Search

Background: The prevalence of asthma severity is not well described at a population level., Objective: We sought to determine the prevalence of phenotypic signs of asthma severity among asthmatic patients in a general population and to describe risk factors for asthma severity., Methods: We performed an epidemiologic study conducted between 2008 and 2012 (West Sweden Asthma Study). A postal questionnaire was sent to a random population (n = 30,000) in west Sweden, with 18,087 responses. A total of 2,006 subjects were carefully phenotyped. Only subjects with "active asthma" (symptoms or medication in the last year, n = 744) were analyzed in this study to determine the degree of severity of the disease within an asthma cohort. Phenotypes of severity were calculated based on (1) multiple symptoms during the day despite ongoing use of asthma medications, (2) FEV 1 of less than 70% of predicted value, (3) daily or almost daily use of rescue medications, (4) nighttime symptoms once a week or more, and (5) oral corticosteroid use/emergency department visits. Asthmatic patients were grouped as having nonsevere disease, 1 sign of severity, or 2 or more signs of severity., Results: A total of 36.2% of asthmatic patients expressed at least 1 sign of asthma severity, and 13.2% had 2 or more signs. The group with 2 or more signs was older in age and had higher body mass index, a higher rate of tobacco smoking, and lower lung function. Bronchial hyperreactivity, airway inflammation, and sensitization were significantly different among the 3 groups. At a population level, the prevalence of asthma severity was 3.1% for 1 sign and 1.3% for at least 2 signs., Conclusion: More than 1 in 3 asthmatic patients show at least 1 sign of asthma severity. The phenotypes of asthma severity are highly diverse, which is important to consider when implementing personalized medicine in asthmatic patients., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Epidemiologic data describing the association between allergic sensitization and asthma and allergic rhinitis in adults are scarce., Objective: To determine the prevalence and impact of specific sensitization to airborne allergens on asthma and allergic rhinitis among adults in relation to age., Methods: A random population sample (age 21-86 years) was examined with structured interview and analysis of specific IgE to 9 common airborne allergens. Of those invited, 692 (68%) subjects participated in blood sampling. IgE level of 0.35 U/mL or more to the specific allergen was defined as a positive test result., Results: Allergic sensitization decreased with increasing age, both in the population sample and among subjects with asthma and allergic rhinitis. In a multivariate model, sensitization to animal was significantly positively associated with asthma (odds ratio [OR], 4.80; 95% CI, 2.68-8.60), whereas sensitization to both animal (OR, 3.90; 95% CI, 2.31-6.58) and pollen (OR, 4.25; 95% CI, 2.55-7.06) was significantly associated with allergic rhinitis. The association between allergic sensitization and rhinitis was consistently strongest among the youngest age group, whereas this pattern was not found for asthma. The prevalence of allergic sensitization among patients with asthma decreased by increasing age of asthma onset, 86% with asthma onset at age 6 y or less, 56% at age 7 to 19 years, and 26% with asthma onset at age 20 years or more., Conclusions: Sensitization to animal was associated with asthma across all age groups; allergic rhinitis was associated with sensitization to both pollen and animal and consistently stronger among younger than among older adults. Early onset of asthma was associated with allergic sensitization among adults with asthma., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

