Food Sublingual Immunotherapy: Safety and Simplicity of a Real Food Updosing Protocol.

BACKGROUND: Sublingual immunotherapy (SLIT) using food extracts is safe and effective in desensitizing patients with food allergy, yet not often used in clinical practice. OBJECTIVES: To propose a cost-effective, expedited SLIT protocol using real food. METHODS: Patients with food allergy aged 5 to 50 years (median, 11 years) initiated food SLIT in a single-clinic setting. The daily maintenance dose was 4 to 11 mg protein in 0.1 to 0.5 mL volume, depending on the food. Some foods were available in liquid form at the local grocery (milk, egg white liquid, and cashew/walnut/sunflower/hazelnut milk), whereas others were prepared in the office using flour and 50% glycerin saline (peanut/sesame/wheat). The first cohort of 20 patients began dosing at a 1:1000 dilution, the next 30 patients at 1:100 dilution. An exercise challenge was performed in a subset of patients on maintenance dosing to evaluate the need for a predose or postdose rest period. RESULTS: The 1:1000 and 1:100 cohorts both completed day 1 without adverse reactions beyond itchy mouth. There were no systemic reactions requiring epinephrine throughout the study period and 88% reached their maintenance dose. Skin testing of 6-month-old peanut flour solution was not diminished from fresh solution and similar to food extract. Exercise challenge test results in 12 patients were negative. CONCLUSIONS: Allergen extract food SLIT as used in published trials has limitations of cost and multiple office visits. Inexpensive real food, at the same or slightly higher protein dose, was well tolerated in 4 updose visits, a minimum of a week apart. Unlike food oral immunotherapy, a predose or postdose rest period may not be necessary.

How can we improve our use of allergen immunotherapy as a treatment option for asthma and severe asthma?

INTRODUCTION: In patients suffering from allergic asthma, especially in the pediatric age-group, allergen immunotherapy (AIT) could be of benefit and has the potential of long-term disease modification. AREAS COVERED: We reviewed the evidence for a beneficial effect of AIT in allergic asthma. A correct selection of the possible candidates for AIT is crucial. We define the comprehensive allergic asthma diagnosis: confirming asthma, confirming allergic sensitization and having symptoms on exposure to the relevant allergens.We analyze why the first trials on AIT for asthma were contradictory; we consider the results of systematic reviews and discuss the high degree of heterogeneity often found in meta-analysis. We assess recent, double-blind, placebo-controlled trials in sublingual AIT that provide robust evidence for a reduction in acute asthma exacerbations and a decrease in the use of inhaled corticosteroids. Further, we demonstrate how real-world trials and large pharmacy data-based analyses confirm these findings for SLIT and SCIT. Finally, we explore the option of AIT in severe asthma patients, once well-controlled on biologic therapy. EXPERT OPINION: Clear indications for AIT in asthma guidelines would benefit allergic asthmatics. AIT is a therapeutic option in appropriately selected asthmatics. Three years treatment has the potential for long-term tolerance, with persisting benefits years after discontinuation.

Efficacy of House Dust Mite Sublingual Immunotherapy in Patients with Atopic Dermatitis: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Sensitization to house dust mites (HDMs) is frequent in patients with atopic dermatitis. OBJECTIVE: To investigate the efficacy of sublingual immunotherapy (SLIT) with Dermatophagoides pteronyssinus extract in patients with atopic dermatitis sensitized to HDM. METHODS: In this randomized, double-blind, placebo-controlled trial, we enrolled 91 patients 3 years or older, with SCORing Atopic Dermatitis (SCORAD) score greater than or equal to 15 and positive skin test result and/or IgE to D pteronyssinus. Patients were stratified according to age (<12 and ≥12 years) to receive HDM SLIT or placebo for 18 months. Primary outcome was a greater than or equal to 15-point decrease in SCORAD score. Secondary outcomes were decreases in SCORAD and objective SCORAD, Eczema Area and Severity Index, visual analog scale for symptoms, and pruritus scale scores; Investigator's Global Assessment 0/1; and decrease greater than or equal to 4 points in Dermatology Life Quality Index. Background therapy was maintained. RESULTS: A total of 66 patients completed the study (35 HDM SLIT, 31 placebo). After 18 months, 74.2% and 58% of patients in the HDM SLIT group and the placebo group, respectively, showed greater than or equal to 15-point decrease in SCORAD score (relative risk, 1.28; 95% CI, 0.89-1.83). Significant SCORAD score decreases from baseline of 55.6% and 34.5% in HDM SLIT and placebo groups (mean difference, 20.4; 95% CI, 3.89-37.3), significant objective SCORAD score decreases of 56.8% and 34.9% in HDM SLIT and placebo groups (mean difference, 21.3; 95% CI, 0.66-41.81), and more patients with Investigator's Global Assessment 0/1 in the HDM SLIT group as compared with the placebo group (14 of 35 vs 5 of 31; relative risk, 2.63; 95% CI, 1.09-6.39) were observed at 18 months. CONCLUSIONS: Our results suggest that HDM SLIT may be effective in HDM-sensitized patients as an add-on treatment for atopic dermatitis.

