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Purpose of Review: To understand the current global scale of drug hypersensitivity (DH) and drug allergy (DA), and to identify possible strategies to increase the accuracy of epidemiological data., Recent Findings: Global patterns of DH/DA seem to be changing and increasing worldwide, but there are still great challenges in capturing quality DH/DA mortality and morbidity statistics (MMS). DH/DA MMS may gain new perspectives with the global implementation of the International Classification of Diseases (ICD)-11. Improving the quality of epidemiological data related to DH/DA should clarify areas of uncertainty, which would lead to better strategies to reduce the burden of these conditions., Summary: DH/DA remains a complex and unaddressed problem globally that often deprives patients of optimal medication choices and places them at risk for life-threatening reactions. DH/DA labels should contribute to people well being, by protecting true allergic individuals from being re-exposed to their allergic drugs and providing needed medications to individuals wrongly labeled as allergic or who have lost allergic sensitivity. The true rate of DH/DA is in fact unknown due to a number of factors, such as misdiagnosis, miscoding and under- and over-notification, among others. Moreover, there is lack of data about DH/DA epidemiology in many countries. Difficulties on collecting accurate and comparable data should be acknowledged, with great impact in the correct labeling DH/DA in electronic health records and official statistics. More accurate definitions, classification and coding may contribute to a better-quality MMS thanks to the ICD-11, under implementation worldwide. Improving the quality of epidemiological data related to DH/DA should clarify areas of uncertainty, which would lead to better strategies to reduce the burden of these conditions. As knowledge derived from populations is key information for more realistic decision-making, the construction of the new section addressed to DH/DA in the ICD-11 will allow the collection of more accurate epidemiological data to support quality management of patients, and facilitate healthcare planning to implement public health measures to prevent and reduce the morbidity and mortality attributable to these conditions., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Machine learning may assist with the identification of potentially inappropriate penicillin allergy labels. Strategies to improve the performance of existing models for this task include the use of additional training data, synthetic data and transfer learning., Aims: The aims of this study were to investigate the use of additional training data and novel machine learning strategies, namely synthetic data and transfer learning, to improve the performance of penicillin adverse drug reaction (ADR) machine learning classification., Methods: Machine learning natural language processing was applied to free-text penicillin ADR data extracted from a public health system electronic health record (EHR). The models were developed by training on various labelled data sets. ADR entries were split into training and testing data sets and used to develop and test a variety of machine learning models. The effect of training on additional data and synthetic data versus the use of transfer learning was analysed., Results: Following the application of these techniques, the area under the receiver operator curve of best-performing models for the classification of penicillin allergy (vs intolerance) and high-risk allergy (vs low-risk allergy) improved to 0.984 (using the artificial neural network model) and 0.995 (with the transfer learning approach) respectively., Conclusions: Machine learning models demonstrate high levels of accuracy in the classification and risk stratification of penicillin ADR labels using the reaction documented in the EHR. The model can be further optimised by incorporating additional training data and using transfer learning. Practical applications include automating case detection for penicillin allergy delabelling programmes., (© 2024 Royal Australasian College of Physicians.)

In this article, members of the American College of Radiology Committee on Drugs and Contrast Media propose a new term for symptoms reported after intravascular exposure to gadolinium-based contrast agents-Symptoms Associated with Gadolinium Exposure, or SAGE. This term is advocated in lieu of other proposed nomenclature that presumes a causal relationship that has not yet been scientifically verified. The purpose of this new term, SAGE, is to assist researchers and clinical providers in describing such symptoms without prematurely causally attributing them to a disease and to standardize reporting of these symptoms to allow for coherent interpretation of related studies., (© RSNA, 2021.)

Vitamins are essential substances for normal cell functions, growth, and development. However, they cannot be produced by the human organism, so intake must be through the diet. Vitamin deficiency causes the onset of different diseases, ranging from pellagra to pernicious anemia, which can be corrected by reintroducing the missing vitamin form. To supply the right amount of vitamins to the body, every vitamin naturally occurring in foodstuff has been identified, extracted and synthetically produced, thus allowing either food fortification with these compounds or their pharmaceutical production. Furthermore, the increased importance attributed nowadays to body wellness and the pursuit of a permanent status of health at all costs has greatly encouraged a high consumption of vitamin supplements in modern society, since vitamin megadoses may be responsible for adverse or toxic effects. However, excessive vitamins can induce hypervitaminosis. In the USA, a national survey confirmed that 52% of adult Americans take at least one or more supplement products, vitamins and minerals being the most popular supplements in that country. Although vitamins are widespread natural substances, they may induce immediate or delayed type hypersensitivity reactions. Such adverse events are still underestimated and poorly recognized because only single cases have been reported in the literature, and no general review has yet investigated the mechanisms underlying sensitization to each vitamin, the diagnosis, and the management strategies adopted for vitamin hypersensitivity. Although delayed-type reactions to different vitamins are described in the literature, in our review, attention has been focused mainly on immediate- type reactions. Due to the importance of vitamins, further information regarding the above aspects (pathomechanisms, diagnosis and management) would be highly desirable to focus the state of the art on this particular, underestimated form of allergy, thus increasing allergists' awareness on these elusive hypersensitivity reactions., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Side effects during hyaluronic acid (HA) injection are considered mild and reversible; however, an alarming trend of increased hypersensitivity reactions has recently been reported., Objective: The goal of this article is to review the hypersensitivity reactions reported in the literature and, in combination with the authors' experience, to create a classification system to sort the timing and clinical manifestations of these reactions, as well as a treatment schema to manage their clinical course., Methods: A literature search using PubMed, Ovid MEDLINE, and Embase databases was performed with no date restrictions. Search terms included "hyaluronic acid and hypersensitivity" and "hyaluronic acid and nodules." Data analyzed included study type, number of subjects, HA filler type, injection location, adverse reaction, timing, treatment, and outcomes., Results: Thirty-six studies were identified, documenting hypersensitivity reactions to HA treatment. Twelve cases described events occurring within a week, 6 within a month, and 31 after a month of treatment. Combined with the authors' experience, a new classification system and management of hypersensitivity reactions to HA fillers is proposed of early (up to a week), intermediate (a week to a month), and late (over a month) hypersensitivity reactions., Conclusion: The classification system proposed provides objective measurements and management options that can be helpful for physicians to navigate these hypersensitivity reactions and design treatment protocols that provide the best clinical outcomes for their patients.

