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- Material and methods
Background: Quantitative relationships between immunological reactivity, non-specific bronchial responsiveness and bronchial responsiveness to allergens have scarcely been investigated in occupational asthma.
Methods: We assessed the above relationships in 24 subjects with baker's asthma. The skin endpoint titration to bakery allergens as a measure of immunological reactivity, together with the methacholine PC20 and allergen PC20 during early asthmatic reaction were determined.
Results: All patients had positive skin tests to some bakery allergens (wheat and rye flour, soybean flour, fungal enzymes and egg white proteins) and bronchial hyperresponsiveness to methacholine. Specific inhalation challenge (SIC) tests were performed with aqueous allergen extracts of cereal flour (n = 14), soybean (n = 8), baking enzymes (n = 12), and egg white proteins (n = 8) in sensitized workers. A positive asthmatic reaction was observed in 84% of the inhalation challenges. SIC elicited isolated early asthmatic reactions in 62%, dual reactions in 32% and isolated late reactions in 5%. Multiple linear regression analysis showed allergen PC20 as a function of skin sensitivity to allergen and methacholine PC20, yielding the following highly significant regression formula: log-allergen PC20 = 0.18 + 0.99 log(skin sensitivity) + 0.343 log(methacholine PC20) (r = 0.89, P < 0.001). This formula predicted allergen PC20 to within one double concentration in 67%, to within two double concentrations in 85% and within three double concentrations in 97%.
Conclusion: The main determinant of bronchial responsiveness to allergen in patients with baker's asthma is the degree of sensitization to occupational allergens as determined by skin reactivity, modulated to a lesser extent by non-specific bronchial hyperresponsiveness.
The relationship between the degree of allergen sensitization, airway hyperresponsiveness to bronchoconstrictive mediators (such as methacholine or histamine) and bronchial responsiveness to allergen was initially proposed by Tiffenau (1). This association was subsequently confirmed by other groups with common aeroallergens (2–4). Cockcroft et al. reported that the severity of the early asthmatic reaction to common aeroallergens can be predicted from skin sensitivity to the allergen and airway responsiveness to histamine (4). A recent study confirmed the dependence of the allergen-induced early asthmatic reaction upon the level of allergen skin test sensitivity and the degree of airway hyperresponsiveness as assessed by methacholine (5).
This relationship, however, has rarely been investigated with occupational allergens. Shirai et al. (6) demonstrated the links between specific and non-specific airway hyperresponsiveness and skin test reactivity to the low-molecular-weight agent epigallocatechin galate, the causative agent of green tea-induced asthma. However, no data are available regarding the relationship between these parameters in occupational asthma (OA) caused by high-molecular-weight agents.
The gold standard in the diagnosis of OA is specific inhalation challenge (SIC) (7). Laboratory-specific inhalation testing should only be performed in specialized centers with trained personnel in order to ensure safety for patients and reliable results. The prediction of the magnitude of airway response to an occupational allergen relying on the assessment of specific skin reactivity and airway responsiveness to methacholine is highly relevant for safety purposes.
The aim of this study was to evaluate the relationship between skin test sensitivity, airway hyperresponsiveness to methacholine and bronchial responsiveness to occupational allergens among bakery workers with asthma.
- Top of page
- Material and methods
The results of this study provide evidence that the magnitude of the EAR to bakery-derived allergens can be satisfactory predicted by skin sensitivity and bronchial hyperresponsiveness to methacholine. Thus, the information obtained from skin endpoint titration and methacholine inhalation test can be used to safely select a starting concentration for allergen inhalation (4–6), but it should not replace the performance of SIC.
The aforementioned equations (4–6) are derived from data of asthmatic patients who have a positive EAR upon allergen inhalation challenge, but do not take into account the results of negative inhalation challenges in sensitized subjects with airway hyperresponsiveness (14). Nonetheless, a recent meta-analysis has concluded that SPT in workers with suspected OA caused by high-molecular-weight agents and bronchial hyperresponsiveness to methacholine correlates with SIC (high specificity, moderate sensitivity) (15).
