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Allergen-specific immunotherapy (AIT) is the mainstay in the treatment of allergic diseases, but the therapeutic effects of AIT need to be improved. CD38We sought to elucidate the role of antigen-specific CD38An analysis was carried out on AIT results of 48 patients with perennial allergic rhinitis (AR), among which peripheral blood immune cells were analyzed by flow cytometry; serum cytokine levels were determined by ELISA. An AR murine model was developed to test the role of CD38A fraction of antigen-specific CD38Antigen-specific CD38

BACKGROUND: Signifying the two-compartments/one-disease paradigm, allergic rhinoconjunctivitis (ARC) and asthma (AA) are prevalent, comorbid conditions triggered by environmental factors (e.g., house dust mites (HDMs)). However, despite the ubiquity of triggers, progression to severe ARC/AA is infrequent, suggesting either resistance or adaptation. OBJECTIVE: Determine if ARC/AA severity relates to maladaptive responses to disease triggers. METHODS: Adults with HDM-associated ARC were challenged repetitively with HDMs in an aeroallergen challenge chamber; associated mechanistic traits were identified. RESULTS: HDM challenges evoked maladaptive (persistently higher ARC symptoms), adaptive (progressive symptom reduction), and resilient (resistance to symptom induction) phenotypes. Symptom severity in the natural environment was an imprecise correlate of the phenotypes. Nasal airway traits, defined by low inflammation-effectual epithelial integrity, moderate inflammation-effectual epithelial integrity, and higher inflammation-ineffectual epithelial integrity, were hallmarks of the resilient, adaptive, and maladaptive evoked phenotypes, respectively. Highlighting a crosstalk mechanism, peripheral blood inflammatory tone calibrated these traits: ineffectual epithelial integrity correlated with CD8+ T-cells, whereas airway inflammation correlated with CD8+ T-cells and eosinophils. Hallmark peripheral blood maladaptive traits were increased NK and CD8+ cells, lower CD4+ MAIT cells, and deficiencies along the TLR-IRF-IFN antiviral pathway. Maladaptive traits tracking HDM-associated ARC also contributed to AA risk and severity models. CONCLUSIONS: Repetitive challenges with HDMs revealed that maladaptation to disease triggers may underpin ARC/AA disease severity. A combinatorial therapeutic approach may involve reversal of loss-of-beneficial-function traits (ineffectual epithelial integrity, TLR-IRF-IFN deficiencies), mitigation of gain-of-adverse-function traits (inflammation), and blocking of a detrimental crosstalk between the peripheral blood and airway compartments. CLINICAL IMPLICATIONS: The wide variation in allergic rhinoconjunctivitis disease severity may be underpinned by an imbalance in epithelial integrity and inflammation manifesting as maladaptation to disease triggers such as house dust mites.

Background Airway eosinophilia is a prominent feature of asthma and chronic rhinosinusitis (CRS), and the endothelium plays a key role in eosinophil trafficking. To date, microRNA-1 (miR-1) is the only microRNA known to be regulated in the lung endothelium in asthma models. Objective We sought to determine the role of endothelial miR-1 in allergic airway inflammation. Methods We measured microRNA and mRNA expression using quantitative RT-PCR. We used ovalbumin and house dust mite models of asthma. Endothelium-specific overexpression of miR-1 was achieved through lentiviral vector delivery or induction of a transgene. Tissue eosinophilia was quantified by using Congo red and anti-eosinophil peroxidase staining. We measured eosinophil binding with a Sykes-Moore adhesion chamber. Target recruitment to RNA-induced silencing complex was assessed by using anti-Argonaute2 RNA immunoprecipitation. Surface P-selectin levels were measured by using flow cytometry. Results Serum miR-1 levels had inverse correlations with sputum eosinophilia, airway obstruction, and number of hospitalizations in asthmatic patients and sinonasal tissue eosinophilia in patients with CRS. IL-13 stimulation decreased miR-1 levels in human lung endothelium. Endothelium-specific overexpression of miR-1 reduced airway eosinophilia and asthma phenotypes in murine models and inhibited IL-13–induced eosinophil binding to endothelial cells. miR-1 recruited P-selectin, thymic stromal lymphopoietin, eotaxin-3, and thrombopoietin receptor to the RNA-induced silencing complex; downregulated these genes in the lung endothelium; and reduced surface P-selectin levels in IL-13–stimulated endothelial cells. In our asthma and CRS cohorts, miR-1 levels correlated inversely with its target genes. Conclusion Endothelial miR-1 regulates eosinophil trafficking in the setting of allergic airway inflammation. miR-1 has therapeutic potential in asthmatic patients and patients with CRS.

Background Data comparing the treatment effect of allergy immunotherapy and pharmacotherapy are lacking. Objective We sought to indirectly compare the treatment effect of sublingual immunotherapy (SLIT)-tablets with pharmacotherapy for seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR). Methods Pooled data from randomized, double-blind, placebo-controlled trials for the clinical development programs of selected allergic rhinitis treatments were evaluated. Total nasal symptom scores (TNSSs) relative to placebo were compared. Subjects scored symptoms daily during entire pollen seasons in 6 timothy grass SLIT-tablet trials (n = 3094) and 2 ragweed SLIT-tablet trials (n = 658) and during the last 8 weeks of treatment in 2 house dust mite (HDM) SLIT-tablet trials (n = 1768). Subjects scored symptoms daily in 7 montelukast (10 mg, n = 6799), 9 desloratadine (5 mg, n = 4455), and 8 mometasone furoate nasal spray (MFNS; 200 μg daily, n = 2140) SAR or PAR trials. SLIT-tablet trials allowed rescue medication use, whereas most pharmacotherapy trials did not. A fixed-effect meta-analysis method estimated differences in on-treatment average TNSSs. Results In grass and ragweed SLIT-tablet trials, overall improvement in TNSSs relative to placebo was 16.3% and 17.1%, respectively. In HDM SLIT-tablet trials, TNSS overall improvement relative to placebo was 16.1%. In the montelukast, desloratadine, and MFNS trials, TNSS overall improvement relative to placebo was 5.4%, 8.5%, and 22.2%, respectively, for SAR trials, and 3.7%, 4.8%, and 11.2%, respectively, for PAR trials. Conclusions Although comparisons were limited by study design heterogeneity and use of rescue medications in SLIT-tablet trials, effects on nasal symptoms with timothy grass and ragweed SLIT-tablets were nearly as great as with MFNS and numerically greater than with montelukast and desloratadine for SAR. HDM SLIT-tablet effects were numerically greater than all pharmacotherapies for PAR. SLIT-tablets offer the additional benefit of long-term efficacy.

Background Idiopathic rhinitis (IR) is a prevalent condition for which capsaicin nasal spray is the most effective treatment. However, the mechanisms underlying IR and the therapeutic action of capsaicin remain unknown. Objective We sought to investigate the molecular and cellular bases of IR and the therapeutic action of capsaicin. Methods Fourteen patients with IR and 12 healthy control subjects (HCs) were treated with intranasal capsaicin. The therapeutic effect was assessed in patients with IR by using visual analog scale and therapeutic response evaluation scores, and nasal hyperreactivity was evaluated by means of cold dry air provocation. Nasal samples served to measure the levels of neuromediators and expression of chemosensory cation channels, protein gene product 9.5 (PGP 9.5), and the mast cell marker c-kit. The effects of capsaicin were also tested in vitro on human nasal epithelial cells and mast cells. Results Patients with IR had higher baseline transient receptor potential cation channel subfamily V, receptor 1 (TRPV1) expression in the nasal mucosa and higher concentrations of substance P (SP) in nasal secretions than HCs. Symptomatic relief was observed in 11 of 14 patients with IR after capsaicin treatment. Expression of TRPV1; transient receptor potential cation channel subfamily M, receptor 8 (TRPM8); and PGP 9.5 was only reduced in patients with IR after capsaicin treatment. Capsaicin did not alter c-KIT expression or nasal epithelial morphology in patients with IR and HCs nor did it induce apoptosis or necrosis in cultured human nasal epithelial cells and mast cells. Conclusion IR features an overexpression of TRPV1 in the nasal mucosa and increased SP levels in nasal secretions. Capsaicin exerts its therapeutic action by ablating the TRPV1-SP nociceptive signaling pathway in the nasal mucosa.

