Occupational asthma PAUL CULLINAN AND ANTHONY NEWMAN TAYLOR INTRODUCTION

Transcription

1 72 Occupational asthma PAUL CULLINAN AND ANTHONY NEWMAN TAYLOR Introduction 941 Causes of occupational asthma 942 Mechanisms of occupational asthma 943 Frequency of occupational asthma 944 Determinants of occupational asthma 945 Prevention of occupational asthma 946 Identification and diagnosis of occupational asthma 947 Management of occupational asthma 951 Outcome of occupational asthma 951 References 952 INTRODUCTION It is estimated that exposures in the workplace account for around one in ten cases of new or recurrent asthma in adulthood. Many general respiratory physicians may be surprised by the magnitude of this proportion which is derived from meta-analysis of epidemiological studies that have examined, in the main, the distribution of asthma in different occupations. 1 Their scepticism probably reflects not only differences in the way that clinicians and epidemiologists understand attribution and the geographical variation in all occupational lung diseases, but also the frequency with which an occupational aetiology for asthma is overlooked. 2 On the other hand, physicians with an interest in occupational disease and especially those concerned directly with the health of employees in high-risk workforces will not be taken aback. Indeed most will agree that work-related asthma is among the most common of occupational respiratory diseases, particularly in the industrialized world. There are two broad categories of work-related asthma. First, the disease may be induced anew by exposure to an airborne sensitizing or irritant agent encountered at work. This, the focus of this chapter, is generally termed occupational asthma. Such asthma may develop in an employee who has or does not have a previous history of asthma from another cause. Alternatively, pre-existing asthma may be provoked by workplace exposure(s) to exacerbating agents which commonly include irritant fumes or dusts, cold air and physical exercise. This, termed work-exacerbated asthma, is probably very common and is generally manageable with careful attention to workplace exposures, protective equipment and appropriate pharmacological treatment of the underlying disease. Occupational asthma almost always develops as an immune response to an airborne sensitizing agent in the workplace. The nature of this hypersensitive response is such that there is a latent ( sensitizing ) period of several months between initial exposure and the development of symptoms and subsequently the provocation of symptoms by very low exposures to the inducing agent. Presumably a reflection of variations in innate susceptibility, not all exposed employees will become sensitized although, depending on the levels of exposure in a workplace, very high proportions may do so. 3,4 In most cases of occupational asthma caused by airborne proteins, the immunological response is characterized by the production of specific IgE antibodies. In cases arising from exposure to chemical agents, the type of immunological response is far less well understood. Occupational asthma may also arise albeit uncommonly from very high exposures to respiratory irritants. The mechanism of this response, originally termed reactive airways dysfunction syndrome, 5 but now more commonly referred to as irritant-induced asthma, is primarily non-immunological. Most well-characterized cases follow single toxic exposures to agents such as chlorine or oxides of nitrogen. It remains unclear whether more frequent, but less intense exposures to irritants in the workplace can give rise to asthma, although domestic exposures to cleaning sprays, etc. have been associated with incident asthmatic symptoms. 6 Respiratory sensitization to an occupational agent is one of very few well-established causes of adult asthma. It is thus

2 942 Occupational asthma potentially preventable and furthermore offers a rare opportunity to cure an asthmatic patient of their disease. Moreover, it seems to be a costly disease. In the UK, the total lifetime costs of cases of occupational asthma reported to a national surveillance scheme each year (a fraction only of the true number of cases) are estimated to be up to 100 million. 7 Only a small proportion of these costs are borne by employers, the rest accruing to the state and the individual. For these reasons, the disease has a high profile in industrial legislation in most of the developed world. CAUSES OF OCCUPATIONAL ASTHMA The published literature includes between 300 and 400 workplace agents reported to have caused occupational asthma. In some instances, the number of cases of asthma is very small. Those agents, and the occupational circumstances under which exposure to them occurs, which are widely recognized to cause a substantial burden of disease are listed in Table Occupational asthmagens are generally categorized as being of either high or low molecular mass. The former are usually proteins that act as complete allergens; the latter are chemical agents, which probably become antigenic only after conjugation with a body protein such as human serum albumen. Currently, the respiratory allergenicity of all recognized chemical allergens is identified, for example on a safety data sheet, by the risk label R42 ( may cause sensitization by inhalation ). This signifies either that there is published evidence in humans that the substance can induce specific respiratory sensitization, or that there have been positive results from appropriate animal tests or that the agent is an isocyanate (unless there is evidence that it does not cause hypersensitivity). In the future, the familiar R42 label is likely to be replaced, under the Globally Harmonized Table 72.1 Selected high and low molecular mass causes of occupational asthma by occupational