The purpose of this study was to evaluate the quality of adverse drug reaction (ADR) documentation in a state-wide electronic health record (EHR), and to assess the impact of the interface design on documentation accuracy and ability to provide decision support. Data were extracted from 43 011 unique records in a state-wide electronic health record in South Australia, Australia. Information obtained included ADR coding as allergy or intolerance, allergen name, reaction, and occupation of those entering data. Categorization into drug allergy or intolerance was assessed for accuracy. Reactions were entered predominantly by nurses (60.1%), also by doctors (31.0%) and pharmacists (6.1%). Of 27 314 reactions, 86.5% were coded as allergy and 13.5% as intolerance. The majority (78.2%) described reactions to drugs (as opposed to food, environmental or contact allergens), predominantly chosen from the drug database (96.4%). Many entries used free text for the reaction description (27.4%). Terms found in the predefined list under the allergy heading were more likely to be categorized as allergy, even when the mechanism was pharmacological intolerance. Only 45.1% (n = 1671/3705) of reactions consistent with intolerance (eg, "nausea," "diarrhea") were correctly categorized as such, although categorization by pharmacists was more accurate (P < .0001). These data suggest that ADR categorization as allergy or intolerance is influenced by the EHR design. The obligatory classification of ADRs into allergy or intolerance was not well understood and does not appear to have practical benefit., (© 2019 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

Background: Most pregnant women who self-report penicillin allergy are not truly penicillin-allergic and this misunderstanding often leads to administration of inappropriate antibiotic therapy. Decision algorithms have been developed to guide antibiotic selection but major discrepancies have been reported between guidelines and clinical practice. We aimed to optimize the prescription of antibiotics for pregnant women who self-reported penicillin allergy, using an educational intervention about the classification of penicillin allergies that targeted gynecologists, anesthesiologists and midwives., Methods: This quasi-experimental study assessed the effect of an educational intervention about the classification of penicillin allergy. For six months, a combination of two strategies was used, namely dissemination of printed educational materials and group education. The principal study endpoint was the appropriateness of the antibiotic therapy, defined in advance for each level of allergic risk., Results: The pre-intervention phase included 903 women; one year after its conclusion, the post-intervention phase began and included 892 women. The prevalence of self-reported penicillin allergy was stable over the two periods (6.8% before vs 5.4% after, P=0.24). The clinical classification of penicillin allergies was more often used after the educational intervention (68% vs 100%, P<0.001). The appropriateness of the antibiotic therapy prescribed to self-reported penicillin allergic-women increased significantly between the two periods, from 5/29 (17.2%) to 18/27 (66.7%, P<0.001)., Conclusion: An educational intervention about penicillin allergy classification was associated with an improvement in the choice of appropriate antibiotic therapy among women who had reported penicillin allergy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The clinical phenotypes of nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity are heterogeneous with various presentations including time of symptom onset, organ involvements, and underlying pathophysiology. Having a correct diagnosis can be challenging. Understanding their respective mechanisms as well as developing a comprehensive classification and diagnostic algorithm are pivotal for appropriate management strategy. Treatment modalities are based on the subtypes and severity of hypersensitivity reactions. Insights into the phenotypes and endotypes of hypersensitivity reactions enable personalized management in patients with suboptimal control of disease. This review updated the recent evidence of pathophysiology, classification, diagnostic algorithm, and management of NSAID hypersensitivity reactions., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2020.)

Adverse drug reactions include drug hypersensitivity reactions (DHRs), which can be immunologically mediated or non-immunologically mediated. The high number of DHRs unconfirmed and/or self-reported is a frequent problem in daily clinical practice, with considerable impact on future prescription choices and patient health. It is important to distinguish between hypersensitivity and non-hypersensitivity reactions by adopting a structured diagnostic approach to confirm or discard the suspected drug, not only to avoid life-threatening reactions, but also to reduce the frequent over-diagnosis of DHRs.

