Needle-free Epicutaneous For t 2 DNA Vaccine is Effective for Preventing and Treating Biting Midge (Forcipomyia taiwana) allergy in a murine modelTo the Editor,Allergen-specific immunotherapy (ASIT) remains the only treatment capable of inducing immune tolerance to the corresponding allergen and potentially treating the root cause of the allergic disease.1 As the treatment course of protein-based vaccines for ASIT is time-consuming, an easily administered epicutaneous anti-allergic DNA-based vaccine is an attractive method, especially in light of the COVID-19 pandemic.2The biting midge, Forcipomyia taiwana , is the most prevalent cause of biting insect allergy in Taiwan. It is a tiny hematophagous midge that attacks en masse. As many as 60% of exposed individuals develop allergic reactions to the bites.3 The midge is widely distributed throughout Taiwan and southern China. For t 2 is the most predominant,with 75% of midge-allergic patients showing specific IgE to For t 2.4 Allergic reactions to midge bites are not limited to humans but also seen in livestock, such as horses, cattle, sheep, and donkeys, causing significant veterinarian problems.E.coli -expressed For t 2 recombinant protein (rFor t 2) was used as an allergen to sensitize and challenge the mice.5For t 2-encoding fragment (GenBank accession EU678971) was amplified by PCR. The PCR products were subcloned into pVAX1 (Life Technologies, Carlsbad, CA) . The experiments were designed using two approaches: therapeutic and prophylactic (Fig 1). The therapeutic approach is to imitate ASIT in human with established allergy while the prophylactic approach to non-allergics. Twenty-five μg For t 2 DNA was determined as the optimal dose after dose-finding experiments (Supplementary Fig S1). For each treatment, the hair of the abdominal area of the mice was removed using a depilatory,tape-stripped,then patched with 25 μg For t 2 DNA vaccine for one hour and removed.A total of three treatments were given spaced one week apart (Fig 1 and Fig S2). For t 2 proteins were detected in the patched skin and the immune organ spleen at 24 hoursand had significantly increased at 48 hours after last treatment (Fig S3). Scratch bouts after rFor t 2 challenge were used as a clinical surrogate of itch. We measured For t 2-specific IgE, IgG1 and IgG2a in the sera as well as mRNA and proteins of IL-13, interferon-gamma, IL-10, and FOXP3 in the culture supernatants of splenocytes after stimulation with various doses of rFor t 2 at 37℃ for 3-5 days by ELISA and real-time quantitative PCR. Histopathology of the challenged skins was examined.After epicutaneous DNA vaccination, the allergen-induced itchin both groups significantly improved, and For t 2-specific IgE and IgG1/IgG2a ratio decreased significantly at week 6 or week 8 (Fig 2). Levels of mRNA and protein of IL-13 decreased significantly, but IFN-gamma and IL-10 remained unchanged. Expression of FOXP3 mRNA increased (Fig 2, protein data not shown). Eosinophils infiltration in the challenged skin significantly decreased (Fig S4).This is the first study to demonstrate an epicutaneous needless anti-allergic DNA vaccine that effectively treats an established allergic condition and prevents the development of an allergic disease using biting midge allergy as a model. After epicutaneous DNA vaccination, in addition to allergen-induced itch, the changes of multiple biomarkers suggest that immune tolerance was induced after the epicutaneous DNA vaccine.Our data show that though the molecular weight of the For t 2 DNA vaccine is as high as 4000 base pairs, it can penetrate the dermal barrier and translate the corresponding protein in the targeted skin and the spleen of the vaccinated mice. It is possible that the DNA vaccine passes the epidermis via the hair follicles as the skin is tape-stripped before epicutaneous vaccination.6The mode of this anti-allergic epicutaneous DNA vaccine may potentially be used in other specific immunotherapies for other allergens.Mey- Fann Lee1Chi-Sheng Wu2 Shyh-Jye Lin3Yi-Hsing Chen2,4*1Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan2Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan3School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan4School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan

Subcutaneous adipose tissue (SAT) is the deepest component of the three-layered cutaneous integument. While mesenteric adipose tissue-based immune processes have gained recognition in the context of the metabolic syndrome, SAT has been traditionally considered primarily for energy storage, with less attention to its immune functions. SAT harbors a reservoir of immune and stromal cells that significantly impact metabolic and immunologic processes not only in the skin, but even on a systemic level. These processes include wound healing, cutaneous and systemic infections, immunometabolic and autoimmune diseases, inflammatory skin diseases, as well as neoplastic conditions. A better understanding of SAT immune functions in different processes, could open avenues for novel therapeutic interventions. Targeting SAT may not only address SAT-specific diseases but also offer potential treatments for cutaneous or even systemic conditions. This review aims to provide a comprehensive overview on SAT’s structure and functions, highlight recent advancements in understanding its role in both homeostatic and pathological conditions within and beyond the skin, and discuss the main questions for future research in the field.

