Allergome-wide peptide microarrays enable epitope deconvolution in allergen-specific immunotherapy.

BACKGROUND: The interaction of allergens and allergen-specific IgE initiates the allergic cascade after crosslinking of receptors on effector cells. Antibodies of other isotypes may modulate such a reaction. Receptor crosslinking requires binding of antibodies to multiple epitopes on the allergen. Limited information is available on the complexity of the epitope structure of most allergens. OBJECTIVES: We sought to allow description of the complexity of IgE, IgG4, and IgG epitope recognition at a global, allergome-wide level during allergen-specific immunotherapy (AIT). METHODS: We generated an allergome-wide microarray comprising 731 allergens in the form of more than 172,000 overlapping 16-mer peptides. Allergen recognition by IgE, IgG4, and IgG was examined in serum samples collected from subjects undergoing AIT against pollen allergy. RESULTS: Extensive induction of linear peptide-specific Phl p 1- and Bet v 1-specific humoral immunity was demonstrated in subjects undergoing a 3-year-long AIT against grass and birch pollen allergy, respectively. Epitope profiles differed between subjects but were largely established already after 1 year of AIT, suggesting that dominant allergen-specific antibody clones remained as important contributors to humoral immunity following their initial establishment during the early phase of AIT. Complex, subject-specific patterns of allergen isoform and group cross-reactivities in the repertoires were observed, patterns that may indicate different levels of protection against different allergen sources. CONCLUSIONS: The study highlights the complexity and subject-specific nature of allergen epitopes recognized following AIT. We envisage that epitope deconvolution will be an important aspect of future efforts to describe and analyze the outcomes of AIT in a personalized manner.

The SQ tree SLIT-tablet is highly effective and well tolerated: Results from a randomized, double-blind, placebo-controlled phase III trial.

BACKGROUND: The SQ tree sublingual immunotherapy (SLIT)-tablet (ALK-Abelló, Hørsholm, Denmark) is developed for treatment of tree pollen-induced allergic rhinoconjunctivitis (ARC). OBJECTIVE: The aim of this pivotal phase III trial was to demonstrate the efficacy and safety of the SQ tree SLIT-tablet. METHODS: This was a randomized, double-blind, placebo-controlled trial with 634 subjects (12-65 years) with moderate-to-severe ARC despite use of symptom-relieving medication. Eligible subjects were randomized 1:1 to active or placebo treatment. The primary end point was the average daily ARC total combined score (TCS) during the birch pollen season (BPS) analyzed for subjects with diary data during the BPS. Secondary end points included average daily symptom scores (DSS) during the BPS, average TCS and DSS during the tree pollen season (TPS), and average daily medication scores (DMS) in the BPS and TPS. RESULTS: The primary and key secondary end points demonstrated statistically significant and clinically relevant effects of the SQ tree SLIT-tablet compared with placebo. For the BPS, absolute (relative) differences from placebo were 3.02 (40%) for TCS, 1.32 (37%) for DSS, and 1.58 (49%) for DMS (all P < .0001). For the TPS, absolute (relative) differences from placebo were 2.27 (37%) for TCS, 0.99 (33%) for DSS, and 1.20 (47%) for DMS (all P < .0001). Treatment was well tolerated. The most frequently reported treatment-related adverse events were mild or moderate local reactions related to sublingual administration. CONCLUSION: The trial demonstrated the efficacy and safety of the SQ tree SLIT-tablet compared with placebo during the BPS and TPS in adolescents and adults with birch pollen-induced ARC (EudraCT 2015-004821-15).

PAP treatment in patients with OSA does not induce long-term nasal obstruction.

