Occupational and Environmental Lung Disease 9781849841245, 9781849841252

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Occupational and Environmental Lung Disease Pantone PASTEL 9081 CMJN Cyan 0 Magenta 0 Yellow 6 Black 8

Edited by Johanna Feary, Hille Suojalehto and Paul Cullinan

Occupational and Environmental Lung Disease Edited by Johanna Feary, Hille Suojalehto and Paul Cullinan Editor in Chief John R. Hurst

This book is one in a series of ERS Monographs. Each individual issue provides a comprehensive overview of one specific clinical area of respiratory health, communicating information about the most advanced techniques and systems required for its investigation. It provides factual and useful scientific detail, drawing on specific case studies and looking into the diagnosis and management of individual patients. Previously published titles in this series are listed at the back of this Monograph. ERS Monographs are available online at books.ersjournals.com and print copies are available from www.ersbookshop.com

Editorial Board: Mohammed AlAhmari (Dammam, Saudi Arabia), Sinthia Bosnic-Anticevich (Sydney, Australia), Sonye Danoff (Baltimore, MD, USA), Randeep Guleria (New Delhi, India), Bruce Kirenga (Kampala, Uganda), Silke Meiners (Munich, Germany) and Sheila Ramjug (Manchester, UK). Managing Editor: Rachel Gozzard European Respiratory Society, 442 Glossop Road, Sheffield, S10 2PX, UK Tel: 44 114 2672860 | E-mail: [email protected] Production and editing: Caroline Ashford-Bentley, Matt Broadhead, Claire Marchant, Kay Sharpe and Ben Watson Published by European Respiratory Society ©2020 November 2020 Print ISBN: 978-1-84984-124-5 Online ISBN: 978-1-84984-125-2 Print ISSN: 2312-508X Online ISSN: 2312-5098 Typesetting by Nova Techset Private Limited All material is copyright to ­European Respiratory Society. It may not be reproduced in any way including electronic means ­without the express permission of the company. Statements in the volume reflect the views of the authors, and not necessarily those of the European Respiratory Society, editors or publishers.

ERS monograph

Contents Occupational and Environmental Lung Disease

Number 89 November 2020

Preface

vi

Guest Editors

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Introduction List of abbreviations

ix xii

1. The global perspective of occupational lung disease 1 Mohamed F. Jeebhay 2. Exposure assessment

19

3. Sensitiser-induced occupational asthma Olivier Vandenplas and Catherine Lemière

34

4. Work-exacerbated asthma Gareth I. Walters

52

5. Acute inhalation injury

70

6. The impact on the aetiology of COPD, bronchitis and bronchiolitis

86

7. Occupational hypersensitivity pneumonitis Christopher Michael Barber and Hayley Barnes

104

8. Asbestosis Kirsten Bennett and Fraser J.H. Brims

125







Ioannis Basinas, Hakan Tinnerberg and Martie van Tongeren

Sherwood Burge

Vivi Schlünssen, Else Toft Würtz, Martin Rune Hassan Hansen, Martin Miller, Torben Sigsgaard and Øyvind Omland

9. Non-malignant pleural disease from asbestos and malignant 141 pleural mesothelioma Arthur William Musk and Jennie Hui 10. Silicosis and other silica-related lung disorders Deborah Helwen Yates and Anthony Rutledge Johnson

150

11. Coal mine dust lung disease Leonard H.T. Go and Robert A. Cohen

176

12. Pneumoconiosis and interstitial lung diseases caused by inorganic dust Jennifer Louise Hoyle

190

13. Cotton, other bioaerosols, inhalation fevers and occupational organising pneumonia

211

14. Granulomatous and allied disorders Joanna Szram

227

15. Interstitial lung disease in welders Martin Paul Cosgrove

238

16. Lung cancer and occupation

252

17. Diving Mark Glover

266

18. Working at high altitude

283

19. Outdoor environment

301

20. Indoor environment Dennis Nowak, Stefan Rakete and Hille Suojalehto

317









David Fishwick

Pierluigi Cocco

Christopher J. Hebert and Andrew M. Luks Elaine Fuertes and Michael Brauer

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Preface John R. Hurst

Given that we spend perhaps 20% of our waking hours across a 75-year life span at work, it is hardly surprising that our work environment can affect our health, including our respiratory health. As respiratory professionals, we are used to taking a careful occupational history but, perhaps, when that suggests an environmental or occupational factor causing or exacerbating respiratory disease, we feel less comfortable and seek extra help and advice. In this context, it is a pleasure to introduce this much-requested latest ERS Monograph, which addresses the clinical science and practice that underpins environmental and occupational respiratory medicine. The Guest Editors Johanna Feary, Hille Suojalehto and Paul Cullinan are giants in the field, and have commissioned and edited a fascinating, informative, comprehensive and state-of-the-art collection across the spectrum of environmental and occupational respiratory diseases. My sincere thanks and appreciation to them, on behalf of the European Respiratory Society, for producing this work, which I have no doubt will be of interest and value to our members and more widely. I also share their hope that the enthusiasm for their subject that shines throughout this work will encourage and support early career clinicians and researchers to consider and pursue a career in this fascinating area. Wherever you work, in whichever branch of respiratory medicine and science, there is a topic here that will be of interest and importance to you. But don’t just take my word for it, read on … Disclosures: J.R. Hurst reports receiving grants, personal fees and non-financial support from pharmaceutical companies that make medicines to treat respiratory disease. This includes reimbursement for educational activities and advisory work, and support to attend meetings.

Copyright ©ERS 2020. Print ISBN: 978-1-84984-124-5. Online ISBN: 978-1-84984-125-2. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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Guest Editors Johanna Feary Johanna Feary is a relative newcomer to occupational lung disease, having arrived in her current position at the Royal Brompton Hospital (London, UK) in 2014 following a series of happy twists. She is a consultant in respiratory medicine and holds an academic position at Imperial College London (London, UK), a combination of roles that allows her to carry out clinical work as well as research and teaching. She enjoys unpicking the close interplay between an individual’s health, their work and the environment, and has a particular interest in occupational asthma and other airways diseases and in the aetiology of hypersensitivity pneumonitis. She was previously a member of the British Thoracic Society Specialist Advisory Group on Occupational and Environmental Medicine and is an active member of GORDS UK (Group of Occupational Respiratory Disease Specialists). Hille Suojalehto Hille Suojalehto has worked with occupational respiratory diseases for 15 years, and is currently Chief Respiratory Physician at the Finnish Institute of Occupational Health (Helsinki, Finland) and Associate Professor at the University of Helsinki (Helsinki, Finland). In clinical practice, she examines patients with suspected occupational respiratory diseases. Her research interests include occupational asthma, the mechanisms of allergic airway diseases and indoor air-related symptoms. In 2015, she co-chaired a European Respiratory Society (ERS) task force on specific inhalation challenge testing in the diagnosis of occupational asthma. Hille is currently a member of the European Academy of Allergy and Clinical Immunology’s (EAACI) Environmental and Occupational Allergy Interest Group and of the EAACI exam committee. She is also a member of the Finnish National Indoor Air and Health Programme expert panel, which aims to improve the treatment of those experiencing indoor air-related symptoms. Copyright ©ERS 2020. Print ISBN: 978-1-84984-124-5. Online ISBN: 978-1-84984-125-2. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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Paul Cullinan Paul Cullinan cannot clearly remember how he became interested in occupational lung diseases but after almost 30 years in the field, he has no regrets. He is a consultant physician at the Royal Brompton Hospital (London, UK) – in some senses, the birthplace of the specialty in the UK – and holds a chair at Imperial College London (London, UK). These posts combine clinical practice with research and teaching. Formerly a member of the Industrial Injuries Advisory Committee – and chair of its research working group – he is now a member of the Health and Safety Executive (HSE) Workplace Health Expert Committee and of the Independent Medical Expert Group, which advises on matters of compensation for members of the UK Armed Forces. In 2015, he co-chaired, with Hille Suojalehto, a European Respiratory Society (ERS) task force on specific inhalation challenge testing in the diagnosis of occupational asthma.

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Introduction Johanna Feary1,2, Hille Suojalehto3 and Paul Cullinan1,2 @ERSpublications The ERS Monograph on Occupational and Environmental Lung Disease includes chapters on global view, many old and some newer diseases, as well as diving, high altitude and outdoor and indoor air. Useful for general respiratory physicians and experts alike. https://bit.ly/3n0d3RK

Respiratory clinicians lucky enough to work in the field of occupational lung disease(s) enjoy an endlessly fascinating specialty. Rarely a week goes by without them encountering either an entirely new condition or a familiar one in a new setting, a reflection largely of seemingly ceaseless developments in industry and in employment patterns. This Monograph will, we hope, not only educate but also enthuse other clinicians to take an increasing interest in the subject. It has been designed for use by the general respiratory physician sitting in a clinic but will also be of sufficient interest to be picked up and read as a standalone text. We are of the firm belief that occupation can be relevant and should at least be considered in most subspecialties of respiratory medicine, and that all respiratory physicians should be aware of the spectrum of diseases caused by exposures encountered at work. Often neglected in training programmes, we are passionate about increasing the profile of occupational lung diseases. The specialty has its own complexities. Most clinical practice involves just two sets of actors, the patient and their health carers. In occupational disease, the cast is broader and includes, potentially, not only the patient in front of you but also their colleagues – occupational respiratory diseases rarely occur in isolation – their employers, other employers in the same sector, regulators, compensators and (regrettably) lawyers. Juggling the often disparate needs of these players is frequently difficult but never dull. It is also why one should never make an occupational diagnosis without firm evidence. While we endlessly exhort clinicians always to consider occupational issues, at the same time we remind them that false-positive diagnoses can have disastrous and widespread consequences. This is especially true for occupational diseases of short latency, such as asthma, infections and many instances of hypersensitivity pneumonitis that arise soon after a new workplace exposure and while a patient is still in employment. Moreover, a failure to identify a current occupational aetiology will make it difficult – if not impossible – to both manage a patient’s condition successfully and to prevent other cases arising. 1 Occupational and Environmental Medicine, National Heart and Lung Institute, Imperial College London, London, UK. 2Dept of Occupational Lung Disease, Royal Brompton Hospital, London, UK. 3Finnish Institute of Occupational Health, Helsinki, Finland.

Correspondence: Johanna Feary, Occupational and Environmental Medicine, Emmanuel Kaye Building, National Heart and Lung Institute, Imperial College London, 1b Manresa Road, London, SW3 6LR, UK. E-mail: [email protected] Copyright ©ERS 2020. Print ISBN: 978-1-84984-124-5. Online ISBN: 978-1-84984-125-2. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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Occupations and respiratory disease intersect in three ways. First, and most familiar, are those instances where a workplace exposure has given rise, de novo, to a condition that would not otherwise have occurred; a truly “occupational” disease. Second, exposures or other circumstances encountered at work may worsen a pre-existing condition – a common example is work-exacerbated asthma, covered in chapter 4 [1]. Third, a pre-existing disease may render a patient relatively or completely unfit to carry out their job. This last, more properly the domain of the occupational health specialist, is brought into sharp relief by an ageing workforce but is a matter also in some specialist areas such as commercial diving (covered in chapter 17 [2]) and work at altitude (chapter 18 [3]). The Monograph opens with a global perspective, a reminder that in a rapidly industrialising world the hazards of work are not only increasing but are too often unregulated and are responsible for literally countless cases of crippling disease (chapter 1) [4]. We then include a chapter that provides an overview on exposure assessment in the workplace (chapter 2) [5]. The chapters that follow cover the full spectrum of occupational respiratory diseases, including: those that are specific to work (such as silicosis in chapter 10 [6], coal worker’s pneumoconiosis in chapter 11 [7] and mesothelioma in chapter 9 [8]); those that can arise from work but are clinically indistinguishable from cases occurring otherwise (COPD in chapter 6 [9], lung cancer in chapter 16 [10] and, arguably, asbestosis in chapter 8 [11]); and those where a workplace aetiology can be determined on a case-by-case basis (occupational asthma in chapter 3 [12]). Finally, we include two chapters on “environmental” exposures. The first, concerned with “outdoor exposures”, includes the often ignored but surely important topic of environmental allergens (chapter 19) [13]. The second weaves a skilful path through the minefield of misconceptions that characterise the issue of “indoor” domestic exposures (chapter 20) [14]. Throughout, we have asked authors to cover the most recent advances in their subject. They have risen to the task with great skill and provided us with a stark reminder that this is a field that never stands still. Few, if any, predicted, for example, that two of the oldest occupational lung diseases would have shown a resurgence in what we had believed to be well-regulated societies. Chapter 10 covers the very recent epidemics of aggressive silicosis among stonemasons and kitchen fitters in countries such as Australia, Spain, Italy and Israel, attributable to the invention of “engineered” stone, a lethal material that could hardly be bettered as a vector for the disease [6]. The depressing return of progressive massive fibrosis in US coalminers, arising from the dysregulation of small mines in the Appalachians, is ably described in chapter 11 [7]. Unpredicted these may have been but unpredictable they were not. After all, we know enough about most occupational lung diseases to prevent them (almost) entirely but, collectively, we lack the will. We recognise that this Monograph has been written primarily from the perspective of a high-income country; that is not to ignore the tremendous importance of occupational and environmental diseases in low- and middle-income countries, but much of the content here is generalisable to all settings. This Monograph was written, reviewed and edited during the height of the first wave of the COVID-19 pandemic. Most of its authors and reviewers were at the forefront of the clinical response and we are especially grateful for their grace and tireless effort in what we know were exhausting times. We thank, too, John R. Hurst (Editor in Chief ), Rachel Gozzard (ERS Monograph Managing Editor) and Caroline Ashford-Bentley (ERS Editorial and

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Library Services Coordinator) who have, throughout, provided wise and patient counsel and support. We very much hope you find this Monograph both a useful resource and an enjoyable read.

References 1. 2. 3. 4.

5.

6.

7. 8.

9.

10. 11. 12.

13. 14.

Walters GI. Work-exacerbated asthma. In: Feary J, Suojalehto H, Cullinan P, eds. Occupational and Environmental Lung Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 52–69. Glover M. Diving. In: Feary J, Suojalehto H, Cullinan P, eds. Occupational and Environmental Lung Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 266–282. Hebert CJ, Luks AM. Working at high altitude. In: Feary J, Suojalehto H, Cullinan P, eds. Occupational and Environmental Lung Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 283–300. Jeebhay MF. The global perspective of occupational lung disease. In: Feary J, Suojalehto H, Cullinan P, eds. Occupational and Environmental Lung Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 1–18. Basinas I, Tinnerberg H, van Tongeren M. Exposure assessment. In: Feary J, Suojalehto H, Cullinan P, eds. Occupational and Environmental Lung Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 19–33. Yates DH, Johnson AR. Silicosis and other silica-related lung disorders. In: Feary J, Suojalehto H, Cullinan P, eds. Occupational and Environmental Lung Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 150–175. Go LHT, Cohen RA. Coal mine dust lung disease. In: Feary J, Suojalehto H, Cullinan P, eds. Occupational and Environmental Lung Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 176–189. Musk AW, Hui J. Non-malignant pleural disease from asbestos and malignant pleural mesothelioma. In: Feary J, Suojalehto H, Cullinan P, eds. Occupational and Environmental Lung Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 141–149. Schlünssen V, Würtz ET, Hansen MRH, et al. The impact on the aetiology of COPD, bronchitis and bronchiolitis. In: Feary J, Suojalehto H, Cullinan P, eds. Occupational and Environmental Lung Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 86–103. Cocco P. Lung cancer and occupation. In: Feary J, Suojalehto H, Cullinan P, eds. Occupational and Environmental Lung Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 252–265. Bennett K, Brims FJH. Asbestosis. In: Feary J, Suojalehto H, Cullinan P, eds. Occupational and Environmental Lung Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 125–140. Vandenplas O, Lemière C. Sensitiser-induced occupational asthma. In: Feary J, Suojalehto H, Cullinan P, eds. Occupational and Environmental Lung Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 34–51. Fuertes E, Brauer M. Outdoor environment. In: Feary J, Suojalehto H, Cullinan P, eds. Occupational and Environmental Lung Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 301–316. Nowak D, Rakete S, Suojalehto H. Indoor environment. In: Feary J, Suojalehto H, Cullinan P, eds. Occupational and Environmental Lung Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 317–334.

Disclosures: None declared.

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List of abbreviations ARDS acute respiratory distress syndrome BAL bronchoalveolar lavage CO carbon monoxide CO2 carbon dioxide CT computed tomography DLCO diffusing capacity of the lung for carbon monoxide FENO exhaled nitric oxide fraction FEV1 forced expiratory volume in 1 s FVC forced vital capacity HRCT high-resolution computed tomography IPF idiopathic pulmonary fibrosis LEV local exhaust ventilation NO2 nitrogen dioxide NOX oxides of nitrogen O2 oxygen PaO2 arterial O2 tension PEF peak expiratory flow PET positron emission tomography PM particulate matter UIP usual interstitial pneumonia VOC volatile organic compound

| Chapter 1 The global perspective of occupational lung disease Mohamed F. Jeebhay Workplace exposures contribute substantially to the burden of chronic lung disease in adults. Occupational lung diseases contributing to the greatest disease burden, mortality and disability globally include COPD (caused by particulate dusts, vapours, fumes and second-hand tobacco smoke), lung cancer and mesothelioma (commonly due to asbestos), work-related asthma, pneumoconioses (silicosis, coal worker’s pneumoconiosis, asbestosis) and occupational infections (pulmonary tuberculosis in silica-exposed and healthcare workers, communityacquired pneumonia). Despite the decrease in per capita disease burden globally over the past two decades, this burden is not shared equitably across regions. It is influenced by rapid economic transition and population growth, unregulated economies, a burgeoning informal sector and inadequate exposure control, as well as poor access to the knowledge and resources to achieve good control of workplace respiratory hazards. Increased physician awareness, diligent disease investigation and regular reporting, as well as ongoing surveillance, will contribute to improved detection and management of occupational lung diseases. Cite as: Jeebhay MF. The global perspective of occupational lung disease. In: Feary J, Suojalehto H, Cullinan P, eds. Occupational and Environmental Lung Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 1–18 [https://doi.org/10.1183/2312508X.10034019].

@ERSpublications Occupational exposures cause >10% of lung diseases. COPD from workplace exposures is common. Most lung cancers are due to asbestos. Work-related asthma patterns are changing. Pneumoconioses persist due to poor dust control. https://bit.ly/3310jTg

T

his chapter will provide a global perspective of the epidemiology of occupational and environmental lung diseases in an ever-evolving landscape. The focus will be on global contemporary patterns and how the burden of occupational lung diseases (OLDs) is influenced by the world of work. Global changes in patterns of OLDs with respect to changes in industrial activity and technology, exposures to hazardous agents, formal versus informal work, and labour force participation by sex and age are traced in both high-income country (HIC) and low- and middle-income country (LMIC) regions. The specific occupational contributions towards chronic lung diseases in relation to Occupational Medicine Division and Centre for Environmental & Occupational Health Research, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa. Correspondence: Mohamed F. Jeebhay, Occupational Medicine Division and Centre for Environmental & Occupational Health Research, School of Public Health and Family Medicine, University of Cape Town, Room 4.45, Fourth Level, Falmouth Building, Anzio Road, Observatory 7925, Cape Town, South Africa. E-mail: [email protected] Copyright ©ERS 2020. Print ISBN: 978-1-84984-124-5. Online ISBN: 978-1-84984-125-2. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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ERS MONOGRAPH | OCCUPATIONAL AND ENVIRONMENTAL LUNG DISEASE

individual host risk factors are outlined, incorporating an integrated view of occupational and environmental exposures (known as the exposome), genetic disease susceptibility and behavioural risk factors [1]. Data sources included the Global Burden of Disease (GBD) study and community-based studies, ecological studies, workforce-based epidemiological studies and registry data from surveillance schemes for OLDs in different regional contexts [2].

The changing nature of the world at work The International Labour Organization estimates that 2.78 million of the world’s 2.7 billion workers die annually from occupational accidents or diseases [3]. One-third of these are attributable to OLDs [1]. The International Labour Organization estimates the economic burden of poor occupational health and safety practices to be 3.94% of global gross domestic product each year. The contribution of inhalational workplace hazards to the burden of chronic lung diseases is therefore substantial. The world of work is characterised by shifts in production and increasing globalisation, deregulation and informalisation of the economy in various regions [4, 5]. Many industries transfer their production to LMICs owing to cheap labour. It is estimated that 60% of the working population is in the informal sector; this is higher in Asia and Africa (70–80%) and lower in Europe (25%) [6]. There is an increasing trend towards multiple small-scale heterogeneous units as opposed to a few traditional large homogeneous manufacturing entities, especially in HICs. Sectoral transformation of manufacturing and mining has resulted in their concentration in LMICs. Contraction of the mining and foundry sector in Europe and Scandinavia and increased mechanisation and automation has resulted in a decline in the incidence of pneumoconiosis as a result of decreased mineral dust (coal, silica dust) exposures [4]. A concomitant rise in manufacturing (e.g. chemical, pharmaceutical and food processing) and service sectors has occurred, resulting in more widespread low-dose exposure to chemicals (e.g. cleaning agents) and food sensitisers (e.g. enzymes), increasing the risk of work-related asthma (WRA) [7]. Major demographic changes have also influenced labour participation rates. The increased participation of women, especially in LMICs, has resulted in hazardous exposures due to inadequate protection in jobs historically occupied by men [4]. Furthermore, employment of vulnerable immigrant workers in HICs has forced many to work under poor working conditions [8]. In some LMICs, child labour continues in jobs with high-risk exposures (e.g. mica mining, asbestos in ship-breaking, cotton farming), with adverse health effects on vulnerable children. An ageing workforce has resulted in a higher proportion of workers with multiple chronic comorbidities. Exclusion of workers with atopy and pre-existing respiratory disease has resulted in employers being less inclined to reduce exposures to respiratory sensitisers for all workers. All these changes have resulted in declining roles of government agencies globally to promulgate and enforce occupational health and safety laws requiring health-protective exposure standards and surveillance of workers in high-risk industries [5]. The resultant disease burden is increasingly shifting from the employer to the individual worker [4]. 2

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THE GLOBAL PERSPECTIVE | M.F. JEEBHAY

Globalisation has resulted in economic disparities between and within regions. While some diseases such as hypersensitivity pneumonitis in farmers and metal workers are declining [9, 10], other well-known previously “eradicated” OLDs have re-emerged or persisted. These include asbestos-related disease and mesothelioma due to asbestos building products, accelerated silicosis from sandblasting of denim jeans, coal worker’s pneumoconiosis (CWP) in surface coal miners and large-scale underground mines, COPD due to indoor air pollution from biomass fuels and heavy-metal exposure from electronic waste recycling. In addition, new technology has introduced potential health effects from carbon nanotubes, man-made fibres (rock wool, fibreglass), biotechnology (including genetic manipulation) and hydraulic fracturing (fracking) [1, 4, 11].

Global patterns and burden of OLDs Mortality, morbidity and disability

In 2017, 545 million people worldwide had a chronic lung disease, representing an increase of 39.8% from 1990 [12]. Chronic lung diseases were the third leading cause of death, especially in HIC regions for both sexes, but were lower in sub-Saharan Africa and South Asia (figure 1). The age- and sex-specific prevalences were variable for most adult chronic lung diseases except for COPD, which increased monotonically (figure 2). Disability was highest in South Asia, where premature mortality is the highest globally. Smoking remained the main risk factor for death and disability across all regions for men. For women, household air pollution from solid biomass fuels and ambient PM was important in Asia and Africa [11, 13, 14]. Overall, the GBD 2016 study revealed that 1.53 million deaths and 76.1 million disability-adjusted life-years (DALYs) were due to occupational factors, accounting for 2.8% of deaths and 3.2% of DALYs [15]. Most deaths were attributable to PM, gases and fumes (PMGF), carcinogens (particularly asbestos), injury risk factors and second-hand tobacco smoke (SHS). Common diseases such as COPD, asthma and pneumoconioses accounted for 34% of all deaths (table 1), followed by lung cancer and mesothelioma [16]. COPD due to PMGF and SHS was by far the largest category for deaths and DALYs, followed by WRA and pneumoconiosis. Carcinogens were responsible for high death numbers in all HICs (80% asbestos-related cancers) but only one LMIC region (Central Europe). The mortality rates and DALYs from OLDs were higher in men, but levels of disability were important in both sexes. The lower rates in women could be due to the distribution of work between the sexes, as women are less likely to be employed in very dusty industries [16]. Older workers (>55 years) were also commonly affected. The population-attributable fraction (PAF) related to occupational exposures from the GBD 2016 study was 17% for COPD and 10% for asthma (table 1) [16]. The recent American Thoracic Society (ATS)/European Respiratory Society (ERS) statement reported PAFs for asthma (16%), COPD (14%), chronic bronchitis (13%), IPF (26%) and community-acquired pneumonia (10%), which were similar to previous studies. For the first time, PAFs for pulmonary alveolar proteinosis (29%), hypersensitivity pneumonitis (19%), sarcoidosis (30%), silica-associated tuberculosis (2.3%) and healthcare worker-associated tuberculosis (1.0%) were reported [17]. https://doi.org/10.1183/2312508X.10034019

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Prevalent cases per 100 000 people (all ages) 5000–7000 7000–9000 3000–5000

ERS MONOGRAPH | OCCUPATIONAL AND ENVIRONMENTAL LUNG DISEASE

4

a)

b)

9000–11 000

11 000–13 000

13 000–15 000

15 000–17 000

Figure 1. All-age chronic respiratory disease prevalence by country in a) 1990 and b) 2017 for females (top) and males (bottom). Reproduced and modified from [12] with permission.

THE GLOBAL PERSPECTIVE | M.F. JEEBHAY

a) 50 000

b) 50 000

Asthma

30 000

20 000

10 000

0

Days

Years

40 000

30 000

20 000

10 000

0

0–6 7–27 28–364 1–4 5–9 10–14 15–19 20–24 25–29 30–34 35–39 40–44 45–49 50–54 55–59 60–64 65–69 70–74 75–79 80–84 85–89 90–94 ≥95

Interstitial lung disease and pulmonary sarcoidosis Pneumoconiosis

Prevalent cases per 100 000 people

40 000

0–6 7–27 28–364 1–4 5–9 10–14 15–19 20–24 25–29 30–34 35–39 40–44 45–49 50–54 55–59 60–64 65–69 70–74 75–79 80–84 85–89 90–94 ≥95

Prevalent cases per 100 000 people

COPD

Days

Years

Figure 2. Global age- and sex-specific prevalences of chronic respiratory diseases by disease category in 2017 for a) males and b) females. Reproduced and modified from [12] with permission.