Background: In Europe, Omalizumab (anti-IgE) is indicated for the treatment of moderate/severe asthma, but not for IgE-mediated food allergy (FA). Objective: We prospectively assessed the impact of Omalizumab for efficacy, safety, and quality of life (FA-QoL) in patients with moderate/severe asthma and history of anaphylaxis to peanut, tree nuts, fish, egg, milk, and/or wheat. Methods: Food-allergic children (6-18yrs) with moderate/severe asthma underwent oral food challenges (OFCs) to establish the threshold of reaction to the culprit food(s) at baseline (T0) and at four-month intervals (T1, T2, T3) during their first year of treatment with Omalizumab. We recorded the number and severity of food-allergic reactions, Asthma Control Test (ACT), FA-QoL, and total IgE. Results: In 65 patients allergic to 107 foods, the No Observed Adverse Events Level (NOAEL) at T1 increased: 243- and 488-fold for raw and baked milk, respectively; 172 and 134-fold for raw and baked egg; 245-fold for hazelnut; 55-fold for peanut; 31-fold for wheat, and 10-fold for fish. Full tolerance was achieved in 66.4% of OFCs at T1, 58.3% at T2, and 75% at T3. Ninety-five foods were liberalized ad libitum in the diet of 55 patients; the remaining 12 were introduced by 10 patients at least in traces. Throughout the study, 40/65 children got a free diet. ACT increased from 17 (Q1-Q3:15-17) to 23.6 (Q1-Q3:23-25). The FA-QoL score in children ≤ 12 years decreased from 4.63±0.74 to 2.02±1.13, in adolescents from 4.68±0.92 to 1.90±1.50. Conclusions: Omalizumab allows safe reintroduction of allergenic foods. Trial registration number: ClinicalTrials.gov, NCT06316414

Response to Correspondence ALL-2023-01107 “Short-course subcutaneous treatment with PQ Grass strongly improves symptom and medication scores in grass allergy”P.J. de Kam1, S. Zielen2, J.A. Bernstein3, U. Berger4, M. Berger5, M. Cuevas6, D. Cypcar7, A. Fuhr-Horst8, W.A. Greisner9, M. Jandl10, S. Laßmann11, M. Worm12, J. Matz13, E. Sher14, C. Smith15, G.C. Steven16, R. Mösges17,18, M.H. Shamji19,20, L. DuBuske21, F. Borghese1, K. Oluwayi1, T. Zwingers1, M. Seybold1, O. Armfield1, M.D. Heath1, S.J. Hewings1, M.F. Kramer1, M.A. Skinner1Allergy Therapeutics plc, Worthing, United KingdomChildren and Adolescents Dept., Allergology, Pulmonology & Cystic fibrosis, Goethe University, Frankfurt, GermanyBernstein Clinical Research Center, LLC, Cincinnati, OH, United States of AmericaAerobiology and Pollen Research Unit, Dept. Oto-Rhino-Laryngology, Medical University Vienna, Vienna, Austria.Wiener Gesundheitsverbund, Hospital Hietzing, Department of Otorhinolaryngology, Vienna, AustriaClinic and Polyclinic of Otorhinolaryngology, University Clinic Carl Gustav Carus, TU Dresden, GermanyAllergy Partners of Western North Carolina, Asheville, NC, United States of AmericaENT Research- Institut für klinische Studien, Essen, GermanyBluegrass Allergy Research, Lexington, KY, United States of AmericaHamburger Institut für Therapieforschung GmbH, Hamburg, GermanyStudienzentrum Dr. Sabine Laßmann, Saalfeld, GermanyUniversitätsmedizin Berlin, Department of Dermatology and Allergy - Charite Campus Mitte, Berlin, GermanyChesapeake Clinical Research, Inc. White Marsh, MD, United States of AmericaAllergy Partners of New Jersey, Ocean, NJ, United States of AmericaCertified Research Associates, Cortland, NY, United States of AmericaAllergy Asthma & Sinus Center, S.C., Greenfield, WI, United States of AmericaIMSB (Institute of Computational Biology and Medical Statistics), University at Cologne, Cologne, GermanyClinCompetence, Cologne, GermanyImmunomodulation and Tolerance Group, Allergy and Clinical Immunology, Department of National Heart and Lung Institute, Imperial College London, London, United KingdomAsthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, United KingdomDivision of Allergy and Immunology, Department of Internal Medicine, George Washington University Hospital, Washington, DC, United States of America

