Occupational asthma

THE LANCET

Occupational medicine

Occupational asthma Katherine M Venables, Moira Chan-Yeung Occupational asthma is a common disorder that may be caused by several hundred agents and has a variety of pathogenetic mechanisms. Level of exposure is an important risk factor, and reduction of exposure is the only certain method of prevention. Atopy and smoking are further risk factors for IgE-mediated asthma but have not been found to increase risk in forms of the disorder that have other mechanisms. The key to diagnosis is a low threshold of suspicion; several investigative procedures can be used to confirm the diagnosis. Many patients suffer from continued asthma despite cessation of exposure; early diagnosis and early removal from exposure are the most important factors for improving the long-term outcome. Asthma is a very common disorder; 5–10% of the general population are affected. The proportion of cases of asthma attributable to occupational exposure is unknown, though estimates range from 15% to 20% in Japan1 and the USA.2 In surveillance programmes in the UK3 and in British Columbia, Canada,4 occupational asthma accounted for 26% and 52% of occupational lung disease, respectively. Occupational asthma is defined as a disease characterised by either or both variable airflow limitation and bronchial hyperresponsiveness due to causes and conditions attributable to a particular working environment and not to stimuli encountered outside the workplace.5 Pre-existing or concurrent asthma aggravated by irritants or physical stimuli in the workplace is excluded by this definition. However, individuals with pre-existing or concurrent asthma may become sensitised to an agent in the workplace and may be at increased risk of developing sensitisation to some occupational exposures, such as animals.

Causative agents About 250 agents capable of causing occupational asthma have been reported.6 Some of the more common agents are shown in the panel. They can be classified into three groups according to the possible pathogenetic mechanisms. In many instances, several mechanisms may be involved.

Specific IgE Some substances cause asthma by inducing specific IgE antibodies. These are mostly high-molecular-weight allergens (>5 kDa) such as proteins in the urine of laboratory rats. Others are low-molecular-weight compounds, such as complex halogenated platinum salts or acid anhydrides; these agents act as haptens and combine with a body protein to form a complete antigen. The reaction between the antigen and specific IgE antibodies initiates an allergic inflammatory reaction in the airways.

Lancet 1997; 349: 1465–69 Department of Occupational and Environmental Medicine, Imperial College School of Medicine, National Heart and Lung Institute, London SW3 6LR, UK (K M Venables MD); and Occupational and Environmental Lung Diseases Unit, Department of Medicine, University of British Columbia, Vancouver, Canada (Prof M Chan-Yeung MD) Correspondence to: Dr Katherine M Venables

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Unknown immunological mechanisms Other substances induce asthma probably by an immunological mechanism, although the exact nature is not known. They are mostly low-molecular-weight compounds such as isocyanates. Specific IgE antibodies Selected major causes of occupational asthma and typical occupations Animals Animal urine and other allergens Grain mite Locusts, moths Prawns, crabs Silkworm larva Egg protein

Animal handlers in laboratories, research scientists Farmers, grain-store workers Entomologists, laboratory workers Processors of these foods Workers in sericulture Egg producers

Plants Grain dust Flour of wheat, rye, soya Latex Green coffee bean Castor bean Henna Gum acacia

Grain-store workers Bakers, millers Health-care workers Coffee roasters Oil industry, dock workers Hairdressers Printers

Enzymes Derived from Bacillus subtilis Pancreatin, papain, pepsin Fungal amylase

Detergent industry workers Pharmaceutical industry workers Bakers

Wood dusts or barks Western red cedar, iroko, cinnamon, oak, mahogany, African apple Toluene diisocyanate Phthalic anhydride Ethylene diamine Azodicarbonamide Reactive dyes Methyl methacrylate Drugs Penicillins, psyllium, methyldopa, cimetidine, salbutamol intermediates

Sawmill workers (joiners, carpenters) Polyurethane, plastics, varnish workers Workers with plastics, epoxy resins, alkyd resins Photography, shellac workers Plastics, rubber workers Dyeing, textile workers Health-care workers Pharmaceutical, health-care workers

