The field of medicine is witnessing an exponential growth of interest in Artificial Intelligence (AI), which enables new research questions and the analysis of larger and new types of data. Nevertheless, applications that go beyond proof of concepts and deliver clinical value remain rare, especially in the field of allergy and immunology. This narrative review provides a fundamental understanding of the core concepts of AI and critically discusses its limitations and open challenges, such as data availability and bias, along with potential directions to surmount them. We provide a conceptual framework to structure AI applications within this field and discuss forefront case examples. Most of these applications of AI and machine learning in allergy concern supervised learning and unsupervised clustering, with a strong emphasis on diagnosis and subtyping. A perspective is shared on guidelines for good AI practice to guide readers in applying it effectively and safely, along with prospects of field advancement and initiatives to increase clinical impact. We anticipate that AI can further deepen our knowledge of disease mechanisms and contribute to precision medicine in allergy.
Insect venom allergy is the most frequent cause of anaphylaxis in Europe and possibly worldwide. The majority of systemic allergic reactions after insect stings are caused by Hymenoptera and among these, vespid genera induce most of the systemic sting reactions (SSR). Honey bees are the second leading cause of SSR. Depending on the global region, other Hymenoptera such as different ant genera are responsible for SSR. Widely distributed hornets and bumblebees or local vespid or bee genera rarely induce SSR. Hematophagous insects such as mosquitoes and horse flies usually cause (large) local reactions while SSR occasionally occur. This position paper aims to identify either rare or locally important insects causing SSR as well as rarely occurring SSR after stings or bites of widely distributed insects. We summarized relevant venom or saliva allergens and intended to identify possible cross-reactivities between the insect allergens. Moreover, we aimed to locate diagnostic tests for research and routine diagnosis, which are sometimes only regionally available. Finally, we gathered information on disposable immunotherapies. Major allergens of most insects were identified, and cross-reactivity between insects was frequently observed. While some diagnostics and immunotherapies are locally available, standardized skin tests and immunotherapies are generally lacking in rare insect allergy.
Meglumine gadoterate induces immunoglobulin-independent human mast cell activation and MRGPRX2 internalizationTo the Editor,Gadolinium-based contrast agents (GBCA) are intravenous drugs used to enhance resolution in magnetic resonance imaging. They can induce immediate hypersensitivity reactions, yet their pathogenic mechanisms remain poorly characterized. This hampers the ability to predict which patients are at risk of developing them.1 In fact, affected patients usually show negative skin-tests and can react upon the first known GBCA exposure, which implies that IgE-independent mechanisms might be driving this inflammatory response.The Mas-related G protein-coupled receptor member X2 (MRGPRX2) has been recently associated with non-IgE mediated immediate hypersensitivity reactions.2 Some drugs, such as fluoroquinolones, vancomycin, neuromuscular blockade agents, icatibant, morphine, leuprolide and iodinated contrast media, have been reported to activate MRGPRX2, which is highly expressed in mast cells (MCs).3To assess the ability of GBCA to induce non-IgE-mediated hypersensitivity reactions, we stimulated the human MC line LAD2 with several commercial GBCA, namely, meglumine gadoterate, gadobutrol, gadoxetate disodium and gadoteridol. Then, we determined cell viability and degranulation by flow cytometry4 (see a detailed material and methods section in this article´s online supplementary ).Of the GBCA tested, only meglumine gadoterate was able to induce significant MC activation (Figure 1A ) without compromising cell viability (Figure 1B ), as compared to unstimulated MCs. We further assessed MRGPRX2 expression on LAD2 cells by flow cytometry, as well as changes in its expression following stimulations with either meglumine gadoterate or vancomycin (a known agonist of MRGPRX2).5 Under basal conditions, LAD2 cells expressed high levels of MRGPRX2 (Figure 1C ). Following incubation with vancomycin, the level of MRGPRX2 expression was reduced, as compared to untreated LAD2 cells. Interestingly, we observed a similar decrease in MRGPRX2 expression levels upon meglumine gadoterate and vancomycin challenges, as compared to controls, suggesting both the signaling and the internalization of this receptor (Figure 1D ).Meglumine gadoterate is an ionic