Epidemiology, Mechanisms, and Diagnosis of Drug-Induced Anaphylaxis (original) (raw)
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Anaphylaxis: Clinical patterns, mediator release, and severity
Journal of Allergy and Clinical Immunology, 2013
Background: Prospective human studies of anaphylaxis and its mechanisms have been limited, with few severe cases or examining only 1 or 2 mediators. Objectives: We wanted to define the clinical patterns of anaphylaxis and relationships between mediators and severity. Methods: Data were collected during treatment and before discharge. Serial blood samples were taken for assays of mast cell tryptase, histamine, anaphylatoxins (C3a, C4a, C5a), cytokines (IL-2, IL-6, IL-10), soluble tumor necrosis factor receptor I, and platelet activating factor acetyl hydrolase. Principal component analysis defined mediator patterns, and logistic regression identified risk factors and mediator patterns associated with reaction severity and delayed reactions. Results: Of 412 reactions in 402 people, 315 met the definition for anaphylaxis by the National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network. Of 97 severe reactions 45 (46%) were hypotensive, 23 (24%) were hypoxemic, and 29 (30%) were mixed. One patient died. Severe reactions were associated with older age, pre-existing lung disease, and drug causation. Delayed deteriorations treated with epinephrine occurred in 29 of 315 anaphylaxis cases (9.2%) and were more common after hypotensive reactions and with preexisting lung disease. Twenty-two of the 29 delayed deteriorations (76%) occurred within 4 hours of initial epinephrine treatment. Of the remaining 7 cases, 2 were severe and occurred after initially severe reactions, within 10 hours. All mediators were associated with severity, and 1 group (mast cell tryptase, histamine, IL-6, IL-10, and tumor necrosis factor receptor I) was also associated with delayed deteriorations. Low platelet activating factor acetyl hydrolase activity was associated with severe reactions. Conclusion: The results suggest that multiple inflammatory pathways drive reaction severity and support recommendations for safe observation periods after initial treatment. (J Allergy Clin Immunol 2013;nnn:nnn-nnn.)
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.
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
A population based case-cohort study of drug-induced anaphylaxis
British Journal of Clinical Pharmacology, 1993
In order to determine the risk of anaphylaxis as an adverse reaction to drugs, a casecohort study was performed. Cases consisted of all admissions in 1987 and 1988 to all Dutch hospitals with anaphylaxis as the principal diagnosis, and a random sample of admissions with related symptoms. Hospital discharge summaries were classified according to probability of anaphylaxis by a blinded Audit Committee. Of admissions classified as probable or possible anaphylaxis, the causative agent was assessed. The reference cohort consisted of all persons in the catchment area of a sample of pharmacies in The Netherlands, in the period between January 1, 1987 and December 31, 1988. 2 Out of 934 admissions, discharge summaries on 811 admissions were received, of which 727 contained enough clinical details. Out of 727, 391 were classified as probable or possible anaphylaxis. In 336 of these 391, anaphylaxis was reason for admission. This group consisted of 158 men and 178 women. Drug-induced anaphylaxis occurred in 107 patients. 3 Drug-induced anaphylaxis was most frequently caused by penicillins, analgesics and non-steroidal antiinflammatory drugs (NSAID) with the highest point estimate of the risk relative to all other drugs of 10.7, 6.9 and 3.7 respectively. 4 In the cases of probable anaphylaxis, the risk of anaphylaxis to glafenine relative to all other drugs was 167.7 in 1987 (95%-CI: 63.0-446.4) and 128.6 in 1988 (95%-CI: 50.4-328.5), to amoxycillin 15.2 in 1987 (95%-CI: 5.0-46.0) and 4.4 in 1988 (95%-CI: 1.03-18.9) and to diclofenac 6.1 in 1988 (95%-Cl: 1.4-26.1). 5 The case-cohort design may be useful for postmarketing surveillance.