Between 1990 and 2016, there was an overall decrease in the per capita burden in mortality rates (31%) and DALYs (25%), probably related to improved air quality and decreased smoking rates [15]. Unlike the situation for COPD-related exposures where the change in the PAF was relatively neglible, these rose considerably for asthma (29%) during this period (table 2). Overall, the burden of OLD is not shared equitably across regions and within countries. It is dependent on access to knowledge and resources, and on the ability to achieve control of workplace respiratory hazards. This is compounded by other factors in LMICs where poverty and unemployment are strong predictors of chronic lung disease at individual and community levels [18–20]. Pneumoconioses The occupational contribution to pneumoconioses is generally considered to be 100%. Globally, pneumoconiosis numbers increased by 66% from 1990 to 2017 (figure 3), although the overall age-standardised incidence rate decreased by 0.6%·year–1 [21]. While the age-standardised incidence rate for silicosis and CWP was reduced in low and middle sociodemographic index (SDI) regions, it increased for asbestosis in some high SDI countries.

In the GBD 2016 study, silicosis (48%) was the largest specific cause of death, followed by asbestosis (16%) and CWP (12%) [16]. Overall, Western Europe and South Asia had high death rates and DALYs. For asbestosis-related deaths, the highest rates (27%) were in Western Europe, while high DALY rates occurred in East Asia, Oceania and southern sub-Saharan Africa. The figures reported in the GBD 2016 study are likely to be an underestimate of the true OLD burden, especially in LMICs such as India and Russia, with poor disease recognition https://doi.org/10.1183/2312508X.10034019

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Table 1. Global occupation-attributable deaths, disability-adjusted life-years (DALYs) and population-attributable fraction (PAF) from chronic respiratory disease due to airborne exposures by risk factor and sex in 2016 Risk factor

Deaths Males Females n n

Asthmagens

26 103

11 471

PMGF+SHS §

343 122 116 958

Pneumoconiotic dusts Total

18 997

2491

388 222 130 920

PAF % #

DALYs Total (%) ¶

Males n

37 574 (7.2) 460 080 (88.6) 21 488 (4.1) 519 142 (100.0)

Females n

1 468 347 871 133 7 969 986 2 717 967 518 917

58 060

9 957 269 3 647 170

Total (%)+

Male Female Total

2 339 480 (17.2) 10 687 953 (78.6) 576 977 (4.2) 13 604 438 (100.0)

13.0

7.1

9.9

21.0

11.0

17.0

100

100

100

19.0

9.0

15.0

PMGF: PM, gases and fumes; SHS: second-hand tobacco smoke. #: PAF % is based on DALYs; ¶ : percentage of chronic respiratory disease deaths due to occupational risk factors that were due to this risk factor; +: percentage of chronic respiratory DALYs due to occupational risk factors that were due to this risk factor; §: PMGF and SHS causing COPD. Reproduced and modified from [16] with permission.

and reporting systems. Furthermore, they are also notably different from the figures reported in the World Health Organization (WHO) Mortality Database. This is likely to be due to coding misclassification, as most of the moderate proportion of pneumoconiosis deaths and DALYs (both 23%) that were coded in the GBD 2016 study as “Other pneumoconioses” were actually silicosis, asbestosis or CWP, because these three have always been considered to be the main pneumoconioses [16]. It is estimated that 11.5 million workers in India are exposed to silica dust [22]. In China, half a million cases of silicosis are associated with 24 000 deaths annually [23]. In South Africa, silicosis prevalence has remained unchanged (6%), and there has not been a decline in silica exposures [24, 25]. High excess mortality rates in ex-miners have been attributed to underground jobs in gold mines [26]. Although well-established preventative strategies and silica exposure limits (0.05– 0.10 mg·m−3) exist, new silicosis cases continue to be reported globally. Nonconventional exposure sources in slate pencil, agate mill, dental supplies, jewellery and semi-precious

Table 2. Change in global occupation-attributable deaths and disability-adjusted life-years (DALYs) from chronic respiratory disease due to occupational exposure to asthmagens and to PM, gases and fumes (PMGF) and second-hand tobacco smoke (SHS) between 1990 and 2016 Risk factor

Asthmagens PMGF+SHS

PAF (deaths) %

PAF (DALYs) %

1990

2016

% change

1990

2016

% change

7.4 16.3

8.9 15.7

20.3 −3.7

7.7 16.4

9.9 16.9

28.6 3.0

PAF: population-attributable fraction. Reproduced and modified from [16] with permission.

6

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b)

Global

20 000

20 000 15 000 10 000 5000 0

1990

2000

2010

Middle SDI

2000

10 000 5000

2010

1990

e)

Low–middle SDI

f)

15 000 10 000 5000

20 000 15 000 10 000 5000 0

0 2010

2000

2010

20 000 15 000 10 000 5000

1990

Year Silicosis

Low SDI

0 1990

Year

2010

25 000 Pneumoconiosis cases n

Pneumoconiosis cases n

20 000

2000 Year

25 000

2000

15 000

Year

25 000

1990

20 000

0 1990

Year d)

High–middle SDI 25 000

Pneumoconiosis cases n

40 000

0

Pneumoconiosis cases n

c)

High SDI 25 000

Pneumoconiosis cases n

Pneumoconiosis cases n

60 000

Asbestosis

2000

2010

Year CWP

OP

Figure 3. Pneumoconiosis cases from 1990 to 2017 with different aetiologies and analysed by region according to the sociodemographic index (SDI): a) global, b) high SDI, c) high-to-middle SDI, d) middle SDI, e) low-to-middle SDI, f ) low SDI. CWP: coal worker’s pneumoconiosis; OP: other pneumoconioses. Reproduced and modified from [21] with permission.

stone, and red rock sandstone workers also contribute [27, 28]. Engineered quartz conglomerates for kitchen countertops and sandblasted denim jeans have been responsible for silicosis outbreaks in young adults [29, 30]. CWP continues to be a major concern in rapidly industrialising countries and HICs with historically strict occupational health and safety standards (figure 4) [1, 4]. This has been attributed to excessive coal dust exposures in small mines and low-seam surface mining [11, 31]. Despite its well-known toxic effects, ∼125 million workers are exposed to asbestos globally. More than 50 countries have banned asbestos use, while others have only restricted its use, posing ongoing challenges to urban built environments and mining rehabilitation [32, 33]. Asbestos continues to be mined and used in rapidly developing countries (figure 5), causing adverse health impacts [1, 34, 35].

WRA WRA, comprising occupational asthma and work-exacerbated asthma, is currently the most commonly reported OLD in many HICs. In the recent ATS/ERS statement, the occupational PAF for incident asthma was 16% [17]. The GBD 2016 study reported a PAF of 10% based on DALYs (table 1), ranging from 4% in Central sub-Saharan Africa to 12% in South Asia [16]. Underdetection and underdiagnosis, as with many other occupational diseases, especially in LMICs, is a contributory factor [36]. These global estimates are consistent with previous studies, with estimates of 10–15% [37]. The highest number of https://doi.org/10.1183/2312508X.10034019

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ERS MONOGRAPH | OCCUPATIONAL AND ENVIRONMENTAL LUNG DISEASE

3.5 3.0

Prevalence %

2.5 2.0 1.5 1.0 0.5 0.0 1970 1975 1980 1985 1990 1995 2000 2005 2010 2015 Year Figure 4. Prevalence of progressive massive fibrosis in underground coal miners with ⩾25 years of exposure in three states of the USA. Reproduced and modified from [31] with permission.

WRA deaths and DALYs occurred in South Asia and South-east Asia, and mortality rates were highest in the low and low-to-middle SDI regions. The PAF for DALYs was higher for men (13%) than for women (7%) and peaked between 35 and 49 years, similar to data in the ATS/ERS statement [17]. The sex distribution of WRA varied across countries and was related to employment and working conditions, distribution of work between the sexes, health consciousness and health-seeking behaviours [38]. Sex differences in farming cohorts globally have revealed a higher prevalence of asthma in women than in men (7.8% versus 6.5%), with allergic asthma being more prevalent [39]. In the GBD 2016 study, a higher proportion of asthma deaths occurred at younger ages, as did DALYs (45–54 years) [16]. While death rates declined by 36% from 1990 to 2016 [16], there was a 28% increase in the PAF for DALYs (table 2). This increase parallels the increasing incidence of asthma globally. Studies indicate that the incidence of occupational asthma is two to five cases per 100 000 of the population per year, which appears to be declining and plateauing (figure 6) [4]. However, these figures are based on national registries and voluntary reporting surveillance systems having inherent biases [40]. Recently, a possible reversal of this downward trend since 2014 has been suggested [41]. Various studies have alluded to an epidemic of nonallergic asthma due to cleaning agents in cleaners and health workers in the past decade [42–44]. In addition, products such as chemicals, pesticides and food additives that were previously not known to be sensitisers or irritants are continually being introduced, increasing the risk of occupational asthma and work-exacerbated asthma [45–47]. Other studies have also shown that workers in jobs with exposure to PMGF were more likely to change their jobs due to respiratory health problems [48, 49]. Occupational COPD The epidemiological evidence supporting the occupational contribution of PMGF to COPD is increasing [1]. The risks associated with silica and coal dust in mining are 8

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Absolute consumption metric ton

2 000 000 1 750 000 1 500 000 1 250 000 1 000 000 750 000 Asia and Middle East Rest of world

500 000 250 000 0 1998

2000

2002

2004 2006 Year

2008

2010

Figure 5. Worldwide consumption of asbestos. Data from the US Geological Survey (www.usgs.gov). Reproduced and modified from [34] with permission.

better established and independent of smoking. The Burden of Obstructive Lung Disease (BOLD) study demonstrated a direct relationship between COPD and years worked in dusty jobs [50]. The European Community Respiratory Health Survey (ECRHS) of young adults also demonstrated an increased COPD incidence in those exposed to biological PMGF and pesticides over a 20-year period [51]. In many LMICs, high exposures to vegetable dusts (e.g. cotton, grain dust) are also associated with COPD. A UK population-based cohort study reported an increased COPD risk in certain occupational groups, even among never-smokers and those who had never had asthma [52]. The ATS/ERS statement reported the occupational PAF for COPD to be 14% (13% for chronic bronchitis) [17]. A higher PAF (31%) among never-smokers suggests that occupational exposures contribute significantly to the COPD burden. These findings are consistent with previous ATS statements, the GBD 2016 study (17% for DALYs; table 1) and the ECRHS study (21%) [16, 53, 54]. The slightly higher estimates in the latter may be due to differences in exposure levels or sources including SHS. COPD deaths and DALYs due to PMGF and SHS were by far the largest contributor to OLDs in the GBD 2016 study (table 1). Among regions, PAF ranged from 10% in Central sub-Saharan Africa to 21% in East Asia. The highest mortality rates and DALYs were in East and South Asia. DALY rates were higher in LMIC regions. Given the distribution of dusty work between the sexes, PAF was higher in men (21%) than in women (11%), peaking at 24% in males aged 60–64 years. From 1990 to 2016, there was little change (4% increase) in COPD deaths due to PMGF and SHS, but the standardised mortality rates declined by 41%. With a decline in global smoking rates, the occupational PAF is likely to increase. The PAF from smoking and SHS together was 43% compared with ambient particulate pollution of 27% [54], whereas in 2000, the estimated occupational PAF was 13% for DALYs [55]. https://doi.org/10.1183/2312508X.10034019

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ERS MONOGRAPH | OCCUPATIONAL AND ENVIRONMENTAL LUNG DISEASE France RNV3P France MCP Italy MALPROF Netherlands (respiratory specialist) Netherlands (occupational physician) UK (respiratory specialist) UK (occupational physician)

Incidence rate ratio relative to 2007

3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 2000

2002

2004

2006 Year

2008

2010

2012

Figure 6. Estimated annual changes in incidence of occupational asthma in Europe based on national reporting surveillance data. RNV3P: Le Réseau National de Vigilance et de Prévention des Pathologies Professionnelles; MCP: Programme de Surveillance des Maladies à Caractère Professionnel (French surveillance system); MALPROF: Malattie Professionali (Italian surveillance system). Reproduced from [4] and modified from [40] with permission.

Occupational lung cancer and mesothelioma Occupational exposure to carcinogens is an important cause of death and disability globally (table 3) [56]. In the GBD 2016 study, the overall occupational PAF for carcinogens was 3.9% for all cancer deaths and 3.4% for DALYs. Asbestos was the major contributor to deaths (63%), followed by SHS, silica and diesel engine exhaust [56]. Lung cancer (86%) and mesothelioma (8%) are most common occupational cancers, with PAFs of 91% for mesothelioma and 18% for lung cancers (table 3). Heavy metals used in brazing/soldering, painting, and chemical and fertiliser manufacture are also important causes, as is diesel exhaust in transport and mineworkers [11].

The occupational PAF for cancer deaths was 5% for men and 2% for women [56]. Men accounted for 77% of DALYs, also having 4-fold higher mortality rates. Deaths increased with age (88% in >55 years group), and so did the PAF. The highest cancer mortality rates and DALYs were in HIC regions (figure 7) [56, 57]. High occupational PAFs were seen for Australasia (9%) and Western Europe (8%). There were high levels of asbestos-related cancer deaths in four HIC regions (78–88%) and in southern sub-Saharan Africa (86%). In other LMIC regions, SHS, silica and diesel engine exhaust were more important. Large-scale studies have shown an increased risk of lung cancer in chrysotile textile workers [58, 59]. In the UK, 40% of occupational cancer deaths (lung cancer and mesothelioma) in construction are due to asbestos and silica exposure [60]. The synergistic effect of asbestos and smoking for all lung cancer subtypes has also been demonstrated [61]. From 1990 to 2016, there has been a decrease in the mortality rates (−10%) and DALYs (−15%) caused by occupational carcinogens, even though the total burden has worsened, suggesting that exposures persist [56]. Mortality rates in high SDI regions (Asia Pacific, 10

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Table 3. Global occupation-attributable respiratory cancer deaths, disability-adjusted life-years (DALYs) and population-attributable fractions (PAFs) by cancer type and carcinogen in 2016 Cancer type/carcinogen

Lung cancer Arsenic Asbestos Beryllium Cadmium Chromium Diesel engine exhaust Nickel Polycyclic aromatic hydrocarbons Second-hand smoke Silica Mesothelioma # Total ¶

Deaths

DALYs

n (%)

PAF

n (%)

PAF

299 998 (86.0) 8073 (2.3) 181 450 (52.0) 259 (0.1) 605 (0.2) 1276 (0.4) 17 500 (5.0) 8101 (2.3) 4526 (1.3) 44 382 (12.7) 47 999 (13.8) 27 612 (7.9) 348 741 (100.0)

17.6

6 091 207 (84.6) 219 218 (3.0) 2 844 282 (39.5) 7223 (0.1) 16 832 (0.2) 35 452 (0.5) 485 693 (6.7) 221 352 (3.1) 125 779 (1.7) 1 185 421 (16.5) 1 303 949 (18.1) 553 967 (7.7) 7 199 850 (100.0)

16.7

91.4 3.9

83.8 3.4

#

: caused by asbestos; ¶: number percentages add to more than 100 due to overlapping causes. Reproduced and modified from [56] with permission.

South and East Asia) increased by 40–60%. The mortality rates and DALYs increased by ∼30% for chromium, cadmium, beryllium, diesel engine exhaust and polycyclic aromatic hydrocarbons but less so for mesothelioma (4%) (table 4). In HIC regions where asbestos use peaked three to four decades ago, mesothelioma mortality rates are 10-fold higher than average. In some LMICs, asbestos use has increased (figure 5), with higher rates expected in the future [62]. Despite asbestos being banned in the 1990s, peaks are imminent or recent [63–68]. In Nordic countries with earlier bans, rates have declined [69]. Occupational respiratory infections While respiratory infections do not feature prominently in the GBD 2016 study, they are important, especially in LMICs [70]. Several respiratory viral pandemics have manifested in the past decade among healthcare workers. While the extent of the SARS-CoV-2 pandemic is still being determined, at least 10% of all COVID-19 infections are among healthcare and social care workers [71].

Among the occupational respiratory infections, pulmonary tuberculosis (PTB) is the most common [1]. In the ATS/ERS statement, the occupational PAF for silica-associated PTB was 2.3% and for healthcare worker-associated PTB was 1% [17]. In high disease burden settings (incidence rate ratio >1 relative to the general population), the PAF was 0.1–8.9%. For PTB in silica-exposed workers, wider ranges were reported for South African gold miners compared with US workers (0.8–7.9% versus 3.2–4.9%, respectively) [17]. Higher age-standardised PTB mortality rates during working age have been reported in South African cleaners and in agricultural, refuse and silica-exposed workers [72]. The occupational contribution to the occurrence of community-acquired pneumonia is also being appreciated. The occupational PAF for pneumonia is ∼10% [17]. It is well known https://doi.org/10.1183/2312508X.10034019

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ERS MONOGRAPH | OCCUPATIONAL AND ENVIRONMENTAL LUNG DISEASE

40

France UK Netherlands Belgium Italy USA Sweden Australia Japan Korea Finland

Mortality per million population

35 30 25 20 15 10 5 0

1980

1985

1990

1995 Year

2000

2005

2010

Figure 7. Mesothelioma and related asbestos-related lung cancer mortality by country, 1980–2012. Reproduced and modified from [4] with permission.

that exposure to metal fume increases the risk of pneumococcal pneumonia. The PAF for metal fume/welding exposures in relation to pneumonia is 52.5% [17]. A recent study provided further evidence that welding fumes and silica dust increase the risk of invasive pneumococcal disease [73]. Risk factors for OLDs

The major risk factors for OLDs are related primarily to the work environment and in certain contexts to their interaction with host-associated genetic susceptibility or individual vulnerability factors in the work environment. The work environment is a complex exposome, generating inhalational exposures to hazardous chemical and biological agents, often in high concentrations, which increase the risk of OLDs [74]. Legal, technological and workplace organisational factors (e.g. migrants, seasonal work, hours of work) mediate these exposures, which are often the result of inadequate exposure control measures as well as surveillance of workers and their environment [4, 75]. The major aspect of hazardous exposures relates to timing of exposures, with some diseases (i.e. pneumoconioses, lung cancer, mesothelioma) having a long latency period, while others (i.e. occupational asthma, PTB) have a relatively short latency period [76]. Equally important is the exposure dose, determined by the exposure level and duration (together termed cumulative exposure). Pneumoconioses and COPD require long periods (often >10 years) of exposure, whereas mesothelioma may result from a short exposure (a few weeks), both manifesting many years after the initial exposure. For occupational asthma, elevated exposures (continuous, isolated or multiple peaks), together with the sensitisation potential of the sensitising agent, are important. Certain exposure cofactors such as smoking may also increase the risk of lung cancer, COPD and occupational asthma (e.g. platinum salt sensitivity). 12

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Table 4. Change in global occupation-attributable deaths due to carcinogens in 1990 and 2016, by carcinogen and cancer type Deaths 1990 Carcinogen Arsenic Asbestos Beryllium Cadmium Chromium Diesel engine exhaust Nickel Polycyclic aromatic hydrocarbons Second-hand smoke Silica Cancer type Lung cancer Mesothelioma All

Deaths per 100 000 population

2016

% change

1990

2016

% change

4829 145 235 125 284 578 7981 4946 2067 30 513 30 680

8073 218 827 259 605 1276 17 500 8101 4526 49 246 47 999

67 51 107 133 121 119 64 119 61 56

0.3 10.1 0.0 0.0 0.0 0.5 0.3 0.1 2.0 1.9

0.3 8.7 0.0 0.0 0.0 0.7 0.3 0.2 1.8 1.8

−2 −14 22 25 30 29 −4 29 −9 −8

193 015 15 206 222 049

299 998 27 612 348 741

55 82 57

13.0 1.0 15.0

11.6 1.1 13.5

−11 4 −10

Reproduced and modified from [56] with permission.

Individual vulnerability factors have also been identified, although not always consistently [4, 77]. It is well known that atopic workers exposed to high-molecular weight agents (e.g. food proteins) are at increased risk of developing occupational asthma [47]. Similarly, workers with human leukocyte antigen class II genetic variants appear to be at increased risk of isocyanate sensitisation-induced occupational asthma. Furthermore, workers with hereditary lung diseases such as cystic fibrosis or homozygous α1-antitrypsin deficiency are at increased risk of developing early COPD.

Surveillance systems for OLDs Surveillance systems for OLDs have historically relied on legally mandated workers’ compensation registries to monitor their incidence and have provided sentinel signals for potentially emerging and new causes of OLDs [2, 78, 79]. Other surveillance schemes, relying on voluntary reporting by physicians, have also been used. Compensation registries are constrained by reporting biases or rigid compensation criteria. Voluntary surveillance schemes often suffer from reporter fatigue over time [80], although some are still active (figure 6) [81–83]. SWORD (Surveillance of work-related and occupational respiratory disease) was the first UK scheme for OLDs within The Health and Occupation Research (THOR) network [82, 84]. It collects information on the industry, occupation and agent in relation to OLDs to identify sentinel events and industry trends (figure 8). Specifically for occupational asthma, suspected low-molecular-weight agents are investigated further using a computer-based quantitative structure–activity relationship (QSAR) model to ascertain their sensitisation hazard [85]. The system has been able to identify newly emerging causes of occupational asthma and hypersensitivity pneumonitis. SWORD data have also provided insights into long-latency OLDs, including silicosis, lung cancer and COPD [86]. In light of https://doi.org/10.1183/2312508X.10034019

13

ERS MONOGRAPH | OCCUPATIONAL AND ENVIRONMENTAL LUNG DISEASE The cases are categorised by disease diagnosis, e.g. asthma.

The least commonly reported disease is reviewed first, e.g. obliterative bronchiolitis, followed by more common diagnoses.

The causal agents for each disease are categorised and ranked, e.g. in occupational asthma, isocyanates and flour would be well-known agents, but at the other end, rare and probably novel causes such as denatonium benzoate could be identified.

The disease and causal agents are categorised and ranked by occupation and industry, e.g. pneumoconiosis caused by silica is common in bricklayers in the construction industry but silicosis in a chemist working in the chemical industry is rare.

A literature review is undertaken on PubMed to see whether any cases of possible interest (disease attributed to new industry, occupation or exposure) have been identified previously in the literature through research or case reports. Other resources accessed include the Health and Safety Executive and National Institute for Occupational Safety and Health websites.

An expert assessment within the team is sought to discuss the existing literature and other resources available. After expert review, a decision to confirm or exclude the cases as an emerging cause of work-related respiratory disease is made.

Potential emerging cases are confirmed if there is no previous association in the literature between the disease, occupation and agent.

Figure 8. A practical approach to identifying emerging instances of respiratory occupational health hazards. Reproduced and modified from [79] with permission.

the inequitable distribution of knowledge, information and research relating to OLDs, some have suggested a globalised surveillance system for capturing international data. Coupled with appropriate training, this could contribute to improvements in the health and well-being of all workers globally [87].

Conclusion An understanding of patterns and disease burden is key to developing preventative strategies for OLDs globally. Improved information dissemination and awareness of respiratory hazards among employers, workers and physicians and their prevention form the bedrock of sound occupational health practice. This is best achieved through implementing workplace interventions aimed at exposure reduction, early disease identification through health surveillance, and appropriate return-to-work rehabilitation and compensation support [1, 4]. Furthermore, ongoing surveillance of OLD occurrence, evaluating the impact of interventions, and approaches to identify and predict new hazards are essential higher-level preventative functions [4]. In order to achieve a sustained reduction in the incidence of OLDs globally, preventative legislation and exposure standards need to be health based and scientifically defensible [88–90]. In their absence, the precautionary principle of “as low as reasonably 14

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practicable” should be followed [4]. Furthermore, demonstrating a clear link between OLD burden and the cost to society can also contribute towards improved exposure standards. Finally, physicians should have a high index of suspicion of the potential risks of exposures to their patients, especially those with unusual or unique presentations [4, 11]. This also calls for more efficient tools, such as “job– or task–exposure matrices” to identify hazardous exposures, electronic chemical databases and medical algorithms, to assist in identifying causes of OLDs and to inform their appropriate management in routine clinical practice.

References 1. 2. 3. 4. 5.

6. 7. 8. 9. 10. 11. 12.

13. 14. 15.

16.

17.

18. 19. 20.

