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Background MicroRNAs (miRNAs) may facilitate cell-to-cell communication via extracellular vesicles (EVs). The biological roles of miRNAs in EVs on allergic airway inflammation are unclear. Methods Airway-secreted EVs (AEVs) were isolated from bronchoalveolar lavage fluid (BALF) of control and house-dust mite (HDM) allergen-exposed HDM-sensitized mice. The expression of miRNAs in AEVs or miRNAs and mRNAs in lung tissue was analysed using miRNA microarray. Results The amount of AEV increased 8.9-fold in BALF from HDM-exposed mice compared with that from sham-control mice. HDM exposure resulted in significant changes in the expression of 139 miRNAs in EVs and 175 miRNAs in lung tissues, with 54 miRNAs being common in both samples. Expression changes of these 54 miRNAs between miRNAs in AEVs and lung tissues after HDM exposure were inversely correlated. Computational analysis revealed that 31 genes, including IL-13 and IL-5Ra, are putative targets of the miRNAs up-regulated in AEVs but down-regulated in lung tissues after HDM exposure. The amount of AEV in BALF after HDM exposure was diminished by treatment with the sphingomyelinase inhibitor GW4869. The treatment with GW4869 also decreased Th2 cytokines and eosinophil counts in BALFs and reduced eosinophil accumulation in airway walls and mucosa. Conclusion These results indicate that selective sorting of miRNA including Th2 inhibitory miRNAs into AEVs and increase release to the airway after HDM exposure would be involved in the pathogenesis of allergic airway inflammation. [ABSTRACT FROM AUTHOR]

Background To date, most studies of the 'allergy epidemic' have been based on self-reported data. There is still limited knowledge on time trends in allergic sensitization, especially among adults. Objective To study allergic sensitization, its risk factors and time trends in prevalence. Methods Within West Sweden Asthma Study ( WSAS), a population-based sample of 788 adults (17-60 years) underwent skin prick tests ( SPTs) for 11 aeroallergens 2009-2012. Specific IgE was analysed in 750 of the participants. Those aged 20-46 years ( n = 379) were compared with the European Community Respiratory Health Survey sample aged 20-46 year from the same area ( n = 591) in 1991-1992. Results Among those aged 20-46 years, the prevalence of positive SPT to pollen increased, timothy from 17.1% to 29.0% ( P < 0.001) and birch from 15.6% to 23.7% ( P = 0.002) between 1991-1992 and 2009-2012. Measurements of specific IgE confirmed these increases. Prevalence of sensitization to all other tested allergens was unchanged. In the full WSAS sample aged 17-60 years, any positive SPT was seen in 41.9%, and the dominating sensitizers were pollen (34.3%), animals (22.8%) and mites (12.6%). Pollen sensitization was strongly associated with rhinitis, whereas indoor allergens were more associated with asthma. Growing up with livestock or furred pets decreased the risk of sensitization, adjusted odds ratio 0.53 (0.28-0.995) and 0.68 (0.47-0.98), respectively. Conclusion Pollen sensitization has increased in Swedish adults since the early 1990s, while the prevalence of sensitization to other allergens has remained unchanged. This is one plausible explanation for the increase in rhinitis 1990-2008 in Swedish adults, during which time the prevalence of asthma, which is more associated with perennial allergens, was stable. Contact with animals in childhood seems to reduce the risk of sensitization well into adulthood. One major factor contributing to the rise in pollen allergy is a significant increase in levels of birch and grass pollen over the past three decades. [ABSTRACT FROM AUTHOR]

Adipose tissue produces multiple mediators that modulate the immune response. Adiponectin is an adipocyte-derived cytokine that exhibits metabolic and anti-inflammatory effects. Adiponectin acts through binding to adiponectin receptor 1 and 2 (AdipoR1/AdipoR2). AdipoR1 is ubiquitously expressed, whereas AdipoR2 is restricted to skeletal muscle and liver. AdipoR1 expression has been reported on a small percentage of T cells; nevertheless, it is still unknown whether Foxp3+ regulatory T cells (Tregs) express AdipoR1. Recently, it has been shown that Tregs accumulate in adipose tissue and that they play a potential role in modulating adipose tissue inflammation. Our aim was to evaluate AdipoR1 expression in adipose tissue-resident Tregs and to evaluate the effect of weight gain on this expression. Male C57BL/6 mice were fed with a high-fat diet for 14 weeks (to develop overweight) or 21 weeks (to develop obesity). Mice on a standard diet were used as age-matched controls. Helios expression was evaluated as a marker to discriminate thymic-derived from peripherally induced Tregs. The majority of Tregs in both adipose tissue and the spleen expressed Helios. Adipose tissue Tregs expressed higher levels of AdipoR1 than Tregs in the spleen. AdipoR1 expression on adipose tissue Helios+ Tregs was negatively correlated with epididymal fat. Overall, we show that AdipoR1 is expressed on adipose tissue-resident Tregs, mainly Helios+ Tregs, and that this expression is dependent on weight and fat accumulation. Because both adiponectin and Tregs play roles in anti-inflammatory mechanisms, our data propose a new mechanism through which weight gain might alter immunoregulation. [ABSTRACT FROM AUTHOR]

Background Population-based studies on aspirin-intolerant asthma (AIA) are very few, and no previous population study has investigated risk factors for the condition. Objective To investigate the prevalence and risk factors of AIA in the general population. Methods A questionnaire on respiratory health was mailed to 30 000 randomly selected subjects aged 16-75 years in West Sweden, 29 218 could be traced and 18 087 (62%) responded. The questionnaire included questions on asthma, respiratory symptoms, aspirin-induced dyspnoea and possible determinants. Results The prevalence of AIA was 0.5%, 0.3% in men and 0.6% in women ( P = 0.014). Sick leave, emergency visits due to asthma and all investigated lower respiratory symptoms were more common in AIA than in aspirin-tolerant asthma (ATA). Obesity was a strong risk factor for AIA ( BMI > 35: odds ratio ( OR) 12.1; 95% CI 2.49-58.5), and there was a dose-response relationship between increasing body mass index (BMI) and risk of AIA. Obesity, airborne occupational exposure and visible mould at home were considerably stronger risk factors for AIA than for ATA. Current smoking was a risk factor for AIA ( OR 2.55; 95% CI 1.47-4.42), but not ATA. Conclusion Aspirin-intolerant asthma identified in the general population was associated with a high burden of symptoms, uncontrolled disease and a high morbidity. Increasing BMI increased the risk of AIA in a dose-response manner. A number of risk factors, including obesity and current smoking, were considerably stronger for AIA than for ATA. [ABSTRACT FROM AUTHOR]

Background: Inhaled glucocorticosteroids (ICS) are the mainstay of treatment in asthma. Fluticasone furoate (FF) is a novel, once-daily ICS asthma therapy. This study investigated the efficacy and safety of FF 50 meg in patients with mild-to-moderate persistent asthma. Methods: A 24-week, multicenter, randomized, placebo-controlled and active-con-trolled, double-blind, double-dummy, parallel-group phase III study. Three hun-dred and fifty-one patients (aged ≥12 years; uncontrolled by non-ICS therapy) were randomized to treatment (1:1:1) with once-daily FF 50 meg dosed in the evening, twice-daily fluticasone propionate (FP) 100 meg or placebo. The primary endpoint was change from baseline in evening trough forced expiratory volume in 1 s (FEV1) at Week 24. Secondary endpoints were change from baseline in the per-centage of rescue-free 24-h periods (powered endpoint), change from baseline in evening and morning peak expiratory flow, change from baseline in the percentage of symptom-free 24-h periods and number of withdrawals due to lack of efficacy. Results: Evening trough FEV, at Week 24 was not statistically significantly increased with FF 50 meg once-daily (37 ml [95% CI: -55, 128]; P = 0.430), but was with FP 100 meg twice daily (102 ml [10, 194]; P = 0.030), vs placebo. No consistent trends were observed across other endpoints, including the powered secondary endpoint. No safety concerns were raised for either active treatment. Conclusions: FP 100 meg twice daily improved evening trough FEV, in patients with mild-to-moderate persistent asthma, but FF 50 meg once daily did not dem-onstrate a significant effect. Secondary endpoints showed variable results. No safety concerns were identified for FF or FP. [ABSTRACT FROM AUTHOR]

