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Published online May 2, 2017 http://dx.doi.org/10.1016/S0140-6736(16)30378-6 Severe cutaneous adverse reactions to drugs Tu Anh Duong, Laurence Valeyrie-Allanore, Pierre Wolkenstein, Olivier Chosidow During the past decade, major advances have been made in the accurate diagnosis of severe cutaneous adverse reactions Classication and diagnosis and greyish-white pseudo membranes coat oral-cavity haemorrhagic erosions, with crusts being the main lesions (appendix p 13). Conjunctival lesions, including hyperaemia, erosions, chemosis, photophobia, and tearing comprise eye involvement. Severe forms lead to corneal ulceration, anterior uveitis, or purulent conjunctivitis Visceral involvement associated with Stevens-Johnson syndrome and toxic epidermal necrolysis consists of transient liver or renal enzyme increases or bronchial and Although rare, specic acute visceral failures in Stevens-Johnson syndrome and toxic epidermal necrolysis should be suspected and documented after eliminating bacterial or viral super infection. No specic score or diagnostic test is available for the diagnosis of Stevens-Johnson syndrome and toxic epidermal necrolysis. The diagnosis mainly relies on identication of a broad range of clinical signs and ). Full-thickness and a negative direct are mandatory for diagnosis. forme major, linear IgA bullous dermatosis (appendix p 15; spontaneous or drug-related), generalised xed drug eruption (appendix p 16), supercial burns, cytotoxic drug It usually begins 26 weeks after drug exposure. The diculty in diagnosing DRESS and SCAR involved Severity Score system for SJS and TEN days Fever 38°C, inuenza-like syndrome, respiratory tract Published online May 2, 2017 http://dx.doi.org/10.1016/S0140-6736(16)30378-6 including fever, lymphadenopathy, inuenza-like symptoms, burning pain, or pruritus, can precede the Clinical dermatological symptoms consist of facial oedema, erythroderma, distal To reduce misdiagnosis, several invest (table 2), such as those to identify blood abnormalities indicating visceral involvement, virus reactivation, hypereosinophilia, atypical lymphocytes, and hypogammaglobulinaemia during the acute stage. As rst hypothesised in 1994, reactivation of a single or multiple human herpesvirus (HHV) family members, with HHV6 being the most described. This HHV6 viral Suggested conrmation tests Tests Erythema multiforme major, Mycoplasma pneumoniae infection*, coxsackievirus infection, linear IgA bullous dermatosis, generalised bullous xed-drug eruption, Several mechanistic models have been proposed to explain the recognition by T cells of small compounds allopurinol-induced Stevens-Johnson syn drome and toxic These associations were rst identied in countries with a high Published online May 2, 2017 http://dx.doi.org/10.1016/S0140-6736(16)30378-6 In allopurinol-induced SCARs, studies have identied Figure : Immune mechanisms of SCARs Schematic diagram showing the immune stimulation, cytotoxic T-cell activation, and key actors in the development of SCARs, adapted from Pichler and colleagues. (covalent) Cytotoxic T-cell Cytotoxic protein Drug-specic T cells T-cell hypothesis Peptide A Drug or Peptide A Peptide B T cells CD8+ T cells T- reg SJS and TEN CD8+ cytoxic T cells CD1+ and CD14+ CD14+ and CD16+ FasFas ligand Perforingranzyme B Identication of specic CD8+ cytoxic T cells CXCL8 CD8+ cytoxic T cells Identication of specic specic immune activation such as occurs in a viral T-reg functions during acute and chronic SCAR stages By comparison with healthy controls, T-reg frequency in early and late stages of Stevens-Johnson syndrome and toxic epidermal necrolysis did not dier, whereas non-T-reg cell frequency was increased upon resolution of Stevens-Johnson syndrome and toxic epidermal In the acute stage of DRESS syndrome, functional T-regs were dramatically expanded, whereas they were profoundly diminished in Stevens-Johnson By contrast, T-regs became functionally decient upon resolution of DRESS syndrome, whereas their functionality was restored after Stevens-Johnson syndrome and toxic Assessment of SCARs Case assessment relies on the eruptions clinical associated symptoms (eg, fever, pruritus, lymphadenopathy), and the Published online May 2, 2017 http://dx.doi.org/10.1016/S0140-6736(16)30378-6 Physical examination includes the description of the distribution of SCAR-specic lesions. Cutaneous or mucous membrane involvement in orices, indicating a severe reaction (external or internal), must be specied. Photos and clinical signs should be collected as often as Treatment stage SJS and Drug withdrawal, no RCT-validated curative treatment* Supportive care strongly feeding, uid-loss treatment, involvement, lung Dystrophic scars, hyperpigmentation, alopecia, nail