Background Whether adiposity indicators other than body mass index (BMI) should be used in studies of childhood asthma is largely unknown. The role of atopy in "obese asthma" is also unclear. Objectives To examine the relationship among adiposity indicators, asthma, and atopy in Puerto Rican children, and to assess whether atopy mediates the obesity-asthma association. Methods In a study of Puerto Rican children with (n = 351) and without (n = 327) asthma, we measured BMI, percent of body fat, waist circumference, and waist-to-hip ratio. The outcomes studied included asthma, lung function, measures of atopy, and, among cases, indicators of asthma severity or control. We performed mediation analysis to assess the contribution of atopy to the relationship between adiposity and asthma. Results BMI, percent of body fat, and waist circumference were associated with increased odds of asthma. Among cases, all 3 measures were generally associated with lung function, asthma severity/control, and atopy; however, there were differences depending on the adiposity indicator analyzed. Atopy considerably mediated the adiposity-asthma association in this population: allergic rhinitis accounted for 22% to 53% of the association with asthma, and sensitization to cockroach mediated 13% to 20% of the association with forced vital capacity and 29% to 42% of the association with emergency department visits for asthma. Conclusions Adiposity indicators are associated with asthma, asthma severity/control, and atopy in Puerto Rican children. Atopy significantly mediates the effect of adiposity on asthma outcomes. Longitudinal studies are needed to further investigate the causal role, if any, of adiposity distribution and atopy on "obese asthma" in childhood.

BACKGROUND: Evidence on the longitudinal association of airway responsiveness with respiratory diseases is scarce. The best indicator of responsiveness is still undetermined. OBJECTIVE: We investigated the association of airway responsiveness with the incidence of asthma, chronic obstructive pulmonary disease (COPD), and allergic rhinitis. METHODS: We studied 3851 subjects who underwent spirometry and methacholine challenge tests both at baseline (1991-1993), when they were 20 to 44 years old, and at follow-up (1999-2002) in the European Community Respiratory Health Survey. Airway responsiveness was defined based on the methacholine dose-response slope on both occasions. Incidence rate ratios for the association of airway responsiveness with disease occurrence were computed by using Poisson regression. RESULTS: With respect to reference (slope of the fourth quintile or greater), subjects with the greatest degree of airway responsiveness (slope less than the first quintile) showed the greatest risk of developing asthma, COPD, and allergic rhinitis (incidence rate ratios of 10.82, 5.53, and 4.84, respectively; all P< .01). Alow slope predicted disease occurrence, even in subjects who did not reach a 20% decrease in FEV1 at the cumulative dose of 1 mg of methacholine (PD20 >1 mg). Adecrease in slope over time was an independent predictor of disease risk. CONCLUSION: Airway responsiveness predicted new-onset asthma, COPD, and allergic rhinitis. Our study supports the use of a continuous noncensored indicator of airway responsiveness, such as the slope of the methacholine dose-response curve, in clinical practice and research because it showed clear advantages over PD20.

Allergic rhinitis (AR) is a prevalent disease that can significantly affect the well-being, productivity, and quality of life of children and adults. Allergen immunotherapy has been used to effectively treat AR for more than 100 years and is unique among available therapeutic interventions in its ability to modify AR’s course. In addition, there is evidence that it prevents new sensitizations. Thus, it is important to establish whether subcutaneously administered allergy immunotherapy (AIT) is associated with lower health care costs. In this issue, Hankin et al examine its cost benefits in adults and children. Hankin et al have previously addressed this question in Florida Medicaid-enrolled children younger than 18 years, newly diagnosedwithARandnot previously exposed toAIT. In the earlier study, only 3% of the children with a new AR diagnosis received AIT, more than half for less than a year, and 84% for less than 3 years. The study compared health care costs and use in the 6months before and after initiatingAITand found pharmacy, outpatient, and inpatient use and costs reduced in children receiving AIT. For the current case-control study, the authors again used Florida Medicaid claims data of health care use and costs. The data set included all ages and compared 18-month health care costs of those newly diagnosed with AR who received de novo AITwith those who did not. The investigators compared children (younger than 18 years) and adults (at least 18 years) separately and all together. They found that AIT-treated subjects had significantly lower average total health care costs than matched controls, with cost reductions observed within 3 months of starting AIT. The cost reductions (30% in adults, 42% in children) remained significant when each group was analyzed separately. The average 18-month health care cost savings conferred by AIT did not significantly differ between age groups. Although adults were less likely to be diagnosed with AR, they were 1.3 times more likely to initiate AIT. To be included in the AIT group, patients had to have received at least 2 AIT injections. They were matched with up to 5 controls with newly diagnosed AR who had not received AIT and according to the following variables: age within 6 months of first

Background Nasal mucus is the first-line defense barrier against (aero-) allergens. However, its proteome and function have not been clearly investigated. Objective The role of nasal mucus in the pathophysiology of allergic rhinitis was investigated by analyzing its proteome in patients with allergic rhinitis (n = 29) and healthy control subjects (n = 29). Methods Nasal mucus was collected with a suction device, tryptically digested, and analyzed by using liquid chromatography–tandem mass spectrometry. Proteins were identified by searching the SwissProt database and annotated by collecting gene ontology data from databases and existing literature. Gene enrichment analysis was performed by using Cytoscape/BINGO software tools. Proteins were quantified with spectral counting, and selected proteins were confirmed by means of Western blotting. Results In total, 267 proteins were identified, with 20 (7.5%) found exclusively in patients with allergic rhinitis and 25 (9.5%) found exclusively in healthy control subjects. Five proteins were found to be significantly upregulated in patients with allergic rhinitis (apolipoprotein A-2 [APOA2], 9.7-fold; α2-macroglobulin [A2M], 4.5-fold; apolipoprotein A-1 [APOA1], 3.2-fold; α1-antitrypsin [SERPINA1], 2.5-fold; and complement C3 [C3], 2.3-fold) and 5 were found to be downregulated (antileukoproteinase [SLPI], 0.6-fold; WAP 4-disulfide core domain protein [WFDC2], 0.5-fold; haptoglobin [HP], 0.7-fold; IgJ chain [IGJ], 0.7-fold; and Ig hc V-III region BRO, 0.8-fold) compared with levels seen in healthy control subjects. Conclusion The allergic rhinitis mucus proteome shows an enhanced immune response in which apolipoproteins might play an important role. Furthermore, an imbalance between cysteine proteases and antiproteases could be seen, which negatively affects epithelial integrity on exposure to pollen protease activity. This reflects the important role of mucus as the first-line defense barrier against allergens.