Background In the European Union (EU), between 44 and 76 million individuals of the 217 million EU employees suffer from allergic disease of the airways or the skin. Up to 90% of these persons are untreated or insufficiently treated. This has major socio-economic consequences such as absence from work (absenteeism), particularly reduced productivity at work (presenteeism). Methods We used published literature and online statistical information from Eurostat and Eurofound to assess the costs of allergic disease to society. Results Allergies have an impact on direct, indirect, intangible and opportunity costs. Most importantly, for the EU, avoidable indirect costs per patient insufficiently treated for allergy range between €55 and €151 billion per annum due to absenteeism and presenteeism, that is, €2405 per untreated patient per year. On the other hand, appropriate therapy for allergic diseases is available at comparatively low costs at an average of €125 per patient annually, equalling only 5% of the costs of untreated disease, allowing potential savings of up to €142 billion. Conclusions A better care for allergies based on guideline-based treatment would allow Europe's economy substantial savings. In addition, allergies have an impact on learning and performance at school and university, leading to opportunity costs for society. This cannot be calculated moneywise but will have an impact in a modern knowledge-based society. Still allergies are trivialized in society, noting that the costs of therapy are paid by patients and healthcare services, whereas economic savings are made by employers and society. A change of this mindset is urgently needed. [ABSTRACT FROM AUTHOR]

Background Geographical variation in the prevalence of sensitization to aeroallergens may reflect differences in exposure to risk factors such as having older siblings, being raised on a farm or other unidentified exposures. Objective We wanted to measure geographical variation in skin prick test positivity and assess whether it was explained by differences in family size and/or farm exposure. We also compared prevalence in younger and older subjects. Methods Within the Global Allergy and Asthma European Network ( GA2LEN) survey, we measured the prevalence of skin prick positivity to a panel of allergens, and geometric mean serum total immunoglobulin E (IgE), in 3451 participants aged 18-75 years in 13 areas of Europe. Estimated prevalence was standardized to account for study design. We compared prevalence estimates in younger and older subjects and further adjusted for age, gender, smoking history, farm exposure, number of older siblings and body mass index ( BMI). Results Skin prick test positivity to any one of the measured allergens varied within Europe from 31.4% to 52.9%. Prevalence of sensitization to single allergens also varied. Variation in serum total IgE was less marked. Younger participants had higher skin prick sensitivity prevalence, but not total IgE, than older participants. Geographical variation remained even after adjustment for confounders. Conclusion Geographical variation in the prevalence of skin prick test positivity in Europe is unlikely to be explained by geographical variation in gender, age, smoking history, farm exposure, family size and BMI. Higher prevalence in younger, compared to older, adults may reflect cohort-associated increases in sensitization or the influence of ageing on immune or tissue responses. [ABSTRACT FROM AUTHOR]

Asthma exacerbations and severe asthma are linked with high morbidity, significant mortality and high treatment costs. Recurrent asthma exacerbations cause a decline in lung function and, in childhood, are linked to development of persistent asthma. This position paper, from the European Academy of Allergy and Clinical Immunology, highlights the shortcomings of current treatment guidelines for patients suffering from frequent asthma exacerbations and those with difficult-to-treat asthma and severe treatment-resistant asthma. It reviews current evidence that supports a call for increased awareness of (i) the seriousness of asthma exacerbations and (ii) the need for novel treatment strategies in specific forms of severe treatment-resistant asthma. There is strong evidence linking asthma exacerbations with viral airway infection and underlying deficiencies in innate immunity and evidence of a synergism between viral infection and allergic mechanisms in increasing risk of exacerbations. Nonadherence to prescribed medication has been identified as a common clinical problem amongst adults and children with difficult-to-control asthma. Appropriate diagnosis, assessment of adherence and other potentially modifiable factors (such as passive or active smoking, ongoing allergen exposure, psychosocial factors) have to be a priority in clinical assessment of all patients with difficult-to-control asthma. Further studies with improved designs and new diagnostic tools are needed to properly characterize (i) the pathophysiology and risk of asthma exacerbations, and (ii) the clinical and pathophysiological heterogeneity of severe asthma. [ABSTRACT FROM AUTHOR]

Background This placebo-controlled study assessed the effects of the once-daily inhaled corticosteroid ( ICS) fluticasone furoate ( FF) and long-acting beta2-agonist ( LABA) vilanterol ( VI) on early and late asthmatic responses ( EAR/ LAR) and airway hyper-responsiveness ( AHR). Methods Patients ( n = 27) were randomized to FF (100 μg), VI (25 μg), FF/ VI (100/25 μg), and placebo for 21 days (four periods). Allergen challenge was performed 1 h post-dose on day 21. AHR was assessed on day 22 using methacholine. Results Allergen challenge caused an early change (0-2 h) in minimum forced expiratory volume in 1 s ( FEV1) of −1.091 l (95% CI: −1.344; −0.837) following placebo therapy; changes were −0.955 l (−1.209; −0.702), −0.826 l (−1.070; −0.581), and −0.614 l (−0.858; −0.370) following VI, FF, or FF/ VI therapy, respectively. Treatment differences were significant for all comparisons between therapies. Mean changes in 0-2 h % FEV1 were as follows: −28.05 (placebo), −23.10 ( VI), −22.33 ( FF), and −16.10 ( FF/ VI). Following placebo, the late change (4-10 h) in weighted mean FEV1 was −0.466 l (−0.589; −0.343) and −0.298 l (−0.415; −0.181) after VI, and was +0.018 l with both FF/ VI (−0.089; 0.124) and FF (−0.089; 0.125). Treatment differences were significant for all comparisons between therapies except FF/ VI vs FF. Mean changes in 4-10 h % FEV1 were as follows: −21.08 (placebo), −14.30 ( VI), −5.02 ( FF), and −5.83 ( FF/ VI). AHR 24 h after allergen challenge was significantly reduced with FF/ VI and FF vs placebo, and FF/ VI was superior to either component. Conclusion Combined treatment with FF/ VI provides additive protection from the EAR relative to its components, significant protection over VI alone from the LAR, and confers sustained protection from hyper-responsiveness 24 h post-dose. [ABSTRACT FROM AUTHOR]

Background The harmful effects of tobacco smoke on human health, including respiratory health, are extensive and well documented. Previous data on the effect of smoking on rhinitis and allergic sensitization are inconsistent. We sought to investigate how smoking correlates with prevalence of allergic and chronic rhinitis among adults in Sweden. Methods The study population comprised 27 879 subjects derived from three large randomly selected cross-sectional population surveys conducted in Sweden between 2006 and 2008. The same postal questionnaire on respiratory health was used in the three surveys, containing questions about obstructive respiratory diseases, rhinitis, respiratory symptoms and possible determinants of disease, including smoking habits. A random sample from one of the cohorts underwent a clinical examination including skin prick testing. Results Smoking was associated with a high prevalence of chronic rhinitis in both men and women and a low prevalence of allergic rhinitis in men. These associations were dose dependent and remained when adjusted for a number of possible confounders in multiple logistic regression analysis. Prevalence of chronic rhinitis was lowest in nonsmokers and highest in very heavy smokers (18.5% vs 34.5%, P < 0.001). Prevalence of sensitization to common airborne allergens was lower in current smokers (25.9%, P = 0.008) and ex-smokers (28.2%, P = 0.022) than in nonsmokers (38.5%). Conclusion We found that smoking was associated with a high prevalence of chronic rhinitis in both sexes and a low prevalence of allergic rhinitis in men. The associations were dose dependent and remained when adjusting for several possible confounders. [ABSTRACT FROM AUTHOR]

To cite this article: Maurer M, Bader M, Bas M, Bossi F, Cicardi M, Cugno M, Howarth P, Kaplan A, Kojda G, Leeb-Lundberg F, Lötvall J, Magerl M. New topics in bradykinin research. Allergy 2011; 66: 1397-1406. Abstract Bradykinin has been implicated to contribute to allergic inflammation and the pathogenesis of allergic conditions. It binds to endothelial B1 and B2 receptors and exerts potent pharmacological and physiological effects, notably, decreased blood pressure, increased vascular permeability and the promotion of classical symptoms of inflammation such as vasodilation, hyperthermia, oedema and pain. Towards potential clinical benefit, bradykinin has also been shown to exert potent antithrombogenic, antiproliferative and antifibrogenic effects. The development of pharmacologically active substances, such as bradykinin receptor blockers, opens up new therapeutic options that require further research into bradykinin. This review presents current understanding surrounding the role of bradykinin in nonallergic angioedema and other conditions seen by allergists and emergency physicians, and its potential role as a therapeutic target. [ABSTRACT FROM AUTHOR]

