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Dr. B. Koletzko: Thank you for a very stimulating and fascinating talk. I was particularly impressed by your observation that early specific sensitization to food allergens is a strong predictor of later respiratory disease. Is this related to your choice of putting IgE on top of your list of atopic phenotypes? From the clinical point of view, IgE is a rather frustrating molecule because we see a lot of patients with allergy who don't have elevated IgE, particularly if they have food allergy or GI manifestations. Moreover, we see a lot of patients with elevated IgE that don't have disease. In your MAS data you found that the frequency of IgE sensitization to food allergens was pretty stable between age 1 and 13 years, even though point prevalence of food allergy varies markedly during this age range. Thus I wonder whether you might be able to offer any better perspective for the future? Would there be an opportunity to develop a better algorithm where IgE may act as one factor, and the combination with other markers, such as genetic polymorphisms or environmental markers, might increase sensitivity and specificity of prediction?

Dr. Wahn: The reason why the prevalence of food allergies seems to decrease with age and not to increase was due to the fact that we always used the same panel of 4 food proteins, food allergens. This was the classical infant-type panel and Dr. Lack would immediately say why didn't you add peanut? We did not add peanut because 15 years ago nobody in this country was concerned about peanut. Now we would have added it. We actually took hen's egg, cow's milk, soy and wheat, which are the top 4 of the German list. Now I would say peanut has entered the top 4 even in this country where there is hazelnut exposure but not peanut exposure in babies. But one thing is quite clear, I don't think total IgE is a good predictor but the specific IgE responses indeed are. Whether this is a causal link between the early response and the subsequent sensitization to anything; whether phase A is a prerequisite for phase B or whether it is the other way round, and is just a co-expression of different atopic phe-notypes that are not causally linked but just associated, I don't know. But for the group of cohort children we know that the concentration for food-specific IgE antibodies in the serum is important in two regards. If you have very high concentrations you are more likely to develop food allergy and not just sensitization, and if you have very high concentrations you are more likely to develop other IgE responses and even clinical phenotypes. Whether this has any preventional aspect, I don't know, I would even doubt it.

Dr. Szajewska: You only briefly mentioned parasites in the prevention and treatment. Could you please comment on whether or not you see any place for the use of parasite antigens in the treatment and/or prevention of all allergic disease?

Dr. Wahn: As I said many people are developing wild ideas. One candidate is Trichuris suis which is known to gastroenterologists and is involved in Crohn's disease and chronic inflammatory disease. We are about to start a placebo-controlled trial on both the prevention and intervention of atopic phenotypes in hay fever.

Dr. Szajewska: Also in children?

Dr. Wahn: We would never recommend this for treatment but we strongly recommend it for study.

Dr Kaulfersch: You mentioned that there is no risk that allergic symptoms are enhanced in children due to vaccinations; but you listed vaccinations as a risk factor. So, I am still confused.

Dr. Wahn: Gruber [1] has studied this extensively and the answer is that the atopic child should have the same rights as any other child to get the whole panel of immunizations. There is no additional risk of developing any allergic phenotype even with injections such as those for measles and rubella, which in public opinion are always the bad guys. Some parent organizations still claim this without any evidence.

Dr. Saavedra: We typically establish respiratory phenotypes such as upper respiratory (rhinitis), lower respiratory (asthma) and skin (atopic dermatitis) as pheno-types. As gastroenterologists we feel a little left out because we think allergy of the GI system also has a phenotype. We don't quite understand these eosinophilia phenomena yet. But they clearly do respond to the protein management children get. So it seems to be one of those phenotypes, and from the nomenclatural point of view we also tend to confuse 'food allergy' as a phenotype, but we don't use 'aero-allergy' as a phenotype. Would you agree with that? It does look like there is a difference or an association between the first and latter manifestations, like atopic dermatitis which is associated with a higher incidence of other phenotypes later in life. With GI allergy some of it seems to be food related. Does the GI tract-associated lymphoid system handle things better than the respiratory tract lymphoid system, and therefore are there different associations? How can we ever decide if we begin with a food versus an air-borne allergen, or is it a GI manifestation versus lung manifestation? Those two organs are not only origins but also targets of the allergic march.

Dr. Wahn: I apologize for not pointing it out clearly enough, food allergy is a phe-notype. I left it out because I know it will be covered elsewhere. If you compare it to the skin or the airway manifestation, we would also say it is an important phenotype. If you look at the first age window of let's say 0-5 years, food allergy is more important than hay fever for example. When it comes to all kinds of food-related allergic reac tions according to our experience it is the second most important manifestation after the skin. Then all kinds of GI symptoms come before we see anything in the airways, but this might actually be due to the kind of patient who you see as a physician. What I am not so clear about and I would like to share my doubts with you, is what we see in the clinics. There apparently is a typical or characteristic sequential manifestation of certain phenotypes and a sequential manifestation of sensitization patterns. Food comes first, then comes inhalant; skin frequently comes before the GI tract, and then come the others. Is it just associated but independent? I would favor this now because many intervention studies aiming at secondary prevention have taken this window of opportunity between phenotype 1 and 2 and tried to intervene for example with the cetirizine, the H1 blocker, and they have failed to show anything. In my opinion it is not unlikely that we are facing independent, associated but not causally linked pheno-types and it will be very difficult to interfere at a later stage in order to block the atopic march.

Dr. S. Koletzko: I assume that language is only a marker for how many generations they have been in this country. But did you look for other environmental and also genetic markers?

