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.

STUDY OBJECTIVES:Subjects with atopic asthma often experience a disappearance of symptoms around puberty. However, airway inflammation and remodeling may persist. It is unknown whether those findings warrant prolonged anti-inflammatory treatment despite the absence of symptoms. In this study, we investigated whether a short course of combined anti-inflammatory treatment would, also in this specific patient population, diminish airway inflammation and/or remodeling. DESIGN:A double-blind, randomized placebo-controlled trial was conducted in 28 asymptomatic subjects with a history of atopic asthma, with established bronchial hyperresponsiveness to methacholine (MCh) as non-invasive indicator of ongoing airway pathology. INTERVENTIONS:Intervention consisted of the salmeterol/fluticasone propionate combination (SFC) product (50/250 microg bid via the Diskus inhaler) or placebo for 3 months. MEASUREMENTS:The change in lung function (FEV1), bronchial response to MCh and adenosine monophosphate (AMP), the fraction of nitric oxide in exhaled air (FENO) and quality of life (QOL) scores were measured. Also, bronchial biopsies were taken and cryo sections immunostained for eosinophils (major basic protein, MBP) and mast cells (tryptase and chymase) before and after treatment. The change in reticular basement membrane (RBM) thickness, one of the parameters of airway remodeling, was also determined. RESULTS:SFC treatment improved hyperresponsiveness to MCh (P = 0.014) as well as AMP (P = 0.011), and reduced FENO (P < 0.001) significantly as compared with placebo. Lung function tended to improve (NS). Furthermore, SFC treatment reduced tryptase in the subepithelium of bronchial biopsy specimens (P = 0.01), and slightly reduced RBM thickness (P = 0.05). However, eosinophils in (sub)epithelium were not significantly affected; neither were chymase levels, blood eosinophils or QOL scores. CONCLUSIONS:We found that 3 months of treatment with fluticasone propionate and salmeterol reduced airway hyperresponsiveness, FENO and tryptase density in the airway mucosa as markers of airway inflammation. MBP density in the airway mucosa and QOL were, however, unchanged. The clinical relevance of these findings, especially with respect to the long-term outcome, has not been determined yet.

SummaryBackground Inhaled corticosteroids are currently regarded as the gold standard in anti‐inflammatory therapy, however, leukotriene receptor antagonists have been ascribed anti‐inflammatory properties.Objective We directly compared the anti‐inflammatory effects of inhaled fluticasone propionate (FP, 100 μg Diskus, twice daily) and oral montelukast (MON 10 mg, nocte) in bronchial biopsies of patients with asthma in a double‐blind, double‐dummy, parallel‐group design.Methods Bronchial biopsies, serum and urine samples were collected from 36 atopic asthmatics before and after 8 weeks of treatment. Activated T cells (CD25+), eosinophils (MBP+) and mast cells (tryptase+) were analysed by immunohistochemistry. Serum eosinophil cationic protein (ECP) and IL‐5 were analysed by radio and enzyme immunoassay (EIA), respectively. Urinary 9α‐11β‐PGF2 and leukotriene E4 (LTE4) were measured by EIA.Results A comparison of changes from baseline [FP/MON ratio (95% confidence interval)] of activated T cells was not different when subjects were treated with FP compared to treatment with MON [1.00 (0.18–4.86); P=0.924]. Following treatment, mast cells in the FP group were significantly lower than in the group treated with MON [0.39 (0.16–0.97); P=0.041]. There was no difference in the number of eosinophils in the lamina propria following either treatment [0.54 (0.05–2.57); P=0.263]. However, treatment with FP resulted in a significantly greater decrease in serum ECP, compared to treatment with MON [0.37 (0.25–0.71); P=0.002].Conclusions FP appears to be superior to MON as an anti‐inflammatory therapy in mild asthmatics.