We hypothesized that positive airway pressure treatment would induce nasal obstruction and decrease nasal cavity due to mucosal swelling. We further hypothesized that subjective and objective nasal obstruction at baseline would negatively affect positive airway pressure adherence. A total of 728 patients with sleep apnea were investigated in the Icelandic Sleep Apnea Cohort at baseline and 2 years after starting positive airway pressure. Patients underwent home sleep apnea testing at baseline. Questionnaires were answered and acoustic rhinometry was completed at baseline and follow-up. The proportion of patients reporting subjective nocturnal nasal obstruction was reduced (baseline: 35% versus follow-up: 24%; p < 0.001). Small interior nasal dimensions increased (p < 0.001) independent of adherence to treatment. Small nasal volume at baseline was a determinant for becoming a non-user of positive airway pressure treatment (odds ratio 2.22, confidence interval 95% 1.35-3.67, p = 0.002). Subjective nasal obstruction decreased 2 years after initiating positive airway treatment in sleep apnea, and objectively small nasal dimensions increased. Small nasal volume at baseline was a negative predictor for positive airway pressure treatment adherence. Maybe most importantly, positive airway pressure treatment did not cause long-term objective or subjective nasal obstruction.

Is it possible to feel at home in a patient room in an intensive care unit? Reflections on environmental aspects in technology-dense environments.

This paper focuses on the patient's perspective and the philosophical underpinnings that support what might be considered optimal for the future design of the intensive care unit (ICU) patient room. It also addresses the question of whether the aspects that support at-homeness are applicable to ICU patient rooms. The concept of "at-homeness" in ICUs is strongly related to privacy and control of space and territory. This study investigates whether the sense of at-homeness can be created in an ICU, when one or more patients share a room. From an interdisciplinary perspective, we critically reflect on various aspects associated with conflicts surrounding the use of ICU patient rooms. Thus, from an architectural and a caring perspective, the significance of space and personal territory in ICU patient rooms is emphasized. Recommendations for further research are suggested. In conclusion, privacy and control are deemed to be essential factors in the stimulation of recovery processes and the promotion of well-being in situations involving severe illness or life-threatening conditions.

Nocturnal nasal obstruction is frequent and reduces sleep quality in patients with obstructive sleep apnea.

The prevalence and consequences of nasal obstruction in untreated obstructive sleep apnea patients are not known. The study objectives were to investigate the frequency of subjective and objective nasal obstruction in untreated sleep apnea patients and the associations with sleep and quality of life. Patients in the Icelandic Sleep Apnea Cohort were subjected to a type 3 sleep study, answered questionnaires and had their nasal dimensions measured by acoustic rhinometry. In total, 810 patients participated (including 153 females), aged 54.5 ± 10.6 years [mean ± standard deviation (SD)] with an apnea/hypopnea index 44.7 ± 20.7 h-1 . Nocturnal nasal obstruction (greater than or equal to three times per week) was reported by 35% of the patients. These patients had smaller nasal dimensions measured by the minimum cross-sectional area within the smaller nasal valve (0.42 ± 0.17 versus 0.45 ± 0.16 cm2 , P = 0.013), reported more daytime sleepiness (Epworth Sleepiness Scale score 12.5 ± 4.9 versus 10.8 ± 5.0; P < 0.001) and slightly lower mental quality of life than patients without nocturnal nasal obstruction. Nocturnal nasal obstruction is reported in one-third of the sleep apnea patients and they are more likely to suffer from daytime sleepiness and slightly reduced quality of life than other sleep apnea patients.

Persistence and evolution of allergen-specific IgE repertoires during subcutaneous specific immunotherapy.

