Changes in airway inflammation following nasal allergic challenge in patients with seasonal rhinitis

BACKGROUND: Seasonal allergic rhinitis could predispose to the development of chronic bronchial inflammation as observed in asthma. However, direct links between nasal inflammation, bronchial inflammation and airway responsiveness in patients with seasonal allergic rhinitis and without asthma are not fully understood. The aim of this study was to analyse the changes induced by allergic nasal challenge outside the pollen season in airway responsiveness and bronchial inflammation of patients with seasonal allergic rhinitis. METHODS: Nine patients were evaluated after either grass pollens or placebo nasal challenge in a randomized cross-over double-blinded trial. Nasal parameters were recorded hourly and airway responsiveness was assessed by methacholine challenge. Cytological examinations and cytokine measurements were performed in nasal lavage and induced sputum. Eosinophil activation was investigated by eosinophil-cationic protein expression and secretion. RESULTS: Airway responsiveness was increased after allergic nasal challenge. Total eosinophils and eosinophils expressing eosinophil-cationic protein were increased in induced sputum after allergic nasal challenge. Both eosinophil number and eosinophil-cationic protein concentration in induced sputum were correlated to methacholine responsiveness. CONCLUSIONS: These results suggest that eosinophils participate to the bronchial inflammation in patients with seasonal allergic rhinitis following allergic nasal challenge outside the pollen season and might explain changes in airway responsiveness.     

The effect of nedocromil sodium on nasal provocation with allergen

We have investigated the effect of nedocromil sodium in preventing the symptoms of rhinitis occurring immediately after allergen provocation in 10 patients with allergic rhinitis. The study had a double-blind, placebo-controlled, crossover design. Nedocromil sodium (1% w/v) and placebo were administered intranasally from identical metered-dose inhalers 20 minutes before allergen provocation. Three variables were measured: nasal airway resistance, the production of secretion, and the number of sneezes. Nedocromil sodium was significantly more effective than placebo in preventing nasal obstruction (p less than 0.01), rhinorrhea (p less than 0.01), and sneezing (p less than 0.05), suggesting that this drug may be useful in the treatment of allergic rhinitis.     

Relationship between nasal and bronchial responsiveness in perennial allergic rhinitic patients with asthma

BACKGROUND: The nasal and bronchial mucosa present similarities and most patients with asthma also have rhinitis, suggesting the concept of 'one airway one disease'. Although many studies may suggest the relationship between nasal and bronchial responsiveness in patients with allergic rhinitis and asthma, few studies have been published which address this question directly. The aim of this study is to investigate whether the relationship between nonspecific nasal and bronchial responsiveness exists in perennial allergic rhinitic patients with asthma. METHODS: Fifty-one perennial allergic rhinitic patients with the definitive or suspected asthma underwent methacholine bronchial provocation tests and nasal histamine challenge tests. A slope of the absolute changes in nasal symptoms score/log concentrations of histamine was calculated by linear regression analysis. A ratio of the final absolute change in nasal symptoms score to the sum of all the doses of histamine given to the subject was also calculated. The degree of bronchial responsiveness to methacholine was categorized as positive bronchial hyperresponsiveness (BHR) if PC(20) (provocative concentration of methacholine resulting in 20% fall in FEV(1)) was <4 mg/ml, borderline BHR if PC(20) was >or=4 but 16 mg/ml. Another index of bronchial responsiveness (BRindex) was calculated as the log [(% decline in FEV(1)/log final methacholine concentration as mg/dl) + 10]. RESULTS: The geometric means of the slope (4.47 vs. 2.95, p < 0.05) and the ratio (1.68 vs. 0.54, p < 0.01) were higher in patients with positive BHR (n = 23) than in patients with negative BHR (n = 19), respectively. The geometric means of the slope (3.50) and the ratio (1.13) in patients with borderline BHR (n = 9) were between the two groups, respectively. In all patients, the log-slope (r = 0.48, p < 0.001) and the log-ratio (r = 0.51, p < 0.001) were correlated well with the BRindex, respectively. Even in allergic rhinitic patients with definitive asthma, the log-slope was correlated with the BRindex (r = 0.39, p < 0.05) or log-PC(20) (r = -0.36, p < 0.05). CONCLUSIONS: The nonspecific nasal responsiveness may be related to the nonspecific bronchial responsiveness in patients with allergic rhinitis and asthma, which may support the viewpoint that allergic rhinitis and asthma represent a continuum of inflammation involving one common airway.     

