Vitamin D supplementation in primary allergy prevention: Systematic review of randomized and non-randomized studies.

BACKGROUND: To date, a systematic review of the evidence regarding the association between vitamin D and allergic diseases development has not yet been undertaken. OBJECTIVE: To review the efficacy and safety of vitamin D supplementation when compared to no supplementation in pregnant women, breastfeeding women, infants, and children for the prevention of allergies. METHODS: Three databases were searched through January 30, 2016, including randomized (RCT) and nonrandomized studies (NRS). Two reviewers independently extracted data and assessed the certainty in the body of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. RESULTS: Among the 1932 articles identified, one RCT and four NRS were eligible. Very low certainty in the body of evidence across examined studies suggests that vitamin D supplementation for pregnant women, breastfeeding women, and infants may not decrease the risk of developing allergic diseases such as atopic dermatitis (in pregnant women), allergic rhinitis (in pregnant women and infants), asthma and/or wheezing (in pregnant women, breastfeeding women, and infants), or food allergies (in pregnant women). We found no studies of primary prevention of allergic diseases in children. CONCLUSION: Limited information is available addressing primary prevention of allergic diseases after vitamin D supplementation, and its potential impact remains uncertain.

The international WAO/EAACI guideline for the management of hereditary angioedema-The 2017 revision and update.

Hereditary Angioedema (HAE) is a rare and disabling disease. Early diagnosis and appropriate therapy are essential. This update and revision of the global guideline for HAE provides up-to-date consensus recommendations for the management of HAE. In the development of this update and revision of the guideline, an international expert panel reviewed the existing evidence and developed 20 recommendations that were discussed, finalized and consented during the guideline consensus conference in June 2016 in Vienna. The final version of this update and revision of the guideline incorporates the contributions of a board of expert reviewers and the endorsing societies. The goal of this guideline update and revision is to provide clinicians and their patients with guidance that will assist them in making rational decisions in the management of HAE with deficient C1-inhibitor (type 1) and HAE with dysfunctional C1-inhibitor (type 2). The key clinical questions covered by these recommendations are: (1) How should HAE-1/2 be defined and classified?, (2) How should HAE-1/2 be diagnosed?, (3) Should HAE-1/2 patients receive prophylactic and/or on-demand treatment and what treatment options should be used?, (4) Should HAE-1/2 management be different for special HAE-1/2 patient groups such as pregnant/lactating women or children?, and (5) Should HAE-1/2 management incorporate self-administration of therapies and patient support measures?

Challenges in the implementation of EAACI guidelines on allergen immunotherapy: A global perspective on the regulation of allergen products.

Regulatory approaches for allergen immunotherapy (AIT) products and the availability of high-quality AIT products are inherently linked to each other. While allergen products are available in many countries across the globe, their regulation is very heterogeneous. First, we describe the regulatory systems applicable for AIT products in the European Union (EU) and in the United States (US). For Europe, a depiction of the different types of relevant procedures, as well as the committees involved, is provided and the fundamental role of national agencies of the EU member states in this complex and unique network is highlighted. Furthermore, the regulatory agencies from Australia, Canada, Japan, Russia, and Switzerland provided information on the system implemented in their countries for the regulation of allergen products. While AIT products are commonly classified as biological medicinal products, they are made available by varying types of procedures, most commonly either by obtaining a marketing authorization or by being distributed as named patient products. Exemptions from marketing authorizations in exceptional cases, as well as import of allergen products from other countries, are additional tools applied by countries to ensure availability of needed AIT products. Several challenges for AIT products are apparent from this analysis and will require further consideration.

Allergen manufacturing and quality aspects for allergen immunotherapy in Europe and the United States: An analysis from the EAACI AIT Guidelines Project.

