This review examines whether allergen immunotherapy (AIT) for grass pollen allergy should expand beyond the recent trend towards a mono-species approach based on Phleum pratense. It explores whether multi-species formulations better reflect natural exposure and could improve clinical outcomes. Research from aerobiology and immunology shows that grass pollen exposure involves diverse species with distinct flowering periods, influenced by climate and geography. Molecular analyses reveal species-specific allergen profiles, including unique peptides and variations in major allergens such as Group 1 and 5. Patient data confirm symptom variability across the season. In-vitro studies have observed limits to the cross-reactivity of T-cell epitopes, and comparative clinical studies suggest benefits for multi-species treatment options. Evidence indicates that mono-species extracts alone do not represent the full allergenic spectrum of grass pollen. Broad-spectrum AIT formulations incorporating multiple grass species provide a more comprehensive repertoire of allergens and epitopes, potentially enhancing immunogenicity and therapeutic benefit. This supports the hypothesis that diversity does not equate to dilution in broad-spectrum formulations. The approach aligns with patient symptom patterns and may improve efficacy and asthma prevention. Future research could further refine species selection and leverage molecular diversity to optimize treatment strategies.

The transitioning of named patient products (NPPs) of therapy allergens is regulated under the German therapy allergen ordinance (TAO) since 2008. The establishment of a sound dose–response relationship constitutes a pivotal aspect in clinical development programs of drugs in general. Up to now, there are only few comprehensive studies dedicated to the determination of a dose–response relationship in allergen immunotherapy (AIT) because of various challenges. Among these aggravating factors are high placebo effects, variability of trial endpoints and especially for native allergens a narrow therapeutic window and safety profile. The phase II trials of the modified allergen tyrosine associated—monophosphoryl lipid A (MATA MPL) platform for birch and grasses established convincing and significant dose–response relationships decisive for AIT product optimization. The significant dose–response relationship for birch and grass allergoids reached an efficacy plateau and allowed the definition of critical milestones in drug development such as the median effective dose (ED50) for the MATA MPL platform combining modified allergens (allergoids) with microcrystalline tyrosine (MCT) and MPL in an adjuvant system. This marked a pivotal milestone in AIT drug development allowing the definition of the “optimal dose” (optimal risk–benefit ratio) to be taken forward to phase III trial. The MATA MPL platform is characterized by a scientifically sound dose–response relationship across allergens which underlines the pivotal role of a well-defined optimal dose as a success factor for phase III.

BACKGROUND:Regulatory authorities recommend a combination of symptom and medication scores during the grass pollen season as a primary endpoint for Phase III allergen immunotherapy (AIT) trials targeting allergic rhinoconjunctivitis. However, many composite primary endpoint scales exist; none are validated, nor do they have a well-justified minimal clinically important difference (MCID). METHODS:Direct patient feedback from 1071 grass-allergic patients was obtained to determine the minimally relevant improvement in allergic symptoms and translated into an MCID for the EAACI recommended CSMS0-6. Additionally, a clinically relevant threshold for the validated Rhinitis Quality of Life Questionnaire (RQLQ(S)) was determined from studies of registered SLIT products and subsequently used as an anchor to derive the MCID for CSMS0-6 using the data of a Phase III clinical trial with PQ Grass 27,600 SU (RESONATE). RESULTS:69% of grass-allergic patients were satisfied with a 1-point-improvement (e.g., from "severe" to "moderate") in their most severe symptom. This translated into an MCID range for CSMS0-6 of -0.23 to -0.21 points or -17% to -16%. Furthermore, a -0.34 point difference in RQLQ(S) compared to placebo was justified as clinically meaningful based on Phase III data from 2 registered SLIT grass tablets. Using this RQLQ(S) threshold as an anchor, an MCID of CSMS0-6 of -0.21 points (-16%) was derived using RESONATE. CONCLUSIONS:Both patient feedback and RESONATE results support an average MCID of -0.22 points on the CSMS0-6 scale and -16% on a composite primary endpoint scale, providing minimal thresholds to be achieved after AIT compared to placebo to conclude a positive Phase III trial outcome.

