A double-blinded, comparative study of the effects of short preseason specific immunotherapy and topical steroids in patients with allergic rhinoconjunctivitis and asthma

BACKGROUND: Both specific immunotherapy (SIT) and nasal steroid (NS) have been shown to effectively reduce symptoms of allergic rhinitis. Although a number of investigators have convincingly shown anti-inflammatory effects of both treatments in separate studies, few comparative studies have been performed. OBJECTIVE: The purpose of this study was to compare the effects of preseason SIT with a standardized allergen extract and NS in seasonal allergic disease (rhinoconjunctivitis and asthma). METHODS: We examined 41 patients allergic to birch pollen, 21 with rhinoconjunctivitis and 20 with both rhinoconjunctivitis and asthma; they were treated in a randomized, double-blinded comparative study with birch SIT and NS (budesonide 400 microg daily). Bronchial hyperresponsiveness was measured before and during the season. Changes in eosinophil number, eosinophil cationic protein, and eosinophil chemotactic activity (ECA) in peripheral blood were investigated. RESULTS: Symptoms of rhinoconjunctivitis increased significantly less in the NS-treated patients than in the SIT-treated patients during the final 2 weeks of the season (P = .03 and P = .04, respectively). Seasonal peak expiratory flow values decreased significantly only in the NS-treated patients (P = .01). In the NS-treated patients, bronchial hyperresponsiveness increased significantly during the season (P = .0001); however, SIT treatment prevented seasonal PC(20) increase in the asthmatic patients. Measurement of blood eosinophils, eosinophil cationic protein, and eosinophil chemotactic activity demonstrated significant seasonal increase only in the NS-treated asthmatic patients. CONCLUSION: Treatment with NS was more effective than short-course preseason SIT in reducing symptoms of rhinoconjunctivitis; however, the 2 therapies were equivalent in terms of the need for rescue medication. SIT prevented seasonal increase in bronchial hyperresponsiveness, eosinophil number, eosinophil cationic protein, and eosinophil chemotactic activity only in asthmatic patients. The mechanisms underlying bronchial hyperresponsiveness developing during allergen exposure in rhinitis might be different from those operating in asthma.     

A comparison of the effects of oral cetirizine and inhaled beclomethasone on early and late asthmatic responses to allergen and the associated increase in airways hyperresponsiveness

Background Cetirizine is a non-sedating H₁ antihistamine which is effective in the treatment of allergic rhinitis and urticaria. It inhibits eosinophil and basophil chemotaxis in late cutaneous allergic reactions in skin windows. Its effect on early (EAR) and late asthmatic reactions (LAR) is less certain. Methods We examined the effect on EAR and LAR of 3 days treatment with oral cetirizine (15mg twice daily) compared with a single dose of inhaled beclomethasone 10min prior to allergen challenge in a placebo-controlled (oral and inhaled) doubleblind cross-over design with three treatment arms separated by 14 days. Results Cetirizine did not significantly inhibit either the EAR or LAR documented by maximum percentage fall in FEV₁ (0-3 and 6-9h) or as area under the curve (AUC between 0 and 3 and 6–9 h), Beclomethasone inhibited the LAR compared with placebo (P = 0.02) when expressed as AUC (6–9h). This did not quite reach statistical significance (P = 0.06) when expressed as maximal percentage late fall in FEV₁ between 6 and 9h. A greater than twofold increase in airways responsiveness to methacholine was observed 3h after challenge which was significantly reduced by beclomethasone compared with placebo (P < 0.02) and cetirizine (P < 0.05). The data suggest that oral cetirizine does not significantly inhibit either the EAR or LAR. Beclomethasone inhibited both the early increase in airways responsiveness and the subsequent LAR. Our study also confirms the view that early increases in airway responsiveness precede the late response and suggests that these associated events are not dissociable by the pharmacological treatments employed in this study.     