Summary Background Local airway inflammation and airway remodelling are considered important in the clinical expression of allergic asthma. Objective The aim of this study was to compare airway inflammation and remodelling in nasal and bronchial mucosa of subjects with allergic rhinitis with or without asthma. Methods Four experimental groups were formed: allergic asthma and rhinitis ( n = 19); allergic rhinitis, no asthma ( n = 18); atopic subjects, no asthma, no rhinitis ( n = 8) and non‐allergic healthy control subjects ( n = 16). Blood samples, nasal and bronchial biopsy specimens were collected during stable disease. Immunohistochemistry was performed for eosinophils (MBP), mast cells (CD117) and vascular endothelium (CD31). Epithelial loss, reticular basement membrane (RBM) thickness and subepithelial vascularity was assessed with a computer‐assisted image analysis system. Results In nasal and bronchial mucosa, numbers of eosinophils were significantly higher in rhinitis patients with and without asthma than in asymptomatic atopics ( P < 0.05) and controls ( P ≤ 0.01). In bronchial mucosa, the RBM was significantly thickened in rhinitis patients with and without asthma compared to asymptomatic atopics ( P < 0.05) and controls ( P < 0.01), while in nasal mucosa no differences were seen. Patients with asthma and rhinitis had increased numbers of blood eosinophils ( P = 0.05) and skin test reactivity ( P = 0.01) compared to patients with rhinitis only. No significant differences could be found between the investigated groups with respect to serum IL‐5 and eotaxin levels, the number of mucosal mast cells and the degree of epithelial loss and subepithelial vascularity. Epithelial desquamation was significantly increased in the bronchial mucosa compared to nasal mucosa, not only in asthmatics ( P < 0.001), but also in atopics without asthma and rhinitis ( P = 0.02). Conclusions This study shows that allergic inflammation, increased basement membrane thickness and epithelial desquamation are present in the lower airways of atopic subjects, even before the onset of clinical symptoms. Despite the presence of inflammatory cells, no structural changes could be assessed in nasal mucosa of allergic patients.

Subjects believed to have grown out of asthma often develop symptoms again later in life. Ongoing airway inflammation may determine the risk of relapse, although the mechanisms involved are still misunderstood. Additionally, patients with asthma during childhood may develop irreversible airflow obstruction ( airway remodeling) as a result of chronic airway inflammation. Recently, airway inflammation and remodeling could be demonstrated in bronchial biopsy specimens from young adults who considered themselves grown out of asthma. It is also shown that evidence of airway inflammation and remodeling can be obtained noninvasively, thereby providing the opportunity to monitor disease activity. If chronic airway inflammation and/or remodeling are consistent findings in asymptomatic subjects with a history of atopic asthma, the question arises whether natural history can be positively altered with prolonged antiinflammatory therapy. Benefits of long-term prognosis are, however, not yet shown. Since epidemiologic work has demonstrated that a certain percentage of subjects with apparently outgrown atopic asthma remains asymptomatic without needing therapy for the rest of their lives, it can be argued that "asthma remission does exist." The question is whether this percentage can be increased with prolonged antiinflammatory therapy and regular control.

Symptoms of atopic asthma often disappear around puberty. The authors recently demonstrated that this clinical remission is accompanied with ongoing airways inflammation in most subjects. The discrepancy between lack of symptoms and persistent airway inflammation suggests that perception of the symptoms is unclear. In the present study, young adults in clinical remission of atopic asthma assigned themselves a modified Borg score during methacholine and adenosine-5′-monophosphate induced bronchoconstriction. Borg scores of subjects in clinical remission were compared with those of symptomatic asthmatic subjects. A marked variation in the Borg scores at a 20% fall in the forced expiratory volume in one second was found. Significant differences in Borg scores between remission patients and asthmatics could not be detected. It was concluded that perception of dyspnoea, induced with methacholine and adenosine challenge, is similar in young adults in clinical remission of atopic asthma compared to that of patients with symptomatic asthma. Hence, an unclear perception seems to be an unlikely explanation for the discrepancy between lack of symptoms and ongoing inflammation. Other factors, including both physical and psychological ones, may play a role in the apparent absence of symptoms, thereby potentially leading to undertreatment.

