House dust mites (HDM) are one of the most important allergen sources containing many different allergenic molecules. The analysis of patients from a double-blind, placebo-controlled allergen-specific immunotherapy (AIT) study indicated that patients may benefit to a different extent from AIT depending on their molecular sensitization profiles.

To investigate in a real-life setting if stratification of HDM allergic patients according to molecular analysis may enhance AIT success.

Serum and nasal secretion samples from HDM allergic patients (n=24) (baseline, 7, 15, 33 and 52 weeks) who had received one year treatment with a well-defined subcutaneous AIT form (Alutard SQ 510) were tested for IgE and IgG reactivity to 15 micro-arrayed HDM allergen molecules with ImmunoCAP ISAC technology. IgG subclass levels to allergens and peptides were determined by ELISA and IgG blocking was assessed by basophil activation. In vitro parameters were related to reduction of symptoms determined by combined symptom medication score (CSMS) and visual analogue (VAS).

Alutard SQ 510 induced protective IgG mainly against Der p 1 and Der p 2 and to a lower extent to Der p 23, but not to the other important allergens such as Der p 5, Der p 7 and Der p 21 showing better clinical efficacy in patients only sensitized to Der p 1 and/or Der p 2 as compared to patients with additional IgE specificities.

Stratification of HDM allergic patients according to molecular sensitization profiles and molecular monitoring of AIT-induced IgG responses may enhance success of AIT.

The placebo (Latin “I will please”) effect commonly occurs in clinical trials. The psychological and physiological factors associated with patients’ expectations about a treatment’s positive and negative effects have yet to be well characterized, although a functional prefrontal cortex and intense bidirectional communication between the central nervous system and the immune system appear to be prerequisites for a placebo effect. The use of placebo raises certain ethical issues, especially if patients in a placebo group are denied an effective treatment for a long period of time. The placebo effect appears to be relatively large (up to 77%, relative to pre-treatment scores) in controlled clinical trials of allergen immunotherapy (AIT), such as the pivotal, double-blind, placebo-controlled (DBPC) randomized clinical trials currently required by regulatory authorities worldwide. The European Academy of Allergy and Clinical Immunology (EAACI) therefore initiated a Task Force, in order to better understand the placebo effect in AIT and its specific role in comorbidities, blinding issues, adherence, measurement time points, variability, and the natural course of the disease. In this Position Paper, the EAACI Task Force highlights several important topics regarding the placebo effect in AIT such as i) regulatory aspects, ii) neuroimmunological and psychological mechanisms, iii) placebo effect sizes in AIT trials, iv) methodological limitations in AIT trial design and v) potential solutions in future AIT trial design. In conclusion, this Position Paper aims to examine the methodological problem of placebo in AIT from different aspects and also to highlight unmet needs and possible solutions for future trials.abs

Sensitization to Blomia tropicalis (Bt) is very frequent in the tropics, and particularly in Cuba, being a significant cause of allergic asthma. Allergen immunotherapy (AIT) with Bt can be a therapeutic option, however, placebo-controlled clinical trials have not been reported.

To assess the therapeutic effect and safety of AIT for asthma using a standardized allergen vaccine of B. tropicalis by subcutaneous route, in allergic asthmatic patients exposed and sensitized to this mite species.

A double-blind, placebo-controlled Phase II trial was conducted in 35 adults (18 with treatment and 17 with placebo), with mild to moderate asthma, predominantly sensitized to Bt. AIT was administered subcutaneously in increasing doses from 4 to 6000 Biological Units using a locally manufactured standardized extract (BIOCEN, Cuba). Patient assessment was performed using symptom-medication score (SMS), peak expiratory flow and skin reactivity relative to Histamine as measured by skin prick test (SPT).

