Eprints



EAACI position paper on how to classify cutaneous manifestations of drug hypersensitivity K. Brockow1, M. Ardern-Jones2, M. Mockenhaupt3, W. Aberer4, A. Barbaud5, JC. Caubet6, R. Spiewak7, M. Torres8, CG Mortz9 1Department of Dermatology und Allergology Biederstein, Division Environmental Dermatology and Allergology Helmholtz Zentrum München/TUM, Technical University Munich, Munich, Germany2Department of Dermatology, Southampton General Hospital, University Hospitals Southampton NHS Foundation Trust Southampton United Kingdom and Dermatoimmunology, Sir Henry Wellcome Laboratories, Clinical, Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom3Dept. of Dermatology, Medical Center and Medical Faculty, University of Freiburg, Freiburg, Germany4Department of Dermatology, Medical University of Graz, Austria5 Department of Dermatology and Allergology, Sorbonne Universities, Pierre et Marie Curie University, Paris 6, Tenon Hospital (AP-HP), Paris, France6 Geneva University Hospitals, Pediatric Allergology Unit, 6 Rue Willy Donzé, 1205 Geneva, Switzerland7Department of Experimental Dermatology and Cosmetology, Jagiellonian University Medical College, Krakow, Poland8Allergy Unit, IBIMA- Regional University Hospital of Malaga-UMA, Aradyal, Malaga, Spain 9 Department of Dermatology and Allergy Center, Odense Research Center for Anaphylaxis (ORCA), Odense University Hospital, Odense, DenmarkThe corresponding author and coordinator declares no conflict of interest. There has not been any conflict of interest by any of the coauthors. All named authors were involved consensus group meetings, retrival of informa-tion of drug allergy documentation in different countries and in the discussion and approval of the final manuscript.Corresponding Author: Prof. Dr.med. K. Brockow Department of Dermatology and Allergology BiedersteinTechnical University Munich, Biedersteiner Str. 29, 80802 München / GermanyTel. 0049 89 4140 3182; Fax 0049 89 4140 3127; Email knut.brockow@tum.deSUMMARYDrug hypersensitivity reactions (DHR) are common and the skin is by far the most frequently involved organ with a broad spectrum of reaction types. The diagnosis of cutaneous DHRs (CDHR) may be difficult because of multiple differential diagnoses. A correct classification is important for the correct diagnosis and management. With these guidelines, we aim to give precise definitions and provide the background needed for doctors to correctly classify CDHR.Abbreviations used: AGEP: Acute generalised exanthematous pustulosisCDHR: Cutaneous drug hypersensitivity reactionDHR: Drug hypersensitivity reactionDRESS: Drug reaction with eosinophilia and systemic symptomsEBV: Epstein-Barr virusFDE: Fixed drug eruptionGBFDE: Generalised bullous fixed drug eruptionMPE: Maculopapular exanthemNSAIDs: Nonsteroidal anti-inflammatory drugsPCR: Polymerase chain reactionSCAR: Severe cutaneous adverse reactionsSDRIFE: Symmetrical drug-related intertriginous and flexural exanthemaSJS: Stevens-Johnson syndrome TEN: Toxic epidermal necrolysisTNF: Tumor necrosis factorIntroductionDrug hypersensitivity reactions (DHR) affect more than 7% of the population and are a concern for doctors and patients alike PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZW1vbHk8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (1, 3), with a broad spectrum of reaction types with different morphology, chronology and mechanisms ADDIN EN.CITE <EndNote><Cite><Author>Brockow</Author><Year>2018</Year><RecNum>96</RecNum><DisplayText>(4)</DisplayText><record><rec-number>96</rec-number><foreign-keys><key app="EN" db-id="z0ftwfpeverxt0eza5fx00w6rw9ff0p2w0xs" timestamp="1513868997">96</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>K Brockow </author></authors><secondary-authors><author>Khan DA, Banerji A</author></secondary-authors></contributors><titles><title>Drug Allergy: Definitions and Phenotypes</title><secondary-title> Drug Allergy Testing</secondary-title></titles><section>p. 19-26</section><dates><year>2018</year></dates><pub-location>St. Louis, USA</pub-location><publisher>Elsevier</publisher><urls></urls></record></Cite></EndNote>(4). Different entities have not only unique clinical features, but also have own implications for causative drugs, diagnostic methods and management. We have described these entities where differences in clinical presentations and prognosis are clear, e.g. FDE (fixed drug eruption), DRESS (drug reaction with eosinophilia and systemic symptoms), SJS/TEN (Stevens-Johnson syndrome/ toxic epidermal necrolysis) and anaphylaxis. For benign cutaneous DHR (CDHR), a sub-classification has been attempted (e.g. morbilliform, lichenoid or maculopapular), but these terms are descriptive only because there is no evidence of pathologic or prognostic implications to distinguish the benign phenotypes. Therefore, we have collectively labelled all benign CDHR as maculopapular exanthems. Misclassification may easily lead to the wrong conclusion regarding diagnosis and management. This guideline focuses on the clinical manifestations of DHR which aid correct diagnostic classification. As recommended by the international consensus on drug allergy, we use the term DHR for objectively reproducible symptoms or signs initiated by exposure to a defined drug at a dose tolerated by a normal person that clinically resembles allergy, and we are focusing on CDHR ADDIN EN.CITE <EndNote><Cite><Author>Demoly</Author><Year>2014</Year><RecNum>70</RecNum><DisplayText>(1)</DisplayText><record><rec-number>70</rec-number><foreign-keys><key app="EN" db-id="05ee900xmpsseyespfu5xapi5x9d95wpvt0x" timestamp="0">70</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Demoly, P.</author><author>Adkinson, N. F.</author><author>Brockow, K.</author><author>Castells, M.</author><author>Chiriac, A. M.</author><author>Greenberger, P. A.</author><author>Khan, D. A.</author><author>Lang, D. M.</author><author>Park, H. S.</author><author>Pichler, W.</author><author>Sanchez-Borges, M.</author><author>Shiohara, T.</author><author>Thong, B. Y.</author></authors></contributors><titles><title>International Consensus on drug allergy</title><secondary-title>Allergy</secondary-title><alt-title>Allergy</alt-title></titles><pages>420-37</pages><volume>69</volume><number>4</number><edition>2014/04/05</edition><keywords><keyword>Drug Hypersensitivity/*diagnosis/etiology/prevention &amp; control/*therapy</keyword><keyword>Humans</keyword></keywords><dates><year>2014</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0105-4538</isbn><accession-num>24697291</accession-num><urls></urls><electronic-resource-num>10.1111/all.12350</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(1). Other terms used for CDHR nomenclature are explained in Table E1. The guideline aims to assist all clinicians managing DHR by providing the approach needed for doctors to correctly classify CDHR. Importantly, we have included precise definitions of CDHR, which we hope can become a standard tool for reference. Included in this guideline are: criteria for when to think of DHR; an overview and a classification of cutaneous drug hypersensitivity reactions (CDHR); a detailed clinical description of morphological aspects in the skin; differences between urticaria and exanthems; differential diagnoses; how to distinguish between different forms of CDHR; danger signs; and important considerations for diagnosis and management.Another part of the guideline is aimed at patients to give a standardised and better description of their skin manifestations as well as for important information to be given to the patient by the physician. Finally, recommendations for audit points are included.Material and methodsThis guideline was commissioned by the European Academy of Allergy and Clinical Immunology (EAACI) and undertaken by the Task Force on the Classification of Cutaneous Drug Hypersensitivity Reactions. It is based on evidence as well as on expert opinion. The preparation included a literature search in MEDLINE focusing on the search words listed in Tab. E1. We restricted the content of this paper to CDHR after systemic exposure. During the development of these guidelines, the consultation process included meetings in Munich in November 2016, in Zurich in April 2017 and in Helsinki in June 2017. Comments and suggestions were carefully considered and consented by the whole group.Description of cutaneous drug hypersensitivity reactionsHow to classify cutaneous drug hypersensitivity reactionsCorrect classification of CDHR into well-defined entities strongly depends on a thorough clinical examination and correct description of morphological features of the skin. As skin lesions constitute the essential foundation for later diagnosis, they are explained and summarised in Fig. E1 and Tab. E2 online. Furthermore, dermatological terms used for the morphological description are given in Table E3 online.DHR have also been classified according to chronology. Immediate (acute) DHR are correspondent to urticaria, angioedema and/or anaphylaxis occurring nearly always within the first hour, and non-immediate (late) exanthems occur later than six hours, mostly 24 hours, after drug intake. Whilst morphological classification from characterisation of primary lesions and clinical features remains most important, sometimes chronology gives further clues to the diagnosis, or aids exclusion of CDHR, or differentiation between CDHR. E.g. chronology is very helpful to distinguish between urticaria and early maculopapular exanthems (MPE) (Tab. 1). It is important to recognise that, post hoc, history of reported chronology is potentially unreliable, because it depends on the information provided by the patient. Morphology is more reliable, if it is assessed by experienced physicians in the acute phase, but needs to be described and classified correctly. Disease extent can be described as generalised (widespread; no major regions of skin are exempt), disseminated (several skin regions are involved), or localised (limited to a certain area of the body). Clinical phenotypes of generalised or disseminated DHRUrticaria, angioedema and anaphylaxisUrticaria is characterised by the sudden appearance of wheals (circumscribed areas of raised erythema and oedema of the superficial dermis) in variable number and size accompanied or not by angioedema (Fig. 1, Fig.2) ADDIN EN.CITE <EndNote><Cite><Author>Zuberbier</Author><Year>2009</Year><RecNum>73</RecNum><DisplayText>(5)</DisplayText><record><rec-number>73</rec-number><foreign-keys><key app="EN" db-id="05ee900xmpsseyespfu5xapi5x9d95wpvt0x" timestamp="0">73</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zuberbier, T.</author><author>Asero, R.</author><author>Bindslev-Jensen, C.</author><author>Walter Canonica, G.</author><author>Church, M. K.</author><author>Gimenez-Arnau, A.</author><author>Grattan, C. E.</author><author>Kapp, A.</author><author>Merk, H. F.</author><author>Rogala, B.</author><author>Saini, S.</author><author>Sanchez-Borges, M.</author><author>Schmid-Grendelmeier, P.</author><author>Schunemann, H.</author><author>Staubach, P.</author><author>Vena, G. A.</author><author>Wedi, B.</author><author>Maurer, M.</author></authors></contributors><auth-address>Department of Dermatology and Allergy, Charite - Universitatsmedizin Berlin, Berlin, Germany.</auth-address><titles><title>EAACI/GA(2)LEN/EDF/WAO guideline: definition, classification and diagnosis of urticaria</title><secondary-title>Allergy</secondary-title><alt-title>Allergy</alt-title></titles><pages>1417-26</pages><volume>64</volume><number>10</number><edition>2009/09/24</edition><keywords><keyword>Allergens/adverse effects</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Humans</keyword><keyword>Hypersensitivity, Immediate/classification/diagnosis</keyword><keyword>Infant</keyword><keyword>Prevalence</keyword><keyword>*Urticaria/classification/diagnosis/physiopathology</keyword></keywords><dates><year>2009</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0105-4538</isbn><accession-num>19772512</accession-num><urls></urls><electronic-resource-num>10.1111/j.1398-9995.2009.02179.x</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(5). Wheals can be localised anywhere on the body. Urticaria has a fleeting nature, with the skin returning to its normal appearance, usually within 24 h ADDIN EN.CITE <EndNote><Cite><Author>Zuberbier</Author><Year>2009</Year><RecNum>73</RecNum><DisplayText>(5)</DisplayText><record><rec-number>73</rec-number><foreign-keys><key app="EN" db-id="05ee900xmpsseyespfu5xapi5x9d95wpvt0x" timestamp="0">73</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zuberbier, T.