Metals Halogenated platinum salts Cobalt

Platinum-refining workers Hard-metal grinders

Other Oil mists Aluminium potroom emissions Colophony in soft solder flux

Tool setters Aluminium-refining workers Electronics workers

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are found in only a small proportion of patients and the pathogenetic significance of these antibodies is not known.7 T lymphocytes may be directly involved in mediating the inflammatory response in the airways in patients with occupational asthma caused by these agents.8

Non-immunological mechanisms Agents that induce asthma by non-immunological mechanisms are mostly irritant gases, fumes, or chemicals (irritant-induced asthma).

Pathological changes Whatever the nature of the agent and its pathogenetic mechanism, the resultant changes in the airways are inflammation with airway hyperresponsiveness. Bronchial biopsy samples from patients with occupational asthma caused by compounds of high and low molecular weight show similar changes, with denudation of airway epithelium, subepithelial fibrosis, and infiltration of the mucosa with inflammatory cells—similar to the changes found in patients with non-occupational asthma.8 Immunostaining showed activation of eosinophils and T lymphocytes.8 Bronchial biopsy samples from patients with irritant-induced asthma also show similar changes with perhaps more widespread subepithelial fibrosis9 and very little activation of T lymphocytes.10

Clinical features The clinical picture of occupational asthma depends on the agents and the pathogenetic mechanism involved. Occupational asthma mediated through immunological mechanisms is characterised by a latency period between first exposure and onset of symptoms; only a proportion of exposed workers develop asthma; and re-exposure to very low concentrations of the causative agent provokes symptoms. Inhalation challenge tests with agents that produce specific IgE antibodies commonly provoke an isolated immediate or a biphasic reaction, an immediate followed by a late reaction. An isolated immediate asthmatic reaction occurs within a few minutes of inhalation challenge, reaches maximum intensity within 30 min, and ends within 60 to 90 min. A late asthmatic reaction occurs 4–6 h after inhalation challenge, reaches maximum intensity within 8–10 h, and ends after 24–48 h (figure 1). Although most of the low-molecular-weight compounds are not thought to induce specific IgE antibodies, the clinical picture produced by these agents is that of an allergic disorder. Inhalation challenge tests with these agents commonly produce an isolated late or biphasic asthmatic reaction. An example of non-immunologically mediated occupational asthma is induced by irritants. The first cases were reported by Brooks and colleagues11 in ten patients who developed cough, wheeze, and dyspnoea within 24 h of an accidental exposure to a very high level of an irritant gas; none of them had a previous history of respiratory disease. All the affected individuals had bronchial hyperresponsiveness. The term reactive airways dysfunction syndrome (RADS) was used to describe this disorder. Irritant-induced asthma may develop after several episodes rather than a single episode of “gassing” in pulpmill settings.10 Clinical studies showed that these patients have less reversibility in their airflow obstruction than patients with other types of occupational asthma, which reflects the pathological changes.9 1466