Cullinan P, Muñoz X, Suojalehto H, et al. Occupational lung diseases – from old and novel exposures to effective preventive strategies. Lancet Respir Med 2017; 5: 445–455. Jaakkola MS, Jaakkola JJK. Assessment of public health impact of work-related asthma. BMC Med Res Methodol 2012; 12: 22. International Labour Organization. Safety and Health at Work. www.ilo.org/global/topics/safety-and-health-atwork/lang–en/index.htm Date last accessed: 22 September 2020. de Matteis S, Heederik D, Burdorf A, et al. Current and new challenges in occupational lung diseases. Eur Respir Rev 2017; 26: 170080. International Labour Organization. Safety and Health at the Heart of the Future of Work: Building on 100 Years of Experience. Geneva, International Labour Organization, 2019. Available from: www.ilo.org/safework/events/ safeday/WCMS_686645/lang–en/index.htm International Labour Organization. Informal Economy. www.ilo.org/global/topics/employment-promotion/ informal-economy/lang–en/index.htm Date last accessed: 22 September 2020. Fazena LE, Lindea B, Redlich CA. Occupational lung diseases in the 21st century: the changing landscape and future challenges. Curr Opin Pulm Med 2020; 26: 142–148. Bønløkke J, Bang B, Aasmoe L, et al. Exposures and health effects of bioaerosols in seafood processing workers – a position statement. J Agromedicine 2019; 24: 441–448. Grant IW, Blyth W, Wardrop VE, et al. Prevalence of farmer’s lung in Scotland: a pilot survey. Br Med J 1972; 1: 530–534. Burton CM, Crook B, Scaife H, et al. Systematic review of respiratory outbreaks associated with exposure to waterbased metalworking fluids. Ann Occup Hyg 2012; 56: 374–388. Moitra S, Puri R, Paul D, et al. Global perspectives of emerging occupational and environmental lung diseases. Curr Opin Pulm Med 2015; 21: 114–120. GBD Chronic Respiratory Disease Collaborators. Prevalence and attributable health burden of chronic respiratory diseases, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Respir Med 2020; 8: 585–596. Burney P. BOLD in Africa: what has it taught us? African J Respir Med 2018; 13: 6–9. Jones R. The scale of the problem of obstructive lung disease in Africa becomes clearer, but where are the solutions? Eur Respir J 2018; 51: 1702562. GBD 2016 Occupational Risk Factors Collaborators. Global and regional burden of disease and injury in 2016 arising from occupational exposures: a systematic analysis for the Global Burden of Disease Study 2016. Occup Environ Med 2020; 77: 133–141. GBD 2016 Occupational Risk Factors Collaborators. Global and regional burden of chronic respiratory disease in 2016 arising from non-infectious airborne occupational exposures. a systematic analysis for the Global Burden of Disease Study 2016. Occup Environ Med 2020; 77: 142–150. Blanc PD, Annesi-Maesano I, Balmes JR, et al. the occupational burden of nonmalignant respiratory diseases. An Official American Thoracic Society and European Respiratory Society Statement. Am J Respir Crit Care Med 2019; 199: 1312–1334. Driscol T, Sim MR. Occupational lung disease – scope of the problem, the role of the SDGs and a framework for prevention. Int J Tuberc Lung Dis 2020; 24: 5. Townend J, Minelli C, Mortimer K, et al. The association between chronic airflow obstruction and poverty in 12 sites of the multinational BOLD study. Eur Respir J 2017; 49: 1601880. Grønseth R, Erdal M, Tan WC, et al. Unemployment in chronic airflow obstruction around the world: results from the BOLD study. Eur Respir J 2017; 50: 1700499.

https://doi.org/10.1183/2312508X.10034019

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ERS MONOGRAPH | OCCUPATIONAL AND ENVIRONMENTAL LUNG DISEASE 21. Shi P, Xing X, Xi S, et al. Trends in global, regional and national incidence of pneumoconiosis caused by different aetiologies: an analysis from the Global Burden of Disease Study 2017. Occup Environ Med 2020; 77: 407–414. 22. Jindal SK. Silicosis in India: past and present. Curr Opin Pulm Med 2013; 19: 163–168. 23. World Health Organization. Silicosis. Factsheet No. 238. Geneva, World Health Organization, 2000. 24. Nelson G, Girdler-Brown B, Ndlovu N, et al. Three decades of silicosis: disease trends at autopsy in South African gold miners. Environ Health Perspect 2010; 118: 421–426. 25. Knight D, Ehrlich R, Fielding K. Trends in silicosis prevalence and the healthy worker effect among gold miners in South Africa: a prevalence study with follow up of employment status. BMC Public Health 2015; 15: 1258. 26. Bloch K, Johnson LF, Nkosi M, et al. Precarious transition: a mortality study of South African ex-miners. BMC Public Health 2018; 18: 862. 27. Barnes H, Goh NSL, Leong TL, et al. Silica-associated lung disease: an old-world exposure in modern industries. Respirology 2019; 24: 1165–1175. 28. Rajavel S, Raghav P, Gupta MK, et al. Silico-tuberculosis, silicosis and other respiratory morbidities among sandstone mine workers in Rajasthan – a cross-sectional study. PLoS One 2020; 15: e0230574. 29. Hoy RF, Chambers DC. Silica-related diseases in the modern world. Allergy 2020; in press [DOI: https://doi.org/10. 1111/all.14202]. 30. Akgun M, Araz O, Akkurt I, et al. An epidemic of silicosis among former denim sandblasters. Eur Resp J 2008; 32: 1295–1303. 31. Blackley DJ, Halldin CN, Laney AS. Resurgence of a debilitating and entirely preventable respiratory disease among working coal miners. Am J Respir Crit Care Med 2014; 190: 708–709. 32. Jacobs N, Kisting S, Braun L. Collaborative research participatory solutions research on asbestos in Kuruman, South Africa. Int J Occup Environ Health 2004; 10: 226–232. 33. Kim HR. Overview of asbestos issues in Korea. J Korean Med Sci 2009; 24: 363–367. 34. Leong S, Zainudin R, Kazan-Allen L, et al. Asbestos in Asia. Respirology 2015; 20: 548–555. 35. Wang X, Lin S, Yu I, et al. Cause-specific mortality in a Chinese chrysotile textile worker cohort. Cancer Sci 2013; 104: 245–249. 36. Jeebhay MF, Quirce S. Occupational asthma in the developing and industrialized world: a review. Int J Tuberc Lung Dis 2007; 11: 122–133. 37. Torén K, Blanc PD. Asthma caused by occupational exposures is common-a systematic analysis of estimates of the population-attributable fraction. BMC Pulm 2009; 9: 7. 38. Moscato G, Apfelbacher C, Brockow K, et al. Gender and occupational allergy (GOA): report from the task force of the EAACI Environmental & Occupational Allergy Interest Group. Allergy 2020; in press [DOI: https://doi.org/ 10.1111/all.14317]. 39. Fix J, Annesi-Maesano I, Baldi I, et al. Gender differences in respiratory health outcomes among farming cohorts around the globe: findings from the AGRICOH Consortium. J Agromedicine 2020; 17: 1–12. 40. Stocks SJ, McNamee R, van der Molen HF, et al. Trends in incidence of occupational asthma, contact dermatitis, noise-induced hearing loss, carpal tunnel syndrome and upper limb musculoskeletal disorders in European countries from 2000 to 2012. Occup Environ Med 2015; 72: 294–303. 41. Seed MJ, Carder M, Gittins M, et al. Emerging trends in the UK incidence of occupational asthma: should we be worried? Occup Environ Med 2019; 76: 396–397. 42. Siracusa A, de Blay F, Folletti I, et al. Asthma and exposure to cleaning products – a European Academy of Allergy and Clinical Immunology task force consensus statement. Allergy 2013; 68: 1532–1545. 43. Mwanga H, Jeebhay MF. Work-related asthma and exposure to cleaning agents in health care settings – a review of literature. Curr Allergy Clin Immunol 2020; 33: 30–40. 44. Carder M, Seed MJ, Money A, et al. Occupational and work-related respiratory disease attributed to cleaning products. Occup Environ Med 2019; 76: 530–536. 45. Kurt OK, Basaran N. Occupational exposure to metals and solvents: allergy and airway diseases. Curr Allergy Asthma Rep 2020; 20: 38. 46. Ratanachina J, de Matteis S, Cullinan P, et al. Pesticide exposure and lung function: a systematic review and metaanalysis. Occup Med (Lond) 2020; 70: 14–23. 47. Jeebhay MF, Moscato G, Bang BE, et al. Food processing and occupational respiratory allergy – a EAACI position paper. Allergy 2019; 74: 1852–1871. 48. Maher M, Olfa EM, Wided B, et al. Epidemiology of occupational asthma in Tunisia: results of a first national study. Occup Dis Env Med 2016; 4: 27–36. 49. Torén K, Zock JP, Kogevinas M, et al. An international prospective general population-based study of respiratory work disability. Thorax 2009; 64: 339–344. 50. Hooper R, Burney P, Vollmer WM, et al. Risk factors for COPD spirometrically defined from the lower limit of normal in the BOLD project. Eur Respir J 2012; 39: 1343–1353. 51. Lytras T, Kogevinas M, Kromhout H, et al. Occupational exposures and 20-year incidence of COPD: the European Community Respiratory Health Survey. Thorax 2018; 73: 1008–1015. 16

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THE GLOBAL PERSPECTIVE | M.F. JEEBHAY 52. de Matteis S, Jarvis D, Darnton A, et al. The occupations at increased risk of COPD: analysis of lifetime jobhistories in the population-based UK Biobank Cohort. Eur Respir J 2019; 54: 1900186. 53. Balmes J, Becklake M, Blanc P, et al. American Thoracic Society statement: occupational contribution to the burden of airway disease. Am J Respir Crit Care Med 2003; 167: 787–797. 54. Institute for Health Metrics and Evaluation. GBD Compare. www.healthdata.org/data-visualization/gbd-compare Date last accessed: 22 September 2020. Date last updated: 8 November 2018. 55. Driscoll T, Nelson DI, Steenland K, et al. The global burden of non-malignant respiratory disease due to occupational airborne exposures. Am J Ind Med 2005; 48: 432–445. 56. GBD 2016 Occupational Carcinogens Collaborators. Global and regional burden of cancer in 2016 arising from occupational exposure to selected carcinogens: a systematic analysis for the Global Burden of Disease Study 2016. Occup Environ Med 2020; 77: 151–159. 57. Abdel-Rahman O. Global trends in mortality from malignant mesothelioma: analysis of WHO mortality database (1994–2013). Clin Respir J 2018; 12: 2090–2100. 58. Elliott L, Loomis D, Dement J, et al. Lung cancer mortality in North Carolina and South Carolina chrysotile asbestos textile workers. Occup Environ Med 2012; 69: 385–390. 59. Wang X, Lin S, Yano E, et al. Exposure-specific lung cancer risks in Chinese chrysotile textile workers and mining workers. Lung Cancer 2014; 85: 119–124. 60. Rushton L, Bagga S, Bevan R, et al. Occupation and cancer in Britain. Br J Cancer 2010; 102: 1428–1437. 61. Olsson AC, Vermeulen R, Schuz J, et al. Exposure–response analyses of asbestos and lung cancer subtypes in a pooled analysis of case–control studies. Epidemiology 2017; 28: 288–299. 62. Algranti E, Saito CA, Carneiro APC, et al. The next mesothelioma wave: mortality trends and forecast to 2030 in Brazil. Cancer Epidemiol 1015; 39: 687–692. 63. Health and Safety Executive. Mesothelioma Mortality in Great Britain 1968–2018. www.gov.uk/government/ statistics/mesothelioma-mortality-in-great-britain-1968-to-2018 Date last accessed: 22 September 2020. Date last updated: 1 July 2020. 64. Soeberg MJ, Leigh J, Driscoll T, et al. Incidence and survival trends for malignant pleural and peritoneal mesothelioma, Australia, 1982–2009. Occup Environ Med 2016; 73: 187–194. 65. Krupoves A, Camus M, de Guire L. Incidence of malignant mesothelioma of the pleura in Québec and Canada from 1984 to 2007, and projections from 2008 to 2032. Am J Ind Med 2015; 58: 473–482. 66. Girardi P, Bressan V, Merler E. Past trends and future prediction of mesothelioma incidence in an industrialized area of Italy, the Veneto region. Cancer Epidemiol 2014; 38: 496–503. 67. Zadnik V, Primic Zakelj M, Jarm K, et al. Time trends and spatial patterns in the mesothelioma incidence in Slovenia, 1961–2014. Eur J Cancer Prev 2017; 26; S191–S196. 68. Muteba KM. Mesothelioma Incidence and Mortality in South Africa From 2003 to 2013. https://hdl.handle.net/ 10539/25423 Date last accessed: 22 September 2020. Date last updated: February 2018. 69. Järvholm B, Englund A, Albin M. Pleural mesothelioma in Sweden: an analysis of the incidence according to the use of asbestos. Occup Environ Med 1999; 56: 110–113. 70. Apriani L, McAllister S, Sharples K, et al. Latent tuberculosis infection in healthcare workers in low- and middleincome countries: an updated systematic review. Eur Respir J 2019; 53: 1801789. 71. The DELVE Initiative. Scoping Report on Hospital and Health Care Acquisition of COVID-19 and its Control. DELVE Report No. 3. http://rs-delve.github.io/reports/2020/07/06/nosocomial-scoping-report.html Date last accessed: 22 September 2020. Date last updated: 6 July 2020. 72. Kootbodien T, Wilson K, Tlotleng N, et al. Tuberculosis mortality by occupation in South Africa, 2011–2015. Int J Environ Res Public Health 2018; 15: 2756. 73. Torén K, Blanc PD, Naidoo RN, et al. Occupational exposure to dust and to fumes, work as a welder and invasive pneumococcal disease risk. Occup Environ Med 2020; 77: 57–63. 74. Cecchi L, d’Amato G, Annesi-Maesano I. External exposome and allergic respiratory and skin diseases. J Allergy Clin Immunol 2018; 141: 846–857. 75. Howse D, Jeebhay MF, Neis B. The changing political economy of occupational health and safety in fisheries: lessons from Eastern Canada and South Africa. J Agrar Chang 2012; 12: 344–363. 76. Occupational risk factors. In: Gibson J, Loddenkemper R, Sibille Y, et al., eds. European Lung White Book. 2nd Edn. Sheffield, European Respiratory Society, 2013; pp. 76–87. 77. Jeebhay MF, Ngajilo D, Le Moual N. Risk factors for nonwork-related adult-onset asthma and occupational asthma: a comparative review. Curr Opin Allergy Clin Immunol 2014; 14: 84–94. 78. Samant Y, Wannag A, Urban P, et al. Sentinel surveillance and occupational disease. Occup Med (Lond) 2015; 65: 611–614. 79. Zhou AY, Seed M, Carder M, et al. Sentinel approach to detect emerging causes of work-related respiratory diseases. Occup Med (Lond) 2020; 70: 52–59. 80. Walters GI, Kirkham A, McGrath EE, et al. Twenty Years of SHIELD: decreasing incidence of occupational asthma in the West Midlands, UK? Occup Environ Med 2015; 72: 304–310. https://doi.org/10.1183/2312508X.10034019

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ERS MONOGRAPH | OCCUPATIONAL AND ENVIRONMENTAL LUNG DISEASE 81. Centre for Occupational and Environmental Health, University of Manchester. The Health and Occupation Research Network. www.research.bmh.manchester.ac.uk/epidemiology/COEH/research/thor/ Date last accessed: 22 September 2020. 82. Bonneterre V, Faisandier L, Bicout D, et al. Programmed health surveillance and detection of emerging diseases in occupational health: contribution of the French national occupational disease surveillance and prevention network (RNV3P). Occup Environ Med 2010; 67: 178–186. 83. Hannaford-Turner K, Elder D, Sim MR, et al. Surveillance of Australian workplace based respiratory events (SABRE) in New South Wales. Occup Med (Lond) 2010; 60: 376–382. 84. Centre for Occupational and Environmental Health, University of Manchester. Surveillance of Work-Related and Occupational Respiratory Disease (SWORD). www.research.bmh.manchester.ac.uk/epidemiology/COEH/research/ thor/schemes/sword/ Date last accessed: 22 September 2020. 85. Seed MJ, Agius RM. Progress with structure–activity relationship modelling of occupational chemical respiratory sensitizers. Curr Opin Allergy Clin Immunol 2017; 17: 64–71. 86. Reynolds CJ, Blanc P. Into ploughshares: forging effective surveillance for work-related lung disease. Occup Environ Med 2019; 76: 783–784. 87. Asanati K, Al Jassasi SH, Sherafat A, et al. Occupational lung disease: the need for a global surveillance system. Occup Environ Med 2020; 77: 506–507. 88. Occupational lung diseases. In: Gibson J, Loddenkemper R, Sibille Y, et al., eds. European Lung White Book, 2nd Edn. Sheffield, European Respiratory Society, 2013; pp. 282–295. 89. Jeebhay MF, Baatjies R. Prevention of baker’s asthma. Curr Opin Allergy Clin Immunol 2020; 20: 96–102. 90. Heederik DJJ. Towards evidence-informed occupational exposure limits for enzymes. Ann Work Expo Health 2019; 63: 371–374.

Disclosures: None declared. Dedication: In loving memory of my mother, Jubeda Jeebhay, who sadly passed away from COVID-19 during the writing of this chapter.

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| Chapter 2 Exposure assessment Ioannis Basinas1, Hakan Tinnerberg2 and Martie van Tongeren3 Practicing respiratory physicians are very likely to see patients with work-related respiratory diseases. It is important for the physician to be aware of potential occupational risk factors that may contribute to the development of the disease or the symptoms. It will not always be easy to obtain a reliable and comprehensive assessment of the occupational exposure (current or past). However, a large volume of information and data is available that can assist the physician in determining the likelihood and level of exposure to hazardous agents in the workplace. Such information should be carefully considered and experts, such as occupational hygienists, can be enlisted to assist with the assessment of exposure, e.g. to identify occupational hazards and estimate exposure using exposure tools or carrying out measurement surveys. Information on exposure could support diagnosis and treatment plans and most importantly, might be used to identify the need for intervention to reduce the risk to health for other workers. Cite as: Basinas I, Tinnerberg H, van Tongeren M. Exposure assessment. In: Feary J, Suojalehto H, Cullinan P, eds. Occupational and Environmental Lung Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 19–33 [https://doi.org/10.1183/2312508X.10035919].

@ERSpublications Understanding the role of occupational exposure in respiratory disease is important to support diagnosis and identify the need for intervention. Occupational hygienists can assist with assessment of exposure using measurement methods and models. https:// bit.ly/3310jTg

O

ther chapters in this Monograph describe a range of respiratory disorders that may be caused or aggravated by occupational exposures. Such diseases include occupational asthma [1], inhalation injuries [2], COPD [3], pneumoconiosis [4], and lung and respiratory tract cancers [5]. For some of these respiratory disorders, the causal links with exposures at the workplace are well established. Probably the best examples are asbestosis and mesothelioma, which occur almost exclusively as a result of occupational exposure to asbestos. For other diseases, such as COPD, occupational exposure (to tobacco smoke, for example) may be one of many contributing factors that causes the disorder. Some of the most important and well-studied exposures that are known to cause respiratory disorders include mineral dusts and fibres (e.g. asbestos, respirable crystalline silica and coal dust),

1 Research Division, Institute of Occupational Medicine, Edinburgh, UK. 2Occupational and Environmental Medicine, School of Public Health and Community Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden. 3Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

Correspondence: Martie van Tongeren, University of Manchester, Ellen Wilkinson Building, Oxford Road, Manchester, M13 9PL, UK. E-mail: [email protected] Copyright ©ERS 2020. Print ISBN: 978-1-84984-124-5. Online ISBN: 978-1-84984-125-2. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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chemicals (e.g. isocyanates), process-generated fumes (e.g. fumes from welding and diesel engines) and biological agents (e.g. wood dust, flour dust, enzymes, micro-organisms). It is important for the respiratory physician to understand the link between work and respiratory health for diagnostic and prognostic reasons. For the patient, an understanding of occupational factors is important in order to make modifications to their work and, in some cases, because they may be eligible for compensation or benefits. This means that the respiratory physician should be aware of workplace hazards and the methods available to estimate the presence and level of exposure to such hazards; they should also have an understanding of the principles of preventing and controlling such exposures. To assess the risk of the exposure, an understanding of occupational exposure limits (OELs) is important as they provide “safe” exposure levels. This chapter provides an introduction to the principles and methods used to estimate occupational exposure that are available to both the respiratory physician and other physicians interested in occupational diseases.

Occupational exposure Many different chemical, physical and biological hazards can be present in the workplace, either because they are used as raw materials, intermediate or final products; because they are by-products of processes (e.g. fumes released from engines); or because they are a component of products used in the workplace (e.g. cleaning agents, paints). Workers are exposed to substances when the surface of their body (e.g. their skin, lungs and respiratory tract, eyes) comes in contact with the medium (e.g. air, surfaces, tools/equipment, water, soil) that contains or is contaminated by the hazardous substances [6]. Following this contact, the hazardous substance may cause a local effect (e.g. at the point of contact) or the substance could be absorbed by and distributed throughout the body (systemic exposure). Human exposure primarily occurs through four different routes: inhalation, ingestion, dermal contact or injection. Inhalation is the most important route of exposure for respiratory disease. However, exposure through other routes may contribute to systemic effects, which could exacerbate or initiate respiratory symptoms in susceptible persons, e.g. those who are allergic to a substance. Conceptual exposure model

Figure 1 shows the conceptual model representing the inhalation exposure pathways [7]. To describe this conceptual model, we will use the example of a worker who uses a spray gun to paint car bodies. The paint contains a diisocyanate, a well-known asthmagen. During spraying, diisocyanates are emitted from the source (the spray gun and the surface that is being treated) into the surrounding air. This can be through: paint aerosols emitted directly from the spray gun; “bounce back” from the surface that is treated; or evaporation of the volatile components (including the isocyanate) in the paint. The level of emission will depend on many factors, such as the spray pressure, the volatility of the diisocyanate and the amount of paint used. Local control measures, such as an exhaust ventilation, represented in the figure by the dotted lines around the source, will act as a barrier to this process. Following emission into the surrounding air, a number of things can happen with the diisocyanate molecules. Larger aerosols tend to settle fairly rapidly on surfaces in the work environment, while vapours may also be released from surfaces that are contaminated 20

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Air

Surfaces

Sources Barrier

Respirator

Clothing

Skin contamination layer

Breathing zone

Inhalation

Injection

Ingestion

Skin

Figure 1. A conceptual representation of the exposure process through inhalation. Reproduced and modified from [7] with permission.

with the paint. The diisocyanate may be captured by general ventilation systems or removed when surfaces are cleaned, before the worker is exposed to them (this is indicated by the two arrows on the top left and top right of the diagram). The worker will breathe the workplace air contaminated with diisocyanate, but this may be reduced or prevented if there is a barrier between the air surrounding the source and the air in the breathing zone. This could be a physical barrier (e.g. the painter may apply the pain remotely, or from behind some form of screen) or it could be in the form of respiratory protective equipment. The diisocyanate molecules that manage to pass these barriers reach the breathing zone and can subsequently be inhaled, deposited in the respiratory tract and lungs or absorbed into the body. Inhalation exposure

What happens after inhalation of an aerosol, fume, vapour or gas will, to a large extent, depend on the physical–chemical characteristics of the exposure agent involved. In principle, volatile agents and gases could be absorbed in the respiratory tract and could cause local effects. Airborne solid particles and liquid aerosols may be deposited in the upper and/or lower respiratory tract, depending on the size and shape of the particle. Figure 2 shows the deposition probability of a spherical particle in different parts of the respiratory tract of an adult by particle size. Normal breathing conditions via the mouth are assumed. In general, the larger particles (1–10 μm in diameter) and nanoparticles ( 10 kd] or a chemical at work [low-molecular-weight (LMW) agent]), which is termed sensitizer-induced OA, or by exposure to an inhaled irritant at work, which is termed irritant-induced OA” [1]. Sensitizer-induced OA is also known as immunological/allergic OA or OA with latency, and irritant-induced OA as nonimmunological/nonallergic OA or OA without latency. The British Occupational Health Research Foundation (BOHRF) defined OA as “asthma induced by exposure in the working environment to airborne dusts, vapours or fumes, in workers with or without pre-existing asthma” [4]. This definition also distinguishes “sensitiser-induced occupational asthma” (i.e. characterised by a latency period between first exposure to a respiratory sensitiser at work and the development of immunologically mediated symptoms) from “irritant-induced occupational asthma” (i.e. asthma occurring typically within a few hours of a high-concentration exposure to an irritant gas, fume or vapour at work). This chapter will focus on sensitiser-induced OA (hereafter simply referred to as OA), while work-exacerbated asthma and irritant-induced asthma are addressed elsewhere in this Monograph [5, 6].

Causal agents The agents causing OA are usually categorised into HMW (glyco)proteins from vegetal or animal origins and LMW agents (1% at work Serial PEF+increase in sputum eosinophils >2% at work

81 73 74 31 28 84

60 79 71 89 89 48

(70–88) (64–81) (66–80) (23–41) (18–40) (69–93)

(42–75) (51–93) (63–77) (85–92) (77–95) (26–72)

First author [ref.] BEACH [45] BEACH [45] LUX [49] BEACH [45] LUX [49] BEACH [45]

67

52

PRALONG [50]

95

40

PRALONG [50]

90 84 79 (68–88)

10 70 51 (35–67)

QUIRCE [51] QUIRCE [51] BEACH [45]

61 (21–90)

82 (54–95)

BEACH [45]

36 (1–96)

85 (48–97)

BEACH [45]

86 92 81 84 63–87 60–88 63–87

89 62 74 61 48–62 37–62 48–62

CÔTÉ [52] CÔTÉ [52] PERRIN [53] PERRIN [53] GIRARD [54] GIRARD [54] GIRARD [54]

50 (24–76)

75 (51–90)

GIRARD [54]

36 (15–65)

80 (55–93)

GIRARD [54]

The sensitivity and specificity of diagnostic tests was compared with specific inhalation challenge as the “reference standard” for occupational asthma and expressed as a percentage, with 95% CI where available. SPT: skin-prick test; HMW: high molecular weight; sIgE: serum-specific IgE antibodies; LMW: low molecular weight; NSBH: nonspecific bronchial hyperresponsiveness.

Wheezing and rhinoconjunctivitis symptoms at work are associated with the highest specificity for OA, especially when HMW agents are involved [57]. NSBH and markers of airway inflammation Following the clinical history, the next step is the documentation of asthma through the demonstration of reversible airflow obstruction or, in cases without airflow obstruction, increased, nonspecific bronchial reactivity to pharmacological agents [1]. NSBH has a low diagnostic specificity (36–64%) and consequently a low positive predictive value (55–63%) for the diagnosis of OA [45, 50, 58]. However, it has been shown that the sensitivity and negative predictive value of NSBH increase to 98% when NSBH is assessed when the subject is still at work [50]. Nevertheless, there have been reports of normal NSBH both before and after a positive SIC in 6–10% of subjects with OA [50, 58]. 40

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The demonstration of levels of FENO ⩾25 ppb and/or sputum eosinophil counts ⩾1% in addition to the assessment of NSBH can improve the sensitivity of NSBH measurements [58]. Combining the presence of NSBH with an FENO ⩾25 ppb or a sputum eosinophil count ⩾1% increased the sensitivity for identifying subjects with OA from 87% (95% CI 80–92%) for the NSBH alone to 91% (95% CI 85–95%) and 94% (95% CI 86–98%), respectively. These sensitivity rates are similar to those of NSBH measurement in subjects still exposed at work. Nevertheless, the FENO level may be influenced by atopy and smoking, while the sputum eosinophil count seems to be less affected by confounding factors than NSBH and FENO [58]. Immunological testing Skin-prick tests (SPTs) and the assessment of sIgE antibodies are useful in demonstrating IgE-mediated sensitisation to most HMW and some LMW occupational agents. However, their contribution is limited by the lack of standardised and validated extracts or reagents for many occupational agents [49, 59–61]. In a systematic review of studies published up to 2004, the pooled sensitivity of SPTs for HMW agents was 81% in comparison with SIC, while the pooled specificity was 60% (table 3) [45]. A recent meta-analysis of studies published between 1967 and 2016 provided a pooled estimate of 74% for sensitivity and 71% for specificity for the assessment of sIgE against HMW allergens [49]. Accordingly, immunological tests alone do not allow the confirmation or exclusion of a diagnosis of OA in workers exposed to HMW agents with an appropriate level of confidence. However, for some HMW agents, it has been demonstrated that increasing the cut-off value for a positive sIgE test (i.e. ⩾2.22 kUA·L−1 for wheat flour, ⩾9.64 kUA·L−1 for rye flour and ⩾4.41 kUA·L−1 for natural rubber latex) increases both the specificity and positive predictive value to >95% [62, 63].