</author><author>Asero, R.</author><author>Bindslev-Jensen, C.</author><author>Walter Canonica, G.</author><author>Church, M. K.</author><author>Gimenez-Arnau, A.</author><author>Grattan, C. E.</author><author>Kapp, A.</author><author>Merk, H. F.</author><author>Rogala, B.</author><author>Saini, S.</author><author>Sanchez-Borges, M.</author><author>Schmid-Grendelmeier, P.</author><author>Schunemann, H.</author><author>Staubach, P.</author><author>Vena, G. A.</author><author>Wedi, B.</author><author>Maurer, M.</author></authors></contributors><auth-address>Department of Dermatology and Allergy, Charite - Universitatsmedizin Berlin, Berlin, Germany.</auth-address><titles><title>EAACI/GA(2)LEN/EDF/WAO guideline: definition, classification and diagnosis of urticaria</title><secondary-title>Allergy</secondary-title><alt-title>Allergy</alt-title></titles><pages>1417-26</pages><volume>64</volume><number>10</number><edition>2009/09/24</edition><keywords><keyword>Allergens/adverse effects</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Humans</keyword><keyword>Hypersensitivity, Immediate/classification/diagnosis</keyword><keyword>Infant</keyword><keyword>Prevalence</keyword><keyword>*Urticaria/classification/diagnosis/physiopathology</keyword></keywords><dates><year>2009</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0105-4538</isbn><accession-num>19772512</accession-num><urls></urls><electronic-resource-num>10.1111/j.1398-9995.2009.02179.x</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(5), but the continual appearance and disappearance of new lesions is characteristic ADDIN EN.CITE <EndNote><Cite><Author>Ardern-Jones</Author><Year>2011</Year><RecNum>64</RecNum><DisplayText>(6)</DisplayText><record><rec-number>64</rec-number><foreign-keys><key app="EN" db-id="05ee900xmpsseyespfu5xapi5x9d95wpvt0x" timestamp="0">64</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ardern-Jones, M. R.</author><author>Friedmann, P. S.</author></authors></contributors><auth-address>Division of Infection, Inflammation and Immunity, University of Southampton School of Medicine, Mailpoint 825, Level F, South Block, Sir Henry Wellcome Laboratories, Southampton General Hospital, Southampton SO16 6YD, UK. m.aj@soton.ac.uk</auth-address><titles><title>Skin manifestations of drug allergy</title><secondary-title>Br J Clin Pharmacol</secondary-title><alt-title>British journal of clinical pharmacology</alt-title></titles><pages>672-83</pages><volume>71</volume><number>5</number><edition>2011/04/13</edition><keywords><keyword>Drug Eruptions/diagnosis/*immunology/therapy</keyword><keyword>Exanthema/chemically induced</keyword><keyword>Humans</keyword><keyword>Stevens-Johnson Syndrome/etiology</keyword><keyword>T-Lymphocytes/immunology</keyword></keywords><dates><year>2011</year><pub-dates><date>May</date></pub-dates></dates><isbn>0306-5251</isbn><accession-num>21480947</accession-num><urls></urls><custom2>PMC3093073</custom2><electronic-resource-num>10.1111/j.1365-2125.2010.03703.x</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(6).When the oedema in the skin is larger and involves the deeper dermis +/- subcutis, the condition is called angioedema. Angioedema often affects the face (cheeks, eyelids, lips or ears) and genitalia, but also buccal mucosa, tongue, larynx and pharynx. It is often accompanied by pain and heat rather than itching. Its resolution is slower than that of wheals and may last for several days ADDIN EN.CITE <EndNote><Cite><Author>Greaves</Author><Year>1991</Year><RecNum>66</RecNum><DisplayText>(7)</DisplayText><record><rec-number>66</rec-number><foreign-keys><key app="EN" db-id="05ee900xmpsseyespfu5xapi5x9d95wpvt0x" timestamp="0">66</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Greaves, M.</author><author>Lawlor, F.</author></authors></contributors><auth-address>Institute of Dermatology, St. Thomas&apos;s Hospital, London, U.K.</auth-address><titles><title>Angioedema: manifestations and management</title><secondary-title>J Am Acad Dermatol</secondary-title><alt-title>Journal of the American Academy of Dermatology</alt-title></titles><pages>155-61; discussion 161-5</pages><volume>25</volume><number>1 Pt 2</number><edition>1991/07/01</edition><keywords><keyword>*Angioedema/drug therapy/etiology/genetics/physiopathology</keyword><keyword>Humans</keyword></keywords><dates><year>1991</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0190-9622 (Print)&#xD;0190-9622</isbn><accession-num>1869690</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(7). Urticaria and angioedema are associated in about half of cases. Urticaria and angioedema can be accompanied by systemic involvement (normally cardiovascular or respiratory involvement), which has been defined as anaphylaxis ADDIN EN.CITE <EndNote><Cite><Author>Simons</Author><Year>2008</Year><RecNum>65</RecNum><DisplayText>(8)</DisplayText><record><rec-number>65</rec-number><foreign-keys><key app="EN" db-id="05ee900xmpsseyespfu5xapi5x9d95wpvt0x" timestamp="0">65</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Simons, F. E.</author></authors></contributors><auth-address>Section of Allergy and Clinical Immunology, Department of Pediatrics and Child Health, the Department of Immunology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada. lmcniven@hsc.mb.ca</auth-address><titles><title>9. Anaphylaxis</title><secondary-title>J Allergy Clin Immunol</secondary-title><alt-title>The Journal of allergy and clinical immunology</alt-title></titles><pages>S402-7; quiz S420</pages><volume>121</volume><number>2 Suppl</number><edition>2008/02/05</edition><keywords><keyword>*Anaphylaxis/diagnosis/etiology/physiopathology/therapy</keyword><keyword>Epinephrine/administration &amp; dosage/therapeutic use</keyword><keyword>Humans</keyword><keyword>Immunologic Tests</keyword><keyword>Injections</keyword><keyword>Risk Reduction Behavior</keyword></keywords><dates><year>2008</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0091-6749</isbn><accession-num>18241691</accession-num><urls></urls><electronic-resource-num>10.1016/j.jaci.2007.08.061</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(8) and can lead to respiratory collapse, shock and death ADDIN EN.CITE <EndNote><Cite><Author>Roujeau</Author><Year>2005</Year><RecNum>67</RecNum><DisplayText>(9)</DisplayText><record><rec-number>67</rec-number><foreign-keys><key app="EN" db-id="05ee900xmpsseyespfu5xapi5x9d95wpvt0x" timestamp="0">67</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Roujeau, J. C.</author></authors></contributors><auth-address>Service de Dermatologie, Hopital Henri Mondor, Universite Paris XII, 94010 Creteil, France. jean-claude.roujeau@hmn.ap-hop-paris.fr</auth-address><titles><title>Clinical heterogeneity of drug hypersensitivity</title><secondary-title>Toxicology</secondary-title><alt-title>Toxicology</alt-title></titles><pages>123-9</pages><volume>209</volume><number>2</number><edition>2005/03/16</edition><keywords><keyword>Animals</keyword><keyword>Drug Eruptions/complications/immunology/pathology</keyword><keyword>Drug Hypersensitivity/complications/*immunology/pathology</keyword><keyword>Humans</keyword><keyword>Skin/pathology</keyword></keywords><dates><year>2005</year><pub-dates><date>Apr 15</date></pub-dates></dates><isbn>0300-483X (Print)&#xD;0300-483x</isbn><accession-num>15767024</accession-num><urls></urls><electronic-resource-num>10.1016/j.tox.2004.12.022</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(9). Anaphylaxis mostly comes with skin lesions such as urticaria or a generalised flush, but rarely may occur without either. Drug-related urticaria, angioedema or anaphylaxis usually begins within one hour of drug administration. However, angioedema alone (without urticaria) induced as a side effect of angiotensin-converting enzyme inhibitors, may begin after months or years of treatment, although this is not a true ‘hypersensitivity’ reaction.Disseminated and generalised exanthemsAn exanthem is not a disease, but a description of a clinical picture. There is no consensus definition of an exanthem. Medical dictionaries define it either as any rash, as a widespread rash, or as a rapidly erupting rash that may have diagnostic features of an infectious disease. In Greek exanthema (?ξ?νθημα exánthēma) stands for “blossoming” or “breaking out” highlighting the sudden appearance and colour change of the eruption. We define an exanthem as an acutely erupting, widespread distribution of multiple small, round to oval erythematous macules and/or papules with different degrees of confluence. The individual lesions persist for several days (in contrast to urticaria wheals which resolve more rapidly). Before the diagnosis of a maculopapular exanthem is made, other entities where exanthems are associated with blisters, pustules, or special distribution have to be ruled out (Tab. 2, Fig. 1, Fig.2). Bullous exanthemsSmall isolated vesicles and pustules may develop in any MPE. The more severe bullous entities are called Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). SJS and TEN are considered as severity variants of the same disease entity, recently referred to as epidermal or epithelial necrolysis (EN) ADDIN EN.CITE <EndNote><Cite><Author>Roujeau</Author><Year>2017</Year><RecNum>93</RecNum><DisplayText>(10)</DisplayText><record><rec-number>93</rec-number><foreign-keys><key app="EN" db-id="z0ftwfpeverxt0eza5fx00w6rw9ff0p2w0xs" timestamp="1513867883">93</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Roujeau, J. C.</author><author>Mockenhaupt, M.</author><author>Guillaume, J. C.</author><author>Revuz, J.</author></authors></contributors><auth-address>University Paris-Est, Creteil, France. Electronic address: jean-claude.roujeau@wanadoo.fr.&#xD;Universitatsklinikum/Medical Center and Faculty of Medicine, University of Freiburg, Germany.&#xD;La Rochelle, France (retired).&#xD;Paris, France (retired).</auth-address><titles><title>New Evidence Supporting Cyclosporine Efficacy in Epidermal Necrolysis</title><secondary-title>J Invest Dermatol</secondary-title><alt-title>The Journal of investigative dermatology</alt-title></titles><periodical><full-title>J Invest Dermatol</full-title><abbr-1>The Journal of investigative dermatology</abbr-1></periodical><alt-periodical><full-title>J Invest Dermatol</full-title><abbr-1>The Journal of investigative dermatology</abbr-1></alt-periodical><pages>2047-2049</pages><volume>137</volume><number>10</number><edition>2017/09/25</edition><keywords><keyword>Cyclosporine/*therapeutic use</keyword><keyword>Humans</keyword><keyword>Immunosuppressive Agents/therapeutic use</keyword><keyword>*Practice Guidelines as Topic</keyword><keyword>Stevens-Johnson Syndrome/*drug therapy</keyword></keywords><dates><year>2017</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0022-202x</isbn><accession-num>28941473</accession-num><urls></urls><electronic-resource-num>10.1016/j.jid.2017.07.828</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(10) and have to be differentiated from erythema multiforme majus (EM with mucosal involvement; EMM). EMM presents with typical target lesions with or without raised atypical target lesions, any minimal epidermal detachment is confined to the very small localised centres of the targets, and the lesions do not show confluence. EMM is often restricted to the limbs, but can sometimes be disseminated. In contrast, the lesions in SJS/TEN are macules and flat atypical targets that do show confluence and on which blisters occur leading to various amounts of skin detachment. Hemorrhagic erosions of mucous membranes and fever are present in both conditions and therefore are no criterion for differentiation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXVsbWFubjwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+

