Search

Background: Most previous epidemiological studies on the relationship between allergy and bronchial hyperresponsiveness (BHR) have made no distinction between sensitization to indoor and outdoor allergens. We studied the relationship between specific sensitization to allergen and BHR and further assessed whether this was different in young adults and older subjects. Methods: Specific IgE to indoor allergens (house dust mite and cat) and outdoor allergens (timothy grass and birch) were measured using the CAP System. BHR was defined as PD20 less than or equal to 2 mg methacholine. Multiple logistic regression analysis was performed to study independent relationships between BHR and specific IgE to indoor and outdoor allergens in 1018 young adults (20-44 years) and 909 older subjects (45-70 years). Results: In the older age group specific IgE to indoor allergens was associated with BHR at a lower level (class 2) than in young adults (class greater than or equal to 3). Young adults with multiple sensitization had the highest risk of BHR. Subjects who were exclusively sensitized to pollen did not show increased BHR in both age groups. Total IgE had, independently of sensitization, only a significant dose-response relationship with BHR in the oldest age group. Conclusions: The association between sensitization and BHR is dependent on the nature of the allergen and the level of specific IgE. Furthermore, this study shows for the first time that total IgE is associated with BHR at older ages, independently of sensitization.

The Prevention and Incidence of Asthma and Mite Allergy (PIAMA) study is a birth cohort study that investigates the influence of allergen exposure on the development of allergy and asthma in the first several years of life. The objectives of this study were to investigate the relationship between a family history of allergy and/or asthma and exposure of newborn children to mite and pet allergen and to study the influence of different home and occupant characteristics on mite allergen exposure. Dust was sampled from the child's mattress and the parental mattress at 3 months after birth of the index child and analyzed for mite and pet allergens. Subjects were divided in groups according to history of asthma and allergy in their parents, and allergen exposure was studied in the different groups. Cat allergen exposure was significantly lower on parental mattresses in families with allergic mothers, but dog allergen exposure was not different. Mite allergen exposure was lower on parental mattresses in families with allergic mothers. Use of mite allergen-impermeable mattress covers reduced mite allergen exposure. Some other characteristics such as age of home and mattress were also found to influence mite allergen exposure. Parental mattresses in homes of allergic mothers had lower cat and mite (but not dog) allergen loadings than mattresses in homes of nonallergic parents. Paternal (as opposed to maternal) allergy seemed to have little influence.

The Prevention and Incidence of Asthma and Mite Allergy (PIAMA) study is a birth cohort study that investigates the influence of allergen exposure on the development of allergy and asthma in the first several years of life. The objectives of this study were to investigate the relationship between a family history of allergy and/or asthma and exposure of newborn children to mite and pet allergen and to study the influence of different home and occupant characteristics on mite allergen exposure. Dust was sampled from the child's mattress and the parental mattress at 3 months after birth of the index child and analyzed for mite and pet allergens. Subjects were divided in groups according to history of asthma and allergy in their parents, and allergen exposure was studied in the different groups. Cat allergen exposure was significantly lower on parental mattresses in families with allergic mothers, but dog allergen exposure was not different. Mite allergen exposure was lower on parental mattresses in families with allergic mothers. Use of mite allergen-impermeable mattress covers reduced mite allergen exposure. Some other characteristics such as age of home and mattress were also found to influence mite allergen exposure. Parental mattresses in homes of allergic mothers had lower cat and mite (but not dog) allergen loadings than mattresses in homes of nonallergic parents. Paternal (as opposed to maternal) allergy seemed to have little influence.

Background: House dust mite (HDM) allergen might induce and maintain atopic dermatitis (AD). Reduction of allergen load by applying encasings might improve the clinical symptoms of AD. Objective: We sought to investigate, in a randomized, double-blind, placebo-controlled study, whether reducing HDM allergen levels by using mattress, duvet, and pillow encasings for 12 months will result in improvement in AD symptoms. Methods: Patients with AD (8-50 years old and allergic to HDM), having a Leicester sign score (a dermatitis score) of at least 1% extent and a severity score of 6 points or greater, were randomly allocated to an active (n = 45) or a placebo allergen-avoidance group (n = 41). Avoidance measures consisted of applying HDM-impermeable encasings for mattresses, pillows, and duvets for the active treatment group and cotton encasings for the placebo group. Effect on allergen concentrations (Der p 1 and Der p 1 plus Der f 1), Leicester sign score extent and severity, visual analogue scale scores for itching and sleeplessness, intradermal test results, atopy patch test results, total serum IgE levels, anti-Der p 1-specific IgE levels, and total blood eosinophil counts were studied. Results: The active encasings reduced the Der p 1 allergen concentration in the mattress after 12 months with a factor 2.1 (P = .007) and the Der p 1 plus Der f 1 allergen concentration with a factor of 2.5 (P = .005); no significant change in allergen concentrations in mattresses was seen in the placebo group. Although the decrease in allergen load was significant, no differences in treatment-induced changes were seen between the placebo and active groups. Conclusions: Use of HDM-impermeable encasings resulted in a significant decrease in Der p 1 and Der p 1 plus Der f 1 allergen concentrations. However, this reduction in allergen load did not result in significant changes in clinical parameters between the groups. Reduction of allergens in other environments (work, school, and outdoors) might be equally important in improving symptoms of AD. (J Allergy Clin Immunol 2002;110:500-6.)

The Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort study was initiated in 1996. Children born to allergic mothers were enrolled in a double-blind placebo-controlled trial for evaluating the use of mite-impermeable mattress and pillow covers. Children born to allergic and non-allergic mothers were enrolled in a 'natural history' study to assess the role of environmental and dietary risk factors for the development of allergic disease in childhood. Recruitment started by distributing a validated screening questionnaire among >10,000 pregnant women during their first visit to a prenatal health clinic. Allergic mothers-to-be were invited to participate in the intervention study. Allergic, and a random sample of non-allergic, mothers-to-be were invited to participate in the 'natural history' arm of the study. In the intervention study, homes were visited before birth, 3 months after birth, and 12 months after birth for the collection of dust samples from floors and mattresses. In addition, the homes of about one-third of the children in the 'natural history' part of the study were visited for dust collection when the children were 3 months of age. The intervention study started with 855 participants and the 'natural history' study with 3,291 participants. Follow-up at 3 years of age has now been completed with satisfactory compliance (>90%,). A medical investigation and home visit at 4 years of age are nearing completion. Preliminary results show that mite-allergen levels were lower than found in previous Dutch studies, and that the intervention measure had a significant effect on mite-allergen levels, without important clinical benefits up to age 2 years old. The allergic families lived in homes with fewer 'triggers' such as pets, smoking and carpets than the non-allergic families, regardless of the intervention. The ongoing PIAMA cohort study will probably reveal useful information concerning effects of allergen load and reduction in the setting of a relatively low mite-allergen exposure, as well as other variables on the development of allergic manifestions and asthma.

The Prevention and Incidence of Asthma and Mite Allergy (PIAMA) study is a birth cohort study that investigates the influence of allergen exposure on the development of allergy and asthma in the first several years of life. The objectives of this study were to investigate the relationship between a family history of allergy and/or asthma and exposure of newborn children to mite and pet allergen and to study the influence of different home and occupant characteristics on mite allergen exposure. Dust was sampled from the child's mattress and the parental mattress at 3 months after birth of the index child and analyzed for mite and pet allergens. Subjects were divided in groups according to history of asthma and allergy in their parents, and allergen exposure was studied in the different groups. Cat allergen exposure was significantly lower on parental mattresses in families with allergic mothers, but dog allergen exposure was not different. Mite allergen exposure was lower on parental mattresses in families with allergic mothers. Use of mite allergen-impermeable mattress covers reduced mite allergen exposure. Some other characteristics such as age of home and mattress were also found to influence mite allergen exposure. Parental mattresses in homes of allergic mothers had lower cat and mite (but not dog) allergen loadings than mattresses in homes of nonallergic parents. Paternal (as opposed to maternal) allergy seemed to have little influence.

Mast cells, best known as effector cells in pathogenic immunoglobulin-mediated responses, can sense a variety of “danger” signals; if manipulated to enhance their resulting inflammatory responses, they also exacerbate inflammatory diseases such as arthritis and lung inflammation., Mast cells are implicated in the pathogenesis of inflammatory and autoimmune diseases. However, this notion based on studies in mast cell-deficient mice is controversial. We therefore established an in vivo model for hyperactive mast cells by specifically ablating the NF-κB negative feedback regulator A20. While A20 deficiency did not affect mast cell degranulation, it resulted in amplified pro-inflammatory responses downstream of IgE/FcεRI, TLRs, IL-1R, and IL-33R. As a consequence house dust mite- and IL-33-driven lung inflammation, late phase cutaneous anaphylaxis, and collagen-induced arthritis were aggravated, in contrast to experimental autoimmune encephalomyelitis and immediate anaphylaxis. Our results provide in vivo evidence that hyperactive mast cells can exacerbate inflammatory disorders and define diseases that might benefit from therapeutic intervention with mast cell function., Author Summary Mast cells mediate allergic and anaphylactic immune reactions. They are also equipped with innate pattern recognition, cytokine, and alarmin receptors, which induce inflammatory responses. Correlative studies in human patients hinted at roles for mast cells in autoimmune and inflammatory diseases. However, studies using mast cell-deficient mice have yielded contradictory results in this context. In this study we determined that A20, the negative feedback regulator, restricts inflammation downstream of the mast cell antigen (allergen) receptor module, innate pattern recognition receptors, and the alarmin receptor IL-33R. By mast cell–specific ablation of A20 we established a mouse model for exaggerated inflammatory but normal anaphylactic mast cell signaling. With these mice we evaluated the impact of increased mast cell-mediated inflammation under experimental conditions aimed at mimicking several inflammatory human diseases. Our results demonstrated that the lack of A20 from mast cells exacerbated disease in mouse models for rheumatoid arthritis and innate forms of asthma, but did not impact disease progression in a mouse model for multiple sclerosis. Our data provide direct evidence that enhanced inflammatory mast cell responses can contribute to disease pathology and do so via sensing and amplifying local inflammatory reactions driven by “danger” stimuli and/or tissue damage that leads to the release of alarmins.

to increasing production and accumulation of mois-ture in homes (frequent showers, new cookingmethods, inadequate airing of bedrooms, etc.).From 1981 to 2000, the Scientific Institute of PublicHealth sampled more than 500 home environments ofallergic and/or asthmatic patients in urban or ruralareas throughout Belgium. Results showed that morethan 150 fungal species, among them