macrocyclic paramagnetic contrast media. It is composed by gadolinium, which together with the chelating agent tetraxetan (also known as DOTA), yields gadoteric acid. The base meglumine and gadoteric acid form the salt meglumine gadoterate (Figure 2A ). Given that MRGPRX2 has affinity for cationic amphiphilic compounds,6 we ascertained the ability of meglumine to induce MC activation. Meglumine itself induced MC degranulation without affecting cell viability, as compared to untreated cells (Figure 2B ), although a reduction in MRGPX2 expression could not be confirmed (data not shown). Interestingly, meglumine caused MC activation at lower concentrations than meglumine gadoterate, according to the half maximal effective concentration (EC50) of both substances (Figure 2C ). The logarithmically transformed EC50 for meglumine gadoterate was 2.04 (R2= 0.75), and for meglumine was about one order of magnitude lower (1.06; R2= 0.71). Considering the EC50 for meglumine and its proportion in meglumine gadoterate (~26%), meglumine could be its main component responsible for MC degranulation.In conclusion, our study demonstrates the ability of meglumine gadoterate to induce MC activation, by an immunoglobulin-independent mechanism that is likely mediated by MRGPRX2. Furthermore, we have delved into the meglumine gadoterate components that are involved in MC activation, and identified meglumine as a potential causative of non-IgE mediated hypersensitivity reactions. These data raise the possibility that immediate hypersensitivity reactions following intravascular administration of ionic iodinated contrast media may be at least partly mediated by meglumine. Further studies should be performed to define clinically relevant interactions between diverse radiological contrast media and MRGPRX2.Authors: Paula H. Ruiz de Azcárate,1#Rodrigo Jiménez-Saiz,1-4 #* Celia López-Sanz,1 Azahara López-Raigada,5Francisco Vega,5 Carlos Blanco,5*# First authors* Corresponding authorsAffiliations: 1Department of Immunology, Instituto de Investigación Sanitaria Hospital Universitario de La Princesa (IIS-Princesa), Universidad Autónoma de Madrid (UAM), Madrid, Spain.2Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB)-CSIC, Madrid, Spain.3Faculty of Experimental Sciences, Universidad Francisco de Vitoria (UFV), Madrid, Spain.4Department of Medicine, McMaster Immunology Research Centre (MIRC), Schroeder Allergy and Immunology Research Institute (SAIRI), McMaster University, Hamilton, ON, Canada.5Department of Allergy, Instituto de Investigación Sanitaria Hospital Universitario de La Princesa (IIS-Princesa), Universidad Autónoma de Madrid (UAM), Madrid, Spain.*Co-correspondence to :1) Rodrigo Jiménez-Saiz, Department of Immunology, Instituto de Investigación Sanitaria Hospital Universitario de La Princesa (IIS-Princesa), Diego de León 62, 28006, Madrid, Spain. Email address: email@example.com) Carlos Blanco, Department of Allergy, Instituto de Investigación Sanitaria Hospital Universitario de La Princesa (IIS-Princesa), Diego de León 62, 28006, Madrid, Spain. Email address: firstname.lastname@example.org Funding information: RJS reports grants by the FSE/FEDER through the Instituto de Salud Carlos III (CP20/00043; PI22/00236; Spain), The Nutricia Research Foundation (NRF-2021-13; The Netherlands), New Frontiers in Research Fund (NFRFE-2019-00083; Canada) and SEAIC (BECA20A9; Spain). PHR is supported by the INVESTIGO Program of the Community of Madrid (Spain), which is funded by “Plan de Recuperación, Transformación y Resiliencia” and “NextGenerationEU” of the European Union (09-PIN1-00015.6/2022).Conflict of interest : All the authors have no significant conflicts of interest to declare in relation to this manuscript.References1. Vega F, Lopez-Raigada A, Mugica MV, Blanco C. Fast challenge tests with gadolinium-based contrast agents to search for an alternative contrast media in allergic patients. Allergy.2022;77(10):3151-3153.2. Kolkhir P, Ali H, Babina M, et al. MRGPRX2 in drug allergy: What we know and what we do not know. J Allergy Clin Immunol. 2022.3. Foer D, Wien M, Karlson EW, Song W, Boyce JA, Brennan PJ. Patient Characteristics Associated With Reactions to Mrgprx2-Activating Drugs in an Electronic Health Record-Linked Biobank. J Allergy Clin Immunol Pract. 2022.4. López-Sanz C, Sánchez-Martínez E, Jiménez-Saiz R. Protocol to desensitize human and murine mast cells after polyclonal IgE sensitization. STAR Protocols. 2022;3(4):101755.5. Navines-Ferrer A, Serrano-Candelas E, Lafuente A, Munoz-Cano R, Martin M, Gastaminza G. MRGPRX2-mediated mast cell response to drugs used in perioperative procedures and anaesthesia. Sci Rep.2018;8(1):11628.6. Wolf K, Kühn H, Boehm F, et al. A group of cationic amphiphilic drugs activates MRGPRX2 and induces scratching behavior in mice. J Allergy Clin Immunol. 2021;148(2):506-522.e508.
