Intranasal and inhaled fluticasone propionate for pollen-induced rhinitis and asthma

BACKGROUND: Studies suggest that nasal treatment might influence lower airway symptoms and function in patients with comorbid rhinitis and asthma. We investigated the effect of intranasal, inhaled corticosteroid or the combination of both in patients with both pollen-induced rhinitis and asthma. METHODS: A total of 262 patients were randomized to 6 weeks' treatment with intranasal fluticasone propionate (INFP) 200 microg o.d., inhaled fluticasone propionate (IHFP) 250 microg b.i.d., their combination, or intranasal or inhaled placebo, in a multicentre, double-blind, parallel-group study. Treatment was started 2 weeks prior to the pollen season and patients recorded their nasal and bronchial symptoms twice daily. Before and after 4 and 6 weeks' treatment, the patients were assessed for lung function, methacholine responsiveness, and induced sputum cell counts. RESULTS: Intranasal fluticasone propionate significantly increased the percentages of patients reporting no nasal blockage, sneezing, or rhinorrhoea during the pollen season, compared with IHFP or intranasal or inhaled placebo. In contrast, only IHFP significantly improved morning peak-flow, forced expiratory volume in 1 second (FEV1) and methacholine PD20, and the seasonal increase in the sputum eosinophils and methacholine responsiveness. CONCLUSIONS: In patients with pollen-induced rhinitis and asthma, the combination of intranasal and IHFP is needed to control the seasonal increase in nasal and asthmatic symptoms.     

Dissimilarity between seasonal changes in airway responsiveness to adenosine-5'-monophosphate and methacholine in patients with grass pollen allergic rhinitis: relation to induced sputum

BACKGROUND: In patients with allergic rhinitis, bronchial hyperresponsiveness (BHR) and airway inflammation may increase during pollen exposure. BHR can be assessed by adenosine-5'-monophosphate (AMP) or methacholine challenge. It has been suggested that BHR to AMP is more closely related to airway inflammation than BHR to methacholine. Seasonal allergic rhinitis offers a dynamic model to study changes in BHR and airway inflammation during natural allergen exposure. METHODS: We measured BHR [provocative concentration causing a 20% fall (PC(20)) in forced expiratory volume in 1 s (FEV(1))] to AMP and methacholine, and induced sputum cells in 16 rhinitis patients before and during the 2001 grass pollen season. RESULTS: There was a decrease in PC(20) methacholine during pollen exposure (geometric mean PC(20) from 3.22 to 1.73 mg/ml, p = 0.0023), whereas no reduction was observed for PC(20) AMP (p = 0.11). There was no increase in sputum eosinophils [pre: 0.69% (95% confidence interval 0.22-2.07); during: 1.85 (0.55- 5.6), p = 0.31]. Although the correlation of log PC(20) methacholine and log PC(20) AMP at baseline was good (r = 0.76, p = 0.001), individual seasonal changes (doubling concentrations) in PC(20) methacholine were not correlated with changes in PC(20) AMP (rho = 0.21, p = 0.44). There was no correlation between baseline log PC(20) methacholine or seasonal changes in PC(20) methacholine and sputum eosinophils (p > 0.12, all correlations). In contrast, there was a significant correlation between seasonal changes in PC(20) AMP and changes in sputum eosinophils (rho = -0.59, p = 0.025). CONCLUSIONS: These data show dissimilarity between seasonal changes in PC(20) AMP and methacholine in patients with seasonal allergic rhinitis. Moreover, PC(20) AMP seems to be more closely related to sputum eosinophils than PC(20) methacholine. The clinical significance of this discrepancy is unclear.     

