Diagnosis and management of anaphylaxis in precision medicine
2017; Elsevier BV; Volume: 140; Issue: 2 Linguagem: Inglês
10.1016/j.jaci.2017.06.012
ISSN1097-6825
Autores Tópico(s)Allergic Rhinitis and Sensitization
ResumoAnaphylaxis is the most severe and frightening of the allergic reactions, placing patients at high risk and demanding prompt recognition and immediate management by health care providers. Yet because its symptoms imitate those of other diseases, such as asthma and urticaria, current data suggest that its diagnosis is often missed, with underuse of tryptase measurement; its treatment is delayed, with little use of epinephrine; and its underlying cause or causes are poorly investigated. Deaths from anaphylaxis are difficult to investigate because of miscoding. Surprisingly, patients treated with new and powerful chemotherapy agents and humanized mAbs present with nonclassical symptoms of anaphylaxis, and patients may present with unrecognized clonal mast cell disorders with KIT mutations may present as Hymenoptera-induced or idiopathic anaphylaxis. The goal of this review is to recognize the presentations of anaphylaxis with the description of its current phenotypes, to provide new insight and understanding of its mechanisms and causes through its endotypes, and to address its biomarkers for broad clinical use. Ultimately, the aim is to empower allergists and heath care providers with new tools that can help alleviate patients' symptoms, preventing and protecting them against anaphylaxis. Anaphylaxis is the most severe and frightening of the allergic reactions, placing patients at high risk and demanding prompt recognition and immediate management by health care providers. Yet because its symptoms imitate those of other diseases, such as asthma and urticaria, current data suggest that its diagnosis is often missed, with underuse of tryptase measurement; its treatment is delayed, with little use of epinephrine; and its underlying cause or causes are poorly investigated. Deaths from anaphylaxis are difficult to investigate because of miscoding. Surprisingly, patients treated with new and powerful chemotherapy agents and humanized mAbs present with nonclassical symptoms of anaphylaxis, and patients may present with unrecognized clonal mast cell disorders with KIT mutations may present as Hymenoptera-induced or idiopathic anaphylaxis. The goal of this review is to recognize the presentations of anaphylaxis with the description of its current phenotypes, to provide new insight and understanding of its mechanisms and causes through its endotypes, and to address its biomarkers for broad clinical use. Ultimately, the aim is to empower allergists and heath care providers with new tools that can help alleviate patients' symptoms, preventing and protecting them against anaphylaxis. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: August 2017. Credit may be obtained for these courses until July 31, 2018.Copyright Statement: Copyright © 2017-2018. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Mariana Castells, MD, PhDDisclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: M. Castells has consultant arrangements with Sanofi, Genentech, Merck, Lytix Biopharma, Contrafect, Arete Discoveries, and Bentham Science and is on the American Academy of Allergy, Asthma & Immunology Board of Directors.Activity Objectives:1.To recognize anaphylaxis phenotypes based on clinical symptoms and potential triggers and to understand their underlying pathogenesis.2.To understand the utility of various biomarkers in diagnosing anaphylaxis.3.To understand appropriate circumstances when rapid desensitization might be considered.4.To recognize cardiac complications that can occur in patients with anaphylaxis.Recognition of Commercial Support: This CME activity has not received external commercial support.List of CME Exam Authors: Roua Azmeh, MD, Julia Shin Lee, MD, Sara D. Powell, MD, and Mark S. Dykewicz, MD.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: The exam authors disclosed no relevant financial relationships.Anaphylaxis is a word recognized and feared by most, if not all, health care providers because of its association with potential death from cardiovascular collapse or asphyxiation caused by laryngeal edema. Yet its diagnosis is missed in 80% of patients who are seen in the emergency department (ED), undergoing anesthesia and surgery or being treated with chemotherapy, mAbs, or biological agents. Patients are given codes for asthma, urticaria, angioedema, or hypotension, but occurrence of the alarming signs and symptoms of anaphylaxis together does not trigger an immediate suspicion for a multiorgan system syndrome and does not result in the prompt use of epinephrine or an evaluation of an acute serum tryptase level. The diagnosis of a toxic reaction is often given mistakenly to chemotherapy-induced anaphylactic events. Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Date of Original Release: August 2017. Credit may be obtained for these courses until July 31, 2018. Copyright Statement: Copyright © 2017-2018. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Mariana Castells, MD, PhD Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: M. Castells has consultant arrangements with Sanofi, Genentech, Merck, Lytix Biopharma, Contrafect, Arete Discoveries, and Bentham Science and is on the American Academy of Allergy, Asthma & Immunology Board of Directors. Activity Objectives:1.To recognize anaphylaxis phenotypes based on clinical symptoms and potential triggers and to understand their underlying pathogenesis.2.To understand the utility of various biomarkers in diagnosing anaphylaxis.3.To understand appropriate circumstances when rapid desensitization might be considered.4.To recognize cardiac complications that can occur in patients with anaphylaxis. Recognition of Commercial Support: This CME activity has not received external commercial support. List of CME Exam Authors: Roua Azmeh, MD, Julia Shin Lee, MD, Sara D. Powell, MD, and Mark S. Dykewicz, MD. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: The exam authors disclosed no relevant financial relationships. Because anaphylaxis mimics common syndromes, such as asthma and urticaria, and because it can present without hypotension, its diagnosis is often missed or delayed. There is a new understanding that atypical symptoms, such as pain, can be seen during chemotherapy-induced anaphylaxis and that clonal disorders, such as monoclonal mast cell activation syndrome, are part of the wide spectrum of anaphylaxis. Anaphylaxis occurs more in women. Anaphylaxis can be one of the most traumatic events in a patient's life, with long-lasting and sometimes incapacitating sequelae. Empowering patients by using the correct label, educating them about the potential triggers and causes, providing them with appropriate acute treatment, and giving them an effective treatment plan have been shown to help increase the quality of life and safety of these patients. The purpose of this review is to redefine the phenotypes and endotypes of anaphylaxis in light of new evidence-based information regarding its presentation and causes. The goal is to help allergists and health care providers recognize newly appreciated anaphylaxis-associated symptoms, look for biomarkers, and apply best practice management and treatment options to improve quality of life for patients with anaphylaxis. This was the opening sentence during the first visit of a 39-year-old man and his wife to the allergy clinic after being seen by no less than 10 specialists. They wanted to start a family but would not because he feared he would die any minute of an unknown cause or trigger. Twenty years ago, as a landscaper at age 19 years, he passed out in the grass after being stung by several wasps. He was revived and given an epinephrine injectable device. A few months later, he had an unexplained L5 fracture and was given a tentative diagnosis of osteoporosis and started on bisphosphonates. He changed jobs because he presented with episodes of flushing, fatigue, fever, abdominal bloating, pain, and diarrhea unexpectedly. He was told he had irritable bowel syndrome, but the symptoms of diarrhea were so unpredictable that he limited his social life. Five years ago, he was cutting bushes, hit a nest, and was stung by many bees. He became flushed with a sense of impending doom, had syncope and seizures, and required an intravenous epinephrine drip before a pulse returned. Last August, he was working at a liquor company moving beer cases, and during a hot and humid day, he felt very flushed, passed out, and was revived in the ED after several epinephrine injections and liters of fluid and told he was dehydrated. He never had a rash and was told that his osteoporosis, bone fractures, and gastrointestinal problems were unrelated and that he could die at any time because nobody