Both meta-analyses found low pooled sensitivity estimates for sIgE against LMW agents (31% [45] and 28% [49]) that were much lower than those of HMW agents, but with a higher specificity (both 89% [45, 49]) (table 3). These data indicate that the presence of sIgE against LMW agents such as isocyanates or acid anhydrides, when available, is associated with a high likelihood of a positive SIC result but a very low sensitivity and poor performance for ruling out a diagnosis of OA. Serial measurements of functional parameters The few available data indicate that cross-shift changes in FEV1 and PEF show a low sensitivity for identifying OA (50–60%) [64, 65] but may have a high specificity (91%) [65].

Serial PEF recordings during periods at and off work are a simple and inexpensive tool to objectively investigate the temporal association between workplace exposures and changes in airway calibre. The serial values can be plotted and assessed by visual inspection by experienced physicians or computer-generated discriminant analysis (OASYS-2, freely available from www.occupationalasthma.com) [66]. A systematic review of published studies found that PEF monitoring interpreted using computer-based discriminant analysis had a moderate sensitivity (82%, 95% CI 76–90%) but a high specificity (88%, 95% CI 80– 95%) compared with SIC and thus seems more reliable in confirming than excluding OA [66]. Comparative measurements of NSBH while exposed at work and at the end of a period away from work yielded variable sensitivities (43–62%) and specificities (52–83%) [52–54]. Combining serial measurements of NSBH at work and away from work with PEF monitoring showed only a slight improvement in sensitivity (84–92%) over PEF recordings alone (81–86%), with a decrease in specificity from 74–89% to 61–62% [52, 53] (table 3). https://doi.org/10.1183/2312508X.10034119

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Serial assessments of airway inflammation markers The concordance between changes in sputum eosinophil counts at and away from work and the outcome of SIC have been investigated by one study [54]. Higher thresholds (i.e. >1%, >2% and >6.4%) for a meaningful increase in eosinophil percentage at work led to lower diagnostic sensitivities (65%, 52% and 26%, respectively) and correspondingly higher specificities (76%, 80% and 92%, respectively). The addition of work-related changes in eosinophil counts to serial PEF measurements increased the specificity of the latter by 27% when using an eosinophil threshold increase of >2%; the sensitivity, however, was not significantly changed (table 3) [54].

Data collected during SICs indicate that an increase in sputum eosinophil counts induced by exposure to the causal agent more accurately reflects a positive SIC than an increase in NSBH [67]. Combining a ⩾2-fold increase in post-challenge NSBH level or an increase in sputum eosinophil count >3% achieved a sensitivity of 84% and a specificity of 74% with a negative predictive value of 91% for the diagnosis of OA. The changes in FENO induced by exposure to occupational agents have been investigated almost exclusively during SIC procedures. In patients with a positive SIC response, an increase in FENO occurs later (24 h) after exposure to the causal agent than an increase in sputum eosinophils (6 h) [68]. A post-challenge increase in FENO ⩾17.5 ppb showed a high specificity (90%) but a low sensitivity (45%) in predicting a positive SIC result and was predominantly associated with asthmatic reactions induced by HMW agents [19]. The diagnostic value of serial measurements of FENO at and away from work has not been investigated prospectively, although some reports suggest that it may be useful [69–72]. SICs The ERS Task Force agreed that the broad categories of clinical indications for performing SIC with an occupational agent include: “1) confirmation of the diagnosis of OA when other objective methods are not feasible, are less efficient or have failed to provide definitive results; 2) identification of the cause of OA when other objective methods are not feasible, are less efficient or have failed to provide definitive results; and 3) the identification of a not formerly described specific cause of OA” [46]. Evidence-based diagnostic algorithm The choice and order of diagnostic tests for an individual patient depend on their employment status, the nature of the suspected workplace agent(s), the available test facilities and the potential consequences of the diagnosis. Evidence-based key messages for investigating WRA symptoms are summarised in table 4.

Outcome Follow-up studies of subjects with OA indicate that persistent exposure to the causal agent is highly likely to result in worsening of the asthma [73–75]. However, complete avoidance of exposure is associated with an overall improvement of asthma severity but a full recovery in only a minority of subjects with OA. Notably, the improvement in NSBH can continue for years after cessation of exposure, but the rate of improvement is steeper during the first 2.5 years [76]. Meta-analysis of the outcome of OA after cessation of exposure yielded estimated rates of symptomatic recovery of 15–32% and persistence of NSBH of 67–73% [75, 77]. 42

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Table 4. Key messages for diagnosing occupational asthma (OA) The clinical history has a high sensitivity but a very low specificity for diagnosing OA The absence of NSBH in subjects recently exposed to the suspected agent makes the diagnosis of OA highly unlikely In subjects removed from exposure who fail to demonstrate NSBH, a normal FENO level and/or sputum eosinophil count make the diagnosis of OA highly unlikely Combining the presence of NSBH with a positive SPT or sIgE for HMW and LMW agents increases the specificity (∼85%) and PPV of each test alone and may be considered confirmatory for probable OA A high level of sIgE against some HMW agents (i.e. wheat, rye, latex) provides a high specificity and PPV (>95%) Serial PEF recordings at and off work provide moderate sensitivity (∼82%) but higher specificity (∼88%) for diagnosing OA and are more reliable in confirming OA than excluding OA Combining an increase in sputum eosinophils ⩾2% at work with serial PEF measurements enhances the specificity of PEF, while the sensitivity is not significantly modified Specific inhalation challenge in the laboratory (or at the workplace) still remains the “reference standard” for diagnosing OA NSBH: nonspecific bronchial hyperresponsiveness; SPT: skin-prick test; sIgE: serum-specific IgE antibody; HMW: high molecular weight; LMW: low molecular weight; PPV: positive predictive value.

The mechanisms leading to the remission or persistence of asthma after avoidance of exposure to the offending agent remain largely unexplored. Some studies reported an association with certain types of underlying immune-mediated inflammatory processes and the prognosis of the disease [78–82]. However, these data need to be confirmed by larger studies. Several host- and exposure-related factors have consistently been found to influence the outcome of OA [83]. A higher level of airflow obstruction at the time of diagnosis, a higher level of NSBH, a longer duration of symptomatic exposure and an older age were associated with a worse outcome, emphasising the importance of an early diagnosis of OA. In contrast, sex, atopy and smoking status did not affect the outcome. The determinants of severe OA and its diverse dimensions [84] at the time of diagnosis have been investigated in a recent European multicentre cohort of subjects with OA [85]. This study identified potentially modifiable risk factors for severe OA (i.e. a persistently high level of exposure to the causal agent and the duration of symptomatic exposure) that should be targeted to reduce the adverse impacts of the disease. The findings of this cohort study also highlighted host-related risk factors for severe OA (i.e. a low level of education, a history of childhood asthma and daily sputum production) that may help clinicians identify those subjects who have a higher risk of more severe asthma.

Management Systematic reviews [73–75] and expert guidelines [1, 86, 87] indicate that complete avoidance of exposure to the causal agent is the most successful treatment strategy for OA. As specific responsiveness to occupational agents very rarely (if ever) disappears, workers with OA should be considered permanently disabled with respect to work involving exposure to the agent that caused their disease [88, 89]. Reduction of exposure to the causal agent can be considered as an alternative with a lower socioeconomic impact than complete avoidance [74, 90], but this approach seems to be less https://doi.org/10.1183/2312508X.10034119

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beneficial than complete cessation [74, 90]. Respiratory protective equipment can result in an improvement of asthma symptoms or prevent symptoms in some but not all workers. However, it should not be considered a safe approach, especially in the long term or in patients with severe asthma [90]. Pharmacological treatment of OA should be adapted to the level of asthma control according to international guidelines issued for the management of asthma in general. However, there is no evidence that treatment with inhaled corticosteroids and long-acting β2-agonists can prevent long-term asthma deterioration in workers who remain exposed to the causative agent, and pharmacological treatment should not be considered as a safe alternative to environmental interventions [75]. A few reports have suggested a beneficial effect of treatment with the anti-IgE monoclonal antibody omalizumab on asthma control and exacerbations in patients with OA who remained exposed to the causal agent [91], although further prospective investigations are required. Specific allergen immunotherapy has been tested for a few agents causing OA, such as latex, flour and laboratory animals [92]. Although s.c. and sublingual immunotherapy with latex extracts reduced cutaneous and respiratory symptoms in allergic healthcare workers, the treatment induced systemic reactions in a substantial proportion of treated subjects [93]. Further investigations are needed to standardise allergen extracts and to evaluate whether immunotherapy can alter the course of OA in the long term when exposure at the workplace cannot be avoided. Patients with established OA should be thoroughly informed about the available data on the outcome of OA and the possibilities for compensation according to national regulations.

Health and socioeconomic impacts There is growing evidence from population-based surveys that WRA is associated with a more severe and less controlled disease than general asthma [94–96]. A recent retrospective multicentre cohort of subjects with OA ascertained by a positive SIC demonstrated that a substantial fraction of subjects with OA (16.2%, 95% CI 14.0–18.7%) experience severe asthma defined according to the multidimensional ERS/American Thoracic Society criteria [84, 85]. This estimate seems higher than those reported in studies of general adult asthma populations that applied the same definition of severe asthma (4.5% [97] and 6.3% [98]). The findings of this cohort further support the data reported by LEMIÈRE et al. [99, 100] who demonstrated that OA is associated with a higher risk of severe asthma exacerbations requiring an emergency room visit or hospitalisation and a greater use of healthcare resources than non-WRA. It was noteworthy that workers with OA still demonstrated an excess rate of visits to physicians and emergency departments after the cessation of exposure compared with other people with asthma. OA is likely to generate higher indirect costs than nonoccupational asthma, as cessation of exposure to the causal agent implies either expensive workplace interventions or job changes [38, 79, 101]. Follow-up studies of workers with OA have consistently documented that the condition is associated with a high rate of prolonged unemployment ranging from 14% to 69% and with a reduction in work-derived income in 44–74% of affected workers [79, 101]. The financial consequences are more pronounced in workers who completely avoid exposure to the causative agent, which may account for the finding that a substantial 44

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fraction of the patients remain in exposed jobs [101]. The adverse socioeconomic consequences of OA are predominantly affected by sociodemographic and workplacerelated factors, including reduced possibilities for relocation to an unexposed job within the same company, the lack of effective retraining programmes, an older age and a low level of education [101]. Asthma severity has been identified as a significant determinant of the impact of OA only in areas where workers affected with OA benefit from efficient financial and rehabilitation support (e.g. Finland and Quebec) [79, 102]. In addition, OA is associated with psychosocial consequences, such as impaired quality of life and psychological distress and anxiety disorders, which cannot be translated into monetary terms (i.e. intangible costs) but should also be addressed when evaluating the socioeconomic burden of the disease [103–107].

Prevention Primary prevention

Primary prevention of OA should focus on control of workplace exposures, as there is strong evidence of dose–response relationships between the level of exposure to sensitising agents and the incidence of disease [108, 109]. Exposure control can be achieved through a hierarchy of interventions that include: 1) avoiding the introduction of new materials with a high asthmagenic potential identified through quantitative structure–activity relationships [17] or other techniques [110], 2) the modification of materials in order to reduce their sensitising potential (e.g. encapsulation of detergent enzymes), 3) the substitution of sensitising agents by similar materials with lower sensitising potential (e.g. nonvolatile oligomers of diisocyanates, latex gloves with a lower protein content and no dusting powder), 4) physical changes to the workplace (e.g. the enclosure of hazardous processes, improvements in exhaust ventilation), 5) education of workers and their employers on safe work practices, and 6) the use of respiratory and dermal protective equipment for tasks that give rise to high-level exposures (e.g. spray painting). Another proposed approach is to identify susceptible individuals at the time of a pre-employment examination and exclude them from employment or from high-risk jobs. However, this strategy aimed at screening for the presence of risk factors is unduly discriminating, as currently identified markers of individual susceptibility offer only a low positive predictive value for the development of OA, especially when these markers, such as atopy, are highly prevalent in the general population [111]. Nevertheless, in a prospective study of 110 subjects starting work with laboratory animals followed up for a 2-year period, the association of atopy with a total IgE level >100 IU·mL−1 contributed significantly to the prediction of sensitisation to rat and/or mouse allergens, with a false-positive prediction rate of 10% [112]. Based on this model, pre-employment counselling to advise against laboratory animal work in atopic applicants with a total IgE level >100 IU·mL−1 might result in a 45% reduction of IgE-mediated sensitisation against rat and mouse allergens. A screening programme based on these criteria would imply the screening of 22 applicants to prevent one case of occupational sensitisation and would result in the exclusion of 3.7 applicants from laboratory animal work to prevent one case. These findings suggest that identifying subjects with an increased risk of occupational sensitisation (e.g. a high total IgE level or sensitisation to common allergens structurally related to occupational allergens) among those with atopy might improve the efficiency of pre-employment counselling. https://doi.org/10.1183/2312508X.10034119

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Regardless, physicians should carefully inform young persons with asthma or other respiratory allergies about careers in which their underlying atopic status may increase the risk of occupational sensitisation [113]. Screening and surveillance

The secondary prevention of OA implies detection of the disease at an early, and preferably pre-clinical, stage to prevent progression [111]. Its rationale is the consistent finding that the prognosis of OA is improved by early diagnosis and worsened by severe disease at the time of exposure avoidance [83]. Secondary prevention programmes are most cost-effective in settings with a high incidence of OA and when medical surveillance shortens the delay before diagnosis compared with passive case finding [111, 114]. However, little is known about the appropriate design of a medical surveillance scheme for identifying OA, as few systematic evaluations of such programmes have been undertaken [111]. Questionnaires to detect work-related respiratory and rhinitis symptoms are the main tools for OA surveillance [111], as spirometry is inefficient [115]. As questionnaires have a low specificity for OA [116], medical surveillance should be based on the sequential use of different screening tools according to evaluated algorithms in order to increase the accuracy and effectiveness of detecting OA [117]. The detection of sensitisation to occupational agents using either sIgE determination or SPTs should be included in surveillance programmes for the identification of subjects at risk of OA in workforces exposed to HMW agents [116, 118]. Questionnaire-based prediction models have been developed to predict the probability of sensitisation in workers exposed to HMW allergens. Used as a screening tool, these models make it possible to select or exclude workers for further immunological or clinical evaluations [118]. LABRECQUE et al. [119] provided formal evidence that a stepwise-designed surveillance programme is effective in identifying OA in subjects with less severe asthma and results in a more favourable outcome 2 years after removal from exposure compared with workers diagnosed after being referred by their physician. Overall, a number of observational studies and historical data have provided convincing evidence that prevention is effective in reducing the incidence of OA caused by various occupational agents, including natural rubber latex in healthcare workers [120, 121], enzymes [122, 123], flour [124], laboratory animals [125, 126], isocyanates [127] and platinum salts [128]. The relative contributions of the diverse components of multicomponent prevention strategies (education, exposure control and health surveillance) cannot readily be distinguished, as they are generally implemented simultaneously.

Conclusion OA remains a prevalent disease that imposes a substantial health and socioeconomic burden on affected workers and society. Patients with work-related respiratory symptoms experience a significant delay in obtaining an appropriate diagnostic assessment. An early and accurate diagnosis of OA is crucial for minimising the adverse health and socioeconomic consequences of the disease. Accordingly, efforts should be made to increase the awareness of OA in primary and secondary care practices and to promote the prompt referral of workers suspected of having OA to specialised centres with the expertise and facilities to conduct appropriate investigations. Diagnosing OA often remains a 46

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challenge for clinicians; the development and standardisation of diagnostic procedures and consensus diagnostic algorithms would be helpful in formulating a consistent evidencebased approach to the investigation of WRA worldwide. OA, as well as asthma in general, is a heterogeneous disease that results from multiple interactions between environmental and host-related factors. Elucidating these complex gene–environment interactions is an important step towards the implementation of optimal prevention policies. Our current understanding of the pathophysiology of OA is limited, especially regarding OA induced by LMW agents. More research is needed to identify biomarkers and develop diagnostic prediction models, allowing an easier and more accurate way of identifying OA, as well as developing cost-efficient surveillance programmes for use in high-risk workforces. Further prospective investigations are also required to evaluate the cost-effectiveness of different management options and to help clinicians identify subjects with OA at high risk for a more severe outcome, allowing a more personalised management approach aimed at minimising the health and socioeconomic impacts of the disease. Evaluating the cost-effectiveness of preventative measures and compensation systems should become a priority in assisting policy makers in elaborating rational strategies.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

Tarlo SM, Balmes J, Balkissoon R, et al. Diagnosis and management of work-related asthma: American College of Chest Physicians Consensus Statement. Chest 2008; 134: 1S–41S. Malo JL, Vandenplas O. Definitions and classification of work-related asthma. Immunol Allergy Clin North Am 2011; 31: 645–662. Henneberger PK, Redlich CA, Callahan DB, et al. An official American Thoracic Society statement: work-exacerbated asthma. Am J Respir Crit Care Med 2011; 184: 368–378. Nicholson P, Cullinan P, Burge P, et al. Occupational Asthma: Prevention, Identification & Management: Systematic Review & Recommendations. London, British Occupational Health Research Foundation, 2010. Walters GI. Work-exacerbated asthma. In: Feary J, Suojalehto H, Cullinan P, eds. Occupational and Environmental Lung Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 52–69. Burge S. Acute inhalation injury. In: Feary J, Suojalehto H, Cullinan P, eds. Occupational and Environmental Lung Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 70–85. Baur X, Bakehe P. Allergens causing occupational asthma: an evidence-based evaluation of the literature. Int Arch Occup Environ Health 2014; 87: 339–363. Cartier A. New causes of immunologic occupational asthma, 2012–2014. Curr Opin Allergy Clin Immunol 2015; 15: 117–123. Vandenplas O, Godet J, Hurdubaea L, et al. Are high- and low-molecular-weight sensitizing agents associated with different clinical phenotypes of occupational asthma? Allergy 2019; 74: 261–272. Jeebhay MF, Quirce S. Occupational asthma in the developing and industrialised world: a review. Int J Tuberc Lung Dis 2007; 11: 122–133. Vandenplas O. Occupational asthma: etiologies and risk factors. Allergy Asthma Immunol Res 2011; 3: 157–167. Paris C, Ngatchou-Wandji J, Luc A, et al. Work-related asthma in France: recent trends for the period 2001–2009. Occup Environ Med 2012; 69: 391–397. Walters GI, Kirkham A, McGrath EE, et al. Twenty years of SHIELD: decreasing incidence of occupational asthma in the West Midlands, UK? Occup Environ Med 2015; 72: 304–310. Reilly MJ, Wang L, Rosenman KD. The burden of work-related asthma in Michigan, 1988–2018. Ann Am Thorac Soc 2020; 17: 284–292. Enoch SJ, Seed MJ, Roberts DW, et al. Development of mechanism-based structural alerts for respiratory sensitization hazard identification. Chem Res Toxicol 2012; 25: 2490–2498. Pralong JA, Seed MJ, Yasri R, et al. A computer based asthma hazard prediction model and new molecular weight agents in occupational asthma. Occup Environ Med 2013; 70: 70.

https://doi.org/10.1183/2312508X.10034119

47

ERS MONOGRAPH | OCCUPATIONAL AND ENVIRONMENTAL LUNG DISEASE 17. 18. 19. 20. 21. 22.

23.

24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36.

37. 38. 39. 40. 41. 42. 43. 44. 45.

48

Seed MJ, Agius RM. Progress with structure–activity relationship modelling of occupational chemical respiratory sensitizers. Curr Opin Allergy Clin Immunol 2017; 17: 64–71. Prince P, Lemiere C, Dufour MH, et al. Airway inflammatory responses following exposure to occupational agents. Chest 2012; 141: 1522–1527. Lemiere C, NGuyen S, Sava F, et al. Occupational asthma phenotypes identified by increased fractional exhaled nitric oxide after exposure to causal agents. J Allergy Clin Immunol 2014; 134: 1063–1067. Suojalehto H, Suuronen K, Cullinan P, et al. Phenotyping occupational asthma caused by acrylates in a multicentre cohort study. J Allergy Clin Immunol Pract 2020; 8: 971–979.e1. Cullinan P, Cook A, Gordon S, et al. Allergen exposure, atopy and smoking as determinants of allergy to rats in a cohort of laboratory employees. Eur Respir J 1999; 13: 1139–1143. Cullinan P, Cook A, Nieuwenhuijsen MJ, et al. Allergen and dust exposure as determinants of work-related symptoms and sensitization in a cohort of flour-exposed workers; a case–control analysis. Ann Occup Hyg 2001; 45: 97–103. Archambault S, Malo JL, Infante-Rivard C, et al. Incidence of sensitization, symptoms, and probable occupational rhinoconjunctivitis and asthma in apprentices starting exposure to latex. J Allergy Clin Immunol 2001; 107: 921–923. Karjalainen A, Kurppa K, Virtanen S, et al. Incidence of occupational asthma by occupation and industry in Finland. Am J Ind Med 2000; 37: 451–458. Ameille J, Pauli G, Calastreng-Crinquand A, et al. Reported incidence of occupational asthma in France, 1996–99: the ONAP programme. Occup Environ Med 2003; 60: 136–141. Reinisch F, Harrison RJ, Cussler S, et al. Physician reports of work-related asthma in California, 1993–1996. Am J Ind Med 2001; 39: 72–83. McDonald JC, Chen Y, Zekveld C, et al. Incidence by occupation and industry of acute work related respiratory diseases in the UK, 1992–2001. Occup Environ Med 2005; 62: 836–842. Piipari R, Keskinen H. Agents causing occupational asthma in Finland in 1986–2002: cow epithelium bypassed by moulds from moisture-damaged buildings. Clin Exp Allergy 2005; 35: 1632–1637. Orriols R, Isidro I, Abu-Shams K, et al. Reported occupational respiratory diseases in three Spanish regions. Am J Ind Med 2010; 53: 922–930. Vandenplas O, Lantin AC, D’Alpaos V, et al. Time trends in occupational asthma in Belgium. Respir Med 2011; 105: 1364–1372. Stocks SJ, Bensefa-Colas L, Berk SF. Worldwide trends in incidence in occupational allergy and asthma. Curr Opin Allergy Clin Immunol 2016; 16: 113–119. Jeebhay MF, Ngajilo D, le Moual N. Risk factors for nonwork-related adult-onset asthma and occupational asthma: a comparative review. Curr Opin Allergy Clin Immunol 2014; 14: 84–94. Mazurek JM, Knoeller GE, Moorman JE, et al. Occupational asthma incidence: findings from the Behavioral Risk Factor Surveillance System Asthma Call-back survey – United States, 2006–2009. J Asthma 2013; 50: 390–394. Karjalainen A, Kurppa K, Martikainen R, et al. Work is related to a substantial portion of adult-onset asthma incidence in the Finnish population. Am J Respir Crit Care Med 2001; 164: 565–568. Kogevinas M, Zock JP, Jarvis D, et al. Exposure to substances in the workplace and new-onset asthma: an international prospective population-based study (ECRHS-II). Lancet 2007; 370: 336–341. Blanc PD, Annesi-Maesano I, Balmes JR, et al. The occupational burden of nonmalignant respiratory diseases. An official American Thoracic Society and European Respiratory Society Statement. Am J Respir Crit Care Med 2019; 199: 1312–1334. Toren K, Blanc PD. Asthma caused by occupational exposures is common – a systematic analysis of estimates of the population-attributable fraction. BMC Pulm Med 2009; 9: 7. Ayres JG, Boyd R, Cowie H, et al. Costs of occupational asthma in the UK. Thorax 2011; 66: 128–133. Baur X, Sigsgaard T, Aasen TB, et al. Guidelines for the management of work-related asthma. Eur Respir J 2012; 39: 529–545. Tarlo SM, Lemiere C. Occupational asthma. N Engl J Med 2014; 370: 640–649. Fishwick D, Bradshaw L, Davies J, et al. Are we failing workers with symptoms suggestive of occupational asthma? Prim Care Respir J 2007; 16: 304–310. Santos MS, Jung H, Peyrovi J, et al. Occupational asthma and work-exacerbated asthma: factors associated with time to diagnostic steps. Chest 2007; 131: 1768–1775. Shofer S, Haus BM, Kuschner WG. Quality of occupational history assessments in working age adults with newly diagnosed asthma. Chest 2006; 130: 455–462. Barber CM, Naylor S, Bradshaw LM, et al. Approaches to the diagnosis and management of occupational asthma amongst UK respiratory physicians. Respir Med 2007; 101: 1903–1908. Beach J, Russell K, Blitz S, et al. A systematic review of the diagnosis of occupational asthma. Chest 2007; 131: 569–578.

https://doi.org/10.1183/2312508X.10034119

SENSITISER-INDUCED OCCUPATIONAL ASTHMA | O. VANDENPLAS AND C. LEMIÈRE 46. 47.

48. 49. 50. 51. 52. 53.

54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73.

