Comparison of nasal immunohistology in patients with seasonal rhinoconjunctivitis treated with topical steroids or specific allergen immunotherapy

BACKGROUND: Specific allergen immunotherapy (SIT) and nasal steroids (NS) are considered effective anti-inflammatory treatments for allergic rhinitis, although their mechanism of action differs. OBJECTIVE: The aim of this study was to examine the effect of treatment with NS and SIT on different populations of inflammatory cells in the nasal mucosa and to compare cell numbers before and during the birch pollen season in patients with seasonal allergic rhinitis. METHODS: In a randomized, double-blind, double dummy comparative study, 41 patients with seasonal rhinoconjunctivitis were treated with birch SIT or NS (budesonide 400 microg daily). Treatment with NS started before the birch pollen season and at the same time SIT-treated patients reached the maintenance dose. Nasal biopsies for immunohistochemistry were obtained before the season and start of the treatments and at the peak of the pollen season during treatment. RESULTS: Symptoms of rhinoconjunctivitis increased significantly in both groups during the pollen season but less in the NS-treated group and the difference between the treatment groups was significant at the end of the season (P = 0.03). Immunohistochemistry of nasal biopsies from NS-treated patients showed significantly fewer CD1a+, IgE+ and Fc epsilonRI+ cells during the season compared with preseason (P = 0.02, P = 0.001 and P = 0.0004, respectively) and with seasonal values of the SIT-treated group (P = 0.002, P = 0.002 and P = 0.0004 respectively). CONCLUSION: Treatment with NS but not SIT decreased the numbers of CD1a+, IgE+ and Fc epsilonRI+ cells during the birch pollen season. Our data indicate that treatment with NS has a broader anti-inflammatory range than SIT.     

Allergen specific immunotherapy attenuates early and late phase reactions in lower airways of birch pollen asthmatic patients: a double blind placebo-controlled study

BACKGROUND: Few placebo-controlled studies have examined the effect of allergen specific immunotherapy (SIT) on early and late phase asthmatic reactions. In this placebo-controlled study we have investigated the effect of 1 year of SIT with standardized birch pollen extract on early and late phase asthmatic reactions in adult asthmatic patients. METHODS: Nineteen patients with a history of birch-pollen-induced seasonal symptoms from upper and lower airways, positive skin prick test and in vitro specific immunoglobulin E to birch pollen extract were included. Allergen and methacholine bronchial challenges were performed and blood samples obtained for analyses of total eosinophil count and eosinophil cationic protein (ECP) in serum, before and after 1 year of immunotherapy treatment. RESULTS: All patients developed early and 16 of 19 both early and late phase asthmatic reactions. A significant increase in allergen dose was required to evoke early asthmatic reaction in the immunotherapy group (P < 0.01) after 1 year of treatment. The difference between the groups was significant (P < 0.01). Also the size of late asthmatic reaction was significantly reduced in the SIT group compared with placebo treated patients (P < 0.01). Twenty-four hours after allergen challenge methacholine sensitivity, number of total eosinophils and ECP increased significantly in the placebo (P < 0.02, P < 0.05 and P < 0.05 respectively), but not in the SIT group. CONCLUSION: Allergen SIT with standardized birch pollen extract decreased early and late asthmatic responses following bronchial challenge in pollen allergic patients, thus confirming anti-inflammatory effect of the treatment.     

Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study

BACKGROUND: 3-year subcutaneous specific immunotherapy (SIT) in children with seasonal allergic rhinoconjunctivitis reduced the risk of developing asthma during treatment and 2 years after discontinuation of SIT (5-year follow-up) indicating long-term preventive effect of SIT. OBJECTIVE: We evaluated the long-term clinical effect and the preventive effect of developing asthma 7-years after termination of SIT. METHODS: One hundred and forty-seven subjects, aged 16-25 years with grass and/or birch pollen allergy was investigated 10 years after initiation of a 3-year course of SIT with standardized allergen extracts of grass and/or birch or no SIT respectively. Conjunctival provocations were performed outside the season and methacholine bronchial provocations were performed during the season and winter. Asthma was assessed by clinical evaluation. RESULTS: The significant improvements in rhinoconjunctivitis and conjunctival sensitivity persisted at the 10-year follow-up. Significantly less actively treated subjects had developed asthma at 10-year follow-up as evaluated by clinical symptoms [odds ratio 2.5 (1.1-5.9)]. Patients who developed asthma among controls were 24/53 and in the SIT group 16/64. The longitudinal treatment effect when adjusted for bronchial hyper-responsiveness and asthma status at baseline including all observations at 3, 5 and 10 years follow-up (children with or without asthma at baseline, n = 189; 511 observations) was statistically significant (P = 0.0075). The odds ratio for no-asthma was 4.6 95% CI (1.5-13.7) in favor of SIT. CONCLUSION: A 3-year course of SIT with standardized allergen extracts has shown long-term clinical effects and the potential of preventing development of asthma in children with allergic rhinoconjunctivitis up to 7 years after treatment. CLINICAL IMPLICATION: Specific immunotherapy has long-term clinical effects and the potential of preventing development of asthma in children with allergic rhino conjunctivitis up to 7 years after treatment termination.     

Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study)

BACKGROUND: Children with allergic rhinitis are likely to develop asthma. OBJECTIVE: The purpose of this investigation was to determine whether specific immunotherapy can prevent the development of asthma and reduce bronchial hyperresponsiveness in children with seasonal allergic rhinoconjunctivitis. METHODS: From 6 pediatric allergy centers, 205 children aged 6 to 14 years (mean age, 10.7 years) with grass and/or birch pollen allergy but without any other clinically important allergy were randomized either to receive specific immunotherapy for 3 years or to an open control group. All subjects had moderate to severe hay fever symptoms, but at inclusion none reported asthma with need of daily treatment. Symptomatic treatment was limited to loratadine, levocabastine, sodium cromoglycate, and nasal budesonide. Asthma was evaluated clinically and by peak flow. Methacholine bronchial provocation tests were carried out during the season(s) and during the winter. RESULTS: Before the start of immunotherapy, 20% of the children had mild asthma symptoms during the pollen season(s). Among those without asthma, the actively treated children had significantly fewer asthma symptoms after 3 years as evaluated by clinical diagnosis (odds ratio, 2.52; P <.05). Methacholine bronchial provocation test results improved significant in the active group (P <.05). CONCLUSION: Immunotherapy can reduce the development of asthma in children with seasonal rhinoconjunctivitis.     

Effects of immunotherapy on the inflammation in pollen asthma

Seasonal asthma is a natural model of airway inflammation where amount of airborne antigen have direct impact and correlates to the clinical disease and degree of inflammation. Bronchial hyperresponsiveness (BHR) is an indirect measure of the degree of airway inflammation and the seasonal increase paralleling clinical disease has been shown in a number of studies. Using a model of seasonal asthma in birch pollen sensitive individuals we intended to prove the anti-inflammatory potential of immunotherapy (IT). Forty birch pollen-allergic patients, 20 IT-treated and 20 untreated participated in a series of studies. BHR expressed as PCzo histamine increased in all patients during the season although most in untreated controls; the difference between the groups was p <0.07. The level of eosinophil cationic protein (ECP) rose in untreated, but not IT-treated, patients during the season (p <0.05). Significant increase in eosinophil chemotactic activity (ECA) in serum of untreated patients during the season was noted. IT-treatment abrogated this response. After 2 years of treatment bronchoalveolar lavage (BAL) was performed on 12 patients (6 in each group). IT-treatment prevented seasonal rise of eosinophil numbers in peripheral blood (PB) and the lung while in the untreated group the increase was significant in both compartments (p <0.05 and p<0.01, respectively). At the same timc, significant increment in ECP and ECA levels in BAL wcre rccordcd in untreated patients comparcd with IT-treated (p <0.05. p <0.01, respectively). It is concluded that IT proved its anti-inflammatory effect by diminishing degree of BHR, prcventing attraction. accumulation and activation of eosinophils in the lung of allergic I asthmatics.     

