Diagnosis of an affected worker

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Occupational asthma should be considered in all workers with symptoms of airflow limitation. Much of the evidence relating to its diagnosis emanates from specialist settings where the prior probability of disease is high; positive predictive values of tests may be lower in other settings. The diagnosis of occupational asthma is an iterative process. The best screening question to ask is whether symptoms improve on days away from work. This is more sensitive than asking whether symptoms are worse at work, as many symptoms deteriorate in the hours after work or during sleep. Occupational asthma can be present when tests of lung function are normal, making these less useful in screening for occupational asthma. Asthmatic symptoms improving away from work can produce false positive diagnoses, so further validation of occupational asthma is needed. The diagnosis is made most easily before exposures or treatments are modified. Serial measurement of peak expiratory flow is the most available initial investigation. When done and interpreted to validated standards there are very few false positive results, but about 20% are false negatives. Skin prick tests or blood tests for specific IgE are available for most high molecular weight allergens, and a few low molecular weight agents but there are few standardised allergens commercially available which limits their use . A positive test denotes sensitisation, which can occur with or without disease. The diagnosis of occupational asthma can usually be made without specific bronchial provocation testing, considered to be the gold standard diagnostic test. The availability of centres with expertise and facilities for specific provocation testing is very limited in the UK and the test is time-consuming. Specific provocation is particularly indicated when the precise cause of the occupational asthma is unclear, but this knowledge is needed for the management of an employee.

What is the sensitivity and specificity of respiratory questionnaires in the diagnosis of validated cases of occupational asthma?

The sensitivity of asthma symptoms has high sensitivity but lower specificity, whereas the question "have you been told by a doctor that you have asthma" has a high specificity but low sensitivity. (Schlunssen 2004). Asthma symptoms better on days away from work derived from questionnaires have a sensitivity of 58-100% for validated occupational asthma. The sensitivity was below 90% in only one study from Quebec. The sensitivity was 100% in only one study of five latex-exposed nurses. The most common symptoms used were wheeze and shortness of breath. No cases of occupational asthma due to latex were asymptomatic (two studies). The Quebec study showed some improvement in sensitivity to 66% when symptoms improved on holiday. Work-related asthma symptoms were common in those with negative specific challenge tests, the specificity of the questionnaires ranged from 45-100%, only one small study being over 70%.

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In the clinical setting questionnaires that identify symptoms of wheeze and/or shortness of breath which improve on days away from work or on holiday have a high sensitivity, but relatively low specificity for occupational asthma.

( Baur 1998, Cote 1993, Malo 1991, Merget 1988, Vandenplas 1995, Vandenplas 2001)

What are the sensitivity and the specificity of an expert medical history and examination in the diagnosis of validated occupational asthma?

There are fewer studies with expert medical histories than questionnaires. The symptoms of occupational asthma are indistinguishable from those of non-occupational asthma . Asking about deterioration at work was an insensitive method of making the diagnosis of occupational asthma (sensitivity 42% in one small study). Seasonal variation was more common in non-occupational asthma. Two experts from Quebec achieved sensitivities of 83% and 95%, substantially more than obtained by the same group from different patients by questionnaire. Expert histories have poor specificity compared with specific challenge testing.

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Free histories taken by experts have high sensitivity, but their specificity may be lower.

( Axon 1995, Baur 1998, Koskela 2003, Malo 1991, Malo 1997, Ricciardi 2003, Vandenplas 2001)

What are the sensitivity and the specificity of pre and post shift changes in lung function in the diagnosis of occupational asthma?

There are no good studies comparing across shift changes with specific challenge testing. Such testing is unlikely to be either sensitive or specific since measures of airflow obstruction, such as FEV1 or PEF, have a diurnal variation in most normal workers that is increased in most asthmatics. Furthermore, pre- and post-shift spirometry are unhelpful in the case of workers who suffer delayed responses after leaving work or with those who have prolonged bronchoconstriction that extends into the next work shift. In one case-control study of day-shift workers in a factory with many cases of colophony asthma, a fall in FEV1 of >10% post-shift was found in 5% of asymptomatic workers and 32% of those with work-related asthma symptoms.

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Pre to post shift changes in lung function cannot be recommended for the validation or exclusion of occupational asthma.