OBJECTIVES:Treatment with inhaled corticosteroids reduces bronchial hyperresponsiveness and relieves airways obstruction in patients with asthma. Up to now, it is unknown whether initial improvements are maintained over a long period of time. Therefore, we assessed whether initial improvements in FEV(1), provocative concentration of histamine causing a 20% fall in FEV(1) (PC(20)), and peak expiratory flow (PEF) persist with a constant dose of inhaled corticosteroids. Furthermore, we investigated whether FEV(1), PC(20), PEF indexes, and symptom scores improve after increasing the dose of inhaled corticosteroids in patients who did not respond sufficiently to treatment with beclomethasone dipropionate (BDP), 800 microg/d.METHODS:Sixty-eight patients with bronchial hyperresponsiveness and airways obstruction completed a previous study on 3 years of treatment with terbutaline, 500 microg qid, and BDP, 200 microg qid. Fifty-eight of these patients participated in the current extension of another 2.5 years of follow-up. Every 6 months, FEV(1) and PC(20) were measured. Five patients dropped out of the study, one for pulmonary reasons. Forty-four patients continued treatment with BDP, 800 microg/d (BDP-800 group), and 9 patients received a higher dose of BDP (500 microg tid; BDP-1,500 group) after the first 3 years because of a rapid decline in FEV(1) (> 50 mL/yr) despite BDP treatment during the previous study period.RESULTS:After the initial improvement, the mean slope of individual regression lines for FEV(1), PC(20), and morning PEF were - 28 mL/yr, - 0.01 doubling concentrations per year, and 0.6 L/min/yr, respectively, in the BDP-800 group. In the BDP-1,500 group, there were no statistically significant improvements in FEV(1), PC(20), PEF indexes, and symptom scores after increasing the dose of BDP.CONCLUSIONS:We conclude that initial improvements in FEV(1), PC(20), and PEF are well preserved over 5 years in patients with obstructive airways diseases who are treated with terbutaline and BDP. In the patients who responded sufficiently to 800 microg/d of BDP, there was no accelerated decline in FEV(1) compared with the general population. Increasing the dose of BDP in a small group of patients with an accelerated fall in FEV(1) (initially treated with a moderate dose of BDP) resulted in no significant improvement in FEV(1), PC(20), PEF indexes, and symptom scores.

Symptoms of atopic asthma often disappear at puberty. However, asthmatic subjects in clinical remission will frequently have a relapse later in life. The aim of this study was to investigate whether subjects in clinical remission of atopic asthma have persistent airway inflammation and/or airway remodeling. Bronchial biopsies were obtained from subjects in clinical remission, asthmatic subjects, and healthy control subjects. The presence and/or activation state of eosinophils, mast cells, macrophages, T lymphocytes, interleukin (IL)-5, eotaxin, and inducible nitric oxide synthase (iNOS) were analyzed. Results were compared with less invasive indicators of airway inflammation. Also aspects of airway remodeling were determined. Eosinophils, T cells, mast cells, and IL-5 were significantly elevated in the airway mucosa of subjects in remission compared with control subjects. Also, blood eosinophil cell counts were significantly higher in subjects in clinical remission. Blood eosinophil cell counts, exhaled nitric oxide (eNO) levels, and bronchial response to adenosine-5'-monophosphate correlated significantly with the quantity of tissue eosinophils. Significant airway remodeling was found in subjects in clinical remission. Our study has shown ongoing airway inflammation and airway remodeling in adolescents in clinical remission of atopic asthma. Subclinical airway inflammation may well determine the risk of an asthma relapse later in life.