Vandenplas O, Suojalehto H, Aasen TB, et al. Specific inhalation challenge in the diagnosis of occupational asthma: consensus statement. Eur Respir J 2014; 43: 1573–1587. Ortega HG, Weissman DN, Carter DL, et al. Use of specific inhalation challenge in the evaluation of workers at risk for occupational asthma: a survey of pulmonary, allergy, and occupational medicine residency training programs in the United States and Canada. Chest 2002; 121: 1323–1328. Suojalehto H, Cullinan P. Specific inhalation challenge tests for occupational asthma in Europe: a survey. Eur Respir Rev 2014; 23: 266–270. Lux H, Lenz K, Budnik LT, et al. Performance of specific immunoglobulin E tests for diagnosing occupational asthma: a systematic review and meta-analysis. Occup Environ Med 2019; 76: 269–278. Pralong JA, Lemiere C, Rochat T, et al. Predictive value of nonspecific bronchial responsiveness in occupational asthma. J Allergy Clin Immunol 2016; 137: 412–416. Quirce S, Swanson MC, Fernandez-Nieto M, et al. Quantified environmental challenge with absorbable dusting powder aerosol from natural rubber latex gloves. J Allergy Clin Immunol 2003; 111: 788–794. Côté J, Kennedy S, Chan-Yeung M. Sensitivity and specificity of PC20 and peak expiratory flow rate in cedar asthma. J Allergy Clin Immunol 1990; 85: 592–598. Perrin B, Lagier F, L’Archeveque J, et al. Occupational asthma: validity of monitoring of peak expiratory flow rates and non-allergic bronchial responsiveness as compared to specific inhalation challenge. Eur Respir J 1992; 5: 40–48. Girard F, Chaboillez S, Cartier A, et al. An effective strategy for diagnosing occupational asthma: use of induced sputum. Am J Respir Crit Care Med 2004; 170: 845–850. Malo JL, Ghezzo H, L’Archevêque J, et al. Is the clinical history a satisfactory means of diagnosing occupational asthma? Am Rev Respir Dis 1991; 143: 528–532. Vandenplas O, Binard-Van Cangh F, Brumagne A, et al. Occupational asthma in symptomatic workers exposed to natural rubber latex: evaluation of diagnostic procedures. J Allergy Clin Immunol 2001; 107: 542–547. Vandenplas O, Ghezzo H, Munoz X, et al. What are the questionnaire items most useful in identifying subjects with occupational asthma? Eur Respir J 2005; 26: 1056–1063. Beretta C, Rifflart C, Evrard G, et al. Assessment of eosinophilic airway inflammation as a contribution to the diagnosis of occupational asthma. Allergy 2018; 73: 206–213. van Kampen V, de Blay F, Folletti I, et al. Evaluation of commercial skin prick test solutions for selected occupational allergens. Allergy 2013; 68: 651–658. van Kampen V, de Blay F, Folletti I, et al. EAACI position paper: skin prick testing in the diagnosis of occupational type I allergies. Allergy 2013; 68: 580–584. Baur X, Akdis CA, Budnik LT, et al. Immunological methods for diagnosis and monitoring of IgE-mediated allergy caused by industrial sensitizing agents (IMExAllergy). Allergy 2019; 74: 1885–1897. van Kampen V, Rabstein S, Sander I, et al. Prediction of challenge test results by flour-specific IgE and skin prick test in symptomatic bakers. Allergy 2008; 63: 897–902. Vandenplas O, Froidure A, Meurer U, et al. The role of allergen components for the diagnosis of latex-induced occupational asthma. Allergy 2016; 71: 840–849. Bardy JD, Malo JL, Seguin P, et al. Occupational asthma and IgE sensitization in a pharmaceutical company processing psyllium. Am Rev Respir Dis 1987; 135: 1033–1038. Park D, Moore VC, Burge CB, et al. Serial PEF measurement is superior to cross-shift change in diagnosing occupational asthma. Eur Respir J 2009; 34: 574–578. Moore V, Jaakkola M, Burge P. A systematic review of serial peak expiratory flow measurements in the diagnosis of occupational asthma. Ann Respir Med 2010; 1: 31–44. Racine G, Castano R, Cartier A, et al. Diagnostic accuracy of inflammatory markers for diagnosing occupational asthma. J Allergy Clin Immunol Pract 2017; 5: 1371–1377.e1. Lemiere C, D’Alpaos V, Chaboillez S, et al. Investigation of occupational asthma: sputum cell counts or exhaled nitric oxide? Chest 2010; 137: 617–622. Hewitt RS, Smith AD, Cowan JO, et al. Serial exhaled nitric oxide measurements in the assessment of laboratory animal allergy. J Asthma 2008; 45: 101–107. Pala G, Pignatti P, Moscato G. The use of fractional exhaled nitric oxide in investigation of work-related cough in a hairdresser. Am J Ind Med 2011; 54: 565–568. Merget R, Sander I, van Kampen V, et al. Serial measurements of exhaled nitric oxide at work and at home: a new tool for the diagnosis of occupational asthma. Adv Exp Med Biol 2015; 834: 49–52. van Kampen V, Bruning T, Merget R. Serial fractional exhaled nitric oxide measurements off and at work in the diagnosis of occupational asthma. Am J Ind Med 2019; 62: 663–671. Beach J, Rowe BH, Blitz S, et al. Diagnosis and Management of Occupational Asthma. Evidence Reports/ Technology Assessments, No. 129. Rockville, US Department of Health and Human Services, Agency for Healthcare Research and Quality, 2005.

https://doi.org/10.1183/2312508X.10034119

49

ERS MONOGRAPH | OCCUPATIONAL AND ENVIRONMENTAL LUNG DISEASE 74.

de Groene GJ, Pal TM, Beach J, et al. Workplace interventions for treatment of occupational asthma. Cochrane Database Syst Rev 2011; 10: CD006308. 75. Vandenplas O, Dressel H, Nowak D, et al. What is the optimal management option for occupational asthma? Eur Respir Rev 2012; 21: 97–104. 76. Malo JL, Ghezzo H. Recovery of methacholine responsiveness after end of exposure in occupational asthma. Am J Respir Crit Care Med 2004; 169: 1304–1307. 77. Rachiotis G, Savani R, Brant A, et al. Outcome of occupational asthma after cessation of exposure: a systematic review. Thorax 2007; 62: 147–152. 78. Maghni K, Lemière C, Ghezzo H, et al. Airway inflammation after cessation of exposure to agents causing occupational asthma. Am J Respir Crit Care Med 2004; 169: 367–372. 79. Piirila PL, Meuronen A, Majuri ML, et al. Inflammation and functional outcome in diisocyanate-induced asthma after cessation of exposure. Allergy 2008; 63: 583–591. 80. Lemiere C, Chaboillez S, Bohadana A, et al. Noneosinophilic responders with occupational asthma: a phenotype associated with a poor asthma prognosis. J Allergy Clin Immunol 2014; 133: 883–885.e3. 81. Froidure A, Vandenplas O, D’Alpaos V, et al. Persistence of asthma following allergen avoidance is associated with proTh2 myeloid dendritic cell activation. Thorax 2015; 70: 967–973. 82. Froidure A, Vandenplas O, D’Alpaos V, et al. Defects in plasmacytoid dendritic cell expression of inducible costimulator ligand and IFN-α are associated in asthma with disease persistence. Am J Respir Crit Care Med 2015; 192: 392–395. 83. Maestrelli P, Schlunssen V, Mason P, et al. Contribution of host factors and workplace exposure to the outcome of occupational asthma. Eur Respir Rev 2012; 21: 88–96. 84. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014; 43: 343–373. 85. Vandenplas O, Godet J, Hurdubaea L, et al. Severe occupational asthma: insights from a multicenter European cohort. J Allergy Clin Immunol Pract 2019; 7: 2309–2318.e4. 86. Nicholson PJ, Cullinan P, Burge S. Concise guidance: diagnosis, management and prevention of occupational asthma. Clin Med 2012; 12: 156–159. 87. Baur X, Aasen TB, Burge PS, et al. The management of work-related asthma guidelines: a broader perspective. Eur Respir Rev 2012; 21: 125–139. 88. Lemière C, Cartier A, Dolovich J, et al. Outcome of specific bronchial responsiveness to occupational agents after removal from exposure. Am J Respir Crit Care Med 1996; 154: 329–333. 89. Lemière C, Cartier A, Malo JL, et al. Persistent specific bronchial reactivity to occupational agents in workers with normal nonspecific bronchial reactivity. Am J Respir Crit Care Med 2000; 162: 976–980. 90. Vandenplas O, Dressel H, Wilken D, et al. Management of occupational asthma: cessation or reduction of exposure? A systematic review of available evidence. Eur Respir J 2011; 38: 804–811. 91. Lavaud F, Bonniaud P, Dalphin JC, et al. Usefulness of omalizumab in ten patients with severe occupational asthma. Allergy 2013; 68: 813–815. 92. Moscato G, Pala G, Sastre J. Specific immunotherapy and biological treatments for occupational allergy. Curr Opin Allergy Clin Immunol 2014; 14: 576–581. 93. Nettis E, Delle Donne P, Di Leo E, et al. Latex immunotherapy: state of the art. Ann Allergy Asthma Immunol 2012; 109: 160–165. 94. Le Moual N, Siroux V, Pin I, et al. Asthma severity and exposure to occupational asthmogens. Am J Respir Crit Care Med 2005; 172: 440–445. 95. Henneberger PK, Mirabelli MC, Kogevinas M, et al. The occupational contribution to severe exacerbation of asthma. Eur Respir J 2010; 36: 743–750. 96. Le Moual N, Carsin AE, Siroux V, et al. Occupational exposures and uncontrolled adult-onset asthma in the European Community Respiratory Health Survey II. Eur Respir J 2014; 43: 374–386. 97. Hekking PP, Wener RR, Amelink M, et al. The prevalence of severe refractory asthma. J Allergy Clin Immunol 2015; 135: 896–902. 98. von Bulow A, Backer V, Bodtger U, et al. The level of diagnostic assessment in severe asthma: a nationwide real-life study. Respir Med 2017; 124: 21–29. 99. Lemière C, Forget A, Dufour MH, et al. Characteristics and medical resource use of asthmatic subjects with and without work-related asthma. J Allergy Clin Immunol 2007; 120: 1354–1359. 100. Lemière C, Boulet LP, Chaboillez S, et al. Work-exacerbated asthma and occupational asthma: do they really differ? J Allergy Clin Immunol 2013; 131: 704–710. 101. Vandenplas O. Socioeconomic impact of work-related asthma. Expert Rev Pharmacoecon Outcomes Res 2008; 8: 395–400. 102. Malo JL, L’Archeveque J, Ghezzo H. Direct costs of occupational asthma in Quebec between 1988 and 2002. Can Respir J 2008; 15: 413–416.

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SENSITISER-INDUCED OCCUPATIONAL ASTHMA | O. VANDENPLAS AND C. LEMIÈRE 103. Malo JL, Boulet LP, Dewitte JD, et al. Quality of life of subjects with occupational asthma. J Allergy Clin Immunol 1993; 91: 1121–1127. 104. Piirila PL, Keskinen HM, Luukkonen R, et al. Work, unemployment and life satisfaction among patients with diisocyanate induced asthma – a prospective study. J Occup Health 2005; 47: 112–118. 105. Yacoub MR, Lavoie K, Lacoste G, et al. Assessment of impairment/disability due to occupational asthma through a multidimensional approach. Eur Respir J 2007; 29: 889–896. 106. Miedinger D, Lavoie KL, L’Archeveque J, et al. Quality-of-life, psychological, and cost outcomes 2 years after diagnosis of occupational asthma. J Occup Environ Med 2011; 53: 231–238. 107. Mazurek JM, Knoeller GE, Moorman JE. Effect of current depression on the association of work-related asthma with adverse asthma outcomes: a cross-sectional study using the Behavioral Risk Factor Surveillance System. J Affect Disord 2012; 136: 1135–1142. 108. Tarlo SM, Liss GM. Prevention of occupational asthma. Curr Allergy Asthma Rep 2010; 10: 278–286. 109. Heederik D, Henneberger PK, Redlich CA. Primary prevention: exposure reduction, skin exposure and respiratory protection. Eur Respir Rev 2012; 21: 112–124. 110. North CM, Ezendam J, Hotchkiss JA, et al. Developing a framework for assessing chemical respiratory sensitization: a workshop report. Regul Toxicol Pharmacol 2016; 80: 295–309. 111. Wilken D, Baur X, Barbinova L, et al. What are the benefits of medical screening and surveillance? Eur Respir Rev 2012; 21: 105–111. 112. Krop EJM, Heederik DJJ, Lutter R, et al. Associations between pre-employment immunologic and airway mucosal factors and the development of occupational allergy. J Allergy Clin Immunol 2009; 123: 694–700. 113. Moscato G, Pala G, Boillat MA, et al. EAACI position paper: prevention of work-related respiratory allergies among pre-apprentices or apprentices and young workers. Allergy 2011; 66: 1164–1173. 114. Wild DM, Redlich CA, Paltiel AD. Surveillance for isocyanate asthma: a model based cost effectiveness analysis. Occup Environ Med 2005; 62: 743–749. 115. Mackie J. Effective health surveillance for occupational asthma in motor vehicle repair. Occup Med (Lond) 2008; 58: 551–555. 116. Brant A, Nightingale S, Berriman J, et al. Supermarket baker’s asthma: how accurate is routine health surveillance? Occup Environ Med 2005; 62: 395–399. 117. Vandenplas O, Delwiche JP, Evrard G, et al. Prevalence of occupational asthma due to latex among hospital personnel. Am J Respir Crit Care Med 1995; 151: 54–60. 118. Meijer E, Suarthana E, Rooijackers J, et al. Application of a prediction model for work-related sensitisation in bakery workers. Eur Respir J 2010; 36: 735–742. 119. Labrecque M, Malo JL, Alaoui KM, et al. Medical surveillance programme for diisocyanate exposure. Occup Environ Med 2011; 68: 302–307. 120. Bousquet J, Flahault A, Vandenplas O, et al. Natural rubber latex allergy among health care workers: a systematic review of the evidence. J Allergy Clin Immunol 2006; 118: 447–454. 121. Vandenplas O, Larbanois A, Vanassche F, et al. Latex-induced occupational asthma: time trend in incidence and relationship with hospital glove policies. Allergy 2009; 64: 415–420. 122. Cathcart M, Nicholson P, Roberts D, et al. Enzyme exposure, smoking and lung function in employees in the detergent industry over 20 years. Occup Med (Lond) 1997; 47: 473–478. 123. Larsen AI, Cederkvist L, Lykke AM, et al. Allergy development in adulthood: an occupational cohort study of the manufacturing of industrial enzymes. J Allergy Clin Immunol Pract 2020; 8: 210–218.e5. 124. Meijster T, Tielemans E, Heederik D. Effect of an intervention aimed at reducing the risk of allergic respiratory disease in bakers: change in flour dust and fungal alpha-amylase levels. Occup Environ Med 2009; 66: 543–549. 125. Gordon S, Preece R. Prevention of laboratory animal allergy. Occup Med (Lond) 2003; 53: 371–377. 126. Folletti I, Forcina A, Marabini A, et al. Have the prevalence and incidence of occupational asthma and rhinitis because of laboratory animals declined in the last 25 years? Allergy 2008; 63: 834–841. 127. Tarlo SM, Liss GM, Yeung KS. Changes in rates and severity of compensation claims for asthma due to diisocyanates: a possible effect of medical surveillance measures. Occup Environ Med 2002; 59: 58–62. 128. Merget R, Caspari C, Dierkes-Globisch A, et al. Effectiveness of a medical surveillance program for the prevention of occupational asthma caused by platinum salts: a nested case–control study. J Allergy Clin Immunol 2001; 107: 707–712.

Disclosures: C. Lemière reports receiving the following, outside the submitted work: grants and personal fees for acting on an advisory board and speaker fees from AstraZeneca, GlaxoSmithKline and TEVA Innovation; personal fees for acting on an advisory board from Sanofi and Novartis. Support statement: This work was funded in part by the Fondation Mont-Godinne (Yvoir, Belgium). Acknowledgements: The authors wish to thank Mr James Hatch for reviewing the manuscript.

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| Chapter 4 Work-exacerbated asthma Gareth I. Walters Work-exacerbated asthma (WEA) has a prevalence comparable to that of occupational asthma (OA) and occurs in approximately one-fifth of working adults with asthma. Workplace exposures that exacerbate pre-existing asthma differ somewhat from those of OA and include airway irritants, aeroallergens, environmental conditions, strenuous physical exertion and emotional stress. A diagnosis of WEA has socioeconomic consequences of a magnitude similar to those in OA. Making the distinction between WEA and OA by sensitisation is a challenge but is important, as the management of individual workers and the workplace is likely to be different. There are a number of other asthma mimics, which may show a relationship with work, that also require consideration and exclusion. For the practising clinician, taking a thorough medical and occupational history is of paramount importance, and onward referral to a specialist and further investigation may be necessary. Primary prevention, worker education, optimisation of asthma treatment and tailored measures to reduce workplace exposures may improve outcomes for individuals, although the effectiveness of workplace interventions in reducing the incidence and impact of WEA is unknown. Cite as: Walters GI. Work-exacerbated asthma. In: Feary J, Suojalehto H, Cullinan P, eds. Occupational and Environmental Lung Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 52–69 [https://doi.org/10.1183/2312508X.10034219].

@ERSpublications Work-exacerbated asthma (WEA) is common and is as prevalent as occupational asthma (OA). Distinguishing WEA from OA and other occupational airways diseases is necessary as the management and socioeconomic consequences for the individual worker may differ. https://bit.ly/3310jTg

A

sthma affects up to 18% of the population, depending on the country studied [1], and exacerbations characterised by increasing symptoms and/or treatment requirements are commonly seen. Thus, asthma remains a substantial burden on global healthcare, with an additional societal cost in terms of sickness absence and loss of productivity. For the affected individual, minimising exacerbation is crucial for the prevention of lung function decline and poor health outcome. Although exacerbations are frequently attributed to viral infection and exposure to environmental allergens, the role of workplace exposures in exacerbations is often overlooked. A recent American Thoracic Society (ATS) systematic review revealed that 16% of incident asthma can now be attributed to occupational

NHS Occupational Lung Disease Service, Birmingham Chest Clinic, Birmingham, UK. Correspondence: Gareth I. Walters, NHS Occupational Lung Disease Service, Birmingham Chest Clinic, 151 Great Charles Street, Birmingham B3 3HX, UK. E-mail: [email protected] Copyright ©ERS 2020. Print ISBN: 978-1-84984-124-5. Online ISBN: 978-1-84984-125-2. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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exposure, based on a meta-analysis of risk estimates from nine general population cohort studies [2]. Surprisingly given its potential consequences, the role of work exposure in exacerbated asthma had been researched less systematically until recently.

Definition Work-exacerbated asthma (WEA) is a disease entity existing under the umbrella term work-related asthma (WRA), as designated by the European Respiratory Society (ERS) Task Force (figure 1) [3]. Synonymous with the term work-aggravated asthma, WEA can be defined simply as “asthma that is worsened, but not caused by, conditions at work”. A definitive ATS review and statement by HENNEBERGER et al. [4] on WEA in 2011 recommended that four diagnostic criteria be applied: 1) the presence of pre-existing or concurrent asthma (where concurrent asthma is defined as asthma with onset while employed but not attributed to work exposure), 2) a temporal relationship between asthma and work, 3) conditions present at work that can exacerbate asthma, and 4) a diagnosis unlikely to be occupational asthma (OA). Other reviews, including the ERS Task Force report, have limited the definition to those with pre-existing and not concurrent asthma [3, 5]. Although both can have significant health, financial and societal costs, WEA must be differentiated from OA caused by either sensitising agents or airway irritants, as the management, outcome and legal implications may differ. There are also a number of diagnostic mimics that may have work-related symptomatology that should be recognised and accounted for (e.g. inducible laryngeal obstruction (ILO), obliterative bronchiolitis); these are discussed in detail in this chapter. WEA has been captured by surveillance schemes, researched in general and hospital-based populations (largely in North America and Europe) and examined in response to more specific exposures. The case definition for WEA varies according to the type of study, and may be clinical or based on objective testing; in epidemiological work in particular, it can be problematic to separate work as the cause of asthma from aggravation of symptoms. Work-related asthma

Occupational asthma

IgEmediated occupational asthma

Occupational asthma due to specific occupational agents with unknown pathomechanisms

Work-aggravated (exacerbated) asthma

Irritant occupational asthma

Figure 1. Work-related asthma and its subgroups, as defined by the European Respiratory Society Task Force on Work-related Asthma. Ig: immunoglobulin. Reproduced and modified from [3] with permission.

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Prevalence Although OA has previously been better evaluated than WEA, there is evidence from >20 years of work in a number of settings that WEA is common and is as prevalent as OA. The 2011 ATS statement, derived from a systematic review of medical literature published before 2009, reported a prevalence of 13–58% (median 21.5%) for WEA in adults with asthma, derived from 12 epidemiological studies performed in the general population or in general healthcare settings, almost all from Western industrialised countries [4]. The range of prevalence estimates is accounted for, at least in part, by the differences in case definition of WEA among studies. Many of the included surveillance reports and general population studies were based on self-reported symptoms, without any lung function measurement, objective testing for OA or expert opinion. Studies using objective criteria, either work-related PEF changes or expert review of exposures and symptomatology, reported lower prevalences (range 13–22%, median 14%) [6–8]. However, monitoring workers for changes in symptomatology, which may be short lived or periodic, with objective physiological changes is difficult to achieve in large-scale general population studies, or indeed outside a specialist clinic setting. Since 2011, other reviewers have concluded broadly that WEA is common and underappreciated [9–11]. A relatively small number of studies undertaken since 2009, and therefore not included in the 2011 ATS review, have addressed the prevalence of WEA; examples are summarised in table 1. Where estimates related specifically to WEA rather than WRA, prevalences ranged from 15% to 41%. The largest population-based study used data from the Asthma Call-back Survey from 29 US states to determine the prevalence of WRA (15%) among current people with asthma, although WEA per se was not discriminated from OA [18]. The definition of WEA again varied among studies, including self-reported symptoms only, specialist review or investigation, and hospital attendance or increased medication use. LUTZKER et al. [12] used a broad and sensitive definition of WEA based on self-reported symptomatology in an expanded version of the Asthma Call-back Survey in three US states. The authors found that 49–50% of people with asthma reported work exacerbation at some point during their working life. When differentiating current and lifetime WEA, 18–24% of asthma sufferers were exacerbated by their current job and 30–37% by previous lifetime exposures.

Causative agents and occupations A number of studies have evaluated the prevalence or risk of WEA by exposure or by job role. Earlier studies have been presented in detail in previously published reviews where compendia of causative exposures have been given [4, 5, 10]. The implicated causative agents and occupations in WEA differ somewhat from those of OA, where the commonly reported exposures are low-molecular weight (LMW) and high-molecular weight (HMW) respiratory sensitisers such as isocyanates and wheat flour, respectively. WEA can be associated with irritant exposures (e.g. chemicals, dusts, second-hand tobacco smoke), aeroallergens and other respiratory sensitisers that are also environmental (e.g. grass pollen, moulds), and other nonspecific workplace conditions such as ambient temperature, physically strenuous work and emotional stress. There are few data on exposure levels or the effectiveness of current workplace exposure limits, although WEA may be triggered by sustained low- or high-level irritant exposures, or by accidental exposure to high levels such as following chemical leaks and spills. 54

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Table 1. Examples of studies reporting the prevalence of work-exacerbated asthma (WEA) in the general population and in specialist healthcare settings since 2009, including studies reporting work-related asthma (WRA) First author [ref.]

LUTZKER [12]

Country

Setting and number of participants

Age of participants years

USA (results from three states)

General population telephone survey with work-related questions in 2408 adults (⩾18 years) reporting doctor-diagnosed asthma, of whom 1666 had current asthma Cross-sectional study of 557 medically insured adults with active asthma by questionnaire and medical records review; occupational exposures examined using a JEM Cross-sectional study in primary healthcare population, using expert review of medical records and interviews, including 368 working-age adults with coded diagnosis of asthma Cross-sectional study in a hospital clinic population of 179 currently employed adults (>17 years of age) with physician-diagnosed asthma Cross-sectional questionnaire of 1289 working-age people with asthma identified from a general population disease register

Average age unclear

WRA: an affirmative response to any of six questions about work-relatedness; WEA: where questions related to aggravation of symptoms

Prevalence of WRA: 53–54%; asthma symptoms aggravated by current job in 18–24%

18–44 (median 34)

WEA: severe exacerbation of asthma in preceding 12 months (i.e. hospitalisation or short-course oral steroid treatment)

16–64 (mean ±SD 45±12)

Participants assigned to groups (OA, WEA or non-WRA) based on expert analysis of data (interview and medical records)

Prevalence of severe exacerbation: 29%; elevated PRs for second-hand tobacco smoke, inorganic dusts or LMW agents Prevalence of WEA: 15%

39±13 (mean ±SD)

Self-reported current work-related symptoms (at least two)

Prevalence of WEA: 22%

35±7 (mean ±SD)

WEA: work-related symptoms on questionnaire; OA positively excluded by further investigation and expert opinion

Prevalence of WEA: 41% (50% if exposed to gas, fume or dust)

HENNEBERGER [13]

USA

VILLA-RIGAT [14]

Spain

Iran

TALINI [16]

Italy

Prevalence measure

Continued

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SADEGHNIIAT-HAGHIGHI [15]

Case definition for WEA or WRA

First author [ref.]

BRADSHAW [17]

DODD [18] https://doi.org/10.1183/2312508X.10034219

Country

Setting and number of participants

Age of participants years

Case definition for WEA or WRA

UK

Responses from 207 postal questionnaires sent to people with asthma (⩾18 years of age) from a mixture of primary and secondary care registers and via a third-sector organisation General population telephone survey with work-related questions in 20 823 adults (⩾18 years of age) reporting doctor-diagnosed asthma, of whom 14 915 had current asthma

48±15 (mean ±SD)

Self-reported diagnosis of current asthma, in employment, with work-aggravated symptoms

Prevalence of WEA: 33.3% (95% CI 24.4– 41.6%)

Average age unclear

WRA: those with current asthma, who were “ever told by a doctor that work caused or exacerbated asthma”

Prevalence of WRA: 14.7%

USA (results from 29 states)

JEM: job–exposure matrix; PR: prevalence ratio; LMW: low molecular weight; OA: occupational asthma.