Antibiotics are the commonest cause of life-threatening immune-mediated drug reactions that are considered off-target, including anaphylaxis, and organ-specific and severe cutaneous adverse reactions. However, many antibiotic reactions documented as allergies were unknown or not remembered by the patient, cutaneous reactions unrelated to drug hypersensitivity, drug-infection interactions, or drug intolerances. Although such reactions pose negligible risk to patients, they currently represent a global threat to public health. Antibiotic allergy labels result in displacement of first-line therapies for antibiotic prophylaxis and treatment. A penicillin allergy label, in particular, is associated with increased use of broad-spectrum and non-β-lactam antibiotics, which results in increased adverse events and antibiotic resistance. Most patients labelled as allergic to penicillins are not allergic when appropriately stratified for risk, tested, and re-challenged. Given the public health importance of penicillin allergy, this Review provides a global update on antibiotic allergy epidemiology, classification, mechanisms, and management., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The study of allergic drug reactions has been limited because of challenges in identifying and confirming cases., Objective: To determine the utility of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for identifying inpatient allergic drug reactions and to compare findings with previous data in the emergency department., Methods: By reviewing medical records of inpatients with ICD-9-CM codes and E codes suggestive of allergic drug reactions at a large urban academic medical center, we determined codes that yielded the most drug allergy cases and identified culprit drugs., Results: In 2005 and 2010, 3337 and 5282 possible allergic drug reactions during hospitalization were identified and 1367 were reviewed. Allergic drug reactions were found in 409 (30.1%) of the reviewed charts, with 172 (29.7%) in 2005 and 237 (30.5%) in 2010. The codes that identified the highest percentage of true allergic drug reactions were dermatitis due to drug (693.0), allergic urticaria (708), angioneurotic edema (995.1), and anaphylaxis (995.0). Antibiotics were the most common cause (44.4%); however, multiple drug classes were often identified as likely culprit drugs., Conclusion: Specific ICD-9-CM codes can identify patients with allergic drug reactions, with antibiotics accounting for almost half of true reactions. Most patients with codes 693.0, 995.1, 708, and 995.0 had allergic drug reactions, with 693.0 as the highest yield code. An aggregate of multiple specific codes consistently identifies a cohort of patients with confirmed allergic drug reactions., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Drug hypersensitivity reactions are clinically heterogenous ranging from mild to severe. Most drug hypersensitivity reactions are accompanied by cutaneous manifestations. Fever, mucous membrane involvement, large blisters, facial oedema, pustulosis and visceral involvement are clinical features that lead to suspicion of severe adverse drug reactions. Severe cutaneous adverse drug reactions (SCARs) include Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis. Serum sickness like reactions, drug induced vasculitis and generalized bullous fixed drug eruptions are less severe clinical entities. SCARs are uncommon but associated with significant morbidity and mortality. Physician should be aware of specific red flags and danger signs to immediately identify these reactions. Immediate drug withdrawal is mandatory. Early diagnosis and appropriate treatment significantly affect the prognosis of the disease. The purpose of our review is to discuss clinical phenotypes of severe cutaneous drug hypersensitivity reactions., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Drug hypersensitivity reactions (DHRs) are common, and the skin is by far the most frequently involved organ with a broad spectrum of reaction types. The diagnosis of cutaneous DHRs (CDHR) may be difficult because of multiple differential diagnoses. A correct classification is important for the correct diagnosis and management. With these guidelines, we aim to give precise definitions and provide the background needed for doctors to correctly classify CDHR., (© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

The use of contrast materials as part of imaging examinations is common in children of all ages, as these compounds increase image contrast, lesion detection and lesion characterization. Though modern iodinated, gadolinium-based and ultrasound microbubble contrast materials generally are quite safe, acute physiological and allergic-like reactions are possible. The majority of acute contrast reactions in children are mild and self-limited; however, life-threatening reactions can occur. It is our obligation as radiologists to recognize and manage these adverse reactions. The objective of this article is to review the frequency, manifestations and appropriate treatment of acute contrast reactions in the pediatric population.

Background: Adverse drug reactions (ADRs) can be divided into pharmacological ADRs (type A) and hypersensitivity reactions (type B). Type B reactions can be further subdivided into immediate (<1 h, urticaria, anaphylaxis) and delayed reactions (>1 h, variable manifestation like exanthema, hepatitis, cytopenias). Prevention of hypersensitivity is often still a challenge., Methods: Selective literature search in Medline and Google Scholar as well as research in ADR databases like OpenVigil or SIDER., Results: Laboratory tests ([specific] IgE, lymphocyte transformation test), histological examination, dermatological tests (prick tests, epicutaneous testing) and-under certain circumstances-provocation tests can be used for diagnostics. There are only a few pharmacogenetic biomarkers to predict hypersensitivity reactions. Currently, testing for defined HLA genes is mandatory before prescription of abacavir and before the use of carbamazepine in Han Chinese or Thai patients. Immediate discontinuation of the trigger is essential in all allergic hypersensitivity reactions. Immediate reactions are treated with antihistamines, glucocorticoids and occasionally with epinephrine. Delayed reactions are usually treated with glucocorticoids., Conclusion: Careful, structured diagnostics in case of suspected hypersensitivity together with adequate documentation (allergy passport) is necessary in order to avoid incidents in patients receiving subsequent treatment. Consistent use of existing resources (diagnostics and documentation) can help to avoid hypersensitivity reactions or to rapidly recognize and treat them, respectively.

Background: The increasing use of mAbs has led to a rise in hypersensitivity reactions (HSRs), which prevent their use as first-line therapy. HSRs' symptoms, diagnostic tools, and directed management approaches have not been standardized., Objective: We propose a novel evidence-based classification of HSRs to mAbs, based on the clinical phenotypes, underlying endotypes and biomarkers, as well as their management with desensitization., Methods: Phenotypes, endotypes, and biomarkers of HSRs to 16 mAbs for 104 patients were described and compared with the outcomes of 526 subcutaneous and intravenous desensitizations., Results: Initial reactions presented with 4 patterns: type I-like reactions (63%), cytokine-release reactions (13%), mixed reactions (21%), and delayed type IV reactions (3%). In contrast, of the 23% breakthrough HSRs during desensitization, 52% were cytokine-release reactions, 32% were type 1, 12% were mixed, and 4% were type I with delayed type IV. Skin testing to 10 mAbs in 58 patients was positive in 41% of patients. Serum tryptase was elevated in 1 patient and IL-6 was elevated in 8 patients during desensitization and was associated with a cytokine-release phenotype., Conclusions: HSRs to mAbs can be defined as type I, cytokine-release, mixed (type I/cytokine-release), and type IV reactions, which are identified by biomarkers such as skin test, tryptase, and IL-6. These phenotypes can be used to improve personalized and precision medicine when diagnosing HSRs to mAbs and providing management recommendations with desensitization. Desensitization provides a safe and effective retreatment option to remain on culprit mAbs as first-line therapy., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Drug hypersensitivity reactions (DHRs) represent growing health problem worldwide, affecting more than 7% of the general population, and represent an important public health problem. However, knowledge in DHRs morbidity and mortality epidemiological data is still not optimal and international comparable standards remain poorly accessed. Institutional databases worldwide increasingly use the WHO International Classification of Diseases (ICD) system to classify diagnoses, health services utilization, and death data. The misclassification of disorders in the ICD system contributes to a lack of ascertainment and recognition of their importance for healthcare planning and resource allocation. It also hampers clinical practice and prevention actions. To further inform the allergy community and to ensure that the revision process is transparent as advised in the WHO ICD-11 revision agenda, we report the advances and use of the pioneering "Drug hypersensitivity" subsection of ICD-11 and implementation in the WHO International Classification of Health Interventions (ICHI). The new classification addressed to DHRs will enable the collection of more accurate epidemiological data to support quality management of patients with drug allergies and better facilitate healthcare planning and decision-making and public health measures to prevent and reduce the morbidity and mortality attributable to DHRs., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

