Observational comparative effectiveness studies in allergen immunotherapy (AIT) represent an important evidence source answering research questions that can be challenging to obtain from randomized controlled trials (RCTs), such as long-term benefits of AIT, the effects on asthma prevention and the onset of new allergen sensitizations. However, observational studies are prone to several sources of bias, which limit their reliability.The REal Life Evidence AssessmeNt Tool (RELEVANT) was recently developed to assist in quality appraisal of observational comparative research to enable identification of useful nonrandomized studies to be considered within guideline development.

To systematically appraise the quality of published observational comparative AIT studies using RELEVANT.

Observational studies comparing AIT to pharmacotherapy for respiratory allergies, assessing as outcome measures reduction of symptoms and/or medication use reduction, were retrieved by computerized bibliographic searches. According to RELEVANT, a failure to meet any one of primary items (background, design, measures, analysis, results, discussion/interpretation, and conflict of interest) represents a critical flaw, significantly undermining the validity of the study results.

The 14 studies identified supported the benefit of AIT in real-life, which persists after treatment discontinuation. However, none of them met all the 7 primary RELEVANT criteria. The main defects were reported in the design (28.6% of studies), measures and analysis (64.3% of studies), and results (78.6% of studies) items, due to selection bias and lack of methods for adjusting controls. Half of the studies did not report on conflict of interest.

There is a need for more robust observational research in AIT. RELEVANT appears as an easy-to-use and sensitive tool for quality appraisal in AIT studies.

Stings by Polistes species frequently cause allergic reactions. However, standard allergy diagnostics are often unable to differentiate between primary sensitization and cross-reactivity, in case of Vespula/Polistes double-sensitization, because Antigen 5 is the only Polistes venom molecule currently available in diagnostics (Pol d 5).

The objectives of this study were to evaluate the frequency of Phospholipase A1 in Polistes venom allergy (Pol d 1) and its diagnostic role in vespid allergy.

Component resolved diagnostics was performed in patients with Vespid allergic reactions who resulted positive to Polistes venom. A prevalence analysis was performed, and the diagnostic accuracy of Pol d 1 evaluated for detection of primary Polistes sensitization, in double-sensitized patients.

Blood samples were collected from 132 patients. Pol d 1 was present in 97-100% of the 128 Polistes-positive patients, and it was frequently involved in case of positivity to one single Polistes molecule (48% in double- and 80% in mono-sensitized patients). Furthermore, Pol d 1 was positive in 95% of Pol d 5 negative subjects. The diagnostic accuracy of Pol d 1 was good (folded type: AUC=87%, 82% sensitivity and 77% specificity at the best cut-off of 5.773), and even better if used in combination with the whole extract ratio (AUC= 99%, 91% sensitivity and 100% specificity).

The study shows that Pol d 1 is the most frequent Polistes allergen in Italian patients, and it can distinguish Polistes primary sensitizations with a good diagnostic accuracy, supporting its use in clinical practice.

Allergen immunotherapy (AIT) must be continued for 3 years, to achieve a long-term modifying effect. Adherence is a key to ensure effectiveness. The objective of this study was, first of all, to evaluate the adherence with subcutaneous immunotherapy (SCIT) and to identify the main causes of SCIT withdrawal in real-life practice in our clinic. Secondly, we also aimed to investigate to what extent the COVID-19 pandemic altered our SCIT receiving patients' treatment adherence behaviors and the factors that affected their decisions.

Retrospective analysis of the medical records of patients ages ≥18 years, who had started SCIT in January 2014 or later until September 2020 in our department for the diagnosis of allergic rhinitis, allergic asthma or venom allergy, were included in the study. Adherence was determined as the accomplishment of 3 years of SCIT.

A total of 124 patients (72 female [58.1%]; median age, 35 [19-77] years) were included. The adherence rate to SCIT in our tertiary center's real-life setting was 56.25% with a follow-up duration of 3 years before COVID-19 pandemic. Dose modification, defined as reducing patient's planned SCIT dose due to a systemic allergic/large local reaction or missed injection, and its frequency, which is the number of dose adjustments done throughout the SCIT, was found to be the only factor related to nonadherence. But with the pandemic only in 6 months, among 63 patients receiving SCIT, 15 patients (23.81%) dropped out, and the most common reason was fear of being infected with COVID-19 virus during receiving SCIT in hospital (93.33%). The only independent predictor of drop-out during the COVID-19 pandemic was short duration of AIT (p = 0.012). When we compare the dropped-out cases before and after the start of pandemic, AIT duration was significantly shorter in pandemic period (p = 0.005).

