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Ten n Sjs Review

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  Vol.10 No.2, June 2002  57 INTRODUCTION The term toxic epidermal necrolysis (TEN) wasintroduced in 1956 by Lyell to describe four patientswith a syndrome featured by extensive epidermaldetachment with mucous membrane involvement,leaving the skin surface looking scalded. 1  Necrolysisdenotes necrosis and full thickness detachment of theepidermis. Toxic means severe constitutional symptomsand complications. Stevens-Johnson syndrome (SJS)and toxic epidermal necrolysis are two-related severecutaneous blistering reactions often related to drugtherapies, with a mortality rate between 16% and 30%for TEN and of less than 5% for SJS. 2  There are stillcontroversies in classification, mechanism, andmanagement of these conditions. EPIDEMIOLOGY The incidence of TEN has ranged from 0.5 casesper million per year in the USA and 1.2 cases per millionper year in France whereas the incidence of SJS andTEN is around 0.93 and 1.1 cases per million per yearin Germany respectively. 2-4  Most cases of TEN are due Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome Dr. C. K. YeungDepartment of Medicine, Queen Mary Hospital, The University of Hong Kong REVIEW ARTICLES Correspondence address:Dr. C. K. YeungDepartment of MedicineQueen Mary HospitalPokfulamHong Kong ABSTRACT Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are uncommon but serious cutaneousreactions with significant mortality and long-term morbidity. Multiple aspects of TEN and SJS are reviewed including classification and therapeutic options with emphasis on the importance of early diagnosis, burnsunit care and the controversies in the use of systemic corticosteroids. Keywords:    Etiology, intravenous immunoglobulin, Stevens-Johnson syndrome, toxic epidermal necrolysis to drugs. It is associated with altered immune states asin HIV infections, mycoplasma pneumonia, immunizationand systemic lupus erythematosus. 5  Bastuji-Garin et alreported 2.7 times higher incidence of TEN in elderlyolder than 65 years attributed to an increased drug use. 6 A slight female preponderance was observed in mostseries with a female: male (F/M) ratio of 1.7:1. TENand SJS have been described in all age groups and races. CLINICAL FEATURES TEN is characterized by extensive full-thicknessepidermal loss and mucous membrane involvement. 5  Itpresents with widespread epidermal sloughing on thebackground of painful purpuric macules and flaccidblisters at involved sites, resembling those of second-degree burns, resulting in denudation of large areas of oozing dermis. However, the prognosis of TEN appearsto be worse than that of second-degree burns with thesame extent because of involvement of the epitheliumof other organs, especially the respiratory tract. 7  Theentire body surface can be involved. Mucous membranesof oral cavity, conjunctivae and genitalia are usuallyseverely eroded (85-95%) with significant pain andcrust. Acute skin failure results in loss of fluid andelectrolyte imbalance and protein depletion. Patientswith TEN are typically preceded by a prodrome of fever,rash and sore throat. It is followed by progressivepurpuric eruption with flaccid blisters and positiveNikolsky's sign predominantly over trunk and face.Involvement of other organs and mucous membranesaccounts for increased mortality and long-term  Hong Kong Dermatology & Venereology Bulletin 58    Review Articles morbidity. Sepsis is the major complication that leadsto death. 8  Most of the skin surface and mucousmembranes are re-epithelialised in two to three weeks,consistent with the reported overall mean length of stayranged from nine days to 21 days in some series. 3,7 TEN and SJS are now considered to be variantswithin a continuous spectrum of different severity. 7 Those patients who initially present with a picture of SJS may progress to full-blown TEN in a few days bythe confluence of individual lesions and the twoconditions share similar aetiologies andhistopathological findings. There is no consensus at themoment as to how best to classify this spectrum of diseases. It is difficult to study these serious skinreactions owing to the lack of unanimous definition,uncertainty in defining its onset, absence of reliable testsfor assessment of risk factors and multitude of aetiological factors predisposing to the reaction. 