Chronic urticaria, defined as having urticaria for over 6 weeks, is divided into two categories; namely, inducible urticaria and chronic spontaneous urticaria (CSU). Inducible urticarias have an initiating stimulus, often “physical”, and actually occur intermittently, but the total duration of symptoms can encompass many years. CSU is more typically chronic, has urticarial lesions most days of the week, has no exogenous cause, and from the patient’s point of view, does seem spontaneous. An algorithm for the diagnosis of CSU is shown in Fig. 1. Angioedema can accompany many inducible urticarias, but is more typically associated with CSU affecting face, extremities, genitalia, lips, tongue, and rarely pharynx, but not the larynx. Thus risk of asphyxiation is nil. The disorder is strongly associated with autoimmunity. The best studied (often referred to as type IIb autoimmunity) involves IgG antibody to the IgE receptor[1](#ref-0001) which cross-links unoccupied IgE receptors of mast cells and activates the cells to cause secretion of histamine, leucotrienes, cytokines, and chemokines. Complement is activated and release of C5a augments the mast cell secretion[2](#ref-0002). There is a second scenario in which patients have IgE antibody to a large variety of autoantigens[3](#ref-0003) including thyroperoxidase and interleukin 24, although which are pathogenic is not yet clear. This is often designated as type I autoimmunity or autoallergy. Clinically, other autoimmune disorders may be present. The most prominent is Hashimoto’s thyroiditis, but also type I diabetes and vitiligo. Antithyroid antibodies (i.e. IgG anti microsomal antigen and IgG antithyroglobulin) are seen in 25% of patients regardless of thyroid status. Total IgE is elevated within this population although much less so than in asthma or atopic dermatitis. Low or very low IgE levels may be seen and such patients are less responsive to omalizumab[4](#ref-0004).

Efficacy and safety of a 7-week immunotherapy protocol with aluminium hydroxide absorbed hymenoptera venomTo the Editor,Hymenoptera venom allergy can cause life threatening anaphylaxis in patients sensitised to wasp and bee venom. Venom immunotherapy is effective in 77%‐84% of patients treated with honeybee venom and in 91%‐96% of patients receiving vespid venom1. Adverse events are usually rare and mild, and symptoms occur in only 4.3%‐11.4% of patients during the updosing1.A variety of therapy regimes exist for the updosing phase, from conventional, rush, ultrarush or clustered modalities1,2. Current conventional protocols are time‐consuming for patients, and some patients decline the potentially life-saving treatment due to the time commitment required for immunotherapy. Adverse events appear to be less frequent in conventional protocols during the updosing phase compared to rush and ultrarush protocols1,2; however, patients may remain unprotected for weeks as it takes considerable time to reach the maintenance dose.The only licensed venom immunotherapy product in the UK is Alutard SQ® (ALK Abelló) for Vespula and Apidae venom. The SPC recommends updosing with a 7-week clustered protocol or 15- or 25-week conventional protocol.To enhance the acceptance of treatment and increase compliance, we reduced the length of the SPC protocol. Another significant factor was the COVID-19 pandemic, which significantly reduced outpatient capacity to comply with social distancing.Based on previous data using the same product3, we introduced a shorter updosing protocol with 8 injections in 7 weeks and monitored its efficacy and safety. We used this in a wider age range of patients, including one patient with indolent mastocytosis and more patients with severe sting reactions.Seventy‐four patients aged 17 to 85 years with a history of a systemic sting reaction to vespid and apidae stings grade 2-4 were included (Table 1). Further information about patient selection and the updosing protocol is in supplementary file S1.We managed to retain all the patients during updosing and maintenance, and no dose reduction was needed.During updosing, there were no objective systemic adverse reactions recorded. Only one objective systemic adverse reaction was documented during maintenance, which was mild and limited to the skin. There were 6 incidences of mild and subjective systemic reactions during updosing and maintenance, which included symptoms of feeling hot, dizzy and itchy. The symptoms were treated with additional antihistamines with no change in regime required. We had a lower incidence of systemic reactions at 1.4% compared to Schrautzer et al3, who reported objective systemic reactions in 3.9% of patients during just the updosing phase.9.5% of our patient cohort reported large localised reactions throughout both the updosing and maintenance phase, which generally only occurred once or twice during the full treatment course.The prevalence of cardiovascular disease and treatment with beta-blockers were not related to the occurrence of side effects.Reactions to field stings were monitored to assess efficacy as sting challenges are not performed in the UK. 20 patients had field stings and all reported localised reactions. Some patients were stung by multiple insects (such as one patient who was stung by 19 insects at one time) and this was more common in beekeepers.We have extended the work of Schrautzer et al3 and demonstrated the efficacy and safety of their 7-week protocol in a large group of patients in a real-world setting. We have also demonstrated safety and efficacy of the 7-week protocol for Alutard SQ® apidae immunotherapy. Our data includes a larger group of patients with more severe reactions. Interestingly, our data also shows a lower number of reactions to immunotherapy treatment.The quicker updosing protocol improved patients’ acceptance of treatment and increased the efficiency of our immunotherapy clinic in terms of time and cost for patients, and medical staff.

