Recommendations on contraindications to allergen immunotherapy (AIT) have been independently developed by National and International Societies/Academies. AIT contraindications are mainly based on case reports, case-series, or experts’ opinion, while evidence-based information is limited. The aim of the present review was to describe existing guidelines on contraindications to AIT and to highlight differences between them.

An extended review of the literature regarding contraindications to AIT for respiratory allergy and venom hypersensitivity was performed. Furthermore, Societies and Academies registered in the World Allergy Organization and EAACI databases, were asked for additional information. Only AIT guidelines published under official auspicies were included. A large heterogeneity among the various recommendations on contraindications was registered. Common contraindications to most of the guidelines were: lack of adherence, pregnancy before the start of AIT, the use of beta-blockers, certain age groups, uncontrolled asthma, autoimmune diseases and malignancies.

As new data arise, revisions might soon be needed allowing AIT in the cases of patients treated with ACE inhibitors and beta-blockers, in elderly patients and in patients with concomitant autoimmune diseases and neoplasias in remission. The decision to prescribe AIT is always tailor-made, balancing risk vs benefit. Creating globally accepted guidelines would help Allergologists in their decision making.

Dietary avoidance is recommended for peanut allergies. We evaluated the sustained effects of peanut allergy oral immunotherapy (OIT) in a randomised long-term study in adults and children.

In this randomised, double-blind, placebo-controlled, phase 2 study, we enrolled participants at the Sean N Parker Center for Allergy and Asthma Research at Stanford University (Stanford, CA, USA) with peanut allergy aged 7-55 years with a positive result from a double-blind, placebo-controlled, food challenge (DBPCFC; ≤500 mg of peanut protein), a positive skin-prick test (SPT) result (≥5 mm wheal diameter above the negative control), and peanut-specific immunoglobulin (Ig)E concentration of more than 4 kU/L. Participants were randomly assigned (2·4:1·4:1) in a two-by-two block design via a computerised system to be built up and maintained on 4000 mg peanut protein through to week 104 then discontinued on peanut (peanut-0 group), to be built up and maintained on 4000 mg peanut protein through to week 104 then to ingest 300 mg peanut protein daily (peanut-300 group) for 52 weeks, or to receive oat flour (placebo group). DBPCFCs to 4000 mg peanut protein were done at baseline and weeks 104, 117, 130, 143, and 156. The pharmacist assigned treatment on the basis of a randomised computer list. Peanut or placebo (oat) flour was administered orally and participants and the study team were masked throughout by use of oat flour that was similar in look and feel to the peanut flour and nose clips, as tolerated, to mask taste. The statistician was also masked. The primary endpoint was the proportion of participants who passed DBPCFCs to a cumulative dose of 4000 mg at both 104 and 117 weeks. The primary efficacy analysis was done in the intention-to-treat population. Safety was assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT02103270.

Between April 15, 2014, and March 2, 2016, of 152 individuals assessed, we enrolled 120 participants, who were randomly assigned to the peanut-0 (n=60), peanut-300 (n=35), and placebo groups (n=25). 21 (35%) of peanut-0 group participants and one (4%) placebo group participant passed the 4000 mg challenge at both 104 and 117 weeks (odds ratio [OR] 12·7, 95% CI 1·8-554·8; p=0·0024). Over the entire study, the most common adverse events were mild gastrointestinal symptoms, which were seen in 90 of 120 patients (50/60 in the peanut-0 group, 29/35 in the peanut-300 group, and 11/25 in the placebo group) and skin disorders, which were seen in 50/120 patients (26/60 in the peanut-0 group, 15/35 in the peanut-300 group, and 9/25 in the placebo group). Adverse events decreased over time in all groups. Two participants in the peanut groups had serious adverse events during the 3-year study. In the peanut-0 group, in which eight (13%) of 60 participants passed DBPCFCs at week 156, higher baseline peanut-specific IgG4 to IgE ratio and lower Ara h 2 IgE and basophil activation responses were associated with sustained unresponsiveness. No treatment-related deaths occurred.

Our study suggests that peanut OIT could desensitise individuals with peanut allergy to 4000 mg peanut protein but discontinuation, or even reduction to 300 mg daily, could increase the likelihood of regaining clinical reactivity to peanut. Since baseline blood tests correlated with week 117 treatment outcomes, this study might aid in optimal patient selection for this therapy.

Grass allergen peptides are in development for the treatment of grass pollen-induced allergic rhinoconjunctivitis (ARC). A previous randomized, placebo-controlled study demonstrated grass allergen peptides significantly improved total rhinoconjunctivitis symptom scores (TRSS) following post-treatment challenges (PTC) to rye grass in an Environmental Exposure Unit (EEU) after one intervening grass pollen season (GPS1).

To evaluate the efficacy/safety of four dosing regimens of grass allergen peptides after a second (GPS2) and third (GPS3) intervening grass pollen season in the EEU.