Inmunoterapia con ácaros Valergen por vía sublingual y subcutánea en pacientes alérgicos. Cabaiguán 2010-2019 / Sublingual and subcutaneous Valergen mite immunotherapy in allergic patients in Cabaiguán 2010-2019

RESUMEN Fundamento: La inmunoterapia consiste en la administración de dosis crecientes del alérgeno para controlar la sensibilidad hacia este. Objetivo: Describir el comportamiento de la inmunoterapia por vía subcutánea o sublingual a ácaros. Metodología: Estudio retrospectivo realizado en Cabaiguán, periodo de 2010 a 2019, el universo de 267 pacientes con pruebas positivas a ácaros y la muestra de 53 pacientes. Los datos se obtuvieron del registro de datos. Resultados: Usó la vía sublingual el 60.4 %, predominó el grupo de edad entre 5-18 años (41.5 %), la vía subcutánea se utilizó en un 39.6 %, fue más frecuente en el sexo masculino (58.5 %). La vía subcutánea se indicó mayoritariamente en la rinitis alérgica (20.7 %) y la sublingual en el asma (32.1 %); para ambas, fue el Dermatofagoide pteronyssinus el ácaro de mayor sensibilidad y utilización (43.4 %), el tiempo de administración dominante fue de 3 años (67.9 %). El control de los síntomas se alcanzó con la vía sublingual (37.7 %). En la vía sublingual no se presentaron eventos adversos en el 43.3 %, con la vía subcutánea 11.3 % de los eventos adversos fueron locales y 7.6 % sistémicos leves. Conclusiones: La vía sublingual fue la más utilizada, la de mayor control de los síntomas y menos eventos adversos en el estudio.

ABSTRACT Background: Immunotherapy consists of the administration of the allergen increasing doses to control sensitivity towards it. Objective: To describe the behavior of subcutaneous or sublingual immunotherapy to mites. Methodology: Retrospective study carried out in Cabaiguán, from 2010 to 2019, the universe of 267 patients with positive tests to mites and the sample 53 patients. Data were obtained from the data record. Results: 60.4 % used sublingual, the age group between 5-18 years prevailed (41.5 %), the subcutaneous was used in 39.6 %, and it was more frequent in males (58.5 %). The subcutaneous was indicated mainly in allergic rhinitis (20.7 %) and sublingual in asthma (32.1 %); for both, Dermatofagoide pteronyssinus was the highest sensitivity and use mite (43.4 %) the dominant administration time was 3 years (67.9 %). Symptom control was achieved by sublingual (37.7 %). In sublingual, there were no adverse events in 43.3 %, with the subcutaneous, 11.3 % of the adverse events were local and 7.6 % were mild systemic. Conclusions: Sublingual was the most used, the one with the highest control of symptoms and the fewest adverse events in the study.

Compromising between European and US allergen immunotherapy schools: Discussions from GUIMIT, the Mexican immunotherapy guidelines.

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.

Sublingual Omp16-driven redirection of the allergic intestinal response in a pre-clinical model of food allergy.

BACKGROUND: IgE-mediated food allergy remains a significant and growing worldwide problem. Sublingual immunotherapy (SLIT) shows an excellent safety profile for food allergy, but the clinical efficacy needs to be improved. This study assessed the effects of the Toll-like receptor 4 agonist outer membrane protein (Omp) 16 from Brucella abortus combined with cow´s milk proteins (CMP) through the sublingual route to modulate cow's milk allergy in an experimental model. METHODS: Mice sensitized with cholera toxin and CMP were orally challenged with the allergen to elicit hypersensitivity reactions. Then, mice were treated with a very low amount of CMP along with Omp16 as a mucosal adjuvant, and finally, animals were re-exposed to CMP. Systemic and mucosal immune parameters were assessed in vivo and in vitro. RESULTS: We found that the sublingual administration of Omp16 + CMP induced a buccal Th1 immune response that modulated the intestinal allergic response with the suppression of symptoms, reduction of IgE and IL-5, and up-regulation of IgG2a and IFN-γ. The adoptive transfer of submandibular IFN-γ-producing α4ß7+ CD4+ and CD8+ cells conferred protection against allergic sensitization. The use of Omp16 + CMP promoted enhanced protection compared to CMP alone. CONCLUSION: In conclusion, Omp16 represents a promising mucosal adjuvant that can be used to improve the clinical and immune efficacy of SLIT for food allergy.

