EAACI Allergen Immunotherapy User's Guide

Abstract

Allergen immunotherapy is a cornerstone in the treatment of allergic children. The clinical efficiency relies on a well-defined immunologic mechanism promoting regulatory T cells and downplaying the immune response induced by allergens. Clinical indications have been well documented for respiratory allergy in the presence of rhinitis and/or allergic asthma, to pollens and dust mites. Patients who have had an anaphylactic reaction to hymenoptera venom are also good candidates for allergen immunotherapy. Administration of allergen is currently mostly either by subcutaneous injections or by sublingual administration. Both methods have been extensively studied and have pros and cons. Specifically in children, the choice of the method of administration according to the patient's profile is important. Although allergen immunotherapy is widely used, there is a need for improvement. More particularly, biomarkers for prediction of the success of the treatments are needed. The strength and efficiency of the immune response may also be boosted by the use of better adjuvants. Finally, novel formulations might be more efficient and might improve the patient's adherence to the treatment. This user's guide reviews current knowledge and aims to provide clinical guidance to healthcare professionals taking care of children undergoing allergen immunotherapy.

Keywords: Allergy; immune regulation; immunotherapy; tolerance.

Figure 1

Inicolortiation of allergic immune responses. Dendritic cells, the professional antigen‐presenting cells uptake and process allergens and present allergen peptides to naïve CD4⁺ T cells. Naïve CD4⁺ T cells differentiate to Th2 cells with the existence of IL‐4 and produce the cytokines IL‐4, IL‐5, IL‐9, and IL‐13, namely type 2 cytokines. Consequently, B cells produce IgE which binds to specific Fcε receptors on basophils and mast cells, the effector cells of allergic inflammation. This occurrence is termed sensitization. Upon encountering the same allergen for the second time, immediate degranulation of these effector cells leads to release and production of histamine and leukotrienes, all of which give rise to immediate hypersensitivity reactions. IL‐9 induces mucus production, while IL‐13 and eosinophil products such as major basic protein can induce barrier leakiness. ILC2 contributes to allergic inflammation by type 2 cytokine production. The epithelium‐derived cytokines: TSLP, IL‐25, and IL‐33 can also be produced by Th2 cells and can activate ILC2. IL‐25 activates DC. (BAS: basophils, DC: dendritic cells, EOS: eosinophils, ILC: innate lymphoid cells, LT: leukotriene, MBP: major basic protein, Th2: T helper type 2 cells, TSLP: thymic stromal lymphopoietin.)

Figure 2

Immune regulation of allergic immune responses as a consequence of AIT. Allergen‐specific immunotherapy‐induced Treg cells that produce IL‐10, TGF‐β, and IL‐35 and also express surface molecules as CTLA4 and PD1 all of which contribute to suppression. Treg cells suppress Th2 cells, basophils, and eosinophils and also induce allergen‐specific Breg cells. The suppressive milieu limits production of IgE and induces production of IgG4 from B cells. Breg cells, NKreg cells, and ILCreg cells contribute to induction and maintenance of allergen‐specific tolerance. (BAS: basophils, EOS: eosinophils, ILCreg: regulatory innate lymphoid cells, NKreg: regulatory natural killer cells, Treg: regulatory T cells.)

Figure 3

Contribution of novel developments in AIT. AIT is the only option to establish a long‐term, medication‐free cure of allergic diseases. Utilization of modified allergens aims increased efficacy and limitation of side effects such as risk of anaphylaxis, helps for better and longer presentation of the allergen peptides, with no binding to IgE present in the patients. ILIT decreases the number of injections required, the total received allergen dose, and also the therapy duration. EPIT does not require injections; therefore, it is more patient‐friendly. Both routes increase patient adherence to therapy. Precision medicine contributes to AIT by better characterization of patients, selection of custom‐tailored therapy per patient, and monitorization of therapy success by biomarkers. (ILIT: intralymphatic immunotherapy, EPIT: epicutaneous immunotherapy, CRD: component‐resolved diagnosis, BAT: basophil activation test, NAC: nasal allergen challenge.)