Grass pollen immunotherapy as an effective therapy for childhood seasonal allergic asthma

BACKGROUND: Few studies have investigated the use of specific immunotherapy (SIT) for childhood seasonal allergic asthma. OBJECTIVE: We sought to examine the efficacy and safety of SIT with Alutard SQ grass pollen (Phleum pratense Alutard SQ; ALK-Abelló, H?rsholm, Denmark) in children with seasonal allergic asthma. METHODS: A randomized, double-blind, placebo-controlled study assessing the efficacy of grass pollen SIT over 2 pollen seasons was performed. Children (3-16 years) with a history of seasonal allergic asthma sensitized to grass pollen (P pratense) and requiring at least 200 microg of inhaled beclomethasone equivalent per day were enrolled. Subjects with symptomatic asthma or rhinoconjunctivitis outside the grass pollen season were excluded. The primary outcome measure was a combined asthma symptom-medication score during the second pollen season. Secondary outcome measures included end-point titration skin prick testing and conjunctival and bronchial provocation testing to allergen, sputum eosinophilia, exhaled nitric oxide, and adverse events. RESULTS: Thirty-nine subjects were enrolled. Thirty-five subjects provided data for analysis. The use of SIT was associated with a substantial reduction in asthma symptom-medication score compared with that after placebo (P = .04). There were also significant reductions in cutaneous (P = .002), conjunctival (P = .02), and bronchial (P = .01) reactivity to allergen after SIT compared with that after placebo. The 2 groups had similar levels of airway inflammation, despite a trend toward less inhaled steroid use in the active group. No serious adverse events were reported, and no subjects withdrew because of adverse events. CONCLUSION: The study has shown that SIT is effective and well tolerated in children with seasonal allergic asthma to grass pollen.     

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.     

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.     

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.     

Combination of omalizumab and specific immunotherapy is superior to immunotherapy in patients with seasonal allergic rhinoconjunctivitis and co-morbid seasonal allergic asthma

Background The treatment of allergic asthma by specific immunotherapy (SIT) is hampered by potential side-effects.
Objective The aim of this study was to study the effect of omalizumab, a monoclonal anti-IgE antibody, in combination with SIT in patients with seasonal allergic rhinoconjunctivitis (SAR) and co-morbid seasonal allergic asthma (SAA) incompletely controlled by conventional pharmacotherapy.
Methods A randomized, double-blind, placebo-controlled, multi-centre trial was performed to assess the efficacy and safety of omalizumab (Xolair^®) vs. placebo in combination with depigmented SIT (Depigoid^®) during the grass pollen season. Omalizumab or placebo was started 2 weeks before SIT; the whole treatment lasted 18 weeks. Primary endpoint was daily 'symptom load', the sum of daily scores for symptom severity and rescue medication use.
Results A total of 140 patients (age 11–46 years) were randomized; and a total of 130 finished the study. Combination therapy reduced the symptom load by 39% ( P =0.0464, Wilcoxon test) over SIT monotherapy. This difference was mainly due to reduced symptom severity ( P =0.0044), while rescue medication use did not change significantly. Combination therapy also improved asthma control (Asthma Control Questionnaire, P =0.0295) and quality of life in the case of asthma (Asthma Quality of Life Questionnaire, P =0.0293) and rhinoconjunctivitis (Rhinoconjunctivitis Quality of Life Questionnaire, P =0.0537). Numbers of patients with 'excellent or good' treatment efficacy according to ratings of investigators (75.0% vs. 36.9%) or patients (78.5% vs. 46.1%) were markedly higher in the combination group than under SIT alone.
Conclusion Combination of omalizumab with SIT for treatment of patients with SAR and co-morbid SAA was safe and reduced the symptom load in a statistically significant and clinically meaningful manner.     