The 12-month treatment achieved a significant (p < 0.001) decrease of SMS. Symptom score showed only 41% (CI: 26-61) of placebo values, whereas medication was 34.5% (22.4%-63.3%). Treatment was regarded clinically effective in 67% of patients (OR 32; 95%CI: 17 to 102). The effect size on symptoms and medication was higher than has been reported with equivalent allergen dosages of D. pteronyssinus and D. siboney in Cuban asthmatic patients. Skin reactivity to Bt was also significantly reduced (p = 0.0001), increasing 148-fold the allergen threshold to elicit a positive skin test. This desensitization effect was specific to Bt and did not modify the reactivity to Dermatophagoides. The change of specific skin reactivity was significantly (p < 0.05) correlated to clinical improvement. All adverse events were local with a frequency of 2.4% of injections.

The 12-month treatment achieved a significant (p < 0.001) decrease of SMS. Symptom score showed only 41% (CI: 26-61) of placebo values, whereas medication was 34.5% (22.4%-63.3%). Treatment was regarded clinically effective in 67% of patients (OR 32; 95%CI: 17 to 102). The effect size on symptoms and medication was higher than has been reported with equivalent allergen dosages of D. pteronyssinus and D. siboney in Cuban asthmatic patients. Skin reactivity to Bt was also significantly reduced (p = 0.0001), increasing 148-fold the allergen threshold to elicit a positive skin test. This desensitization effect was specific to Bt and did not modify the reactivity to Dermatophagoides. The change of specific skin reactivity was significantly (p < 0.05) correlated to clinical improvement. All adverse events were local with a frequency of 2.4% of injections.

Peanut oral immunotherapy is an effective treatment for desensitizing peanut-allergic patients, but the frequency of adverse reactions has limited its widespread use.

To review the frequency of adverse reactions that patients on peanut oral immunotherapy experience during build-up and maintenance phases and explore factors that may contribute to adverse events.

A retrospective chart review of children and adults with peanut allergy undergoing peanut oral immunotherapy at the New England Food Allergy Treatment Center in West Hartford, Conn was performed. Data on patient demographics, allergic profile, peanut allergy testing, and details of reactions in build-up and maintenance phases were collected. A systemic reaction was defined as one of the following: (1) severe reaction involving 1 system, such as generalized hives and/or angioedema; (2) 2 or more of the following symptoms: cutaneous or oral, respiratory, or gastrointestinal symptoms; (3) drop in blood pressure; or (4) need for epinephrine.

Data were available on 783 patients aged 3.5 to 48.3 years. During buildup, 78 patients (10%) experienced at least 1 systemic reaction, 660 (84%) at least 1 gastrointestinal adverse event, 369 (47%) at least 1 cutaneous adverse event, and 157 (20%) at least 1 respiratory adverse event. Thirty-four patients (4%) required epinephrine during buildup. Six hundred ninety-seven patients (89%) completed buildup and progressed to maintenance. During maintenance, 131 patients (19%) experienced at least 1 systemic reaction, 190 (27%) at least 1 gastrointestinal adverse event, 104 (15%) at least 1 cutaneous adverse event, and 50 (7%) at least 1 respiratory adverse event. Seventy-four patients (11%) required epinephrine during maintenance. None of the adverse events required hospitalizations, and there were no mortalities. Nine patients (1%) were diagnosed with eosinophilic esophagitis during buildup or maintenance. Increasing pretreatment peanut specific IgE levels were associated with increased odds of a systemic reaction during buildup. Increasing age, pretreatment peanut specific IgE level, and a systemic reaction in buildup were associated with increased odds of a systemic reaction during maintenance.

Peanut oral immunotherapy may be an effective and safe treatment for carefully selected peanut-allergic patients under the guidance of experienced providers. Specific patient characteristics and immunologic factors may help predict adverse events.

Subcutaneous immunotherapy (SCIT) is the allergen specific curative treatment of allergic rhintis. Adverse effects, most of which are local, can be observed during the immunotherapy. These adverse effects have been reported more frequently during the pollen season. The purpose of this study was to estimate the rate of local, large local and systemic reactions during the treatment, to determine the relationship between adverse reactions and the season in which these reactions occur, as well as the risk factors for adverse reactions during the grass pollen specific SCIT treatment in children.

We retrospectively collected and analyzed the data of 261 children who administered grass pollen SCIT between 2008 and 2018.

