REVIEW ARTICLE

Am J Clin Dermatol 2003; 4 (8): 561-572 1175-0561/03/0008-0561/$30.00/0  Adis Data Information BV 2003. All rights reserved.

Differential Diagnosis of Severe Cutaneous Drug Eruptions
Nicolas Bachot and Jean-Claude Roujeau
ˆ Department of Dermatology, Hopital Henri Mondor, Universit´ e Paris XII, Cr´ eteil, France

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 561 1. Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562 2. Differential Diagnosis of SJS and TEN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 564 2.1 Erythema Multiforme Major . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 564 2.2 Pustular Neutrophilic Eruption: Acute Pustular Psoriasis and Acute Generalized Exanthematous Pustulosis . . . . . . . . . . . . . . . . 565 2.3 Other Bullous Dermatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565 2.3.1 Intermediate Burns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565 2.3.2 Generalized Fixed Bullous Drug Eruption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566 2.3.3 Staphylococcal Scalded Skin Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566 2.3.4 Edematous Erythroderma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566 2.3.5 Autoimmune bullous disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566 2.4 Desquamative Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567 2.4.1 Exfoliative dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567 2.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567 3. Hypersensitivity Syndrome (HSS) or Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567 4. Differential Diagnosis of DRESS/HSS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568 4.1 Other Cutaneous Drug Eruptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568 4.2 Angio-Immunoblastic Lymphadenopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569 4.3 Erythroderma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570 4.3.1 Lymphoma and Leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570 4.3.2 Eczema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570 4.3.3 Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570 4.4 Vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570 4.5 Acute Viral Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570 4.5.1 Primary HIV infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570 4.5.2 Human Herpes Virus 6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571 4.5.3 Epstein Barr Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571 5. Skin Biopsies of Severe Cutaneous Drug Eruptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571 6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571

Abstract

Adverse cutaneous reactions to drugs are frequent, mostly secondary to antibacterials, however, serious adverse cutaneous reactions are infrequent. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are a spectrum of the same disease. They are the more severe drug eruptions, with a mortality around 30% for TEN. The confusion between erythema multiforme major and SJS means that erythema multiforme major is the main differential diagnosis. Skin disorders involving desquamation, in particular after pustulosis, are also common differential diagnoses. Mechanical or autoimmune blistering are also potential misdiagnoses of TEN/ SJS.

Prompt withdrawal of the offending drug is often the most important action to minimize the morbidity. Alternatively. In line with the WHO definition of a serious adverse drug reaction a cutaneous reaction can be considered to be severe “if it results in death. In fact. Am J Clin Dermatol 2003. Table I provides the main differential diagnoses for SJS/TEN and DRESS/HSS. A nosologic confusion exists between SJS and erythema multiforme (EM).4–1.2–6 per million person-years for TEN and SJS. whether caused by psoriasis. the two diseases are quite different as discussed in section 2. Main differential diagnoses of SJS/TEN and DRESS/HSS SJS and TEN: Erythema Multiforme Major Acute generalized erythematous pustulosis Intermediate burns Generalized Fixed Bullous Drug Eruption Staphylococcal Scalded Skin Syndrome Edematous erythroderma Bullous pemphigoid Linear IgA Bullous Dermatosis Lupus erythematosus Paraneoplastic pemphigus Exfoliative dermatitis DRESS/HSS SJS/TEN Acute generalized erythematous pustulosis Angio-immunoblastic lymphadenopathy Erythroderma (lymphoma. the diagnosis is not confirmed on admission. may explain the lack of knowledge about this disease. Adverse cutaneous reactions to drugs are frequent. can be thought of as a differential diagnosis of DRESS/HSS.[8] Skin disorders involving desquamation. HSS = hypersensitivity syndrome.1. Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) In approximately one third of the patients referred to our institution (a referral center for severe cutaneous eruptions for a suspected diagnosis of SJS or TEN). requires hospitalization or prolongation of existing hospital stay. Angio-immunoblastic lymphadenopathy. Although precise diagTable I. Rapid recognition of severe reactions is essential. Prompt recognition of a severe drug reaction and withdrawal of the culprit drug is often the most important therapeutic action.562 Bachot & Roujeau Hypersensitivity Syndrome (HSS) or Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) is a severe cutaneous drug reaction with often a long duration of eruption and serious other organ involvement.[3] and 22%[4] of skin reactions. dermatitis or lymphoma. the discrete red macules typically seen with SJS occur around larger necrolytic areas. and Hypersensitivity Syndrome (HSS) or Drug Rash with Eosinophilia and Systemic Symptoms (DRESS). severe ocular involvement. Exfoliative dermatitis. All rights reserved. viral eruption and vasculitis are other differential diagnoses of DRESS/HSS. eczema. In the main studies on cutaneous reaction rates. or is life threatening”. and a disseminated cutaneous eruption of discrete dark-red macules. Figure 1 shows an example of TEN. respectively. sometimes with a necrotic center. psoriasis) Vasculitis Acute viral infection DRESS = Drug Rash with Eosinophilia and Systemic Symptoms. In severe cases. exfoliation or blistering are sometimes misdiagnosed as SJS or TEN.2 and 1. Other cutaneous drug eruptions. SJS can include extensive areas of epidermal necrolysis. results in persistent or significant disability/incapacity.[9] SJS and TEN are part of the same spectrum: a disease starting as SJS can lead to full-blown TEN. morbilliform drug exanthem accounted for 95%. while urticaria accounted for 5%.[7]  Adis Data Information BV 2003.[5] The reported percentage of cutaneous drug reactions that physicians diagnose as potentially severe varies greatly (17% in a study with spontaneous reports data[6]) but is probably approximately 2%. a delay in starting a specific treatment for a disease misdiagnosed as a drug eruption could be deleterious.[7] The acute drug cutaneous reactions that are most often deemed to be severe are the spectrum of Stevens-Johnson Syndrome (SJS)/ Toxic Epidermal Necrolysis (TEN).[10] TEN was described by Lyell. The low incidence ranging from 0. are the main differential diagnoses for DRESS.[2] Most adverse cutaneous reactions are not severe. 4 (8) . SJS is characterized by febrile erosive stomatitis.[1] 91%[3] and 48%[4] of all skin reactions. 1. and few are fatal.[1] Reaction rates in the general population vary from 0–8% and are highest for antibacterials. TEN = toxic epidermal necrolysis. affecting 2–3% of hospitalized patients. SJS = Stevens-Johnson Syndrome.[11] with extensive loss of epidermis due to necrosis that leaves the skin surface looking scalded. and lymphoma.[1] 6%. In most cases of TEN. some acute viral infections.

