Phenotypes (appearance) of atopic dermatitis
Atopic dermatitis (atopic eczema, neurodermatitis) – an itchy skin disease that leads to dry, reddened and scaling skin and in bad cases will cause open wounds – is relatively common among infants and the trend is upwards. At the same time the condition acts as an entry portal for other allergies.
Children who had atopic dermatitis as babies later suffer more commonly from asthma or some other allergic disease.
For a long time it was assumed that asthma and atopic dermatitis in children were uniform diseases. It has only recently been recognized that different forms of these diseases are concealed behind these disease names and these forms develop differently. We refer to various phenotypes of a disease which differ, for example, based on the age at which the disease starts. This has so far been described primarily in childhood asthma. The work in Research Area B of CK-CARE has yielded initial evidence that different forms also exist in the case of atopic dermatitis.
Recent research has classified asthma into different phenotypes. This classification is based on the age of the child at the onset of the disease and on its natural course. As yet it is not known what factors determine whether atopic dermatitis persists, disappears spontaneously or if the child develops any allergic respiratory disease at all.
Among the children in the PASTURE/EFRAIM study, various phenotypes were identified. The classification is based on the age at onset of the symptoms of atopic dermatitis and the natural course of the disease. It is presented as follows: no symptoms or irregular symptoms (894 children, 85.6%), early onset but symptoms disappearing again (52, 5.0%), early-onset and persistent symptoms (55, 5.3%) and late-onset symptoms (44, 4.2%). Initial data show that children with an early outbreak (in the first year of life, with symptoms disappearing again or persisting) have a higher risk of developing asthma or a food allergy. This contrasts with children in whom the condition starts after the first year of life. In addition, it was shown that there is a link between prenatal environmental exposure and the phenotypes of atopic dermatitis.
Research is now focusing on finding out which type of a disease responds to which treatments. The principle of such targeted clinical trials is to study patients precisely in order to detect which form of the disease they are suffering from; this is referred to as phenotyping of the disease and the patients. With the aid of these patient results thus characterised, various clinical trials can be conducted so that the course of the different types of the disease can be identified and the optimum treatment can be used.
New approaches to the treatment of atopic dermatitis
The epithelium is the outermost layer of cells in an organ and provides a strong barrier function in order to prevent or treat allergic diseases. In the case of an allergy, this cell layer of the skin, nose or lungs becomes permeable. From studies with patients suffering from eczema, asthma or rhinitis, researchers from Area D have learnt that the barrier function of the particular epithelium does not operate properly.
The focus has been placed on tight junctions (TJs). Tight junctions (TJs) are narrow bands of proteins that hold together the outermost cells of a tissue and thereby form a barrier. This prevents penetration by substances from the environment, e.g. allergens, pollutants and bacterial toxins. Defects in the TJs disrupt this barrier function in the airways and lungs therefore play an important role in the development and existence of asthma.
It was suspected that one of the most effective approaches to allergy prevention is to maintain the functionality of these TJs and thereby ensure the tissue does not become permeable.
Early detection of permeability of the epithelium can consequently be used as early diagnosis in allergy-prone children and can help in taking the first necessary precautions. In an initial step, new methods of performing this analysis are being addressed. Thus treatment to protect the barrier function may become the method of choice for some patients with atopic dermatitis or other allergic diseases.
Researchers from Area D have studied the regulation of these TJs by a cell group that is typical of allergies (denTh2 cells) and their released messengers in both healthy and asthmatic individuals. The data showed that these Th2 cells and their messengers reduce the integrity of the TJs and hence the outermost barrier of cells. However, if one specific enzyme (HDAC) has been blocked, the defective barrier function could be restored as the cells increase the formation of TJ molecules.
Four new molecules have been identified which are responsible for the development of eczema in allergy patients. Furthermore, new and promising approaches to the diagnostic criteria and the treatment of the serious form of atopic dermatitis have been defined.
