Background: Serum allergen-specific immunoglobulins E (IgE) play a key role in allergy diagnosis along with clinical history and physical examination. Nowadays, allergen multiplex assays allow complex polyallergic cases to be solved as they assess up to 300 allergen-specific IgE. Recently, machine learning has emerged as a trending tool in medicine. The aim was to build a nationwide, open-access database to create an algorithm that could predict allergy diagnosis, severity, category (airborne, food, venom) and culprit allergens. Methods: A retrospective national database was created by the French Society of Allergology in collaboration with AllergoBioNet and the Health Data Hub. Collected data were de-identified patient profiles with five demographic items, twenty clinical items and sIgE results of one allergen multiplex assay. An international crowdsourced machine learning competition was hosted by the Trustii.io platform. Criteria for algorithm evaluation were the F-score (a measure of a model’s accuracy on a dataset) and external validation on patient profiles outside the database (80%-20%, respectively). Results: Data were collected from 4271 patient files. Two hundred and ninety-two data scientists competed with 3135 algorithms. The best F-scores were comprised between 78% and 80%. Models associated with the highest F-scores used gradient boosting classifiers such as LightGBM, CatBoost, XGBoost adapted for tabular datasets with categorical features. Conclusions: We report here the first artificial intelligence models applied to allergen multiplex arrays interpretation in a nationwide real-world database built to be open access. With F-scores close to 80%, the French Allergen Chip Challenge paves the way for a diagnostic prediction tool for practicing allergists.

Background – While the definition of anaphylaxis is clear, its grade of severity remains a subject of debate, especially since different published classifications provide different grading score, and the same reaction may not receive the same score from different classifications. The objective of this study was to evaluate the possible discrepancies in severity scoring system for anaphylaxis in patients with a positive food challenge (OFC), using the WHO for the 11 th version of the International Classification of Diseases (ICD-11) as the main reference. Methods – We conducted a retrospective observational study at the University Hospital of Montpellier, France, including patients with a positive OFC, between 2018 and 2022. We classified the severity of each reaction, as per the ICD-11 classification, but also as per four other widely used and validated classifications for grading anaphylaxis severity. Results – 235 patients presented a positive OFC between January 2018 and December 2022: 143 suffered from anaphylaxis, according to the ICD-11 classification. 76.2% of them were classified as grade 2 according to the ICD-11 classification, and 23.8% as grade 3. When comparing the different classifications, a complete concordance was recorded in 8 patients (5.6%) only. All classifications showed a good sensitivity (ranging from 99.3 to 100%), but different specificity (from 67.4 to 93.5%), and discrepancies between them were shown in most patients. Conclusion – Our work highlights the need to refine the different scoring systems, to accurately capture anaphylactic reactions and ensure appropriate management, and, in the end, to adopt a universal, intuitive, and easy-to-use classification, such as the ICD-11 one.

Humans inhale, ingest and touch thousands of fungi each day. The ubiquity and diversity of the fungal kingdom are in sharp contrast with their complex and relatively blurred taxonomy and scarce knowledge about their distribution, pathogenic effects, and effective interventions at the environmental and individual levels. Here, we present an overview of salient features of fungi as permanent players of the human exposome and key determinants of human health. Improved understanding of the fungal exposome sheds new light on the epidemiology of fungal-related diseases, their immunological substratum, the currently available methods, and biomarkers for environmental and medical fungi. Unmet needs are described and potential approaches are highlighted as perspectives.

Background: Allergic rhinitis (AR) is a major non-communicable disease that affects the health-related quality of life (HRQoL) of patients. AR is significantly related to asthma also affecting HRQoL. However, data on HRQoL and symptom control in AR patients with comorbid asthma are lacking. Objective: To assess the differences of symptom control and HRQoL in AR patients with and without comorbid asthma. Methods: In this multicentre, cross-sectional study, patients with AR were screened and administered questionnaires of demographic characteristics and health conditions (symptoms/diagnosis of AR and asthma, disease severity level, and allergic conditions). HRQoL was assessed using a modified version of the RHINASTHMA questionnaire and symptom control was evaluated by a modified version of the Control of Allergic Rhinitis/Asthma Test (CARAT). Results: Out of 643 patients with AR, 500 (78%) had asthma as a comorbidity, and 54% had moderate-severe intermittent AR, followed by moderate-severe persistent AR (34%). Patients with both AR and asthma had significantly higher RHINASTHMA scores than the patients with AR alone (e.g., median RHINASTHMA-total score 84 vs. 48.5, respectively). Conversely, CARAT scores were significantly lower in AR with comorbid asthma than in the patients with AR alone (median CARAT-total score 16.5 vs. 23, respectively). Upon stratifying asthma based on severity, AR patients with severe persistent asthma had worse HRQoL and control than AR patients with mild persistent asthma. Conclusions: Our observation of poorer HRQoL and symptoms control in AR patients with comorbid asthma supports the importance of a comprehensive approach for the management of AR in case of a comorbid allergic condition.