and two had Mycoplasma pneumoniae pulmonary infection. in a consensus workshop.[21. All rights reserved. The main cause of death during TEN is sepsis from Streptococcus aureus and Pseudomonas aeuriginosa. Both SJS and TEN occur in patients of all ages (including children.[13] In the authors’ opinion.5 : 0. only a few patients (4.[7. one had a severe herpes simplex virus infection. initial epidermal detachment.[16] In two epidemiologic studies from France and Germany.[15] A strong association with specific medications is observed in approximately 80% of cases. approximately 70 cases of M.18] conducted between 1981 and 1985. pneumoniae infection were found to be related to SJS. 1. and allopurinol.7. cases with limited areas of epidermal detachment are usually labeled SJS and those with an epidermal detachment of >30% are typically labeled as TEN. the excess risk associated with these drugs does not exceed five cases per million users per week. elevated plasmatic levels of urea and glycemia.[9] In cases with detachment of 10–30% of epidermis the two syndromes are considered to overlap. a nonnucleoside reverse transcriptase inhibitor used in the treatment of HIV infection. In children. phenytoin).[17] among the 10 patients with TEN who denied taking any drug intake or having any chemical exposure. respectively) with TEN had not taken any drugs. Systemic lupus erythematosus and bone marrow transplantation may also increase the risk. Toxic epidermal necrolysis. infants and newborns). The risk of developing drug eruptions and also TEN is considerably increased in HIV patients with an incidence of 1 per 1000  Adis Data Information BV 2003.[9] The histopathologic findings are identical.[14] The probably higher among users of nevirapine. The HIV infection itself may predispose patients to developing TEN as well as drug eruptions in general. Fig. Am J Clin Dermatol 2003.5% and 3%. anticonvulsants (carbamazepine.[23] Human intravenous immunoglobulin was credited with halting the disease in small open studies. In 1985. it was agreed that “reaction to drugs was to date the only documented cause of TEN” with the exception of graft-versus-host disease. oxicam NSAIDs.[7] In children. Early on. These cases probably constitute real infection-induced TEN. Further studies are needed.23-26] Mortality rates are below 5% for SJS and are approximately 30% for TEN. The incidence of TEN increases sharply among the elderly. in part.[28-30] A controversy exists between the main open studies of the interest of intravenous immunoglobulin in TEN with halting the disease. there is a full-thickness epidermal necrosis and detachment. and low bicarbonates. nostic boundaries between the two disorders have not been established. SJS/TEN has a better prognosis with a mortality rate below 5%. Macules with limited necrolysis and bullous at the beginning of the disease. by an increased exposure to drugs with elevated risks in HIV patients.[19] In another publication.[17. The drugs with the highest estimated risk include antibacterial sulfonamides (trimethoprim-sulfamethoxazole [cotrimoxazole].[20] Two cases of TEN possibly attributed to Klebsiella pneumoniae are also published. all races and both sexes. phenobarbital.[7] This may be explained. with an only slightly altered underlying dermis. the enhanced knowledge of the role of drug in the physiopathology of TEN and confirmed that TEN is most often related to an adverse drug reaction. A prognostic score has been established.[12] This increase may be explained by an increased utilization of drugs in this population.Different Diagnosis of Severe Cutaneous Drug Eruptions 563 person-years.22] Nevertheless. 4 (8) .[7] Most cases of SJS and TEN are drug induced. tachycardia.[27] Rapid withdrawal of the suspected drug and supportive therapy are still the main principles of treatment. The male : female ratio for TEN is 0. which provides support for this hypothesis. sulfadiazine). which includes variables such as age. In the French study. fewer than 5% of patients report no drug use. TEN has a balanced sex ratio. However. one possible explanation is more frequent drug intake by women. recent malignancy.

in a retrospective evaluation. a Fig. is a source of discussion for the same diagnosis confusion.[9] Patients with EMM have typical target lesions with or without blisters (see figure 2). and SJS is mainly drug induced. the exclusive relationship between HSV and EMM seems to be consensual. 4 (8) . Over 60% of EMM cases are related to HSV infection. Typical target in erythema multiforme.[32] The prognoses of EMM and SJS are also different in adults. Target-like lesions are non-specific lesions present in most patients with TEN as well as patients with other eruptions such as virus. patient with an atypical target usually presents with many lesions (often so many they are difficult to count). based upon previous historic diagnostic criteria. EMM is usually benign.  Adis Data Information BV 2003. pneumoniae and not associated with a poor prognosis. Erythema multiforme. It is important to differentiate these two diseases because of their different causes. prognosis and treatment. painful erosions.564 Bachot & Roujeau 2. For many years.[20] On the other hand. The causes are of EMM and SJS are different. the use of the term EM major (EMM) as a synonym for SJS has been a source of confusion. All rights reserved. the differences in the causes of EMM and SJS are not clear. In contrast. A typical target is defined by at least three concentric rings. only two SJS (out of 17 cases) were clearly related to drugs.or drug-induced maculo-papular eruptions. and often confluent in erythematous patches. There is less frequent involvement of two or more mucous membrane in EMM compared with SJS/TEN.1 Erythema Multiforme Major EM is the main differential diagnosis of SJS. Typical target lesions progress to atypical target lesions within 2 or 3 days. furthermore if following a herpes infection. photophobia and painful micturition are similar to those seen in SJS/TEN. Hypoxemia in EMM is usually related to M. then therapeutic prevention of recurrent EMM Am J Clin Dermatol 2003. The two diseases are usually clinically distinguishable.[13] Differentiating EMM versus SJS/TEN is not a matter of redefined nosology. mainly on the trunk and face. The difficulty of identifying the culprit drug in cases of drug eruption and the importance of a prompt withdrawal of that drug are important considerations at the time of patient admission to determine the prognosis of the condition.[31] Upon reviewing a number of publications it is clear that there is no consensus on the proportion of EMM cases that are drug induced. there is no evidence that infection by HIV increases the incidence of EMM. EMM differs from SJS by a more important infiltrate of mononuclear cells in the superficial dermis (interface and/or perivascular) and by a lesser degree of necrosis of epidermal cells. but SJS can be lethal even if not progressing to TEN.[13] The recurrence of the disease is an essential diagnostic criteria for EMM. EMM is not associated with an increase in mortality.[13] If EM occurs following HSV1. EMM occurs mainly after herpes simplex virus (HSV) infection. 30% versus 4% for TEN/SJS. crusts on any surfaces with impaired alimentation. Whereas patients with SJS have widely distributed purpuric macules and blisters. rather than EMM. Differential Diagnosis of SJS and TEN 2. The symmetric and mainly acral distribution is indicative of EMM. In patients with EMM these lesions are limited in number and characterized by concentric erythematous rings and a central blister. However. In EMM mucosal lesions including erythema. while SJS/TEN is. A drug is confirmed to be responsible for approximately 70% of SJS cases compared with 20% of EMM cases.[13] The exclusive relationship between M. it has practical implications because the prognosis and the treatment are different. If the prevention of TEN/SJS is only founded on avoiding the intake of the culprit drug. 2. In children. while there is evidence that it strongly increases the risk of SJS/TEN.[13] Histologically. pneumoniae and SJS. the extent and severity of mucous membrane erosions are often less marked in EMM than in SJS/TEN.

