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Allergen immunotherapy (AIT) is broadly used all over the world as the only available disease-modifying treatment option. The aim of this experts' perspective is to address 7 important unmet needs for the further direction of AIT and to provide the readership with the authors' positions on these topics. An international group of experts in the field of AIT have formulated 7 important aspects for the future position of AIT, performed a current literature review, and proposed a consented position on these topics. The aspects discussed and consented by the authors include: (1) alternative routes of allergen application in AIT, (2) potential of recombinant vaccines, (3) the role of allergy diagnosis based on component-resolved diagnosis for AIT composition, (4) the impact of COVID-19 vaccination for further innovations in AIT, (5) potential of combining biologics to AIT, (6) future innovations in high-risk children/adolescents, and (7) the future regulatory position on AIT. Important unmet needs and topics for AIT have been addressed in this expert review. The authors' views and personal position on these 7 aspects have also been elaborated., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Introduction: Allergen immunotherapy (AIT) brings along changes in the immune system, restoring dendritic cell function, reducing T2 inflammation and augmenting the regulatory cell activation. Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, interferes with the immune system causing immune suppression during the first phase and over-activation in more advanced disease. We decided to explore the interaction of both in a real-world observational trial., Methods: We registered COVID-19 outcomes in patients with allergic disorders in Latin America, treated with and without AIT. The registry was conducted during the first 1.3 years of the pandemic, with most of the data collected before COVID-19 vaccination was concluded in most countries. Data collection was anonymous via a web-based instrument. Ten countries participated., Results: 630/1095 (57.6%) of the included patients received AIT. Compared to patients without AIT, those treated with AIT had a reduced risk ratio (RR) for COVID-19 lower respiratory symptoms (RR 0.78, 95% CI: 0.6703-0.9024; p = 0.001662) and need for oxygen therapy (RR 0.65, 95% CI: 0.4217-0.9992; p = 0.048). In adherent patients on maintenance sublingual immunotherapy/subcutaneous immunotherapy (SLIT/SCIT) the RR reduction was larger [RR = 0.6136 (95% CI 0.4623-0.8143; p < 0.001) and RR: 0.3495 (95% CI 0.1822-0.6701; p < 0.005), respectively]. SLIT was slightly more effective (NS). We excluded age, comorbidities, level of health care attendance, and type of allergic disorder as confounders, although asthma was related to a higher frequency of severe disease. When analyzing patients with allergic asthma (n = 503) the RR reduction favoring AIT was more pronounced with 30% for lower respiratory symptoms or worse (RR 0.6914, 95% CI 0.5264 to 0.9081, p = 0.0087) and 51% for need of oxygen therapy or worse (RR 0.4868, 95% CI 0.2829-0.8376, p = 0.0082). Among severe allergic patients treated with biologics (n = 24) only 2/24 needed oxygen therapy. There were no critical cases among them., Conclusion: In our registry AIT was associated with reduced COVID-19 severity., Competing Interests: None of the authors has any direct COI related to the content of this manuscript., (© 2023 The Authors.)

Introduction: In light of the current COVID-19 pandemic, during which the world is confronted with a new, highly contagious virus that suppresses innate immunity as one of its initial virulence mechanisms, thus escaping from first-line human defense mechanisms, enhancing innate immunity seems a good preventive strategy., Methods: Without the intention to write an official systematic review, but more to give an overview of possible strategies, in this review article we discuss several interventions that might stimulate innate immunity and thus our defense against (viral) respiratory tract infections. Some of these interventions can also stimulate the adaptive T- and B-cell responses, but our main focus is on the innate part of immunity. We divide the reviewed interventions into: 1) lifestyle related (exercise, >7 h sleep, forest walking, meditation/mindfulness, vitamin supplementation); 2) Non-specific immune stimulants (letting fever advance, bacterial vaccines, probiotics, dialyzable leukocyte extract, pidotimod), and 3) specific vaccines with heterologous effect (BCG vaccine, mumps-measles-rubeola vaccine, etc)., Results: For each of these interventions we briefly comment on their definition, possible mechanisms and evidence of clinical efficacy or lack of it, especially focusing on respiratory tract infections, viral infections, and eventually a reduced mortality in severe respiratory infections in the intensive care unit. At the end, a summary table demonstrates the best trials supporting (or not) clinical evidence., Conclusion: Several interventions have some degree of evidence for enhancing the innate immune response and thus conveying possible benefit, but specific trials in COVID-19 should be conducted to support solid recommendations., Competing Interests: All authors declared or they have no potential conflicts of interest. The following authors, indicated relations with the pharmaceutical industry: Dr. Larenas Linnemann reports personal fees from Allakos, Amstrong, Astrazeneca, Boehringer Ingelheim, Chiesi, DBV Technologies, Grunenthal, GSK, MEDA, Menarini, MSD, Novartis, Pfizer, Novartis, Sanofi, Siegfried, UCB, Alakos, Gossamer, grants from Sanofi, Astrazeneca, Novartis, UCB, GSK, TEVA, Boehringer Ingelheim, Chiesi, Purina institute., (© 2020 The Authors.)