Epidemiology Occupational asthma is common. The frequency may be very high in some industrial settings. For example, an early study in the platinum-refining industry suggested that 46% of workers had occupational asthma.12 30 years later, about 25% of a cohort of platinum-refinery workers developed occupational asthma during 4 years of followup, most within the first year.13 In other industries, only sporadic cases may be reported, but an apparently isolated case may be the first sign of a much more extensive problem. Several factors increase the risk of occupational asthma. The most important, because it is preventable, is the degree of occupational exposure. In a British bakery, for example, the prevalence of work-related chest symptoms was significantly related to level of current exposure to flour dust; bronchial hyperresponsiveness was twice as common among workers who had ever worked in a job with high flour exposure as among workers not so exposed.14 During the epidemics of asthma in the enzymedetergent industry in the 1960s and 1970s, the rate of sensitisation was highest among workers with high exposure, and it fell steadily after measures to suppress dust were taken.15 The effect of exposure is difficult to evaluate because of the healthy-worker effect—ie, workers with occupational asthma tend to leave jobs with high exposure because of intolerable symptoms; those who remain are healthy “survivors”. Some allergens are exceptionally potent sensitising agents. For example, the hessian sacks used to transport castor beans are recycled for transporting other commodities and for making felt. The sacks contain enough castor-bean antigen to sensitise dock workers, and the felt has sensitised furniture workers.16 Atopic individuals are at increased risk of asthma due to some occupational agents that induce specific IgE antibodies. For example, atopic individuals (positive skintest reactivity to common allergens) were five times more likely than non-atopic individuals to have work-related respiratory symptoms in a survey of handlers of laboratory animals.17 The association with atopy may represent genetic predisposition to occupational sensitisation or asthma. Allergy to laboratory animals has been tentatively associated with HLA B15 and DR4,18 and sensitisation to trimellitic anhydride with HLA DR3.19 Smokers are also at increased risk of asthma due to IgEinducing agents. Smokers had a five-fold increased risk of sensitisation to complex platinum salts in a cohort of platinum-refinery workers.13 An association with smoking has been seen for tetrachlorophthalic anhydride, snow crabs, ispaghula, and green coffee bean.20 These findings have been confirmed in a study on rats sensitised with ovalbumen21 and may be related to the smoke-induced inflammation in the respiratory epithelium. Other irritant gases have a similar immunopotentiation effect in animals: for example, ozone potentiated sensitisation by complex platinum salts in a primate model.22 There seems to be some concordance between specific IgE, atopy, and smoking; it is possible that IgE-mediated asthma is potentiated by atopy and smoking. For most low-molecular-weight compounds that are not known to induce specific IgE antibodies, such as western red cedar or isocyanates,20 non-atopic individuals and nonsmokers are at greater risk than atopic individuals and smokers. An association between HLA class 2 genes and

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Challenge test

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Figure 1: Inhalation challenge tests in two patients with asthma caused by maleic anhydride (MA) and tetrachlorophthalic anhydride (TCPA) No response to lactose-dust control challenge, but increasing exposures to MA or TCPA provoked asthmatic responses of increasing size. Late and biphasic responses are shown. FEV 1=forced expiratory volume in 1 s. (Modified and reproduced with permission from Br J Industr Med 1989; 46: 222–32.)

isocyanate asthma has been found: people with HLA DQB1*0503 were predisposed to this type of asthma, whereas those with HLA DQB*0501 were protected. These findings suggest that T lymphocytes are important in the pathogenesis of this type of asthma.23 Newman Taylor24 has reviewed the little known about the epidemiology of irritant-induced asthma. The original report of RADS was a case series.11 In one series of inhalation accidents, around 9% were followed by RADS or asthma.25 In a study of hospital laboratory employees exposed to a spillage of 100% acetic acid, the risk of irritant-induced asthma increased with increasing extent of exposure.26

exposure are the keys to complete recovery. Patients who remain in the same job and continue to be exposed to the same causal agent after diagnosis generally worsen with time. The use of protective respirators did not prevent the worsening of symptoms in one study;30 the use of respiratory protection should therefore be monitored. There are few follow-up data available on patients with irritant-induced asthma. Bherer and colleagues31 found that 75% of pulpmill workers who developed asthma symptoms after acute “gassing” episodes continued to have airway hyperresponsiveness 18–24 months after the accident; the remainder recovered.31

Diagnosis Natural history The risk of occupational asthma appears to be highest soon after first exposure, but the latent interval can vary from months to years.27 Occupational asthma is a potentially fatal condition. Necropsy information on a patient with occupational asthma caused by an isocyanate has been reported.28 A fatal case of asthma in a baker has been reported.29 Withdrawal from exposure may or may not lead to improvement in asthma or bronchial hyperresponsiveness.27 The total duration of exposure, the duration of symptoms, and the severity of asthma at the time of diagnosis are important determinants of outcome.27 Early diagnosis and early withdrawal from