BACKGROUND: Specific immunotherapy (SIT) is the only treatment with proved long-term curative potential in patients with allergic disease. Allergen-specific IgE is the causative agent of allergic disease, and antibodies contribute to SIT, but the effects of SIT on aeroallergen-specific B-cell repertoires are not well understood. OBJECTIVE: We sought to characterize the IgE sequences expressed by allergen-specific B cells and track the fate of these B-cell clones during SIT. METHODS: We used high-throughput antibody gene sequencing and identification of allergen-specific IgE with combinatorial antibody fragment library technology to analyze immunoglobulin repertoires of blood and the nasal mucosa from aeroallergen-sensitized subjects before and during the first year of subcutaneous SIT. RESULTS: Of 52 distinct allergen-specific IgE heavy chains from 8 allergic donors, 37 were also detected by using high-throughput antibody gene sequencing of blood samples, nasal mucosal samples, or both. The allergen-specific clones had increased persistence, higher likelihood of belonging to clones expressing other switched isotypes, and possibly larger clone size than the rest of the IgE repertoire. Clone members in nasal tissue showed close mutational relationships. CONCLUSION: In the future, combining functional binding studies, deep antibody repertoire sequencing, and information on clinical outcomes in larger studies might aid assessment of SIT mechanisms and efficacy.

Biological effects and clinical efficacy of a topical Toll-like receptor 7 agonist in seasonal allergic rhinitis: a parallel group controlled phase IIa study.

OBJECTIVE AND DESIGN: The purpose of the study was to examine effects of pre-treatment with a Toll-like receptor 7 (TLR7) agonist (AZD8848) in allergic rhinitis and to evaluate clinical effects of two dosing regimens. SUBJECTS: The study involved 83 patients with allergic rhinitis. Data on effects of AZD8848 on symptoms were analysed with data from a previous study (n = 68) of identical double blind, parallel group design (NCT00770003). TREATMENT: The treatment involved intranasal AZD8848 20 µg three times weekly, 60 µg once weekly, or placebo for 5 weeks. METHODS: Nasal lavage and plasma were analysed for proof-of-mechanism markers. Daily nasal allergen challenges were given for 7 days, starting 24 h after the final AZD8848 dose. Symptoms were monitored after each challenge and every morning and evening. RESULTS: Markers of TLR-activation increased following AZD8848 administration (CXCL10, TNFα, IL-6, IFNγ). Symptoms recorded soon after allergen challenge were reduced up to eight days after the final dose of AZD8848. Morning and evening symptoms were also reduced, and these changes reached statistical significance for morning observations. Adverse effects were more frequent in the 20 µg three times weekly group. CONCLUSIONS: Repeated administration of AZD8848 activated TLR7 and produced IFN-induced effects. This was associated with a sustained reduction in allergen responsiveness.

Oral challenges with four apple cultivars result in significant differences in oral allergy symptoms.

BACKGROUND: We analyzed the hypoallergenic potential of a recently bred apple selection with unusually low content of Mal d 1, using an oral challenge model with three additional apple cultivars for comparison. METHODS: Sixty-six birch pollen-allergic individuals with a history of oral allergy syndrome after apple intake were subjected to a double-blind oral provocation with two apple cultivars (B:0654 and 'Discovery'). Thirteen also tested two other apple cultivars ('Ingrid Marie' and 'Gloster'). Three doses were given consecutively, 30 min apart: 10 g without peel, and 10 and 50 g with peel. A final assessment was conducted 30 min after the last intake. Oral symptoms were graded from 0 to 5. Total oral symptom score (TOS) included all scores for each cultivar at all time points. RESULTS: B:0654 induced significantly higher TOS than 'Discovery' when tested by 66 individuals, in spite of its lower Mal d 1 content. TOS values were higher in females and increased with increasing age of the individuals when challenged with 'Discovery'. Among the 13 individuals who tested all four cultivars, B:0654 produced a higher score after the second dose compared to 'Ingrid Marie'. This was also the case after the third dose compared to 'Ingrid Marie' and 'Gloster', and again 30 min after the last intake compared to each of the other three cultivars, as well as a higher TOS compared to each of the other three cultivars (all p < 0.01). CONCLUSIONS: Our test was safe and well tolerated, and produced significant differences among the apple cultivars. Contrary to expectations, B:0654 was less well tolerated than the other three cultivars.

Repeated intranasal TLR7 stimulation reduces allergen responsiveness in allergic rhinitis.

