Showing papers in "Allergy in 2004"

The global burden of asthma: executive summary of the GINA Dissemination Committee Report

Abstract: It is estimated that as many as 300 million people of all ages, and all ethnic backgrounds, suffer from asthma and the burden of this disease to governments, health care systems, families, and patients is increasing worldwide. In 1989 the Global Initiative for Asthma (GINA) program was initiated in an effort to raise awareness among public health and government officials, health care workers, and the general public that asthma was on the increase. The GINA program recommends a management program based on the best available scientific evidence to provide effective medical care for asthma tailored to local health care systems and resources. Working in continued collaboration with leaders in asthma care from many countries, GINA sponsors World Asthma Day (first Tuesday in May) which has been extremely successful. A vast number of people have made a commitment to bring awareness about the burden of asthma to their local health care officials, and to implement programs of effective asthma care. Beginning in 2003, the theme of World Asthma Day has been the ‘‘Global Burden of Asthma.’’ GINA commissioned Professor Richard Beasley, Wellington, New Zealand (member, GINA Dissemination Committee) to provide available data on the burden of asthma. A summary of this report is provided in this publication; the full document with data sets for 20 different regions worldwide may be obtained from the GINA website (http://www.ginasthma.com). Professor Beasley and his colleagues obtained data on the burden of asthma from literature primarily published through the International StudyofAsthmaandAllergies in Childhood (ISAAC) and the European Community Respiratory Health Survey (ECHRS). Methodologies differ in these studies, and epidemiological data on asthma are very difficult to collect, as Professor Beasley carefully describes in his segment on ‘‘Methodological Issues.’’ Nonetheless, the full report provides a wealth of information, along with a large number of scientific references. The study regions have been grouped according to geographical, political, historical, and racial considerations based on official data from WHO, the United Nations (UN), and other sources, and to some extent, the availability of asthma epidemiological data within the study region. Using the United Nations World Population Prospect Population Database (http://esa.un.org/unpp) as a source within each region, all countries were included, and in some cases territories and dependencies if specific asthma epidemiological data were available. For simplicity some data from small territories have been omitted or lumped in a larger sub-regional unit. The report will be updated as new information becomes available and following feedback from individual countries and regions. The GINA Executive Committee is indebted to Professor Beasley and his colleagues for providing this report that will be an invaluable source of information for those who wish to explore available data on the burden of asthma by region. It will be extremely useful to develop background materials for World Asthma Day activities in 2004 and well into the future. Matthew Masoli, Denise Fabian, Shaun Holt, Richard Beasley for the Global Initiative for Asthma (GINA) Program

Standardization of food challenges in patients with immediate reactions to foods--position paper from the European Academy of Allergology and Clinical Immunology.

Abstract: At present, the double blind placebo controlled foodchallenge(DBPCFC)representstheonlywaytoestablishorruleoutanadversereactiontoafoodinolderchildrenand adults, whereas an open challenge controlled bytrained personnel is sufficient in infants and youngchildren (1). The challenge procedure is not, however,C.Bindslev-Jensen

The lymphocyte transformation test in the diagnosis of drug hypersensitivity.

Abstract: Diagnosis of drug hypersensitivity is difficult, as an enormous amount of different drugs can elicit various immune-mediated diseases with distinct pathomechanism. The lymphocyte transformation test (LTT) measures the proliferation of T cells to a drug in vitro--from which one concludes to a previous in vivo reaction due to a sensitization. This concept of the LTT has been confirmed by the generation of drug-specific T-cell clones and the finding that drugs can directly interact with the T-cell receptor, without previous metabolism or need to bind to proteins. In this review, technical aspects and usefulness of this test for the diagnosis of drug hypersensitivity are discussed. The main advantage of this test is its applicability with many different drugs in different immune reactions, as drug-specific T cell are almost always involved in drug hypersensitivity reactions. Its main disadvantages are that an in vitro proliferation of T cells to a drug is difficult to transfer to the clinical situation and that the test per se is rather cumbersome and technically demanding. In addition, its sensitivity is limited (for beta-lactam allergy it is in the range of 60-70%), - although at least in our hands - it is higher than of other tests for drug hypersensitivity diagnosis. Consequently, drug hypersensitivity diagnosis needs to rely on a combination of history and different tests, as none of the single tests available has per se a sufficiently good sensitivity. Within this setting, the LTT has proven to be a useful test for the diagnosis of drug hypersensitivity reactions and helped to better understand these reactions. Further work on the simplification of this test and systematic evaluation of its sensitivity and specificity in some main groups of drugs are necessary to make this test more widely available.

A protocol for oral desensitization in children with IgE-mediated cow's milk allergy.

Abstract: Objectives: To desensitize children with severe immunoglobulin (Ig)E-mediated cow's milk allergy in a period of 6 months by introducing increasing daily doses of cow's milk (CM) in order to enable the child to assume 200 ml of CM daily, or to induce tolerance of the highest possible CM dose. Study design: Twenty-one children at least 6 years old with severe IgE-mediated CM allergy were admitted to the study. A convincing history of IgE-mediated CM allergy or a positive double-blind placebo-controlled food challenge with CM confirmed the diagnosis. Oral desensitization was performed with increasing doses starting from 0.06 mg of CM proteins. Results: Overall, 15 of 21 children (71.4%) achieved the daily intake of 200 ml during a 6-month period; three of 21 children (14.3%) tolerated 40–80 ml/day of undiluted CM; three of 21 children (14.3%) failed the desensitization because they presented allergic symptoms after ingesting minimal amounts of diluted CM. Conclusions: We successfully desensitized 15 of 21 children with severe IgE-mediated CM allergy in a period of 6 months. We stress the importance of the partial outcome in those three of 21 children who could not reach the maximum amount of 200 ml/day of whole CM, but were able to tolerate 40–80 ml/day of CM. In this way we dramatically reduced the risk of severe reactions after accidental or unnoticed introduction of low quantities of CM. We do not propose generalizing this method beyond trained staff.

Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in patients with concomitant allergic asthma and persistent allergic rhinitis: SOLAR.

Abstract: Background: Anti-IgE therapy could be particularly beneficial for patients with concomitant disease as it targets a common factor in both diseases. The aim of this study was to evaluate the efficacy and safety of omalizumab in patients with concomitant moderate-to-severe asthma and persistent allergic rhinitis. Methods: This multicentre, randomized, double-blind, parallel-group, placebocontrolled trial evaluated the safety and efficacy of omalizumab. A total of 405 patients (12–74 years) with a stable treatment (‡ 400 lg budesonide Turbuhaler � )a nd‡ 2 unscheduled medical visits for asthma during the past year or ‡ 3 during the past 2 years were enrolled. Patients received omalizumab (‡ 0.016 mg/kg/IgE [IU/ml] per 4 weeks) or placebo for 28 weeks. Results: Fewer patients treated with omalizumab experienced asthma exacerbations (20.6%) than placebo-treated patients (30.1%), P ¼ 0.02. A clinically significant (‡ 1.0 point) improvement in both Asthma Quality of Life Questionnaire and Rhinitis Quality of Life Questionnaire occurred in 57.7% of omalizumab patients compared with 40.6% of placebo patients (P < 0.001). Omalizumab reduced Wasserfallen symptom scores for asthma (P ¼ 0.023), rhinitis (P < 0.001) and the composite asthma/rhinitis scores (P < 0.001) compared with placebo. Serious adverse events were observed in 1.4% of omalizumab-treated patients and 1.5% of placebo-treated patients. Conclusion: Omalizumab is well tolerated and effective in preventing asthma exacerbations and improving quality of life in patients with concomitant asthma and persistent allergic rhinitis.

Clinical efficacy of sublingual and subcutaneous birch pollen allergen‐specific immunotherapy: a randomized, placebo‐controlled, double‐blind, double‐dummy study

Abstract: Background: Both sublingual allergen-specific immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT) have a documented clinical efficacy, but only few comparative studies have been performed. Objective: To investigate the clinical efficacy of SLIT vs SCIT and secondary to compare SLIT and SCIT with placebo and to evaluate the relative clinical efficacy in relation to systemic side-effects. Methods: A 3-year randomized, placebo-controlled, double-blind, double-dummy study including 71 adult birch pollen hay fever patients treated for two consecutive years after a baseline year. Allocation to treatment groups was based on disease severity in the baseline season, gender and age. Results: Clinical efficacy was estimated in 58 patients completing the first treatment year by subtracting baseline data and by calculating the ratio first treatment season vs baseline. SLIT diminished the median disease severity to one-half and SCIT to one-third of placebo treatment. No statistical significant difference between the two groups was observed. Both for symptoms and medication scores actively treated patients showed statistically significant and clinical relevant efficacy compared with placebo. SLIT treatment only resulted in local mild side-effects, while SCIT resulted in few serious systemic side-effects. Conclusion: Based on the limited number of patients the clinical efficacy of SLIT was not statistically different from SCIT, and both treatments are clinically effective compared with placebo in the treatment of birch pollen rhinoconjunctivitis. The lack of significant difference between the two treatments does not indicate equivalent efficacy, but to detect minor differences necessitates investigation of larger groups. Due to the advantageous safety profile SLIT may be favored.

Diagnosis of nonimmediate reactions to beta-lactam antibiotics.

Abstract: Nonimmediate manifestations (i.e. occurring more than 1 h after drug administration), particularly maculopapular and urticarial eruptions, are common during beta-lactam treatment. The mechanisms involved in most nonimmediate reactions seem to be heterogeneous and are not yet completely understood. However, clinical and immunohistological studies, as well as analysis of drug-specific T-cell clones obtained from the circulating blood and the skin, suggest that a type-IV (cell-mediated) pathogenic mechanism may be involved in some nonimmediate reactions such as maculopapular or bullous rashes and acute generalized exanthematous pustulosis. In the diagnostic work-up, the patient's history is fundamental; patch testing is useful, together with delayed-reading intradermal testing. The latter appears to be somewhat more sensitive than patch testing, but also less specific. In case of negative allergologic tests, consideration should be given to provocation tests, and the careful administration of the suspect agents. With regard to in vitro tests, the lymphocyte transformation test may contribute to the identification of the responsible drug. Under the aegis of the European Academy of Allergology and Clinical Immunology (EAACI) interest group on drug hypersensitivity and the European Network for Drug Allergy (ENDA), in this review we describe the general guidelines for evaluating subjects with nonimmediate reactions to beta-lactams.

Cytokine-regulated accumulation of eosinophils in inflammatory disease.

Abstract: The role of cytokines in the accumulation of eosinophil granulocytes in inflamed tissue has been studied extensively during recent years, and these molecules have been found to participate throughout the whole process of eosinophil recruitment. Haematopoietic cytokines such as IL-3, IL-5 and GM-CSF stimulate the proliferation and differentiation of eosinophils in the bone marrow, and the release of mature eosinophils from the bone marrow into the blood is probably promoted by IL-5. Priming of eosinophils in the blood following, for example, allergen challenge is performed mainly by IL-3, IL-5 and GM-CSF. An important step in the extravasation of eosinophils is their adhesion to the vascular endothelium. Adhesion molecules are upregulated by, e.g. IL-1, IL-4, TNF-alpha and IFN-gamma and the same cytokines may also increase the affinity of adhesion molecules both on eosinophils and endothelial cells. Finally, a number of cytokines have been shown to act as eosinophil chemotactic factors, attracting the cells to the inflammatory focus in the tissue. Some of the most important eosinophil chemoattractant cytokines are IL-5, IL-8, RANTES, eotaxin, eotaxin-2, eotaxin-3, MCP-3, MCP-4 and TNF-alpha. Th2 cells, mast cells and epithelial cells are important sources of proinflammatory cytokines, but in recent years, the eosinophils have also been recognized as cytokine-producing and thereby immunoregulatory cells. The aim of this paper is to review the role of cytokines in the process of eosinophil recruitment in asthma, allergy and ulcerative colitis.