Allergic fungal rhinosinusitis (AFRS) is characterized by the growth of fungi, mostly Aspergillus sp., in the paranasal sinuses together with the formation of nasal polyps, peanut-butter like “allergic mucin” with fungal hyphae and typical CT-findings, as well as increased serum total IgE and Aspergillus-specific IgE concentrations. We here hypothesize that the increase in serum total IgE is caused by the local symbiosis of Asp. sp. with Staphylococcus aureus, a germ which is known for the production of enterotoxins with superantigenic properties. We demonstrate the presence of S. aureus specific IgE antibodies in the sera of AFRS patients, correlating with total serum IgE concentrations, as well as the coexistence of both, A. fumigatus and S. aureus, in biofilm-like formations on the sinus mucosa. Similar mechanisms and findings may apply for Allergic Broncho-Pulmonary Aspergillosis/Mykosis (ABPA/M). This knowledge may result in new diagnostic and therapeutic approaches including anti-IgE strategies.

Research demonstrates significant health care cost savings conferred by allergen-specific immunotherapy (AIT) to US children with allergic rhinitis (AR).We sought to examine whether AIT-related cost benefits conferred to US children with AR similarly extend to adults.A retrospective (1997-2009) Florida Medicaid claims analysis compared mean 18-month health care costs of patients with newly diagnosed AR who received de novo AIT and were continuously enrolled for 18 months or more versus matched control subjects not receiving AIT. Analyses were conducted for the total sample and separately for adults (age≥18 years) and children (age18 years).Matched were 4,967 patients receiving AIT (1,319 adults and 3,648 children) and 19,278 control subjects (4,815 adults and 14,463 children). AIT-treated enrollees incurred 38% ($6,637 vs $10,644, P.0001) lower mean 18-month total health care costs than matched control subjects, with significant savings observed within 3 months of AIT initiation. Compared with control subjects, significantly lower 18-month mean health care costs were demonstrated overall (38%; $6,637 for patients receiving AIT vs $10,644 for control subjects, P.0001), and for both AIT-treated adults (30%; $10,457 AIT vs $14,854 controls, P.0001) and children (42%; $5,253 AIT vs $9,118 controls, P.0001). The magnitude of 18-month health care cost savings realized by AIT-treated adults and children did not significantly differ ($4,397 vs $3,965, P=.435).Patients with newly diagnosed AR initiating AIT incurred significantly lower health care costs than matched control subjects beginning 3 months after AIT initiation and continuing throughout the 18-month follow-up period. The significant cost benefits achieved by children with AR diagnoses who initiated AIT were also observed for adults with AR diagnoses who initiated AIT.

Background Not much data are available from large, unselected, birth cohort studies on the natural course and comorbidities of rhinitis in children. Objective To study phenotypes of rhinitis in relation to the natural course and comorbidities of allergic diseases in preschool-age and early school-age children. Methods We analyzed data from a birth cohort of 2024 children, for whom information on IgEs against 8 common inhaled allergens was available, collected at age 4 and 8 years. The children were assigned to groups of allergic rhinitis (rhinitis with sensitization to allergens), nonallergic rhinitis (rhinitis without sensitization), allergic sensitization but no rhinitis, or neither rhinitis nor sensitization. Results The proportion of children with allergic rhinitis increased from 5% to 14% from age 4 to 8 years, whereas the proportion of children with nonallergic rhinitis decreased slightly over the same period of development, from 8% to 6%. Of the children with allergic rhinitis when they were 4 years old, 12% underwent remission by the time they were 8 years old; of the children with nonallergic rhinitis, 73% underwent remission during this period of development. Among 4-year-olds without rhinitis who were sensitized to allergen, 56% had allergic rhinitis when they were 8 years old. Among 4- and 8-year-olds, allergic rhinitis and nonallergic rhinitis were associated with asthma, eczema, and food hypersensitivity. Twenty-five percent of 8-year-olds with allergic rhinitis also had oral allergy syndrome. Conclusions Fewer preschool-age children with allergic rhinitis undergo remission than do those with nonallergic rhinitis. Sensitization to inhaled allergens at an early age (4 years) precedes the development of allergic rhinitis, whereas symptoms of rhinitis do not. Oral allergy syndrome is common among 8-year-olds with allergic rhinitis.

In clinical trials, only about 60% of subjects report an excellent response to intranasal steroids, suggesting a need to add therapies to intranasal steroids to provide additional efficacy.To determine whether the combination of fluticasone furoate and oxymetazoline is more efficacious than either agent alone, and to determine whether rhinitis medicamentosa develops after treatment.We performed a double-blind, double-dummy, randomized, placebo-controlled parallel study. Sixty patients with perennial allergy were randomized to 4 weeks of once-a-night treatment with fluticasone furoate, oxymetazoline hydrochloride, the combination, or placebo. They were monitored during treatment and for 2 weeks posttreatment.The total nasal symptom score over the 4 weeks of treatment was lower with the combination (median, 143; range, 30-316) compared with treatment with placebo (262; 116-358) and oxymetazoline alone (219; 78-385; ANOVA, P = .04). When acoustic rhinometry was compared between the groups at the end of 4 weeks of treatment, the combination resulted in significantly higher nasal volume (mean + SEM, 15.8 + 1.1 mL; P.03) compared with both placebo (12.1 + 0.9 mL) and oxymetazoline (12.4 + 0.8 mL) alone. The quality of life data showed no significant differences among the groups. Peak flow showed a nonsignificant improvement with the groups on fluticasone furoate. There was no evidence of rhinitis medicamentosa.The addition of oxymetazoline adds to the effectiveness of fluticasone furoate in the treatment of perennial allergic rhinitis. The lack of development of rhinitis medicamentosa suggests the need for a large multicenter study to develop a once-a-day combination of an intranasal steroid and a long-acting topical decongestant.

Background Guidelines are the cornerstone of health care decision making and are based on the best available evidence, ideally large randomized controlled trials (RCTs). Although guidelines target typical patients, RCTs are often based on narrow inclusion and exclusion criteria. Objectives We explored to what extent typical patients, such as those consulting general practitioners for allergic rhinitis, differ from patients enrolled in RCTs. Methods We conducted a prospective cohort study including all the consecutive patients with allergic rhinitis cared for by general practitioners in the Languedoc-Roussillon region of France within 2 weeks during the grass pollen season. We evaluated how the characteristics of these patients differed from those of patients included in the 4 largest placebo-controlled RCTs of persistent and intermittent allergic rhinitis. Results Three hundred eleven patients seen by 48 general practitioners were enrolled in this study. Only 7.4% (95% CI, 4.5% to 10.3%) of the patients would have been enrolled in the RCTs. The primary reasons for this difference were as follows: diagnosis of allergy based on skin test results, serum specific IgE levels, or both (20.4%); severity of allergic rhinitis (11.5%); other chronic diseases (11.4%); history of sinusitis (10.4%); and asthma comorbidity (10.1%). A sensitivity analysis excluding contraception and the diagnosis of allergy showed that the percentage of representative patients increased to 20.2% (95% CI, 15.8% to 24.7%). Conclusion Only a small proportion of patients with allergic rhinitis seen in the primary care setting for allergic rhinitis would be eligible for RCTs. Thus guideline developers and health decision makers need to make careful judgments about the directness of the evidence from RCTs conducted in highly controlled settings.

