Allergen Exposure In Subjects Research Articles

Increased specific immunoglobulin G4 antibodies induced by natural exposure to ambrosia pollen in patients with allergy.

Induction of specific immunoglobulin G4 (sIgG4) response (so-called blocking antibodies) in patients who receive specific immunotherapy (SIT) has been observed for many years. Although many other mechanisms have been identified as key regulators of immunologic processes in peripheral tolerance to allergens, the rise of sIgG4 during immunotherapy, together with the clinical improvement, is still believed to be one of the most important mechanisms through which SIT reaches its clinical efficacy. The aim of this prospective study was to measure levels of IgG4 and sIgE in subjects allergic to Ambrosia elatior pollen (common ragweed), before and during natural exposure to A. elatior pollen. Healthy controls were also included. Twenty-four patients with allergic diseases of the respiratory tract and 24 healthy controls entered the study. The sIgG4 and sIgE levels were measured by using the enzyme-linked immunosorbent assay method before and during A. elatior pollination season. A significant increase of the sIgG4 level in subjects with allergy during natural exposure to an allergen (0.676 increased to 0.937; p < 0.05) was shown. An increase in sIgE levels was also observed. Healthy subjects had comparable levels of sIgG4 as in subjects with allergy before the pollination season and no change in sIgG4 and sIgE levels during the pollination season. Increases of sIgG4 and sIgE levels were induced by natural allergen exposure in subjects with allergy but not in healthy individuals. This result support further reevaluation of the "blocking" antibodies concept as one concept responsible for allergen tolerance in patients who receive SIT.

Quantification of atopy, lung function and airway hypersensitivity in adults

BackgroundStudies in children have shown that concentration of specific serum IgE (sIgE) and size of skin tests to inhalant allergens better predict wheezing and reduced lung function than the information on presence or absence of atopy. However, very few studies in adults have investigated the relationship of quantitative atopy with lung function and airway hyperresponsiveness (AHR).ObjectiveTo determine the association between lung function and AHR and quantitative atopy in a large sample of adults from the UK.MethodsFEV1 and FVC (% predicted) were measured using spirometry and airway responsiveness by methacholine challenge (5-breath dosimeter protocol) in 983 subjects (random sample of 800 parents of children enrolled in a population-based birth cohort enriched with 183 patients with physician-diagnosed asthma). Atopic status was assessed by skin prick tests (SPT) and measurement of sIgE (common inhalant allergens). We also measured indoor allergen exposure in subjects' homes.ResultsSpirometry was completed by 792 subjects and 626 underwent methacholine challenge, with 100 (16.0%) having AHR (dose-response slope>25). Using sIgE as a continuous variable in a multiple linear regression analysis, we found that increasing levels of sIgE to mite, cat and dog were significantly associated with lower FEV1 (mite p = 0.001, cat p = 0.0001, dog p = 2.95 × 10-8). Similar findings were observed when using the size of wheal on skin testing as a continuous variable, with significantly poorer lung function with increasing skin test size (mite p = 8.23 × 10-8, cat p = 3.93 × 10-10, dog p = 3.03 × 10-15, grass p = 2.95 × 10-9). The association between quantitative atopy with lung function and AHR remained unchanged when we repeated the analyses amongst subjects defined as sensitised using standard definitions (sIgE>0.35 kUa/l, SPT-3 mm>negative control).ConclusionsIn the studied population, lung function decreased and AHR increased with increasing sIgE levels or SPT wheal diameter to inhalant allergens, suggesting that atopy may not be a dichotomous outcome influencing lung function and AHR.