After sun exposure.[37. and pathological criteria has been proposed for a better definition of the entity. the erythema and blisters of thermal. The acuteness of AGEP and an association with a recent intake of pharmaceuticals are the cornerstones of its identification. with high fever (39°C) accompanying or preceding the rash. Both AGEP and PP are characterized by subcorneal spongiform pustules. aminopenicillins) are arguments for a separate entity. The presence of pustules usually allows for easier distinction between TEN and AGEP. Because AGEP has a more acute onset. Occasionally the pustules coalesce to produce extensive superficial detachment with a positive Nikolsky sign mimicking TEN. A diagnostic score combining clinical. Nevertheless the skin pathology can help to differentiate the two pustular eruptions.  Adis Data Information BV 2003. Thalidomide is an effective second-line treatment in cases with very frequent recurrences. the absence of lesions in protected areas such as folds of skin. whereas it is rarely lacking in TEN. and single-cell necrosis of keratinocytes are suggestive of AGEP. the fever is lower. but (i) AGEP pustules may disappear within 2 or 3 days (they last 5–10 days on average) and (ii) secondary bacterial infection of blisters may occasionally result in pustules in the evolution of SJS or TEN. First described in 1980. the general status of the condition is less altered than in TEN. and confirmed with a series of 60 cases in 1991. The subcorneal split. the initial stage is less acute. Neutrophil counts are elevated above 7000/mm3.Different Diagnosis of Severe Cutaneous Drug Eruptions 565 exists. calcium channel antagonists. perhaps more frequently that might be expected by chance.3. the secondary desquamation may be also confused with epidermal detachment.38] In contrast the lesions of TEN will show an extensive necrosis of keratinocytes. AGEP is considered in Europe to have an incidence of at least 1–5 cases per million inhabitants per year. Following the quick resolution of pustules the stratum corneum may desquamate in large sheets. Extensive superficial detachment after coalescence of pustules. First-line therapy is based on preventing HSV recurrence. These two points are essential for the clinical differential diagnosis with TEN. the differential diagnosis between TEN and pustular neutrophilic eruptions is more frequent with AGEP than with acute PP. 2.1 Intermediate Burns Fig. The perfect delimitation of involved area. The subcorneal aseptic pustules are usually distinctive and easily recognized when they remain distinct. phototoxic or caustic burns of intermediate thickness can mimic TEN (see figure 4). biological. Death occurs mainly in elderly persons with previous chronic disease. some differences can be observed. whereas psoriasiform hyperplasia is suggestive of PP. A history of plaque psoriasis or of pustular lesions on palms and soles is frequent in patients with disseminated PP. When the context is not explicit. which is rapidly covered by dozens of small non-follicular whitish pustules. Mucosal involvement has been given a negative value in the AGEP score.2 Pustular Neutrophilic Eruption: Acute Pustular Psoriasis and Acute Generalized Exanthematous Pustulosis Acute generalized exanthematous pustulosis (AGEP) is the second most common misdiagnosis (EMM being the most common) of TEN (see figure 3). 4 (8) . and the duration of the eruption is longer (usually longer than 3 weeks) compared with AGEP. 3. The prognosis is good with a mortality rate of <1–2%. Acute generalized exanthematous pustulosis. 2. and the lack of mucosal involvement are the main clinical criteria of diagnosis. All rights reserved. In PP. a subepidermal split and a very mild interface infiltrate of mononuclear cells.[34-36] The clinical characteristics and its frequent association with certain drugs (macrolides. There is usually no visceral involvement and spontaneous healing occurs in 10–15 days.[36] If the onset of AGEP is abrupt. The skin biopsy will allow an easy distinction. the presence of pustules. The onset of AGEP is abrupt. but AGEP also occurs in patients with psoriasis. Although the clinical presentation of AGEP and acute PP is very similar. the migration of polymorphonuclears within the epidermis which contains only a few necrotic keratinocytes is characteristic of AGEP. the investigation of a drug that Am J Clin Dermatol 2003. with high fever (39°C) accompanying or preceding a widespread erythematous and edematous rash. vasculitis. but conspicuous edema in the superficial dermis.[33] These patterns of positive Nikolsky signs in the acute phase and of secondary desquamation in large sheets can be observed in patients with AGEP and in patients with acute pustular psoriasis (PP) von Zumbusch type. In addition the incidence of AGEP is probably higher than that of acute disseminated PP.3 Other Bullous Dermatosis 2. exocytosis of eosinophils.

[40] These druginduced cases are characterized by an acute onset. Am J Clin Dermatol 2003. a good prognosis. Both disorders are characterized histologically by full-thickness necrosis of the epidermis and are drug induced. is present in a focal infection of the nose or throat. SSSS is nearly exclusively seen in infants. A context of staphylococcal sepsis is indicative of SSSS. Specific staphylococcal exotoxins (epidermolysins) cause extensive subcorneal separation of the stratum corneum by interacting with desmoglein 1.3. The resolution is very quick after the beginning of appropriate antibacterials. All rights reserved. aureus is not present in the skin lesions. Linear IgA deposition along the basement membrane zone allows the diagnosis and differentiates linear IgA bullous dermatosis from bullous pemphigoid or other bullous disease. which is often poorly diagnosed by general practitioners. The skin biopsy may be of little help.566 Bachot & Roujeau The skin biopsy is distinctive by showing a subcorneal split with or without mild acantholysis. as it can be seen with coma and septic patients in intensive care. limited involvement of mucous membranes. mildness of constitutional symptoms. 2. an absence of visceral involvement. S. which may Staphylococcal Scalded Skin Syndrome (SSSS) resembles TEN and was originally confused with it. Mucosal involvement is a frequent feature of idiopathic forms.[39] Blisters are less prominent here than a very superficial desquamation with a positive Nikolsky sign. GFBDE is characterized by prior episodes of blisters. 2. 2. Generalized fixed bullous drug eruption. vancomycin and diclofenac being the most frequently reported inducers. 4. Fig. Mucosal involvement is absent or restricted to cheilitis or infectious conjunctivitis.2 Generalized Fixed Bullous Drug Eruption In Lyell’s original publication. 2. the typical clinical presentation of GFBDE is quite distinct from that of TEN on so many points that it seems justified to consider them as two distinct diseases. it is not clear whether they are really different. Nevertheless.5 Autoimmune bullous disorders The diagnosis of autoimmune bullous disorders can usually be confirmed by a positive direct or indirect immunofluorescence.3. 4 (8) .3. In adults it is very rare and necessitates both a renal impairment which decreases exotoxin clearance and an abundant staphylococcal exotoxin production by an abscess. but rather.3. 5. Fig. erythematous patches. by showing necrosis of the epidermis with little inflammation. the relatively high incidence of this disease. Linear IgA bullous dermatosis Linear IgA bullous dermatosis is a rare disease characterized by a blistering eruption with ‘sausage-like’ lobulated blisters arranged at the periphery of annular. therefore. The blistering predominates on declive pressure and traumatized areas. may explain why this is one of the conditions that is referred to our emergency department on suspicion of TEN. Drug-induced cases of linear IgA bullous dermatosis have been isolated.3 Staphylococcal Scalded Skin Syndrome Bullous pemphigoid is infrequently associated with mucosal involvement and rarely has an abrupt onset. Intermediate burns. However. and a short lag time between ingestion of the responsible drug and the onset of the reaction (less than 2 days). The skin biopsy will demonstrate a subepidermal blister with a normal non-necrotic epidermis in the roof and linear deposition of immunoglobulin (Ig)G and/or C3 along the basement membrane.4 Edematous Erythroderma Subepidermal blistering can appear on a fragile inflammatory dermis most usually associated to massive edema. The clinical differentiation between TEN and bullous pemphigoid is most often easy. Thermal burn in a bath with erythema and blisters.[11] he retrospectively considered two of the four cases to be generalized fixed bullous drug eruption (GFBDE) rather than TEN (see figure 5). well demarcated large blisters without spots. Bullous pemphigoid induces photosensitivity is necessary.[39]  Adis Data Information BV 2003. Widespread bullous with mildness of constitutional symptoms.