Adequate quality is essential for any medicinal product to be eligible for marketing. Quality includes verification of the identity, content and purity of a medicinal product in combination with a specified production process and its control. Allergen products derived from natural sources require particular considerations to ensure adequate quality. Here, we describe key aspects of the documentation on manufacturing and quality aspects for allergen immunotherapy products in the European Union and the United States. In some key parts, requirements in these areas are harmonized while other fields are regulated separately between both regions. Essential differences are found in the use of Reference Preparations, or the requirement to apply standardized assays for potency determination. As the types of products available are different in specific regions, regulatory guidance for such products may also be available in one specific region only, such as for allergoids in the European Union. Region-specific issues and priorities are a result of this. As allergen products derived from natural sources are inherently variable in their qualitative and quantitative composition, these products present special challenges to balance the variability and ensuring batch-to-batch consistency. Advancements in scientific knowledge on specific allergens and their role in allergic disease will consequentially find representation in future regulatory guidelines.

EAACI Guidelines on Allergen Immunotherapy: Allergic rhinoconjunctivitis.

Allergic rhinoconjunctivitis (AR) is an allergic disorder of the nose and eyes affecting about a fifth of the general population. Symptoms of AR can be controlled with allergen avoidance measures and pharmacotherapy. However, many patients continue to have ongoing symptoms and an impaired quality of life; pharmacotherapy may also induce some side-effects. Allergen immunotherapy (AIT) represents the only currently available treatment that targets the underlying pathophysiology, and it may have a disease-modifying effect. Either the subcutaneous (SCIT) or sublingual (SLIT) routes may be used. This Guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on AIT for AR and is part of the EAACI presidential project "EAACI Guidelines on Allergen Immunotherapy." It aims to provide evidence-based clinical recommendations and has been informed by a formal systematic review and meta-analysis. Its generation has followed the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach. The process included involvement of the full range of stakeholders. In general, broad evidence for the clinical efficacy of AIT for AR exists but a product-specific evaluation of evidence is recommended. In general, SCIT and SLIT are recommended for both seasonal and perennial AR for its short-term benefit. The strongest evidence for long-term benefit is documented for grass AIT (especially for the grass tablets) where long-term benefit is seen. To achieve long-term efficacy, it is recommended that a minimum of 3 years of therapy is used. Many gaps in the evidence base exist, particularly around long-term benefit and use in children.

Prebiotics for the prevention of allergies: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Prevalence of allergic diseases in infants is approximately 10% reaching 20 to 30% in those with an allergic first-degree relative. Prebiotics are selectively fermented food ingredients that allow specific changes in composition/activity of the gastrointestinal microflora. They modulate immune responses, and their supplementation has been proposed as an intervention to prevent allergies. OBJECTIVE: To assess in pregnant women, breastfeeding mothers, and infants (populations) the effect of supplementing prebiotics (intervention) versus no prebiotics (comparison) on the development of allergic diseases and to inform the World Allergy Organization guidelines. METHODS: We performed a systematic review of studies assessing the effects of prebiotic supplementation with an intention to prevent the development of allergies. RESULTS: Of 446 unique records published until November 2016 in Cochrane, MEDLINE, and EMBASE, 22 studies fulfilled a priori specified criteria. We did not find any studies of prebiotics given to pregnant women or breastfeeding mothers. Prebiotic supplementation in infants, compared to placebo, had the following effects: risk of developing eczema (RR: 0.68, 95% CI: 0.40 to 1.15), wheezing/asthma (RR, 0.37; 95% CI: 0.17 to 0.80), and food allergy (RR: 0.28, 95% CI: 0.08 to 1.00). There was no evidence of an increased risk of any adverse effects (RR: 1.01, 95% CI: 0.92 to 1.10). Prebiotic supplementation had little influence growth rate (MD: 0.92 g per day faster with prebiotics, 95% CI: 0 to 1.84) and the final infant weight (MD: 0.10 kg higher with prebiotics, 95% CI: -0.09 to 0.29). The certainty of these estimates is very low due to risk of bias and imprecision of the results. CONCLUSIONS: Currently available evidence on prebiotic supplementation to reduce the risk of developing allergies is very uncertain.