group. Occupational group Agent(s) (a) High molecular mass Laboratory technicians, research scientists, animal handlers Bakers and millers Food processors Detergent powder manufacturers Nurses, dental workers, other healthcare workers Farmers, farm workers and agriculturists Florists, botanists (b) Low molecular mass Spray painters Plastics workers Hairdressers Chemical processors Welders, solderers, electronic workers Woodworkers Pharmaceutical workers, pharmacists Nurses, dental workers, other healthcare workers Metal refiners, electroplaters Food processors Textile/fabric workers Small animal proteins (urine, dander, serum): rats, mice, guinea pigs, ferrets, etc. Insect proteins: cockroach, locust, housefly, fruit fly, gypsy moth, mealworm, etc. Other animal proteins: latex Flour (wheat, barley, rye, oat, soya), fungal -amylase, egg proteins, milk proteins, storage mites Linseed, green coffee bean, castor bean, tea dust, tobacco leaf, rosehip, shellfish proteins, fish proteins, milk proteins, egg proteins, cocoa proteins, proteolytic enzymes Detergent enzymes: protease, amylase, lipase, cellulase Latex Storage mites, meal worms, spider mite, poultry mite, cow dander, cow -lactoglobulin, pig urine, mink urine, insect larvae, poultry feathers, silkworm larvae, fruit, vegetable and flower pollens, fungi, grain dust Pollens, weeping fig, baby s breath, spider mite, vine weevil Hexamethylene diisocyanate, various amines Diphenylmethane diisocyanate, toluene diisocyanate, monomer acrylates, various amines, azodicarbonamide Persulphate salts, henna Phthalic anhydride, trimellitic anhydride, maleic anhydride, azodicarbonamide Colophony fume, stainless steel welding fume, aminoethylethanolamine, cyanoacrylates, toluene diisocyanate, persulphate salts Hard wood dusts: western red cedar, iroko, African maple, mahogany, manosonia, obeche, etc. Psyllium, ispaghula, methyl-dopa, penicillins, cephalosporins, tetracycline, sulphathiazole, spiramycin, isoniazid, piperazine, cimetidine, dichloramine, ipecacuanha, bromelain, morphine Glutaraldehyde, formaldehyde, monomer acrylates, antibiotics, psyllium, hexachlorophane, pancreatic extracts, N-acetyl cysteine Complex platinum salts, hexavalant chromium, nickel Chloramine-t, metabisulphite Reactive dyes, gum acacia

3 Mechanisms of occupational asthma 943 System of Classification and Labelling of Chemicals, by H334 ( may cause allergy or asthma symptoms or breathing difficulties if inhaled ). Under the new regulations, a respiratory sensitizer is defined as a substance that will induce hypersensitivity of the airways following inhalation on the basis of evidence in humans or positive results from an appropriate animal test. The list of agents which can cause occupational asthma is, necessarily, ever expanding. Fairly comprehensive information is available in specialist textbooks and websites It is in any case prudent to assume that any airborne protein (of either animal or vegetable origin) and any highly reactive chemical is capable of inducing respiratory sensitization. MECHANISMS OF OCCUPATIONAL ASTHMA Disease that is induced by exposure to a sensitizing agent encountered at work is the most common form of occupational asthma. It has the characteristic features of an acquired, immunological ( hypersensitive ) reaction. Thus, specific sensitization and asthma develop only in a proportion (usually a minority) of exposed subjects and only after an asymptomatic (latent) period of exposure lasting several weeks or months, but occasionally years. Once asthma has developed, symptoms are provoked by concentrations of the sensitizing agent which are too low to provoke symptoms in non-sensitized workers and which the affected individual would previously have tolerated. Most, if not all, protein respiratory sensitizing agents have the capacity of stimulating a T H 2 lymphocyte, IgE-associated immune response. IgE sensitization is ascertained by skin prick testing with water-soluble extracts of the responsible allergen or a search for specific antibodies in serum. Assuming equivalence of the antigens used in the different methods and with appropriate interpretation of test findings, skin prick and serum IgE tests produce broadly comparable results. On the grounds that occupational asthma from high molecular mass (protein) allergens is an immediate-type hypersensitivity, it should in all cases be accompanied by specific sensitization to the causative allergen. Thus, tests for IgE sensitization, if carried out properly, have a high diagnostic sensitivity and a very low false negative rate. The same cannot be claimed for low molecular mass chemicals which are incomplete allergens. Identifiable immune responses to such agents are usually not to the chemical itself, but to hapten protein conjugates. For example, serum IgE antibodies to antigen human serum albumen (HSA) conjugates may be detected in most cases of occupational asthma caused by acid anhydrides and in some cases of asthma attributable to diisocyanates and reactive dyes. An exception is platinum salt hypersensitivity which is almost always accompanied by positive responses to skin prick testing but not by demonstrable specific IgE production with dilute solutions of complex platinum halide salts. Such examples, however, are rare among the many chemical causes of occupational asthma suggesting that the relevant allergen protein conjugate has yet to be identified or that alternative mechanisms are responsible. Specific IgE to diisocyanate protein conjugates is detectable in only around 25 per cent of cases of asthma caused by this important group of chemicals, 12 and a study of patients with a confirmed asthmatic reaction to controlled exposures, but absent IgE responses did not detect upregulation of IgE receptors. 