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Diagnosing immediate drug hypersensitivity reactions (IDHRs) can pose a significant challenge and there is an urgent need for safe and reliable tests. Evidence has emerged that the basophil activation test (BAT), an in vitro assay that mirrors the in vivo response, can be a complementary test for many drugs. In this position paper, members of Task Force (TF) "Basophil activation test in the evaluation of Drug Hypersensitivity Reactions" from the European Academy of Allergy and Clinical Immunology (EAACI) present the data from a survey about the use and utility of BAT in IDHRs in Europe. The survey results indicate that there is a great interest for using BAT especially for diagnosing IDHRs. However, there are still main needs, mainly in the standardization of the protocols. Subsequently consensus‐based recommendations were formulated for: (i) Technical aspects of BAT in IDHRs including type of sample, management of drugs, flow cytometry protocols, interpretation of the results; and (ii) Drug‐specific aspects that should be taken into account when performing BAT in relation to betalactams, neuromuscular blocking agents, fluoroquinolones, chlorhexidine, opioids, radio contrast media, chemotherapeutics, biological agents, nonsteroidal anti‐inflammatory drugs, COVID vaccine, and excipients. Moreover, aspects in the evaluation of pediatric population have also been considered. All this indicates that BAT offers the clinician and laboratory a complementary tool for a safe diagnostic for IDHRs, although its place in the diagnostic algorithm depends on the drug class and patient population (phenotype, geography, and age). The standardization of BAT is important for generalizing this method beyond the individual laboratory. [ABSTRACT FROM AUTHOR]

The strongest and best-documented risk factor for drug hypersensitivity ( DH) is the history of a previous reaction. Accidental exposures to drugs may lead to severe or even fatal reactions in sensitized patients. Preventable prescription errors are common. They are often due to inadequate medical history or poor risk assessment of recurrence of drug reaction. Proper documentation is essential information for the doctor to make sound therapeutic decision. The European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology have formed a task force and developed a drug allergy passport as well as general guidelines of drug allergy documentation. A drug allergy passport, a drug allergy alert card, a certificate, and a discharge letter after medical evaluation are adequate means to document DH in a patient. They are to be handed to the patient who is advised to carry the documentation at all times especially when away from home. A drug allergy passport should at least contain information on the culprit drug(s) including international nonproprietary name, clinical manifestations including severity, diagnostic measures, potential cross-reactivity, alternative drugs to prescribe, and where more detailed information can be obtained from the issuer. It should be given to patients only after full allergy workup. In the future, electronic prescription systems with alert functions will become more common and should include the same information as in paper-based documentation. [ABSTRACT FROM AUTHOR]

Drug hypersensitivity reactions ( DHRs) are a matter of great concern, both for outpatient and in hospital care. The evaluation of these patients is complex, because in vivo tests have a suboptimal sensitivity and can be time-consuming, expensive and potentially risky, especially drug provocation tests. There are several currently available in vitro methods that can be classified into two main groups: those that help to characterize the active phase of the reaction and those that help to identify the culprit drug. The utility of these in vitro methods depends on the mechanisms involved, meaning that they cannot be used for the evaluation of all types of DHRs. Moreover, their effectiveness has not been defined by a consensus agreement between experts in the field. Thus, the European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology has organized a task force to provide data and recommendations regarding the available in vitro methods for DHR diagnosis. We have found that although there are many in vitro tests, few of them can be given a recommendation of grade B or above mainly because there is a lack of well-controlled studies, most information comes from small studies with few subjects and results are not always confirmed in later studies. Therefore, it is necessary to validate the currently available in vitro tests in a large series of well-characterized patients with DHR and to develop new tests for diagnosis. [ABSTRACT FROM AUTHOR]

Drug hypersensitivity includes allergic ( AR) and nonallergic reactions ( NARs) influenced by genetic predisposition. We performed a systematic review of genetic predictors of IgE-mediated AR and NAR with MEDLINE and PubMed search engine between January 1966 and December 2014. Among 3110 citations, the search selected 53 studies, 42 of which remained eligible. These eligible studies have evaluated genetic determinants of immediate reactions ( IR) to beta-lactams ( n = 19), NAR against aspirin ( n = 12) and other nonsteroidal anti-inflammatory drugs ( NSAIDs) ( n = 8), and IR to biologics ( n = 3). We reported two genomewide association studies and four case-control studies on candidate genes validated by replication. Genes involved in IR to beta-lactams belonged to HLA type 2 antigen processing, IgE production, atopy, and inflammation, including 4 genes validated by replications, HLA- DRA, ILR4, NOD2, and LGALS3. Genes involved in NAR to aspirin belonged to arachidonic acid pathway, membrane-spanning 4A gene family, histamine production pathway, and pro-inflammatory cytokines, while those involved in NAR to all NSAIDs belonged to arachidonic acid pathway and HLA antigen processing pathway. ALOX5 was a common predictor of studies on NAR to both aspirin and NSAIDs. Although these first conclusions could be drawn, this review highlights also the lack of reliable data and the need for replicating studies in contrasted populations, taking into account worldwide allele frequencies, gene-gene interactions, and contrasted situations of environmental exposure. [ABSTRACT FROM AUTHOR]