Background: The European Position Paper on Rhinosinusitis and Nasal Polyps (EP3OS) incorporates symptomatic, endoscopic, and radiologic criteria in the clinical diagnosis of chronic rhinosinusitis (CRS), while in epidemiological studies, the definition is based on symptoms only. We aimed to assess the reliability and validity of a symptom-based definition of CRS using data from the GA2LEN European survey. Methods: On two separate occasions, 1700 subjects from 11 centers provided information on symptoms of CRS, allergic rhinitis, and asthma. CRS was defined by the epidemiological EP3OS symptom criteria. The difference in prevalence of CRS between two study points, the standardized absolute repeatability, and the chancecorrected repeatability (kappa) were determined. In two centers, 342 participants underwent nasal endoscopy. The association of symptom-based CRS with endoscopy and self-reported doctor-diagnosed CRS was assessed. Results: There was a decrease in prevalence of CRS between the two study phases, and this was consistent across all centers ()3.0%, 95% CI: )5.0 to )1.0%, I2 = 0). There was fair to moderate agreement between the two occasions (kappa = 39.6). Symptom-based CRS was significantly associated with positive endoscopy in nonallergic subjects, and with self-reported doctor-diagnosed CRS in all subjects, irrespective of the presence of allergic rhinitis. Conclusion: Our findings suggest that a symptom-based definition of CRS, according to the epidemiological part of the EP3OS criteria, has a moderate reliability over time, is stable between study centers, is not influenced by the presence of allergic rhinitis, and is suitable for the assessment of geographic variation in prevalence of CRS. [ABSTRACT FROM AUTHOR]

To cite this article: Eriksson J, Ekerljung L, Lötvall J, Pullerits T, Wennergren G, Rönmark E, Torén K, Lundbäck B. Growing up on a farm leads to lifelong protection against allergic rhinitis. Allergy 2010; 65: 1397-1403. Background: Various studies have reported a low prevalence of allergic rhinitis in farmers and farmers' children. We sought to investigate whether the protective effect of childhood farm environment is conserved throughout adulthood and how it corresponds to different degrees of urbanization. Methods: A questionnaire on respiratory health was mailed in 2008 to 30 000 randomly selected subjects aged 16-75 in West Sweden, 29 218 could be traced and 18 087 (62%) responded. The questionnaire included questions on allergic rhinitis, asthma, respiratory symptoms and possible determinants. Results: When stratified into age groups of 15 years, subjects that lived on a farm during their first 5 years of life had a lower prevalence of allergic rhinitis in all groups, even among the oldest (61-75 years). The negative correlation between childhood farm living and prevalence of allergic rhinitis was similar in 46-75 years of age (OR 0.82; 95% CI 0.70-0.95) as in 16-45 years of age (OR 0.78; 0.64-0.95). There was a significant trend of increasing prevalence of allergic rhinitis with increasing degree of urbanization independent of the effect of childhood farm living. Conclusions: We found a lifelong protective effect of childhood farm living on the prevalence of allergic rhinitis. In addition, we found an increasing prevalence of allergic rhinitis with increasing degree of urbanization both in those raised on a farm and those not, thus emphasizing the influence of both childhood and adult exposure for the development of allergic disease. [ABSTRACT FROM AUTHOR]

To cite this article: Bousquet J, Schünemann HJ, Zuberbier T, Bachert C, Baena-Cagnani CE, Bousquet PJ, Brozek J, Canonica GW, Casale TB, Demoly P, Gerth van Wijk R, Ohta K, Bateman ED, Calderon M, Cruz AA, Dolen WK, Haughney J, Lockey RF, Lötvall J, O’Byrne P, Spranger O, Togias A, Bonini S, Boulet LP, Camargos P, Carlsen KH, Chavannes NH, Delgado L, Durham SR, Fokkens WJ, Fonseca J, Haahtela T, Kalayci O, Kowalski ML, Larenas-Linnemann D, Li J, Mohammad Y, Mullol J, Naclerio R, O’Hehir RE, Papadopoulos N, Passalacqua G, Rabe KF, Pawankar R, Ryan D, Samolinski B, Simons FER, Valovirta E, Yorgancioglu A, Yusuf OM, Agache I, Aït-Khaled N, Annesi-Maesano I, Beghe B, Ben Kheder A, Blaiss MS, Boakye DA, Bouchard J, Burney PG, Busse WW, Chan-Yeung M, Chen Y, Chuchalin AG, Costa DJ, Custovic A, Dahl R, Denburg J, Douagui H, Emuzyte R, Grouse L, Humbert M, Jackson C, Johnston SL, Kaliner MA, Keith PK, Kim YY, Klossek JM, Kuna P, Le LT, Lemiere C, Lipworth B, Mahboub B, Malo JL, Marshall GD, Mavale-Manuel S, Meltzer EO, Morais-Almeida M, Motala C, Naspitz C, Nekam K, Niggemann B, Nizankowska-Mogilnicka E, Okamoto Y, Orru MP, Ouedraogo S, Palkonen S, Popov TA, Price D, Rosado-Pinto J, Scadding GK, Sooronbaev TM, Stoloff SW, Toskala E, van Cauwenberge P, Vandenplas O, van Weel C, Viegi G, Virchow JC, Wang DY, Wickman M, Williams D, Yawn BP, Zar HJ, Zernotti M, Zhong N, In collaboration with the WHO Collaborating Center of Asthma and Rhinitis (Montpellier). Development and implementation of guidelines in allergic rhinitis – an ARIA-GA2LEN paper. Allergy 2010; 65: 1212–1221. The links between asthma and rhinitis are well characterized. The Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines stress the importance of these links and provide guidance for their prevention and treatment. Despite effective treatments being available, too few patients receive appropriate medical care for both diseases. Most patients with rhinitis and asthma consult primary care physicians and therefore these physicians are encouraged to understand and use ARIA guidelines. Patients should also be informed about these guidelines to raise their awareness of optimal care and increase control of the two related diseases. To apply these guidelines, clinicians and patients need to understand how and why the recommendations were made. The goal of the ARIA guidelines is to provide recommendations about the best management options for most patients in most situations. These recommendations should be based on the best available evidence. Making recommendations requires the assessment of the quality of available evidence, deciding on the balance between benefits and downsides, consideration of patients' values and preferences, and, if applicable, resource implications. Guidelines must be updated as new management options become available or important new evidence emerges. Transparent reporting of guidelines facilitates understanding and acceptance, but implementation strategies need to be improved. [ABSTRACT FROM AUTHOR]

To cite this article: Bossios A, Sjöstrand M, Dahlborn A-K, Samitas K, Malmhäll C, Gaga M, Lötvall J. IL-5 expression and release from human CD34 cells in vitro; ex vivo evidence from cases of asthma and Churg–Strauss syndrome. Allergy 2010; 65: 831–839. Background: Eosinophils develop from hematopoietic CD34+ progenitor cells in the bone marrow (BM) under the influence of Interleukin-5 (IL-5). The primary source of IL-5 is T-lymphocytes, although other sources may exist. The aims of this study were to determine whether CD34+ cells from human peripheral blood (PB) and BM have the capacity to produce IL-5 when stimulated in vitro, and secondly, whether an elevated number of IL-5-producing CD34+ cells can be found in situ in ongoing eosinophilic disease. Methods: CD34+ cells from PB and BM were stimulated in vitro, and IL-5 production and release was assessed by ELISA, ELISPOT, flow cytometry and immunocytochemistry. Blood and BM from a patient with Churg–Strauss syndrome were analyzed by flow cytometry for CD34+/IL-5+ cells, and immunohistochemical staining of CD34+/IL-5+ cells in bronchial biopsies from an asthmatic patient was performed. Results: Both PB and BM CD34+ cells can produce and release IL-5 when stimulated in vitro. In the Churg–Strauss patient, IL-5-producing CD34+ cells were found in PB and BM. Oral glucocorticoid treatment markedly decreased the number of IL-5-positive CD34 cells in the BM. CD34+/IL-5+ cells were present in a patient with asthma. Conclusion: CD34+ cells in blood and BM are capable of producing IL-5 both in vitro and in vivo in humans, arguing that these cells may have the capacity to contribute to eosinophilic inflammation. Consequently, targeting CD34+ progenitor cells that produce and release IL-5 may be effective in reducing the mobilization of eosinophil lineage-committed cells in eosinophilic-driven diseases. [ABSTRACT FROM AUTHOR]