The effect of inhaled gallopamil, a potent calcium channel blocker, on the late-phase response in subjects with allergic asthma.

The effect of gallopamil on the late-phase response to inhaled allergen was evaluated in six young adults with allergic asthma in a crossover manner. During 2 study days, subjects received 20 mg of inhaled gallopamil or placebo 30 minutes before challenge with the same dose of allergen. In addition, a histamine challenge was performed 1 1/2 hours before and 24 hours after allergen challenge. On 2 additional study days, in the absence of allergen, basal airway responsiveness to histamine was measured before and after gallopamil or placebo administration. During the early phase, the mean +/- SD decrease in FEV1 was 28.0% +/- 11.3% after placebo and 25.1% +/- 8.4% after gallopamil administration (p greater than 0.05; beta = 0.14). During the late phase, the maximum decrease in FEV1 was 26.9% +/- 11.9% after placebo and 25.3% +/- 10.3% after gallopamil administration (p greater than 0.05; beta = 0.21). Airway reactivity to histamine 24 hours after allergen challenge could not be measured in three subjects after gallopamil administration and in one subject after placebo administration because of persistent bronchospasm. In contrast, basal responsiveness to histamine in the absence of allergen was modestly decreased by gallopamil. Since gallopamil is one of the most potent calcium channel blockers when it is administered by the inhaled route, it is unlikely that this group of drugs will be clinically useful for allergic asthma.     

Isolated early response after nasal allergen challenge is sufficient to induce nasal hyperreactivity.

Ten rhinitic patients allergic to grass pollen were challenged with histamine intranasally 24 hours before and 24 hours after nasal provocation with grass pollen. Up to ten hours after allergen provocation nasal lavage fluid was obtained to characterize early and late phase reactions by measuring the levels of histamine and leukotrienes as indicators of mediator release, and albumin as a marker of increased vasopermeability. Ten minutes after allergen challenge with 10,000 BU grass pollen extract LTC4,D4, and albumin significantly increased from 62 to 576 pg/mL (P = .008) and from 15 to 81 micrograms/mL (P = .008), respectively, without significant changes after placebo challenge a week earlier. Although the patients showed increased responsiveness to histamine after allergen challenge compared with a placebo-challenged control group (P = .02), one patient only demonstrated a late phase nasal allergic reaction characterized by recurrence of clinical symptoms eight to ten hours after allergen challenge and recurrence of mediators in lavage fluid. It is concluded that an isolated early response after allergen challenge is sufficient to induce nasal hyperreactivity. A biochemically or clinically defined late phase allergic reaction does not necessarily accompany allergen-induced hyperreactivity.     

A single nasal allergen challenge increases induced sputum inflammatory markers in non-asthmatic subjects with seasonal allergic rhinitis: correlation with plasma interleukin-5

BACKGROUND: Seasonal allergic rhinitis (SAR) is a risk factor for asthma in affected individuals. Nasal allergic inflammation enhances bone-marrow eosinophil production, mainly via IL-5, and rhinitis patients have increased airway inflammation during the pollen season. OBJECTIVE: To assess the impact of nasal allergy on sputum inflammatory markers. METHODS: In an open-labelled, randomized, placebo-controlled cross-over study with 16 non-asthmatic SAR patients (median age 25 years, 56% males), the effect of a single nasal allergen challenge performed out of season on induced sputum inflammatory parameters was evaluated. SAR patients were identified by history, skin-prick test and specific IgE. All patients had normal lung function/bronchial hyper-responsiveness out of season and a negative asthma/wheezing history. Sputum cells and supernatant levels of ECP, sICAM, IL-5 and IL-10, and plasma levels of IL-5 and ECP, were measured before and 24 h after nasal allergen challenge. After a washout period of at least 4 weeks, the procedure was repeated with placebo challenge (diluent). RESULTS: Nasal allergen challenge led to an increase in sputum ECP (pre = 60 +/- 12, post = 212 +/- 63 micro g/L, P = 0.02 vs. placebo), and sICAM (4.8 +/- 2.7 to 6.5 +/- 2.9 ng/mL, P = 0.02 vs. placebo), whereas IL-10 decreased after provocation (44 +/- 11 to 29 +/- 6 pg/mL, P = 0.06 vs. placebo). Sputum IL-5 was undetectable in all patients. The absolute number of blood and sputum eosinophils did not change significantly after allergen or placebo challenge (P > 0.07, both comparisons). Plasma levels of IL-5 increased after allergen challenge (8.7 +/- 2.9 to 14.5 +/- 3.9 pg/mL, P = 0.001), and the increase in plasma IL-5 was positively correlated with the rise in sputum ECP in a subgroup of 'responders' (n = 12, r = 0.71, P = 0.01). CONCLUSIONS: A single nasal allergen challenge in SAR patients increased markers of allergic inflammation in the lower respiratory tract, possibly via pronounced activation of inflammatory cells through circulating immediate-type reaction cytokines like IL-5. These findings may provide additional explanatory data for the high susceptibility of SAR patients to incident asthma.     