13 Other important causes of occupational asthma in which specific IgE responses are apparently absent include colophony fumes 14 and plicatic acid. 15 In some cases where specific IgE antibodies are detected, it is unclear that they have any pathological or diagnostic specificity. 16 Consequently, alternative immunological mechanisms for occupational chemical sensitization have been postulated. For example, most T-cell clones collected by bronchial biopsy of patients with diisocyanate-induced asthma are of CD8 phenotype producing gamma interferon and IL-5, rather than IL Such T cells may represent a CD3 /CD4 /CD8 population expressing a / T-cell receptor specific for the diisocyanate. 18 Alternatively, non-immunological pathways may (also) be important in some causes of occupational asthma. 19 For example, plicatic acid in western red cedar can directly activate complement 20 and toluene diisocyanate may have direct actions on bronchial smooth muscle acting as a bronchoconstrictor or as a beta-2 adrenergic blocking agent. 21,22 Neurogenic mechanisms may also be relevant in some instances. Toluene diisocyanate, in addition to its postulated pharmacological effects (above in this section) stimulates, in animal models, neuropeptide release and inhibits neutral endopeptidase. 23,24 Such non-immunological mechanisms do not readily explain the typical pattern of hypersensitivity-induced asthma, arising after a period of latency and associated with increasing sensitivity to low exposures, but they may have important secondary roles in explaining the clinical picture. Alternatively, some chemical agents may be capable of inducing more than one asthma phenotype, one immunological (through IgE-associated mechanisms) and one non-immunological. The distinction of these will require more careful clinical and epidemiological study than is currently available. Irritant-induced asthma Asthma developing shortly after exposure to high concentrations of inhaled respiratory irritants probably reflects non-immunological mechanisms. A small number of bronchial biopsies have been carried out in patients with irritant-induced asthma and indicate bronchial inflammation with lymphocytes and plasma cells, but not eosinophils, suggesting that the clinical response is a manifestation of direct epithelial cell injury. Importantly, there have been no reports which include histological data prior to the initiating event in these cases.

4 944 Occupational asthma FREQUENCY OF OCCUPATIONAL ASTHMA Estimates of the prevalence and less frequently incidence of occupational asthma are available for both occupational and community populations. Occupational populations WORKPLACE STUDIES Most workplace-based studies use standard cross-sectional epidemiological methods; occasionally longitudinal (cohort) designs, most of them prospective, are used. Data may be derived from a purposeful study or by analysis of the records of routine health surveillance. If the methods of surveillance are insensitive, then the latter approach will underestimate the true frequency of disease. In any case, a healthy worker effect, reflecting selection into and survival within a workforce, is likely and cross-sectional approaches to estimation of the prevalence of occupational asthma in a workplace or to examination of its determinants will generally underestimate both disease frequency and the effects of risk factors, such as exposure. This can be overcome, to some extent, by focusing attention on relatively new employees. Despite these important reservations and the further uncertainty of how far findings from one setting can be generalized to others workplace-based estimates of disease frequency have provided much of our knowledge of the detailed epidemiology of occupational asthma. SURVEILLANCE SCHEMES Several countries notably Finland, the UK and France (Table 72.2), but also Ireland, South Africa and parts of Spain, the United States, Canada and Australia have established surveillance schemes for occupational asthma. These measure disease that is newly recognized and reported by specialized physicians, usually in occupational or respiratory medical practice. In some instances, the schemes are closely linked to compensation claims. Where workforce denominators are available, occupation-specific incidence rates may be estimated, although these are often crude and probably underestimate the true incidence. 28 Reports from the longer running surveillance schemes are sometimes used to examine temporal trends or geographical variations in disease incidence within certain industries or in relation to specific agents. The findings of such analyses need to be interpreted with great care. The numerators for specific incidence rates are usually very small and there is good evidence of international variations in diagnostic practice. Nonetheless, surveillance schemes provide valuable information on the approximate size and distribution of the problem at a national level and a good estimate of the relative frequencies of important causes. In any case they have proved to be a powerful incentive for regulators. Table 72.2 Numbers of cases of occupational asthma and estimated annual incidence rates per million workers in the UK, France and Finland from reports to national surveillance schemes, by occupational groups (may be defined differently in different countries). Occupational group UK France Finland ,a No. of Annual No. of Annual No. of Annual cases incidence cases incidence cases incidence Coach and spray painters Chemical processors NA Plastics workers NA Bakers Metal treatment workers NA NA Laboratory workers NA Welders and electronic assemblers NA Food processors (excluding bakers) NA 7 99 Hairdressers Painters (excluding spray painters) NA NA Wood workers NA Farmers NA Healthcare workers Veterinary surgeons NA NA Cleaners Teachers NA NA 6 5 All groups a Men only. NA, not available.