Dr. Wahn: There are a couple of factors which account for this difference. We are in the process of starting a new Turkish cohort called the allergy prevention cohort. We want to understand more but this has to be done separately. A purely cross-sectional study with the school doctors generated hypotheses but did not prove anything, so now we want to understand whether it is related to nutrition or the domestic environment.

Dr. Fusch: One thing that considerably changed during the last 20 years in children is the oral exposure to antibiotics, especially aminopenicillin and erythromycin. What is the influence on allergy?

Dr. Wahn: There has also been a study by Niggemann et al. [2] in a variety of pediatric populations. My current conclusion is we don't have the answer to the question but there is something. Even if the exposure to a lot of antibiotics during the first year of life could be a slight modulatory factor, it still does not explain the whole epidemio-logic trend. It could at least modulate this in terms of favoring manifestations. This has clearly been a candidate for anthroposophic research because this hypothesis was generated in a Swedish study. We don't have the final answer.

Dr. Sorensen: When you talk about atopic dermatitis being a risk factor for the atopic march, atopic dermatitis in the first year of life can be very different from one child to another. Very often it just persists for 1 or 2 months, in others it persists for an entire year. Did you see a relationship between the intensity and the persistence of atopic dermatitis and the risk for developing asthma?

Dr. Wahn: We have followed the natural history of all these children in the cohort with regard to their eczema persistence. Actually by the age of 7, 64% lost their eczema completely, 20% had persistent eczema from infancy to the 7th year of life, and 16% were intermediate, they had eczema which came and went away again. The prediction for persistence was actually the same as for the subsequent manifestation of asthma, which was severe in infancy, and food allergy. Once you had this you had a much lower chance of growing out of it. This was published last year in the Journal of Clinical Investigation.

Dr. Kamenwa: I would like to go back to the issue of infection being protective against developing allergy. I work in a developing country where we have a lot of infections, parasitic, bacterial and viral. In my work as a gastroenterologist, I see more and more gut allergy evolving, which we never saw before. It is possible that these infections are actually a risk factor for developing allergy. Now I hear that they could be protective. So I wonder if some specific infections could be protective while others put the children at risk. In my observation, children who have had previous GI infections, especially viral in etiology, appear to have a higher risk of developing allergy.

Dr. Wahn: This is what the data say so far. I also heard from other developing countries that allergies are really on the rise, particularly hay fever for example. I wouldn't tell anyone that infection might be good because it would be confusing. It is important for us to understand the right message. Certain infections might have long-term consequences on the infantile immune system. If this is true, we must understand the effect in order to mimic it and develop something which might be protective in the end; but so far this is not the final message.

Dr Rivera: My question is related to the issue that we should learn something from infection and allergy. You mentioned the issue of hepatitis A and later on pertussis vaccine; as far as I know good work has been done with pertussis vaccine. I raise this question because we know the relationship of the worsening of wheezing and infection in children, and about hepatitis A and the so-called pertussis relationship. Do we have any scientific data about the difference in hepatitis A and pertussis in relation to infection?

Dr. Wahn: No, again we are just collecting data. It was Matricardi et al. [3] who did a study on Italian conscripts. All the data on these Italian conscripts are available, including their hepatitis A sero status. Two things are clear: the more older siblings they had in the family (if they were born in Italy when families still had many children), the more they were exposed to infections fairly early in their lives and the less likely they were to have developed airway allergies by the age of 18, and the same was true for hepatitis A. They concluded it was just oro-fecal infections which were protective. But then the tuberculosis investigators found that in countries where tuberculosis was still prevalent that allergies were relatively rare, not totally unknown, but relatively rare. Then animal experiments were made; we have several thousand allergic mice here at the Charité and we test for LPS or BCG for example. The mouse does not respond with IgE anymore; the mouse does not develop asthma anymore when exposed, and even if the mother is exposed before birth to LPS this helps her offspring. It is very difficult to come up with a final conclusion. It is an interesting field, research is ongoing, so let's keep an open mind and in the end we will understand.

Dr. Lack: I just want to push you a bit on your comments about the association between early egg allergy and the subsequent development of atopic disease, particularly asthma. You said you thought it was more likely to be an association between food allergies and development of asthma than causality. You also documented very nicely in your MAS study that there is very little inhalant allergen sensitization. If foods are relevant in the genesis of asthma and there is no inhalant sensitization around and the pathways for asthma being laid down very early in the first few years of life, then one could argue that allergy has nothing to do with it because aero allergens aren't there yet, food allergy is but it is irrelevant. I wonder whether there may be a causal link? It is very interesting that Heymann et al. [4] 20 years ago were already able to measure quantities of egg allergen and milk allergen in the dust of children's bed sheets. The same levels can actually be measured for house dust mites, and in fact in adults, in occupational asthma, egg and milk proteins can actually play a very significant role. Do you think there might be a link after all?

Dr. Wahn: I discussed it several times with those authors and they have some support for their idea that sensitization occurs via the skin and not via the route which we usually expect. We are having another meeting in which we will share our confusion on the atopic march. Spergel [5] has suggested that it starts in the skin and it ends up in the airways; this is true for the mouse but whether it is true for babies, we don't know. I would at the present time feel more comfortable with a rather conservative view. I also have to say that we were very enthusiastic about the ETAC and EPAAC trial which unfortunately turned out to be negative. So this confuses us even more. I am not so sure what we will end up with but we should at least leave the option open that the skin is more important than we think with regard to sensitization.

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