Mast cells and basophils are cells that play an important role in the initiation and control of allergic inflammation in asthma and rhinitis. This study was undertaken to determine the presence and dynamics of mast cells and basophils in the nasal and bronchial mucosa of allergic rhinitis patients after segmental bronchial provocation (SBP). Eight nonasthmatic, grass pollen-allergic rhinitis patients and eight healthy controls were included. Bronchial and nasal biopsies, as well as blood samples, were taken before (T(0)) and 24 h (T(24)) after SBP. Immunohistochemical staining was performed for mast cells (tryptase and chymase; phenotypes MC(T), MC(TC), MC(C)) and basophils (BB1). In the bronchial mucosa, the number of BB1(+) cells increased significantly (p < 0.05) in allergic rhinitis patients after SBP. In the nasal mucosa, the numbers of MC(C) and MC(TC) cells decreased significantly, whereas the numbers of [BB1(+)] cells increased significantly in allergic rhinitis patients after SBP (p < 0.05). In blood, the number of basophils decreased (p < 0.05) and the level of interleukin (IL)-5 increased (p < 0.05) in atopic patients after SBP. No significant changes could be observed in healthy controls. This study shows that SBP in nonasthmatic allergic rhinitis patients reduces numbers of mast cells in the nose as a result of enhanced degranulation. At the same time, there is evidence for an influx of basophils from the blood into the nasal and bronchial mucosae.

BACKGROUNDAllergic rhinitis (AR) and asthma are characterized by means of a similar inflammatory process in which eosinophils are important effector cells. The migration of eosinophils from the blood into the tissues is dependent on adhesion molecules.OBJECTIVETo analyze the aspects of nasobronchial cross-talk, we studied the expression of adhesion molecules in nasal and bronchial mucosa after nasal allergen provocation (NP).METHODSNine nonasthmatic subjects with seasonal AR and 9 healthy control subjects underwent NP out of season. Bronchial and nasal biopsy specimens were taken before (T(0)) and 24 hours after NP (T(24)). Mucosal sections were analyzed for the presence of eosinophils, IL-5, eotaxin, intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), E-selectin, and human endothelium (CD31).RESULTSAt T(24), an influx of eosinophils was detected in nasal epithelium (P =.01) and lamina propria (P <.01), as well as in bronchial epithelium (P =.05) and lamina propria (P <.05), of the patients with AR. At T(24), increased expression of ICAM-1, as well as increased percentages of ICAM-1+, VCAM-1+, and E-selectin+ vessels, were seen in nasal and bronchial tissue of patients with AR. The number of mucosal eosinophils correlated with the local expression of ICAM-1, E-selectin, and VCAM-1 in patients with AR.CONCLUSIONThis study shows that NP in patients with AR results in generalized airway inflammation through upregulation of adhesion molecules.

Studies on the role of peptidases in the pathogenesis of asthma have not been able to convincingly demonstrate a dysfunction of these enzymes in the airways of stable asthmatics. Although asthmatic airways are more responsive to tachykinin-induced bronchoconstriction and nasal congestion (Joos et al 1987, Joos et al 1994), no apparent reduction in NEP activity could be found in stable mild asthmatic patients (Cheung et al 1993). Our studies indicate that peptidase activities in BAL fluid and serum do not differ remarkably between healthy controls and allergic asthmatics. In addition, we did not observe major differences in the expression of APN and DPP IV between bronchial biopsies of asthmatics and healthy controls. No data are currently available on the expression of NEP in the airways of asthmatics compared to healthy subjects, although some data may suggest a reduced NEP expression in the bronchial epithelium, but not the lamina propria, from nonsteroid-treated asthmatics (Sont et al 1997). It seems therefore unlikely that there is a generally reduced activity of peptidases in the airways of stable asthmatic patients. To further determine whether peptidases and neuropeptides contribute to asthma, in vivo studies using selective neurokinin receptor antagonists should be performed both in the presence and absence of peptidase inhibitors.