The overlabeling of pediatric antibiotic allergy represents a huge burden in society. Given that up to 10% of the US population is labeled as penicillin allergic, it can be estimated that at least 5 million children in this country are labeled with penicillin allergy. We now understand that most of the cutaneous symptoms that are interpreted as drug allergy are likely viral induced or due to a drug-virus interaction, and they usually do not represent a long-lasting, drug-specific, adaptive immune response to the antibiotic that a child received. Because most antibiotic allergy labels acquired in childhood are carried into adulthood, the overlabeling of antibiotic allergy is a liability that leads to unnecessary long-term health care risks, costs, and antibiotic resistance. Fortunately, awareness of this growing burden is increasing and leading to more emphasis on antibiotic allergy delabeling strategies in the adult population. There is growing literature that is used to support the safe and efficacious use of tools such as skin testing and drug challenge to evaluate and manage children with antibiotic allergy labels. In addition, there is an increasing understanding of antibiotic reactivity within classes and side-chain reactions. In summary, a better overall understanding of the current tools available for the diagnosis and management of adverse drug reactions is likely to change how pediatric primary care providers evaluate and treat patients with such diagnoses and prevent the unnecessary avoidance of antibiotics, particularly penicillins., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Antibiotic allergy labeling is highly prevalent and negatively impacts patient outcomes and antibiotic appropriateness. Reducing the prevalence and burden of antibiotic allergies requires the engagement of key stakeholders such as allergists, immunologists, pharmacists, and infectious diseases physicians. To help address this burden of antibiotic allergy overlabeling, we review 3 key antibiotic allergy domains: (1) antibiotic allergy classification, (2) antibiotic cross-reactivity, and (3) multidisciplinary collaboration. We review the available evidence and research gaps of currently used adverse drug reaction classification systems, antibiotic allergy cross-reactivity, and current and future models of antibiotic allergy care., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The role and importance of thienopyridines such as ticlopidine, clopidogrel, and prasugrel is well-established for several indications, ranging from prevention of acute coronary syndromes to percutaneous coronary interventions, where the dual antiplatelet therapy represents the gold standard to avoid denovo coronary stenosis. However, there is a significant cohort of patients with coronary artery disease who may manifest hypersensitivity reactions to thienopyridines. The examination of the various case reports from medical literature leads to identify mainly four clinical patterns of hypersensitivity to thienopyridines which involves more frequently cutaneous, hematologic, and articular tissues, therefore the kind and predominance of clinical symptoms may determine a different clinical approach to overcome or neutralize thienopyridines hypersensitivity., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs are common and five types of reactions have been defined. The prevalence of such reactions in patients with myocardial infarction is unclear, and so antiplatelet therapy in this population is a challenge. Various desensitization protocols have been developed but there are no specific guidelines for their use. The authors present the case of a patient with acute coronary syndrome and aspirin hypersensitivity referred for urgent coronary angiography. Aspirin desensitization therapy is safe and successful in many patients, but more randomized trials are needed to confirm its benefits in coronary artery disease patients., (Copyright © 2016 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are the main cause of drug-induced hypersensitivity in children. Many classifications have been proposed, focusing on adults. So far, no large study has deeply investigated a pediatric cohort. The aim of the present study was to describe a population of NSAID hypersensitive patients reporting a reaction during their childhood and to verify whether it is possible to classify pediatric patients, following the EAACI/ENDA classification., Methods: We conducted a historical prospective study including patients evaluated from 1996 to 2015 in the allergy unit of the Montpellier University Hospital. We included 635 patients. For each patient, we recorded clinical manifestations and possible comorbidities and tried to identify possible risk factors., Results: NSAID hypersensitivity was diagnosed in 107 of 635 patients (16.9%). In this group, 43 patients (40.2%) could not be classified following the ENDA recommendations. The main discrepancies were on the patients' clinical manifestations and on their possible underlying diseases. We identified, on a multivariate analysis, some risk factors for NSAID hypersensitivity: chronic urticaria (OR 7.737, 3.375-18.296 95%CI), atopic status (OR 2.514, 1.504-4.364 95%CI), and allergic rhinoconjunctivitis (OR 1.799, 1.138-2.837 95%CI). On the basis of our results, we are proposing an adapted classification for NSAID hypersensitivity in children., Conclusions: The current ENDA classification does not seem to be adapted for pediatric patients; a modified version does. Our study could help allergists better understand the differences between adults and children in developing hypersensitivity reactions to NSAIDs, but further large-scale prospective longitudinal analyses are required to validate this new classification., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose of Review: The purpose is to understand the underlying mechanisms of accelerated allergic reactions to drugs, defined here as reactions occurring between 1 and 24 h after drug intake., Recent Findings: Recent publications have shown that accelerated reactions are T cell-mediated, although an IgE mechanism cannot be ruled out in some cases., Summary: Classification of allergic reactions to drugs is complex. Based on the time interval between drug administration and appearance of the clinical reaction, as well as the type of clinical symptoms, they can be classified as: immediate, typically appearing from less than 1 to 6 h after the last drug administration and nonimmediate, occurring at any time from 1 h after drug administration. Therefore, overlap exists in what the Levine classification defined as accelerated reactions, where clinical symptoms are mainly urticaria and less often exanthema and serum sickness-like reactions. The immunological mechanisms involved suggest that they are T cell-mediated reactions with a Th1 pattern, comprising increased production of IFNγ, TNFα, the chemokine CXCL9 and its corresponding receptor CXCR3. In most cases an IgE-mediated response is ruled out because of negative immediate skin test results, no detection of serum-specific IgE antibodies or tryptase, and no skin-secreted tryptase. However, an IgE-mediated response can be demonstrated in exceptional situations. Finally, serum sickness-like reactions have been reported as an immune complex-mediated accelerated reaction. However, the exact mechanism has not been confirmed.