BACKGROUND: Interactions between Th1 and Th2 immune responses are of importance to the onset and development of allergic disorders. A Toll-like receptor 7 agonist such as AZD8848 may have potential as a treatment for allergic airway disease by skewing the immune system away from a Th2 profile. OBJECTIVE: To evaluate the efficacy and safety of intranasal AZD8848. METHODS: In a placebo-controlled single ascending dose study, AZD8848 (0.3-600 µg) was given intranasally to 48 healthy subjects and 12 patients with allergic rhinitis (NCT00688779). In a placebo-controlled repeat challenge/treatment study, AZD8848 (30 and 60 µg) was given once weekly for five weeks to 74 patients with allergic rhinitis out of season: starting 24 hours after the final dose, daily allergen challenges were given for seven days (NCT00770003). Safety, tolerability, pharmacokinetics, and biomarkers were monitored. During the allergen challenge series, nasal symptoms and lavage fluid levels of tryptase and α2-macroglobulin, reflecting mast cell activity and plasma exudation, were monitored. RESULTS: AZD8848 produced reversible blood lymphocyte reductions and dose-dependent flu-like symptoms: 30-100 µg produced consistent yet tolerable effects. Plasma interleukin-1 receptor antagonist was elevated after administration of AZD8848, reflecting interferon production secondary to TLR7 stimulation. At repeat challenge/treatment, AZD8848 reduced nasal symptoms recorded ten minutes after allergen challenge up to eight days after the final dose. Tryptase and α2-macroglobulin were also reduced by AZD8848. CONCLUSIONS: Repeated intranasal stimulation of Toll-like receptor 7 by AZD8848 was safe and produced a sustained reduction in the responsiveness to allergen in allergic rhinitis. TRIAL REGISTRATION: NCT00688779 and NCT00770003 as indicated above.

dsRNA-induced expression of thymic stromal lymphopoietin (TSLP) in asthmatic epithelial cells is inhibited by a small airway relaxant.

RATIONALE: Thymic Stromal Lymphopoietin (TSLP) is considered a hub cytokine that activates dendritic cells and T-cells producing asthma-like Th2-inflammation. Viral stimuli, a major cause of asthma exacerbations, have been shown to induce overexpression of TSLP in asthmatic epithelium. Capsazepine has multiple effects and is of interest because it relaxes human small airways. Here we have explored effects of capsazepine on viral surrogate (dsRNA)-induced TSLP and other cytokines (TNF-alpha, IL-8) in human bronchial epithelial cells (HBEC) from healthy and asthmatic donors. METHODS: HBEC obtained from healthy and asthmatic subjects were grown and stimulated with dsRNA. Cells pre-treated with capsazepine (3-30 µM), dexamethasone (0.1-10 µM) or an IkappaB-kinase inhibitor (PS1145, 30 µM) were also exposed to dsRNA (10 µg/ml). Cells and supernatants were harvested for analyses of gene expression (RT-qPCR) and protein production (ELISA,Western blot). RESULTS: dsRNA-induced TSLP, TNF-alpha, and IL-8 in asthmatic and non-asthmatic HBEC. Dexamethasone attenuated gene expression and protein release whereas capsazepine dose-dependently, and similar to a non-relaxant NFkB inhibitor (PS1145), completely inhibited dsRNA-induced TSLP and TNF-alpha in both healthy and asthmatic HBEC. Capsazepine reduced dsRNA-induced IL-8 and it prevented dsRNA-induced loss of the NF-κB repressor protein IkBα. CONCLUSION: Additional to its human small airway relaxant effects we now demonstrate that capsazepine has potent anti-inflammatory effects on viral stimulus-induced cytokines in HBEC from healthy as well as asthmatic donors. Based on these data we suggest that exploration of structure-activity amongst the multifaceted capsazepinoids is warranted in search for compounds of therapeutic value in viral-induced, steroid-resistant asthma.

The impact of the physical environment for caregiving in ordinary housing: Experiences of staff in home- and health-care services.