Eosinophils, secretory responsiveness and glucocorticoid-induced effects on the nasal mucosa during a weak pollen season

This study examined the seasonal effects on eosinophils and secretory responsiveness of the nasal mucosa in 22 patients with allergic rhinitis due to birch pollen (11 patients received placebo and 11 budesonide, 200 micrograms once daily in each nostril). The pollen counts during the study season were too low to produce a significant symptomatology. Hence, our findings demonstrate threshold alterations of the airway mucosa in allergic rhinitis and their inhibition by anti-inflammatory drug intervention. The patients were monitored for 8 weeks with daily recordings of pollen counts and symptom scores. Once every week a series of laboratory tests was carried out: the local eosinophil influx was determined using a Rhinobrush technique; the levels of eosinophil cationic protein (ECP) were analysed in nasal lavage fluids; and the secretory response to intranasal methacholine was measured. Treatments started after a 2-week run-in period. The proportion of eosinophils increased markedly in the placebo group and was elevated also during the last two study weeks when the pollen counts were practically nil. The secretory responsiveness to methacholine increased during the pollen season and returned to baseline towards the end of the study period. The topical glucocorticoid treatment reduced the proportion of eosinophils, the ECP levels, and the secretory response to methacholine compared to placebo. We conclude that the increased traffic and activity of eosinophils and less conspicuously the increased secretory responsiveness are expressions of the mucosal inflammation that precede the development of symptoms in seasonal allergic rhinitis.     

Effect of nasal triamcinolone acetonide on seasonal variations of bronchial hyperresponsiveness and bronchial inflammation in nonasthmatic children with seasonal allergic rhinitis.

BACKGROUND: Recent evidence suggests that patients with allergic rhinitis have lower airway inflammation and a higher prevalence of bronchial hyperresponsiveness (BHR) regardless of asthma. OBJECTIVE: To investigate markers of lower airway inflammation in nonasthmatic children with seasonal allergic rhinitis (SAR) before and during pollen season and the effect of nasal triamcinolone acetonide on seasonal variations in these parameters. METHODS: Thirty-two nonasthmatic children with SAR in response to grass and/or weed pollens were recruited and separated into 2 groups. Group 1 was treated with triamcinolone acetonide (220 microg once daily) for 6 weeks, and group 2 received no intranasal corticosteroid treatment. Bronchial responsiveness to methacholine [concentration that caused a decrease in forced expiratory volume in 1 second of 20% (PC20)], eosinophil counts in sputum and peripheral blood, and eosinophil cationic protein (ECP) levels in sputum and serum were measured before and during grass pollen season. RESULTS: Twenty-eight patients completed the study. During the pollen season, methacholine PC20 significantly decreased in both groups when compared with the corresponding preseasonal values (P = .01 and P = .003, respectively). The mean percentage of sputum eosinophils increased significantly during the pollen season compared with preseasonal values in group 1 and group 2 (12.7% +/- 2.1% vs 16.5% +/- 2.1%, P = .007, and 11.0% +/- 2.0% vs 20.2% +/- 1.4%, P = .003, respectively). Median [interquartile ranges (IQR)] sputum ECP levels were significantly higher during the pollen season when compared with the preseasonal values in group 1 and group 2 [7.5 microg/L (3.5-36.0 microg/L) vs 35.5 microg/L (13.0-71.7 microg/L), P = .04, and 18.0 microg/L (6.0-36.0 microg/L) vs 69.0 microg/L (39.0-195.0 microg/L), P = .003, respectively], as were the serum ECP levels [6.0 microg/L (2.0-13.0 microg/L) vs 19.0 microg/L (14.0-43.5 microg/L), P = .004, and 6.0 microg/L (3.0-7.0 microg/L) vs 18.0 microg/L (6.0-36.0 microg/L), P = .001, respectively]. Although the mean number of eosinophils in blood increased during the pollen season in both groups, it was only significant in group 2 (70.0 +/- 20.0 vs 161.6 +/- 29.0, P = .02). CONCLUSIONS: Although prophylactic nasal corticosteroid treatment provides significant reduction of nasal symptoms and rescue antihistamine use, there is no significant prevention in the seasonal increase of bronchial inflammation and methacholine BHR.     

Combined mediator blockade or topical steroid for treating the unified allergic airway

