European Respiratory Review 30 (160) 210050
This review aims to provide an overview of pre-transplant antifibrotic therapy on peri-transplant outcomes and to address the possible role of antifibrotics in lung transplant recipients with chronic lung allograft dysfunction.
H. Burke, T.M.A. Wilkinson
doi : 10.1183/16000617.0041-2021
European Respiratory Review 30 (160) 210041
COPD is a major cause of morbidity and mortality worldwide. Multimorbidity is common in COPD patients and a key modifiable factor, which requires timely identification and targeted holistic management strategies to improve outcomes and reduce the burden of disease.
Dave Singh, James F. Donohue, Isabelle H. Boucot, Neil C. Barnes, Chris Compton, Fernando J. Martinez
doi : 10.1183/16000617.0023-2021
European Respiratory Review 30 (160) 210023
Most patients with COPD are recommended to initiate maintenance therapy with a single long-acting bronchodilator, such as a long-acting muscarinic antagonist or long-acting ?2-agonist. However, many patients receiving mono-bronchodilation continue to experience high symptom burden, suggesting that patients are frequently not receiving optimal treatment. Treatment goals for COPD are often broad and not individually tailored, making initial treatment response assessments difficult. A personalised approach to initial maintenance therapy, based upon an individual's symptom burden and exacerbation risk, may be more appropriate.
Elena Schnieders, Elyesa ?nal, Volker Winkler, Peter Dambach, Valérie R. Louis, Olaf Horstick, Florian Neuhann, Andreas Deckert
doi : 10.1183/16000617.0350-2020
European Respiratory Review 30 (160) 200350
Rationale Guidelines recommend pre-/post-bronchodilator spirometry for diagnosing COPD, but resource constraints limit the availability of spirometry in primary care in low- and middle-income countries. Although spirometry is the diagnostic gold standard, we shall assess alternative tools for settings without spirometry.
Irina Kontsevaya, Christoph Lange, Patricia Comella-del-Barrio, Cristian Coarfa, Andrew R. DiNardo, Stephen H. Gillespie, Matthias Hauptmann, Christoph Leschczyk, Anna M. Mandalakas, Antal Martinecz, Matthias Merker, Stefan Niemann, Maja Reimann, Olena Rzhepishevska, Ulrich E. Schaible, Katrin M. Scheu, Erwin Schurr, Pia Abel zur Wiesch, Jan Heyckendorf
doi : 10.1183/16000617.0377-2020
European Respiratory Review 30 (160) 200377
Standardised management of tuberculosis may soon be replaced by individualised, precision medicine-guided therapies informed with knowledge provided by the field of systems biology. Systems biology is a rapidly expanding field of computational and mathematical analysis and modelling of complex biological systems that can provide insights into mechanisms underlying tuberculosis, identify novel biomarkers, and help to optimise prevention, diagnosis and treatment of disease. These advances are critically important in the context of the evolving epidemic of drug-resistant tuberculosis. Here, we review the available evidence on the role of systems biology approaches – human and mycobacterial genomics and transcriptomics, proteomics, lipidomics/metabolomics,
E. Haydn Walters, Shakti D. Shukla, Malik Q. Mahmood, Chris Ward
doi : 10.1183/16000617.0364-2020
European Respiratory Review 30 (160) 200364
Our starting point is that relatively new findings into the pathogenesis and pathophysiology of airway disease in smokers that lead to chronic obstructive pulmonary disease (COPD) need to be reassessed as a whole and integrated into “mainstream” thinking along with traditional concepts which have stood the test of time. Such a refining of the accepted disease paradigm is urgently needed as thinking on therapeutic targets is currently under active reconsideration. We feel that generalised airway wall “inflammation” is unduly over-emphasised, and highlight the patchy and variable nature of the pathology (with the core being airway remodelling). In addition, we present evidence for airway wall disease in smokers/COPD as including a hypocellular, hypovascular, destructive, fibrotic pathology, with a likely spectrum of epithelial–mesenchymal transition states as significant drivers of this remodelling. Furthermore, we present data from a number of research modalities and integrate this with the aetiology of lung cancer, the role of chronic airway luminal colonisation/infection by a specific group of “respiratory” bacteria in smokers (which results in luminal inflammation) and the central role for oxidative stress on the epithelium. We suggest translation of these insights into more focus on asymptomatic smokers and early COPD, with the potential for fresh preventive and therapeutic approaches.