Five-year follow-up on the PAT study: specific immunotherapy and long-term prevention of asthma in children

BACKGROUND: A 3-year course of specific immunotherapy (SIT) in children with hay fever to grass and/or birch pollen significantly reduced the risk of developing asthma. To investigate the long-term preventive effect, we performed a follow up--2 years after termination of immunotherapy. METHODS: A total of 183 children, aged 6-14 years with grass and/or birch pollen allergy could be investigated 2 years after discontinuation of SIT or no treatment. Conjunctival provocation tests (CPTs) and methacholine bronchial provocation tests were carried out during the season and winter after 5 years. The development of asthma was assessed by clinical evaluation. RESULTS: The significant improvement in hay fever and CPT results observed after 3 years of SIT persisted at the 5-year follow-up. No difference in bronchial responsiveness to methacholine was found after 5 years because of spontaneous improvement during the follow-up period in the control patients. The immunotherapy-treated children had significantly less asthma after 5 years as evaluated by clinical symptoms [odds ratio 2.68 (1.3-5.7)] in favor of SIT for prevention of development of asthma and significantly less patients reported an increase in asthma scores (P < 0.01). CONCLUSION: Immunotherapy for 3 years with standardized allergen extracts of grass and/or birch shows long-term clinical effect and preventive effect on development of asthma in children with seasonal rhinoconjunctivitis.     

Clinical pharmacology of H1-antihistamines in the skin

BACKGROUND: Birch pollen is a common allergen in northern, central, and eastern Europe. Earlier studies of specific immunotherapy using birch pollen extract were not placebo-controlled or were only preseasonal. Long-term, placebo-controlled studies with subcutaneously administered standardized birch pollen extract are lacking. OBJECTIVE: The aim of this study was to evaluate the effect of immunotherapy with birch pollen extract on airway symptoms and use of medication in adult birch pollen-allergic patients in a double-blind, placebo-controlled trial. METHODS: Forty-nine patients with histories of birch pollen allergy from the upper and lower airways, positive skin prick test and conjunctival provocation test results, and in vitro specific IgE to birch pollen (Betula verrucosa ) extract were included. Immunotherapy with birch pollen extract was given during 2 consecutive years in a double-blind, randomized, placebo-controlled study. Clinical symptom scores from the upper and lower airways and use of rescue medication were registered throughout the pollen season. RESULTS: Forty-six patients reached the maintenance dose and were maintained on that dose during the 2-year study. The median symptom scores during the 1997 and 1998 seasons were 1.3 and 2.6, respectively, in the specific immunotherapy group and 2.1 and 4.3, respectively, in the placebo group. The differences between the groups were significant (P =.05 in 1997 and P =.005 in 1998). The placebo group used significantly more rescue medication during both seasons than the specific immunotherapy group (P =.004 for 1997 and P =.004 for 1998). CONCLUSION: Specific immunotherapy with birch pollen extract is an effective and safe treatment for reducing clinical allergy symptoms and medication use in birch pollen-allergic patients during the pollen season.     

Serum eosinophil cationic protein (ECP) as a marker of disease activity and treatment efficacy in seasonal asthma

This study was carried out to determine whether serum eosinophil cationic protein (ECP) represents a sensitive marker for disease activity in atopic asthmatic patients during the pollen season. The study, in double-blind fashion, was performed between February and June 1994. Two groups of 10 seasonal asthmatic patients randomly received two different treatments. The first group was treated with inhaled beclomethasone dipropionate (BDP) 500 μg bid; the second received a matched placebo (P). At the beginning and every month, blood samples for determination of ECP and eosinophil count were collected and lung function (FEV₁) and methacholine responsiveness (PD₂₀) were performed. Subjects recorded daily symptoms of asthma, salbutamol consumption, and peak expiratory flow (PEF) values. In the P group, all indices, except FEV₁, showed significant changes during the pollen season ( P < 0.001). In the BDP group, significant changes were detected for symptom score ( P < 0.01), salbutamol consumption ( P < 0.01), and eosinophil number ( P < 0.05). Between the two groups, significant differences for symptom score ( P < 0.001), salbutamol consumption ( P < 0.001), ECP levels ( P < 0.05), eosinophil count ( P < 0.02), PD₂₀ methacholine ( P < 0.02), and PEF values ( P < 0.01) were detected. Changes in serum ECP significantly correlated with changes in other parameters ( P < 0.001), except FEV₁. Our results provide evidence that serum ECP is a sensitive marker for monitoring of the disease activity in seasonal asthma. Furthermore, it may offer a useful tool for estimating treatment efficacy.     