Allergic rhinitis and asthma often coexist and share a genetic background. Pathophysiologic connections between the nose and lungs are still not entirely understood. This study was undertaken to compare allergic inflammation and clinical findings in the upper and lower airways after segmental bronchial provocation (SBP) in nonasthmatic allergic rhinitis patients. Eight nonasthmatic, grass pollen-sensitive patients with allergic rhinitis and eight healthy controls were included. Bronchial biopsies and blood samples were taken before (T(0)) and 24 h (T(24)) after SBP. Nasal biopsies were obtained at T(0), 1 h after SBP (T(1)), and T(24). Immunohistochemical staining was performed for eosinophils (BMK13), interleukin (IL)-5, and eotaxin. The number of eosinophils increased in the challenged and unchallenged bronchial mucosa (p < 0.05) and in the blood (p = 0.03) of atopic subjects at T(24). We detected an increase of BMK13-positive and eotaxin-positive cells in the nasal lamina propria and enhanced expression of IL-5 in the nasal epithelium of atopic subjects only at T(24) (p < 0.05). SBP induced nasal and bronchial symptoms as well as reductions in pulmonary and nasal function in the allergic group. No significant changes could be observed in healthy controls. The study shows that SBP in nonasthmatic allergic rhinitis patients results in peripheral blood eosinophilia, and that SBP can induce allergic inflammation in the nose.

Symptoms of atopic asthma often decrease or even seem to disappear around puberty. The aim of this study was to investigate whether this so-called clinical remission is accompanied by remission of airway inflammation, since symptoms relapse in a substantial proportion of subjects later in life. To assess indicators of inflammation and/or structural damage of the airways, exhaled nitric oxide (eNO) and bronchial responsiveness to adenosine-5'-monophosphate (AMP) and methacholine (MCh) were determined in 21 subjects in clinical remission of atopic asthma. Clinical remission was defined as complete absence of symptoms of asthma without the use of any medication in the year preceding the study. Results were compared with those of 21 patients with current asthma and 18 healthy control subjects. We found significantly higher eNO values in the remission group than in healthy controls (geometric mean, 18.9 and 1.0 ppb, respectively; p < 0.001) whereas eNO values of the remission group and those of the subjects with current asthma (geometric mean, 21.9 ppb) were similar (p = 0.09). The responsiveness to both AMP and MCh of subjects in clinical remission was significantly higher as compared with responsiveness of healthy controls, and lower than responsiveness of subjects with current asthma. A significant correlation could be established between eNO and responsiveness to AMP, but not between eNO and responsiveness to MCh. The results of this study are suggestive of persistent airway inflammation during clinical remission of atopic asthma. We speculate that subclinical inflammation is a risk factor for asthma relapse later in life, and that eNO and responsiveness to both AMP and MCh can be used as different, noninvasive indices of the inflammatory process of the airways.

Chronic inflammation and extracellular remodeling of the airway wall characterize asthma. The purpose of this study was to examine whether these features cause a change in airway mechanical properties. We examined 14 healthy and 10 young adults with long-lasting asthma, the latter treated with inhaled bronchodilators and corticosteroids. To obtain area-versus-transmural pressure (A-Ptm) curves during forced expiration (Pedersen, O. F., et al. J. Appl. Physiol. 1982;52:357-369), we used an esophageal balloon and a Pitot static probe positioned at five locations between the right lower lobe and midtrachea. Cross-sectional area (A), airway compliance (Caw = dA/dPtm), and specific airway compliance (sCaw = Caw/A) were obtained from the A-Ptm curves. Results showed that: (1) A was larger in males than in females; (2) Caw and sCaw decreased with a more downstream position; and (3) Caw and sCaw were significantly lower in the patients with asthma, with the differences between the asthmatic patients and the healthy subjects becoming smaller toward the trachea. The lower Caw and sCaw in the patients with long-lasting asthma support the concept that chronic inflammation and remodeling of the airway wall may result in stiffer dynamic elastic properties of the asthmatic airway.

