Classification and practical approach to the diagnosis and management of hypersensitivity to nonsteroidal anti-inflammatory drugs
TL;DR: 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.
Abstract: 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.
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University of Utah1, University of Colorado Boulder2, Stanford University3, Oregon Health & Science University4, University of Chicago5, Rush University Medical Center6, University of Barcelona7, Harvard University8, Vanderbilt University9, University of Arizona10, University of Texas Health Science Center at Houston11, University of Pennsylvania12, Emory University13, Université de Montréal14, Samsung Medical Center15, University of Auckland16, University of Pittsburgh17, University of Amsterdam18, University of Ioannina19, University of California, San Francisco20, Eastern Virginia Medical School21, University of New South Wales22, Katholieke Universiteit Leuven23, Guy's and St Thomas' NHS Foundation Trust24, University of Lorraine25, University of British Columbia26, Northwestern University27, Georgia Regents University28, Johns Hopkins University29, New York University30, Korea University31, University of Texas at Austin32, Uniformed Services University of the Health Sciences33, Jikei University School of Medicine34, University of Washington35, University of Siena36, Medical College of Wisconsin37, University of Adelaide38, West Virginia University39, Innsbruck Medical University40, Pusan National University41, University of Calgary42, Medical University of South Carolina43, University of North Carolina at Chapel Hill44, Cleveland Clinic45, Loyola University Chicago46, Cornell University47, Temple University48, University of São Paulo49, National University of Singapore50, San Antonio Military Medical Center51, University of Alabama at Birmingham52, University of Alberta53, Capital Medical University54
TL;DR: This dissertation aims to provide a history of Chinese medical practice in the United States from 1989 to 2002, a period chosen in order to explore its roots as well as specific cases up to and including the year in which descriptions of “modern China” began to circulate.
Abstract: Background The body of knowledge regarding rhinosinusitis(RS) continues to expand, with rapid growth in number of publications, yet substantial variability in the quality of those presentations. In an effort to both consolidate and critically appraise this information, rhinologic experts from around the world have produced the International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR:RS). Methods Evidence-based reviews with recommendations(EBRRs) were developed for scores of topics, using previously reported methodology. Where existing evidence was insufficient for an EBRR, an evidence-based review (EBR)was produced. The sections were then synthesized and the entire manuscript was then reviewed by all authors for consensus. Results The resulting ICAR:RS document addresses multiple topics in RS, including acute RS (ARS), chronic RS (CRS)with and without nasal polyps (CRSwNP and CRSsNP), recurrent acute RS (RARS), acute exacerbation of CRS (AECRS), and pediatric RS. Conclusion As a critical review of the RS literature, ICAR:RS provides a thorough review of pathophysiology and evidence-based recommendations for medical and surgical treatment. It also demonstrates the significant gaps in our understanding of the pathophysiology and optimal management of RS. Too often the foundation upon which these recommendations are based is comprised of lower level evidence. It is our hope that this summary of the evidence in RS will point out where additional research efforts may be directed.
645 citations
University Hospital Southampton NHS Foundation Trust1, Boston Children's Hospital2, University of Lisbon3, University Hospital of South Manchester NHS Foundation Trust4, Odense University Hospital5, Catholic University of Leuven6, National and Kapodistrian University of Athens7, Royal Free Hospital8, University of Turku9
TL;DR: Oral and intranasal antihistamines and nasal corticosteroids are both appropriate for first‐line AR treatment although the latter are more effective, and potentially useful add‐on therapies for AR include oral leukotriene receptor antagonists, short bursts of a nasal decongestant, saline douches and nasal anticholinergics.
Abstract: Rhinitis is a common problem in childhood and adolescence and impacts negatively on physical, social and psychological well-being. This position paper, prepared by the European Academy of Allergy and Clinical Immunology Taskforce on Rhinitis in Children, aims to provide evidence-based recommendations for the diagnosis and therapy of paediatric rhinitis. Rhinitis is characterized by at least two nasal symptoms: rhinorrhoea, blockage, sneezing or itching. It is classified as allergic rhinitis, infectious rhinitis and nonallergic, noninfectious rhinitis. Similar symptoms may occur with other conditions such as adenoidal hypertrophy, septal deviation and nasal polyps. Examination by anterior rhinoscopy and allergy tests may help to substantiate a diagnosis of allergic rhinitis. Avoidance of relevant allergens may be helpful for allergic rhinitis (AR). Oral and intranasal antihistamines and nasal corticosteroids are both appropriate for first-line AR treatment although the latter are more effective. Once-daily forms of corticosteroids are preferred given their improved safety profile. Potentially useful add-on therapies for AR include oral leukotriene receptor antagonists, short bursts of a nasal decongestant, saline douches and nasal anticholinergics. Allergen-specific immunotherapy is helpful in IgE-mediated AR and may prevent the progression of allergic disease. There are still a number of areas that need to be clarified in the management of rhinitis in children and adolescents.