Anti-T-cell strategies in the treatment of allergic disease

Specific allergen immunotherapy (SIT) has been shown to be effective in modulating allergic responses in diseases such as rhinitis and asthma. However, the ability of whole allergen to cross link mast cell bound IgE, resulting in release of mediators such as histamine, has limited the application of this therapy to carefully selected patients who have failed conventional pharmacotherapy. The use of peptide sequences corresponding to T cell epitopes of the allergen has been postulated as an alternative to SIT in which high molar doses of T cell epitope can be delivered over a shorter time period and with improved safety. Using peptides from the sequence of the major cat allergen, Fel d 1, we have demonstrated the ability to induce transient T cell activation, resulting in isolated late asthmatic reactions, which are followed by prolonged periods of allergen-specific hyporesponsiveness, both to peptide re-challenge and to cutaneous challenge with whole allergen. Thus, peptide therapy may prove safe and efficacious in the treatment of allergic diseases.     

Measurement of serum levels of eosinophil cationic protein to monitor patients with seasonal respiratory allergy induced by Parietaria pollen (treated and untreated with specific immunotherapy)

This trial studied the behavior of a marker of eosinophilicc inflammation, eosinophil cationic protein (ECP), in the peripheral blood of two groups of subjects with seasonal allergic respiratory symptoms (rhinitis and mild bronchial asthma) induced by pollen allergens of Parietaria judaica (P.j.) (One group treated and another untreated with specific immunotherapy [SIT], to determine what contribution these serial measurements might provide, in comparison with various other tools now available for pollinosis monitoring. In a previously randomized order, we selected 25 patients with monitoring. In a previously randomized order, we selected 25 patients with monosensitization to P.j. pollen allergens: among them, 12 had started SIT with a P.j. extract in autumn 1993. As a control group, 13 patients were untreated. All patients were studied with various tests at four different times: time I - November 1993; time II - February 1994; time III - end of May 1994; and lime IV - September 1994. Blood samples for determination of serum HOP were collected at each time. Methacholine challenge tests were performed at times I and III. A pollen count was also carried out. A statostocally significant difference ( P < 0.05) was observed in mean ECP levels at times I and II in SIT treated and untreated patients The interaction between groups and time was not significant. No statistically significant difference was found between PD₂₀ FEV₁ values at times I and III in either group. After I year of treatment, we did not find any effect of SIT on bronchial hyperresponsiveness or on ECP Serum values.     

Effect of seasonal exposure to pollen on specific bronchial sensitivity in allergic patients

Bronchial provocation tests with aerosol of birch extract were performed before and after pollen season in 11 sensitized subjects. Changes of metacholine bronchial responsiveness and serum-specific IgE level were also assessed. In five patients who did not take steroids to control their symptoms, both early and late asthmatic responses to inhaled allergen were enhanced after season, whereas IgE serum level, but not methacholine sensitivity, was significantly increased. In six patients who needed steroids, neither responses to allergen nor IgE serum level and methacholine sensitivity were significantly changed after season. For the whole group, the increase in immediate bronchial sensitivity to allergen was positively correlated with the increase in specific IgE antibodies. We conclude that seasonal exposure to pollen has, in sensitized patients, a priming effect on bronchial mucosa that may be blunted by steroid treatment. The increased production of specific IgE antibodies appears to be an important mechanism for this priming effect.     

