Top onderzoek voedselallergie Europrevall in Londen gepresenteerd
uitkomst maar ook wensen voor de toekomst - 2 Juni 2010
In Londen wordt het grootste EAACI (allergie en immunologie) congres ooit van 5 tot 9 juni gehouden. Meer dan 7000 wetenschappers, artsen en professionals zullen deze bijwonen.
De afgelopen vier en een half jaar is het grootste onderzoek ooit (Europrevall) naar voedselallergie over vele landen en meer dan 60 partners uitgevoerd. Vele publicaties zullen nog volgen en meer onderzoek op basis van de uitkomsten opgestart. Het project is door de Europese Commissie als excellent beoordeeld!
Tijdens het congres in Londen wordt deze hand-out tijdens de hoofdpresentatie uitgereikt. Natuurlijk in Engels, maar we bieden hem u (iets ingekort) graag aan.
EuroPrevall: outcomes and perspectives
E.N.C Millsa, A. R. Mackiea, P. Burneyb, K. Beyerc, L. Frewerd, C. Madsene, E. Botjesf, R.W.R. Crevelg, R van Reei.
All the data collected in the European cohort studies was entered on-line into a suite of customised databases. This involved developing over 154 forms for the birth cohort study, 18 for the community surveys and 8 for the outpatient clinic study. This centralised data collection has helped develop a cohesive set of data at a single point, to which other data (e.g. from serological analysis of patterns of sensitisation) and genetic profiling can be linked.
Whilst the focus of diagnosis in the birth cohort has focussed on those foods causing allergies in early life, such as egg and milk, in all the community surveys and outpatient cohorts food allergies were diagnosed by assessing sensitization foods by determining serum IgE using a much wider panel of 24 foods which included many foods on Annex IIIa of the labelling directive as follows:
Priority 1: hen’s egg, cow’s milk, fish, shrimp, peanut, tree nuts (hazelnut), apple, peach, celery
Priority 2: kiwi, mustard, sesame, soy, walnut and wheat.
Other foods, such as peach, which are known to be a problem food in the Mediterranean area, and kiwi, an emerging food allergen were included. Serological analysis was complimented with skin prick testing (SPT). Following an extensive data cleaning exercise full data analysis is currently underway and it is anticipated the full results of the EuroPrevall studies will be finalised in the coming months.
It is evident following preliminary analysis of data on all the cohorts that the
<!--[if !supportLists]-->· <!--[endif]-->Incidence of food allergy is higher in infants and young children than in adults
<!--[if !supportLists]-->· <!--[endif]-->Estimated prevalence of food allergies varies widely across Europe, and
<!--[if !supportLists]-->· <!--[endif]-->There is a geographic variation in the patterns of food allergies, although allergy to egg and milk is dominant in infants and young children
2.2 Double blind placebo controlled food challenge
A key feature of the EuroPrevall studies is that the diagnosis of food allergy involves the use of DBPCFC, an activity led by Barbara Ballmer-Weber in Zurich. Clinical protocols have been developed for diagnosis in the Birth cohort, children and adults. The project is focusing on nine “priority 1” foods (peanut, hazelnut, celeriac, apple, peach, egg, milk, shrimp and fish), chosen to represent many of the foods listed in Annex IIIa of EU labeling directive together with soy and wheat which are also being analysed in the birth cohort. This has involved training of clinical partners in the protocols, and development of common recipes to ensure data are as comparable as possible. These include a chocolate mousse desert, a dark chocolate matrix together and a fruit smoothy-type drink for the labile peach and apple allergens. The shrimp burger matrix has been based on a protocol developed by the Food Allergy Research and Resource Programme at the University of Nebraska. The clinical protocols allow both no-observed effect levels (NOEL) and lowest-observed effect levels (LOALs) to be determined. The ingredients and matrices are also being analysed for allergen content. The availability of the same foods (e.g. peanut, hazelnut) in both matrices has also facilitated a comparison of the behaviour of the allergens in these different matrices using in vitro methods and in vivo in man. The data on patient reactivity will also facilitate the development of improved food allergen hazard management and threshold data analysis is now ongoing through a new project funded by the UK Food Standards Agency. Such data will make an important contribution to allowing development of new approaches to allergen management, including probabilistic methods [8].
