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.     

BCG infection during pre-sensitization or even post-sensitization inhibits airway sensitivity in an animal model of allergic asthma

The objective of this study is to investigate whether BCG infection before, during or after sensitization suppresses allergen-induced airway hyperresponsiveness and eosinophilic inflammation in allergic asthma rats, and to determine the required dose of BCG to induce such an inhibition. Eighty-seven Sprague-Dawley (SD) rats were sensitized and provoked with ovalbumin (OA). A pretreatment of 6 x 10(4) or 6 x 10(5) colony forming units (CFUs) of BCG or saline was done at four different times: 3 days before sensitization, at sensitization, 3 days before provocation, or at provocation. The assessment of tracheal smooth muscle (TSM) responsiveness to electrical field stimulation or acetylcholine (ACh) and bronchoalveolar lavage (BAL) were performed 1 day after OA provocation. Doses of 6 x 10(4) CFUs inhibited TSM sensitivity of rats infected 3 days before sensitization or at sensitization, but not 3 days before provocation or at provocation. However, doses of 6 x 10(5) CFUs significantly inhibited not only the airway eosinophilia of rats infected 3 days before sensitization or at sensitization, but also the TSM sensitivity of rats infected 3 days before provocation or at provocation. In conclusion, BCG infection suppresses the development of sensitivity of airway smooth muscle and airway eosinophilic inflammation in allergic asthma rats. Furthermore, a relatively high dose of BCG infection inhibits airway sensitivity, even after allergen sensitization.     

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.     

Induction of airway remodeling of nasal mucosa by repetitive allergen challenge in a murine model of allergic rhinitis.

BACKGROUND: Although many studies regarding airway remodeling in asthma have been reported, only a few studies have investigated airway remodeling in allergic rhinitis. OBJECTIVES: To determine whether repetitive allergen challenge could induce airway remodeling in the nose and evaluate the effect of steroids using a murine model of allergic rhinitis. METHODS: To develop a mouse model of airway remodeling, ovalbumin-sensitized mice were repeatedly exposed to inhaled ovalbumin administration twice a week for 1 month and 3 months. Matched control mice were challenged with phosphate-buffered saline, and the treatment group received intraperitoneal dexamethasone injection. Trichrome, periodic acid-Schiff, hematoxylin-eosin, and immunohistochemical staining against matrix metalloproteinase 9 and tissue inhibitors of metalloproteinase 1 were performed to nasal and lung tissues, and the level of transforming growth factor beta in the nasal lavage fluid was analyzed. RESULTS: Repetitive ovalbumin challenge for 3 months induced circumferential peribronchial fibrosis in the lung. In the nose, subepithelial fibrosis, increased matrix metalloproteinase 9 and tissue inhibitors of metalloproteinase 1 expression, goblet cell hyperplasia, and submucous gland hypertrophy were observed compared with the control group. Features of airway remodeling were more prominent in the lung tissue. Administration of dexamethasone significantly inhibited these histologic changes. CONCLUSION: Airway remodeling associated with long-term allergen challenge can occur in the nasal mucosa and the lung. Steroid treatment prevents airway inflammation in response to acute allergen challenge, as well as airway remodeling by long-term allergen challenge.     

γ-Tocopherol prevents airway eosinophilia and mucous cell hyperplasia in experimentally induced allergic rhinitis and asthma

Background Traditional therapies for asthma and allergic rhinitis (AR) such as corticosteroids and antihistamines are not without limitations and side effects. The use of complementary and alternative approaches to treat allergic airways disease, including the use of herbal and dietary supplements, is increasing but their efficacy and safety are relatively understudied. Previously, we have demonstrated that γ‐tocopherol (γT), the primary form of dietary vitamin E, is more effective than α‐tocopherol, the primary form found in supplements and tissue, in reducing systemic inflammation induced by non‐immunogenic stimuli. Objective We used allergic Brown Norway rats to test the hypothesis that a dietary supplement with γT would protect from adverse nasal and pulmonary responses to airway allergen provocation. Methods Ovalbumin (OVA)‐sensitized Brown Norway rats were treated orally with γT before intranasal provocation with OVA. Twenty‐four hours after two challenges, histopathological changes in the nose, sinus and pulmonary airways were compared with gene expression and cytokine production in bronchoalveolar lavage fluid and plasma. Results We found that acute dosing for 4 days with γT was sufficient to provide broad protection from inflammatory cell recruitment and epithelial cell alterations induced by allergen challenge. Eosinophil infiltration into airspaces and tissues of the lung, nose, sinus and nasolacrimal duct was blocked in allergic rats treated with γT. Pulmonary production of soluble mediators PGE₂, LTB₄ and cysteinyl leukotrienes, and nasal expression of IL‐4, ‐5, ‐13 and IFN‐γ were also inhibited by γT. Mucous cell metaplasia, the increase in the number of goblet cells and amounts of intraepithelial mucus storage, was induced by allergen in both pulmonary and nasal airways and decreased by treatment with γT. Conclusions Acute treatment with γT inhibits important inflammatory pathways that underlie the pathogenesis of both AR and asthma. Supplementation with γT may be a novel complementary therapy for allergic airways disease.     