Allergic asthma is associated with eosinophilic inflammation in the airways. Animal models commonly used to elucidate allergic inflammation mechanisms include BALB/ c and C57BL/6 mice. Our aim was to evaluate lung eosinophilia and the corresponding Th1/Th2 balance in the two strains after allergen exposure. BALB/ c and C57BL/6 mice were subjected to ovalbumin-induced allergic airway inflammation using BrdU to label newly produced cells. The numbers of new eosinophils were evaluated by differential cell count and immunocytochemistry (MBP+BrdU+). Proliferation rate of lung eosinophils was measured by analysis of CD45+CCR3+BrdU+ cells by FACS. Distribution of newly produced eosinophils in the lung and the Th1/Th2 (CD4+T-bet+/CD4+GATA-3+) balance was evaluated by immunohistochemistry. Allergen challenge with ovalbumin induced comparable eosinophilia in bone marrow (BM), blood and lung tissue in both strains of mice compared to phosphate-buffered saline controls, which was confirmed by immunocytochemistry. There was a small increase in the number of lung MBP+BrdU− eosinophils in C57BL/6 mice compared to BALB/ c mice, which suggests a basal increase in this strain following sensitization. While there was no difference in eosinophilic proliferation in the lung, the distribution of the newly produced eosinophils differs between the two strains. BALB/ c mice showed staining primarily around vessels and airways, whereas C57BL/6 mice showed a more even distribution in the lung tissue. No difference in the Th1/Th2 balance was observed between two strains. This study shows that there is a difference in the distribution of eosinophils in the lung between the C57BL/6 and BALB/ c mice, but no difference in eosinophil production or Th1/Th2 balance. [ABSTRACT FROM AUTHOR]

Background Human rhinoviruses (HRVs) and house dust mites (HDMs) are among the most common environmental factors able to induce airway inflammation in asthma. Although epidemiological studies suggest that they also synergize in inducing asthma exacerbations, there is no experimental evidence to support this, nor any information on the possible mechanisms involved. Objective To investigate their interaction on the induction of airway epithelial inflammatory responses in vitro. Methods BEAS-2B cells were exposed to activated HDM Dermatophagoides pteronyssinus major allergen I (Der p I), HRVs (HRV1b or HRV16) or both in different sequences. IL-8/CXCL8 release, intercellular adhesion molecule (ICAM)-1 surface expression and nuclear factor κB (NF-κB) translocation were evaluated. Complementary, primary human bronchial epithelial cells (HBECs) exposed to both Der p I and RVs and IL-8, IL-6, IFN-γ-induced protein (IP)-10/CXCL10, IFN-λ1/IL-29, regulated upon activation normal T lymphocyte expressed and secreted (RANTES)/CCL5 release were measured. Results RV and Der p I up-regulated IL-8 release, ICAM-1 expression and NF-κB translocation in BEAS-2B cells. Simultaneous exposure to both factors, as well as when cells were initially exposed to HRV and then to Der p I, resulted in further induction of IL-8 in a synergistic manner. Synergism was not observed when cells were initially exposed to Der p I and then to HRV. This was the pattern in ICAM-1 induction although the phenomenon was not synergistic. Concurrent exposure induced an early synergistic NF-κB translocation induction, differentiating with time, partly explaining the above observation. In HBECs, both HRV and Der p I induced IL-8, IL-6, IL-29 and IP-10, while RANTES was induced only by HRV. Synergistic induction was observed only in IL-8. Conclusion HRV and enzymatically active Der p I can act synergistically in the induction of bronchial epithelial IL-8 release, when HRV infection precedes or is concurrent with Der p I exposure. Such a synergy may represent an important mechanism in virus-induced asthma exacerbations. [ABSTRACT FROM AUTHOR]

Exercise-induced (EI) hypersensitivity disorders are significant problems for both recreational and competitive athletes. These include EI-asthma, EI-bronchoconstriction, EI-rhinitis, EI-anaphylaxis and EI–urticaria. A group of experts from the European Academy of Allergology and Clinical Immunology and the American Academy of Allergy Asthma and Immunology met to discuss the pathogenesis of these disorders and how to diagnose and treat them, and then to develop a consensus report. Key words (exercise with asthma, bronchoconstriction, rhinitis, urticaria or anaphylaxis) were used to search Medline, the Cochrane database and related websites through February 2008 to obtain pertinent information which, along with personal reference databases and institutional experience with these disorders, were used to develop this report. The goal is to provide physicians with guidance in the diagnosis, understanding and management of EI-hypersensitivity disorders to enable their patients to safely return to exercise-related activities. [ABSTRACT FROM AUTHOR]

Asthma is a T helper 2 (Th2)-driven inflammatory process characterized by eosinophilia. Prolonged airway eosinophilia is commonly observed in asthma exacerbations. Our aim was to evaluate whether eosinophilia in prolonged allergic inflammation is associated with a continuous supply of new eosinophils to the airways, and how this is regulated. Ovalbumin (OVA)-sensitized interferon-γ receptor knockout mice (IFN-γR KO), known to maintain a long-lasting eosinophilia after allergen exposure, were compared to wild type (wt) controls. Animals were exposed to OVA or phosphate-buffered saline on three consecutive days, and bone marrow (BM), blood and bronchoalveolar lavage (BAL) samples were collected 24 h, 7 and 21 days later. Newly produced cells were labelled using bromodeoxyuridine (BrdU). Serum IL-5 was measured and its role was investigated by administration of a neutralizing anti-IL-5 antibody. In-vitro eosinophilopoiesis was examined in both groups by a colony-forming assay. Allergen challenge increased eosinophils in BM, blood and BAL, in both IFN-γR KO and wt mice, both 24 h and 7 days after the last allergen exposure. At 21 days after the last exposure, only IFN-γR KO mice maintained significantly increased eosinophil numbers. Approximately 50% of BAL granulocytes in IFN-γR KO were produced during the last 6 days. Interleukin (IL)-5 concentration was increased in IFN-γR KO mice, and anti-IL-5 reduced eosinophil numbers in all compartments. Increased numbers of eosinophil colonies were observed in IFN-γR KO mice after allergen exposure versus controls. In this model of a Th2-driven prolonged allergic eosinophilia, new eosinophils contribute to the extended inflammation in the airways by enhanced BM eosinophilopoiesis in an IL-5-dependent manner. [ABSTRACT FROM AUTHOR]

Exosomes are nano-sized membrane vesicles which are released extracellularly after fusion of multivesicular endosomes with the cell membrane. Despite their characteristic composition of proteins compared to the cell membrane, no exosome-specific molecule has so far been characterized. Exosomes are found in bronchoalveolar lavage (BAL), urine, serum and breast milk, and are released from several cells implicated in allergy including mast cells, dendritic cells (DC), T cells and epithelial cells. Antigen-loaded exosomes have been shown to be highly immunogenic and we propose that exosomes could be a modulating factor in allergic responses. Allergen-presenting exosomes could transport allergen and stimulate allergen-specific T cells, and possibly also biasing T cell responses depending on the molecules present on the exosome surface. Furthermore, exosomes from mast cells, highly active in allergic reactions, have been found to induce DC maturation and also to be able to transport functional RNA to recipient cells, suggesting a new pathway for cell communication. Reversely, tolerizing exosomes e.g. tolerosomes, from gut or breast milk, could block an allergic response or prevent allergy development. A better understanding of the role of exosomes in allergies could make us understand how allergy can be prevented or lead to the development of more efficient treatments. [ABSTRACT FROM AUTHOR]

