Clinical Statement on Occupational Asthma

Home , Occupational asthma

1 British Thoracic Society Clinical Statement on Occupational Asthma

2 3 4

5 Draft 14 July 2021

8 Available for public consultation from

9 Thursday 5 August to Friday 17 September 2021

14 Contact:

15 British Thoracic Society,

16 17 Doughty St, London WC1N 2PL

18 [email protected] 19 20

21 A response form is available on the BTS website.

22 Please send your responses to Miguel Souto by 5pm on Friday 17th 23 September 2021 24 25 26 27 28

29 Authors: 30 Dr Christopher Barber*, Professor Paul Cullinan, Dr Johanna Feary, Professor David Fishwick, Dr 31 Jennifer Hoyle, Dr Hayley Mainman, Dr Gareth Walters (Author order to be confirmed by the group) 32 * Chair 33 Contents: 34 Section 1: Introduction 35 Section 2: Work context 36 Section 3: Diagnosis 37 Section 4: Management 38 Section 5: Prognosis 39 Section 6: Audit 40 Appendix 1: Irritant induced asthma 41 List of tables and figures 42 Table 1. Frequently reported causes of occupational asthma, by molecular weight. 43 Table 2. Legislation and guidance relevant to workplace respiratory diseases. 44 Table 3. Key elements of the occupational history for patients with suspected OA. 45 Table 4. Diagnostic tests for OA; a summary. 46 Table 5: Summary of factors influencing management of OA. 47 Table 6: Summary of potential employment options following a diagnosis of OA. 48 Table 7. Prognostic indicators in OA. 49 50 Figure 1. Classification of work-related asthma. 51 Figure 2. Diagram representing the “hierarchy of control measures” from most effective at the top, 52 to least effective at the bottom. 53 Figure 3: Recommended algorithm for the assessment and referral of patients with possible 54 occupational asthma presenting in primary or non-specialist secondary care. 55 Figure 4. Diagram summarising the key elements of OA Management. 56 57 Word count: Approx. 10246 (excluding references and Appendix) 58 References: 94 59 60 61 62 63 64 65 66 67 68

69 This British Thoracic Society (BTS) Clinical Statement addresses occupational asthma and includes key 70 clinical practice points. In an era in which medical practice is increasingly determined by evidence- 71 based guidelines, it must be acknowledged from the outset that there is little or no published evidence 72 for some of the areas covered in this Statement; thus, some of the recommendations are based on 73 expert opinion and accumulated clinical experience. 74 Methodology 75 The Clinical Statement Group (CSG) was chaired by Dr Chris Barber. Membership was drawn from 76 current and former members of the BTS Occupational and Environmental Lung Disease Specialist 77 Advisory Group. The CSG identified key areas requiring Clinical Practice Points. The overall content 78 was developed to reflect the scope approved by the BTS Standards of Care Committee (SOCC). 79 Following discussions of broad statement content, individual sections were drafted by group 80 members. A final edited draft was reviewed by the BTS SOCC before posting for public consultation 81 and peer review on the BTS website in (date to be confirmed). The revised document was re-approved 82 by the BTS SOCC in TBC before final publication. A sentence will be added to cover lay input sought at 83 consultation stage. 84

85 SUMMARY OF CLINICAL PRACTICE POINTS 86

SECTION 1 - INTRODUCTION 1. Healthcare professionals should be aware that occupational exposures account for around 1 in 6 cases of asthma in adults of working age. 2. Over 400 causes of OA have been described; these are categorised as high or low molecular weight ‘respiratory sensitisers’. 3. Although individual susceptibility plays a key role, the main risk factor for the development of OA is the level of allergen exposure in the workplace.

SECTION 1 – WORK CONTEXT 1. Health surveillance is a form of workplace screening that can identify OA cases early. In the UK, it usually consists of an annual symptom questionnaire and spirometry. 2. Workers who “fail” health surveillance due to reported symptoms or abnormal lung function should be referred as soon as possible to a specialist with expertise in OA.

SECTION 3 – DIAGNOSIS 1. Many patients with OA in the UK are diagnosed at a late stage; healthcare professionals should be aware of the important benefits of recognising cases early. 2. All patients of working age with new symptoms suggestive of asthma, reappearance of childhood asthma, deteriorating asthma control, or unexplained airway obstruction, should be asked about their job, and whether their symptoms are the same, better or worse on days away from work. 3. Symptomatic asthma patients in high-risk jobs, and those reporting work-related asthma symptoms, should be referred as quickly as possible for specialist assessment (where possible, directly to a specialist occupational lung disease service)

4. A diagnosis of OA has important health and employment implications and should not be made based on a compatible history alone. 5. The diagnosis of OA is most easily made prior to workplace adaptations and starting maintenance treatment. 6. Objective tests commonly used in the UK include skin prick tests, specific IgE antibody levels, and serial measures of PEF or airway responsiveness; workplace and specific inhalation challenges are less commonly required for OA diagnosis.

SECTION 4 - MANAGEMENT 1. Managing patients with OA can be complex and should wherever possible be carried out by a physician with specialist expertise in this condition. 2. It is important to educate patients with OA that the best opportunity for improved asthma control comes from early, and complete, cessation of exposure to the cause. 3. Management of OA includes standard pharmacotherapy, asthma education and smoking cessation advice, following national guidelines. 4. Patients with OA may have co-existing and related conditions (e.g. occupational rhinitis and breathing pattern disorder, ILO, anxiety and depression) that require assessment and treatment. 5. Clinicians should work in partnership with patients to develop (and adapt as necessary) a personalised management plan aiming for the best possible balance between long-term health and employment. 6. Where consent is given, liaising directly with occupational health providers and/or employers gives the best chance of suitable workplace adaptations being made, to keep patients and their co-workers safely employed. 7. Patients with OA should be provided with written information confirming their diagnosis, the implications this has on their current and future jobs, as well as IIDB and civil compensation advice. 8. Whilst there is potential for on-going exposure to the cause, patients with OA should remain under specialist follow up to monitor asthma control, lung function and the impact of any workplace interventions.

SECTION 5 - PROGNOSIS 1. Around 1 in 6 patients with OA meet established criteria for severe asthma. 2. Prognosis in OA is largely determined by asthma severity at the time of diagnosis, and whether workers continue to be exposed to the cause thereafter. 3. Around 25-30% of OA patients who permanently cease exposure will make a full recovery, and another 30-35% will report a reduction in symptoms with treatment. 4. Patients with OA who remain exposed to the cause are at risk of accelerated lung function decline, resulting in fixed airflow obstruction. 5. Patient with OA have an increased risk of unemployment, with approximately 1 in 3 being out of work 3-5 years after diagnosis. 6. Anxiety and depression are common in OA, affecting up to half of patients.

87 88 89

90 Section 1: Introduction 91 Asthma is a common health condition in the UK adult population, affecting over 5 million individuals. 92 For those in employment, asthma control may be adversely affected by factors in the workplace, and 93 the term “work-related asthma” (WRA) is used.1 Although the true frequency of this condition is 94 unknown, it is relatively common, affecting around 20-25% of working individuals with asthma.2-4 95 WRA is subdivided into three main phenotypes – work-aggravated asthma, allergic occupational 96 asthma due to sensitisation, and irritant-induced asthma1 (Figure 1). 97 98 99 100 101 Figure 1. Classification of work-related asthma. 102 103

Work-related asthma

Occupational asthma Work-aggravated asthma

Allergic OA Irritant-induced

(sensitisation) asthma

104 Patients with work-aggravated asthma (WAA) either have pre-existing asthma, or develop 105 coincidental adult-onset asthma, and report symptoms that are made worse by non-specific factors 106 in the workplace. Common causes of WAA include extremes of workplace temperature or humidity, 107 exertion from manual work tasks, workplace stress or anxiety, and exposure to non-specific dusts, 108 fumes, or air pollution. 109 In contrast, occupational asthma is caused by airborne exposures in the working environment, and 110 accounts for around 1 in 6 cases of adult asthma5. This condition is further sub-divided into two 111 separate conditions; irritant-induced asthma (IIA, covered in Appendix 1) and occupational asthma 112 due to allergic sensitisation (the main topic of this document; from now on referred to simply as “OA”). 113 Although there are over 400 known causes of OA (known as asthmagens), most cases in the UK are 114 caused by a small number of workplace allergens, most commonly flour dust or isocyanates6. 115 Asthmagens are usually divided into high (HMW) or low molecular weight (LMW) sensitisers7; 116 commonly reported causes are shown in Table 1. OA caused by repeated exposure to HMW proteins 117 is an IgE-associated response, involving T-helper cells. This immune mechanism is also known to be 118 relevant to a small number of LMW causes (e.g., acid anhydrides and platinum salts), but for the 119 majority the immune pathways responsible for sensitisation remain to be determined8. 120 Whatever the underlying mechanism, OA due to allergic sensitisation requires a period of repeated 121 allergen exposure, the duration of time between first exposure and symptom onset being referred to 122 as the “latent period”. Although the highest risk of OA is within the first year of exposure9, reported 123 latency is variable, ranging from a few weeks to many years10. Sensitised workers (particularly with 124 HMW allergens) are also at risk of other related forms of occupational allergy, such as rhinitis and 125 conjunctivitis, which may precede, or coincide with, the onset of asthma symptoms9. 126 The most important risk factor for the development of OA (and the preceding allergic sensitisation) is 127 the level of exposure to the cause9. In addition, individual susceptibility plays an important role, as 128 only a proportion of similarly exposed workers become sensitised, and only some of these will ever 129 develop OA. Research studies of exposed populations of workers have not established consistent 130 individual risk factors to account for this, but in some cases have found an increased risk amongst 131 workers with an allergic (atopic) tendency, who are cigarette smokers, or have certain genetic 132 polymorphisms9,11. 133 Table 1. Frequently reported causes of occupational asthma, by molecular weight. Agents and source Workers at risk High molecular Animal urine and proteins (eg. Laboratory work, veterinarians, farmers, weight agents mice, rats, cows, horses, animal handlers, greenhouse workers. insects). Cereal grains and flour (eg. Bakers, pizza and pastry makers, grain wheat, rye, barley). storage handlers, millers. Enzymes (eg. amylase, Bakers, pastry makers, food process protease, lipase). workers (amylase), cleaners, healthcare workers, detergent manufacturers. Natural rubber latex. Healthcare workers, rubber glove makers. Other animal or plant-derived Food producers and processors, bakers, products: milk and egg protein, cooks. Pharmaceutical industry, printing, beans (eg. green coffee, castor, carpet making (gums). soy), spices, gums (eg. acacia, guar). Seafood proteins (eg. fish, Fish and seafood processing. crustaceans, molluscs). Low molecular Acid anhydrides (eg. tri-mellitic Makers and processors of epoxy resins weight agents anhydride, phthalic anhydride). (adhesives, surface coatings).

