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Background Methacholine challenge tests (MCTs) are used to diagnose airway hyperresponsiveness (AHR) in patients with suspected asthma where previous diagnostic testing has been inconclusive. The test is time consuming and usually requires referral to specialized centers. Simple methods to predict AHR could help determine which patients should be referred to MCTs, thus avoiding unnecessary testing. Here we investigated the potential use of baseline spirometry variables as surrogate markers for AHR in adults with suspected asthma. Methods Baseline spirometry and MCTs performed between 2013 and 2019 in a large tertiary center were retrospectively evaluated. Receiver-operating characteristic curves for the maximal expiratory flow-volume curve indices (angle β, FEV1, FVC, FEV1/FVC, FEF50%, FEF25–75%) were constructed to assess their overall accuracy in predicting AHR and optimal cutoff values were identified. Results A total of 2983 tests were analyzed in adults aged 18–40 years. In total, 14% of all MCTs were positive (PC20 ≤ 16 mg/ml). All baseline spirometry parameters were significantly lower in the positive group (p 50% showed the best overall accuracy (AUC = 0.688) and proved to be useful as a negative predictor when applying FEF50% ≥ 110% as a cutoff level. Conclusions This study highlights the role of FEF50% in predicting AHR in patients with suspected asthma. A value of ≥ 110% for baseline FEF50% could be used to exclude AHR and would lead to a substantial decrease in MCT referrals.

Background: Coexistence of asthma, rhinitis, and eczema has been studied in children, but data are lacking in adults. As new treatments emerge, epidemiological data on the coexistence are needed. Aims: To study the prevalence of concomitant asthma, rhinitis and eczema in the general adult population and among those sensitized to aeroallergens, and to study associations between background characteristics and risks of phenotypes of asthma, rhinitis, and eczema. Methods: In the West Sweden Asthma Study, phenotypes and sensitization profiles of 1103 randomly selected adults (16–75 years) were assessed. The methods included measures of serum-IgE and structured interviews on asthma, rhinitis, eczema, their associated symptoms, and relevant risk factors. Results: Among all participants and in those sensitized, 2% and 6% had concomitant asthma, rhinitis, and eczema, respectively, and the condition did not differ by age or sex. Corresponding figures for asthma and rhinitis, but not eczema, was 8% and 19%, respectively. Determinants of coexistence of the three conditions were family history of asthma/allergy, body mass index, and occupational exposure to gas, dust and fumes. Allergic sensitization in those with asthma, rhinitis and eczema was found in 78%, in those with asthma and rhinitis but not eczema in 65%, in those with asthma and eczema but not rhinitis in 40%, while only 5% were sensitized among those having asthma only. Conclusions: In the general adult population about 2% have concomitant asthma, rhinitis, and eczema. Of sensitized adults, about 6% has coexistence of the three conditions. publishedVersion

Background: The coexistence of asthma, rhinitis, and eczema has been studied in children, but data are lacking in adults. As new treatments emerge, epidemiological data on the coexistence of these conditions are needed. Aim: In a general adult population, we described the prevalence of concomitant asthma, rhinitis and eczema; compared prevalence between individuals sensitized and not sensitized to aeroallergens; and studied the risk factors for coexistence of the diseases. Methods: In the West Sweden Asthma Study, sensitization profile of 1103 randomly selected adults (16-75 years) was assessed with Phadiatop test. Participants answered clinical interviews on the presence of asthma, rhinitis and eczema. Results: In all study participants and in those with positive Phadiatop, 8% and 19% had concomitant asthma and rhinitis, but not eczema, respectively. Coexistence of the three conditions was 2% in all participants, but 6% in those with positive Phadiatop. Coexistence of the diseases did not differ by age or gender. Those with coexistence of asthma, rhinitis and eczema were most sensitized (78%), followed by those with asthma and rhinitis but not eczema (65%) and those with asthma and eczema but not rhinitis (40%), while those with asthma only had the least sensitization to aeroallergens (5%). Body mass index, exposure to gas, dust and fumes at work, and family history of asthma or allergy were associated with increased risk of coexistence of the three conditions. Conclusions: About 2% of adults have concomitant asthma, rhinitis, and eczema, and the proportion of allergic sensitization is high among them. Of sensitized adults, about 6% has coexistence of the three conditions.

Background Chronic cough is a common symptom and related to several pulmonary, airway and heart diseases . When all likely medical explanations for the coughing are excluded, there remains a large group of patients with chronic coughing, which is mostly a cough reflex easily triggered by environmental irritants and noxious stimuli. The main aim of this study was to improve the diagnostic ability to differentiate chronic idiopathic cough (CIC) from asthma. Methods Twenty-three patients with CIC, 16 patients with mild asthma and 21 control participants were included. The study consisted of three randomised bronchial provocations with osmotic stimuli: mannitol , eucapnic dry air and hypertonic saline. At each provocation lung function was assessed by spirometry and impulse oscillometry (IOS). Results In a comparison of the groups, while the FEV1 measurements did not differ, the CIC group had increased airway resistance and reactance after provocation with hypertonic saline compared to the control subjects. After mannitol provocation the patients with asthma had significantly increased airway resistance compared to the controls and from eucapnic dry air provocations these patients had a significant reduction in spirometry values and increased airway resistance compared to both the patients with CIC and the controls. Conclusion The asthma group reacted in a predictable way with impaired lung function from osmotic provocations, whereas the patients with CIC demonstrated peripheral airway changes from hypertonic saline, also known to be a noxious stimulus. The IOS method uncovers differences between patients with CIC and control participants that contribute to our ability to provide a correct diagnosis.

