Updates from workpackages

Published: 30.03.2017 12:48

Anette Stensgaard WP 1.3 and 1.4

 

DaCAFA

 

Danish Children and Adolescents with Food Allergy

 

Health-related quality of life, family, friends and everyday life perspectives

 

Ph.D. defended  November 24th 2016 by Anette Stensgaard

 

The overall aim of this thesis was to gain more knowledge and understanding about how families handle everyday life having a member of the family diagnosed with food allergy. The thesis looks at food allergy from the perspectives of both the children/adolescents/adults with food allergy, and their family and friends. The thesis incorporates three interdisciplinary studies: i) Health-related quality of life of patients with hazelnut, egg, or peanut allergy from the perspective of the patients (children, adolescents, and adults) and the parents on their child’s behalf, ii) Risk perception using the green (safe), yellow (uncertain), and red (risky) colours in various social situations of everyday life, from the perspective of adolescents/young adults with peanut allergy and parents/siblings/friends, and iii) Lived experience of peanut allergy in adolescence and its impact on siblings and parents.

 

Paper 1:

“Quality of Life in childhood, adolescence and adult food allergy ? patient and parent perspectives”

A. Stensgaard, C. Bindslev?Jensen, D. Nielsen, M. Munch, A. DunnGalvin

https://www.ncbi.nlm.nih.gov/pubmed/27976436

 

Paper 2:

Green, Yellow and Red risk perception in everyday life – a communication tool”

A. Stensgaard, A. DunnGalvin, D. Nielsen, M. Munch, C. Bindslev?Jensen

https://www.ncbi.nlm.nih.gov/pubmed/27886390

 

Paper 3:

Peanut allergy as a family project: social relations and transitions in adolescence”

A. Stensgaard, C. Bindslev?Jensen, D. Nielsen

https://www.ncbi.nlm.nih.gov/pubmed/?term=%E2%80%9CPeanut+allergy+as+a+family+project%3A+social+relations+and+transitions+in+adolescence%E2%80%9D

 

Sigurd Broesby Olsen WP 2.5

Update from Mastocytosis Centre Odense University Hospital – MastOUH. ORCA 2017 annual meeting

Scientific achievements

1. We have developed a highly sensitive technique for detection of KITD816V in peripheral blood in adult patients with mastocytosis – including indolent forms. This has been incorporated in guidelines for diagnostic approach and algorithm in patients under suspicion of mastocytosis.

 

2. Following the point above we have been able to demonstrate that by use of this approach we identify SM patients – e.g. among anaphylaxis patients – who would otherwise have been missed due to lack of other symptoms indicative of mastocytosis. Similarly we are able to exclude mastocytosis by a high level of certainty by a non-invasive procedure in e.g. patients with more diffuse symptoms such as ‘MCAS’

 

3. By use of the Danish Health registries we have assessed epidemiological measures in SM such as the incidence, gender distribution, subcategories and mortality – and further assessed the relative and absolutes risks of known complications such as anaphylaxis and osteoporosis in a population based setting. We have furthermore been able to demonstrate an increased risk of solid cancers – especially melanoma and non-melanoma skin cancers – as well as an increased risk for cardiovascular disease in SM.

 

4. We have identified several families with familial mastocytosis including adult monozygotic twins, adult brothers, as well as a 2-generation family with as of yet unpublished combinations of KIT and other mutations detected by NGS-technique.

 

5. We are gaining experience with mutational profiles in pediatric mastocytosis by the use of a sensitive technique for detection of KITD816V as described above in skin and blood, as well as other mutations by NGS technique.

 

6. Nordic guidelines for mastocytosis were published in 2016 in a collaborative effort by Nordic experts in Denmark, Sweden, Norway and Finland, headed by MastOUH, with the aim of increasing awareness, guide and aid management of the disease, and facilitate the establishment of dedicated mastocytosis centres in all Nordic Countries. Similarly we published a state-of the art review paper on how to handle mastocytosis in the Danish Medical Journal (Ugeskrift for Læger), focusing on the need for a multidisciplinary approach and referral to specialized centres.