Background: The mechanisms of the distant stimulation of the bone marrow (BM) after airway allergen exposure remain largely obscure. T cells have been implicated in allergic airway inflammation but their role in allergen-induced BM eosinophilopoiesis is poorly understood. The aim of this study was to determine the role of CD4+ and CD8+ T cells in allergen-induced BM eosinophilopoiesis. Methods: Ovalbumin (OVA)-sensitized wild type (WT), CD4 knockout (CD4−/−) and CD8 knockout (CD8−/−) mice were exposed intranasally to OVA or saline. Bromo-deoxyuridine (BrdU) was used to label newly produced cells. Bone marrow, blood and bronchoalveolar lavage (BAL) were sampled 24 h after the final exposure. Immunostaining for newly produced eosinophils (i.e. BrdU+/MBP+) and BM eosinophil progenitor [CD34+/CD45+/interleukin-5 (IL-5)Ralpha+] cells was performed. Results: The number of newly produced BM eosinophils (BrdU+/MBP+ cells) was significantly reduced in allergen exposed CD4−/− or CD8−/− mice compared with allergen exposed WT mice, which was followed by a subsequent decrease in newly produced blood and airway eosinophils. Furthermore, BM eosinophil progenitors were significantly reduced in allergen exposed CD4−/− and CD8−/− mice compared with WT mice. Finally, serum IL-5 and Bronchoalveolar lavage fluid eotaxin-2 levels were abolished in allergen exposed CD4−/− mice to levels seen in saline exposed WT mice. Conclusions: These data suggests that both CD4+ and CD8+ T cells have a regulatory role in allergen-induced BM eosinophilopoiesis, whereas CD4+ T cells are obligatory for allergen-induced airway eosinophilia. The subsequent traffic of eosinophils to the airways is likely to be at least partly regulated by a CD4+ T-cell-dependent local airway eotaxin-2 production. [ABSTRACT FROM AUTHOR]

Background: T-regulatory cells (Treg) affect the balance of TH2 and TH1 cells. Treg, TH2 and TH1 cells are regulated by the FOXP3, GATA-3 and T-bet transcription factors respectively. Our aim was to determine the number of FOXP3+, GATA-3+ and T-bet+ cells in nasal mucosa in symptom-free allergic rhinitis (AR) patients vs healthy controls, as well as the effects of natural pollen exposure and concomitant nasal glucocorticoid treatment on these cells. Methods: Nasal biopsies were taken from healthy controls and patients with grass-pollen AR preseason. The AR patients were randomized to receive treatment with either fluticasone propionate (FP) or a placebo, and additional biopsies were taken during the pollen season. FOXP3+, GATA-3+ and T-bet+ cells in nasal mucosa were quantified by immunohistochemistry. Results: The number of FOXP3+ and GATA-3+ cells, but not T-bet+ cells, was significantly higher in AR patients vs controls preseason. The number of FOXP3+ cells remained unchanged in the former group after the pollen season but decreased significantly in the nasal mucosa as a result of FP treatment. The pollen season substantially increased the number of GATA-3+ cells, which was inhibited by FP. The number of T-bet+ cells was not affected by pollen or FP. Conclusion: These data suggest that nasal glucocorticoids attenuate the allergic inflammation partly by reducing the number of TH2 cells, but not by means of local upregulation of Treg cells. The local relationship between TH1 and TH2 cells as well as between Treg and TH2 is maintained by nasal glucocorticoid treatment. [ABSTRACT FROM AUTHOR]

Allergology and Clinical Immunology (ACI) is an area of clinical medicine with a precise identity, relevant recent scientific achievements and well-defined educational and professional needs. In spite of the high individual and socio-economic impact of allergic diseases in Europe, the organization of ACI services is imperfect and varies among countries according to their health policies and priorities. In the firm belief of the role of ACI specialists in addressing clinical issues related to the involvement of the immune system in health and diseases—such as vaccination, immunodeficiencies, susceptibility and response to microbial agents, autoimmune and allergic diseases, immune aspects of transplantation and malignancies, in vivo and in vitro immunological tests, vaccinations, immuno-modifiers—the European Academy of Allergology and Clinical Immunology appointed an ad hoc Task Force to produce standards for ACI Services in Europe. The resulting position paper should be used as a consulting reference for National Health Services as a necessary pre-requisite for the free circulation to patients and health care professionals. [ABSTRACT FROM AUTHOR]

Eosinophils develop from CD34+ haematopoietic progenitor cells. Allergen exposure in susceptible individuals is known to induce a local eosinophilic inflammation, but the effect on progenitor cells is much less understood.We aimed to evaluate how allergen exposure affects the number of tissue CD34+ cells and CD34+ eosinophils in allergic rhinitis (AR) patients and whether any such effect is influenced by local corticosteroid treatment. Also, we evaluated changes in the number of CXC receptor 4-positive cells (CXCR4+), since the CXCR4 ligand (stromal cell-derived factor-1 (SDF-1)) is a potent chemoattractant for haematopoietic progenitors.In a double-blind, randomized study, pollen-sensitized AR patients were treated with a nasal corticosteroid fluticasone propionate (FP, 200 μg/day) or placebo throughout the pollen season. Nasal biopsies were taken before and during the season. CD34 and CXCR4 were stained using immunohistochemistry.The pollen season significantly increased the number of CD34+ cells, CD34+/CXCR4+ cells and CD34+ eosinophils in placebo-treated patients, but not in FP-treated patients. The mean pollen season-induced increase in CD34+ cells, CD34+/CXCR4+ cells and CD34+ eosinophils in FP-treated patients was lower compared with placebo-treated patients.A pollen season increases the number of CD34+ cells in nasal tissue accompanied by an increase in the number of CD34+/CXCR4+ haematopoietic progenitors and also the number of CD34+ eosinophils in subjects with AR. Treatment with a local corticosteroid provides protection against this pollen-induced increase in tissue CD34+ cells and CD34+ eosinophils possibly via inhibition of allergen-induced CXCR4-mediated recruitment of CD34+ haematopoietic progenitors into airways and their further differentiation into eosinophils within the tissue. [ABSTRACT FROM AUTHOR]

The specific mechanisms that alter bone marrow (BM) eosinophilopoiesis in allergen-induced inflammation are poorly understood. The aims of this study were to evaluate (a) whether the number of BM CD34+ cells is altered due to allergen sensitization and exposurein vivoand (b) whether BM CD34+ cells produce and release interleukin (IL)-5, IL-3 and granulocyte macrophage-colony stimulating factor (GM-CSF) after stimulationin vitro. A mouse model of ovalbumin (OVA)-induced airway inflammation was used. Bone marrow CD34+ cells were culturedin vitroand the cytokine release was measured by enzyme-linked immunosorbent assay. The IL-5-production from CD34+ cells was confirmed by immunocytochemistry. Airway allergen exposure increased the number of BM CD34+ cells (P = 0.01). Bone marrow CD34+ cells produced IL-5 when stimulated with the allergen OVAin vitro, but not IL-3 or GM-CSF. Nonspecific stimulus with calcium ionophore and phorbol-myristate-acetate of BM CD34+ cells caused release of IL-5, IL-3 and GM-CSF. The induced release of IL-5 was increased in alum-injectedvsnaive mice (P = 0.02), but was not affected by allergen sensitization and exposure. The release of IL-3 and GM-CSF was increased after allergen sensitization and exposure (P < 0.02). In conclusion, allergen can stimulate BM CD34+ cells to produce IL-5 protein. It is likely that the CD34+ cells have autocrine functions and thereby regulate the early stages of BM eosinophilopoiesis induced by airway allergen exposure. Alum, a commonly used adjuvant, enhances the release of IL-5 and may thereby enhance eosinophilopoiesis. [ABSTRACT FROM AUTHOR]

Patients with severe asthma are often inadequately controlled on existing anti-asthma therapy, constituting an unmet clinical need. This randomized, double-blind, placebo-controlled trial evaluated the ability of omalizumab, a humanized monoclonal anti-IgE antibody, to improve disease control sufficiently to enable inhaled corticosteroid reduction in patients with severe allergic asthma. After a run-in period when an optimized fluticasone dose (⩾1000 μg/day) was received for 4 weeks, patients were randomized to receive subcutaneous omalizumab [minimum 0.016 mg/kg/IgE (IU/mL) per 4 weeks; n=126] or matching placebo ( n=120) at intervals of 2 or 4 weeks. The study comprised a 16-week add-on phase of treatment followed by a 16-week fluticasone-reduction phase. Short-/long-acting β2-agonists were allowed as needed. Median reductions in fluticasone dose were significantly greater with omalizumab than placebo: 60% vs. 50% ( P=0.003). Some 73.8% and 50.8% of patients, respectively, achieved a ⩾50% dose reduction ( P=0.001). Fluticasone dose reduction to ⩽500 μg/day occurred in 60.3% of omalizumab recipients vs. 45.8% of placebo-treated patients ( P=0.026). Through both phases, omalizumab reduced rescue medication requirements, improved asthma symptoms and asthma-related quality of life compared to placebo. Omalizumab treatment improves asthma control in severely allergic asthmatics, reducing inhaled corticosteroid requirements without worsening of symptom control or increase in rescue medication use. [ABSTRACT FROM AUTHOR]

