pulmicort and Hypersensitivity

Exercise-induced bronchoconstriction occurs in a large proportion of children with asthma, limiting everyday activities important for their physical and social development.. The purpose of this randomized, double-blind, placebo-controlled study was to compare the ability of different patterns of antiasthmatic treatment, recommended in childhood asthma, to protect patients from exercise-induced bronchoconstriction.. Children 6 to 18 years of age with atopic asthma were randomized to a 4-week, placebo-controlled, double-blind trial. Patients were randomly allocated to receive daily 200 microg budesonide (twice daily, 100 microg per dose) + 9 microg formoterol (twice daily, 4.5 microg per dose; n = 20); 200 microg budesonide + 5 or 10 mg montelukast (once daily at bedtime; n = 20); 5 or 10 mg montelukast (n = 20); 200 microg budesonide (n = 20); or placebo (n = 20). A standardized treadmill exercise challenge was performed before and after treatment.. Exercise-induced bronchoconstriction, reflected by area under the curve for the FEV1 values from exercise over the 20-minute period and by maximum percent fall in FEV1 after exercise, was significantly diminished after 4 weeks in all active treatment groups, and compared with placebo. Exercise-induced bronchoconstriction protection improved more significantly in the budesonide + montelukast and montelukast groups compared with other therapeutic options.. These data indicate differences in effects on exercise-induced bronchoconstriction between therapeutic options recommended in childhood asthma. Control of childhood asthma with exercise-induced bronchoconstriction can be obtained by using regular controller treatment.

Topics: Acetates; Adolescent; Anti-Asthmatic Agents; Antigens, Dermatophagoides; Asthma; Bronchoconstriction; Bronchodilator Agents; Budesonide; Child; Cyclopropanes; Double-Blind Method; Drug Therapy, Combination; Ethanolamines; Exercise; Female; Forced Expiratory Volume; Formoterol Fumarate; Glucocorticoids; Humans; Hypersensitivity; Male; Quinolines; Sulfides; Treatment Outcome

Although sublingual immunotherapy (SLIT) is accepted to be a viable alternative of specific-allergen immunotherapy, the efficacy of long-term SLIT in asthmatic children is not well established. The efficacy of 3 yr of SLIT in addition to pharmacotherapy was compared with pharmacotherapy alone in a prospective, open, parallel-group, controlled study. Children with asthma aged 4-16 yr, sensitive to house dust mite (HDM) were followed up for a run-in period of 1 yr and then grouped as those who would receive SLIT + pharmacotherapy (n = 62) or pharmacotherapy alone (n = 28). All patients were evaluated based on symptom-medication scores and lung function tests every 3 months, as well as skin-prick test and serum total immunoglobulin E (IgE) levels annually for 3 yr. Children in the SLIT + pharmacotherapy group demonstrated significantly lower mean daily dose and annual duration of inhaled corticosteroid (ICS) usage when compared with controls. At the end of the 3 yr, within-group comparisons revealed statistically significant decreases in the dose and duration of ICS only in the SLIT group. Furthermore, 52.4% of subjects in the SLIT + pharmacotherapy group were able to discontinue ICS treatment for at least 6 months, which was only 9.1% for the pharmacotherapy group. Three years of SLIT as an adjunct to pharmacotherapy resulted in reduction of both the duration and dose of ICSs and successful discontinuation of ICSs along with improvement in lung functions in HDM-allergic children with asthma.

Topics: Administration, Inhalation; Administration, Sublingual; Adolescent; Adrenal Cortex Hormones; Animals; Anti-Asthmatic Agents; Antigens, Dermatophagoides; Asthma; Budesonide; Child; Child, Preschool; Combined Modality Therapy; Desensitization, Immunologic; Female; Humans; Hypersensitivity; Immunoglobulin E; Infant; Male; Prospective Studies; Pyroglyphidae; Respiratory Function Tests; Skin Tests; Time Factors; Treatment Outcome

Exhaled nitric oxide (FE(NO)) was evaluated in children with asthma after 4 to 6 years of treatment with budesonide, nedocromil, or albuterol as needed.. FE(NO), spirometry, total eosinophil count, and serum eosinophil cationic protein levels were obtained from 118 children at the Denver site of the Childhood Asthma Management Program upon completion of treatment and after a 2- to 4-month washout.. Budesonide-treated patients had significantly lower median (1st, 3rd quartile) FE(NO) (21.5 [13.2, 84.4] vs 62.5 [26.2, 115.0] ppb, P <.01) and eosinophil cationic protein levels (17.4 [10.1, 24.3] vs 24.0 [15.4, 33.9] mg/dL, P =.05) compared with placebo, whereas no differences were noted between nedocromil and placebo groups. After washout, FE(NO) levels were similar between the three treatments. FE(NO) levels significantly correlated with degree of bronchial hyperresponsiveness, bronchodilator reversibility, allergen skin prick tests, serum IgE, and total eosinophil count. FE(NO) levels were also higher in patients with nocturnal symptoms and in patients requiring beta-agonist use at least once weekly.. Budesonide therapy was more effective than nedocromil in reducing FE(NO). Unfortunately, the effects of long-term budesonide were not sustained after its discontinuation. FE(NO) may be a complementary tool to current practice guidelines in assessing asthma control and medication response.