Acrylic monomers (eg. Adhesive work, dental professionals, cyanoacrylate, methyl aestheticians, printing. methacrylate). Biocides (eg. aldehydes, Healthcare workers, cleaners, swimming aliphatic amines). pool attendants. Colophony (rosin) in solder flux Electronic soldering, work with adhesives (abietic acid). and surface coatings. Di-isocyanates (eg. toluene di- Spray painters, foundry workers, makers isocyanate, methylene diphenyl and processors of polyurethane substances di-isocyanate, hexa-methylene (eg. adhesives, foams, hard surface di-isocyanate). coatings). Drugs (eg. opiates, penicillins, Pharmaceutical manufacture, healthcare other antibiotics). workers with repeated exposures. Metals (eg. zinc, chromium, Welders, metal platers, hard metal cobalt) manufacturing. and metalworking fluids. CNC grinders and lathe operators. Persulphates and henna. Hairdressers. Platinum salts. Refinery workers. Some wood dust (eg. iroko, Carpenters, joiners, millers, forestry obeche, sapele, western red workers. cedar). 134 135 Clinical Practice Points 136 1. Healthcare professionals should be aware that occupational exposures account for 137 around 1 in 6 cases of asthma in adults of working age. 138 2. Over 400 causes of OA have been described; these are categorised as high or low 139 molecular weight ‘respiratory sensitisers’. 140 3. Although individual susceptibility plays a key role, the main risk factor for the 141 development of OA is the level of allergen exposure in the workplace. 142

143 Section 2: Work Context 144 Being in work is important for long term health and wellbeing, providing individuals with income, 145 social interaction, purpose, and identity12. In the UK, around 32 million adults are employed, with most 146 workplaces being small or medium enterprises with fewer than 250 workers13. The benefits of being 147 employed require workplaces to be safe and free from risks to health; there is a legal duty for 148 employers to consider this under the Health and Safety at Work Act14 and COSHH Regulations15 (Table 149 2). Employers are required to carry out risk assessments to identify any potential asthmagens and 150 decide how to prevent or minimise the risk of OA in their workforce. Based on the hierarchy of 151 controls (Table 2), the most effective measures should be used wherever practical (Figure 2). If there 152 is a residual risk of exposure to an asthmagen, health surveillance for OA is required15,16. 153 154 Health surveillance 155 Although a largely preventable disease, there is no “safe-level” of exposure that will completely 156 prevent OA in all individuals. Health surveillance is a form of secondary prevention (similar in concept 157 to health screening) that aims to identify workers with OA at an early stage, reducing the severity and 158 impact of the disease15,16. When workers are part of a health surveillance programme, there is some 159 limited evidence that the diagnostic process is shorter and that the cases identified are less severe 160 17,18. 161 Surveillance is generally carried out, annually, by an occupational health provider and usually consists 162 of a respiratory symptom questionnaire and spirometry; in some special circumstances such as the 163 detergent and precious metal refining industries, immunological surveillance is also used16. A 164 successful health surveillance programme requires careful planning, engagement of the workforce 165 and a good relationship between managers and employees. Workers will naturally be less likely to 166 report asthma symptoms if they are concerned that this might have a negative impact on their income 167 or employment prospects.19,20. 168 Workers are commonly said to have “failed” health surveillance if they report new symptoms of 169 asthma, are found to have abnormal spirometry, or if serial measures of FEV1 show accelerated annual 170 decline. Use of freely available software (SPIROLA) to plot serial lung function makes identifying 171 excessive loss of lung function much easier, but otherwise a decline in FEV1 of 15% from baseline (in 172 addition to the 25-30mls/year expected due to aging) can be used21. Health surveillance failures may 173 result in a worker being referred to an occupational physician, their GP, or directly to specialist centres. 174 If a case of OA is confirmed, an additional element of the health surveillance cycle is for occupational 175 health providers to review the health of similarly exposed co-workers and reassess the efficacy of the 176 existing control measures.15 Unfortunately, only ~30% of UK workers have access to occupational 177 health22, meaning that most patients developing OA are not identified early through workplace 178 surveillance. 179 Table 2. Legislation and guidance relevant to workplace respiratory diseases. The Health and The primary piece of legislation covering occupational health and safety in Safety at Work Act, Great Britain. It sets out the general duties which: 1974. • employers have towards employees and the public;

• employees have to themselves and to each other;

• certain self-employed have towards themselves and others. The Control of COSHH is the law that requires employers to control exposure to Substances substances that are hazardous to health. Employers are bound to:

• find out what the health hazards are;

Hazardous to Health • decide how to prevent harm to health (‘risk assessment’); Regulations, 2002. • provide control measures to reduce harm;

• make sure these are used and are in good working order;

• provide information, instruction and training for employees;

• provide monitoring and health surveillance in appropriate cases;

• plan for emergencies. The Equality Act, The Equality Act legally protects people from discrimination in the 2010. workplace and elsewhere; it replaced a raft of earlier anti-discrimination legislation. It applies to patients whose occupational asthma has had a ‘substantial’ and ‘long-term’ negative effect on their ability to do normal daily activities. (M)SDS. Every chemical agent used in industry is accompanied by a ‘(Material) Safety Data Sheet’, akin to the warnings’ leaflet in a package of medicine. Safety data sheets are readily available on-line (or through a patient’s employer) and can be scrutinised for the mention of their respiratory sensitising potential, through the ‘risk phrase’ R42 or the ‘hazard phrase’ H334. The ‘hierarchy of An approach to the management of workplace risk through which risk control’. should be reduced to the lowest reasonably practicable level by taking preventative measures, in order of priority. At the ‘top’ of the hierarchy is ‘elimination’ of the hazard at work (in this case a respiratory sensitiser); the provision of respiratory protective equipment (such as a face mask) lies at the bottom of the hierarchy. The Reporting of RIDDOR puts duties on employers, the self-employed and people in control Injuries, Diseases of work premises to report certain serious workplace accidents, and Dangerous occupational diseases (including occupational asthma) and specified Occurrences dangerous ‘near-misses’. Regulations, 2013. Industrial Injuries IIDB is a UK statutory compensation scheme available to employed earners Disablement who have developed one of a list of ‘prescribed’ occupational diseases; Benefit. these include OA due to sensitisation. Surveillance of SWORD is the national reporting scheme for occupational lung disease that Work-related and is funded by the HSE and run through the University of Manchester. Occupational Respiratory Disease. 180 181 182 Figure 2. Diagram representing the “hierarchy of control measures” from most effective at the top, to 183 least effective at the bottom (RPE: respiratory protective equipment). 184

185

186

187 188 189 Clinical Practice Points 190 4. Health surveillance is a form of workplace screening that can identify OA cases early. In the 191 UK, it usually consists of an annual symptom questionnaire and spirometry. 192 5. Workers who “fail” health surveillance due to reported symptoms or abnormal lung function 193 should be referred as soon as possible to a specialist with expertise in OA. 194 Section 3: Diagnosis 195 Statistics from the SWORD reporting scheme (see Table 2) estimate that there are 150-200 new 196 secondary care diagnoses of OA each year in the UK6 – a figure that is substantially lower than the 7- 197 10 000 figure predicted from attributing 1 in 6 of all incident cases to occupational exposures. Whilst 198 it is recognised that SWORD does not reliably collect all cases, the magnitude of the discrepancy 199 reflects a large degree of under-recognition in primary and secondary care23,24. The possibility of OA 200 should therefore be considered in all individuals of working age who present with new symptoms

201 suggestive of asthma, reappearance of childhood asthma, deteriorating asthma control, or 202 unexplained airway obstruction. Healthcare workers should routinely ask these patients:

203 • if they are employed and what sort of work they do; 204 • whether their symptoms are the same, better, or worse on days away from work, (a single 205 day away from work may not always be sufficient to discriminate, so it is important to ask 206 about longer periods as well). 207 Patients reporting symptoms of asthma that improve away from work, or who work in a high-risk job 208 (see Table 1), should have a direct and early referral to a physician with expertise in OA. Whilst the 209 choice of referral centre is decided by the initial health care professional25, where available, this should 210 be directly to a specialist centre with an occupational lung disease outpatient service; the UK has a 211 well-established and linked network of centres that have access to the full range of OA diagnostic 212 facilities (the GORDS group)26. Early assessment of workers with suspected OA is important for both 213 health and employment reasons, and for those who remain exposed in the workplace it is reasonable 214 to expect a first appointment within six-weeks of referral. A suggested algorithm for the assessment 215 and referral of patients presenting with possible OA to healthcare workers in primary or (non- 216 specialist) secondary care is shown in Figure 3. 217 218

219 Figure 3: Recommended algorithm for the assessment and referral of patients with possible 220 occupational asthma presenting in primary or non-specialist secondary care. 221 Patients of working age presenting with:

• new symptoms suggestive of asthma • reappearance of childhood asthma • deteriorating asthma control • or unexplained airway obstruction

Ask all patients: Ask all working patients:

• if they are employed and • are symptoms the same, better or what sort of work they do? worse on days away from work?

High risk job IS identified*? Symptoms are BETTER away from work

DIRECT and EARLY referral for specialist assessment to: • an occupational lung disease service (where available) • or a secondary care asthma service

*High risk jobs for OA include:

• Baking, pastry making and food handling • Cleaning and healthcare work • Chemical processing • Foam, plastic, textile and rubber manufacturing • Laboratory animal, farming and veterinary work • Spray painting • Welding, metalworking and soldering • Woodworking

222 The Diagnostic Process 223 Establishing, or excluding OA has potential serious consequences for individual patients, their co- 224 workers, and the employer. Making an early and accurate diagnosis is therefore important, and, 225 wherever possible, should be based on the results of objective tests. The diagnostic process is reliant 226 on patient engagement and should only begin after a full discussion of the nature and purpose of the 227 tests involved, as some patients will choose not to proceed due to employment concerns. 228 No single diagnostic test exists for OA, and the exact approach used will vary, based on the 229 circumstances of the individual patient, the level of experience of the health care professional, and 230 the testing facilities that are available. Patients with OA must, of course, fulfil the criteria to be 231 diagnosed with asthma. Two recent UK based guidance documents summarise the diagnostic process 232 for asthma and provide an in-depth review of the range of investigations available.27-28. For patients 233 with suspected OA, the additional requirement is to use one or more immunological or physiological 234 tests (discussed later in this section) to confirm, or exclude, a link to a workplace cause. 235 In some cases, it is not possible to make a definitive diagnosis, particularly when patients have left the 236 employment that may have caused their asthma and have no intention of returning to it or similar 237 work. In these cases, the diagnosis is reliant on the clinical and occupational history, available 238 contemporary measurements of lung function and, in suitable circumstances, the identification of 239 specific sensitisation. 240 241 Clinical and occupational history 242 History taking plays a key role in making a diagnosis in OA29, but requires specialist knowledge, 243 training, and experience. In addition to the standard clinical assessment for a patient with suspected 244 asthma, additional time is required to take a full occupational history. Although it is not within the 245 remit of this document to provide detailed guidance, some important elements of the occupational 246 history are listed in Table 3. Patients should be allowed to talk freely about their job and asked to 247 describe the materials that enter their working environment, the processes that are carried out, and 248 the products that leave the workplace. To allow sufficient time for this level of detailed assessment, 249 one-hour outpatient appointments are the recommended standard for new patient consultations.30 250 Table 3. Key elements of the occupational history for patients with suspected OA. Clinical. History of asthma prior to entering employment. Presence of work-related asthmatic symptoms. Any work processes that precipitate acute symptoms. Co-existing nasal or ocular symptoms. Duration, latency, and pattern of any reported symptoms. Results of previous workplace spirometry (“failed blowing test”). Symptomatic co-workers. Constitutional symptoms, hoarseness, or loss of voice. Workplace. Name of employer (useful information may be available on website). Size of workforce. Layout of work site. Shift pattern. Exposure to airborne fumes, dusts, gases, vapours, or mists. Exposure to materials known to cause asthma. Available Safety Data Sheets, COSHH assessments, or hygiene monitoring. Control measures (e.g. masks, enclosures or exhaust ventilation). Occupational health provision. Health surveillance or medical checks at work. Photos/videos of workplace, work tasks or materials used.