[The clinical practice of allergen immunotherapy in Mexico according to 277 allergists who were surveyed during a three-year AIT course]. / La práctica clínica de la inmunoterapia con alérgenos en México según 277 alergólogos encuestados durante un curso trianual.

BACKGROUND: There are different guidelines for the diagnosis of allergic diseases and the application of allergen immunotherapy (AIT). OBJECTIVE: To describe how Mexican allergists diagnose and treat respiratory and food allergies with AIT. METHODS: 227 allergists who attended an immunotherapy symposium were surveyed; the topics investigated were the daily practices in the diagnosis of respiratory and food allergies, as well as ways to apply AIT. RESULTS: The surveyed allergists use skin prick tests for the diagnosis of both respiratory and food allergies in 100 % and 87.7 % of their cases respectively; in vitro diagnosis through serum specific IgE in 55.5 % and 63 %, and molecular diagnostics in 14.1% and 13.2 %. For aeroallergens, 81 % prescribe subcutaneous AIT, 77.9 % use liquid sublingual AIT, and 1.8 % prefer SLIT in tablets; however, 45 % indicated that they would use tablets in the future. Regarding food allergens, most respondents did not prescribe AIT; however, 55% of them are interested in oral AIT and 59% of them are interested in sublingual AIT. CONCLUSIONS: Generally, the diagnosis and treatment of allergic diseases are carried out according to international guidelines; besides, the interviewed allergists expressed flexibility to adopt new schemes.

Antecedentes: Existen lineamientos para el diagnóstico de las enfermedades alérgicas y la aplicación de inmunoterapia con alérgenos (ITA). Objetivo: Describir cómo los alergólogos mexicanos diagnostican y tratan con ITA las alergias alimentaria y respiratoria. Métodos: Se encuestó a 227 alergólogos que acudieron a un simposio de inmunoterapia; se indagaron prácticas cotidianas en el diagnóstico de las alergias respiratoria y alimentaria, así como en la forma de aplicar la ITA. Resultados: Los alergólogos utilizan las pruebas cutáneas por punción para el diagnóstico de las alergias respiratorias y alimentarias en 100 y 87.7 % de los casos de una y otra; diagnóstico in vitro mediante determinación de IgE alérgeno-específica en 55.5 y 63 %; y diagnóstico molecular por componentes en 14.1 y 13.2 %. Para los aeroalérgenos, 81 % emplea ITA subcutánea; 77.9 %, ITA sublingual líquida; 1.8 %, ITA sublingual en tabletas; 45 % indicó que estaba dispuesto a emplear tabletas en el futuro. Para los alérgenos de alimentos, la mayoría no utilizaba ITA, aunque 55 % se interesa en la ITA oral y 59 %, en la ITA sublingual. Conclusiones: En términos generales, el diagnóstico y tratamiento de las enfermedades alérgicas se realizan conforme los lineamientos internacionales, además, los alergólogos encuestados mostraron flexibilidad para adoptar nuevos esquemas.

[GUIMIT 2019, Mexican Guideline on Immunotherapy. Guideline on the diagnosis of IgE-mediated allergic disease and immunotherapy following the ADAPTE approach]. / GUIMIT 2019, Guía Mexicana de Inmunoterapia. Guía de diagnóstico de alergia mediada por IgE e inmunoterapia aplicando el método ADAPTE.

BACKGROUND: In Mexico, allergen immunotherapy (AIT) and immunotherapy with hymenoptera venom (VIT) is traditionally practiced combining aspects of the European and American school. In addition, both types of extracts (European and American) are commercially available in Mexico. Moreover, for an adequate AIT/VIT a timely diagnosis is crucial. Therefore, there is a need for a widely accepted, up-to-date national immunotherapy guideline that covers diagnostic issues, indications, dosage, mechanisms, adverse effects and future expectations of AIT (GUIMIT 2019). METHOD: With nationwide groups of allergists participating, including delegates from postgraduate training-programs in Allergy/Immunology-forming, the guideline document was developed according to the ADAPTE methodology: the immunotherapy guidelines from European Academy of Allergy and Clinical Immunology, German Society for Allergology and Clinical Immunology, The American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma, and Immunology were selected as mother guidelines, as they received the highest AGREE-II score among international guidelines available; their evidence conforms the scientific basis for this document. RESULTS: GUIMIT emanates strong or weak (suggestions) recommendations about practical issues directly related to in vivo or in vitro diagnosis of IgE mediated allergic diseases and the preparation and application of AIT/VIT and its adverse effects. GUIMIT finishes with a perspective on AIT modalities for the future. All the statements were discussed and voted on until > 80 % consensus was reached. CONCLUSIONS: A wide and diverse group of AIT/VIT experts issued transculturized, evidence-based recommendations and reached consensus that might improve and standardize AIT practice in Mexico.