The recent development of biological agents, namely, anti-tumour necrosis factor alpha (TNF-α) agents (infliximab, adalimumab and etanercept), anti- CD20 monoclonal antibody (rituximab) and anti-interleukin 6 receptor (IL-6R) monoclonal antibody (tocilizumab), represents a major breakthrough for the treatment of immune-mediated disorders. Given their structural and functional differences, distinct safety profiles can be expected for each of these agents. Evidence in the literature indicates that patients treated with anti-TNF-α agents and tocilizumab are at increased risk for bacterial infections. However, an increased therapeutic use of these biological agents has disclosed other side-effects, including immediate hypersensitivity reactions, such as anaphylaxis and urticaria. Both under-diagnosis and over-diagnosis of hypersensitivity reactions to biological agents are potential problems. Thus, it is important to identify these reactions and to adopt the right approach to manage them. This article reviews the general aspects of adverse events during biologic treatment, focusing on IgE-mediated hypersensitivity reactions to anti-TNF-α agents, rituximab and tocilizumab, and on the tools for the diagnosis of these life-threatening reactions.

Intravenous (IV) iron therapy is widely used in iron deficiency anaemias when oral iron is not tolerated or ineffective. Administration of IV-iron is considered a safe procedure, but severe hypersensitivity reactions (HSRs) can occur at a very low frequency. Recently, new guidelines have been published by the European Medicines Agency with the intention of making IV-iron therapy safer; however, the current protocols are still non-specific, non-evidence-based empirical measures which neglect the fact that the majority of IV-iron reactions are not IgE-mediated anaphylactic reactions. The field would benefit from new specific and effective methods for the prevention and treatment of these HSRs, and the main goal of this review was to highlight a possible new approach based on the assumption that IV-iron reactions represent complement activation-related pseudo-allergy (CARPA), at least in part. The review compares the features of IV-iron reactions to those of immune and non-immune HSRs caused by a variety of other infused drugs and thus make indirect inferences on IV-iron reactions. The process of comparison highlights many unresolved issues in allergy research, such as the unsettled terminology, multiple redundant classifications and a lack of validated animal models and lege artis clinical studies. Facts and arguments are listed in support of the involvement of CARPA in IV-iron reactions, and the review addresses the mechanism of low reactogenic administration protocols (LRPs) based on slow infusion. It is suggested that consideration of CARPA and the use of LRPs might lead to useful new additions to the management of high-risk IV-iron patients., (© 2015 The British Pharmacological Society.)

Suspected adverse drug reactions may be subdivided on the basis of mechanism e.g. immunological (requiring sensitisation by previous exposure) versus nonimmunological; timing (e.g. immediate or delayed), or whether the phenomenon is dose dependent or not. In the NICE guideline the main approach is to classify the event according to whether it: is immediate (within an hour of drug administration) or delayed (hours or days); affects a single or multiple systems; is clinically severe/life threatening or not. An immediate, immunologically mediated, multisystem, life-threatening reaction would for example include anaphylaxis (type 1 or typically IgE- mediated hypersensitivity) especially if the clinical features (e.g. bronchospasm, hypotension) are suggestive. Serum mast cell tryptase should be tested ideally within two hours and certainly before four hours post reaction. Detailed investigation of suspected cases in a specialist clinic is ideally delayed for 4-6 weeks after the event. Adverse drug reactions need to be meticulously recorded and the patient fully informed. Documentation should include: date of reaction; drug name (chemical and generic); route of administration; time interval between first dose and event; and nature and severity of symptoms. Written guidance should be provided on which other chemically related drugs also need to be avoided. Specialist referral is indicated for: suspected anaphylaxis; severe/life- threatening episodes e.g. Stevens-Johnson syndrome; severe NSAID reactions with ongoing need for NSAID therapy; suspected penicillin allergy (if alternative antibiotics are not available); and problems related to general and local anaesthesia.

Internationally, major efforts are underway to improve medication safety and reduce medication errors during transitions of care. One strategy that has emerged to improve data accuracy and close information gaps is the introduction of software applications and workflow models that allow patients to review, enter, and modify their own patient data (e.g. information about medications they are taking). Evaluating the quality and effectiveness of such patient-facing healthcare applications is critical, especially when this approach is applied to high-stakes clinical tasks such as medication reconciliation. In this paper we describe an approach that has been used to assess the usability of a patient-facing medication reconciliation and allergy review (MRAR) kiosk. The phases involved are described along with implications and challenges of carrying out this work.

In forensic pathology routine, fatal cases of contrast agent exposure can be occasionally encountered. In such situations, beyond the difficulties inherent in establishing the cause of death due to nonspecific or absent autopsy and histology findings as well as limited laboratory investigations, pathologists may face other problems in formulating exhaustive, complete reports, and conclusions that are scientifically accurate. Indeed, terminology concerning adverse drug reactions and allergy nomenclature is confusing. Some terms, still utilized in forensic and radiological reports, are outdated and should be avoided. Additionally, not all forensic pathologists master contrast material classification and pathogenesis of contrast agent reactions. We present a review of the literature covering allergic reactions to contrast material exposure in order to update used terminology, explain the pathophysiology, and list currently available laboratory investigations for diagnosis in the forensic setting.