Background: Proteases in extracts of Aspergillus fumigatus cause epithelial cell desquamation and release of proinflammatory cytokines. Objective: We sought to assess protease activity in Alternaria alternata , Cladosporium herbarum , and Aspergillus fumigatus extracts and study the ability of these extracts to cause desquamation and release of proinflammatory cytokines from epithelial cells. Methods: Protease activities of the fungal extracts were quantified. Changes with respect to cell morphology, cell desquamation, and cytokine production (IL-6 and IL-8) were measured in the absence and presence of the fungal extracts in an airway-derived epithelial cell line (A549) and primary epithelial nasal cells. Results: Fungal proteases differentially induced morphologic changes, cell desquamation, and production of IL-6 and IL-8 in a dose- and time-dependent fashion. Alternaria alternata extracts induced cell shrinking and cell desquamation and strongly enhanced the production of IL-6 and IL-8 at higher concentrations. Aspergillus fumigatus extracts caused cell shrinking, cell desquamation, and production of IL-6 and IL-8, even at low concentrations. The Aspergillus fumigatus –derived extract grown on collagen medium induced a strong dose-dependent decline in cytokine production at higher concentrations. Cladosporium herbarum extracts did not induce morphologic changes or cell desquamation but enhanced IL-6 and IL-8 productions at higher concentrations. The dependence of these effects on intact protease activity was shown by their abrogation by protease inhibitors. Conclusion: Proteases present in fungal extracts interact with epithelial cells, leading to morphologic changes, cell desquamation, and induction of proinflammatory cytokines. It is proposed that these fungal proteases may activate epithelial cells through a protease-activated receptor type 2–driven mechanism. (J Allergy Clin Immunol 2000;105:1185-93.)

Airway diseases, predominantly asthma and chronic obstructive pulmonary disease (COPD), are among the world's most prevalent diseases. The prevalence of asthma has been incasing over the past 20 yr in most countries where this has been studied, and it affects up to 10% of the populations of most developed countries. COPD is the sixth cause of death in the world and affects 4-6% of people more than 45 yr of age. In 1985, more than 5.4 million Americans were estimated to have COPD and COPD is the most rapidly rising cause of death among individuals over the age of 65 yr in the United States (1). These diseases constitute a major financial burden to society, wit both direct and indirect costs. Both asthma and COPD are identified by the presence of characteristic symptoms and functional abnormalities, with airway obstruction being the sine qua non of both diseases. The airway obstruction in asthma must be reversible to establish a diagnosis, whereas COPD is defined as a syndrome characterized by abnormal tests of expiratory flow that do not change markedly over periods of several months of observation (2). Both diseases are now known to be caused by lung inflammation induced by different initiating factors, most likely environmental allergens, occupational sensitizing agents, or viral respiratory infections in asthma and cigarette smoking in COPD. However, some patients wit asthma who do not smoke also develop irreversible airway obstruction similar to COPD. Also, the treatments used to manage both diseases resemble each other. This review compares and contrasts asthma and COPD wit regard to the following aspects: the risks for development, th functional and structural abnormalities,the inflammatory activity and the site of the inflammation, animal models of both diseases and current and potential new treatments for the diseases. The review was developed as a result of a workshop held in Whistler, Canada, involving clinical and basic scientists actively working in these two areas. It is hoped that by comparing the two diseases, new insights can be attained about each.

Airway diseases, predominantly asthma and chronic obstructive pulmonary disease (COPD), are among the world's most prevalent diseases. The prevalence of asthma has been incasing over the past 20 yr in most countries where this has been studied, and it affects up to 10% of the populations of most developed countries. COPD is the sixth cause of death in the world and affects 4-6% of people more than 45 yr of age. In 1985, more than 5.4 million Americans were estimated to have COPD and COPD is the most rapidly rising cause of death among individuals over the age of 65 yr in the United States (1). These diseases constitute a major financial burden to society, wit both direct and indirect costs.Both asthma and COPD are identified by the presence of characteristic symptoms and functional abnormalities, with airway obstruction being the sine qua non of both diseases. The airway obstruction in asthma must be reversible to establish a diagnosis, whereas COPD is defined as a syndrome characterized by abnormal tests of expiratory flow that do not change markedly over periods of several months of observation (2). Both diseases are now known to be caused by lung inflammation induced by different initiating factors, most likely environmental allergens, occupational sensitizing agents, or viral respiratory infections in asthma and cigarette smoking in COPD. However, some patients wit asthma who do not smoke also develop irreversible airway obstruction similar to COPD. Also, the treatments used to manage both diseases resemble each other.This review compares and contrasts asthma and COPD wit regard to the following aspects: the risks for development, th functional and structural abnormalities,the inflammatory activity and the site of the inflammation, animal models of both diseases and current and potential new treatments for the diseases. The review was developed as a result of a workshop held in Whistler, Canada, involving clinical and basic scientists actively working in these two areas. It is hoped that by comparing the two diseases, new insights can be attained about each.

Airway diseases, predominantly asthma and chronic obstructive pulmonary disease (COPD), are among the world's most prevalent diseases. The prevalence of asthma has been incasing over the past 20 yr in most countries where this has been studied, and it affects up to 10% of the populations of most developed countries. COPD is the sixth cause of death in the world and affects 4-6% of people more than 45 yr of age. In 1985, more than 5.4 million Americans were estimated to have COPD and COPD is the most rapidly rising cause of death among individuals over the age of 65 yr in the United States (1). These diseases constitute a major financial burden to society, wit both direct and indirect costs. Both asthma and COPD are identified by the presence of characteristic symptoms and functional abnormalities, with airway obstruction being the sine qua non of both diseases. The airway obstruction in asthma must be reversible to establish a diagnosis, whereas COPD is defined as a syndrome characterized by abnormal tests of expiratory flow that do not change markedly over periods of several months of observation (2). Both diseases are now known to be caused by lung inflammation induced by different initiating factors, most likely environmental allergens, occupational sensitizing agents, or viral respiratory infections in asthma and cigarette smoking in COPD. However, some patients wit asthma who do not smoke also develop irreversible airway obstruction similar to COPD. Also, the treatments used to manage both diseases resemble each other. This review compares and contrasts asthma and COPD wit regard to the following aspects: the risks for development, th functional and structural abnormalities,the inflammatory activity and the site of the inflammation, animal models of both diseases and current and potential new treatments for the diseases. The review was developed as a result of a workshop held in Whistler, Canada, involving clinical and basic scientists actively working in these two areas. It is hoped that by comparing the two diseases, new insights can be attained about each.