Topics: Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Blood Proteins; Bronchoconstrictor Agents; Budesonide; Child; Child, Preschool; Cohort Studies; Eosinophil Granule Proteins; Eosinophils; Female; Forced Expiratory Volume; Humans; Hypersensitivity; Immunoglobulin E; Leukocyte Count; Male; Methacholine Chloride; Nedocromil; Nitric Oxide; Respiration; Respiratory Function Tests; Ribonucleases; Severity of Illness Index; Skin Tests; Spirometry; Statistics, Nonparametric

We investigated the 1-year outcome of children hospitalized for wheezing, paying special attention to the effect of early anti-inflammatory therapy. In addition, we identified risk factors for recurrent wheezing and asthma. Eighty-eight children under 2 years old treated in the hospital for wheezing were followed for 1 year. Nebulized anti-inflammatory therapy was given for 16 weeks: 31 patients received budesonide, 29 patients cromolyn sodium, and 28 control patients received no therapy. The number of subsequent physician-diagnosed wheezing episodes was recorded. Four months of anti-inflammatory therapy did not significantly decrease the occurrence of asthma 1 year later; 45% of patients in the cromolyn group, 42% in the budesonide group, and 61% in the control group had asthma, defined as at least two bronchial obstruction episodes during the 1-year period after the original hospitalization for wheezing. An age over 12 months at the time of the initial bronchial obstructing episode [P=0.009, risk ratio (RR)=5.4, 95% confidence interval (CI)=1.53-19.31], failure to identify a viral cause (P=0.0003, RR=12.0, CI=3.16-45.40), history of wheezing (P=0.02, RR=14.6, CI=1.59-132.10), the presence of atopy (P=0.01, RR=5.3, CI=1.47-19.21), a family history of atopy (P=0.03, RR=3.6, CI =1.15-11.12), and serum eosinophil cationic protein (ECP) > or = 16 microg/L (P=0.005) were significant risk factors for asthma. We conclude that early anti-inflammatory therapy for 4 months does not significantly decrease the occurrence of asthma during the period of 1 year following hospitalization for the original episode of wheezing. Young children requiring hospital admission for wheezing during a respiratory tract infection are at increased risk of having subsequent asthma if they have wheezed previously, if they have atopy or a family history of atopy, if they have elevated serum ECP, if they are over 12 months of age at the original bronchial obstructive episode, and especially when viral studies are negative.

Topics: Administration, Inhalation; Administration, Oral; Analysis of Variance; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Bronchi; Budesonide; Chi-Square Distribution; Child, Preschool; Cromolyn Sodium; Dermatitis, Atopic; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypersensitivity; Infant; Infant, Newborn; Logistic Models; Male; Prospective Studies; Recurrence; Respiratory Sounds; Risk Factors; Theophylline; Time Factors

We challenged 30 pollen-sensitive volunteers with allergen, recorded symptoms and signs over a 10-h period, and rechallenged them after 24 h, in order to characterize the early and late allergic symptom response in the nose. The challenge was performed after topical pretreatment with the glucocorticosteroid budesonide (200 micrograms twice daily) for 14 d and with placebo in a double-blind, cross-over trial. The early response, consisting of sneezing, discharge, and blockage, was followed by a weak late response, consisting of a few sneezes and nose-blowings, and of a sustained nasal blockage. These symptoms did not have a well-defined peak in time, and a biphasic symptom curve could not be identified. The rechallenge response showed increased nasal responsiveness. The degree of budesonide effect on the early response varied, depending on the symptom; there was a marked effect on sneezing (72% reduction; P < 0.01), a moderate effect on discharge (37% reduction; P < 0.01), and a slight effect on blockage (17% reduction of nasal inspiratory peak flow rate; P < 0.02). The degree of inhibition of the rechallenge response was similar to the effect on the initial early response. The effect on the late response was very pronounced for all symptoms and signs (97% reduction of sneezes, 76% reduction of nose-blowings, 96% reduction of blockage; P < 0.01). In conclusion, we found it difficult in the individual subject to identify a well-defined late symptom response by criteria similar to those employed to characterize the late response in the bronchi. The effect of budesonide was more marked on sneezing than on blockage, and the drug was considerably more effective on the late response than on the early response.

Topics: Administration, Topical; Adolescent; Adult; Airway Resistance; Allergens; Anti-Inflammatory Agents; Budesonide; Double-Blind Method; Female; Glucocorticoids; Humans; Hypersensitivity; Male; Nasal Provocation Tests; Nose; Pregnenediones

Twenty two allergic patients with bronchial asthma completed this study. Effects of long-term treatment with inhaled cromoglycate 4 x 2 mg.day-1 were compared to the effects of inhaled budesonide 4 x 0.1 mg.day-1 on symptoms, additional beta 2-agonist use, lung function and bronchial hyperresponsiveness measured by the provocation concentration of histamine producing a 20% fall in forced expiratory volume in one second (FEV1) (PC20 histamine) and exercise-induced fall in FEV1. The study was carried out in a double-blind way with a randomized crossover design using a double-dummy technique. After a single-blind placebo period, the two active treatment periods of 6 weeks were separated by a single-blind placebo period. Symptom score and beta 2-agonist use decreased during both active treatment periods, which showed no mutual differences. Morning and evening peak expiratory flow rates were significantly higher during treatment with budesonide versus placebo (p less than 0.01 and p less than 0.001), and also versus cromoglycate (p less than 0.02 and p less than 0.05). FEV1 showed improvement after a 6 week treatment with budesonide versus placebo (p less than 0.05), although there was no significant difference between the two active treatments. PC20 histamine did not change during treatment with cromoglycate. Budesonide showed a significant increase in PC20 histamine versus placebo (p less than 0.05) and was marginally significantly better than cromoglycate (p = 0.05). Exercise-induced fall in FEV1 was not changed by cromoglycate, but improved significantly during budesonide in comparison with placebo (p less than 0.01) and also with cromoglycate (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Inhalation; Adolescent; Adult; Anti-Inflammatory Agents; Asthma; Bronchial Provocation Tests; Budesonide; Cromolyn Sodium; Double-Blind Method; Exercise Test; Female; Humans; Hypersensitivity; Male; Middle Aged; Pregnenediones; Random Allocation