Background:Allergen Immunotherapy (AIT) is an effective treatment for patients with pollen, house dust mite, or venom allergy, but treatment adherence can be challenging. Patient preferences play a crucial role in acceptance and adherence to AIT, but little is known about these preferences. This study aimed to understand patient preferences for AIT and how these preferences influence treatment acceptance. Methods:A conjoint analysis was conducted among 750 participants from 7 European countries who were allergic to pollen (n = 700) or Hymenoptera venom (n = 50) and had not previously received AIT. Participants were asked to choose between hypothetical AIT products with different attributes, including product type, initial up-dosing posology, potential future risks, and side effects. The relative importance of each attribute was calculated, and sensitivity analyses were performed to assess the impact of specific attribute levels on patient preference. Results:Potential future risk is the attribute with the strongest impact on the importance score for patient preference in both pollen (44%) and venom (41%) allergic patients, followed by side effects (24% for pollen and 35% for venom allergy). Product type was less important, with a 22% importance score in both populations, and dosing schedules were not important at all, with a 2% importance score for pollen and an 11% importance score for venom-allergic patients. Accumulation of foreign material/substance in the body had the largest negative impact on patient preference, with drops of -24.7% (pollen) and -23.6% (venom), respectively. Conclusions:Understanding patient preferences is essential for optimizing the design and delivery of AIT. Different side effects and risk profiles of AIT products can influence patient treatment acceptance the most, and healthcare professionals may not always be aware of it. Future research should focus on developing AIT products that align with patient preferences with simultaneously very high effectiveness to improve adherence and treatment outcomes.

Seit 2008 wird mit dem Beginn der Therapieallergene-Verordnung (TAV) in Deutschland der Zulassungsprozess für die Entwicklung von Produkten zur allergenspezifischen Immuntherapie (AIT) reguliert, die vorher schon als Individualrezepturen erhältlich waren. Ein entscheidender Aspekt im Zulassungsprozess von Medikamenten ist im Allgemeinen die Etablierung einer soliden Dosis-Wirkungs-Beziehung, die für den Behandlungserfolg des am Ende dieses Prozesses zugelassenen Produkts maßgeblich ist. Bisher gibt es jedoch nur wenige umfassende Studien zur Dosis-Wirkungs-Beziehung in der AIT, denn diese zu etablieren war bislang eine Herausforderung in diesem Feld. Faktoren, die diesen Prozess erschweren, sind unter anderem hohe Placeboeffekte, die Variabilität der Studienendpunkte und insbesondere bei nativen Allergenprodukten ein enges therapeutisches Fenster und Sicherheitsprofil. Die Phase-II-Studien zur MATA-MPL-Plattform für Birken- sowie Gräserpollen liefern erstmals klare, signifikante Dosis-Wirkungs-Daten, die entscheidend für die Optimierung der AIT sind. Die MATA-MPL-Plattform, die modifizierte Allergene (Allergoide) mit mikrokristallinem Tyrosin (MCT) und MPL (Monophosphoryl-Lipid-A) als Adjuvanzsystem kombiniert, konnte in den Phase-II-Studien eine ED50 und eine Plateaubildung für das Birken- sowie das Gräserallergoid nachweisen. Dies stellt eine bedeutende Weiterentwicklung im Feld der AIT dar, da so für die nachfolgenden Phase-III-Studien die optimale Dosis für sowohl Dosis-Wirkung als auch Tolerabilität ausgewählt werden konnte. Die MATA-MPL-Plattform zeigt damit eine stabile Dosis-Wirkungs-Beziehung über verschiedene Allergene hinweg und unterstreicht die zentrale Rolle gut definierter Dosisfindungsstudien als Voraussetzung für erfolgreiche Phase-III-Studien für die Weiterentwicklung der AIT. Zitierweise: Werminghaus P, Becker S, Klimek L, Cuevas M, Rosewich M, Hermanns F, Graessel A, de Kam P-J, Kramer M F. The pivotal role of the optimal dose in allergen immunotherapy. Allergo J Int 2025;34:10-4 https://doi.org/10.1007/s40629-024-00322-8