Figure 4

Mechanistic and clinical responses of allergen immunotherapy (AIT) on adults and children. Allergen immunotherapy, administered as subcutaneous (SCIT) or sublingual (SLIT), is associated with various clinical outcomes in adults in children. This is also accompanied by modulation in serological readouts that includes IgE and IgG in both adults and children. The majority of cellular outcomes of AIT have been based on studies in adults. Whether the same cellular modulation is found in children is yet to be fully identified. ILC2s: Group 2 innate lymphoid cells, nTreg: natural regulatory T cells, iTreg: inducible regulatory T cells, Tfr: T follicular regulatory cells, Th2A: allergen‐specific Th2 cells; Tfh: T follicular helper cells, Breg: regulatory B cells.

Figure 5

Trajectories of pollen counts vs symptoms ‐ Symptom severity vs pollen counts in 2 patients with allergic rhinitis. Data on severity of symptoms (collected using a smartphone app) are reported as the Rhinoconjunctivitis Total Symptom Score (RTSS) (A, Patient 1; B, Patient 2). Pollen counts (grains/m3) were obtained from the pollen station of Ascoli Piceno. Data on skin prick test reactions to pollen extracts and on serum IgE levels against major allergenic molecules are shown. We also measured the following serum IgE levels (kUA/L) against pollen extracts: Patient 1, cypress 143, birch 226, olive tree 122, grass 404, pellitory 191, mugwort 96; Patient 2, cypress 2, birch 9, olive tree 24, grass 157 (Reused with the permission from Bianchi A, et al J Investig Allergol Clin Immunol. 2016246).

Figure 6

Electronic diaries for respiratory allergies—the screenshots are examples of electronic clinical diary APPs dedicated to allergic rhinitis and asthma: allergy monitor, MASK‐Air, Pollen.

Figure 7

Linkage between level of evidence and grade of recommendation

Figure 8

Balance between efficacy and safety with immunotherapy

Figure 9

An approach to deciding the best AIT approach for different children and adolescents with allergic rhinoconjunctivitis. Reproduced from Roberts G, et al, Allergy. 20183.

Figure 10

Suggested algorithm for areas with high exposure to grasses and birch pollen

Figure 11

Suggested algorithm for areas with high exposure to grasses and olive pollen. Different major and specific major allergens for Parietaria, Cypress, Artemisia, Salsola, Platanus acerifolia, and Ragweed are included in the algorism, as representative of frequent local pollens.

Figure 12

Suggested algorithm for areas with three clinically relevant pollen species

Figure 13

Suggested algorithm for areas with no dominant pollens. Whenever possible a maximum of two allergens should be formulated. There is a consensus of a working group (37) supporting the use of three allergens, but there is no clinical evidence supporting this practice.

Figure 14

Recommendations for venom immunotherapy (VIT) for children. VIT is recommended in children who suffered from systemic reactions exceeding generalized skin symptoms (adapted from Sturm et al.522). LLR: large local reaction; SSR: systemic sting reactions

Figure 15

Summary of systematic reviews and meta‐analyses on SCIT and SLIT for allergic asthma. AIT, Allergen immunotherapy

Figure 16

Algorithm on the clinical approach of allergen immunotherapy (AIT) in children suffering from allergic respiratory diseases.

Figure 17

Comparison of the actions of alum and MCT. Alum administration leads to immediate activation of the inflammasome and recruitment of APCs. Inflammasome activation can lead to granuloma formation and the formation of a depot for sustained release. Downstream of this, enhanced antigen presentation by APCs promotes activation of Th1 and Th2 cells. Additionally, activated eosinophils can prime naïve B cells to produce IgE and IgG. MCT administration leads to inflammasome and depot formation but not a granuloma as it is biodegradable. Mechanisms are largely similar to alum with preferential induction of Th1 over Th2 and IgG over IgE.

Figure 18

Toll‐like Receptors. TLRs can be classed as recognizing extracellular stimuli (TLR2/1, TLR2/6, TLR4, TLR5) or intracellular stimuli (TLR3, TLR7, TLR8, TLR9). Recruitment of the adaptor protein MyD88 for all TLRs except TLR3, which signals through TRIF, leads to activation of transcription factors NFκB, AP‐1, and interferon response factors (IRFs) 3 and 7. This leads to the production of inflammatory cytokines, regulatory cytokines such as IL‐10 and type I interferons depending on the stimulus.