Background. Food allergy (FA) is associated with poor quality of life and high levels of psychological distress. Psychological support is therefore extremely important but is not always available. As part of the Global Access to Psychological Services for Food Allergy (GAPS) Study, we aimed to assess distress and use of psychological services for adults with food allergy. Methods. Participants (n=1329 adults with FA) from >20 countries were recruited through patient organisations, social media adverts and online survey panels to complete an online survey. Surveys were offered in six languages. Results. A total of 67.7% of adults reported they had experienced FA-related psychological distress with the biggest issue being anxiety about having an allergic reaction (64.1%). Only 19.4% had been assessed for FA-related psychological distress; 22.9% had seen a mental health professional for treatment for their FA-related distress. There were significant differences across countries for levels of distress, screening for distress, seeing a mental health professional and being diagnosed with a FA-related mental health disorder (all p<0.001). The UK and Brazil had the highest number of adults reporting distress. The biggest barriers to seeing a mental health professional were cost, lack of insurance coverage, failure to provide a referral, and lack of practitioner in the area. Conclusions. FA-related distress is common in adults. Few have accessed the psychological care and support they need and there is significant variability across countries. Clinicians should consider routine assessment of adults for distress and easily accessible resources are needed to help support adult patients.

Transcriptomic Profiles of Well-Differentiated Airway Epithelial Cells in Response to Environmental Triggers of Asthma ExacerbationAntonella Marrocco1, Jennifer A. Mitchel1, Margaret Parker2, Maureen McGill1, Robert P. Chase2, Scott T. Weiss2, Diane R. Gold1,2, Peter J. Castaldi2, Jin-Ah Park1, Joanne Sordillo34Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA2Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.3Division of Chronic Disease Research Across the Lifecourse (CoRAL), Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.Corresponding Author: Joanne E. SordilloEmail : [email protected]:Landmark Center West 401 Park Dr., 4th Floor Boston, MA 02115The authors have no conflicts of interest to disclose.Funding: R01HL148152, P30ES000002, T32HL007118, Francis Family FoundationKeywords: Bronchial epithelial cells, gene expression, RNAseq, asthma

Background: Limited information is available on the use of omalizumab (OMA) updosing since its introduction as a second-line therapy in chronic spontaneous urticaria (CSU) in 2014. Practical guidelines from health authorities are lacking, and the specific characteristics of patients requiring higher doses remain unknown. Our objectives were to characterize the patterns of OMA updosing (defined as changes in dose and/or injection intervals), to identify the predictive factors associated with updosing, and to improve CSU management. Methods: We conducted a prospective, multicentric, real-life, observational study, including patients diagnosed with CSU and starting OMA. The data were collected at 0, 3, 6 and 9 months. The primary endpoint was the frequency of OMA updosing at 3 months. The secondary endpoints included an analysis of updosed patients’ profile, and an assessment of OMA efficacy and safety. Results: We included 153 patients. Twenty percent of patients at M3 were updosed, and 27% in total during the 9-month follow-up. Practitioners mainly chose to increase the frequency of injections (66%). At baseline, the updosed patients were more likely, to have inducible urticaria (50% vs. 33%, p=0.046), more severe CSU (UCT 3 vs. 4, p<0.001; DLQI 14 vs. 11, p=0.040), a lower lymphocyte count (1894 vs. 2100, p=0.026) and IgE below 70 UI/mL (65% vs. 45%, p=0.039). The side effects of OMA were not more frequent after updosing. Conclusion: One in five patient underwent updosing within just three months. OMA updosing is frequent in particular in cases of severe disease, inducible urticaria and low IgE blood levels.

Anti-rubella IgG serum levels predict risk for SARS-CoV-2 breakthrough infectionsTo the Editor,

Peanut allergy treatment options remain limited, but novel approaches are being studied, including epicutaneous immunotherapy (EPIT). EPIT uses the cutaneous immune system to promote tolerance to food allergens. Viaskin TM Peanut, an approach to EPIT in late-stage clinical development uses an occlusive patch with a condensation chamber that enables natural epidermal water loss to solubilize dry antigen on the patch, which is then absorbed and captured by skin dendritic cells. This form of EPIT does not require disruption of the skin barrier, thus avoiding a proinflammatory cytokine response by targeting the non-vascularized epidermis and limiting systemic allergen exposure. Extensive preclinical research suggests that Viaskin Peanut has a distinct mechanism of desensitization, including the potential for disease modification, driven by a unique population of regulatory T cells. Numerous clinical studies of Viaskin Peanut have demonstrated desensitization and reductions in reaction severity, particularly in children aged 1 through 11 years, as well as a favorable safety profile with mostly mild to moderate skin reactions that were observed to decrease over time. EPIT with Viaskin Peanut may be a potential therapeutic option for peanut allergy that is clinically practical with long-term efficacy and tolerability.

