EMJ Allergy & Immunology 10.1 2025

Allergy & Immunology

Review of the EAACI Congress 2025

Interview:

EAACI President María Torres discusses the latest in allergy and immunology research

Feature:

How to Diagnose and Treat Food Allergies

Contents

04 Editorial Board

07 Welcome 09 Foreword

Congress Review

10 Review of the European Academy of Allergy and Clinical Immunology (EAACI) Congress 2025, 13ᵗʰ–16ᵗʰ June 2025

Congress Features

24 Updates on Chronic Spontaneous Urticaria: EAACI 2025

Smiley et al.

28 The Interplay Between Immunodeficiencies, Allergies, Immune Dysregulation, and Lymphoproliferation: EAACI 2025

Pulvirenti and Sardella

32 Focus on Interdisciplinarity – Better Together: EAACI 2025

Jens Richter

35 From Barrier Dysfunction to Biologic Breakthroughs – Advances in Airway Allergy and Infection: EAACI 2025

Sümeyra Alan Yalım

Symposium Reviews

38 Closing Gaps in HAE Management: Understanding What Control Means for Your Patients with HAE

46 Normalisation of Life in Hereditary Angioedema: Optimising Outcomes and Individualised Management

56 Did I Hear You Right? How to Ensure Bi-Directional HCP–Patient Communication

Abstract Reviews

65 AllergoOncology: Non-Allergic Urticarial Skin Reactions Associated with MOv18 IgE, a First-in-Class IgE Antibody Recognising FRα

Chauhan et al.

67 Clinical Characteristics, Diagnosis, and Treatment Outcomes in Chronic Cold Urticaria: Insights From a 15-Year Study

Coelho et al.

69 Reference Values of Eosinophil-derived Neurotoxin in Blood: Reasons to Use Ethylenediaminetetraacetic Acid Plasma de Boer et al.

71 Abstract Highlights

Congress Interview

80 María Torres

Interviews

84 Global Perspectives on Challenges and Opportunities in Managing Allergic Rhinitis in Children: Taking the School Environment as a Case

93 Hugh Sampson

100 Mário Morais-Almeida

Features

104 How to Diagnose and Treat Food Allergies Bhatnagar and Stephen

109 An Approach to Diagnosing Primary Immunodeficiencies

Aisha Iftikhar

Article

"EAACI President María Torres welcomed delegates, introducing a new era for the academy driven by transformation, resilience, and a bold vision"

Editorial Board

Editor-in-Chief

Dr Jacques Bouchard

La Malbaie Hospital, Canada

Jacques Bouchard is a distinguished family physician with over 30 years of practice in La Malbaie, Québec, specialising in inpatient care, allergy, and respiratory physiology. An associate professor of clinical medicine at Laval University, Québec City, Canada, he is deeply committed to medical education through his work with the Federation of General Practitioners of Quebec. A recipient of the Prix Gilles-Des Rosiers and the College of Family Physicians of Canada’s Award of Excellence, he has made significant contributions to both rural healthcare and respiratory education.

Prof Igor Kaidashev

Poltava State Medical University, Ukraine

Dr Sarah Karabus

Red Cross War Memorial Children's Hospital, South Africa

Dr Ting Fan Leung

The Chinese University of Hong Kong, Hong Kong

Dr James Woijoo Kim

Family Physician Airway Group of Canada, Canada

Dr Reynold A Panettieri

Rutgers Institute for Translational Medicine and Science, USA

Prof Michael Rudenko

London Allergy and Immunology Centre, UK

Prof Stefan Wöhrl

Floridsdorf Allergy Center, Vienna, Austria

Prof Branimir Nestorovic

University Children's Hospital Belgrade, Serbia

Dr Enrico Heffler

Humanitas University, Italy

Aims and Scope

EMJ Allergy & Immunology is an open-access, peer-reviewed eJournal committed to helping elevate the quality of healthcare for allergic and immunological diseases globally by informing healthcare professionals on all aspects of these conditions.

The journal is published annually, six weeks after the European Academy of Allergy and Clinical Immunology (EAACI) Congress, and features highlights from this congress, alongside interviews with experts in the field, reviews of abstracts presented at the congress, as well as in-depth features on congress sessions. The journal also covers advances within the clinical and pharmaceutical arenas by publishing sponsored content from congress symposia, which is of high educational value for healthcare professionals. This undergoes rigorous quality control checks by independent experts and the in-house editorial team.

EMJ Allergy & Immunology also publishes peer-reviewed research papers, review articles, and case reports in the field. In addition, the journal welcomes the submission of features and opinion pieces intended to create a discussion around key topics in the field and broaden readers’ professional interests.

EMJ Allergy & Immunology is managed by a dedicated editorial team that adheres to a rigorous double-blind peer-review process, maintains high standards of copy editing, and ensures timely publication.

EMJ Allergy and Immunology endeavours to increase knowledge, stimulate discussion, and contribute to a better understanding of the diseases of the immune system.

EMJ Allergy & Immunology focuses on topics that are relevant to healthcare professionals in the field. We do not publish veterinary science papers or laboratory studies that are not linked to patient outcomes. We have a particular interest in topical studies that advance knowledge and inform of coming trends affecting clinical practice in the field.

Further details on coverage can be found here: www.emjreviews.com

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Editorial staff, following consultation with either a member of the Editorial Board or the author(s) if necessary, identify three appropriate reviewers, who are selected based on their specialist knowledge in the relevant area.

All peer review is double blind.

Following review, papers are either accepted without modification, returned to the author(s) to incorporate required changes, or rejected.

Editorial staff have final discretion over any proposed amendments.

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EMJ is available through the websites of our leading partners and collaborating societies. EMJ journals are all available via our website: www.emjreviews.com

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Congress Notice

Staff members attend medical congresses as reporters when required.

This Publication

Launch Date: 2013 Frequency: Annually Peer-Review Model: Double-blind

Indexed by: Directory of Open Access Journals (DOAJ) Online ISSN: 2398-9130

All information obtained by EMJ and each of the contributions from various sources is as current and accurate as possible. However, due to human or mechanical errors, EMJ and the contributors cannot guarantee the accuracy, adequacy, or completeness of any information, and cannot be held responsible for any errors or omissions. EMJ is completely independent of the review event (EAACI 2025) and the use of the organisations does not constitute endorsement or media partnership in any form whatsoever. The cover photo is of Glasgow, UK, the location of EAACI 2025.

Front cover and contents photograph: Glasgow, UK © Sunstopper1st / Shutterstock.com

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Welcome

Dear Readers,

We are delighted to welcome you to the 2025 issue of EMJ Allergy and Immunology, featuring our review of cutting-edge research updates from the European Academy of Allergy and Clinical Immunology (EAACI) Congress 2025. This year’s event provided meaningful insights for clinical practice and honed in on the integration of planetary health for a sustainable future.

The journal includes several expert-written features covering pivotal updates presented across the course of the congress, including chronic spontaneous urticaria, antibiotic delabelling in chronic rhinosinusitis, rare immunological diseases, and interdisciplinarity in allergy and immunology. Alongside this, you will also find multiple abstract reviews exploring allergo-oncology, chronic cold urticaria, and eosinophilic derived-neurotoxin as a serum biomarker for eosinophilic activity. Be sure to not miss our exclusive interview with EAACI President María Torres, as well as interviews with renowned specialists in food and respiratory allergy.

Amongst our peer reviewed content, you will find an original research article on surface-bound IgE in plasmacytoid dendritic cells, and features on diagnosing and treating food allergies and diagnosing primary immunodeficiencies.

We would like to thank our Editorial Board, as well as the authors, peer reviewers, and interviewees for their key contributions to this journal issue. Covering a broad spectrum of the discipline, we hope you enjoy reading and find useful insights for your clinical practice.

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Foreword

Dear Colleagues,

It is with great pleasure that I welcome you to the latest EMJ Allergy & Immunology, an edition issue and innovation in our field. This issue draws on key highlights from the European Academy of Allergy and Clinical Immunology (EAACI) Congress 2025, held in Glasgow, UK, from the 13th–16th June, an event that brought together leaders from across the globe to explore the latest in allergy and immunology research and clinical practice.

This year’s Congress delivered an exceptional programme, featuring a record number of abstracts, impactful symposia, and engaging ‘Flash Talks’. Among the many highlights were breakthroughs in therapies for food and drug allergies, and promising basic science initiatives that hold real potential to transform future patient care. Particular attention was given to drug hypersensitivity, with emerging diagnostic technologies, such as nanotechnology and desensitisation strategies, at the forefront. A major theme was also the importance of accurate allergy diagnosis in tackling antibiotic resistance through EAACI’s public awareness campaign.

We are pleased to share an interview with EAACI President María Torres, who provides expert commentary on the burden of drug allergy and the importance of improving risk stratification and diagnostic precision. Her perspective reinforces the need for innovation at the intersection of science, clinical care, and public health.

Also featured is Mário Morais-Almeida, President of the World Allergy Organization (WAO), who offers a timely discussion on how climate change and air pollution are influencing allergic disease patterns, and the vital role allergists play in advocacy and prevention. Complementing this, Hugh Sampson, Kurt Hirschhorn Professor of Paediatrics, Icahn School of Medicine at Mount Sinai, New York, USA, reflects on progress in food allergy therapies, particularly oral immunotherapy, and the role of biologics in improving both safety and accessibility. His insights highlight the balance between therapeutic benefit and the day-to-day realities of care.

Alongside these highlights, this issue also includes peer-reviewed articles exploring novel findings that enhance our understanding of immune cell behaviour in IgE regulation, and a feature on ‘How to Diagnose and Treat Food Allergies‘, offering a clear and practical overview of a growing public health concern.

Thank you to all contributors, reviewers, and our EMJ Allergy & Immunology Editorial Board. We hope you find this edition informative and inspiring as we look forward to the EAACI Congress 2026 in Istanbul, Türkiye.

Dr Jacques Bouchard

Hôpital de la Malbaie and Université Laval, Quebec, Canada

EAACI 2025

Emphasised EAACI's commitment to breaking boundaries in allergy, asthma, and clinical immunology

Congress Review

Review of the European Academy of Allergy and Clinical Immunology (EAACI)

Congress 2025

Location: Glasgow, UK

Date: 13th–16th June 2025

Citation: EMJ Allergy Immunol. 2025;10[1]:10-23. https://doi.org/10.33590/emjallergyimmunol/DOOV2450

THIS SUMMER, the welcoming city of Glasgow, UK, proudly hosted the European Academy of Allergy and Clinical Immunology (EAACI) Congress 2025, a pivotal event that brought together the global community to address the critical intersection of human health and our planet. The Opening Ceremony, a truly dynamic and inspiring start to the Congress, emphasised EAACI's commitment to breaking boundaries in allergy, asthma, and clinical immunology, integrating planetary health for a sustainable future.

EAACI President María Torres welcomed delegates, introducing a new era for the academy driven by transformation, resilience, and a bold vision. This forwardlooking approach is built upon five foundational pillars. First, ‘Membership Empowerment’: with over 17,000 members across more than 150 countries, EAACI is placing its members at the heart of its strategy. Second, ‘Beyond Borders: EAACI Goes Global’: expanding its reach beyond Europe, EAACI showcased its growing global influence through events like the first allergy school co-hosted with the Korean Society in Seoul, South Korea, and an upcoming allergy school in Hong Kong, China. Third, ‘Patient as a Partner’: reinforcing the commitment to co-creating solutions with patients, EAACI highlighted its close collaboration with the EAACI Patient Organisation Committee (POC). This includes the launch of the EAACI Anaphylaxis Awareness Day in 2024 and an Antibiotic Allergy Awareness Campaign at the congress. Fourth, ‘Science & Learning’:

at its core, EAACI is dedicated to scientific excellence and evolving education. The launch of the EAACI3H framework (Research and Innovation Hub, Public Patients and Outreach Hub, and Knowledge Hub) and the Declaration of Salamanca, which calls for allergy integration in undergraduate medical education, exemplify this commitment. Finally, ‘Digital Future’: embracing digital innovation, EAACI unveiled a new mobile and intelligent website, along with EAACI Nexus, a dynamic media hub featuring podcasts, webinars, online courses, and a rich archive of content. These platforms are designed to empower members, amplify research, and ensure seamless knowledge flow.

A highlight of the Opening Ceremony was the presentation of prestigious awards, recognising outstanding contributions and emerging talent in the fields of allergy, asthma, and clinical immunology. The Clemens von Pirquet Award 2025 was awarded to former EAACI Vice-President,

Ludger Kilmek, Center for Rhinology and Allergology, Wiesbaden, Germany. The Daniel Bovet Award 2025 was presented to Antti Lauerma, University of Helsinki, Finland. The Paul Ehrlich Award 2025 recognised Marianne van Hage, Karolinska Institute, Solna, Sweden, for her groundbreaking work on molecular allergy diagnostics and α-Gal syndrome. The Charles Blackley Award 2025 was given to Tomás Chivato Pérez, Universidad CEU San Pablo, Madrid, Spain, an expert in allergy, anaphylaxis, and respiratory disease. The EAACI Clinical Fellow Award 2025 was granted to 11 experts, including Hugh Sampson, Icahn School of Medicine, Mount Sinai, New York, USA. The EAACI Allergopharma Award 2025 was awarded to Jessy Elst, University of Antwerp, Belgium. Finally, the EAACI Early Career Research Award 2025 was presented to Janice Layhadi, Imperial College London, UK, who specialises in allergen immunotherapy and immune tolerance mechanisms.

A significant focus of the ceremony was planetary health, with a special recorded message from Maria Neira, Director,

Department of Environment, Climate Change and Health at the WHO. Neira passionately called for breaking boundaries between clinical work and environmental health, urging health professionals to influence policies for a healthier planet. The ceremony also featured inspiring words from Abul Abbas, University of California San Francisco, USA, who lauded EAACI's commitment to translating basic science into patient benefit and its global outreach initiatives. The introduction of the new EAACI bee mascot, alongside spirited dancing, the Glasgow NHS choir, and the resonant sound of bagpipes, created a truly memorable and uplifting atmosphere, setting a vibrant tone for the days ahead.

As EAACI embarks on its 70th anniversary next year, in Istanbul, Türkiye, the Congress in Glasgow served as a powerful testament to its enduring legacy of excellence, advocacy, and innovation, reaffirming its vital role in shaping the future of allergy, asthma, and clinical immunology worldwide.

A highlight of the Opening Ceremony was the presentation of prestigious awards, recognising outstanding contributions and emerging talent

Allergy Trajectories From Infancy to Adulthood Explored

A RECENT study, presented at the EAACI Congress 2025, has provided new insight into the complex relationship between eczema, wheeze or asthma, and rhinitis from infancy to early adulthood.1

Using data from 1,184 participants, researchers tracked these conditions at multiple intervals, ages 1, 3, 5, 8, 11, 16, and 20 years, employing a sophisticated trajectory modelling approach to uncover patterns over time.

Children who followed the multimorbidity pattern showed the greatest likelihood (87%) of an asthma diagnosis in early adulthood

Six distinct developmental profiles were identified. The most common was a ‘no disease’ trajectory, affecting around 38% of children. Other groups included persistent eczema with late-onset rhinitis (8.3%), persistent wheeze with later rhinitis (14.7%), eczema only (10%), rhinitis only (22%), and a small but significant group (7.4%) with multimorbidity, experiencing all three conditions.

Boys were significantly more likely to follow the multimorbidity and persistent wheeze with later rhinitis paths. Maternal factors played a notable role: maternal smoking during pregnancy increased the risk of persistent wheeze with later rhinitis, while maternal asthma raised the likelihood of both multimorbidity and persistent wheeze trajectories. Maternal atopy increased the risk across all symptomatic profiles when compared to the no-disease group.

Children who followed the multimorbidity pattern showed the highest rates of allergic sensitisation from infancy through to adulthood, and had the greatest likelihood (87%) of an asthma diagnosis in early adulthood. This group was followed by those with persistent wheeze and lateronset rhinitis (61%), in stark contrast to only 2% in the no-disease group.

The study highlights that the development of eczema, wheeze, and rhinitis does not follow a single, predictable course. Importantly, a small group of children experience a burdensome multimorbidity trajectory, underlining the need for early identification and targeted intervention strategies.

Maternal factors played a notable role: maternal smoking during pregnancy increased the risk of persistent wheeze with later rhinitis

Cold-Induced Urticaria in Children: High Anaphylaxis Risk and Ongoing Challenges

CHILDREN with cold-induced urticaria (coldU) face significant risks of anaphylaxis and impaired quality of life, with the condition often persisting into adulthood, according to new research presented at the EAACI Congress 2025.2

These findings highlight the complex nature of coldU in children

In this multicentre study, 203 paediatric patients diagnosed with coldU before the age of 18 years were recruited from 31 centres. Diagnosis was confirmed through a standardised cold stimulation test, using an ice cube on the forearm, and patient data were collected from medical records. The median age of participants was 14.25 years, with 56.1% being female. Concomitant chronic urticaria was present in 14.7% of cases. Notably, 17.2% of children experienced cold-induced anaphylaxis, a severe and potentially fatal reaction. Quality of life, measured by the Paediatric Quality of Life Inventory (PedsQL), was significantly lower in those with a history of anaphylaxis (p=0.005).

The analysis revealed that female gender was associated with a reduced risk of anaphylaxis, while autoimmune disease and older age increased the risk. Ingestion of cold foods or drinks was also identified as a common trigger for severe reactions. Disease resolution, defined as being symptom-free without treatment or avoidance for at least 1 year, occurred in 30.5% of patients. However, those with a history of anaphylaxis were significantly less likely to achieve remission (p=0.012). Out of the 43 patients who were followed into adulthood, 28% reported disease resolution, but no clear predictors for persistence beyond age 18 were identified.

These findings highlight the complex nature of coldU in children and the need for ongoing vigilance, particularly in those with severe reactions or comorbidities. For clinical practice, regular assessment of quality of life and risk factors is crucial, and families should be educated about the potential for anaphylaxis and the importance of avoiding known triggers.

Dupilumab Improves Clinical and Microbial Outcomes in Paediatric Atopic Dermatitis

A PRELIMINARY observational study presented at the EACCI Congress 2025 showed data from Naples, Italy, offering new supporting evidence of the dual clinical and microbial benefits of dupilumab in children with moderate-to-severe atopic dermatitis (AD).3

Conducted at the University of Campania Luigi Vanvitelli, Naples, Italy, between 2022–2024, the study tracked 30 paediatric participants (aged 6–16 years) across three groups: dupilumab-treated severe AD, untreated moderate AD, and healthy controls.

These findings support the hypothesis that IL-4 and IL13 blockade not only controls inflammation but also indirectly restores the skin’s antimicrobial defence

In the dupilumab group, clinical outcomes improved significantly over 12 months, Eczema Area and Severity Index (EASI) scores dropped from a median of 24.5 to 1.2 (p<0.001), alongside marked improvements in pruritus and quality of life scores. Perhaps, more interestingly, dupilumab also appeared to modulate the microbiota: treated patients showed a reduced colonisation of Staphylococcus aureus on

both the skin and nasal mucosa, compared to untreated peers.

These findings support the hypothesis that IL-4 and IL-13 blockade not only controls inflammation but also indirectly restores the skin’s antimicrobial defence. By improving barrier function and microbiome balance, dupilumab may offer broader protection against secondary infections, a key consideration in severe paediatric AD.

While the sample size was small, this is one of the first studies to demonstrate microbiota modulation in paediatric AD via biologic therapy. It strengthens the case for early, targeted intervention in children with refractory disease and adds a microbial dimension to the growing evidence base for dupilumab.

EASI scores dropped from a median of 24.5 to 1.2 (p<0.001)

Sewage Reveals Allergy Trends Through Antihistamines

PRESENTED at the EAACI Congress 2025, a Swiss study has revealed that what flows through our sewers could help track the nation’s struggle with hay fever.4 Researchers found that residues of commonly used antihistamines in wastewater closely reflected airborne pollen levels, opening the door to a new, cost-effective method for monitoring allergy symptoms across entire populations.

In the case of fexofenadine, around

50 %

of its annual use was tied directly to peak pollen exposure, to steady use during allergy season, and appeared unrelated to pollen 20 % 30 %

Led by Stephan Baumgartner, University of Bern, and colleagues from across Switzerland, the study examined 279 daily wastewater samples collected from Zurich, Switzerland, between 2021–2023. These samples represented the excretions of roughly 471,000 people each day. Using high-resolution mass spectrometry, the team analysed levels of 11 antihistamines, drugs commonly used to relieve allergy symptoms like sneezing, congestion, and itchy eyes.

The results were striking. Levels of bilastine, cetirizine, and particularly fexofenadine surged in line with daily pollen counts. In the case of fexofenadine, around 50% of its annual use was tied directly to peak pollen exposure, 20% to steady use during allergy season, and 30% appeared unrelated to pollen.

Pollen from birch, grasses, hazel, hornbeam, plane, and plantain were identified as the primary drivers of this spike, with grass pollen alone accounting for a quarter of the fexofenadine load. Unexpected increases during low-pollen periods hinted that less commonly monitored allergens, such as yew, may also play a role.

Does the Mandatory Food Allergen List Need Updating?

GOAT’S-SHEEP’S milk (GSM) should be included as a distinct allergen in the mandatory food allergen list, according to breaking research presented at the EAACI Congress 2025, which took place between 13th–16th June, in Glasgow, UK.5

In the current literature, there is limited data characterising GSM-induced anaphylaxis. To overcome this, and to compare the phenotype of GSM-induced anaphylaxis with that induced by other food allergens, researchers performed a retrospective analysis of Allergy-Vigilance Network recorded cases of GSM-induced anaphylaxis between 2002–2024.

GSM-induced anaphylaxis was also associated with greater reaction severity than anaphylaxis induced by other food allergens

In total, 3,285 cases of food-induced anaphylaxis were included in the study, of which 3% (n=97) were caused by GSM. Of the GSM-induced cases, 57.8% (n=56) had a known allergy to GSM, 13.4% (n=13) had a known cow’s milk allergy, 58.8% (n=57) occurred in males, and 75.3% (n=73) occurred in those <18 years of age. Within the GSM-induced allergy group, a total of four Grade IV reactions occurred (4.1%), of which two resulted in death, and 33 Grade III reactions occurred (34.0%). GSM-induced anaphylaxis was significantly associated

with older age (mean: 13.5 years) compared with cow’s milk-induced anaphylaxis (mean: 7.1 years). Moreover, those with GSMinduced anaphylaxis were significantly more likely to have asthma (44.5%) than those with cow’s milk-induced anaphylaxis (17.4%).

When compared with anaphylaxis induced by other food allergens, GSM-induced anaphylaxis was found to be significantly more likely to be associated with younger age (mean: 25.1 years versus 13.5 years) and a history of asthma (26.1% versus 44.5%). GSM-induced anaphylaxis was also associated with greater reaction severity than anaphylaxis induced by other food allergens.

The authors concluded that GSM-induced anaphylaxis occurs frequently, can occur in individuals without an allergy to cow’s milk, and the grade of severity can be high. Taken together, these findings highlight the need to include GSM as an independent allergen on the mandatory food allergen list, and suggest that GSM should no longer be considered solely as a milk product. Allergists should be aware of this new data and consider the findings in their daily practice.

Infant Fish Oil Markers Linked to Lower Asthma Risk

A NEW study, presented at the EAACI Congress 2025, has highlighted a potential link between early-life exposure to fish oil-derived compounds and reduced risk of childhood asthma.6

The study found that higher levels of 3-CMPFP at both time points were significantly associated with a lower risk of developing asthma, with a 34% reduction in risk observed

Researchers focused on the compound 3-carboxy-4-methyl-5-propyl-2-furan propanoic acid (CMPF), a biomarker of fish-oil and fatty fish intake, and its metabolites, including hydroxy-CMPF and 3-CMPFP. Using blood samples collected from mothers at pregnancy Week 24 and their children at age 6 months, scientists examined how these compounds affected metabolic profiles and asthma outcomes by age 10 years.

The study found that higher levels of 3-CMPFP at both time points were significantly associated with a lower risk of developing asthma, with a 34% reduction in risk observed after adjusting for other factors. Additionally, a metabolome score reflecting 3-CMPFP-related pathways, particularly those involved in vitamin A and

sphingomyelin metabolism, was also linked to a reduced asthma risk. CMPF levels at 6 months were similarly protective, while levels during pregnancy and hydroxy-CMPF showed no clear associations.

Interestingly, the strongest protective effects of CMPF and 3-CMPFP at 6 months were seen in children whose mothers received a placebo during pregnancy, suggesting that postnatal, rather than prenatal, exposure may be especially important. The fish oil intervention during pregnancy appeared to diminish these associations, indicating a complex interaction between maternal supplementation and infant metabolite levels.

These findings suggest that early-life blood markers of fish oil exposure may play a key role in shaping long-term respiratory health. The study emphasises the value of metabolomics in identifying potential preventive strategies against asthma and underscores the need for further research into how dietary components influence immune and respiratory development in children.

Miniaturised Allergy Test Promises Breakthrough in Multi-Food Allergy Diagnosis

A RECENT study, presented at the EAACI Congress 2025, has shown that a new streamlined, miniaturised, and multi-allergen basophil activation test (SMMABAT) offers higher predictive value than traditional IgE testing, with the added benefit assessing multiple allergens with minimal blood volume.7

Whilst basophil activation tests are increasingly recognised for their diagnostic potential, their complexity and resource requirements have limited widespread clinical adoption. The development of a simplified, high-throughput approach could help overcome these barriers and enable more precise allergy management.

Whilst basophil activation tests are increasingly recognised for their diagnostic potential, their complexity and resource requirements have limited widespread clinical adoption

In this pilot study, whole blood samples from 81 participants aged 1–36 years were collected and processed within 4 hours using a 96-well plate-based SMMABAT prototype. This miniaturised system enabled testing of 87 different conditions using <2 mL of blood per patient, with each well requiring only 20 µL. The test assessed reactivity to 11 allergenic extracts, such as peanut, tree nuts, sesame, milk, and egg,

across seven concentrations (10,000–0.01 ng/mL), as well as seven individual allergen components at 1,000 ng/mL.

In total, 891 dose-response curves were generated. SMMABAT reactivities showed significant correlations (p<0.0001) with clinical allergic or tolerant status for each allergen. The most informative dose range was 10–1,000 ng/mL, with a positive predictive value of 88.3% at 10 ng/mL, and a negative predictive value of 87% at 1,000 ng/mL. For comparison, specific IgE (sIgE) to raw extracts had a positive predictive value of 64% and a negative predictive value of 92% in a subset of cases. Notably, allergic patients undergoing immunotherapy showed significantly lower SMMABAT reactivities than those not receiving treatment, even though sIgE levels did not differ significantly.

For clinical practice, this approach offers a rapid, high-throughput, and minimally invasive method to complement traditional sIgE testing, providing more nuanced information about allergic status and treatment response.

Re-evaluating Penicillin Allergy Labels in Paediatric Care: Insights from Evelina London

A RECENT audit and interview-based study presented at the EAACI Congress 2025, conducted at Evelina London Children’s Hospital, UK, has shown significant discrepancies in the accuracy and management of penicillin allergy labels (PAL) in paediatric patients.8

Among 7,050 children reviewed between October 2024–December 2024, 194 had a PAL, representing a prevalence of 5.6%. Of the 51 families interviewed, nearly 40% of patients met British Society for Allergy and Clinical Immunology (BSACI) criteria for low-risk status and could have been safely de-labelled by non-allergists.

However, risk stratification was inconsistently applied: only 45% were correctly identified as low-risk in electronic records, and 40% had no risk level documented at all. Additional challenges emerged from both clinician and caregiver perspectives, including fear of re-exposure, lack of education around the safety and benefits of de-labelling, and minimal referral to allergy services. Notably, some children

retained a PAL despite having tolerated penicillin since their initial reaction, while others were labelled solely due to family history.

This study calls for improved clinician training in allergy history-taking and risk assessment, particularly among nonspecialists, as well as enhanced educational efforts aimed at caregivers. Systematic improvements in PAL documentation, clear referral pathways, and targeted education could support more effective de-labelling strategies, reducing inappropriate antibiotic avoidance, improving antimicrobial stewardship, and ultimately enhancing paediatric patient care.

Of the 51 families interviewed, nearly 40% of patients met British Society for Allergy and Clinical Immunology (BSACI) criteria for low-risk status and could have been safely de-labelled by non-allergists

Food Diversity Trends in Infants with Eczema

PRESENTED at the EAACI Congress 2025, a 12-year cross-sectional cohort study investigated national trends and disparities in complementary food diversity among Korean infants aged 9–12 months, focusing on those diagnosed with atopic dermatitis (AD).9

The study analysed data from 3,425,301 infants (mean age: 11.3 months), of whom 17.1% were diagnosed with AD

Using data from the national health screening programme between 2009–2020, the study aimed to evaluate trends in food diversity and identify associated risk factors. Infants were categorised as having high food diversity if they consumed all six complementary food groups, and low diversity if they consumed five or fewer. AD was defined by the 10th version of the International Classification of Diseases (ICD-10) L20 diagnosis recorded at least five times prior to the survey.

The study analysed data from 3,425,301 infants (mean age: 11.3 months), of whom 17.1% were diagnosed with AD. Among those with AD, 55.8% were male. The overall prevalence of high food diversity increased markedly during the study period, from 29.4% to 49.1% among infants with AD,

and from 32.1% to 56.9% in those without. While infants with AD initially exhibited lower food diversity, adjusted analyses revealed no significant interaction between AD and food diversity trends over time. Risk factors associated with low food diversity included preterm birth, low birth weight, and exclusive breastfeeding.

Risk factors associated with low food diversity included preterm birth, low birth weight, and exclusive breastfeeding

Despite overall improvements, disparities in complementary feeding practices persist among infants with AD. The findings highlight the need for targeted public health strategies to ensure equitable nutritional interventions for this vulnerable population, aiming to support healthy growth and reduce allergy-related risks through optimised early-life dietary diversity.

Innovation Improves Sensitivity for Correct Beta-Lactam Allergy Diagnosis

A MODIFIED tool for diagnosing β-lactam (BL) allergy outperforms the original in terms of sensitivity and negative predictive value, according to cutting-edge research presented at the EAACI Congress 2025, which took place in Glasgow, UK, between 13th–16th June.10

Staggeringly, approximately 90% of individuals who self-diagnose as allergic to BL, aren’t. Tools to aid diagnosis of BL allergy, such as PENFAST, have previously been developed. However, research has revealed that a percentage of individuals classified as low risk are, in fact, confirmed as allergic.

In light of this, researchers from Gregorio Marañón General University Hospital, Madrid, Spain, developed a modified version of PENFAST, called PEN-FAST-Allergy (PENFAST-A). In this modified version, urticaria was included as an immediate, severe reaction. They then sought to compare the efficacy of PENFAST and PEN-FAST-A with regard to correctly diagnosing BL allergy by reviewing data from 528 patients aged 17–97 years.

inclusion of urticaria as a severe, immediate reaction in PEN-FAST-A yielded an increase in sensitivity

Of those enrolled in the study, 68.75% were women, and 66.6% (n=352) presented with immediate hypersensitivity reactions (HSR); of whom 11.4% had anaphylaxis, 36.4% had an unknown history, and 52.2% had urticaria-angioedema. In total, 18.75% of participants had confirmed BL allergy.

A PENFAST score <3 (low risk) was seen in 80.1% of those who presented with HSR, of whom 6% were diagnosed with BL allergy. The remaining individuals with HSRs had a PENFAST score >3 (high risk), of whom 51.42% were BL allergic. In contrast, when using the PEN-FAST-A score, 59.9% of individuals with HSRs were categorised as low risk (score of <3), with BL allergy

confirmed in 1.2%. The remaining 40.1% were categorised as high risk (PEN-FAST-A score >3), and allergy was confirmed in 39.7%.

Notably, inclusion of urticaria as a severe, immediate reaction in PEN-FAST-A yielded an increase in sensitivity (84.85% versus 54.55%) and negative predicted value (95.26% versus 89.36%), when compared to PENFAST. However, PEN-FAST-A yielded a lower specificity (70.30% versus 88.1%) and positive predictive value (39.71% versus 51.43%) than PENFAST. The risk of missing a BL allergy diagnosis in those categorised as low risk reduced from 10.6% to 4.7% when using PEN-FAST-A instead of PENFAST.

From their findings, the study authors concluded that use of PEN-FAST-A resulted in an increased percentage of correct diagnoses and reduced the risk of missing individuals categorised as low risk who do, in fact, have a BL allergy. However, the authors cautioned that PEN-FAST-A should be applied under allergy specialist supervision and should not replace a formal allergological study.

References

1. Ullah A. Developmental profiles of eczema, wheeze, and rhinitis from infancy to early adulthood. Abstract 100609. EAACI Congress, 13-16 June, 2025.

2. Gemici Karaaslan HB et al. PECU: a multicenter study on pediatric patients with cold-induced urticaria. Abstract 000288. EAACI Congress, 13-16 June, 2025.

3. Indolfi et al. Treatment of severe atopic dermatitis in pediatric patients with Dupilumab and effects of therapy on nasal and skin microbiota: preliminary experimental evidence. Abstract 000993. EAACI Congress, 13-16 June, 2025.

4. Baumgartner S et al. Antihistamine residues in wastewater may allow to estimate the burden by airborne pollen concentrations. Abstract D2.399.

EAACI Congress, 13-16 June, 2025.

5. Pouessel G et al. Anaphylaxis induced by goat’s and sheep’s milk: an allergen that we should keep under surveillance. Abstract D2.263. EAACI Congress, 13-16 June, 2025.

6. Tingting W et al. Furan fatty acid metabolites in pregnant women and newborns are associated with risk of childhood asthma. Abstract 000654. EAACI Congress, 13-16 June, 2025.

7. Ullrich M et al. Development of a streamlined, miniaturized and multiallergen basophil activation test (SMMABAT) and early evaluation in the clinical research settings. Abstract 100452. EAACI Congress, 13-16 June, 2025.

8. Keogh M et al. Assessing the accuracy of penicillin allergy labels in paediatric care: focusing on educational gaps in both families and healthcare workers.

Abstract D1.254, EAACI Congress, 13-16 June, 2025.

9. Eun L et al. National trendNational trends and disparities in complementary food diversity for infants with atopic dermatitis: A 12year cross-sectional cohort study of births. Abstract 000539. EAACI Congress, 13-16 June, 2025.

10. Jover Walsh A et al. New frontiers in the diagnosis of betalactam allergy. Abstract 001455. EAACI Congress, 13-16 June, 2025.

Updates on Chronic Spontaneous Urticaria: EAACI 2025

Authors: Kathryn Smiley,1,2 Lauren Galli,1,2 *Bob Geng1-3

1. Allergy & Asthma Medical Group and Research Center, San Diego, California, USA

2. Rady Children’s Hospital, San Diego, California, USA

3. University of California, San Diego, California, USA *Correspondence to geng.bob@gmail.com

Disclosure: Smiley has been a consultant for Novartis outside of the submitted work. Geng has received speaker/consultancy fees and/or research support from Sanofi, Regeneron, Genentech, Novartis, Jasper, and Incyte outside of the submitted work. Galli has declared no conflicts of interest.

Acknowledgements Medical writing assistance was provided by Katie Wright, EMJ, London, UK.

Keywords: Angioedema, autoimmune, burden, chronic spontaneous urticaria (CSU), mast cells, pathophysiology.

