Abstracts from the 8th Drug Hypersensitivity Meeting (DHM) (original) (raw)
Related papers
Epidemiology, Mechanisms, and Diagnosis of Drug-Induced Anaphylaxis
Frontiers in immunology, 2017
Anaphylaxis is an acute, life-threatening, multisystem syndrome resulting from the sudden release of mediators by mast cells and basophils. Although anaphylaxis is often under-communicated and thus underestimated, its incidence appears to have risen over recent decades. Drugs are among the most common triggers in adults, being analgesics and antibiotics the most common causal agents. Anaphylaxis can be caused by immunologic or non-immunologic mechanisms. Immunologic anaphylaxis can be mediated by IgE-dependent or -independent pathways. The former involves activation of Th2 cells and the cross-linking of two or more specific IgE (sIgE) antibodies on the surface of mast cells or basophils. The IgE-independent mechanism can be mediated by IgG, involving the release of platelet-activating factor, and/or complement activation. Non-immunological anaphylaxis can occur through the direct stimulation of mast cell degranulation by some drugs, inducing histamine release and leading to anaphyla...
Mouse and human neutrophils induce anaphylaxis
Journal of Clinical Investigation, 2011
Anaphylaxis is a life-threatening hyperacute immediate hypersensitivity reaction. Classically, it depends on IgE, FcεRI, mast cells, and histamine. However, anaphylaxis can also be induced by IgG antibodies, and an IgG1-induced passive type of systemic anaphylaxis has been reported to depend on basophils. In addition, it was found that neither mast cells nor basophils were required in mouse models of active systemic anaphylaxis. Therefore, we investigated what antibodies, receptors, and cells are involved in active systemic anaphylaxis in mice. We found that IgG antibodies, FcγRIIIA and FcγRIV, platelet-activating factor, neutrophils, and, to a lesser extent, basophils were involved. Neutrophil activation could be monitored in vivo during anaphylaxis. Neutrophil depletion inhibited active, and also passive, systemic anaphylaxis. Importantly, mouse and human neutrophils each restored anaphylaxis in anaphylaxis-resistant mice, demonstrating that neutrophils are sufficient to induce anaphylaxis in mice and suggesting that neutrophils can contribute to anaphylaxis in humans. Our results therefore reveal an unexpected role for IgG, IgG receptors, and neutrophils in anaphylaxis in mice. These molecules and cells could be potential new targets for the development of anaphylaxis therapeutics if the same mechanism is responsible for anaphylaxis in humans.
Drug Safety, 2005
Abstract with different classes of drugs and compare it with other reports contained in the same database. Methods: The data were obtained from a database containing all of the spontaneous reports of adverse drug reactions (ADRs) coming from the Italian regions of Emilia Romagna, Lombardy and the Veneto, which are the main contributors to the Italian spontaneous surveillance system. The ADRs reported between January 1990 and December 2003 with a causality assessment of certainly, probably or possibly drug related (according to the WHO criteria) were analysed using a case/ non-case design. The cases were defined as the reactions already coded by the WHO preferred terms of 'anaphylactic shock' or 'anaphylactoid reaction' (this last term also included anaphylactic reaction) and those with a time of event onset that suggested an allergic reaction and involved at least two of the skin, respiratory, gastrointestinal, CNS or cardiovascular systems; the non-cases were all of the other ADR reports. The frequency of the association between anaphylaxis and the suspected drug in comparison with the frequency of anaphylaxis associated to all of the other drugs was calculated using the ADR reporting odds ratio (ROR) as a measure of disproportionality. Results: Our database contained 744 cases (including 307 cases of anaphylactic shock with 10 deaths) and 27 512 non-cases. The percentage of anaphylaxis cases reported in inpatients was higher than that among outpatients (59.1% vs 40.9%). This distribution is significantly different from that of the other ADR reports that mainly refer to outpatients. After intravenous drug administrations, anaphylactic shock cases were more frequent than anaphylactoid reactions or other ADRs, but more than one-third of these reactions were caused by an oral drug. Blood substitutes and radiology contrast agents had the highest RORs. Among the systemic antibacterial agents, anaphylaxis was disproportionally reported more often for penicillins, quinolones, cephalosporins and glycopeptides, but diclofenac was the only NSAID with a significant ROR. As a category, vaccines
Immune Pathomechanism and Classification of Drug Hypersensitivity
Allergy
Drug hypersensitivity reactions (DHR) are based on distinct mechanisms and are clinically heterogeneous. Taking into account that also off target activities of drugs may lead to stimulations of immune or inflammatory cells, three forms of DHR were discriminated: The allergic-immune mechanism relies on the covalent binding of drugs/chemicals to proteins, which thereby form new antigens, to which a humoral and/or cellular immune response can develop. In IgE mediated drug allergies a possible tolerance mechanism to the drug during sensitization and the need of a covalent hapten-carrier link for initiation, but not for elicitation of IgE-mediated reactions are discussed. The p-i ("pharmacological interaction with immune Accepted Article This article is protected by copyright. All rights reserved. receptor") concept represents an off target activity of drugs with immune receptors (HLA or TCR), which can result in unorthodox, allo-immune like stimulations of T cells. Some of these p-i stimulations occur only in carriers of certain HLA-alleles and can result in clinically severe reactions. The third form of DHR ("pseudo-allergy") is represented by drug interactions with receptors or enzymes of inflammatory cells, which may lead to their direct activation or enhanced levels of inflammatory products. Specific IgE or T-cells are not involved. This classification is based on the action of drugs and is clinically useful, as it can explain differences in sensitizations, unusual clinical symptoms, dependence on drug concentrations, predictability and immunological and pharmacological cross-reactivities in DHR.
