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The diagnosis of occupational asthma
Respiratory Medicine (1994) 88, 7192721
Editorial
The diagnosis of occupational asthma The most widely used definition of occupational asthma refers to variable airways narrowing causally related to exposure in the working environment to airborne dusts, gases, vapours and fumes (1). It is obvious why this condition has recently received intensified interest from scientists and decision makers: occupational asthma has become the most common occupational respiratory disease (2-4). The consequences of acquiring occupational asthma should not be underrated; as further exposure should always be avoided, the worker may suddenly be faced with unemployment or even disability retirement. Contrary to earlier belief follow-up studies have revealed that occupational asthma does not necessarily resolve despite avoidance of exposure to the causative agent. The majority of cases may have asthma persisting several years after the initial diagnosis (5,6). Diagnosis plays a central role in the prevention of occupational asthma. As primary prevention, i.e. the control of exposure leading to asthma, often fails, early detection of the disease remains essential (7). Although diagnostic procedures are still far from uniform, efforts have been made to establish guidelines. Consensus on several issues is discernible: diagnosis should be based on Objective investigations; it is necessary to distinguish occupational asthma from asthma not occupationally caused and from chronic airflow limitation; the condition should be recognized as early as possible and the specific cause identified whenever practicable (8-12). Identification of the specific cause needs to be stressed for several reasons. In addition to serving legal interests of the patient it is vital to know what exposures to avoid when relocating or re-educating a patient. Identifying the specific aetiology is also necessary if new inducers of occupational asthma are to be detected. Finally, even though registers on occupational diseases have proven indispensable for studying the occurrence and causes of occupational asthma (2-4), such registers are never better than the data they receive. As in all diagnostics of occupational diseases, history is the corner stone. Confirmed exposure to a recognized cause of occupational asthma and a supportive clinical picture greatly aid the diagnostics, but the history whether via questionnaire or 0954-6111/94/100719+03 $08.00/0
interview lacks the necessary specificity to establish a diagnosis (13). A diagnosis of occupational asthma requires the presence of asthma and its causal relationship with work. Lung function tests are necessary to demonstrate bronchial asthma, but periodic spirometry is virtually useless for picking up new cases of occupational asthma (14,15). Despite the common practice of measuring FEV 1 before and after a workshift, this method is not reliable (14). The most reliable way to prove a causal relationship between a specific exposure and asthma is undoubtedly the inhalation provocation test, often referred to as the 'gold standard' (8,9). However, the facilities and necessary experience are still only found in a few centres with a special interest in occupational asthma. Even then, the provocation test is not always practicable; it cannot be performed if the patient's asthma is too labile, if the causative agent is unidentified, or if the exposure for some reason cannot be generated in an acceptable way. A short period of exposure, e.g. 30 minutes, does not necessarily correspond to the real 8-hour, 5-days a week work situation. Finally, the sensitivity to the offending agent may have been lost during long sick leave (16). It should also be pointed out that provocation tests are not devoid of risks (e.g. 17,18). However, based on experience gained over some 20 years it seems reasonable to consider inhalation tests acceptably safe provided that they remain in the hands of experienced personnel of specialized respiratory units. In summary, inhalation challenge tests are indicated for detecting previously unrecognized causes of occupational asthma, in cases where exposure to more than one agent may be suspected, when uncontrolled exposure at the workplace may jeopardize the patient's health, and where other investigations have proved inconclusive but the history still suggests occupational asthma. For studying mechanisms and exposure-response relationships, inhalation challenge tests are extremely useful. Monitoring peak expiratory flow rates (PEFR) during periods at ~nd off work (14,19) has become routine in diagnosing occupational asthma. P E F R has high sensitivity and specificity when using specific inhalation challenge tests as a reference (20,21). In 9 1994W. B. SaundersCompany Ltd
720
Editorial