Most patients presenting with allergies are first seen by primary care health professionals. The perceived knowledge gaps and educational needs were recently assessed in response to which the LOGOGRAM Task Force was established with the remit of constructing pragmatic flow-diagrams for common allergic conditions in line with an earlier EAACI proposal to develop simplified pathways for the diagnosis and management of allergic diseases in primary care. To address the lack of accessible and pragmatic guidance, we designed flow-diagrams for five major clinical allergy conditions: asthma, anaphylaxis, food allergy, drug allergy and urticaria. Existing established allergy guidelines were collected and iteratively distilled to produce five pragmatic and accessible tools to aid diagnosis and management of these common allergic problems. Ultimately, they should now be validated prospectively in primary care settings.

Addressing Beta-lactam Allergy: A Time for actionElizabeth J. Phillips, MD, FIDSA, FAAAAI, Pascal Demoly, MD, PhD, Maria J Torres, MD, PhD1 Department of Medicine, Center for Drug Safety and Immunology, Vanderbilt University Medical Center, Nashville Tennessee USA, 2Institute for Immunology & Infectious Diseases, Murdoch University, Murdoch Australia, 3Division of Allergy, Department of Pulmonology, University Hospital of Montepellier, and IDESP, Univ. Montpellier – Inserm, Montpellier France,4Allergy Unit, Hospital Regional Universitario de Malaga-IBIMA-BIONAND-ARADyAL, and Departmento de Medicina, Universidad de Malaga, Malaga, SpainCorrespondence:Elizabeth J. Phillips, MD, FIDSA, FAAAAICenter for Drug Safety and ImmunologyVanderbilt University Medical Center1161 – 21st Avenue SouthNashville, TN 37232(615) 322-9174 (tel)[email protected] is now 93 years since the discovery of penicillins, and over 75 years since the first use of penicillin. We have entered yet another wave of challenges plagued with antibiotic resistance accelerating at a rate that well exceeds that of new antibiotic development. In the face of these uphill battles, 8-15% of a global population who has had access to care is labeled as penicillin allergic.1 In the United States (US) there are at maximum 6000 specialists who practice allergy out of a total of 700,000 practicing physicians, and not all allergists are proficient in and practice drug allergy. Conservatively out of 30,000,000 who are labeled as penicillin allergic at any one time in the US, this would mean that each allergist would need to delabel a minimum of 6000 patients. In Europe and the United Kingdom, the figures are proportionately identical, with some differences between countries. Even if all patients had equal access to care, this type of scalability remains impossible. This overwhelming burden that threatens to negatively impact healthcare through delays in treatment, higher healthcare utilization and cost, less effective treatment and increased antibiotic resistance and Clostridioides difficile infection, demands a risk-based approach that simplifies the penicillin allergy delabeling process and establishes bridges with non-allergists.1, 2What have we learned that now makes the population level goal of penicillin delabeling achievable? First off, prevention is better than cure. We should critically examine pediatric populations for antibiotic use to address over-prescription of antibiotics including penicillins for viral infections. We should avoid labeling children with benign delayed exanthems that occur in the setting of a likely viral infection as penicillin allergic. When continued treatment is necessary we should in fact encourage “treating through” such reactions. When a label of penicillin allergy seems inevitable in a child we should address this label early and pay particular attention to antibiotic stewardship. New data on serum sickness-like reaction suggests that many of these are likely virally mediated and do not reproduce on ingestion challenge.3 Community based education programs can help disseminate timely information on penicillin allergy to dispel myths and alleviate fears. A label of penicillin allergy should be both viewed and approached as a threat to both individual and public health. On a public health level addressing penicillin allergy should be seen as a broad stewardship tool that provides a level of herd protectiveness against antibiotic resistance. On an individual level a label of penicillin allergy should be approached with the same routineness as any other preventative health check, and primary care physicians and providers should be trained to understand and manage low-risk penicillin allergy labels.4 Patients should regularly discuss their drug allergy passport with their healthcare providers such as pharmacists and physicians. Allergy passports should enable interoperability, high traceability and time-stamped information solving the problem of frequent unavailability and inaccuracy of drug allergy information.5 Risk stratification should