Effect of natural seasonal pollen exposure and repeated nasal allergen provocations on elevation of exhaled nitric oxide

Background:  Exhaled nitric oxide (FENO) is a marker for allergic airway inflammation. We wondered whether in patients with intermittent allergic rhinitis only (i) natural pollen exposure and (ii) artificial pollen exposure by repeated nasal allergen provocations may lead to an elevation of FENO.
Methods:  In two prospective studies, we compared the FENO of nonatopic controls with the FENO of nonasthmatic individuals with mild intermittent rhinitis to tree and/or grass pollen. Study I: 13 atopic individuals and seven controls had measurements of FENO, blood eosinophils and eosinophilic cationic protein (ECP) before, during and after pollen season. Study II: 16 atopic individuals and 12 controls had nasal allergen provocations on four following days out of pollen season, with daily measurements of FENO before, 2 and 6 h after provocation, and determination of blood eosinophils, ECP and FEV1 at baseline, on days 5 and 10–12.
Results:  Natural pollen exposure (study I) caused a significant elevation of FENO in allergic individuals. Nasal allergen provocations (study II) did not elicit a statistically significant rise neither of FENO nor of blood eosinophils between baseline and day 5. However, a subgroup of four individuals with a rise of blood eosinophils during nasal allergen provocations showed also a rise of FENO.
Conclusions:  We suppose that in allergic rhinitis a concomitant reaction of the bronchial system is dependent on a strong local inflammation leading to a generalized immune stimulation.     

Advances in upper airway diseases and allergen immunotherapy

Evidence for one airway continues to accumulate. Nasal allergen challenges increase lower airway inflammation, and nasal corticosteroid treatment reduces lower airway inflammation. Allergic respiratory inflammation might even spread systemically to involve nonrespiratory organs. Eosinophilic enteritis and eosinophilic esophagitis are reported during pollen seasons in patients with seasonal allergic rhinitis. Chronic hypertrophic sinusitis (CHS) is found in the majority of patients with asthma. Like asthma, the histology of CHS is characterized by epithelial damage, basement membrane thickening, and eosinophilic inflammation. The damaged epithelium might explain the acute bacterial exacerbations seen in patients with CHS. Studies have extended evidence of the safety and efficacy of the second- and third-generation antihistamines to younger children and to patients with perennial rhinitis but continue to show improvement of symptom scores over that seen with placebo of less than 20%. Studies on antihistamine use in the first trimester in nearly 500 women (65% taking loratadine) revealed no increase in the complications of pregnancy or congenital anomalies. Positive skin prick test responses to birch in asymptomatic young adults predicted later development of clinical allergic rhinitis. A dose response was demonstrated for immunotherapy with cat dander extract. The best results were in subjects receiving a dose containing 15 microg of the major cat allergen Fel d 1 (equivalent to approximately 2500 bioequivalent allergen units). Both topical intranasal immunotherapy and high-dose sublingual immunotherapy have been repeatedly proved to be safe and effective in double-blind, placebo-controlled studies. CD4+CD25+ regulatory T cells secreting IL-10, TGF-beta, or both appear important in normal individuals and in patients treated with allergen immunotherapy in maintaining or restoring normal T(H)1/T(H)2 balance and overall suppression of both phenotypes.     