workers suspected of occupational asthma induced by western red cedar, the sensitivity was 86% and the specificity 89%. When combined with a suggestive clinical history, sensitivity increased to 100% rendering inhalation tests with the causative agent, plicatic acid, superfluous (20). Sensitivity of PEFR was somewhat lower (74%) in a series involving a variety of causative agents (21). Thus, PEFR monitoring can be said to have acceptable sensitivity and specificity, especially if there is a definite exposure to a well known cause of occupational asthma and the clinical history suggests this disorder. PEFR monitoring has its weaknesses, however. It is time consuming; to achieve an optimal result a minimum of 4 weeks seems to be required (9,11,12). PEFR monitoring depends on compliance as well as honesty of the worker, both of which to some extent reduce the value of the method. In cases where the specific causative agent needs to be identified, the PEFR recordings are naturally inferior to specific inhalation challenge tests. There may also be difficulties in distinguishing between occupational asthma and deterioration of any asthma due to dusts or irritants at the workplace. Finally, uncontrolled exposure to the detrimental work environment for several weeks is not without risk (e.g. 22,23) and should not be undertaken without due consideration of the severity of the alleged symptoms. There have been attempts to improve sensitivity and specificity of PEFR recordings by serial measurements of non-specific bronchial responsiveness to histamine or metacholine (20,21,24,25). The method may prove useful, although recent studies have failed to prove any advantage in terms of improved sensitivity or specificity (20,26). Measuring the nonspecific responsiveness may help to improve the objectivity of the self-recorded PEFR. The value of serial measurements of non-specific bronchial responsiveness needs further assessment. The presence of specific IgE antibody as demonstrated by skin tests or in biological fluids confirms sensitization. When the causative agent is a highmolecular weight sensitizer and there is a close correlation between IgE antibody and cases of occupational asthma, immunological tests aid the diagnosis (27). This is particularly true when the immunological test is combined with a suggestive history and positive PEFR recordings. With respect to low molecular weight chemicals, the value of immunological tests is so far limited. IgE antibody may be found against typical hapten - protein conjugates such as several organic acid anhydrides, but the finding is far from consistent (28-30). IgE has been demonstrated in only 15-20% of cases positive to
diisocyanates in inhalation challenge tests (31,32). Whereas a positive test can be construed as support for the diagnosis, a negative result by no means precludes it. Although the diagnostics of occupational asthma have improved tremendously over the last few years, the need remains to assess further the sensitivity and specificity of most currently used diagnostic techniques, separately and in various combinations. The potential of cell mediators such as eosinophilic proteins should also be evaluated. H. NORDMAN The Finnish Institute o f Occupational Health Topeliuksenkatu 41 aA 00250 Helsinki Finland
References
1. Newman Taylor AJ. Occupational asthma. Thorax 1980; 35: 241545. 2. Meredith S. Reported incidence of occupational asthma in the United Kingdom, 1989 90. J Epidemiol Community Health 1993; 47: 459463. 3. Lagier F, Cartier A, Malo JL. Medico-legal statistics on occupational asthma in Quebec between 1986 and 1988. Rev Fr Mal Respir 1990; 7: 337-341. 4. Register for Occupational Diseases. Institute of Occupational Diseases, Helsinki, Finland, 1994:1617 (in Finnish). 5. Paggiaro PL, Loi Am, Rosso O et al. Follow up study of patients with respiratory disease due to toluene diisocyanate (TDI). Clin Allergy 1984; 14: 463~469. 6. Chan-Yeng M, MacLean L, Paggiaro PL. Follow-up of 232 patients with occupational asthma due to western red cedar (Thuja plicata). J Allergy Clin Immunol 1987; 79: 79~796. 7. Venables K. Preventing occupational asthma. Br J Ind Med 1992; 49:817 819. 8. Cartier A (Chairman), Bernstein IL, Burge PS et aL Guidelines for bronchoprovocation in the investigation of occupational asthma. Report on the Subcommittee on Bronchoprovocation for Occupational Asthma. J Allergy Clin Immunol 1989; 84: 823-829. 9. Subcommittee on Occupational Allergy of the EAACI. Guidelines for the diagnosis of occupational asthma. Clin Exp Allergy 1992; 22:103 108. 10. Malo JL. Occupational asthma. Lung Biol Health Dis 1993; 68:117 131. 11. Cartier A. Definition and diagnosis of occupational asthma. Eur Resp J 1994; 7: 153-160. 12. Newman Taylor, Picketing CAC. Occupational asthma and byssinosis. In: (ed. Parkes WR) Occupational Lung Disorders (Third edn). Oxford: Butterworth Heinemann, 1994; 710-729. 13. Malo J-L, Ghezzo H, L'Archeveque J, Lagier F, Perrin B, Cartier A. Is the clinical history a satisfactory means of diagnosing occupational asthma? Am Rev Respir Dis 1991; 143:528 532.