4 The two skin eruptions share many clinical featuresand are distinguished by the extent of body surface areainvolved. TEN is defined by full-thickness epidermalnecrosis with epidermal detachment involving greaterthan 30% of total body surface, associated withmorbilliform or confluent erythema and skin tenderness. 7 SJS is defined by less than 10% body surfaceinvolvement with the present of flat atypical targetlesions distributed mainly over trunk and face. OverlapTEN-SJS is the entity that encompasses the skincondition with body surface involvement in the rangeof 10-30%.The classification is further complicated byincluding erythema multiforme major (EMM) in thecategory of TEN. Nevertheless, there are distinguishingfeatures between the two conditions by the pattern anddistribution of skin lesions. EMM typically producestypical target lesions over extremities. The disease runsa benign clinical course and usually occurs afterinfection especially herpes simplex and mycoplasmain children. In contrast, patients suffering from TENhave widespread blisters predominantly over the trunk and face arising on erythematous or purpuric macules.They are usually drug-induced with high mortality rate. 9 DIFFERENTIAL DIAGNOSIS Diseases with extensive desquamation orsuperficial subcorneal blisters include staphylococcalscalded skin syndrome and Kawasaki disease inchildren, and toxic shock syndrome in adults. Acutepustular psoriasis, drug-induced exanthematicpustulosis and linear IgA disease may resemble TENwhen pustules are confluent, leading to positiveNikolsky's sign. Extensive fixed drug eruption and acuteonset of paraneoplastic pemphigus may also mimicTEN. PATHOLOGY The histological examination of advanced skinlesions shows necrosis of entire epidermis in TENstarting from the basal and the Malpighian layers. Thenecrotic epithelium detached from minimally altereddermis. The upper dermis shows moderate infiltrationby mononuclear cells and epidermal changes begin asintercellular oedema with a sparse exocytosis of mononuclear cells, mainly CD8 T-lymphocytes andmacrophages and occasional satellite cell necrosis.Direct immunofluorescence is usually negative. Thehistological pattern shows a predominantly necroticpattern in which major epidermal necrosis andminimally inflammatory infiltration are found. This isin contrast to the more pronounced dermal inflammationand exocytosis in EMM. 9  EMM differs from SJS andTEN by having a denser and deeper lymphocyticinfiltrate, and increased amount of extravasatederythrocytes. 10 PATHOGENESIS The pathogenesis of TEN and SJS is still unclear.TEN is generally considered as a hypersensitivityreaction to drugs such as antibiotics, analgesics andanticonvulsants and to events such as viral infections. 2 One theory suggests that patients with TEN have anabnormal metabolism of the culprit drug. Instead of being metabolized, the offending drug is deposited inthe epidermis leading to a series of immune reactionsand rejection. 11  The epidermis is infiltrated by activatedlymphocytes, mainly CD8 cells and macrophages. Thedermal infiltrate consists of mainly activatedT-lymphocytes, predominantly T helper cells. Thenumber of Langerhans' cells are marked reduced in theepidermis. 12  Severe cases of cutaneous acute graft-vs-host disease can lead to a clinical and histologicsyndrome similar to TEN, thus supporting TEN to be acellular immune reaction. This cell-mediated immune  Vol.10 No.2, June 2002  59    Review Articles response leads to keratinocyte apoptosis by cytotoxicT-lymphocytes and cytokines, especially α -TNF. 13 Acute keratinocyte death in TEN occurs as a result of apoptosis through cytotoxic cell-mediated processinvolving CD95 (Fas) cell surface receptor-ligandsystem. Keratinocytes in TEN express lytically activeFas ligand (FasL). 14 AETIOLOGY TEN is essentially an idiosyncratic, drug-inducedreaction. Roujeau et al showed that only a small numberof patients (4.5%) with TEN had not taken any drugs. 