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Controversies in drug allergy: In vitro testing

2018; Elsevier BV; Volume: 143; Issue: 1 Linguagem: Inglês

10.1016/j.jaci.2018.09.022

1097-6825

Cristobalina Mayorga, Didier G. Ebo, David M. Lang, Werner J. Pichler, Vito Sabato, Miguel A. Park, Joanna Makowska, Marina Atanasković‐Marković, Patrizia Bonadonna, Edgardo Járes,

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Despite their low frequency, drug hypersensitivity reactions (DHRs) can be serious and result in lifelong sequelae. The diagnosis is critical to avert future reactions and should identify the culprit drug or drugs and safe alternatives. However, making the diagnosis can be complex and challenging. Reliable in vitro tests can offer the potential to improve a diagnosis of DHR and influence medical decision making. Importantly, in vitro testing is frequently not performed as a test in isolation but rather as a component of a diagnostic algorithm along with additional tests. There are several in vitro approaches for the different endotypes of DHRs. However, only few are available for routine diagnosis, and many are restricted to research laboratories. In vitro tests exhibit varying sensitivity and specificity depending on the drug involved and the clinical phenotype. In vitro tests can complement skin tests, especially in patients with negative or equivocal skin test responses inconsistent with the clinical presentation and in severe reactions in which drug provocation tests are contraindicated. The main unmet need for many in vitro tests for the diagnosis of DHRs is validation in larger studies with standardized controls that could harmonize diagnostic management between the United States, European Union, and other regions of the world. Despite their low frequency, drug hypersensitivity reactions (DHRs) can be serious and result in lifelong sequelae. The diagnosis is critical to avert future reactions and should identify the culprit drug or drugs and safe alternatives. However, making the diagnosis can be complex and challenging. Reliable in vitro tests can offer the potential to improve a diagnosis of DHR and influence medical decision making. Importantly, in vitro testing is frequently not performed as a test in isolation but rather as a component of a diagnostic algorithm along with additional tests. There are several in vitro approaches for the different endotypes of DHRs. However, only few are available for routine diagnosis, and many are restricted to research laboratories. In vitro tests exhibit varying sensitivity and specificity depending on the drug involved and the clinical phenotype. In vitro tests can complement skin tests, especially in patients with negative or equivocal skin test responses inconsistent with the clinical presentation and in severe reactions in which drug provocation tests are contraindicated. The main unmet need for many in vitro tests for the diagnosis of DHRs is validation in larger studies with standardized controls that could harmonize diagnostic management between the United States, European Union, and other regions of the world. This article is one of a series of international consensus documents developed from the International Drug Allergy Symposium held at the Joint Congress of the American Academy of Allergy, Asthma & Immunology/World Allergy Organization on March 1, 2018, in Orlando, Florida, USA. The symposium was sponsored by The Journal of Allergy and Clinical Immunology, The Journal of Allergy and Clinical Immunology: In Practice, and The World Allergy Organization Journal and chaired by Mariana Castells, MD, PhD, and Pascal Demoly, MD, PhD. This article is one of a series of international consensus documents developed from the International Drug Allergy Symposium held at the Joint Congress of the American Academy of Allergy, Asthma & Immunology/World Allergy Organization on March 1, 2018, in Orlando, Florida, USA. The symposium was sponsored by The Journal of Allergy and Clinical Immunology, The Journal of Allergy and Clinical Immunology: In Practice, and The World Allergy Organization Journal and chaired by Mariana Castells, MD, PhD, and Pascal Demoly, MD, PhD. Drug hypersensitivity reactions (DHRs) can mechanistically be classified as immune (allergic), either