Comparison of allergen-induced late inflammatory reactions in the nose and in the skin in house dust mite-allergic patients with or without asthma

BACKGROUND: It remains to be established which factors contribute to the occurrence of asthma in allergic individuals. We hypothesized that differences in the late allergic inflammatory reaction to allergen between asthmatic and non-asthmatic house dust mite-allergic individuals might contribute to the difference in the clinical presentation of allergy. AIM: To compare allergen-induced changes in parameters for cellular inflammation during the phase of the late allergic reaction in the skin and nose, in house dust mite-allergic individuals with or without asthma. MATERIAL AND METHODS: Nasal and dermal allergen challenges with house dust mite (Dermatophagoides pteronyssinus) extract were performed in 52 house dust mite-allergic individuals, of whom 26 had mild to moderate persistent asthma and 26 had perennial rhinitis without current or past asthmatic symptoms. Serial nasal lavage samples were analyzed for the presence of inflammatory cells (eosinophils and neutrophils) and soluble markers associated with cellular inflammation [interleukin-5 (IL-5), interleukin-8 (IL-8), eosinophil cationic protein (ECP) and myeloperoxidase (MPO)]. Macroscopic late phase skin reactions were studied after intracutaneous skin tests with house dust mite extract. RESULTS: Fixed dose nasal allergen provocation elicited a similar degree of immediate allergic reaction as judged by plasma protein exudation and histamine concentrations in asthma and non-asthmatic rhinitis. Subsequently, no differences between groups were found during the phase of the late allergic reaction (4-24 h) in inflammatory cell influx, plasma protein leakage, ECP or MPO. Likewise, there were no differences in levels of chemotactic cytokines IL-5 and IL-8. In agreement with the results of nasal challenge, the late skin reaction after dermal challenge with a fixed allergen dose and after an allergen dose 10,000 times above the skin threshold for an early skin reaction did not differ between the groups. CONCLUSION: House dust mite-allergic patients with or without asthma have very similar late allergic inflammatory reactions in the skin and in the nose after allergen challenge. Hence, it is unlikely that the occurrence of pulmonary symptoms in asthma is explained by a general tendency of asthmatics to have an enhanced late allergic cellular inflammatory response. Nasal and dermal allergen provocations are adequate models to study allergen-induced inflammation but probably lack the pivotal link which is essential for the development of asthma.     

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.     

Aggravation of bronchial eosinophilia in mice by nasal and bronchial exposure to Staphylococcus aureus enterotoxin B

BACKGROUND: The role of bacterial enterotoxins like Staphylococcus aureus enterotoxin B (SEB) in allergic asthma remains unknown. We used a mouse model of airway allergy to study the effects of nasal or bronchial contact with SEB on bronchial allergic inflammation. METHODS: The features of allergic asthma were induced in ovalbumin (OVA)-sensitized mice (days 1-13) by repeated exposures to nebulized OVA (days 33-37). Nasal or bronchial application of SEB was performed on three occasions (days 33-35-37), and the effects on bronchial inflammation, IgE titres and expression levels of mRNA for T helper type 2 cytokines and other inflammatory mediators were evaluated. RESULTS: Both nasal and bronchial SEB enhanced the allergen-induced bronchial inflammation, as reflected by more eosinophilic inflammation in the airway lumen and in bronchial tissue. Aggravation of experimental asthma correlated with higher expression of mRNA for IL-5, IL-4, IFN-gamma, IL-12 p40, eotaxin-1 and TGF-beta in bronchi. In addition, nasal SEB elevated concentrations of IL-4, IL-5 and IFN-gamma in serum and bronchial SEB increased titres of OVA-specific and total IgE in serum. CONCLUSION: Our data illustrate the potential of both nasal as well as bronchial SEB to aggravate several features of allergic asthma in a mouse model.     

Occupational asthma and rhinitis due to glutaraldehyde: changes in nasal lavage fluid after specific inhalatory challenge test

BACKGROUNDd: Glutaraldehyde (GA) is a known respiratory sensitizers, and some studies have reported occupational asthma in exposed workers. Specific changes in nasal lavage fluid (NLF) induced by high-molecular-weight allergen provocation in sensitized subjects were described previously. The purpose of this study was to evaluate the changes in cytogram, protein content, eosinophil cationic protein (ECP), and mast-cell tryptase concentrations in NLF after GA inhalation challenge in patients with a positive history of GA-induced asthma and late or dual asthmatic response due to exposure to low-level GA. METHODS: A single-blind, placebo-controlled study was performed on 11 health workers with occupational asthma and rhinitis due to GA. The control groups comprised 10 atopic subjects with perennial asthma and rhinitis and 10 healthy ones. A "nasal pool" technique was used to evaluate the examined parameters in nasal washings before and 30 min, 4 h, and 24 h after the inhalatory provocation with GA and placebo. RESULTS: There was a significant increase in eosinophil number and percentage, and albumin, ECP, and tryptase concentrations in NLF from patients with occupational asthma and rhinitis when compared to controls. CONCLUSIONS: The results indicate the immunologic mechanism of GA-induced asthma and the applicability of the "nasal pool" technique as the diagnostic procedure in GA-induced airway allergy.     