knew why his blood pressure went so low or the specific triggers for these events. A diagnosis of anaphylaxis was not attached to his official chart, which contained more than 200 pages, and an investigation of the potential cause or causes was never undertaken. A tryptase measurement was done during his last ED visit, and the level was found to be increased. “Could all this be explained by a mast cell disorder?,” he asked after going online and reading several hundred documents on mastocytosis. Why would a mast cell disorder be associated with anaphylaxis? From the initial definition by Charles Richet and Paul Portier in 1901 as an immune reaction that accomplished the opposite of protection (ana = absence, phylaxis = protection in Greek)1Ring J. Brockow K. Behrendt H. History and classification of anaphylaxis.Novartis Found Symp. 2004; 257: 6-16Crossref PubMed Google Scholar, 2Moon D.H. Lee J.M. Noonan A.M. Annunziata C.M. Minasian L. Houston N. et al.Deleterious BRCA1/2 mutation is an independent risk factor for carboplatin hypersensitivity reactions.Br J Cancer. 2013; 109: 1072-1078Crossref PubMed Scopus (17) Google Scholar to a casual definition given recently by an educated lawyer at a trial of an allergic patient who died after intravenous contrast dye injection as “something that can be treated if properly recognized,” anaphylaxis has eluded definition because of the lack of a single organ target and a broad spectrum of presentations.3Austen K.F. Systemic anaphylaxis in the human being.N Engl J Med. 1974; 291: 661-664Crossref PubMed Google Scholar This is exemplified by the new International Classification of Diseases, 10th Edition (ICD-10), coding system, which provides one code for anaphylaxis without qualifiers (T78.2XXA) and more than 100 codes (the last one in alphabetical order being T63.94XD) for anaphylaxis qualifiers. Despite this plethora of possible diagnoses, the symptoms of anaphylaxis continue to be underrecognized for all age groups, sexes, and races; its diagnosis is often missed; its treatment is often delayed, including the lack of epinephrine use; and the underlying causes are underinvestigated across the globe.4Agelebe E. Musa T.L. Ajayi I.A. Oyedeji O.A. Anaphylaxis complicated by acute respiratory distress and fatal outcome in a Nigerian family.J Clin Diagn Res. 2017; 11: SD01-SD03PubMed Google Scholar, 5Alvarez-Perea A. Ameiro B. Morales C. Zambrano G. Rodríguez A. Guzmán M. et al.Anaphylaxis in the pediatric emergency department: analysis of 133 cases after an allergy workup.J Allergy Clin Immunol Pract. 2017; ([Epub ahead of print])PubMed Google Scholar, 6Banerji A. Rudders S. Clark S. Wei W. Long A.A. Camargo Jr., C.A. Retrospective study of drug-induced anaphylaxis treated in the emergency department or hospital: patient characteristics, management, and 1-year follow-up.J Allergy Clin Immunol Pract. 2014; 2: 46-51Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar From its initial description as a clinical entity with acute onset of symptoms involving 2 or more organs or associated with hypotension or upper respiratory compromise by expert panels,7Sampson H.A. Muñoz-Furlong A. Campbell R.L. Adkinson Jr., N.F. Bock S.A. Branum A. et al.Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium.J Allergy Clin Immunol. 2006; 117: 391-397Abstract Full Text Full Text PDF PubMed Scopus (884) Google Scholar, 8Lieberman P. Nicklas R.A. Oppenheimer J. Kemp S.F. Lang D.M. Bernstein D.I. et al.The diagnosis and management of anaphylaxis practice parameter: 2010 update.J Allergy Clin Immunol. 2010; 126 (e1-42): 477-480Abstract Full Text Full Text PDF PubMed Scopus (347) Google Scholar its definition has evolved to a more mechanistic description based on precision medicine into phenotypes with underlying endotypes supported by diagnostic biomarkers.9Muraro A. Lemanske Jr., R.F. Castells M. Torres M.J. Khan D. Simon H.U. et al.Precision medicine in allergic disease—food allergy, drug allergy, and anaphylaxis—PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology.Allergy. 2017; 72: 1006-1021Crossref PubMed Scopus (3) Google Scholar As seen in Fig 1, A, anaphylaxis phenotypes are defined by clinical presentation into type I–like reactions, cytokine storm–like reactions, and mixed reactions. The endotypes underlying these phenotypes include IgE- and non–IgE-mediated mechanisms, cytokine release, mixed reactions, and direct activation of immune cells. Cellular targets for IgE-mediated reactions include mast cells, basophils, and other immune cells and symptoms related to the actions of mediators on the target organs.10Dombrowicz D. Brini A.T. Flamand V. Hicks E. Snouwaert J.N. Kinet J.P. et al.Anaphylaxis mediated through a humanized high affinity IgE receptor.J Immunol. 