Nasal provocation test in the diagnosis of natural rubber latex allergy

BACKGROUND: Natural rubber latex (NRL) allergy in workers using rubber gloves has been an occupational health problem for the last 10 years. In the case of the occupational agents, clinical history may be far from conclusive; hence, appropriate provocation should be carried out. The objective was to evaluate the usefulness of the nasal challenge test in the diagnosis of allergic rhinitis in subjects occupationally exposed to NRL. METHODS: A single-blind, placebo-controlled study was conducted in 16 nurses with respiratory symptoms (bronchial asthma and/or rhinitis) related to NRL exposure as well as positive skin prick test (SPT) response to NRL. The controls were nine nurses with asthma and/or perennial rhinitis unrelated to NRL exposure; six atopic patients not occupationally exposed to NRL, with asthma and/or perennial rhinitis; and six healthy subjects. All the controls had negative results of SPT with NRL. Patients with a history of anaphylaxis or positive results of RAST to NRL were not considered in the study. The "nasal pool" technique was used to evaluate the cellular response and changes in protein level and ECP concentration in nasal washings after topical provocation with allergen or placebo. RESULTS: A significant increase was noted in eosinophil and basophil number, albumin/total protein ratio, and ECP level only in NRL SPT-positive patients subjected to nasal challenge with NRL. Neither bronchial nor systemic reactions were found after the nasal provocation with NRL. CONCLUSIONS: The nasal challenge test appears to be useful for diagnosing occupational rhinitis in NRL-sensitized patients.     

Eosinophilic rhinitis accompanies the development of lower airway inflammation and hyper-reactivity in sensitized mice exposed to aerosolized allergen

BACKGROUND: Allergic rhinitis is a risk factor for the development of asthma. About 80% of asthmatic patients also have rhinitis. However, the pattern of induction of allergic rhinitis and asthma remains unclear. OBJECTIVE: The purpose of this study was to investigate the development of upper airway inflammation in mice during the development of an asthma-like disease and after an acute allergen provocation. METHODS: BALB-c mice were sensitized intraperitoneally (i.p) to ovalbumin (OA, days 1-13) and were challenged with aerosols of either OA or saline on 8 consecutive days (days 33-40). In a second experiment, chronic exposure for 8 days was followed by 10 days of rest and then an acute nebulized allergen provocation was performed (day 50). Inflammatory parameters were investigated at different time-points. RESULTS: Upper and lower eosinophilic airway inflammation were simultaneously induced in the course of repeated inhalations of nebulized OA, as shown by analyses of nasal and broncho-alveolar lavage fluids and histological sections of the nose and bronchi. Mice that developed bronchial hyper-responsiveness also had increased thickness of the nasal mucosa on magnetic resonance image (MRI) scans. When chronic exposure was followed by acute allergen provocation, the latter caused a systemic increase in IL-5 levels, with a concomitant rise in blood and airway eosinophils, primarily in the nose. CONCLUSIONS: Simultaneous induction of eosinophilic inflammation in the nose and lungs was found in a mouse model of respiratory allergy. These findings support the viewpoint that upper and lower airway disease represent a continuum of inflammation involving one common airway and provide evidence for the concept of global airway inflammation after inhalation of allergen.     