New allergen patterns in beer allergy
Experience shows that people who have an allergic reaction to beer are merely greeted with a grin from those around them. Nevertheless, these reactions can definitely be life-threatening. The prevalence of beer allergy in Germany is low. Therefore cooperation with Chongquing Medical University (China) and a CK-CARE exchange programme provided a useful opportunity to study 20 cases of anaphylaxis following beer consumption.
As well as detailed history-taking and clinical examination, skin tests were performed with 12 different materials. These originated from native beer production in collaboration with the Institute of Brewing and Beverage Technology at the Weihenstephan Science Centre of the Technical University of Munich (TUM) and comprised not only barley and barley malt but also sorghum, millet, maize and yeast, hops and enzymes, substances which are used in China but also in many countries around the world. Furthermore, various original types of beer were introduced into the tests. In addition, oral challenge tests were performed after the success of the skin testing.
75% of the patients showed positive reactions to at least one or more beer ingredients, most commonly to sorghum and sorghum malt. Seventeen patients reacted in the oral challenge with predominantly skin symptoms in the form of flush and urticaria, which lasted up to two hours. A total of 5 patients reacted to hops, 2 of them reacting solely to hops. Seven patients reacted to millet but frequently in concurrent reactions to barley or sorghum. One patient reacted to yeast in isolation. It may be concluded from these tests that beer allergy is not a simple phenomenon, but quite different ingredients in beer can trigger severe reactions. In conjunction with growing globalisation and the availability of foreign beer varieties, an increase in beer allergies might also be observed in Central Europe (Song et al 2013 in press). To pre-empt possible comments, we have also observed cases of anaphylactic reactions to grape juice and wine.
Award for Prof. Dr. Cezmi Akdis
At the general assembly of the American Academy of Allergy Asthma and Immunolgy (AAAAI) in San Diego Prof. Cezmi Akdis received the highest honor, the ELLIOTT MIDDLETON Memorial Lecture and Award and he gave the opening talk of the AAAAI in front of 8000 participants.
“Commitment to Change” – how can CPD be translated into improved practice management of allergy patients?
Effectiveness and sustainability of Continuing Professional Development (CPD) courses are a major challenge. For the first time a Commitment-to-Change (CTC) strategy was applied by Doris Straub Piccirillo, MME Unibe, Head of CK-CARE CPD, within the course “Allergy in everyday paediatric practice”. This helped participants to put into practice what they had learnt on the course and also helps in programme planning. In addition, the question of why paediatricians alter their practice behaviour after the course was explored in a qualitative study.
It requires more than pure knowledge transfer for doctors to change their behaviour in practice as a result of CPD. Although today’s CPD events increasingly focus on the learners and are becoming more targeted in other ways, it remains a challenge to translate the acquired knowledge into everyday practice. One of the reasons for this is that typically CPD courses are not directly linked to changes in the attending physician’s behaviour or to patient outcomes.
Consistently employing a CTC strategy offers a new solution in this respect. CTC is based on a pragmatic, uncomplicated and easy-to-use model which makes the user more aware of personal goals and values and also provides incentives for action.
In English-speaking countries CTC has proved a successful means of stimulating processes of change, but in German-speaking Europe (Germany, Austria, Switzerland) this strategy is a new tool in medical CPD. Doctors take part in CPD programmes for a wide variety of reasons: to consolidate existing knowledge or keep up-to-date with the latest knowledge, to acquire new knowledge or learn new skills, to coordinate procedures and practices or simply to meet their obligation to undertake CPD. They invest time and money to do this. Therefore CPD programmes should basically be structured, effective and designed with a view to achieving sustainable improvements.
Mobile laboratory for pollutant measurement
Anthropogenic factors play a central role in the development of allergies. To understand the effects of these substances on humans and create new approaches to prevention, scientists from Research Area A in cooperation with HICE (Helmholtz Virtual Institute of Complex Environmental Mixtures) analyse various substances in a “mobile lab” in the specific location where they originate.