occur and if in a low-risk category a patient should be given the option of direct oral challenge and delabeling. Risk stratification to identify by clinical history the low-risk penicillin allergic patients who would be appropriate for simple procedures is key. Several mechanisms now exist to risk stratify those labeled as penicillin allergic in routine clinical practice. These clinical prediction rules provide an evidence base to identify the majority of low-risk penicillin allergy labeled patients who are at low risk for rechallenge reactions.6, 7 In current practice it is likely that less than 1% of such low-risk patients will be at risk for a reaction on ingestion challenge.1, 8To make widespread penicillin allergy delabeling an achievable and scalable goal we must be convinced of the safety of direct ingestion challenges. A randomized study allocated children 5 years or older with low-risk cutaneous reaction to penicillin skin testing followed by amoxicillin challenge versus 2 step direct oral challenge with amoxicillin with tolerance of amoxicillin of 96% of those with direct challenge and only minor reactions in the remainder.9These results have recently been confirmed in an European population of children.10 Aside from the inconvenience and potential need for specialty assessment, for very low-risk patients, the use of skin testing would be expected to perform poorly considering their low pre-test probability of a reaction. Several other studies have demonstrated that a single or two-step direct ingestion challenge with penicillins such as amoxicillin is a safe and practical strategy to remove a label of penicillin allergy.11 Although there is evidence to support the use of risk stratification tools to delabel penicillin allergy under allergist guidance, we require an educational program on drug allergy for primary care physicians as well validation of these risk stratification tools, to show that low-risk penicillin delabeling can be achieved in this setting.Even in the face of risk stratification and safety of direct ingestion challenge, populations are not equal in terms of their medical risk or antibiotic needs. Intuitively populations that serve to benefit from penicillins and other beta lactams have been shown to have inferior outcomes when labeled as penicillin allergic that would benefit from a delabeling intervention. This includes the association of penicillin allergy label and use of an alternative antibiotic with post-operative surgical site infections.12 Other settings where research has shown feasibility in delabeling include children in the emergency department, critically ill populations with high antibiotic needs, and pregnant women where the high rates of surgical delivery and group B Streptococcal colonization in pregnancy create a high demand for penicillin and cephalosporins as safe firstline drugs.1, 13, 14 Increasingly, assessment of unverified penicillin allergy has been recognized as an antibiotic stewardship intervention in immunocompromised states such as transplant and cancer where populations have much to gain by being delabeled.15There is a “time for action” for removal of penicillin allergy labels on a population level but how do we achieve widespread implementation (Figure 1)? Policy changes should be driven by collaboration with Infectious diseases specialists and allergists who should join forces to pair antibiotic allergy management with antibiotic stewardship. In the community we need to educate parents and pediatricians to make them aware of the hazards of both unnecessary antibiotics and penicillin allergy labels for mild rashes that are often related to a viral infection and unlikely to recur. Primary healthcare providers should be given greater incentives to delabel penicillin allergic patients at the point-of-care and armed with decision support tools to facilitate risk stratification. For those whose history is not consistent with allergy this could include direct delabeling without testing. In the future, evidence may support that routine direct ingestion challenge with a penicillin and delabeling is safe in the primary care setting. Finally, by off-loading low-risk reactions to primary care providers we can then prioritize care of the patients with a higher-risk allergy and/or medical history by engagement with specialists who can provide more in-depth assessments and give them the best antibiotic options.Figure 1: Addressing Beta-lactam Allergy: An Implementation Roadmap: There are currently many missed opportunities for community members and healthcare providers to take action forward on the “penicillin allergy delabeling” movement. This includes not only active measures to delabel patients by history and direct oral challenge and to identify high risk patients for prioritized penicillin allergy delabeling but also preventive measures to avoid unnecessary use and exposure to antibiotics and avoidance of unnecessary labeling in those with mild rashes of likely viral origin.