Introduction to nasal and pulmonary allergy cascade

The early phase of an IgE-dependent allergic reaction is followed by the activation of a complex network of inflammatory phenomena – T lymphocytes, cytokines, mediators, and adhesion molecules – that mediate late and ongoing allergic symptoms. The kinetics of respiratory inflammation following allergen exposure involve the migration of inflammatory cells to the mucosa within about 30 min, increased inflammatory infiltration over the following hours, and then slow subsidence. A relationship between asthma and allergic rhinitis is supported by epidemiological, histological, physiological, and immunopathological data, and by the response of asthma symptoms in rhinitic patients to intranasal corticosteroids and antihistamines. For example, there is no morphological difference between the bronchial inflammatory response following allergen-specific challenge in patients suffering from asthma alone or rhinitis alone. It is the allergen dose that makes the difference in the airway response to allergen in allergic rhinitis and asthma. Recognition of the relationship between asthma and allergic rhinitis has led to the introduction of new diagnostic terminology and treatment recommendations: 1) patients with persistent rhinitis should be evaluated for asthma; 2) patients with persistent asthma should be evaluated for rhinitis; and 3) a strategy should combine the treatment of upper and lower airways in terms of efficacy and safety.     

Topical glucocorticoids inhibit activation by allergen in the upper respiratory tract.

We have studied the effect of a topically administered glucocorticoid, fluticasone propionate (FP), on infiltration and activation of eosinophils in the nasal mucosa after provocation with allergen. Forty-four patients with seasonal allergic rhinitis entered a double-blind, crossover study in which they underwent treatment with either FP (200 micrograms once daily) or identical placebo for 2 weeks. Patients then underwent nasal-allergen provocation followed by nasal lavage and biopsy at one of several time points between 0 and 8 hours. Patients subsequently received the alternate treatment for 2 weeks before repeat allergen provocation, nasal lavage, and biopsy, as before. Biopsy specimens of nasal mucosa obtained during the immediate allergic response demonstrated an influx of eosinophils (stained by monoclonal antibody EG1) of similar magnitude during both FP and placebo treatment. Significantly, fewer eosinophils in these biopsy specimens were activated (stained by monoclonal antibody EG2) after treatment with FP compared with that after placebo treatment (median values, 8.8 and 36.6 cells per square millimeter, respectively; p less than 0.02). The concentration of eosinophil cationic protein in nasal lavage fluid was significantly elevated above baseline from 2 to 8 hours after allergen, and this increase was abolished by treatment with FP. These results suggest that topical glucocorticoids inhibit allergen-induced activation of eosinophils in allergic rhinitis.     

Effect of cetirizine on bronchial hyperresponsiveness in patients with seasonal allergic rhinitis and asthma

Although H1 antihistamine compounds (H1) are highly effective in the treatment of allergic rhinitis (AR), their role in the treatment of asthma is still controversial. Because a strong association between AR and bronchial hyperresponsiveness (BHR) has been reported, this study was designed to assess the effect of a new H1 anti histamine, cetirizine (C), on nonspecific BHR in patients with AR. Twelve patients were included in a double-blind, crossover, placebo-controlled trial. All patients had positive skin tests for common allergens and showed BHR to inhaled methacholine after specific nasal allergenic challenge. After a washout period of 1 week to ensure the stability of the BHR, the patients received, by crossover randomization, C 10 mg daily or placebo (P) for 2 weeks. After each treatment period, BHR and nasal blocking index (NBI) were measured 1 and 6 h after nasal challenge. Bronchial responsiveness was expressed as methacholine PD20, the provocation dose of methacholine causing a 20% decrease in FEV1. Measurements were then performed after 2 weeks of C and after 2 weeks of P. Baseline values of PD20 (median) measured before challenge showed no difference after cetirizine or after placebo (1.36 mg). Results 1 h after allergen did not show significant differences between C (methacholine PD20=0.522 mg) and placebo (methacholine PD20=0.455 mg). By contrast, 6 h after challenge, methacholine PD20 was 0.918 mg for C and 0.483 mg for P (P=0.042). Similarly, NBI showed no change between C and P 1 h after challenge, whereas the difference was significant 6 h after challenge (P=0.011 ). These data demonstrate a protective nasal effect of C against BHR measured 6 h after nasal allergen challenge in patients with AR. They suggest that C may be useful in patients with asthma associated with AR.     