About the role and underlying mechanisms of cofactors in anaphylaxis
Allergy, 2013
Anaphylaxis is the systemic and most severe presentation of type I allergy. A number of conditions were identified that modulate the onset of anaphylaxis such as co-or augmentation factors, which significantly lower the allergen dose necessary for triggering anaphylaxis. Next to physical exercise or alcohol consumption, co-administration of nonsteroidal anti-inflammatory drugs (NSAID) or concomitant infectious diseases are well-documented cofactors of anaphylaxis. Registries for anaphylaxis document a role for cofactors in about 30% of anaphylactic reactions. Some disease entities such as 'wheat-dependent exercise-induced anaphylaxis' (WDEIA) are explicitly characterized by elicitation of anaphylaxis only in the presence of at least one such cofactor. Using WDEIA as a model disease, studies demonstrated that exercise increases skin prick test reactivity to and bioavailability of the allergen. Additional data indicate that alcohol consumption and NSAID administration display similar effects. Modulation of the cellular activation threshold is another mechanism underlying cofactor-induced anaphylaxis, most likely also functional when infectious diseases orchestrate elicitation of anaphylaxis. Cofactors are increasingly accepted to play a fundamental role in eliciting anaphylaxis. Consequently, to improve patient management modalities, a better understanding of the underlying mechanisms is warranted. This review aims to update clinicians and clinical scientists on recent developments. Classically, the allergen-induced cross-linking of IgE antibodies bound to high-affinity Fce receptors on mast cells initiates signal transduction and the release of preformed mediators like histamine, which elicit the clinical symptoms of type I allergic reactions. The most severe presentation of type I allergy is called 'anaphylaxis', defined as a generalized immediate-type hypersensitivity reaction. Anaphylaxis is clinically characterized by involvement of more than one organ system, in particular the skin, the gastrointestinal tract, the respiratory, and the cardiovascular system. The symptoms comprise relatively mild urticaria or diarrhea but also possibly lifethreatening anaphylactic shock (1). Available epidemiological data regarding anaphylaxis are widely varying, most likely due to incoherent definitions of anaphylaxis and a lack of reporting. Published studies estimate a lifetime prevalence between 0.05% and 2% and an incidence of 3.2-68.4 per 100 000 patient-years (2, 3). Although anaphylaxis seems to be triggered by sole allergen contact in most cases, the role of additional factors, also referred to as co-or augmentation factors, for the elicitation of anaphylaxis is increasingly accepted. For the first time, cofactor-dependent anaphylaxis was described in 1979 by Maulitz et al. (4) who described a patient with 'exercise-induced anaphylaxis to shellfish'. Meanwhile, physical exercise is the best studied cofactor of anaphylaxis and 'food-dependent exercise-induced anaphylaxis' (FDEIA) is accepted as a defined clinical entity. Other well-documented cofactors of anaphylaxis are nonsteroidal anti-inflammatory drugs (NSAID) like acetylsalicylic acid (ASA), alcohol consumption, and infectious diseases in general (5-12). According to the anaphylaxis registries of different European countries, next to exercise, alcohol consumption is a relevant cofactor in up to 15.2% of anaphylactic events and drugs such as ASA were registered as a cofactor in 6.1-9% of severe anaphylactic reactions (Table 1). The role of infections as cofactors of anaphylaxis is reported to be relevant in 2.5-3% of anaphylactic reactions in children and in 1.3-11% in adults (8, 13-18). Infections are particularly dangerous for patients
Drug-induced anaphylaxis: a decade review of reporting to the Portuguese Pharmacovigilance Authority
European Journal of Clinical Pharmacology, 2013
Purpose Anaphylaxis is a potentially fatal systemic adverse drug reaction (ADR). It is an unpredictable and mostly doseindependent event that occurs suddenly following exposure to the causative drug. Our objective was to characterize a case series of anaphylactic reactions reported to the Portuguese Pharmacovigilance authority during the past decade. Patients' demographic data and implicated drugs were analyzed as well as the severity of the ADR and time trends. Methods This study was a retrospective analysis of episodes of anaphylaxis, defined according to the Second Symposium on the Definition and Management of Anaphylaxis Criteria, reported to the Portuguese Pharmacovigilance System between 1 January 2000 and 1 November 2010 Results Amongst the 16,157 ADR reported to the Portuguese Pharmacovigilance System during the 10-year study period, we found 918 (6 %) cases of anaphylaxis that met the proposed criteria. The age of the patients varied from 7 days to 91 years, with 87 cases (9 %) of anaphylaxis involving patients under 18 years of age. There was an overall female predominance (67 %), but the majority of pediatric patients were male (56 %). There was a trend toward increased reporting as the decade progressed, and 31 % (284) of all anaphylaxis cases were reported during the last 2 years of the study period. Of the anaphylaxis episodes reported, 19 % led to hospitalization and 24 (3 %) had a fatal outcome. Antibiotics were responsible for most cases (17 %) followed by nonsteroidal anti-inflammatory drugs/acetaminophen (13 %), antineoplastic/cytotoxic drugs and immune-modulators. Vaccines and radiographic contrast media were also important contributors to an anaphylactic event.
Causes and risk factors for anaphylaxis
Journal der Deutschen Dermatologischen Gesellschaft, 2012
Anaphylaxis is in most cases an IgE-dependent immunologic reaction. Mast cells are activated and release several mediators. Recent data about possible triggers of anaphylaxis indicate a clear age-dependency. The most frequent triggers of anaphylaxis in children are foods; in adults venom and drugs predominate. In 2006 an anaphylaxis registry was established in German-speaking countries. In the registry the triggers, circumstances, and treatment measures are collected from patients with anaphylaxis. However, the registry cannot supply epidemiological data like prevalence or incidence rates since the registration of cases is based on collaboration with allergy centers only. Similarly, other approaches to obtain data on the epidemiology of anaphylaxis are problematic given that allergic reactions of varying severity are covered by a number of codes in the ICD-10. Research in the field of anaphylaxis is focused on the identification of risk factors. Several data indicate the relevance of co-factors and augmentation factors in welldefined patient groups. Among these factors physical activity, infection, alcohol and additives are relevant. In the future a unique coding system with a subtype analysis regarding the triggers and severity should help to provide data on the epidemiology of anaphylaxis. Furthermore the mechanisms of co-factors and identification of biomarkers for risk assessment are important research areas for the future.