1996; 157: 1645-1651Crossref PubMed Google Scholar The common triggers for these reactions include foods, drugs, Hymenoptera venoms, and environmental allergens. Among common allergens are foods, such as peanut, milk, eggs, and nuts; antibiotics, such as β-lactams; chemotherapy agents, such as platins and taxanes; chimeric, humanized, and human mAbs; general anesthetics; and immunotherapy allergens. Flushing, pruritus, hives, angioedema, shortness of breath, wheezing, nausea, vomiting, diarrhea, hypotension, oxygen desaturation, and cardiovascular collapse are classical clinical manifestations caused by the release of inflammatory mediators from mast cells and basophils (Fig 1, B). More recently, in addition to these symptoms, atypical symptoms have emerged, such as chills and fever, during reactions to chemotherapy agents, such as oxaliplatin, and pain during taxane and mAb reactions. These symptoms can also occur during reactions to chemotherapy and mAbs in which no evidence for IgE can be demonstrated. The new G-coupled receptor MRGPRX2, which is expressed on mast cells and other cells, has been shown to be activated by quinolone antibiotics, such as ciprofloxacin and levofloxacin; general anesthetics, such as atracuronium and rocuronium; icatibant; and other drugs with Tetrahydroisoquinoline (THIQ) motifs.11McNeil 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 (92) Google Scholar Its participation in human hypersensitivity reactions and anaphylaxis is being investigated and does not involve IgE. In animal models anaphylaxis can proceed through mechanisms that involve multiple myeloid cells, including mast cells, basophils, neutrophils, and macrophages, and through distinct IgE and IgG pathways.12Finkelman F.D. Anaphylaxis: lessons from mouse models.J Allergy Clin Immunol. 2007; 120: 506-517Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar Whether IgG can participate in human anaphylaxis and whether inhibitory Fc receptors have a role in limiting its extent are subject to debate. A recent human-to-mouse low-affinity FcγR locus swap with expression of human low-affinity FcγR presented cognate passive and active anaphylaxis, indicating that the activatory low-affinity human IgG receptors FcγRIIIb and FcγRIIB dominate over inhibitory receptors, such as FcγRIIb. The differential expression of inhibitory FcγRIIB on myeloid cells and the differential binding and contribution of IgG subclasses to anaphylaxis indicated a high degree of complexity, which is difficult to explore in human subjetcs.13Beutier H. Gillis C.M. Iannascoli B. Godon O. England P. Sibilano R. et al.IgG subclasses determine pathways of anaphylaxis in mice.J Allergy Clin Immunol. 2017; 139: 269-280.e7Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 14Gillis C.M. Jönsson F. Mancardi D.A. Tu N. Beutier H. Van Rooijen N. et al.Mechanisms of anaphylaxis in human low-affinity IgG receptor locus knock-in mice.J Allergy Clin Immunol. 2017; 139: 1253-1265.e14Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Chimeric IgG mAbs, such as rituximab, can induce the release of tryptase and histamine in the context of hypotension and cytokine storm–like symptoms, indicating the potential role for IgG in patients with anaphylaxis. Cytokine storm–like reactions are caused by release of proinflammatory mediators, such as TNF-α, IL-1B, and IL-6, and the target cells include monocytes, macrophages, mast cells, and other immune cells with FcγR. Triggers for these reactions include chimeric, humanized, and human mAbs and chemotherapy, including oxaliplatin. Reactions are characterized by chills, fever, generalized malaise followed by hypotension, desaturation, and cardiovascular collapse. Premedication with anti-inflammatory COX-1 inhibitors and corticosteroids can decrease the intensity of these symptoms but does not protect from severe reactions. Mixed reactions with features of type I– and cytokine storm–like reactions can be seen with chemotherapy and mAbs in which pruritus, hives, and swelling are associated with chills, fever, hypotension, and desaturation. Direct activation of mast cells and other immune cells can occur with vancomycin15Chopra N. Oppenheimer J. Derimanov G.S. Fine P.L. Vancomycin anaphylaxis and successful desensitization in a patient with end stage renal disease on hemodialysis by maintaining steady antibiotic levels.Ann Allergy Asthma Immunol. 