Montelukast as Add-on Therapy to β-Agonists and Late Airway Response

Rosewich M, Rose MA, Eickmeier O, Travaci M, Kitz R, Zielen S. Eur Respir J. 2007;30(1):56–61 PURPOSE OF THE STUDY. To evaluate montelukast's ability to inhibit the late-phase airway response after allergen exposure in adults with house dust mite–induced asthma. STUDY POPULATION. Thirty-five adults (19 men, 16 women) aged 18 to 31 with mild, stable asthma and sensitivity to house dust mites were included. METHODS. This study was designed as a randomized, double-blind, single-dose, placebo-controlled, crossover trial. Subjects underwent serum testing for antigen-specific immunoglobulin E (IgE) to house dust mite. Sensitized subjects were then examined for airway infections and underwent spirometry and determination of their fraction of nitric oxide in exhaled air (FeNO). They were then challenged with increasing concentrations of inhaled Dermatophagoides farinae via a nebulizer system. Testing was stopped when the patient's forced expiratory volume in 1 second (FEV1) decreased at least 20% (early airway response [EAR]), they experienced significant clinical symptoms, or they received a cumulative dose of 1270 mg. Patients were then given 1 puff of salbutamol (0.1 mg) and either montelukast (10 mg) or a placebo. FEV1 was measured for the following 8 hours with a decrease of at least 20% demonstrating a late airway response (LAR). Formoterol (12 μg) was then given to treat those patients. Subjects returned at least 2 weeks later and were crossed-over into the other group. RESULTS. Of the 35 subjects in the study, 12 showed no significant EAR on 1 or both study days, 11 showed only an EAR, and 12 demonstrated both an EAR and LAR. This last group was analyzed further. The difference in FEV1 from baseline values 3 to 8 hours after challenge was expressed as the area under the FEV1 time-response curve (FEV1-AUC). The FEV1-AUC of patients on placebo was −2.47 ± 1.32 vs −0.768 ± 1.68 for the patients on montelukast (P &amp;lt; .005). Subjects with a dual response had a significantly higher baseline FeNO than those with no response (56.4 vs 21.0 ppb; P &amp;lt; .05). CONCLUSIONS. Montelukast was able to block the late-phase airway response in subjects who responded dually to the allergen challenge. In addition, patients with a higher baseline FeNO seemed more likely to develop an LAR than those with lower ones. REVIEWER COMMENTS. The results of this study implicate a role for montelukast as an “add-on,” therapeutic option for symptomatic relief after allergen exposure in subjects with mild asthma. It also suggests a rapid onset of action that allows for its usage in such a setting. This study supports existing ones that have demonstrated the effect of montelukast within 2 to 3 hours for up to 24 hours. There was also a “trend toward significance” showing subjects on montelukast with higher FEV1 values than those on placebo. However, this study was limited in its sample size and should be expanded to fully elicit montelukast's role in acute exacerbations. It would also be worthwhile to investigate its effects on subjects with moderate-to-severe asthma in the same setting. Last, this study also alluded to the fact that a patient's baseline FeNO may be a predictor of whether he or she develops an LAR. This should also be explored further in expanded studies and in children.

Small airways response to naturalistic cat allergen exposure in subjects with asthma

It is currently unclear whether the small airways (diameter <2 microm) contribute significantly to late asthmatic reactions to inhaled allergen. We sought to determine whether naturalistic exposure to cat allergen induced late responses in the small airways as measured by pulmonary function testing and high-resolution computed tomography (HRCT) of the chest performed at end-expiration. In a group of 10 subjects with cat-induced asthma, physiologic studies (spirometry and lung volumes, including closing volume) and HRCT were performed before and 6 and 23 hours after a cat room challenge that caused a 20% or greater acute fall in FEV(1). There was no significant decline in FEV(1) at 6 or 23 hours after cat exposure. Forced expiratory flow at 25% to 75% of forced vital capacity was significantly decreased at 6 hours after the challenge and returned to normal by 23 hours. HRCT image analysis as well as closing volume demonstrated increased air trapping from baseline at both 6 and 23 hours after the challenge. In addition, image analysis demonstrated a significant increase in small airways hyperresponsiveness to methacholine at 23 hours after the challenge. No significant mean changes were noted in lung volumes at either 6 or 23 hours or in PC(20) FEV(1) at 23 hours postchallenge. These findings demonstrate that naturalistic exposure to cat allergen results in significant small airways obstruction and hyperresponsiveness persisting for at least 23 hours, at which time these changes cannot be detected by conventional physiologic measures. Physiologically silent distal lung inflammation persists after an antigenic challenge.