Allergies give rise to the fifth-leading group of chronic diseases. However, the specific prevalence of ocular allergy is poorly described.We sought to provide a more accurate representation of the epidemiology of ocular allergy in the United States.The National Health And Nutrition Examination Survey III performed in the United States from 1988-1994 was the source for the data collected. Items from the questionnaire regarding ocular and nasal allergy symptoms in relation to skin prick testing were stratified by age, race, region, and sex.The sample size is 20,010: 1,285 (6.4%) reported ocular symptoms, 3,294 (16.5%) reported nasal symptoms, 5,944 (29.7%) reported both ocular and nasal symptoms, and 9.487 (47.4%) were asymptomatic. Forty percent of the population reported at least 1 occurrence of ocular symptoms in the past 12 months. Those 50 years and older have a higher frequency of isolated ocular symptoms (P .001). There is an increase in the frequency of symptoms in those younger than 50 years in the populations of subjects with ocular and nasal symptoms combined and isolated nasal symptoms (P .001). Ocular symptoms are more frequent than nasal symptoms in relation to animals (P .001), household dust (P .001), and pollen (P .001).This analysis provides the first representation of the epidemiology of ocular allergy in the United States. Up to 40% of the population, the highest reported to date, have experienced ocular symptoms at least once in their lifetime, with a peak of symptoms in the months of June and July.

Background The recombinant humanized anti-IgE antibody omalizumab rapidly reduces serum free IgE concentrations and alleviates allergic airway disease. It is not known whether stopping or reducing the dose of omalizumab maintains adequate suppression of free IgE levels and IgE-mediated mast cell activation. Objective To determine the effects of omalizumab on serum free IgE and immediate allergen skin test reactivity during initial therapy followed by treatment reduction and cessation. Methods Forty patients with perennial allergic rhinitis were randomized to receive 0.015 or 0.030 mg/kg/IU/mL open-label intravenous omalizumab every 2 weeks for 28 weeks, followed by 0.0015 or 0.0050 mg/kg/IU/mL every 2 weeks for 18 weeks. Serum free IgE levels were measured and titrated dust mite allergen skin tests conducted throughout. Results At day 98, serum free IgE concentrations were decreased by 96% to 99%, and wheal-and-flare reactions to skin tests were markedly suppressed. After reduced omalizumab doses (day 322), serum free IgE and allergen skin test reactivity increased significantly. On complete discontinuation of therapy (day 378), serum free IgE levels and skin test reactivity returned to baseline levels. Patients with lower initial levels of IgE had significantly less suppression of skin test reactivity. Conclusion Omalizumab reduced serum free IgE and immediate skin test reactivity to allergen during initial, high-dose administration. These effects were not fully maintained during dose reduction and returned to baseline after cessation of chronic treatment.

Background Asthma and rhinitis are often comorbid conditions, and several studies have suggested that rhinitis often precedes asthma. Sensitization to allergen has been shown to be one of the strongest determinants of incident asthma, but little is known about the effects of cigarette smoking among individuals with allergic rhinitis. Objective We sought to evaluate the importance of cigarette smoking as an additional risk factor for incident asthma in a cohort of hospital-referred nonasthmatic adult subjects with allergic rhinitis. Methods The study population selected at baseline was invited for a follow-up visit 10 years later to check for possible asthma features. Categories of smokers, exsmokers, and never smokers were used in the analyses together with pack-years to calculate the level of cumulative exposure. Results Complete data were available from 325 patients. Smoking was significantly related to the risk of incident asthma, with the odds ratio (OR) being 2.67 (95% CI, 1.70-4.19) for univariate and 2.98 (95% CI, 1.81-4.92) for multivariate analyses. A clear dose-response association for exposure to tobacco and risk of new-onset asthma was observed in the multivariate analyses: those with 1 to 10 pack-years had an OR of 2.05 (95% CI, 0.99-4.27), those with 11 to 20 pack years had an OR of 3.71 (95% CI, 1.77-7.78), and those with 21 or more pack-years had an OR of 5.05 (95% CI, 1.93-13.20) compared with never smokers. Conclusions The current findings support the hypothesis that cigarette smoking is an important independent risk factor for the development of new asthma cases in adults with allergic rhinitis.

Although research demonstrates that allergy immunotherapy (IT) improves allergic rhinitis (AR) outcomes, little is known about IT patterns of care and associated resource use and costs among US children with diagnoses of AR.We sought to examine characteristics associated with receiving IT, patterns of IT care, and health care use and costs incurred in the 6 months before versus after IT.We performed retrospective Florida Medicaid claims data (1997-2004) analysis of children (18 years of age) given new diagnoses of AR.Of 102,390 patients with new diagnoses of AR, 3048 (3.0%) received IT. Male patients, Hispanic patients, and those with concomitant asthma were significantly more likely to receive IT. Approximately 53% completed less than 1 year and 84% completed less than 3 years of IT. Patients who received IT used significantly less pharmacy (12.1 vs 8.9 claims, P.0001), outpatient (30.7 vs 22.9 visits, P.0001), and inpatient (1.2 vs 0.4 admissions, P = .02) resources in the 6 months after versus before IT. Pharmacy ($330 vs $60, P.0001), outpatient ($735 vs $270, P.0001), and inpatient ($2441 vs $1, P.0001) costs (including costs for IT care) were significantly reduced after IT.Despite suboptimal treatment persistence (only 16% of patients completed 3 years of IT), resource use and costs after treatment were significantly reduced from pre-IT levels.

The efficacy of the intranasal corticosteroid mometasone furoate nasal spray (MFNS) for treatment of nasal polyposis was demonstrated in 2 large clinical trials.To evaluate the onset of MFNS symptomatic effect, data from the 2 trials were pooled and analyzed to determine the first day subjects experienced significant symptom relief.Subjects with nasal polyposis randomized to MFNS 200 microg twice daily or placebo scored symptoms on a 3-point scale (0 = none; 3 = severe) and measured peak nasal inspiratory flow immediately before the morning dose. Onset of symptomatic effect was defined as the first day a statistically significant (P.05) lasting response was observed for MFNS compared with placebo.A total of 447 subjects with bilateral nasal polyps and clinically significant nasal congestion/obstruction were analyzed. Compared with placebo, MFNS 200 microg twice daily demonstrated statistically significant (P.05) relief of anterior rhinorrhea by day 2 (-10.9% vs +5.7%), nasal congestion by day 3 (-15.1% vs -7.6%), postnasal drip by day 5 (+1.1% vs +4.6%), and sense of smell by day 13 (-9.6% vs -5.6%). Significant improvement in peak nasal inspiratory flow was seen by day 2 (increase of 6.22 L/min vs 1.48 L/min for placebo; P = .03).Mometasone furoate nasal spray 200 microg twice daily rapidly improves the symptoms of nasal polyposis, leading to lasting relief of most major symptoms within 2 (24 hours after the first dose) to 5 days of initiating therapy.

The Allergic Rhinitis and its Impact on Asthma document was first published in 2001. Since then, new data on specific immunotherapy have appeared. This review is intended as an update to the original document. MedLine (2001 to June 2006) was searched with appropriate key words, and panelists were asked to identify further relevant articles. Randomized controlled trials were considered for the evaluation of efficacy. For the evaluation of safety and additional effects, studies with lower grades of evidence were included. The clinical efficacy of injection immunotherapy in rhinitis and asthma was confirmed, as well as the safety, provided that recommendations are followed. Studies have demonstrated the long-term efficacy and the preventive effect of immunotherapy in reducing the onset of new sensitizations. One randomized open trial demonstrated that in children with allergic rhinitis, injection immunotherapy may reduce the risk of developing asthma. There is strong evidence that sublingual immunotherapy is effective in allergic rhinitis in adults. Recent meta-analyses demonstrated its efficacy in allergic rhinitis in children and in asthma, although more definitive trials are required. Current data indicate that sublingual immunotherapy is safe and the rate of adverse reactions is not greater below 5 years of age. One randomized open trial showed that in children with allergic rhinitis, sublingual immunotherapy reduced the onset of asthma. Further studies are needed to identify the optimal maintenance dose and to elucidate the mechanism of action. Novel approaches for immunotherapy are currently under evaluation, including the use of adjuvants, peptides, and DNA-conjugated and recombinant allergens.