The strong driving forces for ageing in place demand sustainable solutions for the housing and care of older people and the health and safety of home- and health-care staff. The aim of the study was to elucidate staff experiences of providing home- and health-care to older people living in ordinary housing. This study was part of a larger project investigating the relation between home design and conditions for care in ordinary housing. The data were gathered through focus group interviews with staff in home- and health-care. Three main themes were found according to staff experiences of particular rooms' sizes and proportions, spatial configurations, and aspects to consider when designing new housing. This study contributes important knowledge about essential features of the physical environment for staff providing home- and health-care for older people in their own homes and to aid the development of functionally sustainable housing to minimise injuries to staff.

Aging-in-Place: Residents' Attitudes and Floor Plan Potential in Apartment Buildings From 1990 to 2015.

OBJECTIVES: We investigated apartment designs in apartment blocks built 1990-2015 in Gothenburg, Sweden. We investigated the residents' attitudes toward their previous, present, and future housing and their perceived possibilities for aging-in-place. We analyzed their apartments, focusing on the possibilities for aging-in-place in future care situations concerning bedroom capacity in a care situation; spatial proximity between bathroom, bedroom, storage, and entrance; and functional autonomy in a care situation without too much disturbance for a partner. BACKGROUND: Since the 2000s, the ambition in Sweden is to enable older people to remain in ordinary housing. The possibilities for aging-in-place should therefore be considered already in the design stage, also when producing standard apartments. METHODS: Semi-structured interviews were made with 30 households, with one or more resident 65 years or older. Floor plan analyses were made of their present apartments. RESULTS: The majority displayed a pragmatic attitude toward aging, high satisfaction with their present housing situation, and good chances for aging-in-place in future homecare scenarios. The floor plan analysis shows that the three concepts of bedroom capacity, spatial proximity, and functional autonomy can be used to determine the potential for aging-in-place. CONCLUSIONS: The results suggest that architectural qualities related to aging-in-place are not automatically connected to floor size or number of rooms. Small apartments can perform better than larger ones, depending on spatio-functional organization and connections between different functions. The residents' perceived chances for aging-in-place confirm this relation. Future studies should compare different locations, production periods, and relations between size, space efficiency, and accessibility.

HealthSWEDE: costs with sublingual immunotherapy-a Swedish questionnaire study.

BACKGROUND: The aim of this cross-sectional survey was to compare the health-economic consequences for allergic rhinitis (AR) patients treated with sublingual Immunotherapy (SLIT) in terms of direct and indirect costs with a reference population of patients receiving standard of care pharmacological therapy. METHODS: Primary objective was to analyse the health-economic consequences of SLIT for grass pollen allergy in Sweden vs reference group waiting for subcutaneous immunotherapy (SCIT). A questionnaire was mailed to two groups of AR patients. RESULTS: The questionnaire was distributed to 548 patients, 307 with SLIT and 241 in reference group (waiting for SCIT). Response rate was 53.8%. Mean annual costs were higher for reference patients than SLIT group; € 3907 (SD 4268) vs € 2084 (SD 1623) p < 0.001. Mean annual direct cost was higher for SLIT-patients, € 1191 (SD 465) than for reference, € 751 (SD 589) p < 0.001. Mean annual indirect costs for combined absenteeism and presenteeism were lower for patients treated with SLIT, € 912 (SD 1530), than for reference, € 3346 (SD 4120) p < 0.001, with presenteeism as main driver. CONCLUSIONS: SLIT seems to be a cost-beneficial way to treat seasonal AR. This information might be used to guide future recommendations.

Early phase resolution of mucosal eosinophilic inflammation in allergic rhinitis.