( Burge 1979, Burge 1979)

What is the feasibility of obtaining serial measurements of peak flow in workers suspected of having occupational asthma?

Six publications describe small case series of consecutive patients attending specialist clinics. Three describe workplace surveys, in the context of research studies, with lower frequencies of daily recordings. Publication bias is probable, particularly in the latter group. In four clinical series and each of the workforce populations acceptable records were returned by over 70% of subjects.

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Acceptable peak flow series can be obtained in around two thirds of those in whom a diagnosis of occupational asthma is being considered.

( Cote 1990, Cote 1993, Henneberger 1991, Hollander 1998, Leroyer 1998, Malo 1995, Quirce 1995, Redlich 2001, Revsbech 1989)

What are the minimum criteria for serial measurements of peak flow to maintain a high degree of diagnostic accuracy?

A single case series of 74 patients attending a specialist clinic reports the highest combination of sensitivity and specificity with a measurement frequency of at least four readings a day. Less frequent readings produced a higher specificity but lower sensitivity.

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The diagnostic performance of serial peak flow measurements falls when fewer than four readings a day are made.

( Malo 1993)

Can experts agree on the interpretation of serial measurements of peak flow in the diagnosis of occupational asthma?

Six of seven series report high levels of agreement (averaging 80%) between expert assessors with kappa values of at least 0.6. A single series, where non-expert assessors were used, reports a much lower level of inter-observer agreement. Three series report levels of intra-observer agreement over two occasions. A high level of repeatability was reported in two. The third used non-expert assessors.

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There is high level of agreement between expert interpretations of serial peak flow records.

( Baldwin 2002, Leroyer 1998, Liss 1991, Malo 1993, Malo 1996, Perrin 1992, Zock 1998)

What are the sensitivity and specificity of serial measurements of peak flow in the diagnosis of occupational asthma?

Eight case series report direct and blinded comparisons of serial peak flow measurement and either specific bronchial provocation testing (five studies) or an expert diagnosis (three studies) based on a combination of other types of evidence. Some cases are reported in more than one publication. Reported sensitivities and (particularly) specificities are consistently high: averaging 80% and 90% respectively.

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The sensitivity and specificity of serial peak flow measurements are high in the diagnosis of occupational asthma

( Bright 2001, Burge 1982, Cote 1990, Cote 1993, Leroyer 1998, Liss 1991, Malo 1993, Perrin 1992)

Are statistical or computed methods of peak flow assessment as accurate as expert interpretation in the diagnosis of occupational asthma?

Three case series compare visual inspection of peak flow records by experts with a variety of statistical indices of the same records. In two, visual inspection gave higher values of sensitivity and specificity; in the third an index derived from maximum values away from work and minimum values at work produced a slightly higher value for sensitivity than did visual inspection. Other statistical indices used in the same report were less sensitive and specific than visual inspection. Just one computed method of analysis has been reported. The analysis was calibrated using the diagnostic opinion of a single expert and in cases whose occupational asthma was, for the most part, attributable to low molecular weight agents. A sensitivity of 75% and a specificity of 94% for 67 records (32 cases of occupational asthma) were reported.

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Statistical analysis of serial peak flow measurements is of limited diagnostic value compared to expert interpretation

( Cote 1993, Leroyer 1998, Perrin 1992)

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Computed analysis of peak flow records has good diagnostic performance

( Baldwin 2002, Gannon 1996)

What are the sensitivity and the specificity of a normal measurement of non-specific reactivity while at work in the diagnosis of occupational asthma?

Studies of non-specific reactivity are confounded by different methods used, different cut-offs for normality and the interval between last occupational exposure and the performance of the test (increasing time may allow recovery of initial hyper-reactors). There are however a large number of studies using different methods from many centres showing that non-specific bronchial hyper-reactivity may be normal in 5-40% of specific challenge positive workers. Testing with higher concentrations of methacholine or histamine at which some non-asthmatics react reduces the number of non-reacting occupational asthmatics, but still leaves some non-reactors. One study showed no additional benefit of non-specific bronchial reactivity measurement over and above a history and specific IgE to inhaled antigens. A normal test of non-specific reactivity is not sufficiently specific to exclude occupational asthma in clinical practice.

