• Europe-wide epidemiological studies on occupational allergy, drug allergy, venom hypersensitivity, exposure to various environmental agents

• Interactions between various risk factors of allergy development to explain prevalence differences

• Link between sensitization and clinical allergy development

• Incidence, prevalence studies of various disease phenotypes and endotypes

• Development of pan-European registries

Epidemiology is the study of health and disease in populations. Several landmark studies have defined the global burden of allergic diseases, and have demonstrated that the problem is growing. Major demographic, socio-economic and environmental developments such as urbanization, globalization, upcoming economies (BRIC countries) and climate change will most likely contribute to further increases. The International Study of Asthma and Allergies in Childhood (ISAAC) reports that well over 20% of children in European countries suffer from an allergic disease at some point during their childhood 14 . This study also assessed allergy prevalence sequentially and observed a rise in prevalence especially in areas where allergic diseases were previously less common 2 . Large-scale population-based data from the European Community Respiratory Health Survey (ECRHS) 15 and the Global Allergy and Asthma Network of Excellence (GA2LEN) 16 clearly show that allergic diseases are significant health problems in adults too. A similar initiative for food allergy (EuroPrevall) 17 , has been recently completed, but population-based information is currently lacking for occupational allergy, drug and insect venom hypersensitivity, as well as daily exposures to environmental agents such as pollutants and cosmetics. These studies have revealed significant differences in allergy prevalence even amongst those of the same ethnic background, advocating that, notwithstanding the importance of genetic factors, environmental factors are likely to be responsible for the observed prevalence gradients and time trends. Socio-economic background, family size, urban dwelling, farm exposure, infection history, diet, obesity, use of certain drugs, tobacco smoke exposure and indoor and outdoor air pollution are among the factors associated with atopic disease.

In spite of these clear indications, we are currently missing studies that aim at explaining the prevalence differences and trends between populations taking all known risk factors into account as well as the interactions between risk factors (including gene-environment interactions). Rapid developments in the field of information technologies allowing systems approaches now offer the opportunity to study these complex issues in a comprehensive way.

When it comes to allergies, it is vital to maintain an open mind about the nature of causal influences and be prepared to follow up clues or signals emerging even in, at first sight, unlikely places: for instance, the protective effect of Alpine farms has been an important stimulus to aetiological enquiry 18 . In addition, the link between allergic sensitization and clinical allergy remains poorly understood and new molecular methods may shed further light on this fundamental issue.

One limitation of large population-based studies has been the use of questionnaires in the diagnosis of asthma or allergic rhinitis and that more objective markers, such as spirometry and bronchial hyper responsiveness, do not capture the episodic nature of the disease and often do not correspond to the clinical phenotype. An advantage in atopic dermatitis is that the skin is readily accessible to examination. The strong association between clinical atopic dermatitis and filaggrin skin barrier gene mutation carriage has opened up new avenues to explore gene-environment interactions, not only in the context of atopic dermatitis, but also allergic respiratory disease and food allergy 19 .

Another important area of epidemiological research is the application of epidemiological methods to explore the quality and safety of medical care provided for patients with allergic diseases, for instance through establishing registries with a main focus on the efficacy and safety of treatments, such as immunotherapy, systemic immunosuppressive drugs and biologicals. Registries should also capture trends in disease prevalence and severity and differences between age and/or social groups. Data on emerging allergens, including work-related exposure, could also be monitored.

Overall, we need to find better ways of identifying the phenotypes of allergic disease, using standardized methodology between studies to facilitate direct comparability. This will then allow us to revisit known and hitherto unexplored risk and protective factors, preferably in longitudinal population-based cohorts that take into account environmental, genetic and immunological factors (biomarkers) as well as the fluctuant nature of allergic diseases and disease severity. Novel approaches to genetic and gene-environmental interaction studies will be helpful to identify the ‘missing heritability’.

• Immunological basis of allergy epidemic

• Innate immune response to molecules that are coexposed with allergens

• Role of novel subsets of T cells, B cells and innate lymphoid cells in allergy development

• Epithelial barrier function and its role in allergy development and chronicity

• Mechanisms of development of immune tolerance to allergens and novel ways to induce this

• Understanding epigenetic regulation of the allergic inflammation

• Development of novel biologicals to treat allergy

• Identification of novel biomarkers for endotyping patients for the prediction of treatment response and prognosis

• Development of immunological registries and Europe-wide disease-specific biobanks

In diseases involving the immune system such as allergy, autoimmunity, transplantation rejection, cancer and infections, antigens are either the direct or indirect cause of the disease and can be targeted for treatment 20 . The investigation of what makes a protein an allergen has been a prerequisite of understanding allergic disease to develop strategies for immune intervention. Allergens are almost always proteins, but not all proteins are allergens. A protein with allergenic activity should display two properties a) induction of IgE response, which involves the sensitization phase including T cell, B cell and dendritic cell cooperation, and b) induction of a clinical response to the same or similar protein on subsequent exposures, which involves immediate and late phase responses 21 . Many allergens contain potent stimulatory properties for the epithelium, such as the protease activity of house dust mite. Besides proteases and oxidases, extracts of pollen contain low molecular weight molecules such as pollen-associated lipid mediators or adenosine exhibiting a potential to stimulate and modulate immune cells 22 . Therefore, when exposed to e.g. pollen, it is more than just allergenic proteins that we inhale. More knowledge on the immune stimulatory properties (adjuvant-like activity) of allergens, in addition to their antigenic potential will be of great importance and might help in modifying allergens in the application of allergen specific immunotherapy.