Christina S. Thornton, Madeline Mellett, Julie Jarand, Leila Barss, Stephen K. Field, Dina A. Fisher
doi : 10.1183/16000617.0299-2020
European Respiratory Review 30 (160) 200299
Nontuberculous mycobacteria (NTM) are diverse microbial species encompassing commensals and pathogens with the ability to cause pulmonary disease in both immunocompetent and immunocompromised individuals. In contrast to Mycobacterium tuberculosis, which has seen a reduction in disease rates in developed countries, the incidence and prevalence of NTM disease is increasing. NTM are difficult to treat with standard antimicrobial regimens and may contain both virulence and antibiotic-resistance genes with potential for pathogenicity. With the advent of molecular techniques, it has been elucidated that these organisms do not reside in isolation and are rather part of a complex milieu of microorganisms within the host lung microbiome. Over the last decade, studies have highlighted the impact of the microbiome on host immunity, metabolism and cell–cell communication. This recognition of a broader community raises the possibility that the microbiome may disrupt the balance between infection and disease. Additionally, NTM disease progression and antimicrobial therapy may affect the healthy steady state of the host and function of the microbiome, contributing to further dysbiosis and clinical deterioration. There have been limited studies assessing how NTM may influence the relationship between microbiome and host. In this review, we highlight available studies about NTM and the microbiome, postulate on virulence mechanisms by which these microorganisms communicate and discuss implications for treatment.
Meena Kalluri, Fabrizio Luppi, Ada Vancheri, Carlo Vancheri, Elisabetta Balestro, Francesco Varone, Nesrin Mogulkoc, Giulia Cacopardo, Elena Bargagli, Elisabetta Renzoni, Sebastiano Torrisi, Mariarosaria Calvello, Alessandro Libra, Mauro Pavone, Francesco Bonella, Vincent Cottin, Claudia Valenzuela, Marlies Wijsenbeek, Elisabeth Bendstrup
doi : 10.1183/16000617.0026-2021
European Respiratory Review 30 (160) 210026
Patient-reported outcome measures (PROMs), tools to assess patient self-report of health status, are now increasingly used in research, care and policymaking. While there are two well-developed disease-specific PROMs for interstitial lung diseases (ILD) and idiopathic pulmonary fibrosis (IPF), many unmet and urgent needs remain. In December 2019, 64 international ILD experts convened in Erice, Italy to deliberate on many topics, including PROMs in ILD. This review summarises the history of PROMs in ILD, shortcomings of the existing tools, challenges of development, validation and implementation of their use in clinical trials, and the discussion held during the meeting. Development of disease-specific PROMs for ILD including IPF with robust methodology and validation in concordance with guidance from regulatory authorities have increased user confidence in PROMs. Minimal clinically important difference for bidirectional changes may need to be developed. Cross-cultural validation and linguistic adaptations are necessary in addition to robust psychometric properties for effective PROM use in multinational clinical trials. PROM burden of use should be reduced through appropriate use of digital technologies and computerised adaptive testing. Active patient engagement in all stages from development, testing, choosing and implementation of PROMs can help improve probability of success and further growth.
Xiaoman Zhang, Shengming Wang, Huajun Xu, Hongliang Yi, Jian Guan, Shankai Yin
doi : 10.1183/16000617.0220-2020
European Respiratory Review 30 (160) 200220
Introduction Obstructive sleep apnoea (OSA) is a common sleep disorder with a high social and economic burden. Thus, early prediction and diagnosis of OSA are important. Changes in metabolism and the microbiome may serve as biomarkers for OSA. Herein, we review the literature on the metabolomic and microbiome changes associated with OSA, and identify the metabolites and microorganisms involved.
Charlie McLeod, Jamie Wood, Allison Tong, André Schultz, Richard Norman, Sherie Smith, Christopher C. Blyth, Steve Webb, Alan R. Smyth, Thomas L. Snelling
doi : 10.1183/16000617.0354-2020
European Respiratory Review 30 (160) 200354
There is no consensus on how best to measure responses to interventions among children and adults with cystic fibrosis (CF). We have systematically reviewed and summarised the characteristics and measurement properties of tests and tools that have been used to capture outcomes in studies among people with CF, including their reliability, validity and responsiveness. This review is intended to guide researchers when selecting tests or tools for measuring treatment effects in CF trials. A consensus set of these tests and tools could improve consistency in how outcomes are captured and thereby facilitate comparisons and synthesis of evidence across studies.