antibody mediated (IgE/IgG) or T cell mediated, and nonimmune (nonallergic) when other mechanisms are involved. Despite its relatively low frequency, DHRs can be serious (anaphylaxis and severe cutaneous allergic reactions [SCARs]) and can result in death or lifelong sequelae with decreased quality of life. Establishing that the adverse drug reaction is causal (rather than coincidental) and associated with an increased risk for reoccurrence during re-exposure is a critical aspect of management. Moreover, correct diagnosis not only implies identification of the culprit drug but also investigation of all cross-reactive structures and a search for safe alternatives. In patients with DHRs, both underdiagnosis and overdiagnosis are potential problems.1Demoly P. Adkinson N.F. Brockow K. Castells M. Chiriac A.M. Greenberger P.A. et al.International consensus on drug allergy.Allergy. 2014; 69: 420-437Crossref PubMed Scopus (344) Google Scholar Thus it is critical on one hand to avoid false-positive results that incorrectly classify subjects as allergic and, on the other hand, to reduce the numbers of false-negative results, which can severely impair patient safety, especially in those with severe reactions. An accurate diagnostic test might also help identify patients who could benefit from desensitization and monitor the effect of this procedure. Moreover, the screening of some HLA alleles might be able to predict patients at higher risk for DHRs for specific drugs. The diagnosis of DHRs starts with a detailed clinical history and thorough review of the patient's records complemented with skin tests (STs) when indicated. However, ST responses might not always be predictive of the clinical outcome of subsequent exposure.2Brockow K. Garvey L.H. Aberer W. Atanaskovic-Markovic M. Barbaud A. Bilo M.B. et al.Skin test concentrations for systemically administered drugs—an ENDA/EAACI Drug Allergy Interest Group position paper.Allergy. 2013; 68: 702-712Crossref PubMed Scopus (391) Google Scholar, 3Uyttebroek A.P. Sabato V. Bridts C.H. De Clerck L.S. Ebo D.G. Moxifloxacin hypersensitivity: uselessness of skin testing.J Allergy Clin Immunol Pract. 2015; 3: 443-445Abstract Full Text Full Text PDF PubMed Google Scholar Consequently, the definitive diagnosis of DHR might require additional investigations, such as controlled drug provocation tests (DPTs). However, DPTs should not be performed in high-risk patients (eg, those with Stevens-Johnson syndrome [SJS] or toxic epidermal necrolysis [TEN] and drug rash with eosinophilia and systemic symptoms [DRESS]). In patients with life-threatening anaphylaxis, DPTs after negative ST responses should only be performed after balancing the potential for benefit with the potential for harm in each case.4Aberer W. Bircher A. Romano A. Blanca M. Campi P. Fernandez J. et al.Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations.Allergy. 2003; 58: 854-863Crossref PubMed Scopus (568) Google Scholar Moreover, even DPTs might not exhibit absolute predictive values,1Demoly P. Adkinson N.F. Brockow K. Castells M. Chiriac A.M. Greenberger P.A. et al.International consensus on drug allergy.Allergy. 2014; 69: 420-437Crossref PubMed Scopus (344) Google Scholar, 5Torres M.J. Romano A. Celik G. Demoly P. Khan D.A. Macy E. et al.Approach to the diagnosis of drug hypersensitivity reactions: similarities and differences between Europe and North America.Clin Transl Allergy. 2017; 7: 7Crossref PubMed Scopus (40) Google Scholar and their mainstream use can be hampered by ethical and practical considerations. Reliable in vitro tests offer the potential to improve the ability to accurately diagnose DHRs, particularly because these tests do not pose a risk to the patient. However, many of them require further technical and clinical validation and harmonization, as well as standardization of the protocols. The performance of in vitro tests in the DHR diagnostic algorithm would generally be placed before or after the STs but always before DPTs. Ideally, the performance of these tests should contribute to identifying both offending compounds and safe alternatives and enable investigation of the underlying pathomechanisms and possibly high risk markers. Based on the development of new technologies, there is an expanding array of