The prevalence of sensitization to the storage mites Acarus sire (AS), Tyrophagus putrescentiae (TP), and Lepidoglyphus destructor (LD) was studied in 250 sera of patients with different degrees of sensitization to the house-dust mite Dermatophagoides pteronyssinus (DP) by measuring IgE binding to extracts of the storage mites. Additionally, allergenic crossreactivity between DP and the storage mite species was studied by RAST inhibition with five individual sera (and a pool of these sera) with moderate IgE levels to all three storage mites and to DP. Increased serum IgE to storage mites was found in 46% of the 200 patients sensitized to DP. Increased prevalence rates of IgE titers to storage mites were associated with higher IgE levels to DP. In 50 sera without sensitization to DP, only five sera showed increased IgE to one of the storage mites. Extracts of TP almost completely inhibited the IgE binding to AS, and vice versa. DP inhibited IgE binding to all storage mites up to 60%, whereas IgE binding to DP was only minimally inhibited by extracts of storage mites, In conclusion, cosensitization to storage mites is a frequent finding in patients sensitized to DP Although this is largely the result of cross-reactivity between different mite species, it may nevertheless be of clinical significance in patients exposed to storage mites.

The prevalence of sensitization to the storage mites Acarus siro (AS), Tyrophagus putrescentiae (TP), and Lepidoglyphus destructor (LD) was studied in 250 sera of patients with different degrees of sensitization to the house-dust mite Dermatophagoides pteronyssinus (DP) by measuring IgE binding to extracts of the storage mites. Additionally, allergenic cross-reactivity between DP and the storage mite species was studied by RAST inhibition with five individual sera (and a pool of these sera) with moderate IgE levels to all three storage mites and to DP. Increased serum IgE to storage mites was found in 46% of the 200 patients sensitized to DP. Increased prevalence rates of IgE titers to storage mites were associated with higher IgE levels to DP. In 50 sera without sensitization to DP, only five sera showed increased IgE to one of the storage mites. Extracts of TP almost completely inhibited the IgE binding to AS, and vice versa. DP inhibited IgE binding to all storage mites up to 60%, whereas IgE binding to DP was only minimally inhibited by extracts of storage mites. In conclusion, cosensitization to storage mites is a frequent finding in patients sensitized to DP. Although this is largely the result of cross-reactivity between different mite species, it may nevertheless be of clinical significance in patients exposed to storage mites.

Background Dysfunction of the beta-adrenoceptor (beta AR)/adenylyl cyclase (AC) system can impair the response of different cell types, including lymphocytes. In asthma, impairment of this system as well as changes in cytokine production by lymphocytes have been described. Because the severity of asthma can change over the year, a circannual pattern of the beta AR/AC system activity may also exist.Objectives We set out to examine the activity of this beta AR/AC signal transduction system in peripheral blood mononuclear cells (PBMCs) of allergic asthmatics to asses whether differences existed between seasons. We investigated whether changes were associated with asthma severity and circannual changes in serum cortisol levels.Methods During 19 months, 41 allergic asthmatics (mean age 28 years) with nocturnal airway obstruction were enrolled in the study. AC activity was measured by cyclic AMP production. Resting, stimulated and potentiated AC activities and their relationships with clinical parameters, seasonal influences and serum cortisol levels were assessed.Results The AC activity in resting, stimulated and potentiated cells varied during the year. AC activity was relatively low in the periods June-August and September-November, and higher in December-February and March-May. Receptor-mediated and potentiated responses expressed as percentage of the resting response were equivalent throughout the year. Serum cortisol levels were positively related to AC activity. No relationships were found between clinical parameters and AC activity or serum cortisol levels.Conclusions These results indicate that AC activity in PBMCs of allergic asthmatics shows a seasonal variation. However, seasonal differences in AC activity seems to be unrelated with clinical parameters. Other factors such as serum cortisol levels may have a modulating influence on AC activity. Future studies of AC systems in blood cells of asthmatic patients need to take into account these seasonal influences.

The pathogenetic role of house-dust mites (HDM) in atopic dermatitis (AD) remains controversial, mainly because there is no common agreement on a provocation test that mimics ordinary exposure to HDM. This is related to the lack of knowledge of the mechanism of how HDM allergens enter the body. Theoretically, there are two possible routes: directly through the epidermis, or by inhalation. In "atopy patch testing", a concentrated HDM suspension is tested on the skin under occlusion. This method is frequently used as a model of the epidermal route. The clinical relevance of this method as a provocation test for AD is discussed. As opposed to atopy patch testing, we describe another method, namely, "allergen inhalation testing", as a model of the respiratory route. Twenty patients with AD underwent bronchial provocations with HDM extract in a double-blind, randomized, placebo-controlled study. In nine out of 20 AD patients, bronchial challenge with HDM evoked skin symptoms. All patients with HDM-induced dermatitis had a history of asthma, and as a group they had a higher mean total log-transformed IgE level than the "negative skin responders". Thus, the respiratory route may be relevant in the provocation of AD in a subset of AD patients and may represent an appropriate model of provocation in these patients. Furthermore, the role of HDM in urticaria and allergic rhinitis is discussed.