Summary Background Among patients with chronic unexplained cough, there is a recognized subgroup with respiratory symptoms induced by environmental irritants like chemicals and odours. The diagnosis of sensory hyperreactivity (SHR) has been suggested for this group of patients and can be made using a tidal breathing capsaicin inhalation test. The aim of the present study was to evaluate the ability of a single-breath, dose-response capsaicin threshold test to discriminate such patients from control subjects. Methods A total of 46 patients with chronic cough and SHR who had previously shown a positive reaction in accordance with limits set for a tidal breathing capsaicin test were tested once with a single-breath, dose-response capsaicin cough threshold test, assessing capsaicin concentrations to evoke 2 (C2), 5 (C5) or 10 (C10) coughs. Twenty-nine subjectively healthy control subjects were also included and tested with the threshold method. Results Patients had significantly lower C2, C5 and C10 in comparison to controls. From the results among patients and controls, sensitivity and specificity were calculated, and a receiver operating characteristic curve was constructed, showing excellent ability for C5 and C10 to discriminate patients from control subjects. Conclusions For patients with SHR and chronic cough, capsaicin cough sensitivity was once again confirmed to be increased, in this case, using the single-breath dose-response method. Limits set for cough reactions regarded as more sensitive than normal can be useful in diagnostics and further research. C5 seems to be the best measure to use in research and differential diagnostics.

According to the duration of bronchodilation , beta-2-agonists are divided into short and long acting bronchodilators . The bronchodilatory effect of available long acting beta-2-agonists (LABAs) beyond 12 h is not sufficiently studied. In order to evaluate the bronchodilatory effects of LABA in subjects without airway obstruction , the measurement of specific airway conductance (sGaw) with whole body plethysmography has been demonstrated to be a sensitive method. We aimed to determine the bronchodilatory effects of single doses of salmeterol 25, 50 and 200 μg and salbutamol 200 μg in healthy subjects ( n = 16) over a 24 h period in a randomized, double-blind, triple-dummy, placebo-controlled cross-over-study. At the 12-h endpoint, all three doses of salmeterol significantly increased sGaw compared with placebo. At the 24-h endpoint, there was a significant increase in sGaw with salmeterol 200 μg, while with 25 and 50 μg salmeterol the sGaw increase failed to reach statistical significance. There was no statistically significant increase in sGaw with salbutamol 200 μg at either the 12-h or 24-h endpoints. For weighted means, all three salmeterol doses showed statistically significant increase in sGaw compared with placebo over 0–12, 12–24 and 0–24 h periods, while for salbutamol 200 μg a significant increase in sGaw was recorded only over 0–12 h period. We conclude that sGaw measurement is a suitable method for recording the bronchodilatory effect of beta-2-agonists in healthy subjects. Using this method we could demonstrate that salmeterol 200 μg provides significant increase in specific airway conductance up to 24 h after a single dose.

Background: Various studies have reported a low prevalence of allergic rhinitis in farmers and farmers' children. We sought to investigate whether the protective effect of childhood farm environment is conserved throughout adulthood and how it corresponds to different degrees of urbanization. Methods: A questionnaire on respiratory health was mailed in 2008 to 30 000 randomly selected subjects aged 16-75 in West Sweden, 29 218 could be traced and 18 087 (62%) responded. The questionnaire included questions on allergic rhinitis, asthma, respiratory symptoms and possible determinants. Results: When stratified into age groups of 15 years, subjects that lived on a farm during their first 5 years of life had a lower prevalence of allergic rhinitis in all groups, even among the oldest (61-75 years). The negative correlation between childhood farm living and prevalence of allergic rhinitis was similar in 46-75 years of age (OR 0.82; 95% CI 0.70-0.95) as in 16-45 years of age (OR 0.78; 0.64-0.95). There was a significant trend of increasing prevalence of allergic rhinitis with increasing degree of urbanization independent of the effect of childhood farm living. Conclusions: We found a lifelong protective effect of childhood farm living on the prevalence of allergic rhinitis. In addition, we found an increasing prevalence of allergic rhinitis with increasing degree of urbanization both in those raised on a farm and those not, thus emphasizing the influence of both childhood and adult exposure for the development of allergic disease.