Editorial
14. Burge PS. Single and serial measurements of lung function in the diagnosis of occupational asthma. Eur J Resp Dis 1982; 63: (suppl 123): 47 59. 15. Malo JL, Cartier A. Occupational asthma in workers of a pharmaceutical company processing spiramycin. Thorax 1988; 43: 371-377. 16. Mapp C, Corona PC, DeMarzo N, Fabbri L. A follow-up study of subjects with occupational asthma due to toluene diisocyanate (TDI). Am Rev Respir Dis 1988; 137: 1326-1329. 17. Fabbri LM, Danieli D, Crscioli S, et al. Fatal asthma in a subject sensitized to toluene diisocyanate. Am Rev Respir Dis 1988; 137: 1494-1498. 18. Romano C, Sulotto F, Pavan I, Chiesa A, Scansetti F. A new case of occupational asthma from reactive dyes with severe anaphylactic response to the specific challenge. Am J Ind Med 1992; 21: 209-216. 19. Burge PS. Occupational asthma. In: (eds Brewis RAL, Gibson GJ, Geddes DM), Respiratory Medicine. London: Balli6re Tindall, 1990; 704-721. 20. Cot6 J. Kennedy SM, Chan-Yeung M. Sensitivity and specificity of PC20 and PEFR in cedar asthma. J Allergy Clin Immunol 1990; 85: 592-598. 21. Perrin B, Lagier F, L'Archeveque et al. Occupational asthma: validity of monitoring of peak expiratory flow rates and non-allergic bronchial responsiveness as compared to specific inhalation challenge. Eur Respir J 1992; 5: 40-48. 22. Stern MA. Occupational asthma from a reactive dye. Ann Allergy 1985; 55: 264. 23. Belin L, Hjortsberg U, Wass U. Life-threatening pulmonary reaction to car paint containing a prepolymerized isocyanate. Scand J Work Environ Health 1981; 7: 310-312.
721
24. Cartier A, Pineau L, Malo J-L. Monitoring of maximum expiratory peak flow rates and histamine inhalation tests in the investigation of occupational asthma. Clin Allergy 1984; 14:193 196. 25. Blainey AD, Oilier S, Cundell D, Smith RE, Davies RJ. Occupational asthma in a hairdressing salon. Thorax 1986; 41: 42-50. 26. Ulrik CS, Backer V, Skov PG. Usefulness of repeated measurements of bronchial hyperresponsiveness for the diagnosis of occupational asthma. J Asthma 1994; 31: 35-42. 27. Novey HS, Bernstein IL, Mihalas L, Terr AI, Ynginger JW. Guidelines for the clinical evaluation of occupational asthma due to high molecular weight allergens. J Allergy Clin Immunol 1989; 84:829 833. 28. Butcher BT, Bernstein IL, Schwartz L. Guidelines for the clinical evaluation of occupational asthma due to small molecular weight chemicals. J Allergy Clin Immunol 1989; 84: 834-838. 29. Venables KM. Low molecular weight chemicals, hypersensitivity, and direct toxicity; the acid anhydrides. Br J Ind Med 1989; 46:222 232. 30. Schlueter DP, Banaszak EF, Fink JN, Barboriak J. Occupational asthma due to tetrachlorophthalic anhydride. J Occup Med 1978; 20: 183-188. 31. Keskinen H, Tupasela O, Tiikkainen U, Nordman H. Experiences of specific IgE in asthma due to diisocyanates. Clin Allergy 1988; 18: 597-604. 32. Butcher BT, O'Neill CE, Reed MA, Salvaggio JE. Radioallergosorbent testing of toluene di-isocyanate reactive individuals using p-tolyl isocyanate antigen. J Allergy Clin Immunol 1980; 66: 213-216.