When questioned, about 10% of the parents report suspected hypersensitivity to at least one drug in their children. However, only a few of these reactions can be confirmed as allergic after a diagnostic workup. There is still a lack of knowledge on drug hypersensitivity (DH) epidemiology, clinical spectrum, and appropriate diagnostic methods particularly in children. Meanwhile, the tools used for DH management in adults are applied also for children. Whereas this appears generally acceptable, some aspects of DH and management differ with age. Most reactions in children are still attributed to betalactams. Some manifestations, such as nonsteroidal anti-inflammatory drug-associated angioedema and serum sickness-like reactions, are more frequent among young patients as compared to adults. Risk factors such as viral infections are particularly frequent in children, making the diagnosis challenging. The practicability and validity of skin test and other diagnostic procedures need further assessment in children. This study presents an up-to-date review on epidemiology, clinical spectrum, diagnostic tools, and current management of DH in children. A new general algorithm for the study of these reactions in children is proposed. Data are presented focusing on reported differences between pediatric and adult patients, also identifying unmet needs to be addressed in further research. [ABSTRACT FROM AUTHOR]

Drug hypersensitivity reactions ( DHRs) may be caused by immunologic and non-immunologic mechanisms. According to the World Allergy Organization, drug allergy ( DA) encompasses the subgroup of immunologic DHRs which are mediated either by specific antibodies or specific T lymphocytes. Due to the immunologic memory, DA reactions bear an increased risk for dramatically enhanced reactions on re-exposure. Some current concepts of DA were described decades ago. Drug allergies to soluble macromolecular protein drugs such as biopharmaceuticals are predominantly T cell-dependent drug-specific antibody responses leading to IgE-or IgG-mediated allergy. However, most drugs are too small to be directly recognized by specific B and T cells. Immune reactions to low-molecular drugs have been explained by the hapten model: a hapten drug can bind covalently to soluble autologous proteins (e.g. serum albumin). Resulting compounds may then be recognized by matching B cell receptors ( BCRs) and induce a specific T cell-dependent IgE-or IgG-antibody production. Drug haptens may bind to extra- or intracellular proteins, which are processed and presented by various professional antigen-presenting cells ( APCs). Depending on the APC, they may induce not only specific antibody production, but also non-immediate T cell-mediated DA. More recently, a supplementary effector mechanism for non-immediate DA to low-molecular drugs has been described, namely the pharmacological interaction of native low-molecular drugs with immune receptors (p-i-concept). Low-molecular drugs may directly and reversibly attach to immune receptors. These non-covalent interactions may modify the affinity between autologous major histocompatibility complex ( MHC), presented peptides and specifically primed T cell receptors ( TCRs) and thereby stimulate T cells. A special type of p-i-reaction has been recently described between the antiviral drug abacavir and the F pocket of HLA-B*57:01. This interaction causes an alteration of the MHC-presented self-peptide repertoire and may consecutively lead to a kind of auto-reactivity. Such types of reactions can explain the strong MHC- HLA associations which have been found for some T cell-mediated DHRs. [ABSTRACT FROM AUTHOR]

Mastocytosis is a clonal disorder characterized by the proliferation and accumulation of mast cells ( MC) in different tissues, with a preferential localization in skin and bone marrow ( BM). The excess of MC in mastocytosis as well as the increased releasability of MC may lead to a higher frequency and severity of immediate hypersensitivity reactions. Mastocytosis in adults is associated with a history of anaphylaxis in 22-49%. Fatal anaphylaxis has been described particularly following hymenoptera stings, but also occasionally after the intake of drugs such as nonsteroidal anti-inflammatory drugs, opioids and drugs in the perioperative setting. However, data on the frequency of drug hypersensitivity in mastocytosis and vice versa are scarce and evidence for an association appears to be limited. Nevertheless, clonal MC disorders should be ruled out in cases of severe anaphylaxis: basal serum tryptase determination, physical examination for cutaneous mastocytosis lesions, and clinical characteristics of anaphylactic reaction might be useful for differential diagnosis. In this position paper, the ENDA group performed a literature search on immediate drug hypersensitivity reactions in clonal MC disorders using MEDLINE, EMBASE, and Cochrane Library, reviewed and evaluated the literature in five languages using the GRADE system for quality of evidence and strength of recommendation. [ABSTRACT FROM AUTHOR]