Non-allergic rhinitis: Position paper of the European Academy of Allergy and Clinical Immunology.

This EAACI position paper aims at providing a state-of-the-art overview on nonallergic rhinitis (NAR). A significant number of patients suffering from persistent rhinitis are defined as nonallergic noninfectious rhinitis (NANIR) patients, often denominated in short as having NAR. NAR is defined as a symptomatic inflammation of the nasal mucosa with the presence of a minimum of two nasal symptoms such as nasal obstruction, rhinorrhea, sneezing, and/or itchy nose, without clinical evidence of endonasal infection and without systemic signs of sensitization to inhalant allergens. Symptoms of NAR may have a wide range of severity and be either continuously present and/or induced by exposure to unspecific triggers, also called nasal hyperresponsiveness (NHR). NHR represents a clinical feature of both AR and NAR patients. NAR involves different subgroups: drug-induced rhinitis, (nonallergic) occupational rhinitis, hormonal rhinitis (including pregnancy rhinitis), gustatory rhinitis, senile rhinitis, and idiopathic rhinitis (IR). NAR should be distinguished from those rhinitis patients with an allergic reaction confined to the nasal mucosa, also called "entopy" or local allergic rhinitis (LAR). We here provide an overview of the current consensus on phenotypes of NAR, recommendations for diagnosis, a treatment algorithm, and defining the unmet needs in this neglected area of research.

Constructing a classification of hypersensitivity/allergic diseases for ICD-11 by crowdsourcing the allergist community.

The global allergy community strongly believes that the 11th revision of the International Classification of Diseases (ICD-11) offers a unique opportunity to improve the classification and coding of hypersensitivity/allergic diseases via inclusion of a specific chapter dedicated to this disease area to facilitate epidemiological studies, as well as to evaluate the true size of the allergy epidemic. In this context, an international collaboration has decided to revise the classification of hypersensitivity/allergic diseases and to validate it for ICD-11 by crowdsourcing the allergist community. After careful comparison between ICD-10 and 11 beta phase linearization codes, we identified gaps and trade-offs allowing us to construct a classification proposal, which was sent to the European Academy of Allergy and Clinical Immunology (EAACI) sections, interest groups, executive committee as well as the World Allergy Organization (WAO), and American Academy of Allergy Asthma and Immunology (AAAAI) leaderships. The crowdsourcing process produced comments from 50 of 171 members contacted by e-mail. The classification proposal has also been discussed at face-to-face meetings with experts of EAACI sections and interest groups and presented in a number of business meetings during the 2014 EAACI annual congress in Copenhagen. As a result, a high-level complex structure of classification for hypersensitivity/allergic diseases has been constructed. The model proposed has been presented to the WHO groups in charge of the ICD revision. The international collaboration of allergy experts appreciates bilateral discussion and aims to get endorsement of their proposals for the final ICD-11.

Global classification and coding of hypersensitivity diseases - An EAACI - WAO survey, strategic paper and review.

Hypersensitivity diseases are not adequately coded in the International Coding of Diseases (ICD)-10 resulting in misclassification, leading to low visibility of these conditions and general accuracy of official statistics. To call attention to the inadequacy of the ICD-10 in relation to allergic and hypersensitivity diseases and to contribute to improvements to be made in the forthcoming revision of ICD, a web-based global survey of healthcare professionals' attitudes toward allergic disorders classification was proposed to the members of European Academy of Allergy and Clinical Immunology (EAACI) (individuals) and World Allergy Organization (WAO) (representative responding on behalf of the national society), launched via internet and circulated for 6 week. As a result, we had 612 members of 144 countries from all six World Health Organization (WHO) global regions who answered the survey. ICD-10 is the most used classification worldwide, but it was not considered appropriate in clinical practice by the majority of participants. The majority indicated the EAACI-WAO classification as being easier and more accurate in the daily practice. They saw the need for a diagnostic system useful for nonallergists and endorsed the possibility of a global, cross-culturally applicable classification system of allergic disorders. This first and most broadly international survey ever conducted of health professionals' attitudes toward allergic disorders classification supports the need to update the current classifications of allergic diseases and can be useful to the WHO in improving the clinical utility of the classification and its global acceptability for the revised ICD-11.