Desloratadine reduces systemic allergic inflammation following nasal provocation in allergic rhinitis and asthma patients

BACKGROUND: Preclinical studies have demonstrated that some second-generation antihistamines have anti-inflammatory effects. It is not known whether these effects are also demonstrable in vivo. In this study we investigated the effect of treatment with desloratadine (DL) on systemic inflammation and on nasal and bronchial mucosal inflammation after nasal allergen provocation (NP) in subjects with grass-pollen-allergic rhinitis and asthma. METHODS: Twenty-six subjects with grass-pollen-allergic rhinitis and asthma were randomly allocated to 8 days of treatment with DL (n = 13) or placebo (n = 13) outside the grass pollen season. On day 7 they underwent nasal provocation with grass pollen allergen. Nasal and bronchial biopsies were taken for immunohistochemical evaluation, and blood samples were analysed. Rhinitis and asthma symptoms, peak nasal inspiratory flow and peak expiratory flow, were also measured at specified times. RESULTS: The number of circulating eosinophils decreased during DL treatment, and there was a reduced increase in circulating eosinophils after NP in these subjects. There was also a significant reduction in early bronchial clinical response. There was no significant lessening in the severity of the nasal symptoms. Nasal and bronchial mucosal inflammation parameters did not alter under DL treatment. CONCLUSION: These data suggest that treatment with DL reduces systemic eosinophilia and prevents the increase in circulating eosinophils after NP. DL also significantly reduces the early bronchial clinical response to NP. However, airway mucosal inflammation is not altered by 1 week of treatment.     

Nasal eosinophilia in children: its use in the nasal allergen provocation test

This pediatric cytological and clinical study aimed at assessing the value of nasal eosinophilia during nasal provocation tests for identifying an offending allergen. The population studied comprised 50 children aged from 4 to 18 yr; 39 of these had well-characterized allergic rhinitis, which in 21 cases was combined with asthma, and the remaining 11 had nonatopic chronic rhinitis. Nasal secretions, collected by nose blowing, were stained with May-Grünwald-Giemsa or Wright stain. The percentage of nasal eosinophils was obtained by examining the cells in the whole slides. Counts were carried out on secretions collected before challenge, after insufflation of saline solution (for verification), and 40 min after insufflation into each nostril of an allergen (housedust mite extract). The nasal provocation test was considered positive when insufflation of the allergen increased nasal eosinophilia by more than 10%, provided that the prechallenge proportion of eosinophils was less than 50%. No increase in specific bronchial resistance was noted. These results indicate that nasal provocation tests are safe, even in asthmatic children.     

Comparative effects of inhaled salbutamol, sodium cromoglycate, and beclomethasone dipropionate on allergen-induced early asthmatic responses, late asthmatic responses, and increased bronchial responsiveness to histamine

Single-dose salbutamol (200 micrograms), beclomethasone dipropionate (200 micrograms), and sodium cromoglycate (SCG) (10 mg) administered by inhalation 10 minutes before allergen challenge were examined with regard to inhibition of allergen-induced early (EAR) and late (LAR) asthmatic responses and allergen-induced increase in bronchial responsiveness to inhaled histamine. Ten atopic subjects with asthma participated in a blinded, crossover, placebo-controlled trial. The EAR was inhibited by salbutamol and SCG but not by beclomethasone dipropionate or placebo (p less than 0.01). The LAR (p less than 0.01) and the allergen-induced increased bronchial responsiveness to histamine 7 hours (p less than 0.01) and 30 hours (p less than 0.05 and p less than 0.01 for various comparisons) were inhibited by SCG and beclomethasone diproprionate but not by salbutamol or placebo. The allergen-induced LAR and associated increased responsiveness are now believed to be more important clinically than the EAR. The clinical relevance of these results is to stress the importance of the prophylactic nonbronchodilator drugs (SCG and steroids) and the potential inadequacy of bronchodilators used alone in the treatment of both perennial and seasonal allergic asthma.     

Inhibitory effect of levocabastine on allergen-induced increase of nasal reactivity to histamine and cell influx

For evaluation of the effect of levocabastine pretreatment on allergen-induced rhinitis symptoms, changes in nasal washings, and nasal responsiveness to histamine, 12 asymptomatic patients with documented allergic rhinitis participated in a single-blind, placebo-controlled study. Eight-day treatment with levocabastine (twice in each nostril, four times a day) caused significant reduction in nasal symptoms and inflammatory cell influx after allergen challenge, as compared with placebo administration. Levocabastine inhibited increased nasal reactivity to histamine induced by allergen provocation, as controlled by rhinitis symptoms and albumin level in nasal washings. These data reveal a high effectiveness of levocabastine in the prevention of allergen-induced rhinitis symptoms. Moreover, its inhibitory effect on inflammatory cell influx and hyperresponsiveness to histamine suggest that levocabastine is more than a simple H₁-receptor antagonist.     