Background Lupin is a legume. Its seed can be ground into flour and incorporated into food as a protein source. Cases of rhinitis, urticaria, and anaphylaxis from ingestion of lupin have been reported as well as asthma. Objective To present a cross-sectional study of workers in a food processing company who were exposed to lupin and developed occupational allergy secondary to inhaling lupin products. Methods Subjects were interviewed using a standardized questionnaire, including demographics and current and past symptoms. They underwent skin prick tests (SPTs) to common aeroallergens and lupin products, spirometry, and off-line exhaled nitric oxide measurement. Symptomatic subjects, sensitized to lupin on SPT, underwent methacholine bronchial provocation challenge. Those with bronchial hyperresponsiveness had specific bronchial provocation challenge to lupin. Results A total of 53/54 subjects completed testing (98%). Overall, 21% (11/53) had positive SPT results to lupin. The lupin-sensitive group had a trend toward atopy ( P = .06). Seven of 11 (64%) subjects in this group were symptomatic; all had rhinitis, and 2 had wheeze. Two subjects had positive methacholine challenges, and 1 had a positive specific bronchial provocation challenge to lupin with both an early-phase and a late-phase response. Conclusion Allergy to inhaled lupin occurs in the workplace. A high sensitization rate on SPT was found, which correlated with symptoms. The clinical significance of cross-reactivity between legumes on SPT is unclear. Clinical implications Sensitization to the legume, lupin, can occur from exposure at work and carries a high prevalence of clinical symptoms, which in some cases leads to occupational rhinitis and asthma.

Background Obesity as well as a reduced microbial exposure, 2 markers of Western lifestyle, might be associated with an increased risk of allergic sensitization. Objective We aimed to analyze the interplay of these markers of Western lifestyle on allergic sensitization. Methods A questionnaire survey was completed by rural adults (18-45 years). Clinical assessments included those of sensitization (specific IgE) against inhalant allergens and body mass index (BMI). Subjects were grouped on the basis of their recent BMI (obesity: BMI ≥30 kg/m 2 ) and whether they had regular farm contact during the first 3 years of life (farm subjects). Nonobese nonfarm subjects served as the reference group. Overall, 1861 subjects were included in the analyses. Results Compared with nonobese nonfarm subjects, nonobese farm subjects showed a decreased odds ratio for sensitization (odds ratio, 0.6; 95% CI, 0.5-0.8). This decrease was not observed in obese subjects (obese nonfarm subjects: 1.2, 0.8-1.9; obese farm subjects: 1.0, 0.6-1.6). Associations were similar for symptoms of allergic rhinitis. Conclusion Obesity, as a risk factor for respiratory allergies per se, might diminish or even cancel the protective effect of a farm childhood. Clinical implications The high prevalence of respiratory allergies in inner-city societies despite lower levels of hygiene might be explained by obesity.

Allergic rhinitis (AR) and perennial nonallergic rhinitis (PNAR) represent conditions affecting millions of individuals across the world. Although the diagnosis of AR might be presumptively based on the types of symptoms and the history of allergen triggers, confirmation requires documentation of specific IgE reactivity. In contrast, PNAR is a condition with similar symptomatology but in which the patient has no identifiable specific allergic sensitivities. This review presents the diverse options of currently available pharmacologic agents for the treatment of AR and PNAR, including intranasal corticosteroids, H1-antihistamines, decongestants, cromolyn sodium, antileukotrienes, anticholinergics, capsaicin, anti-IgE, and intranasal saline. Furthermore, appropriate stepped-up, stepped-down pharmacotherapeutic algorithms are described for the various forms of rhinitis.

There is a close link between allergic rhinitis (AR) and lower airways disorders, and this concept has been clarified and confirmed in several studies. AR constitutes a main risk factor for new-onset asthma. Furthermore, numerous epidemiologic surveys indicate that AR is very frequently associated with asthma. Bronchial hyperreactivity, a component of asthma, has often been reported to be present in patients with AR. Bronchial hyperreactivity in AR might represent a prognostic factor for further progress to asthma. In this regard forced expiratory flow at 25% and 75% of pulmonary volume has been proposed as an early marker of bronchial involvement in patients with AR who perceive only nasal symptoms. A close structural and functional relationship between the upper and lower airways has been recently demonstrated. Finally, adequate treatment of AR might positively affect the course of asthma. Taking these facts into consideration, a new diagnostic approach should be considered in managing patients with AR: a possible bronchial involvement must be sought in each patient.

Background The late-phase reaction (LPR) of the skin is an in vivo model of allergic inflammation. Objective We sought to identify disease-associated pathways in the LPR using a network-based analysis. Methods The LPR was examined by means of DNA microarray analysis of skin biopsy specimens from 10 patients with allergic rhinitis and 10 healthy control subjects. The results were further analyzed in 2 different materials consisting of nasal fluids and allergen-challenged CD4 + T cells from patients with allergic rhinitis. Results The DNA microarray analysis revealed several genes of known relevance to allergy. The eosinophil marker Charcot-Leyden crystal protein (CLC) that encodes Charcot-Leyden crystal protein differed most in expression. A network-based analysis showed upregulation of IL-4– and CCL4-dependent pathways and downregulation of a TGF-β–induced pathway. CCL4 is expressed by CD4 + T cells and chemotactic for eosinophils. We hypothesized that allergen induces release of CCL4 from T H 2 cells and that this contributes to influx of eosinophils. Further analysis showed increase of CCL4 protein in nasal fluids from allergic patients during the season. Allergen challenge of PBMCs resulted in proliferation of T H 2 cells and increased production of CCL4 in CD4 + T cells from allergic patients. An analysis of the DNA microarray data revealed a significant correlation between CCL4 and the eosinophil marker CLC. Conclusion A network-based analysis of the LPR showed increased activity of IL-4– and CCL4- dependent pathways and downregulation of the TGF-β–induced pathway. Allergen-induced release of CCL4 from T H 2 cells might contribute to influx of eosinophils during the LPR. Clinical implications Involvement of multiple interacting pathways indicates that it might be difficult to identify one single mediator as a biomarker or drug target in allergic inflammation.

Background Studies show that children in rural environments develop less asthma and allergic rhinitis than their urban counterparts. This may be a result, in part, of neonatal exposure to environmental antigens such as LPS and/or early exposure to allergens. Objective This study examined the effects of neonatal allergen and/or LPS exposure on subsequent immune responses to allergen. Methods Newborn mice were exposed to LPS and/or ovalbumin. At age 6 weeks, these animals were sensitized and challenged with ovalbumin, and airway inflammation, hyperresponsiveness, and cytokine expression were assessed. Results Animals exposed to LPS in the neonatal period developed T cells expressing CD25 and IL-10 on sensitization and challenge. They demonstrated abrogation of airway hyperresponsiveness and significant decreases in IL-13 from bronchoalveolar lavage fluid and in specific IgE. IL-4–expressing spleen cells were also significantly decreased. Mice exposed in the neonatal period to ovalbumin demonstrated airway hyporesponsiveness after subsequent ovalbumin sensitization and challenge and did not produce specific IgE. In contrast, these animals showed increases in IFN-γ. Animals exposed to both LPS and ovalbumin developed a response characterized by IL-10 and IFN-γ–expressing T cells. Conclusion This suggests that mucosal antigen exposure in the neonatal period results in inhibition of allergic responses to environmental allergens. Early LPS exposure directs mucosal responses toward tolerance, whereas ovalbumin exposure follows the T H 1-type response on subsequent sensitization. Clinical implications This study suggests that prevention of airways allergy may be best achieved by appropriate exposure of the airway mucosa early in life to environmental antigens.