To describe the clinical and laboratory profile, natural course, treatment outcome, and risk factors of posttransplant esophageal and nonesophageal eosinophilic gastrointestinal disorders (EGIDs).. All children (aged <18 years) who underwent liver transplantation, between 2011 and 2019, in a single transplant center with a follow-up period of 1 year or more posttransplant and with a history of posttransplant endoscopic evaluation were included in this study.. During the study period, 89 children met the inclusion criteria. Patients were followed for a median of 8.0 years. A total of 39 (44%) patients were diagnosed with EGID after transplantation. Of these, 29 (33%) had eosinophilic esophagitis (EoE), and 10 (11%) had eosinophilic gastritis, gastroenteritis or enterocolitis. In comparison with the non-EGID group, patients with EGID were younger at transplant (P ≤ 0.0001), transplanted more frequently due to biliary atresia (P ≤ 0.0001), and had higher rates of pretransplant allergy (P = 0.019). In the posttransplant period, they had higher rates of mammalian Target of Rapamycin inhibitor use (P = 0.006), Epstein-Barr virus viremia (P = 0.03), post-transplant lymphoproliferative disease (P = 0.005), and allergen sensitization (P ≤ 0.0001). In regression analysis, young age at transplant, age at diagnosis, pretransplant atopic dermatitis, and post-transplant lymphoproliferative disease were associated with an increased risk of EGID or EoE. Laboratory abnormalities such as anemia (P = 0.007), thrombocytosis (P = 0.012), and hypoalbuminemia (P = 0.031) were more commonly observed in the eosinophilic gastritis, gastroenteritis or enterocolitis group than in the EoE group. Following treatment, most patients had symptomatic resolution at 3 months and histologic resolution at 6 months postdiagnosis. Among the patients who had 5 years of follow-up, none recurred.. EGID is a common posttransplant diagnosis, which seems to affect patients who are transplanted earlier and who have pretransplant atopy. Posttransplant EGID is responsive to treatment, but as histologic remission occurs after symptomatic resolution, the decision to perform control endoscopy should be delayed.

Topics: Age Factors; Anti-Allergic Agents; Biliary Atresia; Budesonide; Child; Child, Preschool; Cholestasis, Intrahepatic; Dermatitis, Atopic; Disease Progression; Drug Tapering; Enteritis; Enterocolitis; Eosinophilia; Eosinophilic Esophagitis; Epstein-Barr Virus Infections; Female; Follow-Up Studies; Gastritis; Glucocorticoids; Graft Rejection; Humans; Hypersensitivity; Immunosuppressive Agents; Infant; Ketotifen; Liver Failure, Acute; Liver Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Prevalence; Retrospective Studies; Risk Factors; Tacrolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Viremia

The importance of developing new animal models to assess the pathogenesis of glucocorticoid (GC)-insensitive asthma has been stressed. Because of the asthma-prone background of A/J mice, we hypothesized that asthma changes in these animals would be or become resistant to GCs under repeated exposures to an allergen. A/J mice were challenged with OVA for 2 or 4 consecutive d, starting on day 19 postsensitization. Oral dexamethasone or inhaled budesonide were given 1 h before challenge, and analyses were done 24 h after the last challenge. Airway hyperreactivity, leukocyte infiltration, tissue remodeling, and cytokine levels as well as phosphorylated GC receptor (p-GCR), p-GATA-3, p-p38, MAPK phosphatase-1 (MKP-1), and GC-induced leucine zipper (GILZ) levels were assessed. A/J mice subjected to two daily consecutive challenges reacted with airway hyperreactivity, subepithelial fibrosis, and marked accumulation of eosinophils in both bronchoalveolar lavage fluid and peribronchial space, all of which were clearly sensitive to dexamethasone and budesonide. Conversely, under four provocations, most of these changes were steroid resistant. A significant reduction in p-GCR/GCR ratio following 4- but not 2-d treatment was observed, as compared with untreated positive control. Accordingly, steroid efficacy to transactivate MKP-1 and GILZ and to downregulate p-p38, p-GATA-3 as well as proinflammatory cytokine levels was also seen after two but not four provocations. In conclusion, we report that repeated allergen exposure causes GC-insensitive asthma in A/J mice in a mechanism associated with decrease in GCR availability and subsequent loss of steroid capacity to modulate pivotal regulatory proteins, such as GATA-3, p-p38, MKP-1, and GILZ.

Topics: Allergens; Animals; Asthma; Biological Availability; Bronchoalveolar Lavage Fluid; Budesonide; Cytokines; Dexamethasone; Disease Models, Animal; Down-Regulation; Eosinophils; Glucocorticoids; Hypersensitivity; Inflammation; Lung; Male; Mice; Mice, Inbred BALB C; Ovalbumin; Receptors, Glucocorticoid; Steroids; Transcriptional Activation

Inflammation drives asthma and atherosclerosis. Clinical studies suggest that asthmatic patients have a high risk of atherosclerosis. Yet this hypothesis remains uncertain, given that Th2 imbalance causes asthma whereas Th1 immunity promotes atherosclerosis. In this study, chronic allergic lung inflammation (ALI) was induced in mice by ovalbumin sensitization and challenge. Acute ALI was induced in mice by ovalbumin and aluminum sensitization and ovalbumin challenge. Atherosclerosis was produced in apolipoprotein E-deficient (Apoe(-/-)) mice with a Western diet. When chronic ALI and atherosclerosis were produced simultaneously, ALI increased atherosclerotic lesion size, lesion inflammatory cell content, elastin fragmentation, smooth muscle cell (SMC) loss, lesion cell proliferation, and apoptosis. Production of acute ALI before atherogenesis did not affect lesion size, but increased atherosclerotic lesion CD4(+) T cells, lesion SMC loss, angiogenesis, and apoptosis. Production of acute ALI after atherogenesis also did not change atherosclerotic lesion area, but increased lesion elastin fragmentation, cell proliferation, and apoptosis. In mice with chronic ALI and diet-induced atherosclerosis, daily inhalation of a mast cell inhibitor or corticosteroid significantly reduced atherosclerotic lesion T-cell and mast cell contents, SMC loss, angiogenesis, and cell proliferation and apoptosis, although these drugs did not affect lesion area, compared with those that received vehicle treatment. In conclusion, both chronic and acute ALI promote atherogenesis or aortic lesion pathology, regardless whether ALI occurred before, after, or at the same time as atherogenesis. Antiasthmatic medication can efficiently mitigate atherosclerotic lesion pathology.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Budesonide; Chronic Disease; Disease Progression; Glucocorticoids; Hypersensitivity; Inflammation; Ketotifen; Male; Mast Cells; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin; Pneumonia