Should cashew and pistachio be clinically considered as one allergen?Authors (Last Name and First Name): Manca Enrica1,2, Touati Nidhal1, De Filippo Maria1,3, Carboni Elena1,4, Diaferio Lucia1,5, Demoly Pascal1,6, Caimmi Davide1,6Affiliations :1. Allergy Unit of the Department of Respiratory Diseases, University Hospital of Montpellier, France.2. Pediatric Unit, University Hospital of Foggia, Italy.3. Pediatric Unit, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Italy.4. Pediatric Unit, Ospedale Maggiore, ASST Cremona, Italy.5. Department of Pediatrics, Giovanni XXIII Hospital, Aldo Moro University of Bari, Bari, Italy.6. UMR-S 1136 INSERM-Sorbonne Université, Equipe EPAR – IPLESP, Paris, France.Running title: Allergy to cashew and pistachio

Background: Antiepileptic drugs (AEDs) are widely used for the treatment of epilepsy, but they can be associated with the development of mainly delayed/non-immediate hypersensitivity reactions (HRs). Although these reactions are usually cutaneous, self-limited and spontaneously resolve within days after drug discontinuation, sometime HRs reactions to AEDs can be severe and life threatening. Aim: This paper seeks to show examples on practical management of AEDs HRs in children starting from a review of what it is already known in literature. Results: Risk factors include age, history of previous AEDs reactions, viral infections, concomitant medications and genetic factors. The diagnosis work-up consists of in vivo (Intradermal testing and Patch testing) and in vitro tests [serological investigation to exclude the role of viral infection, lymphocyte transformation test (LTT), cytokine detection in ELISpot assays and granulysin (Grl) in flow cytometry]. Treatment is based on a prompt drug discontinuation and mainly on the use of glucocorticoids. Conclusion: Dealing with AEDs HRs is challenging. The primary goal in the diagnosis and management of HRs to AEDs should be trying to accurately identify the causal trigger and simultaneously identify a safe and effective alternate anticonvulsant. There is therefore an ongoing need to improve our knowledge of HS reactions due to AED medications and in particular to improve our diagnostic capabilities.

