Clinical and Translational Allergy - Latest Articles

Allergen-specific immunotherapy provides immediate, long-term and preventive clinical effects in children and adults: the effects of immunotherapy can be categorised by level of benefit -the centenary of allergen specific subcutaneous immunotherapy

Lars Jacobsen — 2012-04-13T00:00:00Z

Allergen Specific Immunotherapy (SIT) for respiratory allergic diseases is able to significantly improve symptoms as well as reduce the need for symptomatic medication, but SIT also has the capacity for long-term clinical effects and plays a protective role against the development of further allergies and symptoms. The treatment acts on basic immunological mechanisms, and has the potential to change the pathological allergic immune response. In this paper we discuss some of the most important achievements in the documentation of the benefits of immunotherapy, over the last 2 decades, which have marked a period of extensive research on the clinical effects and immunological background of the mechanisms involved. The outcome of immunotherapy is described as different levels of benefit from early reduction in symptoms over progressive clinical effects during treatment to long-term effects after discontinuation of the treatment and prevention of asthma. The efficacy of SIT increases the longer it is continued and immunological changes lead to potential long-term benefits. SIT alone and not the symptomatic treatment nor other avoidance measures has so far been documented as the therapy with long-term or preventive potential. The allergic condition is driven by a subset of T-helper lymphocytes (Th2), which are characterised by the production of cytokines like IL-4, and IL-5. Immunological changes following SIT lead to potential curative effects. One mechanism whereby immunotherapy suppresses the allergic response is through increased production of IgG4 antibodies. Induction of specific IgG4 is able to influence the allergic response in different ways and is related to immunological effector mechanisms, also responsible for the reduced late phase hyperreactivity and ongoing allergic inflammation. SIT is the only treatment which interferes with the basic pathophysiological mechanisms of the allergic disease, thereby creating the potential for changes in the long-term prognosis of respiratory allergy. SIT should not only be recognised as first-line therapeutic treatment for allergic rhinoconjunctivitis but also as secondary preventive treatment for respiratory allergic diseases.

Repeated allergen exposure reduce early phase airway response and leukotriene release despite upregulation of 5-lipoxygenase pathways

Zhi-Hua Cui — 2012-03-22T00:00:00Z

Background: Allergen induced early phase airway response and airway plasma exudation are predominantly mediated by inflammatory mast cell mediators including histamine, cysteinyl leukotrienes (cysLTs) and thromboxane A2 (TXA2). The aim of the present study was to evaluate whether repeated allergen exposure affects early phase airway response to allergen challenge. Methods: A trimellitic anhydride (TMA) sensitized guinea pig model was used to investigate the effects of low dose repeated allergen exposure on cholinergic airway responsiveness, early phase airway response and plasma exudation, as well as local airway production of mast cell derived cysteinyl leukotrienes and thromboxane B2 (TXB2) after allergen challenge. Results: Repeated low dose allergen exposure increased cholinergic airway responsiveness. In contrast, early phase airway response and plasma exudation in response to a high-dose allergen challenge were strongly attenuated after repeated low dose allergen exposure. Inhibition of the airway response was unspecific to exposed allergen and independent of histamine receptor blocking. Furthermore, a significant reduction of cysteinyl leukotrienes and TXB2 was found in the airways of animals repeatedly exposed to a low dose allergen. However, in vitro stimulation of airway tissue from animals repeatedly exposed to a low dose allergen with arachidonic acid and calcium ionophore (A23187) induced production of cysteinyl leukotrienes and TXB2, suggesting enhanced activity of 5-lipoxygenase and cyclooxygenase pathways. Conclusions: The inhibition of the early phase airway response, cysteinyl leukotriene and TXB2 production after repeated allergen exposure may result from unresponsive effector cells.

Retraction: Vitamin C and asthma in children: modification of the effect by age, exposure to dampness and the severity of asthma

Harri Hemila — 2012-03-16T00:00:00Z

We reported that the effect of vitamin C on asthma in Egyptian children was modified by age, exposure to dampness and the severity of asthma, Clinical & Translational Allergy 2011, 1:9. After our paper was published, we found out severe problems in the data set. There were 60 children in the study. The ages were by accident duplicated between the upper and lower halves of the database. Thus, the ages for the first 30 children in the data set were identical and in the same order with the ages for the second set of 30 children. Similar duplication was also found for C-ACT and FEV1 measurements after vitamin C supplementation and for exposure to dampness. This duplication thus directly invalidates the second part of the data set, and thus the reported outcome. We have not been able to sort out the reason for this duplication. The files with the original data are not available any more, making it impossible to reconstruct a valid data set for reanalysis. Therefore we have to retract our paper. The authors deeply regret the inconvenience this has caused to the journal and the scientific community.