Citation: EMJ Allergy Immunol. 2025;10[1]:24-27. https://doi.org/10.33590/emjallergyimmunol/XBEL1976

CHRONIC spontaneous urticaria (CSU) was a key focus at the European Academy of Allergy and Clinical Immunology (EAACI) Congress 2025 in Glasgow, UK, reflecting a growing momentum in the search for better treatments.1 This unpredictable skin condition, marked by wheals, itching, and angioedema, continues to significantly impact patients' quality of life (QoL). Despite available therapies, CSU remains poorly controlled for many individuals, highlighting an unmet need for more effective, lasting solutions. At the EAACI Congress, new data on emerging therapies such as barzolvolimab, briquilimab, and remibrutinib generated interest for their novel mechanisms and potential for long-term disease control.

BURDEN ON QUALITY OF LIFE

A persistent and often debilitating condition, affecting up to 1% of the population at any given time, CSU is characterised by spontaneous wheals, intense pruritus, and angioedema (present in approximately 40% of patients), imposing a significant burden. Among these symptoms, pruritus is widely considered the most distressing, often compelling patients to seek urgent relief.1

The unpredictable nature of CSU takes a substantial toll on patients’ QoL. Flares can occur without warning, disrupting sleep and day-to-day activities. Psychologically,

the disease is linked to heightened rates of anxiety and depression, with patients often feeling isolated and helpless in managing their symptoms. Beyond the physical and emotional strain, CSU carries a notable economic burden, leading to increased healthcare utilisation, absenteeism from work or school, and lost productivity.2 The cumulative effect of these burdens drives the pressing need for more effective and durable treatments.

PATHOPHYSIOLOGY OF CHRONIC SPONTANEOUS URTICARIA

At the heart of CSU pathogenesis lies the mast cell, a key effector of allergic and inflammatory responses. Mast cells interact with a host of other immune cells, including basophils and T cells, to drive the clinical manifestations of CSU. Upon activation, mast cells release histamine and other inflammatory mediators that cause the hallmark wheals and angioedema.

CSU carries a notable economic burden, leading to increased healthcare utilisation, absenteeism from work or school, and lost productivity

Two main autoimmune mechanisms are proposed in CSU: Type I autoimmune CSU involves auto-IgE antibodies that bind to allergens or self-antigens, while Type IIb involves IgG autoantibodies that target Fc epsilon receptor I (FcεRI) or IgE directly.3 Despite these two distinct descriptions, many patients show overlapping features of both types, complicating diagnosis and treatment.

The survival and activation of mast cells is critically dependent on stem cell factor (SCF) and its receptor, cKIT. Disruption of this axis, especially in skin-resident

mast cells, has emerged as a promising therapeutic strategy in CSU.

CURRENT TREATMENT LANDSCAPE AND GOALS

The primary goal in treating CSU is to achieve complete symptom control, defined as an Urticaria Activity Score over 7 days (UAS7) of 0, which reflects the resolution of hives, itch, and angioedema. Reaching this target not only alleviates physical symptoms, but also has the potential to significantly improve mental health and QoL.

The current treatment algorithm begins with second-generation H1-antihistamines. If symptoms persist, guidelines recommend increasing the dose up to fourfold. For those who remain symptomatic, the next step is typically omalizumab, an anti-IgE biologic. In refractory cases, cyclosporin, an immunosuppressant, is considered, though it comes with notable side effects. Despite this structured approach, many patients fail to achieve full control, highlighting the need for newer, more targeted therapies.

CURRENT AND EMERGING TREATMENT OPTIONS

Omalizumab

Omalizumab, a monoclonal antibody that neutralises free IgE, has transformed

Treatment goals are shifting from merely reducing symptoms to achieving complete disease control

CSU management, demonstrating efficacy, particularly in patients who are unresponsive to high-dose antihistamines. In Phase III trials (ASTERIA I and II),2 36–40% of patients achieved UAS7=0 with a 300 mg dose every 4 weeks. Omalizumab acts quickly, with many patients experiencing relief within the first few weeks. Importantly, it is well tolerated, is suitable for use during pregnancy, and carries a low risk of anaphylaxis. Omalizumab was approved in 2014 by the FDA and EMA for the treatment of CSU in patients ≥12 years of age who remain symptomatic despite treatment with H1 antihistamines.

Dupilumab

Dupilumab, another monoclonal antibody, targets IL-4 and IL-13 pathways, disrupting key drivers of Type 2 inflammation. In the LIBERTY-CSU Study A and Study C, also referred to as the CUPID-A and CUPID-C trials, dupilumab achieved UAS7=0 in about 30% of patients by Week 24.3 However, it missed its primary endpoint in the CUPID-B trial, likely due to patient selection (many were not omalizumab-naïve).4 Despite this, dupilumab is well-tolerated and remains a promising option, especially for those with comorbid atopic diseases.3 Dupilumab was recently approved by the FDA in April 2025 for treatment of CSU in patients ≥12 years who remain symptomatic despite antihistamine treatment, and is currently under review with the EMA.

Barzolvolimab

Barzolvolimab introduces a novel approach by targeting the cKIT receptor with a selective covalent monoclonal antibody. This disrupts SCF binding and starves mast cells, leading to their depletion via apoptosis, particularly in the skin. In Phase II trials, barzolvolimab demonstrated high rates of UAS7=0 at both 150 mg and 300 mg doses.6 Remarkably, symptoms remained low for months after the last dose, suggesting a disease-modifying effect, though more research is needed to investigate long-term off-therapy data.7 The safety profile is generally predictable and mild, with side effects such as hair colour changes, neutropenia, and hypopigmentation, all consistent with the drug’s on-target mechanism.8

Briquilimab

Briquilimab is a monoclonal antibody that targets cKIT, offering a similar mechanism to barzolvolimab, but with distinct pharmacological properties. In the BEACON Phase Ib/IIa study,9 early data showed rapid, dose-dependent UAS7 reductions: a single 240 mg dose led to a mean UAS7 decrease of –26.6 at 8 weeks, with 100% of patients (3/3) in that cohort achieving UAS7=0 and maintaining complete responses up to Week 8. Sustained tryptase suppression below quantifiable levels was also documented. Data from the SPOTLIGHT Phase Ib/IIa trial10 in chronic inducible

urticaria showed that in the 180 mg cohort (n=12), 100% achieved a clinical response, and 92% (11/12) reached complete response by Week 8. Moreover, by Week 2, 66% had already responded, and 58% maintained this response at Week 8. Side effects reported to date have included mild-to-moderate events, such as transient neutropenia and skin pigmentation changes, consistent with its on-target effects. Briquilimab is currently undergoing Phase II evaluation in patients with CSU who remain symptomatic despite antihistamines, and may represent another disease-modifying option in the evolving treatment landscape.

Remibrutinib

Remibrutinib, an oral, covalent Bruton’s tyrosine kinase (BTK) inhibitor, offers yet another innovative mechanism. By inhibiting BTK, it blocks downstream signalling that leads to mast cell degranulation, and may also modulate autoimmune processes. In the REMIX-1 and REMIX-2 Phase III trials, remibrutinib showed a rapid onset of action (within 1–2 weeks) and durable efficacy.11

More than 50% of patients achieved UAS7=0 by Week 52 in Phase IIb studies, and about one-third reached complete control at Week 12 in Phase III. It is well tolerated, with most adverse events being

References

1. Gonçalo M et al. The global burden of chronic urticaria for the patient and society. Br J Dermatol. 2021;184(2):226-36.

2. Staubach P et al. The burden of chronic spontaneous urticaria is substantial. Allergy. 2020;75(4): 849-58.

3. Maurer M et al. Dupilumab in patients with chronic spontaneous urticaria (LIBERTY-CSU CUPID): two randomized, double-blind, placebocontrolled, phase 3 trials. J Allergy Clin Immunol. 2024;154(1):184-94.

4. Maurer M et al. Efficacy and safety of dupilumab in patients with chronic spontaneous urticaria refractory to H1-antihistamines and omalizumab: results from the LIBERTY-CSU CUPID studies. J Allergy Clin Immunol. 2023;151(1):188-98.e10.

5. Kolkhir P et al. Autoimmune chronic spontaneous urticaria: what we know

mild to moderate.11 Petechiae were noted in 3.8% of patients versus 0.3% on placebo, but did not raise broader safety concerns.11

CHALLENGES AND FUTURE DIRECTIONS

Despite advances, many patients remain inadequately controlled. Studies estimate that up to 76% of adults continue to experience symptoms,12 with approximately 60% being refractory to antihistamines and 27–30% showing no meaningful response to omalizumab.13 This persistent unmet need highlights the urgency for better therapies.

Moving forward, treatment goals are shifting from merely reducing symptoms to achieving complete disease control. As the therapeutic pipeline expands, especially with agents such as barzolvolimab, briquilimab, and remibrutinib, there is renewed hope for patients who previously had few options. Precision medicine, which involves tailoring treatments to specific disease mechanisms, such as autoimmune markers or mast cell profiles, may soon redefine how CSU is managed.

and what we do not know. J Allergy Clin Immunol. 2021;147(2):488-94.

6. Metz M et al. Treatment with barzolvolimab leads to sustained improvement in angioedema in chronic spontaneous urticaria (CSU) patients: results from 52 weeks of treatment. Presentation 000588. EAACI Congress, 13-16 June, 2025.

7. Saini SS et al. Targeting mast cells in urticaria: clinical data for barzolvolimab and other novel agents. J Allergy Clin Immunol Pract. 2025;13(2):234-42.

8. Kolkhir P, Maurer M. Emerging therapies in chronic spontaneous urticaria: focus on novel biologics. Drugs. 2024;84(3):253-66.

9. Casale TB et al. Updated results from BEACON, a phase 1b/2a study of briquilimab in adults with CSU. Flash Talk LFT08. EAACI Congress, 13-16 June, 2025.

10. Metz M et al. Initial Results from SPOTLIGHT, a Phase 1b/2a dose escalation study of the anti–cKit briquilimab antibody in adults with CIndU who remain symptomatic despite H1 antihistamine treatment. Abstract 000269. EAACI Congress, 13-16 June, 2025.

11. Metz M et al. Remibrutinib in chronic spontaneous urticaria. N Engl J Med. 2025;392(10):984-94.

12. Metz M et al. Antihistamine-resistant chronic spontaneous urticaria remains undertreated: 2-year data from the AWARE study. Clin Exp Allergy. 2020;50(7):857-64.

13. Kolkhir P et al. Current and emerging therapies for chronic spontaneous urticaria. Dermatol Ther (Heidelb). 2023;13(3):459-76.

The Interplay Between Immunodeficiencies, Allergies, Immune Dysregulation, and Lymphoproliferation: EAACI 2025

Authors: *Federica Pulvirenti,1 Germano Sardella2

1. Reference Centre for Primary Immune Deficiencies, AOU Policlinico Umberto I, Rome, Italy

2. Department of Translational and Precision Medicine, Sapienza University of Rome, Italy

*Correspondence to f.pulvirenti@policlinicoumberto1.it

Disclosure: The authors have declared no conflicts of interest.

Keywords: Atopy, autoimmunity, immunodeficiencies, inborn errors of immunity (IEI), interferonopathies, lymphoproliferation.

Citation: EMJ Allergy Immunol. 2025;10[1]:28-31. https://doi.org/10.33590/emjallergyimmunol/EEHI9541

INBORN errors of immunity (IEI) are rare conditions caused by genetic factors that impair the development or function of the immune system. Currently, 559 IEIs are recognised, and this number is expected to grow with advancements in genomic sequencing and molecular immunology. Although IEIs typically present with an unusual tendency for recurrent and/or severe infections, patients often experience other manifestations, including atopy, immune dysregulation, haematological manifestations, and an increased risk of cancer, which highlights the overlap between immunology, rheumatology, allergology, and haematology.

Keeping faith with its dual vocation as a society of allergology and clinical immunology, the European Academy of Allergy and Clinical Immunology (EAACI) Congress 2025 made an effort to provide updates and educational content in the field of rare immunological diseases. Here, the authors review the most impactful presentations and their findings.

MONOGENIC ATOPIC DISEASES

In the NAIS Symposia,1 Anna Sediva, University Hospital Motol, Prague, Czechia, unravelled the perturbed immunological pathways in ‘primary atopic disorders’ (PAD), a group of monogenic IEI characterised by allergic inflammation as a predominant characteristic.2 In PAD, pathways critical to the development of atopy include focal defects in immune cells and epithelial barrier function, as well as global metabolic changes. These lead to chronic Type 2 T helper (Th2) and eosinophil-mediated allergic inflammation, promotion of IgE-class switching in B cells, disruption of peripheral tolerance, and abnormal mast cell degranulation.2 In the thematic symposia ‘Diagnostic Challenges in Patients with Inborn Errors of Immunity with Different Manifestations of Immune Dysregulation’,3 Riccardo Castagnoli, University of Pavia, Italy, proposed a practical approach to identify PAD. Features raising suspicion include early-onset, severe allergic manifestations, failure to respond to standard treatments, IgE levels >2,000 kU/L, and possible additional manifestations like autoimmunity, lymphopenia, or recurrent infections. Additional red flags include growth delay/short stature, connective tissue abnormalities, neurodevelopmental delay, or syndromic features.

The prototype condition is autosomal dominant hyper-IgE syndrome (AD-HIES), characterised by eczema, skin abscesses, chronic mucocutaneous candidiasis, and recurrent pneumonias, resulting from lossof-function variants in the STAT3 gene. Phenocopies of AD-HIES arise from defects in proteins within the STAT3 signalling pathway, such as IL-6 receptor (IL-6R) and Zinc Finger Protein 341 (ZNF341). Other notable related diseases include ComelNetherton disease, autosomal recessive HIES due to DOCK8 deficiency, ERBIN deficiency, and Loeys-Dietz syndrome.2 A condition caused by gain-of-function (GOF) variants in STAT6 is the most recently described PAD, leading to Th2 skewing with early-onset atopic dermatitis, food allergies, eosinophilic oesophagitis, asthma, and short stature.4

For IEI with atopy, Th2-biologics and JAK inhibitors (JAKi) may be beneficial, although data on their safety and efficacy are limited. To provide insight in this field, the EAACI Immunodeficiencies Working Group (WG) has launched the ATO-PID task force (TF) to analyse published cases reports and case series of IEI treated with biologics or small molecule inhibitors due to their atopy. Unpublished results from a metaanalysis on 139 patients were presented during the Immunology Section Business Meeting by Federica Pulvirenti, Academic Hospital Policlinico Umberto I, Rome, Italy. Data collected showed that anti-Th2 biologics and JAKi are highly effective in treating atopy in IEI, especially skin manifestations, with a favourable safety

profile for dupilumab and omalizumab, while the safety profile of JAKi requires careful individual assessment. The ATO-PID TF has also promoted a digital survey to collect consensus statements on indications, concerns, and monitoring strategies related to the use of anti-Th2 and JAKi in treating atopy in IEI. The survey also aimed to collect unpublished patient data. The WG also promoted a TF on drug hypersensitivity reactions (DHR) in IEI, launching a survey to obtain data on DHR classification,5 diagnosis, and treatment in IEI.6

AUTOIMMUNITY AND AUTOINFLAMMATION IN INBORN ERRORS OF IMMUNITY

During the thematic symposium ‘Diagnostic Challenges in Patients with Inborn Errors of Immunity with Different Manifestations of Immune Dysregulation’,3 Mahir Serbes, Çukurova University, Adana, Türkiye, addressed the apparent paradox of immune dysregulation in IEI. The prevalence of autoimmunity in patients with IEI accounts for up to 30%, with about 20% of patients presenting with dysregulation as the initial manifestation, especially autoimmune cytopaenias, conditions affecting the gastrointestinal tract, and autoimmune endocrinopathies.7,8 Common variable immunodeficiency (CVID) and combined immunodeficiencies showed the highest prevalence of autoimmunity. Features that should raise the suspicion of IEI include early onset of autoimmunity, presence

of polyautoimmunity, resistance to conventional treatments, severe clinical presentation with refractory manifestations, association with infections, and a positive family history. Genetic testing is crucial to allow a definitive diagnosis, due to the high phenotypic overlap among distinct IEIs, and to identify patients eligible for targeted therapies. Treatment includes immunosuppressants as well as biologics. Selected patients can be candidates for haematopoietic stem cell transplantation or gene therapy, which represents the only definitive cure for IEI.

Among IEIs with dysregulation, patients with genetic variants of CTLA4 and LRBA display signs of immune dysregulation, lymphoproliferation, and hypogammaglobulinaemia. The diseases arise, respectively, from haploinsufficiency of the gene encoding for CTLA4, an inhibitory receptor that regulates T cell activation, and biallelic loss of the gene encoding LRBA, a protein whose deficiency causes a secondary defect of CTLA4. 9

In the JMA session ‘Inborn Errors of Immunity: Increasing Awareness in Clinical Practice’,10 Ayça Kykim, Istanbul University, Türkiye, provided an update on the management of IEI. In a Turkish multicentric study of 150 patients with genetic variants of CTLA4 and LRBA, 11 the treatment with abatacept, a synthetic and soluble CTLA4 approved for rheumatological indications, was shown to improve lymphoproliferation and immune dysregulation, and also served as bridging treatment for haematopoietic stem cell transplantation. In the same session Petter Brodin, Karolinska Institutet, Stockholm, Sweden, focused on interferonopathies, a group of autoinflammatory diseases characterised by variable clinical phenotypes.

Interferons (IFN), classified as Type I (α, β), Type II (γ), and Type III (λ), are crucial for the immune response. Diagnosis of interferonopathies relies on early patient history and clinical signs, such as recurrent fevers, skin vasculopathy, interstitial lung disease, neurological manifestations, and elevated inflammatory markers. IFN signature gene analysis (a blood test assessing IFN effects) confirms interferonopathy. Whole-

exome or whole-genome sequencing is used to identify the specific genetic anomaly. Notably, complex conditions include STING-associated vasculopathy with onset in infancy linked to STING1 mutations, and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) related to PSMB8 mutations. Therapeutic options like JAKi and anifrolumab (a monoclonal antibody targeting Type I IFN receptor) effectively block IFN signalling and reduce inflammation.

The prevalence of autoimmunity in patients with inborn errors of immunity accounts for up to 30%, with about 20% of patients presenting with dysregulation as the initial manifestation

INBORN ERRORS OF IMMUNITY AND LYMPHOPROLIFERATION

In the ‘Diagnostic Challenges in Patients with Inborn Errors of Immunity with Different Manifestations of Immune Dysregulation’ symposia,3 Francesco Cinetto, University of Padua, Italy, highlighted lymphoproliferation as a key feature of IEI when associated with hypogammaglobulinaemia or immune dysregulation, especially autoimmune cytopaenias. In IEI, lymphoproliferation can manifest as chronic lymphadenopathy, splenomegaly, or lymphoid infiltration of the lungs, liver, and gut, with resulting organ dysfunction. Historically, autoimmune lymphoproliferative disease (ALPS), a condition mediated by defects in the FAS-regulated apoptosis of lymphocytes, has been regarded as the prototype of IEIs with lymphoproliferation and autoimmunity. However, in recent years, many other conditions have been identified, characterised by lymphoproliferation and autoimmune cytopaenias as primary manifestations, including defects of CTLA4, LRBA, NFKB1, PIK3CD, PIK3R1, and STAT3 GOF. For these conditions, in 2024, the term 'autoimmune lymphoproliferative primary immunodeficiencies (ALPID)’ was proposed.12 Among autoimmune lymphoproliferative primary immunodeficiencies, activated

PI3Kδ syndrome (APDS) is a monogenic IEI resulting in lymphadenopathy, splenomegaly, an increased risk of developing lymphomas, and immunodeficiency. APDS arises from GOF mutation in the PI3KCD gene and a loss-of-function mutation in the PIK3R1 gene, both leading to hyperactivation of the PI3Kδ signalling pathway, crucial in lymphocyte growth, differentiation, and survival.

In her speech on IEI management, Kykim reported that leniolisib, a PI3Kδ inhibitor recently released for treating APDS, reduced the signs of lymphoproliferation (lymph node and spleen size), increased the number of circulating naïve T cells, and reduced serum IgM levels.10

CLOSING REMARKS

In conclusion, in IEI, infections are just the tip of the iceberg of a multifaceted and complex phenotype. Advancements in the fields of genetics and molecular diagnostics are contributing to the elucidation of pathogenic pathways involved in IEI and are revealing targets for precision medicine. Delays in diagnosis, due to symptom overlap and the rarity of these diseases, can lead to serious complications. Increasing physician awareness and prompt referrals to specialised centres are vital for better patient outcomes.

In recent years, many other conditions have been identified, characterised by lymphoproliferation and autoimmune cytopaenias as primary manifestations

References

1. Sediva A. Monogenic atophy. Czech Republic - Czech Society of Allergology and Clinical Immunology (CSACI). EAACI Congress, 13-16 June, 2025.

2. Lyons JJ, Milner JD. Primary atopic disorders. J Exp Med. 2018;215(4):1009-22.

3. Castagnoli R et al. Diagnostic challenges in patients with inborn errors of immunity with different manifestations of immune dysregulation inborn errors of immunity with atopic manifestations. Presentation SY27. EAACI Congress, 13-16 June, 2025.

4. Sharma M et al. Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease. J Exp Med. 2023;220(5):e20221755.

5. EAACI Immunodeficiency Working Group. ATO-PID survey. Available at: https://www.surveymonkey.com/r/ KMZQ2CJ. Last accessed: 16 July 2025.

6. EAACI Immunodeficiency Working Group. DHR in PID survey. Available at: https://www.surveymonkey.com/r/ QXSTFLR. Last accessed: 16 July 2025.

7. Fischer A et al. Autoimmune and inflammatory manifestations occur frequently in patients with primary immunodeficiencies. J Allergy Clin Immunol. 2017;140(5):1388-93.e8.

8. Thalhammer J et al. Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations. J Allergy Clin Immunol. 2021;148(5):1332-41.e5.

9. Tessarin G et al. Monogenic forms of

common variable immunodeficiency and implications on target therapeutic approaches. Curr Opin Allergy Clin Immunol. 2023;23(6):461-66.

10. Kiykim A. Inborn errors of immunity: increasing awareness in clinical. EAACI Congress, 13-16 June, 2025.

11. Tesch VK et al. Long-term outcome of LRBA deficiency in 76 patients after various treatment modalities as evaluated by the immune deficiency and dysregulation activity (IDDA) score. J Allergy Clin Immunol. 2020;145(5):1452-63.

12. Toskov V, Ehl S. Autoimmune lymphoproliferative immunodeficiencies (ALPID) inchildhood: breakdown of immune homeostasis and immune dysregulation. Mol Cell Pediatr. 2023;10(1):11.

Focus on Interdisciplinarity –Better Together: EAACI 2025

Author: *Jens Richter1

1. Outpatient Department of Allergology, Department of Respiratory Medicine, Lund University Hospital, Sweden *Correspondence to jens.richter@med.lu.se

Disclosure:

Keywords:

Richter has received financial support for advisory boards and lecture fees outside of the submitted work from AstraZeneca, GSK, and Sanofi.

Asthma, biologicals, chronic rhinosinusitis with nasal polyps (CRSwNP), co-operation, interdisciplinarity.

Citation: EMJ Allergy Immunol. 2025;10[1]:32-34. https://doi.org/10.33590/emjallergyimmunol/HOKS5484

ASTHMA is an inflammatory airway disease with a high prevalence in many parts of the world. It is characterised by variable airway obstruction in response to different triggers, and is shaped by an interplay of host and environmental factors.

Interdisciplinarity in clinical medicine refers to co-operating with clinical colleagues outside of one’s own field of expertise, especially when investigating and treating patients with disease involvement in different organ systems. Presentations from the 2025 European Academy of Allergy and Clinical Immunology (EAACI) Congress showcased these concepts.

ASTHMA

PHYSICIANS AND OTORHINOLARYNGOLOGISTS CAN, DO, AND SHOULD COLLABORATE TO IMPROVE OUTCOMES

FOR PATIENTS WITH GLOBAL AIRWAYS DISEASE

Thanks to the groundbreaking work of our colleagues in clinical and basic immunology over the last decades, we have gained a much more detailed understanding of the pathophysiology driving airway diseases. The similarities of the airway epithelium in the upper and lower respiratory tract have led to a 'systems thinking' approach, where asthma is no longer seen as a disease of the lungs only. The concept of 'global', or 'united' airways has gained traction in the clinical community.

THERAPEUTIC INNOVATIONS HAVE TRANSFORMED CLINICAL CARE

The advent of monoclonal antibodies targeting specific steps in the inflammatory cascade has enabled us to treat and help a group of patients with severe inflammatory pathology and involvement in both the upper and lower airways.

Compounds such as mepolizumab, dupilumab, and tezepelumab have proven efficacy in both chronic rhinosinusitis with nasal polyps (CRSwNP), and Type 2 high asthma. Numerous presenters at the EAACI gathering reported on data from both pivotal studies1-5 and real world evidence.6-13 Interestingly, the latter does not infrequently seem to outperform clinical studies in terms of long-term and sustained efficacy. Access to these medications and the rules for their use (including reimbursement) vary from country to country, even within Europe.

COMORBIDITIES REQUIRE COOPERATION: HOW, AND WITH WHOM?

The rate of comorbidity between severe eosinophilic asthma and CRSwNP is high, estimated at between 50–70%.14-16 The patient journey in the healthcare system can vary substantially. The traditional model of care has, hitherto, usually involved a lead physician trying to coordinate care by means of referrals to other disciplines and collecting their input, often leading to time delays in the process of patient phenotyping and endotyping in order to help choose the best way forward.

The rate of comorbidity between severe eosinophilic asthma and CRSwNP is high, estimated at between 50–70%

Philippe Gevaert, Professor in Rhinology and Allergy, Ghent University, Belgium, stressed the importance of having friendly collegial relations with his ear, nose, and throat colleagues. In some geographical areas, multidisciplinary conferences are established to discuss and determine whether patients potentially qualify for treatment with biologicals.

AN EXAMPLE OF INTERDISCIPLINARITY IN ACTION FROM SCANDINAVIA

A pilot project that took place at Lund University Hospital, Sweden, was presented in poster format at the EAACI Congress 2025.17 In this project, the authors established joint interdisciplinary clinics with both ear, nose, and throat, and asthma physicians in the same consultation room with the individual patient. This was done in order to achieve a holistic assessment and directly discuss the available therapeutic options with the patient, which, in many cases, was biological therapy targeted at both the upper and lower airways. In other cases, it was decided to initially optimise local treatment, whilst others were listed for functional endoscopic sinus surgery as a next step. Patients were selected for this interdisciplinary clinic from both specialities.

The close physical proximity in Lund, well-established collegial relations, and support of clinical leadership enabled this attempt to transform care. Of note, the challenges encountered during this pilot were a lack of clinic space and time.

By implementing the joint interdisciplinary clinic, the time to decision regarding definitive management was shortened

By implementing the joint interdisciplinary clinic, the time to decision regarding definitive management was shortened, and both patient and clinician satisfaction were high. The institution of such interdisciplinary clinics for a select population of patients was deemed well worth the institutional energy spent. Similar clinics in other locations can likely be established by interested clinicians familiar with their local circumstances. Several other examples of this exist in the Nordic countries.

References

1. Lipworth B et al. Dupilumab improves small airway dysfunction in patients with moderate-to-severe asthma: the Phase 4 VESTIGE study. Abstract 100239. EAACI Congress 2025, 13-16 June, 2025.

2. Gevaert P. The differential effect of anti-T2 biologicals in CRSwNP. Session SY11. EAACI Congress 2025, 13-16 June, 2025.

3. Lipworth B et al. Efficacy and safety of tezepelumab in adults with severe chronic rhinosinusitis with nasal polyps overall and in patients with and without co-morbid asthma: results from the Phase 3 WAYPOINT study. Abstract 000642. EAACI Congress 2025, 13-16 June, 2025.

4. Jackson D et al. Tezepelumab reduces OCS use and improves sino-nasal symptoms in OCS-dependent patients with severe asthma and comorbid chronic rhinosinusitis (overall and with nasal polyps): results from the Phase 3b WAYFINDER study. Abstract 001109. EAACI Congress 2025, 13-16 June, 2025.

5. Wagenmann M et al. Improved quality of life, early symptom control and reduced surgery with mepolizumab in chronic rhinosinusitis with nasal polyps (CRSwNP): results from the SYNAPSE study. Abstract 001234. EAACI Congress 2025, 13-16 June, 2025.

6. Cornet M. Real-life use of biologicals in CRSwNP: prescription patterns,

CLOSING REMARKS

In this era of precision medicine, with an ever-growing armamentarium of therapeutic options, we are well-advised to seek improved collaboration with adjoining disciplines in the interest of our patients.

safety and prediction of response. Session SY11. EAACI Congress 2025, 13-16 June, 2025.

7. Cavaliere C et al. Characterization of chronic rhinosinusitis patients based on markers of type 2 inflammation: findings from the European CRS Outcome Registry (CHRINOSOR). Abstract 001300. EAACI Congress 2025, 13-16 June, 2025.

8. Cornet M et al. Distribution of baseline Type 2 inflammation characteristics in chronic rhinosinusitis with nasal polyps (CRSwNP) biologic clinical trials: a comparative assessment. Abstract 000620. EAACI Congress 2025, 13-16 June, 2025.

9. Gevaert P et al. Real-life effectiveness of monoclonal antibody therapy in severe uncontrolled chronic rhinosinusitis with nasal polyps: a prospective study. Abstract 001331. EAACI Congress 2025, 13-16 June, 2025.

10. Canonica GW et al. Real-world effectiveness of dupilumab vs. other biologics in achieving clinical remission as assessed by a composite measure of selected asthma outcomes in patients with severe asthma: EU ADVANTAGE. Abstract 100176. EAACI Congress 2025, 13-16 June, 2025.

11. Quirce S et al. Mepolizumab provides sustained clinical benefits in patients with severe asthma regardless of age of asthma onset: real-world data from the REALITI-A study at 2 years. Abstract 100374. EAACI Congress

2025, 13-16 June, 2025.

12. Ahmed W et al. REALITI-N: first ambidirectional cohort study evaluating real-world mepolizumab use in chronic rhinosinusitis with nasal polyps (CRSwNP). Abstract 001397. EAACI Congress 2025, 13-16 June, 2025.

13. Pinto JM et al. Dupilumab effectiveness through two years in patients with CRSwNP treated in real-world practice: results from the global AROMA registry. Abstract 000559. EAACI Congress 2025, 13-16 June, 2025.

14. Chen S et al. Systematic literature review of the epidemiology and clinical burden of chronic rhinosinusitis with nasal polyposis. Curr Med Res Opin. 2020;36(11):1897-1911.

15. Khan AH et al. Prevalence and severity distribution of type 2 inflammationrelated comorbidities among patients with asthma, chronic rhinosinusitis with nasal polyps, and atopic dermatitis. Lung. 2023;201(1):57-63.

16. Toppila-Salmi S et al. Multidisciplinary expert perspective on the management of type 2 inflammationdriven severe CRSwNP: a brief overview of pathophysiology and recent clinical insights. J Asthma Allergy. 2024;17:431-9.

17. Richter JC. Managing patients with type 2 inflammation in a joint interdisciplinary “United Airways Clinic” at Lund University Hospital, Sweden. Poster D1.112. EAACI Congress 2025, 13-16 June, 2025.

From Barrier Dysfunction to Biologic Breakthroughs – Advances in Airway Allergy and Infection: EAACI 2025

Author: *Sümeyra Alan Yalım1

1. Afyonkarahisar Health Sciences University, Türkiye *Correspondence to alansumeyra@gmail.com

Disclosure: The author has declared no conflicts of interest.

Keywords: Allergic rhinitis, antibiotic allergy, biologics, chronic rhinosinusitis, epithelial barrier.

Citation: EMJ Allergy Immunol. 2025;10[1]:35-37. https://doi.org/10.33590/emjallergyimmunol/XEBS9209

THE European Academy of Allergy and Clinical Immunology (EAACI)

Congress 2025, held in Glasgow, UK, brought together thousands of clinicians, researchers, and industry leaders in the field of allergy, asthma, and clinical immunology. With a diverse programme spanning planetary health, precision medicine, and epithelial science, the Congress offered a rich platform to discuss cutting-edge advances in diagnosis and treatment. Among the many highlights, sessions focusing on antimicrobial allergy delabelling, epithelial barrier dysfunction, and targeted biologic therapies in chronic rhinosinusitis drew particular attention for their clinical relevance and translational potential.

REFRAMING ANTIBIOTIC ALLERGY: DELABELLING AS A STEWARDSHIP STRATEGY

Antibiotic allergy labels, particularly those involving β-lactams, remain prevalent, yet frequently inaccurate. EAACI Congress 2025 emphasised the growing global momentum toward structured delabelling protocols as a means to combat antimicrobial resistance. Experts underscored that >90% of penicillin allergy labels are unsubstantiated, leading to unnecessary broad-spectrum antibiotic use. Practical tools such as point-of-care risk stratification, direct oral challenges, and electronic medical record-integrated decision aids were discussed.1 These approaches not only streamline delabelling protocols but also reduce hospital length of stay, improve antimicrobial selection, and

mitigate resistance patterns, particularly in high-risk populations such as oncology or immunodeficient patients.

During one of the plenary sessions, a poignant case was presented where systematic delabelling reduced secondline antibiotic use by 67% within a year, with no increase in adverse drug reactions. Another presentation from the UK NHS experience highlighted how integrating clinical decision support into electronic medical records significantly increased the uptake of direct oral challenge protocols.

The takeaway: delabelling is not merely an allergy issue; it’s a patient safety and antimicrobial stewardship priority, with measurable clinical and public health benefits.

THE NASAL EPITHELIUM: A CENTRAL PLAYER IN TYPE 2 INFLAMMATION

A major thematic focus this year was the epithelial barrier hypothesis in allergic and non-allergic diseases. Presenters delved into the intricate relationship between epithelial integrity and Type 2 immune responses. Data were presented showing that pollutants, viruses, and even topical medications can disrupt nasal epithelial tight junctions,2 perpetuating inflammation. Cutting-edge research explored biomarkers of barrier dysfunction and therapeutic targets such as IL-33 and thymic stromal lymphopoietin (TSLP).3 The evolving understanding of the nasal epithelium as a regulator, rather than a passive participant, holds promise for precision-based interventions.

A major thematic focus this year was the epithelial barrier hypothesis in allergic and non-allergic diseases

BIOLOGICS IN CHRONIC RHINOSINUSITIS: PERSONALISING CARE FOR A HETEROGENEOUS DISEASE

The use of biologics in chronic rhinosinusitis with nasal polyps (CRSwNP) has rapidly transitioned from experimental to mainstream. EAACI Congress 2025 featured updates on anti-IL-4Rα, anti-IgE, and anti-IL-5 monoclonal antibodies, with particular attention to phenotyping and biomarkers that predict response. Specific endotypes, such as tissue eosinophilia, elevated periostin, or high baseline total IgE, were highlighted as useful in guiding biologic selection, particularly in patients with severe, refractory CRSwNP. In one session, it was noted that serum eosinophil counts >300 cells/μL and tissue IL-5 expression were associated with better responses to anti-IL-5 therapy, while patients with nasal polyps and coexisting asthma tended to respond better to anti-IL-4Rα agents.3 Discussions highlighted the need for real-world data and head-to-head trials to inform treatment algorithms, especially given the cost and heterogeneity of response to biologics.

A recurring theme was the importance of shared decision-making and longterm outcome monitoring.4 Given the chronic, relapsing nature of CRSwNP and variability in symptom burden and treatment adherence, patient engagement in therapy selection is vital. Current literature still lacks high-quality data on long-term comparative outcomes between biologics, and patient preference is increasingly recognised as a key driver of sustained adherence and clinical success.4 These gaps underscore the need for integrative care models that combine biomarker-driven personalisation with patient-centred approaches.