4 The most thorough multi-center study in Europerevealed that antibiotics particularly sulfonamides,NSAIDs, anti-convulsants and allopurinal increased therisk of TEN and SJS in decreasing order. 15  Among non-sulfonamide antibiotics, aminopenicillins, quinolones,cephalosporins, tetracyclines and imidazoles weresignificantly associated with TEN. This study confirmedthe responsibility of the previously reported drugs.Allopurinal is considered to be relatively low risk ascompared with other chronically used drugs. Roujeauet al reported a ratio of 1.3 TEN cases per 10 8  sales(seven cases out of 253 TEN patients) for allopurinalcompared with 230 cases per 10 8  sales for sulphadiazine. 2 In contrast, Chan reported five cases of TEN related toallopurinal out of twenty patients in a five-yearseries in Singapore. 16  The apparent higher incidence of TEN and SJS related to allopurinal in Asians can bedue to differences in genetic background, especiallyHLA types. Lack of an accurate drug history andmultiple medications make identification of culpritdrug difficult. The condition often begins within3 weeks of initiation of therapy or much shorter uponre-exposure.The occurrence of SJS and TEN in the setting of brain metastasis and phenytoin use was well reported. 17 Reduction of the dose of steroids may increase the risk of a hypersensitivity reaction. The authors had suggestedavoiding routine anticonvulsant prophylaxis in allcerebral metastasis because of this potential seriouscomplication. Cautions should be taken if patientsreceiving cranial radiotherapy develop scalp erythemaafter introduction of anticonvulsants and tapering of steroids. This may represent the first sign of SJS andthe drugs should be withheld immediately.Recent viral infections may play a role in TENand SJS patients. Cutaneous drug reactions are morecommon in patients with human immunodeficiencyvirus (HIV) infection and the acquired immuno-deficiency syndrome (AIDS). 18  The incidence of TENand SJS increased to a thousand-fold in patients withAIDS. 19  Sulfonamides are the most frequentlyimplicated agents. Near all patients with acute Epstein-Barr virus (EBV) mononucleosis syndrome treated withampicillin developed skin eruptions. Previous studynoted 6% of TEN patients had clinical and/or serologicalevidence of a recent viral infection. 2  Mycoplasmapneumoniae infections have been related to TEN. 20 Specific viral infections had been shown to increase Fasand/or FasL expression and increased sensitivity to Fas/ FasL-dependent apoptosis. 21  All these findings supportthe hypothesis that underlying viral infections maytrigger and activate the severe cutaneous reactions insusceptible individuals receiving drugs.Recently human herpesvirus type 6 (HHV-6) andcytomegalovirus (CMV) reactivation had been reportedin patients with drug hypersensitivity syndromecharacterized by skin rash, fever, liver dysfunction andlymphadenopathy. One patient developed TEN as partof the hypersensitivity syndrome. 22  The authorsproposed an aetiological role of the viral infection inthe pathogenesis of hypersensitivity syndrome. Theyalso hypothesized that reactivation of HHV-6 mayseriously interact with some of the enzymes thatdetoxify the drugs, such as cytochrome P450, as virusesmay induce antibodies to cytochrome P450 components. COMPLICATIONS Concerning the complications of TEN and SJS,conjunctivitis was a constant feature in most patients.Chronic xerostomia and dry eyes were observed in someTEN patients after the incidents. Most of the patientshad marked and prolonged post-inflammatoryhyperpigmentation that can be disfiguring. The ocularsequelae (30-40%) is potentially disabling in survivors. 7 Synechiae between eyelids and conjunctivae oftenoccur, necessitating frequent use of eye lubricants toprevent this complication. Nail dystrophy, hypertrophicscars and phimosis can occur. Pulmonary complicationscomprise pneumonia and sloughing of tracheobronchialmucosa that worsen the prognosis in particular. Less  Hong Kong Dermatology & Venereology Bulletin 60    Review Articles frequent findings include leukopenia andthrombocytopenia.Appropriate care of extensive epidermal loss andcareful fluid and electrolyte management in a burns unitcontribute substantially to the reduced complication andimproved survival rate in TEN. 23  The overall reportedmortality of TEN is up to 36%, sepsis being the mostimportant complication and cause of death. 