Background: Allergen immunotherapy (AIT) has a longstanding history and still remains the only disease-changing treatment for allergic rhinitis and asthma. Over the years 2 different schools have developed their strategies: the United States (US) and the European. Allergen extracts available in these regions are adapted to local practice. In other parts of the world, extracts from both regions and local ones are commercialized, as in Mexico. Here, local experts developed a national AIT guideline (GUIMIT 2019) searching for compromises between both schools., Methods: Using ADAPTE methodology for transculturizing guidelines and AGREE-II for evaluating guideline quality, GUIMIT selected 3 high-quality Main Reference Guidelines (MRGs): the European Academy of Allergy, Asthma and Immunology (EAACI) guideines, the S2k guideline of various German-speaking medical societies (2014), and the US Practice Parameters on Allergen Immunotherapy 2011. We formulated clinical questions and based responses on the fused evidence available in the MRGs, combined with local possibilities, patient's preference, and costs. We came across several issues on which the MRGs disagreed. These are presented here along with arguments of GUIMIT members to resolve them. GUIMIT (for a complete English version, Supplementary data) concluded the following., Results: Related to the diagnosis of IgE-mediated respiratory allergy, apart from skin prick testing complementary tests (challenges, in vitro testing and molecular such as species-specific allergens) might be useful in selected cases to inform AIT composition. AIT is indicated in allergic rhinitis and suggested in allergic asthma (once controlled) and IgE-mediated atopic dermatitis. Concerning the correct subcutaneous AIT dose for compounding vials according to the US school: dosing tables and formula are given; up to 4 non-related allergens can be mixed, refraining from mixing high with low protease extracts. When using European extracts: the manufacturer's indications should be followed; in multi-allergic patients 2 simultaneous injections can be given (100% consensus); mixing is discouraged. In Mexico only allergoid tablets are available; based on doses used in all sublingual immunotherapy (SLIT) publications referenced in MRGs, GUIMIT suggests a probable effective dose related to subcutaneous immunotherapy (SCIT) might be: 50-200% of the monthly SCIT dose given daily, maximum mixing 4 allergens. Also, a table with practical suggestions on non-evidence-existing issues, developed with a simplified Delphi method, is added. Finally, dissemination and implementation of guidelines is briefly discussed, explaining how we used online tools for this in Mexico., Conclusions: Countries where European and American AIT extracts are available should adjust AIT according to which school is followed., Competing Interests: All authors declared or they have no potential conflicts of interest. The following authors, indicated relations with the pharmaceutical industry: Dr. Larenas Linnemann reports personal fees from Allakos, Amstrong, 10.13039/100004325Astrazeneca, 10.13039/100001003Boehringer Ingelheim, 10.13039/100007560Chiesi, DBV Technologies, Grunenthal, 10.13039/100004330GSK, MEDA, Menarini, 10.13039/100007054MSD, 10.13039/100004336Novartis, 10.13039/100004319Pfizer, 10.13039/100004336Novartis, 10.13039/100004339Sanofi, Siegfried, 10.13039/100011110UCB, Gossamer, grants from 10.13039/100004319Sanofi, 10.13039/100004325Astrazeneca, Novartis, 10.13039/100011110UCB, GSK, 10.13039/100006259TEVA, 10.13039/100001003Boehringer Ingelheim, 10.13039/100007560Chiesi, Purina institute., outside the submitted work; Dr. Moncayo Coello reports personal fees from 10.13039/100004325AstraZeneca, personal fees from 10.13039/100004339Sanofi, personal fees from 10.13039/100004330Grünenthal, personal fees from 10.13039/100011218Sandoz, outside the submitted work; Dr. Partida-Gaytan reports personal fees from 10.13039/100012690Nestlé Nutrition Institute, personal fees from 10.13039/100004330GlaxoSmithKline Mexico, personal fees from Instituto Nacional de Pediatria, personal fees from Healthy Kids Polanco S.C., outside the submitted work., (© 2020 The Authors.)

Percutaneous skin prick tests (SPT) have been considered the preferred method for confirming IgE-mediated sensitization. This reliable and minimally invasive technique correlates with in vivo challenges, has good reproducibility, is easily quantified, and allows analyzing multiple allergens simultaneously. Potent extracts and a proficient tester improve its accuracy. Molecular-based allergy diagnostics (MA-Dx) quantifies allergenic components obtained either from purification of natural sources or recombinant technology to identify the patient's reactivity to those specific allergenic protein components. For a correct allergy diagnosis, the patient selection is crucial. MA-Dx has been shown to have a high specificity, however, as MA-Dx testing can be ordered by any physician, the pre-selection of patients might not always be optimal, reducing test specificity. Also, MA-Dx is less sensitive than in vitro testing with the whole allergen or SPT. Secondly, no allergen-specific immunotherapy (AIT) trial has yet shown efficacy with patients selected on the basis of their MA-Dx results. Thirdly, why would we need molecular diagnosis, as no molecular treatment can yet be offered? Then there are the practical arguments of costs (SPT highly cost-efficient), test availability for MA-Dx still lacking in wide areas of the world and scarce in others. As such, it is hard physicians can build confidence in the test and their interpretation of the MA-Dx results., In Conclusion: as of now these techniques should be reserved for situations of complex allergies and polysensitization; in the future MA-Dx might help to reduce the number of allergens for AIT, but trials are needed to prove this concept.