Background: Skin testing in duplicate, correlation between case history of immediate and nonimmediate reactions and challenge outcome and prolonged oral treatment with penicillin in the diagnostic evaluation of allergic reactions to β-lactam antibiotics, mimicking real-life situations, have only been addressed in few studies., Methods: A total of 342 patients suspected of having β-lactam allergy were investigated according to the European Network for Drug Allergy (ENDA) guidelines and patients found to be negative in the ENDA program were supplemented with a 7-day oral treatment with penicillin. Skin testing with penicillins was performed in duplicate. Patients with case histories of reactions to other β-lactams were also subsequently challenged with the culprit drug., Results: Nineteen patients were IgE-sensitized to penicillin. Then, intracutaneous tests (ICTs) were performed, in which 35 patients tested positive for allergy, 21 with delayed and 14 with immediate reactions. Only three patients tested positive for the major (PPL) and/or minor (MDM) penicillin determinants, all being positive for penicillin G in ICT. The remaining 291 patients were challenged with penicillin: 10 tested positive in single-dose challenge and 23 tested positive in the 7-day challenge. A total of 17 of 78 patients with a negative penicillin challenge tested positive during challenges with other β-lactams. We found no correlation between case histories of immediate and nonimmediate reactions and reaction time during challenge., Conclusion: The data suggest that case history is often insufficient to discriminate between immediate reactors and nonimmediate reactors. A 7-day challenge with the culprit β-lactam may yield more positive reactions than the accepted one- or 2-day challenge. Interpretation of skin testing should be made with caution., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Physicians and scientists use a broad spectrum of terms to classify contrast media (CM)-induced adverse reactions. In particular, the designation of hypersensitivity reactions is quite varied. Consequently, comparisons of different papers dealing with this subject are difficult or even impossible. Moreover, general descriptions may lead to problems in understanding reactions in patients with a history of adverse CM-reactions, and in efficiently managing these patients. Therefore, the goal of this paper is to suggest an easy system to clearly classify these reactions. The proposed three-step systems (3SS) is built up as follows: step 1 exactly describes the clinical features, including their severity; step 2 categorizes the time point of the onset (immediate or nonimmediate); and step 3 generally classifies the reaction (hypersensitivity or nonhypersensitivity reaction). The 3SS may facilitate better understanding of the clinical manifestations of adverse CM reactions and may support the prevention of these reactions on the basis of personalized medicine approaches., (Copyright © 2012 John Wiley & Sons, Ltd.)

Aspirin is the most commonly used antiplatelet agent in patients with coronary artery disease (CAD). It continues to play a key role as an antiplatelet agent given its long-term safety, efficacy and low cost. Aspirin or NSAID hypersensitivity is not an uncommon occurrence and can vary from generalized urticaria and angioedema to exacerbation of upper and lower respiratory tract reactions. It is not uncommon for clinicians to avoid using aspirin and alternative agents when encountering aspirin hypersensitivity among CAD patients. However, given the critical role of aspirin in CAD patients, particularly among those who receive the drug-eluting stents, aspirin desensitization can be useful. This article highlights the importance of aspirin desensitization, the mechanism and the process involved. We draw attention to recently described rapid desensitization protocols and how they can be more useful than the old procedure.

Drug allergy describes clinical adverse reactions that are proved or presumed to be immunologically based. Allergic drug reactions do not resemble pharmacologic actions of the incriminated drug and may occur at fractions of what would be the therapeutic dosage. Allergic drug reactions are unpredictable; nevertheless, there is increased risk of drug hypersensitivity in (1) patients with cystic fibrosis who receive antibiotics; (2) patients with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) who receive trimethoprim/sulfamethoxazole of if HLA-B*5701(+) and receive the antiretroviral agent, abacavir; (3) other genetically susceptible populations such as Han-Chinese who are HLA-B*1502(+) who develop Stevens-Johnson syndrome and toxic epidermal necrolysis from carbamazepine or if HLA-B*5801(+) are at increased risk for such reactions from allopurinol; and (4) patients with a history of previous compatible allergic reaction to the same medication, similar class, or potentially unrelated medication. Specific patient groups at higher risk for drug allergy include those with Ebstein-Barr virus infection, chronic lymphatic leukemia, HIV/AIDS, cystic fibrosis, patients with seizures being treated with antiepileptic medications, and patients with asthma (especially severe asthma) who are at increased risk of anaphylaxis from any cause including drugs compared with patients without asthma. In patients with a history of penicillin allergy, skin testing helps clarify the current level of risk for anaphylaxis by using the major (penicilloyl-polylysine) and minor penicillin determinants where sensitivity is 99%. If penicilloyl-polylysine and penicillin G are used for skin testing, the sensitivity is ∼85%. When skin tests are negative, graded challenges are performed to administer optimal or truly essential antibiotics.

Hypersensitivity reactions to contrast media (CM) are frequent causes of anaphylaxis and drug exanthemas. Adverse events after CM exposure are classified into immediate (≤1 h) and non-immediate reactions (>1 h), with differing mechanisms. In the majority of patients with immediate reactions, IgE-mediated allergy cannot be demonstrated, and the underlying mechanism remains unknown. However, recent data have provided evidence for skin test positivity and/or specific IgE in some patients. T cell-mediated hypersensitivity is the responsible mechanism for the majority of non-immediate skin eruptions. These insights have consequences for diagnosis and prevention. Skin testing evolves to be a useful tool for diagnosis of CM allergy. Skin tests have been employed to confirm this hypersensitivity. Previous reactors have an increased risk to develop new reactions upon repeated exposure; however, other risk factors are poorly defined. The use of skin tests for the selection of a 'safe' CM is under investigation with promising results. In vitro tests to search for CM-specific cell activation include flow cytometric approaches, lymphocyte cultures and construction of cell lines and hybridomas. Premedication of previous reactors is common practice among radiologists; however, breakthrough reactions are a concern, and physicians should not rely on the efficacy of pharmacological premedication., (Copyright © 2012 S. Karger AG, Basel.)