Allergic Rhinitis and its Impact on Asthma (ARIA): achievements in 10 years and future needs.

Allergic rhinitis (AR) and asthma represent global health problems for all age groups. Asthma and rhinitis frequently coexist in the same subjects. Allergic Rhinitis and its Impact on Asthma (ARIA) was initiated during a World Health Organization workshop in 1999 (published in 2001). ARIA has reclassified AR as mild/moderate-severe and intermittent/persistent. This classification closely reflects patients' needs and underlines the close relationship between rhinitis and asthma. Patients, clinicians, and other health care professionals are confronted with various treatment choices for the management of AR. This contributes to considerable variation in clinical practice, and worldwide, patients, clinicians, and other health care professionals are faced with uncertainty about the relative merits and downsides of the various treatment options. In its 2010 Revision, ARIA developed clinical practice guidelines for the management of AR and asthma comorbidities based on the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system. ARIA is disseminated and implemented in more than 50 countries of the world. Ten years after the publication of the ARIA World Health Organization workshop report, it is important to make a summary of its achievements and identify the still unmet clinical, research, and implementation needs to strengthen the 2011 European Union Priority on allergy and asthma in children.

International consensus on (ICON) pediatric asthma.

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

[ARIA (Allergic Rhinitis and its Impact on Asthma) achievements in 10 years and future needs]. / ARIA (allerjik rinit ve astim üzerine etkisi) 10 yildaki kazanimlar ve gelecekteki gereksinimler.

Allergic rhinitis and asthma represent global health problems for all age groups. Asthma and rhinitis frequently co-exist in the same subjects. Allergic Rhinitis and its Impact on Asthma (ARIA) was initiated during a World Health Organization (WHO) workshop in 1999 and was published in 2001. ARIA has reclassified allergic rhinitis as mild/moderate-severe and intermittent/persistent. This classification schema closely reflects the impact of allergic rhinitis on patients. In its 2010 Revision, ARIA developed clinical practice guidelines for the management of allergic rhinitis and asthma co-morbidities based on GRADE (Grading of Recommendation, Assessment, Development and Evaluation). ARIA has been disseminated and implemented in over 50 countries of the world. In Turkey, it is important to make a record of ARIA achievements and to identify the still unmet clinical, research and implementation needs in order to strengthen the 2011 EU Priority on allergy and asthma in children.

Development and implementation of guidelines in allergic rhinitis ­ an ARIA-GA2LEN paper.

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

Epidemiology and current status of allergic rhinitis and asthma in Thailand -- ARIA Asia-Pacific Workshop report.

The allergic diseases of the airway, i.e. allergic rhinitis and asthma, are on the increase in Thailand and their prevalence shows no signs of abating. When compared with a previous study, the incidence of wheezing had increased 4 fold (from 4.2% to 18.3%), and allergic rhinitis increased nearly 3 fold (from 17.9% to 44.2%). The results of the ISAAC phase III study revealed that the frequency of allergic diseases of the respiratory tract increased significantly from the ISAAC phase I survey performed in 1995; i.e. asthma increased from 12.2% to 14.5%, and allergic rhinitis from 37.9% to 50.6%. Allergic rhinitis exerts a major impact on the quality of life of Thai patients. The results of skin prick testing have indicated the leading causes of indoor (house-dust mites, house dust, cockroaches, dogs and cats) and outdoor pollen (Bermuda grass, para grass, sedge, careless weed) allergens. Molds (represented by Cladosporium), although prominent in an aeroallergen survey, returned a low percentage of positive skin prick reactions, and therefore, were considered low in allergenicity. In Thailand, there are clinical practice guidelines for both allergic rhinitis and asthma which are comparable to the international guidelines like ARIA and GINA. Sufficient kinds of pharmacotherapy are on the National List of Essential Drugs. Yet due to the limited number of trained allergists, many patients are seen by general physicians, and often, the appropriate diagnostic tests and treatments are not provided. In addition, the financial burden for quality health care may be prohibitive for those without private health insurance in spite of the implementation of a universal health care system for all Thai citizens, which is less than optimal.