Streptokinase is widely used IV for the treatment of myocardial infarction and intrapleurally for the treatment of loculated pleural effusions. IV administration of streptokinase is known to cause the production of antistreptokinase antibodies.The aim of this study was to evaluate whether the intrapleural administration of streptokinase results in a similar elevation of the serum antistreptokinase antibody level.During 1 year, venous blood samples were taken from 16 consecutive patients (10 men and 6 women; age range, 22 to 60 years) requiring intrapleural streptokinase administration (250,000 IU once a day, for 2 to 6 days). Blood samples were taken before treatment, on day 5, and day 14. Antistreptokinase antibodies were measured using enzyme-linked immunosorbent assay (ELISA) and were expressed in arbitrary ELISA units. Four patients with myocardial infarction treated with IV streptokinase (1,500,000 IU) were included as control subjects for the method.Before treatment, the median antistreptokinase antibody level in patients with loculated pleural effusions was 729 ELISA units (range, 196 to 13,529 ELISA units) and increased to 9,240 ELISA units (range, 1,456 to 77,389 ELISA units) by day 14 (p0.0001). In the control group, the median pretreatment level was 119 ELISA units, and by day 14 it had increased to 20,495 ELISA units. Four patients who developed an elevated body temperature after intrapleural administration of streptokinase had a significantly higher pretreatment antistreptokinase antibody level compared to other patients.The intrapleural administration of streptokinase results in the elevation of the serum antistreptokinase antibody level, which is similar to the case with IV administration. An increased pretreatment antistreptokinase antibody level does not influence the result of intrapleural fibrinolysis but can cause an elevation of body temperature after the administration of streptokinase.

In the complex pathogenesis of airway inflammation seen in asthma, several cytokines are recognized to play a crucial role. Modulation of the effect of these cytokines can provide alternative and more specific treatment approach to currently widely-used systemic immunosuppression by glucocorticoids. Theoretically, cytokine modulation can be achieved via several pathways, including inhibition of released cytokines by using antibodies or soluble receptors, blocking cytokine receptors, inhibiting signal transduction or preventing cytokine gene transcription. Also, some cytokines are known to possess anti-inflammatory effects in allergic inflammation, being thus themselves potentially used as a therapeutic agent. The current review discusses the present knowledge on the involvement of cytokines in the pathogenesis of allergic asthma and the experience on modulation of the effect of these cytokines in clinical situations.

BACKGROUND: Allergic rhinitis is a common disease characterized by infiltration of eosinophils into the nasal mucosa during the periods of symptoms. Among chemokines, which attract cells to the site of inflammation, eotaxin is relatively specific for eosinophils. OBJECTIVE: We examined the influence of grass pollen season on nasal eotaxin expression in patients with seasonal allergic rhinitis, as well as the effect of a nasal glucocorticoid on this eotaxin expression. METHODS: Nineteen patients with allergic rhinitis received treatment with either nasal beclomethasone (400 microgram/day) or placebo over a grass pollen season. In these patients, nasal biopsies were taken prior to and during the peak of the pollen season and stained immunohistochemically for eotaxin and EG2 + eosinophils. Five healthy subjects served as controls and gave nasal biopsies once prior to the pollen season. RESULTS: Prior to pollen season, there was no significant difference in nasal eotaxin expression between patients with allergic rhinitis and healthy subjects. Grass pollen season induced significant increase in eotaxin expression in placebo-treated (P = 0.04; n = 9) but not in beclomethasone-treated rhinitis patients (P = 0.8; n = 10). During peak grass pollen season, the eotaxin expression in placebo-treated patients was significantly higher compared with healthy subjects outside season (P = 0.03). There was no significant correlation between the expression of eotaxin and the number of EG2 + eosinophils in nasal mucosa. The serum levels of eotaxin in rhinitis patients remained stable over the pollen season. CONCLUSION: Expression of eotaxin in nasal mucosa of grass-pollen allergic rhinitis patients is upregulated during pollen season and treatment with a nasal glucocorticoid protects against this upregulation.

Allergic rhinitis is an inflammatory disorder associated with local leukotriene release during periods of symptoms. Therefore, it has been suggested that antileukotrienes may be beneficial in the treatment of this disease. Leukotriene receptor antagonists have recently become available for asthma treatment, but little is known of their effects on allergic rhinitis. We have evaluated the effects of the leukotriene receptor antagonist zafirlukast versus placebo in patients with allergic rhinitis during the grass pollen season, using the nasal glucocorticoid beclomethasone dipropionate (BDP) as a positive treatment control. Thirty-three patients with seasonal allergic rhinitis were in a double-blind, double-dummy fashion randomized to treatments with oral zafirlukast (20 mg twice a day), intranasal beclomethasone dipropionate (200 microg twice a day), or placebo. The treatment was initiated 3 wk prior to the expected beginning of the grass pollen season. Patients completed a daily symptom-score list for sneezing, rhinorrhea, nasal itch, and nasal blockage during the 50-d treatment period. Nasal biopsies for quantification of local tissue eosinophilia (immunohistochemistry; EG2) were taken 1 mo before initiation of treatment and immediately after the peak of grass pollen season. Patients receiving treatment with zafirlukast had degrees of nasal symptoms similar to those in the placebo group, whereas the BDP group had significantly less symptoms compared with both treatments (p = 0.01 and p = 0.005, respectively). The numbers of activated eosinophils in the nasal tissue increased significantly during the pollen season in both the zafirlukast and the placebo groups, but not in the BDP group. These results obtained with a limited number of patients do not support any clinical efficacy of regular treatment with an oral antileukotriene in seasonal allergic rhinitis but rather favor the use of a nasal glucocorticoid.