Nasal nitric oxide: longitudinal reproducibility and the effects of a nasal allergen challenge in patients with allergic rhinitis

BACKGROUND: Exhaled nitric oxide (eNO) is a validated noninvasive marker of airway inflammation in asthma. In patients with allergic rhinitis (AR), increased levels of nasal nitric oxide (nNO) have also been measured. However, the applicability of nNO as a marker of upper airway inflammation awaits validation. AIM: To test the longitudinal reproducibility of standardized nNO measurements in patients with AR and the effects of nasal allergen challenge. METHODS: Twenty patients with clinically stable, untreated AR participated in a combined study design. First, reproducibility of nNO was tested over 1, 7, and 14-21 days. Subsequently, the effect of nasal allergen challenge on nNO was studied in a placebo-controlled, parallel design. Nasal NO was measured with a chemoluminescence analyzer. Ten subjects randomly underwent a standardized nasal allergen challenge; 10 subjects received placebo. Response to nasal challenge was monitored by composite symptom scores. RESULTS: There was a good reproducibility of nNO up to 7 days [coefficient of variation (CV) over 1 (16.45%) and 7 days (21.5%)], decreasing over time [CV (14-21 days): 38.3%]. As compared with placebo, allergen challenge caused a significant increase in symptom scores (P < 0.001), accompanied by a decrease in nNO at 20 min postchallenge (P = 0.001). Furthermore, there was a gradual increase in nNO at 7 h, reaching significance at 24-h postallergen (P = 0.04). CONCLUSIONS: Similar to eNO in asthma, nNO is a noninvasive marker, potentially suitable to monitor upper airway inflammation following allergen-induced late response. Present data show a good reproducibility of nNO measurements, decreasing over time, probably because of subclinical seasonal influences.     

Lipopolysaccharide administration to the allergic nose contributes to lower airway inflammation

Background Allergic rhinitis (AR) is an inflammatory reaction not confined to a single local compartment, but rather involving the whole airway system. Allergens known to induce AR are not always the sole trigger of the inflammatory reaction as infections and organic dust might also cause exacerbations of rhinitis and associated conditions. Objective To examine the effects of intranasal lipopolysaccharide (LPS) exposure, as a surrogate for upper airway bacterial infections, in patients with symptomatic AR. Methods Fourteen patients with a history of moderate to severe pollen‐induced AR were challenged intranasally with LPS. After 3–6 weeks, the same patients were challenged again, first with allergen and 24 h later with LPS. Nasal symptom scores, nasal lavage leucocyte counts and nasal airway resistance were assessed at 6–24 h after each provocation along with measurements of nitric oxide (NO) levels in the nose and lung. Results Six hours after the LPS challenge, an increased level of leucocytes could be obtained in the lavage fluid, but no symptoms were experienced and no increase in nasal resistance could be recorded. The NO production in the upper and lower airways was similar before and 6 h after the provocation. In contrast, in patients exposed to pollen before the LPS challenge, both the nasal and the pulmonary NO levels were enhanced. This was accompanied by an increase in leucocytes. Conclusion The present study demonstrates a priming effect of allergen on the nasal response to LPS as well as the presence of a systemic link between airway mucosal sites in the upper and lower airways. This suggests that exogenously derived signals, like upper airway infections, can interfere with the initiation, maintenance and progression of asthma.     

Effects of allergic inflammation of the nasal mucosa on the severity of rhinovirus 16 cold