Few efficacious topical therapies exist for chronic rhinosinusitis (CRS). The lack of a reproducible mouse model of CRS limits the pilot testing of potential novel anti-inflammatory therapies. Although the ovalbumin-induced mouse model of sinonasal inflammation is commonly used, it is difficult to reproduce and can generate variable histologic results. In this study, we explore a variation of this model in different strains of mice and explore various inflammatory cytokines as reproducible molecular markers of inflammation.. Allergic sinonasal inflammation was generated in BALB/c and C57BL/6 mice using intraperitoneal high-dose injections of ovalbumin (Ova; Sigma Chemical Co.) followed by 10 days of high-dose intranasal sensitization. Real-time polymerase chain reaction (RT-PCR) for eotaxin, interleukin 4 (IL-4), and IL-13 were measured from sinonasal mucosa. We also pilot tested a known topical budesonide to characterize the anti-inflammatory response. Histological sections were analyzed for epithelial thickness and eosinophilia.. Both BALB/c and C57BL/6 mice consistently showed increases in T helper 2 (Th2) cytokines after sensitization with high-dose Ova (p < 0.0001) when compared to controls. There were also significant increases in epithelial thickening in Ova-sensitized mice and eosinophilia in both BALB/c and C57BL/6 strains. In addition, topical budesonide significantly reduced anti-inflammatory cytokines, eosinophilia, and epithelial thickness.. Our variation of the ovalbumin-induced mouse model of sinonasal inflammation in both BALB/c and C57BL/6 mice provides an efficacious model for testing potential topical anti-inflammatory therapies for CRS. The utilization of sinonasal mucosal Th2 cytokines along with histologic markers provides a consistent and quantifiable marker of inflammation in assessing the efficacy of candidate drugs.

Topics: Allergens; Animals; Anti-Inflammatory Agents; Budesonide; Cytokines; Disease Models, Animal; Eosinophilia; Female; Hypersensitivity; Male; Mice, Inbred BALB C; Mice, Inbred C57BL; Nasal Lavage Fluid; Nasal Mucosa; Ovalbumin; RNA, Messenger; Sinusitis

Although CD23-dependent transcytosis of IgE and IgE-derived immune complexes across respiratory epithelial cells is likely to play a pivotal role in the initiation and development of airway allergic inflammation, there is currently a lack of physiological support for this phenomena to suggest that the targeting of CD23 could be used as a means of therapeutic intervention. The present study was designed to detect the CD23 expression in the nasal mucosa of allergic rhinitis (AR) murine model by immunohistochemistry and western blotting, and to investigate whether intranasal anti-CD23 treatment could inhibit allergen-induced upper airway inflammation in the AR model. This is the first report to show that CD23 was constitutively expressed in murine nasal epithelial cells, and its expression was significantly up-regulated in the AR murine model. In vivo, the up-regulation of CD23 expression was correlated with increased serum IL-4 levels. Following intranasal anti-CD23 treatment, nasal symptoms were alleviated and histopathologic examination showed a significant decrease in eosinophilic infiltration. Meanwhile, ELISA analysis showed levels of serum leukotriene C4 (LTC4), eosinophil cation protein (ECP), ovalbumin (OVA)-specific IgE and IL-4 also significantly decreased, as were LTC4 and OVA-specific IgE in the nasal lavage fluid. Furthermore, Western blotting analysis showed that ECP expression in the nasal mucosa was down-regulated. Finally, flow cytometric analysis revealed anti-CD23 treatment inhibited Th2 cell responses. These results indicate that intranasal anti-CD23 treatment can reduce allergic responses in a murine model of allergic rhinitis.

Topics: Administration, Intranasal; Allergens; Animals; Budesonide; Disease Models, Animal; Down-Regulation; Eosinophil Cationic Protein; Eosinophils; Epithelial Cells; Female; Hypersensitivity; Immunoglobulin E; Inflammation; Interleukin-4; Leukotriene C4; Mice; Mice, Inbred BALB C; Nasal Mucosa; Ovalbumin; Random Allocation; Receptors, IgE; Rhinitis, Allergic; Rhinitis, Allergic, Perennial; Th2 Cells; Up-Regulation

Glucocorticoids are widely regarded as the most effective treatment for asthma. However, the direct impact of glucocorticoids on the innate immune system and antibacterial host defense during asthma remain unclear. Understanding the mechanisms underlying this process is critical to the clinical application of glucocorticoids for asthma therapy. After sensitization and challenge with ovalbumin (OVA), BALB/c mice were treated with inhaled budesonide and infected with Pseudomonas aeruginosa (P. aeruginosa). The number of viable bacteria in enflamed lungs was evaluated, and levels of interleukin-4 (IL-4) and interferon-γ (IFN-γ) in serum were measured. A lung epithelial cell line was pretreated with budesonide. Levels of cathelicidin-related antimicrobial peptide (CRAMP) were measured by immunohistochemistry and western blot analysis. Intracellular bacteria were observed in lung epithelial cells.. Inhaled budesonide enhanced lung infection in allergic mice exposed to P. aeruginosa and increased the number of viable bacteria in lung tissue. Higher levels of IL-4 and lower levels of IFN-γ were observed in the serum. Budesonide decreased the expression of CRAMP, increased the number of internalized P. aeruginosa in OVA-challenged mice and in lung epithelial cell lines. These data indicate that inhaled budesonide can suppress pulmonary antibacterial host defense by down-regulating CRAMP in allergic inflammation mice and in cells in vitro.. Inhaled budesonide suppressed pulmonary antibacterial host defense in an asthmatic mouse model and in lung epithelium cells in vitro. This effect was dependent on the down-regulation of CRAMP.