5 Determinants of occupational asthma 945 General population studies A number of epidemiological studies have set out to measure, in general (non-occupational) populations, the proportion of asthma in adulthood that is attributable to workplace exposures. Studies of this sort estimate the prevalence of asthma, usually by self-report, in a representative sample of the community. By comparison with a referent group, usually office workers, any excess risks of asthma in specific occupational groups can be estimated and then summed to generate a measure of the proportion of communal asthma that is attributable to occupational exposures. Meta-analyses of such studies 1,29 indicate attributable proportions of between 10 and 15 per cent for all incident or relapsing cases of adult asthma. Studies of incident asthma are fewer, but provide essentially similar estimates. 30 Epidemiological approaches of this kind employ a probabilistic, rather than individual, approach to the issue of causation. They cannot easily distinguish asthma that is induced from asthma that is provoked by an occupational exposure, nor examine whether there is selection by or of people with asthma into certain occupations. However, they are valuable in quantifying the communal risk of work-related asthma and in identifying increased risks of disease among occupational groups not traditionally recognized in clinical practice. 31,32 DETERMINANTS OF OCCUPATIONAL ASTHMA An understanding of the determinants of occupational asthma beyond its distributions is essential in the development of strategies to reduce its incidence. Broadly, the potential determinants that have been studied in detail include those relating to the environment (the level of workplace exposure to the sensitizing agent) and those that reflect host susceptibility (atopic status and genotype). The limited information on any interaction between host and environment suggests that susceptible individuals have a heightened and perhaps accelerated response to allergen exposure. One important consequence of this is that under conditions of relatively low exposure those factors that determine individual susceptibility are more prominent. 33 This is likely to have important implications in settings where exposure control is improving, while the population prevalence of susceptibility (for example, atopy) is either stable or rising. Exposure Direct relationships between the intensity of workplace allergen exposure and symptoms indicative of occupational asthma have been described for a variety of sensitizing agents. These, and studies confined to the risks of allergic sensitization alone, are summarized in Table Table 72.3 Studies demonstrating positive relationships between antigen exposure and either occupational asthma or specific sensitization, by antigen group. Antigen group References Flour and enzymes (bakery and mill employees) Enzymes (detergent manufacturers) 3, 56, 57, 121, 122 Laboratory animals (research workers) Shellfish proteins (seafood processors) 127, 128 Castor bean (processors) 129 Diisocyanates (spray painters, plastics manufacturers) Acid anhydrides (manufacturers, various) 62, 134, 135 Colophony fume (electronic assemblers) 136 Pharmaceuticals (manufacture) 137, 138 Complex platinum salts (precious metal 139 refiners) Western red cedar (lumber workers) 140 Most are of high molecular mass agents; there are fewer data relating to the exposure-related risks of work with low molecular mass agents. While the existence of a relationship between exposure and occupational asthma is well established, there is little information on its detailed nature and almost none on meaningful threshold values. This probably reflects the difficulties in measuring relevant exposure intensities and their timing. On biological grounds alone, a sigmoid relationship would be expected whereby the risk rises relatively steeply at the lower end of the exposure range and less steeply (or not at all) at the higher end. While this is likely to be true for most agents, there is evidence for laboratory animal exposures that the risk may be attenuated at very high exposures 34 possibly reflecting a form of immunotolerance. Most studies examining exposure response relationships are of prevalent disease in cross-sectional, occupational populations. Few have studied incident disease in working cohorts. The findings of cross-sectional surveys need to be interpreted cautiously since they are prone to an unquantifiable bias from survivor effects. Survival biases, notably the movement of employees who have become sensitized away from situations of continuing exposure, are likely to lead to an underestimate of the effects of exposure. Furthermore, few studies of any design have succeeded in measuring directly the levels of sensitizing agents in exposed workforces and fewer still have characterized the nature, in terms of particle size and deposition of these exposures. There is very little information on the relationship between exposure and response in irritant-induced asthma. Following a spill of glacial acetic acid in a US hospital, the frequency of subsequent asthma was higher (21 per cent) in those who had incurred the greatest exposure than that in those with medium or low exposures

6 946 Occupational asthma (3 and 0 per cent, respectively), suggesting both that the relationship was causal and that it was dependent on the intensity of exposure. 35 Several studies suggest that in some settings cigarette smoking increases the risk of sensitization or of asthmatic symptoms. They include studies of workforces exposed to ispaghula, 36 snow-crab proteins, 37 tetrachlorophthalic anhydride, 38 laboratory animals 39 and complex platinum salts. 