TAKE HOME MESSAGE

EAACI Congress 2025 reflected the allergy community’s pivot toward mechanistic insight, stewardship, and personalisation. From redefining antibiotic allergy to unveiling the active role of epithelial dysfunction in chronic inflammation, the sessions offered a glimpse into the future of airway disease management. As new tools and therapies emerge, implementation science and patient-centred integration will be crucial in translating innovation into clinical reality.

EAACI Congress 2025 reflected the allergy community’s pivot toward mechanistic insight, stewardship, and personalisation

References

1. Macy E. Penicillin allergy: optimizing diagnostic protocols, public health implications, and future research needs. J Allergy Clin Immunol Pract. 2020;8(8):2541-6.

2. Bachert C et al. Biologics in chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2021;147(1):29-36.

3. Steelant B et al. Impaired barrier function in patients with allergic rhinitis. J Allergy Clin Immunol. 2016;137(3):906-15.

4. Fokkens WJ et al. European position paper on rhinosinusitis and nasal polyps 2020. Rhinology. 2020;58(Suppl S29):1-464.

Closing Gaps in HAE Management: Understanding What Control Means for Your Patients with HAE

This symposium took place on 14th June 2025, as part of the European Academy of Allergy & Clinical Immunology (EAACI) Congress held in Glasgow, UK

Support: The symposium and publication of this article was sponsored by KalVista Pharmaceuticals.

Chairperson: Douglas Jones1

Speakers: Stephen Betschel,2 Thomas Buttgereit,3,4 Sinisa Savic5

1. Global Allergy Immune Network, USA

2. Unity Heath, Toronto, Canada

3. Institute of Allergology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and HumboldtUniversität Zu Berlin, Germany

4. Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology, Berlin, Germany

5. University of Leeds, UK

Disclosure:

Betschel has received speaker and/or advisor fees from Astria Therapeutics, BioCryst, CSL Behring, Ionis, KalVista, Pharvaris, and Takeda; and research funding from CSL Behring and Takeda. Buttgereit is, or recently was, a speaker and/or advisor for, and/or received research funding from, Almirall, Aquestive, BioCryst, CSL Behring, Galderma, GSK, Hexal, KalVista, Medac, Novartis, Otsuka, Pharming, Pharvaris, Roche, Sanofi-Aventis, Swixx BioPharma, and Takeda. Jones is a consultant and speaker for Takeda, Pharming, CSL, Genentech, and KalVista; and is a consultant for Pharvaris. Savic has received remuneration for participating in advisory board meetings from KalVista, CSL Behring, Phavaris, Celldex, Novartis, SOBI, Pharming, and Otsuka; research grants from CSL Behring, Takeda, and Pharming; educational events for Takeda, KalVista, Pharming, SOBI, and Novartis; trial steering committee for SOBI; and data monitoring committee for Octopharma.

Acknowledgements: Medical writing assistance provided by Caroline E. Cross, Reading, UK.

Disclaimer The opinions expressed in this article belong solely to the named speakers.

Keywords: Attack burden, hereditary angioedema (HAE), long-term prophylaxis (LTP), on-demand treatment, patient, quality of life (QoL).

Citation: EMJ Allergy Immunol. 2025;10[1]:38-45. https://doi.org/10.33590/emjallergyimmunol/MHTF7314

Meeting Summary

Hereditary angioedema (HAE) attacks are unpredictable and can be debilitating and potentially life-threatening. The burden of HAE disease and its treatment can negatively impact individuals’ quality of life (QoL). A group of internationally recognised HAE experts convened for a sponsored symposium, which took place on 14th June 2025 as part of the European Academy of Allergy & Clinical Immunology (EAACI) Congress held in Glasgow, UK, to discuss gaps in HAE management. They discussed how, despite evidence-based treatment guidelines that make recommendations for all HAE patients to carry on-demand treatment at all times, and that all attacks should be treated as early as possible, many patients do not carry medication or treat attacks early. The panel and audience heard HAE patient perspectives through video clips and survey responses and discussed how patient and physician perspectives differ in terms of disease control and management. The wide-ranging discussions between panel members highlighted some of the barriers that patients face when it comes to following treatment guidelines for on-demand treatment of HAE attacks and offered perspectives on what more needs to be done to overcome these hurdles to allow patients with HAE to be more in control of their disease.

Introduction

Hereditary angioedema (HAE) is a rare genetic condition characterised by unpredictable episodes of cutaneous or submucosal swelling in different parts of the body, which can be life-threatening when affecting the upper respiratory tract.1 The condition can have significant negative impacts on patient quality of life (QoL). Attacks are often debilitating and can result in work or school absences and may require hospital stays.1 In addition, the unpredictable nature of attacks means that patients may adapt their lifestyle to avoid triggers, even avoiding some ‘normal’ activities.2 The treatment burden of having to self-administer parenteral medication or attend hospital to receive treatment leads to delayed or missed treatment of HAE attacks and a prolonged attack duration, and can also negatively impact QoL.1

Despite published international guidelines3 that recommend all patients always carry enough on-demand medication to treat at least two HAE attacks, many patients fail to carry their medication and often delay treatment. This can lead to exacerbation of symptoms and have further negative impacts on QoL. Early treatment is associated with a shorter time to symptom resolution and shorter total attack duration,

regardless of attack severity.4 Indeed, treatment guidelines recommend that all HAE attacks are considered for on-demand treatment and that treatment starts as early as possible after the initiation of the attack.3

In this sponsored symposium, an HAE expert panel chaired by Doug Jones, Global Allergy Immune Network, USA; and including Stephen Betschel, Unity Heath, Toronto, Canada; Thomas Buttgereit, Institute of Allergology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Germany; and Sinisa Savic, University of Leeds, UK, discussed the gaps that exist in HAE management between patient and physician perspectives of disease control. They also identified some of the barriers that patients face when it comes to following treatment guidelines for on-demand treatment of HAE attacks, and asked what more needs to be done to overcome these hurdles to allow patients with HAE to be more in control of their disease.

Treatment Burden and HAE Control

Jones opened the symposium with a stark reminder that HAE attacks can cause significant anxiety, describing a case where

he was called by police to sign a death certificate for a patient with HAE who had potentially failed to access or take ondemand medication. Jones went on to ask the audience whether, in their experience, more than 50% of their patients are in control of their disease. Most participants voted no.

To provide direct insights from patients, the audience was shown video clips from three individuals with HAE who described the challenges they face day-today to stay in control of their HAE. Laura, one of the patients, who was diagnosed with HAE at age 15 years, said: “[It's] always on your mind because you know the potential for how bad it (HAE) can be and how dangerous it can be.” They went on to explain that having on-demand treatment means it is easy to treat an attack without needing to find a hospital. “You have the flexibility of essentially being able to live your life because you can treat wherever you are ” However, Laura continued by explaining that depending on where they are, they have a concern about whether they will be able to find a sterile environment to administer their intravenous medication. Chip, another patient with HAE, is 34 years old, and their partner is expecting a baby. Chip does not take LTP but does treat attacks with on-demand treatment. On a recent trip to the USA, Chip experienced an HAE attack and the only place available to inject the on-demand treatment was in a toilet. “It was not very hygienic,” Chip said, and went on to explain that if you administer medication in a public space, people can get concerned and think you are injecting recreational drugs.

Jones highlighted that there is a worldwide consensus on best practice for treatment with on-demand medication for HAE attacks. International guidelines3 state that all patients should carry sufficient on-demand medication to treat at least two attacks, that all attacks should be considered for treatment, and all attacks should be treated as early as possible.3

Jones emphasised that the consensus is that the goal should be for patients to experience no HAE attacks, but they asked: “How realistic is it for HAE patients

to achieve no angioedema attacks?”

Approximately 50% of people with HAE are not completely attack-free despite taking first-line LTPs.5 In addition, many people, including those who take LTP, face ongoing anxiety regarding the unpredictability of attacks and when anticipating taking current on-demand therapies.6,7 Jones added that on-demand therapy for HAE remains a critical need, even for patients receiving LTP.

Jones opened up the discussion to the panel by asking: “Are patients achieving control of their HAE attacks?” Betschel responded first, highlighting that the guidelines state that patients should be able to achieve total control and normalise their lives.3 This suggests that total control means a complete absence of attacks, Betschel said. However, they do not believe this to be the case, but rather an aspiration. “We know that many people don’t have that total control, and that is the gap we are trying to close.” Betschel added: “How do people who still have attacks maintain control of their disease?”

Savic expanded the discussion, saying: “With HAE, it is not just a physical condition. There is a psychological component to the disease.” The worry and anxiety of having an attack can be significant and varies between patients. “We haven’t explored these [psychological] aspects of the disease fully yet.” For Buttgereit, it is important to be able to distinguish between having control of the disease and having control of attacks. “Does total control mean that you do not have to go to the emergency room to get an injection or infusion, or you don’t need to stay overnight in hospital? Or does it mean doing the things you want to do, to participate in all aspects of life, work, school, without limitations?”

Jones then presented a slide with quotes from patients illustrating that individual patients define control differently and this differs from how physicians might define control. “It is important for us as clinicians and experts to communicate with our patients and understand their perspective, understand their challenges, and align them

with our treatment approach and with the guidelines,” Jones emphasised, inviting the panel to choose a patient comment that resonated with them.

Betschel picked out a patient comment that read, “I start to feel the attack resolving, at least somewhat, and I am able to resume normal activities.” Jones responded: “I like this one, ‘The pain goes away, and my anxiety slows down.’ This says to me that the patient knows things are going to get better.” Buttgereit’s chosen comment was: “I know I’m in control when I feel the swelling or pain start to subside.” “This is key to treating attacks,” Buttgereit explained. “Patients could be in a life-threatening situation. Even if you just have a headache, you want to know when you will get symptom relief. You know the treatment works; you are confident you did the right thing; you are looking for the first sign that the treatment is working.” Sivac selected a quote that read: “I am able to get my medication started before my attack is bad.” “This is important,” Sivac continued. “Being able to use the treatment when you need it, having access to on-demand treatment and treating early, are all key.”

Benefits of Treating Attacks Early and the Barriers Patients Face

Patients who treat early feel in control sooner (Figure 1).8 “This is an ongoing theme,” explained Jones who outlined the results of a survey of 107 patients with HAE that demonstrated the mean time to feel in control of attacks after on-demand treatment was twice as long for those who waited 1 hour or longer, compared to those who waited less than an hour. 9

“So why are people waiting before taking on-demand medication?” Jones asked. “What is creating so much anxiety?” They outlined data from patient surveys that show almost two-thirds of patients don’t always carry on-demand medication with them.10 Moreover, 57% of patients don’t treat all their attacks.6 Patients waited an average of 3.8 hours before initiating treatment after the first signs of an attack.11 Jones went on to explain that a significant number of patients (44%) avoid triggers to prevent attacks from happening, despite being on LTP and having on-demand treatment available,2 with 48.6% of patients experiencing moderate-to-severe anxiety when anticipating on-demand treatment.12 People are changing their lives, not just to

Figure 1: Patients who treat early feel in control sooner. Adapted

avoid attacks, but to avoid triggers,” Jones added. There is consensus that patients are delaying on-demand treatment across healthcare systems and across geographies.13,14

Jones went on to ask the audience whether they thought most of their patients with HAE feel like they live a normal life. The majority voted no. The audience then heard short clips from patients with HAE, Camilla, Laura, and Chip. “It’s difficult because you are trying to be a normal functioning member of society while controlling an unpredictable disease. That is quite isolating because people, quite literally, cannot understand what it is like,” Camilla explained. Laura said: “I don’t think my normal will ever be the same as other people’s normal… It was a weird concept to me that other people had never been to A&E (accident and emergency, also known as the ER, or emergency room) or been in a hospital.” As part of Chip’s contribution, they said: “I don’t have total control, because I don’t have control over when I have attacks, but I do have control of managing them with my medication. It is not ideal, as I need to be more prepared to be ready to inject if I need to.”

I start to feel the attack resolving at least somewhat and I am able to resume normal activities The swelling starts to subside, and I feel more relaxed

My breathing gets more even, I feel more relaxed

I start to feel stronger; the pain is lessened

Jones explained that people with HAE have a unique perception of how to normalise their lives and how to feel in control. Savic expanded on this, saying there are several very effective medications available that can, for some people, completely stop HAE attacks for long periods of time. “I spoke to one patient who said: ‘I feel really weird; you’ve taken my disease away completely.’” Savic explained that many people have grown up with HAE and the disease experience leaves a lasting imprint on their mind. “Treating attacks earlier and controlling the disease from an early age can reduce trauma and makes it easier for individuals to normalise their lives,” they reiterated. This was illustrated by one of the patient quotes presented to the audience: “Normalising my life is access to effective treatment, a good physician, and a good patient–physician relationship.” Savic challenged this perspective, saying, “There is too much ‘physician’ in there! They should not be relying on the relationship with the physician to have a normal life. That is the gap that we are trying to bridge.”

Jones summarised by saying that if you can make the disease course more predictable, then you feel more in control, and asked: “What can we do to help our patients to

If the swelling stops getting worse

Handle my mood better, more comfortable in my body

I feel more normal

The pain goes away and my anxiety slows down

I am able to treat quickly and prevent the attack from becoming worse

My anxiety levels decrease overall, and the pain begins to subside

I am more comfortable and able to do day to day things

I know I am in control when I feel the swelling or pain start to subside

When I start to feel better, and my mind is not focused on the pain

I am able to get my medication started before my attack is bad

Figure 2: How do patients know they are in control of their attack after on-demand treatment?

feel more in control?” Despite treatment guidelines that document the global consensus that patients should have access to effective medications and should treat attacks early with on-demand medication, globally, patients do not follow these guidelines. “Patients’ anxiety levels escalate until they decide to treat (Figure 2).15 This is the key gap that we have to close,” Jones said.

Evolving the Discussion with Patients

“Should we re-examine the current definition of control and normalising patients’ lives?” Jones asked the panel. “Everyone has a different definition of normal life,” Buttgereit said, explaining that clinicians and patients have different perceptions of what is considered normal. In addition, the perception of what defines ‘early treatment’ by patients and physicians differs, Savic believes, saying: “We need to do more to understand what ‘early treatment’ means in our [professional] language and what it means in patients’ language,” adding that, “Surprisingly, some patients think that treating within a few hours of the start of an attack is early treatment.” Other panel members agreed. “Definitions are important, and physicians need to get onto the same page as patients,” Jones confirmed.

Betschel agreed and argued that: “We spend a lot of time collating evidence and publishing guidelines that recommend early treatment, but we are not doing a good enough job at communicating treatment recommendations.” Knowledge translation is key. “We have all this knowledge. So, what are we doing to facilitate change in practice?” Betschel asked. In the clinic, Betschel asks patients whether they have their medication with them, and if not, where it is. “I am learning what the barriers are and what factors are important to patients, so we can start to overcome them and try to reduce attacks on an individual patient level.” Buttgereit added that HCPs must listen to patients about the burden of treatment that they face, the availability

of treatment, and whether they trust the treatment they take. Jones agreed, and expanded, saying that many patients have gone for up to 10 years without a diagnosis of HAE or have been misdiagnosed and treated with medications that have not worked. Therefore, physicians need to gain trust with these patients to individualise their treatment.

Referring to individualised treatment plans, Savic explained: “We need to accept that our definition of normalisation is not necessarily the same as the patients. Some people will tolerate a degree of attacks and discomfort. That is the landscape of their individual condition. But it is important to keep revisiting that question,” Savic added. “With trust in the treatment and trust in the relationship [with their physician], their goals may change.” It is also important, Buttgereit said, that on-demand treatment burden is considered as part of the normalisation of treating attacks. This burden is not normal for patients, nor for the community who may witness parenteral on-demand treatment administration. “The route of administration of ondemand medication plays a central role in the degree of normalisation.” Buttgereit reiterated. Betschel then asked, “What is getting in the way of trust and trusting the recommendations to treat early? What is getting in the way of using the treatment? Is it the drug itself, the cost, access? Are those barriers to trust? It is important to understand this.”

Summary

Jones summarised the session saying that patients are delaying treatment, but when they treat early, they feel more in control (Figure 3). Notably, perception of control is unique to individual patients. Anticipating on-demand treatment causes anxiety to patients, despite it helping them achieve a faster time to attack resolution, and this is an important factor for patients. The experts agree that more needs to be done to remove the barriers to treating HAE attacks early and reinforce that earlier treatment results in a faster time to feeling in control.

3: Summary.

Patients are delaying treatment but when treating early, can feel in control

• Patients delay an average of 3.8 hours to treat attacks

• Anticipating on-demand treatment causes anxiety for most patients

• Faster time to attack resolution and recovery is important to patients

• Patients report early treatment allows them to feel in control faster

Patients want to feel more in control

• Patients describe feeling in control in unique ways

• Early initiation of on-demand treatment is associated with faster time to feeling in control

“We have the data and the consensus guidelines, and we need to encourage more patients to adhere to them. We need to close gaps in trust, in access to treatment and reduce anxiety,” Jones concluded.

Q&A Session

The Q&A session began with one audience member reiterating that whilst trust is important, we need to speak to the patients for their perspective on why they do not treat early. This is key and needs to be explored in depth. Betschel agreed and said physicians need to advocate early treatment and that means treating within an hour of the first symptoms. Savic added that patients are often part of crossgenerational family groups who have different perceptions of control and health, and that should be optimised.

Another audience member then asked whether the panel members believe that prodromes should be treated. Betschel responded, saying that if patients have access to treatment, they should treat, although acknowledging there are varying

degrees of access. “We have data that shows patients can predict attacks from prodromes, and that needs to be acknowledged and discussed.” Buttgereit added, “We need to recognise what the first symptoms of an attack are. They are not always clear. We need more information from patients about those first symptoms to give patients confidence in treating attacks early.” Betschel continued that, in paediatrics, there is a spectrum of symptoms. Nevertheless, if the symptoms of a prodrome are similar to those of an early-stage attack, then it should be treated. “I favour early treatment, especially if swelling is involved. If a patient understands what their symptoms are, then they should treat.”

Drawing the meeting to a close, Jones posed a final question: “What strategies can we use to help patients feel more in control?” Betschel responded: “Individualised care is great if you have [different treatment] options available,” and added that nurse-led clinics are especially important because there is more time for patients to ask questions in that setting. “The nurses can develop a much deeper relationship with the patient than I can. We

Figure

also need to encourage patients to engage with patient organisations because they can connect patients.” Betschel added.

Jones concluded, saying: “It does take a village, physicians, nursing staff, patient advocacy groups, patients. We need to ask

References

1. Chong-Neto HJ. A narrative review of recent literature of the quality of life in hereditary angioedema patients. World Allergy Organ J. 2023;16(3):100758.

2. Mind the Attack. Attack preparation. Available at: https://www. mindthehaeattack.com/h. Last accessed: 19 June 2025.

3. Maurer M et al. The international WAO/ EAACI guideline for the management of hereditary angioedema. The 2021 revision and update. Allergy. 2022;77(7):1961-90.

4. Maurer M et al. Hereditary angioedema attacks resolve faster and are shorter after early icatibant treatment. PLoS One. 2013;8(2):e53773.

5. Longhurst HJ et al. Hereditary angioedema attacks in patients receiving long-term prophylaxis: a systematic review. Clin Rev Allergy Immunol. 2024:67(1-3):83-95.

6. Burnette A et al. Anxiety associated with parenteral on-demand treatment for Hereditary Angioedema (HAE).

patients, and they need to be heard and validated. We need to gain trust, and then we can really start to communicate. The nursing staff has that ability to develop multiple touch points and help to build that trust.”

Poster 433. AAAAI Annual Meeting, 24-27 February, 2023.

7. Busse P et al. The impact of ondemand treatment on quality of life of people with HAE. Poster 265. AAAAI Annual Meeting, 23-26 February, 2024.

8. Cohn D et al. Evaluation of patientreported outcome measures for on-demand treatment of hereditary angioedema attacks and design of KONFIDENT, a phase 3 trial of sebetralstat. Clin Transl Allergy. 2023;13(9):e12288.

9. Longhurst HJ et al. Patient reported benefits of early on-demand treatment of HAE attacks. Poster D3 236. EAACI Annual Meeting, 31 May-3 June, 2024.

10. Betschel SD et al. The complexities of decision making associated with on-demand treatment of HAE attacks. Allergy Asthma Clin Immunol. 2024;20(1):43.

11. Christiansen S et al. Delayed ondemand treatment of hereditary angioedema attacks: patient

perceptions and associated barriers. Poster 270. AAAAI Annual Meeting, 23-26 February, 2024.

12. Radojicic C et al. Patient reported anxiety impacts utilization of injectable on-demand treatment of hereditary angioedema attacks. Annals of Allergy, Asthma, and Immunology. 2024;133(6):s29.

13. Yong P et al. Delays in the on-demand treatment of hereditary angioedema attacks and associated barriers reported in different healthcare systems. Presented at the AAAAI Annual Meeting, 28 February-3 March, 2025.

14. Zanichelli A et al. Barriers to timely on-demand treatment for hereditary angioedema attacks in Italian patients. Poster AB58. ITACA National Congress, 27-29 March, 2025.

15. Jones D. In their own words, patient perspectives on time to feeling in control of an HAE attack. Poster 18, 14th C1-inhibitor Deficiency and Angioedema Workshop, 29 May-1 June, 2025.

Normalisation of Life in Hereditary Angioedema: Optimising Outcomes and Individualised Management

Support: This article was sponsored by BioCryst Pharmaceuticals, who provided funding for the content and were involved in its conception, content, and review. This educational article was based on a symposium that was organised and funded by BioCryst Pharmaceuticals. This article is intended for healthcare professionals only.

Chairperson: Henriette Farkas1

Speakers: Marc Riedl,2 Andrea Zanichelli,3 Tamar Kinaciyan4

1. Hungarian Angioedema Reference Center, Department of Internal Medicine, Semmelweis University, Budapest, Hungary

2. Division of Allergy and Immunology, University of California, San Diego, USA

3. Angioedema Centre, IRCCS Policlinico San Donato, Milan, Italy

4. Allergy and Paediatric Dermatology Clinics, Department of Dermatology, Medical University of Vienna, Austria

Disclosure: Farkas has received research grants from Phavaris; travel grants from Astria, BioCryst, CSL Behring, KalVista, Intellia, Ionis, Pharming, Pharvaris, and Shire/Takeda; speaker fees from CSL Behring, and Shire/Takeda; and has been an advisor/consultant for Astria, BioCryst, CSL Behring, KalVista, Intellia, Ionis, Ono Pharmaceutical, Pharming, Pharvaris, and Shire/Takeda. Riedl has received research support from Astria, BioCryst, Biomarin, CSL Behring, Ionis, KalVista, Pharvaris, and Takeda; has been a consultant for Astria, BioCryst, Biomarin, Celldex, CSL Behring, Cycle Pharma, Grifols, Intellia, Ionis, Kalvista, Novartis, Pharming, Pharvaris, Sanofi-Regeneron, and Takeda; and has received speaker fees from BioCryst, CSL Behring, Grifols, Pharming, and Takeda. Zanichelli has received speaker/consultancy fees from Astria, BioCryst, CSL Behring, KalVista, Pharming, Pharvaris, Otsuka, and Takeda. Kinaciyan has been a speaker/advisor or study physician from BioCryst, CSL Behring, KalVista, Kiniksa Pharmaceuticals, Otsuka Pharmaceutical, Pharvaris, Sanofi-Aventis, and Takeda; and received funding/grants/honoraria from BioCryst, CSL Behring, KalVista, Pharvaris, Sanofi, and Takeda.

Acknowledgements: This symposium review article was written by Jessica Jinks, EMJ, London, UK.

Disclaimer The opinions expressed in this article belong solely to the named speakers and do not necessarily reflect those of BioCryst Pharmaceuticals. BioCryst Pharmaceuticals and the speakers were given the opportunity to review the article ahead of publication.

Keywords: Adolescents, androgen, hereditary angioedema (HAE), long-term prophylaxis (LTP), optimising care, switching, total burden, treatment.

Citation: EMJ Allergy Immunol. 2025;10[1]:46-55. https://doi.org/10.33590/emjallergyimmunol/PRFG1459

Meeting Summary

Hereditary angioedema (HAE) is a rare genetic condition that causes unpredictable, recurrent episodes of swelling, particularly affecting the limbs, face, gastrointestinal tract, and airways. Episodes can be debilitating or even lifethreatening if not managed properly. Beyond the physical burden, HAE profoundly impacts quality of life, leading to pain, anxiety, and significant social and occupational limitations. Many patients face constant fear of the next attack and feelings of isolation. Treatment guidelines focus on normalising patients’ lives by controlling symptoms and reducing attack frequency and severity, aiming to help patients fully participate in daily activities without fear. A BioCryst-sponsored symposium took place at the 14ᵗʰ C1-inhibitor Deficiency and Angioedema Workshop in Budapest, Hungary. The symposium was chaired by Henriette Farkas, Professor of Internal Medicine and Director of the Hungarian Angioedema Reference Center, Department of Internal Medicine, Semmelweis University, Budapest, Hungary. The panellists discussed what the goal of normalisation of patients’ lives means in real-world practice. Marc Riedl, Professor of Medicine, Division of Allergy and Immunology, University of California, San Diego, USA, spoke on the burden of illness of HAE, exploring unmet needs and the importance of a comprehensive assessment to enhance care for adults with HAE. Andrea Zanichelli, Head of Angioedema Centre, IRCCS Policlinico San Donato, Milan, Italy, explored key considerations for switching HAE treatments in adults to optimise outcomes. Tamar Kinaciyan, Head of Allergy and Paediatric Dermatology Clinics, Department of Dermatology, Medical University of Vienna, Austria, discussed practical considerations for individualised HAE management approaches in adolescents to support life normalisation.

Introduction

The symposium opened with a powerful reminder of why patient-centred care must remain at the heart of HAE management. Farkas shared a patient perspective, exploring the emotional and physical toll of living with HAE, ranging from disfiguration and pain to feelings of isolation, fear, and sadness. Through patient-created artwork, the audience was given a unique insight into the lived experience of HAE, emphasising the profound impact beyond clinical symptoms. Farkas noted that “these patients inspire us to help”, setting the tone for a session focused on recognising the burden of illness, addressing unmet needs, and advancing individualised treatment strategies, including in adolescence, to help patients reclaim a sense of normality.

Introduction to Hereditary Angioedema

HAE is a rare genetic disorder characterised by unpredictable, recurrent episodes of angioedema affecting subcutaneous or mucosal tissues.1 HAE attacks typically

involve the skin, gastrointestinal tract, and upper respiratory tract.1 Attacks affecting the upper airways are particularly dangerous due to the risk of sudden airway obstruction and asphyxiation.1 Without treatment, these attacks can gradually intensify over a period of 12–36 hours before resolving spontaneously within 2–5 days.2 On average, untreated patients experience an attack every 2 weeks, with frequencies ranging from very rare to every 3 days.1,2 The two primary types of HAE result from mutations in the SERPING1 gene, leading to either a quantitative deficiency (Type 1) or a functional impairment (Type 2) of the C1-esterase inhibitor (C1-INH).1 C1INH acts on multiple pathways, including the fibrinolysis and coagulation, kallikrein-kinin, and complement systems.3 Dysregulation of these pathways, particularly the kallikreinkinin system, leads to excessive bradykinin production, which is the primary mediator of the vascular permeability and oedema seen in HAE attacks.4 A third, less common form of HAE exhibits a comparable clinical phenotype, but with normal levels and function of the C1-esterase inhibitor protein

(HAE with normal C1INH [HAE-nC1INH])3

Patients still experience similar recurrent angioedema attacks, suggesting the involvement of other genetic factors, such as mutations in the F12 gene (encoding factor XII), plasminogen, or angiopoietin-1.3

Hereditary Angioedema Treatment

At the 14th C1-inhibitor Deficiency and Angioedema Workshop in Budapest, Hungary, both Riedl and Zanichelli discussed the current treatment guidelines for HAE, the goal of which is to normalise patients’ lives by achieving full symptom control and reducing the frequency and severity of attacks, ultimately enabling individuals to participate in daily activities without fear.5 There is a vital role for ondemand treatment in HAE. The WAO/EAACI 2021 guidelines for managing Type 1 and 2 HAE recommend that all patients have immediate access to acute, on-demand medication, and that on-demand treatment is used to treat all attacks as early as possible.5 Zanichelli explained that, in addition to on-demand treatment, long-term prophylactic treatment (LTP) is needed to achieve the goals of total disease control and life normalisation.5 He stressed that the need for LTP should be reassessed at every patient visit, considering disease activity, disease burden, level of control, and patient preferences. He added that “an action plan should be updated at every visit”, in line with guideline recommendations that patients receiving LTP should be routinely monitored to evaluate disease activity and treatment effectiveness, ensuring ongoing optimisation of therapy and outcomes.⁵

LTPs are treatments designed to prevent attacks in patients with HAE. These therapies work by targeting different steps in the disease’s underlying mechanisms. Prophylactic therapies currently recommended by WAO/EAACI include intravenous plasma-derived C1-INH, subcutaneous anti-kallikrein monoclonal antibodies, and kallikrein inhibitors.5 By intervening in these pathways, LTPs help reduce the frequency and severity of HAE attacks, offering patients greater control over their symptoms and improved quality of life (QoL). Attenuated androgens,

such as danazol, were historically used for LTP of HAE.5,6 However, due to their unfavourable side effect profile, current clinical guidelines recommend their use only as a second-line option.5

The Burden of Hereditary Angioedema Beyond Attacks

Riedl described the timeline for a patient with HAE as one marked by intermittent, unpredictable attacks, followed by persistent QoL disruptions in the periods between these attacks,2 illustrated in Figure 1. The direct burden of each attack is determined by the location of the swelling, the severity and duration of symptoms, the need for hospitalisation, and the disruption of daily life caused by the attack itself.2

However, Riedl also noted that “HAE is much more complicated than just the swelling episodes that we see in our clinic,” highlighting the broader impact of the disease on patients’ lives.

The overall disease burden extends beyond the severity of individual attacks, encompassing the psychological and social challenges of living with an unpredictable, potentially life-threatening condition.2 Riedl commented that even during asymptomatic periods, patients often report a constant fear of the next attack, which leads to heightened anxiety, depression, and a sense of uncertainty.2 This anticipatory anxiety can interfere with education, career development, and social interactions, which worsens with increasing frequency of attacks.7 In an effort to prevent attacks, patients frequently modify their lifestyle to avoid known triggers, which can lead to feelings of isolation and a loss of normalcy,2 with Riedl commenting that patients with HAE often experience depression and anxiety.7

Riedl described a non-interventional survey of 445 patients with HAE in the USA, which explored patients’ perspectives on the burden of HAE.7 Health-related QoL worsened with increasing frequency of HAE attacks. However, scores for the “concern about offspring” dimension remained

Total disease burden

Attack Attack Attack QoL disruption QoL disruption

Burden of attacks:

• Location of attacks

• Symptom severity

• Symptom duration

• Hospitalisation

• Disruption of life caused by attack

Burden between attacks:

• Fear of next attack

• Anxiety and depression

• Interference in educational/ career advancement

• Lifestyle modifications to avoid triggers

Burden of treatment AND access to treatment

consistent across all attack frequency categories, indicating that this worry is independent of how often attacks occur. Further to this, Riedl highlighted that even a low frequency of attacks was enough to erode the ability to work and participate in regular activities.

Further supporting these findings, a crosssectional survey of 242 patients with HAE Type 1 or 2 in Australia, Austria, Canada, France, Germany, Spain, Switzerland, and the UK8 revealed that QoL scores worsened with a higher number of attacks. Moderate-to-severe anxiety was reported by 38% of patients, and depression by 17%.

The severity of anxiety and depression was closely associated with poorer QoL and reduced productivity. Of note, attack frequency did not appear to influence the severity of anxiety or depression, nor did it affect scores in the ‘fear and shame’ domain. Riedl commented that how patients feel about living with HAE does not necessarily reflect how frequently they

experience attacks and that, for many people, “the fear and unpredictability is always there”.

Treatment-Related Burdens in Hereditary Angioedema

Riedl explained that patients also suffer treatment-related burdens, such as anxiety around needing to take their medication. He cited a survey that revealed significant emotional burden, with patients feeling nervous (47%), overwhelmed (33%), stressed (31%), and intimidated (26%) when starting a new prophylactic medication.9 Riedl explained: “People do adapt after being on a treatment for a while, but the burden doesn’t go away.” In the study, anxiety was found to be reduced, but not eliminated in patients who started prophylaxis ≥7 months ago (42%) compared to patients who had started prophylaxis in the previous 6 months (71%).9 Riedl noted that these persistent psychological burdens are a key driver for ongoing innovation in

Figure 1: The total disease burden of hereditary angioedema.

Figure adapted from Bork et al.2 QoL: quality of life.

HAE treatments, underscoring the need to develop less burdensome ways to control the condition.

A Comprehensive Approach to Care

Patients and physicians are generally aligned in their selection of prophylactic therapy, as demonstrated by a survey of 109 HAE physicians and 75 patients with HAE-C1INH Type 1 or 2, which explored prescribing trends and the impact of treatment on patients.10 Illustrated in Figure 2, patients placed slightly more importance than physicians on self-administration (77% versus [vs] 65%), while physicians were more concerned with effectiveness (85% vs 81%), side effects (72% vs 57%), and injection site discomfort (60% vs 46%).10 Riedl highlighted that, although patients and practitioners are relatively well aligned, there is a need to understand each patient’s needs and goals on a personal level. He commented: “There is a lot of science to what we do, but also this art of talking to our patients, learning what’s important to them, and helping them make management decisions.”

To explore and understand patient goals, Riedl introduced the 3D Model of Shared Decision-Making in HAE, originally proposed by Banerji et al.11 This cyclical process comprises three stages: DISCOVER, where clinicians and patients explore patient needs, establish goals, and acknowledge the availability of treatment options; DISCUSS, which involves reviewing alternative treatments, ensuring alignment with patient goals, and developing informed preferences; and DECIDE, where shared decisions are made based on accurate information, guided by validated patientreported outcome measures. Riedl emphasised that it is the clinician’s role to offer expert insight into what different treatments involve, enabling patients to make informed choices. He also highlighted that treatment decisions are not a onetime event, but part of an ongoing process in which the care plan is revisited and adjusted as needed.

Many patients with HAE don’t feel in control of their condition, leading them to avoid

certain activities, with a knock-on impact on their QoL.4 Riedl commented: “I am always surprised at what my patients are telling me. They may not be travelling, they may be skipping family activities, not exercising.” This highlights the need to rethink how clinicians approach conversations about HAE management. Rather than starting with broad, open-ended questions like “How are you doing?” or “Tell me about your symptoms,” Riedl advocated for more specific, targeted inquiries that directly address the patient’s experience of living with HAE (Figure 3).

Refocusing the conversation in this way helps uncover unmet needs and guides meaningful, patient-centred care.

Optimising Outcomes: Switching Treatments in Hereditary Angioedema

LTP has been shown to significantly reduce the burden of HAE compared to on-demand therapy, enabling better disease control and improved QoL. Presenting results from Zarnowski et al.12 investigating outcomes in 37 HAE patients in Germany, Zanichelli explained that LTP in HAE was associated with reduced anxiety and depression. In the same study, anxiety was significantly associated with low disease control measured by the Angioedema Control Test (AECT),11 further demonstrating the need for control of HAE attacks as a means of achieving life normalisation and reducing burden of disease.