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A large number of concordant studies from different centres using different methodologies demonstrated that increased non-specific reactivity is often found in workers with occupational asthma. There are however many reports of normal methacholine or histamine reactivity within 24 hours of exposure in workers with confirmed occupational asthma.

( Anees 2002, Baur 1998, Brisman 2003, Burge 1982, Cartier 1989, Hargreave 1984, Koskela 2003, Lemiere 2000, Lin 1995, Malo 1991, Merget 1991, Merget 1996, Moscato 1991, Perrin 1992, Ricciardi 2003, Tarlo 1991, Vandenplas 1995, Vandenplas 2001)

What are the sensitivity and the specificity of changes in non-specific reactivity at work and away from work in the diagnosis of validated cases of occupational asthma?

Three studies were identified where pre and post exposure measurements were attempted. One did not investigate workers further when the at-work reactivity was normal, limiting its interpretation. Using a 3.2 fold change in reactivity (the 95% confidence interval for between test reproducibility), one study found a sensitivity of 48% and a specificity of 64%. Reducing the required change to twofold increased the sensitivity to 67%, reducing specificity to 54%. A smaller study with 14 workers with occupational asthma showed a sensitivity of 62% and specificity of 78%.

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Changes in non-specific reactivity at and away from work alone have only moderate sensitivity and specificity for diagnosis.

( Cote 1990, Perrin 1992, Tarlo 1991)

What is the feasibility of obtaining paired measurements of non-specific reactivity at and away from work?

Paired measurements of non-specific reactivity were possible in 27/54 workers in whom the tests were considered indicated in one study. In another study measurements were made in 194/204 apprentice welders who were there at the time.

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Paired measurements of non-specific reactivity may be achieved in the workplace.

( El-Zein 2003, Tarlo 1991)

What are the sensitivity and the specificity of specific IgE testing in the diagnosis of validated cases of occupational asthma?

The production of specific IgE antibody may be detected by skin prick or serological tests. The respective sensitivities and specificities of the ability of these tests to detect specific IgE vary between allergens but in any case are dependent on the setting of positive cut-offs. Blood testing for specific serum IgE may not be as sensitive as skin prick testing (Park 2001) but may be useful if skin testing cannot be performed. The presence of specific IgE confirms sensitisation to an agent at work, but alone does not confirm the presence of occupational asthma, nor necessarily its cause. In this sense there is a high false positive rate although, with high molecular weight agents, few false negatives. The power of testing for specific IgE is to exclude an allergen as a cause of a worker's asthma. Specific IgE is an insensitive but specific test for isocyanate-induced occupational asthma (Tee 1998) although this is to some extent dependent on the time since last exposure. A small study reported greater sensitivity for MDI (83%) than TDI (27%) (Pezzini 1984).

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Both skin prick and serological tests are highly sensitive for detecting specific IgE and occupational asthma caused by most high molecular weight agents, but are not specific for diagnosing asthma.

( Baur 1995, PlattsMills 1987, Vandenplas 1995)

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Both skin prick and serological tests are sensitive for detecting specific IgE and occupational asthma caused by acid anhydrides and some reactive dyes; but have a lower specificity for diagnosing asthma.

( Grammer 1998, Howe 1983, Park 1989, Park 2001)

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Skin prick tests are highly sensitive but less specific for occupational asthma caused by complex platinum salts.

( Merget 1988, Merget 1991, Merget 1996, Vedal 1986)

What are the sensitivity and the specificity of specific bronchial provocation testing while at work, and after removal from work, in the diagnosis of validated cases of occupational asthma?

Specific provocation challenges are usually used as the gold standard for occupational asthma diagnosis making assessments of their diagnostic validity difficult. There is a lack of standardised methods for many occupational agents. There is evidence that the threshold exposure increases with time since last exposure, making the tests less sensitive after prolonged absence from work. There are individuals who have been shown to have non-specific reactions to specific challenges at concentrations likely to be found in the workplace and negative specific challenges in workers with otherwise good evidence of occupational asthma when challenge concentrations are confined to levels below occupational exposure standards. (Burge 1979a, Burge 1979b, Cartier 1989, Lin 1995, Moscato 1991)

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Carefully controlled specific challenges come closest to a gold standard test for some agents causing occupational asthma.

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A negative test in a worker with otherwise good evidence of occupational asthma is not sufficient to exclude the diagnosis.

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