40 It is not always clear, however, that the effects attributed to smoking are independent of other determinants, such as allergen exposure. Individual susceptibility Even at exposures well above any threshold, not all employees develop respiratory hypersensitivity although in some instances the proportion of workers who are affected can be very high. 3,4 Thus, some employees appear to have an innately high risk. Atopic workers are at increased risk of occupational asthma from a number of workplace allergens. The most consistent evidence is for allergens that induce an identifiable specific IgE response. Thus, atopy increases the risk of asthma or sensitization in workers exposed to flour, laboratory and other animals, detergent and other enzymes, sea foods, castor and green coffee bean, acid anhydrides and some reactive dyes. A useful summary of the evidence is provided by Nicholson et al. 41 In contrast there is little consistent evidence that atopy increases the risk for those who work with western red cedar, glutaraldehyde, complex platinum salts or diisocyanates. As with studies of exposure, the findings from cross-sectional surveys should be interpreted cautiously since reported associations, negative or positive, may reflect selection and survival pressures which are perhaps stronger among atopic employees. The rapid advances in genotyping have been applied, in a limited fashion, to the study of occupational asthma. Two classes of gene have received most attention: those that determine specific antigen responsiveness (genes of the HLA class II complex) and those that relate to antioxidant respiratory responses. In each case, the presence or absence of candidate genes have been compared in case control studies of employees with or without occupational asthma. Studies of this type require very large populations and most have probably been underpowered. All the same, associations sometimes strong between HLA genes and specific sensitization have been reported in workers exposed to trimellitic anhydride, 42 laboratory animal proteins, 43,44 western red cedar, 45 complex platinum salts 33 and diisocyanates The findings from the last of these are not entirely consistent. 49 Similarly, genetic polymorphisms of the glutathione-stransferase and N-acetyltransferase groups, important in determining the antioxidant status of the respiratory tract, have been associated with occupational asthma from a number of diisocyanates PREVENTION OF OCCUPATIONAL ASTHMA Primary prevention Primary prevention eradicates or reduces incident disease. In the context of occupational asthma, it is achieved by elimination of the sensitizing agent from the workplace or where this is not possible by the reduction of exposures to levels at which sensitization does not occur. The former may be impossible, as in the example of flour in a bakery, but notable success has been achieved in some settings including occupational asthma from latex in hospitals either by the substitution of latex gloves with synthetic alternatives or by the use of powder-free gloves which essentially prevent the release of latex particles into the air. 53,54 Because there are important variations in individual susceptibility, reductions in exposure rarely eliminate incident disease altogether, but they may be highly effective in maintaining disease rates at a very low level. The details of the exposure response relationships for most workplace allergens are poorly understood. In all cases it is unclear whether relationships are linear or whether a threshold of zero incidence at low exposures exists. In practice, effective prevention of occupational asthma requires the maintenance of exposures, including occasional peak values, at as low an intensity as is feasible and lower than that which incites symptoms in sensitized subjects. Much current legislation is based on this premise and very little of it includes specified safe thresholds a reflection not only of the paucity of evidence in this area, but also of the essentially immunological nature of the disease. There is very little evidence that the use of protective respiratory equipment alone is effective in the primary prevention of occupational asthma. 55 Published examples of the primary prevention of occupational asthma are few and most describe programmes that include not only improvements in exposure control but also procedures such as targeted pre-employment screening, enhanced surveillance and the increased use of personal protective equipment. It is seldom possible to disentangle the separate effects of different components. Nonetheless, success has been reported in the detergent industry 56,57 and with workforces exposed to laboratory animals, 58,59 diisocyanates, 38,60 acid anhydrides 61,62 and latex. 53,54 In most instances, a reduction in the number of newly identified cases following intervention(s) is reported without reference to the denominator, at-risk population and it is not always clear that this reflects a true reduction in disease incidence. An alternative approach to primary prevention focuses on restricting the exposure or even employment of perceived high-risk persons. Such restrictions are usually based on evidence of prior asthma or other allergy, usually but not always obtained by self-report. The discriminant performance of these methods their ability to predict who will and who will not develop an occupational respiratory sensitization is poor. Increasing understanding of the genetic determinants of occupational asthma may result in the extension of such techniques.

7 Identification and diagnosis of occupational asthma 947 Secondary and tertiary prevention Respiratory surveillance of employees working with respiratory sensitizing agents is widely practised and in many countries is mandated by legislation. The process, which aims to identify workers with occupational asthma at an early stage of their disease and thus allows appropriate action to prevent deterioration ( tertiary prevention ), is based on the premise that early recognition and avoidance of further exposure improve the prognosis of the disease. The most widely used surveillance methods are the questionnaire and regular spirometry. Almost certainly, self-completed questionnaires are an insensitive measure of work-related respiratory symptoms. 63 Similarly, routine measurement of spirometry is insensitive since many employees with occupational asthma will have a normal FEV 1, particularly if it is measured when they are not directly exposed to the causative allergen. There is evidence that routine spirometry detects very few cases of disease that would not otherwise or also have been recognized on the basis of reported symptoms. 