Owing to increasing air pollution by marine traffic, especially in harbours, emissions from ships’ diesel engines running on a variety of fuels were the first to be analysed. It was found that the heavy oil emissions from marine diesel engines have a lot of organic impurities, but that even combustion of diesel EN590 releases plenty of bioactive compounds. The effects on immune processes are still being analysed at present. Dr. Sebastian Öder, CK-CARE, is involved in this project. Prof. Jeroen Buters (CK-CARE/ZAUM) took a leading role in the construction of the mobile lab.
The world’s first safety level 2 mobile laboratory was planned and constructed because a lot of combustion sources are either too big (e.g. marine engines) or are too far from biological laboratories. Safety level S2 is absolutely essential because the experiments are performed with human immortalised cells of safety level S2.
Dietary strategies for allergy prevention in children
There is still no treatment that can fully cure children with asthma and allergic diseases. Treatments are concentrated on tackling the symptoms. The symptoms can thus be relieved but the treatments usually have to be taken by patients for very long periods of time or even their whole lives. The best long-term therapy is still the avoidance of the causative allergen, e.g. certain foods.
As yet no effective strategies for preventing allergies have been found by researchers. There is hence a need to develop new approaches.
The prevention of allergies by means of diet in early childhood is one such approach that deserves consideration. Until recently prevention simply involved advising people to avoid certain foods, especially in infancy and early childhood. However, the latest recommendations no longer point in this direction. This is because it has not been proved that leaving out certain foods or introducing them at a later stage can actually prevent allergies. On the contrary, new proposals concentrate on the fact that early contact with allergens can induce immune tolerance. For instance, a time window might be opened in early childhood for preventing the development of allergies.
In our study on farmers’ children (PASTURE/EFRAIM) we have already shown that varied baby food in the first year of life reduces the risk of atopic dermatitis. We also demonstrated the same effect for asthma, food allergy and allergic sensitisation. Independently of these findings, we were also able to show the protective effect of supplementary baby food, mainly dairy products (e.g. yoghurt), introduced in the first year of life (as described in the Newsletter of October 2012).
Our findings from the farmers’ children study support the hypothesis that early contact with different allergens in the child’s intestinal tract is necessary for immune tolerance to develop. The nature of the diet, the gut flora and the immune response are closely interconnected. One possible explanation for the protective effect might be the early colonisation of the gut with microbes and their metabolic products. It has already been shown that what are known as short-chain fatty acids, metabolic products of certain intestinal bacteria, have an anti-inflammatory effect. These short chain fatty acids are generated by the fermentation of carbohydrates in the intestinal tract but they are also contained in food. One of these fatty acids, butyrate, is found in the triglycerides of cow’s milk. Therefore the natural butyrate content is high in dairy products.
We observed the preventive effect of short-chain fatty acids for the first time in the mouse model of allergic respiratory inflammation (similar to asthma).We gave the short-chain fatty acids orally to the mice throughout the duration of the experiment. In a healthy lung there are normally only a few macrophages passing through the lung. As soon as an allergy is triggered, the cell count in the lung rises sharply, which is mainly due to the migration of eosinophilic cells. We flushed out the lungs of mice in our allergy model and counted the cells they contained. We were able to demonstrate that the administration of short-chain fatty acids can markedly reduce the number of cells contained in the bronchoalveolar lavage (BAL, washing out the lung).
Messengers typical of an allergy also decrease markedly due to the administration of short-chain fatty acids, which further confirms the protective effect of these fatty acids in allergy.
These promising results in the mouse model have prompted us to tackle further projects along these lines. There are plans to administer short-chain fatty acids in combination with a butyrate boosting substrate as well as butyrate-producing probiotics.
In the study on farmers’ children we plan to investigate the level of short-chain fatty acids in stool samples from the first year of life. The link between fatty acid content and diet is to be investigated.
The results outlined above point to possible avenues for developing effective dietary strategies for the prevention of allergic diseases.