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ADDIN EN.CITE.DATA (11). EMM is mainly, if not exclusively caused by infections (especially respiratory viral or mycoplasma pneumoniae infections), and is often associated with a flu-like illness. SJS/TEN cases are, in the majority circumstances, caused by drugs. SJS/TEN typically starts with small blisters arising on purple macules and atypical flat target lesions, which are widespread and usually predominant on the trunk. The skin may be initially painful. Bullous lesions develop fast, often within 12 hours, both on the skin and on mucous membranes (oral, nasal, conjunctival, genital, anal). Patients are severely ill and often develop fever. The area of confluent bullae leading to detachment of the skin is <10 % (as calculated in burns) of the total body surface in SJS, 10-30% in SJS/TEN overlap and > 30% in TEN. Nikolsky’s sign is positive (lateral extension of a blister with light pressure from a finger). Mortality is high (9% in SJS, 29% in SJS/TEN overlap, 48% in TEN) and mainly depends on age of the patient and extent of skin detachment ADDIN EN.CITE <EndNote><Cite ExcludeYear="1"><Author>Mockenhaupt</Author><RecNum>95</RecNum><DisplayText>(12)</DisplayText><record><rec-number>95</rec-number><foreign-keys><key app="EN" db-id="z0ftwfpeverxt0eza5fx00w6rw9ff0p2w0xs" timestamp="1513868135">95</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>M Mockenhaupt </author></authors><secondary-authors><author>Burgdorf W, Plewig G, Wolff H, Landthaler M</author></secondary-authors></contributors><titles><title>Severe Cutaneous Adverse Reactions</title><secondary-title>Braun-Falco?s Dermatology</secondary-title></titles><pages>473-86</pages><volume>3 ed</volume><dates></dates><publisher>Berlin, Heidelberg: Springer</publisher><urls></urls></record></Cite></EndNote>(12). Furthermore, the time to withdrawal of the culprit drug is important prognostically ADDIN EN.CITE <EndNote><Cite><Author>Garcia-Doval</Author><Year>2000</Year><RecNum>75</RecNum><DisplayText>(13)</DisplayText><record><rec-number>75</rec-number><foreign-keys><key app="EN" db-id="05ee900xmpsseyespfu5xapi5x9d95wpvt0x" timestamp="0">75</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Garcia-Doval, I.</author><author>LeCleach, L.</author><author>Bocquet, H.</author><author>Otero, X. L.</author><author>Roujeau, J. C.</author></authors></contributors><auth-address>Department of Dermatology, Hospital Provincial de Pontevedra, Spain.</auth-address><titles><title>Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death?</title><secondary-title>Arch Dermatol</secondary-title><alt-title>Archives of dermatology</alt-title></titles><pages>323-7</pages><volume>136</volume><number>3</number><edition>2000/03/21</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Animals</keyword><keyword>Drug-Related Side Effects and Adverse Reactions</keyword><keyword>Female</keyword><keyword>Half-Life</keyword><keyword>Humans</keyword><keyword>Logistic Models</keyword><keyword>Longitudinal Studies</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Odds Ratio</keyword><keyword>Pharmaceutical Preparations/administration &amp; dosage</keyword><keyword>Prognosis</keyword><keyword>Stevens-Johnson Syndrome/*chemically induced/*etiology/*mortality</keyword><keyword>Time Factors</keyword></keywords><dates><year>2000</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0003-987X (Print)&#xD;0003-987x</isbn><accession-num>10724193</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(13). The typical time latency between first dose of drug and onset of SJS/TEN is 4 days to 4 weeks, but can be up to 8 weeks for drugs with a long half-life. The drugs most commonly implicated in SJS/TEN are allopurinol, antibacterial sulfonamides including sulfasalazine, certain antiepileptics (carbamazepine, lamotrigine, phenobarbital, phenytoin), nevirapine and oxicam NSAIDs ADDIN EN.CITE <EndNote><Cite><Author>Mockenhaupt</Author><Year>2008</Year><RecNum>76</RecNum><DisplayText>(14)</DisplayText><record><rec-number>76</rec-number><foreign-keys><key app="EN" db-id="05ee900xmpsseyespfu5xapi5x9d95wpvt0x" timestamp="0">76</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mockenhaupt, M.</author><author>Viboud, C.</author><author>Dunant, A.</author><author>Naldi, L.</author><author>Halevy, S.</author><author>Bouwes Bavinck, J. N.</author><author>Sidoroff, A.</author><author>Schneck, J.</author><author>Roujeau, J. C.</author><author>Flahault, A.</author></authors></contributors><auth-address>Dokumentationszentrum schwerer Hautreaktionen, Department of Dermatology, University Medical Center, Freiburg, Germany. dzh@uniklinik-freiburg.de</auth-address><titles><title>Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study</title><secondary-title>J Invest Dermatol</secondary-title><alt-title>The Journal of investigative dermatology</alt-title></titles><pages>35-44</pages><volume>128</volume><number>1</number><edition>2007/09/07</edition><keywords><keyword>Adrenal Cortex Hormones/adverse effects</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Analgesics/adverse effects</keyword><keyword>Case-Control Studies</keyword><keyword>Humans</keyword><keyword>Middle Aged</keyword><keyword>Nevirapine/adverse effects</keyword><keyword>Risk</keyword><keyword>Sertraline/adverse effects</keyword><keyword>Stevens-Johnson Syndrome/*etiology</keyword><keyword>Time Factors</keyword><keyword>Triazines/adverse effects</keyword></keywords><dates><year>2008</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0022-202x</isbn><accession-num>17805350</accession-num><urls></urls><electronic-resource-num>10.1038/sj.jid.5701033</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(14).Sometimes multilocular fixed drug eruptions do occur. If they are bullous and widespread over the body, they are called generalised bullous fixed drug eruption (GBFDE). In contrast to patients with SJS/TEN, patients with GBFDE have no systemic symptoms, the lesions are well demarcated and the mucous membranes are rarely or only minimally involved. In contrast to SJS/TEN the culprit drug has usually been taken and tolerated before (sensitisation period) and milder earlier episodes are often reported. However, recurrent events may increase in severity leading to a substantial death rate in elderly patients (up to 22%) ADDIN EN.CITE <EndNote><Cite><Author>Lipowicz</Author><Year>2013</Year><RecNum>77</RecNum><DisplayText>(15)</DisplayText><record><rec-number>77</rec-number><foreign-keys><key app="EN" db-id="05ee900xmpsseyespfu5xapi5x9d95wpvt0x" timestamp="0">77</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lipowicz, S.</author><author>Sekula, P.</author><author>Ingen-Housz-Oro, S.</author><author>Liss, Y.</author><author>Sassolas, B.</author><author>Dunant, A.</author><author>Roujeau, J. C.</author><author>Mockenhaupt, M.</author></authors></contributors><auth-address>Department of Dermatology, Hopital Henri Mondor, Universite Paris-Est-Creteil, Creteil, France.</auth-address><titles><title>Prognosis of generalized bullous fixed drug eruption: comparison with Stevens-Johnson syndrome and toxic epidermal necrolysis</title><secondary-title>Br J Dermatol</secondary-title><alt-title>The British journal of dermatology</alt-title></titles><pages>726-32</pages><volume>168</volume><number>4</number><edition>2013/02/19</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Case-Control Studies</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Drug Eruptions/*mortality</keyword><keyword>Europe/epidemiology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Length of Stay/statistics &amp; numerical data</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prognosis</keyword><keyword>Stevens-Johnson Syndrome/*mortality</keyword><keyword>Young Adult</keyword></keywords><dates><year>2013</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0007-0963</isbn><accession-num>23413807</accession-num><urls></urls><electronic-resource-num>10.1111/bjd.12133</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(15).Acute generalised exanthematous pustulosis (AGEP)Sudden onset of disseminated non-follicular, small sterile pustules on the background of a widespread confluent exanthem are the hallmarks of AGEP. 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ADDIN EN.CITE.DATA (17, 18). The most common type, drug-induced leuko-cytoclastic vasculitis, presents with palpable purpura, petechiae, bullae which can lead to necrosis and is indistinguishable from vasculitis due to other causes. When accompanied by fever, arthralgia, haematuria or proteinurea as well as lymphadenopathy a serum sickness reaction can be suspected. Serum-sickness-like reactions have been particularly described in children after intake of cefaclor PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hb21lczwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (19). Drug reaction with eosinophilia and systemic symptoms (DRESS)DRESS is a severe condition that often starts with maculopapular exanthem also involving internal organs. Erythematous central facial swelling is typical. Fever, malaise and lymphadenopathy are mostly present. In the peripheral blood, eosinophilia, leukocytosis and atypical lymphocytes are often found. Agranulocytosis and anemia may occur. Concerning further involvement of internal organs, hepatitis with elevation of liver enzymes (twice the normal value on at least two different days) is most commonly found. Other visceral organ involvement, such as nephritis, pneumonitis, colitis and pancreatitis or arthritis is less often seen. The exanthem typically starts relatively late after the first dose of medication (2-12 weeks). As in SJS/TEN and most cases of AGEP, DRESS usually arises during the first continuous use of the culprit drug.Mortality has been variably reported, usually related to liver failure, but in a large series of strictly validated cases of DRESS was 2% (20). However, prolonged courses and flare-ups, even after discontinuation of the culprit drug, are common. This has been linked to reactivation of herpes viruses (Human Herpes Virus 6/7, Epstein Barr Virus, Cytomegalovirus), which are commonly detected in DRESS. Drugs with a high risk for DRESS include antiepileptic drugs (e.g. carbamazepine, lamotrigine, phenobarbital and phenytoin), minocycline, allopurinol, and dapsone. In a recent study allopurinol and carbamazepine accounted for 38% of DRESS cases ADDIN EN.CITE <EndNote><Cite><Author>Kardaun</Author><Year>2013</Year><RecNum>80</RecNum><DisplayText>(20)</DisplayText><record><rec-number>80</rec-number><foreign-keys><key app="EN" db-id="05ee900xmpsseyespfu5xapi5x9d95wpvt0x" timestamp="0">80</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kardaun, S. H.</author><author>Sekula, P.</author><author>Valeyrie-Allanore, L.</author><author>Liss, Y.</author><author>Chu, C. Y.</author><author>Creamer, D.</author><author>Sidoroff, A.</author><author>Naldi, L.</author><author>Mockenhaupt, M.</author><author>Roujeau, J. C.</author></authors></contributors><auth-address>Department of Dermatology, Reference Center for Cutaneous Adverse Reactions, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713, GZ, Groningen, the Netherlands.</auth-address><titles><title>Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study</title><secondary-title>Br J Dermatol</secondary-title><alt-title>The British journal of dermatology</alt-title></titles><pages>1071-80</pages><volume>169</volume><number>5</number><edition>2013/07/17</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Drug Eruptions/diagnosis</keyword><keyword>Drug Hypersensitivity Syndrome/*diagnosis</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prognosis</keyword><keyword>Prospective Studies</keyword><keyword>Registries</keyword></keywords><dates><year>2013</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0007-0963</isbn><accession-num>23855313</accession-num><urls></urls><electronic-resource-num>10.1111/bjd.12501</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(20).Symmetrical drug-related intertriginous and flexural exanthem (SDRIFE)A special pattern of a maculopapular exanthem with a characteristic distribution pattern involving flexural and intertriginous areas is called SDRIFE. Typically, a sharply delineated erythema of the perigenital and perianal area as well as the axillae and other intertriginous folds is seen. Males are more often affected than females. Few pustules may be observed and there may be an overlap with acute generalised exanthematous pustulosis. The patients are generally well without systemic symptoms and signs. Postexanthematous desquamation is often seen. The main elicitors of SDRIFE are aminopenicillins (6).Maculopapular ExanthemThe most frequent DHR are maculopapular exanthems (MPE) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GaXN6ZW5zb24tQWxiYWxhPC9BdXRob3I+PFllYXI+MjAw