Heparin attenuates symptoms and mast cell degranulation induced by AMP nasal provocation

BACKGROUND: Previous studies have shown that inhaled heparin attenuated the airway responses to allergen, exercise, and AMP bronchial provocation, possibly through an inhibition of mast cell activation. OBJECTIVE: The aim of this study was to provide the evidence of in vivo inhibition of human mast cell activation by heparin in a noninvasive model. METHODS: Nine atopic and 6 nonatopic subjects received placebo and unfractionated heparin sodium (5000 IU/mL) 15 minutes before an AMP nasal provocation in a double-blind crossover study design. The nasal lavage was collected from these subjects before or 3, 5, 15, or 30 minutes after the AMP nasal challenge, and concentrations of histamine and tryptase in the nasal lavage were measured. RESULTS: AMP nasal provocation produced considerable sneezing and induced a transient increase in histamine and tryptase release, with peak values achieved at 3 to 5 minutes after the challenge in all atopic subjects. Compared with placebo, inhaled heparin significantly attenuated the release of histamine and tryptase induced by AMP challenge (P=.012 and.004, respectively). Moreover, the AMP-induced sneezing was also inhibited by pretreatment with heparin (P=.016). In nonatopic subjects, AMP did not induce a significant increase in histamine and tryptase release on placebo-treated or heparin-treated days. CONCLUSION: These data suggest that AMP nasal provocation and AMP bronchial provocation cause mast cell mediator release in a similar fashion. In addition, the data support the hypothesis that inhaled heparin plays a protective role against AMP provocation by inhibition of mast cell activation.     

The value and safety of specific nasal provocation in the diagnosis of allergic rhinitis in mild persistent asthma under inhaled steroid therapy

Although specific nasal provocation is an objective diagnostic test for allergic rhinitis, it can also increase the lower airway responsiveness in asthmatic patients. Our goal was to determine the value and safety of specific nasal provocation test for the diagnosis of allergic rhinitis in mild persistent asthmatic patients under low-dose inhaled steroid therapy. The study was performed on 32 mild persistent, stable, mite-sensitive allergic asthmatics (group 1), 9 mild persistent nonallergic asthmatics (group 2) and 9 healthy non-smokers (group 3). Nasal symptoms were noted, paranasal sinus computerized tomography (PNCT) and rhinoscopic evaluations were performed. Cases with pathologic-anatomic changes in PNCT and rhinoscopy were excluded. Symptom scoring, flow-volume, peak expiratory flow (PEF), serum and nasal lavage eosinophil cationic protein (ECP) and nasal lavage eosinophil counts were performed before mite specific nasal provocation test and at the 0th, 4th and 24th hours following the test. No adverse effects were observed in all diagnostic procedures. Total diagnostic value of nasal symptoms were found to be at 92%, while being 70% for rhinoscopy and 88% for specific nasal provocation test respectively in the diagnosis of allergic rhinitis in group 1. Statistically significant differences were found between basal nasal lavage eosinophil values (p < 0.001) and ECP levels (p < 0.05) when group 1 was compared with both group 2 and group 3. In the remaining measured values between three groups, no statistically significant differences were found. Specific nasal provocation test is a safe method for mild house dust mite allergic asthma cases under low-dose inhaled steroid therapy, but history of rhinitis might be sufficient for the diagnosis of allergic rhinitis.     

The phosphodiesterase 4 inhibitor roflumilast is effective in the treatment of allergic rhinitis