Current recommended first-line LTP options that target C1-INH or kallikrein, have shown benefits but many patients continue to rely on second-line LTP therapy with androgens such as danazol.5 Zanichelli explained that use of androgens is associated with a broad range of adverse effects. These include mood disturbances, such as depression and anxiety, headaches, acne, voice changes, hypertension, liver function abnormalities, lipid profile changes, polycythaemia, changes in libido, weight gain, and muscle pain or cramps.5,10,13,14 In female patients, additional risks include virilisation effects such as hirsutism, deepening of the

Figure 2: Level of impact on willingness to switch hereditary angioedema prophylaxis medication.

Dosing schedule

Injection-site reactions/discomfort

Time to administer

Preparation/storage

Route of administration

Administration location

Self-administration

Side effects

Patient and physician views: Important factors in selecting HAE prophylactic therapy 0

HAE: hereditary angioedema.

Figure 3: Hereditary angioedema quick guide.

HAE: hereditary angioedema.

voice, reduced breast size, and menstrual irregularities, as well as potential risks to foetal development.5,10,12,13 In adolescents, there are concerns about the impact of androgens on bone development and the potential for premature puberty.13

Androgen use has also been linked to increased rates of comorbidities in adults with HAE.15 Zanichelli presented data from a retrospective cohort study involving 446 adults with Type 1 or 2 HAE who were referred to Milan and Padua angioedema centres between 1979 and 2021.15 The study found that patients on androgenbased LTP (n=175) had a significantly higher incidence of comorbidities, including hypertension, hypercholesterolaemia, diabetes, hepatic angioma, and focal nodular hyperplasia compared to those not receiving androgens.15

Guidelines recommend prescribing androgens only as second-line LTP at the minimum effective dosage, up to 200 mg/day, to limit adverse outcomes;5 however, efficacy has been shown to decline substantially at lower dosages. Zanichelli presented data from a retrospective case series that examined danazol use as LTP in 74 patients with Type I or II HAE.16 Danazol was initiated at 600 mg/day, with the dose tapered in patients who achieved complete control. While 96% of patients (n=71/74) achieved complete control at 600 mg/day, this rate fell to 80% at 400 mg/day (n=57/71), and 28% (n=16/57) at 200 mg/day. These findings underscore the clinical dilemma explored by Zanichelli: while dose reduction is necessary to minimise harm, doing so may significantly compromise disease control. This reinforces the need for patients to utilise alternative therapies that offer both efficacy and improved safety.

Androgen Discontinuation and Switch Management

Discontinuing androgens in patients with HAE requires careful consideration, as abrupt cessation is not recommended and should be avoided where possible.5,13,17 Discontinuation due to adverse events is relatively common and has been associated

with withdrawal symptoms, including mood disturbances such as anxiety, depression, and irritability, fatigue, and elevations in liver transaminases.13,17 Additionally, stopping androgen therapy may result in an increased frequency and severity of HAE attacks.13 Despite these risks, there is currently no consensus on optimal switching strategies to alternative LTP therapies and guidelines highlight the need for further studies to inform best practices for discontinuation and transition to newer agents.5 Zanichelli outlined possible approaches (illustrated in Figure 4), including tapering androgens with or without a washout period. He highlighted that, ideally, tapering should begin only after the initiation of an alternative LTP agent, particularly when the new therapy requires time to reach steady-state concentrations or its minimum effective dose.17 This strategy reduces the risk of breakthrough attacks during the transition, although patients should be prepared for attacks, with on-demand therapy that they feel confident in administering.13 Zanichelli advocated for switching protocols to be individualised based on the patient’s current androgen dose, clinical status, and risk profile,13 and emphasised the importance of regular monitoring post-switch to assess both efficacy and safety, and support with adherence during the transition period.

Optimising Outcomes in Adolescent Hereditary Angioedema

In the final presentation in the symposium, Kinaciyan explored the impacts of HAE on adolescents, including practical considerations for optimising their care.

HAE can have a particularly profound impact on adolescents, who find themselves in a unique and challenging stage of life.18 Kinaciyan discussed that they are no longer children, yet not quite adults, striving for independence while still relying on adult guidance, with limitations that are made even more pronounced by their illness. Kinaciyan commented that many adolescents with HAE feel embarrassed or ashamed about their condition, struggle to keep up with friends, and may be reluctant

Immediate withdrawal

Abrupt discontinuation of AA is not recommended and should be avoided where possible.

There is currently no clear consensus within WHO/EACCI guidelines for discontinuation strategy; however, immediate withdrawal should be avoided.5,13,17 Options for discontinuation include tapering with or without a washout period.13,17 Zanichelli commented that tapering without a washout period, providing a direct overlap, may be important if alternative therapy takes time to reach steady state or minimum effective concentration.

AA: attenuated androgens; LTP: long-term prophylaxis.

to carry or use their acute treatments, often delaying them until absolutely necessary. Further, she discussed how adolescents typically prioritise spending time with friends and mimicking their behaviour, including smoking, drinking, and late-night activities like dancing, all of which can trigger attacks, leading to more frequent or severe episodes. Adolescents may also experience more fatigue than younger children and react more strongly to stress, sometimes becoming aggressive, withdrawn, or depressed.18 Kinaciyan explained: “If the (adolescent) patient is suffering from HAE, you can imagine it is more difficult, and they are limited by their illness.” For these reasons, it is crucial to support adolescents with HAE in living as close to an attack-free, normal life as possible.

Beyond Symptoms: Comprehensive Care for Adolescents with Hereditary Angioedema

Kinaciyan explained that HAE treatment plans for adolescents may differ from those for adults due to the unique life decisions they face, such as choices around education, career aspirations, and family planning. She emphasised that “Understanding individual treatment preferences and goals through shared decision-making is very important.” To support this, a detailed and collaborative discussion should be held when developing an individualised treatment plan.5

Throughout this process, the evolving role of parents as adolescents mature should also be carefully considered. Based on her own experience, Kinaciyan suggested that for patients aged 12–14 years, parents should be involved in discussions to

Figure 4: Potential strategies for androgen discontinuation in hereditary angioedema.

Overlap

facilitate informed decision making, but for those aged 15–18 years, adolescents should have independent discussions with healthcare providers, explaining that “They can say their real needs more openly if the parents are not by their side”. She commented that these conversations should explore the adolescent’s interests, talents, and aspirations, as well as their treatment preferences and goals. Kinaciyan also noted that it is also important to explain the distinction between on-demand treatment and LTP. Key treatment goals for adolescents include the treatment having few side effects, being highly effective, and allowing patients to be able to participate in all activities.18 Kinaciyan explained that LTP is often the most suitable treatment approach to achieve this. However, she commented that an oral route would allow for easier administration, offering a less cumbersome treatment option without the need for injections.

Practical Considerations of Hereditary Angioedema in Adolescents

LTP recommendations for adolescents largely mirror those for adults; however, the dosing interval and dose is often adjusted considering individual response and body weight.5 Wherever possible, androgens should be avoided due to their potential interference with growth and maturation

References

1. Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008;359(10):1027-36.

2. Bork K et al. Assessment and management of disease burden and quality of life in patients with hereditary angioedema: a consensus report. Allergy Asthma Clin Immunol. 2021;17(1):40.

3. Sinnathamby ES et al. Hereditary angioedema: diagnosis, clinical implications, and pathophysiology. Adv Ther. 2023;40(3):814-27.

4. Nussberger J et al. Plasma bradykinin in angio-oedema. Lancet. 1998;351(9117):1693-7.

5. Maurer M et al. The international WAO/ EAACI guideline for the management of hereditary angioedema-the 2021 revision and update. Allergy. 2022;77(7):1961-90.

processes.5 As with adults, individualising treatment in adolescents requires consideration of several factors: clinical aspects of the disease including disease burden, frequency and severity of attacks, comorbidities; the impact on quality of life including missed school, interference with family life, daily functioning, and anxiety about future attacks; and broader practical concerns.2,19 Kinaciyan highlighted, “The most complicated thing is the other factors,” such as variable drug availability across regions.

Key Takeaways

The burden of HAE is substantial and extends beyond the frequency of attacks, significantly affecting QoL and treatment experiences. Personalised management through comprehensive consultations and shared decision-making is crucial to align care with individual patient goals. Regular review and, when appropriate, switching of LTP treatments can help optimise outcomes, especially for those who remain symptomatic or burdened by their current therapy. Additionally, recognising and addressing the unique needs and preferences of adolescents is vital to support their long-term wellbeing and enable a future free from the limitations of HAE.

6. Agostoni A et al. Danazol and stanozolol in long-term prophylactic treatment of hereditary angioedema. J Allergy Clin Immunol. 1980;65(1):75-9.

7. Banerji A et al. Patient-reported burden of hereditary angioedema: findings from a patient survey in the United States. Ann Allergy Asthma Immunol. 2020;124(6):600-7.

8. Mendivil J et al. Clinical characteristics and burden of illness in patients with hereditary angioedema: findings from a multinational patient survey. Orphanet J Rare Dis. 2021;16(1):94.

9. Radojicic C et al. Patient perspectives on the treatment burden of injectable medication for hereditary angioedema. Allergy Asthma Proc. 2021;42(3):S4-10.

10. Riedl MA et al. Physician and patient perspectives on the management of hereditary angioedema: a survey on treatment burden and needs. Allergy Asthma Proc. 2021;42(3):S17-25.

11. Banerji A et al. Optimal management of hereditary angioedema: shared decision-making. J Asthma Allergy. 2021;14:119-25.

12. Zarnowski J et al. Prophylactic treatment in hereditary angioedema is associated with reduced anxiety in patients in Leipzig, Germany. Int Arch Allergy Immunol. 2021;182(9):819-26.

13. Maurer M et al. Attenuated androgen discontinuation in patients with hereditary angioedema: a commented case series. Allergy Asthma Clin Immunol. 2022;13;18(1):4.

14. Bork K et al. Benefits and risks of danazol in hereditary angioedema: a long-term survey of 118 patients. Ann Allergy Asthma Immunol. 2008;100(2):153-61.

15. Zanichelli A et al. Comorbidities in angioedema due to C1-Inhibitor deficiency: an Italian survey. J Allergy Clin Immunol Pract. 2024;12(4):1029-36.

16. Xu Y, Zhi Y. Long-term prophylaxis of hereditary angioedema with danazol. Chin Med J (Engl). 2022;135(21):2642-3.

17. Peter JG et al. Assessment of HAE prophylaxis transition from androgen therapy to berotralstat: a subset

analysis of the APeX-S trial. World Allergy Organ J. 2023;16(11):100841.

18. Broderick L et al. The adolescent experience of hereditary angioedema: a qualitative study of disease burden and treatment experience. Orphanet J Rare Dis. 2025:20(1):16.

19. Anderson J, Maina N. Reviewing clinical considerations and guideline recommendations of C1 inhibitor prophylaxis for hereditary angioedema. Clin Transl Allergy. 2022;12(1):e12092.

Support:

Did I Hear You Right? How to Ensure Bi-Directional HCP–Patient Communication

This symposium took place during the European Academy of Allergy and Clinical Immunology (EAACI) Congress held in Glasgow, UK, 13th–16th June 2025. This was a nonpromotional symposium initiated and funded by Otsuka Pharmaceutical Europe Ltd. This content is intended for healthcare professionals only.

The publication of this article was initiated and funded by Otsuka Pharmaceutical Europe Ltd., who were the organisers of a symposium at the EAACI Congress 2025, 13th–16th June 2025 in Glasgow, UK, upon which the material is based. This content is intended for healthcare professionals only.

Chairperson: Sorena Kiani-Alikhan1

Speakers: Mari Campbell,1 Danny M. Cohn,2 Angela Metcalfe3

1. Royal Free London NHS Foundation Trust, UK

2. Amsterdam University Medical Centre, the Netherlands

3. HAE UK, Bridgwater, UK

Disclosure:

Campbell has received grants from the NHS, PiA, PID UK, and Royal Free Charity; and financial support and honoraria from Biotest, BPL, CSL Behring, Grifols, Otsuka, Shire, and Takeda. Cohn has received consultancy and/or speaker fees from Astria, BioCryst, CSL Behring, Intellia, Ionis Pharmaceuticals Inc, KalVista, Otsuka, Pharming, Pharvaris, and Takeda. Kiani-Alikhan has been the chief and/or principal investigator for studies and in receipt of honoraria for consulting work and advisory boards for Astria therapeutics, BioCryst, Biotest, CSL Behring, Ionis Pharmaceuticals, KalVista, Pharvaris, Shire, Takeda, and X4 Pharmaceuticals. Metcalfe has received speaker fees from Otsuka Pharmaceutical Europe Ltd.

Acknowledgements: Writing assistance was provided by Nicola Humphry, Nottingham, UK.

Disclaimer The opinions expressed in this article belong solely to the speakers at the symposium.

Keywords: Chronic illness, communication, hereditary angioedema (HAE), mental health.

Citation: EMJ Allergy Immunol. 2025;10[1]:56-63. https://doi.org/10.33590/emjallergyimmunol/QGWR3530 PHARMA

Meeting Summary

This symposium, which took place during the 2025 European Academy of Allergy and Clinical Immunology (EAACI) Congress, aimed to explore the underlying psychology of patient and healthcare professional (HCP) expectations of medical consultations, which can undermine bi-directional communication. Practical guidance was presented regarding how to act on these expectations to improve HCP–patient

communication, and objective, real-world evidence of the therapeutic benefits of improved HCP–patient communication were discussed.

Hereditary angioedema (HAE), a rare, genetic condition characterised by acute attacks of swelling, was used throughout the symposium as an example of a chronic condition whereby expectations exist for HCPs and patients regarding medical consultations, and how bi-directional communication can be optimised.

Introduction

The relationship between HCPs and their patients is dynamic, and many studies have focused on understanding what impacts HCP–patient communication and how best to optimise it.1 Effective communication improves patient satisfaction, quality of care, and health outcomes.1

A positive HCP–patient relationship is particularly important for patients with a long-term physical illness that can have a significant impact on wellbeing and quality of life (QoL).1,2 For example, patients with HAE, a long-term condition marked by potentially serious swelling attacks in the extremities, face, trunk, airways, or abdominal area,3,4 have a poorer QoL and higher rates of anxiety/depression than the general population.5-7

This article explores the factors that affect the HCP–patient relationship and how to help ensure quality bi-directional communication, using HAE as an example of long-term physical illness.

Room for Improvement in HCP–Patient Communication

Sorena Kiani-Alikhan, a Consultant Immunologist at the Royal Free London NHS Foundation Trust, UK, presented data from a survey conducted between 2023–2024 showing that there remains room for improvement in HCP–patient communication.8

The real-world survey included 52 physicians and 199 patients with HAE from across France, Germany, Italy, and Spain.8 Physicians completed an online patient record form for

each of their patients with HAE, and patients filled in a self-assessment form.8

While physicians and patients were generally in agreement regarding HAE attack locations, with ‘moderate’ to ‘substantial’ agreement for the majority of locations, there was only ‘fair’ agreement regarding disease burden (κ=0.3422) and attack severity (κ=0.4030).8 In terms of overall disease burden, 11.3% of physicians perceived HAE to be less severe than their patients perceived it to be, and 19.0% of physicians perceived HAE to be more severe than their patients perceived it to be.8 In terms of most recent HAE attack severity, 12.5% of physicians perceived the attack as less severe than their patients did, and 26.7% of physicians perceived the attack as more severe than their patients did.8

Kiani-Alikhan concluded that, although disease burden and attack severity are subjective measures, improved communication between HCPs and patients has the potential to enhance management and overall health outcomes in people with HAE.

Why Good HCP–Patient Communication Matters

Mari Campbell, a Consultant Clinical Psychologist at the Royal Free London NHS Foundation Trust, UK, explained that good HCP–patient communication can improve health outcomes,1,9 patient engagement, and eventually trust,1,10 patient satisfaction,1 adherence to treatment,11 perception of treatment,9 and quality of life1 (Figure 1).

QoL: quality of life.

The Social Graces framework, originally developed by Burnham12 and Roper-Hall,13 is often used to highlight issues of social difference, including power and identity, and may help to make HCPs more aware of biases that may impact therapy.14 The current framework includes 15 areas of social difference: gender, geography, race, religion, age, ability, appearance, class, culture, ethnicity, education, employment, sexuality, sexual orientation, and spirituality.14 Campbell emphasised that HCPs and patients can have different expectations of medical consultations, which can be affected by social differences, and that understanding the value systems and culture of an individual patient supports relationship building.

A Patient’s Expectations of

HCP–Patient Communication

HAE UK is a patient organisation that represents 700 patients with HAE in the UK. Angela Metcalfe, CEO of HAE UK, explained

that, in her experience, patients can feel intimidated by HCPs, which may prevent them from asking questions about their care. They may also be unsure of some of the medical terminology that HCPs use, and although they may have heard about new treatments for HAE, they may not feel they know enough to ask questions about them. Sometimes patients may feel more comfortable speaking with a nurse than a consultant, and in major clinics where a nurse may see the patient before/after their consultation, strong relationships can be built.

Metcalfe stressed that patients often feel that nobody really understands the psychological burden of living with a rare disease like HAE, and the impact that the disease has on their life. Many patients prefer not to discuss their condition with friends or work colleagues due to embarrassment and fear. Patients may feel that the only people who understand are those who have the same disease, and Metcalfe emphasised the importance of directing patients to patient organisations

Figure 1: Why communication matters.1,9-11

like HAE UK, so that patients can support each other.

For bi-directional communication to occur in a consultation, Metcalfe explained that it is critical for the HCP to allow the patient to speak, and actively listen to what they have to say, to reinforce a collaborative HCP–patient relationship. It is equally important that the HCP feels comfortable asking their patients general and personal questions about their lives and their experiences of HAE, to build trust and empathy. These types of questions can help the HCP to understand the patient’s background, relationships, support network, dependencies, and personal beliefs.

Metcalfe also pointed out that providing clear, concise, navigable information supported by evidence-based recommendations and choices can ease the burden of disease for patients. While HCPs should share as much information as possible about new treatments or clinical trials, it is important to ensure that the patient understands the HCP’s recommendations for their treatment by asking them for comments and feedback. Patients should also be encouraged to keep clear records of their symptoms so that the HCP can provide optimal care, and the HCP should explain why this is important. Mental health can be severely affected in those living with HAE, and HCPs should also recognise that patients may need additional support and services outside the clinic.

It may be useful to write down notes on a slip of paper for the patient to take away with them at the end of a consultation, perhaps including details of an appropriate patient organisation such as HAE UK. Metcalfe stressed that patients should also be encouraged to bring in a list of questions for their next consultation, to ensure that they remember to ask everything they want to. Patients can be prompted to check their list at the end of the consultation, with a question such as: ‘Is there anything else that you would like to ask me?’

Metcalfe concluded that, by listening, supporting, educating, informing, and understanding, it may be possible to move

towards the optimal goal of every patient achieving zero HAE attacks.

An HCP’s Expectations of HCP–Patient Communication

Danny M. Cohn, a Professor of Internal and Vascular Medicine at Amsterdam University Medical Centre, The Netherlands, considers there to be six stages of communication at the clinic, from an HCP’s perspective: preparing, scheduling, gathering information, providing information, shared decisionmaking, and concluding/managing follow-up.

Preparing

An HCP might prepare for a consultation by reviewing the patient’s notes, checking their prescribed medications, and reading any test results. They might also formulate an initial management proposal and plan for a follow-up appointment.

Cohn noted that one of the challenges of HCP–patient communication that may occur at the preparation stage is that healthcare records can sometimes be dispersed across many different systems, and that patients may have experienced health events that are not necessarily updated in the healthcare system the HCP has access to.

Scheduling

It is important to set expectations of the agenda at the start of a consultation, and Cohn suggested that a simple introductory statement can be helpful, such as: ‘We have about 15 minutes for this consultation. I will invite you to ask any questions that you have prepared, we will discuss how you are doing, and then we will follow up with some management proposals.’

Misalignment between the expectations of the HCP and patient can be a challenge to HCP–patient communication at the scheduling stage. For example, patients may think something is not relevant enough to mention because of time constraints, and may feel they shouldn’t bother the HCP. Equally, an HCP may want to know what’s

going on in the patient’s life, but may need to encourage the patient to share these details.

Gathering Information

At this stage, the HCP should invite the patient to share information regarding their expectations of the consultation, their general well-being, and the specific history of their primary condition. They should also be asked if there have been any changes with their treatment, such as adverse effects, and how many days they took, or did not take, their medicine. Finally, the patient should be encouraged to talk about upcoming events that may affect their condition, whether they have a desire to adapt the management of their disease, and to ask any questions they may have prepared.

During this stage of the consultation, it is important for the HCP to strike the right balance in terms of factual or sympathetic language choice. It is also crucial that the HCP asks targeted questions to make sure that they receive the information they need. Cohn used the example of a young female patient with HAE who might be unlikely to share menstrual problems with their HCP unless specifically invited to do so. For HAE, this type of question is important because patients with this condition should avoid taking oestrogens.15 Another example might be asking patients if they are planning any dental or surgical procedures, since these may require the HCP to arrange for additional treatment and to liaise with the surgeon and anaesthetist.

Providing Information

At this stage, the HCP generally provides a preliminary conclusion using a ‘mirroring’ approach. Cohn stressed that the HCP should remain open-minded and express their understanding of what the patient has said, and then ask for confirmation.

The HCP then shares their initial thoughts, such as any additional testing that may be needed, or any treatment adjustments. They can also choose to provide further information at this stage, including recent developments in the field that

are pertinent to the patient’s condition. Medical terminology should be avoided, and layman’s terms used wherever possible.

Shared Decision-Making

During this stage of the consultation, the HCP and patient should come to decisions regarding management, follow-up, reporting, and evaluation. Cohn emphasised the importance of ensuring the agreement and cooperation of the patient, and of providing sufficient time in the consultation to achieve this.

Concluding and Managing Follow-Up

In the final stage of the consultation, the HCP should summarise the consultation, provide instructions as needed, and describe the care plan and other management decisions. Cohn encourages the use of a ‘read back’ approach, where the patient is asked to explain or summarise the discussion back to the HCP. This can ensure that the information has been retained and interpreted correctly.

Cohn concluded that it is essential for both the HCP and patient to prepare for a consultation, and that the HCP takes care to listen and ask open-ended questions, as well as targeted questions relevant to the management of the patient’s condition.

The Relationship Between Mental and Physical Health

The WHO defines health as “a state of complete physical, mental and social well-being and not merely the absence of disease,”16 and a bi-directional relationship exists between physical and mental health17 (Figure 2). Campbell emphasised that the integrated treatment of physical and mental health needs has the potential to improve QoL, relationships with HCPs, and overall prognosis.17 Beyond the well-known direct relationship between physical and mental health, mental health can also directly impact disease progression.17 For example, Campbell explained that, in HAE, anxiety

Figure 2: The bi-directional relationship between mental and physical well-being.17

is known to be a trigger for angioedema attacks.18 Indirectly, poor mental health can impact a patient’s ability to manage their condition, leading to poor treatment adherence, difficulties in attending regular appointments, or engaging in less helpful coping strategies such as smoking or drug/ alcohol misuse.17 Campbell also emphasised that poor mental health may affect a patient’s relationship with their HCP.

Campbell stressed that having a longterm health condition like HAE does not predetermine that a patient will have mental health difficulties. This means that HCPs have an opportunity to offer evidencebased treatments to help their patients to develop coping strategies that may ultimately improve their physical health.

QoL among patients with HAE has been shown to be poorer than that of the general population,5,6 and the rates of anxiety, depression,5-7 health-related fear, and health-related fatigue are also higher.19 Some of the factors that may lead to anxiety in patients with HAE include delays in diagnosis,7 inadequacy of some treatments,7 uncertainty around attack onset,3 or feelings of life-limitation due to attacks.3 Alongside the increased risk of HAE attacks at times of emotional

stress,4 this suggests that a negative feedback loop can develop.

The ‘Therapeutic Alliance’ Between HCPs and Patients

Campbell offered practical guidance on how to establish bi-directional communication between HCPs and patients. She explained that there are many patient factors that impact decision-making in healthcare, including patients’ mental health, which can impact their concentration and memory, making it difficult to engage in conversations and absorb new information (Figure 3). Research suggests that 40–80% of the medical information provided by HCPs is forgotten immediately by patients, and almost half of the information recalled is incorrect.20 Campbell stressed that mental health conditions such as anxiety are likely to further impair information recall.

The ‘relationship to help’, a concept explored by Reder and Fredman,21 is another key factor that affects healthcare decisionmaking. This concept suggests that patients have a complex collection of beliefs regarding asking for and receiving help, which may influence their relationship with

Campbell, personal communication.

an HCP.21 Such beliefs may include past experiences, or feelings of their own or of other family members.21 Campbell suggested that helping patients to learn about the treatment experiences of other patients may be one approach to addressing issues caused by a patient’s relationship to help. If a patient has had a negative experience prior to the current consultation, they may seek confirmation that the previous HCP managed their condition poorly. In this situation, Campbell recommended listening to the patient and validating their feelings, before redirecting the conversation towards how the current HCP can make sure that they feel safe in the new relationship.

Harmful or life-threatening events or circumstances experienced by a patient can result in trauma, which may leave a lasting impact, affecting a patient’s mental, physical, emotional, social, or spiritual well-being.22 Trauma can also negatively influence the communication between a patient and an HCP.22 Trauma-informed practice is an approach to healthcare interventions that is grounded in an understanding of

these issues,22 and Campbell explained that she finds it particularly useful when communicating with patients. The six key principles of trauma-informed practice are to consider safety, trustworthiness, choice, collaboration, empowerment, and culture.21

Kiani-Alikhan added that adopting a traumainformed approach may initially feel daunting to an HCP; however, in his experience, taking this empathetic, active listening approach helps consultations to flow more easily. If an HCP feels that they cannot address all the patient’s concerns in the time available, Kiani-Alikhan stressed the importance of remaining transparent and explaining this to the patient, perhaps suggesting the use of email or a follow-up consultation.

In addition to trauma-informed practice, Campbell recommended that, to help establish bi-directional communication between HCPs, consultations should be continuous, dynamic, individually tailored, and patient-centred, and should use supportive language rather than assigning blame.

Figure 3: Patient factors impacting decision-making in healthcare.

Key Messages and Takeaways

There is a considerable psychological burden associated with living with a rare disease, and it is critical that HCPs take this into consideration when communicating with patients.2,17

Bi-directional HCP–patient communication can be improved by preparing for a consultation adequately (both HCP and patient), listening, and asking both open-ended and targeted questions (Cohn, personal communication). Ideally, communication should be patient-centred,1 trauma-informed,22 and

References

1. Çakmak C et al. The effects of patient-centered communication on patient engagement, health-related quality of life, service quality perception and patient satisfaction in patients with cancer: a cross-sectional study in Türkiye. Cancer Control. 2024;31:10732748241236327.

2. NHS. Long-term conditions positive practice guide. Available at: https://assets.uea.ac.uk/f/185167/x/44ab023893/ norwich-medical-school-long-term-conditions-positive-practice-guide.pdf. Last accessed: 6 May 2025.

3. Bygum A et al. The hereditary angioedema burden of illness study in Europe (HAE-BOIS-Europe): background and methodology. BMC Dermatol. 2012;12(1):4.

4. Craig T et al. WAO guideline for the management of hereditary angioedema. World Allergy Organ J. 2012;5(12):182-99.

5. Rosa A et al. Experimental protocol of dental procedures in patients with hereditary angioedema: the role of anxiety and the use of nitrogen oxide. Oral Implantol (Rome). 2016;9(2):49-53.

6. Maurer M et al. Treatment of HAE attacks with oral deucrictibant: RAPIDe-2 extension results. Bradykinin Symposium, 4-6 September, 2024.

7. Fouche AS et al. Depression and anxiety in patients with hereditary angioedema. Ann Allergy Asthma Immunol. 2014;112(4):371-5.

individually tailored (Campbell, personal communication). Having a short consultation time should not mean that a positive HCP–patient relationship should be sacrificed (Kiani-Alikhan, personal communication).

Good HCP–patient communication can improve treatment adherence, patient satisfaction, health outcomes, and QoL.1,9,11 Patients with HAE are at an increased risk of HAE attacks during times of stress,4 which means that good communication, along with a consideration of each patient’s mental health, may help take us closer to the optimal goal of every patient achieving zero HAE attacks (Metcalfe, personal communication).

8. Cancian M. Physician and patient level of agreement in hereditary angioedema attack reporting among a real-world European population. Poster #34. HAENET 2025, 29 May-1 June, 2025.

9. Stewart MA. Effective physician-patient communication and health outcomes: a review. CMAJ 1995;152(9):1423-33.

10. Jiang S et al. How does patient-centered communication influence patient trust?: The roles of patient participation and patient preference. Patient Educ Couns. 2024;122:108161.

11. Zolnierek KBH et al. Physician communication and patient adherence to treatment: a meta-analysis. Med Care 2009;47(8):826-34.

12. Burnham J. Systemic supervision: the evolution of reflexivity in the context of the supervisory relationship. Human Systems 1993;4:349-81.

13. Roper-Hall A, “Working systemically with older people and their families who have ‘come to grief’,” Sutcliffe P et al. (eds.), Working with the Dying and Bereaved: Systemic Approaches to Therapeutic Work (1998) 1st edition, London: Macmillan, pp.177-206.

14. Birdsey N et al. Reviewing the social GRACES: what do they add and limit in systemic thinking and practice? Am J Fam Ther. 2021;49(5):429-42.

15. Banerji A et al. Managing the female patient with hereditary angioedema. Women’s Health (Lond). 2016;12(3):351-61.

16. World Health Organization. Constitution. Available at: https://www.who.int/about/ governance/constitution. Last accessed: 6 May 2025.

17. Naylor C et al. Long-term conditions and mental health: the cost of co-morbidities. 2012. Available at: https://www.kingsfund.org.uk/insight-and-analysis/reports/ long-term-conditions-mental-health. Last accessed: 6 May 2025.

18. Savarese L et al. Psychology and hereditary angioedema: a systematic review. Allergy Asthma Proc. 2021;42(1):e1-7.

19. Hews-Girard J et al. Psychosocial burden of type 1 and 2 hereditary angioedema: a single-center Canadian cohort study. Allergy Asthma Clin Immunol. 2021;17(1):61.

20. Kessels RPC. Patients’ memory for medical information. J R Soc Med. 2003;96(5):219-22.

21. Reder P et al. The relationship to help: interacting beliefs about the treatment process. Clin Child Psychol Psychiatry. 1996;1(3):457-67.

22. UK Government Office for Health Improvement & Disparities. Working definition of trauma-informed practice. Available at: https://www.gov.uk/government/ publications/working-definition-of-trauma-informed-practice/working-definition-of-trauma-informed-practice. Last accessed: 6 May 2025.

MED-00098 July 2025

EACCI 2025

Abstract Reviews

Drawing on insights from the European Academy of Allergy and Clinical Immunology (EAACI) Congress 2025, these abstract reviews highlight significant new developments and emerging priorities in the field of allergy and clinical immunology.

AllergoOncology: Non-Allergic Urticarial Skin Reactions Associated with MOv18 IgE, a First-in-Class IgE Antibody Recognising FRα

Authors: Jitesh Chauhan,1 Chara Stavraka,1,2

Debra H Josephs,1,3 James Spicer,2,3 Heather J Bax,1 *Sophia N Karagiannis1,4

1. St. John's Institute of Dermatology, School of Basic & Medical Biosciences & KHP Centre for Translational Medicine, King's College London, UK

2. School of Cancer & Pharmaceutical Sciences, King's College London, UK

3. Guy’s Cancer Centre, Guy's and St Thomas' NHS Foundation Trust, London, UK

4. Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King's College London, UK

*Correspondence to sophia.karagiannis@kcl.ac.uk

Disclosure: Josephs has declared patents on antibodies for cancer and antibody technologies. Bax has declared patents on antibodies, and has been employed through a fund provided by Epsilogen Ltd, London, UK. Chauhan has been employed through a fund provided by Epsilogen Ltd. Spicer and Karagiannis have declared patents on antibodies for cancer and antibody technologies, hold stock in Epsilogen Ltd, and are founders and shareholders of Epsilogen Ltd.

Acknowledgements: The authors would like to thank all patients and volunteers who participated in this study. They thank both Mariangela Figini and Silvana Canevari, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, for collaborating with the authors on the production and functional evaluation of MOv18 IgE. This research was supported by the King's Health Partners Centre for Translational Medicine, London, UK. The views expressed are those of the author(s) and not necessarily those of King's Health Partners. The authors thank the Nikon Imaging Centre, King's College London, UK, for help with light microscopy. The authors acknowledge the Advanced Cytometry Platform team, Research & Development Department, Guy's and St Thomas' NHS Foundation Trust, London, UK. This study represents independent research part-funded by the National Institute for Health and Care Research, Guy's and St Thomas' NHS Foundation Trust, London, UK. The views expressed are those of the author(s) and not necessarily those of the NHS, the National Institute for Health and Care Research, or the Department of Health, Guy's and St. Thomas' NHS Foundation Trust, London, UK.

Keywords: AllergoOncology, FRα, IgE antibodies, transcriptomic analysis, urticarial skin reactions.

Citation: EMJ Allergy Immunol. 2025;10[1]:65-66. https://doi.org/10.33590/emjallergyimmunol/ CTQN9023

BACKGROUND

MOv18 IgE is a first-in-class IgE antibody targeting FRα, an antigen overexpressed in ovarian and other cancers.1 IgE-based anti-cancer antibodies offer significant advantages, such as the ability to bind strongly to immune effector cells via the FcɛRI receptor and to stimulate tumourinfiltrating immune cells against cancer. In a recent Phase I clinical trial, MOv18 IgE demonstrated promising efficacy, but also triggered transient urticarial skin reactions. The authors aimed to elucidate the immunological basis of these reactions and assess whether they were mediated by allergic mechanisms.

METHODS

Twenty-four patients with FRα-expressing tumours were treated with escalating doses of MOv18 IgE. Clinical data regarding urticarial skin reactions were collected. Immunohistochemistry was conducted to evaluate FRα expression in human skin, and immuno-mass spectrometry and transcriptomic analyses were performed on urticarial and non-involved skin biopsies from a patient who received the highest antibody dose. These analyses evaluated immune cell infiltration and mast cell degranulation in the skin. Circulating immunological markers, including β-tryptase levels and basophil activation, were assessed to investigate any association with a systemic allergic response.

RESULTS

Urticarial skin reactions occurred in 62.5% of patients, with most reactions being mild and diminishing over repeated doses

(Figure 1). These reactions were not associated with serum β-tryptase elevation, indicating an absence of systemic allergic activity. Immunohistochemistry and immuno-mass spectrometry analyses confirmed that FRα was not expressed in normal skin, and MOv18 IgE did not bind to skin antigens. Lesional skin biopsies from a patient who developed a urticarial reaction showed scattered eosinophils and neutrophils, along with mast cell degranulation, but no increased immune cell infiltration. Transcriptomic analysis revealed activation of pro-inflammatory, but not of allergic, pathways. No cytokine markers of allergic hypersensitivity and no basophil activation were detected in the patient’s circulation.

CONCLUSION

The urticarial skin reactions observed in patients treated with MOv18 IgE were not driven by allergic mechanisms or by skin antigen recognition by the antibody. Instead, these reactions likely represent infusion-related phenomena commonly seen with monoclonal antibody therapies. The authors’ findings support the overall safety of MOv18 IgE, with the reactions being manageable. These data are crucial for advancing IgE antibodies in cancer immunotherapy while ensuring patient safety.

Figure 1: Readily manageable urticarial adverse events were associated with higher doses of MOv18 IgE treatment.