Feeding a soluble antigen to an animal is known to cause a state of unresponsiveness against this antigen. If this antigen is given together with another antigen during the sensitization procedure, impairment of the response to the new antigen can also be seen, a phenomenon referred to as bystander suppression. The induction of tolerance against ovalbumin (OvA) and the effect of bystander suppression on the response to the hapten trimellitic anhydride (TMA), a cause of occupational asthma, were studied in Brown-Norway rats. Rats were fed either OvA-containing pellets or standard diet for 16 days before sensitization with the mixture of TMA and OvA. The animals were followed for 6 weeks after sensitization. Animals made tolerant to OvA showed a significantly suppressed delayed-type hypersensitivity (DTH) reaction against both OvA and TMA compared with the nontolerized control group at 5 weeks after sensitization, implying bystander suppression. By contrast, immunoglobulin (Ig)E and IgG antibody levels were suppressed only against OvA, whereas anti-TMA antibody levels were not affected. Airway eosinophilia after a single aerosol challenge at 6 weeks after sensitization using TMA conjugated to rat serum albumin, correlated with IgE anti-TMA levels in the group made tolerant to OvA and was not affected by OvA ingestion. In conclusion, suppressive factors released in ovalbumin-tolerant rats when they are challenged with ovalbumin, can suppress the response to trimellitic anhydride and this suppression is more pronounced for T-helper1-type responses.

Background: Recent in vitro findings show that glucocorticoids in combination with IL-4 can induce the synthesis of IgE, indicating that glucocorticoids may promote allergy. Objective: A double-blind, placebo-controlled study was performed to evaluate the effect of an intranasal glucocorticoid on the levels of birch pollen–specific IgE antibodies in serum from patients with allergic rhinitis. Methods: Eighteen patients with allergic rhinitis received treatment with an intranasal glucocorticoid (beclomethasone dipropionate, 400 μg/day) or placebo for 5 weeks, starting from the beginning of the birch pollen season. Blood samples for anti-birch IgE evaluation were taken before treatment was initiated and at 2 and 5 weeks after the beginning of the study. Results: The beclomethasone group ( n = 9) had significantly lower symptom scores when compared with the placebo group ( n = 9) (0.86 ± 0.26 vs 2.79 ± 0.76, p value = 0.01). Both the treatment group and the placebo group showed a trend of an increase in anti-birch IgE levels 2 weeks after the beginning of the treatment (from 33.1 ± 13.1 kU/L to 44.9 ± 20.9 kU/L in the beclomethasone group and from 53.2 ± 18.9 kU/L to 64.1 ± 22.1 kU/L in the placebo group). Treatment with beclomethasone returned anti-birch IgE levels to baseline by the end of the study, whereas in the placebo group the anti-birch IgE levels continued to increase (final values, 33.1 ± 11.9 kU/L vs 72.6 ± 23.2 kU/L, respectively). The change in IgE antibody levels in the placebo group was significantly higher than that in the beclomethasone group. No statistically significant changes in total IgE or soluble CD23 levels were detected. Conclusion: We conclude that treatment with an intranasal glucocorticoid initiated at the beginning of the pollen season inhibits the induced increase in specific IgE.

Bronchial hyperresponsiveness (BHR) and damage of the epithelium, as well as eosinophilia in the airway wall, induced by trimellitic anhydride (TMA) in sensitized brown Norway rats were studied. Rats were challenged once or seven times with aerosol of TMA conjugated to rat serum albumin (TMA-RSA) 3 weeks after intradermal TMA sensitization. Airway responsiveness (-log PC300 of acetylcholine i.v.) was measured 24 h after allergen challenge. Epithelial lesion and eosinophil infiltration in the airway walls were quantified under light microscopy, and TMA-specific IgE and IgG in serum were evaluated with ELISA. High levels of TMA-specific IgE and IgG were found in all rats in the sensitized groups compared to nonsensitized groups (P < 0.001). Repeated allergen challenges of 0.03% TMA-RSA for 7 consecutive days enhanced the level of TMA-specific IgG, compared to single challenge (P < or = 0.05). Single allergen challenge of 0.3% TMA-RSA had a nonsignificant tendency to produce BHR in sensitized rats compared to nonsensitized rats (P = 0.06). However, repeated allergen challenges (0.003% and 0.03% TMA-RSA for 7 consecutive days) produced significant BHR in sensitized rats (P < 0.05). Furthermore, repeated low-dose (0.003%) TMA-RSA challenge produced more BHR than a 10 times higher single dose (0.03%) (P < 0.05). Slight damage of the airway epithelium was seen in sensitized and repeat-challenged groups. However, bronchial eosinophilia was found in the sensitized and single-challenged groups, but not in nonsensitized nonchallenged, and sensitized repeat-challenged groups (P < 0.005). We conclude that the brown Norway rat can be sensitized with TMA, and that repeated low-dose allergen challenges produce slight epithelial damage and BHR which is independent of ongoing eosinophilia in the airway wall.