AbstractBackgroundThe allergists´ tool box in cat allergy management is limited. Clinical studies have shown that holo beta‐lactoglobulin (holoBLG) can restore micronutritional deficits in atopic immune cells and alleviate allergic symptoms in a completely allergen‐nonspecific manner. With this study, we aimed to provide proof of principle in cat allergy.MethodsA novel challenge protocol for cat allergy in a standardized ECARF allergen exposure chamber (AEC) was developed. In an open pilot study (NCT05455749), patients with clinically relevant cat allergy were provoked with cat allergen for 120 min in the AEC before and after a 3‐month intervention phase (holoBLG lozenge 2x daily). Nasal, conjunctival, bronchial, and pruritus symptoms were scored every 10 min– constituting the total symptom score (TSS). Peak nasal inspiratory flow (PNIF) was measured every 30 min. In addition, a titrated nasal provocation test (NPT) was performed before and after the intervention. Primary endpoint was change in TSS at the end of final exposure compared to baseline. Secondary endpoints included changes in PNIF, NPT, and occurrence of late reactions up to 24 h after exposure.Results35 patients (mean age: 40 years) completed the study. Compared to baseline, holoBLG supplementation resulted in significant improvement in median TSS of 50% (p < 0.001), as well as in median nasal flow by 20 L/min (p = 0.0035). 20% of patients reported late reactions after baseline exposure, but 0% after the final exposure.ConclusionsCat allergic patients profited from targeted micronutrition with the holoBLG lozenge. As previously seen in other allergies, holoBLG supplementation also induced immune resilience in cat allergies, resulting in significant symptom amelioration.

BACKGROUND: Functional iron deficiency facilitates allergy development and amplifies the symptom burden in people experiencing allergies. Previously we selectively delivered micronutrients to immune cells with beta-lactoglobulin as carrier (holoBLG), resulting in immune resilience and allergy prevention. OBJECTIVE: The clinical efficacy of a food for special medical purposes-lozenge containing beta-lactoglobulin with iron, polyphenols, retinoic acid, and zinc (holoBLG lozenge) was assessed in allergic women. METHODS: In a randomized, double-blind, placebo-controlled pilot study, grass- and/or birch pollen-allergic women (n = 51) were given holoBLG or placebo lozenges over 6 months. Before and after dietary supplementation, participants were nasally challenged and the blood was analyzed for immune and iron parameters. Daily symptoms, medications, pollen concentrations, and well-being were recorded by an electronic health application. RESULTS: Total nasal symptom score after nasal provocations improved by 42% in the holoBLG group versus 13% in the placebo group. The combined symptom medication score during the birch peak and entire season as well as the entire grass pollen season improved in allergic subjects supplemented with the holoBLG lozenge by 45%, 31%, and 40%, respectively, compared with the placebo arm. Participants ingesting the holoBLG lozenge had improved iron status with increased hematocrit values, decreased red cell distribution width, and higher iron levels in circulating CD14(+) cells compared with the placebo group. CONCLUSIONS: Targeted micronutrition with the holoBLG lozenge seemed to be effective in elevating the labile iron levels in immune cells and reducing the symptom burden in allergic women in this pilot study. The underlying allergen-independent mechanism provides evidence that dietary nutritional supplementation of the immune system is one of the ways to combat atopy. (C) 2022 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology.