Left Panel: Representative images of urticarial skin reactions, seen in a patient who received a 500 μg dose (orange) and a patient who received a 1.5 mg dose (blue) from the larger cohort of patients treated with MOv18 IgE.

Right panel: Proportion and CTCAE urticarial grade per dosing cohort of patients treated with MOv18 IgE (urticarial: n=15; total N=24). *Intra-patient dose escalation was performed with this patient (n=1), who received three doses at 6 mg, followed by three doses at 12 mg.

Adapted from Stavraka C et al.1

CTCAE: Common Terminology Criteria for Adverse Events.

Reference

1. Stavraka C et al. Non-allergic urticarial skin reactions associated with MOv18 IgE, a first-inclass IgE antibody recognising folate receptor alpha. Allergy. 2025;DOI:10.1111/all.16514.

Clinical Characteristics, Diagnosis, and Treatment Outcomes in Chronic Cold Urticaria: Insights From a 15-Year Study

Authors: *Cristina Coelho,1 Cláudia Maçães,1 Tomás Almeida,1 Susana Cadinha,1 Arminda Guilherme,1 José Ferreira,1 Isabel Rosmaninho1

1. Gaia Espinho Local Health Unit, Vila Nova de Gaia, Portugal *Correspondence to anacristinabrg@gmail.com

Disclosure: The authors have declared no conflicts of interest.

Keywords: Cold stimulation testing, cold urticaria, cryoglobulins.

Citation: EMJ Allergy Immunol. 2025;10[1]:67-69. https://doi.org/10.33590/emjallergyimmunol/ PLKR2955

BACKGROUND AND AIMS

Chronic cold urticaria (CCU) is a physical urticaria triggered by cold exposure, leading to wheals or angioedema that typically develop on rewarming and resolve within an hour.1,2 Though usually mild and selflimiting, it can sometimes lead to severe anaphylactic reactions. Diagnosis relies on patient history and cold stimulation tests.2,3

The aim of the present work was to review the clinical features, diagnosis, and response to therapy in a group of patients with CCU followed in an allergy department.

METHODS

Patients diagnosed with CCU between 2009–2024, followed in the authors’ Allergy Department, were included retrospectively. The authors collected clinical and demographic data from clinical process. The statistical analysis of the data was conducted using IBM SPSS Statistics 28 (IBM, Armonk, New York, USA). A Chi-squared test was used to measure the correlation between categorical variables. The p values below 0.05 indicated statistical significance.

RESULTS

Eighty-two patients were included. The median age was 37 years (range 4–77; interquartile range [IQR]: 32), and 66% (n=54) of the patients were female. Median symptom onset was 31 years (range 1–72; IQR: 29), and median symptom duration at initial consultation was 5 years (range 0.3–45; IQR: 7). Of the patients, 41% had rhinitis, 15% had asthma, 12% had autoimmune diseases, and 4% had neoplasia. Four patients had other inducible urticarias (three dermatographic and one cholinergic). Triggers included cold air (63%; n=52), aquatic activities (62%; n=51), cold surfaces (45%; n=37), and cold foods/drinks (12%; n=10). All underwent the ice cube test (positive in 30; stimulation time: 1–20 min) or TempTest® (Worthing, UK; positive in 21; threshold temperature: 9–20 ºC). A total of 44 (54%) typical CCU cases and 38 (46%) atypical CCU cases were diagnosed. Secondary CCU causes were found in two patients (essential mixed cryoglobulinaemia and HIV); no familial CCU types were identified.

Regarding severity, 77% (n=63) had Type I CCU, 15% (n=12) had Type II, and 9% (n=7) had Type III, with the latter being associated with autoimmune history (p<0.01; Table 1).2,4 Anaphylaxis was noted in 7% (n=6) and angioedema in 18% (n=15). All patients with a history of anaphylaxis reported aquatic activities as a trigger and were equipped with adrenaline autoinjectors. Typical CCU was associated with more severe reactions (p=0.03).

All patients were counselled on avoidance measures. Treatments included antihistamines (76%; n=62), corticosteroids (12%; n=10), montelukast (10%; n=8), and emergency adrenaline (9%; n=7). During follow-up, 51% (n=40) improved, 30% (n=24) remained unchanged, and 19% (n=15) resolved.

wheals and/or angioedema with systemic reactions such as hypotension, dizziness, syncope, and disorientation

CONCLUSION

Although CCU can be life-threatening, Type I severity was the most common in this sample. Cold air and aquatic activities were the main triggers, highlighting the need for patient education and preventive strategies, especially in colder climates or among those exposed to water. Most patients’ symptoms were controlled with lifestyle changes and antihistamines. The association between Type III severity and autoimmune comorbidities (p<0.01) reinforces the need to screen for underlying conditions in severe cases. Diagnosis was supported by cold stimulation tests (ice cube or TempTest®), though variability in results reflects the heterogeneity of CCU. Avoidance measures and non-sedating antihistamines were sufficient for most patients, which supports current first-line treatment recommendations.2

In conclusion, CCU remains an intriguing and clinically relevant condition, offering insights into physical urticaria mechanisms and underscoring the value of individualised diagnosis and management, particularly in patients with comorbidities or severe presentations.

References

1. Coelho C et al. Clinical characteristics, diagnosis, and treatment outcomes in chronic cold urticaria: insights from a 15-year study. Abstract 001004. EAACI Congress, 13-16 June, 2025.

2. Maltseva N et al. Cold urticaria - what we know and what we do not know. Allergy. 2021;76(4):1077-94.

3. Sugiura K, Sugiura M. Localized cold urticaria mimicking livedo in an adult female. Ann Clin Case Rep. 2016;1:1168.

4. Wanderer AA. Cold urticaria syndromes: historical background, diagnostic classification, clinical and laboratory characteristics, pathogenesis, and management. J Allergy Clin Immunol. 1990;85(6):965-81.

Table 1: Severity grading of chronic cold urticaria.2,4

Reference Values of Eosinophil-derived Neurotoxin in Blood: Reasons to Use Ethylenediaminetetraacetic Acid Plasma

Authors: *Douwe de Boer,1 Nadine K.J. Stoop,1 Caroline J.J. Bijnens,1 Marjan C. Slot,2 Chris M.G. Nieuwhof,2 Judith A.P. Bons1

1. Central Diagnostic Laboratory, Maastricht University Medical Center+, the Netherlands

2. Department of Internal Medicine, Immunology and Allergology, Maastricht University Medical Center+, the Netherlands

*Correspondence to douwe.de.boer@mumc.nl

Disclosure: de Boer, Stoop, Bijnens, and Bons have declared contracts between Central Diagnostic Laboratory and ThermoFisher Scientific in order to exchange scientific information regarding in vitro allergy diagnostics; and have an agreement with ThermoFisher Scientific regarding cost reduction when purchasing EDN ImmunoCAP assays. The other authors have declared no conflicts of interest.

Keywords: Eosinophil-derived neurotoxin (EDN), ethylenediaminetetraacetic acid plasma (ETDA), heparin plasma, immunoassay, reference interval, serum.

Citation: EMJ Allergy Immunol. 2025;10[1]:69-70. https://doi.org/10.33590/emjallergyimmunol/ HQJM1006

BACKGROUND

Eosinophil-derived neurotoxin (EDN), as a biomarker of eosinophilic activity, can be measured in blood matrices such as serum, ethylenediaminetetraacetic acid (EDTA) plasma, and heparin plasma.1 For unclear reasons, current EDN studies aim to use serum, even though the manufacturer’s assay validation identifies it as the least suitable matrix of choice.2,3 Moreover, the same validation data do not include reference values for adults.4 The goal of this study is to establish EDN reference intervals, means, and medians in different blood matrices in adults, and to argue which blood matrix should be measured for EDN.

METHODS

Blood samples were randomly selected from a common hospital population. Collections were included if all three matrices were available: EDTA plasma, Barricor™ lithiumheparin plasma (Becton Dickinson and Company, Franklin Lakes, New Jersey, USA), and serum. Samples were treated according to common routine practice: centrifugation of both serum and lithiumheparin samples at 1,855×g for 10 minutes, and EDTA samples at 1,150×g for 10 minutes. EDN values were measured using the ImmunoCAP™ assay (Thermo Fisher Diagnostics Phadia, Uppsala, Sweden).

Values below the lower limit of quantitation (2 μg/L) were fixed at 1.41 μg/L, while those above the upper limit of quantitation (200 μg/L) were diluted five-fold and remeasured. Reference 95% intervals, means, and medians for EDN values were calculated after logarithmic transformation.

RESULTS

The age characteristics of the subjects studied (N=51) were as follows: range 15–78 years, mean age 43.6 years, and median age 35.0 years. These values are shown in Figure 1A. The reference intervals, means, and medians for EDN values were: EDTA plasma 2.1–197, 16.2, and 14.7 μg/L; Barricor™ lithium-heparin plasma 2.7–251, 50.1, and 50.9 μg/L; and serum 2.5–218, 34.7, and 33.2 μg/L, respectively (Figure 1B).

CONCLUSION

Eosinophils are sensitive to both sample collection and treatment conditions, while the post-collection release of EDN should be avoided.5 Among the tested blood matrices, the one with the lowest reference interval, mean, and median is considered ideal. According to the manufacturer’s validation data, EDTA plasma emerges as the logical matrix of choice, while serum is the least favourable choice. This study, conducted under common routine practice, confirms the choice of EDTA plasma, although the author's ranking also proposes that Barricor™ lithium-heparin plasma is the least favourable choice. The manufacturer

of the ImmunoCAP™ assay suggests that EDTA inhibits enzymatic processes, whereas heparin is supposed to leave the eosinophils in a less activated state compared to serum. The authors claim that the treatment of samples, the activation by the applied centrifugation conditions, and the separation by the Barricor™ system, is critical. Therefore, the EDN value measured in EDTA plasma more reflects the true EDN concentration in blood. The author's reference intervals are based on a general hospital population, which includes individuals with both EDN-related and unrelated pathologies, and do not represent a purely healthy cohort.

Figure 1: Eosinophil-derived neurotoxin concentrations, in a common hospital population, measured in three different matrices under matrix-specific pre-analytical conditions.

A) Distribution of data displayed on logarithmic scale. B) Box-and-whiskers plot of the same data, showing the values below the 2.5th percentile and above the 97.5th percentile as individual circles. EDN: eosinophil-derived neurotoxin; EDTA: ethylenediaminetetraacetic acid.

References

1. de Boer D et al. Reference values of eosinophilic derived-neurotoxin in blood of adults: reasons to use EDTA plasma. Abstract 000685. EAACI Congress 2025, 13-16 June, 2025.

2. ThermoFisher Scientific. Eosinophil-derived neurotoxin. 2021. Available at: https://www. thermofisher.com/diagnostic-education/dam/ commercial/temp/library-resources/58824-FINEDN-Scientific_Backgrounder-digital-2.pdf. Last accessed: 2 June 2025.

3. Karsten C et al. Evaluation of an automated assay for eosinophil-derived neurotoxin in serum. Clin Biochem. 2025;136:110890.

4. Rydell N et al. Development of an automated ImmunoCAP research assay for eosinophil derived neurotoxin and its use in asthma diagnosis in children. Pract Lab Med. 2019;17:e00138.

5. Reimert CM et al. Measurement of eosinophil cationic protein (ECP) and eosinophil protein X/ eosinophil derived neurotoxin (EPX/EDN). Time and temperature dependent spontaneous release in vitro demands standardized sample processing. J Immunol Methods. 1993;166(2):183-90.

Abstract Highlights

Citation: EMJ Allergy Immunol. 2025;10[1]:71-79. https://doi.org/10.33590/emjallergyimmunol/NDLR3193

The following highlights spotlight key abstracts from the European Academy of Allergy and Clinical Immunology (EAACI) Congress 2025, held in Glasgow, UK, from the 13th–16th of June. Topics covered include rising food allergies in children, the psychological burden of chronic allergic diseases, predictors of asthma and eosinophilic gastritis, and qualityof-life improvements related to emerging therapies.

Pine Nut Allergy Increasing Among European Children

A RECENT analysis of data from the Allergy Vigilance Network, presented at the EAACI Congress 2025, has revealed that pine nut allergy, once considered rare, is becoming a more frequent cause of food-induced anaphylaxis.1

The study reviewed 3,285 reported cases of food-related anaphylaxis across France, Belgium, and Luxembourg between 2002–2024. Of these, 61 cases, representing 1.9%, were linked to pine nuts, either in their native form or as hidden ingredients in foods such as sauces, salads, pastries, breaded fish, and both commercial and home-cooked meals.

The majority of cases (75.4%) occurred in children aged 1.6–18 years, with males and females affected equally. However, among adults, males were more frequently affected than females. A significant number of patients also had existing sensitisation to other nuts (39.3%) or a history of asthma or atopic dermatitis (29.5%). Notably, anaphylaxis was the first sign of pine nut allergy in 70% of patients, highlighting the potential severity of initial reactions.

Effort-related cofactors were identified in 21.3% of cases, the most common being physical exertion. The severity of the allergic reactions varied, with 80% being Grade 2, 18.2% being Grade 3, and one case being classified as Grade 4. Treatment details were available for 55 cases, with adrenaline used in 34.5%, and antihistamines or corticosteroids administered in over 90%.

These findings point to pine nuts as an emerging and potentially serious allergen, especially among children. Given their growing presence in globalised diets and the hidden nature of their inclusion in many foods, there is a strong case for adding pine nuts to the list of mandatory food allergens requiring labelling in Europe. Greater awareness and improved labelling could play a vital role in preventing severe allergic reactions in at-risk individuals.

These findings point to pine nuts as an emerging and potentially serious allergen, especially among children

Study Reveals Unmet Need in Asthma Care

DEPRESSION prevalence is high amongst individuals with severe asthma, according to new research presented at the EAACI Congress 2025, which took place in Glasgow, UK, between the 13th–16th of June.2

The observational, cross-sectional study included 57 adult (≥13 years) and paediatric (<13 years) patients with severe asthma, from an Allergy and Clinical Immunology department at a single centre in Portugal. To understand the frequency and impact of depression in this cohort, data were obtained from clinical records and standardised questionnaires. Of those included, 68.4% were female, the median age was 33.16 years (range: 7–71), the median BMI was 23.94 (interquartile range: 11.96), and the median fractional nitric oxide concentration in exhaled breath was 24.00 (interquartile range: 26.50).

The Beck Depression Inventory-II (BDI-II) and the Children’s Depression Inventory (CDI) were used to assess depression in adults and children, respectively. A BDI-II score of >28 was considered severe depression in adults, and a CDI score of >24 was considered severe depression in children.

Using these cut-off values, the researchers identified depression in 45.6% of the cohort. A total of 23 adults and adolescents had depression (53.5%), of whom 16.3% (n=7) had severe symptoms, 25.6% (n=11) had moderate symptoms, and 11.6% (n=5) had mild symptoms. In children <13 years of age, three were identified as having depression (21.4%). Of these individuals, none had severe symptoms, two (14.3%) had moderate symptoms, and one (7.1%) had mild symptoms. Additionally, those who were identified as having severe

45.6 %

Researchers identified depression in 45.6% of the cohort

depression were found to have lower Asthma Control test scores, with a median of 17.00 compared to 10.50 for those with mild and moderate depression (p=0.001), as well as an increased number of short-term systemic corticosteroid cycles. The authors noted no significant differences between the two groups for age, BMI, or fractional nitric oxide concentration in exhaled breath levels.

From the findings, the researchers concluded that individuals with asthma experience significant emotional burden, and that the prevalence of depression is high. This indicates that there is a gap in asthma management that needs to be bridged by combining traditional treatments with mental health care.

There is a gap in asthma management that needs to be bridged by combining traditional treatments with mental health care

Quality of Life in Adults with Hereditary Angioedema: New Insights from European Study

ADULTS with hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH) experience significant impairment in quality of life, with disease severity, attack frequency, and psychological factors emerging as key determinants, according to new data presented at the EAACI Congress 2025.3

Hereditary angioedema is a rare, lifelong condition characterised by unpredictable and often painful swelling episodes, which can be life-threatening and have a profound impact on daily functioning and well-being. Understanding the burden of illness and the factors that most affect health-related quality of life (HRQoL) is essential for improving patient care and targeting interventions.

In a prospective observational study, 102 adults with confirmed HAE-C1INH were assessed using a range of validated instruments: the Hereditary Angioedema Quality of Life (HAE-QoL) questionnaire, the Angioedema Quality of Life (AEQoL) questionnaire, the EuroQol fivedimensional five-level (EQ5D5L) index, the Hereditary Angioedema Activity Score (HAE-AS), and the Work Productivity and Impairment questionnaire. The median age of participants was 41.8 years, with 58.8% being female, and 32% receiving long-term prophylaxis. The median HAE-AS was 12.2, indicating moderate disease activity. Median scores reflected substantial impairment: HAE-QoL was 102.5, AE-QoL was 32.4, and the EQ5D5L index was 0.9. The domains most affected were 'Perceived control over illness', 'Fear/shame', and 'Pain'. HRQoL was significantly more impaired in females than males across all measures, with HAE-QoL scores of 93.0 versus 108.0, and AE-QoL scores of 37.5 versus 17.6, both statistically

The domains most affected were 'Perceived control over illness', 'Fear/shame', and 'Pain'

significant. No major differences were found between age groups, except for heightened concern about offspring in those aged 31–45 years. Factors most strongly associated with poorer HRQoL included higher disease severity, frequent attacks, known triggers, need for emergency care, adverse effects of treatment, anxiety, depression, and the need for psychological support. Work and daily activities were also notably affected, with mean absenteeism at 2.7%, presenteeism at 13.4%, overall work productivity loss at 15.2%, and activity impairment at 22.3%. Patients who did not require sick leave reported significantly better HRQoL scores.

These findings highlight the complex and multifaceted burden of HAE-C1INH in adults, underlining the need for a holistic approach to care that addresses not only physical symptoms but also psychological well-being and social participation. In clinical practice, a regular assessment of HRQoL and work impact should be integrated into routine management, with particular attention paid to those with frequent attacks, high disease severity, and psychological distress.

Olfactory Improvement Drives

Quality of Life Gains in Chronic Rhinosinusitis with Nasal Polyps

A REAL-LIFE clinical study has shown that an improved sense of smell during dupilumab treatment is closely linked to better quality of life in patients with chronic rhinosinusitis with nasal polyps (CRSwNP), independent of nasal polyp regression.4

CRSwNP is commonly associated with nasal congestion and anosmia, both of which significantly impact patients’ daily lives. Dupilumab, an IL-4/IL-13 receptor blocker, has emerged as an effective therapy, but the specific contributors to quality-of-life improvements remain under investigation. In this prospective study from Budapest, Hungary, researchers assessed the relationships between olfactory function, nasal obstruction, polyp score, and healthrelated quality of life. Twenty-four adult patients with CRSwNP were followed before and during dupilumab treatment. Olfactory function was quantified using the extended Sniffin’ Sticks test, nasal obstruction was assessed with Visual Analogue Scale (VAS) and Nasal Obstruction Symptom Evaluation (NOSE) scores, and polyp size was graded via the modified Lund-Kennedy scoring system. Quality of life was evaluated using the validated Sino-Nasal Outcome Test (SNOT)-22, with data analysed using R statistical software.

Results revealed a rapid and sustained improvement in olfactory function, with the prevalence of anosmia dropping from 94% at baseline to 22% after 6 months of therapy. SNOT-22 scores significantly improved, with a mean change of 45.83 points (95% CI: 34.1–57.6; p<0.001), and nasal polyp scores also showed a marked reduction (mean

Researchers assessed the relationships between olfactory function, nasal obstruction, polyp score, and health-related quality of life

difference: 3.33; 95% CI: 2.3–4.3; p<0.001). However, while improved olfaction strongly correlated with better quality of life, changes in nasal polyp scores or nasal obstruction did not. Moreover, no correlation was found between the degree of olfactory recovery and a reduction in polyp size.

These findings suggest that the restoration of olfactory function may be the primary driver of patient-reported improvement during dupilumab therapy, rather than structural changes. Further research is needed to clarify the underlying mechanisms of smell recovery in CRSwNP.

Results revealed a rapid and sustained improvement in olfactory function, with the prevalence of anosmia dropping from 94% at baseline to 22% after 6 months of therapy

Rising Prevalence of Walnut and Cashew Nut Allergies in Japan

A NATIONWIDE survey on immediate food allergies in Japan, presented at the EAACI Congress 2025, which has been conducted every 3 years since 2002, has revealed a marked increase in tree nut allergies, particularly to walnuts and cashew nuts, over the past decade.5

The survey involved data collection from around 1,000 physicians per cycle, focusing on patients who experienced allergic reactions within 60 minutes of ingesting specific foods. Cases were analysed based on causative foods, symptoms, treatments, and patient demographics.

From 2005–2023, the number of analysed cases steadily increased, from 2,227 in 2005 to over 6,000 in both 2020 and 2023. Until 2017, the top three allergens (hen’s eggs, cow’s milk, and wheat) remained consistent. However, from 2014 onwards, reports of tree nut allergies began to rise noticeably. Walnut allergies showed the most significant increase, ranking fourth in 2020 (7.6%) and rising to second place in 2023, accounting for 15.2% of cases. Cashew nut allergies also increased, along with other tree nuts such as macadamias, pistachios, almonds, pecans, and hazelnuts.

In children aged 0 years, hen’s eggs, cow’s milk, and wheat continued to dominate, with no major changes. In contrast, walnut allergies rose sharply in older age groups, particularly those aged 1–2, 3–6, and 7–17 years. There was also a marked increase in misfeeding-related reactions involving walnuts in the 3–17 age range.

In conclusion, tree nut allergies in Japan, especially to walnuts and cashews, have become significantly more common in the last 10 years, indicating the need for updated allergen labelling and greater public awareness.

2,227 6,000

Tree nut allergies in Japan, especially to walnuts and cashews, have become significantly more common in the last 10 years

From 2005–2023, the number of analysed cases steadily increased, from 2,227 in 2005 to over 6,000 in both 2020 and 2023

New Data Support Simpler Diet Approach in Childhood Eosinophilic Gastritis

EOSINOPHILIC gastritis (EoG) is a rare chronic inflammatory condition increasingly managed through empiric food elimination diets (FED), despite limited long-term data to guide reintroduction strategies. While FEDs have demonstrated benefit in eosinophilic oesophagitis, their use in EoG, particularly in paediatric populations, raises concerns about nutritional adequacy and quality of life. To address this gap, a retrospective study presented at the EAACI Congress 2025 reviewed the outcomes of food reintroduction in children diagnosed with EoG at a tertiary allergy-gastroenterology-dietetics centre between 2009–2024.6

Children aged 0–18 years with histologically confirmed EoG (defined by gastric eosinophil counts of >30/high-power field [HPF] in >5 separate HPFs) were included. Patients achieving histological remission (either a gastric eosinophil count of <20/HPF or a >75% reduction) underwent stepwise food reintroduction, followed by repeat endoscopy 8–12 weeks later to assess tolerance. Foods were considered tolerated if remission was maintained post-reintroduction. Data were analysed for factors predicting the need for ongoing multi-food avoidance.

Of the 30 patients included (53% female), the median age at diagnosis was 1.3 years (range: 0.3–16), with a median followup of 5 years. Initial treatment involved 3–6 FED in 60% and 1–2 FED in 33% of patients. Endoscopic re-evaluation was available for 25 patients, with 84% (21/25) achieving histological remission. The most frequently tolerated foods were fish (86%), shellfish (76%), and nuts (71%), while cow’s milk (14%) and egg (48%) were the least tolerated. At the end of the study, eight children remained on single-FED, predominantly eliminating cow’s milk. Only two had reintroduced all major allergens without relapse. Risk factors for requiring

ongoing 2–6 FED included concomitant IgE-mediated food allergy (odds ratio [OR]: 51.0; p=0.0129), initial peripheral eosinophilia (OR: 15.7; p=0.0246), and hypoalbuminaemia (OR: 10.7; p=0.0230).

These findings support a more conservative dietary approach in paediatric EoG, beginning with one to two food eliminations rather than extensive FEDs

These findings support a more conservative dietary approach in paediatric EoG, beginning with one to two food eliminations rather than extensive FEDs. Identifying individual food triggers, particularly cow’s milk, may reduce the long-term burden of dietary restrictions and improve quality of life. However, the retrospective nature of the study and small cohort size limit generalisability. Prospective, multicentre studies are needed to confirm optimal dietary management strategies and to further guide clinical decision-making.

Paediatric Asthma Risk Rises with Higher Eosinophil Counts

A NEW retrospective study, presented at the EAACI Congress 2025, has shed light on the potential of eosinophil blood count (EBC) as a predictive marker for asthma in preschool children presenting with acute wheezing.7

Wheezing in early childhood can be transient and benign, but for some children, it marks the beginning of chronic respiratory issues, including asthma. Accurate early prediction remains a clinical challenge, and EBC, a simple blood test, has been suggested as a possible tool, although current recommendations are based largely on expert opinion rather than robust evidence.

Researchers analysed data from 375 children aged 1–5 years old who were hospitalised with wheezing episodes between 2013–2023. Based on respiratory outcomes after the age of 5 years, children were classified into three categories: no recurrent wheezing, transient wheezing, and persistent wheezing or asthma. Results showed that those who went on to develop asthma had a significantly higher mean EBC (410 cells/ µL) compared with children in the other two groups (220 and 260 cells/µL, respectively). Notably, there was no significant difference in EBC between the non-asthmatic groups.

The study identified 230 cells/µL as the most effective cut-off point for predicting asthma, though the sensitivity and specificity, 63% and 61%, respectively, suggest the test alone is not definitive. Importantly, a linear relationship was found: for every 100 cells/µL increase in EBC, the risk of developing asthma rose by 18%.

These findings indicate that, while EBC is not a perfect diagnostic tool, it does provide valuable prognostic information. The data support using EBC as a quantitative indicator of asthma risk in young children with acute wheezing. Clinicians are urged to consider EBC alongside other clinical features, given the moderate predictive accuracy, to guide early management decisions.

A linear relationship was found: for every 100 cells/µL increase in EBC, the risk of developing asthma rose by 18%

References

1. Bradatan E. Pine nuts, an emerging food allergen: data from the AllergyVigilance Network. Abstract D2.275. EAACI Congress, 13-16 June, 2025.

2. Nunes M et al. Severe asthma and depression: the overlooked burden. Abstract D1.113. EAACI Congress, 13-16 June, 2025.

3. Lluncor-Salazar M et al. Burden of illness in adult patients with hereditary

angioedema due to C1 inhibitor deficiency. Abstract 100143. EAACI Congress, 13-16 June, 2025.

4. Kraxner H et al. Association between olfactory function, nasal polyp score, nasal obstruction and quality of life in CRSwNP patients treated with dupilumab. Abstract 001702. EAACI Congress, 13-16 June, 2025.

5. Sugizaki C et al. Walnut and cashew nut allergies have been on the rise in Japan over the past decade. Abstract 434.

EAACI Congress, 13-16 June, 2025.

6. Loh W et al. Outcomes of food reintroduction and identification of food triggers in paediatric eosinophilic gastritis. Abstract 000691. EAACI Congress, 13-16 June, 2025.

7. Adamiec A et al. Predicting asthma in preschool children: the role of eosinophil blood counts during acute wheezing episodes. Abstract 001222. EAACI Congress, 13-16 June, 2025.

Congress Interview

EMJ is delighted to introduce an interview with María Torres, President of the European Academy of Allergy and Clinical Immunology (EAACI), and Head of the Allergy Department, Malaga Regional University Hospital, Spain. As the driving force behind the EAACI Congress 2025, Torres shares her insights on the Congress’s focus on planetary health, the latest innovations in drug allergy, and how EAACI is supporting the next generation of clinicians and researchers in the field.

President of the European Academy of Allergy and Clinical Immunology (EAACI); Head of the Allergy Department, Malaga Regional University Hospital, Spain.

Citation: EMJ Allergy Immunol. 2025;10[1]:80-83. https://doi.org/10.33590/emjallergyimmunol/IAMJ3176

Q1

As the President of the European Academy of Allergy and Clinical Immunology (EAACI) Congress 2025, how would you describe your vision for this year's congress? What key themes or innovations are you most proud to bring to the forefront?

The focus of the EAACI Congress 2025 programme is planetary health and a sustainable future. We anticipate that our Congress in Glasgow, UK, will attract a record number of delegates from across the globe.

Q2

Drug allergy has long been a central focus of your research. How is the EAACI Congress 2025 addressing the global burden of drug hypersensitivity and improving diagnosis and risk stratification?

Managing antibiotic resistance and improving diagnosis and care for patients with drug allergies is absolutely critical

This year’s conference will spotlight both clinical and experimental aspects of allergology, with a strong emphasis on the ‘One Health’ approach and the impact of environmental exposure on human disease. The programme's theme aligns closely with the Academy’s growing focus on environmental science, an area in which allergology plays a particularly prominent role.

Drug allergy has been the main focus of my research for about 25 years. The increasing global prevalence of drug allergies has traditionally been attributed to longer life expectancy and a higher consumption of medications with allergenic potential. However, this alone may not fully explain the rising incidence of the condition.

Other contributing factors could include greater public awareness, as well as the presence of damaged epithelial barriers in the gut or skin, which may promote sensitisation to external agents such as chemical compounds.

At the Glasgow Congress, we will address all of the key aspects of drug hypersensitivity, including epidemiological trends, diagnosis, and management, with a particular

María Torres

focus on in vivo desensitisation techniques. Regarding diagnosis, we’ll explore the promising role of nanotechnology in developing new devices and reagents that can more accurately distinguish between individuals who are allergic and those who are not allergic.

Additionally, as part of EAACI's broader awareness initiatives, we will launch a new campaign at the Congress that focuses on delabelling, antibiotic resistance, and how accurate allergy diagnosis can support public health systems. Awareness campaigns are extremely important to us, especially because managing antibiotic resistance and improving diagnosis and care for patients with drug allergies is absolutely critical.

Q3

You’ve previously spoken about the role of AI in allergy care. How is the EAACI Congress 2025 helping lead the conversation around AI’s potential for predictive modelling, diagnosis, and personalised treatments?

EAACI is making tremendous efforts to integrate AI into the healthcare of individuals with allergic diseases. This emerging technology holds great potential, particularly in diagnosis. For example, AI can aid in accurately predicting the likelihood of a positive test result based on a patient’s specific set of symptoms and signs. It is also highly useful in classifying different types of skin lesions.

AI is being applied to telemedicine as well, allowing for improved monitoring and follow-up of patients. At the Congress in Glasgow, we will feature several Innovation Hub sessions where the role of AI in allergy care will be a key topic of discussion.

Moreover, EAACI is developing a practical initiative on the application of AI in allergic diseases, in collaboration with

the American Academy of Allergy, Asthma & Immunology (AAAAI).

We are already using AI in clinical practice, particularly to achieve more precise diagnosis and management. Looking to the future, especially after the lessons learned during the pandemic, we see that telemedicine and AI will play an increasingly important role in helping us care for our patients in a more efficient and accurate way.

Q4 What emerging diagnostic tools or biomarkers are you most excited about this year, especially those with real potential to enter clinical practice for asthma and allergic rhinitis?

Confirming the diagnosis of allergic rhinitis or allergic asthma remains challenging, particularly when it comes to assessing the clinical relevance of IgE sensitisations. This is a major unmet need in allergology. Understanding the relevance of IgE sensitisation is essential for identifying patients who may benefit from allergen immunotherapy, which is the only treatment that can actually modify the course of the disease.

In recent years, EAACI has made significant efforts to standardise nasal, bronchial, and allergen provocation tests. These procedures are extremely valuable in identifying individuals who are truly allergic among patients with chronic respiratory diseases. However, there are global shortages of allergen extracts for provocation testing, and these procedures can sometimes induce uncomfortable or even severe symptoms in patients.

As a result, we are also exploring the potential of in vitro procedures to assess the clinical relevance of IgE sensitisation in respiratory diseases. In particular, the basophil activation test is showing great promise, and we expect to see very positive results from ongoing research in the coming year.

Q5

Recruiting and mentoring talent is a growing challenge for many research centres. How is the EAACI Congress 2025 creating opportunities for young professionals to engage, collaborate, and grow in the field of allergy and immunology?

For nearly two decades, EAACI has been actively supporting the development of young professionals through a wellestablished and highly engaged Junior Member Assembly Board. This board organises a wide range of activities specifically designed for our youngest members. These include scientific initiatives, such as the Junior Member Poster Session and the Junior Member Case Report Session during the Congress, as well as the EAACI Allergy College for students. We also recognise the importance of networking and community, which is why we host social events like the Junior Member Party at the Congress.

Beyond the Congress, we offer additional scientific opportunities through our various sections and interest groups. One key

programme is our Clinical and Research Fellowship, which allows junior members to undertake educational and research placements at leading centres across Europe.

We also support focused initiatives like the Skin Allergy Club, which is organised annually by the Dermatology Section and provides a dedicated space for junior members who have a special interest in allergic skin diseases to learn, connect, and grow.

Q6

The EAACI is known for bridging basic science and clinical practice. How are omics technologies, AI, and big data helping transform the field, and how is the EAACI helping to translate these advances to the bedside?

We are still a long way from seeing omics science, big data, and AI fully integrated into routine clinical practice. For several years now, we have been collecting data across various variables and disciplines, with the goal of categorising patients into specific disease phenotypes and endotypes.

The integration of data from different omics domains allows us to classify individuals not only by their clinical symptoms, but also by the underlying disease mechanisms. However, analysing such vast datasets requires powerful computational tools, which are not yet available in all settings.

AI has the potential to support this process by evaluating and interpreting complex data more efficiently. EAACI is strongly committed to disseminating these advances throughout the scientific and medical community. However, it will still take some years before these innovations can be fully translated into clinical practice.

Q7 As Deputy Editor of the Allergy journal, you have an excellent view of research trends. What topics do you believe are underexplored or represent the next frontier in allergy and immunology?

Most areas of allergy and clinical immunology still require further research and investigation. There are some specific conditions, such as hereditary angioedema and mastocytosis, that have historically been considered rare. As a result, they were somewhat neglected; however, they are now receiving increased attention from both scientists and clinicians.

This renewed interest is largely driven by the development of novel medications that have the potential to significantly improve a patient’s quality of life and disease control.

Q8 Finally, as we prepare for the EAACI Congress 2025, what would you say to young researchers or clinicians attending for the first time?

I think they should expect a truly great Congress; I would even say the best Congress in the field this year. It’s an outstanding opportunity to learn new things, share your research and clinical experience, and connect with colleagues from all over the world.

I would encourage first-time attendees to ask questions, engage with speakers, and participate in every social event and networking opportunity. These moments are incredibly valuable. Networking is one of the key pillars of our annual Congress. It’s a space where people from very different disciplines come together to find not just the first solution, but the best solution for allergic diseases.

Attendees in Glasgow should feel that they are part of a global community of researchers, clinicians, allied healthcare professionals, and patients. Together, we are all working to move the field of allergology and clinical immunology forward.

Together, we are all working to move the field of allergology and clinical immunology forward

Global Perspectives on Challenges and Opportunities in Managing Allergic Rhinitis in Children: Taking the School Environment

as a Case

Interviewees:

Michael Blaiss,1 Lei Cheng,2 Mário Morais-Almeida3

1. Medical College of Georgia at Augusta University, USA

2. The First Affiliated Hospital with Nanjing Medical University, China

3. Hospital CUF Descobertas, Lisbon, Portugal

Support: The publication of this article was funded by Bayer.