To the Editor, Drug provocation test (DPT) is considered the gold standard test to diagnose drug hypersensitivity reactions (DHR), in absence of contraindications. However, it may be very time consuming. The procedure usually consists in the administration of a medication with cautious incremental doses under close medical observation.1-4Vital sign measurements (e.g., blood pressure (BP), pulse) and surveillance of the patient’ symptoms and signs are usually performed several times during the entire procedure to capture and prevent as soon as possible any severe reaction. However, learned societies only set a frame for DPT performance and do not make specific recommendations about the type and rhythm of these measurements.1, 3, 4 In our center, data-driven DPT (i.e., based on patterns of reactions detected through Kaplan Meier curves) is performed in 4-7 step dosing for beta-lactams (BL),5 2-6 steps for nonsteroidal anti-inflammatory drugs (NSAID),6 3-4 steps for paracetamol,7 and 5-7 steps for fluoroquinolones (article in press), with time increments of 30 or 60 minutes (up to 3h for certain NSAID). The BL pattern is generally applied to DPTs for other drugs. Empirically, we considered the measurement of BP and pulse as mandatory and required before starting the DPT, before every incremental dose and at any time during the DPT if symptoms of a DHR occurred. We presumed this would ensure the best safety for patients undergoing DPT, particularly for those with immediate severe reactions, namely anaphylaxis with or without shock. However, the benefit of such an attitude in patients with non-immediate reactions or immediate non-severe reactions could be questioned and to the best of our knowledge, no study has been published on this issue. In addition, measurement of BP during ST is not common practice.During the past two decades of our center experience, based on clinical observation and previous analyses,8, 9 we observed that isolated symptoms and signs evocative of shock during drug allergy work-up are very rare. Patients usually presented those signs in conjunction with symptoms and signs from other systems, including mucocutaneous (CU), respiratory (RS), and gastrointestinal (GI). Therefore, we hypothesized that BP measurement could be reduced in number in some circumstances, according to risk stratification (that we presumed related to the patient’s individual situation and involved drug class). This retrospective analysis was then carried out in order to identify cases with symptoms and signs evocative of shock during drug allergy investigation in our center. The patients (or their parents, in case of children) gave their written informed consent at the time of the allergy work-up for their anonymous data to be used for research purposes.We conducted a retrospective analysis using data retrieved from the Drug Allergy and Hypersensitivity Database (DAHD) between January 1996 and June 2019 in the Allergy Unit of the University Hospital of Montpellier, France. Patients with suspicions of DHR who underwent drug allergy work-up and presented with symptoms and signs evocative of shock during the tests were included in the analysis. The search terms included: “malaise”, “hypotension”, “collapse”, “loss of consciousness”, and “unspecified cardiovascular problem”. Drug allergy work-up including skin test (ST) and DPT was performed according to the European Network of Drug Allergy (ENDA) recommendations.During the study period, 10 198 patients were tested with 53 059 single tests (a single test is defined as ST or DPT for an allergen). A total of 32 patients (0.3%) (9 males, mean age at tests of 37.0 ± 14.9 years) with 36 reactions (0.06%) who presented with the above mentioned cardiovascular (CV) signs/symptoms were identified (31 during DPT, 5 during ST). Antibiotics were the most frequent drug classes involved (47.2%), followed by NSAIDs (13.9%), and paracetamol (13.9%) (Supplementary Table 1 ). Among these reactions, 4 were found to be isolated CV signs/symptoms (3/11000 DPT (0.03%), and 1/42059 ST (0.002%), while CV with other systemic signs/symptoms were present in 32 reactions (88.9%). (Table 1 and Supplementary Text 1) Using retrospective analysis from the DAHD during the past 25 years, we have demonstrated that patients with CV symptoms and signs evocative of a severe immediate DHR (shock) during the drug allergy investigation are rare, namely 0.3% of all tested patients and 0.06% of all single tests. Amongst them, only 4 patients (0.04%) with 4 reactions (0.007%) were found to have isolated CV signs/symptoms. Whether these signs were markers of true DHR could be debatable for patients no. 1 (considering her multiple similar episodes, ruled out by further investigations) and no. 3 , while patient no. 4 developed anaphylactic shock during positive ST to BL drugs (meaning that the systemic symptoms were associated to positivity at the injection site). Therefore, only one case (patient no. 2) could be classified as having isolated CV signs/symptoms as an allergic reaction.Based on this analysis and previous analyses of patterns of reactivity and severity during DPT for different drug classes (e.g., BL, NSAIDs, paracetamol, quinolones), we propose criteria to reduce the frequency of BP measurements during DPT, according to risk stratification based on patient clinical history and drug class. Clinical history could be classified into three categories: immediate severe (high risk), immediate non-severe (low risk), and non-immediate non-severe (low risk) reactions (i.e., severe non-immediate reactions being classical contraindications to DPT).3 Regarding drug class, we based our risk stratification on previous studies tackling patterns of DPT reactions to BL, NSAIDs, paracetamol and quinolones showing that the frequency of anaphylaxis elicited by DPT was 15%, 10%, 25% and 20% respectively.5-7 For NSAIDs, the immediate non-severe reaction (e.g., urticaria, angioedema, rhino-conjunctivitis) is a typical clinical presentation and for such an index reaction, 90% of the positive DPT are benign cutaneous reactions (6). Thus, NSAIDs could be classified as low risk drug class. Therefore, the criteria of BP measurement could be categorized as in Table 2. Regarding our 4 patients with isolated CV symptoms, all of them would’ve been classified in the high-risk groups (patient no. 1 and no. 3 because of index history of immediate severe reaction, patient no. 2 and no. 4 because of the drug class).It could be argued that by reducing the number of CV vital signs measurements, the professional performing the DPT could be distracted from the very core of the allergy work-up, which is ensuring patient safety during the procedures. However, our study shows that isolated CV signs/symptoms are extremely rare during the drug allergy work-up performed according to safety recommendations (i.e., step-wise exposure to allergen). In contrast, the decrease in this technical workload could be beneficial to patients because physicians/nurses would then have more time to concentrate on patient questioning and reassurance during the tests. In addition, the reduction of this measurement could reduce the uncomfortable, or painful feeling of the BP measurement, particularly for young children.To the best of our knowledge, this is the first study specifically addressing the outcome of the BP measurement during drug allergy work-up in an evidence-based manner. Reporting and analyzing the rarity of cases with isolated CV signs/symptoms enabled us to propose 4 frames for BP measurement. In a prospective trial for 1 month, BP frequency could be reduced by 14.3% (range 10.3-26.5), alleviating the technical task and favoring the medical one instead. The prospective evaluation is ongoing in our center.In conclusion, patients with symptoms and signs evocative of shock are extremely rare during drug allergy work-up, therefore BP measurement could be reduced in number according to patient clinical history of DHR and drug class risk stratification.