Editorial
The diagnosis of occupational asthma The most widely used definition of occupational asthma refers to variable airways narrowing causally related to exposure in the working environment to airborne dusts, gases, vapours and fumes (1). It is obvious why this condition has recently received intensified interest from scientists and decision makers: occupational asthma has become the most common occupational respiratory disease (2-4). The consequences of acquiring occupational asthma should not be underrated; as further exposure should always be avoided, the worker may suddenly be faced with unemployment or even disability retirement. Contrary to earlier belief follow-up studies have revealed that occupational asthma does not necessarily resolve despite avoidance of exposure to the causative agent. The majority of cases may have asthma persisting several years after the initial diagnosis (5,6). Diagnosis plays a central role in the prevention of occupational asthma. As primary prevention, i.e. the control of exposure leading to asthma, often fails, early detection of the disease remains essential (7). Although diagnostic procedures are still far from uniform, efforts have been made to establish guidelines. Consensus on several issues is discernible: diagnosis should be based on Objective investigations; it is necessary to distinguish occupational asthma from asthma not occupationally caused and from chronic airflow limitation; the condition should be recognized as early as possible and the specific cause identified whenever practicable (8-12). Identification of the specific cause needs to be stressed for several reasons. In addition to serving legal interests of the patient it is vital to know what exposures to avoid when relocating or re-educating a patient. Identifying the specific aetiology is also necessary if new inducers of occupational asthma are to be detected. Finally, even though registers on occupational diseases have proven indispensable for studying the occurrence and causes of occupational asthma (2-4), such registers are never better than the data they receive. As in all diagnostics of occupational diseases, history is the corner stone. Confirmed exposure to a recognized cause of occupational asthma and a supportive clinical picture greatly aid the diagnostics, but the history whether via questionnaire or 0954-6111/94/100719+03 $08.00/0
interview lacks the necessary specificity to establish a diagnosis (13). A diagnosis of occupational asthma requires the presence of asthma and its causal relationship with work. Lung function tests are necessary to demonstrate bronchial asthma, but periodic spirometry is virtually useless for picking up new cases of occupational asthma (14,15). Despite the common practice of measuring FEV 1 before and after a workshift, this method is not reliable (14). The most reliable way to prove a causal relationship between a specific exposure and asthma is undoubtedly the inhalation provocation test, often referred to as the 'gold standard' (8,9). However, the facilities and necessary experience are still only found in a few centres with a special interest in occupational asthma. Even then, the provocation test is not always practicable; it cannot be performed if the patient's asthma is too labile, if the causative agent is unidentified, or if the exposure for some reason cannot be generated in an acceptable way. A short period of exposure, e.g. 30 minutes, does not necessarily correspond to the real 8-hour, 5-days a week work situation. Finally, the sensitivity to the offending agent may have been lost during long sick leave (16). It should also be pointed out that provocation tests are not devoid of risks (e.g. 17,18). However, based on experience gained over some 20 years it seems reasonable to consider inhalation tests acceptably safe provided that they remain in the hands of experienced personnel of specialized respiratory units. In summary, inhalation challenge tests are indicated for detecting previously unrecognized causes of occupational asthma, in cases where exposure to more than one agent may be suspected, when uncontrolled exposure at the workplace may jeopardize the patient's health, and where other investigations have proved inconclusive but the history still suggests occupational asthma. For studying mechanisms and exposure-response relationships, inhalation challenge tests are extremely useful. Monitoring peak expiratory flow rates (PEFR) during periods at ~nd off work (14,19) has become routine in diagnosing occupational asthma. P E F R has high sensitivity and specificity when using specific inhalation challenge tests as a reference (20,21). In 9 1994W. B. SaundersCompany Ltd
720
Editorial