Fares Darawshy, Ayman Abu Rmeileh, Rottem Kuint, Neville Berkman
doi : 10.1183/16000617.0374-2020
European Respiratory Review 30 (160) 200374
Waterpipe smoking is an old form of tobacco smoking, originating in Persia and the Middle East. The popularity of the waterpipe is increasing worldwide, particularly among young adults, and there are widespread misconceptions regarding its negative health effects. The inhaled smoke of the waterpipe contain several toxic and hazardous materials including nicotine, tar, polyaromatic hydrocarbons and heavy metals, all of which are proven to be related to lung diseases and cancer. Regular waterpipe smoking is associated with respiratory symptoms, a decrease in pulmonary function and increased risk for lung disease such as COPD. Additional negative health effects include increased risk for arterial stiffness, ischaemic heart disease and several cancer types including lung cancer. This review summarises the negative health effects of waterpipe smoking, with emphasis on cardiorespiratory complications. Increased awareness and knowledge amongst healthcare professionals will hopefully help identify waterpipe smokers and promote patient education. Applying World Health Organization (WHO) regulations will provide a synergistic effect in reducing waterpipe use and associated disease.
François Touchon, Youssef Trigui, Eloi Prud'homme, Laurent Lefebvre, Alais Giraud, Anne-Marie Dols, Stéphanie Martinez, Marie Bernardi, Camille Begne, Pascal Granier, Pascal Chanez, Jean-Marie Forel, Laurent Papazian, Xavier Elharrar
doi : 10.1183/16000617.0022-2021
European Respiratory Review 30 (160) 210022
Prone positioning reduces mortality in the management of intubated patients with moderate-to-severe acute respiratory distress syndrome. It allows improvement in oxygenation by improving ventilation/perfusion ratio mismatching.
Rodrigo Torres-Castro, Elena Gimeno-Santos, Jordi Vilar?, Marta Roqué-Figuls, Jorge Moisés, Luis Vasconcello-Castillo, Tanya Orizaga, Joan Albert Barberà, Isabel Blanco
doi : 10.1183/16000617.0321-2020
European Respiratory Review 30 (160) 200321
Background Pulmonary hypertension (PH) is a frequent complication in patients with COPD.Objective To determine if, in patients with COPD, the presence of PH decreases exercise tolerance.Methods We included studies that analysed exercise tolerance using a cardiopulmonary exercise test (CPET) in patients with COPD with PH (COPD-PH) and without PH (COPD-nonPH). Two independent reviewers analysed the studies, extracted the data and assessed the quality of the evidence.
Simon Malenfant, Marius Lebret, ?milie Breton-Gagnon, François Potus, Roxane Paulin, Sébastien Bonnet, Steeve Provencher
doi : 10.1183/16000617.0284-2020
European Respiratory Review 30 (160) 200284
Exercise intolerance is a cardinal symptom of pulmonary arterial hypertension (PAH) and strongly impacts patients' quality of life (QoL). Although central cardiopulmonary impairments limit peak oxygen consumption (V?O2peak) in patients with PAH, several peripheral abnormalities have been described over the recent decade as key determinants in exercise intolerance, including impaired skeletal muscle (SKM) morphology, convective O2 transport, capillarity and metabolism indicating that peripheral abnormalities play a greater role in limiting exercise capacity than previously thought. More recently, cerebrovascular alterations potentially contributing to exercise intolerance in patients with PAH were also documented. Currently, only cardiopulmonary rehabilitation has been shown to efficiently improve the peripheral components of exercise intolerance in patients with PAH. However, more extensive studies are needed to identify targeted interventions that would ultimately improve patients' exercise tolerance and QoL. The present review offers a broad and comprehensive analysis of the present literature about the complex mechanisms and their interactions limiting exercise in patients and suggests several gaps in knowledge that need to be addressed in the future for a better understanding of exercise intolerance in patients with PAH.