BACKGROUND: Despite the strong association of asthma exacerbations with rhinovirus (RV) infection, inoculation of asthmatic subjects with RV only causes small changes in lower airway function, suggesting that RV infection is not itself sufficient to provoke asthma exacerbations. OBJECTIVE: Our purpose was to test whether allergic inflammation increases the airway response to RV infection. METHODS: We compared the severity of RV type 16-induced colds in 2 groups of 10 subjects with allergic rhinitis. One group received 3 nasal challenges with allergen and the other received challenges with placebo over the week before nasal inoculation with RV type 16 (4000 tissue culture infective dose 50% per subject). Subjects kept symptom diaries and were assessed with spirometry, methacholine challenge, nasal lavage, and sputum induction on days 2, 4, 7, 10, 15, and 30 after inoculation. RESULTS: The 2 groups developed equal rates of infection (90%), similar cold symptoms (Jackson score median [interquartile range], 11 [6-33] vs 20.5 [6-42] for allergen and placebo groups respectively, P =.54), and similar changes in cellular profile and in IL-6 and IL-8 concentrations in nasal lavage fluid and induced sputum after RV inoculation. The incubation period was significantly longer in the allergen group (2.5 [1-5.5] vs 1 [1-1] day, P =.03) and the duration of cold symptoms was shorter (5 [4-7] vs 8.5 [6-10] days, P =.008). We also found an inverse correlation between the percent of eosinophils in nasal lavage fluid before inoculation and the severity of cold symptoms (r = -0.58, P =. 008). CONCLUSION: In subjects with allergic rhinitis, augmented nasal allergic inflammation before inoculation with RV type 16 does not worsen the severity of cold symptoms but delays their onset and shortens their duration.     

Adult-onset eosinophilic airway diseases

Eosinophilic airway inflammation is one of the cardinal features of allergic airway diseases such as atopic asthma and allergic rhinitis. These childhood-onset conditions are mediated by allergen and allergen-specific IgE and often accompanied by other allergic diseases including food allergy and eczema. They can develop consecutively in the same patient, which is referred to as an allergic march. In contrast, some phenotypes of asthma, nonsteroidal anti-inflammatory drugs-exacerbated airway disease (N-ERD), chronic rhinosinusitis with nasal polyps (CRSwNP)/eosinophilic CRS and allergic bronchopulmonary aspergillosis/mycosis (ABPA/ABPM) are adult-onset airway diseases, which are characterized by prominent peripheral blood eosinophilia. Most of these conditions, except for ABPA/ABPM, are nonatopic, and the coexistence of multiple diseases, including an adult-onset eosinophilic systemic disease, eosinophilic granulomatosis with polyangiitis (EGPA), is common. In this review, we focus on eosinophil biology, genetics and clinical characteristics and the pathophysiology of adult-onset eosinophilic asthma, N-ERD, CRSwNP/eosinophilic CRS, ABPA/ABPM and EGPA, while exploring the common genetic, immunological and pathological conditions among these adult-onset eosinophilic diseases.     

Evaluation of the nasal provocation test for its necessity in the diagnosis of nasal allergy to house dust mite

The aim of this study was to evaluate rhinomanometric responses to nasal allergen provocation in children with allergic rhinitis sensitized to house dust mite. We studied 51 children, aged 6-16 years (mean: 11.5 +/- 2.6 years), with clinical symptoms of perennial allergic rhinitis without asthma and 20 non-atopic healthy controls in the same age range (mean: 11.8 +/- 3.8 years). All of the patients had positive skin prick test (SPT) results and serum specific IgE above 0.70 kU/l to Dermatophagoides pteronyssinus (Dp). Nasal provocation testing (NPT) was performed with increasing concentrations of Dp extracts and the nasal response was evaluated by active anterior rhinomanometry. A 100% increase of resistance in one or both nasal cavities was considered positive. There was a statistically significant difference of baseline nasal resistance (total, right and left sides) between the control and the patient groups (p < 0.001). A positive response to house dust mite allergens was recorded in 47/51 (92.2%) patients by rhinomanometry. The NPT presented no significant correlation with age, weight, height, SPT diameter, serum total and specific IgE levels to Dp and baseline nasal airway resistance values. This study suggests that a nasal provocation test with allergen is unnecessary in children with positive skin prick test and serum IgE specific to house dust mite. The rhinomanometric response to the allergen provocation does not correlate with the diameter of the skin prick test and the level of serum specific IgE.     

Involvement of eosinophils in the early-phase allergic reaction in a guinea pig rhinitis model