It has been shown with different high-molecular-weight occupational allergens that the combination of immediate skin reactivity to an allergen and increased bronchial hyperresponsiveness does not necessarily prove that the subject will develop an asthmatic reaction when exposed to this agent (13). For instance, about 20% of subjects with skin reactivity to psyllium (16) or guar gum (17) and bronchial hyperresponsiveness did not experience an asthmatic reaction after inhalation challenge with the specific agent. Carletti et al. (18) reported that the specific bronchial response to flour dust among subjects with suspected OA caused by wheat flour could not be adequately predicted by any clinical, allergological or functional data, and therefore, an accurate aetiological diagnosis needs to be established by SIC.
Although allergen inhalation challenge tests are rarely indicated with common aeroallergens and it has a limited role clinically (4, 14), SIC tests are considered the gold standard in the diagnosis of OA (7, 19). Laboratory inhalation challenge tests with occupational agents are used for both diagnostic and research purposes in specialized centers across Europe and Canada, whereas in the USA they are limited to research settings (20). The reasons why this test is not widely used in the diagnosis of OA have been reviewed (21). To carry out SIC, extensive precautions are needed for safety requirements (13). Improvements in the safety of this test is of crucial importance; thereby, the prediction of the severity of the EAR to occupational agents has clinical relevance. It has been suggested that high-molecular-weight occupational allergens ought to behave in the same way as common aeroallergens, but this had not been established yet.
The choice of baker's asthma as a model to assess these relationships has strengths and limitations. On the one hand, it still is a common occupational disease and the agents implicated in this type of OA are high-molecular-weight allergens that act through an IgE-mediated mechanism (22), and therefore induce EAR on SIC. On the other hand, a caveat to this model is that bakers are usually polysensitized to occupational allergens (8, 22–24) and it is unknown how sensitization and simultaneous exposure to multiple allergens affect the relationships between the specific and non-specific bronchial responsiveness. In our study, we challenged the subjects with different occupational allergens and, in some cases, more than one SIC was carried out in order to identify the causative allergens of their asthma. Although this may have had some influence on the results, it also resembles a real world situation. In fact, one of the indications of SIC is to identify the agent responsible for asthma when there are multiple possible agents in the workplace (13, 19), and in that scenario it may be necessary to perform several challenges to precisely identify the offending agent. Other pitfalls are that flour allergens are not standardized (25), and they may experience some deactivation during the challenge (26), affecting the results of the provocations tests (27).
It has been shown that inhaled corticosteroids reduce bronchial hyperresponsiveness to pharmacological agents in a dose-dependent manner (28). In addition, prolonged administration of inhaled corticosteroids causes some or null inhibition of the EAR to high-molecular-weight allergens, and reduces the magnitude of the LAR (29). The way how inhaled corticosteroids may affect the relationship between bronchial responsiveness to allergen, airway responsiveness to methacholine and skin sensitivity to allergen is unknown. However, in the original study reporting the regression formula, several subjects were receiving inhaled beclomethasone (3).
In spite of these limitations, we were able to demonstrate that bronchial responsiveness to bakery-derived allergens can be satisfactorily predicted by assessing skin sensitivity to allergen and bronchial hyperresponsiveness to methacholine.
Airway hyperresponsiveness is thought to be important in modifying the response to inhaled allergens (30). However, no correlation has been found between specific and non-specific bronchial responsiveness in OA because of platinum salts (31) and with other low-molecular-weight agents the association is inconsistent (32). Lemière et al. (33) examined specific bronchial responsiveness to occupational agents in 16 workers who still showed skin reactivity but had normal airway responsiveness to methacholine after removal from work. They found that the main determinant of specific bronchial responsiveness (including seven SIC with cereal flour) was the level of specific immunization to the allergen (33). In the green tea-induced asthma model, it was also found that the key element for developing an asthmatic reaction was the degree of skin sensitivity (6). Walusiak et al. (34) reported that skin reactivity to common and occupational allergens is the main risk factor of baker's asthma in a cohort of apprentice bakers.
Choudat et al. (35) reported a significant correlation between bronchial hyperresponsiveness to methacholine and the provocative dose of flour dust causing a decrease in FEV1 of 15%, but not with the dose of flour provoking a FEV1 fall of 20%. In the studies by Cockcroft et al. (3–5) the correlation between allergen PC20 and skin sensitivity was closer than that between allergen PC20 and methacholine PC20. Our results also show that the level of specific bronchial responsiveness to bakery-derived aeroallergens is conditioned by specific immunological reactivity to this allergen, as determined by skin sensitivity, modulated by non-specific bronchial hyperresponsiveness, the latter being less essential.