Summary Purpose The long-term effects of targeted micronutrition with the holoBLG lozenge in house dust mite (HDM) allergic rhinoconjunctivitis (ARC) patients were evaluated at a follow-up visit in an allergen exposure chamber (AEC). Methods Patients who were supplemented for 3‑months with the holoBLG lozenge in a previous study with two controlled HDM-AEC challenges [visits: V1, V3] were recruited for a third AEC challenge (V5) 7–8 months after cessation of supplementation. Symptoms (nose, conjunctival, bronchial, others), well-being, and lung function parameters were recorded exactly as in the previous study. Primary endpoint was change in median Total Nasal Symptom Score (TNSS) at V5 compared to V1. Secondary endpoints included e.g. change in median Total Symptom Score (TSS) and the exploratory analysis of temporal evolution of symptom scores using linear mixed effects models. Results Of the 32 patients included in the original study, 27 could be recruited for the follow-up visit with a third AEC challenge. An improvement of 20% (p = 0.15) in the primary endpoint TNSS [V1: 2.5 (interquartile range [IQR]: 1–4), V5: 2.0 (IQR: 1–3)] was observed; 40% (p = 0.04) improvement was seen for the TSS [V1: 5.0 (IQR: 3–9), V5: 3.0 (IQR: 2–5.5)]. Analysis of temporal evolution of all symptom scores, and the personal well-being revealed sustained, clinically meaningful improvement at V5 compared to V1. No relevant lung function parameter differences were observed. Conclusions Sustained long-term reduction of TNSS (primary endpoint) and sustained long-term improvement of secondary endpoints (temporal evolution of all symptom scores and well-being) were demonstrated 7–8 months after cessation of holoBLG supplementation, indicative of a long-lasting nature of immune resilience induced by holoBLG. Trial registration The study was registered at clinicaltrials.gov (NCT04872868).

The prevalence of allergic disorders has increased drastically over the last 50 years to the extent that they can be considered epidemic. At present, allergen-specific immunotherapy (AIT) is the only therapy that targets the underlying cause of allergic disorders, and evidence of its superiority is based on data accumulated from clinical trials and observational studies demonstrating efficacy and safety. However, several aspects remain unresolved, such as harmonization and standardization of manufacturing and quantification procedures across manufacturers, homogeneous reporting of strength, and the establishment of international reference standards for many allergens. This article discusses issues related to the measurement of major allergen content in AIT extracts, raising the question of whether comparison of products from different manufacturers is an appropriate basis for selecting a specific AIT product. Allergen standardization in immunotherapy products is critical for ensuring quality and, thereby, safety and efficacy. However, lack of harmonization in manufacturing processes, allergen quantification (methodologies and references), national regulatory differences, clinical practice, and labeling shows that the comparison of AIT products based solely on major allergen amounts is not rational and, in fact, impossible. Moreover, when rating the information given for a specific product, it is necessary to take into account further inherent characteristics of products and their application in clinical practice, such as the state of extract modification, addition of adjuvant or adjuvant system, route of administration (sublingual/ subcutaneous), and cumulative dose as per posology (including the volume per administration). Finally, only convincing clinical data can serve as the basis for product-specific evaluation and cross-product comparability of individual products.