When drug reactions resembling allergy occur, they are called drug hypersensitivity reactions ( DHRs) before showing the evidence of either drug-specific antibodies or T cells. DHRs may be allergic or nonallergic in nature, with drug allergies being immunologically mediated DHRs. These reactions are typically unpredictable. They can be life-threatening, may require or prolong hospitalization, and may necessitate changes in subsequent therapy. Both underdiagnosis (due to under-reporting) and overdiagnosis (due to an overuse of the term 'allergy') are common. A definitive diagnosis of such reactions is required in order to institute adequate treatment options and proper preventive measures. Misclassification based solely on the DHR history without further testing may affect treatment options, result in adverse consequences, and lead to the use of more-expensive or less-effective drugs, in contrast to patients who had undergone a complete drug allergy workup. Several guidelines and/or consensus documents on general or specific drug class-induced DHRs are available to support the medical decision process. The use of standardized systematic approaches for the diagnosis and management of DHRs carries the potential to improve outcomes and should thus be disseminated and implemented. Consequently, the International Collaboration in Asthma, Allergy and Immunology (i CAALL), formed by the European Academy of Allergy and Clinical Immunology ( EAACI), the American Academy of Allergy, Asthma and Immunology ( AAAAI), the American College of Allergy, Asthma and Immunology ( ACAAI), and the World Allergy Organization ( WAO), has decided to issue an International CONsensus (ICON) on drug allergy. The purpose of this document is to highlight the key messages that are common to many of the existing guidelines, while critically reviewing and commenting on any differences and deficiencies of evidence, thus providing a comprehensive reference document for the diagnosis and management of DHRs. [ABSTRACT FROM AUTHOR]

Hypersensitivity reactions to aspirin (acetylsalicylic acid) and other nonsteroidal anti-inflammatory drugs ( NSAIDs) constitute only a subset of all adverse reactions to these drugs, but due to their severity pose a significant burden to patients and are a challenge to the allergist. In susceptible individuals, NSAIDs induce a wide spectrum of hypersensitivity reactions with various timing, organ manifestations, and severity, involving either immunological (allergic) or nonimmunological mechanisms. Proper classification of reactions based on clinical manifestations and suspected mechanism is a prerequisite for the implementation of rational diagnostic procedures and adequate patient management. This document, prepared by a panel of experts from the European Academy of Allergy and Clinical Immunology Task Force on NSAIDs Hypersensitivity, aims at reviewing the current knowledge in the field and proposes uniform definitions and clinically useful classification of hypersensitivity reactions to NSAIDs. The document proposes also practical algorithms for the diagnosis of specific types of NSAIDs hypersensitivity (which include drug provocations, skin testing and in vitro testing) and provides, when data are available, evidence-based recommendations for the management of hypersensitive patients, including drug avoidance and drug desensitization. [ABSTRACT FROM AUTHOR]

Drug hypersensitivity may deprive patients of drug therapy, and occasionally no effective alternative treatment is available. Successful desensitization has been well documented in delayed drug hypersensitivity reactions. In certain situations, such as sulfonamide hypersensitivity in HIV-positive patients or hypersensitivity to antibiotics in patients with cystic fibrosis, published success rates reach 80%, and this procedure appears helpful for the patient management. A state of clinical tolerance may be achieved by the administration of increasing doses of the previously offending drug. However, in most cases, a pre-existent sensitization has not been proven by positive skin tests. Successful re-administration may have occurred in nonsensitized patients. A better understanding of the underlying mechanisms of desensitization is needed. Currently, desensitization in delayed hypersensitivity reactions is restricted to mild, uncomplicated exanthems and fixed drug eruptions. The published success rates vary depending on clinical manifestations, drugs, and applied protocols. Slower protocols tend to be more effective than rush protocols; however, underreporting of unsuccessful procedures is very probable. The decision to desensitize a patient must always be made on an individual basis, balancing risks and benefits. This paper reviews the literature and presents the expert experience of the Drug Hypersensitivity Interest Group of the European Academy of Allergy and Clinical Immunology. [ABSTRACT FROM AUTHOR]