diagnostic tests that are becoming available for clinical use. It is important for the clinician to understand the potential promise of in vitro tests for confirming or ruling out a diagnosis of DHR and to recognize the limitations of currently available diagnostic tests. An ideal screening test is associated with optimal sensitivity and specificity, is safe to perform, should have been validated in studies with a blind comparison to a reference standard in a representative study population,6Brozek J.L. Akl E.A. Jaeschke R. Lang D.M. Bossuyt P. Glasziou P. et al.Grading quality of evidence and strength of recommendations in clinical practice guidelines: part 2 of 3. The GRADE approach to grading quality of evidence about diagnostic tests and strategies.Allergy. 2009; 64: 1109-1116Crossref PubMed Scopus (123) Google Scholar and will add information that will influence medical decision making. A positive response will lead to an increase in the probability that a diagnosis of DHR is present and to subsequent drug avoidance. A negative test response should lead to a reduction in the probability of the association between the investigated drug and the DHR, such that the potential morbidity associated with treatment, unnecessary avoidance of the suspected drug, and further diagnostic testing can be avoided. DHRs have been classified by different means. In practical terms the time elapsed between intake/administration and onset of symptoms is still the most widely used basis for a subclassification, differentiating immediate drug hypersensitivity reactions (IDHRs) from nonimmediate drug hypersensitivity reactions (NIDHRs). However, some controversies on the classification persist (eg, because some reactions are overlapping7Blanca M. Romano A. Torres M.J. Fernandez J. Mayorga C. Rodriguez J. et al.Update on the evaluation of hypersensitivity reactions to betalactams.Allergy. 2009; 64: 183-193Crossref PubMed Scopus (303) Google Scholar and because the appearance of similar symptoms might be due to quite different immune and even nonimmune mechanisms).7Blanca M. Romano A. Torres M.J. Fernandez J. Mayorga C. Rodriguez J. et al.Update on the evaluation of hypersensitivity reactions to betalactams.Allergy. 2009; 64: 183-193Crossref PubMed Scopus (303) Google Scholar, 8Pichler W.J. Hausmann O. Classification of Drug hypersensitivity into allergic, p-i, and pseudo-allergic forms.Int Arch Allergy Immunol. 2016; 171: 166-179Crossref PubMed Scopus (50) Google Scholar For testing, it is important to consider that IDHRs and NIDHRs usually correspond to different immunopathologic mechanisms (ie, endotypes). In patients with IDHRs, mast cell degranulation through IgE or other mechanisms occurs, whereas NIDHRs generally involve IgG and mainly T cells with specificity to the responsible drug. This needs to be taken into account when selecting the in vitro diagnostic approach to be applied.9Mayorga C. Celik G. Rouzaire P. Whitaker P. Bonadonna P. Rodrigues-Cernadas J. et al.In vitro tests for drug hypersensitivity reactions: an ENDA/EAACI Drug Allergy Interest Group position paper.Allergy. 2016; 71: 1103-1134Crossref PubMed Scopus (98) Google Scholar Moreover, nonimmune/nonallergic DHRs resulting in IDHRs can be based on excessive inhibition of specific enzymes or off-target occupation of (nonimmune) receptors. For example, hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) has been related to the inhibition of COX-1.10Szczeklik A. Stevenson D.D. Aspirin-induced asthma: advances in pathogenesis, diagnosis, and management.J Allergy Clin Immunol. 2003; 111: 913-922Crossref PubMed Scopus (377) Google Scholar, 11Kowalski M.L. Asero R. Bavbek S. Blanca M. Blanca-Lopez N. Bochenek G. et al.Classification and practical approach to the diagnosis and management of hypersensitivity to nonsteroidal anti-inflammatory drugs.Allergy. 2013; 68: 1219-1232Crossref PubMed Scopus (242) Google Scholar IDHRs can also result from an off-target occupation of the Mas-related G-protein receptor (MRGPRX2) by drugs, such as some fluoroquinolones, neuromuscular blocking agent (NMBAs), and opiates.12Spoerl D. D'Incau S. Roux-Lombard P. Harr T. Czarnetzki C. Non-IgE-dependent hypersensitivity to rocuronium reversed by sugammadex: report of three cases and hypothesis on the underlying mechanism.Int Arch Allergy Immunol. 