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ADDIN EN.CITE.DATA (21, 22). MPEs usually appear between four and 14 days after a new drug has been started. However, in a sensitised individual initial symptoms already may appear within few hours and develop into a typical exanthem after one or two days. MPE can also arise a few days after the drug intake has been stopped. Erythematous macules and infiltrated papules are the primary lesions. The trunk and the proximal extremities are most often involved in a symmetric distribution. However, widespread exanthems may generalise, become confluent and develop into erythroderma. Whereas in early phases typically no scaling occurs, desquamation is common in the later clearing phase. Mucous membranes are normally not involved. Pruritus is typical. Fever and systemic involvement may occasionally occur but are very mild. It is important to understand that exanthems with macules and papules can be the early presenting findings of severe CDHR (e.g. DRESS, SJS/TEN), which usually become evident within 48 hours (see danger signs). Distinguishing MPE from other disseminated and generalised exanthemsIt is important to note that MPE is essentially diagnosed by exclusion. Although the patient with MPE may develop fever, mild systemic symptoms, or rarely minimal vesicles or pustules, they do not show the typical features of one of the specific severe entities (as described above). Therefore, the course of the MPE has to be regularly monitored in the initial phase to exclude early signs of DRESS, SJS/TEN or AGEP. A diagnosis of MPE is retained because of the benign course and clinical picture. There are cases, which show features of two different of the described entities, e.g. DRESS and SJS/TEN, AGEP and SJS/TEN or AGEP and SDRIFE, or any of these and MPE. We do not encourage the routine use of the term “overlap” and it is recommended to use one diagnosis based on the most important clinical features, although this may be difficult in some patients. Localised reactionsFixed drug eruptionFixed drug eruption (FDE) manifests with a characteristic erythematous to violaceous, sometimes oedematous plaque, which may become bullous centrally. This lesion always arises at the same site less than two days after re-exposure to the culprit drug. The lesion characteristically resolves with residual hyperpigmentation. Multi-site bullous fixed drug eruptions may occur (see GBFDE above). Systemic photoallergic reactionsPhotoallergic and phototoxic reactions to systemically applied drugs develop after ingestion of the sensitiser medication where light initiates an immune or a phototoxic response. In the case of photoallergic reactions, these are manifested by interaction between the immune system and a photohapten. Phototoxic reactions are mediated by drug induced epidermal photo-oxidative stress, and not classical hypersensitivity. Systemic photoallergy induces dermatitis (eczema) predominantly affecting the sun-exposed areas (may also spread to covered body sites), whereas phototoxic reactions causes sunburn-like changes (sharply demarcated erythema, with or without vesicles and blisters, and subsequent hyperpigmentation). The onset of photoallergy after drug exposure varies from a few days to 3 years of daily drug intake PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib3JpbzwvQXV0aG9yPjxZZWFyPjE5Nzk8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (23-26). Such variability may be due to the fact that the development of photoallergy is also dependent upon the highly unpredictable exposure of individuals to provoking light. Differentiating photoallergic and phototoxic reactions can difficult and will often require specialist assessment. In the case of photoallergic reactions, borders of involved areas are typically less well demarcated, with erythema, oedema and papules often spreading to covered skin areas. The eruption often demonstrates an aggravating “crescendo” pattern lasting for a few days after discontinuation of exposures, whereas phototoxic reactions usually subside immediately after withdrawal of either provoking factor (drug, light) ADDIN EN.CITE <EndNote><Cite><Author>Spiewak</Author><Year>2010</Year><RecNum>85</RecNum><DisplayText>(24)</DisplayText><record><rec-number>85</rec-number><foreign-keys><key app="EN" db-id="05ee900xmpsseyespfu5xapi5x9d95wpvt0x" timestamp="0">85</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Spiewak, R.</author></authors></contributors><auth-address>Institute of Dermatology, ul. Lentza 6M17, 31-312 Krakow, Poland. spiewak@onet.eu</auth-address><titles><title>Systemic photoallergy to terbinafine</title><secondary-title>Allergy</secondary-title><alt-title>Allergy</alt-title></titles><pages>1071-2</pages><volume>65</volume><number>8</number><edition>2010/02/04</edition><keywords><keyword>Antifungal Agents/*adverse effects</keyword><keyword>Dermatitis, Photoallergic/diagnosis/drug therapy/*etiology</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Naphthalenes/*adverse effects</keyword><keyword>Patch Tests/methods</keyword><keyword>Steroids/therapeutic use</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2010</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0105-4538</isbn><accession-num>20121763</accession-num><urls></urls><electronic-resource-num>10.1111/j.1398-9995.2009.02311.x</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(24). Photopatch testing with suspected drugs is essential for diagnosis ADDIN EN.CITE <EndNote><Cite><Author>Bruynzeel</Author><Year>2004</Year><RecNum>88</RecNum><DisplayText>(27)</DisplayText><record><rec-number>88</rec-number><foreign-keys><key app="EN" db-id="05ee900xmpsseyespfu5xapi5x9d95wpvt0x" timestamp="0">88</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bruynzeel, D. P.</author><author>Ferguson, J.</author><author>Andersen, K.</author><author>Goncalo, M.</author><author>English, J.</author><author>Goossens, A.</author><author>Holzle, E.</author><author>Ibbotson, S. H.</author><author>Lecha, M.</author><author>Lehmann, P.</author><author>Leonard, F.</author><author>Moseley, H.</author><author>Pigatto, P.</author><author>Tanew, A.</author></authors></contributors><auth-address>Photobiology Unit, Ninewells Hospital, Medical School, Dundee DD19SY, UK.</auth-address><titles><title>Photopatch testing: a consensus methodology for Europe</title><secondary-title>J Eur Acad Dermatol Venereol</secondary-title><alt-title>Journal of the European Academy of Dermatology and Venereology : JEADV</alt-title></titles><pages>679-82</pages><volume>18</volume><number>6</number><edition>2004/10/16</edition><keywords><keyword>Dermatitis, Photoallergic/*diagnosis</keyword><keyword>Europe</keyword><keyword>Humans</keyword><keyword>Patch Tests/*standards</keyword><keyword>Sunscreening Agents/*adverse effects</keyword></keywords><dates><year>2004</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0926-9959 (Print)&#xD;0926-9959</isbn><accession-num>15482294</accession-num><urls></urls><electronic-resource-num>10.1111/j.1468-3083.2004.01053.x</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(27). Injection-site reactionsInjection site CDHR are typically non-immediate indurated pruritic erythematous patches or plaques, sometimes oedematous swellings, developing few hours to days after intramuscular or subcutaneous injection of drugs PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aZWx0c2VyPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48

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ADDIN EN.CITE.DATA (28). In extreme cases, MPE may develop, if the application of the drug is continued. More serious reactions may reveal vesicles or bullae, necrosis or ulceration.Specific clinical reaction patterns to chemotherapeutic and biopharmaceuticalsChemotherapy and biopharmaceuticals are associated with urticaria and anaphylaxis (often elicited by platinum salts ADDIN EN.CITE <EndNote><Cite><Author>Leguy-Seguin</Author><Year>2007</Year><RecNum>2</RecNum><DisplayText>(29)</DisplayText><record><rec-number>2</rec-number><foreign-keys><key app="EN" db-id="05ee900xmpsseyespfu5xapi5x9d95wpvt0x" timestamp="0">2</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Leguy-Seguin, V.</author><author>Jolimoy, G.</author><author>Coudert, B.</author><author>Pernot, C.</author><author>Dalac, S.</author><author>Vabres, P.</author><author>Collet, E.</author></authors></contributors><auth-address>Dermatology Department, University Hospital, Dijon Cedex, France.</auth-address><titles><title>Diagnostic and predictive value of skin testing in platinum salt hypersensitivity</title><secondary-title>J Allergy Clin Immunol</secondary-title><alt-title>The Journal of allergy and clinical immunology</alt-title></titles><pages>726-30</pages><volume>119</volume><number>3</number><edition>2007/01/30</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Antineoplastic Agents/*immunology</keyword><keyword>Carboplatin/immunology</keyword><keyword>Cisplatin/immunology</keyword><keyword>Cross Reactions</keyword><keyword>Drug Hypersensitivity/*diagnosis</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Organoplatinum Compounds/immunology</keyword><keyword>Platinum/*immunology</keyword><keyword>Prognosis</keyword><keyword>Prospective Studies</keyword><keyword>Salts/*immunology</keyword><keyword>*Skin Tests</keyword></keywords><dates><year>2007</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0091-6749 (Print)&#xD;0091-6749</isbn><accession-num>17258305</accession-num><urls></urls><electronic-resource-num>10.1016/j.jaci.2006.11.640</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(29), taxanes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GZWxkd2VnPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48