Background In mild asthma exercise-induced bronchoconstriction (EIB) is usually treated with inhaled short-acting β 2 agonists (SABAs) on demand. Objective The hypothesis was that a combination of budesonide and formoterol on demand diminishes EIB equally to regular inhalation of budesonide and is more effective than terbutaline inhaled on demand. Methods Sixty-six patients with asthma (>12 years of age) with verified EIB were randomised to terbutaline (0.5 mg) on demand, regular budesonide (400 μg) and terbutaline (0.5 mg) on demand, or a combination of budesonide (200 μg) + formoterol (6 μg) on demand in a 6-week, double-blind, parallel-group study (ClinicalTrials.gov identifier: NCT00989833). The patients were instructed to perform three to four working sessions per week. The main outcome was EIB 24 h after the last dosing of study medication. Results After 6 weeks of treatment with regular budesonide or budesonide+formoterol on demand the maximum post-exercise forced expiratory volume in 1 s fall, 24 h after the last medication, was 6.6% (mean; 95% CI −10.3 to −3.0) and 5.4% (−8.9 to −1.8) smaller, respectively. This effect was superior to inhalation of terbutaline on demand (+1.5%; −2.1 to +5.1). The total budesonide dose was approximately 2.5 times lower in the budesonide+formoterol group than in the regular budesonide group. The need for extra medication was similar in the three groups. Conclusions The combination of budesonide and formoterol on demand improves asthma control by reducing EIB in the same order of magnitude as regular budesonide treatment despite a substantially lower total steroid dose. Both these treatments were superior to terbutaline on demand, which did not alter the bronchial response to exercise. The results question the recommendation of prescribing SABAs as the only treatment for EIB in mild asthma.

Trimellitic anhydride (TMA) is a low-molecular-weight compound which causes occupational allergy. Brown Norway rats were sensitized to TMA injected intradermally (0.3% TMA suspended in oil). Three weeks later, we examined responses to either free TMA injected intradermally, or TMA conjugated to rat serum albumin (TMA-RSA) given by inhalation (0.5%, nebulized for 15 min). Twenty-one days after the sensitization, Evans blue dye was given i.v. (20 mg/kg), and extravasation of dye in skin was measured 30 min after oil or TMA injections (0.03-10% in oil). In a separate series of experiments, we evaluated the accumulation of eosinophils in the skin after single and repeated injections of TMA (0.03-0.3%). The injection sites were removed and fixed in formalin 18-24 h after the last injection. In a third series of experiments, we evaluated the effects of airway exposure to TMA-RSA (0.5% in 0.9% saline) on the accumulation of eosinophils in the bronchial wall counted with quantitative light microscopy. Intradermal injections of free TMA caused a dose-dependent increase of Evans blue dye extravasation which was significantly higher in sensitized animals than in controls. Skin histology revealed a significant and dose-dependent increase in eosinophils after repeated TMA injections in sensitized animals. Exposure to aerosolized TMA-RSA caused a significant increase of eosinophils in the bronchial wall of sensitized rats compared with nonsensitized rats. Sensitized animals showed significantly higher levels of specific IgG and IgE. We conclude that brown Norway rats can be used as a model of TMA-induced allergic inflammation, mimicking occupational asthma.

Background: There are few population-based studies on chronic nasal symptoms and little is known about their prevalence and determinants, or their association with allergic rhinitis and asthma. Methods: A questionnaire focused on respiratory symptoms and conditions was mailed in 2008 to 30,000 randomly selected subjects aged 16–75 years in West Sweden, 29,218 could be traced and 18,087 (62%) responded. The questionnaire included questions on self-reported allergic rhinitis, asthma, lower respiratory and nasal symptoms and possible determinants. Results: Nasal congestion was reported by 14.9% and runny nose by 13.1% of subjects. In total, 19.8% had chronic nasal symptoms. Subjects with chronic nasal symptoms had considerably more symptoms from the lower airways compared with nonrhinitic subjects and vice versa. Forty-seven percent of the subjects with chronic nasal symptoms had concurrent self-reported allergic rhinitis. Several hereditary and environmental factors were associated with chronic rhinitis, including family history of asthma [odds ratio (OR) 1.27; 95% confidence interval 1.07–1.50], family history of allergy (OR 1.74; 1.57–1.92) and current smoking (OR 1.39; 1.25–1.54). Further, chronic nasal symptoms were increasingly prevalent with an increasing degree of urbanization. Conclusion: The prevalence of chronic nasal symptoms in West Sweden was found to be high and strongly associated both with self-reported allergic rhinitis and symptoms from the lower airways. Moreover, several risk factors were identified for chronic nasal symptoms, including family history of allergy and asthma and smoking.