Algorithms in allergy: Diagnosis and management of atopic dermatitis in adulthoodM. Grace Hren1,2, Ester Del Duca1, Helen He1, Andrew L. Ji1,2, Emma Guttman-Yassky1*1Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA2Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA*Correspondence:Emma Guttman-Yassky, MD, PhDAtopic dermatitis (AD) is a chronic inflammatory skin disease characterized by significant pruritus, eczematous lesions, and a relapsing course.1,2 Once mainly considered a pediatric disease that diminishes with age, current epidemiologic studies suggest a prevalence of ~7% among adults in the United States.3 Associated with atopic (e.g. asthma, rhinitis, food allergy) and non-atopic (e.g. psychiatric, autoimmune, infectious) comorbidities, as well as diminished life quality, appropriate treatment of AD is crucial.4,5 This algorithm offers a practical guide for management of AD in adults.As a purely clinical diagnosis, there are no biomarkers or confirmatory laboratory tests for AD, and with a highly heterogenous presentation, the differential for AD is extensive.2,3 Lacking specific diagnostic criteria, a combination of history, morphology/distribution of lesions, and exclusion of differentials reinforces diagnosis.1,2,3 Several groups have proposed criteria for AD (Hanifin and Rajka (1980), United Kingdom Working Party (1994), among others).3 More recently, the American Academy of Dermatology released an updated set of criteria with essential (must be present), important (support diagnosis), and associated (suggest diagnosis) features of AD (Figure 1 ).6 If diagnosis remains unclear, a skin biopsy or patch test can exclude alternative diagnoses or determine underlying triggers, respectively.3,6After establishing diagnosis, stratification of AD as mild, moderate, or severe may assist in management. Scoring Atopic Dermatitis (SCORAD), Eczema Area and Severity Index (EASI), and Patient-Oriented Eczema Measure (POEM) are AD severity scores validated for clinical trials, but these scores are not routinely utilized in clinical practice.6 Rather, physician assessment of cutaneous involvement, plus patient-reported frequency of itching and impact on daily living, psychosocial well-being, and sleep can direct stratification (Figure 1 ).7At any severity, general management of AD consists of patient education and encouragement of proactive measures. Instruct patients to apply emollients and moisturizers multiple times per day, maintain healthy bathing routines, and avoid exacerbating factors (Figure 2 ).8Among patients with mild AD, use of low-to-medium potency topical corticosteroids (TCS) 1-2 times daily for maximum of two weeks is first-line management. Due to potential risk of skin atrophy, consistent use of TCS for greater than two weeks is not recommended.8If low-to-medium potency TCS use leads to disease resolution, commence maintenance treatment, employing frequent use of moisturizers plus intermittent use of low-to-medium potency TCS to reduce flares and relapse.8 If unresolved, consider topical calcineurin inhibitors (TCI), crisaborole ointment, or ruxolitinib cream. Allow 2-4 weeks to elapse before reassessing response.8 Consider other potential etiologies, such as non-adherence (assess for fear of TCS side effects impeding use), contact allergy (conduct patch testing), infection (consider antibiotics or 0.005% diluted bleach baths), or misdiagnosis (consider biopsy).8For those lacking in response to above therapies, along with patients presenting with moderate-to-severe AD, commence treatment with medium-to-high potency TCS daily for two weeks.8 Low potency TCS, TCI, or crisaborole ointment can be utilized for areas with increased risk for skin atrophy.8Consider systemic therapies for patients with moderate-to-severe AD nonresponsive to topicals, or as first-line therapy for patients with severe/extensive skin involvement. First-line systemic agents include dupilumab and tralokinumab, two monoclonal antibodies that target the Th2 pathway with excellent safety profiles.9 Other systemic options include oral Janus kinase inhibitors (e.g. upadacitinib, abrocitinib) or conventional immunosuppressants (e.g. methotrexate, azathioprine, cyclosporine, mycophenolate mofetil). However, these therapeutics possess their own respective safety concerns, warranting increased caution and monitoring.9 Narrow-band ultraviolet B (NB-UVB) phototherapy can be considered, but the commitment (2-3x/week in office) may be prohibitive for patients.9 Systemic corticosteroids are not recommended due to risk of rebound flare.9 Once moderate-to-severe AD is controlled, proceed with long-term maintenance therapy, consisting of a systemic agent plus TCS or other topical therapies to prevent flares and relapse.