Previous visits by the Health and Safety Executive. 251 252 A detailed discussion of respiratory symptoms should be documented, as well as their relationship to 253 work, using neutral questions such as: 254 “Is your [cough, wheeze, chest tightness] the same, better or worse on your days away from work” 255 While most patients with OA will report symptoms typical of work-related asthma, the diagnosis 256 cannot be made based on history alone. Working conditions may also result in worsening symptoms 257 for patients with WAA, and also other conditions (e.g. inducible laryngeal obstruction (ILO), chronic 258 obstructive pulmonary disease (COPD), interstitial lung disease (ILD), and bronchiectasis), meaning 259 that a significant proportion of patients reporting work-related respiratory symptoms do not have OA. 260 Equally, an absence of work-related symptoms cannot be used in isolation to definitively exclude the 261 diagnosis of OA. A small proportion of patients with OA (some with markedly abnormal physiology) 262 report no, or very minimal, symptoms, due to either poor health perception or employment concerns. 263 For others with OA, a clear link between their asthma symptoms and work may not be obvious for 264 several reasons. First, for some patients with long-standing symptoms, short periods away from work 265 on rests days or holidays may not be sufficient to notice any improvement. Second, those with poorly 266 controlled asthma may have multiple additional triggers outside of the workplace. Finally, in some 267 cases of OA, isolated late asthmatic reactions predominate, with symptoms that mainly occur at home, 268 several hours after finishing a work shift. 269 Eliciting a history of exposure to a known respiratory sensitizing agent is therefore of paramount 270 importance, as this, in combination with work-related asthma symptoms, significantly increase the 271 probability of OA9. The presence of a latent period is a typical feature of OA and should be estimated 272 as part of the initial assessment; conversely, the absence of an asymptomatic period of exposure prior 273 to the onset of symptoms, makes OA by sensitization improbable. 274 In addition to the respiratory history, patients should also be routinely asked whether they have any 275 symptoms suggestive of related occupational allergies, such as rhinitis, conjunctivitis or protein 276 contact dermatitis. Questions related to other conditions that may mimic or co-exist with OA should 277 also be included, particularly to cover the possibility of breathing pattern disorders, ILO, anxiety, and 278 depression31,32. 279 280 281 First line diagnostic tests 282 In general, diagnostic tests for OA lose sensitivity over time when exposure to the cause has ceased 283 or is significantly reduced33 and can also be affected by asthma medication34. Where it is safe to do 284 so, investigations should therefore be carried out as early as possible, prior to the commencement of 285 maintenance therapy, and while patients are still working in the job considered to be the possible 286 cause of their asthma. A summary of the diagnostic tests used in OA is provided in Table 4. 287 Spirometry

288 All patients with suspected OA should have their FEV1 and FVC measured and interpreted according 289 to international guidelines21. Measured values are commonly within normal limits, but in some cases 290 bronchodilator testing confirms reversible airways obstruction. In addition to its diagnostic value, 291 spirometry is also important to provide a baseline for future monitoring, and to use as a prognostic 292 indicator. 293 Cross shift changes in FEV1 have previously been investigated as a diagnostic tool in OA, but the 294 available evidence points to this being an insensitive approach35. Where available, the pattern of 295 previous spirometry results (often from health surveillance) can be more helpful diagnostically in OA, 296 for example if there is evidence of progressive deterioration in FEV1, followed by marked 297 improvement, that can be clearly linked to a reduction in exposure. In some patients with chronic OA 298 who continue to be exposed to the cause, accelerated decline in FEV1 of 100-200 mls per year

299 (expected 25-30 mls per year in a non-smoker) occurs over several years36, resulting in fixed airflow 300 obstruction that does not show any significant response to bronchodilator testing, or improvement 301 with prolonged treatment with inhaled or oral corticosteroids. 302 303 Fractional exhaled nitric oxide (FeNO) and sputum eosinophils 304 Assessing eosinophilic airway inflammation with markers such as FeNO or induced sputum has an 305 established role in the assessment of patients with suspected asthma27,28, but their diagnostic role in 306 OA remains to be fully determined9. Limited data support their use in assessing the inflammatory 307 responses after specific inhalation challenge testing (SIC)34, with a rise in FeNO occurring later (at ~24 308 hours) than that seen for sputum eosinophils (at~6 hours). Such tests are more useful with OA due to 309 high molecular weight (HMW) agents, as LMW chemicals are less likely to cause eosinophilic 310 disease37,38. 311 The utility of using serial measures of airway inflammation, comparing periods at and away from work, 312 has also been investigated39-40. In one small study, a work-related increase in FeNO of 20 ppb was 313 found in 50% of patients with OA, but also 20% without the disease; the authors concluding that serial 314 FeNO may be a useful adjunct in diagnosis, especially where SIC cannot be performed or results are 315 equivocal40. Serial measures of FeNO may also have a role in diagnosing occupational non-asthmatic 316 eosinophilic bronchitis41. Work-related changes in sputum eosinophilia have also been compared with 317 the results of SIC, with a work-related rise >1% having a sensitivity of 76% and specificity of 65% for 318 diagnosis42. 319 Further studies are required to establish the role of repeated tests of airway inflammation in OA 320 diagnosis, and practical logistic issues may limit their availability. 321 322 Non-specific Bronchial Hyper-responsiveness (NSBHR) testing 323 Single measures of airway reactivity using, for example, mannitol or histamine inhalation, are well 324 established diagnostic tests for asthma but have a relatively low sensitivity (36-64%) for OA diagnosis. 325 NSBHR fully resolves in some patients when they are not exposed to the causal agent; in early disease, 326 this may happen within a few days of being off work. The sensitivity and negative predictive values of 327 a single measure of NSBHR are therefore very dependent on the timing of the test. For symptomatic 328 workers with recent exposure (i.e. tested within a few hours of leaving work), the absence of NSBHR 329 makes OA very unlikely43. Limited data suggest that the overall diagnostic sensitivity of NSBHR testing 330 may be improved by the addition of FeNO and sputum eosinophil measurements44. 331 Serial measures of airway reactivity (often over periods of work and rest), or pre- and post-specific 332 inhalation challenge), are also used in investigating OA, although the evidence to support their use is 333 confounded by many methodological factors including different challenge techniques, different 334 definitions of normal reactivity, and variable intervals between last occupational exposure and the 335 performance of the test.9 336 337 Immunological testing (specific IgE and skin-prick testing) 338 The use of skin-prick testing (SPT) and measurement of specific IgE antibodies to occupational agents 339 is generally reserved for HMW allergens with a clear immunological mechanism (e.g. enzymes, 340 laboratory animals, latex, and wheat flour). These tests are less useful for most LMW causes as their 341 performance relies on whether the antibodies have been properly characterised, and the availability 342 of appropriate hapten conjugates that bind the LMW allergen in vivo. Despite these limitations, 343 specific IgE tests are available for a limited number of LMW agents (e.g. acid anhydrides and 344 isocyanates), and when present have high specificity for diagnosis9. 345 If detected, a positive SPT or elevated level of specific IgE antibodies confirm sensitisation to a 346 workplace allergen, but not the presence (or definite future risk) of OA. The diagnostic utility of such 347 testing has recently been reviewed45. Lux et al identified 71 pertinent studies, and 62 were used to

348 develop a meta-analysis. The latter identified a pooled sensitivity of 0.74 and specificity of 0.71 for 349 HMW allergen testing for OA; the corresponding figures for LMW allergens being 0.28 and 0.89. 350 351 352 Serial peak expiratory flow (PEF) recordings 353 In UK practice, serial PEF measures are an important investigation when OA is suspected and have a 354 considerable evidence base to support their use. In specialist settings, acceptable PEF records can be 355 obtained in up to two-thirds of those in whom a diagnosis of OA is being considered9. For many 356 patients, they offer a cheap and simple first-line approach to assessing the physiological response to 357 inhaled agents in the workplace. They are only helpful if the patient is still exposed to the potential 358 causal agent and require measurements during periods of time at, and away, from work. Work-related 359 PEF changes do not usually confirm a specific cause for OA, and may also be seen in WAA, and other 360 occupational diseases that affect the airway, such as hypersensitivity pneumonitis46. 361 Patients may need to be taught how to use the PEF meter (standard or data-logging) and how to keep 362 a record of the readings (a YouTube video is available)47. Copies of all charts should be retained by the 363 patient, and these should ideally be completed on a pro forma that aids data entry into software that 364 permits their interpretation48. Suitable record forms and support are available online49,50. 365 The following are evidence based minimum requirements for serial PEF recordings9:

366 • at least 4 readings a day (taking the best of three each time as the recorded value). It is ideal 367 to aim for 2 hourly recordings during waking hours in order that at least 4 readings will be 368 recorded. 369 • carried out for at least three weeks. Ideally, there should be at least three days in each 370 consecutive work period, four evenly spaced readings per day and three series of consecutive 371 days at work with three periods away. 372 • work times, tasks, exposures and medication use should also be recorded. 373 • ideally, the doses of maintenance asthma medication should be kept constant during the 374 recording period. 375 The method of analysis of serial PEF records is a matter of choice, although most UK centres use a 376 computerised quantitative approach to ease comparison between cases and between centres; the 377 OASYS software permits pattern recognition and produces an Oasys score (>2.5 confirming a positive 378 work-effect). A previous meta-analysis of 31 serial PEF studies reported a pooled sensitivity of 75% 379 and specificity of 79% for a diagnosis of OA, with higher values (82% and 88%) for records with more 380 complete data51. In addition to the Oasys score, three other diagnostic metrics are also calculated 381 from the same raw data. 52-54 382 The results of serial PEF testing must be interpreted in the context of the individual case, with due 383 consideration given to prescribed asthma medication, shift patterns, previous workplace adaptations, 384 and the quality of the data provided. Where findings are equivocal, it is recommended that the 385 monitoring is repeated over a longer period, ideally including a more prolonged time away from work55 386 (e.g. before, during, and on return from a week or more of annual leave). 387 388 Specific Inhalation Challenge (SIC) 389 Although SIC is often regarded as the gold standard test,34 the technique is not widely available in the 390 UK, and most patients are diagnosed from the results of other investigations9. A positive SIC result is 391 not required for IIDB (see Table 2) or civil compensation, and the usual indications include:

392 • confirming new causes of OA 393 • identifying the exact cause to allow suitable workplace modifications 394 • confirming the diagnosis where other tests are not feasible or have been inconclusive

395 SIC with occupational agents should only be carried out in centres with relevant expertise and 396 experience26. It is generally a safe procedure; excessive reactions are rare with ~3% of patients needing 397 treatment with oral or intravenous steroids34. A control day should be included, and on active 398 challenge days exposure to the putative causative agent should be increased gradually. It is essential 399 to monitor the patient closely throughout the challenge period, and to take regular measures of 400 physiology to judge the response. Increasing the duration of the allergen exposure phase of the SIC 401 may also improve its sensitivity for OA. 402 A positive SIC is defined by the magnitude of fall in lung function following exposure to an allergen; an 403 FEV1 fall of ≥15% from baseline is generally accepted as a positive test result, which may be seen as 404 an early (within a few minutes), or late (after 2 hours) reaction. 34 In some cases a dual response is 405 seen, with a combination of early and late reactions. Alternatively, for late responses, two 406 measurements below the 95% CI for three days away from exposure have also been validated as 407 determining a positive test. Equivocal reactions can sometimes be clarified by finding changes in non- 408 specific bronchial responsiveness, sputum eosinophils or FeNO,44. 409 The sensitivity and specificity of SIC are high but not easily quantified as the method is usually used as 410 the reference standard for the diagnosis of OA. False negative tests may occur if the patient has not 411 been exposed to the cause for a prolonged period or is challenged with either the wrong allergen or 412 too low a concentration of the causative agent; irritant responses may result in false positive early 413 responses.34 414 415 Workplace challenge 416 Challenges can also be carried out in the workplace, by collecting regular measurements of airway 56 417 function (e.g. PEF or FEV1) during a working shift . These are indicated when SIC is not possible; for 418 example, where complex mixed exposures are present and cannot easily be replicated in the 419 laboratory. Workplace challenges may also be helpful in confirming OA where a high index of suspicion 420 remains, despite a negative SIC, particularly for workers with potential exposure to more than one 421 asthmagen in the workplace57. Analysis of the data produced can be carried out using the method 422 described by Stenton et al.58. This uses physiology data collected on the non-exposed days to calculate 423 a mean and 95% CI for PEF (or FEV1) values at each time point through the day. Any values recorded 424 during the exposed workdays falling below the 95% CI from the same time point of the non-exposed 425 days, are used to identify a work-relationship. 426 427 Exhaled breath condensate 428 Exhaled breath condensate (EBC) testing, collected from cooling passive exhaled breath, is not widely 429 available, and is still regarded primarily as a research tool. Its utility in diagnosing OA is not 430 established59-60. Whilst a recent study has measured various EBC based parameters over OA follow up 431 periods1, they do not yet point to inclusion in the diagnostic process. 432 433 Further sources of information 434 There are over 400 known causes of OA, and it may not be possible to confirm or exclude exposure to 435 a sensitising agent based on the history alone. Many workers will not know the names of the 436 substances that they work with, and there may be additional bystander exposures from other work 437 tasks carried out by co-workers. Following a detailed occupational history, where there is still 438 uncertainty around process and/or potential exposures, further information may be readily available 439 from employer websites, or photos and video clips that patients have taken on their mobile phone. 440 Documents providing data about the composition of chemical-based substances used in industry, 441 known as Material Safety Data Sheets (see Table 2), are readily available on the Internet or via a 442 patient’s employer. Substances containing known respiratory sensitizing agents should be given a