Non-specific airway hyperresponsiveness in mono-sensitive Sicilian patients with allergic rhinitis. Its relationship to total serum IgE levels and blood eosinophils during and out of the pollen season

Background Initial attempts to evaluate the association between allergic rhinitis and nonspecific bronchial responsiveness has produced conflicting results. In fact, some studies showed a strong correlation and other failed to find an association. However, little is known about the effect of natural specific allergen exposure on the bronchial reactivity of mono-sensitive patients with rhinitis in the southern Mediterranean area, in relation to skin reactivity to allergens, total serum IgE levels and blood eosinophiis. Objectives The significance of the association between allergic rhinitis, and abnormal airway responsiveness with regard to the pathogenesis of asthma is unclear. For this reason, we have studied non-specific bronchiai hyperreactivity. in patients with seasonal allergic rhinitis, with reference to the responsible allergen. The aim of the study was to correlate the responsiveness to bronchoprovocation with methacholine in subjects a with allergic rhinitis during and out of the pollen season with total serum IgE and blood eosinophils. Methods Fourty-nine non-smoking patients with clinical diagnosis of allergic rhinitis and mono-sensitive skinprick tests to pollen allergens were enrolled in the study. Twenty patients suffered from seasonal rhinitis to Parietaria pollen. 15 patients to Gramineae pollen and 14 patients to Olea pollen. In all patients lung function measurements (assessed as response to methacholine). tolal serum IgE and blood eosinophii counts were measured during and out of the pollen season. Results During pollen season. 16 out of 49 rhinitis patients demonstrated values of bronchial responsiveness measured as response to inhaled metbacholine in the asthmatic range whereas out of the pollen season only eight patients were in the asthmatic range. By analysing the results with reference to the responsible allergen, during the pollen season 5 out of 16 patients were Parietaria -sensitive and out of the pollen season seven out of eight patients. Finally, in Parietaria -sensitive rhinitis bronchial responsiveness signifi-cantly correlated, during and out of the pollen season, with total serum IgE and with blood eosinophil counts. Conclusions Our results are consistent with the hypothesis that Parietaria is more important than Olea and Gramineae as a risk for developing non- specific bronchial hyperresponsiveness. On the whole, present observations provide further evidence that there is an interrelationship of allergen kind, total serum IgE. eosinophil and bronchial hyperressponsiveness suggesting that they may play a role in the development of bronchial asthma in rhinitis patients.     

Asthma, bronchial hyperreactivity and mediator release in children with birch pollinosis. ECP and EPX levels are not related to bronchial hyperreactivity

Background Symptoms of allergic asthma are triggered by allergen exposure inducing allergic inflammation and hyperreactivity of the bronchi. Objectives To investigate the possible relationship between clinical symptoms and signs of asthma, i.e. bronchial variability as measured by peak expiatory flow rate (PEFR). bronchial hyperreactivity (BHR) and mediators of allergic inflammation. Methods Twenty-eight children with pollinosis. but no obvious history of asthma, were studied at three occasions, i.e. before, during and after (autumn) the birch pollen season. Twelve children sensitive to birch pollen were considered as the case group. Sixteen children, who were only clinically sensitive to grass pollen, served as controls. Subjective symptoms of asthma were recorded by visual analogue scale, BHR was estimated by methacholine bronchial provocation tests, bronchial variability PEFR and circulating mediators of inflammation, i.e. eosinophil cationic protein, eosinophil protein X, myeloperoxidase and tryptase in serum. Results Bronchial hyperreactivity and by PEFR was more pronounced after than during the season (P < 0.01), whereas eosinophil mediators and the peak expiratory flow rate increased during the season (P < 0.05). Except for between PEFR variability and BHR in the autumn (r= 0.45; P= 0.014). no correlations were found. However, in the autumn, the majority of children were still hyperreactive in the bronchi and showed PEFR variability but the levels of eosinophil mediators in serum had returned to normal levels. Conclusion Signs and symptoms of asthma did not correlate with serum levels of mediators of allergic inflammation. Bronchial hyperreactivity and PEFR variability persisted after the pollen season when signs of bronchial inflammation had disappeared. We hypothesize that eosinophil mediators and other markers of allergic inflammation disappear after the late-phase reaction, whereas BHR persists. This would explain the lack of correlation between the levels of eosinophil mediators in serum and symptoms of asthma and BHR.     