Adherence rate to SCIT in our real-world setting study was 56.25% before the COVID-19 pandemic. Our results indicated that patients requiring dose modification were more prone to be non-adherent. Approximately one quarter of patients dropped-out with the start of pandemic, almost all due to fear of being infected during receiving SCIT in hospital. Since short SCIT follow-up time was found to be the only risk factor for drop-out during the COVID-19 pandemic, we believe that patients who are in the early phases of their treatment should be observed more closely and their concerns should be answered by their doctors.

Intralymphatic immunotherapy (ILIT) is a new route of allergen-specific immunotherapy. Data confirming its effect is restricted to a small number of studies.

A systematic review with meta-analysis was conducted. The short-term (less than 24 weeks), medium-term (24-52 weeks), and long-term (more than 52 weeks) effects of ILIT in patients with allergic rhinoconjunctivitis (ARC) were assessed. The outcomes were combined symptom and medication scores (CSMS), symptoms visual analog scale (VAS), disease-specific quality of life (QOL), specific IgG4 level, specific IgE level, and adverse events.

Eleven randomized controlled trials and 2 cohorts (483 participants) were included. Compared with placebo, short term benefits of ILIT for seasonal ARC improved CSMS, improved VAS and increased specific IgG4 level but did not change QOL or specific IgE level. Medium-term effect improved VAS. Data on the long-term benefit of ILIT remain unavailable and require longer term follow-up studies. There were no clinical benefits of ILIT for perennial ARC. ILIT was safe and well-tolerated.

ILIT showed short-term benefits for seasonal ARC. The sustained effects of ILIT were inconclusive. It was well tolerated.

Few patients with food allergy are "highly allergic," meaning they always have severe reactions and always react to very small amounts of allergen. Standard medical approaches for allergy management have focused on the safety and lifestyle modifications this group truly needs, but consequently families with food allergy are typically advised to strictly avoid any exposure to their implicated allergens. Most food-allergic subjects are actually not reactive to very low doses, and many never experience severe reactions. There are also notable conditions where a different care plan is already commonly offered: patients with pollen-related food allergy syndrome, with food-associated exercise-induced anaphylaxis, and with resolving or mild milk or egg allergy might be advised to ingest the allergens in specific circumstances with detailed instructions. Because oral immunotherapy and allergy prevention by early exposure have emphasized alternatives to strict avoidance, there is increasing interest in prospects to forego strict avoidance in those with food allergy. For patients with a high threshold of reactivity (low-dose tolerant, high-dose mildly reactive), there may be options such as allowing the ingestion of products with precautionary allergen labels, allowing dietary indiscretions with small amounts of the allergen, or even encouraging ingestion of subthreshold amounts with therapeutic intent. These practices have not been extensively studied and could be considered controversial. If these approaches are considered, shared decision making is needed in discussing them with patients and families. This review considers the potential approaches to those who are "not highly allergic": the risks, benefits, shared decision making, and research needs.

Selecting an appropriate allergen-specific immunotherapy (AIT) regimen for polysensitised allergic rhinitis (AR) patients is challenging for clinicians. Although previous studies showed comparable effectiveness of single-allergen AIT with house dust mite (HDM) extract between monosensitised and polysensitised AR patients, there is no systematic review and meta-analysis demonstrating the comparable effectiveness of HDM AIT. In this meta-analysis, we analysed nine studies to compare the clinical effectiveness of HDM AIT. The primary outcome was nasal symptom score and secondary outcomes were medication and quality of life scores. The changes in nasal symptom score after HDM AIT did not significantly differ between monosensitised and polysensitised patients. The clinical effectiveness of HDM AIT regarding medication and quality of life score was not significantly different between monosensitised and polysensitised patients). In conclusion, single-allergen AIT with HDM extract showed comparable clinical effectiveness between polysensitised and monosensitised patients with AR.

Food allergy (FA) is a growing global problem that can affect patients' health-related quality of life (HRQoL) owing to increased anxiety as well as social and economic restrictions. Interventions such as oral food challenges (OFCs) and oral immunotherapy (OIT) have been shown to improve HRQoL. However, meta-analyses and systematic synthesis of these data are lacking.

To review and quantitatively synthesize potential benefits of interventions (OIT and OFC) systematically to address FA to a variety of foods.

We conducted a systematic search through PubMed and Cochrane Medical Library databases and performed a meta-analysis focusing on studies assessing changes in HRQoL after OIT and/or OFCs in FA participants and caregivers from 2010 to July 2020. Random effects model and I2 statistics were used to assess overall intervention effects and heterogeneity across studies.