443 health hazard label ‘H334’(formerly R42). Any LMW chemical molecules identified that are not known 444 causes of OA can also be examined for their potential to cause respiratory sensitization, by using the 445 quantitative structure-activity relationship (QSAR) programme, available freely, online at University of 446 Manchester. This model performs well as a predictor of asthma hazard (sensitivity=90%, 447 specificity=96%)61. 448 Specialist centres may also offer to undertake workplace visits, often arranged with help from the 449 occupational health provider, but these are time consuming, and require the consent of the patient, 450 and the permission of the employer. 451 452 Differential diagnosis 453 In addition to WAA and IIA, there are several other conditions with similar clinical presentations to 454 allergic OA, which may also be work-related; these need to be considered carefully during the 455 diagnostic process, and in many cases actively excluded62.

456 • Inducible laryngeal obstruction (ILO)32 and breathing pattern disorder are distinct and well- 457 described clinical entities that can be caused or exacerbated by work but may also co-exist 458 with OA. The presence of certain clinical features such as throat tightness, hoarseness, and 459 “air hunger” are clues that may be identified in the history. Fibre-optic nasal endoscopy whilst 460 symptomatic (in some centres following specific provocation tests), cardio-pulmonary 461 exercise tests and specialist physiotherapy assessment may be helpful in confirming these 462 conditions. 463 • Hypersensitivity pneumonitis may present with work-related symptoms of cough, wheeze and 464 breathlessness mimicking asthma, which may, or may not, be accompanied by constitutional 465 symptoms of weight loss, fever, and general malaise. The most frequent cause in the UK is 466 now metal working fluid, though exposures to avian proteins, moulds (including famers’ lung) 467 and some chemical causes (eg. di-isocyanates, epoxy resins) are all reported 63. 468 • Obliterative bronchiolitis is a rare condition, characterized by sub-mucosal bronchiolar 469 inflammation and peri-bronchiolar fibrosis. Occupationally, it is recently described in popcorn 470 workers exposed to di-acetyl in butter flavourings,64 but cases have also occurred in coffee 471 processors.65 Onset of cough and breathlessness is usually insidious. Serial spirometry often 472 shows rapidly progressive and fixed airflow obstruction, and full lung function testing confirms 473 air trapping. HRCT may be very suggestive of the diagnosis, with air trapping and oligaemia 474 (sharply defined mosaic attenuation), but lung histology may be required for diagnosis. 475 • Chronic obstructive pulmonary disease (COPD); although smoking is the principal cause, 476 occupational exposures contribute significantly to the burden of disease (population 477 attributable fraction reported to be 14%5) and there is good evidence that COPD can be caused 478 by exposures to silica, coal mine dust, agricultural dust, textile dust, welding fume and 479 cadmium fume. In some cases, differential diagnosis may be challenging, as some cigarette 480 smokers with OA have co-existing COPD, and in other cases, patients with chronic OA have 481 fixed airflow obstruction. 482 483 484 485 486 487

488 489 Table 4. Diagnostic tests for OA; a summary. Test Sensitivity / specificity for a Diagnostic utility diagnosis of OA

History (expert). Sensitivity ~90%, but specificity Many patients with work-related 27-50%. symptoms do not have OA.

Questionnaires. Generally sensitive but less Used for health surveillance. specific. May be falsified. Spirometry. Single and cross-shift measures Used for asthma diagnosis and have low sensitivity. health surveillance. Baseline value useful for prognosis, and to judge changes over time in exposed workers. Exhaled nitric oxide Single measures have low Used for asthma diagnosis and as and sputum sensitivity for OA. an additional test with SIC. eosinophils. Increases the sensitivity of SIC.

Non-specific Single measures: sensitivity of Single measures used for asthma bronchial hyper- 34-64% and specificity of 84-87%. diagnosis. responsiveness Serial measures: sensitivity of 43- May resolve within a few days of (NSBHR). 62% and specificity of 52-83%. ceasing exposure in early OA. Increases the sensitivity of SIC. Serial measures more useful for confirming OA. Additional test with SIC.

Immunological HMW: sensitivity of 0.74 and Confirm sensitisation if +ve. More testing (skin prick specificity of 0.71. useful for HMW allergens. testing and specific LMW: sensitivity of 0.28 and IgE). specificity of 0.89. Serial PEF. Sensitivity of 75-82% and Generally regarded as the best first- specificity of 79-88%. line approach to assessing the Low quality data significantly physiological response to inhaled alter sensitivity and specificity. agents in the workplace. Does not confirm the cause, except in cases when exposure varies by day or time of day. Also positive in WAA. Specific inhalation Difficult to assess sensitivity and Most UK patients do not require SIC challenge (SIC). specificity as regarded as the for a diagnosis of OA. gold standard diagnostic test Only available in specialist centres. (although false positive and Useful for confirming novel causes negative responses occur). and for diagnosis if other tests are Increasing time since last not feasible or inconclusive. occupational exposure reduces May cause asthma exacerbations. sensitivity. NSBHR, FeNO and induced sputum improve sensitivity.

Workplace challenge. Difficult to assess sensitivity and Alternative to SIC if exposures specificity. cannot be safely replicated. May confirm OA after -ve SIC. 490 491 The diagnostic process in real life 492 Although there is good evidence that early diagnosis of OA is important, delays are common, with 493 most cases never reaching specialist occupational lung disease centres. A UK based multi-centre study 494 previously found an average duration of symptoms prior to diagnosis of four years66; similar to the 495 diagnostic delays of between 1.5 and 5 years reported elsewhere67-70. The reasons for late diagnosis 496 are multifactorial; in some cases, a lack of awareness or engagement is responsible, as patients are 497 reluctant to disclose symptoms or undertake investigations due to fear of losing work time or 498 employment20,72. 499 In many other cases however, diagnostic delays for UK patients result from the failure to consider the 500 diagnosis in primary and secondary care, with missed opportunities to ask simple screening 501 questions23.24. Other contributory healthcare factors reported include a lack of awareness of disease 502 prevalence, poor understanding of the importance of making the diagnosis, and a perceived lack of 503 access to specialist care71,73. 504 Clinical Practice Points 505 6. Many patients with OA in the UK are diagnosed at a late stage; healthcare professionals 506 should be aware of the important benefits of recognising cases early. 507 7. All patients of working age with new symptoms suggestive of asthma, reappearance of 508 childhood asthma, deteriorating asthma control, or unexplained airway obstruction, 509 should be asked about their job, and whether their symptoms are the same, better or 510 worse on days away from work. 511 8. Symptomatic asthma patients in high-risk jobs, and those reporting work-related asthma 512 symptoms, should be referred as quickly as possible for specialist assessment (where 513 possible, directly to a specialist occupational lung disease service) 514 9. A diagnosis of OA has important health and employment implications and should not be 515 made based on a compatible history alone. 516 10. The diagnosis of OA is most easily made prior to workplace adaptations and starting 517 maintenance treatment. 518 11. Objective tests commonly used in the UK include skin prick tests, specific IgE antibody 519 levels, and serial measures of PEF or airway responsiveness; workplace and specific 520 inhalation challenges are less commonly required for OA diagnosis. 521

522 Section 4: Management 523 Managing OA is a form of personalised (also known as precision) medicine74, aiming to attain the best 524 balance between long-term health and employment for each individual patient. Careful consideration 525 must be given to individual demographic, medical and workplace factors that vary between patients, 526 and often change in importance over the course of the illness (some of these are summarised in Table 527 5). In addition to standard asthma medication, the cornerstone of management in OA is for patients 528 to be advised to permanently avoid any further exposure to the cause. Although OA is, by definition, 529 induced by sensitisation to a workplace allergen, patients with poorly controlled disease frequently 530 report worsening symptoms due to common asthma triggers, such as exercise, emotion, extremes of 531 temperature, viral infections, and exposure to non-specific airborne irritants. A key element of 532 individual case management is therefore the requirement to correctly identify the causative exposure, 533 and to differentiate this from other non-specific asthma triggers that may also be present in the 534 workplace. Figure 4 shows a summary of the key aspects of OA management. 535 536 Table 5: Summary of factors influencing management of OA. 537 Individual. Ability to work in other roles. Age; planned age of retirement. Duration of employment in current work role. Enjoyment of current work role. Financial stability. Patient needs and preferences.

Medical. Asthma phenotype. Control of asthma symptoms. Degree of spirometry impairment and airway obstruction. Likely prognosis. Response to medication. Severity of asthma. Workplace. Access to occupational health provision. Attitudes of employer/management. Availability and effectiveness of workplace adaptations. Frequency of exposure to sensitiser. Sector of employment. Size of workforce. Workplace culture.

538 539 540 Figure 4. Diagram summarising the key elements of OA Management. (*Liaison with OH or employer 541 and contacting HSE require patient consent. +Management of any co-existing conditions including 542 rhinitis, breathing pattern disorder, ILO, anxiety and depression.) 543 544

Standard asthma education and treatment

Prevention or Liaison with reduction of OH and/or exposure employer*

Patient- centred management Treatment of Contact with related HSE* conditions+

IIDB and Report case compensation to SWORD advice

545 546 Medical management 547 Once a diagnosis has been established, the pharmacological treatment of OA is the same as that of 548 asthma unrelated to work and should follow national guidelines.27,28 Treatment regimens and action 549 plans need to be flexible, to allow for the marked variability in symptoms that may occur between 550 periods at and away from work, particularly with long absences (e.g., holidays, furlough, or sick leave). 551 In addition, smoking cessation is important, and patients should also be treated for related conditions 552 that may co-exist with OA, including occupational rhinitis, breathing pattern disorder, ILO, anxiety and 553 depression. 31,32,62 554 Few studies have specifically investigated the pharmacological treatment of OA, and those available 555 have been limited by small sample size. One study of 20 patients with OA who remained exposed to 556 the cause, found that inhaled corticosteroid and bronchodilator treatment resulted in half the study 557 population remaining clinically stable over the 3-year study period (with the remainder having left or 558 changed employment prior to the end of the study) 75. Specific allergen immunotherapy has also been 559 used in a small number of cases of OA with, at most, modest results, but the lack of available extracts, 560 potential side effects, associated time commitments and costs limit its use76. Expensive biological 561 therapies targeting immune pathways are increasingly used in the management of severe asthma but 562 the current published evidence in OA is limited to case reports of the use of omalizumab77-9. The effect 563 of inhaled corticosteroids on the recovery from OA after cessation of exposure has also been 564 investigated, with a randomised cross-over double-blind trial of 32 subjects finding small, but 565 significant improvements in symptoms, peak flow and quality of life80.