2000; 84: 633-635Abstract Full Text PDF PubMed Google Scholar or through complement activation by highly charged chondroitin sulfate glycosaminoglycans16Kishimoto T.K. Viswanathan K. Ganguly T. Elankumaran S. Smith S. Pelzer K. et al.Contaminated heparin associated with adverse clinical events and activation of the contact system.N Engl J Med. 2008; 358: 2457-2467Crossref PubMed Scopus (412) Google Scholar and contrast media,17Simon R.A. Schatz M. Stevenson D.D. Curry N. Yamamoto F. Plow E. et al.Radiographic contrast media infusions. Measurement of histamine, complement, and fibrin split products and correlation with clinical parameters.J Allergy Clin Immunol. 1979; 63: 281-288Abstract Full Text PDF PubMed Google Scholar with generation of the anaphylatoxins C3a and C5a, which can bind to complement receptors.18Fregonese L. Swan F.J. van Schadewijk A. Dolhnikoff M. Santos M.A. Daha M.R. et al.Expression of the anaphylatoxin receptors C3aR and C5aR is increased in fatal asthma.J Allergy Clin Immunol. 2005; 115: 1148-1154Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar The resulting release of histamine, leukotrienes, and prostaglandins can induce flushing, hives, hypoxia, vasodilation, and hypotension. Within a few minutes after the initial symptoms of anaphylaxis, including hypotension, mature tryptase released from mast cells and basophils can be detected in serum. This increase is transient and typically resolves in 24 to 48 hours. Commercial immunoassays allow for detection of total (baseline release, reflecting mast cell and basophil burden) and mature (released only at the time of activation) tryptase but do not discriminate between the two. Increases to greater than the normal range of 11.4 ng/mL are indicative of acute mast cell/basophil activation.19Schwartz L.B. Metcalfe D.D. Miller J.S. Earl H. Sullivan T. Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis.N Engl J Med. 1987; 316: 1622-1626Crossref PubMed Google Scholar At least 4 tryptase genes (alpha, beta, gamma and delta) have been identified,20McNeil H.P. Adachi R. Stevens R.L. Mast cell-restricted tryptases: structure and function in inflammation and pathogen defense.J Biol Chem. 2007; 282: 20785-20789Crossref PubMed Scopus (0) Google Scholar and 27% of white patients can have an absence of α-tryptase genes,21Caughey G.H. Tryptase genetics and anaphylaxis.J Allergy Clin Immunol. 2006; 117: 1411-1414Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar but the expression of tryptase haplotypes does not seem to influence tryptase expression or levels. Patients with low baseline tryptase levels can have increases during anaphylaxis that do not reach the normal range, and levels of 2 ng/mL plus 1.2 times baseline22Akin C. Soto D. Brittain E. Chhabra A. Schwartz L.B. Caughey G.H. et al.Tryptase haplotype in mastocytosis: relationship to disease variant and diagnostic utility of total tryptase levels.Clin Immunol. 2007; 123: 268-271Crossref PubMed Scopus (0) Google Scholar are considered significantly increased. Tryptase specificity is high but its sensitivity is low because it is released from different mast cell subsets and basophils, depending on the trigger. Tryptase levels are lower in mucosal mast cells than in cutaneous and perivascular mast cells, and anaphylactic reactions to intravenous drugs can elicit greater and more persistent increases than oral triggers, such as foods. A recent syndrome of familial tryptasemia has been described in which several members of a family present with increased tryptase levels because of more than 2 α-tryptase genes in the absence of mastocytosis.23Lyons J.J. Yu X. Hughes J.D. Le Q.T. Jamil A. Bai Y. et al.Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number.Nat Genet. 