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ADDIN EN.CITE.DATA (30) and biological drugs such as cetuximab, infliximab or rituximab). In addition, chemotherapeutic and biopharmaceuticals may lead to a variety of CDHRs with a distinct chronology and specific clinical features characteristic to the individual drug. Whereas severe cutaneous adverse reactions, such as SJS/TEN or DRESS are rare, cutaneous toxicities, such as alopecia and stomatitis are frequent to many chemotherapeuticals. Additionally, it is important to recognise that immunologically mediated but non-allergic cutaneous drug reactions are associated with many modern chemotherapy treatments. Whilst a full review of these reactions is beyond the scope of this manuscript, selected important issues are discussed: 1) Antiangiogenic agents, such as sorafenib can cause hand-foot syndrome, eczema-like lesions and palmoplantar erythrodysesthesia ADDIN EN.CITE <EndNote><Cite><Author>Lipworth</Author><Year>2009</Year><RecNum>34</RecNum><DisplayText>(32)</DisplayText><record><rec-number>34</rec-number><foreign-keys><key app="EN" db-id="05ee900xmpsseyespfu5xapi5x9d95wpvt0x" timestamp="0">34</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lipworth, A. D.</author><author>Robert, C.</author><author>Zhu, A. X.</author></authors></contributors><auth-address>Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.</auth-address><titles><title>Hand-foot syndrome (hand-foot skin reaction, palmar-plantar erythrodysesthesia): focus on sorafenib and sunitinib</title><secondary-title>Oncology</secondary-title><alt-title>Oncology</alt-title></titles><pages>257-71</pages><volume>77</volume><number>5</number><edition>2009/11/20</edition><keywords><keyword>Antineoplastic Agents/*adverse effects</keyword><keyword>Benzenesulfonates/*adverse effects</keyword><keyword>Drug Eruptions/drug therapy/*etiology/pathology</keyword><keyword>Erythema/*chemically induced/drug therapy/pathology</keyword><keyword>Foot Dermatoses/*chemically induced/drug therapy/pathology</keyword><keyword>Hand Dermatoses/*chemically induced/drug therapy/pathology</keyword><keyword>Humans</keyword><keyword>Indoles/*adverse effects</keyword><keyword>Niacinamide/analogs &amp; derivatives</keyword><keyword>Paresthesia/*chemically induced/drug therapy/pathology</keyword><keyword>Phenylurea Compounds</keyword><keyword>Prognosis</keyword><keyword>Pyridines/*adverse effects</keyword><keyword>Pyrroles/*adverse effects</keyword><keyword>Risk Factors</keyword><keyword>Syndrome</keyword></keywords><dates><year>2009</year></dates><isbn>0030-2414</isbn><accession-num>19923864</accession-num><urls></urls><electronic-resource-num>10.1159/000258880</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(32). 2) Hand-foot syndrome is a specific CDHR that begins 2 days to 3 weeks after a chemotherapy course with redness and a tingling or burning sensation on palms and soles, develops into a symmetric, sharply demarcated erythema of the palms and soles and can involve painful blisters, fissures and oedema. Lesions may spread to the rest of the body, especially intertriginous zones (e.g., axilla, groin). 3) Flagellate dermatoses are pruritic erythematous linear streaks with or without induction by scratching, which heal with hyperpigmentation on the trunk or extremities PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZXllcy1IYWJpdG88L0F1dGhvcj48WWVhcj4yMDE0PC9Z

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ADDIN EN.CITE.DATA (31) and may occur 12 hours to 6 months after chemotherapy initiation (e.g. bleomycin). 4) Injection site reactions are commonly caused by injectable biopharmaceuticals, whereas exanthems are less common. 5) Checkpoint inhibitors typically induce pruritus, and vitiligo. However, genuine CDHR are also frequent, varying from mild (MPE) to severe (e.g. bullous drug eruptions). 6) Phototoxicity is also a common problem, especially for erlotinib and vemurafenib. The latter also often causes folliculitis, cysts, pruritus, and exanthems ADDIN EN.CITE <EndNote><Cite><Author>Sinha</Author><Year>2012</Year><RecNum>36</RecNum><DisplayText>(33)</DisplayText><record><rec-number>36</rec-number><foreign-keys><key app="EN" db-id="05ee900xmpsseyespfu5xapi5x9d95wpvt0x" timestamp="0">36</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sinha, R.</author><author>Edmonds, K.</author><author>Newton-Bishop, J. A.</author><author>Gore, M. E.</author><author>Larkin, J.</author><author>Fearfield, L.</author></authors></contributors><auth-address>Department of Dermatology, Chelsea and Westminster Hospital, London SW10 9NH, U.K.</auth-address><titles><title>Cutaneous adverse events associated with vemurafenib in patients with metastatic melanoma: practical advice on diagnosis, prevention and management of the main treatment-related skin toxicities</title><secondary-title>Br J Dermatol</secondary-title><alt-title>The British journal of dermatology</alt-title></titles><pages>987-94</pages><volume>167</volume><number>5</number><edition>2012/08/24</edition><keywords><keyword>Clinical Trials as Topic</keyword><keyword>Drug Eruptions/diagnosis/*etiology/prevention &amp; control</keyword><keyword>Humans</keyword><keyword>Indoles/*adverse effects</keyword><keyword>Melanoma/*drug therapy</keyword><keyword>Protein Kinase Inhibitors/*adverse effects</keyword><keyword>Proto-Oncogene Proteins B-raf/*antagonists &amp; inhibitors</keyword><keyword>Skin Neoplasms/*drug therapy</keyword><keyword>Sulfonamides/*adverse effects</keyword></keywords><dates><year>2012</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0007-0963</isbn><accession-num>22913467</accession-num><urls></urls><electronic-resource-num>10.1111/bjd.12010</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(33) ADDIN EN.CITE <EndNote><Cite><Author>Luu</Author><Year>2007</Year><RecNum>41</RecNum><DisplayText>(34)</DisplayText><record><rec-number>41</rec-number><foreign-keys><key app="EN" db-id="05ee900xmpsseyespfu5xapi5x9d95wpvt0x" timestamp="0">41</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Luu, M.</author><author>Lai, S. E.</author><author>Patel, J.</author><author>Guitart, J.</author><author>Lacouture, M. E.</author></authors></contributors><auth-address>Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.</auth-address><titles><title>Photosensitive rash due to the epidermal growth factor receptor inhibitor erlotinib</title><secondary-title>Photodermatol Photoimmunol Photomed</secondary-title><alt-title>Photodermatology, photoimmunology &amp; photomedicine</alt-title></titles><pages>42-5</pages><volume>23</volume><number>1</number><edition>2007/01/27</edition><keywords><keyword>Aged</keyword><keyword>Carcinoma, Non-Small-Cell Lung/drug therapy</keyword><keyword>Dermatitis, Phototoxic/*etiology</keyword><keyword>Erlotinib Hydrochloride</keyword><keyword>Humans</keyword><keyword>Lung Neoplasms/drug therapy</keyword><keyword>Male</keyword><keyword>Protein Kinase Inhibitors/*adverse effects</keyword><keyword>Quinazolines/*adverse effects</keyword></keywords><dates><year>2007</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0905-4383 (Print)&#xD;0905-4383</isbn><accession-num>17254038</accession-num><urls></urls><electronic-resource-num>10.1111/j.1600-0781.2007.00273.x</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(34). 7) Epidermal growth factor receptor inhibitors (cetuximab, panitumumab, cefitinib, erlotinib) may cause a papulopustular eruption (acneiform rash), which develops after 1-2 weeks or later. Papules and pustules can be itchy or painful PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWd1aWFpPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48

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ADDIN EN.CITE.DATA (35). Cutaneous appendages may be involved with nail or hair abnormalities and painful paronychia. Diagnostic problems, pitfalls and cluesIdentification of the clinical pictureAn important and sometimes very difficult differentiation is between urticaria and an exanthem. Both manifestations can be differentiated by their different primary skin lesions (Table E2). The single wheal in urticaria is always temporary and will disappear within 24 (-36) hours, whereas every single lesion in an exanthem will persist for several days, because it is composed by a cellular infiltrate in the skin. Prior therapy with corticosteroids or antihistamines may reduce the oedematous component leaving only the macular aspect of an urticaria. It is recommended to circle around one or several lesions of a patient with a pen and check the persistence of these outlines for differentiation after one and two days. Chronological information, monitoring the course of the disease and duration of wheals (+/- histology rarely) may be needed to make the distinction. Exanthems may be morphologically subdivided according to their dominant primary skin lesions, shape or resemblance of other diseases into maculopapular, lichenoid (resembling lichen planus), urticarial (resembling urticaria, but longer lasting lesions), morbilliform (measles-like), vesicular (with vesicles), pustular (with pustules), acneiform (resembling acne vulgaris) exanthem (Table E4). We are summarising all these forms under the diagnosis maculopapular exanthem to avoid confusion in nomenclature and because the predominant picture may change with time as well as not be consistent in all skin areas. Danger signsImportantly, MPE and SJS/TEN or DRESS are different entities and it is believed that a severe CDHR cannot develop out of a persistent MPE. However, CDHR in early phases (within the first 2 days) may resemble MPE and identifying features (danger signs) for the severe CDHR may have to be looked for repeatedly. Specific early danger signs pointing to SJS/TEN are tiny vesicles or crusts, grey-violaceous or dusky colour of lesions, painful or burning skin and/or mucosa in addition to fever and malaise. When hemorrhagic erosions of mucous membranes and skin detachment are present, the reaction is obviously more severe, and differential diagnosis of SJS/TEN and other bullous conditions has to be considered. In cases of DRESS, the cutaneous lesions may appear like MPE for several days, but progression to more than 50% of the body surface area should prompt to further diagnostic means such as repeated check of laboratory values (differential blood count, liver and kidney parameters etc.). Furthermore, facial oedema and oedematous and infiltrated skin inflammation may point to a more severe reaction. Facial oedema can arise in DRESS as well as AGEP and blood counts may differentiate by revealing eosinophilia or neutrophilia respectively. Of the severe CDHR, AGEP is less likely to be misdiagnosed as MPE in the early stages, since it typically presents with larger areas of erythema, often predominantly in body folds and flexures of extremities. Dozens of non-follicular pustules usually occur within 1-2 days after occurrence of erythema. Acute fever of 38.5°C and higher is typically seen in AGEP, DRESS and SJS/TEN, but may rarely also accompany MPE.In AGEP and SJS/TEN transient elevation of liver enzymes and kidney parameters can be observed, but neither are diagnostic. However, biochemical abnormalities are hallmarks of DRESS, where the sequence of events is rather variable. The majority of reactions start with a skin eruption, followed by eosinophilia after several days (occasionally more than one week later), and by liver involvement another week later. Therefore, repeated lab tests are needed to confirm or exclude DRESS, especially when an extensive skin eruption with constitutional symptoms is present PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXVsbWFubjwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+

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ADDIN EN.CITE.DATA (37, 38).Differential diagnosisThere are multiple differential diagnoses for CDHR. The most important differential diagnosis of a drug-induced exanthem is an exanthem caused by an infection PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXViZXQ8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS

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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXViZXQ8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (39, 40).On a population level, the most common cause of an exanthem is a viral infection, particularly in children ADDIN EN.CITE <EndNote><Cite><Author>Goodyear</Author><Year>1991</Year><RecNum>59</RecNum><DisplayText>(41)</DisplayText><record><rec-number>59</rec-number><foreign-keys><key app="EN" db-id="05ee900xmpsseyespfu5xapi5x9d95wpvt0x" timestamp="0">59</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Goodyear, H. M.</author><author>Laidler, P. W.</author><author>Price, E. H.</author><author>Kenny, P. A.</author><author>Harper, J. I.</author></authors></contributors><auth-address>Department of Paediatrics, Queen Elizabeth Hospital for Children, London, U.K.</auth-address><titles><title>Acute infectious erythemas in children: a clinico-microbiological study</title><secondary-title>Br J Dermatol</secondary-title><alt-title>The British journal of dermatology</alt-title></titles><pages>433-8</pages><volume>124</volume><number>5</number><edition>1991/05/01</edition><keywords><keyword>Acute Disease</keyword><keyword>Adolescent</keyword><keyword>Bacterial Infections/complications/*diagnosis/pathology/prevention &amp; control</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Erythema/*etiology/pathology</keyword><keyword>Female</keyword><keyword>Fever/*etiology</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Infant, Newborn</keyword><keyword>Male</keyword><keyword>Pharynx/microbiology</keyword><keyword>Prospective Studies</keyword><keyword>Seasons</keyword><keyword>Skin/*pathology</keyword><keyword>Specimen Handling/methods</keyword><keyword>Virus Diseases/complications/*diagnosis/pathology</keyword></keywords><dates><year>1991</year><pub-dates><date>May</date></pub-dates></dates><isbn>0007-0963 (Print)&#xD;0007-0963</isbn><accession-num>2039718</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(41). Traditionally, six classic infectious exanthems have been described, i.e. measles (measles virus infection), scarlet fever (group A streptococcus infection), rubella (rubella virus infection), erythema infectiosum (syn. slapped cheek / fifth disease; parvovirus B19 infection), and exanthema subitum (syn. Roseola infantum; HHV-6 infection). Duke disease, syn. fourth disease, is no longer considered a specific entity. These exanthems are characterised by pathognomonic features (Tab. E5). “Atypical” exanthems ADDIN EN.CITE <EndNote><Cite><Author>Folster-Holst</Author><Year>2009</Year><RecNum>60</RecNum><DisplayText>(42)</DisplayText><record><rec-number>60</rec-number><foreign-keys><key app="EN" db-id="05ee900xmpsseyespfu5xapi5x9d95wpvt0x" timestamp="0">60</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Folster-Holst, R.</author><author>Kreth, H. W.</author></authors></contributors><auth-address>University Clinic Schleswig-Holstein-Campus Kiel, Clinic for Dermatology, Venerology and Allergology, Germany. rfoelsterholst@dermatology.uni-kiel.de</auth-address><titles><title>Viral exanthems in childhood--infectious (direct) exanthems. Part 2: Other viral exanthems</title><secondary-title>J Dtsch Dermatol Ges</secondary-title><alt-title>Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG</alt-title></titles><pages>414-9</pages><volume>7</volume><number>5</number><edition>2008/09/24</edition><keywords><keyword>Child</keyword><keyword>Exanthema/*diagnosis/*therapy/virology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Skin Diseases, Viral/*diagnosis/*therapy/virology</keyword></keywords><dates><year>2009</year><pub-dates><date>May</date></pub-dates></dates><isbn>1610-0379</isbn><accession-num>18808380</accession-num><urls></urls><electronic-resource-num>10.1111/j.1610-0387.2008.06869.x</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng&#xD;ger</language></record></Cite></EndNote>(42) caused by a variety of viruses or bacteria, such as Streptococcus are even more common and difficult to differentiate from drug exanthems, especially as drugs are often prescribed during a viral and/or bacterial infection. It has been shown that the vast majority of exanthems occurring during an antibiotic treatment are due to a viral infection PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXViZXQ8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (39, 40). Distinction between those and drug-induced exanthems during the acute phase is difficult. The chronology of the exanthem development, in comparison with the drug exposure timeline may give important clues (Tab. 1). Sometimes histology is helpful, although it is seldom solely diagnostic. Serology or PCR can be helpful during the diagnostic process, although a concomitant acute infection does not totally exclude drug hypersensitivity (i.e. EBV and amoxicillin hypersensitivity) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Pbm9kaS1OYWd5PC9BdXRob3I+PFllYXI+MjAxNTwvWWVh

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ADDIN EN.CITE.DATA (39, 43). In cases, where a CDHR cannot be ruled out based on clinical grounds, drug avoidance is mandatory after resolution of the disease until drug allergy testing can be arranged if indicated ADDIN EN.CITE <EndNote><Cite><Author>Demoly</Author><Year>2014</Year><RecNum>70</RecNum><DisplayText>(1)</DisplayText><record><rec-number>70</rec-number><foreign-keys><key app="EN" db-id="05ee900xmpsseyespfu5xapi5x9d95wpvt0x" timestamp="0">70</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Demoly, P.</author><author>Adkinson, N. F.</author><author>Brockow, K.</author><author>Castells, M.</author><author>Chiriac, A. M.</author><author>Greenberger, P. A.</author><author>Khan, D. A.</author><author>Lang, D. M.</author><author>Park, H. S.</author><author>Pichler, W.</author><author>Sanchez-Borges, M.</author><author>Shiohara, T.</author><author>Thong, B. Y.</author></authors></contributors><titles><title>International Consensus on drug allergy</title><secondary-title>Allergy</secondary-title><alt-title>Allergy</alt-title></titles><pages>420-37</pages><volume>69</volume><number>4</number><edition>2014/04/05</edition><keywords><keyword>Drug Hypersensitivity/*diagnosis/etiology/prevention &amp; control/*therapy</keyword><keyword>Humans</keyword></keywords><dates><year>2014</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0105-4538</isbn><accession-num>24697291</accession-num><urls></urls><electronic-resource-num>10.1111/all.12350</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(1). Also other dermatological diseases may mimic CDHR and have to be recognised. The most important differential diagnosis for drug-induced urticaria is spontaneous acute urticaria. Urticaria, angioedema and anaphylaxis often have triggers other than drugs and may occur spontaneously (idiopathic). Chronology is important to suspect drugs as a trigger (Tab. 1). Acute urticaria can be the first sign of evolving anaphylaxis. However, if urticaria is ongoing for some time without other organ involvement in the first few hours, development of anaphylaxis is highly unlikely. Differential diagnoses for exanthems include psoriasis, lichen planus, eczema, and pityriasis rosea. Characteristic lesions of psoriasis typically present with silvery, white scales on sharply demarcated erythematous plaques, coin-sized or guttate lesions in typical distribution of the lesions involving the scalp, extensor elbows, and extensor knees. A pustular variant of psoriasis has to be distinguished from AGEP. Several drugs may elicit or exacerbate psoriasis (such as beta-blockers or even TNF alpha-blockers) in a non-immunological manner PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb25naW9sZXR0aTwvQXV0aG9yPjxZZWFyPjIwMDk8L1ll

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ADDIN EN.CITE.DATA (44-46). In a person with genetic background for psoriasis, a drug-induced exanthem may induce psoriasis. Lichen planus is characterised by flat-topped violaceous papules favouring the wrist, forearms and often the buccal mucosa with different clinical variants. The differentiation between a lichenoid appearing drug-induced MPE and lichen planus may be challenging. In eczema, the clinical presentation of lesions is more diffuse and shows primary scaling reflecting epidermal inflammation (as compared to disseminated smaller lesions without scaling in the first days of MPE). Erythroderma (Table E3) may also be induced by drugs, but more commonly erythroderma is induced by atopic dermatitis, psoriasis, pityriasis rubra pilaris and cutaneous lymphoma. Pityriasis rosea is a, sometimes pruritic, self-limited eruption mainly in adolescents and young adults. In this disease a primary well-demarcated plaque on the trunk is followed by eruption of numerous smaller plaques with central fine scales often in a “Christmas tree” pattern. Other dermatological diseases that may mimic drug exanthems include systemic lupus erythematosus and dermatomyositis, and in cases with blisters, autoimmune blistering skin diseases, such as bullous pemphigoid or IgA-linear dermatosis. Kawasaki disease, unilateral laterothoracic exanthem and Sch?nlein-Henoch purpura are primarily differential diagnoses to CDHR in children. Conclusions and future needsThe diagnosis of CDHR may be difficult because of multiple differential diagnoses, particularly acute spontaneous urticaria and infectious exanthems, but also other dermatological diseases. In order to suspect a CDHR; A new drug (or repeated intake of a drug) has to be introduced to the patient with a specific time interval between intake and development of first symptoms (Tab. 1) and Typical clinical manifestations should be present (Tab. 2). These features differ substantially between the various clinical conditions. To make the correct diagnosis based on morphology, it is crucial to identify primary and secondary lesions (Tab. E2) and to use allergological (Tab. E1) and dermatological terms appropriately (Tab. E3). Most cases are elicited by classical culprit drugs (Tab. 1). However, this CDHR must be considered due to non-classical drugs if points 1 & 2 are met. The history and the clinical picture have important implications for management in the acute stage of the disease and for planning of diagnostic tests to be done later. If possible, patients should be assessed by experts during the acute phase of a reaction, enabling exclusion of several differential diagnoses both from the clinical picture and by histopathology, classification of clinical manifestations, recording of drugs used and follow-up of the course of the reaction. A standardised questionnaire to collect relevant information is available ADDIN EN.CITE <EndNote><Cite><Author>Demoly</Author><Year>1999</Year><RecNum>94</RecNum><DisplayText>(47)</DisplayText><record><rec-number>94</rec-number><foreign-keys><key app="EN" db-id="z0ftwfpeverxt0eza5fx00w6rw9ff0p2w0xs" timestamp="1513867907">94</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Demoly, P.</author><author>Kropf, R.</author><author>Bircher, A.</author><author>Pichler, W. J.</author></authors></contributors><auth-address>Maladies Respiratoires-INSERM U454, Hopital Arnaud de Villeneuve, University Hospital of Montpellier, France.