Background: CD4+ T cells constitute a major source of cytokines in allergic diseases such as allergic rhinitis. Interleukin (IL)-16 selectively recruits CD4+ cells. Methods: We evaluated the effect of natural allergen exposure during a grass-pollen season on IL-16 expression and number of CD4+ cells in nasal mucosa. Patients with allergic rhinitis (n=16) were treated with either a nasal glucocorticoid beclomethasone (BDP; 400 µg/day) or placebo, and gave nasal biopsies prior to and during the grass-pollen season. The evaluated markers in allergic rhinitis patients were also compared to those in healthy control subjects (n=5). Results: Prior to the pollen season, the expression of IL-16, but not the number of CD4+ cells, was significantly higher in patients with allergic rhinitis than in healthy control subjects. The grass-pollen season further increased IL-16 expression and also increased the number of CD4+ cells in placebo-treated, but not in BDP-treated, allergic rhinitis patients. The pollen-season-induced change in IL-16 expression and in CD4+ cells was significantly more pronounced in placebo- than in BDP-treated patients. There was a significant correlation between the change in IL-16 expression and the number of CD4+ cells. Conclusions: These data suggest that local upregulation of IL-16 expression contributes to the inflammation observed in seasonal allergic rhinitis. Hypothetically, inhibition of IL-16 expression can be one of several mechanisms by which nasal glucocorticoids achieve their anti-inflammatory effect in allergic rhinitis. [ABSTRACT FROM AUTHOR]

Background Allergic rhinitis is a common disease characterized by infiltration of eosinophils into the nasal mucosa during the periods of symptoms. Among chemokines, which attract cells to the site of inflammation, eotaxin is relatively specific for eosinophils. Objective We examined the influence of grass pollen season on nasal eotaxin expression in patients with seasonal allergic rhinitis, as well as the effect of a nasal glucocorticoid on this eotaxin expression. Methods Nineteen patients with allergic rhinitis received treatment with either nasal beclomethasone (400 μg/day) or placebo over a grass pollen season. In these patients, nasal biopsies were taken prior to and during the peak of the pollen season and stained immunohistochemically for eotaxin and EG2 + eosinophils. Five healthy subjects served as controls and gave nasal biopsies once prior to the pollen season. Results Prior to pollen season, there was no significant difference in nasal eotaxin expression between patients with allergic rhinitis and healthy subjects. Grass pollen season induced significant increase in eotaxin expression in placebo-treated (P = 0.04; n = 9) but not in beclomethasone-treated rhinitis patients (P = 0.8; n = 10). During peak grass pollen season, the eotaxin expression in placebo-treated patients was significantly higher compared with healthy subjects outside season (P = 0.03). There was no significant correlation between the expression of eotaxin and the number of EG2 + eosinophils in nasal mucosa. The serum levels of eotaxin in rhinitis patients remained stable over the pollen season. Conclusion Expression of eotaxin in nasal mucosa of grass-pollen allergic rhinitis patients is upregulated during pollen season and treatment with a nasal glucocorticoid protects against this upregulation. [ABSTRACT FROM AUTHOR]

Prolonged exposure to allergen has been proposed to be important for the development of bronchial hyperresponsiveness and airway remodelling in asthma. The present study was designed to examine the effect of chronic allergen exposure on bronchial responsiveness, eosinophil infiltration, and airway remodelling. We sensitized brown Norway rats with the occupational allergen trimellitic anhydride (TMA) and exposed the animals to TMA conjugated to rat serum albumin (TMA‐RSA) on 5 consecutive days each week for 9 weeks, starting 4 weeks after sensitization. IgE and IgG anti‐TMA antibodies in serum and bronchial responsiveness to acetylcholine were evaluated before and at weeks 3, 6, and 9 of allergen exposure. Thickness of the airway wall, airway luminal narrowing, and the number of goblet cells and eosinophils in the airway wall were evaluated with an image analysis system in lungs resected after the last assessment of bronchial responsiveness, at the end of the 9‐week allergen exposure. All rats developed IgE and IgG anti‐TMA antibodies after sensitization. The levels of antibodies increased with allergen exposure until week 6, and then declined. Bronchial hyperresponsiveness to acetylcholine was induced in allergen‐exposed rats without ongoing airway eosinophilia. Bronchial hyperresponsiveness induced by chronic allergen exposure via inhalation was accompanied by significantly increased thickness of smooth muscle and airway narrowing in the small airways, and goblet cell hyperplasia in the large airways. We conclude that chronic exposure to allergen can induce bronchial hyperresponsiveness and airway wall remodelling. Airway wall remodelling may contribute to bronchial hyperresponsiveness. Abbreviations: ACh: acetylcholine; BHR: bronchial hyperresponsiveness; BN rat: brown Norway rat; ELISA: enzyme‐linked immunosorbent assay; IgE: immunoglobulin E; IgG: immunoglobulin G; PC: provocative concentration; Ptp: transpulmonary... [ABSTRACT FROM AUTHOR]

Trimelliic anhydride (TMA) is a low molecular weight chemical which can cause occupational asthma. We studied the role of eicosanoids in airway responses lo TMA al different times after sensitization in actively sensitized guinea-pigs. Sensitization was performed by two intradermal injections of free TMA (0.1 ml of 0.3% TMA in corn oil). At 3 and 8 weeks after sensitization, the guinea-pigs were anaesthetized and challenged with intratracheal instillation of 0.5% TMA conjugated to guinea-pig scrum albumin (TMA-GPSA; 50 μl). Lung resistance (RL) was measured to assess airflow obstruction. and the tissue content of Evans Blue dye was measured to assess airway plasma exudation. Intratracheal instillation of TMA-GPSA induced a slowly progressing increase in RL, reaching a peak at approximately 3.5 min after [he challenge (6.0 ± 2.0 cm H2O/ml/s in the 3-wcok group and 3.8 ± 0.6 in the 8-week group). Pretreatment before challenge with pyrilamine (anti-histamine: 2 mg/kg. intravenously) slowed the onset of the increase in RL following challenge with TMA-GPSA, and significantly attenuated the peak response. A combination of pyrilamine and lCI-192/i()5 (thromboxane receptor antagonist; 0.5 mg/kg, intravenously) completely abolished the increase in RL in both week groups. A combination of pyrilamine and ICI-198,615 (leukotriene C4/D4/E4 receptor antagonist: 0.5 mg/kg. intravenously) did not further attenuate the increase in RL compared with pretreatment with pyrilamine alone, but the induced Evans Blue dye extravasation was completely inhibited in the 3-week group, whereas a remaining extravasation was observed in the 8-week group. We conclude that the bronchoconstrictor response to TMA-GPSA in actively sensitized guinea-pigs is mediated by histamine and thromboxane A2 both early and late after sensitization, whereas leukotrienes and histamine partially mediate TMA-induced airway plasma exudation. [ABSTRACT FROM AUTHOR]

We used frontally opened tracheal rings, contracted with 10 μM of histamine to produce β-adrenoceptor tachyphylaxis by isoprenaline incubation and to evaluate whether theophylline can prevent this tachyphylaxis. Two concentration-response experiments with isoprenaline were performed in each ring. Between the concentration-response experiments the rings were incubated using four different treatments, isoprenaline (3 μM), theophylline (1 mM), theophylline + isoprenaline or vehicle for 60 min. Tachyphylaxis was evaluated as the difference in pD2 (-log EC50) during the first and second concentration-response experiment. Isoprenaline incubation produced a shift to the right of the concentration-response curve. The shift was small (approximately 0.2 log units) but significantly different from the control group. Theophylline failed to influence the process either alone or in combination with isoprenaline. In conclusion, β-adrenoceptor tachyphylaxis after isoprenaline incubation in isolated guinea-pig trachea proved to be a very small effect and we observed no influence by theophylline. [ABSTRACT FROM AUTHOR]