320 citations
University of Manchester1, Royal College of Anaesthetists2, University of Bristol3, Royal United Hospital4, University of Oxford5, Aberdeen Royal Infirmary6, University of Sheffield7, Royal College of Pathologists8, Imperial College London9, Great Ormond Street Hospital10, Northwick Park Hospital11, Cambridge University Hospitals NHS Foundation Trust12, Imperial College Healthcare13, Leeds Teaching Hospitals NHS Trust14, University of Leeds15, Medicines and Healthcare Products Regulatory Agency16
TL;DR: The overall incidence of perioperative anaphylaxis was estimated to be 1 in 10 000 anaesthetics, and poor outcomes were associated with increased ASA, obesity, beta blocker, and angiotensin‐converting enzyme inhibitor medication.
Abstract: Background Anaphylaxis during anaesthesia is a serious complication for patients and anaesthetists. Methods The 6th National Audit Project (NAP6) on perioperative anaphylaxis collected and reviewed 266 reports of Grades 3–5 anaphylaxis over 1 yr from all NHS hospitals in the UK. Results The estimated incidence was ≈1:10 000 anaesthetics. Case exclusion because of reporting delays or incomplete data means true incidence might be ≈70% higher. The distribution of 199 identified culprit agents included antibiotics (94), neuromuscular blocking agents (65), chlorhexidine (18), and Patent Blue dye (9). Teicoplanin comprised 12% of antibiotic exposures, but caused 38% of antibiotic-induced anaphylaxis. Eighteen patients reacted to an antibiotic test dose. Succinylcholine-induced anaphylaxis, mainly presenting with bronchospasm, was two-fold more likely than other neuromuscular blocking agents. Atracurium-induced anaphylaxis mainly presented with hypotension. Non-depolarising neuromuscular blocking agents had similar incidences to each other. There were no reports of local anaesthetic or latex-induced anaphylaxis. The commonest presenting features were hypotension (46%), bronchospasm (18%), tachycardia (9.8%), oxygen desaturation (4.7%), bradycardia (3%), and reduced/absent capnography trace (2.3%). All patients were hypotensive during the episode. Onset was rapid for neuromuscular blocking agents and antibiotics, but delayed with chlorhexidine and Patent Blue dye. There were 10 deaths and 40 cardiac arrests. Pulseless electrical activity was the usual type of cardiac arrest, often with bradycardia. Poor outcomes were associated with increased ASA, obesity, beta blocker, and angiotensin-converting enzyme inhibitor medication. Seventy per cent of cases were reported to the hospital incident reporting system, and only 24% to Medicines and Healthcare products Regulatory Agency via the Yellow Card Scheme. Conclusions The overall incidence of perioperative anaphylaxis was estimated to be 1 in 10 000 anaesthetics.
247 citations
TL;DR: Recommendations for the most effective management of a patient with N‐ERD stressing the potential high morbidity and severity of the underlying asthma and rhinosinusitis are discussed and proposed.
Abstract: NSAID-exacerbated respiratory disease (N-ERD) is a chronic eosinophilic, inflammatory disorder of the respiratory tract occurring in patients with asthma and/or chronic rhinosinusitis with nasal polyps (CRSwNP), symptoms of which are exacerbated by NSAIDs, including aspirin. Despite some progress in understanding of the pathophysiology of the syndrome, which affects 1/10 of patients with asthma and rhinosinusitis, it remains a diagnostic and therapeutic challenge. In order to provide evidence-based recommendations for the diagnosis and management of N-ERD, a panel of international experts was called by the EAACI Asthma Section. The document summarizes current knowledge on the pathophysiology and clinical presentation of N-ERD pointing at significant heterogeneity of this syndrome. Critically evaluating the usefulness of diagnostic tools available, the paper offers practical algorithm for the diagnosis of N-ERD. Recommendations for the most effective management of a patient with N-ERD stressing the potential high morbidity and severity of the underlying asthma and rhinosinusitis are discussed and proposed. Newly described sub-phenotypes and emerging sub-endotypes of N-ERD are potentially relevant for new and more specific (eg, biological) treatment modalities. Finally, the document defines major gaps in our knowledge on N-ERD and unmet needs, which should be addressed in the future.