PI3-Kinase Regulates Eosinophil and Neutrophil Degranulation in Patients with Allergic Rhinitis and Allergic Asthma Irrespective of Allergen Challenge Model

The PI3K pathway plays a major role in many vital cell processes. Our primary aim was to investigate signalling through PI3K for in vitro degranulation from allergen-primed eosinophils and neutrophils in allergic rhinitis and allergic asthma after seasonal and experimental allergen challenge. Nine patients with allergic rhinitis, eight with allergic asthma and four controls were studied during birch pollen season and after nasal and bronchial allergen challenge. Primed blood eosinophils and neutrophils were stimulated for in vitro degranulation with C3b-coated Sephadex particles, after prior incubation with Wortmannin, a PI3K inhibitor. The released amounts of eosinophil cationic protein (ECP), eosinophil peroxidase (EPO) and myeloperoxidase (MPO) were measured by radioimmunoassay. Wortmannin (10⁻⁶ to 10⁻⁹ M) inhibited ECP, EPO and MPO release in a dose-dependent manner in allergic rhinitis and allergic asthma in all three allergen challenge models. Inhibition of ECP release tended to be lower in the asthmatics in all allergen challenge models, statistically significant compared to the controls during season for 10⁻⁸ M Wortmannin (p = 0.01). A clear propensity towards less inhibition in the rhinitic patients was seen after nasal and bronchial challenge compared to seasonal exposure, significant for ECP (10⁻⁸ M Wortmannin; p = 0.034 and 0.002, respectively). Signalling through PI3K is clearly involved in ECP, EPO and MPO release in allergic rhinitis and allergic asthma irrespective of allergen challenge model. Allergic asthma demonstrated less inhibition of ECP release via PI3K during pollen season, indicating that other pathways play a greater role in eosinophil degranulation in allergic asthma than allergic rhinitis.     

The effect of immunotherapy on eosinophil accumulation and production of eosinophil chemotactic activity in the lung of subjects with asthma during natural pollen exposure

Two groups of birch pollen--allergic patients with seasonal rhinoconjunctivitis and asthma were followed during two consecutive birch-pollen seasons, one group, N = 10, during a season with high pollen load, and one group, N = 15, during a season of low pollen load. Half the patients were treated with immunotherapy (IT) for 3 and 4 years, respectively. The other half of the patients served as control group (non-IT). Bronchoalveolar lavage (BAL) was performed once before each season and once during the pollen season. Eosinophil (EOS) numbers in BAL were increased (p less than 0.01) during the season with high pollen load but not in the season with a low pollen load, and this increment was absent in the IT-treated group. Also, the EOS cationic protein levels were raised in the non-IT-treated group during the season with a high pollen load. The levels of EOS and neutrophil chemotactic activity were raised in BAL in both seasons in the non-IT-treated group compared with the IT-treated group (p less than 0.02, p less than 0.003, p less than 0.04, and p less than 0.005 in high- and low-load pollen season, respectively). Serum and BAL eosinophil chemotactic activity (ECA) were positively correlated (p less than 0.001). We conclude that there is an influx of active EOSs into the lung of pollen-allergic patients with asthma during a pollen season, which may be abrogated by IT. Furthermore, the generation of ECA appears to be an extremely sensitive marker of antigenic exposure, and the potent inhibition of the generation of ECA by IT may provide a clue as to the mechanism of this treatment.     

Effect of specific immunotherapy with house dust mite extract on the bronchial responsiveness of paediatric asthma patients