Topics: Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Budesonide; Cathelicidins; Colony Count, Microbial; Down-Regulation; Epithelial Cells; Host-Pathogen Interactions; Hypersensitivity; Immunosuppression Therapy; Inflammation; Interferon-gamma; Interleukin-4; Lung; Mice; Mice, Inbred BALB C; Ovalbumin; Pseudomonas aeruginosa; Pseudomonas Infections

Inhaled glucocorticosteroids reduce airway inflammation in asthma patients, thereby improving lung function and reducing airway hyperresponsiveness and symptoms. The response to glucocorticosteroids can be measured with the glucocorticosteroid skin-blanching test. We investigated if asthmatics have a lower skin-blanching response to glucocorticosteroids than non-asthmatic subjects and if asthmatics with airway obstruction have lower skin-blanching response than those without obstruction. Finally, we assessed which clinical and inflammatory parameters influence the variability in skin-blanching response.. We evaluated the skin-blanching response to topical budesonide in a large group of 315 well-characterized asthmatics and their relatives (asthma n = 114, healthy n = 140, other = 61).. The skin-blanching scores of the asthma probands and their healthy spouses were not significantly different. The skin-blanching score of patients with FEV(1) < 80% predicted was lower than of patients without obstruction. Lower skin-blanching score was significantly associated with lower FEV(1) %predicted, higher age, female gender, absence of allergy and summer season, but not with use of inhaled or oral glucocorticosteroids or packyears smoking.. Asthmatics do not have lower skin-blanching response to glucocorticosteroids than healthy subjects. Furthermore, lower skin-blanching response to glucocorticosteroids is associated with lower FEV(1), female gender, higher age and the absence of allergy.

Topics: Adolescent; Adult; Age Factors; Airway Obstruction; Asthma; Budesonide; Child; Cohort Studies; Family; Female; Forced Expiratory Volume; Glucocorticoids; Humans; Hypersensitivity; Male; Middle Aged; Pigmentation; Sex Factors; Skin Tests; Young Adult

Glucocorticoids (GCS) have been shown to induce IgE synthesis in human peripheral blood mononuclear cells (PBMCs) and purified B cells in vitro. However, the differences in immunoglobulin E (IgE) response to GCS between allergic and non-allergic individuals and the mechanism this interaction have not been elucidated.. We aimed to compare the effect of GCS (budesonide) on interleukin (IL)-4-driven IgE production in vitro in allergic and non allergic subjects and assess the engagement of intracellular mechanisms.. The study included 22 patients with allergic asthma and/or allergic rhinitis and 24 healthy volunteers. PBMCs were cultured for 11 days with IL-4 and budesonide and IgE concentrations in supernatants were assessed by immunoassays. T and B cell markers were assessed by flow cytometry.. Budesonide enhanced IgE synthesis to higher extent in healthy donors than in allergic patients (mean increase of 16.5 vs 6.3 kU/L, P< .05 respectively) acting through glucocorticoid receptor. Budesonide significantly increased lymhoplasmocytoid cells percentage in both media-controlled (2.5-fold increase) and IL-4-stimulated PBMCs (2-fold increase). Added to IL-4 budesonide decreased the percentage of both T cells and CD40L(+) T cells, but strongly increased the percentage of B cells. Protein tyrosine kinase (PTK) inhibitor decreased, but NF-κB and protein kinase A (PKA) inhibitors expressed modulatory effects on budesonide-induced IgE synthesis.. Budesonide-induced IgE generation in PBMCs differs in magnitude and seems to involve different mechanisms in atopic and non-atopic subjects.

Topics: Adult; Asthma; B-Lymphocytes; Budesonide; CD40 Ligand; Female; Glucocorticoids; Humans; Hypersensitivity; Immunoglobulin E; Interleukin-4; Leukocytes, Mononuclear; Male; Middle Aged; NF-kappa B; Protein Kinase Inhibitors; Rhinitis, Allergic, Perennial; T-Lymphocytes; Young Adult

Corticosteroids are known to inhibit bronchial hyperresponsiveness (BHR) and allergic inflammation but there is little information on its dose-dependence. We examined the effect of different doses of the glucocorticosteroid budesonide in an allergic model. Brown-Norway rats were sensitised to ovalbumin (OVA) and pretreated with an intra-gastric dose of budesonide (0.1, 1.0, or 10 mgkg(-1)). Exposure to OVA induced BHR, accumulation of eosinophils in the bronchoalveolar lavage (BAL) fluid and in the airways submucosa. Budesonide dose-dependently inhibited BAL fluid influx of lymphocytes, eosinophils and neutrophils, tissue eosinophils and lymphocytes and BHR. At 0.1 mgkg(-1), budesonide did not inhibit these parameters but at 1 mgkg(-1), BAL fluid eosinophils and T-cells, and submucosal T-cells were significantly reduced. At 10 mgkg(-1), budesonide suppressed BHR, BAL fluid inflammatory cells numbers and tissue eosinophilia. T-cell numbers were more related to BHR than eosinophil numbers. Budesonide inhibited both airway inflammation and BHR, but BAL fluid eosinophil cell counts may be dissociated from BHR.

Topics: Acetylcholine; Animals; Blood Cell Count; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Budesonide; Disease Models, Animal; Dose-Response Relationship, Drug; Glucocorticoids; Hypersensitivity; Male; Ovalbumin; Rats

Clara cells are nonciliated secretory cells implicated in lung homeostasis by the synthesis of immunomodulatory and host defense products, being one of the most important the CC16 protein. In this study, we compared the effects of budesonide (BUD), an inhaled corticoid, on Clara cell biology and its ability to reverse morphofunctional changes induced in an allergic airway hyper-responsiveness mouse model. In normal mice, exposure to BUD induced morphological changes compatible with a state of maximal differentiation on CC16 positive cells which developed a prominent cupola filled up with numerous mitochondria rich in CYP2E1, a member of the cytochrome P450 family. Consequently, CYP2E1 expression raised significantly. Exposure to OVA provoked hypertrophy of Clara cells and an increment in their number per millimeter of basal membrane. These cells acquired a mucous cell phenotype characterized by a notorious expansion of the secretory granular content. Synthesis of CC16 was greatly up-regulated concurrent to the finding of MUC5AC expression and the increment of epidermal growth factor receptor (EGFR). Mitochondrial content decreased significantly with a consequent reduction in CYP2E1 expression. After BUD treatment of OVA-challenged animals, the majority of Clara cells regained their normal morphology and functional characteristics; CYP2E1 levels raised when compared to the OVA exposed group. The BUD potential to differentiate Clara cells appeared to be important for the regression of the profound changes generated by the allergic injury. These results demonstrated the wide range of stimuli that can modify different aspects of Clara cell biology, and highlighted the effects of budesonide as a modulator of P450 enzymes, which probably contributes to a complementary antiinflamatory activity.