Ziel: Untersuchung von langfristigen Effekten durch gezielte Mikronährstoff-Supplementierung durch die holoBLG-Lutschtablette. Nachuntersuchung in der Allergenexpositionskammer (AEC) bei Patienten mit Hausstaubmilben(HSM)-assoziierter allergischer Rhinokonjunktivitis (ARC), bei denen die letzte Supplementierung mit der holoBLG-Lutschtablette vor sieben bis acht Monaten endete. Methoden: In einer vorangegangenen Studie nutzten Patienten drei Monate lang die holoBLG-Lutschtablette und wurden zwei Mal (Visite: V1, V3) in der AEC unter kontrollierten Bedingungen mit HSM-Allergen provoziert. Diese Patienten wurden sieben bis acht Monate nach Ende der Supplementierung für eine dritte Provokation (V5) rekrutiert. Die Symptome (nasal, konjunktival, bronchial, andere), allgemeines Wohlbefinden und Lungenfunktion wurden exakt wie in der vorangegangenen Studie aufgezeichnet. Der primäre Endpunkt war die Veränderung im Median der nasalen Symptome (TNSS, totaler nasaler Symptomscore) bei V5 im Vergleich zu V1. Als sekundäre Endpunkte wurden die Veränderung im totalen Symptomscore (TSS) und die zeitliche Entwicklung aller Symptomscores während V5 zu V1 mittels eines linearen gemischten Modells explorativ analysiert. Ergebnisse: 27 der 32 Patienten konnten für die Nachuntersuchung inklusive dritte Provokation in der AEC rekrutiert werden. Der primäre Endpunkt TNSS (V1: 2,5 [IQR: 1-4], V5: 2,0 [IQR: 1-3]) war um 20 % (p = 0,15) verbessert. 40 % Verbesserung (p = 0,04) wurden für den TSS (V1: 5,0 [IQR: 3-9], V5: 3,0 [IQR: 2-5,5]) gezeigt. Die Analyse des zeitlichen Verlaufs aller Symptomscores und des persönlichen Wohlbefindens zeigte eine anhaltende, klinisch relevante Verbesserung bei V5 im Vergleich zu V1. Es ergaben sich keine wesentlichen Änderungen bei der Lungenfunktionsmessung. Schlussfolgerung: Der nachhaltige und langfristige Rückgang im TNSS (primärer Endpunkt) und die anhaltende Verbesserung der sekundären Endpunkte (zeitlicher Verlauf aller Symptomscores und allgemeines Wohlbefinden) konnten auch sieben bis acht Monate nach Ende der Supplementierung mit holoBLG bestätigt werden. Dies weist auf einen längerfristigen Effekt der Immunresilienz hin, die durch holoBLG induziert wird. Zitierweise: Bergmann K-C, Raab J, Krause L, Becker S, Kugler S, Zuberbier T, Roth-Walter F, Jensen-Jarolim E, Kramer MF, Graessel A. Long-term benefits of targeted micronutrition with the holoBLG lozenge in house dust mite allergic patients. Allergo J Int 2022;31:161-71 https://doi.org/10.1007/s40629-021-00197-z

Ziel: Evaluierung einer Lutschtablette zur Mikronährstoff-Supplementierung basierend auf dem Bauernhof-Effekt, bei Patienten mit Hausstaubmilben(HDM)- assoziierter allergischer Rhinokonjunktivitis (ARC) in einer standardisierten Allergen-Expositionskammer (AEC). Methoden: Vor (V1) und nach (V3) täglicher Supplementierung mit holo-BLG (BLG, β-Lactoglobulin) über einen Zeitraum von drei Monaten wurden Patienten mit HDM-Allergie für jeweils zwei Stunden in einer AEC mit einem HDM-Extrakt provoziert. Die durch die HDM-Exposition ausgelösten nasalen, konjunktivalen, bronchialen und sonstigen Symptome wurden im Abstand von jeweils zehn Minuten durch die Patienten bewertet. Allgemeines Wohlbefinden, "peak nasal inspiratory flow" (PNIF) sowie Lungenfunktion wurden alle 30 Minuten evaluiert. Primärer Endpunkt der Studie war die Änderung der Summe der nasalen Symptome (TNSS, totaler nasaler Symptomscore) am Ende der zweiten Exposition (V3) im Vergleich zur ersten (V1). Ein wichtiger sekundärer Endpunkt war die vergleichende Analyse des zeitlichen Verlaufs aller Symptomscores während V1 zu V3 mittels eines gemischten linearen Modells. Ergebnisse: 32 Patienten wurden in die Analyse eingeschlossen. Es wurde eine signifikante Verbesserung von 60 % (p = 0,0034) im primären Endpunkt-TNSS (V1: 2,5 [IQR: 1-4]; V3: 1,0 [IQR: 1-3]) gemessen sowie eine 40 %ige Verbesserung im totalen Symptomscore (TSS; V1: 5,0 [IQR: 3-9]; V3: 3,0 [IQR: 2-4]; Wilcoxon-Test: CI: 1,5-4,0; p < 0,0003). Sowohl der zeitliche Verlauf aller Symptomscores als auch das persönliche Wohlbefinden verbesserten sich in einem klinisch relevanten Ausmaß, beispielsweise sichtbar durch den geringeren Anstieg der Symptome während der finalen HDM-Exposition. Es gab keine wesentlichen Änderungen für PNIF und Lungenfunktion. Die Sicherheit und Verträglichkeit der Lutschtablette wurden als hervorragend eingestuft. Schlussfolgerung: Die Wirkung von holo-BLG, das durch gezielte Mikronährstoff-Supplementierung zur Immunresilienz bei Immunzellen führt, bietet einen neuen Ansatz zur Eindämmung der aktuellen Allergie-Epidemie. Zitierweise: Bergmann K-C, Graessel A, Raab J, Banghard W, Krause L, Becker S, Kugler S, Zuberbier T, Ott VB, Kramer MF, Roth-Walter F, Jensen-Jarolim E, Guethoff S. Targeted micronutrition via holo-BLG based on the farm effect in house dust mite allergic rhinoconjunctivitis patients - first evaluation in a standardized allergen exposure chamber. Allergo J Int 2021;30:141-9 https://doi.org/10.1007/s40629-021-00163-9