Antecedentes: En México, la inmunoterapia con alérgenos (ITA) y con veneno de himenópteros (VIT) se practica tradicionalmente combinando criterios de las escuelas europea y estadounidense; los dos tipos de extractos están comercialmente disponibles en México. Para una ITA adecuada es crucial un diagnóstico oportuno. Objetivo: Presentar GUIMIT 2019, Guía Mexicana de Inmunoterapia 2019, de base amplia, actualizada, que abarca temas de diagnóstico, indicaciones, dosificación, mecanismos, efectos adversos de la ITA y expectativas con esta modalidad de tratamiento. Método: Con la participación de múltiples grupos mexicanos de alergólogos, que incluían los centros formadores universitarios en alergia e inmunología, se desarrolló el documento de la guía según la metodología ADAPTE. Las guías de inmunoterapia de la European Academy of Allergy and Clinical Immunology, The American Academy of Allergy, Asthma and Immunology, German Society for Allergology and Clinical Immunology y del American College of Allergy, Asthma, and Immunology se seleccionaron como guías fuente, ya que recibieron la puntuación AGREE-II más alta entre las guías internacionales disponibles; su evidencia conforma la base científica de GUIMIT 2019. Resultados: En GUIMIT 2019 se emiten recomendaciones fuertes o débiles (sugerencias) acerca de temas directamente relacionados con el diagnóstico in vivo o in vitro de las enfermedades alérgicas mediadas por IgE, la preparación y aplicación de ITA o VIT y sus efectos adversos; se incluye la revisión de las modalidades de ITA para el futuro. Todos los argumentos que se exponen fueron discutidos y votados con > 80 % de aprobación. Conclusión: Un grupo amplio y diverso de expertos en ITA y VIT emitió recomendaciones transculturizadas basadas en evidencia, que alcanzaron consenso; con ellas se pretende mejorar y homologar la práctica de la inmunoterapia en México.

[Allergen extracts for immunotherapy in Latin America]. / Extractos alergénicos para inmunoterapia en Latinoamérica.

BACKGROUND: The Latin American Society of Allergy, Asthma, and Immunology (SLAAI) presents a document about the use of immunotherapy (IT) in Latin America, where administration patterns, indications and contraindications, effects on health, adverse events and socioeconomic impact are reviewed. OBJECTIVE: To review publications analyzing the use of IT in Latin America. METHODS: A literature review was carried out in order to identify works addressing IT in Latin America. This review was focused on practical scientific information available on IT in the region, and a parallel comparison was made with practices observed in the United States and European countries. RESULTS: Of the 21 Latin American countries included, only 9 had original articles meeting the selection criteria; a total of 82 articles were selected, most of them from Brazil and Mexico. Most widely used allergenic extracts in Latin America tropical and subtropical regions were those of mites and pollen. CONCLUSION: Although it is true that there are huge challenges for the future of IT in Latin America, studies on subcutaneous IT and sublingual IT are increasing, but most of them are retrospective and some have design bias, and more prospective studies are therefore required, using internationally validated scales for clinical evaluation.

Antecedentes: La Sociedad Latinoamericana de Alergia, Asma e Inmunología (SLAAI) presenta un documento acerca del uso de la inmunoterapia en Latinoamérica en el que se revisan los patrones de administración, indicaciones y contraindicaciones, efectos sobre la salud, eventos adversos e impacto socioeconómico. Objetivo: Revisar las publicaciones que abordaron el uso de la inmunoterapia en América Latina. Métodos: Se llevó a cabo revisión de la literatura para identificar trabajos enfocados en la inmunoterapia en América Latina. Esta revisión se enfocó en la información científica práctica disponible en la región sobre la inmunoterapia y se realizó un paralelo a lo observado en Estados Unidos y países europeos. Resultados: De los 21 países latinoamericanos incluidos, solo nueve tenían artículos originales que cumplían con los criterios de selección; en total se seleccionaron 82 artículos, la mayoría de Brasil y México. Los extractos alergénicos más utilizados fueron los de ácaros y polen en las regiones tropicales y subtropicales de América Latina. Conclusión: Si bien hay grandes desafíos para el futuro de la inmunoterapia en América Latina y los estudios de inmunoterapia subcutánea e inmunoterapia sublingual están aumentando, la mayoría son retrospectivos y algunos con sesgo de diseño, por lo que se requieren más trabajos prospectivos en los que se utilicen escalas validadas internacionalmente para la evaluación clínica.