Global associations of macronutrient supply and asthma disease burden Duan Ni1,2,3, Alistair M. Senior3,4,5, David Raubenheimer3,4, Stephen J. Simpson3,4, Laurence Macia3,6,7, Ralph Nanan1,2,3,*1 Sydney Medical School Nepean, The University of Sydney, Sydney, NSW, Australia2 Nepean Hospital, Nepean Blue Mountains Local Health District, Sydney, NSW, Australia3 Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia4 School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW, Australia5 Sydney Precision Data Science Centre, The University of Sydney, Sydney, NSW, Australia6 School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia7 Sydney Cytometry Core Research Facility, Charles Perkins Centre, The University of Sydney and Centenary Institute, Sydney, NSW, Australia* Correspondence:Ralph [email protected] Medical School Nepean, The University of Sydney.Nepean Hospital, Level 5, South Block, Penrith NSW, 2751, AustraliaTelephone: +61 2 4734 1614Fax: +61 2 4734 1144To the Editor,We read with interest the work by Shin et al. 1, investigating the global disease burden of allergic disorders. They showed that the age-standardized prevalence of asthma has decreased over time on a global level.Following a similar theme, we curated asthma disease burden, macronutrient (protein, carbohydrate and fat) supply and gross domestic product (GDP) data around the globe (Supplementary Methods). Our analysis found that in parallel to changes in asthma disease burden, GDP per capita 2 has increased, and the global nutritional landscape has also changed (Figure 1A-B). Both socioeconomic status and nutritional factors, are emerging critical confounders for asthma1. However, so far, most studies have neglected to consider their correlations and interactions, including among nutrients within diets (Figure 1C-E). They instead focused on individual parameters alone, like specific diets or foods 3. Here, we adopted a recently published approach 2 to systematically interrogate the relationship between nutrient supply, a good proxy of food environment, socioeconomic status and asthma disease burden at a global scale over time. We focused on macronutrient supplies and their interactions, considering their important associations with many facets of health.Various multi-response generalized additive mixed models (GAMMs) were used to analyze the effects on asthma disease burden from macronutrient supplies and GDP over time (Supplementary Methods). In all analyses, a model considering the interactions of macronutrient supply and GDP, and an additive effect of time was favoured (Supplementary Table 1, 3). This suggested combinatory effects of macronutrients on asthma and the impacts of socioeconomic changes.The most recent year with all data available, 2018, is shown as a representative (Figure 1F-G, Supplementary Table 1-2). In brief, predicted association between asthma prevalence and macronutrient supplies were visualized using response surfaces on macronutrient supply plots. We focused on the fat (x -axis) and carbohydrate (y -axis) supplies while holding protein at 25%, 50% and 75% quantiles of global supply. Across the response surfaces, red indicated higher asthma disease burden, while blue indicated lower.In our modelling, carbohydrate supply was most strongly associated with increases of asthma prevalence rates, while fat supply had the opposite effects (Figure 1F). This is reflected by the purple isocaloric line, along which the total energy from macronutrients remained constant but increasing fat:carbohydrate ratio decreased the allergy prevalence. Protein supply conferred less influences. Similar patterns were found for asthma incidences (Figure 1G, Supplementary Table 3-4) independent of gender (Supplementary Figure 1-2) and were not confounded by the total macronutrient energy supply, as changing total energy while holding fat:carbohydrate ratio constant (red radial in figures) minimally impacted asthma disease burden.This represents the first study to link asthma to global food environment. Our results imply a driving role of carbohydrate supply for the asthma disease burden, after adjusting for the plausible interactions between macronutrients, total energy supply and socioeconomic status.Interestingly, previous studies found that ketogenic diets, low in carbohydrates, might ameliorate established asthma 4, supporting our findings that ketogenic-like food environments are associated with lower asthma disease burden. Although further in-depth investigations are needed, diet quality might be an intriguing explanation for the positive association between carbohydrate supply and asthma. For example, high- and ultra-processed foods low in fibre have been found to be related to asthma development 3,5, while we have previously shown that dietary fibre exhibited a strong immune regulatory influence, protecting against asthma6.Hence, future studies in more depth are warranted to investigate the associations between macronutrient supply and asthma, including also other related socioeconomic and environmental factors. Such studies will be critical for guidance to future clinical research and practice and public health interventions.Figure 1. Association of global macronutrient supply and asthma disease burden. A. Age-standardized asthma prevalence (blue) and incidence rate (red) of both sexes as functions of year. B.Global GDP per capita (in US dollars, black) and supplies of carbohydrate (green), protein (red) and fat (brown) as functions of year. C-E. Correlations among variables for global data from 1990-2018 (C ) and for different countries in 1990 (D ) and 2018 (E ). Correlation coefficients are shown. F-G.Predicted effects of macronutrient supply on age-standardized asthma prevalence rate (F ) and incidence rate (G ) of both sexes (See Supplementary Information for statistics and interpretation).