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The diagnosis of occupational asthma should be considered in every case of adult-onset asthma or worsening asthma in adult life. In immunologically mediated asthma, the characteristic symptoms are of asthma that improves during weekends and holidays. Improvement may take several days, and the patients feel best in the second week of a 2-week holiday or on Monday morning after Saturday and Sunday off work. Nocturnal or early-morning asthma may occur after a shift working with the causal agent. Asthma may be associated with rhinitis, conjunctivitis, or urticaria. Over a period of weeks or months, symptoms usually become more severe and acute asthma may be provoked after even low exposures, such as to a workmate’s clothing. 1467

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Max imum

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Peak expiratory flow (L/min)

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this advice for economic reasons. Larger companies may be able to relocate the patient to reduce exposure and provide respiratory protection. If there is a possibility of low or occasional exposure, the patient should remain under medical supervision and peak-flow records and symptoms should be followed. If present, specific IgE can be monitored. If exposure has ceased, specific IgE concentrations should fall with a half-life of around 1 or 2 years over the first few years.34 Spirometry and bronchial responsiveness should improve, with a plateau at about 1 or 2 years, respectively.35 Many countries provide worker’s compensation for occupational asthma. Some employers with high-risk exposures have negotiated compensation packages with employees’ representatives. In most countries, a negligent employer can be sued for damages by his employee.

Minimum

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Impairment/disability assessment 300 1

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Days Figure 2: Peak-flow record in patient with asthma caused by tetrachlorophthalic anhydride Readings taken every 2 h from waking to sleeping for 25 days and charted as daily mean, maximum, and minimum. During work weeks (shaded), mean peak expiratory flow falls and daily variation increases.

The doctor should ask the patient whether there is anything that makes the asthma worse. Questioning about whether any work colleagues are affected may uncover outbreaks of asthma. The employer can be approached for details of work processes if the patient gives permission. Documentation of objective changes in lung function— improvement away from work or deterioration on returning to work—is desirable. If the patient is still working with the causal agent, a record of peak flow made every 2 h from waking to sleeping over several weeks may be invaluable to confirm work-related airway narrowing (figure 2).32 Alternatively, spirometry or testing of bronchial responsiveness while the patient has symptoms may show deterioration compared with tests when there has been no exposure for several days or more. For some agents, such as platinum salts, laboratory animals and insects, and acid anhydrides, immunological tests are available to confirm sensitisation. A positive skinprick or serum specific IgE test, coupled with a clear history of work-related asthma, may be sufficient for the diagnosis to be made. Inhalation challenge testing should be done in a specialised centre33 and may be necessary if: the cause has not been reported previously; the patient works with several sensitisers, the cause is not clear despite other investigations; or the patient has such severe asthma that supervised, controlled exposure in hospital is safer than unsupervised exposure at the workplace. In the case of irritant-induced asthma, symptoms follow an accidental exposure to an irritant and the sequence of events is usually clear.

Management Avoidance of exposure is the mainstay of patient management. Ideally, patients should withdraw from the causal exposure permanently, retraining if necessary for alternative employment. In practice, patients may reject 1468

Patients with asthma are characterised by variable airflow obstruction and airway hyperresponsiveness. They have to avoid exposure to dust, gases, and fumes, and they may be at a disadvantage in their future employment. The results of their lung function tests may be normal with the use of drugs. The guidelines for assessment of impairment and disability for patients with chronic irreversible disease are inappropriate for patients with asthma. The guidelines recommended by the American Thoracic Society take into account all the special features of asthma.36 Important points are that assessment of impairment/disability should take place when the asthma is under control; the patient should be reassessed when there is a change in clinical status; and in the rating of impairment, the degree of reversibility of airflow obstruction or airway hyperresponsiveness and the minimum dose of drugs required to maintain asthma control should be included with the degree of airflow obstruction.