Eligible individuals who were randomized in the parent study (GPS1) during the first year of recruitment were invited to participate in GPS2 and GPS3, which took place 1 and 2 years after treatment cessation respectively. Participants were not treated further and both participants and study personnel remained blinded. The primary efficacy endpoint was the change in mean TRSS (reported every 30 minutes) from GPS1 baseline to the follow-up PTC, calculated across all time points over days 2-4 for GPS2, and across hours 1-3 over days 2-4 for GPS3. Secondary efficacy endpoints and safety were also assessed.

122 and 85 participants were enrolled in GPS2 and GPS3 respectively. A greater improvement from baseline in mean TRSS at PTC was observed in the 8x6nmol Q2W group compared to placebo in GPS2 (-6.0 vs. -3.6, P=.0535) and GPS3 (-6.2 vs. -3.6, P=.1128). Similar findings were observed for the 4x12nmol Q2W group at GPS3 (-6.4 vs. -3.6, P=.0759). No adverse safety signals were detected.

Treatment with grass allergen peptides led to an improvement in ARC symptoms after three intervening grass pollen seasons, corresponding to up to 2 years off treatment.

Aeroallergen immunotherapy is a safe and effective disease-modifying treatment associated with rare therapy-associated fatality. Significant practice variation surrounds universal or contextual prescription of self-injectable epinephrine (SIE) for patients receiving AIT.

To characterize the cost-effectiveness of a universal vs. contextual SIE requirement for patients receiving AIT.

Economic evaluation using cohort and microsimulation was performed from both the societal and healthcare sector perspectives for AIT patients, assessing a universal requirement to fill SIE prescriptions at the outset of therapy compared with requiring this only after a systemic reaction to immunotherapy (SRIT).

A universal SIE requirement for AIT is not cost-effective, with the incremental cost-effectiveness ratio (ICER) for this strategy estimated at $669,327,730 per quality-adjusted life year (QALY). In the microsimulation (n=10,000) costs of a universal approach exceeded that of a more context-specific strategy where SIE was only prescribed for patients after an initial SRIT ($19,653.36, SD $4,296.66 vs $16,232.14, SD $5,204.32), and given impacts on rates of AIT discontinuation, the universal approach was less effective (25.555 QALY, SD 2.285) compared with a contextualized approach (25.579 QALY, SD 2.345). Universal SIE prescription could be cost-effective it provided a 1000x protection against AIT fatality at a value-based cost of $24, and the annual AIT fatality rates unrealistically exceed 2.6 per 10,000 patients.

In a simulation of potential SIE prescribing strategies for patients receiving AIT, a universal approach to an epinephrine autoinjector requirement was not cost-effective when compared to an approach in which an SIE is prescribed only to patients with prior SRIT.

Subcutaneous allergen immunotherapy (SCIT) is a very effective treatment modality; however, it can be associated with both local and systemic reactions (SR). Identifying patient factors that predict SR remains paramount.

Our aim was to identify the rate of SRs to SCIT as well as identify patient risk factors associated with the development of SRs.

We conducted an institutional review board approved 10-year retrospective chart review of 459 patients who received SCIT in our clinic. The patients were placed into cohorts according to age, which included pediatric (5-18 years), adult (19-64 years), and senior (>65 years) patients.

An SR (N = 177) was identified in 24.8% of the patients (n = 114). The incidence of SR per injection was 0.2% (177 SRs of 74,183 total injections). SRs were identified as class 1 (n = 152), class 2 (n = 21), class 3 (n = 2), and class 4 (n = 2) according to the 2010 World Allergy Organization’s SR grading system. There were no observed differences in the number of SRs with respect to age group. Female patients were more likely to have an SR (p = 0.02) overall as well as more than one reaction (p = 0.002). Other risk factors included the following: a patient-reported history of food allergy (p = 0.05), drug allergy (p = 0.005), or positive skin test result to cat and/or dog (p = 0.01). In addition, patients who were receiving SCIT to cat and/or dog (p = 0.004) or to dust mite (p = 0.03) were more likely to have an SR.

In our patient population, the majority of SRs to SCIT occurred in female patients, patients with a history of drug or food allergies, and those who were receiving pet or dust-mite SCIT.

Specific immunotherapy is an important immune-modifying treatment for patients with allergic rhinitis (AR). We compared the early efficacy and safety of cluster and conventional immunotherapies for patients with AR.

One hundred forty-nine patients with persistent AR were enrolled in a randomized and open-label trial and were divided into the following 4 groups: 60 children treated conventionally, 33 children treated using the cluster schedule, 23 adults treated conventionally, and 33 adults treated using the cluster schedule. Patients in the cluster groups reached the maintenance dose within 6 weeks, while those receiving conventional therapy reached the maintenance dose within 14 weeks. Symptom scores and skin prick test scores (SPTs) were used to evaluate clinical efficacy and adverse reactions.

After buildup phase of treatment, symptom scores, and SPTs were significantly lower than those prior to treatment in each group (P .05).However, the efficacy of SPTs using conventional schedule was higher than cluster schedule in children groups (group A and B, 57.7 vs 30.2%, P = .001). Besides, the efficacy of SPTs in adults was higher than children when using the cluster treatment (group D and B, 53.0 vs 30.2%, P = .008). No severe adverse reaction occurred.