It is increasingly clear that asthma is a complex disease made up of number of disease variants with different underlying pathophysiologies. Limited knowledge of the mechanisms of these disease subgroups is possibly the greatest obstacle in understanding the causes of asthma and improving treatment and can explain the failure to identify consistent genetic and environmental correlations to asthma. Here we describe a hypothesis whereby the asthma syndrome is divided into distinct disease entities with specific mechanisms, which we have called "asthma endotypes." An "endotype" is proposed to be a subtype of a condition defined by a distinct pathophysiological mechanism. Criteria for defining asthma endotypes on the basis of their phenotypes and putative pathophysiology are suggested. Using these criteria, we identify several proposed asthma endotypes and propose how these new definitions can be used in clinical study design and drug development to target existing and novel therapies to patients most likely to benefit. This PRACTALL (PRACtical ALLergy) consensus report was produced by experts from the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Eosinophils develop from CD34+ bone marrow progenitors, and evidence increasingly suggests that these progenitors are recruited to the airways in atopic asthmatics after allergen challenge. Moreover, it has been shown that the number of CD34+ progenitors in bronchial tissue correlates with asthma severity. To date, however, little is known about how these cells are recruited into the airways., Objective: Our aim was to evaluate the role of 2 chemokines, eotaxin-I and/or eotaxin-2, in the recruitment of newly produced and CD34+ eosinophils to the airways after allergen exposure., Methods: BALB/c mice sensitized and exposed to ovalbumin were pretreated intraperitoneally or intranasally with a neutralizing anti-eotaxin-1 and/or anti-eotaxin-2 antibody.A thymidine analogue, 5-bromo-2'-deoxyuridine (BrdU), was used to mark newly produced cells. Bronchoalveolar lavage (BAL), blood, and bone marrow were collected 24 hours after the final exposure., Results: Anti-eotaxin-1 and/or anti-eotaxin-2 given intranasally(ie, locally to airways) significantly decreased BAL eosinophils. This decrease was paralleled with a decrease in both BrdU+and CD34+ eosinophils. In contrast, systemically administered(ie, intraperitoneally) anti-eotaxin-1 and/or anti-eotaxin-2 resulted in a significant decrease in BAL eosinophils only when the combined treatment was of a sufficiently high dosage to produce measurable concentrations in the airways.Furthermore, neither of the treated groups showed any significant decrease in blood or bone marrow eosinophils., Conclusion: Both eotaxin-1 and eotaxin-2 are involved locally within the airways in the regulation of the recruitment of newly produced and CD34+ eosinophils after allergen exposure.

Background: Allergic rhinitis requires active intervention for symptom relief. A combination of antileukotriene and antihistamine drugs has been suggested to provide additive treatment benefits for patients with allergic rhinitis., Objective: We evaluated how such a combination treatment would affect symptoms and local mucosal eosinophilia in comparison with a nasal glucocorticoid., Methods: In a double-blind, randomized study 62 patients with grass pollen-induced allergic rhinitis received a nasal glucocorticoid (fluticasone propionate aqueous nasal spray [FPANS], 200 microg/d), an antileukotriene (montelukast, 10 mg/d), a combination of montelukast with an antihistamine (loratadine, 10 mg/d), or placebo throughout the season. Cromoglycate eyedrops and a limited amount of loratadine were allowed as rescue medication for severe symptoms. Patients recorded their symptoms for nasal blockage, itching, rhinorrhea, and sneezing. Before and during the season, nasal biopsy specimens were obtained from patients for evaluation of local eosinophilic inflammation., Results: During the peak season, both FPANS and combined montelukast-loratadine were significantly more effective than placebo and montelukast alone for daytime symptom prevention. For nighttime symptoms, FPANS was significantly more effective compared with all other treatments, whereas combined montelukast-loratadine and montelukast alone did not provide significant symptom prevention compared with placebo. The pollen-induced increase in the numbers of epithelial eosinophils was significantly lower for FPANS-treated patients compared with that seen in all other treatment groups., Conclusion: In patients with seasonal allergic rhinitis, intranasal glucocorticoids are more effective than an antileukotriene drug or combined antileukotriene-antihistamine for the reduction of pollen-induced nasal eosinophilic inflammation and for control of nasal symptoms.

Background: It has been suggested that R-albuterol produces bronchodilation that is comparable with that of racemic albuterol (RS-albuterol) on a 4:1 dose-for-dose basis but systemic side effects on a 2:1 basis, implying better therapeutic ratio for R-albuterol., Objective: We sought to carefully compare the bronchodilating and systemic effects of R- and RS-albuterol by using a crossover study design., Methods: Twenty asthmatic patients (15.1%-28.7% FEV(1) reversibility) were given R-albuterol (6.25-1600 microg), S-albuterol (6.25-1600 microg), RS-albuterol (12.5-3200 microg), or placebo in a crossover, double-blind, placebo-controlled fashion. Cumulative doses were given with a Mefar dosimeter, and FEV(1), heart rate, and plasma K(+) levels were measured 20 minutes after each dose., Results: Both R- and RS-albuterol produced dose-related improvement in FEV(1) and, at higher doses, increased heart rate and decreased plasma K(+) levels. Neither placebo nor S-albuterol had any significant effect. Individual estimates of the potency ratio for R-albuterol/RS-albuterol were calculated and summarized across all subjects. The geometric mean potency ratio for effects on FEV(1) was 1.9 (95% CI, 1.3-2.8), on HR of 1.9 (95% CI, 1.3-2.9), and on K(+) level of 1.7 (95% CI, 1.3-2.1)., Conclusion: All pharmacologic effects of RS-albuterol reside with the R-enantiomer, and S-albuterol is clinically inactive. The R-albuterol/RS-albuterol potency ratios for local (FEV(1)) and systemic effects (heart rate and K(+)) are similar, suggesting a comparable therapeutic ratio for R-albuterol and RS-albuterol in asthmatic subjects.