Allergen-specific immunotherapy in birch- and grass-pollen-allergic rhinitis. II. Side-effects

BACKGROUND: Allergen-specific immunotherapy (IT) involves the risk of side-effects. Different side-effect profiles have been reported for different allergens, and it would be of great benefit to be able more precisely to predict patient- and allergen-related risk factors. METHODS: Fifty-two patients with rhinoconjunctivitis and allergy to birch as well as grass pollen participated in a 3-year IT study, with a baseline year followed by 2 years of treatment. During the first treatment year, the patients received double-blinded IT with either birch (Betula verrucosa) or grass (Phleum pratense) pollen extracts adsorbed to aluminum hydroxide. The following year, the other allergen extract was added. Assessment of systemic reactions (SRs) was performed, and related to patient pretreatment parameters such as seasonal symptoms and medication requirement, skin prick test (SPT), conjunctival provocation test (CPT), nasal provocation test (NPT), total and specific IgE, basophil histamine release (HR), eosinophil count (EOS), eosinophil cationic protein (ECP), and eosinophil protein X (EPX). RESULTS: In total, 44 and 47 patients started IT with birch- and grass-pollen extracts, respectively. All SRs occurred during the dose-increase phase. No life-threatening SRs were observed. There were a higher number of patients with SRs during IT with grass pollen than IT with birch pollen, 21 vs five patients (P<0.001), with SRs to 3.3% of grass-pollen injections compared to 0.7% of birch-pollen injections (P<0.0001). The SRs of birch-pollen IT were mild, consisting of rhinoconjunctivitis and oral-pharyngeal itching, whereas asthma and urticaria episodes were observed in the grass-pollen IT. No difference was found in sensitivity to birch and grass, when measured by SPT, CPT, NPT, specific IgE, or HR, and no difference was found in age, duration of allergic symptoms, prevalence of asthma, mean seasonal birch/grass symptom score, eye-drop use, or antihistamine or prednisolone intake between the group with and without subsequent SRs to IT. No difference was found in EOS, serum ECP, or EPX, between the group with and without subsequent SRs to IT. CONCLUSIONS: IT with grass-pollen extract seems to be associated with a higher number and more severe SRs than birch-pollen IT. Neither demographic data nor diagnostic tests of allergy such as specific IgE, HR, SPT, CPT, and NPT could identify the patients with subsequent SRs.     

Density of eosinophils reflects activity of disease in allergic asthmatic children

Background Low density eosinophils are more prominent in asthmatic patients compared with healthy subjects, LDH are metabolically more active and produce more tissue-injuring and spasmogenic proteins than normal cosinophils. Objective and methid With a method providing information about eosinophils of 12 different densities we were able to study eosinophil density characierislics in 24 young patients in detail with allergic asthma in a stable phase, and in 21 patients after a bronchial allergen challenge. Results Study of the eosinophil density profile of patients and healthy controls revealed two density populations. Patients had more low density eosinophils than controls. In the patients eosinophil density characteristics and in particular the number of low density eosinophils correlated strongly with both FEV₁% predicted (ρ=?0.66, P < 0.001) and REV₁/FVC (ρ=?0.47, P < 0.01) as well as with bronchial responsiveness to histamine (ρ=?0.68, P < 0.001) and house dust mite (ρ=?0.37, P < 0.05). Allergen induced bronchial reactions were associated with an increase in the number (P < 0.001) and percentage (P < 0.05) of low density eosinophils. A selective rise in the number of eosinophils collected from fractions with a low density accounted for the observed rise in the total number of eosinophils, Density changes did not differ between patients with an isolated early reaction and patients with both an early and a late reaction, nor was there a relation between the severity of the late reaction and the shift in eosinophil density. Conclusion In conclusion, peripheral blood eosinophil density characteristics and in particular numbers of low density eosinophils are closely related with indicators of the asthma severity under stable conditions. Allergen inhalation induces a further shift towards lower density suggesting additional activation of the eosinophils.     