FAST: Towards safe and effective subcutaneous immunotherapy of persistent life-threatening food allergies

Laurian Zuidmeer-Jongejan — 2012-03-09T00:00:00Z

The FAST project (Food Allergy Specific Immunotherapy) aims at the development of safe and effective treatment of food allergies, targeting prevalent, persistent and severe allergy to fish and peach. Classical allergen-specific immunotherapy (SIT), using subcutaneous injections with aqueous food extracts may be effective but has proven to be accompanied by too many anaphylactic side-effects. FAST aims to develop a safe alternative by replacing food extracts with hypoallergenic recombinant major allergens as the active ingredients of SIT. Both severe fish and peach allergy are caused by a single major allergen, parvalbumin (Cyp c 1) and lipid transfer protein (Pru p 3), respectively. Two approaches are being evaluated for achieving hypoallergenicity, i.e. site-directed mutagenesis and chemical modification. The most promising hypoallergens will be produced under GMP conditions. After pre-clinical testing (toxicology testing and efficacy in mouse models), SCIT with alum-absorbed hypoallergens will be evaluated in phase I/IIa and IIb randomized double-blind placebo-controlled (DBPC) clinical trials, with the DBPC food challenge as primary read-out. To understand the underlying immune mechanisms in depth serological and cellular immune analyses will be performed, allowing identification of novel biomarkers for monitoring treatment efficacy. FAST aims at improving the quality of life of food allergic patients by providing a safe and effective treatment that will significantly lower their threshold for fish or peach intake, thereby decreasing their anxiety and dependence on rescue medication.

Subtropical grass pollen allergens are important for allergic respiratory diseases in subtropical regions

Janet Davies — 2012-03-05T00:00:00Z

Background: Grass pollen allergens are a major cause of allergic respiratory disease but traditionally prescribing practice for grass pollen allergen-specific immunotherapy has favoured pollen extracts of temperate grasses. Here we aim to compare allergy to subtropical and temperate grass pollens in patients with allergic rhinitis from a subtropical region of Australia. Methods: Sensitization to pollen extracts of the subtropical Bahia grass (Paspalum notatum), Johnson grass (Sorghum halepense) and Bermuda grass (Cynodon dactylon) as well as the temperate Ryegrass (Lolium perenne) were measured by skin prick in 233 subjects from Brisbane. Grass pollen-specific IgE reactivity was tested by ELISA and cross-inhibition ELISA. Results: Patients with grass pollen allergy from a subtropical region showed higher skin prick diameters with subtropical Bahia grass and Bermuda grass pollens than with Johnson grass and Ryegrass pollens. IgE reactivity was higher with pollen of Bahia grass than Bermuda grass, Johnson grass and Ryegrass. Patients showed asymmetric cross-inhibition of IgE reactivity with subtropical grass pollens that was not blocked by temperate grass pollen allergens indicating the presence of species-specific IgE binding sites of subtropical grass pollen allergens that are not represented in temperate grass pollens. Conclusions: Subtropical grass pollens are more important allergen sources than temperate grass pollens for patients from a subtropical region. Targeting allergen-specific immunotherapy to subtropical grass pollen allergens in patients with allergic rhinitis in subtropical regions could improve treatment efficacy thereby reducing the burden of allergic rhinitis and asthma.

What factors affect the carriage of epinephrine auto-injectors by teenagers?

Clare Macadam — 2012-02-02T00:00:00Z

Background: Teenagers with allergies are at particular risk of severe and fatal reactions, but epinephrine auto-injectors are not always carried as prescribed. We investigated barriers to carriage. Methods: Patients aged 12-18 years old under a specialist allergy clinic, who had previously been prescribed an auto-injector were invited to participate. Semi-structured interviews explored the factors that positively or negatively impacted on carriage. Results: Twenty teenagers with food or venom allergies were interviewed. Only two patients had used their auto-injector in the community, although several had been treated for severe reactions in hospital. Most teenagers made complex risk assessments to determine whether to carry the auto-injector. Most but not all decisions were rational and were at least partially informed by knowledge. Factors affecting carriage included location, who else would be present, the attitudes of others and physical features of the auto-injector. Teenagers made frequent risk assessments when deciding whether to carry their auto-injectors, and generally wanted to remain safe. Their decisions were complex, multi-faceted and highly individualised. Conclusions: Rather than aiming for 100% carriage of auto-injectors, which remains an ambitious ideal, personalised education packages should aim to empower teenagers to make and act upon informed risk assessments.

Mechanisms of allergen-specific immunotherapy

Hiroyuki Fujita — 2012-01-05T00:00:00Z

Allergen-specific immunotherapy (allergen-SIT) is a potentially curative treatment approach in allergic diseases. It has been used for almost 100 years as a desensitizing therapy. The induction of peripheral T cell tolerance and promotion of the formation of regulatory T-cells are key mechanisms in allergen-SIT. Both FOXP3+CD4+CD25+ regulatory T (Treg) cells and inducible IL-10- and TGF-β-producing type 1 Treg (Tr1) cells may prevent the development of allergic diseases and play a role in successful allergen-SIT and healthy immune response via several mechanisms. The mechanisms of suppression of different pro-inflammatory cells, such as eosinophils, mast cells and basophils and the development of allergen tolerance also directly or indirectly involves Treg cells. Furthermore, the formation of non-inflammatory antibodies particularly IgG4 is induced by IL-10. Knowledge of these molecular basis is crucial in the understanding the regulation of immune responses and their possible therapeutic targets in allergic diseases.