BACKGROUND AND OBJECTIVE: Allergic asthma is common in children, and house dust mite (HDM) is an important source of perennial allergens. Bronchial hyperresponsiveness is a functional hallmark of asthma. Specific immunotherapy (SIT) with HDM extracts were shown to decrease symptoms, but its effect on bronchial responsiveness, as measured by non-pharmacological challenges, has not been evaluated. METHODS: Twenty-six paediatric asthma patients allergic to HDM participated in this study. Fourteen patients received SIT with a HDM extract (Alavac, Bencard) for 2 years, and 12 served as controls. Bronchial responsiveness was assessed non-pharmacologically by cold dry air challenge (CACh) before and 3, 6, 12 and 24 months after SIT, and 12 months after termination of SIT. RESULTS: After 24 months, the SIT group showed a statistically significant reduction of the mean CACh-induced changes of both forced expiratory volume in one second (-21.8+/-2.7% vs. -13.7+/-2.4%; P = 0.03) and maximal expiratory flow at 25% remaining vital capacity (-48.9+/-4.9% vs. -27.9+/-6.2%; P = 0.01). In contrast, no significant changes of bronchial responsiveness were observed in the control group. In the SIT group more patients lost their bronchial hyperresponsiveness than in the control group (6/14 vs. 1/12; P<0.05). One year after terminating SIT, the treatment group showed a tendency towards returning bronchial hyperresponsiveness. CONCLUSION: These results demonstrate that during 2 years of SIT there was a reduction of bronchial hyperresponsiveness in HDM-allergic paediatric asthma patients.     

Cysteinyl-leukotriene levels in sputum differentiate asthma from rhinitis patients with or without bronchial hyperresponsiveness

BACKGROUND: We have previously reported that asthma differs from rhinitis with or without bronchial hyperresponsiveness in the perception and degree of lower airway inflammation. OBJECTIVE: The aim of the present study was to investigate whether sputum levels of inflammatory markers could further distinguish these patient groups. METHODS: Patients with seasonal allergic rhinitis with or without asthma or bronchial hyperresponsiveness to methacholine were investigated. Induced sputum was performed during as well as off season, and analysed for cysteinyl-leukotrienes, hyaluronan, eosinophilic cationic protein (ECP) and other inflammatory markers. RESULTS: Asthmatic patients differentiated from those with rhinitis with or without bronchial hyperresponsiveness in levels of cysteinyl-leukotrienes [geometric mean: 3.3 (lower 95%-upper 95% confidence interval (CI) of geometric mean: 1.9-5.1) vs. 1.4 (0.9-2.2) and 0.7 (0.3-1.6) pg/microg total protein] and hyaluronan [0.30 (0.22-0.43) vs. 0.15 (0.10-0.20) and 0.20 (0.12-0.35) ng/microg total protein] in sputum. The levels of cysteinyl-leukotrienes decreased in sputum from the asthmatic patients, while the levels of hyaluronan remained elevated off-season. Furthermore, elevated levels of ECP were noticed among both the asthmatic and rhinitis patients with hyperresponsiveness compared with controls [0.022 (0.014-0.033) and 0.015 (0.011-0.021) compared with 0.010 (0.007-0.014) ng/microg total protein]. The level of ECP remained elevated off season. CONCLUSION: Cysteinyl-leukotrienes are possibly more related to mast cell-mediated inflammation and remodelling, also indicated by increased levels of hyaluronan during and off season. This inflammation may be partly different from the eosinophil-driven inflammation.     

The effect of immunotherapy on nonspecific bronchial hyperresponsiveness in bronchial asthma and allergic rhinitis

Allergen injection therapy may improve nonallergic bronchial hyperresponsiveness, but results at the moment are less than convincing. The present study was conducted to evaluate the effect of immunotherapy on the degree of nonspecific bronchial hyperresponsiveness in patients with allergic bronchial asthma (BA) and/or allergic rhinitis (AR). Methacholine challenge bronchial provocation test, allergic skin test, serum IgE and peripheral blood eosinophil counts were performed before and after 12 months or more of immunotherapy. The improved group, as determined by a shift of at least two doubling concentrations of methacholine, was 75% of AR (n=16), 41.7% of BA (n=24) and 53.8% of BA+ AR (n=13). The geometric mean of the methacholine provocational concentration (PC20) changed from 3.40 to 14.36 mg/ml (P <0.05) in AR, from 0.73 to 1.04 mg/ml in BA (not significant), and from 1.43 to 5.07 mg/ml (P <0.05) in BA+ AR. In conclusion, nonspecific bronchial hyperresponsiveness was improved by immunotherapy in three quarters of the allergic rhinitis cases and in about a half of the allergic bronchial asthma patients, which suggests that immunotherapy might be helpful at preventing the development of bronchial hyperresponsiveness in allergic rhinitis patients, and that it does not improve bronchial hyperresponsiveness in about a half of allergic bronchial asthma patients.     