Topics: Animals; Anti-Inflammatory Agents; Bronchi; Bronchial Hyperreactivity; Bronchodilator Agents; Budesonide; Cytochrome P-450 CYP2E1; Epithelial Cells; Glucocorticoids; Hypersensitivity; Inflammation; Mice; Up-Regulation; Uteroglobin

Chronic inflammation in asthma and chronic obstructive pulmonary disease drives pathological structural remodelling of the airways. Using tiotropium bromide, acetylcholine was recently identified as playing a major regulatory role in airway smooth muscle remodelling in a guinea pig model of ongoing allergic asthma. The aim of the present study was to investigate other aspects of airway remodelling and to compare the effectiveness of tiotropium to the glucocorticosteroid budesonide. Ovalbumin-sensitised guinea pigs were challenged for 12 weeks with aerosolised ovalbumin. The ovalbumin induced airway smooth muscle thickening, hypercontractility of tracheal smooth muscle, increased pulmonary contractile protein (smooth-muscle myosin) abundance, mucous gland hypertrophy, an increase in mucin 5 subtypes A and C (MUC5AC)-positive goblet cell numbers and eosinophilia. It was reported previously that treatment with tiotropium inhibits airway smooth muscle thickening and contractile protein expression, and prevents tracheal hypercontractility. This study demonstrates that tiotropium also fully prevented allergen-induced mucous gland hypertrophy, and partially reduced the increase in MUC5AC-positive goblet cell numbers and eosinophil infiltration. Treatment with budesonide also prevented airway smooth muscle thickening, contractile protein expression, tracheal hypercontractility and mucous gland hypertrophy, and partially reduced MUC5AC-positive goblet cell numbers and eosinophilia. This study demonstrates that tiotropium and budesonide are similarly effective in inhibiting several aspects of airway remodelling, providing further evidence that the beneficial effects of tiotropium bromide might exceed those of bronchodilation.

Topics: Adrenal Cortex Hormones; Allergens; Animals; Bronchodilator Agents; Budesonide; Cholinergic Antagonists; Eosinophilia; Extracellular Matrix; Glucocorticoids; Guinea Pigs; Humans; Hypersensitivity; Inflammation; Male; Muscle, Smooth; Ovalbumin; Scopolamine Derivatives; Tiotropium Bromide; Trachea

Topics: Anti-Inflammatory Agents, Non-Steroidal; Budesonide; Cross Reactions; Female; Flurbiprofen; Humans; Hypersensitivity; Ketoprofen; Middle Aged; Pancreatitis; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Pathological features of the airway in young children with severe recurrent wheeze suggest an association between bacterial colonization and the initiating events of early asthma. We conducted a study to investigate a possible association between bacterial colonization of the hypopharynx in asymptomatic neonates and later development of recurrent wheeze, asthma, and allergy during the first 5 years of life.. The subjects were children from the Copenhagen Prospective Study on Asthma in Childhood birth cohort who were born to mothers with asthma. Aspirates from the hypopharyngeal region of asymptomatic 1-month-old infants were cultured for Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus. Wheeze was monitored prospectively on diary cards during the first 5 years of life. Blood eosinophil count and total IgE and specific IgE were measured at 4 years of age. Lung function was measured and asthma was diagnosed at 5 years of age.. Hypopharyngeal samples were cultured from 321 neonates at 1 month of age. Twenty-one percent of the infants were colonized with S. pneumoniae, M. catarrhalis, H. influenzae, or a combination of these organisms; colonization with one or more of these organisms, but not colonization with S. aureus, was significantly associated with persistent wheeze (hazard ratio, 2.40; 95% confidence interval [CI], 1.45 to 3.99), acute severe exacerbation of wheeze (hazard ratio, 2.99; 95% CI, 1.66 to 5.39), and hospitalization for wheeze (hazard ratio, 3.85; 95% CI, 1.90 to 7.79). Blood eosinophil counts and total IgE at 4 years of age were significantly increased in children colonized neonatally with S. pneumoniae, M. catarrhalis, H. influenzae, or a combination of these organisms, but specific IgE was not significantly affected. The prevalence of asthma and the reversibility of airway resistance after beta2-agonist administration at 5 years of age were significantly increased in the children colonized neonatally with these organisms as compared with the children without such colonization (33% vs. 10% and 23% vs. 18%, respectively).. Neonates colonized in the hypopharyngeal region with S. pneumoniae, H. influenzae, or M. catarrhalis, or with a combination of these organisms, are at increased risk for recurrent wheeze and asthma early in life.

Topics: Asthma; Bacterial Infections; Bronchodilator Agents; Budesonide; Child, Preschool; Cohort Studies; Female; Haemophilus influenzae; Humans; Hypersensitivity; Hypopharynx; Immunoglobulin E; Infant; Infant, Newborn; Kaplan-Meier Estimate; Male; Moraxella catarrhalis; Neutrophils; Respiratory Sounds; Respiratory Tract Infections; Risk Factors; Staphylococcus aureus; Streptococcus pneumoniae