Conventional epidemiology underestimates the incidence of asthma and wheeze - a longitudinal population-based study among teenagers

Linnea Hedman — 2012-01-04T00:00:00Z

Background: Because of shifts in the gender ratio and incidence and remission rates of asthma during the teen ages, the methodology of incidence studies among teenagers is important, i.e. if the time intervals between surveys are too long, the incident cases might not be properly identified. The aim was to study the impact of study design on the incidence rates of asthma and wheeze during the teen ages. Methods: In a study about asthma and allergic diseases within the OLIN studies (Obstructive Lung Disease in northern Sweden), a cohort of school children (n = 3,430) was followed annually by questionnaire from age 8 yrs. In the endpoint survey (age 18 yrs) 2,582 (75% of original responders) participated. Incident cases from age 12-18 yrs were identified by two methods: annual questionnaire reports (AR) and baseline-endpoint surveys only (BE). Results: The cumulative incidence of asthma and wheeze was significantly higher based on AR compared to BE. Compared to the incidence rates based on all the annual surveys, the calculated average annual rates based on BE were in general lower both among the boys and among the girls. There were no differences between boys and girls in incidence rates of asthma or wheeze during the early teen years. However, from the age of 15 years, the annual incidence rates were significantly or borderline significantly higher among girls than boys. At onset, the additional cases of current asthma identified by AR had significantly less severe asthma than those identified in BE (p < 0.02). Conclusion: the size of the incidence of asthma and wheeze during the teen ages was influenced by study design. By using the conventional prospective study design with longer follow-up time, the incidence was underestimated.

Difference in symptom severity between early and late grass pollen season in patients with seasonal allergic rhinitis

Letty de Weger — 2011-12-21T00:00:00Z

Background: For the development of forecasts for seasonal allergic rhinitis symptoms, it is essential to understand the relationship between grass pollen concentrations and the symptoms of grass pollen allergic patients.ObjectiveThe aim of this study was to delineate this relationship between seasonal allergic rhinitis symptoms and grass pollen concentrations in the Netherlands. Methods: Grass pollen allergic patients (n = 80 [2007] - 84 [2008]) were enrolled into the study. They were asked to enter their seasonal allergic rhinitis symptoms (runny nose, sneezing, blocked nose, post nasal drip, and eye symptoms) daily on a scale from 0 to 3 to the study centre either by short message service (SMS) or by internet from May-July 2007 and April-July 2008. Daily pollen counts were used to define the early and the late grass pollen season as the period 'before and during' respectively 'after' the first grass pollen peak (more than 150 pollen/m3). Results: At similar grass pollen concentrations, the daily mean of the individual maximum symptom scores reported in the early season were higher as compared to that reported in the late season [differences of -0.41 (2007) and -0.30 (2008)]. This difference could not be explained by medication use by the patients nor by co-sensitization to birch. Conclusions: We conclude that seasonal allergic rhinitis symptoms at similar grass pollen concentrations are more severe in the early flowering season as compared to those in the late flowering season. This finding is not only relevant for development of forecasts for seasonal allergic rhinitis symptoms but also for understanding symptom development and planning and analysis of clinical studies.

Quantification of atopy, lung function and airway hypersensitivity in adults

Susana Marinho — 2011-12-12T00:00:00Z

Background: Studies in children have shown that concentration of specific serum IgE (sIgE) and size of skin tests to inhalant allergens better predict wheezing and reduced lung function than the information on presence or absence of atopy. However, very few studies in adults have investigated the relationship of quantitative atopy with lung function and airway hyperresponsiveness (AHR).ObjectiveTo determine the association between lung function and AHR and quantitative atopy in a large sample of adults from the UK. Methods: FEV1 and FVC (% predicted) were measured using spirometry and airway responsiveness by methacholine challenge (5-breath dosimeter protocol) in 983 subjects (random sample of 800 parents of children enrolled in a population-based birth cohort enriched with 183 patients with physician-diagnosed asthma). Atopic status was assessed by skin prick tests (SPT) and measurement of sIgE (common inhalant allergens). We also measured indoor allergen exposure in subjects' homes. Results: Spirometry was completed by 792 subjects and 626 underwent methacholine challenge, with 100 (16.0%) having AHR (dose-response slope>25). Using sIgE as a continuous variable in a multiple linear regression analysis, we found that increasing levels of sIgE to mite, cat and dog were significantly associated with lower FEV1 (mite p = 0.001, cat p = 0.0001, dog p = 2.95 × 10-8). Similar findings were observed when using the size of wheal on skin testing as a continuous variable, with significantly poorer lung function with increasing skin test size (mite p = 8.23 × 10-8, cat p = 3.93 × 10-10, dog p = 3.03 × 10-15, grass p = 2.95 × 10-9). The association between quantitative atopy with lung function and AHR remained unchanged when we repeated the analyses amongst subjects defined as sensitised using standard definitions (sIgE>0.35 kUa/l, SPT-3 mm>negative control). Conclusions: In the studied population, lung function decreased and AHR increased with increasing sIgE levels or SPT wheal diameter to inhalant allergens, suggesting that atopy may not be a dichotomous outcome influencing lung function and AHR.