Disclosure: Blaiss has consulted for ALK, Bayer, GSK, Nectar, Novartis, Opella, Prollergy, and SoundHealth; and been a paid as a speaker by AstraZeneca, Regeneron, and Sanofi. Cheng declares no conflicts of interest. Morais-Almeida has received research, educational, and lecture grants from AstraZeneca, Bayer, Eurodrugs, FAES Farma, GSK, Menarini, MSD, OM Pharma, Sanofi, and Viatris.

Acknowledgements: Medical writing assistance was provided by Caroline E. Cross, Reading, UK.

Disclaimer: The KOLs interviewed in this article were selected by Bayer, and the manuscript was reviewed by Bayer. Opinions expressed in this article belong solely to the named interviewees.

Keywords: Allergens, allergic rhinitis (AR), allergy, allergy-friendly schools, antihistamines, asthma, nasal corticosteroids, non-sedating medication, paediatrics, rhinitis, second-generation antihistamines.

Citation: EMJ Allergy Immunol. 2025;10[1]:84-92. https://doi.org/10.33590/emjallergyimmunol/AYPT3809

Interview Summary

The prevalence of allergic rhinitis (AR) varies between countries but is increasing globally as urbanisation and climate change increase exposure to allergens and irritants such as pollution. For children, schools are a problematic source of allergens and irritants that exacerbate the disease. AR can negatively impact a child’s capacity to attend and perform in school. Appropriate treatment of AR can help to mitigate this

PHARMA

impact, but avoidance strategies are also crucial in managing this chronic disease. In select children, allergen immunotherapy may also play an important role. EMJ spoke to three experts in allergy and immunology from China, Portugal, and the USA, who described how and why the prevalence of AR is evolving, and what impacts AR can have on children. They emphasised the importance of early diagnosis and effective treatment for children using standardised treatment guidelines; controlling allergen and irritant exposure in the school environment; and improving the quality of health education among patients, caregivers, school staff, policy makers, and HCPs including paediatricians, general practitioners, and pharmacists, to promote and optimise AR management. They also highlighted the need for strategies to provide allergy-friendly schools to ensure that children with AR can thrive academically, physically, and socially.

INTRODUCTION

AR, the most prevalent allergic disease across all age groups, causes a substantial and increasing burden on the health of individuals around the world. Prevalence data suggest that 10.5–19.9% of children globally suffer from AR.1,2 The increasing prevalence and complexity of AR is a consequence of climate change causing increased air temperatures, longer pollen seasons, increased pollen production, and allergenicity of the pollen.3 Increased urbanisation is also driving these changes, exposing children to greater levels of air pollution, which acts as an irritant, increasing their susceptibility to develop AR and exacerbate symptoms.4,5 These environmental changes impact children more significantly compared to adults.6 AR can present in pre-school children as young as 2–3 years old,2 with symptoms including sneezing, itching, nasal congestion, and rhinorrhoea, often misdiagnosed as viral infections.7 Comorbidities such as asthma are common, and estimates suggest that 80% of people with asthma also have AR, while up to 40% of individuals with AR also have asthma.8

School-age children spend significant amounts of time in educational settings. Many schools have inadequate ventilation and ageing infrastructure that can increase the presence of allergens and contribute to poor health among staff and students, increasing absenteeism, presenteeism, and impacting academic performance.9 Even modern school buildings can increase allergen and irritant levels, when natural ventilation is reduced to help increase energy efficiency. In heavily polluted

cities, air pollutants can enter the classroom, including sulphur dioxide (SO2), and particulate matter (PM) 2.5 and PM10, at levels higher than recommended by the WHO. Exposure to these pollutants can exacerbate respiratory symptoms,10-13 and perpetuate educational inequalities in settings where school revenues are linked to student attendance rates.14

AR can have far-reaching effects on a child’s quality of life, mental health, and academic performance.6 Poorly controlled AR has been shown to result in lower academic productivity due to AR symptoms, use of sedating antihistamines, poor sleep quality, and increased absenteeism.15,16 Studies show that children with allergic conditions are more likely to be in a lower quartile for reading ability,17 and can be at increased risk of bullying and victimisation compared to children without respiratory conditions.18,19 Achieving good AR and asthma control can return school performance to normal.20

Current treatment recommendations for paediatric AR are based on the frequency of symptoms and the impact on the quality of life.21 In the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines,22 symptoms experienced less than 4 days a week or less than 4 consecutive weeks are considered intermittent, whereas in persistent AR, symptoms last more than 4 days a week and 4 consecutive weeks.23 AR severity is categorised as mild when there is no impact on daily activities or sleep, or moderate-tosevere when symptoms interfere with sleep, daily activities, or school, or trigger serious sequelae like asthma attacks (Table 1).24

1: ‘Intermittent’

2: ‘Persistent’

3: ‘Mild’

4: ‘Moderate-to-severe’

To understand how the management of AR can be improved to reduce the burden of disease on children, particularly in the school environment, EMJ spoke to three allergy experts: Michael Blaiss, Clinical Professor of Paediatrics, Medical College of Georgia, Augusta Georgia, USA, and Past President of the American College of Allergy, Asthma, and Immunology (ACAAI); Lei Cheng, Professor of Otorhinolaryngology & Director of Clinical Allergy Center, The First Affiliated Hospital with Nanjing Medical University, China, and current President of the Chinese Society of Allergy; and Mário Morais-Almeida, Head of Allergy Center, CUF-Descobertas Hospital, Lisbon, Portugal, and current President of the World Allergy Organization (WAO). The experts’ wide-ranging insights into the impact of AR on children highlight the need for better education among stakeholders to ensure best practices are understood, shared, and implemented consistently around the world. In addition, the experts agreed that existing policies to create allergy-friendly schools

Symptoms are present:

<4 days per week, or <4 weeks

Symptoms are present:

>4 days per week, and >4 weeks

None of the following items are present:

Sleep disturbance

Impairment of daily activities, leisure, and/or sport

Impairment of school or work

Troublesome symptoms

One or more of the following items are present:

Sleep disturbance

Impairment of daily activities, leisure and/or sport

Impairment of school or work

Troublesome symptoms

should be more widely adopted to reduce health inequalities and allow every child to thrive both in, and outside of, the classroom.

EVOLVING ALLERGIC RHINITIS PREVALENCE, SEVERITY, AND COMORBIDITIES

The number of children experiencing AR is increasing across the globe. “In China, we have observed a rapid increase in both population-based surveys and hospitalbased diagnosis data in the past decades. People affected by self-reported AR increased by almost 100 million in 2011 compared to 2005,” Cheng explained. A meta-analysis of Chinese epidemiological studies of children found that the diagnosed prevalence of allergic rhinitis from 2012–2021 was higher (19.75%) than that from 2001–2011 (14.81%).2,25 “These are astonishing figures,” Cheng said, explaining that increasing urbanisation, pet ownership, and air pollution are driving

Table 1: Classification of allergic rhinitis.24

the AR epidemic. Blaiss and MoraisAlmeida agreed, adding that, in the USA and Europe, AR prevalence has reached up to 40%, with children increasingly affected, and comorbidities including asthma, eczema, chronic rhinosinusitis, and sleep-disordered breathing increasing too, particularly in urban areas.4

Morais-Almeida stated that, in his experience, more young children (3–5 years old) are presenting with chronic rhinitis,26 and about 25% of them with moderate-to-severe symptoms, although not all in the allergic form. In addition, Morais-Almeida explained that many people in Portugal and other parts of southern Europe are experiencing persistent AR. This is most likely because of the effects of climate change, which is lengthening pollen seasons and increasing air pollution. Cheng outlined how, in China, the predominant allergens vary according to region. In Southern regions of China, dust mites are the leading cause of AR, whereas plant allergens, including mugwort, ragweed, and dandelion, are the most common allergens in the Northwest of the country. In urban areas, afforestation with anemophilous plants can cause seasonal allergies in the spring. This contrasts with summer and autumn allergies that are mostly caused by weed pollen from species including Atermisia spp., Hummulus spp., and Chenopodium quinoa, Cheng added. Blaiss concurred and said that outdoor allergens in the USA also vary depending on region. “Knowing the particular allergens in your area and time of pollination is important in limiting outdoor exposure,” Blaiss added.

Data from the International Study of Asthma and Allergies in Childhood (ISAAC) has shown that AR often begins in early life, with prevalence increasing with age.27 The experts noted that comorbidities such as asthma are increasingly common. “This is concerning because, apart from genetics, AR is the main risk factor for asthma in early life,”28,29 Morais-Almeida emphasised. “We need to treat AR effectively as early as possible to prevent progression to asthma.” In the USA, in 2021, 18.9% of children experienced seasonal allergies,30 Blaiss explained, adding that severity

appears to be increasing too, with a recent study suggesting that airconditioned environments may increase disease severity in children.31

DEVELOPMENT OF EFFECTIVE AR TREATMENT GUIDELINES

Evidence-based guidelines for the treatment of AR are being implemented across the globe. In Europe and the USA, the ARIA guidelines7,21 form the basis for the treatment of mild and moderate-to-severe, intermittent, or persistent AR. In China, guidelines were first developed in the 1990s by the Chinese Medical Association and allergy experts, with regular updates every 6–7 years.3 According to Cheng, the publication of the ARIA guidelines in 2001 had an important impact on the Chinese guidelines.32 Now, the Chinese guidelines, informed by research in China and internationally, align closely with the ARIA guidelines, recommending four types of drugs as first-line treatments for AR, including oral second-generation antihistamines, nasal glucocorticoids, nasal antihistamines, and leukotriene receptor antagonists (LTRA).25 “Our guidelines focus on continuous improvement, which has led us to a system with Chinese characteristics that incorporates international experience to improve diagnosis and treatments,” explained Cheng. In 2022, the updates included separate guidelines for adults and children that are very specific and easy for HCPs to follow. Cheng also outlined that the Chinese guidelines follow the principle of combining prevention and treatment, with a ‘four in one’ approach: environmental control, pharmacotherapy, immunotherapy, and health education.33 In the Chinese guidelines, first-line drug monotherapy is usually effective in mild, intermittent AR. For moderate-to-severe, persistent AR, a combination of a nasal glucocorticoid and a second-generation antihistamine and/or LTRA, is recommended.33 Allergen-specific immunotherapy (AIT) is also recommended as first-line treatment for AR in Chinese guidelines.33

CHALLENGES OF IMPLEMENTING GUIDELINES: TRIVIALISATION OF ALLERGIC RHINITIS AND RISE OF MISINFORMATION

Despite the availability of evidence-based guidelines for the management of AR, in many cases, AR is not managed effectively. The experts agreed that paediatric AR is too often trivialised by caregivers and HCPs, and outlined some challenges encountered with implementing the guidelines in practice. AR symptoms may start with an itchy nose and sneezing, but can develop to nasal obstruction, persistent cough, and sleep disruption. Morais-Almeida explained that, often, when patients go to the doctors to talk about their AR symptoms, they end up focusing on other conditions or symptoms, such as experiencing a high number of respiratory infections, restless sleep, snoring, and headaches. The HCPs may also feel that some symptoms are more important to discuss, and the AR may not be considered fully. “Several of these manifestations that came to the ‘podium’ at the consultation are common complications or comorbidities of an under-recognised and under-treated allergic rhinitis,” Morais-Almeida emphasised.

However, many people self-medicate for AR with over-the-counter medications without consulting with an HCP. Blaiss is worried that misinformation circulating on social media is exacerbating noncompliance and creating fear among patients. “In the USA, we are increasingly seeing non-compliance to medication among patients, and lack of understanding of how to use medication. For example, parents may delay taking their child to see a paediatric allergist due to their belief in online testimonials claiming AR can be managed ‘without doctors’ or ‘cured naturally’.” Also, according to Blaiss, many people with AR are unaware that they need to medicate before symptoms worsen. “Patients and caregivers need to understand that individuals with AR will maintain better symptom control if they start medication before symptoms build up, rather than waiting until symptoms become severe, and that they should be taking medication regularly,” Blaiss explained.

Another issue, Morais-Almeida said, is that people buy medication from pharmacies that are sold in small boxes, which can create issues for compliance and consequently for control. Patients could benefit from an AR management plan, with clear recommendations on treatment duration. Another concern, said Blaiss, is that people are increasingly using homeopathic remedies, advertised on social media, for which there is no scientific evidence on efficacy or safety.

OPTIMISING TREATMENTS FOR PAEDIATRIC PATIENTS WITH ALLERGIC RHINITIS

To standardise treatment in paediatric patients with AR in the USA and Europe, the EUFOREA algorithm for treatment escalation and de-escalation in children is closely followed.7 First-line care for mild intermittent or persistent, and moderateto-severe intermittent AR includes second-generation antihistamines, and addition or replacement with nasal corticosteroids when symptoms are not controlled.7 In China, there are specific AR guidelines for children, with detailed recommendations on pharmacotherapy.33 Cheng emphasised the need to use second-generation antihistamines to minimise sedation and other cognitive adverse events. “For the treatment of AR in children, non-sedating second-generation antihistamines are recommended to avoid central nervous system inhibition that may affect cognitive function,” Cheng said. He continued: “In patients with moderate-to-severe and persistent AR, we would recommend combining secondgeneration antihistamines with intranasal corticosteroids that have low systemic bioavailability because it is important to ensure growth is not affected, especially when some children with persistent AR require corticosteroids for 12 weeks or more.” It is also very important that clinicians pay particular attention to age limits for medications, choose appropriate doses, and consider potential adverse drug reactions. “Every doctor should know that children are not mini versions of adults,” Cheng emphasised.

The challenges of optimising treatment for paediatric AR are not limited to HCP recommendations, as many caregivers choose to treat without consulting with an HCP, which the experts believe can sometimes lead to either suboptimal treatment selection or incorrect administration. All three experts highlighted the importance of the role of the HCP to ensure prompt and effective control of AR in children to avoid progression to more severe symptoms and comorbidities, in particular asthma. Morais-Almeida summarised the point saying: “It is important to control AR today and next week, to reduce the impact on everyday activities and school performance, but it is also important to treat for the future.” If pharmacotherapy is not sufficient to improve quality of life and sleep to an acceptable level, the individual should be referred to a specialist and allergen-specific immunotherapy (AIT) may be appropriate, Blaiss added.

Encouraging shared decision-making between children, caregivers, and HCPs is also crucial for successful management of AR, the experts said. Morais-Almeida recommends starting conversations with young patients as early as possible. Blaiss agreed, saying: “When you have the patient and their caregiver in the room, you need to explain the treatment options, and work with them to decide what they find most acceptable. For example, there is no point in prescribing an intranasal corticosteroid if they say they won’t use a nasal spray. The patient is a partner, and you need to agree on what treatment regimen will best suit the patient’s lifestyle.”

IMPACT OF THE SCHOOL ENVIRONMENT ON PAEDIATRIC ALLERGIC RHINITIS

Most children spend many of their waking hours at school, an environment that can trigger allergies. Allergens in schools range from dust mites in carpeting, bookshelves, and toys, to animal dander on classmates’ clothes, and mould and cockroaches in poorly maintained buildings. Allergy symptoms can be further exacerbated by

irritants from cleaning products and air pollutants due to insufficient ventilation systems. As Blaiss explained, children and adolescents spend much of their time either in their bedroom or the classroom, and while the home environment can be adapted to reduce allergen exposure, the school environment is more difficult for the individual or caregiver to control.

The impacts of uncontrolled AR on children are significant. Sleep disruption, sneezing, and rhino-conjunctivitis make it difficult for children to concentrate and function as normal during the day. Children who experience AR symptoms, or need to take medication at school, also often have feelings of social isolation and self-consciousness.16 Blaiss highlighted studies showing that AR and allergic rhinoconjunctivitis (ARC) can affect academic performance, with students performing less well in summer exams than similar level tests taken during the winter months.16 A questionnaire-based study of academic productivity in people aged 13–29 years also demonstrated the negative impacts of AR.15 The findings of these studies emphasise the importance of ensuring that clinicians gain a better understanding of the unique burden that AR places on children. Ensuring HCPs, school staff, and caregivers understand the impact of AR on children would help them to receive prompt and appropriate treatment to improve both clinical and academic outcomes. Blaiss and Morais-Almeida noted that, in the USA and Europe, there is limited education in medical schools on AR, and, in the USA, no mandatory training for resident doctors in allergy and immunology. Increasing education about allergies for new doctors can enable them to make better informed recommendations on AR management, particularly by avoiding medications that impair concentration, like first-generation antihistamines. The experts agreed that better education for HCPs, caregivers, and patients would improve awareness of AR and its triggers, help to reduce the detrimental impact of AR symptoms and suboptimal medication, and support better quality of life and academic performance for young people.

STRATEGIES TO REDUCE THE IMPACT OF ALLERGIC RHINITIS ON SCHOOL CHILDREN

Environmental Control

Environmental control strategies can help reduce exposure to allergens and irritants. Cheng reiterated that many children’s AR symptoms can be significantly improved through environmental control measures, which is one of the four priority areas for primary intervention outlined in the most recent Chinese AR treatment guidelines.25,33 Some urban schools in China are reducing air pollution and pollen concentration in classrooms and trying to avoid stimuli, like cold and heat alternation, that can exacerbate allergic symptoms, Cheng said.

The experts agreed that more should be done to help reduce exposure to allergens in the school environment. Conditions vary hugely between regions and between individual schools in the same region; however, the experts identified adaptations that help, including removal of soft furnishings and carpets, regular maintenance of air filtration systems, use of allergy-friendly cleaning products, and limiting pets in the classroom. Children with pollen allergies could be allowed to stay indoors during break times when pollen forecasts are high.

Health Education

In China, the most recent AR guidelines introduce advice on prevention measures, and in the children’s guidelines emphasise the value of health education to improve disease awareness, avoidance of allergens through environmental control, and treatment compliance.33 Following recommendations from the WAO to standardise treatment and management through the education of HCPs, the Chinese Society of Allergy developed a programme of talks to encourage utilisation of guidelines through continuing medical education (CME). “At the same time, by combining doctor education and patient education, we are vigorously promoting medical science popularisation projects,” Cheng said. He went on to explain that

there are two benefits to this: “The first is to increase awareness of AR and to increase compliance of treatment. The second benefit is that HCPs are better equipped to make accurate diagnosis and standardise treatment, adhering closely to published guidelines and thereby improving the quality of AR management.”

An important element of health education, said Blaiss and Morais-Almeida, is to advise patients and caregivers on the sedative effects of first-generation antihistamines. Portugal has approximately 10 million inhabitants and, according to Morais-Almeida, each year, approximately one million packs of first-generation antihistamines are dispensed from community pharmacies, many of them as over-the-counter medicines without prescription. “These medicines cause drowsiness and have other potentially harmful side-effects in a significant percentage of our population, including in the paediatric age group,” MoraisAlmeida explained. “This is problematic for children, impacting their ability to concentrate in school, and for adults where, for example, the sedation impairs driving performance and psychomotor function, including reaction time.34 Both Blaiss and Morais-Almeida noted first-generation antihistamines no longer have a place in AR treatment, and are not recommended in any AR treatment guidelines, a view that is widely supported by a recent publication in the WAO journal, and others.35,36

Public Engagement

Projects to engage and educate physicians, pharmacists, and the general public on AR management are helping to raise awareness of AR and strategies to reduce exposure and achieve more effective symptom control. ‘’We have a project in Portugal called ‘News about pollen’ which is a weekly TV show that started 18 years ago to empower people with information about allergens, pollution, and the impact of allergic diseases, including AR, asthma, and atopic dermatitis,” explained MoraisAlmeida. “This helps us to empower the population to choose medications wisely,

and at the same time to involve HCPs and pharmacists. We highlight the right way of using the treatments and promote non-sedating medications.”

The Control of Allergic Rhinitis and Asthma Test (CARAT) is a tool to assess control of AR and asthma in adults and children37-39 that was developed in Portugal and promoted and used widely. CARAT has been translated into more than fifteen languages and is used in countries around the world, being recommended by ARIA, Morais-Almeida explained. “This is important because it is very difficult to get control of asthma if you don’t get control of AR.” New digital tools are also helping to empower patients to take control of their condition in terms of symptom management, allergen avoidance, and treatment.40-42

In China, public lectures and academic forums are used to engage with the public to increase awareness of AR and encourage early diagnosis, treatment, and prevention, to avoid exacerbation, recurrence of symptoms, and exposure to new allergens. Cheng highlighted the WAO’s World Allergy Week43 as an important event that is helpful to raise awareness of AR with public audiences. “For children and adolescents with AR, education can improve the relevant knowledge level and treatment compliance of patients, help reduce the recurrence rate and complications of AR, and improve patient quality of life by alleviating their physical and psychological symptoms,” Cheng reiterated.

Promoting Allergy-Friendly Schools

The experts believe that teachers and school staff need to be better informed about the impact AR can have on their students, and what mitigation strategies can be put in place. Environmental control measures are important to reduce allergen

References

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CONCLUSION

The impact of AR on children and their ability to thrive in and out of the classroom should not be underestimated. More needs to be done to optimise diagnosis, treatment, and education to enable and encourage schools to create environments that are free from allergens, so that all children can thrive academically, physically, and socially. Raising awareness of best practices in the management of AR, including shared decision-making between patients, caregivers, and HCPs, is vital to improve adherence, quality of life, and treatment outcomes.

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29. Pereira AM et al. Severity of rhinitis and wheezing is strongly associated in preschoolers: a population-based study. Pediatr Allergy Immunol. 2015;26:618-27.

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Interviews

EMJ had the pleasure of speaking to two key opinion leaders, Hugh Sampson and Mário Morais-Almeida, in interviews exploring key developments in the field of allergy and immunology. Sampson reflects on his unexpected path into food allergy research and shares his expert perspective on advancing oral immunotherapy, including the role of biologics like omalizumab in improving safety and accessibility. Meanwhile, Morais-Almeida highlights major shifts in allergy care since the 1990s, from the rise of molecular diagnostics to the impact of biologic therapies in respiratory diseases, and offers a forward-looking view on personalised approaches in allergic rhinitis and the influence of environmental factors.

Featuring: Hugh Sampson & Mário Morais-Almeida

Hugh Sampson

Kurt Hirschhorn Professor of Paediatrics, Icahn School of Medicine, Mount Sinai; Director Emeritus, Jaffe Food Allergy Institute, New York, USA

Disclosure: Sampson receives grant support from the NIAID and DBV Technologies; serves as a consultant for Allertein therapeutics, Genentech/Roche, Sanofi, Stallergenes, Sanone, and Merck; is a part time employee of DBV Technologies; receives royalties from UpToDate and Elsevier; and received stock from DBV Technologies.

Citation: EMJ Allergy Immunol. 2025;10[1]:93-99. https://doi.org/10.33590/emjallergyimmunol/HVLD7317

Q1What initially drew you to the field of allergy and immunology, and how did your focus come to centre on food allergic disorders?

I got interested in immunology before I even went to college. I had a cousin who did a fellowship with Robert Good, a pioneer in the field of immunodeficiency diseases, and he had told me a lot about it. I got quite excited about the field of immunology once I got to medical school and then into my residency. I was always intrigued by various immunodeficiency diseases, and really looked forward to going into the field of clinical immunology.

When I got to Duke University, Durham, North Carolina, USA, which is where I did my fellowship, my mentor really wanted me to look more at allergy, and I, to be honest, never wanted to do allergy. I never even thought I would think about doing food allergy. However, there was a very nice Emeritus Professor who kept telling me how important food allergy was, and maybe I should look at it. I was doing basic research at the time, and one of my findings brought the train of research that I was doing to a bit of a halt. I started looking at food allergy and Charlie May, at the University of Colorado Medical School in Denver, USA, had, just a couple of years

previously, published on doubleblind, placebo-controlled food challenges. It brought science to the field of food allergy, which at the time nobody really considered to be a science.

So, I started doing it, and when I began doing these food challenges and looking at it a little bit more, I became very interested. Then, as would happen, my middle daughter ended up having an egg allergy, so I got to see a little bit of it first-hand and just got more intrigued with it as I got more and more involved.

Q2

Oral immunotherapies (OIT) have shown promise in increasing tolerance to food allergens, but they also come with risks and challenges. What do you see as the key advancements needed to make OIT safer, more accessible, and better tailored to the diverse needs of patients with severe food allergies?

I think the work that's been done in oral immunotherapy has been very good. I've spent most of my career telling people they need

to avoid food, so it's nice that we finally have something we can do proactively.

The problem with what we see with oral immunotherapy is that there is a high adverse reaction rate, and also it takes a lot of time out of your day. When you initiate the therapy, there are many visits to the physician’s or allergist’s office as you increase your dose. There's a lot of time required by the parents and the child to go to these different sessions, and that takes about 6 months in most cases.

Also, here in the USA, you're supposed to wait 2 hours before you do any exercise, before you have a hot shower, and you have to be careful about taking certain medications like aspirin and nonsteroidal anti-inflammatories. If you get sick, you have to decrease your dose. There's just a lot of interference with your daily life to do oral immunotherapy; however, it does allow you to desensitise the patient, so that if they were to ingest a peanut, for example, they would be able to ingest small

amounts of it without having any problem, which is certainly a good thing.

I think one of the biggest things that we have to do is figure out a way to be able to give it more rapidly. One of the things that we've done studies on, and other people have done studies on, is using omalizumab, which is an anti-IgE monoclonal antibody that raises what we call your threshold of reactivity, or the amount of that particular food it takes to cause an allergic reaction. Using that in conjunction with oral immunotherapy, we can get them up to maintenance dose much more quickly, with about a third of the number of adverse reactions. That, in a way, is a step forward, but we're going to have to find other ways to be able to do it much more rapidly. People have thought about modifying the protein, taking out some of the allergenic components of that food protein. So far, we've done very well in our mouse models, and I always tell people, I've cured most mice of peanut allergy and milk allergy, but many of these

methods don’t quite translate into humans yet. There's a lot to learn.

The one thing that I've really been encouraged by is that when I started in this field, there were only a couple of us working in food allergy, and now it's one of the most prominent areas in allergy. When we go to national meetings, a third to a half of the presentations are related to food allergy, which never happened before. There are now dozens of companies that are interested in coming up with different forms of therapy for food allergy. I think the field is very promising, we have a lot yet to learn, but I think we're definitely going in the right direction.

I think having something like oral immunotherapy, while we certainly want to do much better than that, is at least allowing us to offer patients something. One more thing that I'm very excited about is some of the early findings looking at doing oral immunotherapy in very young children, like 1–3-yearolds. We're finding that by starting at that early age, we may actually be curing some of their allergies, making them go permanently into remission, which you don't often see when you do oral immunotherapy in older patients.

Q3With the growing body of research around biomarkers and immunological markers, how do you envision their role in predicting responses to OIT for severe food allergies?

The whole area of biomarkers is also a really interesting area, and that comes largely from a lot of the basic research that's been going on. With better understanding of what the immune mechanisms are that lead to food allergies, we're finding things that better tell us what's happening and how we can predict things.

Our lab has been very interested in something called epitope profiling. What that means is we look specifically at where the IgE antibody attaches to a food. For example, peanuts are made up of several different proteins, and we can now measure those clinically. We see that, for example, in peanuts, the two proteins that seem most important are what we call Ara h 2 and Ara h 6, and what we're doing with this epitope profiling is looking at exactly where the antibodies are attaching to this Ara h 2 protein. By doing this with colleagues who are experts in biostatistics and machine learning, we are able to generate algorithms that help us predict ahead of time what's going to happen when we do immunotherapy.

and knowing how much time that's going to take out of their life, if you have somebody who's likely to have a very good response, they might be much more willing to undergo oral immunotherapy than someone where you can say, you know, this just doesn't look like it's going to work for you.

I always tell people, I've cured most mice of peanut allergy and milk allergy, but many of these methods don’t quite translate into humans yet

We've done this now with both milk and peanut. We have looked at the way a certain patient’s allergic antibodies see a protein and are able to tell whether they're going to have a successful time with oral immunotherapy, meaning they may even obtain what we call sustained unresponsiveness, or a more long-term remission. The advantage to that is that when we start talking to patients about oral immunotherapy, for example,

Then people are looking at more biologic assays, where we look at the response of basophils and mast cells in lab experiments, which show what kind of response we get there. That, and the epitope profiling, are allowing us to get a better handle on not only how people are likely to respond but also give us some idea of how much food they might be able to tolerate before experiencing a reaction. One of the things we've learnt is that when you are food allergic, there are some people who will react to the most minute amount of that particular food, and there are other people who could eat one or maybe even two peanuts and not react, but if they ate more, they would have an allergic reaction. Some of these biomarkers are helping us identify these people, and again, where that may be important is if you know you can ingest the full peanut without having a reaction, it's not so likely that small contaminating amounts will make you react. Therefore, that would definitely change your lifestyle, as you might be much more willing to go out to restaurants or go to your friend's house and things like that. You still need to be cautious, but a small mistake wouldn't end up with you having an allergic reaction.

I think these biomarkers are going to help us in prediction, but then we're also trying to identify biomarkers that tell us, at the end of some form of therapy, how likely you are to be protected without having to do a food

challenge in order to know how much they have to ingest before a reaction will occur.

Q4

How do you think genetic factors or microbiome analysis might improve patient stratification, and what advancements are needed to translate these findings into clinical practice?

Well, I'll admit this is not my area of expertise, but I think one of the things we clearly see is that food allergy does have a genetic component, although it's largely environmentally dependent. The reason we know that is because we've been involved in things like twin studies where you have identical twins. If it was all genetics, the two of them should have exactly the same thing happen, and yet we don't see that.

The other thing is, we know that when we look at the prevalence of food allergy, it really seemed to start increasing in the late 1990s and early 2000s, and there's been a tripling of peanut allergy, for example, in that period of time. Something like that is not genetically controlled; it's too short of a time period. Genetics takes years and years, but there certainly is a component, and

there certainly have been some genes that have been identified that seem to correlate with those people likely to go on to have a particular food allergy.

Food allergy does have a genetic component, although it's largely environmentally dependent

But we have a whole lot more to learn. Food allergy is something that is most likely what we would call a multi-gene disorder. It's not just one gene causing the problem, there's a whole bunch of them that get together in a certain environmental situation, and when that combination hits you end up with that food allergy. We have a lot to learn there; the research is going on, and I think it will get better.

The whole microbiome story is fascinating, and I think there's a lot of really interesting work going on now. There are real strides going forward in looking at potential probiotics that may be used to actually help prevent the development of food allergy.

A number of investigators on both sides of the ocean have been very involved in this area and have identified what they call certain ‘communities of bacteria’ that people have who are more likely to develop a food allergy.

The one thing that's been very clear, as in very young children, is that the bacteria in your gastrointestinal (GI) tract is incredibly important in helping you develop a normal immune system. For example, one of the studies that we're hoping to finish up in the next month or so has been looking at babies born by caesarean (C) section. We've known for a long time that babies born by C-section have a higher rate of allergy, food allergy, autoimmune disease, and some other types of disorders. The feeling has been that because these babies don't come through the birth canal, they don't get the appropriate bacteria from the mother. They tend to get bacteria from the skin or the hospital environment. So, a colleague of mine conducted a study where they demonstrated that by doing vaginal seeding, or taking a swab from the mother's vaginal canal and swabbing a baby who was born by C-section, with it at birth, their microbiome, or the bacteria

in their GI tract, looks much more like a baby born vaginally.

The study we've been doing is taking babies born by C-section and randomly assigning them to get the vaginal seeding with the material from the vaginal canal versus babies getting placebo. We’re looking to see whether that is sufficient to prevent the development of allergy or the early forms of allergy. I'll be very excited to see how that turns out as we have a month left to get the final patient in, and then we get to start analysing all the data. In the USA now, 35% of babies are born by C-section, so that's a huge number of babies that are put at higher risk. If we can do something as simple as this swabbing, or vaginal seeding, to prevent a lot of that allergy, that would be a tremendous step forward in our health system.

This is a fascinating area, and I think that over the next several years there will be more of these studies. They've been doing this using probiotics, giving babies active bacteria. There are even studies now where they're looking at giving faecal material, that's obviously been cleaned up, but you give this faecal material from people with normal bacteria to individuals who have food allergy to see if they can modify their immune system or their response from the bacteria in the GI tract to help treat some of these food allergies.

I think in the next 5 years we're going to see some really interesting studies, but the thing that's so fascinating to me is the fact that these bacteria that live in your GI tract have so much power over how your immune system develops. It's probably also the same with the bacteria on our skin. That's another area that's just being started to be looked at,

and there’s so much to come in that area.

Q5Based on a recent paper you co-authored entitled ‘Epicutaneous Immunotherapy for the Treatment of Peanut Allergy’, what do you consider to be the most significant implications of EPIT for clinical practice, particularly in terms of its suitability for younger children compared to current therapies such as oral immunotherapy?

So, for full disclosure, I consult for the company that did that, DBV Technologies, so I could have some bias. The thing that really intrigued me about this is the idea that you can put this really minuscule amount of peanut protein in a patch on somebody's back on a daily basis and bring about this big change in the immune system.

When I started out in my career, I did a lot with atopic dermatitis, which is the allergic, itchy rash babies and older people get on their skin, and I had never really considered how immunologically potent the skin is. It's really an immune organ, and the concept of being able to do something through the skin in a way that can bring about a big change in food allergy was really intriguing.

Simply putting on this patch, which is a little disc that contains a very small amount of a peanut protein, daily for 3 years will expose a patient to the equivalent of one peanut over the 3-year period. That's how little it is. What they've been able to show, especially in very young children (1–3 years old), is that it's highly effective in damping down or turning off the immune response to peanuts. With that, a study was published a couple of years ago showing that it met their primary

endpoint, which was protection from reacting to a challenge following therapy, or a certain amount of peanut during therapy.

The part that I find interesting, though, and which in a way I would expect based on how the immune system of the skin works, is that it takes longer to do that. So, children who went through that study were offered a chance to go on a second year of the patch, which they did. After the second year, it showed that even more of the children were able to tolerate larger amounts of peanut protein without reacting. Then they were offered a third year. Now, 3 years on, about two-thirds of those children who were still in the study were able to eat the entire challenge dose without a reaction; this was around 15 peanuts. Overall, about 85% of the children had significant improvement in their peanut allergy. During that period of time, they got major protection from reactions to peanuts.

The thing that's nice about epicutaneous immunotherapy is you see much less in the way of adverse reactions, partly because you're putting it on the skin, and I won't go through all the immunology, but it basically doesn't go through the bloodstream, it goes through the lymphatic system. It's not exposing all these mast cells in basophils to the protein, and therefore, you see much less in the way of adverse reactions, and you don't have to modify it up and down for illness or activities. Parents do the patch at home after the first visit; there's no need for multiple visits, there's no restriction on exercise and showers, and all this other kind of stuff. It's just a much easier way to do it, much less of an interference on a patient’s daily life.

To me, it's a potentially exciting way to be able to treat a patient and get a good result. It does take longer than it would with oral immunotherapy, but it's also much less in the way of adverse reactions and in the long-term reach comparable results. That's an exciting way to get started, and my big push is in the 1–3-yearolds, because that's when the parents have much more control anyway, and the results appear to be much better.

Q6

The dual allergen exposure hypothesis presents a fascinating paradox: how the skin can mediate both sensitisation and desensitisation to food allergens. Based on your findings in the paper titled ‘The riddle of response to cutaneous allergen exposure in patients with atopic dermatitis’, what do you see as the most critical factors influencing whether cutaneous allergen exposure leads to tolerance or allergy, particularly in patients with atopic dermatitis?

That's a great question. I think we're still trying to get all allergists to understand what the difference is. Typically, what happens if you have what I'll call normal, uninflamed skin, or non-irritated skin, and you get a food protein on your skin, or dust mites or pollens, is you become tolerant to that protein just the way you would if you ingest something orally.