566 567 Workplace interventions to prevent (or reduce) exposure to the cause 568 After making a diagnosis of OA, clinicians have a key role in educating patients about the nature of 569 their condition and the likely long-term health outcomes that may occur if they remain exposed in the 570 workplace81. In addition, experienced OA specialists will explore the individual’s preferences and work 571 circumstances, to discuss whether it is likely that the patient’s work could be adapted to prevent or 572 substantially reduce exposure to the causal agent. The principles of occupational hygiene, including 573 the hierarchy of control measures (Figure 1), can be used as a guide to discuss possible workplace 574 adaptations. Completely removing a workplace allergen (elimination) or replacing it with a substance 575 that is not a known cause of OA (substitution) are effective control measures, but in many cases are 576 not possible due to a lack of practical alternatives. Respiratory protective equipment (RPE) is often 577 seen as a simple and cheap solution to prevent further exposure for patients with OA but is the least 578 effective control measure. RPE is only effective if worn appropriately, with a good fit on the face, and 579 proper procedures are followed for removal, storage and maintenance. Tight fitting masks should be 580 formally “fit tested”, require workers to be clean shaven, and are not suitable (or comfortable) to wear 581 for long periods of time (e.g. longer than one hour); patients with poorly controlled asthma symptoms 582 or co-existing rhinitis may have difficulty working whilst wearing this type of RPE. Battery powered air- 583 fed helmet respirators offer an alternative form of RPE with a high protection factor that does not rely 584 on maintaining a tight seal with the face and can, if necessary, be worn for full shifts. This type of RPE 585 is however more expensive and may not be acceptable to workers if it affects their ability to do their 586 job by causing problems with vision or heat tolerance. There are no large studies of long-term 587 outcomes of the effectiveness of air-fed helmet respirators, but their use may allow some workers 588 with OA to remain at work with continued exposure to the causative agent9,82. 589 Where available, workers may be offered work relocation to a non-exposed role, but often the only 590 option is to either stay in the same job, or to leave work. For many patients, receiving standard asthma 591 medication and remaining employed in a role with the same or reduced levels of exposure offers a 592 more acceptable compromise than long-term unemployment81. The pros and cons of potential 593 employment options are summarised in Table 6. 594 Table 6: Summary of potential employment options following a diagnosis of OA. 595 Options after diagnosis Advantages Disadvantages No change: continue in Minimal socioeconomic Poorer prognosis for asthma. current role with same impact. Risk of increasing sickness absence. level of on-going exposure. Continue in current role Minimal socioeconomic Reduction in exposure may not be but with reduced impact. sufficient to improve OA. exposure. Risk of increasing sickness absence. Needs supportive employer. Redeployment within same May have minimal May be lower paid or less skilled company to non-exposed socioeconomic impact. position. role. Better prognosis for Relocation may impact on commute to asthma. work (distance, time, cost). Needs supportive employer. Move to alternative Variable socioeconomic May be lower paid or less skilled employment without impact. position. exposure. Retraining opportunities. Relocation may impact on commute to Better prognosis for work (distance, time, cost). asthma. Retraining may be costly. Ill health retirement / stop Better prognosis for Socioeconomic impact of early work. asthma. retirement. 596

597 598 Liaison with Occupational Health/employers 599 An employer has a duty under the Equality Act 2010 (Table 2), to make reasonable adjustments for 600 employees with disability due to OA, and it is therefore preferable that they are made aware that one 601 of their workers has been diagnosed with this condition. All patients have a right to confidential 602 medical care however, and where workers expressly state that they do not want their employer to be 603 contacted, often due to concerns about their job security, this should be respected. In general, 604 communication is easier, and outcomes are often better, where access to an occupational health 605 service is available18. Any communication needs to be handled carefully, requiring explicit consent 606 (preferably in writing) by the patient. It is also considered best practice to allow patients to review and 607 comment on the factual content of letters or medical reports prior to their being sent to the employer 608 or occupational health provider. 609 Communication with the workplace is usually necessary to facilitate modifications to the patient’s job, 610 to prevent or significantly reduce exposure to the cause, and to give them the best chance of recovery. 611 Where one case is identified, there are frequently co-workers also being exposed and therefore at risk 612 of OA. If the employer or occupational health provider is not notified of the index case, they will not 613 be aware of the need to conduct a survey of the health of the co-workers, or to review the existing 614 control measures. Following a diagnosis of OA in one of their employees, an employer is also legally 615 obliged under RIDDOR83 (see Table 2) to report the case to the UK Health and Safety Executive, the 616 regulator of workplace safety and health. This notification usually leads to a formal visit to the 617 workplace by HSE Inspectors, and if necessary, a series of enforcement measures to be put into place 618 to avoid further cases. It is also possible for patients themselves to contact HSE directly to make a 619 complaint about their health and working conditions, but they should be made aware of the possible 620 positive and negative implications this may have on their current employment. 621 622 Benefits and compensation advice 623 In the UK, patients with OA, whether diagnosed by a doctor or not, are eligible to make a claim for 624 Industrial Injuries Disablement Benefit84 (IIDB; see Table 2). This is a statutory benefit payable, without 625 consideration of fault, to employed earners who have acquired a ‘prescribed’ workplace disease such 626 as OA due to sensitisation. Claims can be made on-line or by post and are followed by a face-to-face 627 assessment by an appointed doctor who will confirm (or otherwise) the diagnosis and estimate the 628 level of resulting disability. Only those judged to have a disability >14% are awarded benefit for OA; 629 around half of claims are successful in this respect. The self-employed are not eligible to make a claim 630 for IIDB, and those in the Armed Forces have access to a different but similar scheme (the Armed 631 Forces Compensation Scheme). 632 As an alternative, or in addition to a claim for IIDB, patients with OA may wish to make a legal claim in 633 civil law against their employer for a ‘personal injury’30; this is best done with the advice of an 634 experienced solicitor given the potential complexities. Patients who are members of a Trade Union 635 can seek advice through their local representative. A successful claim needs not only to demonstrate 636 that, on the balance of probabilities (i.e. more likely than not), their OA arose in the course of that 637 employment but also that the employer was negligent in this respect. Patients should be advised that 638 claims for personal injury are subject to a statute of limitations and must be submitted within three 639 years of knowingly having the problem. The Asthma UK website can also provide helpful information85. 640 641 Communication with patients 642 Patients with a confirmed diagnosis of OA should be given a clear explanation of their condition, ideally 643 confirmed in writing and in appropriate (lay) language; this will need additional consideration for 644 individuals who do not speak English or who are illiterate. Letters should include a description of the 645 evidence that supports the diagnosis, and the implications for future employment9. Patients should 646 also be advised of the likely health consequences of on-going exposure, and that clinical outcomes are

647 improved by early, complete and permanent removal from the cause. Finally, letters should also 648 include a mention of relevant benefits and compensation they may wish to explore. 649 650 651 Follow Up 652 The natural history of OA varies markedly between patients depending on disease severity and, 653 importantly, whether exposures are on-going. Follow up arrangements should be patient-centred and 654 planned on a case-by-case basis. Where possible, OA patients who remain exposed to the causal agent 655 should have regular follow up in a specialist clinic indefinitely. Regular outpatient consultations should 656 include serial assessments of asthma control, medication requirements, and spirometry, as well as 657 discussing the impact of any workplace interventions. Documenting objective measures of asthma 658 control at each visit (e.g. using the Asthma Control Questionnaire), and calculating annual FEV1 decline 659 are useful tools that can be used longitudinally, both to assess responses to treatment, and changes 660 in exposure. Repeating serial peak flow monitoring after workplace adjustments can also be valuable 661 for monitoring purposes with loss of previously noted work-related variability being reassuring. 662 Depending on severity, patients who are no longer exposed but have persistent asthma symptoms 663 can be managed by their GP, in non-specialist respiratory clinics, or referred into a specialist severe 664 asthma service. Symptoms of OA may take two to three years to stabilise following cessation of 665 exposure, and it is generally preferable to have outstanding work issues resolved before discharge. 666 Individuals with persistent symptoms and features of severe asthma may need to be referred for 667 consideration of biological therapy, regardless of whether or not they remain exposed to the cause. 668 669 670 Reporting cases to the national surveillance scheme 671 All respiratory physicians are encouraged to report anonymised cases of OA to the national SWORD86 672 (see Table 2) scheme that is funded by the HSE and run through the University of Manchester. 673 Consultants with a specialist interest in occupational lung disease (“core reporters”) report the 674 suspected cause and basic demographics of every new case of OA diagnosed, whereas non-specialists 675 (“sample reporters”) are invited to participate for one month each year. HSE review the annual data 676 collected to analyse trends in causation6, and to identify relevant industry sectors that may benefit 677 from future research or inspection campaigns. 678 679 680 Clinical Practice Points 681 682 12. Managing patients with OA can be complex and should wherever possible be carried out 683 by a physician with specialist expertise in this condition. 684 13. It is important to educate patients with OA that the best opportunity for improved asthma 685 control comes from early, and complete, cessation of exposure to the cause. 686 14. Management of OA includes standard pharmacotherapy, asthma education and smoking 687 cessation advice, following national guidelines. 688 15. Patients with OA may have co-existing and related conditions (e.g. occupational rhinitis 689 and breathing pattern disorder, ILO, anxiety and depression) that require assessment and 690 treatment. 691 16. Clinicians should work in partnership with patients to develop (and adapt as necessary) a 692 personalised management plan aiming for the best possible balance between long-term 693 health and employment. 694 17. Where consent is given, liaising directly with occupational health providers and/or 695 employers gives the best chance of suitable workplace adaptations being made, to keep 696 patients and their co-workers safely employed.

697 18. Patients with OA should be provided with written information confirming their diagnosis, 698 the implications this has on their current and future jobs, as well as IIDB and civil 699 compensation advice. 700 19. Whilst there is potential for on-going exposure to the cause, patients with OA should 701 remain under specialist follow up to monitor asthma control, lung function and the impact 702 of any workplace interventions. 703 704 705 706 707 708 Section 5: Prognosis 709 If diagnosed and managed early enough, OA can effectively be “cured”81 by making suitable workplace 710 adaptations that prevent further exposure to the causal agent., Despite this, the prognosis for most 711 patients in the UK remains poor, with a combination of chronic asthma (around 1 in 6 patients 712 developing severe disease)87 and adverse socioeconomic outcomes contributing to a high risk of 713 anxiety, depression, and impaired quality of life18,88,89. 714 Demographic factors such as gender and atopic status have not been found to influence prognosis, 715 and the reported effects of tobacco smoking are contradictory. Although older patients with OA may 716 also have worse health outcomes, duration of employment and age are variables that are commonly 717 related and are not well studied independently. A summary of prognostic factors in OA is provided in 718 Table 7. 719 Whatever methodology is used to attain a diagnosis, prognosis in OA is largely determined by two 720 main factors, relating to the duration and level of exposure to the cause.9,81,90-92. Longer delays in case 721 recognition, with more prolonged periods of symptomatic exposure, adversely affect prognosis, 722 resulting in increased asthma severity at the time of diagnosis (measured by the degree of airflow 723 obstruction, the level of NSBHR, and, where available, the magnitude of fall in FEV1 seen at SIC). 724 Following confirmation of the diagnosis, the second main prognostic factor relates to the degree of 725 on-going exposure to the sensitising agent. If complete cessation is possible, 25-30% of patients can 726 expect a full recovery over a 3-5 year period, and another 30-35% will report a reduction in asthma 727 symptoms with treatment81. Clinical improvement is mostly seen in the first two years but may 728 continue at a slower pace over a longer period93. Although the underlying mechanisms responsible 729 remain to be established44, the remaining patients do not get better despite completely avoiding the 730 cause, and in some cases asthma severity progresses despite good compliance with appropriate 731 medication. Workplace interventions resulting in total cessation of exposure carry the greatest risk of 732 job loss, with over half being out of work 3-5 years post-diagnosis. Although the prospect of a good 733 health outcome is lower for those who remain at work with reduced exposures (e.g., from relocation 734 to a lower exposure role, or use of RPE), a recent meta-analysis found the risk of unemployment to be 735 ~14-15 times lower than for workers who had completely ceased exposure to the cause81. 736 For workers who continue in the same job, exposed without adaptations, OA clinical outcomes are 737 usually worse, with the majority (~80%) reporting no improvement, or worsening of symptoms, 738 despite treatment. These patients are also at an increased risk of accelerated lung function decline, 739 resulting in a degree of fixed airflow obstruction. One study of individuals with OA (primarily arising 740 from low molecular weight agents) showed a mean decline in FEV1 of around 100 ml/year with on- 741 going exposure to the cause36. After removal from exposure to the agent there was an improvement 742 in mean FEV1 by around 12ml in the first year and a subsequent decline at a rate of 26 ml/year. The 743 rate of decline in FEV1 did not appear to be influenced by the type of causal agent, current smoking, 744 or treatment with inhaled corticosteroids. 745 746 Clinical practice points: 747