Eosinophil chemotactic activity in allergic patients during the birch pollen season: the effect of immunotherapy

Recently, heat-labile eosinophil chemotactic activity (ECA) has been found in serum after challenge of allergic asthmatic patients. In this study, we investigated changes in ECA in 40 birch-allergic patients during the birch pollen season; 20 of them had been treated with immunotherapy of birch pollen extract before the season. ECA raised significantly (p less than 0.001) in the untreated birch pollen-allergic patients during the season. Immunotherapy completely abolished this activity.     

Late asthmatic responses induced by ragweed pollen allergen

Allergen inhalation tests with ragweed pollen extract were performed in 15 ragweed-allergic asthmatic subjects. Isolated early asthmatic responses were induced in 6 subjects, dual (early and late) responses in 8 subjects, and predominantly or isolated late responses in 1 subject. The frequency and magnitude of late asthmatic responses (LAR) indicate that they are important in the disease. LAR occurred in the more sensitive subjects; in general, these subjects required smaller doses of inhaled ragweed pollen extracts, exhibited larger skin test responses, and had higher serum levels of IgE antibodies to ragweed antigen E. Intradermal tests with ragweed pollen extract elicited early (wheal and flare) or dual (early followed by late) cutaneous allergic responses. With relatively large concentrations of injected ragweed allergen, dual responses could be elicited in virtually all subjects.     

The effect of anti-IgE treatment on in vitro leukotriene release in children with seasonal allergic rhinitis

BACKGROUND: Binding of allergens with IgE to the IgE receptors on mast cells and basophils results in the release of inflammatory mediators as sulfidoleukotrienes (SLTs), triggering allergic cascades that result in allergic symptoms, such as asthma and rhinitis. OBJECTIVE: We sought to investigate whether anti-IgE (Oma-lizumab), a humanized monoclonal anti-IgE antibody, in addition to specific immunotherapy (SIT) affects the leukotriene pathway. METHODS: Ninety-two children (age range, 6-17 years) with sensitization to birch and grass pollens and with seasonal allergic rhinitis were included in a phase III, placebo- controlled, multicenter clinical study. All subjects were randomized to one of 4 treatment groups. Two groups subcutaneously received birch SIT and 2 groups received grass SIT for at least 14 weeks before the start of the birch pollen season. After 12 weeks of SIT titration, placebo or anti-IgE was added for 24 weeks. The primary clinical efficacy variable was symptom load (ie, the sum of daily symptom severity score and rescue medication score during pollen season). Blood samples taken at baseline and at the end of study treatment after the grass pollen season were used for separation of leukocytes in this substudy. After in vitro stimulation of the blood cells with grass and birch pollen allergens, SLT release (LTC4, LTD4, and LTE4) was quantified by using the ELISA technique. RESULTS: Before the study treatment, SLT release to birch and grass pollen exposure did not differ significantly among the 4 groups. Under treatment with anti-IgE + SIT-grass (n = 23), a lower symptom load occurred during the pollen season compared to placebo + SIT-grass (n = 24, P =.012). The same applied to both groups receiving birch SIT (n = 23 and n = 22, respectively; P =.03). At the end of treatment, the combination of anti-IgE plus grass SIT, as well as anti-IgE plus birch SIT, resulted in significantly lower SLT release after stimulation with the corresponding allergen (416 ng/L [5th-95th percentile, 1-1168] and 207 ng/L [1-860 ng/L], respectively) compared with placebo plus SIT (2490 ng/L [384-6587 ng/L], P =.001; 2489 ng/L [1-5670 ng/L], P =.001). In addition, treatment with anti-IgE was also followed by significantly lower SLT releases to the allergens unrelated to SIT (grass SIT: 300 ng/L [1-2432 ng/L] in response to birch allergen; birch SIT: 1478 ng/L [1-4593 ng/L] in response to grass pollen) in comparison with placebo (grass SIT: 1850 ng/L [1-5499 ng/L], P =.001; birch SIT: 2792 ng/L [154-5839 ng/L], P =.04]. CONCLUSION: Anti-IgE therapy reduces leukotriene release of peripheral leukocytes stimulated with allergen in children with allergic rhinitis undergoing allergen immunotherapy independent of the type of SIT allergen used.     