</auth-address><titles><title>Drug hypersensitivity: questionnaire. EAACI interest group on drug hypersensitivity</title><secondary-title>Allergy</secondary-title><alt-title>Allergy</alt-title></titles><periodical><full-title>Allergy</full-title><abbr-1>Allergy</abbr-1></periodical><alt-periodical><full-title>Allergy</full-title><abbr-1>Allergy</abbr-1></alt-periodical><pages>999-1003</pages><volume>54</volume><number>9</number><edition>1999/10/03</edition><keywords><keyword>Diagnosis, Differential</keyword><keyword>Drug Hypersensitivity/*diagnosis</keyword><keyword>Humans</keyword><keyword>*Surveys and Questionnaires</keyword></keywords><dates><year>1999</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0105-4538 (Print)&#xD;0105-4538</isbn><accession-num>10505466</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(47) (Tab. E6) and its use is recommended for recording the relevant information to plan the management of the patient. Translations of this questionnaire into different languages are available under (website address EAACI). Often, information regarding the clinical reaction is only available from the patient or caregiver, in some cases with medical records (e.g., discharge letter, medical chart, anaesthesia protocols). In these cases, photography of the clinical reaction by the patient (often with smartphones) to identify the lesion pattern and body distribution, is very helpful and should be asked for. Appendix 1 describes a questionnaire for the patient to identify the principal information about the reaction. However, it is important to recognise that the information given by the patient is prone to error with significant limitations because of the lack of medical training. To monitor internal standards of these recommendations, audit points are given (Tab. E7)Figure legendsFigure 1. Algorithm for cutaneous drug hypersensitivity reactionFigure 2. Clinical pictures of cutaneous drug hypersensitivity reactions. A. Urticaria with wheals persisting only for <24 hours at the same spot, B. Stevens-Johnson syndrome with mucosal erosions and crusts as well as atypical target lesions and macules with confluent bullae and erosions, C. generalized bullous fixed drug eruption with central bullae on sharply demarcated violaceous erythema, D. acute generalized exanthematous pustulosis with superficial pustules on erythemas, E. vasculitis with palpable purpura, F. drug reaction with eosinophilia and systemic symptoms with widespread erythematous infiltrated lesions, G. Symmetrical drug-related intertriginous and flexural exanthem with intertriginous distribution, H. maculopapular exanthem with widespread erupting macules and papules, and I. injection site reaction with an indurated violaceous plaque after subcutaneous injection of a drug.Figure E1. Photographs of primary skin lesions important for drug hypersensitivityFigure 1. Algorithm for cutaneous drug hypersensitivity reaction*Figure 2. Clinical pictures of cutaneous drug hypersensitivity reactions. A. Urticaria with wheals persisting only for <24 hours at the same spot, B. Stevens-Johnson syndrome with mucosal erosions and crusts as well as atypical target lesions and macules with confluent bullae and erosions, C. generalized bullous fixed drug eruption with central bullae on sharply demarcated violaceous erythema, D. acute generalized exanthematous pustulosis with superficial pustules on erythemas, E. vasculitis with palpable purpura, F. drug reaction with eosinophilia and systemic symptoms with widespread erythematous infiltrated lesions, G. Symmetrical drug-related intertriginous and flexural exanthem with intertriginous distribution, H. maculopapular exanthem with widespread erupting macules and papules, and I. injection site reaction with an indurated violaceous plaque after subcutaneous injection of a drug.Table 1: Typical time intervals between initial drug use and first onset of symptoms (adapted from Brockow et al. Allergo J Int 2015 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ccm9ja293PC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48

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ADDIN EN.CITE.DATA (48))Hypersensitivity reactionTime interval from intake to reactionMost common elicitorsProportion of cases drug-inducedUrticaria/angioedemaa, anaphylaxisTypically within 1 haPenicillinCephalosporinNSAIDOften spontaneous or non-drug inducedSJS/TEN4–28 Days after start of usebAllopurinol, Certain antiepilepticsAntibacterial sulfonamides NevirapineOxicam-NSAIDsMostly drug inducedAGEP1–12 Days after start of usecBeta-lactam antibioticsMacrolidesDiltiazemTerbinafine(Hydroxy-) ChloroquineVast majority drug inducedVasculitis7-21 days after start of useBeta-lactam antibioticsNSAIDsAntibacterial sulfonamides CephalosporinsSeldom drug inducedDRESS2–8 Weeks after start of useCertain antiepilepticsAllopurinolDapsoneAntibacterial sulfonamidesVast majority drug inducedSDRIFEdUp to 7 daysBeta-lactam antibioticsVast majority drug inducedMaculopapular exanthem4–14 Days after start of useeAntibioticsAntiepilepticsAllopurinolNSAIDsOften infectious exanthems, exanthematic diseasesFDE30 minutes-8 hours after re-administrationAntibacterial sulfonamides NSAIDsBarbituratesTetracyclinesCarbamazepineMetamizoleVast majority drug inducedSystemic photoallergic reactionsDays-yearsNSAIDsPromethazineChlorpromazineMostly drug inducedSJS: Stevens-Johnson syndrome; TEN: toxic epidermal necrolysis; AGEP: acute generalised exanthematous pustulosis; DRESS: drug reaction with eosinophilia and systemic symptoms; SDRIFE: symmetrical drug-related intertriginous and flexural exanthema; FDE: fixed drug eruption; aACE (angiotensin-converting enzyme) inhibitors specifically induce angioedema, not associated with urticaria, that may begin even after months or years of treatment; bsometimes longer with allopurinol; cmostly 1–2 days with antibiotics, often 7–12 days with other medications; dsystemic reactivation of ACD; etime interval in repeated reactions typically shorter compared with the first reaction. In maculopapular drug eruptions, reaction typically seen after 1–4 days, typical time interval for repeated reactions has not been investigated in AGEP, SJS,TEN, and DRESS. Table 2. Typical clinical manifestations of cutaneous drug hypersensitivity reactions*See text for diagnostic detailsPrimary lesion & typical featuresDistributionOther importantsymptoms/ findings / complicationsPreferred method of diagnosisUrticariaWheals (hives)Single or widespread wheals Eventually concomitant angioedema, beware of anaphylaxisClinical, duration of a whealAngioedemaDeep swellingUsually face (eyelids, lips), less often extremities and genitalsOften asymmetricEventually concomitant urticaria, beware of anaphylaxis, Involvement of larynx, epiglottis -> upper airway obstruction (stridor)ClinicalSJS/TENaDusky red macules and flat atypical target lesions with blisters on topIsolated lesions/confluence of lesionsProdromal fever, upper respiratory tract symptomsMucosal involvement Usually systemic symptoms Clinical, Histology (subepidermal blisters, full thickness necrosis, IMF negative)GBFDEErythematous well-demarcated patches / plaques with blistersWidespread lesions with large areas of uninvolved skinMucous membranes may be involved No systemic symptomsClinical, often no mucosal involvement, patients are wellAGEP Pustules on oedematous erythemaBegins typically on face or intertriginous area, dissemination within hoursFeverLeucocytosis, Neutrophilia, Transient renal failure can occurClinical, Histology (intraedidermal pustules)VasculitisPurpuric papules Lower extremities primarilySystemic organ involvement may be present, hemorrhargic and/or necrotic lesionsClinical, Histology (leucocytoclasia)DRESSVariable: macules, papules, small superficial pustules, or vesicles, eczema-like, target-like lesions, purpuraFace, upper trunk, extremities FeverEosinophiliaLymphadenopathyHepatitis, myocarditis, interstitial pneumonitis and nephritis, thyroiditis, arthritisClinical, differential blood count and organ function abnormalities, profound lymophadenosisSDRIFE Sharply delineated erythemaFlexural and intertriginous areasUsually no systemic involvementClinical (involvement of the body folds)Maculopapular exanthemMacules, papulesTrunk > extremitiesMay be accompanied by low grade fever, pruritus and eosinophiliaClinical, Histology, Blood tests (lack of systemic involvement) FDEErythematous macule(s), plaque(s)Solitary lesion(s)By re-administration recurrence at the same sites Clinical, typical elicitor, rechallengeSystemic photoallergic reactionsDermatitisSun exposed areas, may spreadDoes not arise immediately on sun exposure (delay)Clinical (sun-exposed sites) Diagnosis by photopatch testInjection site reactionErythematous plaqueDrug injection site No systemic symptomsIn extreme cases can spread into MPEClinical (history of injection)SJS: Stevens-Johnson syndrome; TEN: toxic epidermal necrolysis; GBFDE: Generalised bullous fixed drug eruption; AGEP: acute generalised exanthematous pustulosis; DRESS: drug reaction with eosinophilia and systemic symptoms; SDRIFE: symmetrical drug-related intertriginous and flexural exanthema; FDE: fixed drug eruption; a detachment SJS < 10%, SJS/TEN overlap 10-30%, TEN>30%; Online Tables and FiguresFigure E1. Photographs of primary skin lesions important for drug hypersensitivity(Editing: can online photos of primary lesions electronically linked to terms in Table E2??)Bulla (blister)Detachment of the epidermis filled with clear fluid >5mm. Note that the precise level of the detachment (split) in the skin gives an indication of the cause and can arise intraepidermally or at the basement membrane zone. 2a1Tense large blisters in bullous pemphigoid2a2Confluence of blisters in TENTypical target lesionDescriptive term for a lesion with regular round shape, < 3cm in diameter, well-defined border and with three distinct zones showing colour change: a circular centre with epidermal damage in form of a vesicle, bulla, erosion or crust, an often edematous pale intermediate and a peripheral erythematous concentric rings. Typical target lesions often together with atypical two-zone papular target lesions are seen in in erythema multiforme. Atypical, but flat (macular, non-palpable) two-zone target-like lesion (multiform lesions) with poorly described border are seen in TEN/SJS2a3Typical target lesion, showing bullous center2a4Widespread EM exanthem with typical and atypical papular target lesionsMaculeA small (<1.5cm) area of colour change in the skin. May arise from changes in pigmentation, vascular supply, inflammation or deposition. In severe eruptions macules may coalesce.2a5MiliaSmall (<0.5mm) inclusion cysts in the epidermis as a consequence of trauma at the basement membrane (e.g. blistering)2a6NoduleDermally arising elevated lump, without involvement of the overlying epidermis2a7PapuleA small (<0.5cm) elevated lump protruding above the skin2a8PatchA large flat area of colour change, with smooth surface. ?2a9Patch of eczema following application of a drug allergenPetechiaA haemorrhagic punctuate spot measuring 1–2 mm in diameter.See purpuraPlaqueElevated plateau-like lesion, usually more than 2 cm in diameter. Plaques are rarely more than 5 mm in height. 2a10Post-inflammatory hyperpigmentationMelanosis arising as a result of inflammation. The increased pigment is visible for many months.2a11Pigmentation at the site of a fixed drug eruptionPurpuraExtravasation of red blood cells resulting in red discoloration of the skin or mucous membranes. Comprised of individual petechia.2a12Purpuric rash of the lower legsPustuleA circumscribed elevated lesion containing pus.2a13VesicleA small blister (less than 5 mm in diameter) consisting of clear fluid accumulated within or below the epidermis. 2a14Vesicles, some with incipient rupture.Wheal (Hive)Edematous red or white swelling of variable size and form, mostly surrounded by a reflex erythema and associated with itching. A wheal has a fleeting nature, with the skin returning to its normal appearance usually within 24 hours. Wheals are the characteristic sign of urticaria. 