BACKGROUND: Asthma and allergic rhinitis are manifestations of a single unified allergic airway, for which the best treatment is uncertain. OBJECTIVE: To compare the anti-inflammatory efficacy in the unified allergic airway of combined oral mediator antagonism and combined topical steroid. METHODS: Subjects with asthma and perennial allergic rhinitis entered a randomized double blind crossover study comparing montelukast 10 mg and cetirizine 10 mg to extra-fine inhaled beclomethasone 400 mcg/day and intranasal beclomethasone 200 mcg/day, each taken once daily for 2 months, after 2-week placebo washouts. Measurements were made after each washout and randomized treatment, comprising: methacholine PC20, exhaled and nasal nitric oxide, blood eosinophils and eosinophilic cationic protein, symptoms, lung and nasal function tests. RESULTS: Seventeen patients completed per protocol. For PC20 and exhaled nitric oxide, only combined topical steroid produced improvements (P < 0.005) from placebo baseline. Combined steroid was superior by a 0.93 (95% CI 0.14-0.93, P < 0.05) doubling dilution difference for PC20 and a 0.99 (95% CI 0.9-15.1, P < 0.01) doubling difference for exhaled nitric oxide. Both treatments attenuated eosinophils and eosinophilic cationic protein, and reduced nasal symptoms (P < 0.05). Only steroid improved nasal nitric oxide (P=0.05) and asthma symptoms (P < 0.05). Neither treatment affected lung or nasal function tests. CONCLUSION: Combined topical steroid and combined mediator antagonism both attenuated systemic inflammation in the unified allergic airway, but only the former reduced bronchial and nasal inflammatory markers. The relevance of this to exacerbations and airway remodelling needs to be defined.     

Nasal beclomethasone prevents the seasonal increase in bronchial responsiveness in patients with allergic rhinitis and asthma.

Experimental studies have demonstrated that induction of a nasal allergic reaction can lead to an increase in bronchial responsiveness (BR). To assess the clinical relevance of these experimental changes to chronic asthma, we sought to determine the effect of nasal beclomethasone dipropionate (Bdp) on BR in patients with seasonal allergic rhinitis and asthma. Eighteen subjects with histories of seasonal allergic rhinitis and asthma during the fall pollen season with positive skin tests to short ragweed and bronchial hyperresponsiveness to inhaled methacholine were assigned to receive either nasal Bdp (336 micrograms/day) or placebo for the entire ragweed season. Patients recorded daily nasal and chest symptoms, nasal blockage index, oral peak expiratory flow rates, and supplemental medication use. BR to methacholine was measured during the baseline period and 6 weeks into the ragweed season. Although the Bdp group did have a significant improvement in nasal blockage index, there was no improvement in daily asthma symptom scores, oral peak expiratory flow, or asthma medication use. However, subjects treated with Bdp were protected from the increase in BR seen in the placebo group (geometric mean PC20 placebo group: baseline = 0.70, week 6 = 0.29; Bdp group: baseline = 0.80, week 6 = 0.93; intergroup difference, p = 0.022). We conclude that nasal corticosteroid therapy can prevent the increase in BR associated with seasonal pollen exposure in patients with allergic rhinitis and asthma.     

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.     

Airway inflammation in asthma and perennial allergic rhinitis. Relationship with nonspecific bronchial responsiveness and maximal airway narrowing

BACKGROUND: Eosinophilic airway inflammation is the hallmark of asthma, but it has also been reported in other conditions such as allergic rhinitis. We have tested whether the analysis of cells and chemicals in sputum can distinguish between patients with mild allergic asthma, those with allergic rhinitis, and healthy controls. The relationship between inflammation markers in sputum and nonspecific bronchial hyperresponsiveness to methacholine (BHR) (PD20 and maximal response plateau [MRP] values) was also evaluated. METHODS: We selected 31 mild asthmatics and 15 rhinitis patients sensitized to house-dust mite. As a control group, we studied 10 healthy subjects. Every subject underwent the methacholine bronchial provocation test (M-BPT) and sputum induction. Blood eosinophils and serum ECP levels were measured. Sputum cell differentials were assessed, and eosinophil cationic protein (ECP), tryptase, albumin, and interleukin (IL)-5 levels were measured in the entire sputum supernatant. RESULTS: Blood eosinophils and serum ECP levels were higher in asthma patients and rhinitis than in healthy controls, but no difference between asthma patients and rhinitis patients was found. Asthmatics had higher eosinophil counts and higher ECP and tryptase levels in sputum than rhinitis patients or control subjects. Sputum albumin levels were higher in asthmatics than in controls. Rhinitis patients exhibited higher sputum eosinophils than healthy controls. An association between sputum eosinophil numbers and MPR values (r= -0.57) was detected, and a trend toward correlation between sputum ECP levels and PD20 values (r= -0.47) was found in the rhinitis group, but not in asthmatics. No correlation between blood eosinophilic inflammation and lung functional indices was found. CONCLUSIONS: Induced sputum is an accurate method to study bronchial inflammation, allowing one to distinguish between rhinitis patients and mildly asthmatic patients. The fact that no relationship was detected between sputum inflammation and BHR suggests that other factors, such as airway remodeling, may be at least partly responsible for BHR in asthma.     