748 20. Around 1 in 6 patients with OA meet established criteria for severe asthma. 749 21. Prognosis in OA is largely determined by asthma severity at the time of diagnosis, and whether 750 workers continue to be exposed to the cause thereafter. 751 22. Around 25-30% of OA patients who permanently cease exposure will make a full recovery, and 752 another 30-35% will report a reduction in symptoms with treatment. 753 23. Patients with OA who remain exposed to the cause are at risk of accelerated lung function 754 decline, resulting in fixed airflow obstruction. 755 24. Patient with OA have an increased risk of unemployment, with approximately 1 in 3 being out 756 of work 3-5 years after diagnosis. 757 25. Anxiety and depression are common in OA, affecting up to half of patients. 758 759 760 Table 7. Prognostic indicators in OA. 761 762 Better Prognosis

Individual. Younger age. Normal BMI. Higher level of education. No childhood asthma. Short duration of symptoms. No dependents. Medical. Normal spirometry. Mild NSBHR. NSBHR recovery <2 years. No sputum production Workplace. Skilled work role. Cessation of exposure.

763 764 765 766 767

768 Section 6: Audit 769 Audit tool for primary care 770 The following audit criteria have been developed by the Clinical Statement Group, for use in a primary 771 care setting. The possibility of OA should be considered in all individuals of working age with new 772 symptoms suggestive of asthma, reappearance of childhood asthma, deteriorating asthma control, or 773 unexplained airway obstruction. The following should be documented in the healthcare records:

774 • what sort of work they do; 775 • if employed, whether symptoms are better on days away from work; 776 • for patients with either high risk jobs, or symptoms that improve away from work, what 777 actions have been taken to ensure early referral for specialist assessment. 778 779 Audit tool for occupational asthma specialist services 780 Previous OA audit criteria were developed and published for the original Standard of Care in 200830 781 and, based on user feedback, adapted for the 2012 update94. A survey of UK specialist centres, carried 782 out in 2018, found consensus agreement that it was important to have nationally agreed audit criteria 783 to assess the quality of care received by patients with OA. Specialists were given the opportunity to 784 agree or disagree with the existing audit criteria (published in 2012), and to suggest improvements. 785 The following audit tool has been produced based on the existing audit criteria, and the results of the 786 survey recommendations. 787 All patients with suspected OA should, as a minimum, have the following clearly documented in their 788 health records. 789 By first visit:

790 • a full list of relevant occupations held, their durations, and likely exposures; 791 • whether their current job is likely to involve exposure to a known asthmagen; 792 • presence or absence of asthma prior to entering their current job (or trade); 793 • presence or absence of work-related respiratory symptoms; 794 • presence or absence of work-related eye or nasal symptoms; 795 • duration and latency of any work-related symptoms reported; 796 • whether their workplace has occupational health provision; 797 • whether they are under OA health surveillance; 798 • whether they are aware of other affected workers in the same workplace; 799 • FEV1, FVC, and the degree of airflow limitation, compared to predicted values. 800 By second visit:

801 • if performed, the results of serial PEF measurements for at least 3 continuous weeks 802 including rest days, with at least 4 good quality readings per day, analysed to assess 803 work relatedness; 804 • if performed, the results of other respiratory function tests (e.g. bronchodilator 805 reversibility, FeNO, non-specific bronchial responsiveness); 806 • if performed, the results of appropriate specific IgE or skin prick tests. 807 808 Once a diagnosis of OA has been made:

809 • letter to patient confirming the diagnosis and (where appropriate) advice regarding 810 likely health outcomes of continued exposure; 811 • compensation advice (IIDB and civil action) where appropriate to the case.

812 28

813 Disclaimer 814 A Clinical Statement reflects the expert views of a group of specialists who are well versed on the topic 815 concerned, and who carefully examine the available evidence in relation to their own clinical practice. 816 A Clinical Statement does not involve a formal evidence review and is not developed in accordance 817 with clinical practice guideline methodology. Clinical Statements are not intended as legal documents 818 or a primary source of detailed technical information. Readers are encouraged to consider the 819 information presented and reach their own conclusions. 820 821 Declarations of interest 822 Declarations of interest were completed in line with BTS Policy and are available from the BTS Office 823 on request. 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847

848 7: References 849 1. Maestrelli P, Henneberger PK, Tarlo S, Mason P and Boschetto P. Causes and Phenotypes of 850 Work-Related Asthma Int. J. Environ. Res. Public Health 2020, 17, 4713. 851 2. Henneberger PK, Redlich CA, Callahan DB, et al. ATS Ad Hoc Committee on Work-Exacerbated 852 Asthma. An official American Thoracic Society Statement: work exacerbated asthma. Am J 853 Respir Crit Care Med 2011; 184:368–78. 854 3. Fishwick D. Work aggravated asthma; a review of the recent evidence British Medical Bulletin, 855 2014, 110:77–88. 856 4. Kim JL, Henneberger PK, Lohman S, Olin A, Dahlman-Höglund A, Andersson E, Torén K and 857 Holm M. Impact of occupational exposures on exacerbation of asthma: a population based 858 asthma cohort study. BMC Pulmonary Medicine (2016) 16:148 859 5. Blanc PD, Annesi-Maesano I, Balmes JR, Cummings KJ, Fishwick D, Miedinger D, Murgia N, 860 Naidoo RN, Reynolds CJ, Sigsgaard T, Torén K, Vinnikov D, Redlich CA. The Occupational 861 Burden of Nonmalignant Respiratory Diseases. An Official American Thoracic Society and 862 European Respiratory Society Statement. Am J Respir Crit Care Med. 2019 Jun 1;199(11):1312- 863 1334 864 6. Work-related asthma in Great Britain 2020 – HSE https://www.hse.gov.uk › statistics › causdis 865 › asthma.pdfImmunology last accessed 2/2/21 866 7. Vandenplas O, Godet J, Hurdubaea L, Rifflart C, Suojalehto H, Wiszniewska M, Munoz X, 867 Sastre J, Klusackova P, Moore V, Merget R, Talini D, Svanes C, Mason P, dell'Omo M, Cullinan 868 P, Moscato G, Quirce S, Hoyle J, Sherson DL, Kauppi P, Preisser A, Meyer N, de Blay F. Are 869 high‐ and low‐molecular‐weight sensitizing agents associated with different clinical 870 phenotypes of occupational asthma? Allergy. 2019;74:261–272. 871 8. Maestrelli P, Boschetto P, Fabbri LM, Mapp CE. Mechanisms of occupational asthma. J Allergy 872 Clin Immunol. 2009;123:531‐542. 873 9. Nicholson PJ, Cullinan P, Burge PS & Boyle C. Occupational asthma: Prevention, identification 874 & management: Systematic review & recommendations. British Occupational Health Research 875 Foundation. London. 2010. 876 10. Walters GI, Robertson AS, Moore VC and Burge PS. Occupational asthma caused by acrylic 877 compounds from SHIELD surveillance (1989–2014). Occupational Medicine 2017;67:282–289 878 11. Jeebhaya MF, Ngajiloa D, and le Moualb N. Risk factors for nonwork-related adult-onset 879 asthma and occupational asthma: a comparative review. Curr Opin Allergy Clin Immunol 2014, 880 14:84–94 881 12. Waddell G, Burton K. Is work good for your health and well-being? 882 https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_ 883 data/file/209510/hwwb-is-work-good-for-you-exec-summ.pdf Last accessed 2/2/21 884 13. foresight-report-2018.pdf (hse.gov.uk) Last accessed 2/2/21 885 14. Health and Safety at Work etc Act 1974 – legislation explained (hse.gov.uk) Last accessed 886 2/2/21 887 15. COSHH basics - COSHH (hse.gov.uk) Last accessed 2/2/21 888 16. Fishwick D, Forman S. Health surveillance for occupational asthma. Curr Opin Allergy Clin 889 Immunol. 2018 Apr;18(2):80-86. 890 17. Tarlo SM, Liss GM, Yeung KS. Changes in rates and severity of compensation claims for asthma 891 due to diisocyanates: a possible effect of medical surveillance measures. Occup Environ Med 892 2002;59:58-62. 893 18. Feary J, Cannon J, Fitzgerald B, et al. Follow-up survey of patients with occupational asthma. 894 Occup Med (Lond) 2020;70(4):231-34. 895 19. Brant A, Nightingale S, Berriman J, et al. Supermarket baker's asthma: how accurate is routine 896 health surveillance? Occup Environ Med 2005;62:395-9.