Background: A recent study demonstrated that intratracheal administration of the T-lymphocyte cytokine IL-17 recruits neutrophils into airways in vivo by C-X-C chemokine release. It is not known whether IL-17 may also activate airway neutrophils., Objective: Our purpose was to evaluate whether IL-17 activates neutrophils in airways in vivo and, if so, whether the proinflammatory cytokine IL-1beta modulates this action of IL-17., Methods: Intratracheal administration of human (h) IL-17 or rat (r) IL-1beta or hIL-17 plus rIL-1beta in anesthetized, spontaneously breathing rats was followed by bronchoalveolar lavage (BAL) 6 hours later. The BAL fluid was characterized in terms of neutrophil count, of the activity for myeloperoxidase (MPO), and in some cases of the activity for elastase (ELA). Isolated rat neutrophils were stimulated with hIL-17 in vitro, followed by characterization of MPO activity in the cell medium., Results: hIL-17 (1 microg) increased the ELA and the MPO activity, as well as the neutrophil count in BAL fluid, whereas the proinflammatory cytokine rIL-1beta (2.5 ng) did not. Pretreatment with rIL-1beta enhanced IL-17induced ELA and MPO activity, without increasing the neutrophil count. The BAL ELA activity was inhibited by a specific inhibitor of neutrophil serine proteases. Stimulation with hIL-17 in vitro did not increase MPO activity in isolated neutrophils., Conclusion: IL-17 can activate neutrophils in association with their recruitment into the airways in vivo and this effect is probably achieved through induced release of mediators from other airway cells.

Background: Expression of high-affinity IL-2 receptor (IL-2R) on T lymphocytes, key cells in chronic inflammation, is a T-cell activation marker., Objective: We sought to evaluate the effect of the fusion protein DAB389IL-2, which kills cells bearing IL-2R, on delayed-type hypersensitivity and antibody production in Brown Norway rats sensitized with trimellitic anhydride (TMA)., Methods: DAB389IL-2 (25 micrograms/kg/day) or placebo was administered intraperitoneally for 8 days over the period of sensitization, starting 2 days before sensitization., Results: The administration of DAB389IL-2 resulted in a one-third reduction in the number of IL-2R-bearing cells and significant weight loss of animals. Delayed-type hypersensitivity, evaluated at 5 weeks after sensitization, was significantly inhibited by treatment with DAB389IL-2. In contrast, production of IgE anti-TMA antibodies after sensitization was increased by treatment with DAB389IL-2. DAB389IL-2 affected neither IgG anti-TMA antibody nor total IgE levels., Conclusion: These data imply that systemic administration of DAB389IL-2 in Brown Norway rats influences cells that have regulatory effects on the immune system, resulting in a switch from a TH1 to a TH2 type of immune response.

Background: Recent in vitro findings show that glucocorticoids in combination with IL-4 can induce the synthesis of IgE, indicating that glucocorticoids may promote allergy., Objective: A double-blind, placebo-controlled study was performed to evaluate the effect of an intranasal glucocorticoid on the levels of birch pollen-specific IgE antibodies in serum from patients with allergic rhinitis., Methods: Eighteen patients with allergic rhinitis received treatment with an intranasal glucocorticoid (beclomethasone dipropionate, 400 microg/day) or placebo for 5 weeks, starting from the beginning of the birch pollen season. Blood samples for anti-birch IgE evaluation were taken before treatment was initiated and at 2 and 5 weeks after the beginning of the study., Results: The beclomethasone group (n = 9) had significantly lower symptom scores when compared with the placebo group (n = 9) (0.86 +/- 0.26 vs 2.79 +/- 0.76, p value = 0.01). Both the treatment group and the placebo group showed a trend of an increase in anti-birch IgE levels 2 weeks after the beginning of the treatment (from 33.1 +/- 13.1 kU/L to 44.9 +/- 20.9 kU/L in the beclomethasone group and from 53.2 +/- 18.9 kU/L to 64.1 +/- 22.1 kU/L in the placebo group). Treatment with beclomethasone returned anti-birch IgE levels to baseline by the end of the study, whereas in the placebo group the anti-birch IgE levels continued to increase (final values, 33.1 +/- 11.9 kU/L vs 72.6 +/- 23.2 kU/L, respectively). The change in IgE antibody levels in the placebo group was significantly higher than that in the beclomethasone group. No statistically significant changes in total IgE or soluble CD23 levels were detected., Conclusion: We conclude that treatment with an intranasal glucocorticoid initiated at the beginning of the pollen season inhibits the induced increase in specific IgE.

