Summary

Occupational asthma is a type of asthma caused by exposure to an agent in the workplace. In the most common type of occupational asthma, an “allergy” to certain substances in the workplace is developed. Demonstration of this “allergy” is thus an essential step in the clinical investigation and the development of a prevention program, as, by definition, the disease cannot be considered present if no allergy is demonstrated. With the current state of knowledge, an immediate-type allergen-specific immumoglobulin E (IgE) mediated allergy associated with sensitization can be demonstrated by allergy skin tests for protein-derived agents, that is, high-molecular weight (HMW) agents (flours, for example). However, the allergens used for these tests are not standardized. In addition, there are no allergy tests for most chemical agents, which are low-molecular weight (LMW) agents (isocyanates, for example).

The specific inhalation challenge (SIC) is the gold standard for diagnosis of occupational asthma induced by specific agents. However, administering an SIC is technologically challenging and the controlled test protocol is demanding, especially in case of exposure to LMW agents. In addition, SICs with HMW as well as LMW agents must be performed in a hospital under medical supervision, so that immediate action can be taken in case of severe asthmatic reaction. SICs with LMW agents such as isocyanates are rarely performed in certain countries (the United States, for example). However, as occupational asthma is rarely reversible when diagnosed late, identification of early biomarkers of the disease is crucial. A biomarker is a biological marker whose presence in an individual (a particular protein present in a blood sample, for example) can indicate early onset, persistence or remission of a disease. Hence, if a biomarker demonstrates development of an allergy to an occupational agent, the investigation can be completed by lung function tests and SICs.

The basophil activation test (BAT) is a non-invasive diagnostic test (blood test) that can identify IgE-type sensitization to common inhaled allergens (pollen, for example) and certain food allergens (peanuts, for example). A positive agent-specific BAT is defined as a statistically significant increase in basophil activation over baseline BAT (measured by expression of the activation marker CD203c, for example). An agent-specific BAT is performed by measuring the response of a blood sample to stimulation by a specific allergen to which the individual providing the sample is possibly sensitized. Hence a negative specific BAT would indicate absence of an allergen-specific IgE-type sensitization and a positive specific BAT would indicate its presence. The BAT has never been studied in the past as a possible tool for identifying sensitization to HMW and LMW occupational agents.

One of the most important findings of our study is the demonstration that a positive BAT specific to an HMW agent is associated with a positive SIC and a diagnosis of occupational asthma induced by that agent. Hence, a positive BAT on exposure of a worker’s blood sample to an HMW agent could be a predictor of a positive SIC and a subsequent diagnosis of occupational asthma. However, given the small size of our sample, these findings must be considered preliminary data only and must be confirmed by studies of larger cohorts.

With respect to LMW occupational agents, our results did not indicate that LMW agent-specific BATs could distinguish between workers whose SIC with these agents was negative and those whose SIC with these agents was positive. In other words, BAT results could not predict a negative or positive SIC or subsequent diagnosis of occupational asthma due to LMW agents. However, a second data analysis was performed excluding all workers exposed to formaldehyde, an exclusion warranted by failure, in the literature, to demonstrate IgE-type sensitization in the development of occupational asthma attributable to formaldehyde. This analysis showed a statistically significant correlation between a positive isocyanate-specific BAT and a positive SIC with isocyanates. However, a positive isocyanate-specific BAT was also noted in workers whose SIC with isocyanates was negative, though the results were not statistically significant. Thus a positive isocyanate-specific BAT alone cannot serve as a predictor of a positive SIC and subsequent diagnosis of occupational asthma.

Atopy is defined as a genetic predisposition to become easily sensitized to different substances in the environment, such as pollens. Sensitization to occupational agents is often followed by onset of allergy symptoms associated with rhinitis or asthma. Our data showed an association between a positive HMW-agent specific BAT and atopy, and, in this case, occupational asthma due to these agents. However, as mentioned, this conclusion must be confirmed by larger studies with a larger group of negative control subjects.

With respect to LMW occupational agents, our results showed that a positive BAT when stimulated with the tested LMW agents did not correlate with a positive SIC, even when the workers tested were divided according to presence or absence of atopy. For the reasons mentioned above, workers exposed to formaldehyde (IgE-independent) in the LMW group were excluded. We were then able to demonstrate a positive LMW-agent specific BAT significantly different from baseline BAT in atopic workers but not in non-atopic workers. Hence a BAT positive for isocyanates in combination with positive atopic status could be a predictor of a positive SIC and subsequent diagnosis of occupational asthma.

In conclusion, an agent-specific BAT positive for HMW agents or isocyanates together with atopic status (presence or absence of atopy) could offer a better characterization of a worker’s risk of developing occupational asthma and thus contribute to the assessment and management of workplace related risks. A risk management approach of this type would be easy to introduce in the workplace as a BAT requires only that a blood sample be drawn from the worker, for subsequent analysis on the same day by a hospital or clinic laboratory with the required expertise in flow cytometry. Additional research is nonetheless required, in particular to determine BAT sensitivity and specificity as well as positive and negative predictive values.