Organic acid anhydrides (OAAs) are industrial chemicals that may cause induction of specific IgE and airway symptoms in exposed workers. They are a good model for studies of relationships between chemical structure and the sensitizing potential of reactive low-molecular-weight compounds. Hexahydrophthalic anhydride (HHPA) is such a compound. This study aimed to evaluate the relationship between specific IgG1 levels and airway responses in a model to predict the sensitizing potential of OAAs. Guinea pigs were either actively or passively sensitized to HHPA. For active sensitization, guinea pigs were injected i,d, with 0.1 ml of olive oil (vehicle) or 0.05, 0.5, or 5% HHPA in olive oil. Passive sensitization was performed by i.p. injection of different volumes of antisera (0,75-6 ml, either unheated to keep IgE or heated to destroy IgE) taken from HHPA-sensitized guinea pigs. Specific antibody levels were evaluated with ELISA and passive cutaneous anaphylaxis. Animals were challenged 16-18 days after active sensitization, or 2 days after passive sensitization. by intratracheal instillation with HHPA conjugated to guinea pig serum albumin (HHPA-GPSA: 0.05% in saline), and the immediate effects on lung resistance (R1), and plasma extravasation, measured as Evans blue dye extravasation, for up to 6 min were recorded. Active sensitization caused production of specific IgG1. Provocation with HHPA-GPSA caused an increase of both R1, and Evans blue dye extravasation, which was dependent upon the active sensitization dose. Challenge with HHPA-GPSA in passively sensitized guinea pigs also produced an increase in both R^ and Evans blue dye extravasation which was related to the IgG1 level. In the guinea pig model of HHPA-induced airway allergy, the airway responses are closely related to the serum levels of specific IgG1. Thus, the IgG1 levels induced by the immunization may reflect the sensitizing potential of HHPA. [ABSTRACT FROM AUTHOR]

Bronchial hyperresponsiveness (BHR) and damage of the epithelium, as well as eosinophilia in the airway wall, induced by trimellitic anhydride (TMA) in sensitized brown Norway rats were studied. Rats were challenged once or seven times with aerosol of TMA conjugated to rat serum albumin (TMA-RSA) 3 weeks after intradermal TMA sensitization. Airway responsiveness (-log PC300 of acetylcholine i.v.) was measured 24 h after allergen challenge. Epithelial lesion and eosinophil infiltration in the airway walls were quantified under light microscopy, and TMA-specific IgE and IgG in serum were evaluated with ELISA. High levels of TMA-specific IgE and IgG were found in all rats in the sensitized groups compared to nonsensitized groups (P < 0.001). Repeated allergen challenges of 0.03% TMA-RSA for 7 consecutive days enhanced the level of TMA-specific IgG, compared to single challenge (P ≤ 0.05). Single allergen challenge of 0.3% TMA-RSA had a nonsignificant tendency to produce BHR in sensitized rats compared to nonsensitized rats (P=0.06). However, repeated allergen challenges (0.003% and 0.03% TMA-RSA for 7 consecutive days) produced significant BHR in sensitized rats (P < 0.05). Furthermore, repeated low-dose (0 003%) TMA-RSA challenge produced more BHR than a 10 times higher single dose (0.003%) (P < 0.05). Slight damage of the airway epithelium was seen in sensitized and repeat-challenged groups. However, bronchial eosinophilia was found in the sensitized and single-challenged groups, but not in nonsensitized nonchallenged, and sensitized repeat-challenged groups (P < 0.005). We conclude that the brown Norway rat can be sensitized with TMA, and that repeated low-dose allergen challenges produce slight epithelial damage and BHR which is independent of ongoing eosinophilia in the airway wall. [ABSTRACT FROM AUTHOR]

Trimellitic anhydride (TMA) is a low-molecular-weight compound which causes occupational allergy. Brown Norway rats were sensitized to TMA injected intradermally (0.3% TMA suspended in oil). Three weeks later, we examined responses to either free TMA injected intradermally, or TMA conjugated to rat serum albumin (TMA-RSA) given by inhalation (0.5%, nebulized for 15 min). Twenty-one days after the sensitization. Evans blue dye was given i.v. (20 mg/kg). and extravasation of dye in skin was measured 30 min after oil or TMA injections (0.03-10% in oil). In a separate series of experiments, we evaluated the accumulation of eosinophils in the skin after single and repeated injections of TMA (0.03-0.3%). The injection sites were removed and fixed in formalin 18-24 h after the last injection. In a third series of experiments, we evaluated the effects of airway exposure to TMA-RSA (0.5% in 0.9% saline) on the accumulation of eosinophils in the bronchial wall counted with quantitative light microscopy. Intradermal injections of free TMA caused a dose-dependent increase of Evans blue dye extravasation which was significantly higher in sensitized animals than in controls. Skin histology revealed a significant and dose-dependent increase in eosinophils after repeated TMA injections in sensitized animals. Exposure to aerosolized TMA-RSA caused a significant increase of eosinophils in the bronchial wall of sensitized rats compared with nonsensitized rats. Sensitized animals showed significantly higher levels of specific IgG and IgE. We conclude that brown Norway rats can he used as a model of TMA-induced allergic inflammation, mimicking occupational asthma. [ABSTRACT FROM AUTHOR]

We have studied the induction of nitric oxide during late allergic responses, using a guinea pig model of trimellitic anhydride (TMA)-induced airway allergy. TMA is a low molecular weight chemical which can cause occupational asthma. The activity of nitric oxide synthase (NOS) was investigated by the detection of ³H-labeled citrulline formation from ³H-labeled arginine. In sensitized animals, challenge with TMA conjugated to guinea pigs albumin (TMA-GPSA) increased the activity of Ca2+-independent NOS (inducible NOS; iNOS) in lung and bronchial tissues at 15-17 h after challenge compared to nonsensitized animals. The induction of iNOS activity was associated with an associated with an increased level of nitrite, an end metabolite of the l-arginine-NO pathway, in bronchoalveolar lavage fluid. In contrast to iNOS, the activity of Ca2+-dependent NOS (constitutive NOS; cNOS) was not affected by the allergen challenge. These results demonstrate that iNOS in bronchial tissue is induced late after allergen challenge in sensitized guinea pig. [ABSTRACT FROM AUTHOR]

We have studied the effects of tachykinin-depletion on airway microvascular leakage induced by allergen challenge in ovalbumin-sensitised guinea pigs. Tachykinin-depletion was obtained by capsaicin pretreatment 1 week before inhaled allergen challenge. Capsaicin pretreatment did not change airway microvascular permeability induced by allergen challenge. Thus, sensory neuropeptides may not be important in allergen-induced acute airway microvascular leakage in guinea pig in vivo. [ABSTRACT FROM AUTHOR]

The author reflects on the study that discusses the efficacy of steroid in asthma through the use of electronic nose. The author cites the misuse of the electronic nose by the researchers as the latter is a nobel device for smell analysis or in the detection of infections. The author adds that the 25 respondents particularly with the use of clinical trials also experienced success in predicting the responsiveness to steroids.

The article focuses on the collaborative outreach program termed the International Collaboration in Asthma, Allergy and Immunology (iCAALL). It states that the program aims to increase and coordinate the communication of information about asthma, allergies, and immunologic diseases on a global level. Moreover, the first project for iCAALL is the production of international consensus statements (ICONs) which will serve as important resources for physicians and other healthcare professionals.

Editorial. Focuses on the reduction on the levels of Immunoglobulin E (IgE) antibodies in vitro through glucocorticoid treatment. Treatment of asthma and allergic rhinitis; Effectiveness for patients with inflammatory airway disease; Demonstration of the inhibitory effect of local glucocorticoids on allergen-specified IgE production.

Asthma is the most common chronic lower respiratory disease in childhood throughout the world. Several guidelines and/or consensus documents are available to support medical decisions on pediatric asthma. Although there is no doubt that the use of common systematic approaches for management can considerably improve outcomes, dissemination and implementation of these are still major challenges. Consequently, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), recently formed by the EAACI, AAAAI, ACAAI, and WAO, has decided to propose an International Consensus on (ICON) Pediatric Asthma. The purpose of this document is to highlight the key messages that are common to many of the existing guidelines, while critically reviewing and commenting on any differences, thus providing a concise reference. The principles of pediatric asthma management are generally accepted. Overall, the treatment goal is disease control. To achieve this, patients and their parents should be educated to optimally manage the disease, in collaboration with healthcare professionals. Identification and avoidance of triggers is also of significant importance. Assessment and monitoring should be performed regularly to re-evaluate and fine-tune treatment. Pharmacotherapy is the cornerstone of treatment. The optimal use of medication can, in most cases, help patients control symptoms and reduce the risk for future morbidity. The management of exacerbations is a major consideration, independent of chronic treatment. There is a trend toward considering phenotype-specific treatment choices; however, this goal has not yet been achieved., (© 2012 John Wiley & Sons A/S.)