drug eruptions and lymphoma. the absence or mildness of mucous membrane erosions as well as the absence of ‘target-like’ or spot lesions will aid in the ruling out of SJS and TEN in the diagnosis. The rarity of this variant of pemphigus means that its differential diagnosis with TEN is infrequent.[46] The upper half of the trunk. The stomatitis consists of painful erosions.[51] Nevertheless. Most patients also have a severe pseudomembranous conjunctivitis. the severity of mucous membranes involvement in linear IgA bullous dermatosis is less important. papules and plaques are always present and may be more prominent than blisters. Furthermore the removal of the desquamation leaves a normal epidermis in exfoliative dermatitis and not the red oozing dermis that is seen under detached epidermis in TEN. The pathology of exfoliative dermatitis confirms the lack of full-thickness necrosis of the epidermis. 2. 2. Desquamation occurs usually more than 1 week after the onset of erythema. inflammatory lesions are not usually present.4. necrotizing crusting.[41] Mucosal involvement has been reported uncommonly in drug-induced disease. and immune deposits around the epidermal cells and along the basement membrane.[48] 2. The degree of mucosal involvement is usually more severe in extent and intensity than with classic pemphigus. often with the denomination of Rowell syndrome. 3. consisting of a mixture of blisters. which is usually the earliest present sign. and bullous lesions are separated by uninvolved skin without exanthema. Nevertheless one case has been reported with clinical features of SJS. Skin biopsy with direct fluorescent testing permits the diagnosis. blisters and erosions arise from otherwise normalappearing skin. whereas epidermal detachment and blisters occur at the beginning of skin disease in TEN. blisters are rare and may resemble other bullous dermatoses. ulcerations of the oropharynx and vermilion border of the lips. this acronym doesn’t include closely related eosinophilic drug reactions that are without eruptions.5 Summary In the presence of epidermal detachment. Compared with TEN.[49] Since the report of similar reactions with several different types of drugs. head and neck. it  Adis Data Information BV 2003. and proximal extremities are the main areas that are affected. Systemic Lupus Erythematosus is relatively rare (particularly rare in children). inflammatory macules.[7] The main causes are psoriasis. another denomination was necessary. HSS has been initially isolated as the anticonvulsant HSS. and is extremely resistant to therapy. Although paraneoplastic pemphigus has a wide geographical distribution. In classic pemphigus. 4 (8) .[43-45] In all cases the buccal erosions had started progressively. albeit rarely.4 Desquamative Lesions Skin disorders leading to desquamation (exfoliation) are sometimes misdiagnosed as SJS or TEN. All rights reserved.[42] The skin biopsy will demonstrate a subepidermal blister with a normal non-necrotic epidermis in the roof and linear deposition of IgA along the basement membrane. Exfoliative dermatitis is characterized by generalized erythema and scaling. Paraneoplastic pemphigus Paraneoplastic pemphigus of acute onset may be confused with TEN. especially on the palms and the soles. Here.Different Diagnosis of Severe Cutaneous Drug Eruptions 567 rarely mimic TEN. The issue is complicated by the fact that a history of SLE is a risk factor for the occurrence of drug-induced SJS or TEN. Involvement of all mucosal sites has also been observed. DRESS. precise and clinically relevant term has been proposed. desquamation may be clinically confused with full-thickness epidermal detachment. Nevertheless. As in TEN. several cases of EM or SJS-like lesions with severe hemorrhagic. secondary to damage of epithelial cells with possible obstruction of small airways with sloughed epithelial cells. considered in the diagnosis of intermediate epidermal necrosis. respiratory failure can occur in patients with paraneoplastic pemphigus. The most characteristic clinical feature is an intractable stomatitis. There have been no published cases of lupus mimicking TEN. A more informative. The skin biopsy will allow the diagnosis by showing acantholysis. multiple vesicobullous and necrotic lesions on the trunk and extremities have been reported. erosions and target lesions. Hypersensitivity Syndrome (HSS) or Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) There is no consensus for the definition of this drug eruption.1 Exfoliative dermatitis Among the many patterns of skin lesions observed in systemic lupus erythematosus (SLE). which is never a feature of TEN. Drug Reactions (instead of Rash) with Eosinophilia and Systemic Symptoms might be a more appropriate term that would Am J Clin Dermatol 2003. however.[47] The main neoplasms associated with paraneoplastic pemphigus include non-Hodgkin lymphoma.[50] The name of hypersensitivity itself is ambiguous as it may apply to any idiosyncratic reaction fitting one phase of the classic Gell and Coombs classification.[47] They may mimic morphologically the appearance of EM/SJS. When the scales separate in large sheets. oral ulceration. A clinical improvement can be observed within 1–3 weeks following drug withdrawal. eczema. chronic lymphocytic leukemia and Castleman tumor. TEN is sometimes. The cutaneous lesions of paraneoplastic pemphigus are quite variable.