 

7. Patient reported challenges and needs were assessed in a qualitative manner, emphasizing the impaired quality of life in everyday life of patients bearing a rare disease with limited knowledge and awareness among health care providers, and the need for expert knowledge and counselling

 

Publications: www.pubmed.com

 

In Press/Submitted

Sigurd Broesby-Olsen, Hanne Vestergaard, Charlotte Gotthard Mortz, Britt Jensen, Troels Havelund, Anne Pernille Hermann, Frank Siebenhaar, Michael Boe Møller, Thomas Kielsgaard Kristensen, Carsten Bindslev-Jensen. Omalizumab prevents anaphylaxis and improves symptoms and quality of life in systemic astocytosis; efficacy and safety observations.

 

Submitted (JACI in Practice) February 2017.

 

Thomas Kristensen, Hanne Vestergaard, Carsten Bindslev-Jensen, Charlotte Gotthard Mortz, Henrik Fomsgaard Kjaer, Markus Ollert, Michael Boe Møller, Sigurd Broesby-Olsen. High diagnostic value of sensitive KIT D816V mutation analysis of blood in adults with suspected systemic mastocytosis.

 

Submitted (Allergy) February 2017.

 

Under final preparation

Sigurd Broesby-Olsen, Stinus Hansen, Hanne Vestergaard, Trine Torfing, Michael Boe-Møller, Thomas Kristensen, Anne Pernille Hermann, Carsten Bindslev-Jensen, Kim Brixen. Bone microarchitecture in Systemic mastocytosis. A Cross-Sectional Case-control Study using HR-pQCT.

 

Britt Jensen, Sigurd Broesby-Olsen, Carsten Bindslev-Jensen, Dorthe Nielsen.  Mastocytosis and everyday life – a qualitative study of the patient perspective.

 

Planned/ongoing projects:

Premasto – precision medicine in mastocytosis (outline/application)

 

Establisment of a humanized mouse model of systemic mastocytosis (protocol)

 

Characteristics and functional properties of circulating KITD816V-positive cells, and MC precursors in systemic mastocytosis.  (pilot study/protocol)

 

Description of clinical and mutational findings in familial cases of mastocytosis. (Data ready)

 

Longitudinal assessment of quality of life in systemic mastocytosis by use of a disease specific PRO/questionnaire (MastoQoL) (routine evaluation)

 

Mastocytosis in Acute Myelogenous leukemia (AML) with Core Binding Factors (CBF) – a multicenter study.

 

Microdialysis in patients with systemic mastocytosis

 

Prevalence of depression and psychiatric disease in systemic mastocytosis – a nationwide study

 

Gastroenterological manifestations of systemic mastocytosis – a nationwide study

 

 

“Organizational matters/achievements”

1. From 2010 we have built a multidisciplinary centre – MastOUH - with close collaboration between Dermatology, Allergy, Hematology, Pediatrics, Endocrinology, Gastroenterology, Pathology, Radiology and other specialties using a “one-entrance” approach to all patients, meaning that all patients are seen and evaluated at the Allergy Centre and work-up and treatment is closely coordinated between specialties using a tailored/personalized approach to the individual patient. Standard operating procedures and disease management programs are established. The centre’s homepage www.mastocytose.dk, is used by colleagues and patients from all over Denmark.

 

2. In the new national plan for the organization of medical specialties ‘Specialeplanen’ that was published by The Danish Health Authorities in March 2017, MastOUH was appointed National Centre for mastocytosis (among several competitors within hematology, dermatology, pediatrics) and mastocytosis accepted as a highly specialized diagnosis

 

3. A patient organization has recently been established www.mastocytoseforeningen.dk, by the support of MastOUH – and a start-up meeting scheduled with a focus on collaboration and patient involvement

 

4. International collaborations have been established within the EAACI, ECNM and Nordic network as well as with centres at the NIH, in Berlin, Munich, Boston, London among others.   The 2014 European mastocytosis Conference (ECNM) was organized and hosted by MastOUH, in Odense.