If you ingest food, typically, your immune system ensures you become tolerant to it. If you put the food on normal, non-irritated skin, it will also lead to tolerance induction. Where the problem comes in is if the skin is inflamed, such as in atopic dermatitis, or if it's irritated. The latter occurs in part due to our “overwashing” of babies and the change in soap composition, as there are higher amounts of

surfactants in those soaps today. This is because it cleans better, but it also damages and irritates the skin a bit, causing what we call the keratinocytes to release “alarmins.” Keratinocytes are the cells that make up the outer layer of the skin to protect you and respond to the external environment.

This responsiveness probably evolved during times when we used to have parasites attack our skin, and when you have what you call a “danger signal,” they release something called alarmins, which are cytokines. Cytokines tell other cells: ‘This is bad, we've got to react against it.’ With parasites, IgG responses that we use against bacteria weren't potent enough, so we evolved IgE, which is like a cannon instead of a pistol. It's a major response. Unfortunately, this system has now redirected its response to things that it shouldn't. When the skin is irritated and you get those proteins on the skin, you may develop an IgE-mediated response, which can lead to allergy.

One of the things I don't think we appreciated was how much food protein there is in our environment. Gideon Lack, King’s College London, UK, is the one that put forward this dual allergen exposure. One of the things his group did was look at the amount of peanut protein in the house dust of British families, and found very high levels of peanut protein. Babies with this irritated skin are exposed to these proteins, peanut, egg, and milk, in house dust, but also on the hands of the parents and their siblings. They're getting this exposure. One of the questions, especially one that I always had when I started out, was how were these infants becoming peanut allergic when they weren't ingesting any peanut? We didn't realise that it was the environmental peanut on the skin

that was leading to this allergy. So, if the skin was totally normal, if it's not irritated, you're going to tolerise. It's not going to be a problem. Most of the kids we see with food allergy have a history of atopic dermatitis, and because they're getting this exposure to allergens on inflamed skin, they develop food (or other) allergies.

There's also something we call the ‘atopic march’, which is where children who start out with atopic dermatitis end up eventually getting allergic rhinitis and oftentimes asthma. Part of that, again, is due to the fact that they're getting these proteins, dust mites, cat dander, dog dander, all these other proteins on their skin, which is then leading to allergic responses. Previously, we hadn't appreciated this dual role, that if things are all normal, it goes one way but if the skin is inflamed, you have these alarmins secreted, which make it go the other way.

The one thing I always found sort of funny, I'm not sure my patients’ parents did, but occasionally we see people who are allergic to Brazil nuts. We don't eat much in the way of Brazil nuts in the USA, whereas in the UK, you have much more exposure to Brazil nuts. So, sometimes, when I find a young child who is allergic to Brazil nuts, I ask the parents, ‘Oh, have you lived in England?’ More than 50% of the time they say ‘Yes’.

Additionally, cashew, to us, is the new peanut, because cashew, at least in the USA, and I know in Australia and the UK as well, has become much more available, and people use it a lot more. So, we're seeing much higher rates of cashew allergy now. In Australia, there was a study published not too long ago showing cashew allergy is just about as common as peanut allergy in young children.

Q7

What key changes or advancements do you anticipate in the field of oral immunotherapies for food allergies in the near future?

One of the biggest problems we see now is that when I started, which was a long time ago, I spent most of the time showing people they weren't reactive to many foods. They might be sensitised, meaning they would have a positive skin test or a positive blood test, but if they ingested it, they were totally fine. Usually, we would find that children would react to one food and occasionally two foods. Today it is almost the reverse. I almost never find somebody who only reacts to a single food.

This multi-food allergy is becoming a real problem, which suggests that we have to come up with methods to be able to treat many food allergies at one time.

Now, some people are looking at doing things like what we call multi-food oral immunotherapy, where you treat them with a whole group of foods. Omalizumab, an anti-IGE antibody, can decrease their reactivity to the particular food, and then you can try to treat them orally with many foods at once, or eventually you might be able to do it with a with a patch or sublingually. But this will still be a pretty onerous process.

A lot of people are now looking at ways to try to turn off mast cells or try to be able to block the development of the IgE antibody in a more global way, not just to be food-specific. It's going to require that we really understand much better how these allergic reactions happen. Again, we see people who have IgE antibodies to peanuts, who don't react to peanuts, and we're still trying to figure out exactly why they’re different. We'll have people with

very high levels of certain foods and have no problem. We have other people who have really small amounts of IgE, say, peanuts, that we can detect in their serum and yet have terrible reactions. There's still a lot we have to learn about it.

As we understand these mechanisms better and better, I think we have to really be looking at more global ways to dampen the allergic response and, like I said, there are a lot of companies now that are also involved in this. I'm pretty optimistic that at some point we're going to come up with a more multi-allergen approach that will enable us to treat these people who really have multiple food allergies.

This multi-food allergy is becoming a real problem, which suggests that we have to come up with methods to be able to treat many food allergies at one time

Mário Morais-Almeida

Head of Immunoallergy

Department, Hospital CUF Centre, Lisbon, Portugal; President, World Allergy Organization, Milwaukee, Wisconsin, USA

Biologic therapies have revolutionised, for instance, the management of severe asthma and chronic urticaria

Citation:

EMJ Allergy Immunol. 2025;10[1]:100-103. https://doi.org/10.33590/emjallergyimmunol/ CPVU3728

Q1With your extensive experience heading Immunoallergy Departments and your long-standing clinical practice, what do you consider the most significant shifts in the landscape of allergic diseases that you've observed since becoming a specialist in 1994?

Since 1994, the field of allergy and clinical immunology has undergone a profound transformation, both in terms of scientific understanding and clinical practice. One of the most significant shifts has been the move from symptom-based diagnoses to a more precise, endotype-driven approach, particularly in conditions such as asthma and atopic dermatitis, to name a few. This has allowed us to better stratify patients and personalise treatment across all age groups. The increased global prevalence of allergic diseases, especially in urbanised and industrialised regions, has also drawn attention to the complex interplay between genetic predisposition and environmental factors, including the effect of climate change. Another critical achievement has been the development of molecular allergology, which has enabled more refined diagnostic tools and improved the safety and efficacy of allergen immunotherapy. Biologic therapies have revolutionised, for instance, the management of severe asthma and chronic urticaria, and we are now seeing similar advances in food allergy, atopic dermatitis, and chronic rhinosinusitis. For instance, the progress in the management of hereditary angioedema

has been tremendous. Finally, there has been a recognition of immunoallergic diseases as a global health issue, supported by more structured guidelines and increased advocacy from international bodies such as the World Allergy Organization (WAO).

Q2

Your expertise spans a wide range of allergic conditions, with a special research interest in respiratory and food allergy. Looking at respiratory allergy, what are the most exciting recent advancements in diagnosis and management that you believe are truly impacting patient outcomes today?

Recent advances in respiratory allergy have significantly improved both diagnostic precision and treatment outcomes. One of the most exciting developments is the integration of functional and molecular diagnostics into clinical practice. Respiratory functional tests and the measurement of inhaled biomarkers, when available, are nowadays essential tools in clinical management. Component-resolved diagnostics particularly allow clinicians to identify specific allergenic molecules responsible for sensitisation, which is useful in polysensitised patients and in deciding on the most appropriate allergen immunotherapy. This level of granularity helps reduce misdiagnosis and tailors the therapy to the individual.

On the management side, the advent of biologic therapies has dramatically changed the outlook for patients with severe allergic asthma. Monoclonal antibodies, namely those

targeting IgE (omalizumab), IL-5 (mepolizumab, reslizumab), IL-5 receptor (benralizumab), IL-4/ IL-13 (dupilumab), and TSLP (tezepelumab), have shown impressive results in improving control and reducing both exacerbations and oral steroid consumption. These therapies are now being matched to patients based on low-cost biomarkers, such as blood eosinophils or fractional exhaled nitric oxide, ushering in a truly personalised approach.

Furthermore, digital health tools and telemedicine have enhanced patient monitoring and treatment adherence, especially during the COVID-19 pandemic. Together, these innovations are shifting the paradigm towards precisionbased and proactive care in respiratory allergy.

Q3Given your involvement with chronic rhinitis and rhinosinusitis, what are the most promising avenues of research currently being pursued in allergic rhinitis, especially concerning personalised approaches or environmental factors?

In allergic rhinitis, research, as promoted by the Allergic Rhinitis and its Impact on Asthma (ARIA) initiative, is increasingly focused on personalised medicine, integrating biomarkers,

phenotyping, and environmental profiling to tailor management strategies. One of the most promising areas is the identification of endotypes, distinct pathophysiological mechanisms underlying clinical phenotypes, which may respond differently to specific therapies. For example, patients with predominant eosinophilic inflammation may benefit more from intranasal corticosteroids, including in association with inhaled antihistamines, while patients with predominantly non-allergic rhinitis triggers may require alternative approaches.

Environmental exposome research is also gaining traction. Understanding the cumulative impact of air pollution, aeroallergen exposure, climate change, and indoor environmental factors on allergic rhinitis expression and severity is key to preventive strategies. Additionally, advances in wearable sensors and mobile apps, such as MASK-air® (MASK-air SAS, Montpellier, France), now enable real-time tracking of symptom patterns, environmental exposures, and therapeutic outcomes, contributing to adaptive treatment plans.

Another active research domain involves immunomodulatory therapies, including molecules that can prevent respiratory infections and modulate the allergic

response, as well as allergen immunotherapy, from infancy to adulthood. These approaches aim to not only alleviate symptoms but also modify disease progression and prevent asthma onset.

Q4

In the realm of food allergy, particularly from preschool age to the elderly, where do you see the greatest unmet needs, and what emerging research or therapies hold the most promise for addressing these challenges?

Food allergy presents significant unmet needs across all age groups, particularly in terms of early diagnosis, risk stratification, and disease-modifying therapies. In children, the need for accurate early diagnosis is critical, as misdiagnosis can lead to unnecessary dietary restrictions or missed opportunities for tolerance induction. The use of molecular diagnostics and oral food challenges remains underutilised in many clinical settings, largely due to resource limitations.

One of the most promising therapeutic advances is oral immunotherapy, which has shown efficacy in desensitising children to major allergens such as peanut, milk, and egg. However, concerns about safety and long-term efficacy remain. The introduction of epicutaneous immunotherapy and other novel

immunotherapy routes, currently under investigation, may offer safer alternatives with better adherence.

In older patients, comorbidities and polypharmacy pose additional challenges. Furthermore, adultonset food allergy is often underrecognised and requires more targeted epidemiological research.

Preventive strategies, such as early allergen introduction, are well supported by several well-controlled studies and are beginning to reshape clinical guidelines, offering longterm hope. However, access to omalizumab to prevent anaphylaxis in patients with food allergy is only available in the US, and adrenaline auto-injector devices for self-administration are absent in so many countries.

Q5

As a co-coordinator of Portuguese guidelines on asthma management, what key lessons have you learnt from translating global recommendations like the Global Strategy for Asthma Management and Prevention (GINA) into national practice, and what unique challenges does asthma management continue to present in real-world settings?

Adapting international guidelines to national contexts requires both scientific rigour and pragmatic sensitivity to local healthcare realities. One of the key lessons has been the importance of simplifying messages for primary care and ensuring that asthma management is integrated into the routine practice of several health care providers, rather than being viewed as a specialist domain. As an example, while GINA offers an excellent framework, national or regional guidelines must reflect local disparities,

namely in medication availability, reimbursement systems, and health literacy.

A persistent challenge is ensuring correct inhaler technique and adherence, which remain major barriers to asthma control. Digital tools and structured education programmes have been valuable, but more systematic implementation is needed. Another key issue is timely phenotyping, particularly in moderate-tosevere asthma and all forms of uncontrolled asthma. Many patients with asthma remain underassessed for eligibility for the most indicated therapies due to limited access to simple biomarker testing or referral pathways.

We’ve also learnt that involving general practitioners and paediatricians in the co-creation and dissemination of guidelines and recommendations increases uptake and improves patient outcomes, emphasising the need for multidisciplinary collaboration.

Q6

Your research interests include epidemiology and environmental risk factors for allergic diseases. How are current climate trends and environmental changes impacting the prevalence and severity of allergies, and what role can allergists play in public health advocacy in this regard?

Climate change is a growing driver of the immunoallergic disease burden. Rising temperatures and increased CO₂ levels are leading to longer pollen seasons, higher allergenicity of pollens, and shifts in plant distribution. Urbanisation and air pollution, particularly fine particulate matter and ozone, exacerbate respiratory, ocular, and cutaneous allergic symptoms, and may even contribute to primary sensitisation.

Wildfire smoke and extreme weather events are also emerging as acute triggers of asthma exacerbations.

Climate change is a growing driver of the immunoallergic disease burden

Allergists are uniquely positioned to bridge the gap between clinical care and environmental health. As public health advocates, we can raise awareness about the health impacts of climate change, contribute to policy discussions, and support mitigation strategies. This includes promoting urban green spaces, clean air initiatives, and sustainable healthcare practices.

In research, we must continue to develop and validate exposureresponse models and push for the inclusion of climate-related variables in epidemiological studies of allergy and clinical immunology. Clinically, individualised professional and patient education should now routinely include environmental risk counselling and exposure minimisation strategies.

Q7 As the incoming President of the WAO for 2025–2026, what are your top 2–3 strategic priorities for the organisation during your tenure?

As we begin this mandate at the WAO, our action plan is guided by three central priorities:

First, we aim to reduce both local and global disparities in access to immunoallergy care. This involves developing and disseminating

targeted recommendations for both public and private healthcare stakeholders in order to ensure equitable access to allergy prevention, diagnosis, and treatment, especially in underserved and vulnerable populations. There are pronounced inequalities in allergy diagnosis and management, particularly in low- and middleincome countries. For this reason, through regional training hubs, guideline adaptation, and support for local leadership, we would like to contribute to building long-lasting capacity.

Second, we seek to position WAO as a ‘lighthouse’, a global beacon of harmony, safety, and quality in allergy and clinical immunology care. We are committed to promoting the highest standards of practice and inclusiveness, fostering a universal approach to patient care that transcends regional and socioeconomic differences. Equipping frontline healthcare providers worldwide with essential knowledge is critical to closing the implementation gap.

Third, we will work to enhance the global visibility and impact of WAO through a cohesive strategy spanning scientific leadership, education, communication, and patient engagement.

This includes amplifying our voice in international health dialogues, consolidating our reputation as a leader in awareness and best practices dissemination, and empowering patients and healthcare professionals worldwide.

Together, these pillars will reinforce WAO’s mission to unify and elevate the field of allergy and clinical immunology, driving meaningful change through global, regional, and local collaboration, scientific excellence, and patient-centred values. Our extremely motivated WAO Board of Directors and our WAO Executive Medical Director must be a catalytic force for change, empowering the allergy community to deliver equitable, evidence-based care worldwide.

Q8What insights can you share regarding the balance between the clinical demands of heading a busy department and your significant roles in research and international leadership?

Balancing clinical leadership, research, and international responsibilities requires clear prioritisation, team empowerment, and personal discipline. One key insight is that delegation is not about relinquishing responsibility but about cultivating trust and developing others.

I have been fortunate to work with outstanding colleagues, members of the WAO Board of Directors, and 115 member organisations, who share a common vision and commitment to excellence in patient care and academic growth. The support of our dedicated staff must also be recognised.

Structuring time for research amidst clinical duties demands careful planning. I reserve protected time for scientific writing and collaboration, often working early mornings or late evenings. Strategic alignment of clinical activities with research objectives, such as embedding registries into clinical workflows, also enhances productivity and relevance.

International leadership requires a broader perspective and adaptability. It is essential to remain grounded in local realities while embracing global challenges. My leadership roles have made me more attentive to cultural and systemic diversity, and more committed to advocacy and inclusive dialogue. Ultimately, passion for the field and a sense of purpose are what sustain the balance.

And, the unwavering support of my family, always in my mind, is essential to fulfilling my mission of serving WAO.

Authors:

How to Diagnose and Treat Food Allergies

Saheba Bhatnagar,1 *Ellen Daily Stephen2

1. Kaiser Permanente San Francisco Medical Center, California, USA

2. Kaiser Permanente Modesto Medical Center and Medical Offices, California, USA

*Correspondence to ellen.d.stephen@kp.org

Disclosure: The authors have declared no conflicts of interest.

Received: 16.05.25

Accepted: 11.06.25

Keywords: Allergy treatment, anaphylaxis, food allergy.

Citation: EMJ Allergy Immunol. 2025;10[1]:104-108. https://doi.org/10.33590/emjallergyimmunol/QGMO5141

INTRODUCTION

Food allergies affect up to 10% of the population in the USA and have been increasing in prevalence over the last 2–3 decades.1 These allergies typically present with a reproducible, specific set of symptoms that occur immediately after ingesting a food. In this article, the authors discuss the approach to diagnosing food allergy, which centres on a thorough clinical history, followed by skin, blood, and/or oral testing if indicated. The authors also review current management options for food allergy, which are likely to expand in the future, given the ongoing research focus on this important public health concern, with several new treatments currently under investigation.

DIAGNOSIS

Clinical History

The clinical history is the most critical ‘test’ for diagnosing a food allergy. For most patients, symptoms of IgE-mediated food allergy occur within minutes to 1–2 hours after exposure.1-3 The following elements of the clinical history should be obtained: (1) the food causing the symptoms and its preparation (cooked or uncooked); (2) the specific symptoms experienced; (3) the timing of symptom onset in relation to

ingestion; (4) the length of the reaction; (5) contributing factors, such as viral illness or medication use; (6) treatments given to stop the reaction; and (7) the reproducibility of the reaction with subsequent exposure. The clinician should also assess for other forms of atopy, such as atopic dermatitis, asthma, or allergic rhinitis (Table 1).2,4

Signs and Symptoms

The typical symptoms of an IgEmediated allergic reaction include:

• Skin manifestations (erythematous rashes, urticaria, angioedema)

• Respiratory symptoms (rhinorrhoea, nasal itching, wheezing, stridor)

• Gastrointestinal symptoms (vomiting, diarrhoea, abdominal pain)

More severe manifestations affect the cardiovascular or nervous systems, and may cause dizziness, tachycardia, or altered mental status. The most serious allergic reaction is anaphylaxis, a severe, multi-organ response that may potentially progress to shock and death, if not immediately treated.2,4

Table

World Allergy Organization grading scale for systemic allergic reactions.

Skin (hives, flushing, swelling)

Skin (widespread hives, erythema, angioedema)

Lower respiratory (bronchospasm, cough)

Respiratory (severe bronchospasm not improving with two doses epinephrine, stridor with increased work of breathing)

Respiratory (failure requiring positive pressure ventilation or arrest)

Or And/or And/or And/or And/or

Upper respiratory (nasal symptoms, throat discomfort, cough)

Gastrointestinal (persisting >20 min, non-distractable pain, vomiting/diarrhoea

Upper respiratory (throat tightness, stridor without increased work of breathing, persisting odynophagia > 20 min)

Cardiovascular (hypotension with end-organ dysfunction

Or - And/or And/or

Gastrointestinal (nausea, mild abdominal pain) -

Gastrointestinal AND cutaneous (severe vomiting, repetitive vomiting)

Cardiovascular (anaphylactic shock requiring IV vasopressor, cardiac arrest)

Neurological (Glasgow Coma Scale <13)

Or - And/or -

Conjunctival irritation or metallic taste - Uterine cramps/bleeding -

Adapted from World Allergy Organization Anaphylaxis Committee and Allergen Immunotherapy Committee 2024 Joint Statement.5

Grade 3–5 reactions are considered anaphylaxis by World Allergy Organization Anaphylaxis definition.

Diagnostic Testing

Once the clinical history is collected, diagnostic testing is the next step to confirm the culprit allergens. The gold standard for diagnosing food allergy is the oral food challenge (OFC), performed under medical supervision. During this test, the allergist administers escalating doses of the suspected food, monitoring carefully for any signs of an IgE-mediated reaction. OFCs are considered positive when objective symptoms are observed. While subjective symptoms may indicate a positive reaction, especially if worsening, repeated, or persistent, the decision to stop the challenge ideally should be based on the occurrence of objective signs of an allergic reaction.6,7

Skin prick tests (SPT) or food-specific IgE (sIgE) blood tests are commonly used initially in clinical practice. However,

these tests should only be performed in combination with a detailed clinical history suggestive of IgE-mediated food allergy, as false positives are common. Both SPTs and sIgE testing have a sensitivity >90%, but a specificity of <50%. A negative result has a high negative predictive value, indicating a low risk of proceeding with an oral challenge to confirm the absence of the allergy. With a positive result, the size of the wheal formed during SPT, or the magnitude of sIgE, correlates with the likelihood of reactivity, but not the severity of a potential reaction. These test results can thus help the allergist and patient/ family to better understand the likelihood of reaction if an OFC is performed. However, due to the low specificity of sIgE and SPTs, positive findings alone cannot definitively confirm the presence of food allergy. If skin and blood testing

1:

is negative, but the food has been avoided in the diet, or if test results are conflicting, an OFC can be helpful.4

TREATMENT

Current treatment options for food allergy include avoidance, oral immunotherapy (OIT), and omalizumab, with several promising new therapies currently in development. Given the risks, benefits, and logistical challenges associated with each treatment, it is critical that allergists engage in shared decision-making with the patients and their families to ensure that the treatment plan aligns with their individual goals and lifestyles.

Avoidance

Management for most patients with food allergy involves strict avoidance of allergens and treatment for acute reactions. Patients and their families should be counselled, ideally by a registered dietician, about strategies to avoid specific allergens. It is important for clinicians to provide practical guidance on allergen avoidance, including how to read food labels, strategies for dining out, and age-appropriate education that begins in childhood and continues into adulthood.4 Since there always exists a risk of accidental ingestion, patients should also carry an epinephrine autoinjector pack (2 doses) at all times, as this can be a lifesaving therapy in the case of an anaphylactic food reaction. Barriers to this approach, unfortunately, include the high cost of epinephrine autoinjectors, inadequate reimbursement by some insurance plans, and global shortages due to production issues.

Oral Immunotherapy

Historically, the only option for managing food allergy was strict allergen avoidance. However, the use of OIT has been becoming increasingly recognised as a method to attenuate allergic responses over time. OIT is time- and labour-intensive, carries a risk of adverse reactions, and its effectiveness as a definitive cure remains uncertain. Of note, in the USA, there is only one FDA-approved product for peanut OIT

called Palforzia® (Aimmune Therapeutics, Brisbane, California, USA). However, OIT for other food allergens is being performed by some allergists using products that do not carry FDA approval.6-8

Treatment course

When initiating OIT, patients first undergo a supervised rapid dose-escalation phase in the clinic to demonstrate the safety and tolerability of doses of the allergen, prior to starting at-home dosing at a lower dose level. Then, during the build-up phase, this amount of daily home dose is increased every few weeks during up-dosing clinic visits until a target maintenance dose is reached. The last phase is the maintenance phase, during which home OIT daily dosing continues to maintain desensitisation. This phase typically lasts 3–5 years, as immune changes typically plateau after this period. Some patients prefer to continue dosing indefinitely for protection, while others opt to discontinue daily dosing and perform an OFC to assess for remission while off therapy.9

Benefits of oral immunotherapy

Several studies have demonstrated that, while desensitised, patients with food allergy are protected against accidental exposures to amounts below their reactivity threshold. Some have been able to include substantial amounts of the allergen in their diet. Protection against even small amounts has been shown to improve anxiety and quality of life significantly. Through the IMPACT trial, OIT has also been shown to increase the chance of achieving remission, defined as an absence of symptoms upon exposure to the allergen for 26 weeks after discontinuation of OIT.9,10

Key considerations before starting oral immunotherapy

Because OIT requires a significant commitment of time and effort, it is important to carefully evaluate whether it is the right option for each patient.

Before starting OIT, comorbidities such as asthma, allergic rhinitis, allergic dermatitis, and chronic sinusitis must be well controlled. Additionally, it is important to evaluate the patient’s anxiety and determine whether any interventions are needed in advance. The

caregiver’s relationship with the patient, as well as any family logistics that may affect adherence to treatment, should also be addressed.11 Moreover, patients with very elevated IgE levels or body weight may not be eligible for treatment.12

Factors to consider for patients who may benefit from OIT include the likelihood of not outgrowing their food allergy, the impact of the allergy on their quality of life, a history of anaphylaxis, and the patient’s individual goals, such as the desire to tolerate larger amounts of the allergen. However, risks may include reactions ranging from mild-(e.g., rash, oral itching) to-severe/fatal (e.g., anaphylaxis), as well as the development of eosinophilic gastrointestinal disorders.

Therefore, especially in children, dosing fatigue, food aversion, and anxiety may affect treatment adherence.11

Omalizumab

Based on data from the landmark Phase 3 clinical trial, Omalizumab as Monotherapy and as Adjunct Therapy in Children and Adults (OUtMATCH), omalizumab is the only FDA-approved treatment to reduce allergic reactions following incidental exposure to food allergens. It binds to the FcεR1 epitope of human IgE, thereby interfering with the binding of IgE to the IgE receptor. Over time, this results in the inhibition of mast cell and basophil activation upon allergen exposure.13

Benefits of omalizumab

Omalizumab offers the advantage of treating several allergic comorbidities along with food allergy. Furthermore, it can treat multiple food allergies by targeting free IgE. Adverse reactions usually involve injection site reactions, with anaphylaxis in rare cases. However, compared to OIT, omalizumab offers a less intensive monitoring regimen, with self-administration at home a potential option based on careful assessment of risk for anaphylaxis. Therefore, omalizumab may be better suited for patients with a difficult-to-control asthma, multiple food allergies, or those who prefer less frequently dosed therapy.14

Key considerations before starting omalizumab

Despite the availability of an FDA-approved dosing table, the ideal dose and dosing schedule are still not well understood. Additionally, patients with very high total IgE levels or body weight would fall outside of the dosing table parameters for omalizumab. There are no studies that can guide when omalizumab should be initiated, it can be started at any stage of having a food allergy, whether recently diagnosed or having lived with the allergy for years.14 It is also important to consider that some patients will not experience a significant clinical response to omalizumab for food allergy. In the OUtMatch study, only 67% of patients achieved the primary endpoint of consuming one dose of 600 mg of peanut protein without any significant symptoms.13

CONCLUSION

The diagnosis of food allergy poses a clinical challenge. Obtaining a clinical history consistent with an IgE-mediated food reaction is essential before pursuing SPT or sIgE blood testing, since these tests have low specificity, and a positive result does not necessarily indicate that a reaction will occur. Negative testing, however, has a high negative predictive value. Oral food challenges are utilised to attempt to clarify tolerance versus reactivity, typically when initial skin or blood testing indicates low risk of reaction.

Although strict avoidance has traditionally been the main management strategy for food allergy, and remains so at this time, there have been significant recent advances in developing novel treatments to achieve desensitisation and remission. OIT has gained more recognition as a potential method for decreasing the risk of severe life-threatening accidental food reactions if the amount ingested is below the reactivity threshold. However, it is a time-intensive process and potentially cost-prohibitive for some patients. OIT does carry potential risks of adverse reactions, and while it often does not enable patients to fully incorporate the food into their diet, it can often allow them to consume partial amounts without

significant reactions. There is now an FDA-approved OIT for peanut allergy, which is likely to expand the use of this treatment option to more health systems and clinical sites. Even more recently, although significantly more expensive,

References

1. Sicherer SH, Sampson HA. Food allergy: a review and update on epidemiology, pathogenesis, diagnosis, prevention, and management. J Allergy Clin Immunol. 2018;141(1):41-58.

2. Mendonca CE, Andreae DA. Food allergy. Med Clin North Am. 2024;108(4):655-70.

3. Seth D et al. Food Allergy: a review. Pediatr Ann. 2020;49(1):e50-8.

4. Anvari S et al. IgE-mediated food allergy. Clin Rev Allergy Immunol. 2019;57(2):244-60.

5. Turner PJ et al. Updated grading system for systemic allergic reactions: joint statement of the World Allergy Organization Anaphylaxis Committee and Allergen Immunotherapy Committee. World Allergy Organ J. 2024;17(3):100876.

omalizumab has been approved by the FDA for use in food allergy to prevent reactions to accidental ingestions. Further study is needed to understand the ideal dosing and the practical use of this treatment option.

6. Sampson HA et al. AAAAI-EAACI PRACTALL: Standardizing oral food challenges-2024 update. Pediatr Allergy Immunol Off Publ Eur Soc Pediatr Allergy Immunol. 2024;35(11):e14276.

7. Savage J, Johns CB. Food allergy: epidemiology and natural history. Immunol Allergy Clin North Am. 2015;35(1):45-59.

8. Anagnostou A et al. Addressing common questions on food oral immunotherapy: a practical guide for paediatricians. Arch Dis Child. 2024;109(9):697.

9. McHenry M et al. Food oral immunotherapy. Allergy Asthma Clin Immunol Off J Can Soc Allergy Clin Immunol. 2025;20(Suppl 3):82.

10. Jones SM et al. Efficacy and safety of oral immunotherapy in children aged 1-3 years with peanut allergy (the Immune Tolerance Network IMPACT trial): a randomised placebo-

controlled study. Lancet Lond Engl. 2022;399(10322):359-71.

11. Mack DP et al. Preparing Patients for Oral Immunotherapy (PPOINT): international delphi consensus for procedural preparation and consent. J Allergy Clin Immunol. 2024;153(6):1621-33.

12. El-Qutob D. Off-label uses of omalizumab. Clin Rev Allergy Immunol. 2016;50(1):84-96.

13. Wood RA et al. Protocol design and synopsis: Omalizumab as Monotherapy and as Adjunct Therapy to Multiallergen OIT in Children and Adults with Food Allergy (OUtMATCH). J Allergy Clin Immunol Glob. 2022;1(4):225-32.

14. Casale TB, Fiocchi A, Greenhawt M. A practical guide for implementing omalizumab therapy for food allergy. J Allergy Clin Immunol. 2024;153(6):1510-7.

An Approach to Diagnosing Primary Immunodeficiencies

Author: *Aisha Iftikhar1

1. Ameer-ud-Din Medical College/ PGMI, Lahore General Hospital, Pakistan

*Correspondence to draishaqaisar@gmail.com

Disclosure: The author has declared no conflicts of interest.

Received: 19.04.25

Accepted: 20.06.25

Keywords: Failure to thrive, genetic testing, immune system, primary immunodeficiency (PID), recurrent infections.

Citation: EMJ Allergy Immunol. 2025;10[1]:109-114. https://doi.org/10.33590/emjallergyimmunol/MZPK3009

INTRODUCTION

Primary immunodeficiencies (PID) are a heterogeneous group of genetic disorders that render the affected child susceptible to life-threatening infections, due to the absence or defect of one or more components of the immune system.

The diagnosis of PID is not only a complex process for a physician but also fills the lives of families of children with PID with dilemmas and queries. There is a dire need to raise awareness among physicians to streamline and accelerate the diagnostic process, help prevent end-organ damage, and provide definitive treatments, such as bone marrow transplantation (BMT) or other interventions.

So far, 485 distinct genetic defects have been identified, owing to advancements in genetic analysis.1 However, these, along with basic diagnostic workups, are not easily accessible due to high costs and a lack of physician awareness.1

For physicians performing workups for PID, it has become imperative to use resources cautiously, judiciously, and wisely, particularly in resource-limited countries. A methodical approach should be adopted, incorporating a detailed history, clinical evaluation, and laboratory investigations

to elucidate and identify the deficient component of the immune system, even when diagnostic facilities are scarce.

CLASSIFICATION SYSTEMS

At a global level, two distinct systems are employed for the diagnosis and classification of PID. One is the International Union of Immunological Societies (IUIS) classification system devised by the IUIS Expert Committee. According to this, PID is now regarded as inborn errors of immunity (IEI), as there is not only a higher propensity of recurrent infections, but also autoimmunity, autoinflammatory conditions, allergic manifestations, and malignancies.1 In this classification, genotypic criteria complement the phenotypic criteria, ultimately categorising over 485 gene defects into 10 groups. Diagnosis is based on clinical features, immunological laboratory findings, and genetic confirmation where available.

The following are the 10 major categories of IEIs:

1. Immunodeficiencies affecting cellular and humoral immunity.

2. Combined immunodeficiencies with associated or syndromic features.

3. Predominantly antibody deficiencies.

4. Diseases of immune dysregulation.

5. Congenital defects of phagocyte number or function.

6. Defects in intrinsic and innate immunity.

7. Autoinflammatory disorders.

8. Complement deficiencies.

9. Bone marrow failure syndromes.

10. Phenocopies of IEI (acquired defects that mimic IEIs).

Another classification, by the European Society for Immunodeficiencies (ESID), provides practical diagnostic criteria for clinical and research use, especially when genetic confirmation is not available.2

The ESID defines PID diagnosis at three levels for each disease:

1. Definite PID

The patient can be declared a definite PID case if a pathogenic mutation is found in a known PID-causing gene, or if the patient has a very specific clinical picture and family history along with immunophenotyping.

2. Probable PID

When there are strong clinical and immunological features suggesting PID, but no genetic confirmation is available.

3. Possible PID

When there is limited clinical or immunological data and further work-up is needed.

Depending on the specific clinical scenario and available facilities, one can adopt a system that is feasible, with a clear preference for the use of genetic testing for precise delineation.

USE OF SCREENING TOOLS IN SUSPECTED PATIENTS

Presentation of PID is often complex as the primary hallmark i.e., recurrent infections can be seen in other conditions, e.g., repeated infections in malnourished children living in unhygienic and poor sanitary conditions is specifically significant in developing countries. Thus, screening tools such as the warning signs published by JMF can be a useful guide for initial scrutiny.3

These include:

1. four or more new ear infections within 1 year;

2. two or more pneumonias within 1 year;

3. two or more serious sinus infections within 1 year;

4. two or more months on antibiotics with little effect;

5. failure of an infant to gain weight or grow normally;

6. recurrent deep skin or organ abscesses;

7. persistent thrush in mouth or fungal infection on skin;

8. need for IV antibiotics to clear infections;

9. two or more deep-seated infections (e.g., sepsis, osteomyelitis); and

10. family history of primary immunodeficiency.

In addition to these factors, the author has observed that recurrent and persistent diarrhoea is an important presenting complaint in T cell defects and severe combined immunodeficiency.

SALIENT FEATURES OF HISTORY AND EXAMINATION IN PRIMARY IMMUNODEFICIENCY EVALUATION

It is imperative to navigate the important points in history and examination to gather the basic information about patients with PID.

While evaluating history, the most important component is a detailed account of infection including age at symptom onset; site or location of infection; type of infection; and the frequency, severity, and seriousness of illness.4 The latter can be gauged by asking whether the patient only required outpatient visits or needed hospital and ICU admissions, and how the child responded to therapy.4

Over years of encountering such patients, it has been found that diagnostic delay should be evaluated by asking the age of symptom onset and the age of final diagnosis. This has multiple implications for the evolution of knowledge about PID. By evaluating the difference in diagnostic delay in specific types of PID documented in various studies at different points in time, one can determine not only the awareness level of physicians but also the effectiveness of diagnostic techniques like genetic testing. Besides determining the level of awareness among physicians and the general public, it enables the researcher to assess the nature and type of the underlying disease.

It is essential to ask the parents if they can tell or show any previously available reports indicating microorganisms that have grown in the past, which can potentially signal the deficient component of the immune system. This question should be asked explicitly, as parents are frequently not aware of the significance of such information and may forget to mention it when the history is taken.

It is of utmost importance that we try to find out the type of organisms by taking appropriate samples for identification, culture, and sensitivity. This gives a very strong indication regarding the deficient component of the immune system. For example, recurrent meningitis may raise the possibility of complement deficiencies.

