Allergen immunotherapy (AIT) is a safe, effective treatment for allergic rhinoconjunctivitis and allergic asthma. However, AIT’s clinical effect is still contested – primarily due to heterogeneity in clinical trial designs, study populations, therapeutic formulations and efficacy criteria. After discussing current concepts and unmet needs, an international panel of experts made several recommendations: (i) explore and validate definitions for [clinical] responders in AIT-trials; (ii) use of well-documented, standardized provocation tests prior to inclusion of subjects with relevant diseases in AIT trials; (iii) monitoring neo-sensitizations and occurrence of new allergy in extended AIT trials, and exclusion of polyallergic participants; (iv) validation of allergen exposure chambers with regard to natural exposure; (v) in studies of seasonal allergies, focus on peak exposure but also consider organizing two parallel, geographically distinct but otherwise identical trials; (vi) discuss adaptive trial designs with the regulatory authorities; (vii) use e-health and m-health technologies to capture more information on individual exposure to allergens; (viii) initiate research on potential psychological, biochemical, immune, neural and even genomic markers of the placebo response; (ix) identify trial designs and primary endpoints that will give children with allergies easier, faster access to AIT formulations; and (x) promote and apply standardized methods for reporting systemic and local adverse events. The latest technologies and trial designs may provide novel, ethical ways of reducing bias and heterogeneity in AIT clinical trials. There is scope for physicians, patient organizations, companies and regulators to improve clinical trials in AIT and, ultimately, to provide patients with better treatments.

Venom immunotherapy is effective in preventing systemic allergic reactions (SARs), but the diagnosis of venom allergy is problematic.

To compare the performance of component-resolved diagnosis and conventional tests in patients referred for venom immunotherapy.

We measured serum-specific immunoglobulin E to yellowjacket and honeybee venoms (Ves v 1 and Ves v 5 and Api m 1), cross-reactive carbohydrate determinants, serum basal tryptase (ImmunoCAP, ThermoFisher Scientific, Uppsala, Sweden), and skin prick test reactions in 84 patients referred to receive venom immunotherapy. History of SAR and its severity were evaluated.

Of the 78 patients with suspected yellowjacket venom (YJV) allergy, a history of SAR was confirmed in 47 (60%) and 31 (40%) had a non-SAR reaction. The most accurate tests to confirm venom allergy after a SAR were serum-specific immunoglobulin E to yellowjacket whole-venom extract spiked with Ves v 5 (area under the curve 0.87, 95% confidence interval 0.77-0.97, P < .001) and Ves v 5 (area under the curve 0.86, 95% confidence interval 0.76-0.96, P < .001). Sensitization to Ves v 1 was infrequent and its area under the curve was low (0.62, 95% confidence interval 0.47-0.76, P = .106). Sensitivity of the YJV skin prick test was 86%, but its specificity was low at 54%. Double sensitization to yellowjacket and honeybee occurred frequently in skin prick tests. Of the patients without a SAR, 26% showed a positive reaction to YJV in any serum test and 46% showed a positive reaction in skin tests.

Specific immunoglobulin E to the YJV spiked with Ves v 5 confirmed the allergy after a SAR. A history of SAR should be confirmed before testing, because venom sensitization is frequent in other types of reactions.

Medication persistence and adherence in allergy immunotherapy (AIT) has been reported to be lower in real life than in clinical studies, with manufacturers’ sales figures often indicating poorer adherence and persistence than postmarketing studies. This might result from patients tending to be more compliant when their behavior is being recorded, which is commonly known as the Hawthorne effect.

Grastek® is a standardized sublingual immunotherapy tablet(SLIT-T) approved for the treatment of grass pollen-induced allergic rhinitis(AR) and conjunctivitis. Many grass-allergic patients are also co-sensitized to birch pollen. Whether Grastek® can confer symptomatic benefits for birch pollen-induced AR symptoms is unknown.

To evaluate the treatment effect of Grastek® for birch pollen-induced AR in participants sensitized to both grass and birch pollen using the Environmental Exposure Unit (EEU).

Phase IV, randomized, double-blind, placebo-controlled, parallel-group study enrolling participants aged 18-65 years allergic to both timothy grass and birch pollen. Following a baseline EEU birch pollen challenge where a minimum Total Nasal Symptom Score(TNSS) of 6/12 was required for enrollment, participants were randomized to receive Grastek® or placebo taken once daily for 4 months. No confirmatory grass pollen challenge was performed. The primary endpoint was the change in TNSS averaged from assessments from hours 2 to 5 during the post-treatment birch pollen challenge(PTC) compared to baseline. Secondary/exploratory endpoints included temporally identical changes in Total Ocular Symptom Score(TOSS), Total Rhinoconjunctivitis Symptom Score(TRSS), and individual symptom scores.