Title: Assessment of sIgE to rLep d 2 for DetectingLepidoglyphus destructor SensitizationConclusion: The novel recombinant allergen rLep d 2 exhibits excellent specificity, although its sensitivity is lower compared to specific IgE tests and skin prick tests using Lepidoglyphus destructor . Its additional diagnostic utility for respiratory allergies related to L. destructor is minimal.To the Editor:Recently, rLep d 2 has been introduced to diagnose IgE-mediated allergy to Lepidoglyphus destructor. We aimed to analyze the sensitivity, specificity, and likelihood ratios of sIgE against rLep d 2.We retrospectively analyzed 95 sera of patients previously diagnosed with respiratory allergy to L destructor , to whom an IgE determination of L destructor had been requested. The protocol was approved by the Hospital Ethics Committee for Clinical Research (PI 2023/09/1425). Material and methods are specified in Supplementary material.Statistically significant differences were found between patients sensitized and not sensitized to L destructor . Patients with a sIgE positive to L destructor were younger, had a higher percentage of asthma and moderate/severe persistent rhinitis, and had higher levels of total IgE and sIgE to rLep d 2 and rDer p 2 than non-sensitized patients. (Table 1).There was a high correlation between L destructor and rLep d 2 (R=0.940, p<0.001), although no correlation was observed between L. destructor and r Der p 2 (R= 0.117, p= 0.260) (Figure S1).The sensitivity of sIgE to rLep d 2 was 71.64% (95% CI, 59.31-81.99), and specificity was 96.43% (95% CI, 81.65-99.91). PLR was 20.06 (95%CI, 2.91-138.28) and NLR 0.29 (95% CI, 0.20-0.43). The Receiver Operating Characteristic (ROC) curve for sIgE to rLep d 2 had an area under the curve of 0.931 (Figure S2). The results of the patients’ test are summarized in Figure 1.This is the first study to examine the accuracy of the commercially available major allergen rLep d 2 in a population of patients allergic and non-allergic to L destructor with rhinitis and/or asthma. Good sensitivity (71.64%), excellent specificity (96.43%), remarkable PLR (20.06) and NRL (0.29), and a noteworthy ROC result (0.931) were observed.Data analysis showed a high correlation between sIgE to rLep d 2 and sIgE to L destructor (0.94) (Figure S1A), much higher than that previously obtained by Johansson et al. (1), who used a non-commercial recombinant extract of Lep d 2, finding a correlation coefficient of 0.70. Additionally, the lack of correlation between sIgE to rDer p 2 and sIgE to L destructor , with a correlation coefficient of 0.117 (Figure S1B), agrees with the lack of cross-reactivity between group 2 allergens of L destructor andD pteronyssinus (2). Therefore, most patients who test positive for rLep d 2 and rDer p 2 can be considered co-sensitized.The sensitivity and specificity data for sIgE to rLep d 2 indicate that a positive result suggests sensitization to L. destructor . In contrast, a negative result does not necessarily rule out sensitization, as almost 30% of patients can still be sensitized to L destructor . The PLR of 20.06 provides robust evidence for L destructor allergy when rLep d 2 values are ≥0.35 kU/L. However, it is noteworthy that the ability to exclude L destructor allergy is weaker when rLep d 2 values fall below that threshold.Patients’ test results (Figure 1) suggest that both SPT and sIgE should be used when evaluating a patient with suspected allergy to L destructor . In addition, 19 patients had sIgE positive to L destructor but negative sIgE to rLep d 2. It could happen that some patients may have been sensitized to allergens other than Lep d 2. Accordingly, rLep d 2 should not be initially used when evaluating a patient with a suspected allergy to L destructor . Notwithstanding, sIgE against Lep d 2 might be helpful before initiating specific immunotherapy with L destructor (3).To conclude, despite an excellent specificity, determining sIgE to rLep d 2 does not seem to offer additional diagnostic value when compared SPTs and/or sIgE to L destructor .REFERENCESJohansson E, Eriksson TLJ, Olsson S, et al. Evaluation of Specific IgE to the Recombinant Group 2 Mite Allergens Lep d 2 and Tyr p 2 in the Pharmacia CAP System. Int Arch Allergy Immunol. 1999;120(1):43-49.Parvaneh S, Johansson E, Elfman LH, et al. An ELISA for recombinant Lepidoglyphus destructor, Lep d 2, and the monitoring of exposure to dust mite allergens in farming households. Clin Exp Allergy. 2002 Jan;32(1):80-6Ansotegui IJ, Melioli G, Canonica GW, et al. IgE allergy diagnostics and other relevant tests in allergy, a World Allergy Organization position paper. World Allergy Organ J. 2020 Feb 25;13(2):100080.