The links between asthma and rhinitis are well characterized. The Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines stress the importance of these links and provide guidance for their prevention and treatment. Despite effective treatments being available, too few patients receive appropriate medical care for both diseases. Most patients with rhinitis and asthma consult primary care physicians and therefore these physicians are encouraged to understand and use ARIA guidelines. Patients should also be informed about these guidelines to raise their awareness of optimal care and increase control of the two related diseases. To apply these guidelines, clinicians and patients need to understand how and why the recommendations were made. The goal of the ARIA guidelines is to provide recommendations about the best management options for most patients in most situations. These recommendations should be based on the best available evidence. Making recommendations requires the assessment of the quality of available evidence, deciding on the balance between benefits and downsides, consideration of patients’ values and preferences, and, if applicable, resource implications. Guidelines must be updated as new management options become available or important new evidence emerges. Transparent reporting of guidelines facilitates understanding and acceptance, but implementation strategies need to be improved.

Viral infections of the respiratory tract are the most common precipitants of acute asthma exacerbations. Exacerbations are only poorly responsive to current asthma therapies and new approaches to therapy are needed. Viruses, most frequently human rhinoviruses (RV), infect the airway epithelium, generate local and systemic immune responses, as well as neural responses, inducing inflammation and airway hyperresponsiveness. Using in vitro and in vivo experimental models the role of various proinflammatory or anti-inflammatory mediators, antiviral responses and molecular pathways that lead from infection to symptoms has been partly unravelled. In particular, mechanisms of susceptibility to viral infection have been identified and the bronchial epithelium appeared to be a key player. Nevertheless, additional understanding of the integration between the diverse elements of the antiviral response, especially in the context of allergic airway inflammation, as well as the interactions between viral infections and other stimuli that affect airway inflammation and responsiveness may lead to novel strategies in treating and/or preventing asthma exacerbations. This review presents the current knowledge and highlights areas in need of further research.

Early asthmatic responses (EAR) and late asthmatic responses (LAR) to allergen are induced by the local release of a series of bronchoconstrictor mediators, including leukotrienes and histamine. Both anti-leukotrienes and other anti-asthma drugs, such as inhaled glucocorticoids, have been shown to reduce both EAR and LAR. The aim of the present study was to directly compare the effects of regular treatment with an oral anti-leukotriene, montelukast (Mont; 10 mg once daily, for 8 days), and an inhaled glucocorticoid [fluticasone propionate (FP) 250 microg twice daily for 8 days] on the EAR and LAR to an inhaled allergen challenge. Patients with a documented EAR and LAR at a screening visit were randomized to these treatments, or placebo, in a double-blind, double-dummy, crossover fashion. Allergen challenge at a dose causing both an EAR and LAR was given on the eighth day of treatment. The maximum fall in FEV1 during the EAR was 17.8% during placebo treatment, 8.3% during Mont and 16.3% during FP (P <0.05 for Mont vs placebo). The maximum fall during the EAR was 13.8% during placebo treatment, 11.8% during Mont and 2% during FP treatment (P <0.05 for FP vs placebo and FP vs Mont). PC20 methacholine was significantly higher 24 h after allergen challenge during FP-treatment compared with Mont (P <0.05). Both montelukast and fluticasone reduced the relative amount of sputum eosinophils after allergen compared with placebo treatment. This study shows that anti-leukotrienes are effective to attenuate the EAR, whereas inhaled glucocorticoids are more effective than anti-leukotrienes in attenuating the EARs and improves bronchial hyperresponsiveness to a greater extent. In conclusion, inhaled glucocorticoids have overall greater efficacy than oral anti-leukotrienes to attenuate allergen-induced airway responses in mild asthmatic patients.

Background: Airway allergen exposure causes local eosinophilic cell infiltration. This cellular inflammatory response is likely to involve the release of eosinophils from peripheral storage pools, and possibly also regeneration of eosinophils in the bone marrow. IL-12 is an inhibitory cytokine in allergic inflammation, shown to reduce eosinophilic cell infiltration. The aim of the present study was to determine whether airway allergen exposure increases bone marrow eosinophil production, and, if so, whether IL-12 modulates this effect., Methods: Ovalbumin-sensitized C57BL/6 mice and IL-12 knockout (KO) mice were exposed to allergen via the airway route, and the inflammatory cell response was evaluated in bronchoalveolar lavage fluid, blood, and bone marrow., Results: Allergen instillation intranasally produced a dose-dependent inflammatory response in the lower airways of sensitized mice. This inflammatory response was dominated by eosinophils, but there were also increases of both lymphocytes and neutrophils. Sensitization and airway allergen exposure also increased the IL-5-dependent growth of bone marrow cells in vitro. The enhanced bone marrow responsiveness in vitro was paralleled by an increased number of bone marrow eosinophils in vivo. After sensitization and repeated allergen exposure, IL-12 KO mice showed higher eosinophil levels in both BAL and bone marrow than parallel wild-type control mice. Furthermore, BAL-eotaxin levels were increased in IL-12 KO mice as opposed to parallel wild-type controls after allergen exposure., Conclusions: Airway allergen exposure induced systemic immunologic responses, including increased eosinophil numbers in both airways and bone marrow, and also enhanced IL-5 responsiveness in bone marrow cells. IL-12 may regulate airway eosinophilia at both the level of eosinophilopoiesis and the level of local recruitment of eosinophils into the airways.

We have studied the induction of nitric oxide during late allergic responses, using a guinea pig model of trimellitic anhydride (TMA)-induced airway allergy. TMA is a low molecular weight chemical which can cause occupational asthma. The activity of nitric oxide synthase (NOS) was investigated by the detection of 3H-labeled citrulline formation from 3H-labeled arginine. In sensitized animals, challenge with TMA conjugated to guinea pigs albumin (TMA-GPSA) increased the activity of Ca(2+)-independent NOS (inducible NOS; iNOS) in lung and bronchial tissues at 15-17 h after challenge compared to nonsensitized animals. The induction of iNOS activity was associated with an associated with an increased level of nitrite, an end metabolite of the l-arginine-NO pathway, in bronchoalveolar lavage fluid. In contrast to iNOS, the activity of Ca(2+)-dependent NOS (constitutive NOS; cNOS) was not affected by the allergen challenge. These results demonstrate that iNOS in bronchial tissue is induced late after allergen challenge in sensitized guinea pig.

Salmeterol is a new beta 2-receptor agonist with a prolonged duration of action after inhalation, exceeding 12 h in most patients. We have performed a 12-month open follow-up study on 11 patients with reversible asthma. All patients were given salmeterol inhalations (50 micrograms twice daily). Additional asthma treatment included inhaled corticosteroids in all patients, and oral slow-release theophylline or beta 2-receptor agonists in a minority of patients (3 and 1, respectively). Before salmeterol treatment was initiated and after 3, 6, 9 and 12 months of salmeterol treatment, a cumulative dose-response curve to inhaled salbutamol (100, 300 and 900 micrograms) was performed, and FEV1 measured. We also evaluated the effect of each salbutamol dose on finger tremor, systemic blood pressure and heart rate. Blood tests, including white blood count and electrolytes, were taken at each visit. After salmeterol treatment was initiated, morning FEV1, measured before the morning asthma medication, was significantly improved (p < 0.05). The responsiveness to inhaled salbutamol was not decreased during salmeterol treatment, except in one patient with asthma worsening over the study year. Baseline finger tremor measured before salbutamol dose-response curves, was significantly lower at the 12-month visit than before treatment was initiated (p < 0.05). Effects of salbutamol on systemic blood pressure, heart rate or finger tremor was not significantly changed during salmeterol treatment. We found a successive and significant decrease in blood eosinophils (p < 0.05) during the 12 months of salmeterol treatment, when the patient with asthma worsening was excluded in the analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway inflammation is a common feature of asthma, and one of the cardinal features of inflammation is increased microvascular permeability. We investigated the characteristics of inhaled ovalbumin challenge-induced airflow obstruction and airway microvascular leakage in vivo in mechanically ventilated guinea pigs actively sensitized to ovalbumin. A method was used to quantify both airflow obstruction and airway microvascular leakage in order to investigate the relationship between these 2 pathophysiological features in the same animal. Airway microvascular leakage was assessed by Evans blue dye extravasation into airway tissues. Actively sensitized guinea pigs developed both acute airflow obstruction (increased lung resistance and reduced dynamic lung compliance) and Evans blue dye extravasation in response to exposure to aerosolised ovalbumin. Evans blue dye extravasation was preferentially distributed in the distal airways and correlated with airflow obstruction. The results show that inhaled allergen induced both acute airflow obstruction and airway microvascular leakage.