The difference in TNSS reduction following 4 months of therapy between the Grastek® and placebo group was not significant(P=0.83). Reductions in TOSS(P=0.19) and TRSS(P=0.67) were also comparable between groups. Findings between groups for individual symptom scores were similar(all P>0.4) except watery eyes where symptom reduction was slightly better in the placebo arm (P=0.014). Grastek® was well tolerated and no serious AEs occurred.

A by-stander effect of grass SLIT-T on birch pollen-induced AR symptoms was not detected. Symptomatic benefits of grass SLIT-T are likely allergen specific.

It has been recommended that sublingual immunotherapy (SLIT) safety be assessed using solicited adverse event (AE) collection methods.

The objectives of this study were to describe the impact on the safety profile of SQ house dust mite (HDM) SLIT-tablet (12 SQ-HDM dose) when prespecified local application site reactions were solicited versus unsolicited, and discuss ramifications of AE solicitation.

Subjects were randomized to daily 12 SQ-HDM or placebo for up to 52 weeks in 4 double-blinded, multicenter trials. In one trial (NCT01700192; N = 1272), subjects documented daily the presence or absence of 15 World Allergy Organization-defined local application site reactions using a structured questionnaire of closed-ended questions (solicited AEs). Subjects in the other trials were not asked about specific AEs (unsolicited AEs), and AE data were pooled (N = 1287). Analysis was limited to adults aged 18 to 65 years.

Whether AEs were solicited or unsolicited, the most common AEs leading to study discontinuation with 12 SQ-HDM were throat irritation and oral pruritus. Approximately 95% of treatment-related AEs were mild to moderate. Placebo-subtracted frequencies of local application site reactions associated with 12 SQ-HDM were higher when solicited versus unsolicited (ie, throat irritation, 46% vs 13%, respectively; oral pruritus, 47% vs 17%; ear pruritus, 40% vs 4%; mouth swelling, 8% vs 2%; tongue ulceration, 10% vs 0%; mouth ulceration, 7% vs <1%).

Qualitatively, the safety profile of 12 SQ-HDM was similar when AEs were solicited versus unsolicited; hence, solicitation did not alter the safety profile. Higher observed frequencies of local application site reactions with AE solicitation may be partly due to suggestive reporting bias, as observed in placebo-treated subjects.

In ascertained allergic sensitization to Vespa crabro (VC) venom, the European guidelines still consider venom immunotherapy (VIT) with Vespula (VE) venom sufficient to achieve an adequate protection against VC. However, antigen 5 immunoblotting studies showed that a genuine sensitization to VC venom may exist. In such cases, a specific VC venom would be preferable for VIT treatment. Since in the last few years, VC venom extracts became available for diagnosis and desensitization, we assessed the efficacy and safety of VIT with a VC-VIT, compared to VE extract.

Patients stung by VC, and carefully diagnosed for specific sensitization and indication to VIT underwent a 5-year course of immunotherapy with either VE or VC extracts. The severity of reactions at the first sting (pre-VIT) and after field re-stings (during VIT) were compared.

Eighty-three patients, treated with VE extract and 130 patients treated with VC extract completed the 5-year course of VIT. Only a fraction of those patients (43,8%) were field-re-stung by VC: 64 patients on VC VIT and 69 on VE VIT. In the VC VIT group, reactions at re-sting were: 50 negative, 12 large local reactions, 4 systemic reactions (Muller grade I). In this group the VC VIT efficacy was 93,8%. In the VE VIT treated group the reactions at VC re-sting were: 51 negative, 10 large local reactions and 9 systemic reactions (5 Muller I, 3 Mueller III, 1 Muller IV). In this group the overall efficacy of VIT was 87,0%. The difference in efficacy between the two groups was not statistically significant, as previously reported in literature. Nonetheless, field sting systemic reactions Muller III and IV were recorded only in those patients receiving VE VIT.

This observation suggests that in patients with ascertained VC-induced allergic reactions a specific VC VIT, where available, would be more adequate, at least concerning the safety profile.

During the past few decades, modified allergens have been developed for use in allergen-specific immunotherapy(AIT) with the aim to improve efficacy and reduce adverse effects. This review aims to provide an overview of the different types of modified allergens, their mechanism of action and their potential for improving AIT.