The field of food allergy has seen tremendous change over the past 5-10 years with seminal studies redefining our approach to prevention and management and novel testing modalities in the horizon. Early introduction of allergenic foods is now recommended, challenging the previous paradigm of restrictive avoidance. The management of food allergy has shifted from a passive avoidance approach to active interventions that aim to provide protection from accidental exposures, decrease allergic reaction severity and improve the quality of life of food-allergic patients and their families. Additionally, novel diagnostic tools are making their way into the clinical practice with the goal to reduce the need for food challenges and assist physicians in the -- often complex -- diagnostic process. With all the new developments and available choices for diagnosis, prevention and therapy, shared decision-making has become a key part of the medical consultation, enabling patients to make the right choice for them, based on their values and preferences. Communication with patients has also become more complex over time, as patients are seeking advice online and through social media, but the information found online may be outdated, incorrect, or lacking in context. The role of the allergist has evolved to embrace all the above exciting developments and provide patients with the optimal care that fits their needs. In this review, we discuss recent developments, as well as the evolution of the field of food allergy in the next decade.
Prodromes predict attacks of Hereditary Angioedema: results of a prospective StudyTo the Editor,Hereditary Angioedema (HAE) is a lifetime disease characterized by repetitive bouts of tissue edema.1 Early signs, symptoms and perceptions (prodromes) are manifested by subjective and objective signals, preceding attacks by several hours.2-3 Using an new HAE-specific instrument, we have recently shown that patients can identify prodromes and able to predict oncoming attacks.4 However, that study was retrospective, which might have been affected by recall bias.In the present study a cohort of 48 HAE patients prospectively reported four events of prodromes followed by attack, attacks not preceded by a prodrome and incidents with only a prodrome. Pre-defined domains (clusters of body locations) and scalable dimensions (pain, severity, impairment and functionality), time of onset and termination were assessed in each episode.3-4 (Statistical methods are described in the supplementary data ). The study was approved by the ethics committees of Tel-Aviv University, Sheba Medical Center and Barzilai Medical center. All patients signed an informed-consent form. Mean age was 35.25 years (SD ±16.4), Median 30.0 (age range 10-70) and 27 (56.25%) were females. Mean age of onset was 8.3 years and age at diagnosis 10.9 years (2.7 years diagnostic gap) (Table S1 ).We received reports on 119 prodromes and 192 attacks. The majority experienced a prodrome before at least one of their attacks, and 64% affirmed that they can predict an oncoming attack by having a prodrome.(Table S1) .Significant differences were found between prodromes and attacks across all dimensions of the predefined clusters of body locations. Statistical analysis verified that prodromes could be discriminated from attacks for all parameters. (Table 1) Positive correlations were found between the same attributes of prodromes and attacks, most notably in the abdominal and extremity clusters (Table S2, Fig S1A-E) . Mean duration of prodromes was significantly shorter than attacks, and prodromes overlapped the attack in 24.3% of cases. The predictive power analysis indicates that individuals who experience a prodrome had higher risk for having an attack in the same region. Sensitivity of the prodrome as a predictor of attack was 95% to 99%, and specificity 18% to 64%. (Table 2).HAE prodromes represents a continuity of pathophysiologic events, initiated by the activation of the bradykinin-forming cascade and ending with a breach in vascular endothelial integrity.2, 5(Fig S2 ) In this study we aimed to capture the critical elements of prodromes and their association with consequent attacks and evaluate their predictive power as an early warning sign.2-4 The HAE-EPA instrument reliably captures patient’s experience by using the same metrics, and the prospective design better reflects patients’ experience in real-time, which may have been missed in our previous study.The study shades light on the predictive value of prodromes as forecasters of attacks.2-4 It affirms that patients can clearly distinguish prodromes from attacks. The positive correlations support our basic assumption that prodromes could predict attack location and severity, which is particularly germane in the abdomen. In most cases a high intensity attack was predated by a