Conventional and cluster immunotherapy schedules have similar efficacies, which do not vary with age; both schedules are safe and reliable. Also, SPT facilitate evaluation of clinical efficacy.

The SQ house dust mite (HDM) sublingual immunotherapy (SLIT)-tablet has demonstrated efficacy and safety for allergic asthma (AA) in European trials.

To evaluate the efficacy and safety of SQ HDM SLIT-tablet treatment for up to 19 months in Japanese adults with AA.

In this randomized, double-blind, placebo-controlled trial, patients aged 18-64 with AA were randomly assigned (1:1:1) to SQ HDM SLIT doses of 10,000 or 20,000 Japanese Allergy Unit (JAU) or placebo. Subjects had Asthma Control Questionnaire score of 1.0-1.5 and daily inhaled corticosteroid (ICS) use of 200-400 μg of fluticasone propionate at randomization. The primary endpoint was the time from randomization to the first asthma exacerbation as the ICS dose was being reduced.

Of the 826 randomized subjects, 693 (84%) completed the trial. No statistically significant differences between the active groups and placebo group were observed for the primary or any other efficacy endpoints. However, post-hoc analysis indicated a significant difference between the 20,000 JAU and placebo groups among subjects who used a short-acting β2-agonist (SABA) during the baseline period (hazard ratio 0.70, 95% confidence interval 0.48-1.00, P=0.04997). No deaths or anaphylactic reactions were reported. Most adverse events were mild to moderate in severity.

The trial demonstrated a favorable safety profile of the SQ HDM SLIT-tablet in Japanese adult patients with AA. The treatment appeared to be efficacious in patients requiring rescue medication (i.e., SABA) at baseline in the efficacy assessment using asthma exacerbation during ICS reduction (JapicCTI number 121847).

Allergic rhinoconjunctivitis is the most common manifestation of allergic disease. This break in the normal natural function of the immune system to ignore harmless molecules such as pollen and pet dander to now aggressively react has lead to a substantial disease burden that is not always recognized and adequately treated.

Individual molecular component testing may increase the predictive value of blood sIgE and clinical symptoms. Defining the most symptoms inducing allergenic protein has led to advances in peptide-based allergen immunotherapy. There have been steady consistent reports that allergy immunotherapy for children with symptomatic allergic rhinitis prevents the onset of asthma.

Allergy immunotherapy is an effective disease-modulating treatment that alters the underlying immune dysfunction which is a currently underutilized therapy especially as it is likely effective in preventing the onset of asthma in children, at least in the short term.

Shellfish allergy is one of the most common food allergies, with tropomyosin as the major cross-reactive allergen. However, no allergen-specific immunotherapy is clinically available. Recently, we designed two shrimp hypoallergens MEM49 and MED171. This study aimed to examine and compare the efficacy of the MEM49- and MED171-based DNA vaccines (pMEM49 and pMED171) in modulating shrimp allergy in a murine model of shrimp tropomyosin sensitivity. Intradermal immunization of BALB/c mice with pMEM49 or pMED171 effectively down-modulated allergic symptoms, tropomyosin-specific IgE levels, intestinal Th2 cytokines expression, and inflammatory cell infiltration. Both pMEM49 and pMED171 increased the frequency of regulatory T cells, but to a greater extent by pMED171 with upregulation of gut-homing molecules integrin-α4β7. The functionality of the pMED171-induced Treg cells was further illustrated by anti-CD25-mediated depletion of Treg cells and the adoptive transfer of CD4+CD25+Foxp3+Treg cells. Collectively, the data demonstrate that intradermal administration of pMED171 leads to the priming, activation, and migration of dermal dendritic cells which subsequently induce Treg cells, both locally and systemically, to downregulate the allergic responses to tropomyosin. This study is the first to demonstrate the potency of hypoallergen-encoding DNA vaccines as a therapeutic strategy for human shellfish allergy via the vigorous induction of functional Treg cells.

Difficult-to-treat or severe persistent asthma accounts for 5-10% of the asthma population worldwide. However, this group of patients creates a higher burden on health systems due to their morbidity and need for long-term and additional treatment. Biological drugs constitute an alternative therapy in the treatment of patients with refractory asthma. In cases where inhalant allergy is part of the pathomechanism, allergen-specific immunotherapy (SIT) is a causative treatment option for allergic asthma. However, SIT is contraindicated for uncontrolled asthma and cannot be administered according to the guidelines. This is due to the risk of further worsening of uncontrolled asthma during treatment.

We herein report a case of a 67-year-old male with severe allergic asthma who was successfully treated with SIT after asthma control was achieved by using target treatments.

Complete control of asthma was achieved, and SIT with allergens from early flowering trees (birch-alder-hazel) was administered. Further, no asthmatic exacerbations or decrease in respiratory function occurred during the 15 months of treatment with mepoluzimab. He did not need any oral glucocorticosteroids.

The case report presented here suggests the effectiveness of an individualized approach and phenotype-specific treatment of patients who cannot receive allergen-specific immunotherapy due to the contraindication uncontrolled asthma and who receive SIT after asthma control is achieved by using target treatments.