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Background: Standardized experimental allergen challenges are usually adopted to investigate the effect of allergen exposure on the lower airways. Environmental (natural) allergen challenges are used less often, mainly because of difficulties in standardizing the method, safety reasons and costs. The aim of this study was to investigate the relationship between an experimental and an environmental bronchial challenge. For this reason a natural challenge model was developed.
Methods: Sixty-two patients with a history of cat allergen-induced symptoms involving the lower airways, positive skin prick test, positive in vitro specific IgE to cat allergen and bronchial hyper-responsiveness were included. All 62 patients underwent an experimental challenge in the laboratory followed by an environmental allergen challenge.
Results: All 62 patients developed an early asthmatic response [≥20% fall in forced expiratory volume in 1 s (FEV1)] in the experimental challenge and 60% (37/62) during the environmental challenge. A late asthmatic response (≥15% fall in FEV1 within 3–24 h) was seen in 56% (35/62) of the patients after the experimental challenge. Following the environmental challenge 47% (29/62) of the patients developed a late response. Thirty-four per cent (21/62) of the patients developed a late response in both challenge models and 31% (19/62) did not develop a late response in any model. Thus, there was consistency in 65% (40/62) of the patients in both challenge models.
Conclusion: We found consistency in the pattern of response to inhaled allergen between the two challenge models and we believe that experimental bronchial challenge is likely to reflect the development of relevant inflammation in the lower airways after low-dose allergen exposure in the environment.
Allergy to cat dander is the most common perennial allergy in Sweden and positive skin tests can be found in approximately 15% of the population aged 20–45 years (1). Many of these sensitized individuals are at risk of acquiring asthma symptoms upon cat allergen exposure (2, 3). As the number of cat-allergic individuals is large and cat allergen is widely distributed in the indoor environment, this type of allergy has become a significant medical and social problem in the western world (4, 5).
Inhalation of allergen by sensitized individuals with a history of asthma results in bronchoconstriction that develops within 10–20 min and resolves within 1–2 h (early asthmatic response, EAR). In some individuals this immediate reaction is followed by a second phase of decreased lung function starting after 3–4 h, which may persist for 24 h or more (late asthmatic response, LAR) (6).
Late asthmatic response has often been used as an experimental allergic-asthmatic model of the inflammatory process because of its close resemblance to chronic asthmatic disease. The features of a patient's asthma that determine whether or not they develop LAR are unknown. It has been suggested that the level of allergen sensitivity (mirrored by skin prick test (SPT) responses and amount of allergen specific IgE), allergen dose and the degree of bronchial hyper-responsiveness could be of importance (7–11).
Experimental challenges are usually adopted in asthma studies to investigate the effect of allergen exposure. Environmental (natural) exposure is used in pollen studies, but less often in perennial allergen studies because of difficulties in standardizing the method, safety reasons and costs. In an experimental challenge, high doses of allergen extract solution are nebulized and inhaled over a short-time interval. On the other hand, in an environmental challenge low amounts of allergen in particle form are dispersed in the inhaled air. The duration of an environmental exposure is longer and allergen deposition in the upper and lower airways differs from an experimental challenge (12, 13).
The aim of this study was to investigate, in the same cat-allergic asthmatic patient population, the occurrence of EAR and LAR in two different challenge models – the experimental and the environmental. In the experimental challenge, we used a dosimeter nebulizer for administration of allergen and in the environmental challenge model a domestic environment inhabited by cats was used.
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We have shown that around 65% of allergic asthmatic patients display a similar pattern of response (LAR or no LAR) to inhaled allergen in both the experimental and the environmental models of bronchial challenge.