Eosinophils in asthma.

Eosinophils, a prominent feature of asthma, are found in increased numbers in the circulation and sputum, usually in relation to the severity of asthma. As a consequence of these clinical observations, investigators now speculate that the eosinophil has a central role in the pathogenesis of asthma. Recent evidence has begun to confirm these speculations. The allergic reaction of the airway to antigen and the development of the late asthmatic reaction have provided a clinical model to study asthma and the contribution of eosinophils to bronchial reactivity. In the late asthmatic reaction, airway eosinophilia occurs. Through a series of independent observations, the following eosinophil-related events have been noted with the development of late asthmatic reactions. With either laboratory or natural exposure to antigen, eosinophilic chemotactic factors are released. Although the sources of eosinophil chemotaxis are multicellular, this is an early step in the attraction of eosinophils to the airway. As this process is initiated, a series of events occurs to cause eosinophils to arrive in the airway and promote obstruction, injury, and bronchial hyperresponsiveness. These steps include eosinophil migration through the vascular endothelium, upregulation of eosinophils (characterized by a change in cell density), adhesion of eosinophils to airway epithelium, and release of eosinophil toxic products. This presentation will review some of the eosinophil-dependent factors that can cause asthma. Furthermore, the eosinophil may be a good target for future therapeutic interventions.     

Cc-chemokine eotaxin as a marker of efficacy of specific immunotherapy in patients with intermittent IgE-mediated allergic rhinoconjunctivitis

BACKGROUND: Allergen-specific immunotherapy (SIT) is believed to be a valuable remedy in several allergic diseases; however, an accurate immunological marker of the efficacy of this treatment method has not been found yet. Cc-chemokine eotaxin, owing to its selective action on eosinophils, seems to play an important role in the pathophysiology of allergic response. The purpose of this study was to assess the usefulness of eotaxin in monitoring of SIT efficacy in patients with IgE-mediated allergic rhinoconjunctivitis. METHODS: One hundred and twenty-two patients with seasonal IgE-mediated allergic rhinoconjunctivitis due to tree- (birch, n = 42; hazel/alder, n = 14) or grass/cereal- (n = 66) pollen received allergen-specific immunotherapy.Serum eotaxin levels were determined four times in every patient, shortly before immunotherapy (Evaluation 0), immediately after the treatment (Evaluation 1), in the height of pollen season (Evaluation 2) and at least 2 weeks after the pollen season (Evaluation 3). Serum eotaxin levels were simultaneously measured in 59 healthy people from the control group. Changes in serum eotaxin levels were assessed in the healthy and allergic groups. Clinical symptoms of IgE-mediated rhinoconjunctivitis were evaluated and compared with serum eotaxin concentration changes. RESULTS: Mean values of eotaxin concentrations in serum during Evaluations 0-3 did not significantly differ in the healthy subjects and the patients with IgE-mediated rhinoconjunctivitis (P > 0.05). Moreover, no statistically significant differences in the serum eotaxin levels between the visits were observed in the patients who received immunotherapy (P > 0.05); however, immediately after immunotherapy (Evaluation 1) the mean serum level of eotaxin was lowest and closest to the serum eotaxin concentration in the control group at the same visit. No significant correlation between the mean value of the serum eotaxin level in the height of pollen season (r = -0.12, P > 0.05) or mean changes of the eotaxin levels between Evaluations 2 and 1 (r = -0.03, P > 0.05), on the one hand, and the cumulative score of symptoms and drug, on the other, were found. CONCLUSIONS: The results allow to conclude that although eotaxin plays a significant role in the mechanism of antigen-specific immunotherapy, its serum expression remains a poor marker of SIT efficacy.     

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.