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- Brandström, Josef
(författare)
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Diagnostics and treatment of nut and peanut allergy
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 2. |
- Brandström, Josef, et al.
(författare)
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Individually dosed omalizumab facilitates peanut oral immunotherapy in peanut allergic adolescents
- 2019
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Ingår i: Clinical and Experimental Allergy. - : Wiley. - 0954-7894 .- 1365-2222. ; 49:10, s. 1328-1341
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Tidskriftsartikel (refereegranskat)abstract
- Background: Peanut oral immunotherapy (pOIT) has showed good short-term outcomes, but allergic reactions may prevent effective up-dosing and is a major cause of stopping OIT. In placebo-controlled trials, omalizumab has been shown to facilitate allergen immunotherapy and increase tolerance to peanut.Objective: We hypothesized that by combining omalizumab with pOIT, and monitor treatment effects with basophil allergen threshold sensitivity tests (CD-sens), peanut allergic patients could safely initiate pOIT and thereafter slowly withdraw omalizumab.Methods: This is the 2nd part of a one-armed open phase-2 study where peanut allergic adolescents (n = 23) started pOIT after an individualized omalizumab treatment. The pOIT dose was increased from 280 to 2800 mg peanut protein in 8 weeks followed by an individualized step-wise withdrawal of omalizumab, based on clinical symptoms and CD-sens levels. pOIT continued for 12 weeks followed by an open peanut challenge. Peanut CD-sens and allergen-binding activity (ABA) and IgE-ab, IgG-ab and IgG4-ab to peanut and its components were measured during the study.Results: All 23 patients successfully reached the 2800 mg maintenance dose. Moderate/systemic allergic reactions were rare while receiving full-dose omalizumab. Eleven of 23 (48%) successfully continued with pOIT after omalizumab was stopped. Compared to treatment failures, median baseline IgE-ab to peanut components Ara h 1-3 and CD-sens to peanut were significantly lower among successfully treated patients and IgG4-ab to peanut, Ara h 2 and 6 increased significantly more during treatment.Conclusions and clinical relevance: This study indicates that omalizumab is an effective adjunctive therapy for initiation and rapid up-dosing of pOIT; however, adverse events from pOIT become more frequent as omalizumab doses are decreased.
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| 3. |
- van der Heiden, Marieke, et al.
(författare)
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A pilot study towards the immunological effects of omalizumab treatment used to facilitate oral immunotherapy in peanut-allergic adolescents
- 2021
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 93:4
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Tidskriftsartikel (refereegranskat)abstract
- Anti-IgE treatments, such as omalizumab, have shown promising effects in allergy treatment. Our previous work has shown that individualized omalizumab treatment (OT) allows a safe initiation and rapid up-dosing of peanut oral immunotherapy (OIT) in peanut-allergic adolescents. However, the broader immunological effects of this OT are incompletely understood. In this pilot study, we longitudinally followed the total B- and T-cell immunity during OT, using flow cytometry, ELISpot and ELISA. Peripheral blood mononuclear cells (PBMCs) and plasma were collected from participants (n = 17) at several timepoints during treatment, before starting OT (baseline), prior to starting OIT during OT (start OIT) and at maintenance dose OIT prior to OT reduction (maintenance). OT did not affect the total B-cell compartment over treatment time, but our results suggest an association between the OT dosage scheme and the B-cell compartment. Further, in vitro polyclonal T-cell activation at the different timepoints suggests a cytokine skewing towards the Th1 phenotype at the expense of Th2- and Th9-related cytokines during treatment. No differences in the frequencies or phenotype of regulatory T cells (Tregs) over treatment time were observed. Finally, plasma chemokine levels were stable over treatment time, but suggest elevated gut homing immune responses in treatment successes during the treatment as compared to treatment failures. The novel and explorative results of this pilot study help to improve our understanding on the immunological effects of OT used to facilitate OIT and provide guidance for future immunological investigation in large clinical trials.
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