The concept of treatment of an allergy with the offending allergen was introduced more than a century ago. Allergen immunotherapy (AIT) is the only disease modifying treatment of allergic diseases caused by inhalational allergens and insect venoms. Despite this, only few AIT products have reached licensure in the US or an official marketing authorization status in European countries. Moreover, most of these AIT products are provided on an individual patient basis as named patient products (NPP) in Europe, while individualized preparations of (mixed) allergenic extract vials for subcutaneous administration (compounding) is common practice in the US. AIT products are generally considered safe and well tolerated, but the major practical clinical development challenge is to define the optimal dose and prove the efficacy and safety of these products using state-of-the art Phase II and pivotal Phase III studies. In planning Phase II-III AIT studies, a thorough understanding of the study challenges is essential (e.g. variability and non-validated status of subjective primary endpoints, limitations of pollen season definitions) and dogmas of these products (e.g., for sublingual immunotherapy (SLIT) trials double-blinding conditions cannot be maintained, resulting in stronger placebo responses in the active treatment group and inflated treatment effects in Phase III). There is future promise for more objective biomarker endpoints (e.g. basophil activation (CD63 and CD203c), subsets of regulatory dendritic, T and B cells, IL-10-producing group 2 innate lymphoid cells; alone or in combination) to overcome several of these dogmas and challenges; innovation in AIT clinical trials can only progress with integral biomarker research to complement the traditional endpoints in Phase II-III clinical development. The aim of this paper is to provide an overview of these dogmas, challenges and recommendations based on published data, to facilitate the design of Phase III studies and improve the evidence basis of safe and effective AIT products.

BackgroundAllergic rhinitis/rhinoconjunctivitis is the most common immune disease worldwide, but still largely underestimated, underdiagnosed, and undertreated. Dysbiosis and reduced microbial diversity is linked to the development of allergies, and the immunomodulatory effects of pro- and prebiotics might be used to counteract microbiome dysbiosis in allergy. Adequate symbiotic (multi-strain pro-, plus prebiotic) supplementation can be suggested as a complementary approach in the management of allergic rhinitis.ObjectiveThe effects of the daily intake of a symbiotic food supplement (combination of Lactobacillus acidophilus NCFM and Bifidobacterium lactis BL-04 with Fructo-Oligosaccharides) for 4 months in birch pollen allergic rhinoconjunctivitis patients were investigated for the first time in an allergen exposure chamber (AEC) allowing standardised, reproducible pollen exposure before and after intake.MethodsEligible patients were exposed to birch pollen (8000 pollen/m³ for 120 min) at the GA2LEN AEC, at baseline (V1) and final visit (V3) outside the season. The Total Symptom Score (TSS) and the scores for nose, eye, bronchial system, and others were evaluated every 10 min during exposure. Other secondary endpoints were the changes in well-being, Peak Nasal Inspiratory Flow (PNIF), lung function parameters, and safety. Co-primary endpoints were differences in Total Nasal Symptom Score (TNSS) and TSS after 120 min of exposure between both visits. Temporal evolution of symptom scores were analysed in an exploratory way using linear mixed effects models.Results27 patients (mean age 45 years, 15% male) completed the study. Both co-primary endpoints showed significant improvement after intake of the symbiotic. Median TNSS and TSS were decreased 50% and 80% at 120 min (adjusted p-value = 0.025 and p < 0.01 respectively).All four symptom scores and the personal well-being, improved to a clinically relevant extent over time, visible by a weaker increase in symptoms during 120 min of the final birch pollen exposure. No relevant differences were observed for PNIF, PEF, and spirometry. There were no airway obstructions or lung restrictions before and after both exposures. Late phase reactions after exposure were reduced after V3, documenting a better birch pollen tolerability of the patients. The safety and tolerability profile of the symbiotic food supplement was excellent, no adverse events (AEs) were observed.ConclusionsThis first evaluation of a symbiotic food supplement in an AEC in rhinoconjunctivitis patients with or without asthma induced by birch pollen revealed a significant beneficial effect, harnessing significant improvements of symptoms and well-being while maintaining an excellent safety and tolerability profile.