Prevalence of adverse reactions to food in Germany - a population study.

Abstract: Adverse reactions to food have been recognized sinceancient times, but only recently the many heterogeneousmechanisms have been identified. These include not onlyimmunological IgE-mediated food allergy and nonimmu-nological reactions like pseudoallergy, enzyme deficien-cies, toxic effects of food, but also rare reactions like fooddependent exercise-induced anaphylaxis. The frequencyof perceived adverse reactions to food is higher than thenumber of confirmed reactions (1, 2). However, thediagnosis of adverse reactions to food is very sophisti-cated and till date there is no large population-basedstudy worldwide investigating all kinds of adverse reac-tions to food using the required selective patient-orientedapproach.Investigationofnonimmunologicalreactionsisdifficult because of the lack of simple in vitro and in vivotests, but even for allergic, IgE-mediated reactions andespecially cross-reactions these tests have low predictivevalue (3–7). The recommended way of diagnosis,therefore, in addition to skin and blood tests, is toestablish food intolerance by dietary exclusion anddouble-blind, placebo-controlled food challenge tests(DBPCFC) (8–10).Due to this difficult situation and the lack of existingdata, the German Ministry of Health initiated this studyto investigate the prevalence of food intolerance in theGerman population and to identify the eliciting agents.The study was performed in the Berlin population, asingle-center approach was chosen since an especiallyequipped allergy centre was required, to handle severeanaphylactic reactions during provocation tests and toavoid an inter-investigator bias. Data were then compu-ted for the whole German adult population on the basisof the existing data of the nationwide German healthSurvey from 1998, which was performed in the age groupof 18–79 years concentrating on general health issues butnot on food allergy in particular.Objective:A population study was performed to identify the prevalence of allkinds of adverse reactions to food.Methods: In a representative cross-sectional survey performed in 1999 and 2000in Berlin, 13 300 inhabitants of all ages were addressed by questionnaire. Thisquestionnaire was answered by 4093 persons. All respondents mentioning anysign of food intolerance or the existence of allergic diseases (n ¼ 2298) werefollowed up by telephone and, in case food intolerance could not be ruled out bypatient history, were invited to attend to the clinic for personal investigationincluding double-blind, placebo-controlled food challenge tests (DBPCFC).Results: The self-reported lifetime prevalence of any adverse reaction to food inthe Berlin population (mean age 41 years) was 34.9%. Eight hundred andfourteen individuals were personally investigated according to the guidelines.The point prevalence of adverse reactions to food confirmed by DBPCFC testsin the Berlin population as a mean of all age groups was 3.6% (95% confidenceinterval [3.0–4.2%]) and 3.7% in the adult population (18–79 years, 95% con-fidence interval [3.1–4.4.%]). Two and a half percent were IgE-mediated and1.1% non-IgE-mediated, females were more frequently affected (60.6%). Basedon a statistical comparison with available data of adults from the nationwideGerman Health Survey from 1998, adverse reactions to food in the adult pop-ulation of Germany (age 18–79) were calculated with 2.6% [2.1–3.2%]).Conclusions: The study gives for the first time information about the pointprevalence of both immunological and nonimmunological adverse reactions tofood and underlines the relevance of this issue in public health. The data alsoshow that an individualized stepwise approach including provocation tests ismandatory to confirm the diagnosis.T.Zuberbier

Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in patients with poorly controlled (moderate-to-severe) allergic asthma

Abstract: Background: Patients with poorly controlled asthma have greater morbidity and mortality. This study evaluated the efficacy and tolerability of omalizumab in patients with poorly controlled, moderate-to-severe allergic asthma. Methods: This was a randomized, open-label, multicentre, parallel-group study. A total of 312 patients (12–73 years) receiving ≥400 μg/day (adolescent) or ≥800 μg/day (adult) inhaled beclomethasone dipropionate, or equivalent were included. Patients received best standard care (BSC) with or without omalizumab [at least 0.016 mg/kg/IgE (IU/ml) every 4 weeks] for 12 months. Results: The annualized mean number of asthma deterioration-related incidents was reduced from 9.76 with BSC alone (n = 106) to 4.92 per patient-year with omalizumab (n = 206) (P < 0.001). Mean clinically significant asthma exacerbation rates were 2.86 and 1.12 per patient-year, respectively (P < 0.001). Omalizumab-treated patients (41.4%) required rescue medication <1 day/week compared with 20.7% for BSC alone (P < 0.001). Omalizumab improved absolute forced expiratory volume in 1 s (FEV1) compared with BSC alone (2.48 and 2.28l, respectively; P < 0.05) and reduced symptom scores relative to BSC alone (decrease of 6.5 and 0.7 respectively; P < 0.001). Omalizumab was well-tolerated. Conclusions: Omalizumab administered as add-on therapy to BSC benefits patients with poorly controlled, moderate-to-severe allergic asthma.