An increasing body of evidence indicates that immune responses in allergy involve a comprehensive network of cellular and molecular interactions (Figure 1). Novel insights from implicated environmental influences on the development of allergy have increased interest in innate immune responses preceding and directing the adaptive immune response. In parallel, we have now identified a role of the local tissue immune response, not only in determining the implication of a specific tissue in allergy (i.e. atopic asthma vs. atopic dermatitis) but also the role of structural cells such as epithelial cells in the innate immune responses to environmental triggers, including allergens.

As a direct result of epidemiological findings of reduced incidence of allergy in farm environments, and many others on the so-called hygiene hypothesis, there has been interest in the development of early and innate immune responses. Pattern recognition receptors such as Toll like receptors (TLR) are important in these reactions, essentially deciding over the pro- or anti-inflammatory nature of subsequent adaptive immune responses. It is becoming clear that these receptors do not only play a role on innate immune cells directing their response to e.g. lipopolysaccharide, double stranded RNA or bacterial DNA, but also on tissue cells such as epithelial cells or keratinocytes 25 . Very recently, a novel category of innate lymphoid cells with still a wide variety of names, such as nuocytes, lymphoid tissue–inducer cells (LTi cells) or innate lymphoid cells (ILCs) have been described. The demonstration of IL-13 and IL-5 production by so-called type-2 ILCs in allergic inflamed tissue is a strong hint that these cells can have an important role in the Th2-type skewing in allergic tissues, even in the absence of direct involvement of antigens 26 . The epithelial cells at environmental interfaces (skin, respiratory tract and gut mucosae) are also important for allergy development, possibly through reduced barrier function and/or the inherent properties of epithelial cells to induce Th2 responses 27 . There is increasing evidence that the composition of the microbiota of the gut (and possibly of the airways or even skin) play an important role in deciding over development towards allergy or protection against it 28 . The epigenetic regulation of allergic inflammation rendering certain genes or gene areas more accessible to translation should be extensively studied and is expected to provide better links to the influence of the environmental changes. Also, multigenerational epigenetic memory can help us to explain the inherited influence of the environmental exposure 29 .

In addition to the almost classical definition of T helper cells in Th1 and Th2, many more T cell subsets have recently been described, including regulatory T cells, Th17, Th9 and Th22 cells 30 31 32 33 . Moreover, for all T cell subsets it is evident that their role can differ in different tissue types. Accordingly, there is increasing evidence that differentiated Th cell populations can alter the range of cytokines they produce, indicating a certain degree of “cell plasticity”. Understanding the molecular basis of the process through which cells modify their cytokine-producing potential is likely to provide interesting insights that may allow the development of strategies to alter Th cell function in immune-mediated pathologies, including allergic diseases. Amongst T-cell subsets, it is becoming clearer that CD8 T cells, classically called cytotoxic T cells, contain potent immunomodulatory subsets, which may be potent in the release of several cytokines, including IL-13. In addition, the immune regulatory and immune suppressive roles of various T and B cell subsets, such as T regulatory cells and B regulatory cells still remain to be elucidated.

In many inflammatory diseases, application of biologicals is an important option in treating severe forms of the disease. It is surprising that there is only limited potential of the known biologicals developed specifically for allergy 34 . Anti-IgE has major IgE decreasing effects, but is only indicated in a small subset of allergic asthmatics 35 at present although licensing studies for chronic urticaria are in an advanced stage. Blocking eosinophil differentiation and activation by anti-IL-5 is effective in vitro, but results from clinical studies 36 , suggest the need for identifying responsive populations. The outcome of the application of these agents has indicated that our knowledge of the immunological mechanisms responsible for allergic inflammatory diseases remains incomplete. Although improved forms of anti-IgE or blocking of IL-5 effects may provide better drug efficacy, it is also important to design new biologicals and find novel application of established ones. Combined application of allergen-specific immunotherapy (SIT) with anti-IgE treatment, might improve safety and efficacy of immunotherapy.

SIT is the only treatment that alters the immunological basis of the disease. The immune responses to allergen observed during SIT are being described at increasing level of detail, but there is a continuous debate around mechanisms of induction and maintenance of tolerance. It is absolutely essential to further elucidate the immune mechanism of SIT. Only in this way new leads can be found to transform SIT from a therapy requiring “chronic administration” for years in a row into an effective therapeutic vaccination based on a small number of shots, and perhaps even a preventive vaccination 34 .