2a15Table E1 Definitions used in the context of cutaneous drug hypersensitivity reactions (adapted from ADDIN EN.CITE <EndNote><Cite><Author>Brockow</Author><Year>2018</Year><RecNum>1</RecNum><DisplayText>(4)</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="2xtp9f2tjdx0pqe5dew5paf1pr9wsswzwf2f" timestamp="1516218977">1</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>K Brockow </author></authors><secondary-authors><author>Khan DA, Banerji A</author></secondary-authors></contributors><titles><title>Drug Allergy: Definitions and Phenotypes</title><secondary-title> Drug Allergy Testing</secondary-title></titles><section>p. 19-26</section><dates><year>2018</year></dates><pub-location>St. Louis, USA</pub-location><publisher>Elsevier</publisher><urls></urls></record></Cite></EndNote>(4) ? Adverse drug reaction: Any harmful and unintended reaction that occurs alongside the intended principal effect of a drug, for which a causal relationship between the use of the drug and the adverse reaction is suspected except therapeutic failures, intentional overdosage, abuse of the drug, or errors in administration. Adverse drug reactions (ADR) have been subdivided into: - Type A (?augmented“: pharmacological/toxic drug reaction): Disease manifestations due to predictable, dose-dependent pharmacological/toxic effects typical for a drug at the recommended dose (e.g., sedative effect of older anti- histamines, hair loss caused by cytostatics) or at higher doses (intoxication) - Type B (?bizarre“: hypersensitivity reactions): Individual, unpredictable clinical reaction to a drug, i.e., disease manifestations occur in specifically predisposed patients- Type C: ADR associated with long-term therapy (e.g. benzodiazepine dependence)- Type D: Carcinogenic and teratogenic effects of drugs? Cutaneous adverse drug reaction: Any adverse drug reaction, which occurs on the skin.? Drug hypersensitivity reactions: They are objectively reproducible symptoms or signs initiated by exposure to a defined drug at a dose tolerated by a normal person. They cannot be explained by the normal toxic properties of a drug and need a special predisposition of a patient to develop a reaction. They are further subdivided into drug allergy and nonallergic drug hypersensitivity. ? Cutaneous drug hypersensitivity reaction: Any drug hypersensitivity reaction, which occurs on the skin.? Drug allergy: Immunologically mediated response to a drug (pharmaceutical agent and/or excipient) in a sensitised person. ? Nonallergic drug hypersensitivity: Drug hypersensitivity not associated with immunologic humoral or cellular sensitisation, i.e., not explainable by one of the four immunologic mechanisms described by Coombs and Gell. Nonallergic drug hypersensitivity can be further subdivided into drug intolerance, drug idiosyncrasy, pseudoallergy, and PI reactions (see below). ? Drug intolerance: Undesirable and unexpected pharmacologic toxic effect that occurs at unusually low doses of a drug. It may be caused by underlying abnormalities of metabolism, excretion, or bioavailability of the drug. ? Drug idiosyncrasy: Abnormal and unexpected effect unrelated to the intended pharmacologic action of a drug. The mechanism is often unknown but the reaction is reproducible on re-administration. ? Pseudoallergy: Drug idiosyncrasy with immediate systemic symptoms that mimic anaphylaxis but are caused by non- IgE-mediated release of mediators from mast cells and basophils. ? Pharmacologic interaction with the drug (PI reaction): Nonallergic idiosyncratic reaction caused by non-covalent, HLA-dependent direct activation of a T cell receptor as an off-target effect. Table E2. Dermatological definitions of primary and secondary skin lesions in drug hypersensitivity reactions (if possible, on-line linked to pictures in Fig E1)AngioedemaTransient soft swelling by a deep dermal and/or subcutaneous edema with or without erythema.Bulla (blister)Larger (>5mm in diameter) elevated circumscribed lesion filled with clear fluid leading to detachment of the epidermis. Note that the precise level of the detachment (split) in the skin gives an indication of the cause and can arise intraepidermally or at the basement membrane zone. See Fig E1 CrustDried serum, blood or pus on the skin Erythema A large area arising from vascular dilation causing redness. ErosionPartial loss of the epidermis Macule Area of flat colour change in the skin. May arise from changes in pigmentation, vascular supply, inflammation or deposition. In severe eruptions macules may coalesce. Some centers use macule only for small lesions (<1.5cm) and use the term patch for larger areas (see below). See Fig E1Nodule Elevated circumscribed dermal lump (≥ 0.5cm), without involvement of the overlying epidermis, which may extend into the subcutis. See Fig E1 dfPapule A small (<0.5cm) raised circumscribes lump protruding above the skin. See Fig E1PatchA large area of colour change, with smooth surface. See Fig E1Petechia A haemorrhagic punctuate spot measuring 1–2 mm in diameter. See Fig E1 Plaque Elevated plateau-like lesion, usually more than 2 cm in diameter. Plaques are rarely more than 5 mm in height. See Fig E1Pustule A circumscribed elevated lesion containing pus. See Fig E1Scale (Squama)Scale is the accumulation of thickened, horny layer keratin in the form of readily detached fragments because of increased proliferation or delayed desquamation. UlcerationFull-thickness loss of the epidermisVesicle Small (< 5 mm in diameter) elevated circumscribed lesion filled with clear fluid within or below the epidermis. See Fig E1Wheal (Urtica)A wheal is a transient itching compressible dermal oedema of variable size and form, red or white in colour. An urticaria is defined by presence of wheals. See Fig E1Table E3. Dermatological terms used for morphological descriptions in drug hypersensitivityDesquamation Detachment of the upper epidermal layers following severe skin inflammation ErythrodermaReddening of the whole skin (>95% of body surface area)EnanthemRed skin eruption arising on the mucous membranes, including: buccal (mouth), tongue, lips, oropharynx, ocular surface, glans penis, vagina, anus Exanthem Acutely erupting, widespread distribution of multiple small, round to oval erythematous macules and/or papules with different degree of confluence, where the single lesions persist for several daysFlexural Arising on the inner surfaces of limbs (body folds); also known as intertriginous. Induration Thickened dermis (usually implying minimal epidermal involvement) suggestive of an underlying cellular infiltrateTarget lesionConcentric rings with different grades of erythema and edema resembling targets. They consist of a circular centre with epidermal damage in form of a vesicle, bulla, erosion or crust, an often edematous pale intermediate and a peripheral erythematous concentric ring (3 concentric zones). Photo-exposed sites Areas of skin routinely exposed to direct sunlight (e.g. bridge of nose, chin, cheeks, ‘V’ of neck, lateral neck, but not anterior neck, upper eyelids, nasal philtrum) Purpura Extravasation of red blood cells resulting in red discoloration of the skin or mucous membranes. Comprised of individual petechia. RashUnspecific term for a sudden cutaneous eruption regardless of etiology also including urticariaViolaceous The description of a skin change coloured violet. Typically suggests deep inflammation. . Table E4. Non-standardised terms sometimes used in the literature for describing features of maculopapular exanthems acneinformResembling acne in areas with seborrhoic glandslichenoidResembling lichen planus lesions, i.e. flat, elevated, red, polygonal papulesmorbilliformMeasles-like, i.e. consisting of red, flat macules of 2-10 mm in diameter that maybecome confluentpustularFeaturing pustules, i.e. inflammatory papules, the inner space of which is filled with yellowish liquid exsudate containing abundant pusurticarialMacules and papules resembling urticarial wheals, but with cellular infiltrate andlasting longervesicularFeaturing vesicles, i.e. small white or red efflorescences, the inner space of which is filled with serous watery exsudateDisease Incubation PeriodProdromal PeriodCharacteristics of the RashCharacteristic SignsMeasles8-12 daysFever, cough, rhino-conjuntivitis.Duration: 3-4 daysRed macules and papules, often confluent.Spreads from the face to the trunk and limbs.Duration: 5-6 days.Mild desquamation possibleKoplik spots in oralmucosaRubella16-18 daysMalaise, low-gradefever, headache, rhinoconjuntivitis. Duration: 1-5 daysPink to red macules and papules. Mostly non-confluent.Spreads from face to trunk and limbs. Duration: 2-3 daysTypical lymphadenopathy(retroauricular andsuboccipital)Scarlet fever1-5 daysFever, pharyngitis,vomiting, headache.Duration:1 - 2 daysErythema starting on the neck spreading to trunk, with generalisation and appearance of sandpaper-like tiny papules and petechial streaks in body folds. Circumoral pallor.Typical desquamation after 7–10 days, most prominently on hands and feet. Duration: variableTonsillitis, cervicallymphadenopathy.Strawberry tongueExanthemaSubitum (syn. Roseola infantum)5-15 daysHigh fever.Duration: 3-4 daysRash appears when fever disappears: discreterose red macules and papules often with a white halo. Onset in thorax and trunk, progression to face and limbs.Non-confluent.Colour: pink-reddish.Duration: 2 daysIrritability.Palpebral edema and erythematous papules on soft palate may preceede exanthemErythemaInfectiosum (Syn slapped-cheek disease)4-14 daysLow-grade fever, headache, rhinoconjuntivitis possible.Duration: 2 daysIndurated erythema of cheeks followed bysymmetrical sometimes reticular pink to red macules and papules on the extensor face of upper andlower limbs. Duration: 5-10 days(recurrences)Erythema of Cheeks (“slapped cheeks”). Reticulate pattern of exanthemEnterovirusinfectionsAround 3-5 daysVariableRed discrete non-itchy macules and papules possible Aseptic meningitis possibleInfectiousmononucleosis4-6 weeksProlonged fever. Duration: 6-10 days- Copper-colored, partially confluent macules and papules as seen in measles or scarlet fever. Clearance with desquamation. More frequent after taking ampicillin. Triad of fever, lymphadenopathy and pharyngitis. Membranous tonsillitis.Hepatosplenomegaly.Table E5. Clinical features of common viral exanthems as differential diagnoses for drug exanthemsTable E6. Drug hypersensitivity questionnaire ADDIN EN.CITE <EndNote><Cite><Author>Demoly</Author><Year>1999</Year><RecNum>4</RecNum><DisplayText>(47)</DisplayText><record><rec-number>4</rec-number><foreign-keys><key app="EN" db-id="2xtp9f2tjdx0pqe5dew5paf1pr9wsswzwf2f" timestamp="1516218978">4</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Demoly, P.</author><author>Kropf, R.</author><author>Bircher, A.</author><author>Pichler, W. J.</author></authors></contributors><auth-address>Maladies Respiratoires-INSERM U454, Hopital Arnaud de Villeneuve, University Hospital of Montpellier, France.</auth-address><titles><title>Drug hypersensitivity: questionnaire. EAACI interest group on drug hypersensitivity</title><secondary-title>Allergy</secondary-title><alt-title>Allergy</alt-title></titles><pages>999-1003</pages><volume>54</volume><number>9</number><edition>1999/10/03</edition><keywords><keyword>Diagnosis, Differential</keyword><keyword>Drug Hypersensitivity/*diagnosis</keyword><keyword>Humans</keyword><keyword>*Surveys and Questionnaires</keyword></keywords><dates><year>1999</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0105-4538 (Print)&#xD;0105-4538</isbn><accession-num>10505466</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(47)Table E7. Audit points (Checklist)Of the last 10 cases with a diagnosis of a skin reaction caused by drug allergy (hypersensitivity), in what proportion was the data in Tab. E6 captured and recorded in their clinical records?Of the last 10 cases with a diagnosis of a skin reaction caused by drug allergy (hypersensitivity), what proportion were classified according to the algorithm Fig. 1?Of the last 10 cases with a diagnosis of a skin reaction caused by drug allergy (hypersensitivity), what proportion were classified into a diagnostic label as per Table 1?Of the last 10 cases with a diagnosis of a skin reaction caused by drug allergy (hypersensitivity), in what proportion were the appropriate differential diagnoses considered and excluded?References ADDIN EN.REFLIST 1.Demoly P, Adkinson NF, Brockow K, Castells M, Chiriac AM, Greenberger PA, et al. International Consensus on drug allergy. Allergy 2014;69(4):420-437.2.Gomes ER, Demoly P. Epidemiology of hypersensitivity drug reactions. Curr Opin Allergy Clin Immunol 2005;5(4):309-316.3.Bigby M. Rates of cutaneous reactions to drugs. Arch Dermatol 2001;137(6):765-770.4.Brockow K. 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Guideline for the diagnosis of drug hypersensitivity reactions: S2K-Guideline of the German Society for Allergology and Clinical Immunology (DGAKI) and the German Dermatological Society (DDG) in collaboration with the Association of German Allergologists (AeDA), the German Society for Pediatric Allergology and Environmental Medicine (GPA), the German Contact Dermatitis Research Group (DKG), the Swiss Society for Allergy and Immunology (SGAI), the Austrian Society for Allergology and Immunology (OGAI), the German Academy of Allergology and Environmental Medicine (DAAU), the German Center for Documentation of Severe Skin Reactions and the German Federal Institute for Drugs and Medical Products (BfArM). Allergo J Int 2015;24(3):94-105. ................
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