Background: Trimellitic anhydride (TMA) is a low molecular weight chemical that may cause occupational asthma in human beings. The objectives of this study were to determine the time course of immune and airway responses to TMA in guinea pigs and to relate the immunologic response to the immediate responses in lung resistance (RL) and plasma exudation induced by allergen challenge., Methods: We studied the effects of time course after sensitization on airway response to TMA in guinea pigs actively sensitized to free TMA, given by intradermal injection (0.1 ml of 0.3% TMA in corn oil). During weeks 1, 2, 3, 5, and 8 after sensitization, anesthetized animals were challenged with TMA conjugated to guinea pig serum albumin (TMA-GPSA), instilled via the airway route. Nonsensitized animals were challenged with the same amount of conjugate 4 weeks after intradermal injection of corn oil only. In the same animal, we measured both RL to monitor airflow obstruction and extravasation of Evans blue dye (20 mg/kg) to quantify airway plasma exudation., Results: Instillation of TMA-GPSA (0.5%; 50 microliters) into the tracheal lumen caused a significant increase in RL, reaching a maximum at 2.5 minutes after the instillation in the 1-week group (9.0 +/- 5.9 cm H2O/ml/sec) and between 5 and 6 minutes in the 2-, 3-, 5-, and 8-week groups (9.4 +/- 4.8, 12.7 +/- 5.5, 3.7 +/- 1.1, and 1.7 +/- 0.2 cm H2O/ml/sec, respectively). The maximal increase in RL after the challenge in nonsensitized animals was 0.39 +/- 0.05 cm H2O/ml/sec. TMA-GPSA also produced significant extravasation of Evans blue dye at all airway levels in the sensitized groups, and the amount of dye in the peripheral airways was significantly greater than that in the trachea. Furthermore, the level of Evans blue dye in airway tissue increased with the time after sensitization, up to the latest time point tested (8 weeks). Specific IgG1 antibodies to TMA-GPSA demonstrated by ELISA were detected in all animals in the 3-, 5-, and 8-week groups, with maximal levels 5 weeks after sensitization. Specific IgG1 titers to TMA-GPSA significantly correlated with the level of Evans blue dye induced by challenge with TMA-GPSA but not with the increase in RL., Conclusions: Intradermal sensitization to free TMA induces specific airway allergy for a long period after sensitization. Specific IgG1 antibodies to allergen may influence allergen-induced plasma exudation rather than the airflow obstruction in this animal model of TMA-induced asthma.

Bronchial responsiveness to inhaled acetylcholine (ACh) and inflammatory cell recruitment in bronchoalveolar lavage fluid (BALF) were studied in inbred Brown-Norway rats actively sensitized to, and later exposed to, ovalbumin (OA). We examined animals 21 days after initial sensitization at 18 to 24 hours, or 5 days after a single challenge, or after the last of seven repeated exposures administered every 3 days. BALF was examined as an index of inflammatory changes within the lung. Animals repeatedly exposed to OA aerosols had an increased baseline lung resistance and a significant increase in bronchial responsiveness to inhaled ACh compared to control animals at both 18 to 24 hours and 5 days after the last OA exposure. Sensitized animals receiving a single OA aerosol also demonstrated bronchial hyperresponsiveness (BHR) to inhaled ACh (p less than 0.01) at 18 to 24 hours of a similar order as the multiple-exposed group. There was a significant increase in eosinophils, lymphocytes, and neutrophils in BALF at 18 to 24 hours but not at 5 days after single or multiple exposure to OA aerosol in the sensitized groups. Control animals demonstrated no changes in bronchial responsiveness, although a small but significant increase in inflammatory cells was observed compared to saline-only treated animals. There was a significant correlation between bronchial responsiveness and eosinophil counts in the BALF in the single allergen-exposed group (Rs = 0.68; p less than 0.05). We conclude that (1) BHR after allergen exposure in sensitized rats is associated with the presence of pulmonary inflammation but persists despite the regression of inflammatory cells in BALF after multiple OA exposures, and (2) this rat model has many characteristics of human allergen-induced BHR.