Evidence is gathering that the complex interplay between the innate and adaptive immune response both of the myeloid and lymphoid lineages, in combination with the immune response of the tissue ultimately determines the development and expression of allergic diseases. A further important issue comprises adjuvant factors from the allergen carriers. We face an interesting and challenging era that will implicate all novel immunological insights in understanding better the immune-pathophysiological mechanisms in allergic diseases. This will lead to improved insight in the disease itself and also in new treatment options that may even result in allergy prevention, which is a major concern not only for parents thinking about their children, but for society as a whole.

• Improvement of molecular diagnostics methods

• Diagnosis of biomarkers for endotyping

• Easy and standardized tests for cellular diagnosis

• Development of point of care assays and devices

• Development of tests for endotyping, follow up of exacerbations and treatment response

The challenges in allergy diagnosis lie in developing methods that are objective, rapid, reproducible, cost-effective, sensitive and specific for the disease. They need to be able to identify exposures and contribute to decision making for treatment, preferably also in primary care. In addition, tests monitoring the response to treatment and allowing the comparison of preclinical and clinical effects across large cohorts and in several countries are needed. As recombinant molecular therapies are becoming available, there is a need to tailor treatment to disease burden, phenotype and/or endotype more effectively, which has always been a key request by patient groups; in this respect improved allergy diagnosis is a prerequisite. Molecular diagnostic methods enable a much more detailed analysis of the allergen molecules and their association with clinical presentations. Molecular approaches have great potential to significantly improve the prognostic value of diagnostic tests, but large-scale clinical studies are needed for their validation. Both allergen molecules and recombinant antibodies are made available to enlarge the repertoire of diagnostic tests 37 . The first allergen molecule-based multiplex tests have reached the market 38 , significantly increasing diagnostic and epidemiological options 39 .

Improvement and standardization of cellular tests, such as the basophil activation test, 40 will enable laboratories to more closely monitor disease status and advance allergy diagnosis and monitoring from the mere assay of IgE affinity, concentration and avidity to an integrated evaluation of the burden of allergic disease on the individual. Such an approach is not feasible at the moment. A similar methodology to the one used to produce standardized T cell tests, should be adopted. The involvement of reference centers and standardized comparisons of efficacy can lead to standardized methods of analysis. In combination with molecular tools, this will enable improved-resolution diagnosis with a higher prognostic value, which in turn will result into more precise diagnosis and superior monitoring of allergic disease. Recent advances in multicolor flow-cytometry are expected to contribute to cellular diagnosis and disease phenotyping/endotyping. In addition, detection of recently discovered microRNAs and/or exosomes in body fluids may open new ways for non-invasive diagnosis and monitoring of patients. Development of a standardized mast cell line similar to resident tissue mast cells would revolutionize the understanding and diagnosis of mast cell-mediated immediate hypersensitivity reactions.

In the diagnosis of drug allergy, cellular tests can be more useful both for diagnosis of type I allergy 41 and for diagnosis of the more severe type IV allergy 42 . As treatment options expand and life expectancy increases, people will require more frequent medical treatment and ex vivo diagnostic approaches will become more important.

Ex vivo tests for type I allergy will play a role in both the diagnosis of occupational allergy and food allergy. Moreover, they are an important element in diagnosis of paediatric allergy, since they constitute an alternative to allergen exposure tests currently considered as the gold standard in diagnosis of allergy.

In the near future, individualized –omics analyses will provide a wealth of detailed information.

A new integrated approach, combining data of genomics (genome-wide SNP association studies) and metabolomics with disease-specific proteome and transcriptome data from biopsies and body fluids (blood, saliva, nasal lavage) will allow a comprehensive characterization of complex diseases for the first time. Furthermore, diagnostic tools to characterize the environment such as microbiome, pollen counts, mite counts, allergen quantification, mould counts, smoke, and other pollutants need to be developed and standardized across Europe.

In addition to diagnostic approaches based on large laboratory-intensive methods, individualized point of care testing should be developed as this can/will remove a burden from the health sector with patients eventually capable of partly monitoring their own allergic disease and optimizing their treatment in order to rely more on a predefined plan and electronic support (ICT and e-health) and less on frequent visits to the allergy clinic.

• Mechanisms and management of severe cases

• Characterization of phenotypes and identification of novel biomarkers for endotypes

• Devise a consensus definition for severe asthma and exacerbations

• Identification of factors increasing the risk of asthma exacerbations and preventing them

• Vaccine development against viruses that trigger exacerbations and severity

• Patient-tailored treatment

• Development of biologicals

• Establish European registry and biobank for respiratory allergies in meticulously phenotyped patients