Steroid treatment of allergic eosinophilic airway diseases is considered to attenuate cell recruitment by inhibiting several chemokines and to cause eosinophil clearance through inducement of apoptosis of these cells. However, roles of these mechanisms in the actions of steroids in vivo have not been fully established. Also, as regards clearance of tissue eosinophils other mechanisms than apoptosis may operate in vivo.. This study explores anti-inflammatory effects of steroids instituted during either development or resolution of airway allergic inflammation.. Immunized mice were subjected to week-long daily allergen challenges (ovalbumin). Steroid treatment was instituted either amidst the challenges or exclusively post-allergen challenge. CC chemokines, goblet cell hyperplasia, occurrence of eosinophil apoptosis, and airway tissue as well as lumen eosinophilia were examined at different time-points.. Daily steroids instituted amid the allergen challenges non-selectively attenuated a range of chemokines, permitted egression of tissue eosinophils into airway lumen to increase, and reduced development of lung tissue eosinophilia. Steroid treatment instituted post-challenge selectively inhibited the CC-chemokine regulation upon activation, normal T cell expressed and secrted (RANTES), permitted continued egression of eosinophils into airway lumen, and resolved the tissue eosinophilia. Eosinophil apoptosis rarely occurred at development and resolution of the allergic eosinophilic inflammation whether the animals were steroid treated or not. However, anti-Fas monoclonal antibodies given to mice with established eosinophilia post-challenge produced apoptosis of the tissue eosinophils indicating that apoptotic eosinophils, if they occur, are well detectible in vivo.. Airway tissue eosinophils are likely eliminated through egression into airway lumen with little involvement of apoptosis and phagocytosis. Our data further suggest that therapeutic steroids may resolve airway inflammation by permitting clearance of tissue eosinophils through egression and inhibiting RANTES-dependent cell recruitment to lung tissues.

Topics: Allergens; Animals; Apoptosis; Biomarkers; Bronchoalveolar Lavage Fluid; Budesonide; Chemokine CCL11; Chemokine CCL4; Chemokine CCL5; Chemokines, CC; Eosinophils; Epithelial Cells; Glucocorticoids; Hypersensitivity; Interleukin-5; Lung; Macrophage Inflammatory Proteins; Male; Mice; Mice, Inbred C57BL; Models, Animal; Ovalbumin; RNA, Messenger; Staining and Labeling

To evaluate the clinical outcome and changes in allergen-specific antibodies during sublingual immunotherapy (SLIT) in house dust mite (HDM)-allergic asthma patients and to compare levels of allergen-specific antibodies in HDM-allergic patients before and after treatment with that of healthy controls.. Thirty-one asthma patients allergic to HDM were studied. Patients in groups I (n=17) and II (n=14) received SLIT with a standardized Dermatophagoides pteronyssinus plus Dermatophagoides farinae 50/50 extract for 6 and 12 months, respectively. A group of healthy children (n=8) were enrolled as controls. Patients in both groups were evaluated at the start and at the end of treatment according to daily symptom and medication scores, lung function and skin prick tests, PC20, blood eosinophil count, and Der-p-1-specific IgE, IgA, IgG1 and IgG4 levels.. Drug consumption decreased significantly in both groups. Furthermore, PC20 and forced expiratory flow between 25 and 75% of vital capacity of patients in group II improved significantly. Although specific IgA, IgG1 and IgG4 levels did not change throughout the treatment period, total eosinophil count and specific IgE decreased significantly in both groups. According to baseline measurements, specific IgA levels of patients in groups I and II were significantly lower than that of controls. This difference disappeared at the end of the treatment period in both groups.. SLIT seems to be effective in ameliorating clinical symptoms, drug consumption and bronchial hyperreactivity, and results in downregulation of Der-p-1-specific IgE production. Furthermore, at the end of SLIT, specific IgA levels, which were decreased compared to healthy controls initially, did no longer differ between patients and controls.

Topics: Administration, Sublingual; Asthma; Bronchial Provocation Tests; Budesonide; Case-Control Studies; Child; Eosinophils; Humans; Hypersensitivity; Immunoglobulins; Immunotherapy; Nose; Pulmonary Ventilation; Pyroglyphidae; Rhinitis; Skin Tests; Turkey

Topics: Abdominal Pain; Administration, Oral; Anti-Inflammatory Agents; Budesonide; Child; Eosinophilia; Esophagitis; Female; Humans; Hypersensitivity; Male; Suspensions

Nasal polyposis is a model for the study of inflammatory processes. We analyzed the expression of galectin-7, a growth regulator, in surface epithelium, glandular epithelium, and connective tissue in human nasal polyps, and examined the effect of the glucocorticoid budesonide on its expression in human nasal polyps ex vivo.. Using quantitative, computer-assisted microscopy and immunohistochemistry, we measured galectin-7 expression in nine nasal polyps obtained by surgical resection. Five polyps came from allergic patients and four came from non-allergic patients.. Galectin-7 was expressed in all three polyp tissues analyzed. Treatment of polyps from allergic and non-allergic patients with 50 ng/ml budesonide increased the extent of galectin-7 expression in the connective tissue (p = 0.01). Conversely, budesonide at this concentration did not apparently affect galectin-7 expression in glandular epithelium; only a slight decrease in the percentage of the galectin-7-immunopositive cells was observed. In the surface epithelium of nasal polyps from non-allergic patients, the percentage of galectin-7-immunopositive cells was decreased (p = 0.03) by treatment with 250 ng/ml budesonide. In nasal polyps from allergic patients, this percentage was increased by treatment with 50 ng/ml budesonide (p = 0.0001).. These data are consistent with a role for galectin-7 in the regulation of cell growth through a pro-apoptotic effect. Galectin-7 expression coincides with the degree of epithelial stratification, and is subject to upregulation in the connective tissue in response to treatment with 50 ng/ml budesonide. Budesonide modulates galectin-7 expression differently in the surface epithelia of polyps from allergic and non-allergic patients.

Topics: Anti-Inflammatory Agents; Budesonide; Connective Tissue; Galectins; Humans; Hypersensitivity; Nasal Mucosa; Nasal Polyps; Tissue Culture Techniques

Glucocorticoids (GCs) are routinely believed to work solely through genomic mechanisms. Recent evidence indicates that GCs can act at the membrane to exert rapid nongenomic effects on various tissues and cells. To ascertain whether nongenomic effects of GCs exist on the allergic asthma reaction, Hartley guinea pigs were sensitized with ovalbumin and challenged with the same antigen given by aerosol. Some animals received inhaled budesonide (3 mg/ml suspended in Hydroxypropyl methylcellulose vehicle) for 5 minutes before ovalbumin challenge; Other animals received saline or blank vehicle as control. We measured the changes of lung resistance and dynamic lung compliance, the pulmonary function used to evaluate allergic asthma severity. Inhaled budesonide inhibited allergic reaction within 10 minutes, which would preclude genomic-mediated responses that normally takes several hours to occur. This study infers for the first time that rapid nongenomic effect of GCs exists on allergic asthma reaction, and provides a new way to investigate nongenomic mechanism of GCs. Further study would raise the possibility of new therapeutic strategies for allergic disease including asthma.