2016; 169: 256-262Crossref PubMed Scopus (6) Google Scholar, 13McNeil B.D. Pundir P. Meeker S. Han L. Undem B.J. Kulka M. et al.Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions.Nature. 2015; 519: 237-241Crossref PubMed Scopus (365) Google Scholar, 14Ebo D.G. Faber M. Elst J. Van Gasse A.L. Bridts C.H. Mertens C. et al.In vitro diagnosis of immediate drug hypersensitivity during anesthesia: a review of the literature.J Allergy Clin Immunol Pract. 2018; 6: 1176-1184Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar In patients with NIDHRs, stimulation of drug-reactive T cells can occur not only through the covalent binding of haptenic drugs to carrier proteins (allergic-immune stimulations) but also if the drug binds through noncovalent means to immune receptors (HLA: pharmacologic interaction [p-i] with immune receptors).8Pichler W.J. Hausmann O. Classification of Drug hypersensitivity into allergic, p-i, and pseudo-allergic forms.Int Arch Allergy Immunol. 2016; 171: 166-179Crossref PubMed Scopus (50) Google Scholar, 15Pichler W.J. Adam J. Watkins S. Wuillemin N. Yun J. Yerly D. Drug hypersensitivity: how drugs stimulate T cells via pharmacological interaction with immune receptors.Int Arch Allergy Immunol. 2015; 168: 13-24Crossref PubMed Scopus (27) Google Scholar There are several in vitro approaches for identifying the pathologic process involved and evaluating the different DHRs.9Mayorga C. Celik G. Rouzaire P. Whitaker P. Bonadonna P. Rodrigues-Cernadas J. et al.In vitro tests for drug hypersensitivity reactions: an ENDA/EAACI Drug Allergy Interest Group position paper.Allergy. 2016; 71: 1103-1134Crossref PubMed Scopus (98) Google Scholar One might differentiate between assays that measure a general activation, tests that try to identify the eliciting drug, and genetic testing that can identify high-risk markers in the host, such as HLA haplotypes. The potential diagnostic utility and limitations of in vitro diagnostics in DHRs have been reviewed elsewhere9Mayorga C. Celik G. Rouzaire P. Whitaker P. Bonadonna P. Rodrigues-Cernadas J. et al.In vitro tests for drug hypersensitivity reactions: an ENDA/EAACI Drug Allergy Interest Group position paper.Allergy. 2016; 71: 1103-1134Crossref PubMed Scopus (98) Google Scholar, 16Schrijvers R. Gilissen L. Chiriac A.M. Demoly P. Pathogenesis and diagnosis of delayed-type drug hypersensitivity reactions, from bedside to bench and back.Clin Transl Allergy. 2015; 5: 31Crossref PubMed Google Scholar, 17Ebo D.G. Leysen J. Mayorga C. Rozieres A. Knol E.F. Terreehorst I. The in vitro diagnosis of drug allergy: status and perspectives.Allergy. 2011; 66: 1275-1286Crossref PubMed Scopus (71) Google Scholar, 18Decuyper II, Mangodt E.A. Van Gasse A.L. Claesen K. Uyttebroek A. Faber M. et al.In vitro diagnosis of immediate drug hypersensitivity anno 2017: potentials and limitations.Drugs R D. 2017; 17: 265-278Crossref PubMed Scopus (22) Google Scholar and are summarized in Table I. Although in vitro tests can contribute to correct diagnosis of DHRs, mainly IgE-dependent DHRs, it appears that there is significant room for improvement before these assays can enter mainstream use. Actually, from these reviews, it appears that one of the most important hurdles hampering their application in daily clinical practice is the absence of methodologically sound studies executed in significant numbers of well-characterized patients and (exposed) control subjects that included comparison with a reference (ie, “gold”) standard: the DPT. However, because DPTs are frequently not performed for ethical reasons, for the time being, in many cases a convincing clinical history and use of STs are considered the “reference test.” For evaluation of the role of different tests for this review, we have included only studies that selected patients receiving diagnoses based on STs, DPTs, or both and enrolled more than 5 patients and control subjects.Table IIn vitro tests for evaluating different types of DHRsAdvantagesLimitationsIDHRs at the acute phase: Markers for severity and type of reaction Tryptase determination•Assessment of mast cell involvement•There are difficulties in performing the test in the right time kinetic of peak tryptase caused by short half-life (30-120 min).