Zjala Ebadi, Yvonne M.J. Goërtz, Maarten Van Herck, Daisy J.A. Janssen, Martijn A. Spruit, Chris Burtin, Melissa S.Y. Thong, Jean Muris, Jacqueline Otker, Milou Looijmans, Christel Vlasblom, Joëlle Bastiaansen, Judith Prins, Emiel F.M Wouters, Jan H. Vercoulen, Jeannette B. Peters
doi : 10.1183/16000617.0298-2020
European Respiratory Review 30 (160) 200298
Background Fatigue is a distressing symptom in patients with COPD. Little is known about the factors that contribute to fatigue in COPD. This review summarises existing knowledge on the prevalence of fatigue, factors related to fatigue and the instruments most commonly used to assess fatigue in COPD.
Matthew Watson, Maria Florina Ionescu, Karl Sylvester, Jonathan Fuld
doi : 10.1183/16000617.0182-2020
European Respiratory Review 30 (160) 200182
Dysfunctional breathing refers to a multi-dimensional condition that is characterised by pathological changes in an individual's breathing. These changes lead to a feeling of breathlessness and include alterations in the biomechanical, psychological and physiological aspects of breathing. This makes dysfunctional breathing a hard condition to diagnose, given the diversity of aspects that contribute to the feeling of breathlessness. The disorder can debilitate individuals without any health problems, but may also be present in those with underlying cardiopulmonary co-morbidities. The ventilatory equivalent for CO2 (VeqCO2) is a physiological parameter that can be measured using cardiopulmonary exercise testing. This review will explore how this single measurement can be used to aid the diagnosis of dysfunctional breathing. A background discussion about dysfunctional breathing will allow readers to comprehend its multidimensional aspects. This will then allow readers to understand how VeqCO2 can be used in the wider diagnosis of dysfunctional breathing. Whilst VeqCO2 cannot be used as a singular parameter in the diagnosis of dysfunctional breathing, this review supports its use within a broader algorithm to detect physiological abnormalities in patients with dysfunctional breathing. This will allow for more individuals to be accurately diagnosed and appropriately managed.
Susan A. Ward
doi : 10.1183/16000617.0160-2020
European Respiratory Review 30 (160) 200160
“Ventilatory efficiency” is widely used in cardiopulmonary exercise testing to make inferences regarding the normality (or otherwise) of the arterial CO2 tension (PaCO2) and physiological dead-space fraction of the breath (VD/VT) responses to rapid-incremental (or ramp) exercise. It is quantified as: 1) the slope of the linear region of the relationship between ventilation (V?E) and pulmonary CO2 output (V?CO2); and/or 2) the ventilatory equivalent for CO2 at the lactate threshold (V?E/V?CO2Embedded Image) or its minimum value (V?E/V?CO2min), which occurs soon after Embedded Image but before respiratory compensation. Although these indices are normally numerically similar, they are not equally robust. That is, high values for V?E/V?CO2Embedded Image and V?E/V?CO2min provide a rigorous index of an elevated VD/VT when PaCO2 is known (or can be assumed) to be regulated. In contrast, a high V?E–V?CO2 slope on its own does not, as account has also to be taken of the associated normally positive and small V?E intercept. Interpretation is complicated by factors such as: the extent to which PaCO2 is actually regulated during rapid-incremental exercise (as is the case for steady-state moderate exercise); and whether V?E/V?CO2Embedded Image or V?E/V?CO2min provide accurate reflections of the true asymptotic value of V?E/V?CO2, to which the V?E–V?CO2 slope approximates at very high work rates.
Sebastian F.N. Bode, Jan Rohr, Joachim Müller Quernheim, Maximilan Seidl, Carsten Speckmann, Andrea Heinzmann
doi : 10.1183/16000617.0152-2020
European Respiratory Review 30 (160) 200152
Granulomatous inflammation of the lung can be a manifestation of different conditions and can be caused by endogenous inflammation or external triggers. A multitude of different genetic mutations can either predispose patients to infections with granuloma-forming pathogens or cause autoinflammatory disorders, both leading to the phenotype of pulmonary granulomatosis. Based on a detailed patient history, physical examination and a diagnostic approach including laboratory workup, pulmonary function tests (PFTs), computed tomography (CT) scans, bronchoscopy with bronchoalveolar lavage (BAL), lung biopsies and specialised microbiological and immunological diagnostics, a correct diagnosis of an underlying cause of pulmonary granulomatosis of genetic origin can be made and appropriate therapy can be initiated. Depending on the underlying disorder, treatment approaches can include antimicrobial therapy, immunosuppression and even haematopoietic stem cell transplantation (HSCT). Patients with immunodeficiencies and autoinflammatory conditions are at the highest risk of developing pulmonary granulomatosis of genetic origin. Here we provide a review on these disorders and discuss pathogenesis, clinical presentation, diagnostic approach and treatment.