Prevalence measure

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Table 1. Continued

WORK-EXACERBATED ASTHMA | G.I. WALTERS

Population-based studies and reports from surveillance schemes included in the 2011 ATS review have identified occupations with a higher prevalence of WEA, often using job– exposure matrices (JEMs) to determine exposures [4]. These have included manufacturing, agriculture, cleaning, waste handling, hairdressing, wholesale and retail trade, sales and administrative support, public service work, educational services, police and security work, and garment or textile work [19–21]. More recent data from a large-scale US annual health survey [22] revealed a variation in the prevalence of self-reported current asthma, exacerbations and emergency hospital attendances among major occupational groups; crudely, the prevalence of asthma was highest in healthcare, social care and education industries and occupations. In a Canadian workers’ compensation scheme, the most frequently encountered industries implicated in claims for asthma were healthcare and education, as well as services [23]. In a cross-sectional questionnaire study in adults with asthma aged 18–44 years, HENNEBERGER et al. [13] observed elevated prevalence ratios (PRs) for several specific-airway irritants: second-hand tobacco smoke (PR 1.84, 95% CI 1.34–2.51), inorganic dusts in men (PR 2.53, 95% CI 1.37– 4.67) and LMW reactive agents in women (PR 1.97, 95% CI 1.08– 3.60), although the small sample size prevented analysis of a dose–response effect. KIM et al. [24] undertook a cross-sectional study in participants of four previous Swedish cohorts, assigning job and exposure according to a JEM, and establishing the prevalence of different exposures in WEA. Any gas, smoke or dust was associated with severe exacerbation of asthma (OR 1.7, 95% CI 1.2–2.6), as were organic dust (OR 1.7, 95% CI 1.2–2.5), dampness and mould (OR 1.8, 95% CI 1.2–2.7), cold conditions (OR 1.7, 95% CI 1.1–2.7) and a physically strenuous job (OR 1.6, 95% CI 1.03–2.3). Asthmagens and LMW agents classified by the JEM were associated with mild exacerbation, with an OR of 1.6 (95% CI 1.1–2.5) and 2.2 (95% CI 1.1–4.4), respectively. Work in educational services confers a risk of WEA [21], and exposures frequently implicated are indoor air pollutants, mould, dust and cleaning products. Populationbased studies have demonstrated an increased risk of both OA and WEA for individuals exposed to cleaning agents and disinfectants at work [25]. Occupations at risk of WRA include professional cleaners, healthcare workers, and education, leisure and swimming pool work [26, 27]. Respiratory sensitisation and OA are well described for some of these agents, particularly in healthcare workers (e.g. quaternary ammonium compounds, glutaraldehyde, chloramine-T), although teasing out chronic airway irritation in pre-existing asthma from sensitisation, in the context of multiple healthcare exposures, can be a difficult task [28]. Irritant exposures have been identified: bleaches, and in particular sodium hypochlorite, hydrochloric acid and alkaline agents including ammonia and sodium hydroxide [29]. Some specific job tasks such as mixing, bleaching, spraying and waxing are closely associated with asthma symptoms, as is a history of acute inhalations following accidental exposure (e.g. mixing bleach with ammonium salts) [30]. With respect to agents, aldehydes, hypochlorite bleach, hydrogen peroxide and enzymatic cleaners have all been associated with poor asthma control in current asthmatic healthcare workers [31].

Risk factors Few specific risk factors other than those associated with causative exposures have been identified. There have been conflicting findings from studies, due in part to variations in https://doi.org/10.1183/2312508X.10034219

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study setting, analysis and case definition; the majority of studies have been cross-sectional, which makes discerning cause and effect difficult. Demographic features of individuals with WEA have been compared with those of individuals with asthma unrelated to work and/or OA in a handful of studies. WEA has been associated with older age in general population studies [16, 19], and both male [8] and female [16, 32] preponderances have been described in WEA and may relate to the type of work encountered. Atopy and rhinitis are common features preceding a diagnosis of WEA but perhaps less so than in OA [33, 34]. The severity of asthma may play a role in WEA, although again conflicting results have been seen. Measures of asthma severity such as symptomatic days, asthma control, maintenance treatments and healthcare visits are variously worse in WEA than in non-WRA in some studies [18, 19, 35, 36] but not in others [8, 37]. In direct comparisons between WEA and OA, some authors have described similarities in symptomatology, asthma control and treatments [32, 38, 39]. Indeed, in the 2011 ATS statement, HENNEBERGER et al. [4] stated that WEA and OA were similar in severity and treatment requirements. More recently, a prospective observational study by LEMIÈRE et al. [40] observed that those with WEA had greater inhaled corticosteroid requirements than those with OA (OR 4.4, 95% CI 1.4–13.6), although both OA and WEA had 10-fold increases in healthcare costs compared with non-WRA.

Diagnosis Making an objective diagnosis of WEA is especially important where exposures could be causative, employment outcome may be affected or other workers’ health is also at risk. The degree of proof required depends on the consequences for the individual worker. The key diagnostic steps in WEA are: 1) establish the diagnosis of asthma and its onset, 2) demonstrate the relationship between exacerbation of asthma and work exposure, 3) exclude other diagnoses, including OA, acute irritant-induced asthma and other clinical mimics, and 4) identify triggers that exacerbate asthma. Onset and presence of asthma

A careful medical history should be taken, noting the onset of asthma symptoms, family history, childhood asthma history, previous medication trials and use, and concurrent atopy and allergy. The results of any investigations undertaken prior to the offending work exposure, such as spirometry and reversibility testing in primary care, nonspecific bronchial hyperreactivity or serial measures of health surveillance, may provide some objective evidence of reversible airflow obstruction and/or hyperreactivity. Concurrent asthma is difficult to establish and usually requires detailed investigation with evaluation of exposures and a specific inhalation challenge (SIC) for potential sensitisers to exclude OA. Clinical presentation

WEA should be considered in any individual with asthma who has work-related symptoms (cough, wheeze, chest tightness, breathlessness) or worsening asthma control [4]. Typically, asking patients whether asthma symptoms are better on days away from work and/or on holiday is a sensitive measure for identifying the presence of work-related symptoms and is recommended by a number of guidelines when investigating WRA [3, 41]. Exacerbation may also be documented by increasing use of inhaled medication related to work, and more severe exacerbation by healthcare visits, oral corticosteroid use or periods of sickness 58

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absence. Some workers typically may not recognise their symptoms or be able to discriminate between work and away from work, or may be reluctant to disclose information for fear of losing their job or financial loss [42], and workplace deterioration may be evident on health surveillance results. The best-validated physiological method of demonstrating WRA is by analysis of serial PEF at work and away from work, with a minimum criterion of 3 weeks of usual work exposure with measurements at least four times a day (figure 2) [43]; this is recommended by all major WRA guidelines [3, 5, 41]. A change in nonspecific bronchial reactivity at and away from work, pre- and post-shift FEV1, and biomarkers of airway inflammation are not currently recommended as they lack sensitivity in WRA. Demonstration of workplace PEF variability does not distinguish OA from WEA [44], and other features or tests are required to establish the cause or trigger, respectively. As with OA, establishing the work relationship beyond taking a thorough occupational history is usually not possible objectively once the employee has left their job; tests should be undertaken while the employee is still at work to maximise the chance of a good employment and financial outcome for the individual. Differentiating WEA from OA

Distinguishing between WEA and OA is ordinarily important, as health outcomes, workplace control measures, legislation and compensation advice to the worker may differ between the two disorders [45]. Exposure to a known occupational asthmagen should raise the suspicion of OA, and respiratory sensitisation can occur in individuals with current asthma or reactivated childhood asthma. However, absence of common sensitisers in the workplace does not exclude OA, as new causes are frequently identified and over 300 have currently been reported [46]. A careful enquiry into the relationship between exposure and worsening of symptoms will help here. The level of exposure to an asthmagen may well be important, as major exacerbations or large PEF changes with very small exposures may support sensitisation as the mechanism. Unusual or high-level exposures well above the workplace limits, causing relatively short-lived aggravation of symptoms, may point to airway irritation [10]. Respiratory sensitisation can be established by serological measurement of specific IgE, which is commercially available for many HMW asthmagens but for very few LMW substances. Care should be taken with interpretation of specific IgE levels, as sensitivity can be low, particularly for LMW agents or when individuals have reduced exposure. Moreover, with respect to specificity, in a population of bakery workers described as either OA or WEA based on SIC positivity, 62% of those with OA and 29% with WEA had IgE specific for flour [47]. SIC undertaken in expert hands is usually considered the gold standard for diagnosis of OA, provided it is undertaken in accordance with guidance and that work exposure is adequately reproduced [48]. Identifying exacerbation triggers

A thorough occupational history should be taken with reference to the common causes of WEA and “at-risk” occupations and job tasks. Clarification should be sought on any changes in the workplace environment (e.g. new processes or substances), affected colleagues, coexisting use of respiratory protective equipment (RPE) and any control measures already in place; obtaining material safety data sheets relating to current exposures is important to identify any potential respiratory sensitisers, causes of other https://doi.org/10.1183/2312508X.10034219

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DV %

50

20 580 560

4

4 4

540

4 4

4

3 3

4

4

520 500

PEF L·min–1

480 460 440 420 400 380 360 340 320 Date

Readings Work hours Additional

M T W T F S S 30 01 02 03 04 05 06 01 02 03 04 05 06 07 April 2012 May 8 8 8 8 8 9 8 8 8 8 8 8 w

M T W T F S S M T W T F S S M T W T F S S 07 08 09 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 08 09 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 8 8 9 8 9 8 8 8 8 w

By whole record mean Daily maximum Daily mean Daily minimum OASYS 2b score for period

8 8 8 9 8 9 9 8 8 8 9 8 9 9 8 8 8 8 8 8 8 8 8 8 8 w w w w Patient rested Patient worked a day shift w Missing waking reading(s)

Figure 2. Occupational Asthma SYStem (OASYS) analysis of PEF from a delivery driver with pre-existing asthma and persistent work-related exacerbation of symptoms, caused by exposure to cold air and diesel exhaust. The record shows low daily mean PEF readings on day shifts, improving on days away from work. The OASYS score was 3.9 and the score for the area between the curves was 812 L·min–1, both confirming a significant work effect on PEF. DV: diurnal variation.

airway diseases (e.g. OB) and airway irritants. Other sources of information that may be useful include detailed PEF records where exposures differ by day, industrial hygiene reports, publications relating to previous cases or outbreaks in similar workplaces, and site visits. 60

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Other diagnostic mimics There are a number of other disorders with similar clinical features to WEA that may also be work related; these need to be considered, and in many cases positively excluded, as part of the diagnostic work-up of an individual. Discriminatory clinical and laboratory features are detailed in table 2. Irritant-induced asthma

Synonymous with (and originally described as) reactive airways dysfunction syndrome (RADS), acute irritant-induced asthma (IIA) is highly likely if the clinical and physiological criteria of BROOKS et al. [49] are met (table 2). It is characterised by new and immediate-onset asthma following a single large accidental exposure to a substance with irritant properties, such as various gases, dusts, fumes and volatile liquids. However, in many cases, onset of asthma is delayed following acute exposure, or occurs following further episodic exposure or ongoing daily moderate exposures to airway irritants. In these situations, it is difficult to distinguish WEA with concurrent-onset asthma from “not so sudden” IIA. Causality is inferred from general population studies that have shown increased odds of new-onset asthma in work with cleaning products, wood dust, dusts in swine and dairy production, and welding fumes [9]. In these circumstances, the authors of a position paper on IIA by the European Academy of Allergy and Clinical Immunology (EAACI) suggest that a diagnosis of “probable or possible IIA” can be considered [50]. OB

OB is a rare condition, characterised by bronchiolar inflammation and fibrosis sparing alveolar structures, synonymous with bronchiolitis obliterans, associated predominantly with organ transplant and/or collagen vascular disease. Clusters of OB have been seen in flavourings and popcorn manufacturers exposed to diacetyl, used as a butter flavouring. Cases have also been reported in individuals exposed to World Trade Centre dusts, iron oxide, sulfur mustard gas and NOx [51]. Epidemiologically, flavourings workers suffer an excess of respiratory symptoms (breathlessness and cough) and more airflow obstruction compared with unexposed individuals. However, in occupational OB, clinical presentation is usually insidious, and lung function may be normal or restrictive. HRCT is the most helpful investigation, although where there is uncertainty, a lung biopsy may be required. Hypersensitivity pneumonitis

Occupational hypersensitivity pneumonitis (HP) is covered in detail elsewhere in this Monograph [52]. From surveillance data in the UK, the commonest occupational cause of HP is now metal-working fluid [53], although avian proteins, moulds (e.g. refuse, mouldy hay, mushrooms) and some chemicals (e.g. isocyanates, pharmaceuticals) are also identified [54]. Inflammatory and fibrotic forms of HP exist, with a heterogeneous radiological appearance and a clinical spectrum; the natural history appears to be varied and is not well understood. Workers with occupational HP may have recurrent work-related symptoms of cough and breathlessness mimicking asthma, although often accompanied by systemic symptoms of weight loss, malaise and fever. The onset can be insidious with chronic cough and breathlessness if the fibrotic form predominates [55]. https://doi.org/10.1183/2312508X.10034219

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Disease Bronchial disorders OA by sensitisation

Clinical presentation

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Similar work-related asthma symptomatology to WEA. Usually arising de novo or as reactivated childhood asthma (>90% of cases); challenging to recognise new sensitisation in those with pre-existing active asthma. Exposure to a known sensitiser; other workers may be affected. History of atopy, coexistent rhinitis and smoking are all risk factors for OA caused by many agents. Acute irritant-induced Strict diagnostic criteria must be met ([49]): asthma (RADS) No pre-existing asthma; Onset of symptoms following a single large exposure, within 24 h of the exposure and persisting for ⩾3 months; Exposure to a gas, smoke, fume or vapour with irritant qualities, in high concentration; Supportive objective evidence of asthma (e.g. NSBR, reversibility testing); Other diseases excluded Disorders affecting small airways/lung parenchyma Obliterative bronchiolitis Exertional breathlessness and cough are the commonest symptoms. Onset is often insidious but can be rapid in some cases. No clear day-to-day work relationship usually evident. Occupational exposures may be long and persistent or brief. Toxic exposure-related obliterative bronchiolitis usually takes a more benign course than is seen with solid-organ transplant-related disease.

Investigations

SIC is the gold standard for demonstrating respiratory sensitisation. Specific IgE is commercially available for many HMW agents but only a few LMW agents (e.g. chemical substances), where they lack. sensitivity and specificity. PEF is the best-validated test for confirming work-related asthma but does not discriminate between OA and WEA without clinical context and in some cases demonstration of respiratory sensitisation. Agents can be known sensitisers, although at exposure levels consistent with airway irritation. A firm diagnosis of asthma with objective evidence of bronchial hyperreactivity and/or variable airflow obstruction is required to meet diagnostic criteria, to avoid misattribution. Role of exhaled biomarkers (e.g. FENO) is not established; bronchial eosinophilia not established.

Classically, spirometry shows fixed airflow obstruction, but normal and restrictive patterns are seen. HRCT shows air trapping and mosaic attenuation during expiration, and may show bronchial dilation and bronchial wall thickening. Lung histology may be required to differentiate from other disorders affecting small airways, e.g. hypersensitivity pneumonitis, smoking-related respiratory bronchiolitis. Continued

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Table 2. Frequently encountered diagnostic mimics for work-exacerbated asthma (WEA)

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Table 2. Continued Disease Hypersensitivity pneumonitis

Upper airway disorders ILO (including classical vocal cord dysfunction)

Investigations

Onset of symptoms varies among acute, recurrent acute or subacute (days to weeks) and chronic (weeks to months). Symptoms may show a temporal relationship with work. Breathlessness, cough and chest tightness are common; wheeze is much less frequent. Systemic features (e.g. fever and weight loss) are also common.

Spirometry is typically restrictive, with low lung volumes and low gas transfer, but may be normal with mild disease or away from work exposure. HRCT may show inflammatory (ground-glass nodules with or without mosaic attenuation) or fibrotic (reticulation, honeycombing) changes, or both. Poor correlation between onset of symptoms and radiological appearance, and the natural history is variable. BAL lymphocytosis and evidence of sensitisation (positive specific IgG) support a diagnosis in the right context. Lung biopsy is sometimes required for challenging cases

Wheeze, breathlessness and cough are common symptoms, along with dysphonia, neck tightness, inspiratory noise and air hunger (difficulty getting air in). Episodic symptoms of variable intensity, in response to exposure to airway irritants, emotion, stress, exercise, reflux or viral infections. Episodes may cause respiratory distress. Can occur solely on exertion (exercise-induced ILO). Audible high-pitched inspiratory noise or stridor often present, and absence of polyphonic expiratory wheeze on examination.

Spirometry and FVL are usually normal between episodes. Variable extrathoracic obstruction and inspiratory flow limitation may be seen. Note that this FVL pattern is not specific to ILO and cannot differentiate between glottic and supraglottic ILO. NSBR testing cannot reliably differentiate ILO from asthma, and ILO and asthma often coexist. The gold standard is direct visualisation of the larynx by FL examination, which can also be done during exercise or as a provocation challenge to irritants.

Intermittent or persistent symptoms of unexplained breathlessness and cough, along with other features similar to ILO. Features of hyperventilation may be prominent: paraesthesia, dizziness, general fatigue and panic. Prevalent in chronic respiratory disease (particularly asthma) and also associated with neurological and psychosomatic disorders.

Visual footage (e.g. mobile phone capture) or a witness account of any episodes may provide diagnostic clues. A respiratory physiotherapy assessment of breathing pattern is essential. Spirometry may be abnormal if associated respiratory or neurological disorders are present. FL to look for associated ILO may be prudent, depending on symptomatology. A search for underlying comorbid disease should be undertaken (e.g. neuromuscular disorder). Provocation testing (e.g. CPET) may be helpful in unexplained breathlessness, or if symptoms are triggered by specific exposures.

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OA: occupational asthma; Ig: immunoglobulin; RADS: reactive airways dysfunction syndrome; ILO: inducible laryngeal obstruction; SIC: specific inhalation challenge; HMW: high molecular weight; LMW: low molecular weight; NSBR: nonspecific bronchial reactivity; FVL: flow–volume loop; FL: flexible laryngoscopy; CPET: cardiopulmonary exercise testing.

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Other Breathing pattern disorder (dysfunctional breathing)

Clinical presentation

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ILO

ILO is synonymous with irritable larynx syndrome and refers to inappropriate, transient and reversible narrowing of the larynx in response to external triggers [56]. It is a frequently missed cause of wheeze, chest tightness and breathlessness, and the symptoms are often misattributed to asthma, although ILO is increasingly well documented. ILO can be seen in the occupational setting following acute inhalation injury, or on exposure to airway irritants and noxious substances, mimicking WRA [57–59], and sometimes coexisting. The triggers are not usually sensitising agents, and include perfumes, paints and cleaning agents [59]. Provided a careful diagnosis is made, vocal and respiratory therapy, together with withdrawal of standard inhaled asthma treatments, can achieve a good outcome.

Outcomes Socioeconomic impact

Studies evaluating socioeconomic outcome from WEA differ in terms of the populations studied, the case definitions for WEA and the comparison groups (e.g. OA and/or non-WRA). Nevertheless, these were evaluated in the ATS review by HENNEBERGER et al. [4] and were the subject of more recently published research [60, 61]. Following a diagnosis, WEA has a similar rate of unemployment (31–46%) to OA (38–39%) and non-WRA (32– 38%) [36, 39, 62]. The number of job role or employment changes was either equal to or less for WEA than for OA [32, 38, 39, 60, 62, 63]. The proportion of workers suffering loss of income, and the value of income loss was similar for both WEA and OA (55–63%) [39, 62], but greater for OA in one study [61]. Further research into the long-term health and socioeconomic outcomes of WEA is recommended. Health outcomes

A handful of studies have examined health and psychosocial outcomes with WEA. A cross-sectional study using an asthma-related quality of life (QoL) instrument in a general population with asthma showed that, after adjusting for confounders, self-reported work exacerbation was associated with a lower QoL than non-WRA (with respect to mood, breathlessness, social disruption and health concern) [64]. In a postal questionnaire of working-age people with asthma, with a prevalence of WEA of 33%, those individuals with WEA reported increased asthma severity, inhaled treatment use and work-related stress; the QoL instrument score was lower in the WEA group but not statistically significantly so. In a large US cross-sectional telephone survey of ever-employed adults with current asthma, individuals with WRA were significantly more likely than those with non-WRA to have poor self-rated physical and mental health and activity limitation [65]. PELISSIER et al. [38] studied OA and WEA following cessation of exposure, and although asthma severity improved with both, there was no difference between OA and WEA. In a study in tertiary clinic populations in Canada, LEMIÈRE et al. [66] revealed that diagnosis and management of WRA led to a reduction in healthcare use (in terms of emergency visits or hospital admissions) at 2 years after diagnosis, but no differences between WEA and OA or by region studied. In another Canadian study in a tertiary clinic population, WEA subjects reported higher anxiety and depression scores than those with OA, although QoL was comparable between groups and those with WEA had fewer work limitations [61]. 64

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Prevention and workplace management

In general, preventative measures may be primary, aiming to prevent onset of WEA, or secondary and tertiary, aiming to prevent mild disease becoming severe, or recurrence of episodes. Any suggestions are currently pragmatic and drawn from recommendations in previous reviews, in the absence of data on the effectiveness of any particular preventative intervention [4, 9, 10]. Optimum management of asthma is essential to reduce any associated risk of exacerbation; any subsequent work-related symptoms may then become easier to recognise, and at an earlier stage. Workers with asthma should have access to reliever medication while at work in case of acute exacerbation. Within allowable exposure limits, individuals without asthma may tolerate exposure levels at work that those with asthma do not, and/or asthma control may vary according to nonoccupational factors (e.g. seasonal pollen exposures, winter viral exacerbations), so workplace adjustments may be required to accommodate these individually. Education of the workforce by various means (e.g. web-based, external occupational health providers) about the effects of workplace exposures on asthma may improve adherence to treatments and control measures such as RPE, if indicated. FISHWICK [10] recommended that employers follow a stepwise approach to risk assessment in the workplace, similar to guidance given by the UK Health and Safety Executive (table 3), including the provision of adequate and suitable control measures. Where elimination of risk

Table 3. UK Health and Safety Executive steps to risk assessment Steps to risk assessment

Description

Identify the hazards

An accurate assessment of potential hazards in the workplace; hazards can be categorised, e.g. physical (temperature, humidity), biological (respiratory viruses), chemical (chlorine-releasing agents) or psychosocial (emotional stress)

Decide who might be harmed and how

An assessment of which employees, visitors or members of the public might be at risk, and the nature of harm

Evaluate the risks

Evaluate how likely it is that harm will occur; the severity and frequency of harm should be considered, as well as the effectiveness of any control measures already in place

Record significant findings and implement precautions

Include the hazards identified, any risks of harm and the control measures in place Include a plan to eliminate or reduce the risk and implement; written risk assessment templates exist (e.g. www.hse.gov.uk/risk)

Review the risk assessment regularly

Few workplaces remain the same, and risk assessments should be subject to regular review in light of new information, e.g. new hazards and/or processes may have been introduced, or incidents or near misses may have occurred

Data from [67].

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is not possible, the aim should be to reduce irritative exposures as far as possible, within allowable exposure limits, as exacerbation (and indeed sensitisation) can occur within legal limits. Control measures may include elimination or substitution of substances, engineering controls (e.g. LEV, automated machining), changes in work patterns, worker education, relocation of the worker to an unexposed area or task, and RPE. The ERS Task Force on the Management of Work-related Asthma strongly recommends the use of control measures that eliminate or minimise exposures at source in preference to RPE, which has a limited evidence base for effectiveness [68]. Management of individuals with WEA

An individual with WEA will require treatment, as for any asthmatic person with exacerbation or poor disease control (i.e. the use of inhaled and/or oral reliever medication, and consideration of “stepping up” prevention treatments). A severe exacerbation will usually require immediate removal from exposure if it can be identified and/or time away from work to recover. If the exposure is recognised and unusual for work (e.g. outbreak of respiratory virus, dusts from building renovations), then the individual can return to work once the trigger is no longer present. If symptoms are triggered by usual occupational levels of exposure, then consideration will need to be given to eliminating or reducing exposure on their return to work. For workers with persistent and undiagnosed symptoms, a degree of judgement is required as to whether symptoms are mild and stable enough that they can remain in the area of work while further tests are carried out. Following a diagnosis of WEA, an individual may be able to remain in the same job with reduced exposures, depending on the severity of their asthma and the extent of exacerbating triggers at work, once control measures have been taken into account. Ultimately, however, relocation to a different role or a change in employment may become necessary if the approaches outlined here fail to prevent significant WEA. Clinical management with a shared focus on respiratory and workplace aspects (using an occupational hygienist and a return-to-work coordinator) has been shown to reduce psychological impairment for workers with WRA and could help facilitate the return to work [69]. Compensation

Compensation systems for occupational respiratory disease and their eligibility vary nationally, and sometimes regionally within a country. This is due to differences in administration (e.g. state or insurance based), case definition, evaluation of disability, the burden of proof required to determine causality and historical precedent. Furthermore, systems that compensate for a diagnosis of OA do not necessarily do so for WEA. BAUR et al. [70] noted that current financial compensation for OA does not offset the socioeconomic consequences of the disease, and this could perhaps be extrapolated to WEA.

Conclusion WEA has suffered from a lack of systematic research and translatable evidence until fairly recently, the focus historically being on recognising and diagnosing OA and its impact. It has become clear, however, that the burden and socioeconomic impact of WEA is substantial. The nature of causative exposures differs somewhat from OA, and thus a different approach to managing the individual worker is often required. Clinicians should be aware of prevalent workplace exposures leading to WEA, including the emergence of 66

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cleaning agents as a major factor, and the “at-risk” occupational groups. The key to an accurate diagnosis is a thorough medical and occupational history to evaluate pre-existing illness and the nature and timing of inhalational exposure, and careful elucidation of any factors that distinguish WEA from other airway disorders. Where diagnostic uncertainty remains, specialist investigations are usually required. Studies on the effectiveness of interventions that aim to prevent exacerbation of asthma in specific industries, or that reduce or prevent ongoing exposure in affected individuals, are needed.

References 1. 2.

3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.

23.

Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention. 2020. Available from: http://ginasthma.org/ Blanc PD, Annesi-Maesano I, Balmes JR, et al. The occupational burden of nonmalignant respiratory diseases. An Official American Thoracic Society and European Respiratory Society Statement. Am J Respir Crit Care Med 2019; 199: 1312–1334. Baur X, Sigsgaard T, Aasen TB, et al. Guidelines for the management of work-related asthma. Eur Respir J 2012; 39: 529–545. Henneberger PK, Redlich CA, Callahan DB, et al. An official American Thoracic Society Statement: workexacerbated asthma. Am J Respir Crit Care Med 2011; 184: 368–378. Tarlo SM, Balmes J, Balkissoon R, et al. Diagnosis and management of work-related asthma: American College of Chest Physicians Consensus Statement. Chest 2008; 13: Suppl., 1S–41S. Caldeira RD, Bettiol H, Barbieri MA, et al. Prevalence and risk factors for work related asthma in young adults. Occup Environ Med 2006; 63: 694–699. Bolen AR, Henneberger PK, Liang X, et al. The validation of work-related self-reported asthma exacerbation. Occup Environ Med 2007; 64: 343–348. Henneberger PK, Derk SJ, Sama SR, et al. The frequency of workplace exacerbation among health maintenance organisation members with asthma. Occup Environ Med 2006; 63: 551–557. Tarlo SM. Update on work-exacerbated asthma. Int J Occup Med Environ Health 2016; 29: 369–374. Fishwick D. Work aggravated asthma; a review of the recent evidence. Br Med Bulletin 2014; 110: 77–88. Lau A, Tarlo SM. Update on the management of occupational asthma and work-exacerbated asthma. Allergy Asthma Immunol Res 2019; 11: 188–200. Lutzker LA, Rafferty AP, Brunner WM, et al. Prevalence of work-related asthma in Michigan, Minnesota, and Oregon. J Asthma 2010; 47: 156–161. Henneberger PK, Liang X, Lillienberg L, et al. Occupational exposures associated with severe exacerbation of asthma. Int J Tuberc Lung Dis 2015; 19: 244–250. Vila-Rigat R, Panadès Valls R, Hernandez Huet E, et al. Prevalence of work-related asthma and its impact in primary health care. Arch Bronconeumol 2015; 51: 449–455. Sadeghniiat-Haghighi K, Aminian O, Najafi A, et al. Work-related exacerbation of asthma among adults treated by pulmonary specialists. Arch Environ Occup Health 2016; 71: 35–42. Talini D, Ciberti A, Bartoli D, et al. Work-related asthma in a sample of subjects with established asthma. Respir Med 2017; 130: 85–91. Bradshaw L, Sumner J, Delic J, et al. Work aggravated asthma in Great Britain: a cross-sectional postal survey. Prim Health Care Res Dev 2018; 19: 561–569. Dodd KE, Mazurek JM. Asthma medication use among adults with current asthma by work-related asthma status, Asthma Call-back Survey, 29 states, 2012–2013. J Asthma 2018; 55: 364–372. Saarinen K, Karjalainen A, Martikainen R, et al. Prevalence of work-aggravated symptoms in clinically established asthma. Eur Respir J 2003; 22: 305–309. Berger Z, Rom WN, Reibman J, et al. Prevalence of workplace exacerbation of asthma symptoms in an urban working population of asthmatics. J Occup Environ Med 2006; 48: 833–839. Mazurek JM, Filios M, Willis R, et al. Work-related asthma in the educational services industry: California, Massachusetts, Michigan, and New Jersey, 1993–2000. Am J Ind Med 2008; 51: 47–59. Mazurek JM, Syamlal G. Prevalence of asthma, asthma attacks, and emergency department visits for asthma among working adults – National Health Interview Survey, 2011–2016. MMWR Morb Mortal Wkly Rep 2018; 67: 377–386. Lim T, Liss GM, Vernich L, et al. Work-exacerbated asthma in a workers’ compensation population. Occup Med (Lond) 2014; 64: 206–210.

https://doi.org/10.1183/2312508X.10034219

67

ERS MONOGRAPH | OCCUPATIONAL AND ENVIRONMENTAL LUNG DISEASE 24. Kim JL, Henneberger PK, Lohman S, et al. Impact of occupational exposures on exacerbation of asthma: a population-based asthma cohort study. BMC Pulm Med 2016; 16: 148. 25. Dumas O, Le Moual N. Do chronic workplace irritant exposures cause asthma? Curr Opin Allergy Clin Immunol 2016; 16: 75–85. 26. Walters GI, Burge PS, Moore VC, et al. Cleaning agent occupational asthma in the West Midlands, UK: 2000–16. Occup Med (Lond) 2018; 68: 530–536. 27. Wiszniewska M, Walusiak-Skorupa J. Occupational allergy: respiratory hazards in healthcare workers. Curr Opin Allergy Clin Immunol 2014; 14: 113–118. 28. Li RWH, Lipszyc JC, Prasad S, et al. Work-related asthma from cleaning agents versus other agents. Occup Med (Lond) 2018; 68: 587–592. 29. Quirce S, Barranco P. Cleaning agents and asthma. J Investig Allergol Clin Immunol 2010; 20: 542–550. 30. Siracusa A, de Blay F, Folletti I, et al. Asthma and exposure to cleaning products – a European Academy of Allergy and Clinical Immunology task force consensus statement. Allergy 2013; 68: 1532–1545. 31. Dumas O, Wiley AS, Quinot C, et al. Occupational exposure to disinfectants and asthma control in US nurses. Eur Respir J 2017; 50: 1700237. 32. Goe SK, Henneberger PK, Reilly MJ, et al. A descriptive study of work aggravated asthma. Occup Environ Med 2004; 61: 512–517. 33. Lemiere C. Occupational asthma and work aggravated asthma. Similarities and differences. Expert Rev Respir Med 2007; 1: 43–49. 34. Vandenplas O, van Brussel P, d’Alpaos V, et al. Rhinitis in subjects with work-exacerbated asthma. Respir Med 2010; 104: 497–503. 35. Henneberger PK, Hoffman CD, Magid DJ, et al. Work-related exacerbation of asthma. Int J Occup Environ Health 2002; 8: 291–296. 36. Breton CV, Zhang Z, Hunt PR, et al. Characteristics of work related asthma: results from a population based survey. Occup Environ Med 2006; 63: 411–415. 37. Tarlo SM, Leung K, Broder I, et al. Asthmatic subjects symptomatically worse at work: prevalence and characterization among a general asthma clinic population. Chest 2000; 118: 1309–1314. 38. Pelissier S, Chaboillez S, Teolis L, et al. Outcome of subjects diagnosed with occupational asthma and work-aggravated asthma after removal from exposure. J Occup Environ Med 2006; 48: 656–659. 39. Larbanois A, Jamart J, Delwiche JP, et al. Socioeconomic outcome of subjects experiencing asthma symptoms at work. Eur Respir J 2002; 19: 1107–1113. 40. Lemière C, Boulet LP, Chaboillez S, et al. Work-exacerbated asthma and occupational asthma: do they really differ? J Allergy Clin Immunol 2013; 131: 704–710. 41. Fishwick D, Barber CM, Bradshaw LM, et al. Standards of care for occupational asthma: an update. Thorax 2012; 67: 278–280. 42. Walters GI, Soundy A, Robertson AS, et al. Understanding health beliefs and behaviour in workers with suspected occupational asthma. Respir Med 2015; 109: 379–388. 43. Moore VC, Jaakkola M, Burge P. A systematic review of serial peak expiratory flow measurements in the diagnosis of occupational asthma. Ann Respir Med 2010; 1: 31–44. 44. Chiry S, Cartier A, Malo JL, et al. Comparison of peak expiratory flow variability between workers with work-exacerbated asthma and occupational asthma. Chest 2007; 132: 483–488. 45. Smith AM, Bernstein DI. Management of work-related asthma. J Allergy Clin Immunol 2009; 123: 551–557. 46. Baur X. A compendium of causative agents of occupational asthma. J Occup Med Toxicol 2013; 8: 15. 47. Wiszniewska M, Walusiak-Skorupa J. Diagnosis and frequency of work-exacerbated asthma among bakers. Ann Allergy Asthma Immunol 2013; 111: 370–375. 48. Vandenplas O, Suojalehto H, Aasen TB, et al. Specific inhalation challenge in the diagnosis of occupational asthma: consensus statement. Eur Respir J 2014; 43: 1573–1587. 49. Brooks SM, Weiss MA, Bernstein IL. Reactive airways dysfunction syndrome (RADS): persistent asthma syndrome after high level irritant exposures. Chest 1985; 88: 376–384. 50. Vandenplas O, Wiszniewska M, Raulf M, et al. EAACI position paper: irritant-induced asthma. Allergy 2014; 69: 1141–1153. 51. Fechter-Leggett ED, White SK, Fedan KB, et al. Burden of respiratory abnormalities in microwave popcorn and flavouring manufacturing workers. Occup Environ Med 2018; 75: 709–715. 52. Barber CM, Barnes H. Occupational hypersensitivity pneumonitis. In: Feary J, Suojalehto H, Cullinan P, eds. Occupational and Environmental Lung Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 104–124. 53. Barber CM, Wiggans RE, Carder M, et al. Epidemiology of occupational hypersensitivity pneumonitis; reports from the SWORD scheme in the UK from 1996 to 2015. Occup Environ Med 2017; 74: 528–530. 54. Quirce S, Vandenplas O, Campo P, et al. Occupational hypersensitivity pneumonitis: an EAACI position paper. Allergy 2016; 71: 765–779. 68

https://doi.org/10.1183/2312508X.10034219

WORK-EXACERBATED ASTHMA | G.I. WALTERS 55. Walters GI, Mokhlis JM, Moore VC, et al. Characteristics of hypersensitivity pneumonitis diagnosed by interstitial and occupational lung disease multi-disciplinary team consensus. Respir Med 2019; 155: 19–25. 56. Halvorsen T, Walsted ES, Bucca C, et al. Inducible laryngeal obstruction: an official joint European Respiratory Society and European Laryngological Society statement. Eur Respir J 2017; 50: 1602221. 57. de la Hoz RE, Shohet MR, Bienenfeld LA, et al. Vocal cord dysfunction in former World Trade Center (WTC) rescue and recovery workers and volunteers. Am J Ind Med 2008; 51: 161–165. 58. Brooks SM. Vocal cord dysfunction after an inhalation exposure. J Allergy Ther 2017; 8: 3. 59. Feary J, Fitzgerald B, Szram J, et al. Inducible laryngeal obstruction masquerading as work-related asthma; a new approach. Thorax 2016; 71: A71. 60. Moullec G, Lavoie KL, Malo JL, et al. Long-term socioprofessional and psychological status in workers investigated for occupational asthma in Quebec. J Occup Environ Med 2013; 55: 1052–1064. 61. Lipszyc JC, Silverman F, Holness DL, et al. Comparison of psychological, quality of life, work-limitation, and socioeconomic status between patients with occupational asthma and work-exacerbated asthma. J Occup Environ Med 2017; 59: 697–702. 62. Cannon J, Cullinan P, Newman Taylor A. Consequences of occupational asthma. Br Med J 1995; 311: 602–603. 63. Tarlo SM, Liss G, Corey P, et al. A workers’ compensation claim population for occupational asthma: comparison of subgroups. Chest 1995; 107: 634–641. 64. Lowery EP, Henneberger PK, Rosiello R, et al. Quality of life of adults with workplace exacerbation of asthma. Qual Life Res 2007; 16: 1605–1613. 65. Knoeller GE, Mazurek JM, Moorman JE. Health-related quality of life among adults with work-related asthma in the United States. Qual Life Res 2013; 22: 771–780. 66. Lemière C, To T, de Olim C. Outcome of work-related asthma exacerbations in Quebec and Ontario. Eur Respir J 2015; 45: 266–268. 67. Health and Safety Executive. Risk Assessment: A Brief Guide to Controlling Risks in the Workplace. Bootle, Health and Safety Executive, 2014. www.hse.gov.uk/pubns/indg163.pdf 68. Heederik D, Henneberger PK, Redlich CA, et al. Primary prevention: exposure reduction, skin exposure and respiratory protection. Eur Respir Rev 2012; 21: 112–124. 69. Lipszyc JC, Silverman F, Holness DL, et al. Comparison of clinic models for patients with work-related asthma. Occup Med (Lond) 2017; 67: 477–483. 70. Baur X, Aasen TB, Burge PS, et al. The management of work-related asthma guidelines: a broader perspective. Eur Respir Rev 2012; 21: 125–139.

Disclosures: None declared.

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| Chapter 5 Acute inhalation injury Sherwood Burge Inhalation injuries can cause acute breathlessness within minutes of exposure or be delayed for days or occasionally weeks. Pathologies range from asphyxiation to acute mucosal injury to ulceration, asthma, pulmonary oedema and fibrosis of the airways or lung parenchyma. Some agents exert their toxicity by systemic effects. Exposures may be from natural disasters such as volcanic eruptions, from fires and industrial accidents, or from terrorist and warfare agents. This chapter classifies acute lung injury by the major site of damage, which is where emergency care should be directed, as the exact agent inhaled is often unknown in the acute situation. In addition, irritant-induced asthmas, both acute and chronic, are discussed. Cite as: Burge S. Acute inhalation injury. In: Feary J, Suojalehto H, Cullinan P, eds. Occupational and Environmental Lung Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 70–85 [https://doi.org/10.1183/2312508X.10034319].

@ERSpublications Inhalation injuries can cause acute breathlessness within minutes of exposure or be delayed for days or occasionally weeks. Pathologies include asphyxiation, acute mucosal injury, asthma, pulmonary oedema and systemic effects. https://bit.ly/3310jTg

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cute inhalation injury usually applies to an airway or lung injury caused by a single inhaled exposure over a short period of time. How short is variably interpreted, but most would include exposures following a single event, such as a volcanic eruption, the release of methyl isocyanate from the Union Carbide pesticide factory in Bhopal in 1984 or the collapse of the twin towers in New York in 2001, even if the exposure lasted several days. The response may be immediate (as in asthma induced by a chlorine leak) or delayed (such as bronchiolitis induced by an acute exposure to NOx). The acute lung injury may resolve without any obvious sequelae, or may lead to long-term diseases such as asthma, bronchiectasis or pulmonary fibrosis, or problems in other systems, particularly neurological or psychiatric symptoms, malignancy and teratogenicity. All treatment regimens in humans are based on anecdotal evidence and need to be interpreted as such.

Determinants of the body’s response to inhaled material The body’s response to inhalation accidents depends on the amount and toxicity of the agent inhaled, the duration of exposure, and the temperature and pressure of the air during Occupational Lung Disease Unit, Birmingham Heartlands Hospital, Birmingham, UK. Correspondence: Sherwood Burge, Occupational Lung Disease Unit, Birmingham Heartlands Hospital, Bordesley Green East, Birmingham B9 5ST, UK. E-mail: [email protected] Copyright ©ERS 2020. Print ISBN: 978-1-84984-124-5. Online ISBN: 978-1-84984-125-2. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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inhalation; important factors are aerodynamic diameter and pH for PM, density for gases and solubility for mists. The eyes and upper airways are the main sites of toxicity of highly water-soluble chemicals such as ammonia. Chlorine is intermediate in solubility and affects the upper and lower airways, while NOx are largely water insoluble and mostly affect the bronchioles and alveoli. The density of gases is important, particularly in the open, when gases heavier than air (e.g. CO2, hydrogen sulfide (H2S), methyl isocyanate) can accumulate in depressions in the landscape and appear to affect people indiscriminately. The smaller the particle, the more chance it has of being inhaled; only when a particle impacts on the bronchial mucosa or diffuses as a gas can lung damage occur. The aerodynamic diameter of an irregular particle is defined as the diameter of a spherical particle, with a density equal to that of water, that sediments (settles) at the same rate as the irregular particle. Thus, it does not relate to the actual size of the particle; for instance, some asbestos fibres of 10 μm in length can have an aerodynamic diameter of 10 μm will deposit in the nose and upper airways, while particles 700 ppm causes rapid death from asphyxia. Blood or urine thiosulfate measurement can be used to confirm the diagnosis if taken within 15 h of exposure, and blood thiocyanate measurement may be helpful in identifying the cause of death [7]. There is information in the literature on the use of nitrites for treatment of H2S inhalation. This usually starts with inhalation of amyl nitrite (for 30 s·min–1) followed by sodium nitrite intravenously, in the same dosages as for cyanide poisoning: infusion of 300 mg of fluid containing 10 mL of 3% sodium nitrite over 4 min has been suggested, titrating the infusion rate against the drop in blood pressure to maintain systolic pressure >80 mmHg [8]. Cyanide (hydrogen cyanide)

Cyanide is the fastest-acting known lethal agent and was used in Nazi concentration camps and for judicial killings in the USA. Cyanide poisoning should be suspected in all cases of smoke inhalation with severe hypoxia, particularly those with a raised carboxyhaemoglobin level. It is difficult to diagnose; exhaled breath or vomit may smell of almonds, which can https://doi.org/10.1183/2312508X.10034319

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be a clue. If suspected, it is best to treat before waiting for diagnostic tests. There is a semi-quantitative paper test strip, and whole-blood cyanide can be measured [9]. Lactic acidosis and a raised lactate dehydrogenase level may be seen. After inhalation, cyanide molecules bind to cytochrome a/a3, inhibiting mitochondrial O2 utilisation. The venous O2 tension may be nearer PaO2 than usual, as cyanide impairs the release of O2 into the tissues. Major exposure can come from its use in electroplating or in precious metal recovery from scrap. There is specific treatment with i.v. hydroxocobalamin (5 g over 15 min), but it is difficult to give this in time unless there is a known source of cyanide poisoning. Its efficacy may be modest [10]. Cholinesterase inhibitors

From a respiratory point of view, high levels of exposure to cholinesterase inhibitors cause paralysis of respiratory muscles, usually preceded by unconsciousness, bradycardia, sweating, vomiting, diarrhoea and small pupils, which should alert the clinician to this possibility. The most common exposures are from accidental or deliberate ingestion of organophosphorus pesticides containing anticholinesterases. The level of acetylcholinesterase activity confirms the diagnosis and severity. Organophosphorus pesticides are still widely used all over the world. According to the World Health Organization (WHO), accidental and self-poisoning cause some 3 million intoxications worldwide per year and more than 200 000 deaths [11, 12]. These are not, however, inhalation exposures, which are usually from deliberate terrorist or warfare use. Organophosphates are irreversible inhibitors of serine hydrolases, especially cholinesterases. Inhibition is due to rapid, time-dependent phosphorylation of serine at their active site. In some cases, strong nucleophiles such as oximates can reverse the phosphorylation. However, some organophosphate adducts undergo a first-order de-alkylation, a process called ageing, which is refractory to re-activation by oximes. This applies to sarin and the Novichoks [13]. Organophosphorus warfare agents were developed from insecticides. Members of the first G-series (tabun, sarin and soman) were synthesised in the 1930s and developed in Germany, but were not used as warfare agents in World War II (1939–1945). This was followed by the V-series, which are well absorbed through the skin, including the British and Russian VX agents, which were prototypes for the increasingly toxic A-series including the Russian Novichoks [14]. Sarin and tabun were used by the Iraqi army against Iranian troops in the 1980s. Sarin was used in Syria in 2013. Sarin and VX were used in the Japanese underground railway terrorist attack in 1994–1995 and VX for the assassination of Kim Jong-Nam in Malaysia in 2017 [15]. The acute management of poisoned patients is difficult as the warfare agents are absorbed through the skin, posing serious risks to immediate carers. All clothes need removal, followed by wet or dry decontamination by suitable protected personnel. Atropine may need to be given before the victim is decontaminated. Current emergency treatment of acute organophosphate poisoning requires a pyridinium aldoxime reactivator such as pralidoxime, an anticholinergic drug such as atropine and an anticonvulsant such as diazepam. Assisted ventilation is implemented in the case of respiratory failure [15]. Atropine is given at a starting dose of 2 mg; if there is only a partial response after 5 min, 4 mg can be given, and if the response is still inadequate, 8 mg can be given after a further 5 min. Pralidoxime chloride at 30 mg·kg–1 i.v. should be given as soon as possible and 74

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repeated after 4–6 h, or as a continuous infusion of 8–10 mg·kg–1·h–1 (obidoxime at 250 mg i.v. immediately and then 750 mg·day–1 is an alternative) [16]. Upper airways irritation and laryngeal oedema

Many agents causing upper airway irritation are water soluble and usually result in severe eye irritation or temporary blindness at the same time. Asphyxia due to obstructive laryngeal oedema may also occur following large exposures. Larger exposures may result in chemicals reaching the lung and causing acute airflow obstruction or pulmonary oedema. Most patients make a complete recovery, but if symptoms and signs persist >24 h, long-term effects are more likely [17, 18]. Ammonia, hydrochloric acid, the crowd control agents tear gas (2-chlorobenzalmalononitrile; also known as CS) and Mace (2chloroacetophenone; also known as CN), and pepper spray (capsaicin, a direct TRPV1 receptor stimulator resulting in neurogenic inflammation by reflex action) are some of the commoner agents reported in patients attending emergency departments. Water-soluble agents should be treated with decontamination and washing. There is debate about the optimal treatment for CS-contaminated patients, with some believing that water dissolves the crystalline powder on the skin and makes things worse and that blowing the material off with a fan is better (however, this can contaminate the treatment room). There is some evidence that irrigation is at least as good as a fan [19]. Trauma from the shells delivering CS gas may cause more problems than the gas itself. Following high exposures, patients may develop bronchiectasis, airflow obstruction in the small and large airways, and interstitial lung disease [20]. Cough and sputum

Inhalation of PM with an aerodynamic diameter small enough to reach the trachea and bronchi (24 h after exposure). The alveoli are also the principal site of damage following inhalation of acetaldehyde and particularly methyl isocyanate, where long-term bronchiolitis and interstitial lung diseases are seen in survivors [54, 55]. Vaping

Although not strictly occupational, the current outbreak of vaping lung disease in the USA has entered the differential diagnosis of acute lung injury. Onset is over days to weeks with 78

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cough, chest pain and shortness of breath, often with fatigue, fever and weight loss. Nausea, abdominal pain and diarrhoea may precede the breathlessness. Hypoxia and tachycardia are common. There is often neutrophilia and raised inflammatory markers (C-reactive protein and erythrocyte sedimentation rate) but no evidence of infection [56]. Many of the patients have an acute presentation fulfilling the criteria for acute lung injury. Others have subacute presentations with eosinophilic pneumonia, lipoid pneumonia, giant cell interstitial pneumonia, organising pneumonia or diffuse alveolar haemorrhage [57–60]. Lung CT usually shows basal-predominant consolidation and ground-glass opacity, often with areas of lobular or subpleural sparing. The basal predominance is unusual for lung diseases due to inhaled material, where upper lobe disease usually predominates [61]. BAL is usually neutrophilic with normal levels of lymphocytes; however, a characteristic feature is a high proportion of foamy macrophages containing lipid [62, 63]. The histology is acute lung injury including acute fibrinous pneumonitis, diffuse alveolar damage or organising pneumonia, usually bronchiolocentric and accompanied by bronchiolitis [64]. Treatment has often required intensive care unit ventilation, and most patients have been given steroids. There have been some deaths and so far no follow-up of survivors, although there are reports of relapse after further vaping [65]. Those affected have mostly been young and previously healthy. Although ∼80% have been vaping cannabinoids, 20% have not. The particle size of the vape depends on the temperature of the heating element. Higher temperatures increase the proportion of particles in the nanometre range and are required to vaporise more viscous fluids, particularly cannabinoids [66]. The outbreak has been attributed to the inclusion of vitamin E acetate in the vaping mixture, but other causes are possible, including lipids and cobalt (from the heating element) and more nanoparticles from hotter vapes. Why most of the cases have been from the USA is currently unexplained [63, 67, 68]. Pulmonary haemorrhage

Paraquat is unusual in that respiratory problems are very rare when it is sprayed as a herbicide but very common when it is ingested accidentally. It reaches the lungs via the pulmonary circulation and over the next few days leads to pulmonary haemorrhage, ARDS and death. It is also toxic to the kidneys and liver [69, 70]. Pulmonary haemorrhage is also common after methyl isocyanate exposure.