BACKGROUND: Eosinophils are found in the nasal lavage fluid (NLF) and nasal biopsies of patients with allergic rhinitis after a nasal antigen challenge, and associated not only with a late-phase allergic reaction (LPR) but also an early phase allergic reaction (EPR). Numerous studies have been carried out to clarify the participation of eosinophils in LPR or airway hyperresponsiveness. However, there has been no published report describing in detail the role of eosinophils during EPR. To better understand the involvement of eosinophils in EPR, we studied the effects of repeated antigen challenges on nasal airway responsiveness and eosinophilic inflammation in EPR using a guinea pig rhinitis model. METHODS: Nasal airway responsiveness was measured as the nasal airway resistance (NAR) after nasal antigen provocation. Eosinophilic inflammation during EPR was assessed by nasal lavage and histopathological examination using two groups of animals: those in group 1 were subjected to a sensitization pretreatment only, and those in group 2 were subjected to a pretreatment of sensitization followed by repeated nasal challenges. RESULTS: Repeated antigen challenges induced nasal hyperresponsiveness as indicated by a decrease in the antigen provocation dose and a significant increase in NAR. Furthermore, significant increases in eosinophil counts, eosinophil peroxidase (EPO) activity and protein content in NLF during EPR were observed following antigen provocation in group 2. There were significant correlations between the levels of these parameters, and albumin was the most prevalent of the proteins in NLF. Histopathological examination showed that the degree of eosinophil infiltration into the lamina propria of the nasal mucosa of the animals in group 2 was significantly and apparently higher than in group 1. Particularly, epithelial disruption and mucosal edema were significantly elevated after antigen provocation in group 2. CONCLUSIONS: These results suggest that chronic eosinophil accumulation is induced by repeated antigen challenges in the nasal tissue, and that once antigen provocation occurs, eosinophils in the tissue are activated and responsible for the amplification of EPR such as vascular permeability and mucosal edema.     

Eosinophilic inflammation, remodeling of lower airway, bronchial responsiveness and cough reflex sensitivity in non-asthmatic subjects with nasal allergy

BACKGROUND: It has been reported that nasal allergy influences the lower airway inflammation and functions. We elucidated whether nasal allergy would contribute to lower airway inflammation and functions. METHODS: 266 subjects aged 21-39 years were interviewed with special emphasis on history of asthma and nasal allergies (perennial allergic rhinitis (PAR) and seasonal allergic rhinitis (Japanese cedar pollinosis; PO)). Symptomatic subject was defined when nasal symptoms were present during a 3-week study period. Pulmonary function, provocative concentration of methacholine causing a 20% fall in forced expiratory volume in 1 s (PC20), capsaicin cough threshold defined as capsaicin concentration eliciting 5 or more coughs (C5) and eosinophil percentage in hypertonic saline-induced sputum were measured. RESULTS: Based on the interview, 232 subjects without asthma were divided into symptomatic (n = 25) and asymptomatic (n = 22) PAR, PO on-season (n = 15) and off-season (n = 36), and non-nasal allergy subjects (control) (n = 134). Sputum eosinophils were significantly greater in symptomatic PAR than another four groups (p < 0.01). FEV1/FVC ratio was significantly lower in PAR than control (p < 0.05). Maximum mean expiratory flow was lower in PAR than control (asymptomatic: p < 0.05, symptomatic: p = 0.06). C5 was not different among groups. PAR tended to have a lower PC20 compared to control (symptomatic: p = 0.078; asymptomatic: p = 0.086). CONCLUSIONS: These results suggest that eosinophilic inflammation occurred in symptomatic period of PAR may contribute to development of lower airway remodeling and bronchial hyperresponsiveness. Reversely, PO may not be associated with lower airway eosinophilic inflammation or abnormal bronchial functions. Nasal allergy dose not influence the cough reflex sensitivity.     

Nasal conditioning in perennial allergic rhinitis after nasal allergen challenge

BACKGROUND: Antigen challenge in seasonal allergic rhinitis is considered to be associated with an increased ability of the nose to condition inspired air. In contrast, little is known about air conditioning after antigen challenge in perennial allergic rhinitis (PAR). OBJECTIVE: The aims of this study were to investigate whether antigen challenge in PAR changes nasal air conditioning and to assess the relationship between nasal conditioning and nasal patency and geometry. METHODS: Nineteen subjects with PAR were enrolled into this study. Measurement of nasal conditioning, active anterior rhinomanometry (AAR), acoustic rhinometry (AR), and clinical symptom evaluation were performed before and after nasal allergen challenge with allergen extracts from house dust mites. RESULTS: Ten and 20 min after nasal allergen challenge, the total water content of the air measured in the nasopharynx and the water gradient across the nose were significantly higher in the nasal cavity in which the allergen extract was sprayed. The temperature on both sides of the nose increased non-significantly after nasal allergen challenge. No correlation to data obtained by AAR, AR, and clinical symptom evaluation after nasal allergen challenge was found. CONCLUSION: We suggest that an increase in mucosal humidity due to the allergic provocation might be responsible for the increase in nasal conditioning capacity because no correlation to changes in nasal perimeter and patency was found.     

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.