© 2002 American Thoracic Society
Diagnostic Tests for Occupational AsthmaUniversity of Newcastle upon Tyne Royal Victoria Infirmary Newcastle upon Tyne, England Presumed sensitizers in the workplace make an important, if relatively small, contribution to the incidence of asthma in adults. The importance lies with the unusual possibility (for adults) that the asthma may resolve—providing there is prompt recognition that it is occupational and further exposure to the inducing sensitizer is avoided. The possibility of resolution becomes a probability, though by no means a certainty, if this intervention occurs within as short a period as 6 months from symptom onset, but after approximately 2 years the balance of probabilities tips the other way. The window of opportunity for a favorable outcome is consequently small. It points to a need for a readily available test by which asthma can be confirmed to be (or not to be) occupational in origin; an incorrect attribution to occupation is likely to lead to unemployment and financial loss without any medical benefit. The actual contribution of occupational exposures to the incidence of asthma in adults varies necessarily with the nature of employment opportunities from region to region and from country to country. At the extremes, the annual incidence has been reported at 205 per employed million in Finland but only 5 per employed million in Massachusetts (1, 2). Most estimates suggest that 5–15% of asthma beginning in adult life is occupational, and so the crude odds in favor are around 1 in 10. This is consistent with estimates from the United Kingdom that the annual average incidence is approximately 40 per employed million (3). In certain employment groups the risk is substantially greater; for spray painters (who generally use diisocyanates and epoxy resins) the estimated incidence from 1992 to 1997 was 38-fold greater than average for the United Kingdom workforce (4). The confidence that can be attached to such estimates is unfortunately limited. Although asthma itself may be readily confirmed objectively from bronchodilator tests or measurements of airway responsiveness, there is considerable difficulty in establishing whether occupational exposure is truly responsible. Most analyses of reported cases rely simply on the opinions of individual reporters. All use a ‘more likely than not’ approach, drawing conclusions from the evidence available in each case, and in many cases the evidence involves no more than a history of work-related exacerbations in environments where dusts, gases, or fumes are said to be present. The gold standard investigation tools—inhalation provocation tests—are used in a tiny minority of cases only, with notable exceptions in Finland and Quebec. Unsupervised serial peak flow measurements during periods at and away from the workplace offer a reasonably satisfactory procedure if the test subject is still employed and if a recognized asthma inducer is present. However, double-blind inhalation tests in the laboratory, monitored using supervised measurements of spirometry and airway responsiveness, provide the most persuasive method of showing either that a given subject is sensitized or that a novel agent is causal. Some objectivity in favor of hypersensitivity can be obtained from immunologic tests, most particularly specific immunoglobulin (Ig) E responses. These responses can be demonstrated by skin tests or by a variety of serologic assays. The practical limitations are allergenic impurities and cross reactivity for preparations of naturally occurring allergens of high molecular weight, and difficulty in producing functional hapten–protein complexes for reactive chemicals of low molecular weight. Even with reliable test systems, positive results tend to correlate more closely with exposure than with disease, and so their value lies primarily in monitoring the adequacy of exposure controls and identifying exposed subjects with enhanced risk. Specific IgG responses are probably related even more closely to exposure than to disease and, intriguingly, may be suppressed by smoking. Antibody tests are thus disappointing, as is nicely illustrated by Bernstein and colleagues (5) in this issue of AJRCCM (pp. 445–450). The sensitivities and specificities they report for IgE (and IgG) tests against diisocyanate-protein conjugates were merely 21% and 89% (and 47% and 74%), respectively. They describe a much more promising test, which was admirably assessed against laboratory-based inhalation provocation tests in 54 subjects with suspected occupational asthma and regular exposure to diisocyanates. The new kid on the block is the stimulated production in vitro of monocyte chemoattractant protein-1 (MCP-1) from peripheral blood mononuclear cells by diisocyanates conjugated with human serum albumin. The inhalation tests indicated that 19 subjects had diisocyanate asthma, whereas 35 did not, and the respective sensitivity and specificity of the MCP-1 test in this population were 79% and 91%. The study population was usefully separated into 39 subjects with current exposure or exposure within 6 months, and 15 subjects with more distant exposure ranging from 7 to 96 months. Curiously, the test performed better in the latter group, but participant numbers were small and the differences may not be meaningful. Because many subjects come for evaluation more than 6 months after the exposure of possible relevance has ceased, the observation provides encouragement for this extended use of the test. That the MCP-1 test was also compared against assays for specific IgE and IgG was especially valuable and demonstrated that antibody assays alone do not provide adequate diagnostic information in occupational asthma—at least in diisocyanate asthma. Here lies the rub. Can the MCP-1 test be adapted for other causes of occupational asthma, in particular agents of high as well as low molecular weight, and can other reactive chemicals of low molecular weight be suitably conjugated? More critically, will it stand the test of time when used in other populations of workers developing asthma? Reservations lie with the use of three separate diisocyanates in the test systems and with the use of all three in each subject irrespective of the actual workplace exposure. The impressive results depend on ignoring, in some instances, the outcome obtained with the diisocyanate encountered occupationally in favor of that which gave a more clearly positive outcome. They justify this, not unreasonably, because of known cross-reactivity between diisocyanates and because participant numbers were too small to assess whether each diisocyanate test system is similarly efficient. Of lesser concern was a greater level of airway responsiveness in the subjects giving positive compared with negative results to the inhalation tests, implying that the MCP-1 test might in some way reflect greater asthmatic activity rather than diisocyanate hypersensitivity. Reassuringly, no relation was noted between MCP-1 results and airway responsiveness. The MCP-1 test therefore provides a welcome innovation for the diagnosis of occupational asthma; it remains to be seen whether its early promise will be fulfilled in practice, and whether it can be extended with similar benefit to other causes of occupational asthma. At the very least, it may stimulate new avenues of investigation and hence a much-needed evolution of objective laboratory tests that can match the efficiency of inhalation provocation tests. REFERENCES
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