loss, visual loss, synechiae, dry eye, symblepharon, dental agenesia, sialadenitis, tooth decay, genital synechiae, psychiatric disorders Patch testing at month 6; follow-up at least at month 2, month 6, month 12, and every year for 5 years; specialist consultations: dermatology, ophthalmology, ear, nose, and throat examination, gynaecology, psychiatry, Drug withdrawal, no RCT-validated curative treatment; topical or according to disease severity amides) are not recommended. When necessary, non-adhesive (eg, hydrocellular) dressings are used to cover pressure points, particularly on the During the acute phase, ocular, oral, nasal, genital, or anal mucosa lubrications with emollient are recommended to reduce mucosal adhesion formation and functional Mucosal bleeding or erosions are treated with topical analgesia, mouthwashes, application of swabs, Ocular management relies on inammatory debris removal with daily saline rinses, and, after topical anaesthesia, removal with a moist cotton bud or smooth blunt instrument. Prophylactic topical antibiotics, topical ciclosporin, or corticosteroids have been used, but were To protect and reduce conjunctival or corneal sequelae, amniotic membrane transplantation has been proposed to For DRESS syndrome and AGEP, dermatological care mainly relies on appropriate skin moisturisation. When necessary, mucous-membrane management should be the same as that used for Stevens-Johnson syndrome and anti-TNF /MCI; 12; 0;/MCI; 12; 0;89,90/MCI; 12; 0;/MCI; 12; 0; or steroids with or without IVIg, complication or mortality rates did not signicantly dier with the addition of IVIg, whereas hospital stays were signicantly shorter for those receiving Furthermore, mortality did not signicantly dier in patients receiving IVIg or corticosteroids in comparison Drug withdrawal Facial oedema Facial oedema Fixed drug eruption Published online May 2, 2017 http://dx.doi.org/10.1016/S0140-6736(16)30378-6 progression after a short-term administration of This potential benet of ciclosporin on mortality of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis, compared with IVIg, was also In an uncontrolled series of ten patients with toxic SCARsmainly Stevens-Johnson syndrome, toxic epi dermal necrolysis, and DRESS syndromeare life threatening and carry a non-negligible risk of severe Johnson syndrome and toxic epidermal necrolysis, visceral involvement (eg, renal failure, intestinal, ocular- specic pulmonary lesions, or sepsis) is the main Respiratory insuciency in patients with SCARs can result from direct eects of the SCAR on the organs or inhalation of foreign substances leading to superinfection, and pulmonary infection is signicantly associated with severe laryngeal lesions caused by Stevens-Johnson syndrome or toxic epi During the acute stage, impaired skin barrier function or translocation of gut bacteria might facilitate bacterial Sepsis is the Johnson syndrome and toxic epidermal necrolysis. In a Johnson syndrome or toxic epidermal necrolysis, therapy SCORTEN successfully predicts 3-day mortality Johnson syndrome and toxic epidermal necrolysis when A ve-point auxiliary score that does not require laboratory data has also been devised, and might be useful to predict severity of illness In a cohort study, the overall cumulative incidence of long-term DRESS sequelae was 11·5%, and If PTSD, Published online May 2, 2017 http://dx.doi.org/10.1016/S0140-6736(16)30378-6 HIV association might be aected by the severity of the patients immunodeciency or the use of drugs that are (eg, co-trimoxazole or abacavir) in this even though for nevirapine, hypersensitivity predominated in non-HIV-infected patients with high prophylactic treatment after HIV exposure. For abacavir, in-vitro T-cell reactivity can also occur in drug-naive individuals with the HLA-B*57:01 allele. Supported by the results of extensive HLA-B*15:02 screening in Taiwanese neurology clinics, the US Food and Drug Administration recommends for AGEP than for Stevens-Johnson syndrome, toxic Patch tests are reportedly safe, with few reported relapses or severe reactions. Neither prick nor intradermal tests are higher sensitivity than the prick test, and an oral drug tests are done 6 months after the acute stage to avoid In-vitro tests can be used to measure peripheral blood mononuclear cell activity in patients with SCARs, with the culprit drug displaying pharmacological activity. For Neither are done routinely. Although LLT shows promise as a culprit-drug test in patients with DRESS syndrome or AGEP, it has low relevance in Stevens-Johnson syndrome and toxic epidermal necrolysis, even after enhancement of its sensitivity after removal of T-reg CD25+ cells. ELISPOT Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. 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