Background Allergic rhinitis is one of the most common allergic inflammatory diseases characterized by a predominant T H 2 response with antigen-specific IgE synthesis. IL-15 plays important roles in activation and maintenance of memory CD8 + T cells capable of producing IFN-γ, which regulates T H 2 responses. Objective To investigate the roles of endogenous IL-15 in allergic inflammation, we examined allergic rhinitis in IL-15 knockout (KO) mice sensitized with ovalbumin followed by intranasal rechallenge with ovalbumin. Methods IL-15KO mice were sensitized intraperitoneally with ovalbumin/complete Freund's adjuvant on day 0 and ovalbumin/IFA on day 7, and then were intranasally challenged with ovalbumin on days 21, 22, 23, 24, and 25. Nasal symptoms and histologic changes were examined. IgE production and T H 2 responses were measured by ELISA. Purified CD8 + T cells or recombinant IL-15 were administered into ovalbumin-sensitized mice. Results The levels of IgE production and T H 2 responses in IL-15KO mice were comparable to those in control mice after ovalbumin sensitization. However, sneezing, infiltration of eosinophils into the nasal mucosa, and T H 2 cytokine production were aggravated in ovalbumin-sensitized IL-15KO mice after intranasal challenge with ovalbumin. Adoptive transfer of CD8 + T cells from ovalbumin-sensitized mice suppressed the T H 2 responses in mice but not in IL-15KO mice. Administration of IL-15 with ovalbumin significantly prevented the development of allergic rhinitis in ovalbumin-sensitized mice. Conclusion We demonstrate with IL-15KO mice that endogenous IL-15 plays an important role in suppression of allergic rhinitis at effector phase. Intranasal administration of IL-15 is useful as a therapeutic approach to control allergic rhinitis. Clinical implications Intranasal administration of recombinant IL-15 might become new immunotherapy for allergic rhinitis.

Allergic rhinitis represents a global health care problem, affecting an estimated 10% to 25% of the population, with higher figures from some countries, in which approximately 40% of children have symptoms compatible with allergic rhinitis. Allergic rhinitis has been calculated to affect 20 to 40 million individuals within the United States annually. The effect of the disease is often underestimated. Because rhinitis is not life-threatening and the nose can be bypassed, so to speak, by oral breathing, the disease is often trivialized. Quality of life evaluation reveals, however, that allergic rhinitis has a significant effect on well-being beyond the presence of nasal symptoms. Allergic rhinitis has been found to impair work and school performance as well as learning ability and is a major cause of lost school attendance and work absenteeism. It has been calculated that in 1 year in the United States, there are a staggering 811,000 missed workdays, 4,230,000 reduced productivity days, and 824,000 school absences caused by rhinitis. Thus, there

Background There have been few reports using animal models to study the development of allergic rhinitis. Characterization of such a model in mice would be advantageous given the availability of reagents and gene-manipulated strains. Objective We sought to develop a murine model of allergic rhinitis in the absence of lower airway changes. Methods After sensitization and challenge, both wild-type and FcɛRI-deficient mice were studied for their ability to develop early- and late-phase nasal responses. In the invasive approach, direct measurements of nasal airway resistance (R NA ) were obtained; in the noninvasive approach using whole-body plethysmography, respiratory frequency and expiratory and inspiratory times were monitored. In both approaches, nasal responses were determined either acutely after challenge (early phase) or 24 hours after challenge (late phase). Results After challenge of sensitized mice, R NA significantly increased. In parallel, respiratory frequency significantly decreased and was highly correlated with the increases in R NA . Sensitized wild-type mice had an early-phase nasal response and persistent nasal blockage (late-phase response) after allergen challenge. In contrast, sensitized and challenged FcɛRI α-chain–deficient mice did not have an early-phase nasal reaction and exhibited reduced nasal blockage and lower IL-13 levels in nasal tissue homogenates. Conclusions These data indicate that FcɛRI is essential to development of an early-phase nasal response and contributes to the development of the late-phase nasal response. These invasive and noninvasive approaches provide new opportunities to evaluate the mechanisms underlying the development of nasal responses to allergen and to assess various therapeutic interventions.

Background Chronic replication of cytomegalovirus and EBV in early life may affect the immune system and play a role in the development of allergy in children. Objective To assess the relation between cytomegalovirus infection and allergic disorders in children, including a possible interaction with EBV infection. Methods From a prospective birth cohort study in Stockholm, on factors of importance for development of allergy, 2581 four-year-old children were enrolled. The classification of allergic diseases was based on questionnaire answers and determination of IgE antibodies to common airborne and food allergens. IgG to cytomegalovirus was determined by a commercial ELISA and to EBV by indirect immunofluorescence. Results A total of 1191 (46%) children were cytomegalovirus-seropositive. There were no significant associations between seropositivity to cytomegalovirus and allergic manifestations, such as bronchial asthma, suspected allergic rhinitis, or atopic dermatitis. Seropositivity to cytomegalovirus alone, ie, without seropositivity to EBV, was related to IgE antibodies to airborne and food allergens (adjusted odds ratio, 1.8; 95% CI, 1.2-2.9).An antagonism between cytomegalovirus and EBV in relation to sensitization to airborne and food allergens was suggested ( P =.05). Conclusion The study does not support the hypothesis that previous cytomegalovirus infection plays an important role in the pathogenesis of bronchial asthma, suspected allergic rhinitis, or atopic dermatitis in children. However, in the absence of EBV infection, cytomegalovirus infection may be related to sensitization to airborne and food allergens.

Allergic Rhinitis and its Impact on Asthma in collaboration with the World Health Organization initiative reclassified allergic rhinitis, like asthma, by duration and severity. The Xyzal in Persistent Rhinitis Trial is the first large, long-term clinical trial studying patients with persistent rhinitis as defined by Allergic Rhinitis and its Impact on Asthma.Two primary objectives were defined: comparison of the Rhinoconjunctivitis Quality of Life Questionnaire overall score and Total 5 Symptoms Score (rhinorrhea, sneezing, nasal congestion, and nasal and ocular pruritus) over a period of 4 weeks between levocetirizine 5 mg and placebo. Secondary endpoints included similar evaluations at 1 week and 3, 4.5, and 6 months, summary scores for a general health status questionnaire (Medical Outcomes Survey Short Form 36), a pharmacoeconomic assessment, comorbidities, and a safety evaluation.The Xyzal in Persistent Rhinitis Trial was a 6-month double-blind, placebo-controlled, multicenter, multinational trial in 551 patients. Adults with persistent rhinitis sensitized to both grass pollen and house dust mite were randomized to receive levocetirizine 5 mg/d or placebo.A total of 421 patients completed the full study. Levocetirizine significantly improved both the Rhinoconjunctivitis Quality of Life Questionnaire overall score and the Total 5 Symptoms Score from week 1 to 6 months (all P values.001). Medical Outcomes Survey Short Form 36 summary scores were also improved in the levocetirizine group compared with the placebo group. Treatment cessation because of lack of effect, comorbidities, and overall costs of disease, and comorbidities per working patient per month (160.27 vs 108.18) were lower in the levocetirizine group.Levocetirizine was shown to improve quality of life and symptoms and to decrease the overall costs of the disease over the 6-month treatment period.