Raphaël Borie, Bruno Crestani, Alice Guyard, Olivier Lidove
doi : 10.1183/16000617.0363-2020
European Respiratory Review 30 (160) 200363
Lysosomes are intracellular organelles that are responsible for degrading and recycling macromolecules. Lysosomal storage diseases (LSDs) are a group of inherited diseases caused by mutations affecting genes that encode the function of the lysosomal enzymes. Three LSDs are associated with lung involvement and/or interstitial lung disease (ILD): Gaucher disease (GD); Niemann–Pick disease, also known as acid sphingomyelinase deficiency (ASMD); and Fabry disease (FD). In GD and in ASMD, analysis of bronchoalveolar lavage fluid and lung biopsy can be informative, showing foamy cells. In GD, ILD is rare. Enzyme replacement therapy (ERT) has been available since 1991 and has greatly changed the natural history of GD, with pulmonary failure and death reported before the ERT era. In ASMD, ILD is frequent and is usually associated with spleen enlargement, low platelet cell count and low level of high-density lipoprotein-cholesterol. Results of ERT are promising regarding preliminary results of olipudase alfa in paediatric and adult ASMD populations. The most frequent respiratory manifestation in FD is COPD-like symptoms regardless of smoking habit and dyspnoea due to congestive heart failure. Early diagnosis of these three LSDs is crucial to prevent irreversible organ damage. Early initiation of ERT can, at least in part, prevent organ failure.
Tobias Finazzi, Famke L. Schneiders, Suresh Senan
doi : 10.1183/16000617.0224-2020
European Respiratory Review 30 (160) 200224
Radiation therapy is a cornerstone of modern lung cancer treatment alongside surgery, chemotherapy, immunotherapy and targeted therapies. Advances in radiotherapy techniques have enhanced the accuracy of radiation delivery, which has contributed to the evolution of radiation therapy into a guideline-recommended treatment in both early-stage and locally advanced nonsmall cell lung cancer. Furthermore, although radiotherapy has long been used for palliation of disease in advanced lung cancer, it is increasingly having a role as a locally ablative treatment in patients with oligometastatic disease.
Rudolf M. Huber, Diego Kauffmann-Guerrero, Hans Hoffmann, Michael Flentje
doi : 10.1183/16000617.0227-2020
European Respiratory Review 30 (160) 200227
Locally advanced nonsmall cell lung cancer, due to its varying prognosis, is grouped according to TNM stage IIIA, IIIB and IIIC. Developments over the last 3?years have been focused on the integration of immunotherapy into the combination treatment of a locally definitive therapy (surgery or radiotherapy) and chemotherapy. For concurrent chemoradiotherapy, consolidation therapy with durvalumab was established. Adjuvant targeted therapy has again gained increasing interest. In order to adapt treatment to the specific stage subgroup and its prognosis, fluorodeoxyglucose positron emission tomography/computed tomography and pathological evaluation of the mediastinum are important. Tumours should be investigated for immunological features and driver mutations. Regarding toxicity, evaluation of pulmonary and cardiac function, as well as symptoms and quality of life, is of increasing importance. To improve the management and prognosis of this heterogeneous entity, clinical trials and registries should take these factors into account.
Hans J. Lee, Lorenzo Corbetta
doi : 10.1183/16000617.0025-2020
European Respiratory Review 30 (160) 200025
As the breadth of interventional pulmonology continues to expand, training in this discipline gains further importance. Interventional pulmonology training in the USA and Europe has common roots and similar concepts; however, there are variations in its delivery. We discuss the similarities, differences, challenges and goals of interventional pulmonology training in both continents. Collaboration and exchange of experiences between the USA and Europe are fundamental to entering the new era of competency/mastery training to implement a multidimensional approach to procedure-related education.
Alex Dipper, Hayley E. Jones, Rahul Bhatnagar, Nancy J. Preston, Nick Maskell, Amelia Clive
doi : 10.1183/16000617.0025-2021
European Respiratory Review 30 (160) 210025
doi : 10.1183/16000617.6039-2021
European Respiratory Review 30 (160) 216039
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