Consenso Brasileiro sobre Alergia Alimentar: 2018 - Parte 2 - Diagnóstico, tratamento e prevenção. Documento conjunto elaborado pela Sociedade Brasileira de Pediatria e Associação Brasileira de Alergia e Imunologia / Brazilian Consensus on Food Allergy: 2018 - Part 2 - Diagnosis, treatment and prevention. Joint position paper of the Brazilian Society of Pediatrics and the Brazilian Association of Allergy and Immunology

Na última década o conhecimento sobre a etiopatogenia da alergia alimentar (AA) avançou muito. A identificação de novas formas clínicas de apresentação, aliada à aquisição de novos métodos laboratoriais, possibilitaram a realização do diagnóstico etiológico de modo mais preciso, sobretudo quanto à reatividade cruzada entre alimentos e mesmo na identificação de marcadores indicativos de formas clínicas transitórias, persistentes e quadros mais graves. A padronização dos testes de provocação oral permitiu a sua realização de forma mais segura e possibilitou a sua inclusão entre as ferramentas disponíveis para uso na confirmação etiológica da AA. Apesar disso, a exclusão do alimento responsável pelas manifestações clínicas continua sendo a principal conduta terapêutica a ser empregada. Entre os pacientes alérgicos às proteínas do leite de vaca, a disponibilidade de fórmulas especiais, por exemplo parcialmente hidrolisadas, extensamente hidrolisadas à base da proteína do leite de vaca e fórmulas de aminoácidos, tem facilitado o tratamento substitutivo do leite de vaca para esses pacientes. A abordagem atual da anafilaxia é revisada, uma vez que os alimentos são os principais agentes etiológicos em crianças. Avanços na conduta de algumas manifestações gastrintestinais também são abordados. Na atualidade, a imunoterapia oral tem sido cada vez mais utilizada. A aquisição de novos agentes, os imunobiológicos, também são apresentados à luz das evidências científicas e clínicas atuais. Considerações sobre história natural da AA, assim como sobre formas de prevenção da AA também são abordadas. Em conclusão, o Consenso Brasileiro sobre Alergia Alimentar de 2018 objetivou rever os métodos diagnósticos e esquemas de tratamento disponíveis e empregados no acompanhamento de pacientes com AA, visando a melhor abordagem terapêutica desses pacientes.

Over the last decade, knowledge about the etiopathogenesis of food allergy (FA) has advanced a great deal. The identification of new clinical presentations, associated with the acquisition of new laboratory methods, have made the diagnostic process more accurate, especially with regard to cross-reactivity between foods and the identification of biomarkers suggestive of transitory, persistent clinical forms and/or more severe manifestations. The standardization of oral provocation tests has made their performance safer and has allowed their inclusion among the tools available for use in the etiological confirmation of FA. Despite this, exclusion of the food involved in the clinical manifestations remains as the main therapeutic strategy. Among patients allergic to cow's milk proteins, the availability of special formulas, e.g., partially hydrolyzed and extensively hydrolyzed cow's milk protein-based formulas, in addition to amino acid formulas, has facilitated the introduction of substitute formulas for these patients. The current approach to anaphylaxis is reviewed, since food is the major etiological agent in children. Advances in the management of some gastrointestinal manifestations are also addressed. Currently, oral immunotherapy has been increasingly used. The acquisition of new agents, namely, immunobiological agents, is also described in light of current scientific and clinical evidence. Considerations on the natural history of FA, as well as on ways how to prevent FA, are addressed. In conclusion, the 2018 Brazilian Consensus on Food Allergy aimed to review the diagnostic methods and treatment schemes available and used in the follow-up of patients with FA, with a view to adopting the best possible therapeutic approach to these patients.

Systemic IL-2/anti-IL-2Ab complex combined with sublingual immunotherapy suppresses experimental food allergy in mice through induction of mucosal regulatory T cells.

BACKGROUND: Therapeutic tolerance restoration has been proven to modify food allergy in patients and animal models and although sublingual immunotherapy (SLIT) has showed promise, combined therapy may be necessary to achieve a strong and long-term tolerance. AIMS: In this work, we combined SLIT with systemic administration of IL-2 associated with an anti-IL-2 monoclonal antibody (IL-2/anti-IL-2Ab complex or IL-2C) to reverse the IgE-mediated experimental allergy. MATERIALS AND METHODS: Balb/c mice were sensitized with cholera toxin and milk proteins and orally challenged with allergen to elicit hypersensitivity reactions. Then, allergic mice were treated with a sublingual administration of very low amounts of milk proteins combined with intraperitoneal injection of low doses of IL-2C. The animals were next re-exposed to allergens and mucosal as well as systemic immunological parameters were assessed in vivo and in vitro. RESULTS: The treatment reduced serum specific IgE, IL-5 secretion by spleen cells and increased IL-10 and TGF-ß in the lamina propria of buccal and duodenal mucosa. We found an augmented frequency of IL-10-secreting CD4+ CD25+ Foxp3+ regulatory T cells (Treg) in the submaxilar lymph nodes and buccal lamina propria. Tregs were sorted, characterized and adoptively transferred to naïve mice, which were subsequently sensitized. No allergy was experienced in these mice and we encouragingly discovered a faster and more efficient tolerance induction with the combined therapy compared with SLIT. CONCLUSION: The combination of two therapeutic strategies rendered Treg-mediated tolerance more efficient compared to individual treatments and reversed the established IgE-mediated food allergy. This approach highlights the ability of IL-2C to expand Tregs, and it may represent a promising disease-modifying therapy for managing food allergy.