BACKGROUND: It is widely assumed that apoptosis of eosinophils is a central component of resolution of allergic airway disease. However, this has not been demonstrated in human allergic airways in vivo. Based on animal in vivo observations we hypothesised that steroid-induced resolution of human airway eosinophilic inflammation involves inhibition of CCL5 (RANTES), a CC-chemokine regulating eosinophil and lymphocyte traffic, and elimination of eosinophils without evident occurrence of apoptotic eosinophils in the diseased tissue. OBJECTIVE: To determine mucosal eosinophilia, apoptotic eosinophils, general cell apoptosis and cell proliferation, and expression of CCL5 and CCL11 (eotaxin) in human allergic airway tissues in vivo at resolution of established symptomatic eosinophilic inflammation. METHODS: Twenty-one patients with intermittent (birch and/or grass) allergic rhinitis received daily nasal allergen challenges for two seven days' periods separated by more than two weeks washout. Five days into these "artificial pollen seasons", nasal treatment with budesonide was instituted and continued for six days in a double blinded, randomized, placebo-controlled, and crossover design. This report is a parallel group comparison of nasal biopsy histochemistry data obtained on the final day of the second treatment period. RESULTS: Treatments were instituted when clinical rhinitis symptoms had been established. Compared to placebo, budesonide reduced tissue eosinophilia, and subepithelial more than epithelial eosinophilia. Steroid treatment also attenuated tissue expression of CCL5, but CCL11 was not reduced. General tissue cell apoptosis and epithelial cell proliferation were reduced by budesonide. However, apoptotic eosinophils were not detected in any biopsies, irrespective of treatment. CONCLUSIONS: Inhibition of CCL5-dependent recruitment of cells to diseased airway tissue, and reduced cell proliferation, reduced general cell apoptosis, but not increased eosinophil apoptosis, are involved in early phase steroid-induced resolution of human allergic rhinitis.

Effects of a dual CCR3 and H1-antagonist on symptoms and eosinophilic inflammation in allergic rhinitis.

BACKGROUND: The CC-chemokine receptor-3 (CCR3) has emerged as a target molecule for pharmacological intervention in allergic inflammation. OBJECTIVE: To examine whether a dual CCR3 and H1-receptor antagonist (AZD3778) affects allergic inflammation and symptoms in allergic rhinitis. METHODS: Patients with seasonal allergic rhinitis were subjected to three seven days' allergen challenge series. Treatment with AZD3778 was given in a placebo and antihistamine-controlled design. Symptoms and nasal peak inspiratory flow (PIF) were monitored in the morning, ten minutes post challenge, and in the evening. Nasal lavages were carried out at the end of each challenge series and alpha2-macroglobulin, ECP, and tryptase were monitored as indices of allergic inflammation. RESULTS: Plasma levels of AZD3778 were stable throughout the treatment series. AZD3778 and the antihistamine (loratadine) reduced rhinitis symptoms recorded ten minutes post challenge during this period. AZD3778, but not the anti-histamine, also improved nasal PIF ten minutes post challenge. Furthermore, scores for morning and evening nasal symptoms from the last five days of the allergen challenge series showed statistically significant reductions for AZD3778, but not for loratadine. ECP was reduced by AZD3778, but not by loratadine. CONCLUSIONS: AZD3778 exerts anti-eosinophil and symptom-reducing effects in allergic rhinitis and part of this effect can likely be attributed to CCR3-antagonism. The present data are of interest with regard to the potential use of AZD3778 in allergic rhinitis and to the relative importance of eosinophil actions to the symptomatology of allergic rhinitis. TRIAL REGISTRATION: EudraCT No: 2005-002805-21.

Effects of intranasal TNFalpha on granulocyte recruitment and activity in healthy subjects and patients with allergic rhinitis.