BACKGROUND: The beneficial effects of phosphodiesterase 4 (PDE4) inhibitors in allergic asthma have been shown in previous preclinical and clinical studies. Because allergic rhinitis and asthma share several epidemiologic and pathophysiologic factors, PDE4 inhibitors might also be effective in allergic rhinitis. OBJECTIVE: The main objective of this study was to investigate the efficacy of oral roflumilast (500 microg/day) in allergic rhinitis. METHODS: In a randomized, placebo-controlled, double-blinded, crossover study, 25 subjects (16 male, 9 female; median age, 28 years) with histories of allergic rhinitis but asymptomatic at screening received roflumilast (500 microg once daily) and placebo for 9 days each with a washout period of at least 14 days in between treatment periods. In each of the treatment periods, controlled intranasal allergen provocation with pollen extracts was performed daily beginning the third day of treatment, each time approximately 2 hours after study drug administration. Five and 30 minutes after each allergen provocation, rhinal airflow was measured by means of anterior rhinomanometry and the subjective symptoms obstruction, itching, and rhinorrhea were assessed by means of a standardized visual analog scale. RESULTS: Rhinal airflow improved almost consistently during the 9 days of roflumilast treatment, and it was significantly higher at study day 9 on roflumilast in comparison with placebo, a result also found for itching and rhinorrhea. With respect to the subjective obstruction score, a significant difference in comparison with placebo could be demonstrated within 4 days. CONCLUSION: This study shows that a PDE4 inhibitor, roflumilast, effectively controls symptoms of allergic rhinitis. Thus PDE4 inhibitors might be a future treatment option not only in allergic asthma but also in allergic rhinitis or the combination of the 2 diseases.     

Relationship between cutaneous allergen response and airway allergen-induced eosinophilia

BACKGROUND: Determinants of changes in airway caliber after allergen challenge include nonallergic airway responsiveness, immune response and dose of allergen given. However, determinants of the airway inflammatory response to allergens remain to be determined. AIM: To assess the relationship between skin reactivity to airborne allergens and lower airway eosinophilic response to allergen exposure in asthma and allergic rhinitis. METHODS: Forty-two subjects with mild allergic asthma (mean age 24 years) and 14 nonasthmatic subjects with allergic rhinitis (mean age 25 years) had allergen skin prick tests and titration with the allergen chosen for subsequent challenge. On a second visit, 31 asthmatic subjects had a conventional challenge while 11 asthmatic subjects and all rhinitic subjects had a low-dose allergen challenge over four subsequent days. Induced sputum samples were obtained at 6 and 24 h after the conventional challenge and at days 2 and 4 of the low-dose challenge. RESULTS: In the asthmatic group, there was a weak correlation between wheal diameter induced by the concentration used for challenge and increase in eosinophils 6 h postconventional challenge (r = 0.372, P = 0.05), but no correlation was observed following the low-dose challenge. Rhinitic subjects showed a correlation between wheal diameter with the allergen dose used for bronchoprovocation and increase in eosinophils at day 2 of low dose (r = 0.608, P = 0.02). CONCLUSION: This study suggests that immediate immune responsiveness to allergen, assessed by the magnitude of the skin response, is a significant determinant of allergen-induced airway eosinophilia and can help to predict the airway inflammatory response.     

A comparison of the airway response to segmental antigen bronchoprovocation in atopic asthma and allergic rhinitis

BACKGROUND: Patients with allergic asthma and those with allergic rhinitis (without asthma) share many immunopathologic features but differ in the presence of lower airway symptoms in response to antigen. OBJECTIVES: We sought to compare the airway inflammatory response to antigen in patients with atopic asthma and allergic rhinitis. METHODS: Segmental bronchoprovocation with saline or ragweed antigen was performed in 9 patients with atopic asthma and 9 patients with allergic rhinitis without asthma. The antigen dose used in segmental bronchoprovocation was 10% of the dose that caused a 20% decrease in FEV1 in response to inhalation challenge. Bronchoalveolar lavage (BAL) was performed from the saline- and antigen-challenged segments at 5 minutes and 48 hours after challenge. BAL fluid was analyzed for cell count and differential, distribution of lymphocytes, and concentration of soluble factors (histamine, IL-5, matrix metalloproteinase 9, tissue inhibitor of metalloproteinase 1, and fibronectin). In addition, BAL cells were cultured ex vivo, and IL-5, IFN-gamma, and IL-10 generation was measured. RESULTS: Antigen challenge led to similar patterns of cellular recruitment, mediator levels, and BAL cell cytokine generation in both groups; however, the dose of antigen required to promote comparable responses in the airway was significantly less in patients with asthma. CONCLUSION: These data suggest that the pattern of acute airway inflammation in response to allergen does not by itself explain antigen-induced lower airway obstruction and asthma symptoms. We speculate that other factors, such as increased airway sensitivity to allergen or preexisting airway injury and remodeling, might explain why patients with asthma and rhinitis differ in their clinical and physiologic response to antigen exposure.