The European Academy of Allergy and Clinical Immunology (EAACI) organized the first European Strategic Forum on Allergic Diseases and Asthma. The main aim was to bring together all relevant stakeholders and decision‐makers in the field of allergy, asthma and clinical Immunology around an open debate on contemporary challenges and potential solutions for the next decade. The Strategic Forum was an upscaling of the EAACI White Paper aiming to integrate the Academy’s output with the perspective offered by EAACI’s partners. This collaboration is fundamental for adapting and integrating allergy and asthma care into the context of real‐world problems. The Strategic Forum on Allergic Diseases brought together all partners who have the drive and the influence to make positive change: national and international societies, patients’ organizations, regulatory bodies and industry representatives. An open debate with a special focus on drug development and biomedical engineering, big data and information technology and allergic diseases and asthma in the context of environmental health concluded that connecting science with the transformation of care and a joint agreement between all partners on priorities and needs are essential to ensure a better management of allergic diseases and asthma in the advent of precision medicine together with global access to innovative and affordable diagnostics and therapeutics.

BACKGROUND:Allergic and non-allergic childhood asthma has been characterized by distinct immune mechanisms. While interferon regulating factor 1 (IRF-1) polymorphisms (SNPs) influence atopy risk, the effect of SNPs on asthma phenotype-specific immune mechanisms is unclear. We assessed whether IRF-1 SNPs modify distinct immune-regulatory pathways in allergic and non-allergic childhood asthma (AA/NA). METHODS:In the CLARA study, asthma was characterized by doctor's diagnosis and AA vs NA by positive or negative specific IgE. Children were genotyped for four tagging SNPs within IRF-1 (n = 172). mRNA expression was measured with qRT-PCR. Gene expression was analyzed depending on genetic variants within IRF-1 and phenotype including haplotype estimation and an allelic risk score. RESULTS:Carrying the risk alleles of IRF-1 in rs10035166, rs2706384, or rs2070721 was associated with increased risk for AA. Carrying the non-risk allele in rs17622656 was associated with lower risk for AA but not NA. In AA carrying the risk alleles, an increased pro-inflammatory expression of ICAM3, IRF-8, XBP-1, IFN-γ, RGS13, RORC, and TSC2 was observed. NOD2 expression was decreased in AA with risk alleles in rs2706384 and rs10035166 and with risk haplotype. Further, AA with risk haplotype showed increased IL-13 secretion. NA with risk allele in rs2070721 compared to non-risk allele in rs17622656 showed significantly upregulated calcium, innate, mTOR, neutrophil, and inflammatory-associated genes. CONCLUSION:IRF-1 polymorphisms influence the risk for childhood allergic asthma being associated with increased pro-inflammatory gene regulation. Thus, it is critical to implement IRF-1 genetics in immune assessment for childhood asthma phenotypes.