5. Grants from

 

Oral Presentations

2017 (scheduled):

EAACI/ESCD Skin Allergy Meeting – Skin Allergy Meeting, Zürich 2017: The many clinical faces of mastocytosis

 

EAACI - European Academy of Allergy and Clinical Immunology 2017, Helsinki: Comorbidities in mastocytosis

 

European Competence Network for Mastocytosis, Annual Meeting 2017, Paris: Diagnostic algorithm in suspected mastocytosis: the Nordic experience

 

2016:

Danish Dermatologic Society, Annual meeting, Odense: News from MastOUH

 

EAACI - European Academy of Allergy and Clinical Immunology 2016, Vienna: Mastocytosis; diagnostic tools and comorbidity

 

Danish Society of Allergology, Kolding: Mast Cell Activation Syndrome

 

European Competence Network for Mastocytosis, Annual Meeting 2016, Verona: Morbidity in systemic mastocytosis: a nationwide study and Pro/con: Is KIT D816V mutation analysis of peripheral blood sufficient for diagnostic screening of suspected mastocytosis in the absence of skin lesions?

 

2015:

Danish Society for Pediatric Allergology and Pulmonology, Annual Meeting 2015, Kolding, DK: Pediatric mastocytosis

 

World Congress of Dermatology, Vancouver, Canada: Systemic mastocytosis and clinical diagnostic algorithm

 

European Competence Network for Mastocytosis, Annual Meeting 2015, Munich: Diagnostic Algorithm for Patients with Suspected Mastocytosis

 

PAAM - Pediatric Allergy and Asthma Meeting 2015, Berlin: Mastocytosis

 

Esben Eller WP 2.6

 

 

 

Annemarie Senders WP 2.7

 

The Role of Co-factors in Primary and Secondary Hazelnut Allergy

 

The research project, The Role of Co-factors in Primary and Secondary Hazelnut Allergy, was approved by the PhD School, University of Southern Denmark and the commencement of the course of the PhD program planned from April 1st 2017.

 

In the PhD project’s first sub-study it is aimed to investigate the influence of co-factors (exercise, alcohol and acetylsalicylic acid) on the allergic reaction in primary and secondary hazelnut allergic patients in a human model. Healthy volunteers will undergo passive cutaneous sensitization using the ORCA test based on the Prausnitz-Küstner method. 24 hours subsequent to priming, the recipients will be orally challenged with hazelnut protein, and the strength of the expected allergic reaction (time to reaction and size of wheal) will be examined on separate study days with or without co-factor exposure (standardized exercise and intake of alcohol and ASA .

 

In sub-study 2 we wish to investigate the clinical importance of co-factors (exercise, alcohol and ASA) on the allergic reaction in secondary hazelnut allergic patients. The study subjects will be orally challenged with hazelnut protein until the occurrence of objective or severe subjective symptoms. Subsequently, on separate study days, oral food challenges with exposure to one or more co-factors (exercise, alcohol and ASA) will be undertaken.

 

In sub-study 3 the objectives are to study whether co-factors (exercise, alcohol and ASA) lower the threshold dose of hazelnut at which the allergen elicits a clinical reaction in primary hazelnut allergic patients, and if so, if these co-factors will display an additive effect. This will be conducted similarly to examinations undertaken in sub-study 2.

 

Preliminarily, in the fall of 2016, blood samples from five primary and five secondary hazelnut allergic patients were secured. This in collaboration with the Department of Clinical Immunology, Odense University Hospital, who were and are undertaking blood sampling, handling, storage and dispensing of the sera. The final blood dispenses were released on April the 3rd 2017.

 

Hence, on April the 3rd and 4th 2017 a pilot study with the released sera using the ORCA test was conducted. Data assessment from the pilot study will give rise to further planning of and investigations for sub-study one. The first sub-study is expected to be completed at the end of 2017.

 

Line Kring Tannert WP 3.1 and 3.2

 

Papers

 

In press:

 

Positive skin test or specific IgE to penicillin does not reliably predict penicillin allergy

 

Line Kring Tannert, MD, PhD1,2, Charlotte Gotthard Mortz, MD, PhD1,2, Per Stahl Skov, MD, DmSci1,2,3, Carsten Bindslev-Jensen, MD, PhD, DmSci1,2

 

1ORCA, Odense Research Center for Anaphylaxis; 2Department of Dermatology and Allergy Center, Odense University Hospital, Denmark; 3RefLab Aps., Copenhagen, Denmark.

 

Submitted:

 

Is a positive intracutaneous test induced by penicillin mediated by histamine?

 

A cutaneous microdialysis study in penicillin-allergic patients.