897 20. Walters GI, Soundy A, Robertson AS, Burge PS, Ayres JG. Understanding health beliefs and 898 behaviour in workers with suspected occupational asthma. Respir Med. 2015 Mar;109(3):379- 899 88. 900 21. Carrie A. Redlich, Susan M. Tarlo, John L. Hankinson, Mary C. Townsend, William L. 901 Eschenbacher, Susanna G. Von Essen, Torben Sigsgaard, and David N. Weissman; on behalf of 902 the American Thoracic Society Committee on Spirometry in the Occupational Setting Official 903 American Thoracic Society Technical Standards: Spirometry in the Occupational Setting. Am J 904 Respir Crit Care Med Vol 189, Iss 8, pp 984–994, Apr 15, 2014. 905 22. Carder M, Money A, Turner S, Agius R. Workforce coverage by GB occupational physicians and 906 disease incidence rates. Occup Med (Lond). 2014 Jun;64(4):271-8. 907 23. Walters GI, McGrath EE, Ayres JG. Audit of the recording of occupational asthma in primary 908 care. Occup Med 2012;62(7):570-3. 909 24. Ellis PR, Walters GI. Missed opportunities to identify occupational asthma in acute secondary 910 care. Occup Med 2018;68(1):56-59. 911 25. Barber CM, Naylor S, Bradshaw L et al. Facilities for investigating occupational asthma in UK 912 non-specialist respiratory departments. Occup Med 2008;58:71-3. 913 26. Group of Occupational Respiratory Disease Specialists (GORDS). 914 https://www.hsl.gov.uk/centreforworkplacehealth/gords#:~:text=The%20Group%20of%20O 915 ccupational%20Respiratory%20Disease%20Specialists%20(or,(HSL)%20for%20the%20Health 916 %20and%20Safety%20Executive%20(HSE). Last accessed 2/2/21. 917 27. SIGN158 British guideline on the management of asthma. A national clinical guideline. First 918 published 2003. Revised edition published July 2019. 919 28. Asthma: diagnosis, monitoring and chronic asthma management. NICE guideline [NG80] 920 Published date: November 2017. Last updated: February 2020. 921 29. Vandenplas O, Ghezzo H, Munoz X, Moscato G, Perfetti L, Lemière C, Labrecque M, 922 L'Archevêque J, Malo J-L. What are the questionnaire items most useful in identifying subjects 923 with occupational asthma? Eur Respir J. 2005 Dec;26(6):1056-63 924 30. Fishwick D, Barber CM, Bradshaw LM, Harris-Roberts J, Francis M, Naylor S, Ayres J, Burge PS, 925 Corne JM, Cullinan P, Frank TL, Hendrick D, Hoyle J, Jaakkola M, Newman-Taylor A, Nicholson 926 P, Niven R, Pickering A, Rawbone R, Stenton C, Warburton CJ, Curran AD; British Thoracic 927 Society Standards of Care Subcommittee Guidelines on Occupational Asthma. Standards of 928 care for occupational asthma. Thorax. 2008 Mar;63(3):240-50 929 31. Lavoie KL, Joseph M, Favreau H, Lemiere C, Labrecque M, Cartier A, Malo JL, Gautrin D, Bacon 930 SL. Prevalence of psychiatric disorders among patients investigated for occupational asthma: 931 an overlooked differential diagnosis? Am J Respir Crit Care Med. 2013 May 1;187(9):926-32 932 32. Halvorsen T, Walsted ES, Bucca C, Bush A, Cantarella G, Friedrich G, Herth FJF, Hull JH, Jung H, 933 Maat R, Nordang L, Remacle M, Rasmussen N, Wilson JA and Heimdal J-H. Inducible laryngeal 934 obstruction: an official joint European Respiratory Society and European Laryngological 935 Society statement. Eur Respir J 2017; 50:1602221 936 33. Cullinan P, Vandenplas O, Bernstein D. Assessment and Management of Occupational Asthma. 937 J Allergy Clin Immunol Pract. 2020 Nov-Dec;8(10):3264-3275 938 34. Vandenplas O, Suojalehto H, Aasen TB, Baur X, Burge PS, de Blay F, Fishwick D, Hoyle J, 939 Maestrelli P, Muñoz X, Moscato G, Sastre J, Sigsgaard T, Suuronen K, Walusiak-Skorupa J, 940 Cullinan P; ERS Task Force on Specific Inhalation Challenges with Occupational Agents. Specific 941 inhalation challenge in the diagnosis of occupational asthma: consensus statement. Eur Respir 942 J. 2014 Jun;43(6):1573-87. 943 35. Park D, Moore VC, Burge CB et al. Serial PEF measurement is superior to cross-shift change in 944 diagnosing occupational asthma. Eur Respir J, 2009; 34: 574-578 945 36. Anees W, Moore VC, Burge PS. FEV1 decline in occupational asthma. Burge Thorax 2006 946 Sep;61(9):751-5.

947 37. Walters GI, Moore VC, McGrath EE, Burge S. Fractional exhaled nitric oxide in the 948 interpretation of specific inhalational challenge tests for occupational asthma. Lung. 2014 949 Feb;192(1):119-24. 950 38. Engel J, van Kampen V, Lotz A, et al. An increase of fractional exhaled nitric oxide after specific 951 inhalation challenge is highly predictive of occupational asthma. Int Arch Occup Environ 952 Health. 2018;91:799‐809. 953 39. Merget R, Sander I, van Kampen V, Raulf-Heimsoth M, Hagemeyer O, Marek E, Brüning T. 954 Serial measurements of exhaled nitric oxide at work and at home: a new tool for the diagnosis 955 of occupational asthma. Adv Exp Med Biol. 2015 956 40. van Kampen V, Brüning T, Merget R. Serial fractional exhaled nitric oxide measurements off 957 and at work in the diagnosis of occupational asthma. Am J Ind Med. 2019 Aug;62(8):663-671. 958 41. Wiggans R, Barber CM. Metalworking fluids: a new cause of occupational non-asthmatic 959 eosinophilic bronchitis.Thorax. 2017 Jun;72(6):579-580r 960 42. Girard F, Chaboillez S, Cartier A, Côté J, Hargreave FE, Labrecque M, Malo JL, Tarlo SM, Lemière 961 C. An effective strategy for diagnosing occupational asthma: use of induced sputum. Am J 962 Respir Crit Care Med. 2004 Oct 15;170(8):845-50 963 43. Pralong JA, Lemière C, Rochat T, L'Archevêque J, Labrecque M, Cartier A. Predictive value of 964 nonspecific bronchial responsiveness in occupational asthma.J Allergy Clin Immunol. 2016 965 Feb;137(2):412-6 966 44. Vandenplas O, Lemiere C. Sensitiser-induced occupational asthma. In: Feary J, Suojalehto H, 967 Cullinan P, eds. Occupational and Environmental Lung Disease (ERS Monograph). Sheffield, 968 ERS, 2020: 34-51 969 45. Lux H, Lenz K, Budnik LT, Baur X. Performance of specific immunoglobulin E tests for 970 diagnosing occupational asthma: a systematic review and meta-analysis. Occup Environ Med 971 2019 Apr;76(4):269-278 972 46. Burge PS, Moore VC, Burge CB, Vellore AD, Robertson AS, Robertson W. Can serial PEF 973 measurements separate occupational asthma from allergic alveolitis? Occup Med (Lond). 974 2015 Apr;65(3):251-5. 975 47. Occupational asthma. https://www.youtube.com/watch?v=fK2ErOYRUPg&feature=youtu.be 976 Last accessed 5/2/21 977 48. Gannon PF, Newton DT, Belcher J, Pantin CF, Burge PS. Development of OASYS-2: a system for 978 the analysis of serial measurement of peak expiratory flow in workers with suspected 979 occupational asthma. Thorax. 1996;51(5):484-489. 980 49. www.occupationalasthma.com (last accessed 10.3.20) 981 50. https://www.lungsatwork.org.uk/clinical-services/peak-flow-surveillance-questionnaire-and- 982 other-information (last accessed 5.05.21) 983 51. Moore VC, Jaakkola MS, Burge PS. A Systematic Review of Serial Peak Expiratory Flow 984 Measurements in the Diagnosis of Occupational Asthma. Ann Respir Med 2009;1(1):31-44. 985 52. Moore VC, Jaakkola MS, Burge CB, Pantin CF, Robertson AS, Vellore AD, et al. PEF analysis 986 requiring shorter records for occupational asthma diagnosis. Occupational Medicine (Oxford) 987 2009;59(6):413-7. 988 53. Moore VC, Jaakkola MS, Burge CBSG, Robertson AS, Pantin CFA, Dev Vellore A, Burge PS. A 989 new diagnostic score for occupational asthma: the area between the curves (ABC score) of 990 peak expiratory flow on days at and away from work. Chest. 2009 Feb;135(2):307-314. 991 54. Burge CBSG, Moore VC, Pantin CFA, Robertson AS, Burge PS. Diagnosis of occupational asthma 992 from time point differences in serial PEF measurements. Thorax 2009;64(12):1032-6. 993 55. Vicky C Moore 1, Maritta S Jaakkola, Cedd B S G Burge, Charles F A Pantin, Alastair S Robertson, 994 P Sherwood Burge. Do long periods off work in peak expiratory flow monitoring improve the 995 sensitivity of occupational asthma diagnosis? Occup Environ Med . 2010 Aug;67(8):562-7. 996 56. Vandenplas O, Burge PS, Moscato G, Malo J-L. Functional assessment. In: In: Malo J-L, Chan- 997 Yueng M, Bernstein DI, eds. Asthma in the Workplace 4th Edition CRC Press. 2013:113-132

998 57. Rioux JP, Malo JL, L'Archevêque J, Rabhi K, Labrecque M. Workplace-specific challenges as a 999 contribution to the diagnosis of occupational asthma. Eur Respir J. 2008 Oct;32(4):997-1003 1000 58. Stenton SC, Avery AJ, Walters EH, Hendrick DJ. Statistical approaches to the identification of 1001 late asthmatic reactions. Eur Respir J 1994;7(4):806-12. 1002 59. Munoz X, Velasco MI, Culebras M, Roca O, Morell F, Cruz MJ. Utility of exhaled breath 1003 condensate pH for diagnosing occupational asthma. International archives of allergy and 1004 immunology 2012;159(3):313-20. 1005 60. Sanchez-Vidaurre S, Cruz MJ, Gomez-Olles S, Morell F, Munoz X. Diagnostic utility of exhaled 1006 breath condensate analysis in conjunction with specific inhalation challenge in individuals with 1007 suspected work-related asthma. Ann Allergy Asthma Immunol 2012;108(3):151-6. 1008 61. Jarvis J, Seed MJ, Stocks SJ, Agius RM. A refined QSAR model for prediction of chemical asthma 1009 hazard. Occup Med (Lond). 2015 Nov;65(8):659-66. 1010 62. Cartier A, Sastre J. Clinical assessment of occupational asthma and its differential diagnosis. 1011 Immunol Allergy Clin North Am. 2011 Nov;31(4):717-28 1012 63. Barber CM, Wiggans RE, Carder M, et alEpidemiology of occupational hypersensitivity 1013 pneumonitis; reports from the SWORD scheme in the UK from 1996 to 2015Occupational and 1014 Environmental Medicine 2017;74:528-530. 1015 64. Cox-Ganser JM, White SK, Fedan KB, Bailey RL, Fechter-Leggett E, Cummings KJ. Spirometric 1016 Abnormalities and Lung Function Decline in Current and Former Microwave Popcorn and 1017 Current Flavoring Manufacturing Workers. J Occup Environ Med. 2020 Jun;62(6):412-41 1018 65. Hubbs AF, Kreiss K, Cummings KJ, Fluharty KL, O'Connell R, Cole A, Dodd TM, Clingerman SM, 1019 Flesher JR, Lee R, Pagel S, Battelli LA, Cumpston A, Jackson M, Kashon M, Orandle MS, Fedan 1020 JS, Sriram K. Flavorings-Related Lung Disease: A Brief Review and New Mechanistic Data. 1021 Toxicol Pathol. 2019 Dec;47(8):1012-1026 1022 66. Fishwick D, Bradshaw L, Davies J, et al. Are we failing workers with symptoms suggestive of 1023 occupational asthma? Prim Care Respir J 2007;16:304–10. 1024 67. Sauni R, Kauppi P, Helaskoski E et al. Audit of quality of diagnostic procedures for occupational 1025 asthma. Occup Med 2009;59:230-6. 1026 68. Moscato G, Pignatti P, Yacoub M-R et al. Occupational asthma and occupational rhinitis in 1027 hairdressers. Chest 2005;128:3590-8. 1028 69. Santos MS, Jung H, Peyrovi J, Lou W, Liss GM, Tarlo SM.Occupational asthma and work- 1029 exacerbated asthma: factors associated with time to diagnostic steps. Chest. 2007 1030 Jun;131(6):1768-75. 1031 70. Poonai N, van Diepen S, Bharatha A, Manduch M, Deklaj T, Tarlo SM. Barriers to diagnosis of 1032 occupational asthma in Ontario. Can J Public Health. 2005 May-Jun;96(3):230-3. 1033 71. MacKinnon M, To T, Ramsey C, Lemière C, Lougheed MD. Improving detection of work-related 1034 asthma: a review of gaps in awareness, reporting and knowledge translation. Allergy Asthma 1035 Clin Immunol. 2020 Aug 6;16:73 1036 72. Bradshaw LM, Barber CM, Davies J, et al. Work-related asthma symptoms and attitudes to the 1037 workplace. Occup Med 2007;57(1):30-5. 1038 73. Parhar A, Lemiere C, Beach JR. Barriers to the recognition and reporting of occupational 1039 asthma by Canadian pulmonologists. Can Respir J 2011;18(2):90-6. 1040 74. Tarlo SM, Maestrelli P. Precision medicine in the area of work-related asthma. Curr Opin 1041 Allergy Clin Immunol . 2018 Jun;18(3):277-279. 1042 75. Marabini A, Siracusa A, Stopponi R, Tacconi C, Abbritti G. Outcome of occupational asthma in 1043 patients with continuous exposure: a 3-year longitudinal study during pharmacologic 1044 treatment. Chest. 2003 Dec;124(6):2372-6 1045 76. Sastre J, Quirce S. Immunotherapy: an option in the management of occupational asthma? 1046 Current opinion in allergy and clinical immunology 2006;6(2):96-100. 1047 77. Olivieri M, Biscardo CA, Turri S, et al. Omalizumab in persistent severe bakers' asthma. Allergy 1048 2008;63(6):790-1.