Background By design, omalizumab binds free IgE in the circulation and prevents its attachment to the surface of mast cells and basophils, thereby preventing them from responding to allergens. Previously, omalizumab rapidly reduced free IgE levels, as well as basophil high-affinity IgE receptors, leading to significant reductions in basophil mediator response to allergen. It is assumed that tissue mast cells are similarly altered in their FceRI density and function. Objective We examined the phenotypic shift of skin mast cells in parallel to that of blood basophils in 3 subjects infused with omalizumab. Methods Three subjects with allergic rhinitis underwent intradermal skin test titration with house dust mite antigen at days 0, 7, 70, and 196 of omalizumab treatment. As control subjects, 5 untreated subjects with allergic rhinitis were evaluated at similar time points. All subjects underwent skin biopsy 18 to 24 hours later at the site of allergen injection. Biopsy specimens were characterized by means of immunohistochemisty for tryptase and FceRIα immunoreactivity, as well other markers (CD3, CD45RO, CD68, cutaneous lymphocyte antigen, and major basic protein). Results Omalizumab recipients, but not control subjects, demonstrated reductions in FceRIα immunoreactivity at days 70 and 196 in parallel with reductions in the acute wheal response to allergen. However, no reductions in tryptase-positive cells were noted at these time points. Conclusion Reductions in free IgE levels by omalizumab leads to a rapid reduction in basophil FceRI receptor expression. In contrast, the time course for the decrease of FceRI expression in skin mast cells is slower and associated with decreased acute allergen wheal size.

Although clinical trials have demonstrated that rhinitis therapy improves subjective and objective measures of asthma, it is uncertain whether treatment of allergic rhinitis significantly affects the frequency of asthma exacerbations.The objective of this study was to determine whether treatment with intranasal corticosteroids and/or second-generation antihistamines is associated with changes in rates of asthma exacerbations resulting in emergency room visits and/or hospitalizations in patients with asthma and allergic rhinitis.This was a nested, case-control study.Treatment with either nasal corticosteroids or second-generation antihistamines was associated with a lower risk of asthma-related emergency room treatment and hospitalization (adjusted odds ratio [OR], 0.51; 95% CI, 0.34 to 0.77 and 0.34, 0.18 to 0.62, respectively). Patients who used nasal corticosteroids had a significantly lower risk of both asthma-related emergency room treatment and hospitalization (adjusted OR, 0.75; 95% CI, 0.62 to 0.91 and 0.56, 0.42 to 0.76, respectively), whereas there was a trend toward lower risk of emergency room treatment and hospitalization in patients who used second-generation antihistamines (adjusted OR, 0.88; 95% CI, 0.62 to 1.26 and 0.68, 0.40 to 1.14, respectively). Combined treatment with both medications was associated with a further lowering of the risk of both emergency room treatment and hospitalization (adjusted OR, 0.37; 95% CI, 0.19 to 0.73 and 0.22, 0.07 to 0.63).In patients with asthma, treatment of concomitant allergic rhinitis was associated with significant reductions in risk of emergency room treatment and hospitalization for asthma.

The nasal and bronchial mucosa present similarities and differences. Remodeling is defined as "model again or differently, reconstruct" and is present in the airways of most if not all asthmatic patients. Even though inflammation is similar in allergic rhinitis and asthma, the pathologic extent of nasal remodeling in patients with rhinitis seems to be far less extensive than that in the bronchi of asthmatic patients. Epithelial damage is only minimal, and the reticular basement membrane does not appear to be largely pseudothickened. Moreover, the demonstration of fibrogenic growth factors in the nasal mucosa of patients with allergic rhinitis is lacking because of the paucity of studies. The reasons why remodeling appears to be less extensive in the nasal mucosa than in the bronchial mucosa are still unclear, but 2 hypotheses can be put forward. On one hand, the cytokine production of smooth muscle cells might partly explain differences in remodeling of the 2 sites of the airways. On the other hand, the genes of the embryologic differentiation might persist in the nose and bronchi or might be re-expressed in asthma and rhinitis. Because the nose is of ectodermal origin and the bronchi of endodermal origin, these genes might also govern remodeling patterns. More studies are urgently required to better characterize nasal remodeling in patients with rhinitis. A better understanding of nasal and bronchial remodeling might help to identify new pathways and new therapeutic strategies to reduce long-term remodeling in asthma.

Allergic rhinitis triggers a systemic increase of inflammation. Within minutes of allergen exposure, immune cells release histamine, proteases, cysteinyl leukotrienes, prostaglandins, and cytokines. Some produce the early symptoms, while others augment the production, systemic circulation, and subsequent infiltration of the nasal mucosa with inflammatory cells that sustain the symptoms. Systemic circulation of inflammatory cells permits their infiltration into other tissues where chemoattractant and adhesion molecules already exist. Consequently, allergic rhinitis is linked to comorbid conditions: asthma, chronic hyperplastic eosinophilic sinusitis, nasal polyposis, and serous otitis media. Effective therapy should be directed at underlying inflammation and its systemic manifestations. It should improve the rhinitis and the comorbid conditions. Antihistamines relieve early symptoms by blocking basophil- and mast cell-generated histamine, but they do not significantly influence the pro-inflammatory loop. They are often little better than placebo. Oral corticosteroids provide the systemic anti-inflammatory efficacy, but their toxicity precludes such an approach. Intranasal corticosteroids effectively target the local inflammatory processes of rhinitis, reducing local inflammatory cells within the nares, but they do not directly access tissues involved in the comorbid conditions. Leukotriene modifiers have both systemic anti-inflammatory effects and an acceptable safety profile.

Background Unlike other chemokines, fractalkine is expressed as a membrane-bound form, mainly on endothelial and epithelial cells, and can be shed as a soluble chemotactic form. Fractalkine can capture leukocytes expressing its receptor (CX 3 CR 1 ), including T lymphocytes, rapidly and firmly in an integrin-independent manner. Because of its dual activity, fractalkine plays a major role in the transendothelial and transepithelial migration of leukocytes during inflammation. Objective We sought to study the fractalkine-CX 3 CR 1 axis in patients with allergic airways diseases. Methods Plasma fractalkine levels were measured by means of ELISA in 19 control subjects and 55 patients with symptomatic allergic rhinitis, asthma, or both, and CX 3 CR 1 function was studied by using triple-color flow cytometry in circulating T-lymphocyte subpopulations. Segmental allergen challenge was performed in 16 allergic asthmatic patients to analyze fractalkine expression and inflammatory cell recruitment in bronchoalveolar lavage fluid and bronchial biopsy specimens. Results Compared with control subjects, patients with symptomatic allergic rhinitis and asthmatic patients had increased circulating fractalkine levels, and CX 3 CR 1 function was upregulated in circulating CD4 + T lymphocytes. Twenty-four hours after segmental allergen challenge, bronchoalveolar lavage fluid soluble fractalkine concentrations increased and correlated with the total number of recruited cells. Bronchial epithelial and endothelial cells expressed high levels of the membrane-bound form of fractalkine before and after challenge. Conclusion Allergic asthma and rhinitis are associated with systemic and bronchial upregulation of the chemotactic axis fractalkine-CX 3 CR 1 . This might contribute to the rapid recruitment of circulating CD4 + T lymphocytes in the airways after allergen stimulation.