 

Line K. Tannert, MD1,2, Sidsel Falkencrone, MSc, PhD3, Charlotte G. Mortz, MD, PhD, Professor1,2, Carsten Bindslev-Jensen, MD, PhD, DMSci, Professor1,2, Per Stahl Skov, MD, MDSci, Professor1,2,3

 

1 Odense Research Center for Anaphylaxis

 

2 Department of Dermatology and Allergy Center, Denmark

 

3 Reflab®, Copenhagen, Denmark

 

In preparation:

 

Functionality of specific IgE to penicillins investigated by passive cutaneous sensitization.

 

Line Kring Tannert, MD,1,2 Charlotte G. Mortz, MD, PhD,1,2 Per Stahl Skov, DMSci,1,2,3 Ulrik Sprogøe, MD, PhD,4 Torben Barington MD, DMSci,4 Carsten Bindslev-Jensen, MD, PhD, DMSci,1,2

 

1ORCA, Odense Research Center for Anaphylaxis

 

2Department of Dermatology and Allergy Center, Odense University Hospital, Denmark

 

3RefLab Aps., Copenhagen, Denmark

 

4Department of Clinical Immunology, Odense University Hospital, Denmark

 

Presentations:

 

Drug Hypersensitivity Meeting  2016, poster ” Positive skin test or positive specific IgE to penicillin does not predict penicillin allergy”

 

DDS annual meeting 2016, oral presentation ”Kan en positiv hudtest med penicillin eller positiv specifik IgE for penicillin forudsige penicillinallergi?”  

 

EAACI 2016, e-poster ”Positive skin test or positive specific IgE to penicillin does not predict penicillin allergy”

 

DSA Koldingfjord, annual meeting 2016, oral presentation ”Penicillinallergi 2016”

 

Foreningen af Lunge- og Allergisygeplejerskes annual meeting 2017, oral presentation ”Penicillinallergi”

 

Microdialysis projects 2017/2018

 

Ex vivo model combining microdialysis and ORCA-test

 

Aim: To establish an ex vivo model as a parallel to the in vivo ORCA-test that is based on the Prausnitz-Küstner method.

 

Method: Surgically removed excess skin from cosmetic surgery will be passively sensitized with serum from patients with peanut allergy and penicillin allergy that has already been used in the ORCA test will be included.    

 

Skin testing in performed with:

 

1.                  

Allergens (peanut and penicillins) similar to those used in vivo will be performed followed by microdialysis and measurement of histamine and if possible other inflammatory markers.

 

2.                  

Serum from persons after intake of either peanut or penicillin will be injected in passively sensitized skin followed by microdialysis. The aim is to measure biologically active allergen components to follow the fate and kinetics of orally ingested allergens.  

 

3.                  

Codeine will be used as positive control.

In the phase of establishing the model, histamine will be measured in the microdialysis eluate. Subsequently, when the model is well-established, other mediator will be measured in addition, e.g. cytokines, prostaglandins, tryptase.

 

The advantage of the ex vivo model is that serum from allergic patients can be used without including the time consuming safety precautions needed in the in vivo model.  Further, the ex vivo model allows testing with allergens in higher concentrations or with substances not allowed to be applied in vivo.

 

Mesurement of mediators released in a positive penicillin-induced skin test

 

Aim: To search for other mediators than histamine in a positive intracutaneous test elicited by penicillin, since histamine can only be detected in the minority of positive intracutaneous tests with penicillin.

 

Method: Patients with a positive intracutaneous test to ? 1 penicillin will be investigated. Microdialysis with both low and high flux probes will be performed simultaneously to measure histamine, prostaglandins and tryptase, and other inflammatory biomarkers if possible, in the microdialysis eluate upon skin testing with penicillin. Grass pollen allergic patients will serve as controls.

 

This will hopefully shed some light on the mechanism of penicillin allergy that is seemingly different from the classical allergic reaction.    

 

Does rupatadine inhibit histamine release in the skin?

 

Aim: To investigate the effect of rupatadine and cetirizine on histamine release in wheals.

 

One study in human cord blood-derived cultured mast cells has demonstrated inhibition of histamine release from LAD2 cells after pre-treatment with rupatadine.

 

Method: Skin microdialysis will be done in grass allergic patients. Histamine in the eluate will be measured at baseline and after intracutaneous injection of grass extract (allergen), saline (negative control) and codeine (positive control). This experiment will be performed twice in each grass allergic patient on two separate days.