An additional significant unresolved problem in the management of asthma is the failure to prevent and/or promptly treat asthma exacerbations, which are associated with significant morbidity, risk of death and high treatment cost 54 and whose prevention in children may reduce the risk of subsequent adulthood asthma 55 (Figure 2). Identifying the factors increasing the risk of asthma exacerbations and designing novel treatments that reduce the risk are key priorities. Virus infections have a major role in asthma exacerbations and preventive vaccines or passive immunizations are awaited to prevent virus infection-induced exacerbations. In addition, to allow for a rational approach to the management of asthma, we must consider the emerging evidence for pathophysiological heterogeneity of the disease, particularly in its more severe forms. The conceptual framework of asthma endo/phenotypes developed by the EAACI 56 57 can offer the basis for an improved perception of the pathophysiological mechanisms involved in severe asthma and asthma exacerbations and enable target identification and development of novel treatments. Prediction of the outcomes and personalization of treatment through innovative approaches and new technologies can contribute to an effective intervention in terms of prevention and reduction of healthcare costs, with improved quality of life for asthma patients 58 . So, asthma research should aim to implement a consensus definition of severe asthma and asthma exacerbations that could usefully guide treatment and match this with diagnostic tools for “scoring” the asthma patient in terms of disease severity and future risk for the use in primary care. The recognition of asthma as a heterogeneous disease is a prerequisite for planning studies aimed at differentiating between different endo/phenotypes and the sequential creation of robust clinically-relevant and endo/phenotype-specific biomarkers and therapies targeting specific pathophysiology, including longitudinal outcomes. In this effort, we must also identify relevant environmental factors and the influence of current and prior medication. The accomplishment of the above aims also necessitates the establishment of large Research Tissue Banks (including DNA, serum, lavage fluids and other biological samples) in meticulously clinically phenotyped patients and the execution of clinical studies to improve the evidence-base, since most randomized, controlled trials to date have been carried out in highly selected patients; we should now aim for effectiveness, rather than efficacy studies.

• Identification of molecular, genetic and environmental determinants of the atopic march

• Targeting skin barrier function for novel treatments and prevention

• Role of skin microbiota and colonizing pathogens

• Better characterization and identification of novel biomarkers for endotypes

• Monitor new contact sensitizers and promote patch testing

• Develop and evaluate new drug classes including biologicals

• Epidemiological monitoring of urticaria and hereditary angioedema

Atopic dermatitis is one of the most common chronic inflammatory skin diseases with an estimated prevalence of 20% in children and 5% in adults 67 68 . The direct and indirect costs of atopic dermatitis are significant and comparable to other common chronic diseases with large annual economic burdens. However, compared to psoriasis, the most closely analogous complex inflammatory skin disease, treatment options are limited. There is a need for new classes of drugs, such as biologicals for treating it, including those targeting the immune system, skin barrier, and skin microbiota. Developing methods for improving the skin barrier function should be an important focus of future research 69 . It is increasingly clear from advances in molecular genetics that a close interaction and reciprocal regulation of epithelial function by immunological events underlie allergic disease, and epithelial barrier function is becoming more and more important in other forms of allergic diseases, such as asthma and rhinitis 70 . A bench to bedside approach is necessary to identify the key elements of these interactions systematically.

Allergic contact dermatitis is one of the most common work-related diseases and is of appreciable public health importance because of its significant economic impact. As knowledge on its diagnostics through patch testing is waning, promoting patch test education is a paramount issue. New contact sensitizers continue to appear 71 and older ones become important in new situations, emphasizing the need to monitor their appearance in Europe and worldwide and integrate new knowledge to relevant regulations at all levels. Contact allergy in children continues to be underdiagnosed and should be studied, tested and publicized more often. The potential role of food chemicals as a possible cause of dermatitis and food allergy requires study and, conversely, exposure to shared haptens in cosmetics and food could potentially be a cause of food allergies 72 . Increasing exposure to palladium, with its high sensitizing potential, in electronic appliances, dental alloys, jewellery and car exhaust catalytic converters, presents a real risk of it becoming the ‘metal allergy of the 21^st century’ 73 . The epidemiology and dynamics of palladium sensitization call for an in depth study of palladium allergy from the scientific viewpoint and further regulation of its use.

Urticaria in all its presentations has an estimated lifetime prevalence of around 20% 74 . However, reliable epidemiologic data are scarce, and most of the published literature deals with adults. Thus, there is a need for epidemiological research into urticaria, as well as good diagnostic markers defining the subgroups within urticaria patients. In addition, treatment with new classes of drugs, including novel antihistamines, mast cell stabilizing drugs and biologicals, such as omalizumab 75 , should be evaluated thoroughly for their clinical effectiveness and understanding the biology of mast cell disease. Development of specific mediator antagonists for hereditary angioedema and cryopyrin associated periodic fever syndrome will help to define the phenotype of specific subsets of disease.

Airborne allergens are a major trigger of allergic diseases, especially of the respiratory tract. Monitoring of biological airborne particles (pollen and moulds) is currently done by private networks. All over Europe, these national networks are underfunded and on the verge of collapse. In addition, European Union (EU)-citizens and scientists have limited access to pollen and mould data due to diffuse property rights, as most stations are funded with private money.

Therefore, there is an urgent need to secure, harmonize and open the existing networks with a European-scale pollen, allergen and air pollution/air quality forecasting network, also capable of predicting future developments in migration of allergenic plants (like Ambrosia artemisiifolia), and the environmental change in allergen exposure due to climate change. Thus, we will be able to sufficiently serve allergic sufferers and policy makers. The existing networks could be incorporated in the Global Monitoring for Environment and Security (GMES) Network for air quality monitoring and forecasting, in combination with the modeling communities.