Eosinophils, bronchial hyperreactivity and late-phase asthmatic reactions

We have measured airways reactivity (methacholine PC₂₀) and blood eosinophils in eleven asthmatics with allergen-induced late-phase reactions. Before challenge there was a significant (P<0.05) inverse correlation between blood eosinophils and the methacholine PC₂₀. After allergen inhalation eosinophil counts were significantly (P<0.01) elevated at 24 hr. These increases in blood eosinophil counts were not observed in patients who developed single early responses. The magnitude of the changes in eosinophil counts (24 hr minus pre-challenge values) also correlated with the baseline methacholine PC₂₀ (P<0.01) in the late-phase responders. These observations suggest that there may be a direct association between eosinophils and airway reactivity in subjects who develop late-phase asthmatic reactions.     

Twenty-four-hour time course of eosinophil granule proteins ECP and EPX during bronchial allergen challenges in serum of asthmatic children

To study in vivo monitoring variables for bronchial allergen challenges, we investigated the time course of the eosinophil granule proteins, eosinophil cationic protein (ECP) and eosinophil protein × (EPX) after allergen provocation in serum. Thirty-two asthmatic children sensitive to house-dust mites and six healthy young adult controls were challenged by bronchial allergen provocations with Dermatophagoides pteronyssinus and D. farinae. Blood samples were taken at regular intervals up to 24 h. Base-line concentrations of ECP ( P <0.004), EPX ( P <0.002), and eosinophils ( P <0.001) were found to be increased in asthmatic children, as compared with healthy controls. ECP and EPX concentrations showed a uniform pattern with two characteristic features: 1) a rapid increase for both mediators up to 30 min after provocation over base-line values ( P <0.0001 and P <0.001), followed by a rapid decrease nearly to base-line values in the next 30 min; and 2) a steady increase for ECP and EPX up to 10 h ( P <0.02 and P <0.01), and even higher levels at 24 h, after challenge ( P <0.002 and P <0.003). We conclude that although eosinophils are activated in asthmatic children after bronchial allergen challenge, ECP and EPX concentrations are not suitable monitoring variables. Base-line eosinophils seem to predict the occurrence of a late-phase asthmatic reaction after allergen provocation.     

Frequency and intensity of late asthmatic reactions after bronchial allergen challenge in asthma and rhinitis

The occurrence of late asthmatic reactions after bronchial allergen challenge was studied in 50 house dust mite allergic patients subdivided in three groups: one group had asthma without nasal symptoms, another group had rhinitis without pulmonary symptoms and a third group had a combination of both asthma and rhinitis. Late asthmatic reactions were present in 80% of asthmatic patients and in 18.7% of rhinitis patients. The degree of non-specific bronchial reactivity to histamine (provocative dose 15 or PD15 histamine) and the degree of immediate reactivity to allergen (PD15 house dust mite) did not differ significantly between patients with and without late asthmatic reactions. These findings suggest that an important difference between asthma and rhinitis is the lack of late asthmatic reactions in rhinitis patients, whereas the degree of immediate bronchial reactivity to the allergen is similar in asthma and rhinitis.     