Changes in bronchial responsiveness following nasal provocation with allergen.

The relationship between upper airway inflammation and asthma is controversial. In the current study, we sought to investigate the relationship between allergic rhinitis and lower airway dysfunction by performing double-blind, randomized nasal challenges with allergen or placebo. Subjects were selected for a prior history of asthma exacerbations after the onset of seasonal allergic rhinitis symptoms. After the induction of a marked nasal-allergic reaction (with a technique of nasal provocation that limited allergen delivery to the nose), there were no changes in FEV1, specific conductance, or lung volumes either 30 minutes or 4 1/2 hours after nasal allergen challenge, nor any changes in peak flow rates followed hourly until the next day. However, nasal provocation with allergen resulted in a relative increase in bronchial responsiveness to methacholine compared with that to placebo (p = 0.011 at 30 minutes and p = 0.0009 at 4 1/2 hours after challenge). Our study suggests that, although a nasal-allergic response does not induce airflow limitation of the lower airways, it can alter bronchial responsiveness.     

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.     

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.     

Upregulation of nasal mucosal eotaxin in patients with allergic rhinitis during grass pollen season: effect of a local glucocorticoid

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.     

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.     

Nasal eosinophilic inflammation contributes to bronchial hyperresponsiveness in patients with allergic rhinitis

There are increasing evidences that allergic rhinitis (AR) may influence the clinical course of asthma. We conducted methacholine challenge test and nasal eosinophils on nasal smear to patients with allergic rhinitis in order to investigate the mechanism of connecting upper and lower airway inflammation in 35 patients with AR during exacerbation. The methacholine concentration causing a 20% fall in FEV1 (PC20) was used as thresholds of bronchial hyperresponsiveness (BHR). Thresholds of 25 mg/dL or less were assumed to indicate BHR. All patients had normal pulmonary function. Significant differences in BHR were detected in the comparison of patients with cough or postnasal drip and without cough or postnasal drip. There were significant differences of PC20 between patients with cough or postnasal drip and those without cough or postnasal drip (3.41+/-3.59 mg/mL vs 10.2+/-1.2 mg/mL, p=0.001). The levels of total IgE were higher in patients with seasonal AR than in patients with perennial AR with exacerbation (472.5+/-132.5 IU/L vs. 389.0+/-70.9 IU/L, p<0.05). Nasal eosinophils were closely related to log PC20 (r=-0.65, p<0.01). These findings demonstrated that nasal eosinophilic inflammation might contribute to BHR in patients with AR.     

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.     

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.     

Effect of immunotherapy on asthma progression, BHR and sputum eosinophils in allergic rhinitis

BACKGROUND: Bronchial hyperresponsiveness (BHR) and airway inflammation are frequently associated with allergic rhinitis, and may be important risk factors for the development of asthma. Specific immunotherapy (SIT) reduces symptom in subjects with allergic rhinitis, but the mechanisms are not clear. AIMS OF THE STUDY: To assess the effect of Parietaria-SIT on asthma progression, rhinitic symptoms, BHR, and eosinophilic inflammation. METHODS: Nonasthmatic subjects with seasonal rhinitis were randomly assigned to receive Parietaria pollen vaccine (n = 15) or matched placebo (n = 15). Data on symptoms and medication score, BHR to methacholine, eosinophilia in sputum were collected throughout the 3-year study. RESULTS: By the end of the study, in the placebo group, symptoms and medication scores significantly increased by a median (interquartile range) of 121% (15-280) and 263% (0-4400) respectively (P < 0.01), whereas no significant difference was observed in the SIT group. We found no significant changes in sputum eosinophils and BHR to methacholine in both groups throughout the study. Nine of 29 participants developed asthma symptoms during the study; of these, only two subjects (14%) in the SIT-treated group (P = 0.056). CONCLUSIONS: Parietaria-SIT reduces symptom and rescue medication scores, but no changes in BHR to methacholine or sputum eosinophilia were observed. Moreover, Parietaria-SIT appears to prevent the natural progression of allergic rhinitis to asthma, suggesting that SIT should be considered earlier in the management of subjects with allergic rhinitis.     