Skin tests are of paramount importance for the evaluation of drug hypersensitivity reactions. Drug skin tests are often not carried out because of lack of concise information on specific test concentrations. The diagnosis of drug allergy is often based on history alone, which is an unreliable indicator of true hypersensitivity.To promote and standardize reproducible skin testing with safe and nonirritant drug concentrations in the clinical practice, the European Network and European Academy of Allergy and Clinical Immunology ( EAACI) Interest Group on Drug Allergy has performed a literature search on skin test drug concentration in MEDLINE and EMBASE, reviewed and evaluated the literature in five languages using the GRADE system for quality of evidence and strength of recommendation. Where the literature is poor, we have taken into consideration the collective experience of the group.We recommend drug concentration for skin testing aiming to achieve a specificity of at least 95%. It has been possible to recommend specific drug concentration for betalactam antibiotics, perioperative drugs, heparins, platinum salts and radiocontrast media. For many other drugs, there is insufficient evidence to recommend appropriate drug concentration. There is urgent need for multicentre studies designed to establish and validate drug skin test concentration using standard protocols. For most drugs, sensitivity of skin testing is higher in immediate hypersensitivity compared to nonimmediate hypersensitivity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Nonallergic hypersensitivity and allergic reactions are part of the many different types of adverse drug reactions (ADRs). Databases exist for the collection of ADRs. Spontaneous reporting makes up the core data-generating system of pharmacovigilance, but there is a large under-estimation of allergy/hypersensitivity drug reactions. A specific database is therefore required for drug allergy and hypersensitivity using standard operating procedures (SOPs), as the diagnosis of drug allergy/hypersensitivity is difficult and current pharmacovigilance algorithms are insufficient. Although difficult, the diagnosis of drug allergy/hypersensitivity has been standardized by the European Network for Drug Allergy (ENDA) under the aegis of the European Academy of Allergology and Clinical Immunology and SOPs have been published. Based on ENDA and Global Allergy and Asthma European Network (GA2LEN, EU Framework Programme 6) SOPs, a Drug Allergy and Hypersensitivity Database (DAHD®) has been established under FileMaker® Pro 9. It is already available online in many different languages and can be accessed using a personal login. GA2LEN is a European network of 27 partners (16 countries) and 59 collaborating centres (26 countries), which can coordinate and implement the DAHD across Europe. The GA2LEN–ENDA–DAHD platform interacting with a pharmacovigilance network appears to be of great interest for the reporting of allergy/hypersensitivity ADRs in conjunction with other pharmacovigilance instruments. [ABSTRACT FROM AUTHOR]

Nonimmediate manifestations (i.e. occurring more than 1 h after drug administration), particularly maculopapular and urticarial eruptions, are common duringβ-lactam treatment. The mechanisms involved in most nonimmediate reactions seem to be heterogeneous and are not yet completely understood. However, clinical and immunohistological studies, as well as analysis of drug-specific T-cell clones obtained from the circulating blood and the skin, suggest that a type-IV (cell-mediated) pathogenic mechanism may be involved in some nonimmediate reactions such as maculopapular or bullous rashes and acute generalized exanthematous pustulosis. In the diagnostic work-up, the patient's history is fundamental; patch testing is useful, together with delayed-reading intradermal testing. The latter appears to be somewhat more sensitive than patch testing, but also less specific. In case of negative allergologic tests, consideration should be given to provocation tests, and the careful administration of the suspect agents. With regard toin vitrotests, the lymphocyte transformation test may contribute to the identification of the responsible drug.Under the aegis of the European Academy of Allergology and Clinical Immunology (EAACI) interest group on drug hypersensitivity and the European Network for Drug Allergy (ENDA), in this review we describe the general guidelines for evaluating subjects with nonimmediate reactions toβ-lactams. [ABSTRACT FROM AUTHOR]

Discusses the general principles for skin test procedures in the diagnosis of drug hypersensitivity. Four types of skin test methods; Common clinical indications for skin testing; Time interval between drug hypersensitivity and skin testing; Pathomechanism of the drug hypersensitivity; Establishment of besk skin test concentrations; Testing of patients at higher risk.

Adverse drug reactions include drug hypersensitivity reactions (DHRs), which can be immunologically mediated (allergy) or non-immunologically mediated. The high number of DHRs that are unconfirmed and often 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. Primary care physicians are often the first point of contact for the sufferer of a reaction, as such they have a key role in deciding whether to discard the diagnosis or send the patient for further investigation. In this review, we highlight the importance of diagnosing DHRs, analysing in detail the role of primary care physicians. We describe the common patterns of DHRs and signs of its progression, as well as the indications and contraindications for referring the patient to an allergist. The diagnostic process is described and the possible tests are discussed, which often depend on the drug involved and the type of DHR suspected. We also describe recommendations regarding the avoidance of medication suspected to have caused the reaction and the use of alternatives. [ABSTRACT FROM AUTHOR]