Management The immediate decision requires an assessment of whether it is safe to approach or touch the victim, or whether full protective clothing and decontamination are required before treatment. Getting this wrong can cause the unnecessary death of a victim in whom resuscitation is delayed but would have been safe, and unnecessary deaths in rescuers if approach was unsafe. If the victim is in an enclosed space, such as a tank, the rescuer is likely to be overcome by the same agent, and proper rescue procedures must be followed. Rescuers entering a sewer to rescue a colleague have died from the same H2S that overcame the first worker [71] and from hydrogen cyanide in a tank used for edible bamboo pickling [72]. Table 1 shows a summary of various agents, their hazard to rescuers and the principal sites of toxicity. If the victim is in the open, the situation is easier: those marked “(+)” in the table can usually be treated in the open unless there are pockets of heavier-than-air gases in depressions https://doi.org/10.1183/2312508X.10034319

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Table 1. Main effects of agents causing acute lung injury Agent

Danger to first-aider Enclosed space

Open space

CO CO2 Hydrogen sulfide

+++ +++ +++

− (+) (+)

Hydrogen cyanide Methyl isocyanate

++++ ++

++++ ++

Sarin, Novichoks, cholinesterase inhibitors Ammonia, CS, Mace

++++

++++

+

(+)

Pepper spray

+

(+)

Airway burns

−

−

Inhaled PM Acid PM Sulfur dioxide Chlorine

− − + +

− − − −

Methyl bromide

+

−

Sulfur mustard

+++

+++

NOx

+

−

Vaping Waterproofing spray Phosgene Paraquat

− − ++ −

− − ++ −

Main acute effects

Possible long-term effects

Asphyxiation Asphyxiation, skin bullae Asphyxiation, pneumonitis/ ARDS Asphyxiation, ARDS Asphyxiation, pneumonitis/ ARDS Asphyxiation

Neurological None Neurological

Eye irritation, laryngeal oedema, asthma, pneumonitis/ARDS Eye irritation, laryngeal oedema Laryngeal oedema, pneumonitis/ARDS Cough and sputum Asthma Eye irritation, asthma Eye irritation, asthma, pneumonitis/ARDS Acute bronchitis, pneumonitis/ARDS, haemorrhagic pleural effusions Eye and skin damage, tracheobronchitis Asphyxia, pneumonitis/ ARDS, bronchiolitis ILD ILD Pneumonitis/ARDS Pulmonary haemorrhage, ARDS

Unknown# Bronchiolitis, bronchiectasis (ILD) Unknown# Asthma, bronchiectasis, ILD Unknown# Asthma, bronchiectasis Possible FEV1 loss Asthma None Asthma Neurological

Bronchiectasis, tracheal stenosis, ILD Obliterative bronchiolitis HP HP Pneumonitis ILD

CS: 2-chlorobenzalmalononitrile; Mace: 2-chloroacetophenone; ILD: interstitial lung disease; HP: hypersensitivity pneumonitis. –: no danger; (+): casualties can usually be treated in the open unless there are pockets of heavier-than-air gases in depressions in the ground, and cardiopulmonary resuscitation and mouth-to-mouth ventilation can usually be done safely; +: some risk to rescuer, mainly from external exposure; ++ to ++++: increasing risk of contamination to the rescuer, mouth-to-mouth ventilation is contraindicated and full protective clothing is required. #: most people with long-term severe exposures have died.

in the ground. In these patients, cardiopulmonary resuscitation and mouth-to-mouth ventilation can usually be done safely. In the other situations where open-space rescue is indicated as “++” or more, there is a risk of contamination to the rescuer, mouth-to-mouth ventilation is contraindicated and full protective clothing is required [73]. 80

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On a Sunday night in December 1984, two doctors on call in a large urban hospital were overwhelmed by a sudden influx of patients of all ages with cyanosis, burning eyes, cough, extreme breathlessness, expectoration of frothy blood-stained sputum, vomiting and diarrhoea [74]. By 07:00, 70 people were dead, and by 09.00, 260 had been taken to the mortuary and the figures continued to rise. Early triage put living patients into four categories: 1) life threatening, with convulsions followed by cardiorespiratory arrest, 2) severe pulmonary oedema leading to cardiorespiratory distress, 3) severe conjunctivitis, keratitis, acute bronchitis and drowsiness, and 4) minor symptoms, with cough, throat and eye irritation. Intense fatigue and muscular weakness were also common. They discovered that all of the patients came from an area downwind of a chemical factory that was said to have been closed down but from which there had been a leak of stored chemicals. There was no information on the gas(es) released or the availability of any specific treatment. This is a common situation in patients exposed to fires and explosions, where it is usually better to treat the symptoms seen (here they were pulmonary oedema, airflow obstruction and eye irritation). However, CO poisoning (less likely here because of the cyanosis) and hydrogen cyanide poisoning ( possible here) should be specifically excluded as there was an almond aroma from some of the bodies, and specific treatment may have helped. The doctors called for help, which was escalated to the WHO, who phoned many experts in this field, including myself, during the night, but nobody was able to provide information about the toxicity of monoisocyanate exposure (as opposed to diisocyanates), which managers of the chemical factory had identified as being stored in the works [75, 76]. This is a description of the leak from a tank containing methyl isocyanate, which had reacted exothermally with water and exploded, releasing gasses from the Union Carbide factory in Bhopal, India. At the time, there were no published data on the toxicity of methyl isocyanate, an intermediary used together with phosgene in the synthesis of Sevin (1-naphthyl methylcarbamate), a carbamate insecticide. Several thousands of people died, some suddenly, suggesting possible hydrogen cyanide poisoning (which may have been present in the gas cloud). Many tried to escape, and deaths in the subsequent hours were mainly due to pulmonary oedema. The burning and inflamed eyes suggested a soluble gas. Methyl isocyanate is water soluble and denser than air, particularly affecting those sleeping at ground level. It also causes erosive bronchitis. Follow-up of survivors showed airflow obstruction centred on the small airways (obliterative bronchitis), as well as interstitial lung diseases, symptoms of post-traumatic stress, teratogenicity and possible carcinogenicity. Much of the eye inflammation improved [54, 77].

Prognosis Severe long-term sequelae following sulfur mustard poisoning are common. Data from surveillance schemes suggest that long-term respiratory sequelae of workers reported by occupational or respiratory clinicians are not very common. Workers exposed to a wide range of acute inhalation injuries reported absence from work for >1 month in 26%, with persisting symptoms including 9% with acute irritant-induced asthma, 11% with other respiratory diseases and 3% with nonrespiratory diseases [78]. Surveillance scheme data are likely to exclude the most serious accidents where death or serious disability has occurred. Post-traumatic stress is common in these circumstances. For example, in 1996, lorries transported by train in the tunnel connecting France and England caught fire. The drivers in the tunnel were trapped in a separate carriage while their lorries exploded in front of them. They waited for 24 min lying on the floor face down in the thick smoke, and all https://doi.org/10.1183/2312508X.10034319

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thought that they were going to die before help arrived at the last moment via the service tunnel. The drivers all had acute respiratory symptoms and some developed acute irritant-induced asthma, but the major long-term disabilities were related to post-traumatic stress, and some drivers were unable to take further loads through the tunnel, threatening their employment [79, 80].

Conclusion and principles of management The story from Bhopal illustrates the difficulties that can occur in the management of acute inhalation injuries. Many involve multiple patients from the very young to the very old, and may follow fires, explosions, warfare or natural events such as volcanic eruptions. Sometimes a worker arrives with the name of a chemical involved in a fire or spill. Although this substance may have been involved, reaction products and other chemicals are often involved. I believe that the most important priorities are to observe the casualty, look for evidence of burns and debris particularly in the mouth, check for airflow obstruction, and measure O2 saturations and carboxyhaemoglobin levels (venous blood is sufficient). If there has been a fire, cyanide poisoning should also be considered in those with raised carboxyhaemoglobin levels. Hypoxic patients, and those with a raised carboxyhaemoglobin level, should receive supplemental O2. If the patient has been unconscious, they should be admitted and observed for 24 h to identify delayed pneumonitis/oedema. If there is evidence of ARDS, it is probably better to aim for the lowest level of supplemental O2 needed to keep saturations around 90–94%, as oxidant damage is one of the principal mechanisms for toxic alveolar damage. If mechanical ventilation is needed, the aim should be to keep ventilation pressures as low as possible. The role of steroids in the absence of airflow obstruction remains controversial; they may help when there is an inflammatory response but worsen a fibrotic response. A long-acting β-agonist and inhaled corticosteroid are likely to be the best treatment for acute airflow obstruction, continued until follow-up assessment (although the evidence for this is anecdotal). It is good practice to measure lung function, preferably FEV1 and FVC, for all patients before discharge. This is more important than a chest radiograph, which is more often done but is usually uninformative in those with modest exposures. Without measurements of lung function at the time of exposure, it is difficult to interpret follow-up measurements, particularly when recovery is incomplete.

References 1. 2. 3. 4. 5. 6. 7. 8. 82

Hendrick DJ, Sizer KE. “Breathing” coal mines and surface asphyxiation from stythe (black damp). Br Med J 1992; 305: 509–510. Gavino RR, Salva ES, Gregorio SP, et al. Occupational fatalities associated with exposure to epoxy resin paint in an underground tank – Makati, Republic of the Philippines. MMWR Morb Mortal Wkly Rep 1990; 373: 379–380. Baxter PJ, Kapila M, Mfonfu D. Lake Nyos disaster, Cameroon, 1986: the medical effects of large scale emission of carbon dioxide? Br Med J; 1989: 1437–1441. Parkinson RB, Hopkins RO, Cleavinger HB, et al. White matter hyperintensities and neuropsychological outcome following carbon monoxide poisoning. Neurology 2002; 58: 1525–1532. Weaver LK, Hopkins RO, Chan KJ, et al. Hyperbaric oxygen for acute carbon monoxide poisoning. N Engl J Med 2002; 347: 1057–1067. Rose JJ, Wang L, Xu Q, et al. Carbon monoxide poisoning: pathogenesis, management, and future directions of therapy. Am J Respir Crit Care Med 2017; 195: 596–606. Jones K. Case studies of hydrogen sulphide occupational exposure incidents in the UK. Toxicol Lett 2014; 231: 374–377. Guidotti TL. Hydrogen sulphide. Occup Med (Lond) 1996; 46: 367–371. https://doi.org/10.1183/2312508X.10034319

ACUTE INHALATION INJURY | S. BURGE 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.

31. 32. 33. 34. 35.

36. 37. 38.

Sun M, Wang S, Yang Q, et al. A new colorimetric fluorescent sensor for ratiometric detection of cyanide in solution, test strips, and in cells. RSC Adv 2014; 4: 8295–8299. Thompson A, Dunn M, Jefferson RD, et al. Modest and variable efficacy of pre-exposure hydroxocobalamin and dicobalt edetate in a porcine model of acute cyanide salt poisoning. Clin Toxicol 2012; 58: 190–200. Gunnell D, Eddleston M, Phillips MR, et al. The global distribution of fatal pesticide self-poisoning: systematic review. BMC Public Health 2007; 7: 357. Agrawal V, Agrawal S, Agrawal U, et al. A study of serum cholinesterase activity with clinical correlation in patients with acute organophosphorous poisoning. J Med Research 2018; 4: 219–222. Masson P, Nachon F. Cholinesterase reactivators and bioscavengers for pre- and post-exposure treatments of organophosphorus poisoning. J Neurochem 2017; 142: Suppl. 2, 26–40. Nepovimova E, Kuca K. Chemical warfare agent NOVICHOK – mini-review of available data. Food Chem Toxicol 2018; 121: 343–350. Masson P, Nachon F. Cholinesterase reactivators and bioscavengers for pre- and post-exposure treatments of organophosphorus poisoning. J Neurochem 2017; 142: 20–40. Vale JA, Marrs TC, Maynard RL. Novichok: a murderous nerve agent attack in the UK. Clin Toxicol 2018; 56: 1093–1097. Montaguea TJ, Macneil AR. Mass ammonia inhalation. Chest 1980; 77: 496–498. Boyce SH, Simpson KA. Hydrochloric acid inhalation: who needs admission? J Accid Emerg Med 1996; 13: 422–424. Schep LJ, Slaughter RJ, McBride DI. Riot control agents: the tear gases CN, CS and OC – a medical review. J R Army Med Corps 2013; 161: 94–99. Padappayil RP, Borger J. Ammonia Toxicity. Treasure Island, StatPearls Publishing, 2020. Prezant DJ, Weiden M, Banauch GI, et al. Cough and bronchial responsiveness in firefighters at the World Trade Center site. N Engl J Med 2002; 347: 806–815. Weakley J, Webber MP, Gustave J, et al. Trends in respiratory diagnoses and symptoms of firefighters exposed to the World Trade Center disaster: 2005–2010. Prev Med 2011; 53: 364–369. Buist AS, Johnson LR, Vollmer WM, et al. Acute effects of volcanic ash from Mount Saint Helens on lung function in children. Am Rev Respir Dis 1983; 127: 714–719. Horwell CJ, Baxter PJ. The respiratory health hazards of volcanic ash: a review for volcanic risk mitigation. Bull Volcanol 2006; 69: 1–24. Banauch GI, Hall C, Weiden M, et al. Pulmonary function after exposure to the World Trade Center collapse in the New York City Fire Department. Am J Respir Crit Care Med 2006; 174: 312–319. Sabri A, Dabbous H, Dowli A, et al. The airway in inhalational injury: diagnosis and management. Ann Burns Fire Disasters 2017; 30: 24–29. Brooks SM, Weiss MA, Bernstein IL. Reactive airways dysfunction syndrome (RADS): persistent asthma syndrome after high level irritant exposure. Chest 1985; 88: 376–384. Shakeri MS, Dick FD, Ayres JG. Which agents cause reactive airways dysfunction syndrome (RADS)? A systematic review. Occup Med 2008; 58: 205–211. Henneberger PK, Derk SJ, Davis L, et al. Work-related reactive airways dysfunction syndrome cases from surveillance in selected US states. J Occup Med 2003; 45: 360–368. Bherer L, Cushman R, Courteau JP, et al. Survey of construction workers repeatedly exposed to chlorine over a three to six month period in a pulpmill: II. Follow up of affected workers by questionnaire, spirometry, and assessment of bronchial responsiveness 18 to 24 months after exposure ended. Occup Environ Med 1994; 51: 225–228. Brooks SM, Hammad Y, Richards I, et al. The spectrum of irritant-induced asthma: sudden and not-so-sudden onset and the role of allergy. Chest 1998; 113: 42–49. Karjalainen A, Martikainen R, Oksa P, et al. Incidence of asthma among Finnish construction workers. J Occup Environ Med 2002; 44: 752–757. Omland O, Hjort C, Pedersen OF, et al. New-onset asthma and the effect of environment and occupation among farming and nonfarming rural subjects. J Allergy Clin Immunol 2011; 128: 761–765. Mountjoy M, Fitch K, Boulet L, et al. Prevalence and characteristics of asthma in the aquatic disciplines. J Allergy Clin Immunol 2015; 136: 588–594. Karjalainen EM, Laitinen A, Sue-Chu M, et al. Evidence of airway inflammation and remodeling in ski athletes with and without bronchial hyperresponsiveness to methacholine. Am J Respir Crit Care Med 2000; 161: 2086–2091. Price OJ, Ansley L, Menzies-Gow A, et al. Airway dysfunction in elite athletes – an occupational lung disease? Allergy 2013; 68: 1343–1352. Nitter TB, Hirsch Svendsen KV. Covariation amongst pool management, trichloramine exposure and asthma for swimmers in Norway. Sci Total Environ 2020; 723: 138070. Thickett KM, McCoach JS, Gerber JM, et al. Occupational asthma caused by chloramines in swimming-pool air. Eur Respir J 2002; 19: 827–832.

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ERS MONOGRAPH | OCCUPATIONAL AND ENVIRONMENTAL LUNG DISEASE 39. Moore VC, Burge PS, Robertson AS, et al. What causes occupational asthma in cleaners? Thorax 2017; 72: 581–583. 40. Adewole F, Moore VC, Robertson AS, et al. Diesel exhaust causing low-dose irritant asthma with latency? Occup Med 2009; 59: 424–427. 41. Burge PS, Moore VC, Robertson AS. Sensitization and irritant-induced occupational asthma with latency are clinically indistinguishable. Occup Med 2012; 62: 129–133. 42. Kehe K, Szinicz L. Medical aspects of sulphur mustard poisoning. Toxicology 2005; 214: 198–209. 43. Balali-Mood M, Hefazi M. Comparison of early and late toxic effects of sulfur mustard in Iranian veterans. Basic Clin Pharmacol Toxicol 2006; 99: 273–282. 44. Amaza IP, Kreidy MP. Silo-filler’s disease: one health system’s experience and an update of the literature. J Agromedicine 2020; 25: 8–13. 45. Rose CS. Early detection, clinical diagnosis, and management of lung disease from exposure to diacetyl. Toxicology 2017; 388: 9–14. 46. Cullinan P, McGavin CR, Kreiss K, et al. Obliterative bronchiolitis in fibreglass workers: a new occupational disease? Occup Environ Med 2013; 70: 357–359. 47. Wallace GMF, Brown PH. Horse rug lung: toxic pneumonitis due to fluorocarbon inhalation. Occup Environ Med 2005; 62: 414–416. 48. Heinzer R, Fitting JW, Ribordy V, et al. Recurrence of acute respiratory failure following use of waterproofing sprays. Thorax 2004; 59: 541–542. 49. Hoyle JL. Pneumoconiosis and interstitial lung diseases caused by inorganic dust. In: Feary J, Suojalehto H, Cullinan P, eds. Occupational and Environmental Lung Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 190–210. 50. Walters GI, Trotter S, Sinha B, et al. Biopsy-proven hypersensitivity pneumonitis caused by a fluorocarbon waterproofing spray. Occup Med 2017; 67: 308–310. 51. Hong S, Kim HJ, Huh JW, et al. A cluster of lung injury associated with home humidifier use: clinical, radiological and pathological description of a new syndrome. Thorax 2014; 69: 694–702. 52. Andujar P, Bensefa-Colas L, Descatha A. Acute and chronic cadmium poisoning. Rev Med Interne 2010; 31: 107–115. 53. Collins JJ, Molenaar DM, Bowler LO, et al. Results from the US industry-wide phosgene surveillance: the Diller Registry. J Occup Environ Med 2011; 53: 239–244. 54. Cullinan P, Acquilla S, Ramana Dhara V, et al. Respiratory morbidity 10 years after the Union Carbide gas leak at Bhopal: a cross sectional survey. Br Med J 1997; 314: 338. 55. Kamat SR, Patel MH, Pradhan PV, et al. Sequential respiratory, psychologic, and immunologic studies in relation to methyl isocyanate exposure over two years with model development. Environ Health Perspect 1992; 97: 241–253. 56. Layden JE, Ghinai I, Pray I, et al. Pulmonary illness related to e-cigarette use in Illinois and Wisconsin – final report. N Engl J Med 2020; 382: 903–916. 57. Arter ZL, Wiggins A, Hudspath C, et al. Acute eosinophilic pneumonia following electronic cigarette use. Respir Med Case Rep 2019; 27: 100825. 58. Viswam D, Trotter S, Burge PS, et al. Respiratory failure caused by lipoid pneumonia from vaping e-cigarettes. Case Reports 2018; 2018: bcr-2018-224350. 59. Elliott DRF, Shah R, Hess CA, et al. Giant cell interstitial pneumonia secondary to cobalt exposure from e-cigarette use. Eur Respir J 2019; 54: 1901922. 60. Edmonds PJ, Copeland C, Conger A, et al. Vaping-induced diffuse alveolar hemorrhage. Respir Med Case Rep 2020; 29: 100996. 61. Henry TS, Kanne JP, Kligerman SJ. Imaging of vaping-associated lung disease. N Engl J Med 2019; 381: 1486–1487. 62. Maddock SD, Cirulis MM, Callahan SJ, et al. Pulmonary lipid-laden macrophages and vaping. N Engl J Med 2019; 381: 1488–1489. 63. Eissenberg T, Wasim Maziak W. Are electronic cigarette users at risk for lipid-mediated lung injury? Am J Respir Crit Care Med 2020; 201: 1012–1013. 64. Butt YM. S, Maxwell L, Tazelaar HD, et al. Pathology of vaping-associated lung injury. N Engl J Med 2019; 381: 1780–1781. 65. Evans ME, Twentyman E, Click ES, et al. Update: interim guidance for health care professionals evaluating and caring for patients with suspected e-cigarette, or vaping, product use-associated lung injury and for reducing the risk for rehospitalization and death following hospital discharge – United States, December 2019. MMWR Morb Mortal Wkly Rep 2020; 68: 1189–1194. 66. Lechasseur A, Altmejd S, Turgeon N, et al. Variations in coil temperature/power and e-liquid constituents change size and lung deposition of particles emitted by an electronic cigarette. Physiol Rep 2019; 7: e14093. 67. Blount BC, Karwowski MP, Morel-Espinosa M, et al. Evaluation of bronchoalveolar lavage fluid from patients in an outbreak of e-cigarette, or vaping, product use-associated lung injury – 10 states. MMWR Morb Mortal Wkly Rep 2019; 68: 1040–1041. 84

https://doi.org/10.1183/2312508X.10034319

ACUTE INHALATION INJURY | S. BURGE 68. Blount BC, Karwowski MP, Shields PG, et al. Vitamin E acetate in bronchoalveolar-lavage fluid associated with EVALI. N Engl J Med 2020; 382: 697–705. 69. Senanayake N, Gurunathan G, Hart TB, et al. An epidemiological study of the health of Sri Lankan tea plantation workers associated with long term exposure to paraquat. Br J Ind Med 1993; 50: 257–263. 70. Dinis-Oliveira RJ, Duarte JA, Sánchez-Navarro A, et al. Paraquat poisonings: mechanisms of lung toxicity, clinical features, and treatment. Crit Rev Toxicol 2008; 38: 13–71. 71. Adelson L, Sunshine I. Fatal hydrogen sulfide intoxication. Report of three cases occurring in a sewer. Arch Pathol 1966; 81: 375–380. 72. Sang-A-Gad P, Guharat S, Wananukul W. A mass cyanide poisoning from pickling bamboo shoots. Clin Toxicol 2011; 49: 834–839. 73. World Health Organization. Initial Clinical Management of Patients Exposed to Chemical Weapons: Interim Guidance Document. WHO/HSE/GCR/2014.3. Geneva, World Health Organization, 2014. Available at: www.who.int/ publications/i/item/initial-clinical-management-of-patients-exposed-to-chemical-weapons-interim-guidance-document 74. Dureja GP, Saxena RS. The methyl isocyanate (MIC) gas tragedy in Bhopal (India). Indian J Anaesth 1987; 35: 264–268. 75. Sriramachari S. The Bhopal gas tragedy: an environmental disaster. Curr Sci 2004; 86: 905–920. 76. Lapierre D, Moro J. Five Past Midnight in Bhopal. London, Simon & Schuster UK, 2002. 77. Andersson N, Muir MK, Mehra V, et al. Exposure and response to methyl isocyanate: results of a community-based survey in Bhopal. Br J Ind Med 1988; 45: 469–475. 78. Sallie B, McDonald C. Inhalation accidents reported to the SWORD surveillance project 1990–1993. Ann Occup Hyg 1996; 40: 211–221. 79. Santos-Reyes J, Beard AN. An analysis of the emergency response system of the 1996 Channel tunnel fire. Tunn Undergr Sp Technol 2017; 65: 121–139. 80. Kirkland CJ. The fire in the Channel Tunnel. Tunn Undergr Sp Technol 2002; 17: 129–132.

Disclosures: None declared.

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| Chapter 6 The impact on the aetiology of COPD, bronchitis and bronchiolitis Vivi Schlünssen1,2, Else Toft Würtz3, Martin Rune Hassan Hansen Martin Miller4, Torben Sigsgaard1 and Øyvind Omland5

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,

COPD, a leading cause of death worldwide, is defined as the presence of a relevant respiratory symptom plus spirometrically proven irreversible airways obstruction in the absence of other diseases. Environmental exposures are the main contributors to COPD and chronic bronchitis. Smoking is the most influential risk factor in high-income countries, whereas biofuel smoke is a major risk factor in low- and middle-income countries. Environmental exposures result in an accelerated decline in lung function. Importantly, environmental exposures early in life including infections and smoking may hamper the maximally attained lung function, resulting in COPD without an accelerated decline in lung function. An important proportion of COPD, chronic bronchitis and bronchiolitis cases are due to occupational exposure to vapour, gases, dust and fumes, and this aspect presents an unsolved challenge for epidemiology and occupational medicine. Knowledge of the impact of specific exposures and exposure levels is urgently needed in order to implement an effective strategy for prevention. Cite as: Schlünssen V, Würtz ET, Hansen MRH, et al. The impact on the aetiology of COPD, bronchitis and bronchiolitis. In: Feary J, Suojalehto H, Cullinan P, eds. Occupational and Environmental Lung Disease (ERS Monograph). Sheffield, European Respiratory Society, 2020; pp. 86–103 [https://doi.org/10.1183/ 2312508X.10034419].

@ERSpublications Smoking, air pollution and occupational exposures are the main causes of COPD by restricting lung growth, reducing the maximally attained lung function, and accelerating lung function decline https://bit.ly/3310jTg

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OPD is a leading cause of death worldwide [1]. COPD is a lung disease characterised by chronic obstruction of lung airflow that interferes with normal breathing and is not fully reversible [2]. Bronchitis, characterised by long-term productive cough, is also a common condition. Bronchitis and COPD share occupational and environmental risk factors, and patients often present with both conditions. Smoking is the main cause of COPD and chronic bronchitis, but occupational exposures also contribute substantially to

1

Dept of Public Health, Environment, Occupation and Health, Danish Ramazzini Centre, Aarhus University, Aarhus, Denmark. National Research Center for the Working Environment, Copenhagen, Denmark. 3Dept of Occupational Medicine, Danish Ramazzini Centre, Aarhus University Hospital, Aarhus, Denmark. 4Institute of Applied Health Sciences, University of Birmingham, Birmingham, UK. 5Dept of Occupational and Environmental Medicine, Danish Ramazzini Center, Aalborg University Hospital, Aalborg, Denmark. 2

Correspondence: Vivi Schlünssen, Bartholins Alle 2, Bg 1260, 8000 Aarhus C, Aarhus, Denmark. E-mail: [email protected] Copyright ©ERS 2020. Print ISBN: 978-1-84984-124-5. Online ISBN: 978-1-84984-125-2. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

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COPD, BRONCHITIS AND BRONCHIOLITIS | V. SCHLÜNSSEN ET AL.

the burden of these diseases [3]. For low- and middle-income countries (LMICs), smoke from burning of biomass is considered the most important environmental risk factor for COPD and bronchitis, at least in females [3]. Bronchiolitis is less common, but within the occupational field, clusters of bronchiolitis have been recognised due to specific exposures, such as diacetyl among microwave popcorn manufacturing workers [4], and e-cigarette vaping is also a suspected cause [5]. In this chapter, we will touch on the definition of COPD, discuss the evidence for occupational and other environmental causes of COPD, bronchitis and bronchiolitis, and comment on the aetiological assessment from the individual perspective, such as the COPD patient where occupational risk factors are suspected.

Definition of COPD The World Health Organization (WHO) definition of COPD is a lung disease characterised by chronic obstruction of lung airflow that interferes with normal breathing and is not fully reversible [2]. Defining the term “disease” is not a simple task, but a disease involves a pathophysiological process that leads to some deviation from a biological norm [6]. Some definitions use the term “airflow limitation” [7], which is problematic in that airflow limitation is a normal physiological phenomenon in human lungs; hence, the terminology “airways obstruction” should be used. The European Lung White Book causes further confusion by stating that COPD is a syndrome, with many phenotypes [8]. COPD is a disease, which is implicit in its name, and a disease is different from a syndrome in requiring a specified abnormality of function. For COPD, this abnormality is in lung function, specifically the FEV1/FVC ratio, which must be below the normal expected range for the individual concerned. This abnormality must be present after treatment with a bronchodilator, indicating that it is not fully reversible and so defines chronic airways obstruction. However, for COPD to be diagnosed, a patient must have in addition to this abnormality at least one relevant respiratory symptom (chronic cough, sputum, wheeze or breathlessness) and absence of other diseases known to cause this (e.g. bronchiectasis, asthma, tuberculosis). The Global Initiative for Chronic Obstructive Lung Disease (GOLD) definition puts symptoms first: “COPD is a common preventable and treatable disease that is characterised by persistent respiratory symptoms and airflow limitation” [9]. There has been confusion about how to define the expected normal range for FEV1/FVC. For symptomatic patients, the lower limit of normal (LLN) has been taken as the lower 5th percentile value, which is the lower 90% confidence interval. The GOLD consortium has stated that a fixed ratio of FEV1/FVC