workers suspected of occupational asthma induced by western red cedar, the sensitivity was 86% and the specificity 89%. When combined with a suggestive clinical history, sensitivity increased to 100% rendering inhalation tests with the causative agent, plicatic acid, superfluous (20). Sensitivity of PEFR was somewhat lower (74%) in a series involving a variety of causative agents (21). Thus, PEFR monitoring can be said to have acceptable sensitivity and specificity, especially if there is a definite exposure to a well known cause of occupational asthma and the clinical history suggests this disorder. PEFR monitoring has its weaknesses, however. It is time consuming; to achieve an optimal result a minimum of 4 weeks seems to be required (9,11,12). PEFR monitoring depends on compliance as well as honesty of the worker, both of which to some extent reduce the value of the method. In cases where the specific causative agent needs to be identified, the PEFR recordings are naturally inferior to specific inhalation challenge tests. There may also be difficulties in distinguishing between occupational asthma and deterioration of any asthma due to dusts or irritants at the workplace. Finally, uncontrolled exposure to the detrimental work environment for several weeks is not without risk (e.g. 22,23) and should not be undertaken without due consideration of the severity of the alleged symptoms. There have been attempts to improve sensitivity and specificity of PEFR recordings by serial measurements of non-specific bronchial responsiveness to histamine or metacholine (20,21,24,25). The method may prove useful, although recent studies have failed to prove any advantage in terms of improved sensitivity or specificity (20,26). Measuring the nonspecific responsiveness may help to improve the objectivity of the self-recorded PEFR. The value of serial measurements of non-specific bronchial responsiveness needs further assessment. The presence of specific IgE antibody as demonstrated by skin tests or in biological fluids confirms sensitization. When the causative agent is a highmolecular weight sensitizer and there is a close correlation between IgE antibody and cases of occupational asthma, immunological tests aid the diagnosis (27). This is particularly true when the immunological test is combined with a suggestive history and positive PEFR recordings. With respect to low molecular weight chemicals, the value of immunological tests is so far limited. IgE antibody may be found against typical hapten - protein conjugates such as several organic acid anhydrides, but the finding is far from consistent (28-30). IgE has been demonstrated in only 15-20% of cases positive to
diisocyanates in inhalation challenge tests (31,32). Whereas a positive test can be construed as support for the diagnosis, a negative result by no means precludes it. Although the diagnostics of occupational asthma have improved tremendously over the last few years, the need remains to assess further the sensitivity and specificity of most currently used diagnostic techniques, separately and in various combinations. The potential of cell mediators such as eosinophilic proteins should also be evaluated. H. NORDMAN The Finnish Institute o f Occupational Health Topeliuksenkatu 41 aA 00250 Helsinki Finland
References
1. Newman Taylor AJ. Occupational asthma. Thorax 1980; 35: 241545. 2. Meredith S. Reported incidence of occupational asthma in the United Kingdom, 1989 90. J Epidemiol Community Health 1993; 47: 459463. 3. Lagier F, Cartier A, Malo JL. Medico-legal statistics on occupational asthma in Quebec between 1986 and 1988. Rev Fr Mal Respir 1990; 7: 337-341. 4. Register for Occupational Diseases. Institute of Occupational Diseases, Helsinki, Finland, 1994:1617 (in Finnish). 5. Paggiaro PL, Loi Am, Rosso O et al. Follow up study of patients with respiratory disease due to toluene diisocyanate (TDI). Clin Allergy 1984; 14: 463~469. 6. Chan-Yeng M, MacLean L, Paggiaro PL. Follow-up of 232 patients with occupational asthma due to western red cedar (Thuja plicata). J Allergy Clin Immunol 1987; 79: 79~796. 7. Venables K. Preventing occupational asthma. Br J Ind Med 1992; 49:817 819. 8. Cartier A (Chairman), Bernstein IL, Burge PS et aL Guidelines for bronchoprovocation in the investigation of occupational asthma. Report on the Subcommittee on Bronchoprovocation for Occupational Asthma. J Allergy Clin Immunol 1989; 84: 823-829. 9. Subcommittee on Occupational Allergy of the EAACI. Guidelines for the diagnosis of occupational asthma. Clin Exp Allergy 1992; 22:103 108. 10. Malo JL. Occupational asthma. Lung Biol Health Dis 1993; 68:117 131. 11. Cartier A. Definition and diagnosis of occupational asthma. Eur Resp J 1994; 7: 153-160. 12. Newman Taylor, Picketing CAC. Occupational asthma and byssinosis. In: (ed. Parkes WR) Occupational Lung Disorders (Third edn). Oxford: Butterworth Heinemann, 1994; 710-729. 13. Malo J-L, Ghezzo H, L'Archeveque J, Lagier F, Perrin B, Cartier A. Is the clinical history a satisfactory means of diagnosing occupational asthma? Am Rev Respir Dis 1991; 143:528 532.