a differential diagnosis of the condition Table II. The maculopapular eruption later becomes infiltrated and indurated with an edematous follicular accentuation. A morbilliform eruption. and the risk of relapses when they are tapered.[52] Reactivation of human herpes virus (HHV)-6 is partly responsible probably as a result of immunodeficiency or lymphocyte activation induced by drug hypersensibility. which is later than most other serious skin reactions. often above 1500/mm3. Other visceral manifestations include pneumonitis interstitial nephritis.[52] In its complete form this syndrome includes a severe eruption. 4. however. Lastly.[7] The criteria proposed for the diagnosis of DRESS (see table II) are not yet validated. The most characteristic biological alteration is eosinophilia. and may involve other organs. include drug reactions that are without eruptions. allopurinol. Exfoliative dermatitis is another clinical presentation which may be associated with mucosal involvement. Because there is no necrosis in the epidermis. upper trunk.  Adis Data Information BV 2003. Vesicules and tight blisters may be induced by dermal edema.568 Bachot & Roujeau Fig. The face. Drug rash eosinophilia systemic symptoms. these blisters are different from those of TEN but can be confusing in the absence of pathological examination. myocarditis and thyroiditis. Hepatitis is also frequent (present in approximately 50% of cases) and may be life threatening in severe cases. Sterile follicle-centered pustules may exist. 6. The aromatic antiepileptic agents (phenytoin.1 Other Cutaneous Drug Eruptions Although the consensus on the definition of DRESS is not completely affirmed. especially interstitial pneumonitis. A person shall be said to have DRESS if three criteria are present. fever. hematologic abnormalities with eosinophilia and atypical lymphocytes. however. but evolution of symptoms can persist for weeks. carbamazepine.. erosions.5 109/L or Presence of atypical lymphocytes Systemic involvementa Adenopathies ≥2cm in diameter or Hepatitis (liver transaminases values ≥2 N) or Interstitial nephritis or Interstitial pneumonitis or Carditis a The proposed classification is based on three criteria. Corticosteroids can be suspected. Corticosteroid therapy improves systemic manifestations dramatically. lymphadenopathy. They differ from the typical pattern of AGEP in which pustules are more numerous and predominant in main folds. there have been no published controlled studies assessing the involvement of corticosteroids in DRESS. hepatitis. All rights reserved. is suggestive of the diagnosis and may be severe enough to make affected individuals unrecognizable. are not completely known. Fever and cutaneous eruption are frequently the first signs of DRESS/HSS. some authors prefer to not separate cutaneous drug reactions and included SJS and TEN in the drug HSS.[51] with permission] Cutaneous drug eruptiona Hematologic abnormalitiesa Eosinophilia ≥1. often more marked in periorbital regions. dapsone. to date. phenobarbital).[51] Lymphadenopathy is frequent (present in approximately 75% of cases) and usually due to benign lymphoid hyperplasia. Differential Diagnosis of DRESS/HSS 4. such as cheilitis. mononucleosis-like atypical lymphocytosis is also common.[53] Patients with DRESS usually fully recover. and influence the T-cell response. gold salts. The interplay of multiple constitutional and/or acquired factors that impair the ability to detoxify reactive drug metabolites. Proposed criteria of the diagnosis for Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) [reproduced from Bocquet et al. of increasing the risk of HHV6 reactivation. erythematous pharynx and enlarged tonsils (see figure 6). Am J Clin Dermatol 2003. DRESS typically develops 2–6 weeks after a drug is first used. 4 (8) . and not accepted by all authors. which is at first indistinguishable from more benign drug eruptions. eruption and eosinophilia. Relapses can occur with this drug reaction without rechallenge of the culprit drug. particularly that of hepatitis. and minocycline are the main responsible drugs. and upper extremities are affected first with later involvement of the lower extremities. is usually found initially. as well as nonfollicular small pustules. sulfonamides. Erythroderma may occur. Erythroderma with edema associated to superficial desquamation. The multivisceral involvement differentiates DRESS from common cutaneous drug eruptions. Edema of the face.

the liver. + indicates the presence of the symptom. lymph nodes. Cutaneous features are present in nearly half of the cases. ↓ indicates a reduction. Angio-immunoblastic lymphadenopathy is usually treated with corticosteroids. eosinophils. a polymorphous infiltrate including immunoblasts. +++ NI or ↑ ↑↑↑ ++ + ↓ NI – + ↑↑↑ ↑ + Lymphocytic infiltrate Lymphoid hyperplasia pseudolymphoma Epidermal necrolysis NA Subcorneal pustules NA 2–6 weeks Several weeks +++ +++ +++ + +a + Cheilitis +++ +++b if edema is present 1–3 weeks 1–3 weeks +++ – – – +++ +++ +++ – +++c 48 hours <1 week +++ ++ ++ +++ +a if edema is present Rarely – + + SJS/TEN AGEP AGEP = acute generalized erythematous pustulosis. Involvement of the skin is typically a pruritic. In more than one third of the cases. plasma cells. generalized lymphadenopathy. with the number of plus signs indicating the degree of severity of that symptom. NI = normal.. drug use has been identified as the cause of the eruption at the onset of the disease. the spleen and the lung is common.2 Angio-Immunoblastic Lymphadenopathy This disease.[54] The prognosis is poor with a median survival of 11–30 months. Differential patterns of selected severe drug cutaneous adverse reaction (reproduced from Bocquet et al. Interstitial nephritis. immunoblasts and lymphopenia. but plaques. thyroiditis. NA = not applicable. and transformation into an aggressive lymphoma. It typically shows an effacement of lymph node architecture. While the clinical signs of TEN/SJS. AGEP and DRESS/ HSS are usually quite distinct. tubular nephritis. either given alone or with Am J Clin Dermatol 2003. nodules. Other common hematologic abnormalities are hyperleucocytosis with eosinophilia. The establishment and evaluation of diagnosis criteria for drug cutaneous reactions are lacking. epithelioids histiocytes. night sweats. and a prominent arborizing postcapillary vasculature. Tracheobronchial necrosis. polyclonal hypergammaglobulinemia. sometimes an eruption can present as at least two of these three types (see table III). considered to be a subtype of peripheral T-cell lymphoma. 4. The diagnosis is affirmed by histopathological examination of a biopsy specimen of  Adis Data Information BV 2003.[51] with permission) DRESS Clinical signs Typical onset of eruption Typical duration of eruption Fever Infiltrated papules Facial edema Pustules Blisters Atypical target Mucous membrane involvement Lymph node enlargement Other organ involvement Histological pattern Histological pattern of the skin Histology of lymph nodes Laboratory values Hepatitis Neutrophil count Eosinophil count Atypical lymphocytes a b c Tight blisters. Systemic involvement of bone marrow. Death is usually secondary to infection due to immunodeficiency resulting from the disease and/or from chemotherapy. carditis. All rights reserved. SJS = Stevens-Johnson Syndrome. – indicates that the symptom is not present. interstitial pneumonitis. occurs most often in elderly patients and is associated with fever. includes other cutaneous drug reactions such as SJS/TEN and AGEP. weight loss. DRESS = drug rash with eosinophilia and systemic symptoms. 4 (8) . maculopapular rash. small lymphocytes. with the number of arrows indicating the extent of the elevation.Different Diagnosis of Severe Cutaneous Drug Eruptions 569 Table III. generalized maculopapular eruption. subcutaneous nodules and angiomatous plaques have also been reported. and Coombs’-positive hemolytic anemia. TEN = toxic epidermal necrolysis. ↑ indicates elevation.