2.3 Diagnosis
The components in foods, known as allergens, are protein molecules which are responsible for triggering allergic reactions. An allergen library, representing all the major allergens from all the priority foods identified in the project has been prepared together with novel allergens identified in foods found to be relevant from the outpatient clinic studies. The final library comprised 51 component molecules prepared from allergenic foods of plant (peanut, hazelnut, celery, apple, peach, walnut, soybean, wheat, walnut, sesame, mustard, kiwi fruit, sunflower seed, tomato and carrot) and animal (cow’s milk, goats milk, shrimp and fish) origin. Additional panels of “novel” allergens not previously characterised, have been prepared from kiwi fruit and shrimp. All the allergens in the EuroPrevall allergen library have been characterised and authenticated in terms of the structure and conformation, sequence and IgE binding capacity and ability to elicit histamine release in an in vitro cell based assay. This authentication has capitalised on the EuroPrevall serum bank. The EuroPrevall allergen library represents an important landmark in standardization of allergen preparation and authentication [9] and has facilitated the development of novel diagnostic methods (see below) and will form an important platform from which other methods that rely on purified allergens, notably those determining allergens in foods.
Using this platform of allergens and working closely with the clinical researchers in the project, the concept of component resolved diagnosis will be explored to ascertain whether assessing patterns of sensitization to individual allergens offers additional diagnostic power with regards to food allergies than is currently possible with serological analysis using food extracts.
Component resolved diagnosis: Using a subset of 31 purified and authenticated allergens from the EuroPrevall Allergen Library was used to prepare allergen specific ImmunoCAPs and allergen chips. These new diagnostic tools underwent a technical validation which proceeded well and subsequently led to a full validation using panels of allergic sera drawn from the EPSB and building on the availability of sera from patients whose allergy has been confirmed by DBPCFC. A workflow for semi-automated processing of samples has been established for the allergen chips in preparation for the screening of ~ 6,000 EuroPrevall serum samples to define patterns of sensitization to different allergens in the cohorts, rather than simply using food extracts. These were used to profile the sera from the cohorts with regards IgE-binding to foods, with over 6,000 sera having been processed in the final phase of the project. Further data analysis will be required to link such molecular profiling to the clinical and epidemiological data on the cohorts to realize the impact of this data. Single allergen CAPs were prepared for celeriac [10] and kiwi [11] allergens and evaluated using pre-existing panels of human allergic sera. These studies are contributing to demonstrating the utility of this serological approach to diagnosis of food allergy and have proven to be important in informing partners how to undertake data analysis in the complex study EuroPrevall study populations. The approach will be taken forward in the future using panels of allergens and sera from DBPCFC positive patients arising from the outpatient clinic studies for other priority 1 foods such as hazelnut. However, the linking of such serological analysis to clinical data to assess the full value of the component resolved approach to diagnosis in the other priority 1 foods will not be realized within the project lifetime.
2.4 Socioeconomic studies
The cohorts developed in EuroPrevall give a tremendous opportunity to define the socioeconomic impact of food allergies [12]. A team of psychologists, clinical researchers and economists led by Lynn Frewer has developed a suite of questionnaires for assessing impact of food allergies on quality of life (QoL) for children, teenagers, adults and parents of allergic children. A validated questionnaire has also been developed to assess the economic impact of food allergies. These are now being applied in depth in Ireland, The Netherlands, Spain and Poland. Communication of information about allergens in foods through labelling is an important part of allergic consumers managing their condition. Five information scenarios capitalising on ICT approaches to convey information about foods, including a standardised label, a small electronic personal shopping assistant (SPSA) and an Infoterminal (IFT) amongst others are being assessed as novel means of providing food allergy sufferers with the information they need to manage their condition.