Polarization of the immune response towards T(h)1 or T(h)2 profiles is under the control of several, not yet well known, mechanisms. The present study was undertaken to investigate whether immune responses generated against major protein antigens, of parasitic (Schistosoma mansoni) and bacterial (Clostridium tetani) origin, present characteristic T-h profiles. Mice were immunized with a single dose of S. mansoni 28 kDa glutathione-S-transferase (Sm28-GST) or tetanus toxin fragment c (TTc) in combination with different adjuvants, or Salmonella typhimurium expressing these antigens as a fusion protein. Antigen-specific IgG isotypes and cytokine mRNA expression in vivo, as well as cytokine secretion after in vitro antigen stimulation were studied. Immunizations with either protein in aluminum hydroxide induced a strong T(h)2-associated antibody (IgG1) and cytokine (IL-4) response. In contrast, the recombinant S. typhimurium, expressing the TTc/Sm28-GST fusion protein, induced a T(h)1-like response, associated with the production of IFN gamma- and IgG2a antibodies against both antigens. When complete Freund's adjuvant was used, a non-polarized profile was observed, characterized by expression of both IL-4 and IFN-gamma as well as strong specific IgG1 and IgG2a antibody responses. These results indicated that some protein antigens play a weak role in polarizing the immune response and that contrasting cytokine profiles could be induced against the same antigen, depending on the adjuvant employed. Int Immunol

BACKGROUND: No longitudinal studies exist on the natural history of food hypersensitivity and IgE sensitisation to food allergens in adults. OBJECTIVE: To examine the natural history of food hypersensitivity, the natural history of IgE sensitisation to food allergens and to investigate the risk factors for new onset food hypersensitivity. METHODS: Food hypersensitivity was questionnaire-assessed in 2307 individuals (aged 20-45 years) from Iceland and Sweden during the European Community Respiratory Health Survey both at baseline and follow-up 9 years later. IgE food and aeroallergen sensitisation were assessed in a subgroup of these individuals (n = 807). Values of 0.35 kU/L and above were regarded as positive sensitisation. RESULTS: Food hypersensitivity was reported by 21% of the subjects and this proportion remained unchanged at follow-up (p = 0.58). Fruits, nuts and vegetables were the three most common causes of food hypersensitivity, with a similar prevalence at baseline and follow-up. The prevalence IgE sensitisation to food allergens decreased in general by 56% (pDe sista två förtfattarna delar sista författarskapet.

Allergic asthma is characterized by bronchial hyperresponsiveness, a defective barrier function, and eosinophilic lower airway inflammation in response to allergens. The inflammation is dominated by Th2 cells and IgE molecules and supplemented with Th17 cells in severe asthma. In contrast, in healthy individuals, allergen-specific IgA and IgG4 molecules are found but no IgE, and their T cells fail to proliferate in response to allergens, probably because of the development of regulatory processes that actively suppress responses to allergens. The presence of allergen-specific secretory IgA has drawn little attention so far, although a few epidemiological studies point at a reverse association between IgA levels and the incidence of allergic airway disease. This review highlights the latest literature on the role of mucosal IgA in protection against allergic airway disease, the mechanisms described to induce secretory IgA, and the role of (mucosal) dendritic cells in this process. Finally, we discuss how this information can be used to translate into the development of new therapies for allergic diseases based on, or supplemented with, IgA boosting strategies.

Allergic disease is renected in a chronic inflammatory response to an allergen. It is thought that local allergen priming underlies this chronicity. To assess the effect of allergen priming on the amplitude and histologic effect of the allergic reaction, four sequential, intracutaneous skin tests were done with 48-h intervals in 13 patients allergic to the house-dust mite Dermatophagoides pteronyssinus (Dpt). Reactions were measured at 15 min, and at 6, 24, and 48 h. Subsequently, epicutaneous tests were done on Dpt-primed spots (n=5). At 6, 24, and 48 h, reactions increased after priming (P

Twenty-three Dermatophagoides pteronyssinus (Dpt)-sensitive asthmatic children aged 7-14 years entered a double-blind, placebo-controlled trial of standardized immunotherapy (IT) (Alpare) while resident at high altitude. Dpt sensitivity was evaluated by skin prick tests at different allergen concentrations at the enrollment and after 6 and 12 months of treatment. Bronchial hyperreactivity was evaluated at the same time points, and on each occasion, histamine challenge and, the following day, Dpt bronchial challenge were performed. All patients, irrespective of active treatment, improved clinically and in lung function with increased PC20 and Dpt-PD20. Alpare-treated patients had a significantly decreased sensitivity on Dpt skin testing (P < 0.009) and felt that their asthma had improved (P < 0.001) compared with placebo-treated subjects, but there was no difference between the treatment groups in lung function or bronchial challenge response. IT neither increased nor decreased bronchial histamine sensitivity. Our results indicate that Dpt IT benefits asthmatic children, but improvement by allergen avoidance at high altitude is even greater.

Asthma is a chronic obstructive airway disease characterised by airway hyperresponsiveness (AHR) and airway wall remodelling. The effector of airway narrowing is the contraction of airway smooth muscle (ASM), yet the question of whether an inherent or acquired dysfunction in ASM contractile function plays a significant role in the disease pathophysiology remains contentious.The difficulty in determining the role of ASM lies in limitations with the models used to assess contraction. In vivo models provide a fully integrated physiological response but ASM contraction cannot be directly measured. Ex vivo and in vitro models can provide more direct assessment of ASM contraction but the loss of factors that may modulate ASM responsiveness and AHR, including interaction between multiple cell types and disruption of the mechanical environment, precludes a complete understanding of the disease process.In this review we detail key advantages of common in vivo, ex vivo and in vitro models of ASM contraction, as well as emerging tissue engineered models of ASM and whole airways. We also highlight important findings from each model with respect to the pathophysiology of asthma. (C) 2012 Elsevier Ltd. All rights reserved.