Topics: Administration, Inhalation; Animals; Asthma; Budesonide; Glucocorticoids; Guinea Pigs; Hypersensitivity; Male; Models, Animal; Time Factors

We characterized the anti-inflammatory effects of budesonide on the expression of adhesion molecules involving Lewis(a) (Le(a)) epitope, its sialylated derivative (sLe(a)), and their respective binding sites in human nasal polyposis. By computer-assisted microscopy, we quantitatively characterized the level of histochemical expression of L- and P-selectins, sialylated and nonsialylated Le(a) epitopes, and their respective binding sites in both surface epithelium and glandular epithelium of human nasal polyps obtained from surgical resection, maintained under ex vivo tissue culture conditions for 24 hours, and treated or not with budesonide. Intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) were chosen as methodological controls, because data already published in the literature clearly indicated budesonide-mediated effects on ICAM-1 and VCAM-1 levels of expression. The present data show that budesonide significantly modified the levels of expression of ICAM-1 and VCAM-1, and to a lesser extent that of P-selectin, in the surface and glandular epithelia. Budesonide markedly decreased the levels of expression of the binding sites for both Le(a) and sLe(a), while those of Le(a) and sLe(a) remained globally unchanged. In conclusion, the present study documents that glucocorticoid-induced effects can encompass receptors for Le(a) epitopes different from E- and P-selectins on epithelial cells of human nasal polyps.

Topics: Anti-Inflammatory Agents; Binding Sites, Antibody; Budesonide; CA-19-9 Antigen; Culture Techniques; Drug Evaluation, Preclinical; E-Selectin; Eosinophils; Epitopes; Gangliosides; Gene Expression Regulation; Humans; Hypersensitivity; Immunohistochemistry; Intercellular Adhesion Molecule-1; Lewis Blood Group Antigens; Nasal Polyps; P-Selectin; Vascular Cell Adhesion Molecule-1

Topics: Abnormalities, Drug-Induced; Acetates; Administration, Inhalation; Administration, Intranasal; Administration, Oral; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Albuterol; Animals; Anti-Allergic Agents; Anti-Asthmatic Agents; Asthma; Budesonide; Chlorpheniramine; Cyclopropanes; Ephedrine; Female; Histamine H1 Antagonists; Humans; Hydroxyurea; Hypersensitivity; Indoles; Ipratropium; Leukotriene Antagonists; Metaproterenol; Nasal Decongestants; Nebulizers and Vaporizers; Nedocromil; Phenylcarbamates; Pregnancy; Pregnancy Complications; Quinolines; Salmeterol Xinafoate; Sulfides; Sulfonamides; Terbutaline; Tosyl Compounds; Tripelennamine

In this paper, the effect of azelastine hydrochloride, a potent inhibitor of leukotrienes (LTs) and H1 receptors for histamine, was assessed as regards modulation of in vitro eosinophilic chemotaxis. In this respect, chemotaxis of eosinophils (EOS), isolated from the peripheral blood of untreated allergic subjects in the acute phase, was significantly diminished after in vitro treatment with azelastine in comparison to values before treatment. When EOS were pre-incubated with serial dilutions of the drug, it was observed that azelastine inhibited chemotaxis in a dose-dependent fashion. Since azelastine acts in vitro as a regulator of the calcium pump, EOS were pre-incubated with different concentrations (0.6 and 3.0 mM) of Ca++. In these experimental conditions azelastine was able to reduce EOS chemotactic activity only in the presence of 0.6 mM Ca++, whereas with higher Ca++ concentrations (3.0 mM) the inhibitory effect of the drug was abrogated. On the other hand, particular attention was paid to inhaled budesonide, a non halogenated glucocorticosteroid derivative, structurally related to 16 alpha-hydroxy prednisolone, which represents a helpful for treatment mild to moderate asthma. Data obtained after in vitro treatment with budesonide of a group of allergic patients demonstrated that EOS chemotactic activity was significantly reduced in these subjects. Conclusively our data show that 1) azelastine acts as a dose-dependent antagonist of chemotaxis; 2) it may exert this action by inhibiting Ca++ flow into cells; 3) inhaled budesonide may induce inhibition of bronchial inflammation by downregulating EOS chemotactic capacity.

Topics: Adolescent; Adult; Anti-Allergic Agents; Budesonide; Calcium; Chemotaxis, Leukocyte; Cyclic AMP; Eosinophils; Humans; Hypersensitivity; Middle Aged; Phthalazines

The effect of glucocorticosteroid (GCS) treatment on ovalbumine-induced IgE-mediated immediate and late allergic response was studied in sensitized guinea pigs. The results show that the GCS budesonide (BUD) inhibits the allergen-induced IgE-mediated immediate and late bronchial obstruction. The effect on the early reaction is correlated to the inhibition of leukotrienes and histamine release. The importance of mediator release inhibition for the antianaphylactic effect of GCS is discussed. In examining the effect on the late reaction, it was found that BUD had to be present during the early reaction but did not inhibit the early reaction. Furthermore, the effect on the late reaction was correlated to the inhibition of vascular leakage but not to the infiltration of inflammatory cells as examined in bronchoalveolar lavage. The results indicate that some triggering factors important for the development of the late reaction are released during the early reaction. Inhibition of the release of that factor or the activation of inflammatory cells by that factor might be the mechanism behind the antiinflammatory activities of GCS.

Topics: Anaphylaxis; Animals; Antigens; Bronchi; Bronchial Provocation Tests; Budesonide; Cromolyn Sodium; Dimercaprol; Guinea Pigs; Histamine Release; Hypersensitivity; Hypersensitivity, Delayed; Immunoglobulin E; Leukotriene B4; Lung; Ovalbumin; Peptide Hydrolases; Pregnenediones; SRS-A