Clinical and laboratory parameters in predicting chronic urticaria duration: a prospective study of 139 patients

Abstract: Background: Despite the disabling nature of chronic urticaria (CU), little is known about the disease's duration or the efficacy of adopting aggressive therapeutic regimens such as cyclosporine A. Objectives: The aim of this study was to evaluate whether parameters such as angioedema, autologous serum test, anti-thyroid antibodies, and total IgE could predict both CU duration and severity. Patients and methods: One hundred and thirty-nine patients suffering from CU were prospectively followed over a 5-year period for disease duration, severity and the presence of angioedema. Also investigated was the association between these clinical parameters and the subsequent detection of autologous serum test, anti-thyroid antibodies, and total IgE. Results: CU lasted over 1 year in more than 70% of cases and in 14% it still existed after 5 years. Angioedema co-existed or appeared during the course of CU in 40% of patients and was associated with disease duration. Autologous serum test and anti-thyroid antibodies were found positive in 28 and 12% of patients, respectively, compared to none of normal individuals, P = 0.001. CU duration was associated with the presence of both autologous serum test and anti-thyroid antibodies; however, autologous serum test and not anti-thyroid antibodies was found in association with CU severity. Conclusion: We demonstrate for the first time that CU duration is associated with clinical parameters such as severity and angioedema, and with laboratory parameters such as autologous serum test and anti-thyroid antibodies. The ability to predict CU duration may facilitate decisions regarding the possible early initiation of cyclosporine A as a means by which to reduce disease severity and duration.

Allergic cross-reactivity: from gene to the clinic.

Abstract: A large number of allergenic proteins have now their complete cDNA sequences determined and in some cases also the 3D structures. It turned out that most allergens could be grouped into a small number of structural protein families, regardless of their biological source. Structural similarity among proteins from diverse sources is the molecular basis of allergic cross-reactivity. The clinical relevance of immunoglobulin E (IgE) cross-reactivity seems to be influenced by a number of factors including the immune response against the allergen, exposure and the allergen. As individuals are exposed to a variable number of allergenic sources bearing homologous molecules, the exact nature of the antigenic structure inducing the primary IgE immune response cannot be easily defined. In general, the 'cross-reactivity' term should be limited to defined clinical manifestations showing reactivity to a source without previous exposure. 'Co-recognition', including by definition 'cross-reactivity', could be used to describe the large majority of the IgE reactivity where co-exposure to a number of sources bearing homologous molecules do not allow unequivocal identification of the sensitizing molecule. The analysis of reactivity clusters in diagnosis allows the interpretation of the patient's reactivity profile as a result of the sensitization process, which often begins with exposure to a single allergenic molecule.

The prevalence of positive reactions in the atopy patch test with aeroallergens and food allergens in subjects with atopic eczema: a European multicenter study.

Abstract: Background: The atopy patch test (APT) was proposed to evaluate IgE-mediated sensitizations in patients with atopic eczema (AE). Objective: The prevalence and agreement with clinical history and specific IgE (sIgE) of positive APT reactions was investigated in six European countries using a standardized method. Methods: A total of 314 patients with AE in remission were tested in 12 study centers on clinically uninvolved, non-abraded back skin with 200 index of reactivity (IR)/g of house dust mite Dermatophagoides pteronyssinus, cat dander, grass, and birch pollen allergen extracts with defined major allergen contents in petrolatum. Extracts of egg white, celery and wheat flour with defined protein content were also patch tested. APT values were evaluated at 24, 48, and 72 h according to the European Task Force on Atopic Dermatitis (ETFAD) guidelines. In addition, skin-prick test (SPT) and sIgE and a detailed history on allergen-induced eczema flares were obtained. Results: Previous eczema flares, after contact with specific allergens, were reported in 1% (celery) to 34% (D. pteronyssinus) of patients. The frequency of clear-cut positive APT reactions ranged from 39% with D. pteronyssinus to 9% with celery. All ETFAD intensities occured after 48 and 72 h. Positive SPT (16–57%) and elevated sIgE (19–59%) results were more frequent. Clear-cut positive APT with all SPT and sIgE testing negative was seen in 7% of the patients, whereas a positive APT without SPT or sIgE for the respective allergen was seen in 17% of the patients. APT, SPT and sIgE results showed significant agreement with history for grass pollen and egg white (two-sided Pr > |Z| ≤ 0.01). In addition, SPT and sIgE showed significant agreement with history for the other aeroallergens. With regard to clinical history, the APT had a higher specificity (64–91% depending on the allergen) than SPT (50–85%) or sIgE (52–85%). Positive APT were associated with longer duration of eczema flares and showed regional differences. In 10 non-atopic controls, no positive APT reaction was seen. Conclusion: Aeroallergens and food allergens are able to elicit eczematous skin reactions after epicutaneous application. As no gold standard for aeroallergen provocation in AE exists, the relevance of aeroallergens for AE flares may be evaluated by APT in addition to SPT and sIgE. The data may contribute to the international standardization of the APT.

Eosinophils and atopic dermatitis

Abstract: In spite of the progress regarding the description of immunological phenomena associated with atopic dermatitis (AD), the pathogenesis of this disease still remains unclear. The presence of eosinophils in the inflammatory infiltrate of AD has long been established. Eosinophil numbers as well as eosinophil granule protein levels in peripheral blood are elevated in most AD patients and appear to correlate with disease activity. Moreover, eosinophil granule proteins, which possess cytotoxic activity, are deposited in the skin lesions. These observations indicate a role of eosinophils in the pathogenesis of AD. Furthermore, AD is associated with increased production of T helper 2 cytokines including interleukin (IL)-5, which specifically acts on eosinophils, resulting in accelerated eosinophilopoiesis, chemotaxis, cell activation, and delayed apoptosis. Therefore, IL-5 is an interesting target for experimental therapy in this inflammatory disorder of the skin. Such studies might result in new insights into the pathogenetic role of eosinophils in AD.

The burden of atopy and asthma in children.