•Comparison with basal levels is needed. Histamine determination•Assessment of mast cell and/or basophil involvement•Short half-life•Comparison with basal levels is needed.•No commercial test is available.IDHRs at the resolution phase: Identifying the relevant drug or drugs sIgE by using an immunoassay•Identification of the culprit drug•Serum sample can be easily stored and transported•Available for a limited number of drugs•Time interval from reaction is critical for sensitivity. BAT•Identification of the culprit drug•Available for a wide panel of drugs•Blood samples cannot be stored.•BAT is not useful for nonallergic DHRs.•Time interval from reaction is critical for sensitivity.NIDHRs at the resolution phase: Identifying the relevant drug or drugs LTT•Identification of the culprit drug based on proliferation•Highly dependent on clinical entities•Low sensitivity in severe bullous skin reactions Cytokine determination by means of ELISA, ELISpot, and bead assay•Identification of the culprit drug based on cytokine secretion•Highly dependent on clinical entities•Low sensitivity in severe bullous skin reactions Combined cytokine and cytotoxicity assays (Cyto-LTT)•Identification of the culprit drug based on cytokine production and cytotoxicity•Increased sensitivity and still excellent specificity; might even help in diagnosis of subset of patients with SJS/TEN Open table in a new tab IDHRs can be evaluated at the acute phase of the reaction or at the resolution phase. The main goal of the in vitro test performed during the acute phase of the reaction is assessment of mast cell and/or basophil involvement and activation by means of quantification of inflammatory mediators, such as tryptase, histamine, and prostaglandins or leukotrienes.19Sanz M.L. Gamboa P.M. Garcia-Figueroa B.E. Ferrer M. In vitro diagnosis of anaphylaxis.Chem Immunol Allergy. 2010; 95: 125-140Crossref PubMed Scopus (0) Google Scholar The determination of peak serum tryptase levels during the acute phase with subsequent quantification of baseline tryptase disclosed mast cell activation in a variable percentage of patient (31% to 67%).20Mertes P.M. Laxenaire M.C. Alla F, Groupe d'Etudes des Reactions Anaphylactoides P. Anaphylactic and anaphylactoid reactions occurring during anesthesia in France in 1999-2000.Anesthesiology. 2003; 99: 536-545Crossref PubMed Scopus (0) Google Scholar, 21Dybendal T. Guttormsen A.B. Elsayed S. Askeland B. Harboe T. Florvaag E. Screening for mast cell tryptase and serum IgE antibodies in 18 patients with anaphylactic shock during general anaesthesia.Acta Anaesthesiol Scand. 2003; 47: 1211-1218Crossref PubMed Scopus (61) Google Scholar, 22Berroa F. Lafuente A. Javaloyes G. Ferrer M. Moncada R. Goikoetxea M.J. et al.The usefulness of plasma histamine and different tryptase cut-off points in the diagnosis of peranaesthetic hypersensitivity reactions.Clin Exp Allergy. 2014; 44: 270-277Crossref PubMed Scopus (26) Google Scholar In the case of histamine, it is also quite variable in different studies (61% to 92%).20Mertes P.M. Laxenaire M.C. Alla F, Groupe d'Etudes des Reactions Anaphylactoides P. Anaphylactic and anaphylactoid reactions occurring during anesthesia in France in 1999-2000.Anesthesiology. 2003; 99: 536-545Crossref PubMed Scopus (0) Google Scholar, 21Dybendal T. Guttormsen A.B. Elsayed S. Askeland B. Harboe T. Florvaag E. Screening for mast cell tryptase and serum IgE antibodies in 18 patients with anaphylactic shock during general anaesthesia.Acta Anaesthesiol Scand. 2003; 47: 1211-1218Crossref PubMed Scopus (61) Google Scholar, 22Berroa F. Lafuente A. Javaloyes G. Ferrer M. Moncada R. Goikoetxea M.J. et al.The usefulness of plasma histamine and different tryptase cut-off points in the diagnosis of peranaesthetic hypersensitivity reactions.Clin Exp Allergy. 2014; 44: 270-277Crossref PubMed Scopus (26) Google Scholar This variability could be related to the severity of the reaction.23Komericki P. Arbab E. Grims R. Kranke B. Aberer W. Tryptase as severity marker in drug provocation tests.Int Arch Allergy Immunol. 2006; 140: 164-169Crossref PubMed Scopus (0) Google Scholar, 24Sala-Cunill A. Cardona V. Labrador-Horrillo M. Luengo O. Esteso O. Garriga T. et al.Usefulness and limitations of sequential serum tryptase for the diagnosis of anaphylaxis in 102 patients.Int Arch Allergy Immunol. 