Sex hormones may be associated with the risk of onset of asthma.To study the association between maternal sex hormone concentrations during early pregnancy and the risk of asthma among offspring.A case-control study of 129 asthmatic children and 125 control children 5 to 6 years of age. Maternal sera in early pregnancy were obtained from the Finnish Maternal Cohort serum bank.The means of serum progesterone and estradiol and free estradiol in mothers of asthmatic and control children were 81.0 and 82.8 nmol/L (P =.60), 7.87 nmol/L and 7.65 nmol/L (P =.99), and 149.5 pmol/L and 148.0 pmol/L (P =.95), respectively. There were also no differences in the mean concentrations of maternal sex hormones according to the presence of allergic rhinitis or atopic eczema among the children.The current results do not support an association between maternal sex hormone concentrations during early pregnancy and onset of allergic disease in early childhood.

Background Nasal polyps are a common problem that is difficult to diagnose and treat, in part because the cause of nasal polyposis is unknown. Although information on the pathogenesis of polyposis is lacking, there are reports suggesting that a genetic predisposition underlies this disorder. Objective We sought to better understand the basis of nasal polyposis associated with allergic rhinitis. We hypothesize that the expression of unique genes is associated with the nasal polyposis phenotype. Methods We examined 12,000 human genes transcribed in the nasal mucosa of patients with allergic rhinitis with and without nasal polyps. Biopsy specimens of the mucosa of patients with and without polyps were obtained after the patients refrained from the use of topical or systemic steroid therapy for 2 weeks. Results Thirty-four genes were differentially expressed between the patient groups, including those for inflammatory molecules and putative growth factors. The greatest differential expression identified by the array analysis was for a group of genes associated with neoplasia, including mammaglobin, a gene transcribed 12-fold higher in patients with polyps compared with control patients with rhinitis alone. Quantitative RT-PCR confirmed this differential expression and documented that the number of mammaglobin mRNA copies is actually 64-fold greater in tissues of patients with polyps versus control patients. The specificity of mammaglobin protein expression was evaluated by means of immunohistochemistry, which showed specific staining in nasal polyp mucosal goblet cells only in patients with polyps. Conclusion These data suggest that nasal polyposis involves deregulated cell growth, using gene activation in some ways similar to a neoplasm. In addition, mammaglobin, a gene of unknown function associated with breast neoplasia, might be related to polyp growth.

There is renewed interest in antihistamines for the treatment of allergic asthma. A growing body of literature has shown that the newer compounds can affect inflammatory cell accumulation and cytokine/chemokine production. In a murine model of allergen-induced airway inflammation and hyperresponsiveness, the ability of fexofenadine to affect these outcomes was tested in a primary sensitization and challenge model and after treatment of donor mice before the adoptive transfer of T cells into recipients receiving limited allergen exposure. Mice were sensitized and challenged with allergen (ovalbumin). Airway function after inhaled methacholine was monitored in parallel to the assessment of tissue and airway inflammation and cytokine production. In further experiments, lung T lymphocytes from sensitized/challenged donor mice were transferred into naive recipients before limited airway challenge with the allergen. Administration of fexofenadine before challenge but after sensitization was effective in preventing tissue eosinophilia and airway hyperresponsiveness. Moreover, the treatment of donor mice with fexofenadine before transfer of lung T cells effectively prevented airway hyperresponsiveness and eosinophilia in naive mice exposed to limited airway challenge. These data therefore support the potential for fexofenadine in the treatment of allergen-induced airway hyperresponsiveness and inflammation.

Atopic dermatitis, allergic rhinitis, and asthma are atopic diseases that develop on a complex genetic background, the so-called atopic diathesis. Although they target different organs, in most patients they are characterized by the presence of elevated total serum IgE levels. However, a subgroup of atopic patients exhibits normal IgE levels and mechanisms contributing to the so-called "intrinsic" or "nonallergic form" have been the matter of intensive research work in the last years. Because of the rapid advancements in the research field of atopic diseases, it now becomes possible for the first time to delineate a new disease classification of allergic and nonallergic subtypes of atopic diseases, thereby bringing hope to the clinician for a more specific treatment approach for each subgroup of these patients.

Allergic rhinitis is an inflammation involving T(H)2-type cytokine production, with pathologic eosinophil infiltration in the nasal mucosa. Although TNF-alpha is thought to be a pro-inflammatory cytokine, the relationship between TNF-alpha and allergic rhinitis has not been clarified.The role of TNF-alpha in a murine model of ovalbumin (OVA)-sensitized allergic rhinitis was investigated by using mice deficient in the gene encoding TNF-alpha (TNF-alpha(-/-) mice).Both wild-type (TNF-alpha(+/+)) and TNF-alpha(-/-) mice were sensitized with OVA by means of intraperitoneal injection. They were then challenged with intranasal OVA, and various allergic responses were assessed.The production of OVA-specific IgE in the serum (P.05) and the frequency of sneezes (P.05) and nasal rubs (P.05) decreased significantly in TNF-alpha(-/-) mice after OVA sensitization compared with that in TNF-alpha(+/+) mice (P.05). The mRNA expression of IL-4, IL-10, and eotaxin in nasal mucosa in TNF-alpha(-/-) mice was also significantly suppressed compared with that in TNF-alpha(+/+) mice after OVA sensitization (P.05). Furthermore, the expression of both endothelial-leukocyte adhesion molecule 1 and vascular cell adhesion molecule 1 mRNA in the nasal mucosa was significantly suppressed (P.05), although intercellular adhesion molecule 1 mRNA expression did not decrease significantly in TNF-alpha(-/-) mice compared with that in TNF-alpha(+/+) mice after OVA sensitization. In addition, the effect of TNF-alpha on endothelial-leukocyte adhesion molecule 1 and vascular cell adhesion molecule 1 expression by means of Western blot analysis was compatible with the mRNA results. Pathologically, eosinophil infiltration in nasal mucosa was significantly restricted in TNF-alpha(-/-) mice compared with in TNF-alpha(+/+) mice after OVA sensitization (P.05).TNF-alpha is necessary for antigen-specific IgE production and for the induction of T(H)2-type cytokines and chemokines. Furthermore, TNF-alpha might be important for the expression of adhesion molecules to recruit eosinophils to the allergic inflammatory site. We conclude that the lack of TNF-alpha inhibited the development of allergic rhinitis.

Antihistamines are effective medications that have been used for decades in the management of allergic rhinitis; however, they may be administered or selected in an inappropriate fashion and may be the source of drug-related morbidity. Our objective is to present relevant background information and an expert consensus statement on the use of antihistamines in treatment of allergic rhinitis. In July 2002, 14 experts in allergy, clinical immunology, pharmacology, and impairment assessment were invited to participate in a roundtable conference to present current concepts and develop a consensus statement on the clinical management of allergic rhinitis with antihistamines. Many of the antihistamines used to treat allergic rhinitis, as well as the disease itself, may produce sedation, impairment, and reduced quality of life. Allergic rhinitis is more appropriately managed with the relatively nonimpairing second-generation antihistamines (eg, loratadine, desloratadine, cetirizine, and fexofenadine), because older agents (eg, diphenhydramine, chlorpheniramine, and brompheniramine) produce sedation and impairment and worsen sleep architecture. Although there is some debate surrounding the varying degrees of efficacy of second-generation antihistamines, it is known that some agents may produce varying levels of drowsiness or impairment, especially at higher than recommended doses. The differences with regard to safety among the second-generation antihistamines are smaller than are the differences between the first and second generations. A nonsedating, nonimpairing (even at higher than recommended doses), second-generation antihistamine is preferred for all patients, particularly those with a higher risk for the development of adverse effects. We recommend that primary care and specialist physicians, nurse practitioners, physician assistants, pharmacists, and all other health professionals involved in the diagnosis and treatment of allergic rhinitis follow this consensus document and share this information with patients for whom antihistamine therapy is recommended. In addition, further epidemiologic studies on the effects of antihistamines should be performed.