Abstract: Background: There has been a world-wide increase in the prevalence of atopic diseases. These atopic diseases, including asthma, allergic rhinoconjunctivitis and atopic eczema/dermatitis, are common in childhood and create a challenge of management for physicians and parents. Methods: MEDLINE was searched for articles related to atopy, allergy asthma, allergic rhinoconjunctivitis and atopic eczema/dermatitis. Results and conclusions: The conditions of asthma, allergic rhinoconjunctivitis and atopic eczema/dermatitis cause very significant burdens regarding the discomfort to the affected individual, management problems for the parent and physician and the economic cost to the family and the nation.

Eosinophils: ‘new’ roles for ‘old’ cells

Abstract: Prominent blood and tissue eosinophilia is manifested in a number of inflammatory states, particularly in allergic diseases. Eosinophils are a source of numerous cytokines and growth factors, thus in principle they can display both pro-inflammatory and anti-inflammatory activities as well as immunoregulatory ones. In this review, we will discuss the cross-talk between eosinophils and other cell types that they come in contact with in the inflammatory milieu, such as mast cells, fibroblasts and endothelial cells. 'New' roles for eosinophils in cancer and novel activatory signals will also be described.

Matrix metalloproteinases MMP-7, MMP-9 and their tissue inhibitor TIMP-1: expression in chronic sinusitis vs nasal polyposis.

Abstract: Background: Nasal polyps (NP) are characterized by pseudocyst formation, whereas the mucosa in chronic sinusitis (CS) only shows a limited oedema. Matrix metalloproteinases (MMPs) are a family of endopeptidases able to degrade the extracellular matrix. Differences in histological features between CS and NP might be related to the respective expression of MMPs and their tissue inhibitors (TIMPs). Objective: The aim of this study was to investigate MMP-7, MMP-9 and TIMP-1 proteins in NP and CS in comparison with normal mucosa. Methods: Nasal samples, obtained from controls (n = 10), from NP (n = 8) and from CS (n = 10), were analysed by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). Results: In NP, compared with controls, staining for MMP-9 and MMP-7 appeared in blood vessels. Matrix metalloproteinase-9-positive inflammatory cells could be detected in increased numbers in pseudocyst formations. Concentrations of MMP-9 protein was found significantly increased in both CS and NP compared with controls, while MMP-7 was significantly increased in NP compared with controls and CS. Tissue inhibitors of metalloproteinase-1 protein was significantly increased in CS and NP when compared with controls. Conclusions: Chronic sinusitis and NP show different pattern of MMP-7/-9 and TIMP-1 expression. We suggest that this difference in regulation of enzymes is related to the respective tissue remodelling observed in both diseases.

Neurogenic mechanisms in bronchial inflammatory diseases.

Abstract: Neurogenic inflammation encompasses the release of neuropeptides from airway nerves leading to inflammatory effects. This neurogenic inflammatory response of the airways can be initiated by exogenous irritants such as cigarette smoke or gases and is characterized by a bi-directional linkage between airway nerves and airway inflammation. The event of neurogenic inflammation may participate in the development and progression of chronic inflammatory airway diseases such as allergic asthma or chronic obstructive pulmonary disease (COPD). The molecular mechanisms underlying neurogenic inflammation are orchestrated by a large number of neuropeptides including tachykinins such as substance P and neurokinin A, or calcitonin gene-related peptide. Also, other biologically active peptides such as neuropeptide tyrosine, vasoactive intestinal polypeptide or endogenous opioids may modulate the inflammatory response and recently, novel tachykinins such as virokinin and hemokinins were identified. Whereas the different aspects of neurogenic inflammation have been studied in detail in laboratory animal models, only little is known about the role of airway neurogenic inflammation in human diseases. However, different functional properties of airway nerves may be used as targets for future therapeutic strategies and recent clinical data indicates that novel dual receptor antagonists may be relevant new drugs for bronchial asthma or COPD.

Randomized controlled open study of sublingual immunotherapy for respiratory allergy in real‐life: clinical efficacy and more

Abstract: Background: Some aspects of sublingual immunotherapy (SLIT) still need to be addressed: magnitude of the clinical efficacy, effect on the bronchial hyperreactivity adherence to treatment, preventive effect. We attempted to clarify these points in a randomized open, controlled, two parallel group study in a real-life setting. Methods: Five hundred and eleven patients with allergic rhinitis with or without intermittent asthma were randomized to drugs only or drugs + SLIT (rate 2 : 3) for 3 years. The clinical score (symptoms + drug intake) was measured each year during the allergen exposure. Pulmonary function test, methacholine challenge and skin tests were performed at the beginning and at the end of the study. Adherence to treatment was assessed by measuring the consumed extract. Results: Three hundred and nineteen patients received SLIT and 192 drugs only. Dropouts were 15% in the SLIT group and 12% in the controls. There was a significant improvement of clinical scores in the SLIT group: baseline 147 ± 3.3, first year 72.9 ± 1.3, second year 68.3 ± 1.8, third year 54.7 ± 2.8 (P 80% in 72% and >60% in 18% of patients. The number of patients with a positive MCh challenge decreased significantly after 3 years only in the SLIT group. New skin sensitizations appeared in 38% of the controls and in 5.9% of the SLIT patients (P = 0.01). Conclusion: Sublingual immunotherapy approximately halved the clinical scores and significantly reduced the bronchial hyperreactivity. Similarly to subcutaneous immunotherapy, SLIT displayed a preventive effect on the onset of new skin sensitizations. The adherence rate was quantitatively satisfactory.