64,65 In some settings, surveillance includes the use of immunological methods to measure specific sensitization: either skin prick testing or specific IgE assay directed to the workplace allergen(s). The purpose of such immunological surveillance varies. In some parts of the platinum refining industry, for example, regular skin prick testing with complex platinum salts forms part of a health surveillance programme. A positive prick test result, highly specific for platinum salt asthma, is used to identify employees who require rapid relocation away from exposure. Similarly respiratory surveillance in much of the detergent manufacturing sector includes a measure of immunological sensitization. There, however, where sensitization is a highly sensitive but not wholly specific adjunct of detergent enzyme asthma, the practice is designed to identify areas of the workplace where further attention to exposure control is necessary. A further example, in the baking sector as described by Brant et al. 63 is the assay of serum-specific IgE antibodies to flour and -amylase for employees who report work-related respiratory symptoms. This improves the specificity of the surveillance programme and aids the selection of those employees who require further investigation. Any use of immunology in routine surveillance requires access to validated test methods and an intimate knowledge of their diagnostic properties, and an explicit understanding of the purpose of testing. In carefully selected instances, immunological approaches can be a useful adjunct to other methods and are likely to be increasingly used in the future. IDENTIFICATION AND DIAGNOSIS OF OCCUPATIONAL ASTHMA Accuracy in the diagnosis of occupational asthma is critically important. A positive diagnosis frequently leads to a change in job and too frequently to the loss of current employment or a major change in occupation. A false positive diagnosis can lead to unnecessary financial and social hardship and a lack of clinical improvement once exposure has ceased. In legal terms the burden of proof is generally set at a level of more likely than not. Most occupational health practitioners and their patients will prefer a more certain standard than this. On the other hand, the early and accurate identification of an occupational cause of asthma has several advantages. First, it will explain the onset of new or recurrent asthma in adult life and make a search for alternative causes unnecessary. Second, it allows a rational approach to both pharmacological and non-pharmacological management, and third, it identifies, for other employees, potential risks that may be prevented. Guidelines to the diagnosis of occupational asthma, derived from systematic review of the published literature, are available both electronically 66 and in print. 41 Other, consensus-developed, guidance is also available An outline of available methods in the diagnostic pathway is shown in Figure In essence the process is iterative and should include each of the following: an assessment of relevant exposures, the identification of an asthmatic airway response in relation to exposure(s) and, where appropriate, the identification of specific immunological sensitization. None of these is sufficient alone. Adult asthma: Onset/relapse/deterioration in working life Symptoms/severity work-related? Worse at/after work Better away from work Detailed clinical history: Timing of symptoms Nature of symptoms Pattern of symptoms Previous asthma? Consider work-related asthma Evidence for asthma with temporal relationship to work? Serial measurement of peak flow Serial measurement of NSBHR Specific provocation testing Yes Detailed occupational history: Agents (recognized sensitizer(s))? Tasks Dates Previous jobs Occupational health service? Immunological tests of sensitization available? Skin prick test Serum specific IgE Other Figure 72.1 Summary of diagnostic approaches to occupational asthma. NSBHR, non-specific bronchial hyperreactivity.

8 948 Occupational asthma History The prior likelihood of occupational asthma is higher in employees with exposure to a recognized sensitizing agent and familiarity with these agents and the occupations in which they are encountered is important. At the same time, patients may develop sensitivity to a rare or previously unrecognized agent and in all cases a low threshold of suspicion is sensible. Patients with occupational respiratory sensitization characteristically develop symptoms after a relatively short latent period following first exposure to the sensitizing agent. First exposure often reflects a new job, but may reflect a qualitative or quantitative change in exposure in a long-held job. The latent, asymptomatic period, during which sensitization is presumed to be developing, is usually between three and 24 months. Symptoms that develop sooner after a new exposure are more likely to have an irritant mechanism. Thus careful attention to the timing of the onset of symptoms and any changes in exposure that may have preceded them, is diagnostically helpful. The symptoms themselves are characteristic of asthma, but are frequently accompanied by upper respiratory symptoms of nasal obstruction, sneezing and discharge and itching or running of eyes as well as, if the causative agent is a protein, by itching of the skin or even urticaria. Occupational rhinitis is probably more common than occupational asthma, but the two conditions frequently occur together. 71 The frequency and intensity of nasal symptoms may be greater in cases caused by sensitization to high molecular mass agents. 72 A history of previous or coexistent respiratory disease does not preclude a diagnosis of occupational asthma, but raises the possibility of aggravation of pre-existing asthma or other airways disease by one of the many workplace respiratory irritants. In cases of occupational asthma, symptoms are typically present during or immediately after periods of exposure at work and improve when away from work. This pattern may be complicated by varying shift patterns, by isolated late-phase symptoms that are present only after a period at work and in cases where, with repeated exposures, recovery is only achieved, if at all, by an absence from work of several days or more. Further confusion can arise when the non-specific bronchial hyperreactivity that is typical of asthma gives rise to symptoms provoked by a variety of irritants encountered at and away from the workplace. In these cases, employees (and their clinicians) frequently attribute the cause of the disease to the obviously irritant exposure rather than the sensitizing agent. In cases of irritant-induced asthma (reactive airways dysfunction syndrome (RADS)), the history is very different, partly because of constraints imposed by the current disease definition. Here symptoms develop within minutes or hours after a defined, high-intensity and sometimes dramatic exposure to a respiratory irritant, frequently in an individual without known previous respiratory disease. Unlike those with occupational sensitization, patients with irritant-induced asthma can usually identify precisely the time of onset of their disease which may or may not be many years after the onset of employment and of exposure, at lower levels, to the responsible agent. Investigations Relevant investigations are, broadly, either immunological or functional. The former aim to identify a specific immunological response to the putative agent, the latter to establish a relationship between variable airflow obstruction ( asthma ) and one or more specific occupational exposures. IMMUNOLOGICAL TESTS As described above under Mechanisms of occupational