1049 78. Pimiento AP, Fernández AB, Loria JG, et al. Effect of omalizumab treatment in a baker with 1050 occupational asthma. J Investig Allergol Clin Immunol 2008;18(6):490-1. 1051 79. Lavaud F, Bonniaud P, Dalphin JC, et al. Usefulness of omalizumab in ten patients with severe 1052 occupational asthma. Allergy 2013;68(6):813-5. 1053 80. Malo JL, Cartier A, Côté J, et al. Influence of inhaled steroids on recovery from occupational 1054 asthma after cessation of exposure: an 18-month double-blind crossover study. Am J Respir 1055 Crit Care Med 1996;153(3):953-60. 1056 81. Henneberger PK, Patel JR, de Groene GJ, Beach J, Tarlo SM, Pal TM, Curti S. Workplace 1057 interventions for treatment of occupational asthma. Cochrane Database Syst Rev. 2019 Oct 1058 8;10(10):CD006308 1059 82. Ilgaz A, Moore VC, Robertson AS, et al. Occupational asthma; the limited role of air-fed 1060 respiratory protective equipment. Occup Med (Lond) 2019;69(5):329-35. 1061 83. RIDDOR. Reporting of Injuries, Diseases and Dangerous Occurrences Regulations. 1062 https://www.hse.gov.uk/riddor/ last accessed 7.2.20. 1063 84. IIDB. Industrial Injuries Disablement Benefit. https://www.gov.uk/industrial-injuries- 1064 disablement-benefit/further-information last accessed 7.2.20. 1065 85. UK A. accessed 22/09/2020 [Asthma UK website]. Available from: 1066 https://www.asthma.org.uk/advice/understanding-asthma/types/occupational-asthma/ 1067 accessed 22/09/2020 2020. 1068 86. Seed MJ, Carder M, Gittins M, Sen D, Money A, Fishwick D, Barber CM, van Tongeren M. 1069 Emerging trends in the UK incidence of occupational asthma: should we be worried? Occup 1070 Environ Med 2019;76(6):396-397 1071 87. Vandenplas O, Godet J, Hurdubaea L, Rifflart C, Suojalehto H, Walusiak-Skorupa J, et al. 1072 Severe Occupational Asthma: Insights From a Multicenter European Cohort. J Allergy Clin 1073 Immunol Pract. 2019;7(7):2309-18.e4. 1074 88. Moullec G, Lavoie KL, Malo JL, Gautrin D, Lʼarchevêque J, Labrecque M. Long-term 1075 socioprofessional and psychological status in workers investigated for occupational asthma in 1076 quebec. J Occup Environ Med. 2013 Sep;55(9):1052-64 1077 89. Lipszyc JC, Silverman F, Holness DL, Liss GM, Lavoie KL, Tarlo SM. Comparison of Psychological, 1078 Quality of Life, Work-Limitation, and Socioeconomic Status Between Patients With 1079 Occupational Asthma and Work-Exacerbated Asthma. J Occup Environ Med. 2017;59(7):697- 1080 702. 1081 90. Vandenplas O, Dressel H, Nowak D, Jamart J. What is the optimal management option for 1082 occupational asthma? Eur Respir Rev. 2012;21(124):97-104. 1083 91. Maestrelli P, Schlünssen V, Mason P, Sigsgaard T; ERS Task Force on the Management of Work- 1084 related Asthma.Contribution of host factors and workplace exposure to the outcome of 1085 occupational asthma.Eur Respir Rev. 2012 Jun 1;21(124):88-9lli 2012 1086 92. Paggiaro P, Vagaggini B, Bacci E, Bancalari L, Carrara M, Di Franco A, et al. Prognosis of 1087 occupational asthma. European Respiratory Journal. 1994;7(4):761-7. 1088 93. Malo JL, Ghezzo H. Recovery of methacholine responsiveness after end of exposure in 1089 occupational asthma. Am J Respir Crit Care Med 2004;169(12):1304-7. 1090 94. Fishwick D, Barber CM, Bradshaw LM, Ayres JG, Barraclough R, Burge S, Corne JM, Cullinan P, 1091 Frank TL, Hendrick D, Hoyle J, Curran AD, Niven R, Pickering T, Reid P, Robertson A, Stenton C, 1092 Warburton CJ, Nicholson PJ. Standards of care for occupational asthma: an update. Thorax. 1093 2012 Mar;67(3):278-80 1094

1095 Appendix 1: Irritant induced asthma 1096 The focus of this BTS statement is occupational asthma (OA) due to sensitisation. Irritant induced 1097 asthma (IIA) is a separate entity but is included here for completeness and to highlight important 1098 differences between the two diseases. IIA refers to asthma that arises as a direct consequence of 1099 exposure to agents that irritate the respiratory tract once inhaled and is distinct from allergic OA in 1100 many ways, most notably by the absence of immunological sensitisation as the underlying 1101 mechanism.1,2 In contrast to allergic OA, there is no period of latency and no clear associations with 1102 smoking or atopy have been identified for specific causal agents. 1103 Acute IIA was previously known as reactive airways dysfunction syndrome (or RADS) and first 1104 described by Brooks in 19853, who set out strict diagnostic criteria in a series of ten cases:

1105 • the absence of pre-existing asthma symptoms 1106 • a rapid onset of asthma symptoms within the first 24 hours following a single exposure to very 1107 high levels of irritant vapour, gas, fume or smoke 1108 • demonstrable airflow obstruction with bronchodilator reversibility or non-specific bronchial 1109 hyper-responsiveness 1110 • exclusion of other diagnoses that might explain the symptoms. 1111 Brooks originally described persistence of these symptoms for at least three months, but it is now 1112 recognised that, in some cases, they may resolve over a few weeks2-4. The exposure frequently occurs 1113 in, but is not limited to, the workplace; in cases of industrial accidents, more than one person may be 1114 affected. In the original Brooks paper3, acute IIA was caused by exposure to uranium hexafluoride, 1115 floor sealant, spray paints, hydrazine, heated acid, fumigating fog, metal coat remover and fire/smoke. 1116 There is inconsistent reporting of acute IIA in the literature but, based on results of a recent review, 1117 the most commonly implicated agents are chlorine-containing compounds. 5 This is supported by 1118 unpublished data from SWORD (2010-2019), with the most common reported agents being cleaning 1119 products; dusts; cement, plaster and masonry; sterilising agents and disinfectants; and fuels, oils and 1120 diesel. [personal communication] 1121 1122 In almost all cases, there are no accurate measurements of the irritant compounds generated during 1123 inhalation accidents. Therefore, estimation of the intensity of exposure is generally qualitative (and 1124 may be affected by recall bias) and can be difficult to prove. This may be an important point to 1125 acknowledge with the patient. Management should be focused on objective assessment of the 1126 presence (or absence) of disease including the assessment of non-specific bronchial hyper- 1127 responsiveness or demonstration of significant bronchodilator reversibility of reproducible 1128 spirometry. Treatment of acute IIA is with standard asthma therapy including inhaled corticosteroids 1129 and bronchodilators. There is a paucity of data on the long-term prognosis of acute IIA but evidence 1130 suggests a range of responses from complete resolution to persistent respiratory disability.6-8 Asthma 1131 medication should be reviewed regularly and withdrawn and stopped if possible. Because the 1132 underlying mechanism is not due to IgE mediated allergy, individuals can continue in their usual work 1133 environment so long as there are measures to prevent further high-level exposures. 1134 Physicians should be aware that some of the situations in which the exposure occurred may have been 1135 extremely frightening (e.g. explosion at work) and psychological factors which arise as a result may 1136 impact on recovery. 8 An inhalation injury can result in anxiety and fear about returning to the 1137 workplace. Hyperventilation and other breathing pattern disorders, inducible laryngeal obstruction, 1138 chronic rhinitis, perceived issues with chemical sensitivity and post-traumatic stress disorder may 1139 mimic asthma symptoms and should be explored and managed. IIA is not a prescribed disease and 1140 thus affected individuals are not eligible for IIDB, but not infrequently a personal injury claim will 1141 ensue.

1142 In addition to acute IIA, other possible phenotypes of IIA have been described, including asthma 1143 occurring as a result of repeated symptomatic high-level exposure to irritants (Brookes used the term 1144 “not-so-sudden-onset” IIA4) or chronic exposure to moderate dose irritants;1, the underlying 1145 mechanisms responsible for these conditions are less clearly defined and remain an active area of 1146 research interest. 1147 1148 1149 References 1150 1. Vandenplas O, Wiszniewska M, Raulf M, et al. EAACI position paper: irritant-induced asthma. Allergy 1151 2014;69(9):1141-53. doi: 10.1111/all.12448 [published Online First: 2014/05/24] 1152 2. Tarlo SM, Balmes J, Balkissoon R, et al. Diagnosis and management of work-related asthma: 1153 American College Of Chest Physicians Consensus Statement. Chest 2008;134(3 Suppl):1s-41s. 1154 doi: 10.1378/chest.08-0201 [published Online First: 2008/09/26] 1155 3. Brooks SM, Weiss MA, Bernstein IL. Reactive airways dysfunction syndrome (RADS). Persistent 1156 asthma syndrome after high level irritant exposures. Chest 1985;88(3):376-84. 1157 4. Brooks SM, Hammad Y, Richards I, et al. The spectrum of irritant-induced asthma: sudden and not- 1158 so-sudden onset and the role of allergy. Chest 1998;113(1):42-9. d 1159 5. Walters GI, Huntley CC. Updated review of reported cases of reactive airways dysfunction 1160 syndrome. Occup Med (Lond) 2020;70(7):490-95. doi: 10.1093/occmed/kqaa133 [published 1161 Online First: 2020/10/17] 1162 6. Chang-Yeung M, Lam S, Kennedy SM, et al. Persistent asthma after repeated exposure to high 1163 concentrations of gases in pulpmills. Am J Respir Crit Care Med 1994;149(6):1676-80. doi: 1164 10.1164/ajrccm.149.6.8004329 [published Online First: 1994/06/01] 1165 7. Malo JL, Cartier A, Boulet LP, et al. Bronchial hyperresponsiveness can improve while spirometry 1166 plateaus two to three years after repeated exposure to chlorine causing respiratory 1167 symptoms. Am J Respir Crit Care Med 1994;150(4):1142-5. doi: 1168 10.1164/ajrccm.150.4.7921449 [published Online First: 1994/10/01] 1169 8. Malo JL, L'Archevêque J, Castellanos L, et al. Long-term outcomes of acute irritant-induced asthma. 1170 Am J Respir Crit Care Med 2009;179(10):923-8. doi: 10.1164/rccm.200810-1550OC [published 1171 Online First: 2009/02/24]