Influence of natural exposure to pollens and domestic animals on airway responsiveness and inflammation in sensitized non-asthmatic subjects

BACKGROUND: Atopy may be a risk factor in the development of asthma. Indoor allergens are considered to be more potent asthma inducers than outdoor ones such as pollens. Lower airway inflammation may be present in non-asthmatic subjects during natural exposure to relevant allergens and may eventually lead to the development of asthma. AIMS: To document seasonal variation in lower airway responsiveness and inflammation in sensitized non-asthmatic subjects, during natural exposure to allergens, and to determine whether it is more marked in those exposed to animals to which they are sensitized. METHODS: Twenty-two atopic subjects were seen during and out of the pollen season. All (but the controls) were sensitized to domestic animals, and to trees, grasses or ragweed. Eleven were not exposed to animals at home and 8 were exposed. They were compared with 3 normal controls. A respiratory questionnaire was administered, allergy skin prick tests, spirometry, methacholine challenge, blood and induced sputum with differential cell counts were obtained during the pollen season for all subjects. These tests were repeated out of the pollen season. RESULTS: Throughout the study, none of the subjects had asthma symptoms. Mean PC(20) was significantly lower in subjects exposed to animals compared with unexposed subjects or controls, both during and out of the pollen season. In season, subjects exposed to animals had significantly higher sputum eosinophil numbers than unexposed or normal control subjects. CONCLUSIONS: Non-asthmatic atopic subjects show variable degrees of airway responsiveness and inflammation. However, subjects exposed to animals show higher airway eosinophilia, which may suggest they are at increased risk of developing airway hyperresponsiveness and asthma.     

Bronchial responsiveness and airway inflammation in patients with nonallergic rhinitis with eosinophilia syndrome

Background: Nonallergic rhinitis with eosinophilia syndrome (NARES) is characterized by persistent nasal symptoms without allergy and by a marked eosinophil recruitment in the nasal cavities. Objective: We studied whether patients with NARES had bronchial responsiveness to methacholine and airway inflammation and examined the relationship between these factors. Methods: We selected a group of 39 patients referred to our allergy clinic for symptoms of perennial rhinitis. Atopic status was excluded by skin prick tests and RASTs. None of the patients had a history of respiratory symptoms. We preliminarily performed nasal lavage in all patients, and the diagnosis of NARES was made on the basis of the presence of at least 10% eosinophils in nasal lavage fluid. A methacholine challenge and sputum induction were also done on two different days. Results: Eosinophils in nasal lavage fluid ranged between 10% and 86%. Serum IgE levels were within normal range. Total circulating eosinophils ranged between 40 and 890/mm³. Methacholine PD₂₀ values were measurable in only 18 patients (range, 0.32 to 22.56 μmol; group 1). In the remaining 21 patients, methacholine PD₂₀ values were greater than 24 μmol (group 2). We found that differential cell counts in nasal lavage fluid in group 1 were not different from those in group 2. Methacholine PD₂₀ values were not significantly related to any cell count in the nasal lavage fluid. Induced sputum was accomplished only in 22 patients. Eosinophils in induced sputum ranged between 0% and 56.5%. Numbers of total cells, macrophages, lymphocytes, neutrophils, and epithelial cells in the two subgroups were not different. The number of metachromatic cells tended to be higher in group 1 compared with group 2 (0.31% vs 0.05%), but the difference was not significant. The eosinophil count in the induced sputum was significantly higher in group 1 compared with group 2 (16.8% vs 3.1%; p < 0.05). In the entire population, methacholine PD₂₀ values were significantly correlated with the number of eosinophils in sputum (r = –0.63; p < 0.001). Conclusion: We showed that 46% of patients with NARES but without histories of respiratory symptoms had a measurable bronchial responsiveness. The presence of bronchial responsiveness was associated with an increased number of eosinophils in induced sputum but not with the inflammatory process in the nose. (J Allergy Clin Immunol 1997;100:775-80.)     

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

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