high intensity prodrome. This substantiate our observation on inter-personal differences between subjects4 Mean disease duration of the cohort (27 years) may surmise that the study subjects were experienced patients, who could recognize early pre-attack cues.Treating oncoming attack at the prodromal stage may enhance resolution of attacks.6, 7 Therefore; experienced patients can use prodromes as an efficient strategy in managing attacks by employing early interventions. Such approach can apply in other diseases with relapsing-remitting pattern and advance the concept of prodrome-triggered intervention.8In conclusion , the study ascertained that HAE patients can distinguish prodromes from attacks and a prodrome may predict attack in the same location. Having a prodrome increase the likelihood of subsequent attack, alerting the patients and assisting in early initiation of therapy.Table 1: Within-subject differences between prodrome and attacks
The incidence of food allergy (FA) has continued to rise over the last several decades, posing significant burdens on health and quality of life. Significant strides into the advancement of FA diagnosis, prevention, and treatment have been made in recent years. In an effort to lower reliance on resource-intensive food challenges, the field has continued work toward the development of highly sensitive and specific assays capable of high-throughput analysis to assist in the diagnosis FA. In looking toward early infancy as a critical period in the development of allergy or acquisition of tolerance, evidence has increasingly suggested that early intervention via the early introduction of food allergens and maintenance of skin barrier function may decrease the risk of FA. As such, largescale investigations are underway evaluating infant feeding and the impact of emollient and steroid use in infants with dry skin for the prevention of allergy. On the other end of the spectrum, the past few years have been witness to an explosive increase in clinical trials of novel and innovative therapeutic strategies aimed at the treatment of FA in those whom the disease has already manifested. A milestone in the field, 2020 marked the approval of the first drug, oral peanut allergen, for the indication of peanut allergy. With a foundation of promising data supporting the safety and efficacy of single- and multi-allergen oral immunotherapy, current efforts have turned toward the use of probiotics, biologic agents, and modified allergens to optimize and improve upon existing paradigms. Through these advancements, the field hopes to gain footing in the ongoing battle against FA.
Fast gadolinium-based contrast agent challenge test searching for an alternative contrast mediaTo the Editor,Gadolinium-based contrast agents (GBCA) are used in contrast-enhanced magnetic resonance imaging. Hypersensitivity reactions (HSR) to GBCA are scarce, with an incidence of 0.07% and a recurrence rate of 30%, being urticaria the most common presentation (91%), with 0.52/10000 of severe reactions reported1. Recommendation of an alternative GBCA without checking tolerance is dangerous, due to high cross-reactivity between them2. Moreover, premedication is not enough1, showing an overall rate of breakthrough reactions of 39%3.Allergy studies to achieve a safe recommendation in HSR to GBCA have been performed. Negative predictive value of skin-tests to GBCA has been estimated in 84%1. Therefore, more than 10% of patients could react using an alternative negative skin-tested GBCA, and thus, good tolerance to GBCA should be confirmed through a drug challenge-test (DCT)4. These tests are usually performed at graded administrations, and with observation periods between doses1,5. However, since GBCA is usually given as a bolus during radiologic exams, DCT at slow rates cannot be extrapolated to further administrations. Trying to avoid this limitation, we study the tolerance of an alternative GBCA, by means of a fast DCT, approaching the infusion rates used in clinical practice.In accordance with the safety warnings to avoid linear GBCA, we have only used the macrocyclic drugs gadobutrol (Gb) and gadoteric acid (Ga). After obtaining signed informed consent from the patients, skin pricktests (SPT) with undiluted macrocyclic GBCA commercial solutions were done. When SPT at 20 min yielded negative results, intradermal tests (IDT) with 1:10 dilutions were performed, with subsequent readings at both 20 min and 24 hours.A fast DCT with negative skin-tested GBCA was then performed, following our methodology to study HSR to iodinated contrast media, previously described elsewhere6. Doses were 0.2 mg/kg for Ga and 0.1 mg/kg for Gb. First, one third of the total dose of Ga was administered at a rate of 120 cc/hour and, immediately after, the remaining 2/3 at 80 cc/hour. In case of Gb, infusion rates were half those