Heterogeneous response of nasal and lung fibroblasts to transforming growth factor-beta 1.

BACKGROUND: Nasal polyposis is characterized by marked oedema, sparse extracellular matrix (ECM) and proliferating blood vessels. Pulmonary fibrosis is characterized by inflammatory cells accumulation, considerable ECM deposition and vascular abnormalities. Although lung fibrosis is not only and necessarily an inflammatory disorder, we hypothesized that the difference between nasal polyposis and pulmonary fibrosis may, in part, be due to the heterogeneity between nasal and lung fibroblasts. Fibroblasts participate in the inflammatory response by releasing ECM proteins and cytokines. TGF-beta is thought to participate in chronic inflammation and fibrosis. Myofibroblasts are the activated form of fibroblasts. A phenotypic hallmark of myofibroblasts is the expression of smooth muscle alpha-actin (SMA). OBJECTIVE: We examined whether there is any heterogeneity between nasal and lung fibroblasts upon stimulation with TGF-beta(1) with regard to the synthesis of SMA, pro-collagen type I and vascular endothelial growth factor (VEGF) as well as translocation of Smad proteins. METHODS: Fibroblasts lines were established from human biopsy tissue. The expression of SMA, pro-collagen type I, VEGF mRNA was evaluated by reverse transciptase RT-PCR. The amount of pro-collagen type I and VEGF was measured by ELISA. By immunocytochemistry, we analysed the expression of SMA and Smad2, 3, 4 in cultured fibroblasts. RESULTS: TGF-beta(1) induced SMA and pro-collagen type I synthesis in lung, but not in nasal fibroblasts. By contrast, TGF-beta(1) induced VEGF synthesis in both lung and nasal fibroblasts. After stimulation with TGF-beta(1), Smad2, 3, 4 were translocated from the cytoplasm to the nucleus in lung fibroblasts, whereas only Smad3 was translocated in nasal fibroblasts. CONCLUSION: These results establish the heterogeneous responsiveness of fibroblast populations in the airways to TGF-beta(1) and that such a heterogeneity may contribute, at least in part, to the different pathological outcomes of inflammation in the upper and lower airways.

Nasal mast cells in perennial allergic rhinitics exhibit increased expression of the Fc epsilonRI, CD40L, IL-4, and IL-13, and can induce IgE synthesis in B cells.

Cross-linking of allergen specific IgE bound to the high affinity IgE receptor (FC epsilonRI) on the surface of mast cells with multivalent allergens results in the release of both pre-formed and newly generated mediators, and in the manifestation of allergic symptoms. The expression of Fc epsilonRI, and the synthesis of IgE are therefore critical for the development of allergic diseases. In this study, we report that nasal mast cells (NMC) from patients with perennial allergic rhinitis (PAR) expressed significantly greater levels of the Fc epsilonRI, CD40L, IL-4, and IL-13 as compared to NMC from patients with chronic infective rhinitis (CIR). The level of Fc epsilonRI expression in NMC of PAR patients strongly correlated with the levels of serum total (r = 0.8, P < 0.003) and specific IgE (r = 0.89, P < 0.0004) antibodies. In addition, stimulation of NMC with IL-4, upregulated the Fc epsilonRIalpha chain expression both at the protein and mRNA levels, as detected by flow cytometry and reverse transcriptase-polymerase chain reaction. Furthermore, NMC from PAR, but not CIR, patients induced IgE synthesis by purified B cells in the presence of Der fII (mite antigen). These results suggest novel and critical roles for mast cells in promoting the allergic reaction through the increased expression of Fc epsilonRI and by enhancing and amplifying the IgE production, within the local microenvironment.