Allergy Against Different Species of Fish in Children and Adolescents Allergic to Fish
Condition: Fish Allergy
MeSH terms: Hypersensitivity
Study type: Interventional

Summary: 
      Study hypothesis:

      Some children and adolescents with fish allergy can tolerate eating some species of fish

      Purpose of the study:

      The purpose of this study is to determine to which degree fish allergic children and
      adolescents can tolerate some species of fish and find the minimal eliciting allergen dose to
      which only 10% of participants get allergic reaction.

      Participants:

      Participants are 40 patients recruited from children and adolescents outpatient clinics at
      the University Hospital of North Norway with a history of fish allergy and sensibilisation of
      one or more fish species with either positive specific IgE in serum or skin prick test.
      Patients with sensibilisation to one or more fish species that never have eaten fish are also
      recruited.

      Method:

        -  All participants undergo a clinical examination including lung function test with
           spirometry before inclusion in the study.

        -  All participants are tested for allergic sensibilisation with measure of specific IgE
           against common food and inhalation allergens in addition to 10 different fish species.

        -  All participants are challenged with cod, salmon, mackerel and placebo, disguised in a
           chocolate mousse. The challenges are performed in randomized order with Double Blind
           Placebo Controlled Food Challenge (DBPCFC) on 4 different challenge days with minimum 6
           weeks in between each challenge day.

        -  Participant with allergy to pollen will not be challenged during pollen season.

        -  Test food is developed especially to this study in cooperation with The National
           Institute of Food Research in Norway and The University of Manchester. The National
           Institute of Food Research in Norway have produced a dried powder of cod, salmon and
           mackerel. The "Molecular Allergology group at Manchester Institute of Biotechnology, the
           University of Manchester, have produced test kits based on chocolate mousse containing
           low and high doses of the fish powders. The National Institute of Food Research have
           measured protein content and microbiology in the fish powders. The Molecular Allergology
           group have provided quality measurements of the final product and tested the disguise in
           a sensoric test panel.

        -  Participants with no allergic reaction to one or more of the blinded challenges undergo
           open food challenge with larger doses of cooked fish than used in the DBPCFC, after the
           randomization has been broken.
    

Detailed description: 
      Introduction:

      Fish have an important role in human food providing a valuable source of highly assimilated
      proteins and consumption of fish is increasing all over the world. Fish allergy is one of the
      most common food allergies together with milk, egg, nuts, peanuts, fruits, wheat, soy and
      seafood. It is more common in coastal countries and countries with traditions in fish
      industry and where fish plays an important role in food traditions. This is the situation in
      Northern Norway where fishing and fish industry have been the most important way to make a
      living and fish an important part of the food. Allergy to fish is particularly common in
      children and young adults. The symptoms related to fish allergy vary from mild symptoms to
      anaphylaxis. Most patients with fish allergy avoid all species of fish and health care
      workers often advice them to do so. The major allergen in fish is a muscle parvalbumin
      resistant to heat, chemical denaturation and proteolytic enzymes. Due to homology in the
      amino acid sequence in parvalbumins in different fish species, cross-reactivity exists.

      However, clinical experience, studies on sensibilisation, and some open food challenge
      studies indicates that some patients with fish allergy can tolerate some species of fish. The
      main purpose of this study is to find to which degree fish allergic children and adolescents
      can tolerate some species of fish, using DBPCFC as the gold standard in diagnosis of food
      allergy, and thereby avoid unnecessary food restrictions in their diet.

      The food industry often label their products with "main contain allergen" because they lack
      information about threshold doses for allergic reactions. Unnecessary labeling of food
      results in less variation in the diet for food allergic patients. Another purpose of this
      study is to find the Minimal Eliciting Dose to which 10% of the participants get allergic
      reaction, and thereby contribute to a more precise labeling of food.

      Method:

      DBPCFC is the gold standard in the diagnosis of food allergy. To disguise the taste and smell
      from fish in a standardized test food with good taste and texture is difficult. It is
      especially difficult with children, who are less likely to eat food with bad taste and where
      the volume of test food they can manage is limited.

      In cooperation with The National Institute of Food Research in Norway we have produced dried
      fish powders from cod, salmon and mackerel. Frozen filets have been cooked, dried and made
      into powders. The powders have been checked for microbiologic content and protein content.
      The procedure involves removing as much fat as possible. The powders are stored in a freezer
      with a temperature of -20°C. The volume is decreased with about 80% compared with cooked
      fish.

      In cooperation with Professor Clare Mills in the Molecular Allergology group, Manchester
      Institute of Biotechnology, The University of Manchester, the fish powders is put into a
      chocolate dessert based on a recipe used in a EuroPrevall study on food allergy. The
      production of chocolate desserts is performed at the University of Manchester together with
      quality check regarding allergen content, content of parvalbumin, microbiology and speciation
      of the fish. The disguise of taste and smell are tested in a sensoric test panel.

      Recruitment of participants:

      Patients aged 5-20 yr, with a history of fish allergy and sensibilisation to fish who had
      visited one of the outpatient clinics for children and adolescents at the university hospital
      of Northern Norway, are invited to participate. Patients with sensibilisation to fish that
      never have eaten fish are also invited. In addition, patients registered with sensibilisation
      against cod at the allergology lab, University Hospital of Northern Norway since 2008 , that
      not already had been picked up from an outpatient clinic is invited to participate. The
      laboratory is the only allergology laboratory in the region the participants are recruited
      from.