A total of 261 children (177, 67.8% male), who received grass pollen SCIT, with a mean (±SD) age of 12.0±3.0 years at the initiation of SCIT were enrolled to the study. The number of the patients who experienced local and large local reactions were 109 and 30, respectively. In addition, the number of the patients with systemic reactions were 35. After the 12,284 injections, local reactions occurred in 357 (2.9%), and this was followed by systemic reaction as 55 (0.4%) and large local reactions as 40 (0.3%). Frequency of local (p<0.001) and systemic reactions (p=0.003) were higher during grass pollen season than out of the grass pollen season. In multivariate analysis, initiation of SCIT during the grass pollen season [OR:7.351, 95%CI:1.532-35.279, p=0.013] and experiencing local reactions [OR:4.214, 95%CI:2.159-8.224, p<0.001] were independent predictors for the development of large local and systemic reactions.

SCIT, in which only mild to moderate systemic reactions occurred, is safe for the treatment of allergic rhinitis in children. Our study revealed that previous local reactions and initiation of immunotherapy during the grass pollen season were the predictors for large local and systemic reactions during SCIT in children.

Parietaria judaica and P. officinalis are the two most common subspecies of the Parietaria genus. P. judaica and P. officinalis have exhibited cross-reactivity in previous studies. P. judaica pollen is the main cause of allergy in the Mediterranean area. It has been shown that a high percentage of patients sensitized to P. judaica with allergic rhinitis (AR) have an increased risk of developing asthma. The present study aimed to confirm the cross-reactivity between P. judaica and P. officinalis and to evaluate the use of a single P. officinalis extract in patients allergic to both subspecies as a preferable option for the diagnosis and treatment of allergy in a highly pollinated area of the Spanish Mediterranean coast. The present study was a single centre, observational cross-sectional study of adult patients diagnosed with AR and/or bronchial asthma who were sensitized to Parietaria pollen. A total of 24 patients were enrolled in the study and included in the analysis. Allergovit® immunotherapy extracts were selected for the study based on the protein content (P. officinalis pollen extract). The results of an in vitro ELISA revealed that 79.1% (n=19) of the patient sera were reactive to immunotherapy extracts. ELISA inhibition assay of the IgE binding to P. officinalis demonstrated inhibition values >70% in the sera of highly reactive patients, confirming the cross-reactivity between the two Parietaria subspecies. In addition, all patients enrolled in the study exhibited double skin positivity against P. judaica and P. officinalis extracts, as assessed by the skin prick test, further supporting the in vivo reactivity between the two subspecies. The present study demonstrated that P. judaica and P. officinalis pollen extracts were highly cross-reactive, and that a unique P. officinalis pollen extract may be used for the diagnosis and immunotherapy of patients allergic to Parietaria.

Allergen immunotherapy (AIT) is aimed at inducing tolerance to allergens, such as pollens, dust mites or moulds, by administering increasing amounts of the causative allergen through subcutaneous or sublingual route. The evidence of efficacy of AIT is high, but the issue of safety, especially for the subcutaneous route, must be taken into account. The search for safer AIT products aimed at reducing the allergenicity, and thus adverse reactions, while maintaining the immunogenicity, that is essential for effectiveness, gave rise to the introduction of allergoids, which were conceived to fulfill these requirements. In the first allergoids glutaraldehyde or formaldehyde were used as cross-linking agent to polymerize allergens, this resulting in high molecular weight molecules (200,000 to 20,000,000 daltons) which were significantly less allergenic due to a decreased capacity to bridge IgE on its specific receptor, while maintaining the immunogenicity and thus the therapeutic efficacy. In recent years further agents, acting as adjuvants, such as L-tyrosine, monophosphoryl lipid A, aluminium hydroxide, were added to polymerized extracts. Moreover, a carbamylated monomeric allergoid was developed and, once adsorbed on calcium phosphate matrix, used by subcutaneous route. At the same time, in virtue of its peculiarities, such allergoid revealed particularly suitable for sublingual administration. A lot of clinical evidences show that it is well tolerated, largely safer and effective. Importantly, the higher safety of allergoids allows faster treatment schedules that favor patient compliance and, according to pharmaco-economic studies, they might be more cost-effective than other AIT options.