BACKGROUND AND OBJECTIVES Data on the onset of action of COPD medications are lacking. This study compared the onset of bronchodilation following different inhaled therapies in patients with moderate-to-severe COPD and reversible airway obstruction. METHODS In this double-blind, double-dummy, crossover study, 90 patients (aged >or=40 years; FEV(1) 30-70% predicted) were randomized to a single dose (two inhalations) of budesonide/formoterol 160/4.5 microg, salmeterol/fluticasone 25/250 microg, salbutamol 100 microg or placebo (via pressurized metered-dose inhalers) on four visits. The primary end-point was change in FEV(1) 5 min after drug inhalation; secondary end-points included inspiratory capacity (IC) and perception of onset of effect. RESULTS Budesonide/formoterol significantly improved FEV(1) at 5 min compared with placebo (P < 0.0001) and salmeterol/fluticasone (P = 0.0001). Significant differences were first observed at 3 min. Onset of effect was similar with budesonide/formoterol and salbutamol. Improvements in FEV(1) following active treatments were superior to placebo after 180 min (all P < 0.0001); both combinations were better than salbutamol at maintaining FEV(1) improvements (P

Summary Introduction The effect of ethnicity on the efficacy of salmeterol (S)+fluticasone propionate (FP) has not been examined in Japanese and Caucasian asthmatics. In this study, the efficacy of combination treatment with S and FP from a single inhaler (SFC) was compared with concurrent treatment with S and FP administration from separate inhalers (S+FP) in Japanese and Caucasian asthmatics. Methods This was a randomised, double-blind, crossover study in male and female Japanese (n=18) and Caucasian (n=17) asthmatics (50–100% predicted FEV1; >35% reversibility in sGaw). Subjects received SFC (S 50 mcg/FP 250 mcg b.i.d.) and S+FP (S 50 mcg b.i.d.+FP 250 mcg b.i.d.) for 14 days. sGaw and FEV1 were determined 0–12 h after the first and last doses. Results Treatment with both SFC and S+FP produced marked bronchodilation, which was maintained 0–12 h after the first dose. Baseline sGaw and FEV1 increased up to 51% and 180 mL, respectively, in Japanese subjects over 2 weeks of treatment, with similar improvements in Caucasian subjects. On Day 14 the 0–12 h S+FP:SFC treatment ratios (90% CI) for sGaw AUC and peak were 1.05 (0.98, 1.12) and 1.05 (0.97, 1.14), respectively, in Japanese subjects, and 0.99 (0.92, 1.07) and 0.98 (0.89, 1.07), respectively, in Caucasian subjects, with no difference between the two ethnic groups. Conclusions The finding of a similar significant bronchodilator response in Japanese and Caucasian asthmatics following concurrent and combination treatment with salmeterol and FP suggests that the therapeutic response to these agents is comparable and independent of ethnicity in Japanese and Caucasian asthma patients.

Background Diagnosis of severe peanut allergy is difficult and delays in making an accurate diagnosis may place the patient at risk. Adults with a history of anaphylaxis must strictly avoid any contact with peanuts or products that may contain traces of peanuts. For these persons, conventional evaluations with skin prick testing (SPT) and IgE tests may not be sufficient to assess the risk of anaphylaxis. Therefore, we investigated whether the basophil activation test (BAT) could be used for the diagnosis of severe peanut allergy in adults. We compared the non-invasive BAT with conventional laboratory diagnostic tests, including SPT and specific IgE to allergen extracts and components, for the diagnosis of severe peanut allergy. Methods Forty-seven persons with severe allergy to peanuts and a clinical diagnosis of anaphylaxis (PA-group), 22 subjects with peanut sensitization (PS-group) and 22 control (C-group) subjects, all in the age range of 18–60 years, were recruited retrospectively and prospectively into the study. Thirty-four patients with peanut allergy and 11 peanut-sensitized patients were sensitized to soy, while 36 patients in the PA-group and 20 patients in the PS-group were sensitized to birch pollen. All the patients and control subjects were investigated with BAT and SPT for responses to peanut, soy and birch extracts and their serum samples were assayed for the presence of specific IgE to peanut, soy and birch extracts, as well as IgE to allergen components (ISAC). Results In a multivariate factor analysis, severe peanut allergy (PA) was positively associated with SPT to peanut, IgE to peanut, BAT to peanut and IgE to rAra h 1, 2, 3 and 6 peanut components, as well as to soy components (nGly m 5 and nGly m 6). In contrast, peanut sensitization was positively associated with increased levels of IgE to rAra h 8, birch and birch-related components. BAT-detected reactivity to peanut was significantly higher in patients who had a history of severe allergy to peanuts, as compared with patients who were sensitized to peanuts (p

Local corticosteroids are currently the most efficient safe anti-allergic treatment, which attenuate eosinophilic tissue inflammation through several mechanisms. We evaluated the effect of local airways corticosteroid on repeated allergen exposure-induced bone marrow activation and airway eosinophilia using the number of eosinophils in bone marrow, bronchoalveolar lavage fluid (BALf) and airways tissue as study end-points. Male BALB/c mice were sensitized by intraperitoneal injections of aluminum-precipitated ovalbumin (OVA) on two different days (5 days apart). Eight days after the second sensitization, the animals were challenged intranasally with OVA or phosphate-buffered saline (PBS) on 5 consecutive days. Concomitantly with challenges mice were treated with fluticasone propionate or respective vehicle. OVA exposures induced a significant increase in eosinophil numbers in bone marrow, BALf and airways tissue (P