National clinical practice guidelines for allergen immunotherapy: An international assessment applying AGREE-II.

BACKGROUND: Since 1988, numerous allergen immunotherapy guidelines (AIT-GLs) have been developed by national and international organizations to guide physicians in AIT. Even so, AIT is still severely underused. OBJECTIVE: To evaluate AIT-GLs with AGREE-II, developed in 2010 by McMaster University methodologists to comprehensively evaluate GL quality. METHODS: Allergist, from different continents, knowledgeable in AIT and AGREE-II trained were selected into the project team. The project received methodologists' guidance. AIT-GLs in any language were sought from 1980 to 2016; AIT-GLs were AGREE II-evaluated by at least 2 team members, independently; discrepancies were resolved in a second round, by team discussion or methodologists' consulting. RESULTS: We found 31 AIT-GLs (15 post-2010), ranging from local consensus reports to international position papers (EAACI, AAAAI-ACAAI, WAO). Pre-2010 GLs scored 1.6-4.6 (23%-67%) and post-2010 GLs scored 2.1-6 (30%-86%), on a 7-point Likert scale. The highest scores went to: German-Austrian-Swiss (6.0), Mexican (5.1), and the AAAAI/ACAAI AIT-GL (4.7). These were also the only 3 GLs that received "yes" of both evaluators to the item: "I would recommend this GL for use." The domains of "Stakeholder involvement" and "Rigor of Development" only scored 3/7, and "Applicability" scored the lowest. Strikingly, newer GLs only scored clearly better in "Editorial independence" and "Global evaluation." CONCLUSIONS: In AIT-GLs, there is still a lot of room for improvement, especially in domains crucial for the dissemination. For some GLs, the "Scientific rigor" domain flawed. When resources are limited, transculturizing a high-quality GL might be preferable over developing a GL from zero. Our study and AGREE-II could help to select the best candidate. CLINICAL IMPLICATIONS: We here evaluate allergen immunotherapy guideline (AIT-GL) quality. Only high-quality AIT-GLs should be consulted for AIT management decisions. In low-resource settings, transculturization of these is preferred over developing low-quality guidelines.

Effect of sublingual immunotherapy on platelet activity in children with allergic rhinitis / Efeito da imunoterapia sublingual sobre a atividade plaquetária em crianças com rinite alérgica

Abstract Introduction: The role of platelet activation in allergic inflammation is receiving increasing attention. Sublingual immunotherapy for allergic rhinitis can modify the immunological process to an allergen, rather than simply treating symptoms. Objective: The aim of this study was to explore the role of platelet activation during sublingual immunotherapy in children with allergic rhinitis. Methods: Forty-two House Dust Mite - sensitized children with allergic rhinitis were enrolled and received House Dust Mite allergen extract for sublingual immunotherapy or placebo. Serum of different time points during treatment was collected and used for detection of Platelet Factor-4 and Beta-Thromboglobulin concentration by Enzyme-Linked Immuno Sorbent Assay. Results: Our data showed decreased expression of Platelet Factor-4 and Beta-Thromboglobulin protein after one year's sublingual immunotherapy. In addition, the decrease of symptom scores and serum Platelet Factor-4 and Beta-Thromboglobulin protein concentrations was positively related. Conclusion: During sublingual immunotherapy, platelet activation was inhibited significantly. Our results might indicate that inhibition of platelet activation within the systemic circulation is an important mechanism during sublingual immunotherapy.

Resumo Introdução: O papel da ativação de plaquetas na inflamação alérgica recebeu atenção crescente. A imunoterapia sublingual para rinite alérgica pode modificar o processo imunológico a um alérgeno, em vez de tratar os sintomas simplesmente. Objetivo: Explorar o papel da ativação plaquetária durante a imunoterapia sublingual em crianças com rinite alérgica. Método: Quarenta e duas crianças com rinite alérgica sensibilizadas por ácaros de poeira domiciliar (APD) foram inscritas e receberam extrato de alérgeno de APD para imunoterapia sublingual ou placebo. O soro de diferentes pontos no tempo durante o tratamento foi recolhido e usado para a detecção de fator 4 plaquetário e concentração de beta-tromboglobulina por ensaio imunoenzimático. Resultados: Nossos dados mostraram diminuição da expressão de fator 4 plaquetário e proteína beta-tromboglobulina após imunoterapia sublingual de um ano. Além disso, a diminuição dos escores de sintomas e o fator 4 plaquetário sérico e concentrações de proteína beta-tromboglobulina foram relacionados de maneira positiva. Conclusão: Durante imunoterapia sublingual, a ativação plaquetária foi inibida significativamente. Os nossos resultados podem indicar que a inibição da ativação de plaquetas dentro da circulação sistêmica é um mecanismo importante durante imunoterapia sublingual.