• Harmonization of existing networks for monitoring biological airbourne particles

• Monitoring of the ‘exposome’ in conjunction with epidemiology in sensitization and symptom monitoring

• Identification of the socioeconomic burden of different biological airbourne particles to define strategies to fight pollution

• Identification of the role of climate change in allergic diseases

• Epigenetics studies to link the environmental factors with inherited inflammatory thresholds

The causes of allergic diseases are multifaceted. Thus, multiple exposure monitoring (‘exposome’) in conjunction with symptom and sensitization monitoring may reveal novel associations and interactions. Assessment of the ‘exposome’ (biological and chemical, indoor and outdoor) EU-wide, in concert with ongoing epidemiological studies/registries of allergic symptoms and sensitizations, will produce important synergies 76 . The climate change and its impact on development of allergies, microbiota, virus epidemics, parasites, moulds and food resources should be specifically focused on 77 .

Pollen, moulds, parasites, viruses and bacteria are the carriers of allergens and/or innate immune system danger signals. These biological properties (not the pollen or the mould but the allergen and the danger signal) in ambient air are currently only partly monitored and should be an addition to current research. Cross border comparison, also with non-EU countries will enlarge the biological variance and thus facilitate the finding of allergy modulating factors 78 79 .

• Differential immune response to various microorganisms

• Helminth infections as a paradigm to prevent/treat allergy

• Evolution and dynamics of the microbiome

• Viral-bacterial interactions

• Development of vaccination and other targeted interventions against human rhinoviruses

• Determine mechanisms underlying deficient antiviral immune responses in asthma

Both infections and commensal micro-organisms have a crucial role in the development and severity of allergic disorders and are involved in their resolution or chronicity. To harness their properties for prevention and treatment of allergies, we need to better understand which micro-organisms affect allergies naturally and how they interact with immune and inflammatory responses in allergy. This requires considerable epidemiological, clinical and mechanistic research both in human and animal models.

Helminth infections are associated with reduced skin prick test responsiveness to environmental allergens, especially if the parasite burden is high and occurs in early life. The evidence with regard to allergic disease is more heterogeneous, but some studies show a negative relationship between allergy and certain parasite infections, such as hookworm and schistosomiasis 80 . However, clinical trials treating people with established allergy with a single parasite dose have not shown beneficial effects so far. Future research will need to include trials of multi-dose administration resulting in higher worm burden and stronger immunomodulation. Another approach could be to develop allergy therapies and prophylaxis based on parasite-derived products; such products should be assessed for efficacy and safety, especially in young children, who are likely targets for primary prevention of allergy 81 .

There is also emerging evidence that exposure to both commensal and pathogenic bacteria may influence the development of allergy 82 . We need to understand in detail how the microbiomes of gut, skin, and airways evolve from early life to senescence, which factors (e.g. birth mode, breastfeeding, diet, puberty, pregnancy, infections) influence their composition and how this relates to the development and severity of allergies. Such studies will also contribute to investigations aiming at the development of preventive and therapeutic applications of pre-, pro- and symbiotics.

During the last decades, it has become evident that viral infections, particularly those caused by human rhinoviruses (RV) are the most frequent triggers of acute exacerbations of asthma; in some cases viral agents have been detected in more than 90% of such events 83 84 . RVs are also responsible for the majority of mild rhinitis, i.e. common colds, therefore contributing further to symptoms in respiratory allergic patients. Viral bronchiolitis in infants is associated with an increased asthma risk. Once again RVs appear to be the agents most strongly associated, with a remarkable 40-fold increase of risk of wheezing at age 6 after an early symptomatic RV infection 85 . Whether early life episodes of respiratory viral infections also predispose to the induction of sensitization is less well-established, but has potentially great impact on strategies for allergy prevention. Given the lack of effective treatment or prevention of virus-induced asthma symptoms, future research must focus on developing diagnostic, therapeutic and prophylactic modalities for virus induced respiratory allergy. Our incomplete understanding of the role that respiratory viruses play in immune and inflammatory responses of the respiratory tract, their regulation and resolution, requires research in both animal models and in well-defined patient populations 86 . This needs to include studies to determine mechanisms underlying deficient antiviral immune responses reported in asthma 87 and define the roles of interactions between different viruses, including the recently identified rhinovirus-C 88 , viral-bacterial synergistic effects, which accentuate airway inflammation 89 , repeated infections, and interactions between viruses and other factors including allergens and pollutants, in establishing chronic respiratory allergies. Prospective cohort studies involving comprehensive microbiological detection and identification of other potential triggers of asthma development and exacerbations may be required to provide accurate information on natural microbial exposures and the relative impact of individual respiratory pathogens.