Background: Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) is one of the most common drug hypersensitivities. Several clinical subtypes have been distinguished depending on symptomatology (respiratory, cutaneous, anaphylaxis), timing (immediate, delayed), underlying chronic disease (asthma, chronic urticaria) or putative mechanism of the reaction (allergic, nonallergic mediated). The aim of the present study was to better classify the many hypersensitivity reactions to NSAIDs., Methods: In the present retrospective study, during an 11-year study period, we collected data from all patients with a proven NSAID hypersensitivity. Reactions were classified according to clinical patterns, chronology, underlying diseases and the results of oral provocation tests into 5 and 7 groups in line with two published classifications, respectively., Results: Forty-nine and 88 out of 307 reactions (in 122 patients) could not be classified on the basis of the two previously published classifications. We created a new classification which could include all patient reactions., Conclusions: Our new classification is more suitable for clinical expression of NSAID hypersensitivity. It allows clinicians to identify patients at a high risk, based on the clinical history and clinical manifestations. Moreover, it is helpful for a better understanding and teaching of these reactions., (Copyright © 2012 S. Karger AG, Basel.)

Anesthesia may often be considered as a high-risk procedure and anaphylaxis remains a major cause of concern for anesthetists who routinely administer many potentially allergenic agents. Neuromuscular blocking agents, latex and antibiotics are the substances involved in most of the reported reactions. Besides these three agents, a wide variety of substances may cause an anaphylactic reaction during anesthesia. Basically all the administered drugs or substances may be potential causes of anaphylaxis. Among them, those reported the most in literature include hypnotics, opioids, local anesthetics, colloids, dye, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), Iodinated Contrast Media (ICM), antiseptics, aprotinin, ethylene oxyde and formaldehyde, and protamine and heparins. No premedication can effectively prevent an allergic reaction and a systematic preoperative screening is not justified for all patients; nevertheless, an allergy specialist should evaluate those patients with a history of anesthesia-related allergy. Patients must be fully informed of investigation results, and advised to provide a detailed report prior to future anesthesia.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are responsible for 21-25% of reported adverse drug events which include immunological and nonimmunological hypersensitivity reactions. This study presents up-to-date information on pathomechanisms, clinical spectrum, diagnostic tools and management of hypersensitivity reactions to NSAIDs. Clinically, NSAID hypersensitivity is particularly manifested by bronchial asthma, rhinosinusitis, anaphylaxis or urticaria and variety of late cutaneous and organ-specific reactions. Diagnosis of hypersensitivity to a NSAID includes understanding of the underlying mechanism and is necessary for prevention and management. A stepwise approach to the diagnosis of hypersensitivity to NSAIDs is proposed, including clinical history, in vitro testing and/or provocation test with a culprit or alternative drug depending on the type of the reaction. The diagnostic process should result in providing the patient with written information both on forbidden and on alternative drugs., (© 2011 John Wiley & Sons A/S.)

Antibiotics are commonly injected during the perioperative period and are responsible of 15 percent of the anaphylactic reactions. Anaphylaxis triggered by antibiotics primarily involves penicillin and cephalosporin. The management of patients with histories of allergic reactions to antibiotics is a common situation in clinical practice. The confirmation or invalidation of the allergic nature of the reported reaction is not based on in vitro tests, but on a rigorous allergological work-up based on detailed analysis of clinical history, skin tests and drug provocation test. Considering a possible cross-reactivity between penicillins, once an immediate penicillin allergy has been diagnosed, skin testing with the alternative molecule (cephalosporin, carbapenem, aztreonam) is mandatory and, if negative, the relevant drug should be given in an appropriate setting at increasing doses.

This review focuses on several basic mechanisms of allergy and when a rheumatologist should consider an external agent as being responsible for seemingly 'rheumatic' manifestations. Typical allergic diseases are discussed in order to help the physician to recognise them. In addition, allergic aspects and adverse drug reactions of antirheumatic drugs and biopharmaceutical agent therapies will be discussed.

Adverse drug reactions (ADRs) result in major health problems in the United States in both the inpatient and outpatient setting. ADRs are broadly categorized into predictable (type A and unpredictable (type B) reactions. Predictable reactions are usually dose dependent, are related to the known pharmacologic actions of the drug, and occur in otherwise healthy individuals, They are estimated to comprise approximately 80% of all ADRs. Unpredictable are generally dose independent, are unrelated to the pharmacologic actions of the drug, and occur only in susceptible individuals. Unpredictable reactions are subdivided into drug intolerance, drug idiosyncrasy, drug allergy, and pseudoallergic reactions. Both type A and B reactions may be influenced by genetic predisposition of the patient

Background: Accurate medical history information is essential for good patient care and should be notified in the letter of referral. The aim of this study was to investigate the subjective opinion that the medical information in a large number of referrals is either inaccurate or non-existent., Methods: Medical histories from 54 patients with positive medical history findings upon taking the medical history at the initial consultation appointment were compared to the medical information supplied in the referral letter., Results: Overall, medical information was only 58.8% complete with dental referrals being 55.2% complete and medical referrals 62.4%. The majority of referral letters (70.4%) missed at least one relevant finding and only 29.6% of referrals were 100% complete., Conclusions: The results of this study suggest that the standard of referral letters needs to be improved as the received referrals were generally incomplete and contained inaccurate information. This highlights the need for each and every practitioner to take their own detailed medical history and not rely on the information supplied in the referral.

Although the incidence of insulin allergy decreased after the introduction of recombinant human insulin preparations, it is still a major problem which may be life-threatening in some cases. In this article, we attempted to review current knowledge concerning allergic reactions to human insulin and discuss the available treatment options of insulin allergy.