Additional forms include ulcers. Patients with lymphoma and leukemia generally have a long-term history of symptoms. immunohistology and clonality are the main arguments for lymphoma diagnosis. 4.1. Scaling appears after a few days. antimalarial agents and NSAIDs. (ii) hemorrhagic lesions ranging from petechie to extensive ecchymosis. can also be responsible for the exacerbation of severe eruptions. Some cases with widespread maculopapular eruptions are also published. can aid in the diagnosis of lymphoma.[62] Specific cutaneous lesions occur in approximately two thirds of the patients with Churg-Strauss syndrome and can be classified in three categories: (i) erythematous maculopapules sometimes resembling EM.3. exanthema or maculopapular eruption were reported in one publication. such as terbinafine. which have failed to be characterized despite repeated investigations. Nevertheless. psoriasis and cutaneous drug reactions with erythroderma are often not distinguishable.[57] Some drugs. which becomes rapidly generalized.5. Primary HIV infection is associated with clinical signs presenting manifestations in approximately 45–85% of cases. myalgias.2 and 4. Some clinical signs (provided in sections 4.3) may be helpful to orient the diagnosis.[61] 4. and (iii) cutaneous and subcutaneous nodules.[66] The main manifestations are mononucleosic syndrome associated with fever. and more so in the skin. and annular. cutaneous lesions are present during the development of this condition in at least once in 50% of patients. permits the diagnosis. Am J Clin Dermatol 2003.3.3 Psoriasis 4. Mucosal and cutaneous involvement are present in approximately 70% of patients. although occasionally a new onset of psoriasis has followed treatment with certain drugs. angio-immunoblastic lymphadenopathy and HSS may have a similar clinical pattern. neurologic) involvement with eosinophilia includes vasculitis and especially Churg-Strauss syndrome. In periarteritis nodosa. However purpura. The infiltration of the skin may be severe. in addition to various mis Adis Data Information BV 2003. Establishing cell clonality in the blood.3.[55] Primary erythrodermic forms of mycosis fungoides are rare. senile erythroderma with eosinophilia and hyper-IgE can lead to this condition being misdiagnosed as DRESS. Atopic erythroderma may occur at any age. 4. Irritation. most often cyclosporine or corticosteroids. Therefore.2 Eczema The differential diagnosis of a cutaneous eruption associated with multi-organ (pulmonary. following patchy erythema. associated with a swelling and fissural nature of the skin.570 Bachot & Roujeau cytotoxic agents. feeling cold and a sensation of tightness are typical of erythroderma. The extension can spread rapidly to be universal in 12–48 hours. hepatitic. β-adrenergic antagonists.[63] Wegener granulomatosis has been associated with a skin eruption mimicking a cutaneous drug eruption.[54] 4. are associated with severe reactions. leukemia and myelodysplasia have also been reported. although this association is rare. histology.[55] Hodgkin disease. renal. headache and weight loss.5 Acute Viral Infections The exacerbation of existing lesions usually precedes the generalization of eczema. Resistance to corticosteroids is characteristic.1 Lymphoma and Leukemia Cutaneous T-cell lymphoma (mycosis fungoides and S´ ezary syndrome) is seen most commonly in approximately 10% of patients with erythroderma.[56] 4. 4. S´ ezary syndrome is characterized by erythroderma with specific lymph node involvement. 4 (8) . The histopathologic features of the first two types are nonspecific. non-Hodgkin lymphoma. livedo reticularis and facial edema. Atypical lymphocytes with epidermotropism are necessary for the diagnosis. The scales may be large.3. but have a different lymph node histological pattern and evolution. most commonly pustular eruptions and erythroderma. urticarial lesions have rarely been reported. The suspect drugs include lithium. Wheals. These cases occur mostly in patients with a history of psoriasis.1 Primary HIV infection The limits between spontaneous psoriasis and drug-induced or exacerbated psoriasis are not always clear.3. often associated with wheals.[65] SLE is recognized as a risk factor for severe cutaneous drug eruptions such as SJS/TEN and DRESS.[58-60] Abrupt withdrawal of treatment.[66] Nonspecific maculopapular eruption of the trunk with buccal erosions or erythema and genital ulceration are indicative of cutaneous eruptions associated with HIV infection. nodules and livedo are not suggestive of a drug eruption.3. 4. often first in the flexures. All rights reserved. including tetracycline. or fine and wet. which occur 20–30 days after contamination.4 Vasculitis Erythroderma developing as primary eczema or associated with lymphoma is often of sudden onset.[64] SLE with multiorgan involvement could be misdiagnosed but the presence of a typical malar eruption. usually progress to form erythematous atrophic plaques. lymphoma. arthralgia.3 Erythroderma cellaneous agents. Taken together. eczema.