• Understand molecular mechanisms of tolerance and its disruption in food allergy

• Improve diagnosis with individual allergen components, food matrix interactions and threshold identification

• Establish food allergy phenotypes

• Establish novel immunotherapeutic approaches

• Evaluate the socioeconomic cost of food allergies

• Standardize nutritional interventions

For improved diagnosis of food allergy, complete panels of well characterized individual allergens and knowledge on their food matrix interactions regarding allergenicity, are still lacking. Identification of thresholds for each individual food is also needed. In component resolved diagnosis, investigation of allergen specific IgE recognition with clinical implications and the identification of marker allergens is needed at least for the most important food allergen sources. These well-characterized diagnostic tools will contribute to patient tailored dietary recommendations and to design avoidance strategies, accordingly; such approaches have been initiated within the context of the FP6-funded project EuroPrevall. On the other hand in depth knowledge of allergens and certified reference material available for the food industry will help them to fine tune their allergenic risk management. Furthermore, individual food allergens including their hypoallergenic variants will contribute to novel immunotherapeutic applications for food allergy.

Epidemiological and clinical studies suggest that there are different phenotypes in food allergy and that the onset (early, late), natural course (short term, persistent), and clinical presentation (mild, severe) differ. Multicentre studies involving a comprehensive clinical, immunological and (epi)genetic evaluation are needed to establish the different phenotypes in food allergy. This will further guide the management and specific treatment of food allergic patients.

Specific immunotherapy in food allergy, especially oral but also sublingual, has provided promising results. With the availability of hypoallergens, also subcutaneous immunotherapy has regained interest 98 . Studies ranging from basic science to clinical application are urgently needed regarding indications, underlying immunological mechanisms, safety, efficacy and cost-effectiveness of this treatment 98 .

Recently, methods were developed to assess and record the reduced quality of life of the food allergic patient. However, the implementation of these findings in improved dietary recommendations, training of the patient or production of safer foods is still lacking and calls for a multidisciplinary approach to address the relevant issue. In parallel, the socioeconomic cost of food allergy is largely unknown. Capitalizing on a specific instrument built in the EuroPrevall project 99 , the economic burden of food allergy can be studied across Europe, and the impact on costs of diagnostic and therapeutic interventions evaluated.

Despite the importance of diet and nutrition in immune development, only a small number of studies have evaluated their role on the prevention and natural course of food allergy and allergic diseases in general. There is therefore a need for descriptive studies on preventive nutritional aspects. These would include nutritional analysis around conception, during pregnancy, but also in early life and evaluation of atopic disease outcomes longitudinally. Nutritional analysis in lactating women as related to the composition of breast milk may also provide important insights. The role of specific nutrient levels, e.g. vitamin D, should be part of an extensive nutritional analysis 100 .

The influence of the nutritional composition of avoidance diets on both nutritional status, but also disease severity, of children and adults with food allergy should be further evaluated 101 .

Unlike other diagnostic tools, the removal of a suspected food from the diet has not been properly standardized nor validated. Furthermore, there is an important diagnostic value of a standardized allergy-focused diet history. Based on expert consensus opinion, both the recent NIH US guidelines and the UK NICE guidelines 102 reported that diet history is the cornerstone of food allergy diagnosis. Research efforts should gather evidence to substantiate this opinion, including the role of the dietitian in both diagnosis and individual dietary counseling.

Food labeling remains an important issue and EFA is actively involved in the elaboration and follow-up of the new EU regulation on food information to consumers.

• Training (multiple drugs, complex manifestations and mechanisms)

• Standardization of test procedures (still not achieved)

• Development of new diagnostic tools

• Reliable epidemiological data with proven hypersensitivity

• Clinical multicenter studies on diagnosis and therapy with well-phenotyped patients

• Mechanistic studies (pharmacological interaction with immune receptors (PI) concept, genetic pretesting, risk factors)

The availability of tissue and serum samples from immune-mediated drug hypersensitivity reaction (IDHR) patients is a prerequisite for basic research in the mechanism of DHRs, which may be allergic or non-allergic, with immunological or pharmacological recognition and with the allergenic determinants mostly unknown. In this effort, the study of genetic variants, especially of the major histocompatibility complex (MHC) molecules, should be included, in order to enable personalized recommendations for the risk to develop a DHR. To generate preclinical testing methods to assess the risk of potential DHRs in new drugs, research should also encompass the characterization of drug-specific (chemical structure, metabolites, exposure), intrinsic (genetics) and extrinsic risk factors (viral infections, other danger signals), complemented by preclinical prediction models.

On the socioeconomic level, as in other allergy manifestations, studies should define the impact of DHRs on the quality of life of patients and their cost on the health system.

A moderate physical activity favors health and well-being whereas a sedentary lifestyle and obesity are associated with a higher prevalence of allergic diseases in both children and adults 107 . Interestingly, however, an intense physical training, as a stress event, may induce several changes in immune parameters and response to environmental agents, which essentially result in an increased susceptibility to infections and in a preferential Th2 (allergic) phenotype 108 .