216 citations
TL;DR: A task force to provide data and recommendations regarding the available in vitro methods for DHR diagnosis has found that although there are many in vitro tests, few can be given a recommendation of grade B or above mainly because of a lack of well‐controlled studies.
Abstract: 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.
207 citations
Cites background from "Classification and practical approa..."
...Proliferation of drug-specific T cells from patients with DHR upon the stimulation with the suspected drug(s) is measured by the incorporation of [3H] or carboxyfluorescein diacetate succinimidyl ester (CFSE) content using flow cytometry....
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...However, expert consensus has not been reached on the value of in vitro methods for DHR diagnosis....
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...Diagnosis of DHRs is primarily based on a detailed clinical history and in vivo procedures, such as skin testing (ST) and drug provocation tests (DPT)....
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...• For carbamazepine-induced DHR, the most powerful association has been established with HLA-B*15:02 and SJS/TEN in Han Chinese (119), Thai (120), Indian (121) and Malaysian (122) populations....
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...This means that in a large number of cases, DPT is the only test that can confirm the reaction (4, 9)....
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TL;DR: The burden ofADRs on the NHS is high, accounting for considerable morbidity, mortality, and extra costs, and measures need to be put into place to reduce the burden of ADRs and thereby further improve the benefit:harm ratio of the drugs.
Abstract: Objective To ascertain the current burden of adverse drug reactions (ADRs) through a prospective analysis of all admissions to hospital. Design Prospective observational study. Setting Two large general hospitals in Merseyside, England. Participants 18 820 patients aged > 16 years admitted over six months and assessed for cause of admission. Main outcome measures Prevalence of admissions due to an ADR, length of stay, avoidability, and outcome. Results There were 1225 admissions related to an ADR, giving a prevalence of 6.5%, with the ADR directly leading to the admission in 80% of cases. The median bed stay was eight days, accounting for 4% of the hospital bed capacity. The projected annual cost of such admissions to the NHS is £466m (€706m, $847m). The overall fatality was 0.15%. Most reactions were either definitely or possibly avoidable. Drugs most commonly implicated in causing these admissions included low dose aspirin, diuretics, warfarin, and non-steroidal anti-inflammatory drugs other than aspirin, the most common reaction being gastrointestinal bleeding. Conclusion The burden of ADRs on the NHS is high, accounting for considerable morbidity, mortality, and extra costs. Although many of the implicated drugs have proved benefit, measures need to be put into place to reduce the burden of ADRs and thereby further improve the benefit:harm ratio of the drugs.
2,954 citations
TL;DR: A revised system of determining levels of evidence and grades for guideline recommendations is published, based on the work of the US Agency for Healthcare Research and Quality and its applicability to the target population of the guideline.
Abstract: The Scottish Intercollegiate Guidelines Network (SIGN) develops evidence based clinical guidelines for the NHS in Scotland. The key elements of the methodology are (a) that guidelines are developed by multidisciplinary groups; (b) they are based on a systematic review of the scientific evidence; and (c) recommendations are explicitly linked to the supporting evidence and graded according to the strength of that evidence.
Until recently, the system for grading guideline recommendations was based on the work of the US Agency for Healthcare Research and Quality (formerly the Agency for Health Care Policy and Research). 1 2 However, experience over more than five years of guideline development led to a growing awareness of this system's weaknesses. Firstly, the grading system was designed largely for application to questions of effectiveness, where randomised controlled trials are accepted as the most robust study design with the least risk of bias in the results. However, in many areas of medical practice randomised trials may not be practical or ethical to undertake; and for many questions other types of study design may provide the best evidence. Secondly, guideline development groups often fail to take adequate account of the methodological quality of individual studies and the overall picture presented by a body of evidence rather than individual studies or they fail to apply sufficient judgment to the overall strength of the evidence base and its applicability to the target population of the guideline. Thirdly, guideline users are often not clear about the implications of the grading system. They misinterpret the grade of recommendation as relating to its importance, rather than to the strength of the supporting evidence, and may therefore fail to give due weight to low grade recommendations.