Background: Exposure to high levels of house dust mite (HDM) allergens is associated with the development of allergic sensitization to HDM, a risk factor for the development of asthma, rhinitis, and allergic dermatitis. We studied the effect of an early intervention with mite-impermeable mattress covers on HDM allergen levels and the development of asthma and mite allergy throughout the first 8 years of life. Methods: High-risk children (allergic mother) were prenatally recruited and randomly allocated to two groups receiving mite allergen–impermeable (n = 416) and placebo mattress covers (n = 394) or no intervention (n = 472). Asthma and allergies were assessed yearly by questionnaire. Specific immunoglobulin E and bronchial hyper-responsiveness were measured at the age of 8 years. Mattress dust samples collected at different time points were analyzed for HDM allergens. Results: At the age of 8 years, levels of HDM allergen Der f1 but not Der p1 were lower in the active than the placebo mattress cover group. In repeated measures analyses, we found a temporary decreased risk of asthma symptoms at the age of 2 years in the intervention group compared to the placebo group and a temporary association between higher HDM allergen exposure at the age of 3 months and more asthma symptoms. Conclusion: Early intervention with mite-impermeable mattress covers is successful in reducing exposure to Der f1; it only temporarily reduces the risk of asthma symptoms and does not reduce the risk of hay fever, eczema, and allergic sensitization.

Allergic asthma is a disease characterized by persistent allergen-driven airway inflammation, remodeling, and airway hyperresponsiveness. CD4(+) T-cells, especially T-helper type 2 cells, play a critical role in orchestrating the disease process through the release of the cytokines IL-4, IL-5, and IL-13. Allergen-specific immunotherapy (SIT) is currently the only treatment with a long-term effect via modifying the natural course of allergy by interfering with the underlying immunological mechanisms. However, although SIT is effective in allergic rhinitis and insect venom allergy, in allergic asthma it seldom results in complete alleviation of the symptoms. Improvement of SIT is needed to enhance its efficacy in asthmatic patients. Herein, the immunoregulatory mechanisms underlying the beneficial effects of SIT are discussed with the ultimate aim to improve its treatment efficacy.

Background: Only a few studies have analyzed the value of early sensitization in predicting the development of atopic disease. The relevance of low immunoglobulin (Ig) E antibody levels in this respect also remains unclear. Objective: To investigate the relevance of sensitization in 12-month-old children in the development of atopic disease by the age of 6 years. Methods: We analyzed data for 1290 children with a positive family history of atopy from the prospective, multicenter German Infant Nutritional Intervention (GINIplus) study and investigated the relationship between the presence of detectable specific IgE antibodies at the age of 12 months and the development of atopic disease by the age of 6 years. Results: In all, 10.9% of children analyzed developed sensitization. At the age of 6 years, 20.6% of children with early sensitization had eczema compared to 9.4% of those without (odds ratio [OR], 2.31; 95% confidence interval [CI), 1.42-3.74). The corresponding figures were 15.4% vs 7.3% for allergic rhinitis (OR, 2.22; CI, 1.31-3.78) and 10.2% vs 2.6% (OR, 3.93; 95% Cl, 1.98-7.76) for asthma. Children with early sensitization to aeroallergens had the greatest risk of subsequent atopic disease. Early sensitization did not increase risk in children without eczema within the first year of life. Very low specific IgE levels (0.18-0.34 kU/L) were not significantly associated with any of the outcomes analyzed. Conclusion: Sensitization to common food allergens and to aeroallergens in particular during the first year of life was found to be a strong predictor for the development of atopic disease by the age of 6 years in children with a positive family history of atopy.

Background: Sustained and disease-modifying effects of sublingual immunotherapy have never before been confirmed in a large-scale randomized, double-blind, placebo-controlled trial.Objective: We sought to investigate sustained efficacy I year after a 3-year period of daily treatment with the SQ-standardized grass allergy immunotherapy tablet Grazax (Phleum pratense 75,000 SQ-T/2,800 BAU; ALK-Abello, Horsholm, Denmark).Methods: A randomized, double-blind, placebo-controlled, phase III trial including adults with a history of moderate-to-severe grass pollen induced rhinoconjunctivitis inadequately controlled by symptomatic medications. The analysis set comprised 257 subjects at the follow-up. Efficacy end points were rhinoconjunctivitis symptom and medication scores, quality of life, and percentages of symptom and medication free days. Immunologic end points included grass pollen-specific serum IgG4 and IgE-blocking factor. Safety was assessed based on adverse events.Results: Significant improvements in efficacy were consistently shown during 3 years' treatment. One year after treatment, the active group showed sustained reductions in mean rhinoconjunctivitis symptom scores (26%, P Conclusion: Three years of treatment with the SQ-standardized grass allergy immunotherapy tablet resulted in consistent clinical improvement and accompanying immunologic changes that were sustained I year after treatment, which is indicative of disease modification and associated long-term benefits. (J Allergy Clin Immunol 2010;125:131-38.)

The aim of this study was to determine the relationship between the house-dust mite allergy and prevalence of house-dust mites in dwellings of children who were tested for specific IgE against Dermatophagoides pteronyssinus (D. pteronyssinus) and D. farinae on the suspicion of allergic rhinitis, dermatitis and asthma. All dust specimens collected from children's houses were investigated under a light microscope. House-dust mites were found in 31.7% of houses of children with a specific IgE, while the rate was 27.5% in houses of those without a specific IgE. Overall, house dust specimens collected from a total of 92 houses were examined, and mites were found in 27 (29.3%) of them. Both Der p and Der f were found in 38 (92.7%), while mixed allergy (D. pteronyssinus + D. farinae) was found in 3 (7.3%). Der p allergy (100%) was found in all of the allergic children, while no child was found with specific IgE for Der f allergy, except in mixed allergies.