Allergen-specific immunotherapy (AIT) is an allergen-specific form of treatment for patients suffering from immunoglobulin E (IgE)-associated allergy; the most common and important immunologically mediated hypersensitivity disease. AIT is based on the administration of the disease-causing allergen with the goal to induce a protective immunity consisting of allergen-specific blocking IgG antibodies and alterations of the cellular immune response so that the patient can tolerate allergen contact. Major advantages of AIT over all other existing treatments for allergy are that AIT induces a long-lasting protection and prevents the progression of disease to severe manifestations. AIT is cost effective because it uses the patient´s own immune system for protection and potentially can be used as a preventive treatment. However, broad application of AIT is limited by mainly technical issues such as the quality of allergen preparations and the risk of inducing side effects which results in extremely cumbersome treatment schedules reducing patient´s compliance. In this article we review progress in AIT made from its beginning and provide an overview of the state of the art, the needs for further development, and possible technical solutions available through molecular allergology. Finally, we consider visions for AIT development towards prophylactic application.

The introduction of high-quality and standardized extracts for immunotherapy has renewed the interest in the treatment of pediatric allergic asthma that represents a high-prevalence disease.

In addition to clinical trials, several systematic reviews and metaanalyses were published, confirming overall the clinical efficacy of allergen immunotherapy in pediatric asthma. In addition, new data on the preventive effective of the treatment on asthma onset were published. Despite this, many intriguing questions emerged, in parellel to the development of knowledge.

Allergen immunotherapy is overall effective fo the treatment of asthma in children, but a class-effect should not be claimed, rather the efficacy of each single product. According to the recent findings, the challenge for the future reseach will be to clarify: when to start immunotherapy in children, which are (if they exist) the predictive biomarkers for efficacy in the single individual, the magnitude of the preventive effect and the optimal duration of the treatment.

Previous proof-of-concept studies have shown that a short course of omalizumab can safely accelerate the oral immunotherapy schedule for multiple allergens simultaneously. Considering the high cost of medication, the dose-related efficacy of omalizumab at decreasing the duration of oral immunotherapy up-dosing phase must be objectively quantified before cost-benefit analyses can be performed. The primary objective of this trial will be to compare the efficacy of 2 omalizumab dosages to placebo at decreasing time-to-maintenance dose during a symptom-driven multi-food OIT protocol.

A total of 90 participants aged 6 to 25 with multiple food allergies (3 or more) will be enrolled at four sites in Canada. Participants will be randomized to: (A) Omalizumab 8 mg/kg per month (n = 36); (B) Omalizumab 16 mg/kg per month (n = 36); or (C) Placebo (n = 18). Study drug will be administered at full dosage for 12 weeks, then progressively tapered at 50% dosage (8 mg/kg vs 4 mg/kg vs placebo) for 4 weeks and at 25% dosage (4 mg/kg vs 2 mg/kg vs placebo) for another 4 weeks. After a pre-treatment period of 8 weeks, participants will undergo an initial food escalation (IFE) to an OIT mix containing 3 allergens and start daily home dosing with biweekly increases until a target daily maintenance of 1500 mg protein is achieved. The amount escalated at each visit will vary based on treatment tolerance according to a standardized up-dosing algorithm. Participants will be followed for at least 12 months following the initial food escalation. The primary endpoint will be time from IFE to the target maintenance dose of 1500 mg protein. Time-to-event analytic methods, including the log-rank test, will be used to compare the 3 arms.

This trial uses a novel pragmatic approach to compare OIT with omalizumab to OIT without omalizumab in a blinded manner, which allows to single out the effect of this anti-IgE medication on treatment effectiveness speed without the recourse to predetermined schedules. The innovative patient-centered up-dosing algorithm allows to maximise treatment effectiveness speed without compromising patient safety, regardless of whether the patient is on omalizumab or not. This study will also provide novel prospective data to inform on the optimal and most cost-effective dosage for this indication.