Background: There has been an increasing interest in the potential systemic effects of inhaled corticosteroids. Methods: The effect of locally inhaled corticosteroids in the nose and lung on blood lymphocytes was measured in two studies. In the first study, budesonide (BUD) (200 and 800 μg), fluticasone propionate (FP) (200 and 800 μg), and placebo were administered in the nose, and BUD (1600 μg) and FP (1500 μg) were inhaled into the lungs in a blinded, randomized fashion by 12 healthy volunteers. Blood samples were taken before and 4 h after the administration of the drug, and total lymphocyte count and different subpopulations were determined. In the second study, 15 healthy volunteers were randomized to BUD (1600 μg), FP (1600 μg), or placebo inhaled into the lungs. Blood samples were taken before and 4, 8, 24, 48, and 148 h (=7 days) after inhalation of the medication. Results: Neither the nasal applications nor the inhalation of FP (1500 μg/1600 μg) showed significant differences in total lymphocyte count or different subpopulations between baseline and 4 h after the administration. In both studies, a significant reduction was found in the total lymphocyte count, B cells, T cells, and the CD4+ and the CD8+ fractions 4 h after application of BUD 1600 μg. Conclusions: Nasal application of BUD or FP in doses up to 800 μg do not induce lymphopenia. BUD 1600 μg inhalation in the lung reduces lymphocytes and their subfractions. Further studies have to be done to determine whether the results obtained in this study in healthy volunteers will also be found in patients with diseased mucosa and whether there is any correlation with adverse effects such as growth inhibition or osteoporosis.

Background Neuropeptides may be involved in the pathogenesis of asthma by evoking neurogenic inflammation. Since the effects of neuropeptides are limited by peptidases, reduced activity of peptidases may contribute to the inflammatory process. Objective We hypothesized that soluble peptidase activities are decreased in asthmatics and that inhaled glucocorticoids exert part of their anti‐inflammatory action by increasing soluble peptidase activities. Methods Serum and bronchoalveolar lavage (BAL) fluid was obtained from non‐smoking and smoking volunteers and from allergic asthmatics both before and after treatment for 12 weeks with placebo or inhaled fluticasone propionate. Activities of neutral endopeptidase (NEP), aminopeptidase N (APN) and dipeptidyl peptidase IV (DPP IV) were determined using colourometric assays. Results Reduced DPP IV activity in serum and reduced NEP activity in BAL fluid were found in healthy smokers compared with non‐smokers. In contrast, no differences in peptidase activities in serum or BAL fluid were observed between allergic asthmatics and healthy non‐smokers. Fluticasone propionate treatment did not affect peptidase activities in the asthmatic patients. Conclusions We conclude that reduced peptidase activities in serum or BAL fluid can be found in healthy smokers, but not in allergic asthmatics, and that inhaled glucocorticoids do not affect peptidase activities in BAL fluid or serum of asthmatics. Our results do not support the hypothesized dysfunction of peptidases in the asthmatic airways.

Asthma is characterized by both local infiltration of eosinophils in the bronchial mucosa and bronchial hyperreactivity (BHR). A detailed characterization of BHR implies analysis of a histamine or methacholine dose-response curve yielding not only the dose at 20% fall of baseline forced expiratory volume in 1 s (FEV1), but also a plateau (P) representing the maximal narrowing response in terms of percent change in FEV1 and reactivity as the steepest slope at 50% of P (%FEV1/doubling dose). In the baseline condition, the specific airway conductance (sGaw) may be considered closely related to airway lumen diameter. In 20 nonsmoking asthmatic patients, methacholine dose-response curves were obtained, and a sigmoid model fit yielded the BHR indexes. Immunohistochemistry with the monoclonal antibodies (EG(1) and EG(2)) was used to recognize the total number of eosinophils and activated eosinophils, respectively. The number of activated eosinophils was significantly correlated to both P (r = 0.62; P < 0.05) and sGaw (r = -0.52; P < 0.05), whereas weaker and nonsignificant correlations were found for dose at 20% fall of baseline FEV1 and the total number of eosinophils. We conclude that the number of activated eosinophils can be considered a marker of the inflammation-induced decrease of airway lumen diameter as represented by the plateau index and sGaw.