Auquier-Dunant A. Bigby M. 68: 355-61 12. alternative causes should be excluded. and management. Rasmussen JE. Mockenhaupt M. Arch Dermatol 1991. et al. HHV-6 can cause clinical illness during reactivation. et al. 331: 1272-85 8. Lancet 2000. Cutaneous reactions to drugs: an analysis of spontaneous reports in four Italians regions. 256: 3358-63 2.5. Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death? Arch Dermatol 2000. et al. Huff JC. Picard E. While the majority of drug eruptions are not severe. 5. Klapholz L. Br J Clin Pharmacol 1999. Rechallenge should not be performed after a serious reaction. Nevirapine and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. Toxic epidermal necrolysis probably due to Klebsiella pneumoniae sepsis. Stern RS. Curr Opin Allergy Clin Immunol 2001. The withdrawal of the culpit drug is the most important therapeutic action. Toxic epidermal necrolysis associated with Klebsiella pneumoniae sepsis. Mentec H. Guillaume JC. JAMA 1986. Stevens-Johnson syndrome and erythema multiforme. Cutaneous drug reactions: an attempt to quantitative estimation. guidelines had been proposed for performing skin testing in the investigation of cutaneous drug reactions. Toxic epidermal necrolysis (Lyell syndrome): incidence and drug etiology in France.Different Diagnosis of Severe Cutaneous Drug Eruptions 571 4. Febre JP. Roujeau JC. All rights reserved. Lancet 1998. Toxic epidermal necrolysis: an eruption resembling scalding of the skin. 138: 1019-24 14. Erythema Multiforme Majus. Lyell A. N Engl J Med 1994. Gillis D. Swanbeck G. et al. et al. Oranje AP. 6. In adults. 11: 331-4 23. et al. Pediatr Dermatol 1994. 48: 839-46 7. Ewards IR. Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: correlations between clinical patterns and causes. The difference of evolution and severity between SJS/ TEN. Update to the Stevens-Johnson syndrome. 52: 388-93 4. Results of an international prospective study. Vuzevski VD. Roujeau JC. Rzany B. Am J Dis Child 1922. 1: 293-8 24. The lack of sensitivity and specificity of in vitro and in vivo tests for the diagnosis of a severe cutaneous drug eruption means that they must be considered together with other clinical evidence in order to reach a diagnosis. 126: 37-42 18. Zahedi M. Adverse drug reaction: definition. Today. Roujeau JC. Weston WL. diagnosis. Jick H. Jick S. Arch Dermatol 2002. encephalitis. but it does not help in establishing whether the disease is drug induced. interstitial pneumonitis. Rates of cutaneous reactions to drugs.[68] The administration of ampicillin or amoxicillin increases the eruption rate by up to 30–70%. Roujeau JC. Drug-induced cutaneous reactions: a report from the Boston Collaborative Drug Surveillance Program on 15 438 consecutive inpatients. 14: 558-9 20. et al. 22: 450-6 13. Hunziker T. Dahlberg E. and bone marrow suppression after bone marrow transplantation. et al. Bigby M. 35: 757-60 21. 24: 526-33 11. A clinical classification of cases of toxic epidermal necrolysis.[67] These manifestations are similar to DRESS. 129: 92-6 10. severe disease. 351: 1417-20 Am J Clin Dermatol 2003. 4 (8) A nonspecific maculopapular eruption is classically associated with Epstein Barr Virus primary infection. Eur J Clin Microbiol Infect Dis 1995. Johnson FC. the only method to confirm the suspected culprit drug is responsible for the eruption is via a rechallenge. LeCleach L. Arch Dermatol 1990. 127 (6): 839-42 19. 1981-1985. including encephalitis. Cleve Clin J Med 1988. Aronson JK. Naldi L. but it could be helpful to incriminate a specific drug when several pharmacological treatments are suspected. 28: 1843-8 16. Guillaume JC. et al. 4. Sch¨ opf E. Bachot N. Bastuji-Garin S. A new eruptive fever associated with stomatitis and ophtalmia: report of two cases in children. Rzany B. primary infection or reactivation with HHV-6 can produce a mononucleosis-like illness and. Arch Dermatol 1993. and vesicular rash. et al. AIDS 2001. it is important for clinicians to recognize a severe reaction. Tay YK. Naldi L. Braunschweig S. Medication use and the risk of StevensJohnson syndrome or toxic epidermal necrolysis. Naldi L. Stevens AM. It has been shown that HHV-6 might be associated with fever and skin rash resembling acute graft-versushost disease. Allergy 1997. Approximately 4–13% of eruptions are associated mainly with exanthema. Toxic epidermal necrolysis (Lyell syndrome) in 77 elderly patients. not erythema multiforme (von Hebra). et al. N Engl J Med 1995. . Becker DS. 284: 215-8 5. Garcia-Doval I. Physiopathology and treatment of severe drug eruptions.  Adis Data Information BV 2003. Mycoplasma pneumoniae infection is associated with Stevens-John syndrome. particularly in immunocompromised persons. The improvement of skin testing and in vitro methods to confirm the causality of the drug will be an interesting development. Severe cutaneous reactions to drugs. Bastuji-Garin S. Bastuji-Garin S. Kunzi UP. Nevertheless. Kelly JP. a 20-year survey. Skin Biopsies of Severe Cutaneous Drug Eruptions A skin biopsy is often critical for an accurate diagnosis. the interval between the introduction of a drug and the onset of a reaction should be assessed. 55: 412-4 17. 169: 88-9 22. Dermatologica 1984. Toxic epidermal necrolysis.[69] This test is not recommended in routine practice. more rarely. Secondly. Venegoni M. St¨ uhmer A. In addition to primary infections. Mockenhaupt M. et al. 1975 to 1982. Bouwes-Bavinck JN.2 Human Herpes Virus 6 Acknowledgements The authors have provided no information on sources of funding or on conflicts of interest directly relevant to the content of this review. de Groot R.[68] This illustrates the interaction between drugs and viral infections in hypersensitivity. 333: 1600-7 15. Arch Dermatol Res 1992. Conforti A.5. Toxic epidermal necrolysis associated with mycoplasma pneumoniae infection [letter]. et al. Conclusion There are many types of eruptions that can be induced by various drugs. Br J Dermatol 1956. J Am Acad Dermatol 1996. Bocquet H. et al. 136: 323-7 9. DRESS/HSS and AGEP and may help to distinguish between these drug eruptions. Comprehensive hospital drug monitoring: adverse skin reactions. which is not appropriate for severe drug reactions. Firstly. Toxic epidermal necrolysis and StevensJohnson syndrome: an epidemiologic study from West Germany. 137: 765-70 3. Arch Dermatol 2001. Fournier S.3 Epstein Barr Virus References 1. 356: 1255-9 6. Age Ageing 1993. Stern RS. Fagot JP.