2016; 48: 1564-1569Crossref PubMed Scopus (6) Google Scholar Other mast cell proteases, such as chymase and carboxypeptidase, have been detected during anaphylaxis, but no commercial assays are available. Other mast cell and basophil mediators can be released during anaphylaxis, such as histamine and its metabolite methylhistamine, prostaglandin D2 and its metabolite 9-α-11-β prostaglandin F2, and leukotrienes E4 and C4, and can be measured in 24-hour urine collection. Although specific for anaphylaxis, the sensitivity might be low because of the difficulties in timing 24-hour urine collections to symptom onset. One study indicated an inverse correlation between serum platelet-activating factor and acetylhydrolase levels and the severity of anaphylaxis, with low enzymatic levels associated with high platelet-activating factor levels, severe hypotension, and fatal and near-fatal anaphylaxis. Levels of other serum inflammatory mediators, such as TNF-α, IL-6, and IL-1β, can be increased in patients with cytokine storm–like reactions and anaphylaxis, but their sensitivity or specificity has not been demonstrated. Their measurement provides insight into the phenotype of reactions and can help guide recommendations for desensitization and premedications. Skin testing can be done within 2 to 4 weeks after anaphylaxis, and results provide evidence of IgE and mast cell involvement. Skin tests are highly specific for type I reactions to foods, drugs (eg, platins), β-lactams, general anesthetics, and Hymenoptera venoms. Because current extracts for skin testing might not contain all allergenic components, after a negative skin test result, the gold standard to demonstrate the lack of food and drug allergy is a challenge. Skin testing is safe for patients with a history of anaphylaxis and mastocytosis provided comorbidities, such as asthma, are controlled and medications, such as β-blockers and angiotensin-converting enzyme (ACE) inhibitors, are discontinued before testing. Patients with cytokine storm–like reactions and complement activation are likely to have negative skin test results, indicating the lack of IgE participation, but patients with mixed reactions can have positive skin test results.24Sloane D. Govindarajulu U. Harrow-Mortelliti J. Barry W. Hsu F.I. Hong D. et al.Safety, costs, and efficacy of rapid drug desensitizations to chemotherapy and monoclonal antibodies.J Allergy Clin Immunol Pract. 2016; 4: 497-504Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar The specificity and sensitivity of mAb skin testing have not been defined because allergenic components are not known for most mAbs and non–IgE-mediated mechanisms can be active. For chimeric mAbs, such as rituximab and infliximab, mouse epitopes are thought to be involved in the allergic response, and skin test results are positive in 60% to 70% of patients with type I and mixed reactions for rituximab, but only 50% of patients with infliximab-induced type I reactions have positive skin test results.25Brennan P.J. Rodriguez Bouza T. Hsu F.I. Sloane D.E. Castells M.C. Hypersensitivity reactions to mAbs: 105 desensitizations in 23 patients, from evaluation to treatment.J Allergy Clin Immunol. 2009; 124: 1259-1266Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar The negative predictive value for most mAbs is not known. Of 23 patients desensitized to trastuzumab, infliximab, or rituximab, 13 had positive skin test results, but all had symptoms compatible with type I or mixed reactions.25Brennan P.J. Rodriguez Bouza T. Hsu F.I. Sloane D.E. Castells M.C. Hypersensitivity reactions to mAbs: 105 desensitizations in 23 patients, from evaluation to treatment.J Allergy Clin Immunol. 2009; 124: 1259-1266Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar For humanized and human mAbs, glycosylation patterns during manufacturing can differ from natural human IgG glycosylation, generating allergenic epitopes, as seen in patients with positive skin test results to trastuzumab.26Galvao V.R. Castells M.C. Hypersensitivity to biological agents-updated diagnosis, management, and treatment.J Allergy Clin Immunol Pract. 2015; 3: 175-186Abstract Full Text Full Text PDF PubMed Google Scholar For evaluation of penicillin allergy, skin testing requires major and minor determinants because patients with anaphylaxis are likely to be sensitized to minor determinants, which are not currently commercially available.27Lin E. Saxon A. Riedl M. Penicillin allergy: value of including amoxicillin as a determinant in penicillin skin testing.Int Arch Allergy Immunol. 2010; 152: 313-318Crossref PubMed Scopus (29) Google Scholar For patients with a distant history of penicillin allergy and symptoms inconsistent with type I reactions, a direct oral challenge with penicillin might be indicated.28Demoly 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 (121) Google Scholar, 29Fox S. 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