Allergen-induced bronchial inflammation in house dust mite-allergic patients with or without asthma

BACKGROUND: It is presently unknown which factors determine the occurrence and persistence of asthma in house dust mite-allergic individuals. The level of allergen-specific IgE antibodies does not seem to be decisive for asthmatic symptoms. Moreover, levels of exposure to mite allergens do not seem to differ significantly between asthmatic and non-asthmatics individuals. AIM: It was hypothesized that the presence or absence of asthmatic symptoms in house dust mite-allergic patients is associated with quantitative or qualitative differences in the cellular bronchial inflammatory response during the late phase of the allergic reaction. This hypothesis was tested in the bronchial allergen challenge model. MATERIAL AND METHODS: Whole lung challenges with house dust mite extract were performed in 52 house dust mite-allergic subjects, of whom 26 had asthma and 26 had perennial rhinitis without asthmatic symptoms. Primary outcomes were parameters for bronchial inflammation in serial samples of induced sputum (cell differentials, eosinophil cationic protein (ECP), interleukin-8 (IL-8), myeloperoxydase (MPO)). In addition, lung function, non-specific bronchial hyper-responsiveness and serial blood samples (eosinophils and IL-5) were analysed. RESULTS: At baseline sputum eosinophils and ECP were similar in both groups but neutrophils and IL-8 were higher in asthmatics. The early bronchoconstriction after allergen challenge was similar in asthma and non-asthmatic rhinitis (median decrease in FEV1: asthma -31.7% vs. non-asthmatics -29.1%, P > 0.1). The late phase bronchoconstriction was significantly greater in asthma (median decrease in FEV1: asthma -27.6% vs. non-asthmatics -18.9%, P = 0.02). Induction of bronchial hyper-responsiveness was similar in both groups. Bronchial allergen challenge elicited significant increases in sputum eosinophils and ECP, which were indistinguishable for both groups (P > 0.1 and P = 0.07, respectively). In contrast, higher numbers of neutrophils persisted in asthma 24h after challenge and were accompanied by significant increases in IL-8 and MPO, which were absent in non-asthmatics (difference between groups P = 0.007 and P = 0.05, respectively). CONCLUSION: Allergen challenge inducedvery similar increases in eosinophils and ECP in induced sputum in allergic asthmatics and in allergic non-asthmatic patients. The difference in bronchial inflammation between asthma and non-asthmatic rhinitis appeared to be more closely related to indices for neutrophilic inflammation.     

Der p 1 and Der p 2 induce less severe late asthmatic responses than native Dermatophagoides pteronyssinus extract after a similar early asthmatic response

Background The models for exposure to house dust in research and clinical practice are selected with respect to their role in IgE‐mediated immediate hypersensitivity. The use of isolated major allergens instead of complex allergen extracts is becoming increasingly popular as it offers some important advantages for quantitative measures in diagnosis and research. Objective To compare house dust mite extract and isolated mite major allergens with respect to their ability to induce early and late asthmatic responses and bronchial hyperreactivity. Methods Bronchial responses to house dust mite (HDM, Dermatophagoides pteronyssinus) extract and isolated major allergens from HDM (Der p 1 and Der p 2) were compared in a double‐blind, randomized, cross‐over study in 20 patients with mild to moderate asthma who were allergic to HDM. Allergen was titrated to a standardized early asthmatic response. Bronchial hyper‐responsiveness to histamine (PC₂₀histamine) was determined before and after allergen inhalation to assess allergen‐induced bronchial hyper‐responsiveness and IL‐5 was measured in serum. In addition, the allergens were applied in intracutaneous skin tests and activation of basophil leucocytes and proliferation of peripheral blood mononuclear cells was tested in vitro. Results After a similar early asthmatic response (mean Δforced expiratory volume in 1 s (FEV₁)_,max?29.4 (SD 7.2) vs. ?33.1 (8.6) %; mean difference 3.6 (95% CI ?0.9 to 8.2) %), the late asthmatic response (mean ΔFEV_1,max?45.9 (21.9) vs. ?32.7 (22.3) %; mean difference 13.2 (3.8–22.3) %), the degree of allergen‐induced bronchial hyper‐responsiveness (mean ΔPC₂₀histamine, 1.8 (1.0) vs. 1.2 (0.9) doubling dose; mean difference 0.6 (0.2–1.1) doubling dose) and serum IL‐5 at 6 h were found to be significantly higher after bronchial challenge with HDM extract than after challenge with an isolated HDM major allergen. Likewise, there was an increased late skin reaction with HDM compared with isolated major allergen after a similar early skin reaction. Conclusion Constituents of HDM extract, other than Der p 1 or Der p 2, with no significant influence on the IgE‐mediated early asthmatic response contribute significantly to the allergen‐induced late asthmatic response and bronchial hyper‐reactivity.     