Background Adherence is essential for effective treatment. Although several trials on the efficacy of sublingual immunotherapy (SLIT) in youngsters have been published, few contain data on medication intake. Objective We aimed to quantify adherence both to study protocol and medication intake as well as to identify factors that may influence adherence to SLIT in youngsters with rhinoconjunctivitis. Methods Two hundred and four youngsters (6-18 years) with hayfever participated in a randomized controlled trial and used grass pollen extract or placebo for 2 years. The primary Outcome of the trial was the mean daily total rhinoconjunctivitis symptom score in the second grass pollen season. Participants having completed the follow-up were considered adherent to the study protocol. Adherence to medication intake was assessed by weighing the study medication. Participants who completed the follow-up and used >= 80% of the prescribed medication were considered adherent to medication intake. Patient-, disease- and treatment-related factors were analysed. Results One hundred and fifty-four youngsters completed the study. The main reason for discontinuation was the inability to take medication according to schedule. Drop-outs were older, had more difficulty following the medication instructions and their overall evaluation of the treatment effect was lower. The number and reasons for drop-out did not differ between treatment groups. In total, 77% of the participants was adherent to medication intake. Self-reported adherence was 99%. Non-adherent participants experienced more severe symptoms before the trial. Symptom scores did not differ between adherent and non-adherent participants. In adherent as well as non-adherent participants, no difference was found between verum and placebo group with respect to symptom scores. Conclusion Adherence to both study protocol and medication intake was good. Drop-out was affected by age, evaluation of the treatment effect and medication instructions. Nonadherence to medication intake was influenced by the severity of the disease before the trial. The ineffectiveness of SLIT could not be explained by non-adherence.

Background Sublingual immunotherapy (SLIT) is considered safer and more convenient than subcutaneous therapy and therefore has been proposed as especially suitable for children and in primary care. Most efficacy studies in children lack power to be conclusive, and all have been performed in referral centers. Objective To investigate the efficacy of SLIT with grass pollen allergen in children and adolescents with rhinoconjunctivitis in a primary care setting. Methods Youngsters aged 6-18 years with hay fever were enrolled from general practices and randomly assigned to receive placebo or grass pollen mix for 2 years. The primary outcome was the mean daily total symptom score (scale 0-15) comprising sneezing, itching nose, watery running nose, nasal blockage, and itching eyes during the months May-August of the second treatment year. Results Out of 204 youngsters randomized, 168 entered the intention-to-treat analysis (91 verum, 77 placebo). The mean daily total symptom score did not differ between participants allocated to verum and those allocated to placebo (difference for verum minus placebo: −0.08, 95%CI, −0.66-0.50; P = .78). No differences were found for rescue medication–free days, disease-specific quality of life, and overall evaluation of the treatment effect. Local side effects were more frequent in the verum group (39% vs 17% of participants; P = .001). Conclusion Sublingual immunotherapy with grass pollen in a primary care setting is not effective in children and adolescents. Clinical implications Currently, SLIT cannot be recommended for general practitioners as a therapeutic modality in youngsters with grass pollen allergy.

To examine the relationship and confounding factors of sensitization to house-dust mites with nonspecific bronchial reactivity (NBR) in nonasthmatic asymptomatic subjects. Retrospective study (2001-2003) included all subjects that underwent medical history, physical examination, spirometry, nonspecific bronchoprovocation, skin prick test to Dermatophagoides pteronyssinus (DP) and measurements of total and specific IgE. There were 234 (114 women ; 146 smokers) subjects included into analysis. The mean (SD) age of the subjects was 29.4 (6.4) years. None of them had asthma. All subjects had lung function parameters inside normal range. 69 subjects (29.5%) had clinically relevant positive skin prick test (≥ 3 mm). The number of subjects who had specific IgE to DP>0 kU/L was 98 (41.9%). When two subgroups (specific IgE 0 or >0 kU/L) were compared, the second one had all lung function parameters significantly lower with NBR significantly higher (P

Background: Most previous epidemiological studies on the relationship between allergy and bronchial hyperresponsiveness (BHR) have made no distinction between sensitization to indoor and outdoor allergens. We studied the relationship between specific sensitization to allergen and BHR and further assessed whether this was different in young adults and older subjects. Methods: Specific IgE to indoor allergens (house dust mite and cat) and outdoor allergens (timothy grass and birch) were measured using the CAP System. BHR was defined as PD20 less than or equal to 2 mg methacholine. Multiple logistic regression analysis was performed to study independent relationships between BHR and specific IgE to indoor and outdoor allergens in 1018 young adults (20-44 years) and 909 older subjects (45-70 years). Results: In the older age group specific IgE to indoor allergens was associated with BHR at a lower level (class 2) than in young adults (class greater than or equal to 3). Young adults with multiple sensitization had the highest risk of BHR. Subjects who were exclusively sensitized to pollen did not show increased BHR in both age groups. Total IgE had, independently of sensitization, only a significant dose-response relationship with BHR in the oldest age group. Conclusions: The association between sensitization and BHR is dependent on the nature of the allergen and the level of specific IgE. Furthermore, this study shows for the first time that total IgE is associated with BHR at older ages, independently of sensitization.

The allergen bronchoprovocation test is a long-standing exacerbation model of allergic asthma that can induce several clinical and pathophysiologic features of asthma in sensitized subjects. Standardized allergen challenge is primarily a research tool, and when properly conducted by qualified and experienced investigators, it is safe and highly reproducible. In combination with validated airway sampling and sensitive detection techniques, allergen challenge allows the study of several features of the physiology of mainly T(H)2 cell-driven asthma in relation to the kinetics of the underlying airway pathology occurring during the allergen-induced late response. Furthermore, given the small within-subject variability in allergen-induced airway responses, allergen challenge offers an adequate disease model for the evaluation of new (targeted) controller therapies for asthma in a limited number of subjects. In proof-of-efficacy studies thus far, allergen challenge showed a fair positive predicted value and an excellent negative predictive value for the actual clinical efficacy of new antiasthma therapies, underscoring its important role in early drug development. In this review we provide recommendations on challenge methods, response measurements, sample size, safety, and harmonization for future applications.

