Allergen Immunotherapy in Children User’s Guide

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

How safe are the biologicals in treating asthma and rhinitis?

A number of biological agents are available or being investigated for the treatment of asthma and rhinitis. The safety profiles of these biologic agents, which may modify allergic and immunological diseases, are still being elucidated. Subcutaneous allergen immunotherapy, the oldest biologic agent in current use, has the highest of frequency of the most serious and life-threatening reaction, anaphylaxis. It is also one of the only disease modifying interventions for allergic rhinitis and asthma. Efforts to seek safer and more effective allergen immunotherapy treatment have led to investigations of alternate routes of delivery and modified immunotherapy formulations. Sublingual immunotherapy appears to be associated with a lower, but not zero, risk of anaphylaxis. No fatalities have been reported to date with sublingual immunotherapy. Immunotherapy with modified formulations containing Th1 adjuvants, DNA sequences containing a CpG motif (CpG) and 3-deacylated monophospholipid A, appears to provide the benefits of subcutaneous immunotherapy with a single course of 4 to 6 preseasonal injections. There were no serious treatment-related adverse events or anaphylaxis in the clinical trials of these two immunotherapy adjuvants. Omalizumab, a monoclonal antibody against IgE, has been associated with a small risk of anaphylaxis, affecting 0.09% to 0.2% of patients. It may also be associated with a higher risk of geohelminth infection in patients at high risk for parasitic infections but it does not appear to affect the response to treatment or severity of the infection

Sublingual immunotherapy in children with allergic rhinoconjunctivitis mono-sensitized to house-dust-mites: a double-blind-placebo-controlled randomised trial.

Background Although sublingual immunotherapy (SLIT) has been demonstrated to be a safe and efficient treatment in children with seasonal allergic rhinitis (AR), there is little evidence on the efficacy of SLIT with house-dust-mite (HDM) extract in children with isolated perennial AR. Objectives We sought to assess the clinical efficacy and safety of HDM-SLIT in children with isolated allergic rhinitis-conjunctivitis mono-sensitized to HDM without asthma symptoms. Methods Twenty-two children (aged 5-10 years) with perennial AR and conjunctivitis symptoms mono-sensitized to Dermatophagoides pteronyssinus and Dermatophagoides farinae were enrolled. During a 2 months run-in period, symptom and medication scores, lung functions, bronchial hyperreactivity, nasal provocation and skin prick tests were evaluated. Subjects were randomized to active or placebo using a double-blind method. A total of eighteen subjects were randomised to receive either active SLIT or placebo for 12 months. Daily symptom and medication scores, baseline lung functions, bronchial hyperreactivity, nasal provocation and skin prick tests were recorded and re-evaluated at the end of treatment. Results After one year of treatment, no significant differences were detected in the between groups and within group comparisons based on total rhinitis symptom/medication scores (p > 0.05). Skin reactivity to Dermatophagoides pteronyssinus was significantly reduced in HDM-SLIT compared to placebo group (p = 0.018). A significant reduction in nasal sensitivity was observed in SLIT group after one year treatment when compared to baseline (p = 0.04). Total conjunctivitis symptoms were reduced significantly in both active and lacebo group at the end of treatment compared to baseline. The proportion of patients with non-specific bronchial hyperreactivity increased to almost 3-fold in placebo group compared to baseline. Conclusion HDM-SLIT was not superior to placebo in reducing isolated rhinoconjunctivitis symptoms within 12 months of treatment. However, HDM-SLIT has a modulating effect on allergen-specific nasal and skin reactivity in isolated perennial AR children. Clinical Trial Registration The trial was registered at Anzctr.org.au number, ACTRN12613000315718. © 2013 Elsevier Ltd. All rights reserved

Duration of allergen immunotherapy for long-term efficacy in allergic rhinoconjunctivitis

Rationale Subcutaneous and sublingual immunotherapy are effective for allergic rhinitis. An important question is whether allergen immunotherapy provides a sustained clinical effect after treatment cessation. In view of potential side effects, cost and the necessary patient commitment, long-term benefit is an important consideration for the recommendation of immunotherapy over standard pharmacotherapy. Purpose of review In this review, we analyse the existing evidence for long-term effects of both routes of administration in the context of double-blind, placebo-controlled, randomised clinical trials that included a follow-up phase of at least 1 year after treatment cessation. Recent findings Overall, evidence suggests that 3 years of either subcutaneous or sublingual immunotherapy result in clinical benefit and immunological changes consistent with allergen-specific tolerance sustained for at least 2–3 years after treatment cessation. Summary The data presented here support recommendations in international guidelines that both routes of administration should be continued for a minimum of 3 years. Gaps in the evidence remain regarding the long-term efficacy of immunotherapy for perennial rhinitis and studies performed in children

Repetitive nasal allergen challenge in allergic rhinitis: priming and Th2-type inflammation but no evidence of remodelling.

BACKGROUND: Local tissue eosinophilia and Th2-cytokines are characteristic features of seasonal allergic rhinitis. Airway-remodelling is a feature of asthma whereas evidence for remodelling in allergic rhinitis (AR) is conflicting. OBJECTIVE: By use of a novel human repetitive nasal allergen challenge (RAC) model, we evaluated the relationship between allergic inflammation and features of remodelling in AR. METHODS: Twelve patients with moderate-severe AR underwent 5-alternate day challenges with diluent which after 4-weeks were followed by 5-alternate day challenges with grass pollen extract. Nasal symptoms, Th1/Th2 cytokines in nasal secretion and serum were evaluated. Nasal biopsies were taken 24 hours after the 1st and 5th challenges with diluent and with allergen. Sixteen healthy controls underwent a single challenge with diluent and with allergen. Using immunohistochemistry, epithelial and sub-mucosal inflammatory cells, and remodelling markers were evaluated by computed image analysis. RESULTS: There was an increase in early and late-phase symptoms after every allergen challenge compared to diluent (both p<0.05) with evidence of both clinical and immunological priming. Nasal tissue eosinophils and IL-5 in nasal secretion increased significantly after RAC compared to corresponding diluent challenges (p<0.01, p=0.01, respectively). There was a correlation between submucosal mast cells and the early-phase clinical response (r=0.79, p=0.007) and an association between epithelial eosinophils and IL-5 concentrations in nasal secretion (r=0.69, p=0.06) in allergic rhinitis. No differences were observed after RAC with regards to epithelial integrity, reticular basement membrane thickness, glandular area, expression of markers of activation of airway-remodelling including α-SMA, HSP-47, extracellular matrix (MMP7, 9 and TIMP-1), angiogenesis and lymphangiogenesis for AR compared to healthy controls. CONCLUSION: Novel repetitive nasal allergen challenge in participants with severe persistent seasonal allergic rhinitis resulted in tissue eosinophilia and increases in IL-5 but no structural changes. Our data support no link between robust Th2-inflammation and development of airway-remodelling in AR