Induction of nasal hyper‐responsiveness by allergen challenge in allergic rhinitis: the role of afferent and efferent nerves

Hyper-responsiveness of nasal secretory function and volume changes are features of allergic rhinitis (AR) that are mediated in part by neural mechanisms. The finding of nasal hyper-responsiveness in subjects with AR who are currently symptomatic, but not in those who are currently out of season and asymptomatic, suggests that induction of neural reflexes in allergic subjects occurs as a result of allergic inflammation. To investigate whether allergen exposure in subjects with asymptomatic seasonal allergic rhinitis (SAR) may lead to induction of neural reflexes, and to investigate the components of the reflexes involved in this induction. Asymptomatic subjects with (out-of-season) SAR underwent a nasal bradykinin challenge, before and 24 h after preceding ipsilateral (n = 11) and contralateral (n = 11) antigen challenge. Challenges were performed and nasal secretions collected using filter paper disks, and changes in nasal minimal cross-sectional area (A(min)) were measured using acoustic rhinometry. Preceding ipsilateral antigen challenge led to the induction of a contralateral secretory reflex (P = 0.01), which was absent in control experiments (P = 0.34). Ipsilateral secretion weights were also enhanced. Preceding contralateral antigen challenge also induced a contralateral secretory reflex (P = 0.03). Enhancement of the reduction in contralateral A(min) was also seen (P = 0.02). Ipsilateral responses were unchanged. Allergen exposure in asymptomatic allergic subjects leads to induction of neural reflexes, resulting in nasal hyper-responsiveness, which persists beyond the resolution of the acute allergic response. Our data suggest that the mechanisms of allergen-induced hyper-responsiveness involve both afferent and efferent components.

Oligoclonality of lung T lymphocytes following exposure to allergen in asthma.

We were interested in studying the lung allergen-specific T cell repertoire in different conditions of allergen exposure in subjects with atopic asthma. Twenty-one allergic individuals were studied: 17 subjects suffering mainly from asthma and 4 from rhinitis. They all performed spirometry and methacholine challenge. All patients were subjected to bronchoalveolar lavage (BAL), either at base line (no challenge) or after allergen or histamine challenge, and the TCR repertoire of their lung T cells was studied with heteroduplex analysis. Expansion of single T cell clones was observed in one (of seven) asthmatic subject that reported a recent exposure to allergen and had high bronchial hypersensitivity to methacholine, and in seven/seven asthmatic subjects who underwent BAL after they suffered an early asthmatic reaction to experimental allergen inhalation. Remarkably, ex vivo expanded clones included allergen-specific T cells. In two of the seven subjects who underwent BAL after allergen challenge, two different lung segments were lavaged. A strikingly symmetrical distribution of the expanded clones was found in these samples. Control subjects and six of seven asthmatic patients studied at base line showed polyclonality of lung T cells. In conclusion, T lymphocytes are clonally expanded in the lower respiratory tract only in asthmatic subjects exposed to allergen. These results suggest that in allergic asthma, the inhalation of sensitizing allergens can recruit to the lung T lymphocytes that include allergen-specific T cell clones.

Effect of inhaled frusemide on the early response to antigen and subsequent change in airway reactivity in atopic patients.

The purpose of this study was to investigate whether inhaled frusemide was able to inhibit the increase in nonspecific bronchial reactivity that occurs after the early response to allergen exposure in subjects with allergic rhinitis or asthma (or both). Ten symptom free patients initially underwent a challenge with methacholine, to determine the dose of methacholine that caused a 15% fall in FEV1 (PD15 FEV1 meth) and a challenge with a specific allergen, to determine the concentration of allergen that caused a fall in FEV1 of at least 15%. On two further occasions they inhaled allergen concentration that had caused the greater than or equal to 15% fall in FEV1 preceded by inhaled frusemide (40 mg frusemide in 4 ml buffered saline) or placebo (4 ml of diluent solution), according to a randomised, double blind, crossover design. All allergen studies were separated by at least seven days. A methacholine challenge was performed two hours after the allergen challenge, a time when the early response to allergen had completely resolved. Frusemide inhibited the early response to antigen, causing mean (95% confidence interval) protection of 87.6% (96-80%) for the maximum fall in FEV1. The increase in non-specific airway reactivity that occurred after antigen when this was preceded by placebo was reduced by frusemide. The mean (95% CI) difference in PD15 values between the placebo and the frusemide days was 1.73 (2.30-1.16) doubling doses of methacholine. These results confirm that frusemide is highly effective in preventing the early response to allergen, and show that it inhibits the increase in reactivity to methacholine that follows the early response.