of Ga, i.e., 1/3 at 60 cc/hour and 2/3 at 40 cc/hour. Total infusion time was 8 minutes for both of them. Well-tolerated GBCA was finally recommended for subsequent examinations, and its tolerance was recorded if it was used later.Study results of sixteen patients that were enrolled are summarized in Table 1. They were 12 women and 4 men, with median age of 45.5 years (range 28-73). Adverse reactions to GBCA were immediate in 13 patients (12 urticaria or exanthema, and 1 anaphylaxis), and delayed exanthema in the remaining 3. Gb was involved in 11 reactions, and unknown GBCA in the other 5. Most of the patients (14/16) had been previously exposed to GBCA.Median delay to perform the allergy study was 10 months (range 2-72 months). All skin-tests were negative, except in one patient who showed an immediate positive SPT to Gb, which had been the GBCA involved in the adverse reaction. In our study, we have estimated a negative predictive value of skintests to GBCA of 89%. DCT were negative in 14 patients (12 with Ga, and 2 with Gb). Finally, 15 out of 16 patients had an alternative GBCA, avoiding the use of premedication. In fact, tolerance has been confirmed in 7 of them in subsequent examinations.Safety of our protocol has been confirmed because our 2 positive DCT showed only mild reactions (delayed exanthema and immediate urticarial, both with Ga), and also by including a patient with previous anaphylaxis to GBCA.Here we present a prospective protocol to identify a safe alternative GBCA, including DCT at high infusion rates. Further studies will be necessary on this item/to check this.
Similar IgE Binding Patterns in Gulf of Mexico and Southeast Asian Shrimp Species in US Shrimp Allergic PatientsSara Anvari1,2*, Shea Brunner1,2*, Karen Tuano1,2, Brenda Bin Su1,2, Shaymaviswanathan Karnaneed3, Andreas L. Lopata3, Carla M. Davis1,21Baylor College of Medicine, Texas Children’s Hospital, Department of Pediatrics, Section of Immunology, Allergy and Retrovirology, Houston, Texas2Baylor College of Medicine, William T. Shearer Center for Human Immunobiology, Houston, Texas3James Cook University, Australian Institute of Tropical Health and Medicine, Centre for Molecular Therapeutics, Douglas, QLD, Australia*co-first authors
Background Cow’s milk protein allergy (CMPA) is one of the most common food allergies in infancy. Most infants with CMPA tolerate baked milk from diagnosis and gradually acquire increased tolerance. Nevertheless, parents often display significant anxiety about this condition and a corresponding reluctance to progress with home introduction of dairy due to concerns about possible allergic reactions. Objective: To evaluate the impact on gradual home introduction of foods containing cows milk after a supervised, single low dose exposure to whole milk at time of diagnosis. Methods Infants less than 12 months old, referred with suspected IgE-mediated cow’s milk allergy were recruited to an open-label randomised, controlled trial of intervention - a single dose of fresh cow’s milk, using the validated dose of milk that would elicit reactions in 5% of CMPA subjects - the ED 05 – vs routine care. Both groups implemented graded exposure to CM (using the 12 step MAP Milk Tolerance Induction Ladder), at Home. Parents completed food allergy quality of life and State and Trait Anxiety Inventories (STAI). Main outcome measures were milk ladder position at 6 months and 12 months post randomisation. Results: Sixty patients were recruited, 57 (95%) were followed to 6 months. By 6 months 27/37 (73%) intervention subjects had reached step 6 or above on the milk ladder compared to 10/20 (50%) control subjects (p=0.048). By 6 months 11/37 (30%) intervention subjects had reached step 12 (ie drinking unheated cow’s milk) compared to 2/20 (10%) of the controls (p=0.049). Twelve months post randomisation 31/36(86%) of the intervention group and 15/19(79%) of the control group were on step 6 or above. However, 24/37 (65%) of the intervention group were at step 12 compared to 7/20 (35%) of the control group (p=0.03). Maternal STAIs were significantly associated with their infants’ progress on the milk ladder and with changes in skin prick test and spIgE levels at 6 and 12 months. Conclusion This study demonstrates the safety and effectiveness of introduction of baked milk implemented immediately after diagnosis of cows milk allergy in a very young cohort. A supervised single dose of milk at the ED 05 significantly accelerates this further, probably by giving parents the confidence to proceed. Maternal anxiety generally reflects infants’ progress towards completion of the milk ladder, but pre-existing high levels of maternal anxiety are associated with poorer progress.
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)Elizabeth.email@example.comIt 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.