Effect of sublingual immunotherapy on platelet activity in children with allergic rhinitis.

INTRODUCTION: The role of platelet activation in allergic inflammation is receiving increasing attention. Sublingual immunotherapy for allergic rhinitis can modify the immunological process to an allergen, rather than simply treating symptoms. OBJECTIVE: The aim of this study was to explore the role of platelet activation during sublingual immunotherapy in children with allergic rhinitis. METHODS: Forty-two House Dust Mite - sensitized children with allergic rhinitis were enrolled and received House Dust Mite allergen extract for sublingual immunotherapy or placebo. Serum of different time points during treatment was collected and used for detection of Platelet Factor-4 and Beta-Thromboglobulin concentration by Enzyme-Linked Immuno Sorbent Assay. RESULTS: Our data showed decreased expression of Platelet Factor-4 and Beta-Thromboglobulin protein after one year's sublingual immunotherapy. In addition, the decrease of symptom scores and serum Platelet Factor-4 and Beta-Thromboglobulin protein concentrations was positively related. CONCLUSION: During sublingual immunotherapy, platelet activation was inhibited significantly. Our results might indicate that inhibition of platelet activation within the systemic circulation is an important mechanism during sublingual immunotherapy.

Similar biological activity in skin prick test for Oralair® (8200 BAU) and Grazax® (6200 BAU) reinforces effective SLIT dosing level.

In Europe, allergen extracts are standardized based on skin prick wheal size in 20-30 allergic subjects. To understand the biological activity of clinically effective Sublingual immunotherapy, we used this method to determine the biological activity of solution and tablet Timothy grass pollen (TIM) extracts, compared to an FDA-approved extract (Reference) of 10 000 BAU/ml. Blinded, quadruplicate skin prick tests with concentrate and three serial half-log dilutions allowed the construction of a semilogarithmic regression line per extract. Bioequivalent allergy units (BAU) values were obtained from the comparison with reference. Extracts and dilutions showed a neat linear dose response (all: R2 > 0.98) in 33 rhinitis patients. Relative potencies: Staloral® 12 000 BAU/ml, Soluprick® 10 300 BAU/ml, Oralair® 8200 BAU, and Grazax® 6200 BAU. Even though all extract concentrates differed in wheal size (P = 0.01-0.001), Grazax® producing a 25% smaller wheal size than Oralair® , and the biological activity of these clinically effective TIM tablets led in the same range (6200-8200 BAU; 0.92-1.23 cm2 ). SLIT dose-finding studies for other pollens might start with allergen extracts producing 1.1 cm2 wheal surface.

[Successful desensitization to latex by sublingual immunotherapy in a health worker]. / Desensibilización exitosa al látex con inmunoterapia sublingual en una trabajadora de salud.

Latex allergy is still a public health problem responsible for some occupational diseases tough to be treated without removing the patient from his/her workspace. For patients allergic to latex, sublingual immunotherapy (SLIT) for latex is a tool that can be very useful. We report the case of a nurse with latex allergy who underwent successful desensitization to latex by SLIT, and discuss about possible causes of the success of this therapy.

La alergia al látex todavía es un problema de salud pública responsable de algunas enfermedades laborales difíciles de ser tratadas sin la remoción del profesional de su ambiente de trabajo. En caso de alergia al látex, la inmunoterapia sublingual es una herramienta que puede ser muy útil. Comunicamos el caso de una enfermera con alergia al látex que se sometió a la desensibilización exitosa a través de la inmunoterapia sublingual y se discuten las posibles causas del éxito de este tratamiento.

Modulation of mucosal/systemic antibody response after sublingual immunotherapy in mite-allergic children.

