Allergy diagnosis in children IgE-sensitized to peanut : clinical and immunological evaluation

Background: Peanut allergy is often life-long and affects quality of life since accidental ingestion may lead to severe or even fatal reactions. Sensitization to peanut can be due to genuine peanut allergy or to cross-sensitization due to birch pollen. Peanut allergy diagnosis is usually based on clinical history, skin prick test (SPT) and presence of IgE-antibodies (IgE-ab) to peanut but these tests often need to be confirmed with an oral food challenge which may cause severe allergic reactions. Measurements of IgE-ab to specific proteins in an allergen source (component resolved diagnostics [CRD]) and basophil allergen threshold sensitivity (CD-sens) may be valuable tools for diagnosis of peanut allergy. Important allergen proteins in peanut are the storage proteins: Ara h 1, Ara h 2 and Ara h 3 and the PR-10 protein [birch-homologue] Ara h 8.

Aim: The aim of this thesis was to evaluate different diagnostic methods in children IgE-sensitized to peanut with a suspected peanut allergy.

Method: Paper I investigated if it is possible to predict the outcome of double-blind placebo-controlled food challenge (DBPCFC) with peanut by measuring CD-sens to peanut and Ara h 2 as well as IgE-ab to peanut components (Ara h 1, Ara h 2, Ara h 3, Ara h 8 or Ara h 9) (n=38). In Paper II, the reproducibility of DBFCFC and CD-sens were investigated. Twenty-seven children underwent DBPCFC followed by a single-blinded food challenge with peanut, and CD-sens was measured before the two first peanut challenges. Paper III reports a birch pollen allergic child with cross-sensitization to peanut who had a severe reaction after eating a large amount of peanuts. The fourth paper investigated the outcome of a peanut challenge in relation to IgG4-ab (n=58). Paper V studied 20 birch pollen allergic children cross-sensitized to peanut in relation to CD-sens to peanut and Ara h 8.

Results: In Paper I, 25 children had a positive DBPCFC and 92% of the children were positive in CD-sens. The remaining two children were low responders and could not be evaluated. Children with positive DBPCFC reactions had significantly higher levels of IgE-ab to peanut, Ara h 1, Ara h 2 and Ara h 3 than children with negative reactions. All children negative in CD-sens to peanut and Ara h 2 were also negative in challenge. In paper II, 14/27 children were positive at both active challenges but not placebo. Only three of these children reacted consistently at the same dose with the same severity score. All children with a positive or a negative CD-sens at the first challenge were also CD-sens positive/negative at the second challenge. Paper III revealed that the girl with birch pollen allergy who reacted with anaphylaxis after peanut ingestion was mono-sensitized to Ara h 8. Paper IV showed that children positive at peanut challenge had significantly higher levels of IgG4-ab to peanut and Ara h 2 than children negative at the challenge. The peanut and Ara h 2 IgG4/IgE-ab ratios were significantly higher in children who tolerated peanut than in allergic children. In Paper V, all children passed peanut challenge without any objective symptoms, but five experienced subjective symptoms from the oral cavity. CD-sens to peanut was negative in 19/20 children but 17/20 were positive in CD-sens to Ara h 8.

Conclusion: CD-sens is a promising diagnostic method with good reproducibility in the diagnosis of peanut allergy and may exclude a peanut allergy. IgE-ab to the peanut storage proteins (Ara h 1, Ara h 2 and Ara h 3) seem to confirm a genuine peanut allergy. A peanut challenge can discriminate between positive and negative reactions but does not predict the severity of an allergic reaction. Birch-pollen allergic children IgE-sensitized to peanut and Ara h 8 but not to Ara h 1, Ara h 2 and Ara h 3 have basophils sensitized with IgE-ab to Ara h 8 which can be activated by Ara h 8 proteins and initiate allergic inflammation. Children IgE-sensitization to peanut who nonetheless tolerate peanuts are characterized by low levels of IgG4-antibodies to peanut and Ara h 2 but relatively high IgG4/IgE antibody ratios.

List of scientific papers

I. Glaumann S, Nopp A, Johansson S.G.O., Rudengren M, Borres MP, Nilsson C. Basophil allergen threshold sensitivity, CD-sens, IgE-sensitization and DBPCFC in peanut-sensitized children. Allergy. 2012 Feb; 67(2):242-7.
https://doi.org/10.1111/j.1398-9995.2011.02754.x

II. Glaumann S, Nopp A, Johansson S.G.O., Borres MP, Nilsson C. Oral peanut challenge identifies an allergy but the peanut allergen threshold sensitivity is not reproducible. PLoS One. 2013; 8(1).
https://doi.org/10.1371/journal.pone.0053465

III. Glaumann S, Nopp A, Johansson S.G.O., Borres MP, Lilja G, Nilsson C. Anaphylaxis to peanuts in a 16-year-old girl with birch pollen allergy and with monosensitization to Ara h 8. J Allergy Clin Immunol Pract. 2013 Nov-Dec; 1(6):698-9.
https://doi.org/10.1016/j.jaip.2013.08.010

IV. Glaumann S, Nilsson C, Asarnoj A, Movérare R, Johansson S.G.O., Borres M.P, Lilja G, Nopp A. IgG4-antibodies and peanut challenge outcome in children IgE-sensitized to peanut. [Manuscript]

V. Glaumann S, Nilsson C, Johansson S.G.O., Asarnoj A, Wickman M, Borres MP, Nopp A. Basophil allergen threshold sensitivity (CD-sens) to peanut and Ara h 8 in children IgE-sensitized to birch and Ara h 8. [Submitted]