Objectives: To systematically evaluate the clinical characteristics of ADRs caused by Shuanghuanglian Injection (SHLI) and to provide reference for post-market evaluation and clinical application of SHLI., Methods: We searched electronic databases such as the Chinese National Knowledge Infrastructure (CNKI, 1979-2009.9), the Chinese Science and Technology Journal Full-text Database (VIP, 1989-2009.9), and the Chinese Biomedical Disc (CBMdisc, 1978-2009.9). ADR cases were analyzed according to occurrences categorized. Available data was assessed using the Chi-square test including relative ratios (RR) with 95% confidence intervals (95%CI). Different medicine combinations and comparisons between SHL powder injection and SHL injection were calculated using the statistical software Stata 9.1., Results: (1) A total of 452 articles were included with a total of 2,799 ADR cases reported. Case reports were the main design type of included literature, which account for 84.51%. According to 31,165 cases of SHLI treatment and 1,013 corresponding ADRs, the incidence of SHLI ADR was calculated as 3.25%. (2) The ratio of male to female in the reported ADR cases was 1.13:1. (3) Allergy to Penicillin, which account for 13.38% of the total cases, was at the top for past allergic history, followed by sulfonamides and asthma (2.68%). (4) In terms of disease treated respiratory disease accounted for 91.75% of all cases of SHLI ADRs, followed by digestive diseases (5.17%), and urinary diseases (1.11%). (5) Penicillins were the most common combination choice with SHLI, and such combination showed higher ADR risk than SHLI used alone (RR = 3.14, 95%CI 2.58 to 3.81). (6) Multiple systems/organs were involved in SHLI ADRs, and were ranked downwards according to proportion as: skin, digestive system, general reactions, respiratory system, nervous system, cardiovascular system, local reactions, urinary system, hematologic system and others. (7) According to the WHO ADR Classification Criteria, ADR cases were divided into four grades. There were 6.36%, 5.48%, 45.62%, and 2.12% cases of Grade I, II, III, and IV respectively. And the prognoses of the rest 52.42% cases were reported unclearly. (8) All cases of death were caused by allergic shock, except for one, which was caused by myocardial infarction induced by pain at the injection site. The fastest ADR case occurred 1 minute after being injected. (9) There was a remarkable difference (P < 0.05) in the rate of ADR caused by SHLI in power form (2.25%) and as a solution (4.14%)., Conclusion: The clinical manifestations of ADRs caused by SHLI mainly include skin allergic reactions and gastrointestinal reactions. There is an increased risk of ADR induced by combined uses of SHLI and other drugs, especially antibiotics. Compared to the solution, the powder has lower ADR occurrence and higher safety with statistical significance. We propose strengthening management and surveillance on SHLI from manufacturing to application, and improving the level of the risk management for post-market drugs., (© 2010 Blackwell Publishing Asia Pty Ltd and Chinese Cochrane Center, West China Hospital of Sichuan University.)

Importance of the Field: The incidence of hypersensitivity reactions (HSRs) to chemotherapy agents has increased because of increasing number of cancer survivors are exposed to repeated courses of sensitizing agents. Replacement with an alternative chemotherapy regimen is often limited by tumor sensitivity. Rapid desensitization offers an effective mean to allow continuation of the treatment to which patients have presented HSRs., Areas Covered in This Review: We review the methods, outcome and safety of the rapid desensitization protocol developed at Brigham and Women's Hospital, Harvard Medical School Affiliate, based on our recent publication "'Hypersensitivity reactions to chemotherapy: outcome and safety of rapid desensitization in 413 cases". Literature search was conducted through Medline (from January 1976 to September 2009), using PubMed., What the Reader Will Gain: The article will give insight to clinical manifestations of immediate HSR to various chemotherapy agents and their presumably different immunopathomechanism. Risk assessment, including skin testing in those presented HSRs to platins and details on rapid desensitization process and its pitfalls will be discussed., Take Home Message: Standa"rd protocol of rapid desensitization, administering under multidisciplinary team approach, is safe and effective in overcoming immediate HSRs to platins, taxanes, doxorubicin and rituximab via both intravenous and intraperitoneal routes.

Background: Drug hypersensitivity is responsible for substantial mortality and morbidity, and increased health costs. However, epidemiological data on drug hypersensitivity in general or specific populations are scarce., Methods: We performed a cross-sectional survey of 1015 university students, using a self-reported questionnaire., Results: The prevalence of self-reported drug hypersensitivity was 12,11% (123/1015). The most frequently implicated drugs were non-steroidal anti-inflammatory drugs (45,9%) and beta-lactam and sulfonamide antibiotics (25,40%). The majority of the patients reported dermatological manifestations (99), followed by respiratory (40), digestive (23) and other (19). Forty-five patients had an immediate type reaction, and 76,72% (89) had the drug by oral route., Conclusion: The results showed that drug hypersensitivity is highly prevalent in university students, and that nonsteroidal anti-inflammatory drug and antibiotics (beta-lactams and sulfonamide) are the most frequently concerned drugs.

Anaphylaxis as the maximal variant of an acute systemic hypersensitivity reaction can involve several organ systems, particularly the skin, respiratory tract, gastrointestinal tract and the cardiovascular system. The severity of anaphylactic reaction is variable and can be classified into severity grades I-IV. Some reactions are fatal. Most frequent elicitors of anaphylaxis are foods in childhood, later insect stings and drugs. The phenomenon itself has been described in ancient medical literature, but was actually recognized and named at the beginning of the 20th century by Charles Richet and Paul Portier. In the course of experiments starting on the yacht of the Prince of Monaco and continued in the laboratory in Paris, they tried to immunize dogs with extracts of Physalia species in an attempt to develop an antitoxin to the venom of the Portuguese man-of-war. While Charles Richet believed that anaphylaxis was a 'lack of protection', it has become clear that an exaggerated immune reaction, especially involving immunoglobulin E antibodies, is the underlying pathomechanism in allergic anaphylaxis besides immune complex reactions. Non-immunologically mediated reactions leading to similar clinical symptomatology have been called 'anaphylactoid' or 'pseudo-allergic'--especially by Paul Kallos--and are now called 'non-immune anaphylaxis' according to a consensus of the World Allergy Organization (WAO). The distinction of different pathophysiological processes is important since non-immune anaphylaxis cannot be detected by skin test or in vitro allergy diagnostic procedures. History and provocation tests are crucial. The intensity of the reaction is not only influenced by the degree of sensitization but also by concomitant other factors as age, simultaneous exposure to other allergens, underlying infection, physical exercise or psychological stress or concomitant medication (e.g. beta-blockers, NSAIDs); this phenomenon has been called augmentation or summation anaphylaxis., (Copyright 2010 S. Karger AG, Basel.)