Diagnostics and treatment of nut and peanut allergy

Sammanfattning: Background: The prevalence of allergy to foods has increased over the last decades and among children in Europe as many as 8 % have an allergy to one or more types of food. However, many children have received an incorrect diagnosis of food allergy due to shortcomings of available diagnostic tests, especially in the case of suspected allergy to nuts or peanuts. Newer diagnostic tools, like component-resolved diagnostics (CRD) and basophil activation test (BAT), e.g., basophil allergen threshold sensitivity (CD-sens), have shown an improved diagnostic accuracy compared with older tests. The most severe acute manifestation of allergy, the anaphylactic allergic reaction, is most commonly caused by an allergy to peanut or nuts, and there have been no treatments available that might change the course of the disease. While disease-modifying allergen immunotherapy has for decades been offered as routine practice for the treatment of pollen or house dust mite allergy, severely food-allergic patients have had to settle for strict elimination diets and use of emergency medication in case of accidental intake. During the past decade, oral immunotherapy (OIT) has emerged as a potential disease-modifying treatment for food allergies, but OIT needs to be refined before it can become widely implemented. Major limitations of OIT have been frequent allergic reactions and that patients with a more severe allergy have a less favorable treatment outcome. The anti-IgE antibody omalizumab has been shown to increase the tolerated amount of food allergen among food-allergic patients (as long as the treatment continues) and facilitate initiation of immunotherapy in patients with severe allergies. Objectives: Hazelnut study: To evaluate the new diagnostic tests CRD and CD-sens in children with a suspected hazelnut allergy. FASTX study (Food Allergen Suppression Therapy with Xolair®): To evaluate safety and efficacy of oral immunotherapy with adjuvant omalizumab in severely peanut-allergic patients. Methods: In the study of diagnostic tests for hazelnut allergy, we used CRD to measure IgE antibody (ab) levels to the hazelnut components Cor a 1, Cor a 8, Cor a 9 and Cor a 14 in 40 children with a doctor’s diagnosis of suspected hazelnut allergy. We also assessed basophil allergen threshold sensitivity (CD-sens) to hazelnut and CRD to hazelnut components and compared the concordance of these tests to double-blind placebo-controlled food challenge (DBPCFC). In the FASTX study, open-label omalizumab was given to 23 severely peanut-allergic adolescents, with the aim of increasing the amount of peanut they could safely ingest so that OIT could be safely initiated. Omalizumab doses were titrated until CD-sens analyses indicated a very low reactivity to peanut allergen stimulation. Thereafter, an open peanut challenge was performed, assessing the tolerated peanut dose while on omalizumab, and peanut OIT was started the following day. After reaching the maintenance dose of 10 g of peanuts, the protective omalizumab treatment was phased out with guidance from CD-sens and the clinical picture. Results: DBPCFC revealed that only 8/40 of the patients with a suspected hazelnut allergy were allergic to hazelnuts. The diagnostic accuracy of the new diagnostic tests, CD-sens and IgE-ab to Cor a 9 and Cor 14, were far superior to the previously available tests (IgE-ab to hazelnut, Cor a 1 and Cor a 8). IgE-abs to Cor a 9 and Cor a 14 were present in all hazelnut-allergic patients; for Cor a 9 the median IgE-ab level was 4.5 kUA/l (range 0.7–97.5) among hazelnut-allergic children, compared with 0.1 kUA/l (range < 0.10–36.2) (P < 0.01) in the hazelnut-tolerant group. The levels of IgE-ab to Cor a14 were 5.6 kUA/l (0.9–78.7) for the hazelnut-allergic group and 0.04 kUA/l (< 0.10–13.9) in the hazelnut-tolerant group (P < 0.001). Median CD-sens among allergic patients was 8.9 compared with 0.05 in tolerant patients (P = 0.05). The diagnostic accuracy of CD-sens to hazelnut was maintained in subgroup-analyses where patients without IgE-ab to Cor a 9 or Cor a 14 > 0.35 kUA/l were excluded from analyses. After omalizumab treatment, all 23 patients passed a peanut challenge of > 3 g of peanuts (median 10 g) and were started on OIT the following day. Among the 14 patients who went through a peanut challenge prior to enrollment, the tolerated dose increased at least 50-fold (median). However, 15/23 patients needed an increased omalizumab dose in order to accomplish a suppression of CD-sens. All 23 patients successfully reached the 10 g maintenance dose. After a median of 23 months of OIT, 11/23 (48 %) of the study subjects had been able to discontinue omalizumab while continuing and tolerating OIT and thereafter passing an open peanut challenge. Systemic reactions (n = 43) occurred with a frequency of 0.3 % of OIT doses and adrenaline was administered after 0.1 % of the doses. We found that successfully treated patients had significantly lower baseline CD-sens and lower IgE-ab to peanut and peanut components Ara h 1, Ara h 2 and Ara h 3 compared with patients unable to discontinue the protective omalizumab treatment. OIT induced an increase of IgG4-ab to peanut, Ara h 2 and Ara h 6 that was significantly higher in successfully treated patients. A substantial proportion, 6/23 (26 %) of the patients dropped out of the study, mainly due to fear of allergic reactions and an abomination for the taste of peanuts. Conclusions: CD-sens to hazelnut and component-resolved diagnostics can improve the accuracy when diagnosing hazelnut allergy in pediatric patients. CD-sens may further improve the diagnostic accuracy in cases when the diagnostic work-up using CRD has been inconclusive. The anti-IgE-ab omalizumab can efficiently increase the tolerated peanut dose, which in turn allows for a safer practice of peanut oral immunotherapy in severely allergic patients. Peanut oral immunotherapy induces an increased tolerance to peanuts; the increased tolerance is at least partially explained by the production of protective allergen-specific antibodies of IgG4-subtype. Despite the increased tolerance, allergic reactions continuously occur during pOIT. We need to find ways to minimize this major limitation before OIT can be widely implemented; development of hypoallergenic OIT preparations, use of immune stimulatory adjuvants and improved patient selection might help in accomplishing a safer and more effective treatment.