We included 13 publications in this meta-analysis (OIT = 7; OFCs = 6). Mean change in HRQoL scores after OIT and OFCs was -1.25 (P < .001) and -0.78 (P = .052), with a significant I2 of 87% (P < .001) and 90% (P < .001), respectively. Five OIT studies found significant improvements in HRQoL in the OIT group compared with the placebo group, with an overall standardized mean difference of -0.56 (P = .007; I2 = 42%, P = .099).

This meta-analysis showed that in FA patients, both OIT and OFCs are associated with an improvement in HRQoL. Well-designed and long-term HRQoL studies are necessary to ascertain sustained benefits of OIT and OFCs.

Despite the effectiveness of allergen immunotherapy (AIT), some patients are unresponsive for reasons still unknown; yet validated response biomarkers remain unavailable.

To analyze immunological parameters as biomarkers to monitor and predict clinical response to a MicroCrystalline Tyrosine-adjuvanted house dust mite (HDM) AIT in patients with allergic rhinitis (AR).

Observational, prospective, multicenter study including adult patients (aged 18-65 years) with AR, with and without asthma, sensitized to the HDM Dermatophagoides pteronyssinus (DP) and prescribed Acarovac Plus® DP 100% in the routine practice. Serum concentrations of total IgE, specific IgE, specific IgG4, IL-4, IL-5, IL-10, IL-13, and IFN-γ were compared between baseline and 12 months after AIT. The relationship between patients' baseline immunological profiles and classification as low, high, and non-responders and between their sensitization profile to DP allergens and effectiveness were analyzed.

Of 141 patients recruited, 118 (mean [SD] age of 33.6 [9.5] years) were evaluable. One year after treatment, Der p 1-specific IgE, DP-specific IgG4, and IL-10 increased by a mean (SD) of 3.4 (13.6) kU/L (p = 0.016), 0.43 (0.55) mg/L (p < 0.0001), and 1.35 (7.56) pg/mL (p = 0.033), respectively. Non-responders showed increased baseline levels of IL-13 compared to high responders (p = 0.037). Changes in effectiveness variables between baseline and after AIT were similar regardless of the sensitization profile.

Non-responsive patients to AIT showed increased baseline IL-13 concentrations, suggesting its value as prognostic biomarker. DP-specific AIT increased Der p 1-specific IgE, DP-specific IgG4, and IL-10 concentrations in patients with AR. All patients benefited from treatment regardless of their sensitization profile to major DP allergens.

The prevalence of food allergy is increasing on a global scale, and therefore increased attention is being paid to specific food allergy epidemiology and management. There has been a large amount of progress made in the last decade on human trials of wheat oral immunotherapy (WOIT).

To date, there has been one multicenter, double-blind, randomized controlled trial of WOIT, one randomized, noncontrolled trial of WOIT, and several smaller, nonrandomized clinical trials of WOIT. WOIT trials are generally limited by smaller sample sizes, affecting the demographic skew of evaluated patients. In addition, there is minimal standardization of efficacy and safety outcomes between trial protocols, making head-to-head comparison challenging. However, some common themes emerge. The majority of WOIT regimens result in successful desensitization, and success is more likely with higher maintenance dosing for longer periods of time. Limited studies have looked at sustained unresponsiveness in WOIT. WOIT can induce allergic reactions, including anaphylaxis, but more severe reactions often have an associated augmenting factor, such as exercise. Lower maintenance doses likely are associated with less severe reactions, and food modification and/or adjunct therapeutics may also decrease the risk of reactions.

WOIT trials are ongoing and will optimize updosing protocols and maintenance doses to improve efficacy and safety.

Despite the COVID-19 pandemic, progress continued in the field of peanut oral immunotherapy over the past 12 to 18 months. Of importance, the first oral immunotherapy product for the treatment of peanut allergy was approved by the US Food and Drug Administration in January 2020.

Suggested modifications to the practice of oral immunotherapy, some of which may have lasting impacts, were circulated as a result of the pandemic. New advances in pathophysiology, sustained unresponsiveness, quality of life, safety, and cost effectiveness were also published.

During 2020, COVID-19 influenced the daily practice of allergy and immunology, with peanut oral immunotherapy being no exception. However, clinicians now have a FDA-approved treatment option for peanut allergy in children, a welcome development for a difficult disease. Future research is needed to clarify several knowledge deficits surrounding the best use of peanut OIT.