Thaumatin‐like proteins – a new family of pollen and fruit allergens

Abstract: Pathogenesis-related proteins (PRs) are now widely regarded as a rich source of allergens (1, 2). The PRs are defined as proteins that are encoded by the plant genome and induced specifically in response to infections by pathogens such as fungi, bacteria, or viruses, or by adverse environmental factors. Pathogenesis-related proteins do not constitute a superfamily of proteins but represent a collection of unrelated protein families which function as part of the plant defence system. Today, PRs are classified into 14 families (3). Many important plant food allergens are homologues to proteins that are members of PR families (4, 5). The family 5 of PRs comprises unique proteins with diverse functions. Because of the sequence homologies between PR-5 proteins and thaumatin, an intensely sweet tasting protein isolated from the fruits of the West African rain forest shrub Thaumatococcus daniellii, members of this family of proteins are referred to as thaumatin-like proteins (TLPs). TLPs can be classified into three groups, (i) those produced in response to pathogen infection, (ii) those produced in response to osmotic stress, also called osmotins, and (iii) antifungal proteins present in cereal seeds. The TLPs are generally resistant to proteases and pHor heat-induced denaturation. This is likely due to the presence of 16 conserved cysteines that form eight disulfide bridges. The crystal structure of three PR-5 type proteins, PR-5d from tobacco (6), zeamatin from Z. mays (7), and thaumatin from T. daniellii (8) that are known to date illustrate the high conformational similarity between these proteins. Several allergenic TLPs from fruits have been described. Mal d 2 is a 23 kDa allergenic TLP of apple fruits that induces IgE-mediated symptoms in apple allergic individuals. This apple protein whose amino-terminal sequence shares about 50% identity with PR-5 family members was the first TLP described as an allergen (9). The cDNA sequence of Mal d 2 was expressed in Nicotiana benthamiana plants using a recombinant tobacco mosaic viral vector (10). Purified recombinant Mal d 2 displayed the ability to bind IgE from appleallergic individuals equivalent to natural Mal d 2. In addition, the recombinant thaumatin-like Mal d 2 exhibited antifungal activity against Fusarium oxysporum and Penicillium expansum, indicating a function in plant defense against fungal pathogens. In sweet cherry (Prunus avium), a 23 kDa thaumatin-like protein was identified as a major allergen, designated Pru av 2 and its cDNA cloned (11). The N-terminal sequence of a 23 kDa bell pepper allergen was determined to be identical to the corresponding portion of the osmotin-like protein P23 from tomatoes (12). The complete coding sequence (EMBL AJ297410) of this bell pepper fruit allergen designated Cap a 1 was obtained (13). An allergenic 24 kDa TLP from kiwi fruit was shown to be glycosylated and to possess antifungal activity against Saccharomyces carlsbergensis and Candida albicans (14). Very recently, a 24 kDa TLP was identified as a minor allergen of grape with an amino acid sequence highly similar to Mal d 2 and Pru av 2 (15). This brings the number of allergenic plant food TLPs up to five. So far, only one allergenic pollen TLP had been identified, the mountain cedar (Juniperus ashei) pollen allergen Jun a 3 which was also the first allergenic TLP whose expression in the cytoplasm of Escherichia coli was published (16). In this issue of Allergy, Cortegano et al. (17) describe the PCR cloning and expression of the Cupressus Heimo Breiteneder Department of Pathophysiology, Medical University of Vienna, Vienna, Austria

Stabilization of asthma prevalence among adolescents and increase among schoolchildren (ISAAC phases I and III) in Spain.

Abstract: Background: Most studies show a steep increase in asthma prevalence in the last decades, although few studies had applied the same methodology. Recent reports point out the possibility that the epidemic has come to an end. We have studied the prevalence of asthma in a very large sample of children, repeating the study eight years apart. Methods: Repeated cross-sectional studies using the International Study of Asthma and Allergies in Childhood (ISAAC) protocol in a sample of Spanish schoolchildren 6–7 (parent-reported) and 13–14 (self-reported) years old in 1994–95 (phase I) and 2002–2003 (phase III). The number of participants was 42 417 in phase I and 42 813 in phase III. The participation rate was over 87% (13–14 years) and 70% (6–7 years). Results: The prevalence of wheezing in the previous year in children aged 13–14 years was 9.0 and 9.3% for boys and 9.6 and 9.2% for girls for phases I and III, respectively. Children 6–7 years of age showed a substantial increase in wheezing in the previous year (7.0 and 10.7% for boys and 5.3 and 8.2% for girls). Other symptoms and severity indexes followed the same patterns. Conclusions: In the last 8 years, the prevalence of asthma has not changed in 13–14-year-old Spanish children but has increased substantially in 6–7-year olds.

Asthma and atopy - the price of affluence?

Abstract: Irrespective of improved knowledge of many aspects of atopic diseases, the unfavorable trends in their prevalence particularly among children could not have been reversed. A growing body of evidence suggests that something may lack from our societal affluence that has the capacity to provide protection against the development of atopic diseases. Much attention during the last years has been devoted to the hygiene hypothesis. This review outlines the impact of environment and lifestyle, particularly from the perspective of the East-West gradient, on the development of atopic diseases, with a special emphasis on the hygiene hypothesis in its broadest sense.

Hypoallergenic formulas--when, to whom and how long: after more than 15 years we know the right indication!