The safety and efficacy of subcutaneous birch pollen immunotherapy - a one-year, randomised, double-blind, placebo-controlled study

BACKGROUND: There is only very limited documentation of the efficacy and safety of high-dose subcutaneous birch pollen immunotherapy (IT) in double-blind, placebo-controlled (DBPC) studies. Birch pollen is a major cause of allergic morbidity in northern Europe and in eastern parts of North America. METHODS: Thirty-five patients with severe rhinoconjunctivitis (hay fever) to birch pollen were allocated to double-blinded clustered IT with a depot birch pollen extract (Betula verrucosa) or placebo injections. Seven patients in each group had concomitant self-reported seasonal asthma. Treatment was conducted as a clustered regimen and was performed in a specialist unit. Symptom scores from nose, eyes, and lungs, and use of oral and topical antihistamines, beta-2-agonists, and oral corticosteroids were recorded daily during the season of 2000. Sensitivity to allergen provocation in skin, conjunctiva, and nasal mucosa was measured before and after 10 months of treatment. Post-seasonal assessment of symptom severity was performed using a simple questionnaire. RESULTS: IT reduced the symptom score for both rhinoconjunctivitis and asthma (P-values < 0.05), total medication score (P < 0.02) and use of oral antihistamines (P < 0.01). IT reduced specific conjunctival sensitivity (P < 0.05), skin prick test, and especially cutaneous late-phase response diameters (P < 0.00001), and increased general well-being on post-seasonal evaluation (P < 0.01). IT was safe, with side-effects at the same level as placebo. CONCLUSIONS: High-dose, subcutaneous IT is efficacious and safe in patients with severe birch pollen rhinoconjunctivitis and asthma.     

The effect of salmeterol on the early- and late-phase reaction to bronchial allergen and postchallenge variation in bronchial reactivity, blood eosinophils, serum eosinophil cationic protein, and serum eosinophil protein X

The late asthmatic response to bronchial allergen challenge and the associated increase in nonspecific bronchial reactivity provides a model for studying the acute inflammatory mechanisms in asthmatic airways. In 12 asthmatic patients (aged 22–37 years) with known dual reaction to allergen challenge, salmeterol 50 μg, 100 μg, or placebo was administered as a single dose 10 min before allergen challenge in a double-blind, randomized order on three different study days 2 weeks apart. The bronchial reactivity (BH) to histamine was measured the day before and 24 and 48 h after allergen challenge. Salmeterol significantly inhibited the early ( P <0.02) and the late ( P <0.05) asthmatic reactions. After placebo, mean BH was significantly increased above base line at 24 and 48 h ( P <0.02). After 50 and 100 μg salmeterol, BH was less than base line at 24 h and returned to prechallenge values at 48 h. Blood eosinophils increased significantly ( P <0.05) 24 and 48 h after allergen challenge, and no difference was found between treatments. After pretreatment with placebo, serum eosinophil cationic protein (s-ECP) and serum eosinophil protein X (s-EPX) increased significantly ( P <0.05) 24 and 48 h after allergen challenge. After treatment with salmeterol 50 μg, s-EPX, but not s-ECP, increased significantly 24 h after challenge, but was normal at 48 h. After salmeterol 100 μg, no change in s-EPX or s-ECP was found. The results showed that salmeterol eliminated the allergen-induced dual asthmatic reaction and gave protection against increased BH. Measurement of blood eosinophils, s-ECP, and s-EPX indicated that salmeterol may modify this inflammatory cell activity, because raised s-levels of ECP and EPX may be linked to eosinophil activation and granule secretion. In addition to inducing a long-lasting bronchodilation, salmeterol may influence acute inflammation.