More than half of CRSwNP patients treated with dupilumab experience olfactory improvement within 28 days To the Editor,Olfactory dysfunction is one of the main complaints of patients suffering from Chronic Rhinosinusitis with Nasal Polyps, significantly affecting their quality of life. Dupilumab has proven to effectively enhance olfactory function within six months of treatment (1-3). However, the speed and efficacy of this effect on olfactory function improvement within the initial weeks of treatment has yet to be determined.The data reported in this letter stem from a prospective observational cohort (PolyREG) aimed to evaluate the therapeutic efficacy of biological therapy in chronic rhinosinusitis with nasal polyps. Eligible patients from this cohort were treated with dupilumab subcutaneously (300mg 1x/2 weeks) for chronic rhinosinusitis with nasal polyps in our tertiary centre. Patients were asked to use the Galenus Health App reporting Visual Analogue Scale (VAS) scores of their complaints in their Health Diary (4, 5). With special regard to olfaction, the question ‘How much does your smell loss bother you today?’ was answered with a VAS score ranging from 0 to 10 (cm) (0 being not bothersome at all, 10 the most bothersome thinkable) with a cut-off of >5.2 for olfactory dysfunction (hyposmia or anosmia) (6). In total, 72 patients filled out a VAS score on olfactory dysfunction at baseline and at least one other day during the first 28 days of dupilumab treatment. Also, the outcomes of the Sniffin’ Sticks-12 Identification test were collected at baseline and after 28 days of treatment.Baseline demographics of these 72 patients were comparable to the complete prospective cohort described by van der Lans et al (1) (data not shown). At baseline, the median Sniffin’ Sticks-12 Identification Test score was 3 (IQR 2) indicating anosmia. After 28 days, the median Sniffin’ Sticks-12 Identification Test score was 6 (IQR 6, Wilcoxon signed-rank test: p<0.001). 93.7% of patients reported a Visual Analogue Scale score on olfaction of >5.2, indicating olfactory dysfunction. Over the subsequent 28 days of treatment, this percentage significantly declined to 44.2% (Figure 1A: Pearson Correlation r=0.924, p<0.001). 50% of the patients scored >6, indicating hyposmia or normosmia (Figure 1B). The mean VAS score in the first week of treatment significantly predicted the outcome of the Sniffin’ Sticks-12 Identification Test after four weeks of treatment (linear regression F(1,97)= 6.7, p=0.012). As such, the data show a rapid olfactory function improvement in more than half of the patients treated with dupilumab, starting after 1-2 injections.Lastly, a retrospective analysis of these 72 patients’ medical records was conducted to see if olfactory function improvement was previously reported during a course of oral corticosteroids prior to the initiation of dupilumab treatment. Subsequently, data was available for 63 of 72 patients. These patients were categorized into either the oral corticosteroid-responsive (n=51) or oral corticosteroid-unresponsive (n=12) group. Stratifying for oral corticosteroid-responsiveness showed enhanced results of dupilumab treatment in the oral corticosteroid-responsive group (Figures 1A and 1B). At best, 70.8% of patients in the oral corticosteroid-responsive group had a VAS score of ≤5.2 compared to 16.7% in the oral corticosteroid-unresponsive group and 55.8% of the total cohort.While acknowledging the limitations of the study, including a relatively small patient group, missing data in the Health Diary, a cut-off corresponding not directly to Sniffin’ Sticks-12 Identification Test and the setting in a tertiary medical center, the implications of our findings are profound. Dupilumab emerges as a fast and efficacious treatment option for improving olfactory function in patients with chronic rhinosinusitis with nasal polyps. Our data also suggest a potential need for stratification of treatment response based on oral corticosteroid responsiveness, as more patients experience olfactory function improvement if they ever had olfactory function improvement upon oral corticosteroids.(600 words)

Background: Subcutaneous immunotherapy has emerged as an effective option for treating allergic diseases. Here, we assessed the clinical impact of the mannan-conjugated birch pollen polallergoid T502 in birch pollen-induced allergic rhinoconjunctivitis. Methods: In this prospective, randomized, double-blind placebo-controlled phase III trial, 298 birch pollen–allergic adult patients were treated across 28 trial sites in Germany. Patients received either placebo or 23,000 mTU T502 subcutaneously over five pre-seasonal visits. Efficacy was assessed by comparing the combined symptom and medication score (CSMS) between placebo and T502 during the peak birch pollen season 2022. Safety, tolerability and immunologic effects were also analysed. Results: During the peak birch pollen season, the median CSMS of the T502 group was reduced by 33.00% (p=0.002) compared to placebo. The median daily symptom score and daily medication score were reduced by 30.43% (p<0.001) and 56.25% (p=0.045), respectively. Health related quality of life improved as reflected by reduction of RQLQ values by 31.54% (p<0.0001). Production of Bet v 1 sIgG4 and sIgG increased up to 6.2-fold and 3-fold respectively in the T502 group (p<0.0001). The sIgE/sIgG4 ratio was strongly reduced in the T502 group at V7 (-62.90%, p<0.0001). No fatalities nor serious adverse events were reported. In total, 16 systemic allergic reactions occurred (Grade I/II). Conclusions: Treatment with T502 significantly reduced symptoms and medication need in rhinoconjunctivitis patients. The treatment is well tolerated and safe.

Immunoglobulin E (IgE)-mediated food allergies are reported to affect around 3.5% of children and 2.4% of adults, with symptoms varying in range and severity. While being the gold standard for diagnosis, oral food challenges are burdensome, and diagnostic tools based on specific IgE can be flawed. Furthering our understanding of the mechanisms behind food allergy onset, severity, and persistence could help reveal immune profiles associated with the disease, to ultimately aid in diagnosis. Alterations to cytokine levels and immune cell ratios have been identified, though further research is needed to fully capture the heterogenous nature of food allergy. Moreover, the existence of such immune alterations also raises the question of potential wider systemic effects. For example, recent research has emphasised the existence and impact of neuro-immune interactions and implicated behavioural and neurological changes associated with food allergy. This review will provide an overview of such food allergy-driven neuro-immune interactions, with the aim of emphasising the importance of furthering our understanding of the immune mechanisms underlying IgE-mediated food allergy.

A document by Jonathan Zalevsky. Click on the document to view its contents.