• Describe mechanisms of exercise-induced bronchoconstriction and identify biomarkers

• Understand the immune derangement after strenuous exercise

• Therapeutic trials in athletes

• Standardization of specific diagnostic tests

Physical exercise may also play a direct role on target organs triggering symptoms such as bronchial obstruction and anaphylaxis. Indeed, allergic diseases, asthma and exercise-induced bronchoconstriction (EIB) are present with high and increasing prevalence in athletes, significantly affecting their health status and performance and therefore representing a major concern in Sports Medicine 109 . The necessity therefore in Sports Allergy research is to describe the mechanisms of EIB, so as to clarify the clinical relevance and natural course of this phenotype and also identify markers of epithelial stress and inflammation. In this line of research, it would also be feasible to identify putative danger signals of immune derangement linked to the transient immune deficiency, which forms the basis for recurrent infections in elite athletes and is caused by strenuous and continuous training loads. Research efforts recruiting the –omics approaches should allow understanding of the impact of acute and chronic exercise as well as any correlation of gender on the immune functions.

With regard to clinical pharmacology in Sports Allergy, this is often extrapolated from data obtained in the general population, creating a need for randomized controlled clinical trials solely in athletes. Allergy and asthma in athletes is underdiagnosed 110 but this would be remedied if athletes were to be routinely evaluated through a standardized protocol for sensitization and immune function; such a policy would also allow improved management of their condition and permit the accurate study and screening of the effects on physical performance of anti-allergic and anti-asthmatic drugs (with special reference to beta-2 agonists). There is a need for guidelines for the diagnosis and management of allergic diseases and these should be widely diffused and applied by Sports physicians, in compliance with the World Anti-Doping Agency (WADA) rules, in the adequate management of these clinical pictures 111 . Some special attention should be paid to the usefulness of different methods of non-specific bronchial provocations in diagnosis of athletes’ asthma. Since metacholine provocation does not prove useful in a substantial percentage of cases, more comparative research involving other stimuli is needed in order to create feasible and unified algorithms to be used in professional athletes.

• Changes of occupational allergy with time

• Public health impact of occupational allergy

• Monitor allergen exposure at workplaces

Occupational allergy and particularly occupational asthma can be caused by more than 300 agents and about 15% of adult-onset asthma can be attributed to workspace exposures 112 113 . Exposure-specific studies on occupational asthma have focused on substances of high and low molecular weight- e.g. flour, enzymes, isocyanates and latex 114 . While in developing countries the workforces probably have more extensive occupational exposures than in high-income countries, lower figures of the occurrence of occupational asthma have been reported, probably indicating a problem of underdetection and methodology. In addition, protective mechanisms described for respiratory allergies (hygiene hypothesis) may also play a role for occupational allergies. Still, the public health impact and burden to society related to occupational or work-related asthma have been scarcely investigated. Assessment of excess burden of disease due to specific occupational exposure is a useful measure, when there is valid information on population exposure and attributable fractions. Changes in the working conditions and implementation of new substances lead to the introduction of new allergens in some workplaces and the onset of new, so far unknown cases of occupational allergy. However, there is only little available information on the changes in the pattern of occupational allergy over time. An objective evaluation of the time trends in the incidence and causes of immunological occupational asthma in the EU, using workers' compensation data or registry-based data would be of great importance 115 116 117 118 . Prevention of occupational asthma related to a work-sensitizing agent would ideally be achieved by avoidance of exposure causing immunological sensitization and subsequent asthma. Especially apprenticeship is a period of increased risk of developing work-related respiratory allergic diseases and therefore is a need for appropriate professional advice to young adults aiming to reduce unsuitable job choices and prevent impairment from their careers 119 . Different forms and different steps of prevention exist, like primary prevention (the ideal form of prevention), where workers do not become sensitized to agents that can cause asthma. Since primary prevention is not always successful, secondary prevention by medical surveillance has some evidence to support benefit for those working with common occupational sensitizers. On the other hand it is necessary to optimize workers’ education and also the diagnosis and medical management to minimize further impairment of the airways 120 121 122 123 124 . There is a need to increase the implementation of airborne allergen quantification at workplaces to be used as scientific background e.g. for the discussion of health-based occupational exposure limits for high molecular weight sensitizers.

• More studies in children of different ages are needed, both on the development of allergy and to evaluate differential responses to treatment

• Large, primary prevention intervention programs to confirm current hypotheses and reverse the epidemic

• Improved, non-invasive diagnostic tools

• Prevention and/or treatment of asthma exacerbations

• Evaluate the long-term effects of immunotherapy in children

• Focus on adolescence

Asthma is an important problem in childhood affecting many children and resulting in significant morbidity 128 . It has been suggested that vitamin D deficiency may play an important role in the development of asthma as well as being associated with severe asthma 129 . Like many findings in paediatric allergy, these are based on observational data that are very susceptible to confounding. There is a research need for multi-centre randomized controlled trials to assess the role of vitamin D in the development of asthma and/or severe asthma. Another unmet need in paediatric asthma is the study of exacerbations, many of which are associated with viral respiratory tract infections 83 ; we also do not currently have any therapies capable of preventing or treating such exacerbations. A possible role of early respiratory virus exposure in facilitating sensitization to allergens requires attention as well. A further unexplained association exists between food allergy and severe exacerbations of asthma 130 , which is important particularly as asthma is also associated with severe allergic reactions to foods. Severe asthma in childhood, and adult life, is poorly understood. In an attempt to understand this area, a novel unbiased “omics” systems biology approach is currently being used to explore the underlying pathophysiological mechanisms 131 . A similar approach is also being used in other allergic diseases and both studies can be expected to highlight many novel pathways that have the potential to deliver new therapeutic approaches for allergic disease.