asthma (p. 943), sensitization to almost all high molecular mass occupational agents and to some of low molecular mass is accompanied by the presence of specific IgE antibody production. This can be identified through skin prick tests with extracts of soluble antigens or in serum using standardized immunoassays. In cases of occupational asthma caused by exposure to a high molecular mass agent, the test is highly sensitive. In other words, it is almost always positive and a negative result makes the diagnosis improbable. On the other hand, a positive result can occur in the absence of clinical disease, presumably reflecting an asymptomatic state of specific sensitization. In all cases, it is important to include well-validated tests for all relevant allergens and liaison with an experienced (specialized) laboratory is valuable. The general absence of an identifiable IgE response in diisocyanate asthma has prompted the search for alternative immunological tests for this common type of occupational asthma. They include the measurement of monocyte chemotactic protein-1 (MCP-1) produced by peripheral blood mononuclear cells after stimulation with a relevant isocyanate conjugate. The results of a pilot study suggest that this method has a sensitivity of about 80 per cent and a specificity of 91 per cent, respectively far higher than and similar to methods based on specific IgE production. 73 This technique requires replication in other populations before it can be widely applied. FUNCTIONAL TESTS OF VARIABLE, WORK-RELATED AIRFLOW OBSTRUCTION The most sensitive and specific method of examining the existence and pattern of airflow limitation is through the use of serial, self-recorded measurements of peak flow or FEV Workers under investigation are supplied with a portable meter and invited to make repeated measurements over a period of time including both periods at and away from work. A protocol that demands, during waking hours, two-hourly measurements for four weeks has higher sensitivity than less frequent measurements 78,80 and is generally acceptable to patients. Where possible, especially in cases

9 Identification and diagnosis of occupational asthma 949 Overall mean: 425 litres/minute Predicted mean: 376 litres/minute Completeness: 100% Variability Peak flow (max, mean min) L/minute Predicted mean No treatment Days Figure 72.2 Serial peak flow record of an employee with laboratory-animal asthma. The shaded columns represent days at work. On each day the mean, maximum and minimum peak flow measurements only are plotted. The figures in boxes are measurements of peak flow variability. where symptoms have been present for many months or years, it is helpful to include within the period of measurement a prolonged absence from work, such as a holiday of several days or more. Potential confounding by concurrent asthma treatment is avoided by asking patients to maintain the same treatment throughout the measurement period. On completion, the readings are best plotted on a daily basis as the maximum, minimum and mean values from each day. An example of such a plot, using peak flow, is shown in Figure The pattern of lung function in relation to work is then examined usually visually, but sometimes by computed statistical analysis. 81 Agreement of visual analyses by experienced clinicians is high, but there are important variations among less-experienced observers. Statistical analyses, intended to provide a more objective analysis, have proved to be little more valid or reliable than visual inspection. 76,79,82 Confusion and even misdiagnosis may arise if, particularly through early morning shift patterns, readings are made at different times on work and rest days. 83 Serial measurements of lung function may also fail to distinguish immunologically mediated occupational asthma from asthma that is provoked by workplace-irritant exposures. Thus, the method should only be interpreted in the light of other diagnostic evidence. Other techniques for assessing the pattern of airflow obstruction include the cross-shift measurement of lung function (FEV 1 or peak flow) or non-specific bronchial responsiveness immediately before and after one or more periods at work. These methods may be less time consuming than a lengthy series of functional measurements, but have lower diagnostic specificity and sensitivity and produce a higher proportion of false positive and false negative results. 75,79,84 86 As with FEV 1, bronchial responsiveness may be normal in patients with confirmed occupational asthma if measurements are made outside periods of exposure to the causative allergen. SPECIFIC PROVOCATION (INHALATIONAL) TESTING The gold standard of diagnostic tests for occupational asthma is often claimed to be the specific provocation test, whereby patients are observed and their lung function measured during and after carefully controlled exposures, under laboratory conditions, to the suspected sensitizing agent. The first use of such tests, for the diagnosis of occupational asthma, was in Indications for specific provocation testing vary between centres. In some jurisdictions it is conducted as a necessary step in the process of establishing a diagnosis and thereby allocating compensation. In others, such as the United Kingdom and many other European countries, it is used as an occasional adjunct to the diagnostic process, particularly when other, simpler techniques have failed or cannot be used to establish a diagnosis with sufficient accuracy. If, for example, a patient is not currently exposed to

10 950 Occupational asthma (a) (b) Figure 72.3 Specific provocation testing using (a) traditional ( Pepys ) method in which the patient is asked to recreate, in a sealed chamber, exposures at their workplace (in this case a baker is tipping a mixture of flour and lactose to create a dust cloud) and (b) machine for generating controlled exposures to vapours. Figure 72.3(b) courtesy of J-L Malo, Hôpital du Sacré-Coeur de Montréal, Montreal, Canada. the suspected agent, but an accurate diagnosis is still required to assist in decisions about continuing employment, serial measurement of lung function as described above will be uninformative. Alternatively, a patient may be exposed to more than one sensitizing agent at work and it may be considered important to identify which (if any) is responsible for their disease. In rare cases, the symptoms provoked by exposure at work are too severe (or unpleasant) to justify serial measurement of lung function. In such cases, the judicious use of specific provocation testing can be an appropriate and even essential diagnostic method. Finally, a further indication may be the investigation of response to an agent that is not recognized to be a respiratory sensitizer. Provocation testing solely in support of a legal claim for personal injury is difficult to justify. Specific provocation tests are hazardous and should be undertaken only by experienced staff in specialist centres where the risks are very low. Most tests use a single-blind 88 methodology which aims to recreate as closely as possible exposures encountered by the patient in the workplace (Figure 72.3). More recently, some centres have developed sophisticated delivery techniques of mechanized dust or fume generation. 