 

Day 1) Baseline microdialysis

 

Day 2) The patient will be randomized to a single dose of rupatadine, cetirizine or placebo. Two hours after intake of the antihistamine/placebo, skin microdialysis will be performed.

 

Histamine concentrations and wheal sizes will be compared.

 

Anja Pahlow Mose WP 3.3

Ongoing research project

 

Quantification of peanut allergen absorption using autologous serum in a human model of passive cutaneous anaphylaxis

 

In this study, the absorption kinetics of immunoreactive peanut proteins will be evaluated. The study has two purposes: 1) to measure the uptake of peanut allergens in the circulation and 2) to determine the absorption peak for peanut allergens. We will include healthy, non-atopic volunteers as recipients of a human serum obtained from a donor with severe peanut allergy through the passive transfer of cutaneous anaphylaxis and perform intracutaneous “challenges” with the recipients own serum containing absorbed peanut proteins. The recipients will undergo the following sequential experimental steps: 1) autologous serum sampling during oral peanut challenge with 100 g of defatted peanut flour, 2) passive transfer of donor serum, and 3) intracutaneous injections of the autologous serum into the donor-sensitized skin sites (autologous Prausnitz-Küstner test).

Published articles

 

Mose AP, Mortz CG, Eller E, Sprogøe U, Barington T, Bindslev-Jensen C. Dose-time-response relationship in peanut allergy using a human model of passive cutaneous anaphylaxis. J Allergy Clin Immunol 2017 Feb 8. Epub ahead of print

 

Upcoming presentations

EAACI Congress 2017, Helsinki. Hot topic session: Prausnitz-Küstner test revisited

EAACI Congress 2017, Helsinki. Thematic Poster Session

Miscellaneous

2016             maternity leave

 

Henrik Fomsgaard Kjær WP 4.3

 

 

1. VENOM RESEARCH

PRAUSNITZ-KÜSTNER EXPERIMENTS

Healthy individuals primed with sera from venom allergic patients followed by culprit allergen exposure 24 hours later (injection of extract or sting challenge). Size of resulting wheals and time to reaction at different priming sites will be recorded. During these experiments blood will be obtained and different mediators of anaphylaxis measured for detailed analysis.

This model of passive cutaneous anaphylaxis, offers an opportunity to scrutinize the pathogenesis of venom anaphylaxis. Since the uptake of venom allergen (in contrast to food allergens) bypass absorption in the gastrointestinal tract, the experiments could possibly add to the knowledge of anaphylaxis mechanistic in general.

ESTABLISHMENT OF A VENOM ALLERGY COHORT

Numerous patients with venom allergy/anaphylaxis are evaluated every year in the Allergy Centre. These patients will be gathered in a venom allergy cohort aiming to study:

Diagnostic methods in venom allergy (Specific IgE, CRD, HR, BAT and skin tests)

Serological response to venom immunotherapy

Real-life protection from immunotherapy (including sting challenges) and immunologic characterization of vaccination failures

QoL evaluation before, during and after venom immunotherapy (including sting challenges)

Mastocytosis in venom allergic patients

2. PLASMAPHERESIS AND FOOD ANAPHYLAXIS

The aim of this study is to investigate if the combination of initial plasmapheresis and subsequent therapy with Omalizumab can protect food allergic patients against accidental food anaphylaxis by reducing their level of specific IgE to the offending food allergen.

Omalizumab has been shown to be able to do. In certain patients though, especially those with concomitant atopic dermatitis, very high levels of total IgE hamper the efficacy of Omalizumab. Plasmapheresis using IgE-binding columns is an effective, but short lived way of reducing the level of IgE, (IgE are reverted to entry levels within less than two weeks), but a combination of initial cycles of IgE-apheresis followed by immediate initiation of Omalizumab treatment might be an effective tool on the long haul.

The study will include adult food allergic patients with low thresholds to the offending food. Pre-study threshold will be determined by standardized oral food challenge. Three cycles of plasmapheresis (using specific IgE columns) will then be performed on three consecutive days followed by a second oral challenge to determine the efficacy of plasmapheresis. Immediately after this second challenge, treatment with Omalizumab will be initiated and continued every second week for a total duration of twelve weeks. The day after the final administration of Omalizumab – and again four weeks later – a third and fourth oral food challenge will be performed and efficacy of the combined treatment evaluated.

 

 

 

 

 

 

 

 

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