The majority of our therapies for allergic disease only suppress the disease process while they are taken. The exception is immunotherapy, which would appear to have the potential to alter the natural history of allergic disease in childhood, for example preventing the development of asthma in children with hay fever 132 . Again though, as the quality of the paediatric evidence in this area is not optimal there is a need for well designed, double-blind, placebo-controlled studies to assess the long-term effects of immunotherapy in childhood. While such studies are ethically challenging, it is important to characterize the long-term effects, as this would substantially alter the perceived cost-effectiveness and trade-off between efficacy and safety of immunotherapy in childhood.

Adolescents and young adults are at higher than expected risk of morbidity and mortality from both asthma and food allergy. While this is poorly understood, it may result from the disengagement of adolescent patients from their medical needs as they are challenged by the usual process of adolescence 133 . It is also not assisted by the lack of continuity between paediatric and adult medical care in many countries. There is a need to develop a better, adolescent-focused approach to this at risk group to tackle this unmet need 134 and to develop better transition strategies to ease the progression from paediatric to adult services.

• Mechanisms of induction and long term maintenance of allergen tolerance

• Molecular mechanisms of how T-reg cells and B-reg cells are generated in vivo and how to affect their life span

• Role of resident tissue cells in immune tolerance

• Molecular mechanisms of spontaneous healing, remissions and exacerbations of allergic disease

• Local tissue events during SLIT and epicutaneous SIT

• Better adjuvants that specifically induce immune tolerance

• Early biomarkers and predictors to decide to start, stop and success

• Phase III clinical trial primary outcomes equivalent to real-life exposure

• Efficient short term and long lasting treatment modalities

Outcome measures for both clinical trials and routine clinical practice should be further standardized and validated. To date, the required primary outcome is real-life exposure, which by its nature is very poorly standardized. Alternatives are urgently needed, not only because costs of failed trials due to lack of pollen exposure are a great financial burden to the sponsor, but perhaps even more importantly it is not ethical to subject patients to double-blind, placebo-controlled (DBPC) trials in which exposure is at best poorly controlled. Another issue is the dominance of poly-sensitization in clinical trials conducted for one allergy. Clear indications and guidelines, especially in regard to polysensitized patients are therefore needed. Multi-allergen immunotherapy needs more supporting data to be validated. The use of surrogate antigen challenges in the eye and nose and their relationship to clinical efficacy of SIT should be evaluated for both, seasonal and perennial allergens. The use of pollen chambers in dose–response studies has to be adequately studied. Surrogate allergen challenges should also be evaluated as an alternative primary outcome for phase III clinical trials. New modalities of allergen-applications such as the epicutaneous and the direct injection of allergens in the lymph node are promising and need to be further evaluated. The long-term efficacy and safety of these modalities needs to be confirmed.

In children, there is a need to identify an optimal dose, dosing frequency and duration. Most importantly however, long-term efficacy, including the preventive capacity for asthma and new sensitisations, and the safety profile of allergen specific immunotherapy should be further addressed in the paediatric population. This will facilitate the recognition and approval of allergen specific immunotherapy in children by regulatory national and international agencies. The demonstration of long-term efficacy is required for the current mandatory paediatric investigation plan (PIP) that must accompany applications for marketing authorization submitted to the European Medicine Agency (EMA). In addition, a role of SIT for secondary prevention in already sensitized children has been evoked, but requires further evaluation. Studies exploring this hypothesis are definitely needed. Furthermore, there is a need to perform economic assessments in high-quality prospective and long-term clinical studies comparing immunotherapy with pharmacotherapy in real-life practice.

Understanding the mechanisms of immunotherapy will ultimately lead to advanced, curative treatments of allergic diseases, therefore research focusing on the generation, life span and different roles of T-regulatory cells is needed 34 139 . Furthermore, long-term immune tolerance and local tissue events should be studied in detail, in parallel to the understanding of spontaneous healing, remission and exacerbations of allergic disease. Specific issues in relation to immune tolerance include the molecular mechanisms of how T regulatory cells are generated in vivo, their life span induced by allergen immunotherapy, whether they have any deleterious roles, tolerance to tumour antigens and chronic infectious agents and the role of resident tissue cells 140 . Increased knowledge on tolerance induction may also lead to strategies for preventive vaccination 141 .

Biomarkers able to predict clinical response, treatment outcome and/or monitor progression of the treatment are also key to enhance clinical decisions. Any differences in the mechanisms of high-dose and low-dose allergen specific immunotherapy need also to be assessed.