The main differences between the two models are (i) the form of inhaled allergen (as a solution of allergen extract in ExBPT or as particles dispersed in the inhaled air in EnBPT), which also influences; (ii) deposition in the airways; and (iii) the time factor. The knowledge about the relationship between experimental and environmental allergen bronchial challenges is limited. Van Metre et al. (12) used a cat-exposure room to quantify the doses of cat allergen inhaled from ambient air required to induce a 20% fall in FEV1. They found that these doses correlated with the doses of cat extract required to induce a 20% fall in FEV1 in an experimental challenge model. However, the necessary doses were uniformly lower in the environmental challenge. Other studies have also reported that the doses required to induce symptoms during an environmental challenge were much lower when compared with those used in experimental challenge (17, 18). In an experimental challenge, a nebulized solution of allergen extract (drop size 2–5 μm) is inhaled during a short-time period and deposited mainly in smaller airways. Lieutier-Colas et al. (13) found that the allergen PD20 obtained using an aerosol with a particle size of 10.3 μm (mainly deposited in proximal airways) was much lower than with aerosols with particles sizes of 1.4 and 4.8 μm, respectively (mainly deposited in smaller airways). In an environmental challenge, inhaled cat allergen represents a wide range of particle size and is therefore deposited in different parts of the airways including the proximal airways and is inhaled continuously during a longer period of time (12). This may be the reason why a lower allergen dose could evoke EAR in the environmental challenge compared with standard experimental challenges where a nebulizer releases particles of 2–5 μm. In our study, larger allergen doses were also required to evoke an immediate fall in FEV1 in the experimental challenge compared with the environmental challenge. Earlier studies have shown that in average 25% of the airborne allergen content in houses with cats were small particles <5 μg (19). However, no particle size measurement was performed in our study.
The pollen seasons, for example birch, grass and ragweed seasons (20–22), are often used as a natural challenge model, while in perennial allergy environmental challenges are employed less often due to standardization problems, safety reasons and costs. Still, environmental challenge allows evaluation of both upper and lower airways and has been used in previous cat immunotherapy studies (23–25), as well as in other studies using a cat-exposure model (26–28). It is desirable, however, that the airborne allergen content is measured to ensure levels high enough to induce symptoms and facilitate comparison of allergen levels between provocations.
Commonly an EAR is defined as a reduction in FEV1 of 20% following allergen challenge. In our study, patients in the experimental challenge inhaled relatively high doses of allergen and all developed an EAR (as this was inclusion criterion). In the environmental challenge the provocation was terminated after 3 h (for practical reasons) and only 60% of patients developed an EAR. Among 25/62 patients without EAR, nine developed a LAR. In 5/9 FEV1 decrease was close to 20% and we believe that extended exposure would probably lead to further FEV1 decrease. Our findings agree with results of an earlier study that showed an isolated LAR following a repeated low-dose allergen exposure (29). This is of clinical importance as the allergic individual may not always be aware of allergen exposure before onset of symptoms.
A LAR is usually defined as a fall in FEV1 starting about 3–4 h and peaking after 6–12 h following allergen challenge. In both challenge models the median value for the time of maximal FEV1 decrease was 9 h. In a few patients the maximal FEV1 fall occurred between 12 and 24 h after the challenge. Nocturnal asthma and morning FEV1 dips following a single allergen exposure have been previously reported (30). We therefore recommend that the recording of FEV1 changes should be extended to at least 24 h.
There are few previous studies examining the development of a LAR following bronchial challenge with cat allergen. Mosimann et al. (31) found a LAR in eight of 21 patients (38%) after ExBPT with cat allergen and in another study Rohatgi et al. (32) demonstrated a LAR in four of seven patients (57%). In a much larger population of cat allergic asthmatics we have found a LAR following allergen challenge in about 50% of the patients in both ExBPT and EnBPT.
In 22 patients who developed a LAR in one challenge model, but not in the other, the data of some showed FEV1 decreases close defined arbitrary cut-off point of 15%. As a consequence, patients below this cut-off point were excluded from the evaluation. In reality, there is probably a little difference between patients around the cut-off point. It is possible that a few more patients would have developed a LAR if exposed to higher doses of allergen. A number of studies in the literature indicate this possibility (33, 34).
The allergen-specific and nonspecific bronchial hyper-responsiveness seem to be the main factors behind the development of a LAR in our study, while SPT and allergen-specific IgE-levels are of less importance. It should however be emphasized that only patients with a rather high degree of allergen sensitivity (SPT and levels of specific IgE in serum) were included in the study.
In conclusion, an environmental allergen challenge is closer to the natural allergen exposure compared with allergen challenge in laboratory. It is however, difficult to perform, time consuming and requires special safety proceedings. Still, while consistency between both challenge methods is not complete our study indicates that an experimental challenge reflects reasonably well the allergen response in environmental conditions.