Prevention Primary prevention includes elimination of the agent from the workplace by substitution or process change. Reduction of exposure can also be achieved through isolation, enclosure, and improved local exhaust. Good housekeeping, maintenance, waste disposal, and sanitation practice are important. Exclusion of susceptible individuals from high-risk workplaces after preemployment examination is another method. However, very little is known about host susceptibility factors, with the exception of atopy in those with exposure to highmolecular-weight occupational allergens. Even then, the value of excluding atopic individuals is debatable. Secondary prevention aims at the early detection of disease. Although such detection can be accomplished by periodic examination of workers in high-risk industries, it is costly because no simple and objective screening tests are available. Tertiary prevention aims at the prevention of permanent asthma. This aim can be achieved by early recognition and early removal from exposure. References 1

2

Kobayashi S. Occupational asthma due to inhalation of pharmacological dusts and other chemical agents with some reference to other occupational asthma in Japan. In: Yamamura Y, Frick OL, Horiuchi Y, et al, eds. Allergology. Amsterdam: Excerpta Medica, 1974: 124–32. Blanc P. Occupational asthma in a national disability survey. Chest 1987; 92: 613–17.

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Meredith SK, Taylor VM, McDonald JC. Occupational respiratory disease in the United Kingdom 1989: a report to the British Thoracic Society and the Society of Occupational Medicine by the SWORD project group. Br J Industr Med 1991; 48: 292–98. Contreras G, Rousseau R, Chan-Yeung M. Short report: occupational respiratory diseases in British Columbia. Occup Environ Med 1994; 51: 710–12. Bernstein IL, Chan-Yeung M, Malo JL, Berstain DI. Definition and classification of asthma. In: Bernstein IL, Chang-Yeung M, Malo JL, Bernstein DI, eds. Asthma in the workplace. New York: Marcel Dekker, 1993: 1–4. Chan-Yeung M, Malo J. Etiologic agents in occupational asthma. Eur Respir J 1994; 7: 346–71. Frew A, Chan H, Dryden P, Salari H, Lam S, Chan-Yeung M. Immunologic studies of the mechanisms of occupational asthma caused by western red cedar. J Allergy Clin Immunol 1993; 92: 466–78. Mapp CE, Saetta M, Maesrelli P, et al. Mechanisms and pathology of occupational asthma. Eur Respir J 1994; 7: 544–54. Gautrin D, Boulct L, Boutet M, Dugas M, Cote J, Malo J. Is reactive airways dysfunction syndrome (RADS) a variant of occupational asthma. J Allergy Clin Immunol 1994; 93: 12–22. Chan-Yeung M, Lam S, Kennedy S, Frew A. Persistent asthma after repeated exposure to high concentrations of gases in pulpmills. Am J Respir Crit Care Med 1994; 149: 1676–80. Brooks S, Weiss M, Bernstein I. Reactive airways dysfunction syndrome (RADS); persistent asthma syndrome after high level irritant exposures. Chest 1985; 88: 376–84. Hunter D, Milton R, Perry KMA. Asthma caused by the complex salts of platinum. Br J Industr Med 1945; 2: 92–98. Venables KM, Dally MB, Nunn AJ, et al. Smoking and occupational allergy in workers in a platinum refinery. BMJ 1989; 299: 939–42. Musk AW, Venables KM, Crook B, et al. Respiratory symptoms, lung function, and sensitisation to flour in a British bakery. Br J Industr Med 1989; 46: 636–42. Juniper CP, How MJ, Goodwin BFJ, Kinshott AK. Bacillus subtilis enzymes: a 7-year clinical, epidemiological and immunological study of an industrial allergen. J Soc Occup Med 1977; 27: 3–12. De Zotti R, Palussi V, Fiorito A, Larese F. Sensitisation to green coffee bean (GCB) and castor bean (CB) allergens among dock workers. Int Arch Occup Environ Health 1988; 61: 7–12. Venables KM, Tee RD, Hawkins ER, et al. Laboratory animal allergy in a pharmaceutical company. Br J Industr Med 1988; 45: 660–66. Low B, Sjostedt L, Willers L. Laboratory animal allergy: possible association with HLA B15 and DR4. Tissue Antigens 1988; 31: 224–26. Young RP, Barker RD, Pile KD, Cookson WOCM, Newman Taylor AJ. The association of HLA-DR3 with specific IgE to inhaled acid anhydrides. Am J Respir Crit Care Med 1995; 151: 219–21. Chan-Yeung M. Occupational asthma. Chest 1994; 98: 124S–61S.