In-depth research in the field of allergen modifications as well as the advance of recombinant DNA technology have paved the way for improved diagnosis and research on human allergic diseases. A wide range of structurally modified allergens has been generated including allergen peptides, chemically altered allergoids, adjuvant-coupled allergens, and nanoparticle-based allergy vaccines. These modified allergens show promise for the development of AIT regimens with improved safety and long-term efficacy. Certain modifications ensure reduced IgE reactivity and retained T cell reactivity, which facilities induction of immune tolerance to the allergen. To date, multiple clinical trials have been performed using modified allergens. Promising results were obtained for the modified cat, grass and birch pollen, and house dust mite allergens. The use of modified allergens holds promise for improving AIT efficacy and safety. There is however a need for larger clinical studies to reliably assess the added benefit for the patient of using modified allergens for AIT.

Allergen-specific immunotherapy (AIT) in its subcutaneous and sublingual forms is currently a well-established and experimentally supported treatment for respiratory allergy and hymenoptera venom allergy. There have been advances in its use linked strictly to the advancement in the knowledge of the molecular mechanisms of allergy, the production of well-characterized extracts, and diagnostic techniques. The use of AIT in asthma and the application of new approaches are expanding. We briefly review the advances and concerns in the use of AIT.

PubMed and Scopus.

The most recent and clinically relevant literature was selected and reviewed.

The introduction of high-quality products supported by large dose-finding trials has yielded better defined indications, contraindications, and modalities of use. Some specific products in tablet form have recently been approved in the United States. Sublingual immunotherapy has been found to be effective in asthma, which until recently had been a matter of debate. Another promising therapy is oral and sublingual desensitization for food allergy, for which encouraging results have recently been reported. In the near future, other options will be available, including new routes of administration (intralymphatic and epicutaneous), allergoids, engineered allergens, and peptides. The use of component-resolved diagnosis techniques will further refine and target AIT prescriptions.

This condensed and updated review shows that AIT remains a viable treatment option, especially after the introduction of standardized tablets for some allergens. Food allergy and new administration routes represent a promising expansion.

The incidence of allergic conditions has continued to rise over the past several decades, with a growing body of research dedicated toward the treatment of such conditions. By driving a complex range of changes in the underlying immune response, immunotherapy is the only therapy that modulates the immune system with long-term effects and is presently utilized for the treatment of several atopic conditions. Recent efforts have focused on identifying biomarkers associated with these changes that may be of use in predicting patients with the highest likelihood of positive clinical outcomes during allergen immunotherapy (AIT), providing guidance regarding AIT discontinuation, and predicting symptomatic relapse and the need for booster AIT after therapy. The identification of such biomarkers in food allergy has the additional benefit of replacing oral food challenges, which are presently the gold standard for diagnosing food allergies. While several markers have shown early promise, research has yet to identify a marker that can invariably predict clinical response to AIT. Skin prick testing (SPT) and specific IgE have commonly been used as inclusion criteria for the initiation of AIT and prediction of reactions during subsequent allergen challenge; however, existing data suggests that changes in these markers are not always associated with clinical improvement and can be widely variable, reducing their utility in predicting clinical response. Similar findings have been described for the use of allergen-specific functional IgG4 antibodies, basophil activation and histamine release, and type 2 innate lymphoid cells. There appears to be a promising association between changes in the expression of dendritic cell-associated markers, as well as the use of DNA promoter region methylation patterns in the prediction of allergy status following therapy. The cellular and molecular changes brought about by immunotherapy are still under investigation, but major strides in our understanding are being made.

Viral infection and allergy have been identified as major risk factors for exacerbation in asthma, especially in the presence of both. However, whether patients with allergic asthma are more susceptible to respiratory infections requiring antibiotics remains unknown.

To investigate allergy as a risk factor for respiratory infections requiring antibiotics based on register data from a nationwide population of patients with asthma.

A register-based prospective follow-up study was performed using the Danish prescription database. In the inclusion period from 2010 through 2011, we identified patients with allergic asthma 18 to 44 years old. Patients were investigated during the follow-up period from 2012 through 2013, depending on their prescription drug use of antiallergic medication and antibiotics. Odds ratios were adjusted for age, sex, asthma severity, education, and urban vs rural residence.

In a nationwide population we identified 60,415 patients with asthma. Based on prescriptions fillings for antiallergic medication, patients were subdivided into (1) nonallergic asthma (n = 35,334, 51.5%) and (2) allergic asthma (n = 25,081, 48.5%). Allergic asthma was associated with an increased risk of filling at least 2 antibiotic prescriptions per year compared with nonallergic asthma (odds ratio 1.28, 95% confidence interval 1.24–1.33, P < .0001). Interestingly, a subgroup analysis showed a protective effect of immunotherapy against the risk of requiring antibiotics (odds ratio 0.76, 95% confidence interval 0.66–0.87, P = .0001).

Patients with allergic asthma have an increased risk of being prescribed antibiotics for respiratory infections compared with those with nonallergic asthma. Treatment with allergen immunotherapy appears to have a protective effect against this risk