Abstract: Hypoallergenic formulas are processed by enzymatic hydrolysis of different protein sources such as bovine casein/whey and soy followed by further processing such as heat treatment and/or ultrafiltration, or they are based on amino acid mixtures. The products have been classified according to the degree of protein hydrolysis as 'extensively' or 'partially' hydrolysed protein products. Product properties may be characterized by biochemical techniques, and reduction of allergenicity may be assessed in vitro with various immunological methods, and in vivo with skin prick tests, patch tests and challenge tests. In vitro tests do not predict the allergenic effects in humans, and at present there is no evidence of a specific threshold of immunogenic protein. Only pure amino acid mixtures are considered to be nonallergenic. Other 'hypoallergenic' products contain residual allergenicity. At present, the potential of a product for treatment and prevention of food allergy can only be determined by clinical trials using scientifically appropriate standards. It has been recommended that dietary products for treatment of cow's milk protein allergy in infants should be tolerated by at least 90% (with 95% confidence) of infants with documented cow's milk protein allergy. Some extensively hydrolysed products and amino-acid-based products have met these criteria. Formulas intended for prevention should have a very low, if any, allergenic activity until otherwise proven. So far there are no firm criteria available for the design of hypoallergenic foods for prevention. Newborns included in prevention studies should be from high-risk families; they should be randomized at birth and fed the formula when supplements are needed for at least the first 4-6 months of life. Follow-up should be at least 18 months, and children should be investigated when symptoms appear. Validated clinical criteria, including controlled food challenges, should be used for diagnosis. Infants fed formulas that claim to prevent or delay allergy should have a statistically significant lower prevalence of allergy when compared with infants fed a standard cow's milk formula. Feeding high-risk infants a documented hypoallergenic formula combined with avoidance of solid foods during the first 4-6 months reduces the cumulative incidence of cow's milk protein allergy and atopic dermatitis as compared with a standard cow's-milk-based formula. Partially hydrolysed formulas may have an effect, though it seems to be less than that of extensively hydrolysed formulas at present. Thus, if exclusive breast-feeding for 4-6 months is not possible in high-risk infants, a documented hypoallergenic formula and avoidance of solid foods are recommended for the first 4 months of life.

Recent advances in pathogenesis and management of hypereosinophilic syndromes.

Abstract: Idiopathic hypereosinophilic syndrome is a largely heterogeneous disorder defined until now as persistent marked hypereosinophilia of unknown origin generally complicated by end-organ damage. Recent studies clearly indicate that many patients fulfilling the diagnostic criteria of this syndrome can now be classified as presenting one of two major disease variants: the myeloproliferative or the lymphocytic variant. Research in cellular and molecular biology has provided firm evidence for the existence of discrete hematological disorders underlying these variants, questioning the pertinence of continued reference to 'idiopathic' hypereosinophilic syndrome in such patients. Furthermore, identification of these variants has a number of prognostic and therapeutic implications that must be taken into consideration for adequate management of these patients.

Effect of tree pollen specific, subcutaneous immunotherapy on the oral allergy syndrome to apple and hazelnut

Abstract: Background: The efficacy of specific immunotherapy (SIT) in pollen allergy is well established. However, its effect on pollen associated food allergy particularly the oral allergy syndrome (OAS) is not definitely ascertained. Objective: The purpose of this controlled prospective study was to investigate whether SIT with tree pollen, mainly birch, has an effect on OAS induced by apple or hazelnut in birch pollen-allergic individuals. Methods: Twenty-seven birch pollen-allergic subjects with OAS induced by apple or hazelnut underwent open oral provocation tests (OPT) with increasing doses (1 to 128 g) of fresh apple or ground hazelnut 1 year apart. Fifteen of 27 subjects were treated with SIT and 12 were not. Skin-prick test with birch pollen, apple and hazelnut, and specific serum IgE, IgG and IgG4 to rBet v 1, apple and hazelnut were determined. Results: Thirteen of 15 (87%) SIT-treated subjects could eat significantly (P < 0.001) more of apple or hazelnut without any symptoms/signs. The average tolerated quantity increased from 12.6 to 32.6 g apple after 1 year in this group. In contrast, only one of 12 (8%) individuals without SIT was able to consume a higher amount without symptoms. On evaluating laboratory parameters, only IgG4 antibodies to rBet v 1 were found to be significantly (P < 0.01) increased in the SIT-treated group after 1 year. Conclusions: The study shows that SIT with extracts containing birch pollen has a positive impact on OAS to apple or hazelnut in birch pollen-allergic individuals. In spite of this outcome, the amount of apple/hazelnut tolerated is still small. Thus, the effect of SIT on the patients’ management of OAS remains limited.

Efficacy of sublingual swallow immunotherapy in children with severe grass pollen allergic symptoms: a double‐blind placebo‐controlled study

Abstract: Background: Local application of allergen extracts in specific immunotherapy is accompanied by increased compliance and significantly reduced side effects. However, efficacy of local immunotherapy in children has yet not been sufficiently demonstrated. This study was performed to determine clinical efficacy of high dose sublingual swallow immunotherapy (SLIT) by a double-blind placebo-controlled study in children with grass pollen allergy using high dose allergen extracts. Methods: A total of 161 children with seasonal rhinoconjunctivitis of which, 68 had also asthma symptoms were enrolled in a multicenter double-blind placebo-controlled study for 1 year and treated on a daily basis with sublingually applied allergen drops. After 1 year all children were given treatment for another 2 years in an open-controlled setting. Symptom scores and medication were assessed during the pollen seasons with structured interviews. Applied allergen dosage, compliance, and side effects were documented by daily diary cards. Primary endpoint was a clinical index (CI) combining symptom scores with medication index. Titrated skin prick tests (SPT) and specific antibody measurements were performed each year. Results: Combining symptom with medication scores to CI was highly reliable (reliability coefficient = 0.89, standard error = 9.6%). Allergen-specific IgE- and IgG-subclass antibodies increased significantly in patients treated with SLIT indicating an activation of the immune response induced by the locally applied grass pollen extract. SPT reactivity did not change during therapy. After 1 year of SLIT in the original design we observed no significant difference in the CI between treatment and placebo analyzing all patients included in the study per intention to treat and per protocol. However, subgroup analysis in a repeated measures model revealed that patients with SLIT and severe symptoms before the beginning of treatment (CI > mean/ > 1.51) showed a significant improvement of clinical symptoms after 3 years. Conclusion: In this study SLIT was accompanied by a significant placebo effect. Efficacy of treatment could only be seen in children with severe clinical symptoms and this became clinically marked after 3 years of therapy.