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21 Zetterstrom O, Nordvall SL, Bjorksten B, Ahlsted S, Stelander M. Increased IgE antibody responses in rats exposed to tobacco smoke. J Allergy Clin Immunol 1985; 75: 594–98. 22 Biagini RE, Moorman WJ, Lewis TR, Bernstein IL. Ozone enhancement of asthma in a primate model. Am Rev Respir Dis 1986; 134: 719–25. 23 Balboni A, Baricordi OR, Fabbri LM, Gandini E, Ciaccia A, Mapp CE. Association between toluene diisocyanate-induced asthma and DQB1 markers: a positive role for aspartic acid at position 57. Eur Respir J 1996; 9: 207–10. 24 Newman Taylor AJ. Respiratory irritants encountered at work. Thorax 1996; 51: 541–45. 25 Sallie B, McDonald C. Inhalation accidents reported to the SWORD surveillance project 1990–1993. Ann Occup Hyg 1996; 40: 211–21. 26 Kern DG. Outbreak of the reactive airways dysfunction syndrome after a spill of glacial acetic acid. Am Rev Respir Dis 1991; 144: 1058–64. 27 Chan-Yeung M, Malo J-L. Natural history of occupational asthma. In: Bernstein IL, Chan-Yeung M, Malo JL, Bernstein DI, eds. Asthma in the workplace. New York: Marcel Dekker, 1993: 299–322. 28 Fabbri LM, Danieli D, Cresciolli S, et al. Fatal asthma in a toluene diisocyanate sensitised subject. Am Rev Respir Dis 1988; 137: 1494–98. 29 Ehrlich RI. Fatal asthma in a baker: a case report. Am J Industr Med 1994; 26: 799–802. 30 Cote J, Kennedy S, Chan-Yeung M. Outcome of patients with cedar asthma with continuous exposure. Am Rev Respir Dis 1990; 141: 373–76. 31 Bherer L, Cushman R, Courteau JP, et al. Survey of construction workers repeatedly exposed to chlorine over a three to six month period in a pulpmill: II follow up of affected workers by questionnaire, spirometry, and assessment of bronchial responsiveness 18 to 24 months after exposure ended. Occup Environ Med 1994; 51: 225–28. 32 Burge PS. Single and serial measurements of lung function in the diagnosis of occupational asthma. Eur J Respir Dis 1982; 63 (suppl 123): 47–59. 33 Cartier A, Malo JL. Occupational challenge tests. in: Bernstein IL, Chan-Yeung M, Malo JL, Bernstein DI, eds. Asthma in the workplace. New York: Marcel Dekker, 1993: 215–48. 34 Venables KM, Topping MD, Nunn AJ, Howe W, Newman Taylor AJ. Immunologic and functional consequences of chemical (tetrachlorophthalic anhydride) induced asthma after four years of avoidance of exposure. J Allergy Clin Immunol 1987; 80: 212–18. 35 Malo J-L, Cartier A, Ghezzo H, Lafrance M, McCants M, Lehrer SFB. Patterns of improvement in spirometry, bronchial hyperresponsiveness, and specific IgE antibody levels after cessation of exposure in occupational asthma caused by snow-crab processing. Am Rev Respir Dis 1988; 138: 807–12. 36 American Thoracic Society. Guidelines for the evaluation of impairment/disability in patients with asthma. Am Rev Respir Dis 1993; 147: 1056–61.

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