Br J Dermatol 2002. J Am Acad Dermatol 1998. Schneck B. Pinching AJ. 30: 187-92 41. Br J Dermatol 1998. Machet L. Mockenhaupt M. Toxin levels in serum correlate with the development of staphylococcal scalded skin syndrome in a murine model. Ann Dermatol Venereol 1980. J Am Acad Dermatol 1991. 139: 39-43 30. Anticonvulsivant hypersensitivity syndrome: in vitro assessment of risk. Martel P. Laroche L. Arch Dermatol 2003. Bioulac P. J Clin Invest 1988. et al. Br J Dermatol 1999. 15: 250-7 52. Roujeau JC. et al. Intravenous immunoglobulin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis: a prospective noncomparative study showing no benefit on mortality or progression. 115: 149-53 28. Schacker T. Clinical. Amoxicillin-induced exanthema in young adults with infectious mononucleosis: demonstration of drug-specific lymphocyte reactivity. Adkins B. Arch Dis Child 2000. Acute generalized exanthematous pustulosis (AGEP): a clinical reaction pattern. 27: 258-64 64. 37: 199-203 63. et al. Benton EC. Bassler KD. 69: 5193-7 40. Cagnano E. Mohan H. Salas C. Chawki D.fr Am J Clin Dermatol 2003. Giomi B. Diagnosis. Termeer C. Bastuji-Garin. Trent JT. Roujeau JC. Godeau P. Evans S. Shear NH. Le THD. Kaur S. Roujeau JC. 11: 269-74 58. Lupus erythematosus with an erythema multiforme-like eruption. and immunopathological mechanisms of the epithelial variant of paraneoplastic autoimmune multiorgane syndrome. 208: 435-60 65. 107: 37-48 35. Padilla RS. Avakian R. Ann Dermatol Venereol 2001. Renn CN. Vaillant L. Araujo OE. 137: 357-64 53. Br J Rheumatol 1988. Fouchard N. 83: 347-52 33. Edlinger C. 40: 649-71 47. Bruynzeel D. et al. Acute generalized exanthematous pustulosis induced by paracetamol: a case with severe hemodynamic disturbances. Int J Dermatol 1989. Saltzstein S. Abel EA. Bachot N. Pustulose exanth´ ematique aigu¨ e g´ en´ eralis´ ee. Erythema multiforme with mucous membrane involvement and Stevens-Johnson syndrome are clinically different disorders with distinct causes. Pussel BA. Annu Rev Med 2000. Linear IgA dermatosis in an adult with clinical signs of Stevens-Johnson syndrome. Dermatol Clin 2001. 9: 713-6 66. Lamireay T. Caeiro JP. 25: 69-79 26. 138: 529-32 61. Bastuji-Garin S. Bertocchi M. Classification. Pediatr Dermatol 2001. 82: 1826-32 51. Descamp V. Infect Immun 2001. Valence A. Thami GP. A propos de 4 cas. with special emphasis on survival. et al. Clinical and epidemiologic features of primary HIV infection. 18: 421-3  Adis Data Information BV 2003. Woischnik M. and immunohistologic features of Vancomycin-Induced Linear Bullous Disease of the skin. 24: 10-3 62. 131: 539-43 32. Wegener’s granulomatosis: observations on 18 patients with severe renal disease. Caproni M. Arch Dermatol 2003. 139: 33-6 31. A clinical and follow-up study of 102 patients. Gupta AK. Drug-induced linear IgA bullous dermatosis: report of six cases and review of the literature. Br J Dermatol 1998. classification and management of erythema multiforme and Stevens-Johnson syndrome.nicolas@wanadoo. The drug hypersensitivity syndrome: what is the pathogenesis? Arch Dermatol 2001. Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins: multicenter retrospective analysis of 48 consecutive cases. Lockwood CM. McEvoy MT. J Am Acad Dermatol 1999. clinical manifestations. 139: 26-32 29. et al. Tidman MJ. J Burn Care Rehabil 1997. Bagot M. et al. et al. Plano LR. Dorfm¨ uller A. Clinical findings and prognosis of polyarteritis nodosa and Churg and Strauss angiitis: a study in 165 patients. Davis MDP. Goncalo M. 4 (8) . Bourseau C. 141: 720-4 46. Beylot C. J Am Acad Dermatol 1997. Contact Dermatitis 2001. The spectrum of human herpesvirus 6 infection: from roseola infantum to adult disease. et al. et al. 19: 697-709 27. Drug induced pseudolymphoma and drug hypersensitivity syndrome (drug rash with eosinopholia and systemic symptoms-DRESS). Amagai M. Acute generalized exanthematous pustulosis. Flowers FP. Medicine 1999. Acute generalized exanthematous pustulosis mimicking toxic epidermal necrolysis. Assier H. S. Bioulac-Sage P. Speron S. Barbaud A. Papa CA. Halevy S. et al. Asai T. 40: 458-61 38. et al. 139: 168 59. Cohen AD. J Am Acad Dermatol 1994. J Cutan Pathol 2001. Spielberg S. Romanelli P. 51: 423-30 68. 137: 301-4 54. et al. Hopital Henri Mondor. et al. Lauzon GJ. Sidoroff A. Straff W. Lynde CW. Hezemans-Boer M. De Coninck AL. Bavinck JN. All rights reserved. Cutaneous adverse effects associated with terbinafine therapy: 10 case reports and a review of the literature. Semin Cutan Med Surg 1996. 12: 164-82 50. et al. Berti E. Gamelli R. Arch Dermatol 2001. Toxic epidermal necrolysis: a review. Q J Med 1983. et al. Roustan G. et al. Pustuloses exanth´ ematiques aigu¨ es g´ en´ eralis´ ees. 10: 459-62 45. 28: 225-8 57. Severe pustular psoriasis provoked by oral terbinafine. Hautarzt 1999. Maculopapular lupus rash in a young woman with systemic involvement. 127: 1333-8 36. Senile erythroderma with serum hyper-IgE. 128: 73-9 34. et al. et al. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. Hashimoto T. De Silva BD. J Invest Dermatol 2000. et al. Lupus 2000. Gasparini G. Hughes J. Generalized pustular psoriasis following withdrawal of oral cyclosporin treatment for palmo-plantar pustulosis. Toonstra J. 125: 257-64 67. Arch Dermatol 2001. Pipeleers-Marichal MA. Nguyen VT. et al. Eur J Dermatol 2000. et al. Sullivan JR. et al. 39: 115-7 60. Horiuchi Y. Martin L. New advances in severe adverse drug reactions. Maynard B. Int J Dermatol 2001. Revuz J.572 Bachot & Roujeau 25. Van Strubarq AS. Ann Intern Med 1996. et al. et al. Doutre MS. Clin Exp Dermatol 1999. Kuechle MK. Shear N. The new pemphigus variants. Semin Dermatol 1992. Lymphadenopathy induced by anticonvulsivant drugs and mimicking clinically and pathologically malignant lymphomas. Arch Dermatol 1991. Association of human herpes virus 6 infection with drug reaction with eosiniphilia and systemic symptoms. 94010 Cre E-mail: bachot. et al. Revuz J. Cutaneous mainfestations of ChurgStrauss syndrome: a clinicopathologic correlation. Prins C. 137: 193-206 48. Kerdel FA. 45: 321-8 ˆ Correspondence and offprints: Dr Nicolas Bachot. Toxic epidermal necrolysis syndrome versus mycosis fungoides. demographic. Ndoye A. Kikuchi disease with facial rash and erythema multiforme. Stoeckle MY. 78: 1-8 42. Diagnosis of drug-induced psoriasis. Leaut´ e-Labreze C. 50: 288-91 43. 18: 403-5 44. Bocquet H. Arch Dermatol 1995. Cutaneous involvement in patients with angioimmunoblastic lymphadenopathy with dysproteinemia. 49. ´ teil Cedex. Halevy S. Sigurdsson V. 193: 338-41 39. et al. Cancer 1959. Arch Dermatol 2000. Miller OF. Collier AC. Kirsner RS. Daoud MS. 28: 113-9 37. Ackerman L. Dermatology 1996. Cardinali C. Kimyai-Asadi A. J Am Acad Dermatol 1996. 147: 1166-70 69. Barbadillo C. Robinson ND. et al. 136: 881-6 55. et al. Marzano AV. Stegemeir E. Pustular psoriasiform eruption with leukocytosis associated with terbinafine. Arch Dermatol 2003. 35: 53-7 56. Analysis of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis using SCORTEN: The University of Miami Experience. Guidelines for performing skin tests with drugs in the investigation of cutaneous adverse drug reactions. Courville P. Nousari HC. Guillevin L. Lupus erythematosus with antiphospholipid syndrome and erythema multiforme-like lesions. Wilson NJ. France.

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