Background: Allergy is witnessing major advances, in particular with the advent of biological therapies for treating allergic diseases. Given the novelty of these therapeutics, we aimed to explore by a worldwide survey, the prescription and the management of hypersensitivity reactions (HR) of biological agents (BA) in Allergy. Method: We built up an anonymous online questionnaire, sent out by mail and social media and circulated for 40 days. Results: 348 responses were from 59 countries, with a majority from Europe (62.6%). 97% of responders practiced allergy and 48.5%, exclusively so. Allergy was mentioned as a full specialty in 69.5 % of cases. 71% of responders confirmed the right of prescription of BA for allergists in their country and 78.4 % prescribed BA in their clinical practice. Europe included almost all the allergists who did not have the right of prescribing BA (95.5%), specifically France (91%). The most prescribed BA were Anti IgE (78.1%) and anti IL5 (43.9%). The most declared HR to BA were local reactions (74.1%) followed by anaphylaxis like symptoms (6.8%) and delayed exanthemas (5.1%). Desensitization was considered in 18.9% of cases. These HR were reported in 48.8% of cases. Conclusion: Although BA are now a pillar in the treatment of allergic diseases and allergists are familiar with management of HR associated with BA, their prescription is not authorized for allergists in all countries. BA showed to be generally safe but HR, which may be severe, could occur with a lack of consensus on the management.

Anaphylaxis in children is a potential acute life-threatening systemic hypersensitivity reaction. Anaphylaxis fatality rate is estimated to be 0.65% to 2%. Food is the main anaphylaxis trigger in children, notably cow’s milk, peanuts and tree nuts. Mucocutaneous manifestations are observed in more than 90% of cases, but it is not essential for diagnosis. Deaths are rather secondary to the laryngeal edema, observed in 40-50% of cases. Personal history of asthma, allergy to particular foods such as peanuts and tree nuts, and adolescence are known risk factors for anaphylaxis and more severe reactions. Epinephrine (adrenaline) is the medication of choice for the first-aid treatment of anaphylaxis. However, adrenaline auto-injectors (AAIs) are commercially available in only 32% of world countries. There are still considerable unmet needs in the field of anaphylaxis in children. Therefore, the Montpellier WHO Collaborating Centre aims to start the global actions plan applied to anaphylaxis.

The International Classification of Diseases (ICD) provides a common language for use worldwide as a diagnostic and classification tool for epidemiology, clinical purposes and health management. Since its first edition, the ICD has maintained a framework distributing conditions according to topography, with the result that some complex conditions, such as allergies and hypersensitivity disorders (A/H) including anaphylaxis, have been poorly represented. The change in hierarchy in ICD-11 permitted the construction of the pioneer section addressed to A/H, which may result in more accurate mortality and morbidity statistics, including more accurate accounting for mortality due to anaphylaxis, strengthen classification, terminology and definitions. The ICD-11 was presented and adopted by the 72nd World Health Assembly in May 2019 and the implementation is ongoing worldwide. We here present the outcomes from an online survey undertaken to reach out the allergy community worldwide in order to peer review the terminology, classification and definitions of A/H introduced into ICD-11 and to support their global implementation. Data are presented here for 406 respondents from 74 countries. All of the sub-sections of the new A/H section of the ICD-11 had been considered with good accuracy by the majority of respondents. We believe that, in addition to help during the implementation phase, all the comments provided will help to improve the A/H classification and to increase awareness by different disciplines of what actions are needed to ensure more accurate epidemiological data and better clinical management of A/H patients.