Background: Allergic rhinitis requires active intervention for symptom relief. A combination of antileukotriene and antihis-tamine drugs has been suggested to provide additive treatment benefits for patients with allergic rhinitis. Objective: We evaluated how such a combination treatment would affect symptoms and local mucosal eosinophilia in comparison with a nasal glucocorticoid. Methods: In a double-blind, randomized study 62 patients with grass pollen-induced allergic rhinitis received a nasal glucocorticoid (fluticasone propionate aqueous nasal spray [FPANS], 200 μg/d), an antileukotriene (montelukast, 10 mg/d), a combination of montelukast with an antihistamine (loratadine, 10 mg/d), or placebo throughout the season. Cromoglycate eyedrops and a limited amount of loratadine were allowed as rescue medication for severe symptoms. Patients recorded their symptoms for nasal blockage, itching, rhinorrhea, and sneezing. Before and during the season, nasal biopsy specimens were obtained from patients for evaluation of local eosinophilic inflammation. Results: During the peak season, both FPANS and combined montelukast-loratadine were significantly more effective than placebo and montelukast alone for daytime symptom prevention. For nighttime symptoms, FPANS was significantly more effective compared with all other treatments, whereas combined montelukast-loratadine and montelukast alone did not provide significant symptom prevention compared with placebo. The pollen-induced increase in the numbers of epithelial eosinophils was significantly lower for FPANS-treated patients compared with that seen in all other treatment groups. Conclusion: In patients with seasonal allergic rhinitis, intranasal glucocorticoids are more effective than an antileukotriene drug or combined antileukotriene-antihistamine for the reduction of pollen-induced nasal eosinophilic inflammation and for control of nasal symptoms. (J Allergy Clin Immunol 2002;109:949-55.)

Background Birch pollen allergic patients frequently experience gastrointestinal upset accompanied by a local allergic inflammation in the small intestine especially during the pollen season. However, it is not known if the GI pathology is connected to the subjective symptoms of the patient. The objective of this study was to evaluate the immune pathology of the duodenal mucosa and the serum IgE antibody profiles in birch pollen allergic patients in relation to their gastrointestinal symptoms, during and outside the birch pollen season. Methods Thirty-two patients with birch pollen allergy and sixteen healthy controls were enrolled in the study. Twenty allergic patients had gastrointestinal symptoms and twelve did not. All participants underwent an allergy investigation and gastroscopy with duodenal biopsy. The duodenal biopsies were retrieved during the pollen season (May-June) and off-season (November-March). The biopsies were immunostained for mast cells (IgE and tryptase), eosinophils, T cells (CD3), and dendritic cells (CD11c). Pollen-specific IgE antibodies were determined by ImmunoCAP and component microarray (ISAC). Results Patients in both pollen allergic groups showed similar degree of intestinal allergic inflammation during the pollen season regardless of gastrointestinal symptoms. The eosinophils, mast cells and dendritic cells were increased in the mucosa. Patients with gastrointestinal symptoms had significantly elevated IgE antibodies to birch (rBet v 1), hazelnut (rCor a 1), and apple (rMal d1) during the pollen season. Conclusions Patients allergic to birch pollen have clear signs of an ongoing allergic inflammation in their intestinal mucosa, which is aggravated during the pollen season. The magnitude of the allergic intestinal inflammation is not associated with subjective gastrointestinal symptoms of the individual patient.

Background: Expression of high-affinity IL-2 receptor (IL-2R) on T lymphocytes, key cells in chronic inflammation, is a T-cell activation marker. Objective: We sought to evaluate the effect of the fusion protein DAB 389 IL-2, which kills cells bearing IL-2R, on delayed-type hypersensitivity and antibody production in Brown Norway rats sensitized with trimellitic anhydride (TMA). Methods: DAB 389 IL-2 (25 μg/kg/day) or placebo was administered intraperitoneally for 8 days over the period of sensitization, starting 2 days before sensitization. Results: The administration of DAB 389 IL-2 resulted in a one-third reduction in the number of IL-2R–bearing cells and significant weight loss of animals. Delayed-type hypersensitivity, evaluated at 5 weeks after sensitization, was significantly inhibited by treatment with DAB 389 IL-2. In contrast, production of IgE anti-TMA antibodies after sensitization was increased by treatment with DAB 389 IL-2. DAB 389 IL-2 affected neither IgG anti-TMA antibody nor total IgE levels. Conclusion: These data imply that systemic administration of DAB 389 IL-2 in Brown Norway rats influences cells that have regulatory effects on the immune system, resulting in a switch from a T H1 to a T H2 type of immune response. (J Allergy Clin Immunol 1999;103:843-9.)

Background A previous study by our group (JACI 2003;112:45-50) showed a significant allergic gastrointestinal inflammation in birch pollen allergic patients with gastrointestinal symptoms during the birch pollen season. The pathophysiological mechanisms of this type of allergic reaction are still poorly studied. However it is not yet explored if all birch pollen patients have signs of gastrointestinal inflammation during the pollen season.