2013; 160: 192-199Crossref PubMed Scopus (79) Google Scholar Moreover, different definitions for mast cell activation have been used, and results depend on the half-life of these molecules. In fact, determination of histamine levels in blood is limited because of the circadian variations, and efforts are ongoing to determine an optimal time for collection before full validation. Regarding tryptase results, it has been suggested that the threshold of 11.4 μg/L should be revised, and as an alternative, an international consensus equation (ie, 1.2 × [Basal tryptase value] + 2 μg/L) should be applied,23Komericki P. Arbab E. Grims R. Kranke B. Aberer W. Tryptase as severity marker in drug provocation tests.Int Arch Allergy Immunol. 2006; 140: 164-169Crossref PubMed Scopus (0) Google Scholar, 25Baretto R.L. Beck S. Heslegrave J. Melchior C. Mohamed O. Ekbote A. et al.Validation of international consensus equation for acute serum total tryptase in mast cell activation: a perioperative perspective.Allergy. 2017; 72: 2031-2034Crossref PubMed Scopus (26) Google Scholar which has shown high specificity and positive predictive value but moderate sensitivity and negative predictive value in patients with perioperative anaphylaxis. The determination of other inflammatory mediators can also have clinical utility. Urinary leukotriene E4 has been associated with a high negative predictive value for identifying asthmatic patients with aspirin-exacerbated respiratory disease, such that compared with clinical parameters alone, the determination of urinary leukotriene E4 levels combined with clinical parameters enhances the accuracy of the aspirin-exacerbated respiratory disease diagnosis.26Bochenek G. Stachura T. Szafraniec K. Plutecka H. Sanak M. Nizankowska-Mogilnicka E. et al.Diagnostic accuracy of urinary LTE4 measurement to predict aspirin-exacerbated respiratory disease in patients with asthma.J Allergy Clin Immunol Pract. 2018; 6: 528-535Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar Confirmatory testing for identification of the responsible drug or drugs performed in the resolution phase can involve quantification of serum drug-specific IgE (sIgE) measurements and direct/indirect basophil activation tests (BATs). sIgE detection in serum is traditionally performed by using a solid-phase immunoassay; however, only a restricted number of drug sIgE assays are currently available. DHRs to β-lactams (BLs; using the major determinant, penicilloyl), NMBAs, quinolones, and biological agents have been evaluated in different studies.18Decuyper II, Mangodt E.A. Van Gasse A.L. Claesen K. Uyttebroek A. Faber M. et al.In vitro diagnosis of immediate drug hypersensitivity anno 2017: potentials and limitations.Drugs R D. 2017; 17: 265-278Crossref PubMed Scopus (22) Google Scholar, 27Mayorga C. Dona I. Perez-Inestrosa E. Fernandez T.D. Torres M.J. The value of in vitro tests to diminish drug challenges.Int J Mol Sci. 2017; 18Crossref PubMed Scopus (7) Google Scholar Performance varies depending on the drug involved, with a range of positivity of 38% to 85% for BLs,28Vultaggio A. Virgili G. Gaeta F. Romano A. Maggi E. Matucci A. High serum beta-lactams specific/total IgE ratio is associated with immediate reactions to beta-lactams antibiotics.PLoS One. 2015; 10: e0121857Crossref PubMed Scopus (24) Google Scholar, 29Vultaggio A. Matucci A. Nencini F. Pratesi S. Parronchi P. Rossi O. et al.Anti-infliximab IgE and non-IgE antibodies and induction of infusion-related severe anaphylactic reactions.Allergy. 2010; 65: 657-661Crossref PubMed Scopus (151) Google Scholar, 30Torres J. Romano A. Mayorga C. Carmen M. Guzman A.E. Reche M. et al.Diagnostic evaluation of a large group of patients with immediate allergy to penicillins: the role of skin testing.Allergy. 2001; 56: 850-856Crossref PubMed Scopus (199) Google Scholar, 31Fontaine C. Mayorga C. Bousquet P.J. Arnoux B. Torres M.J. Blanca M. et al.Relevance of the determination of serum-specific IgE antibodies in the diagnosis of immediate beta-lactam allergy.Allergy. 2007; 62: 47-52Crossref PubMed Scopus (140) Google Scholar, 32Blanca M. Mayorga C. Torres M.J. Reche M. Moya M.C. Rodriguez J.L. et al.Clinical evaluation of Pharmacia CAP System RAST FEIA amoxicilloyl and benzylpenicilloyl in patients with penicillin allergy.Allergy. 