The basophil activation test in wasp venom allergy: sensitivity, specificity and monitoring specific immunotherapy.

Abstract: Background: As in vitro diagnosis of wasp venom sensitization by specific serum IgE has a sensitivity of only 60–80%, additional in vitro tests are desirable. Basophil activation is associated with the expression of CD63 and its measurement has been proposed as a novel in vitro test for immediate-type allergy. Furthermore, to date, no in vitro test exists to monitor successful specific immunotherapy (SIT) with wasp venom. Therefore, the potentially harmful sting challenge is still recommended. Objective: We compared the CD63-based basophil activation test (BAT) in the diagnosis of wasp venom allergy with skin tests and measurement of specific IgE. Furthermore, we investigated whether BAT can predict the outcome of the sting challenge in patients on SIT. Methods: Fifty patients with a systemic reaction caused by a wasp sting and 20 controls were studied. Intracutaneous tests were performed with wasp and bee venom in the suspected allergics. Specific IgE was determined by the CAP-FEIA method and basophil activation by flow cytometry upon double staining with anti-IgE/anti-CD63 mAb. Twenty-five patients were sting challenged 6 months after starting SIT and the BAT was repeated before challenge. Results: Sensitivity of the intracutaneous tests, specific IgE and BAT was 100, 76, and 92%, respectively. Specificity of specific IgE and the BAT was 85 and 80%, respectively. The cut-off for a positive BAT was 15% CD63+ basophils. There was a positive correlation between IgE reactivity to wasp venom and the number of CD63+ basophils (r = 0.65). Although no patient had a systemic reaction upon sting challenge, in most subjects basophil activation did not decrease when compared with the BAT before SIT. Conclusions: Quantitation of basophil activation by CD63 expression is a valuable new in vitro method for diagnosis of allergy to hymenopteran venoms. The CD63-based BAT is a helpful tool for the complementation of routine diagnostic tests such as specific IgE as it increases sensitivity of in vitro detection of sensitization. However, this in vitro method does not offer an alternative to the sting challenge in monitoring successful SIT.

Monitoring the allergic inflammation

Abstract: Individual symptoms of allergy such as asthma, dermatitis, rhinitis have many different underlying mechanisms. The detailed characterization of the inflammatory mechanisms underlying symptom development in the individual patient is important in order to optimally control treatment. Measurement of eosinophil cationic protein (ECP) in sputum or blood and eosinophil protein X/eosinophil derived neurotoxin (EPX/EDN) in urine may be used to read the involvement of the eosinophil granulocyte in the process. An important information as eosinophil dominated processes seem to be particularly sensitive to corticosteroid treatment. The possibilities to measure the involvement of other inflammatory cells exist today, but are only used to a small extent. The dream would be that every patient with an inflammatory disease is characterized with respect to the profile of involving cells and mediators. Such information would provide us with a unique understanding of the underlying mechanisms of the development of disease symptoms and the possibilities of treating these.

Allergenic pollen records (15 years) and sensitization in patients with respiratory allergy in Thessaloniki, Greece

Abstract: Summary Backround: The prevalence of respiratory allergy to fungi spores (FS) is not precisely known but is estimated at 20-30% of atopic patients. There are no aerobiological records, necessary for respiratory allergy diagnosis and treatment, in Thessaloniki and generally in Greece. Aim: Creation of a database on FS circulation and investigation of skin sensitivity (SS) of asthmatics by using skin prick tests (SPT). Material and methods: Daily records and identification of 15 airborne FS species were conducted, using a Burkard trap during 1987-2001. SS to 5 most common FS extracts was investigated, by using SPT in a total of 1311 asthmatics with atopy, submitted to the Out-Patient Clinic of Asthma (Pulmonary Dept, Aristotle Univ, Thessaloniki) in1990-2001. Results: The FS recorded in the 15-year period were as follows: Cladosporium spp. (72.2%), Alternaria spp. (9.8%), Ustilago spp. (8.1%), Ascospores (2.7%), Agrocybe spp. (1.5%), Helminthosporium spp. (1.4%), Leptosphaeria spp (1.2%), Agrogybe spp. (1.1%), whereas the species Botrytis, Stemphylium, Pleospora, Nigrospora, Epicoccum, Fusarium, Torula and Phoma presented concentrations <1%. The highest numbers of airborne FS were recorded during summer. Positive skin reaction to FS was observed in 421 (32%) patients of the 1311 asthmatics. Positive skin reaction to Alternaria species was observed in 177 patients (13.5%), in 98 (7.4%) to Cladosporium, 65 (5%) to Aspergillus, 45 (3.4%) to Fusarium and 36 (2.7%) to Rhizopus. FS sensitivity is much more frequent in younger men. Conclusions: For the first time in Thessaloniki-Greece, 15 allergenic FS species circulation has been recorded for the last 15 years. SS was more frequently detected for the species of Alternaria, Cladosporium and Aspergillus.

Influence of a multidisciplinary paediatric allergy clinic on parental knowledge and rate of subsequent allergic reactions

Abstract: Background: Studies have demonstrated that families of children with food allergy have significant deficiencies in their knowledge of how to avoid allergen exposure and how to manage allergic reactions. This study aims to assess the impact of a multidisciplinary paediatric allergy clinic consultation on parental knowledge of food allergy and to determine the rate of subsequent allergic reactions. Methods: Sixty-two subjects ( Results: After one visit to the paediatric allergy clinic, there was a significant improvement in parental knowledge of allergen avoidance (26.9%, P Conclusions: A single visit to a multidisciplinary allergy clinic considerably improves families' abilities to manage allergic reactions to foods with an accompanying reduction in allergic reactions. Young children with egg, milk or multiple food allergies were at greatest risk of further reactions.