Prolonged exposure to allergen has been proposed to be important for the development of bronchial hyperresponsiveness and airway remodelling in asthma. The present study was designed to examine the effect of chronic allergen exposure on bronchial responsiveness, eosinophil infiltration, and airway remodelling. We sensitized brown Norway rats with the occupational allergen trimellitic anhydride (TMA) and exposed the animals to TMA conjugated to rat serum albumin (TMA-RSA) on 5 consecutive days each week for 9 weeks, starting 4 weeks after sensitization. IgE and IgG anti-TMA antibodies in serum and bronchial responsiveness to acetylcholine were evaluated before and at weeks 3, 6, and 9 of allergen exposure. Thickness of the airway wall, airway luminal narrowing, and the number of goblet cells and eosinophils in the airway wall were evaluated with an image analysis system in lungs resected after the last assessment of bronchial responsiveness, at the end of the 9-week allergen exposure. All rats developed IgE and IgG anti-TMA antibodies after sensitization. The levels of antibodies increased with allergen exposure until week 6, and then declined. Bronchial hyperresponsiveness to acetylcholine was induced in allergen-exposed rats without ongoing airway eosinophilia. Bronchial hyperresponsiveness induced by chronic allergen exposure via inhalation was accompanied by significantly increased thickness of smooth muscle and airway narrowing in the small airways, and goblet cell hyperplasia in the large airways. We conclude that chronic exposure to allergen can induce bronchial hyperresponsiveness and airway wall remodelling. Airway wall remodelling may contribute to bronchial hyperresponsiveness.

Background: Trimellitic anhydride (TMA) is a low-molecular-weight compound capable of inducing occupational asthma in man. We have characterized the TMA-induced antibody responses in Brown-Norway rats (BNR) and evaluated the effects of treatment with the glucocorticoid betamethasone or with cyclosporin A (CsA) on this response. Methods: Animals were sensitised by two intradermal injections of 0.1 ml TMA suspended in corn oil, and development of specific antibodies was assessed using ELISA. Results: Both IgE and IgG anti-TM A antibodies started to rise between weeks 1 and 3 after immunisation, reached their highest levels 7 weeks after sensitisation with 3% of TMA and then started to decline. Betamethasone and CsA given orally over the time of sensitisation (8 days in total) inhibited the development of specific IgE and IgG anti-TMA antibodies. Betamethasone given 10–17 days after sensitisation attenuated the IgE and IgG antibody responses as well while treatment with CsA after sensitisation had no effect on the production of specific antibodies. Levels of total IgE and IgG were not affected except for a small decrease in total IgE using medium-dose betamethasone after sensitisation. Conclusion: We conclude that TMA-sensitised BNR develop specific IgE and IgG anti-TMA antibodies, and that glucocorticoids and CsA attenuate this response.

Background: CD4+ T cells constitute a major source of cytokines in allergic diseases such as allergic rhinitis. Interleukin (IL)-16 selectively recruits CD4+ cells. Methods: We evaluated the effect of natural allergen exposure during a grass-pollen season on IL-16 expression and number of CD4+ cells in nasal mucosa. Patients with allergic rhinitis (n=16) were treated with either a nasal glucocorticoid beclomethasone (BDP; 400 µg/day) or placebo, and gave nasal biopsies prior to and during the grass-pollen season. The evaluated markers in allergic rhinitis patients were also compared to those in healthy control subjects (n=5). Results: Prior to the pollen season, the expression of IL-16, but not the number of CD4+ cells, was significantly higher in patients with allergic rhinitis than in healthy control subjects. The grass-pollen season further increased IL-16 expression and also increased the number of CD4+ cells in placebo-treated, but not in BDP-treated, allergic rhinitis patients. The pollen-season-induced change in IL-16 expression and in CD4+ cells was significantly more pronounced in placebo- than in BDP-treated patients. There was a significant correlation between the change in IL-16 expression and the number of CD4+ cells. Conclusions: These data suggest that local upregulation of IL-16 expression contributes to the inflammation observed in seasonal allergic rhinitis. Hypothetically, inhibition of IL-16 expression can be one of several mechanisms by which nasal glucocorticoids achieve their anti-inflammatory effect in allergic rhinitis.

Background Osteopontin (OPN) is a multifunctional cytokine that has been primarily investigated in Th1 diseases. Recently, it has also been implicated in Th2-mediated allergic diseases, such as asthma. The expression of OPN in allergic rhinitis (AR) is currently unknown, as is the effect of intranasal glucocorticosteroids (GCs) on that expression. Methods Subjects with AR were randomised to receive treatment with fluticasone propionate (FP) (n = 12) or a placebo (n = 16) over the grass pollen season and nasal biopsies were taken prior to, and during the season. OPN expression in the nasal mucosa was examined with immunohistochemistry. Healthy non-AR controls (n = 5) were used as a comparator. Results OPN expression was detected in epithelial cells, subepithelial infiltrating/inflammatory cells and cells lining the vessels and glands of all subjects. Comparison of the pre- and peak-pollen season biopsy sections in placebo treated patients revealed no increase in OPN expression during the grass pollen season (5.7% vs 6.4%). Treatment with a local glucocorticosteroid did not alter the expression of OPN during pollen exposure (6.2% vs 6.7%). Conclusion OPN has been increasingly associated with the pathogenesis of various Th2-mediated diseases. However, our finding that the OPN expression in the nasal mucosa of AR patients is not significantly affected by allergen exposure and is comparable to that of the healthy controls, suggests that intracellular OPN is not directly involved in the pathogenesis of allergic rhinitis.