      Examination before inclusion:

      All patients that give their consent to participate undergo clinical examination, including
      spirometry, before inclusion to ensure eligibility. The clinical examination contains
      measurements of weight and height, heart and lung auscultation, examination of skin,
      conjunctiva, nose and oral cavity.

      Special attention is given to uncontrolled asthma and eczema and to ensure optimized
      treatment before inclusion. Pollen allergic patients will not undergo food challenges during
      pollen season.

      Measurement of specific Immunoglobulin E (IgE) in serum:

      In all participants, specific IgE in serum against the following allergens are measured:

        1. Fx5 (Egg, milk, cod, wheat, soy, peanut)

        2. Inhalation panel 6 (Birch, timothy, mugwort, alternaria, cladosporium)

        3. Inhalation panel 7(Cat, horse, dog, house dust mite, rabbit)

        4. Gad c1, f426 (Parvalbumin from cod)

        5. Cyp c1, f355 (Parvalbumin from carp)

        6. Salmon, f41

        7. Mackerel, f206

        8. Halibut, f303

        9. Pollock, f413

       10. Haddock, f42

       11. Herring, f205

       12. Plaice,4254

       13. Tuna, f40

       14. Shrimp,f24

       15. f351 (recombinant shrimp tropomyosin)

      Questionnaire:

      Parents answer a questionnaire for research in allergy. The questionnaire is translated to
      Norwegian and an electronic survey is used. The parents answer the questionnaire during the
      first challenge day. The questionnaire is extended with questions regarding fish allergy.

      Double Blind Placebo Controlled Food Challenge with cod, salmon, mackerel and placebo:

      All participants undergo DBPCFC with cod, salmon, mackerel and placebo in randomized order,
      disguised in a chocolate dessert on 4 separate challenge days with minimum 6 weeks between
      each challenge day. Participants that have experienced anaphylaxis, verified and treated in
      hospital , are not challenged with the species that have given anaphylaxis. Symptoms are
      recorded on a clinical manifestations record sheet based on a protocol from the University
      Hospital of South Manchester with grading of the symptoms and defined stop criteria. The
      protein doses are based on the experience of a EuroPrevall study with DBPCFC with cod:

      3µg, 600µg, 12mg, 120mg and1g for DBPCFC

      Open challenges with cod and/or salmon and mackerel:

      Participants that have no allergic reactions after DBPCFC with either cod, salmon and
      mackerel, undergo open challenge(s) with 2 g, 6 g and 12 g of protein , served as cooked
      fish, with the species that gave negative DBPCFC. The open challenges are done on separate
      days after the randomization code has been broken.

      Ceasing of medication before DBPCFC and open challenges:

      Systemic corticosteroid therapy are ceased at least one week before challenges. Antihistamine
      treatment are ceased at least 72 hours before the challenges. Short acting β-2 agonists are
      ceased at least 6 hours before the challenges and Long acting β-2 agonists at least 24 hours
      before the challenges. Participants are allowed to continue inhalant corticosteroids and
      leukotriene receptor antagonists.

      Postponing of DBPCFC and open challenges:

      The challenges are postponed if the participants have ongoing infections, ongoing allergic
      reactions, uncontrolled eczema or uncontrolled asthma. Participants with pollen allergy are
      not challenged during pollen season.

      Observation and treatment of allergic reactions:

      All fish challenges are performed at the research unit at the University Hospital of North
      Norway in the period of September 2014 - February 2015. Two participants are challenged each
      challenge day and all participants are observed by one blinded research nurse. Unblinded
      staff prepare the test meals every morning. One blinded doctor examines the participants
      before, during and after the challenges and decides whether challenges are positive or
      negative. The challenges are stopped if participants develop objective signs of allergic
      reactions. Stop criteria are predefined. Participants are observed in the hospital at least
      two hours after the challenges have been stopped. Allergic and anaphylactic reactions are
      treated according to European Academy of Allergology and Clinical Immunology position paper
      of Anaphylaxis. Participants are contacted by blinded research nurse by phone next day to
      record late reactions after discharge.
    

Intervention name(s): Cod_Double Blind Placebo Controlled Food Challenge; Salmon_Double Blind Placebo Controlled Food Challenge; Mackerel_Double Blind Placebo Controlled Food Challenge; Placebo_Double Blind Placebo Controlled Food Challenge
Intervention type(s): Other; Other; Other; Other
Intervention description(s): DBPCFC Food Challenge with cod in the following doses: 3µg, 600µg, 12 mg, 120 mg, and 1g covered in chocholate dessert over one day; DBPCFC Food Challenge with salmon in the following doses: 3µg, 600µg, 12 mg, 120 mg, and 1g covered in chocholate dessert over one day; DBPCFC Food Challenge with mackerel in the following doses: 3µg, 600µg, 12 mg, 120 mg, and 1g covered in chocholate dessert over one day; DBPCFC Food Challenge with placebo covered in chocholate dessert over one day
Other intervention name(s): DBPCFC with cod; DBPCFC with Salmon; DBPCFC with Mackerel; DBPCFC with placebo
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Diagnostic
Keywords: Fish allergy