BACKGROUND: There have been no data on sublingual immunotherapy (SLIT) in Brazilian patients sensitized to house dust mites. This study aimed to evaluate the mucosal/systemic antibody response changes and clinical efficacy after SLIT using Dermatophagoides pteronyssinus (Dpt) allergens with or without bacterial extracts in mite-allergic Brazilian children. METHODS: Patients with allergic rhinitis and asthma were selected for a double-blind, placebo-controlled trial randomized to three groups: DPT (Dpt extract, n = 34), DPT+MRB (Dpt plus mixed respiratory bacterial extracts, n = 36), and Placebo (n = 32). Total symptom and medication scores for rhinitis/asthma, skin prick test (SPT) to Dpt, and measurements of Dpt-, Der p 1-, Der p 2-specific serum IgE, IgG4, IgG1, and specific salivary IgA were evaluated at baseline and after 12 and 18 months of treatment. RESULTS: A significant long-term decline in total symptom/medication scores was observed only in active groups (DTP and DPT+MRB). There was no significant change in SPT results in all groups. SLIT using Dpt allergen alone induced increased levels of serum IgG4 to Dpt, Der p 1, and Der p 2, serum IgG1 and salivary IgA to Dpt and Der p 1. SLIT with Dpt plus bacterial extracts was able to decrease IgE levels, particularly to Der p 2, to increase salivary IgA levels to Der p 1, but had no changes on specific IgG4 and IgG1 levels. CONCLUSIONS: All children undergoing SLIT showed clinical improvement, but a long-term reduction in symptom/medication scores with modulation of mucosal/systemic antibody responses were seen only in active groups (DPT and DPT+MRB).

Eficácia clínica da imunoterapia nasal comparada com imunoterapia sublingual em pacientes com rinite alérgica / Clinical efficacy of nasal immunotherapy compared to sublingual immunotherapy in patients with allergic rhinitis

A eficácia da imunoterapia (IT) com extratos alergênicos em pacientes com rinite alérgica (RA) tem sido demonstrada por via subcutânea ou sublingual, não existindo comprovação da eficácia terapêutica da IT tópica nasal. Objetivo: Comparar a eficácia da IT sublingual com a IT tó¬pica nasal em pacientes com RA. Pacientes e Método: Quarenta indivíduos com RA persistente, leve ou moderada, foram divididos em dois grupos em estudo prospectivo, duplo-cego, randomizado, com duração de doze meses. O grupo I utilizou IT tópica nasal com extratos alergênicos de ácaros da poeira domiciliar + placebo sublingual e o grupo II foi submetido a IT sublingual com extratos alergênicos + placebo tópico nasal. Foram realizadas oito avaliações durante o estudo, determinando-se a gravidade da RA e o consumo de medicamentos, além das alterações das mucosas nasais ao exame físico. Níveis de IgE e IgG4 anti-Oermatophagoides pteronyssinus foram determinados em amostras de soro de 22 pacientes, antes e após tratamento. Resultados: Vinte e cinco pacientes concluíram o estudo (grupo I, n=l1 e grupo lI, n=14). Redução significante na gravidade da RA e no consumo de medicamentos foi observada após tratamento nos dois grupos, enquanto que a redução nas alterações da mucosa nasal só foi observada no grupo Il. Não se observaram alterações significantes nos níveis de IgE e IgG4 anti-D. pteronyssinus nos dois grupos. Conclusão: Ambos os procedimentos de IT (sublingual e nasal) são eficazes na redução dos sintomas e do consumo de medicamentos de pacientes com RA por alérgenos de ácaros da poeira domiciliar. No grupo de pacientes que receberam IT sublingual, houve redução nas alterações da mucosa nasal.

Several studies have demonstrated the efficacy of subcutaneous or sublingual immunotherapy (IT) with allergen extracts for the treatment of perennial allergic rhinitis (AR), but there are no actual data on nasal IT efficacy. Aim: Evaluate the efficacy of topical nasal IT compared to sublingual IT in AR patients. Patients and Methods: Forty patients with mild or mederate perennial AR were selected to participate on this prospective, one-year follow-up, doubleblind randomized study. They were divided in 2 groups: group I (n=20) was treated with sublingual IT containing mite allergen extracts plus placebo on nasal mucosa and group II (n=20) was treated with topical nasal IT containing mite allergen extracts plus placebo via sublingual. A total of eight evaluations were performed during the follow-up to determine rhinitis severity and medicine consumption, as well as abnormalities of nasal mucosa. IgE and IgG4 antibodies anti-Oermatophagoides pteronyssinus were determined in serum samples of 22 subjects before and after IT. Results: Twenty-five subjects concluded the study (group I, n=l1 and group lI, n=14). There was a significant reduction on rhinitis severity and medicine consumption before and after the treatment in both groups. In addition there was a significant reduction on nasal mucosa abnormalities before and after treatment in group II patients. There were no changes on leveis of IgE or IgG4 antibodies anti-D. pteronyssinus before and after IT in both groups. Conclusion: The efficacy of sublingual and nasal IT was demonstrated in patients with AR, by reducing symptoms and medicine consumption. In addition, sublingual IT also reduced nasal mucosa abnormalities.