8  Commonsources of sepsis include skin, lungs, urinary catheterand intravenous lines. The increased body surfaceinvolvement may predispose the patient to greater risk of disseminated sepsis. Bastuji-Garin et al identifiedseven independent risk factors for death, namely ageabove 40 years, malignancy, tachycardia above 120/min,initial percentage of epidermal detachment above 10%,serum urea above 10 mmol/L, serum glucose above 14mmol/L and bicarbonate below 20 mmol/L. 24 MANAGEMENT The main principles of symptomatic therapy arethe same as for major burns. The timely treatment of TEN patients offered by specialized burns centers maycontribute to the lowered mortality in recent series.There is a trend of improving survival and reducingcomplications over the last decades with the promptidentification and treatment of patients with TEN inburns unit. 23 All potential aetiological drugs are to bediscontinued immediately when any early suggestivefeatures of TEN or SJS arise, as prompt withdrawal of suspected drugs might decrease mortality, especiallyfor drugs with short half-life. 25  All patients shouldreceive meticulous wound care with antibiotic cream,paraffin and emulsifying ointment, but topical silversulphadiazine is avoided owing to the strongestassociation with the conditions. 15  Adequate supportivecare is needed for wound dressings and isolationtechniques. Intravenous fluid for volume, electrolytesand nutritional support are often required especiallywhen the patients are unable to swallow. Surveillanceof sepsis and careful fluid and electrolyte balance areachieved through regular monitoring. Systemicantibiotics are given only in patients with evidence of sepsis. Patients should receive regular eye and mouthcare and are followed up regularly by ophthalmologists.Pain management includes use of paracetamol andmorphine, and regular chest physiotherapy is alsonecessary. A skin biopsy for light microscopy andimmunofluorescence is warranted to confirm thediagnosis and rule out other blistering diseases notrelated to drugs.Any effective specific treatment for TEN or SJSshould be able to halt the progression of necrolysis andpromote early re-epithelialisation. The use of systemiccorticosteroids to abate the inflammatory reaction forthe treatment of TEN remains the most controversialissue. 8  Small case numbers and lack of well-designedcontrolled studies produced contrasting results. Sincethe most important cause of death in TEN isoverwhelming sepsis, many authorities believe thatsystemic corticosteroids are contraindicated based on anumber of recent studies reporting a higher morbidityand mortality with their usage. 26  Corticosteroids can alsodelay healing, masking early signs of sepsis and inducegastrointestinal bleeding. TEN can develop in patientswho are receiving high-dose corticosteroids. 5  On theother hand, some authors suggest use of a short courseof systemic corticosteroids at earlier stages for few daysto no more than a week, but their benefits have neverbeen proven in controlled clinical trials as the diseasesare self-limiting upon discontinuation of the offendingdrugs. 27  Others have tried plasmaphoresis andcyclosporin. Thalidomide appears deleterious andincreased mortality rate. 28 Intravenous immunoglobulin has the soundtheoretical basis as a promising therapeutic agent of TEN. Fas-blocking antibodies contained in IVIG inhibitthe interaction between Fas receptors expressed onkeratinocytes and FasL and prevent the apoptotic processthat plays a pivotal role in TEN. 29  Previous open studyand isolated case reports had demonstrated decreasedkeratinocyte apoptosis, prompt interruption of progression of skin disease and shortening of durationof complete healing after IVIG were given to TENpatients. Although IVIG therapy is generally safe, thetreatment costs are immense. One course of IVIGtherapy to administer 1 g/kg/day for 3 days costs about$30,000 for an average-size adult. CONCLUSION Early diagnosis, prompt withdrawal of allpotentially responsible drugs and initiation of supportive

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