Background Dysfunction of the β-adrenoceptor (βAR)/adenylyl cyclase (AC) system can impair the response of different cell types, including lymphocytes. In asthma, impairment of this system as well as changes in cytokine production by lymphocytes have been described. Because the severity of asthma can change over the year, a circannual pattern of the βAR/AC system activity may also exist. Objectives We set out to examine the activity of this βAR/AC signal transduction system in peripheral blood mononuclear cells (PBMCs) of allergic asthmatics to asses whether differences existed between seasons. We investigated whether changes were associated with asthma severity and circannual changes in serum cortisol levels. Methods During 19 months, 41 allergic asthmatics (mean age 28 years) with nocturnal airway obstruction were enrolled in the study. AC activity was measured by cyclic AMP production. Resting, stimulated and potentiated AC activities and their relationships with clinical parameters, seasonal influences and serum cortisol levels were assessed. Results The AC activity in resting, stimulated and potentiated cells varied during the year. AC activity was relatively low in the periods June–August and September–November, and higher in December–February and March–May. Receptor-mediated and potentiated responses expressed as percentage of the resting response were equivalent throughout the year. Serum cortisol levels were positively related to AC activity. No relationships were found between clinical parameters and AC activity or serum cortisol levels. Conclusions These results indicate that AC activity in PBMCs of allergic asthmatics shows a seasonal variation. However, seasonal differences in AC activity seems to be unrelated with clinical parameters. Other factors such as serum cortisol levels may have a modulating influence on AC activity. Future studies of AC systems in blood cells of asthmatic patients need to take into account these seasonal influences.

The pathogenetic role of house-dust mites (HDM) in atopic dermatitis (AD) remains controversial, mainly because there is no common agreement on a provocation test that mimics ordinary exposure to HDM. This is related to the lack of knowledge of the mechanism of how HDM allergens enter the body. Theoretically, there are two possible routes: directly through the epidermis, or by inhalation. In "atopy patch testing", a concentrated HDM suspension is tested on the skin under occlusion. This method is frequently used as a model of the epidermal route. The clinical relevance of this method as a provocation test for AD is discussed. As opposed to atopy patch testing, we describe another method, namely, "allergen inhalation testing", as a model of the respiratory route. Twenty patients with AD underwent bronchial provocations with HDM extract in a double-blind, randomized, placebo-controlled study. In nine out of 20 AD patients, bronchial challenge with HDM evoked skin symptoms. All patients with HDM-induced dermatitis had a history of asthma, and as a group they had a higher mean total log-transformed IgE level than the "negative skin responders". Thus, the respiratory route may be relevant in the provocation of AD in a subset of AD patients and may represent an appropriate model of provocation in these patients. Furthermore, the role of HDM in urticaria and allergic rhinitis is discussed.

Allergic disease is reflected in a chronic inflammatory response to an allergen. It is thought that local allergen priming underlies this chronicity. To assess the effect of allergen priming on the amplitude and histologic effect of the allergic reaction, four sequential, intracutaneous skin tests were done with 48-h intervals in 13 patients allergic to the house-dust mite Dermatophagoides pteronyssinus (Dpt). Reactions were measured at 15 min, and at 6, 24, and 48 h. Subsequently, epicutaneous tests were done on Dpt-primed spots (n = 5). At 6, 24, and 48 h, reactions increased after priming (P < 0.006), with unaltered early reactions. Epicutaneous reactions to Dpt on primed spots were larger than in epicutaneous controls on similarly primed skin. Local intradermal priming results in greater inflammatory responses at both intra- and epicutaneous challenge. This mechanism may explain the chronicity of allergic reactions at epithelial surfaces

The Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort study was initiated in 1996. Children born to allergic mothers were enrolled in a double-blind placebo-controlled trial for evaluating the use of mite-impermeable mattress and pillow covers. Children born to allergic and non-allergic mothers were enrolled in a 'natural history' study to assess the role of environmental and dietary risk factors for the development of allergic disease in childhood. Recruitment started by distributing a validated screening questionnaire among >10,000 pregnant women during their first visit to a prenatal health clinic. Allergic mothers-to-be were invited to participate in the intervention study. Allergic, and a random sample of non-allergic, mothers-to-be were invited to participate in the 'natural history' arm of the study. In the intervention study, homes were visited before birth, 3 months after birth, and 12 months after birth for the collection of dust samples from floors and mattresses. In addition, the homes of about one-third of the children in the 'natural history' part of the study were visited for dust collection when the children were 3 months of age. The intervention study started with 855 participants and the 'natural history' study with 3,291 participants. Follow-up at 3 years of age has now been completed with satisfactory compliance (>90%,). A medical investigation and home visit at 4 years of age are nearing completion. Preliminary results show that mite-allergen levels were lower than found in previous Dutch studies, and that the intervention measure had a significant effect on mite-allergen levels, without important clinical benefits up to age 2 years old. The allergic families lived in homes with fewer 'triggers' such as pets, smoking and carpets than the non-allergic families, regardless of the intervention. The ongoing PIAMA cohort study will probably reveal useful information concerning effects of allergen load and reduction in the setting of a relatively low mite-allergen exposure, as well as other variables on the development of allergic manifestions and asthma.