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A revised system of determining levels of evidence and grades …
1,500 citations
"Classification and practical approa..." refers background in this paper
...Grades of recommendations are defined according to the SIGN statement (2)....
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788 citations
"Classification and practical approa..." refers background in this paper
...Clinical presentation • Bronchial obstruction induced by aspirin/NSAIDs develops within 30–180 min after ingestion of the drug and may be accompanied by extrabronchial symptoms including nasal (rhinorrhea, nasal congestion), ocular, cutaneous (flushing of the upper thorax, urticaria and/or angioedema), or gastric symptoms (19)....
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TL;DR: A drug provocation test (DPT) is the controlled administration of a drug in order to diagnose drug hypersensitivity reactions under medical surveillance, whether this drug is an alternative compound, or structurally/pharmacologically related, or the suspected drug itself.
Abstract: A drug provocation test (DPT) is the controlled administration of a drug in order to diagnose drug hypersensitivity reactions. DPTs are performed under medical surveillance, whether this drug is an alternative compound, or structurally/pharmacologically related, or the suspected drug itself. DPT is sometimes termed controlled challenge or reexposure (1), drug challenge (2), graded (2) or incremental challenge (3), test dosing (2), W. Aberer, A. Bircher, A. Romano, M. Blanca, P. Campi, J. Fernandez, K. Brockow, W. J. Pichler, P. Demoly for ENDA, and the EAACI interest group on drug hypersensitivity Department of Environmental Dermatology, University of Graz, Graz, Austria; Department of Dermatology, Basle, Switzerland; Allergy Service, Catholic University of Rome, Italy; Allergy Service, University La Paz, Madrid, Spain; Clinic for Allergy and Immunology, Florence, Italy; Allergy Section, Dept. Clin. Med., UMH, Elche, Spain; Klinik und Poliklinik f1r Dermatologie und Allergologie, Muenchen, Germany; Clinic for Rheumatology and Clinical Immunology/Allergology, Inselspital, Bern, Switzerland; Maladies Respiratoires-INSERM U454, H7pital Arnaud de Villeneuve, Montpellier, France
757 citations
"Classification and practical approa..." refers background in this paper
...• There is no standardized protocol for drug provocation tests in delayed reactions to NSAIDs (86)....
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TL;DR: This review presents newer concepts of the role of T cells in drug hypersensitivity, which evolved from the study of drug-specific T Cells in various drug-induced hypersensitivity diseases.
Abstract: Immune reactions to small molecular compounds, such as drugs, can cause a variety of diseases involving the skin, liver, kidney, and lungs. In many drug hypersensitivity reactions, drug-specific CD4+ and CD8+ T cells recognize drugs through their alphabeta T-cell receptors in an MHC-dependent way. Drugs stimulate T cells if they act as haptens and bind covalently to peptides or if they have structural features that allow them to interact with certain T-cell receptors directly. Immunohistochemical and functional studies of drug-reactive T cells in patients with distinct forms of exanthema reveal that distinct T-cell functions lead to different clinical phenotypes. In maculopapular exanthema, perforin-positive and granzyme B-positive CD4+ T cells kill activated keratinocytes, while a large number of cytotoxic CD8+ T cells in the epidermis is associated with formation of vesicles and bullae. Drug-specific T cells also orchestrate inflammatory skin reactions through the release of various cytokines (for example, interleukin-5, interferon) and chemokines (such as interleukin-8). Activation of T cells with a particular function seems to lead to a specific clinical picture (for example, bullous or pustular exanthema). Taken together, these data allow delayed hypersensitivity reactions (type IV) to be further subclassified into T-cell reactions, which through the release of certain cytokines and chemokines preferentially activate and recruit monocytes (type IVa), eosinophils (type IVb), or neutrophils (type IVd). Moreover, cytotoxic functions by either CD4+ or CD8+ T cells (type IVc) seem to participate in all type IV reactions.
693 citations
"Classification and practical approa..." refers background in this paper
...• T-cell-dependent mechanisms have been documented in delayed urticaria, MPE induced by aceclofenac and metamizol and in SCAR induced by ibuprofen (80, 81)....
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