2001; 56: 862-870Crossref PubMed Scopus (165) Google Scholar 44% to 92% for NMBAs,33Rouzaire P. Proton G. Bienvenu F. Guilloux L. Benoit Y. Piriou V. et al.IgE antibody detection in the diagnosis of hypersensitivity to neuromuscular blocking agents.Acta Anaesthesiol Scand. 2012; 56: 263-264Crossref PubMed Google Scholar, 34Monneret G. Benoit Y. Debard A.L. Gutowski M.C. Topenot I. Bienvenu J. Monitoring of basophil activation using CD63 and CCR3 in allergy to muscle relaxant drugs.Clin Immunol. 2002; 102: 192-199Crossref PubMed Scopus (103) Google Scholar, 35Mata E. Gueant J.L. Moneret-Vautrin D.A. Bermejo N. Gerard P. Nicolas J.P. et al.Clinical evaluation of in vitro leukocyte histamine release in allergy to muscle relaxant drugs.Allergy. 1992; 47: 471-476Crossref PubMed Google Scholar, 36Leysen J. Bridts C.H. De Clerck L.S. Vercauteren M. Lambert J. Weyler J.J. et al.Allergy to rocuronium: from clinical suspicion to correct diagnosis.Allergy. 2011; 66: 1014-1019Crossref PubMed Scopus (54) Google Scholar, 37Laroche D. Chollet-Martin S. Leturgie P. Malzac L. Vergnaud M.C. Neukirch C. et al.Evaluation of a new routine diagnostic test for immunoglobulin e sensitization to neuromuscular blocking agents.Anesthesiology. 2011; 114: 91-97Crossref PubMed Scopus (52) Google Scholar, 38Ebo D.G. Venemalm L. Bridts C.H. Degerbeck F. Hagberg H. De Clerck L.S. et al.Immunoglobulin E antibodies to rocuronium: a new diagnostic tool.Anesthesiology. 2007; 107: 253-259Crossref PubMed Scopus (0) Google Scholar 26% to 68% for biological agents,39Matucci A. Pratesi S. Petroni G. Nencini F. Virgili G. Milla M. et al.Allergological in vitro and in vivo evaluation of patients with hypersensitivity reactions to infliximab.Clin Exp Allergy. 2013; 43: 659-664PubMed Google Scholar, 40Chung C.H. Mirakhur B. Chan E. Le Q.T. Berlin J. Morse M. et al.Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose.N Engl J Med. 2008; 358: 1109-1117Crossref PubMed Scopus (883) Google Scholar and 59% to 75% for platins.41Caiado J. Venemalm L. Pereira-Santos M.C. Costa L. Barbosa M.P. Castells M. Carboplatin-, oxaliplatin-, and cisplatin-specific IgE: cross-reactivity and value in the diagnosis of carboplatin and oxaliplatin allergy.J Allergy Clin Immunol Pract. 2013; 1: 494-500Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar For BL hypersensitivity evaluation, the inclusion of all suspected drugs has been associated with an increase in sensitivity, as has been observed for patients with IDHRs to the combination of amoxicillin-clavulanic acid.42Torres M.J. Ariza A. Mayorga C. Dona I. Blanca-Lopez N. Rondon C. et al.Clavulanic acid can be the component in amoxicillin-clavulanic acid responsible for immediate hypersensitivity reactions.J Allergy Clin Immunol. 2010; 125: 502-505.e2Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 43Salas M. Laguna J.J. Dona I. Barrionuevo E. Fernandez-Santamaria R. Ariza A. et al.Patients taking amoxicillin-clavulanic can become simultaneously sensitized to both drugs.J Allergy Clin Immunol Pract. 2017; 5: 694-702.e3Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 44Salas M. Fernandez-Santamaria R. Mayorga C. Barrionuevo E. Ariza A. Posadas T. et al.Use of the basophil activation test may reduce the need for drug provocation in amoxicillin-clavulanic allergy.J Allergy Clin Immunol Pract. 2018; 6: 1010-1018.e2Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar For NMBAs, it has been shown that the diagnosis should not rely on quantification of sIgE in isolation45Leysen J. Uyttebroek A. Sabato V. Bridts C.H. De Clerck L.S. Ebo D.G. Predictive value of allergy tests for neuromuscular blocking agents: tackling an unmet need.Clin Exp Allergy. 2014; 44: 1069-1075Crossref PubMed Scopus (41) Google Scholar and that sIgE to the opiate morphine used as a marker for sensitization to tertiary and quaternary substituted ammonium structures can add to the diagnosis of anaphylaxis from rocuronium38Ebo D.G. Venemalm L. Bridts C.H. Degerbeck F. Hagberg H. De Clerck L.S. et al.Immunoglobulin E antibodies to rocuronium: a new diagnostic tool.Anesthesiology. 2007; 107: 253-259Crossref PubMed Scopus (0) Google Scholar and suxamethonium but not atracurium.46Uyttebroek A.