Trends in hypersensitivity drug reactions: more drugs, more response patterns, more heterogeneity
Journal of investigational allergology & clinical immunology, 2014
Hypersensitivity drug reactions (HDRs) vary over time in frequency, drugs involved, and clinical entities. Specific reactions are mediated by IgE, other antibody isotypes (IgG or IgM), and T cells. Nonspecific HDRs include those caused by nonsteroidal anti-inflammatory drugs (NSAIDs). beta-Lactams--the most important of which are amoxicillin and clavulanic acid--are involved in specific immunological mechanisms. Fluoroquinolones (mainly moxifloxacin, followed by ciprofloxacin and levofloxacin) can also induce HDRs mediated by IgE and T cells. In the case of radio contrast media, immediate reactions have decreased, while nonimmediate reactions, mediated by T cells, have increased. There has been a substantial rise in hypersensitivity reactions to antibiotics and latex in perioperative allergic reactions to anesthetics. NSAIDs are the most frequent drugs involved in HDRs. Five well-defined clinical entities, the most common of which is NSAID-induced urticaria/angioedema, have been pro...
Journal of Allergy and Clinical Immunology, 2002
Immune-mediated drug hypersensitivity reactions (IDHR) have a significant impact on clinical practice, drug development, and public health. However, research to understand IDHR mechanisms and to develop diagnostic and predictive tests has been limited. To stimulate more research, a task force with representatives from the key stakeholders (research clinicians, regulatory scientists, and immunotoxicologists from the pharmaceutical industry) was assembled to identify critical data gaps and opportunities and to make recommendations on how to overcome some of the barriers to IDHR research and address research needs. It is hoped that this report will act as a springboard for future discussions and progress toward increased funding and development of organizational structures for IDHR research. (J Allergy Clin Immunol 2002;109:S461-78.)
Anaphylaxis to drugs: overcoming mast cell unresponsiveness by fake antigens
2020
Our understanding of IgE-mediated drug allergy relies on the hapten concept, which is well established in inducing adaptive reactions of the immune system to small molecules like drugs. The role of hapten-carrier adducts in re-challenge reactions leading to mast cell degranulation and anaphylaxis is unclear. Based on clinical observations, the speed of adduct formation, skin and in vitro tests to inert drug molecules, a different explanation of IgE-mediated reactions to drugs is proposed: These are (a) A natural role of reduced mast cell (MC) reactivity in developing IgE-mediated reactions to drugs. This MC unresponsiveness is antigen-specific and covers the serum drug concentrations, but allows reactivity to locally higher concentrations. (b) Some noncovalent drug-protein complexes rely on rather affine bindings and have a similar appearance as covalent hapten-protein adducts. Such drug-protein complexes represent so-called "fake antigens," as they are unable to induce immunity, but may react with and cross-link preformed drug-specific IgE. As they are formed very rapidly and in high concentrations, they may cause fulminant MC degranulation and anaphylaxis. (c) The generation of covalent hapten-protein adducts requires hours, either because the formation of covalent bonds requires time or because first a metabolic step for forming a reactive metabolite is required. This slow process of stable adduct formation has the advantage that it may give time to desensitize mast cells, even in already sensitized individuals. The consequences of this new interpretation of IgE-mediated reactions to drugs are potentially wide-reaching for IgE-mediated drug allergy but also allergy in general.
Frontiers in Immunology
Drug allergy is a rising problem in the twenty-first century which affects all populations and races, children, and adults, and for which the recognition, diagnosis, management, and treatment is still not well standardized. Classical and new chemotherapy drugs, monoclonal antibodies (MoAbs), and small molecules to treat cancer and chronic inflammatory diseases are aimed at improving quality of life and life expectancy of patients, but an increasing number of reactions including anaphylaxis precludes their use in targeted populations. Women are more affected by drug allergy and up to 27% of women with ovarian and breast cancer develop carboplatin allergy after multiple cycles of treatment. Carriers of BRCA genes develop drug allergy after fewer exposures and can present with severe reactions, including anaphylaxis. Atopic patients are at increased risk for chemotherapy and MoAbs drug allergy and the current patterns of treatment with recurrent and intermittent drug exposures may favor the development of drug allergies. To overcome drug allergy, desensitization has been developed, a novel approach which provides a unique opportunity to protect against anaphylaxis and to improve clinical outcomes. There is evidence that inhibitory mechanisms blocking IgE/antigen mast cell activation are active during desensitization, enhancing safety. Whether desensitization modulates drug allergic and anaphylactic responses facilitating tolerance is currently being investigated. This review provides insight into the current knowledge of drug allergy and anaphylaxis to cancer and chronic inflammatory diseases drugs, the mechanisms of drug desensitization and its applications to personalized medicine.