Editorial
14. Burge PS. Single and serial measurements of lung function in the diagnosis of occupational asthma. Eur J Resp Dis 1982; 63: (suppl 123): 47 59. 15. Malo JL, Cartier A. Occupational asthma in workers of a pharmaceutical company processing spiramycin. Thorax 1988; 43: 371-377. 16. Mapp C, Corona PC, DeMarzo N, Fabbri L. A follow-up study of subjects with occupational asthma due to toluene diisocyanate (TDI). Am Rev Respir Dis 1988; 137: 1326-1329. 17. Fabbri LM, Danieli D, Crscioli S, et al. Fatal asthma in a subject sensitized to toluene diisocyanate. Am Rev Respir Dis 1988; 137: 1494-1498. 18. Romano C, Sulotto F, Pavan I, Chiesa A, Scansetti F. A new case of occupational asthma from reactive dyes with severe anaphylactic response to the specific challenge. Am J Ind Med 1992; 21: 209-216. 19. Burge PS. Occupational asthma. In: (eds Brewis RAL, Gibson GJ, Geddes DM), Respiratory Medicine. London: Balli6re Tindall, 1990; 704-721. 20. Cot6 J. Kennedy SM, Chan-Yeung M. Sensitivity and specificity of PC20 and PEFR in cedar asthma. J Allergy Clin Immunol 1990; 85: 592-598. 21. Perrin B, Lagier F, L'Archeveque et al. Occupational asthma: validity of monitoring of peak expiratory flow rates and non-allergic bronchial responsiveness as compared to specific inhalation challenge. Eur Respir J 1992; 5: 40-48. 22. Stern MA. Occupational asthma from a reactive dye. Ann Allergy 1985; 55: 264. 23. Belin L, Hjortsberg U, Wass U. Life-threatening pulmonary reaction to car paint containing a prepolymerized isocyanate. Scand J Work Environ Health 1981; 7: 310-312.
721
24. Cartier A, Pineau L, Malo J-L. Monitoring of maximum expiratory peak flow rates and histamine inhalation tests in the investigation of occupational asthma. Clin Allergy 1984; 14:193 196. 25. Blainey AD, Oilier S, Cundell D, Smith RE, Davies RJ. Occupational asthma in a hairdressing salon. Thorax 1986; 41: 42-50. 26. Ulrik CS, Backer V, Skov PG. Usefulness of repeated measurements of bronchial hyperresponsiveness for the diagnosis of occupational asthma. J Asthma 1994; 31: 35-42. 27. Novey HS, Bernstein IL, Mihalas L, Terr AI, Ynginger JW. Guidelines for the clinical evaluation of occupational asthma due to high molecular weight allergens. J Allergy Clin Immunol 1989; 84:829 833. 28. Butcher BT, Bernstein IL, Schwartz L. Guidelines for the clinical evaluation of occupational asthma due to small molecular weight chemicals. J Allergy Clin Immunol 1989; 84: 834-838. 29. Venables KM. Low molecular weight chemicals, hypersensitivity, and direct toxicity; the acid anhydrides. Br J Ind Med 1989; 46:222 232. 30. Schlueter DP, Banaszak EF, Fink JN, Barboriak J. Occupational asthma due to tetrachlorophthalic anhydride. J Occup Med 1978; 20: 183-188. 31. Keskinen H, Tupasela O, Tiikkainen U, Nordman H. Experiences of specific IgE in asthma due to diisocyanates. Clin Allergy 1988; 18: 597-604. 32. Butcher BT, O'Neill CE, Reed MA, Salvaggio JE. Radioallergosorbent testing of toluene di-isocyanate reactive individuals using p-tolyl isocyanate antigen. J Allergy Clin Immunol 1980; 66: 213-216.