BACKGROUND: TNFalpha may contribute to the pathophysiology of airway inflammation. For example, we have recently shown that nasal administration of TNFalpha produces late phase co-appearance of granulocyte and plasma exudation markers on the mucosal surface. The objective of the present study was to examine indices of granulocyte presence and activity in response to intranasal TNFalpha challenge. METHODS: Healthy subjects and patients with allergic rhinitis (examined out of season) were subjected to nasal challenge with TNFalpha (10 microg) in a sham-controlled and crossover design. Nasal lavages were carried out prior to and 24 hours post challenge. Nasal biopsies were obtained post challenge. Nasal lavage fluid levels of myeloperoxidase (MPO) and eosinophil cationic protein (ECP) were analyzed as indices of neutrophil and eosinophil activity. Moreover, IL-8 and alpha2-macroglobulin were analyzed as markers of pro-inflammatory cytokine production and plasma exudation. Nasal biopsy numbers of neutrophils and eosinophils were monitored. RESULTS: Nasal lavage fluid levels of MPO recorded 24 hours post TNFalpha challenge were increased in healthy subjects (p = 0.0081) and in patients with allergic rhinitis (p = 0.0081) (c.f. sham challenge). Similarly, alpha2-macroglobulin was increased in healthy subjects (p = 0.014) and in patients with allergic rhinitis (p = 0.0034). Lavage fluid levels of ECP and IL-8 were not affected by TNFalpha challenge. TNFalpha increased the numbers of subepithelial neutrophils (p = 0.0021), but not the numbers of eosinophils. CONCLUSION: TNFalpha produces a nasal inflammatory response in humans that is characterised by late phase (i.e., 24 hours post challenge) neutrophil activity and plasma exudation.

Specific nasal symptoms and symptom-provoking factors may predict increased risk of developing COPD.

In a 1992 questionnaire study, we found that certain nasal symptoms and symptom-provoking factors were associated with prevalence of self-reported chronic bronchitis/emphysema (CBE). In this follow-up study, we examined whether any nasal features could predict an increased incidence of self-reported physician's diagnosis of CBE/chronic obstructive pulmonary disease (COPD). In 2000, a survey was performed similar to the one in 1992. Of a paired follow-up group of 4933 participants aged 28-67 years, 4280 (86.8%) returned the questionnaire. Odds ratios (ORs) for cumulative incidence (between 1992 and 2000) of self-reported physician-diagnosed CBE/COPD and asthma, respectively, were calculated by logistic regression with adjustment for age, gender and smoking habits. Reports of thick, yellow nasal discharge and nasal blockage in 1992 predicted incidence of CBE/COPD: OR 2.3 (1.2-4.2) and 1.8 (1.1-2.8) respectively. Moreover, nasal symptoms provoked by exposure to damp/cold air and tobacco smoke predicted CBE/COPD: OR 3.4 (1.9-6.0) and 2.5 (1.4-4.2). Nasal itching and nasal symptoms provoked by exposure to grass pollen and furred animals predicted incidence of asthma. These results suggest that certain nasal symptoms and nasal symptom-provoking exposures, different from those commonly associated with asthma, may predict increased risk of developing CBE/COPD. This supports the possibility of nasal co-morbidity in COPD.

Nasal treatment with a microemulsion reduces allergen challenge-induced symptoms and signs of allergic rhinitis.

CONCLUSIONS: Intranasal microemulsion treatment can attenuate allergen challenge-induced nasal symptoms and plasma exudation in allergic rhinitis. We hypothesize that the mechanism of action involves modification of the allergen-mucosa interaction. The present observation suggests a novel principle for prevention in allergic rhinitis. OBJECTIVE: To evaluate a specific microemulsion as a treatment for allergic rhinitis in an acute allergen challenge model. PATIENTS AND METHODS: Patients with allergic rhinitis were examined out of the pollen season. Treatment with a single dose of a specific microemulsion was given in a single-blind, placebo-controlled, and crossover design using a nasal pool device. Nasal allergen challenges were carried out and symptoms of allergic rhinitis were scored. Furthermore, nasal lavages were performed and levels of the plasma protein alpha 2-macroglobulin were measured as an index of exudative inflammation. RESULTS: The allergen challenges produced significant increases in nasal symptoms (p=0.007) and in nasal lavage fluid levels of alpha 2-macroglobulin (p=0.008). The challenge-induced symptoms as well as the plasma exudation were attenuated by treatment with the microemulsion (p=0.016 and 0.012, respectively, compared with placebo).