89 The advantage of these over the simpler techniques is yet to be established. Whichever method is used, great care must be taken over the dosing and frequency of exposures which should be of lower intensity than those in the workplace and several orders lower than occupational safety limits. Responses to inert and active exposures are generally assessed and compared by the subsequent measurement of FEV 1 at frequent intervals. This is more reliable than peak flow measurement. The measurement of changes in nonspecific bronchial responsiveness following exposure (using histamine or metacholine) is a very useful additional test, helping to distinguish irritant from immunologically mediated responses. The specificity of provocation testing is increased if reproducibility of the responses to repeated active and control exposures is confirmed (Figure 72.4). Several patterns of response are taken to be indicative of specific sensitization, but their interpretation requires an experienced clinician. An immediate or early response is one in which a fall in baseline lung function occurs and recovers within one or two hours of provocation. If isolated and unaccompanied by evidence of a concurrent

11 Outcome of occupational asthma 951 Bakers flour/amylase-specific provocation test Control 0 Daily histamine PC 20 (mg/ml) % change in baseline FEV 1 inert control (lactose) 0.1% amylase 1% flour 10 min 0.1% amylase 1% flour 15 min C (mins) Time after challenge (hours) 0.1% amylase 1% flour, 10 min 0.1% amylase 1% flour, 15 min Pre-challenge Pre-challenge hrs post challenge Daily baseline FEV 1 (L) Control % amylase 1% flour, 10 min 0.1% amylase 1% flour, 15 min hrs post challenge Figure 72.4 Specific inhalation challenge to bakers flour and -amylase: positive result with dual asthmatic response and increase in non-specific bronchial reactivity. Note the reproducible findings and the lack of any consistent change in baseline FEV 1. increase in bronchial responsiveness, an immediate response may be an indication of either respiratory sensitization or reflex irritation. Late reactions are those that develop only one or more hours after exposure. They may persist for 24 hours or longer and are frequently accompanied by an increase in bronchial reactivity measurable three 90 or 24 hours after provocation. Dual (combined early and late) responses are common, especially in cases of sensitization to high molecular mass agents. Specific provocation testing is very difficult in patients with unstable baseline asthma when it can be difficult to distinguish an irritant from a hypersensitivity response. False negative results may occur when patients have been away from workplace exposures for prolonged periods, 37,91 if an inappropriate form of the test material is used or if patients continue to use anti-inflammatory asthma treatments during the period of testing. MANAGEMENT OF OCCUPATIONAL ASTHMA Optimal management of occupational asthma will in most cases abolish or control symptoms and prevent the development of persistent disease. In general, these are achieved only by complete avoidance of exposure to the causative allergen, ideally through a change in work practice or relocation within the same workplace or industry to a nonexposed area but in practice often requiring a major change in occupation. Some patients, particularly those who are self-employed or those who have significant investment in a current occupation such as research scientists working with animal models are especially reluctant to make changes sufficient to prevent further exposure. 92 At present, further allergen exposure even at very low intensity cannot be advised, but support to those determined to continue can be provided by the prevention, as far as is possible, of exposure at levels high enough to incite symptoms or changes in lung function. Repeated, serial measurements of peak flow during periods at and away from work are often helpful in these situations, as is good pharmacological control of symptoms. (Enhanced) respiratory protective equipment is often considered, but is only effective if it is worn appropriately and if it is removed, stored and maintained correctly. There is some evidence that helmet-type respirators can improve symptoms in some but not all employees who continue to work in conditions where there may be further allergen exposure Pharmacological treatment is as for non-occupational asthma, but is generally ineffective in the face of continuing allergen exposure. Conversely, little or no treatment may be needed once allergen exposure has ceased. There is only limited evidence that treatment with inhaled steroids improves the prognosis in occupational asthma, whether allergen exposure continues or otherwise. 99 OUTCOME OF OCCUPATIONAL ASTHMA Following avoidance of further exposure to the causative allergen, the symptoms of most patients with occupational asthma improve, and many recover completely. However, this is not always the case. Most studies of the outcome of occupational asthma are of patients attending specialist centres. These are likely to have more severe and more refractory disease and their experience may not be representative. A systematic review of 39 publications with a median length of follow up of 31 months following diagnosis suggests that only one-third of patients recovered completely from their asthma after the cessation of exposure. Individual estimates ranged however from 0 to 100 per cent. 100 The same review examined a number of potential determinants of recovery. Complete symptomatic recovery was significantly lower with increasing age at diagnosis, in studies of patients seen in specialist clinics and in patients with the longest durations of employment, or of symptomatic exposure (Figure 72.1). No studies examined the independent effects of age and exposure duration. There were no clear differences in recovery between patients with disease caused by agents of different molecular mass or between those who were or were not smokers. Any recovery in lung function and bronchial hyperresponsiveness seems to take place in the first two years after