Complement deficiencies and complement regulatory protein deficiencies are rare but important causes of immunodeficiency. A history of recurrent infections, particularly with encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria species, must be noted, manifesting as sinusitis, otitis media, pneumonia, or severe conditions

such as meningitis and sepsis.5 Recurrent sinopulmonary infections and autoimmune diseases involving classical pathway deficiencies, and repeated Neisseria infection involving both alternate and terminal pathway deficiencies are significant features.5

Past medical history, including delayed shedding of primary teeth, recurrent fractures, previous surgery (incision and drainage/biopsy), delayed separation of umbilical cord, previous hospitalisation, the number of previous admissions in hospital, and the duration of hospital stays, should be documented.

It is crucial to obtain detailed vaccination history, as live vaccines in patients with PID are dangerous and even life-threatening, depending on the type and severity of the immune defect.6 Document whether Bacillus Calmette-Guérin (BCG) was given, the use of polio and rotavirus drops, and any adverse events following vaccination.

A detailed family history needs to be elaborated, including early infant deaths due to infections, history of consanguinity, affected siblings with similar illnesses, and any other family members affected.6

It is important to recognise that autoimmune cytopenias like immune thrombocytopenia (ITP) and autoimmune haemolytic anaemia may be the initial or sole manifestation of common variable immunodeficiency, with one study reporting occurrences in 17.8% of cases.7 This can complicate the clinical picture and lead to diagnostic delays.

Patients may present with symptoms such as unexplained bruising, fatigue, or pallor, which are indicative of thrombocytopenia or haemolytic anaemia.

Assess for environmental or occupational exposures that may predispose patients to infections.6 Careful history-taking is required to rule out the possibility of recurrent chest infections due to anatomical defects or congenital conditions (e.g., repeated infections in congenital heart defects like ventricular septal defect, due to left ventricular volume overload; recurrent chest infections in cystic fibrosis

and primary ciliary dyskinesia). A detailed history of early neonatal events can give clues for such diagnoses.

Recurrent chest infections are very common in patients with cerebral palsy, highlighting the significance of birth and developmental history (any history of delayed cry, and delayed achievement of milestones). A history of gastroesophageal reflux disease is equally crucial to discern.

It is also necessary to rule out any possibility of secondary immunodeficiency by taking detailed account of caloric intake for malnutrition assessment, any history of blood transfusions, and parental occupation (to rule out HIV infection). Features of protein-losing enteropathy or nephrosis which can lead to hypogammaglobulinaemia, should be inquired about. A history of drug intake, such as steroids or rituximab, must also be incorporated.

A detailed history should be followed by a complete physical examination. Foremost importance should be given to documenting signs of chronic ill health, such as pallor and failure to thrive. Perform anthropometric measurements and plot on centile charts; and if possible, ask for previous growth charts to compare with the current status.

Next, examine for signs of active infections like fever, cough, or lymphadenopathy. Specifically check for dysmorphic features, as they are distinctive for certain defects.8 For example, the following are classically observed in DiGeorge syndrome (DS): underdeveloped chin due to mandibular hypoplasia, low-set or posteriorly rotated ear, wide-set eyes, hypertelorism, antimongoloid slant to the eyes, and a short philtrum of the upper lip.

In hyper IgE syndrome, we may find prominent forehead, deep-set, widelyspaced eyes, a broad nasal bridge, a wide, fleshy nasal tip, mild prognathism, and facial asymmetry. However, it is important to note that these features may not be present at birth, but the patient develops these over the years due to multiple skin and other infections.

Clinical features of utmost importance include silver hair or hypopigmented hair, and partial albinism, seen in ChediakHigashi syndrome. Ocular Telangiectasia seen in ataxia telangiectasia; hearing loss (due to repeated infections); absence of lymphoid tissue, tonsils, and lymph nodes (severe combined immunodeficiency disease and Bruton’s disease); gingivitis (phagocytic defect); oral thrush (seen in severe combined immunodeficiency disease, T cell defect, and phagocytic defects); and presence of clubbing (bronchiectasis). Moreover, a detailed skin evaluation should be conducted to discern rash and petechiae (Wiskott-Aldrich syndrome), evidence of scar tissue, abscess or granuloma formation, candidal infections, and any allergic manifestations. Additional features like lymphadenopathy and hepatosplenomegaly (suggestive of phagocytic defect or autoimmune lymphoproliferative syndrome), pallor, splenomegaly, bruises (indicative of autoimmune haemolytic anaemia and immune thrombocytopenia),7 gait disturbances (i.e., ataxia in ataxia telangiectasia, and Chediak-Higashi syndrome) should be noted.9 The physician must conduct a detailed examination of the primarily affected system, along with a systemic overview. Signs for immune dysregulation, like joint swellings, rashes, and alopecia, should also be noted.

DIAGNOSTIC WORKUP

In light of the information gathered, the physician can plan a list of investigations (Table 1), including complete blood count with neutrophils counts (neutropenia). It is imperative to determine absolute lymphocyte count and absolute neutrophil count; platelet number, size, and morphology (especially for WiskottAldrich syndrome); reticulocyte count (autoimmune haemolytic anaemia); erythrocyte sedimentation rate (chronic Infection); and HIV screening (to rule out secondary Immunodeficiency).10

Serum immunoglobulin levels including IgG, IgA, IgE, and IgM should be determined. Flow cytometry should be conducted for lymphocyte subset analysis as follows:

Table 1: Tiered investigations for

Preliminary and supportive investigations

CBC with neutrophils count, ALC, ANC, platelet number, size and morphology, reticulocyte count, ESR, HIV screening, CH50, AH50, C3, C4.

CXR, ECG, or CT chest, echocardiography for structural abnormalities.

Serum Ca, Phos, Alk Pase, and PTH level. CXR for thymus.

Abdominal USG for deep abscesses or, lymphadenopathy or, hepatosplenomegaly.

CT abdomen.

Blood culture and sensitivity (C&S), urine C&S, pus C&S, gastric aspirate for GeneXpert and fungal hyphae.

Confirmatory tests

Serum Ig levels (IgG, IgA, IgE, IgM) should be determined.

Flow cytometry for lymphocyte subset analysis as follows:

T cell: CD3, CD4, CD8

B cell: CD19, CD20

NK Cells: CD56

LAD1: CD11b, CD11c, CD18

For CGD DHR test.

Individual complement protein levels.

Advanced and confirmatory tests

Genetic testing.

NGS or targeted gene panels.

AH50: alternative haemolytic complement; ALC: absolute lymphocyte count; Alk Pase: alkaline phosphatase; ANC: absolute neutrophil count; C&S: culture and sensitivity; Ca: calcium; CBC: complete blood count; C3: complement component 3; C4: complement component 4; CD3: cluster of differentiation 3; CD4: cluster of differentiation 4; CD8: cluster of differentiation 8; CD11b: cluster of differentiation 11b; CD11c: cluster of differentiation 11c; CD18: cluster of differentiation 18; CD19: cluster of differentiation 19; CD20: cluster of differentiation 20; CD56: cluster of differentiation 56; CGD: chronic granulomatous disease; CH50: total haemolytic complement activity; CXR: chest X-ray; DHR: dihydrorhodamine; ESR: erythrocyte sedimentation rate; LAD1: leukocyte adhesion deficiency Type 1; NGS: next generation sequencing; NK: natural killer; Phos: phosphate; PTH: parathyroid hormone; USG: ultrasound scan.

• T cells: cluster of differentiation (CD)CD3, CD4, CD8

• B cells: CD19, CD20

• Natural killer cells: CD56

• Leukocyte adhesion deficiency Type 1: CD11b, CD11c, CD18

In case there is a suspicion of chronic granulomatous disease and find hypergammaglobulinaemia, the dihydrorhodamine test should be done by flow cytometry. For screening of complement deficiencies, CH50, AH50, C3, and C4 can be done with further confirmation through individual complement protein levels. Advanced testing includes enzyme assays, such as adenosine deaminase (ADA). Genetic testing should be utilised when available with next-generation sequencing or targeted gene panels to identify the

pathogenic mutations in PID. This is most helpful for precise delineation of the underlying mechanism. Such precise diagnosis can facilitate genetic counselling and prenatal diagnosis for future children.11

Supportive investigations include: chest X-ray, ECG, CT chest, and echocardiography for structural abnormalities; serum calcium, phosphate, alkaline phosphatase, parathyroid hormone level (DS); α-fetoprotein; and chest X-ray for thymus (lateral and frontal projection; T cell, severe combined immunodeficiency disease, DS).Abdominal ultrasound to document deep abscesses, or lymphadenopathy, or hepatosplenomegaly. If required, CT abdomen can be planned (chronic granulomatous disease).

One should aim to identify the offending microorganism from the appropriate sample depending upon the site of infection, e.g., blood culture and sensitivity (C&S), urine

C&S, pus C&S, gastric aspirate for GeneXpert and fungal hyphae. Tests such as 50% haemolytic complement assay, antibody response to vaccines, and functional assays (e.g., lymphocyte proliferation assay) are practically not easily available.

CONCLUSION

Although approaching patients with PID is a cumbersome and complex process, a systematic approach incorporating targeted history, thorough examination, and appropriate investigation can streamline the process to not only eliminate the diagnostic burden on the patient but also to improve patient outcomes by enabling timely treatment. By delineating the specific defect and guiding treatment decisions, genetic testing has been a game-changer in this process.

References

1. Tangye SG et al. Human inborn errors of immunity: 2022 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2022;42(7):1473-507.

2. Seidel MG et al. The European Society for Immunodeficiencies (ESID) registry working definitions for the clinical diagnosis of inborn errors of immunity. J Allergy Clin Immunol Pract. 2019;7(6):1763-70.

3. McCusker C et al. Primary immunodeficiency. Allergy Asthma Clin Immunol. 2018;14(Suppl 2):61.

4. Nepesov S et al. Diagnosis of primary immunodeficiency diseases in pediatric patients hospitalized for recurrent, severe, or unusual

There is a grave and pressing need to establish multinational and specialised centres, especially in developing countries, with the contribution of international bodies, where sustained availability of diagnostic facilities, including genetic testing, along with treatment facilities like Ig and haematopoietic stem cell transplantation is ensured.

The lack of such facilities in resourceconstrained countries is evidence that global collaboration is the only solution to facilitate patients with PID, for whom not only is the diagnostic journey cumbersome and expensive, but the provision of Ig and preparation for bone marrow transplantation also impart a huge burden. One must not forget that these patients possess the right to live a normal and productive life. This right should not be stripped away on account of unaffordability.

infections. Allergol Immunopathol (Madr). 2022;50(4):50-6.

5. Meri S, Jarva H. Complement regulatory proteins and related diseases. 2013. Available at: https://onlinelibrary.wiley.com/ doi/abs/10.1002/9780470015902. a0001434.pub3. Last accessed: 12 June 2025.

6. Bonilla FA et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015;136(5):1186-205.

7. Mormile I et al. Common variable immunodeficiency and autoimmune diseases: a retrospective study of 95 adult patients in a single tertiary care center. Front Immunol. 2021;12:652487.

8. Ng KF et al. The multifaceted syndromic primary immunodeficiencies in children. J Clin Med. 2023;12(15):4964.

9. Tavakol M et al. Diagnostic approach to the patients with suspected primary immunodeficiency. Endocr Metab Immune Disord Drug Targets. 2020;20(2):157-71.

10. Branch A et al. Diverse clinical features and diagnostic delay in monogenic inborn errors of immunity: a call for access to genetic testing. Pediatr Allergy Immunol. 2021;32(8):1796-803.

11. Arunachalam AK et al. Primary immunodeficiencies in India: molecular diagnosis and the role of next-generation sequencing. J Clin Immunol. 2021;41(2):393-413.

Plasmacytoid Dendritic Cells Display Surface but Not Membrane-Bound IgE Across a Broad Range of Total Serum IgE Levels

Authors: Jonathan H. Chen,1 Donald W. MacGlashan,2 Amanda McCormack,3 John T. Schroeder,2 *Jody R. Tversky2

1. Department of Internal Medicine, Lankenau Medical Center, Main Line Health System, Wynnewood, Pennsylvania, USA

2. Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

3. Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA

*Correspondence to jodytversky@jhmi.edu

Disclosure: MacGlashan declares a National Institutes of Health (NIH) grant paid to their institution. Schroeder declares an NIAID/NIH grant paid to their institution. Chen, McCormack, and Tversky declare no conflicts of interest.

Received: 22.04.24

Accepted: 07.10.24

Keywords: Dendritic cell, flow cytometry, IgE, membrane bound, plasmacytoid, quilizumab.

Citation: EMJ Allergy Immunol. 2025;10[1]:115-124. https://doi.org/10.33590/emjallergyimmunol/GQUF2135

Abstract

Introduction: Plasmacytoid dendritic cells (pDC) are unique antigen-presenting cells that may be implicated in allergic disease because they bind IgE on their surface and modulate important Th1/Th2 cytokine responses. The authors previously discovered that IgE is not readily removed from pDCs using omalizumab to the same extent observed for basophils, suggesting that a portion of the IgE on pDCs may be membrane bound.

Methods: A cross-sectional study was performed and recruited adult volunteers from Johns Hopkins Asthma & Allergy Clinic, Baltimore, Maryland, USA, between 2022–2023. Individuals with varying levels of serum IgE were selected, and those on subcutaneous immunotherapy or biologic therapy were excluded. Basophils and pDCs were isolated using established protocols. In order to isolate peripheral blood mononuclear cells, blood was also drawn from consenting donors with a wide range in total serum IgE levels. B cells and pDCs were identified by flow cytometry by gating on CD19/CD27 and blood dendritic cell antigen 2/CD123, respectively. Quilizumab, a mouse anti-human monoclonal IgG1 antibody with specificity only for membrane-bound IgE and surrogate for omalizumab, was used to detect this molecule in both cell types.

Results: When used in vitro at 1.5 mg/mL, omalizumab removed ~80–90% of the IgE expressed by basophils. In contrast, IgE expression decreased only 30–40% on similarly treated pDCs. There was no significant difference in the number of pDCs staining for membrane-bound IgE between the isotype control and quilizumab (P=0.125, 0.165). However, the proportion CD19+27+ B cells staining for quilizumab compared to other PBMC was 54:1 (P=0.015).

Conclusion: While pDCs express significant levels of surface-bound IgE, there is no appreciable amount of membrane-bound IgE noted. The reason for omalizumab’s poor ability to remove pDC-bound IgE compared to its effectiveness at removing circulating IgE remains unknown.

Key Points

1. Plasmacytoid dendritic cells (pDC) are a unique subset of antigen-presenting cells known to be involved in innate immunity, cancer, and immune tolerance.

2. It is not clear why pDC express a variant of the IgE (FcεRI) receptor on their surface, or if they also exhibit a membrane-bound version of this receptor.

3. This study confirms that pDCs do express high levels of FcεRI that very tightly bind IgE on their surface, but no appreciable amount of membrane-bound IgE was detected.

INTRODUCTION

Plasmacytoid dendritic cells (pDC) primarily function as weak antigen-presenting cells (APC), but have also been shown to express functional receptors for key elements of both the innate and adaptive immune responses.1,2 pDCs induce the proliferation of naïve T cells towards Th1, Th2, or Th17 immune responses and have been implicated in allergic disease processes, most prominently in allergic asthma and atopic dermatitis.1-5 pDCs express a unique variant of the FcεRI highaffinity IgE receptor. Unlike mast cells and basophils, which express prodigious amounts of FcεRI on their surface, pDCs express approximately 10-fold less, and the receptor itself lacks a beta subunit.6-8 It is not entirely clear what the specific function of the IgE receptor may be on pDCs, but its expression is thought to contribute to the severity of atopic disease.9-12 It has been proposed that FcεRI-expressing pDCs use IgE for antigen sampling and/or antigen focusing and modulation.13 It is known that pDCs can prime Th1-like responses with secretion of IFN-α and IFN-β.14 The authors have previously shown that TLR9 expression and activation enhance these processes, while IgE crosslinking inhibits these important innate and adaptive immune responses.1,15 Others later

reported similar findings by evaluating the function of TLR7 on pDCs, thus indicating that critical virus-induced IFN-α responses of pDCs can be deficient in patients with allergic asthma.16,17

Current literature is mixed on the specific role of pDC-derived IgE signals.18 pDCs express a unique trimeric isoform of FcεRI, a key element of the IgE network comprised of an IgE-binding α chain and a dimer of the common Fc receptor γ chain. It does not express the β chain, which mast cells and basophils have in the tetrameric isoform, responsible for cell signal amplification.16 Increased expression of FcεRI on pDCs correlates with decreased severity of food allergy and asthma, suggesting a role of IgE/ FcεRI signals in modulating atopic disease. Furthermore, since TLR9 activation of pDCs attenuates IgE/FcεRI-mediated production of pro-inflammatory cytokines, it suggests a possible role of the pDC in restraining allergic inflammation.16,17 In contrast, allergen immunotherapy increases pDC TLR9mediated innate immune function, which is impaired at baseline in allergic subjects.15

Given the possible role of pDC IgE/FcεRI in allergic inflammation, the authors aimed to further uncover how IgE may be organised

on this cell type. The authors’ preliminary observations suggested that, despite the fact that pDCs display less IgE on their surface, use of the anti-IgE monoclonal antibody, omalizumab, only removed a small portion of IgE from the cell surface. This prompted a new hypothesis that pDC may secure a significant amount of IgE bound within the cell membrane. The presence of membrane-bound IgE (mIgE) on pDCs is not currently reported or known. To achieve this, the authors sought to quantify the presence of membrane-IgE on pDCs by using quilizumab, which is specific for membranebound but not receptor-bound IgE.

METHODS

Subject Selection

Blood was drawn from adult volunteers between 2022–2023 at the Johns Hopkins Allergy & Asthma Center, Baltimore, Maryland, USA, according to a protocol approved by the Johns Hopkins Institutional Review Board (IRB). In this cross-sectional study, subjects were selected based on a range of representative serum IgE levels. All subjects were followed in the allergy clinic for some underlying disease such as atopic dermatitis, allergic rhinitis, or asthma. Exclusion criteria included active subcutaneous allergen immunotherapy, immune modulators, oral prednisone, or biologic therapy, such as omalizumab or dupilumab. Other medication status was not known or excluded.

Cell Preparation

Blood specimens were processed as described previously.19,20 Briefly, whole blood in 10 mM ethylenediaminetetraacetic acid underwent centrifugation at 500 g to isolate a buffy coat. Buffy coats were diluted 1:1 (vol/vol) with PIPES albumin glucose-ethylenediaminetetraacetic acid and then subjected to single-Percoll (1.081 g/mL) density centrifugation, producing a peripheral blood mononuclear cells (PBMC) suspension. Platelets were removed from the PBMC suspension using four low-speed (100 g) centrifugations and washes. Cells were fixed in a 1:1 dilution of

2% paraformaldehyde and stored overnight for staining and flow cytometry. To purify basophils and pDCs, a double Percoll (Sigma-Aldrich, St. Louis, Missouri, USA) gradient was used to generate a basophildepleted cell fraction and a basophilenriched cell fraction. Basophils were purified to >99% using negative selection antibodies and beads.21 The pDC were prepared from the basophil-depleted cell suspension using blood dendritic cell antigen (BDCA)-4+ selection after conducting two cycles of CD14+ selection to first remove monocytes.22

IgE Competitive Binding of Purified pDCs and Basophils

The authors first more rigorously attempted to remove IgE bound to FcεRI on the surface of pDC with omalizumab in a dose-response fashion to compare this outcome with methods previously utilised for basophils and mast cells.6,23 Omalizumab was used to strip IgE from pDCs and basophils (as a control). Omalizumab concentrations used were 0, 100, 500, and 1,500 µg/mL, which also included omalizumab stock dilution reagents as a control. The authors then used a ‘tubewithin-a tube’ culture method by inserting a 1.5 mL tube within a 15 mL culture tube with a loosely fit top so that gas exchange is possible. Basophils were cultured at a concentration of 5x105 and pDCs at 2.5x105 in Complete Iscove’s Modified Dulbecco’s Medium culture medium that contained IL-3 (10 ng/mL). Cells were cultured overnight for 16 hours in a humidified incubator at 37 °C and 5% CO2. The next day, the cells were pelleted, washed three times in phosphate buffered saline, and then checked for IgE expression using flow cytometry.

Antibody Selection

The authors used quilizumab (a mouse antihuman monoclonal IgG1 antibody) to detect the presence of IgE on the membrane of circulating pDCs. Quilizumab is a humanised monoclonal IgG1 antibody directed against the M1 segment exclusively expressed only on human membrane-bound but not receptor-bound IgE. They utilised CD19 and CD27 fluorescent antibodies to focus on a juvenile IgE-switched B cell subset

in order to increase the probability of identifying membrane-bound IgE on these cells in the circulation. If mIgE is indeed present on pDCs this may help explain why omalizumab only weakly removes IgE from these cells and may suggest an additional role for pDCs in allergic response.

Flow Cytometry

Approximately 6 mL of blood was drawn from each of six consenting individuals, some of whom have self-reported sensitivity to aeroallergens. PBMCs were isolated using standard methods that have been previously described.19,20 All cells were first prepared for flow cytometry staining by incubating with a non-specific human IgG blocking antibody (1 mg/mL). The cells were split into six tubes: two for B cells and four for pDCs. Target staining antibodies included quilizumab (mouse anti-human IgE, used at 10 µg/mL and obtained courtesy of Genentech, Inc. [South San Francisco, California, USA]), anti-human FcεRI (0.5 µg/ mL, AER-37, eBioscience/Thermo Fisher, Waltham, MA, USA), and appropriate isotype controls. B cells were gated for using 1:20 dilution commercial mouse antihuman CD19-Alexa488 (BioLegend, San Diego, California, USA) and 1:20 dilution mouse anti-human CD27-PE (stock 50 µg/ mL, BioLegend, San Diego, California, USA), which has been reported as a marker for juvenile B cells. pDCs were gated for flow cytometry with 1:20 dilution commercial mouse anti-human BDCA-2-Alexa488 (stock 200 µg/mL, BioLegend, San Diego, California, USA) and 1:20 dilution mouse anti-human CD123 (IL-3)-PE (stock 200 µg/mL, BD Biosciences, Franklin Lakes, New Jersey, USA). A 1:1,000 dilution of anti-mouse IgG Alexa-647 (stock 1 mg/mL, SouthernBiotech, Birmingham, Alabama, USA) was added for secondary labelling of the authors’ target antibody. The samples were analysed to approximately 600,000 total cells via a BD Accuri C6 Plus flow cytometer, and mean fluorescence intensity (MFI) was measured.

Statistical Methods

A paired t-test was used to compare proportions of counted cells of both the

isotype controls and target antibodies. Data are presented as means and confidence intervals, as appropriate. Statistical analysis was performed with InStat software (GraphPad, San Diego, California, USA) by a paired t-test and two-tailed non-parametric Mann–Whitney test. Linear regression and Spearman’s rank formula were used to calculate correlations. Chi-squared test was used to compare counts among counted groups. A P value of <0.05 was considered significant.

RESULTS

Blood obtained from the six adult subjects had total serum IgE levels ranging from 37–1,301 kU/L. As shown in Figure 1A, as a control experiment, omalizumab behaved in a dose-response fashion, with a concentration of 1,500 µg/mL effectively outcompeting all IgE from the surface of basophils. In contrast, while pDCs generally have approximately 10-fold less IgE bound to the surface compared to basophils, omalizumab resulted in incomplete competitive inhibition of IgE (Figure 1B). This suggested that there might be some mIgE on the pDC that wouldn’t be inhibited by omalizumab’s facilitated dissociation characteristic when used at high concentrations. Figure 1C shows the fraction of IgE levels outcompeted from basophils is significantly higher than that of pDCs, which reinforces the finding that IgE is significantly more difficult to out-compete from pDCs than basophils using omalizumab. It should be noted that omalizumab has a relatively low binding affinity for IgE, so it is unlikely that all of these antibodies would be competitively unbound from the cell membranes.

The primary outcome was to determine the presence of mIgE on pDCs. As shown in Table 1, BDCA-2+ CD123 (IL-3)+ pDCs did not significantly stain positive for quilizumab compared to isotype in the overall proportion or MFI (0.18% versus 0.19%, P=0.125; and 2,448 versus 2,534, P=0.165, respectively). These data indicate that these rare pDCs do not express an appreciable level of membrane-bound IgE in the bloodstream. A representative

Figure 1: Effects of varying doses of omalizumab on IgE expression.

In vitro removal of IgE from human basophils using omalizumab

FL1: anti-lgE/FITC

B

Blue line: isotype Red line: IgE

In vitro removal of IgE from human pDC using omalizumab (representative histograms)

In vitro removal of IgE from basophils versus pDC using omalizumab (normalised data from 5 experiments)

A) Representative histograms of basophils treated with increasing doses of omalizumab are shown. At 500 and 1,500 mg/mL, nearly all of the IgE was outcompeted (P<0.0001). B) Similar histograms of pDCs treated using a single maximum high dose of 1,500 mg/mL omalizumab are shown. Even at 1,500 mg/mL, a large proportion of IgE remained bound to the pDC but did reach significance (P=0.046). C) Comparing basophils and pDCs, omalizumab outcompeted significantly more IgE from the basophil compared with the pDC (P=0.02).

FITC: fluorescein isothiocyanate; pDC: plasmacytoid dendritic cells.

positive B cells

(Alexa647)

Quilizumab positive pDC

Quilizumab (Alexa647)

All cells of interest were initially filtered using FSC and SSC gating based on previously published location of B cells and pDCs among PBMCs. A) B cells were then identified with CD19 (Alexa488) and CD27 (PE) indicated by a red rectangular gate. (B) CD19+ B cells were then sub-selected for CD27 (PE) and quilizumab in an effort to identify possible membrane-bound IgE-bearing B cells (upper right quadrant). In a similar manner C) pDC were first identified with BDCA2 (Alexa488) and CD123 (PE) indicated by a red circle. D) Finally, BDCA+ pDC were then sub-selected for CD123+ (PE) and quilizumab to identify possible membrane-bound IgE bearing pDC (upper right quadrant).

FSC: forward scatter; PBMC: peripheral blood mononuclear cells; pDC: plasmacytoid dendritic cells; SSC: side scatter.

subject demonstrating the pDC and B cell gating protocols along with quilizumab staining cell selection strategy is shown in Figure 2A-D. The primary outcome was to determine the presence of membranebound IgE on pDCs. pDCs are uncommon cells in the peripheral bloodstream, with typically only about 700 pDC per 500,000 total cells in circulation. The number of cells identified as pDC in the authors' study were likewise rare, amounting to only about 0.18% of total PBMC.

As a control experiment, B cells were separated by cell surface markers to determine whether the membrane-bound IgE target antibody was present in higher proportions in certain subtypes of B cells (Table 1). As expected, the proportion of cells staining positive for quilizumab were highest among the CD19+CD27+ B cells compared to CD19+CD27- B cells and CD19-sub-groups (0.17% versus 0.03% and 0.004%, respectively; P=0.008). However, the proportion of cells staining positive for the equivalent isotype-control-stained

Figure 2: B cell and plasmacytoid dendritic cells gating strategies.

Table 1: Quantification of plasmacytoid dendritic cells and B cells that bind quilizumab (n=6).

There was no difference in the number of BDCA2+ IL3+ pDCs that bound quilizumab compared to isotype (P=0.125). The MFI was also similar between the isotype and quilizumab-bound cells (P=0.165). In a similar manner, CD19+CD27+ and CD19+CD27- B cells, thought to express membrane-bound IgE, did not statistically bind quilizumab more than isotype control (P=0.103 and P=0.402, respectively). Of note, CD19+CD27+ B cells bound quilizumab to a much higher degree than CD19- PBMC at a ratio of 54:1 (P=0.015); however, this was also true, to a lesser degree, for the isotype control with a CD19+CD27+/CD19- PBMC ratio of 32:1 (P<0.001). The rarity of the events may make it difficult to distinguish true positive CD19+CD27+ quilizumab binding from non-specific binding of the isotype, and therefore the possibility cannot be excluded.

+: positive; MFI: mean florescence intensity; PBMC: peripheral blood mononuclear cells; pDC: plasmacytoid dendritic cells.

CD19+CD27+ B cell sub-group was also highest compared to other subtypes (0.12% versus 04% and 0.006%, respectively; P=0.014). Overall, among all CD19+ B cells, there was no significant difference in cells staining positive for quilizumab compared to isotype (P=0.487).

B cells identified as CD19+CD27+ were targeted specifically in the authors' study because these cells are thought to more likely express mIgE. Although the total number of CD19+CD27+ B cells for each patient was greater than the number of pDCs, these CD19+CD27+ cells are likewise rare. As shown in Table 1, while there was a trend of higher proportion of CD19+CD27+ cells staining for quilizumab compared to isotype, this did not quite reach statistical significance (0.17% versus 0.12%, P=0.103). The MFI for isotype versus quilizumab were also similar among the CD19+CD27+ B cells, with the isotype actually having a slightly higher MFI (P=0.043).

Given the significantly higher affinity of Alexa647 stain to CD19+CD27+ sub-group cells in both the isotype and quilizumab target groups, and given the expectation that mIgE expressing B cells would be rare, a comparison of those cells to the rest of the PBMC cells (CD19-27-, CD19-27+) was calculated. In both the isotype and quilizumab groups, there was a statistically significant higher proportion of Alexa647 target-bound cells (P<0.001 and P=0.015, respectively), suggesting that these cells appear to have a higher binding affinity than the CD19- PBMC. A ratio of the proportions was calculated for both groups, comparing CD19+27+ to the CD19- cells. Nearly twice as many CD19+CD27+ cells stained positive for quilizumab compared to isotype 54:1 versus 32:1, respectively (P=0.234), although this was not statistically significant due to the small sample size and large variance. There was no significant difference in the proportions or ratio of target cell staining when comparing CD19+27+ versus CD19-27- cells.

Isotype

Quilizumab

DISCUSSION

This study is the first to examine the presence of membrane-bound IgE in both circulating B cells and plasmacytoid dendritic cells using quilizumab, a monoclonal antibody that specifically targets the M1 segment that is exclusive to membrane-bound IgE. Overall, the authors did not identify a significant number of circulating plasmacytoid dendritic cells that bind quilizumab. This study demonstrates that circulating pDCs do not express appreciable amounts of membrane-bound IgE, regardless of the patient’s total IgE level up to 1,300 kU/L. Therefore, the presence, or lack thereof, of membranebound IgE on pDCs does not explain their finding that omalizumab insufficiently removes IgE from the surface of pDCs compared to basophils. It is also possible that the antibody could not effectively bind quilizumab due to innate isosteric properties of the antibody interaction.

pDCs are involved in the pathogenesis of multiple allergic conditions, including atopic dermatitis, asthma, and chronic rhinitis, in addition to their antiviral immunity and modulation of the innate immune axis through the production of Type 1 interferons. In the lungs of patients with allergic asthma, for example, pDCs mediate tolerance to inhaled antigen through induction of regulatory T cells compared to conventional DCs that promote Th2 sensitisation to inhaled antigen after reaching the lymph nodes.24 Most studied in allergic asthma, pDCs negatively regulate allergic airway inflammation and Type 2 immune responses via IFN-α and in pDCdeficient mouse models, more severe allergic airway responses developed upon allergen exposure.25 pDCs have also been implicated in atopic dermatitis. Patients with atopic dermatitis had an increased intralesional dendritic cell proportion, with pDCs as the predominant cell type.26 pDC infiltration in these lesions were in close association with blood vessels expressing peripheral neural addressins, thereby altering Th1/Th2 differentiation and leading to more severe disease.

It has been shown, quite interestingly, that the IgE-specific receptor (FcεRI) and TLR9 molecules oppose each other on pDCs.1 pDCs have TLR9 molecules through which ligation with CpG DNA favours Th1 responses. Additionally, while pDCs stimulate allergen-dependent T cell proliferation and Th2 production, CpG-activated pDCs inhibited allergendependent proliferation in Th2 memory cells and markedly increased IFN-γ production.27 The results of this study demonstrated that pDCs are not only extremely rare cells in the peripheral blood, but likely do not express membrane-bound IgE. Given the role of pDCs as balance mediators in the Th2-mediated allergic response, a probable postulate is that they do so only through the high affinity IgE surface receptor, FcεRI, and not a membrane-bound form.

The lack of significant binding of quilizumab to pDC does not help explain why IgE is more difficult to outcompete from these circulating dendritic cells compared to basophils. While it has certainly been demonstrated that the FcεRI on pDCs are present in much lower abundance compared to conventional DCs, mast cells, and basophils (with a ratio of about 10:1), the receptor is unique in that it lacks the β-subunit. Omalizumab does not bind IgE already attached to FcεRI on cells;28 therefore, omalizumab would presumably bind circulating IgE in the same manner and with the same affinity whether or not it dissociated from a basophil or a pDC. Jardetzky and his collaborators have shown that omalizumab has the capability of inducing facilitated dissociation.29 The underlying concept is that omalizumab first weakly binds to some portion of IgE not specifically engaged in the receptor pocket, and then a conformation change is induced in the IgE that weakens its association with the receptor, leading to more dissociation. When this occurs, it effectively captures the IgE to prevent re-association, although the concentrations required to induce this behaviour are extreme, i.e., 100 to 1,000-fold above stoichiometric levels. This process may be dependent on the precise nature of the molecular environment of bound IgE on pDCs.

One hypothesis, therefore, is that the unique αγ2 trimeric form of the FcεRI receptor on plasmacytoid dendritic cells binds IgE more tightly, or differently, compared to the αβγ2 tetrameric form expressed on basophils and mast cells. No studies have been done specifically examining the kinetics of these two receptor types. However, supporting the concept that the trimer form of FcεRI is handled differently by the pDCs, several studies suggest that glycosylated FcεRI traffics to the cell surface faster in pDCs compared to basophils30,31 and could sequester IgE more readily. Further, studies in transgenic mice expressing human FcεRI suggest that DCs and monocytes internalise IgE to a greater extent than basophils and mast cells and that overall, IgE is bound less frequently to DCs on the surface.30 How these differences affect the binding and dissociation of IgE on these cells is unknown. More detailed kinetic studies of the interaction of IgE with FcεRI on pDCs and its implications on omalizumab binding need further exploration.

To have a positive control for quilizumab, the authors attempted to use circulating B cells, specifically the CD19+CD27+ subset. However, membrane-bound IgE was determined to be scarce among this cell population. Of note, the CD19+CD27+ cells, which are thought to be a maturing B cell subtype, did, in fact, bind to quilizumab in a much higher proportion compared to the CD19- PBMC (P=0.015) and CD27- B cells (P=0.091). However, while CD19+CD27+ B cells were more likely to bind quilizumab compared to all CD19PBMC with a proportion of about 50:1, these cells also bound to the isotype control with

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One of the strengths of this study is that it presented a novel protocol using an antibody specific to membrane-bound IgE to stain pDCs. Quilizumab has never been used to determine whether pDCs express membrane-bound IgE. One of the potential limitations of the study is the preferential binding of isotype control antibody to CD19+CD27+ B cells causing high background. From the data, the MFI range of the isotype is close to that of the target antibody. It is possible that there may have been a small number of quilizumab staining B cells that were masked by the high background binding of the isotype control. A larger powered study analysing >1 million cells in additional subjects may have identified more target-bound cells or PBMC. Interestingly, like quilizumab, the isotype-control antibody seemed to bind CD19+CD27+ B cells more specifically than other subtypes as well. The selection of another alternative isotype may also have circumvented this.

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