Effects of TNFalpha on the human nasal mucosa in vivo.

BACKGROUND: TNFalpha is a cytokine that may contribute to the pathophysiology of airway inflammation. Inhalation of TNFalpha produces granulocyte recruitment and airway hyperresponsiveness in man. Anti-TNFalpha treatment may inhibit allergen-induced plasma exudation in guinea-pig airways. Increased nasal mucosal output of TNFalpha has been demonstrated in allergic rhinitis, but the effect of TNFalpha on the human nasal mucosa has not been examined in vivo. OBJECTIVE: To examine effects of topical TNFalpha on the human nasal mucosa in vivo. METHODS: In a dose-finding study, healthy subjects received intranasal TNFalpha (0-7.5 microg). Nasal lavages were carried out before as well as 10 min and 24 h post challenge and alpha(2)-macroglobulin was measured as an index of plasma exudation. In a second study, involving patients with allergic rhinitis examined out of season, a sham-controlled nasal challenge with TNFalpha (10 microg) was performed and followed 24 h later by an allergen challenge. Lavages were performed before the TNFalpha challenge, 24 h thereafter, and 10 min post allergen challenge. alpha(2)-Macroglobulin, eosinophil cationic protein (ECP), myeloperoxidase (MPO), and IL-8 were analyzed as indices of plasma exudation, eosinophil activity, neutrophil activity, and pro-inflammatory cytokine production, respectively. RESULTS: In the dose-finding study, TNFalpha produced significant increases in alpha(2)-macroglobulin 24h post challenge (p<0.01). In allergic rhinitis, 10 microg of TNFalpha also produced this effect (p<0.01) as well as increases in ECP and IL-8 (p<0.01). MPO was increased 24 h post challenge, but this change did not reach statistical significance. TNFalpha did not produce any acute effects and did not affect the responsiveness to allergen. CONCLUSION: The present study demonstrates that topical TNFalpha produces a human nasal inflammatory response. These data suggest a role of TNFalpha in nasal conditions characterized by mucosal inflammation.

Effects of topical formoterol alone and in combination with budesonide in a pollen season model of allergic rhinitis.

BACKGROUND: beta(2)-Agonists may exert mast cell stabilizing and anti-plasma exudation effects. While available data suggest no or only marginal effects of beta(2)-agonists on symptoms of allergic rhinitis, little is known about whether these drugs may add to the efficacy of anti-rhinitis drugs. OBJECTIVE: To examine effects of a beta(2)-agonist, alone and in combination with an intranasal glucocorticosteroid, on symptoms and signs of allergic rhinitis. METHODS: Patients were examined in a pollen season model. Budesonide 64 microg, alone and in combination with formoterol 9 microg, as well as formoterol 9 microg alone was given in a placebo-controlled and crossover design. After 7 days of treatment, the patients received allergen challenges for 7 days. Symptoms and nasal peak inspiratory flow (PIF) were recorded. Nasal lavages with and without histamine were carried out at the end of each challenge series. These lavages were analysed for tryptase, eosinophil cationic protein (ECP), and alpha(2)-macroglobulin as indices of mast cell activity, eosinophil activity, and plasma exudation, respectively. RESULTS: Budesonide reduced symptoms of allergic rhinitis and improved nasal PIF in the morning, in the evening as well as post allergen challenge. Formoterol alone did not affect symptoms or nasal PIF and did not affect the efficacy of budesonide. Tryptase, ECP, and alpha(2)-macroglobulin were significantly reduced by budesonide. Formoterol alone did not affect these indices and did not affect the anti-inflammatory effect of budesonide. CONCLUSION: The present dose of formoterol does not affect symptoms and inflammatory signs of allergic rhinitis and does not add to the efficacy of topical budesonide.