Conclusions
In addition to the data and biological resources the EuroPrevall project has formed a network of pan-European (and beyond) researchers spanning disciplines from epidemiology to economics, from molecular genetics to clinical science, risk management to food science. This is unique and necessary to realize the potential of the data and resources, in particular to ensure its delivery in a form which can be used by risk assessors and risk manager, such as the European Food Safety Authority and DG SANCO. It is also important with respect to maintaining competitiveness of European industry – spanning food safety and allergen management issues in the food industry to exploitation of new knowledge in the development of improved diagnostics and treatments for allergic disease. Europe is the envy of the world for having developed such a network. As part of ensuring a cohesive transition and effective use of the resources developed by the project, the partnership has developed and implemented a plan under which the collective value of the EuroPrevall outputs, particularly in terms of shared biological resources and other know-how, can continue to be accessed. A workable management system has been put in place in order that the project’s collective resources can be assessed in a way that maximized their value to the allergy scientific community. This has led to the establishment of a EuroPrevall Resource Access Committee (RAC) and agreed mechanisms for partners and third parties to use the RAC to access the projects outputs for further allergy research. An amendment to the Consortium Agreement has been drafted and agreed amongst most of the partnership, which establishes the RAC and how it will operate in the future.
The future realization of these resources can be envisaged under three different topic headings:
Food allergen risk management: The data from EuroPrevall provides a significant advance but still needs to be translated into validated evidence methods for risk management that can be used effectively by the food industry to manage allergens in foods. The data and tools are directly relevant ot assessing the risks posed by novel foods and processes, spanning GMOs and novel technologies such as nano-scale food structures. Allergenic risk assessment is a significant barrier to approval of such novel technologies and is likely to prove to be a barrier to their implementation In the coming years. This is likely to adversely impact on the ability of the European Community to respond to the challenges facing it regarding food security, sustainability and an aging population. Addressing these issues will require new approaches. The lack of effective tools for allergenic risk assessment of GMOs intended for food use has already been highlighted by EFSA GMO Panel draft opinion (2009) which when linked to the lack of know-how and approaches to assess the safety of nanotechnology in the food arena (EFSA Scientific Committee 2009) makes a compelling case for further research in this area. Any approach needs to take into account the effects of the food matrix and food processing procedures on allergenic potential which is still poorly understood. There is also a clear need to ensure aspects relating to stakeholder and public engagement are incorporated in to this. Given that a significant proportion of food allergies in Europe can be linked to pollen allergies, the effect of global warming will change the pattern found by Europrevall and should be addressed
Preventive and curative strategies; there are clearly gaps relating to the prevention and cure of food allergies which need to be underpinned by a knowledge of mechanisms involved in sensitization/tolerance induction which are currently lacking. There is considerable interest in dietary interventions using pre- and probiotics, and other nutritional interventions such as ω-unsaturated fatty acids where timing of interventions maybe crucial. It is emerging that prenatal rather than postnatal interventions maybe more effective in determining positive outcomes in infants. This also implies epigenetic effects are involved; such an assertion is also emerging from studies using animal models. It is also clear that linking such interventions to improving quality of life and economic functioning and targeting interventions and advice to specific groups, an activity linked to patient stratification. The EuroPrevall know-how and partnership can make an important contribution to the future development of these aspects. The EuroPrevall birth cohort study would provide a good platform from which to explore such issues and will be essential to reliase the potential of the investment (in monetary terms and the commitment of families recruited into the cohorts) in EuroPrevall.
Non-IgE mediated adverse reactions to foods; these are still poorly defined and unexplored and yet are a source of problems to patients. The EuroPrevall birth cohort has documented evidence that such reactions have a prevalence equivalent to IgE-mediated reactions to certain foods and, like IgE-mediated allergies, show a heterogeneous pattern across Europe. They may be related to a failure of serological methods for detecting IgE or actually have a completely distinct pathogenesis. This topic requires further research to explain these differences and either remedy them by improving diagnosis of IgE-mediated allergies OR define a new type of adverse reaction to food.
Acknowledgements
This work was funded by the EU through EuroPrevall (FP6- FOOD-2005-514000).
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