BJD. Summary. British Journal of Dermatology THERAPEUTICS

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1 THERAPEUTICS BJD British Journal of Dermatology Drug reaction with eosinophilia and systemic symptoms: is cutaneous phenotype a prognostic marker for outcome? A review of clinicopathological features of 27 cases S. Walsh, 1 S. Diaz-Cano, 2 E. Higgins, 1 R. Morris-Jones, 1 S. Bashir, 1 W. Bernal 3 and D. Creamer 1 Departments of 1 Dermatology, 2 Histopathology, and 3 Hepatology, King s College Hospital, Denmark Hill, London SE5 9RS, U.K. Summary Correspondence Sarah Walsh. sarahwalsh1@nhs.net Accepted for publication 27 September 2012 Funding sources This work was supported by a grant from the British Skin Foundation. Conflicts of interest None declared. DOI /bjd Background Drug reaction with eosinophilia and systemic symptoms (DRESS) describes a heterogeneous group of severe adverse reactions to medications. The cutaneous phenotype has a number of guises, accompanied by a variety of systemic features including fever, haematological abnormalities and visceral involvement, most commonly the liver. Clinical markers of prognosis have not been identified. Objectives To assess the cutaneous signs and dermatopathological features of DRESS in order to identify potential prognostic markers. Methods We reviewed the clinical features, dermatopathology and outcomes of 27 consecutive cases of DRESS presenting to a single unit. Results Four distinct patterns of cutaneous involvement were identified: an urticated (13 27 patients), a morbilliform erythema (three of 27), an exfoliative erythroderma (three of 27) and an erythema multiforme-like (EM-like) reaction consisting of atypical targets (eight of 27). All patients mounted a fever, most developed lymphadenopathy (24 27) and peripheral eosinophilia (25 27) and the most common organ involved was the liver (27 27). Review of the dermatopathic features of patients with DRESS demonstrated a superficial spongiotic dermatitis in the majority of cases (16 27). A smaller number of cases showed basal cell vacuolar degeneration and necrotic keratinocytes (nine of 27). The patients with these biopsy findings more commonly had an EM-like cutaneous phenotype, and more severe hepatic involvement. Three patients died, two following failed liver transplants. Conclusions Our series is the first in which a detailed dermatological assessment has been made of consecutive patients presenting with DRESS, and the largest U.K. series to date. Our results suggest a possible prognostic role of the cutaneous and dermatopathic findings in DRESS in predicting the severity of visceral involvement in this syndrome. Drug reaction with eosinophilia and systemic symptoms (DRESS) describes a severe medication-induced adverse reaction that has cutaneous, haematological and solid-organ manifestations. The major morbidity in DRESS arises from visceral involvement with liver disturbance occurring in the majority of cases. 1,2 Both hepatocellular and cholestatic damage are encountered, while in severe cases fulminant hepatic failure may necessitate liver transplantation. 3,4 The cutaneous involvement in DRESS is also typically extensive and symptomatic. Although a mild maculo eruption can occur in DRESS, more significant cutaneous inflammation is usual, with a widespread dermatosis often complicated by polymorphic features. Reports of DRESS in the dermatological literature have described numerous skin signs, including vesicles, bullae, pustules, targets, cheilitis, purpura, facial oedema, occurring alongside a variety of s. 1,5,6 To date, no detailed assessment of clinical skin features in a series of patients with DRESS has been published. The dermatopathological features of DRESS are also varied and reflect the spectrum of skin involvement. While commentary is made in the literature on the histopathological findings of delayed drug-induced reactions, 7 there has been no attempt to classify tissue reaction patterns in DRESS. Studies in Stevens Johnson syndrome (SJS) toxic epidermal necrolysis (TEN), another life-threatening adverse drug reaction, have identified phenotypic features that carry prognostic significance. 8,9 The SJS TEN scoring system, SCORTEN, predicts mortality 391

2 392 DRESS: review of clinicopathological features, S. Walsh et al. based on an assessment of several clinical features including physiological and laboratory parameters at presentation, and comorbidities. 8 Dermatopathological features have also been found to be of prognostic significance in TEN, with the extent of inflammatory infiltrate being negatively correlated with survival. 10 There is a range of clinical severity in DRESS, some patients having a modest constitutional upset, others developing significant morbidity. Mortality in DRESS has been estimated at 10% with most patients dying from liver failure. 11 Although authors have observed that pancytopenia and certain medications may be associated with increased mortality, currently there are no recognized phenotypic markers of disease severity in DRESS, and therefore no mechanism by which outcome can be predicted. 5,6 The demonstration of prognostic indicators would help identify patients benefiting from intervention with potent therapy and rapid transfer to an intensive care unit. 12 In this study, 27 patients with DRESS underwent assessment of their cutaneous signs and dermatopathological features. In order to identify potential prognostic markers, we looked for clinical or pathological signs that were over-represented in those with severe liver involvement. Methods Patients Over a 6-year period (August 2005 to September 2011), 27 consecutive patients with DRESS were prospectively recruited following admission to a south London teaching hospital (King s College Hospital). Written informed consent to participation and collection of data was obtained. All patients fulfilled the DRESS diagnostic criteria of Bocquet et al. 1 A standard set of laboratory tests was performed in all cases, including blood count, blood film, renal function, liver function, inflammatory markers and viral hepatitis serology. Investigation for human herpesvirus 6 reactivation was not available. Application of the DRESS classification scoring system proposed by Kardaun et al. demonstrated that all patients were either definite or probable cases (Table 1). 13 For each patient a standard dataset was recorded on the SCAR-UK database (severe cutaneous adverse reactions to drugs). This tool has been designed specifically to collect the following information on patients with severe drug eruptions: demographic data, medical history, drug exposure history, sequential clinical findings during the acute illness, investigation results, disease course and outcome. Assessment of cutaneous features Each patient underwent daily clinical examinations by a consultant dermatologist (D.C., S.W.) during the acute illness. Clinical findings were recorded at diagnosis (day 0), day 2 and day 4. Clinical photographs were performed in the first 4 days of the illness. A further clinical examination was performed in all cases at 2 weeks and 1 month post-diagnosis. Examination at 6 months was achieved in the majority of cases (18 27). At case validation meetings (D.C., S.W.) the dermatological features in each patient were assessed from clinical photographs and the case report forms. The predominant eruption in the acute phase was noted in every case, as was the presence of any secondary cutaneous signs. Assessment of dermatopathological features Skin biopsies were taken from all patients within 72 h of presentation. The specimens from all 27 patients were reviewed retrospectively by a single dermatopathologist (S.D.-C.). The presence of the following specific histopathological features was sought: spongiosis, necrotic keratinocytes, basal cell vacuolation, vasculopathic changes and inflammatory cell infiltrate. The examining histopathologist was aware that the skin reaction was suspected to be drug related, but was unaware of the associated systemic features and their severity. Assessment of systemic involvement The RegiSCAR grading system for DRESS quantifies cutaneous features and systemic involvement to generate an overall score which assigns a patient to one of four groups: definite case, probable case, possible case or no case. A cumulative score is calculated on the basis of the presence or absence of the following features: fever, lymphadenopathy, eosinophilia, a rash and involvement of a solid organ. The parameters for lymphadenopathy, eosinophilia and solid-organ involvement are defined in the footnote to Table 1. Standard laboratory investigations were performed, including full blood count, INR (international normalized ratio), liver and renal function. Autoantibodies, Epstein Barr virus, cytomegalovirus, hepatitis B and C serology, and mycoplasma titres were also measured. The RegiSCAR criteria define hepatic dysfunction as: transaminase > 2 upper limit of normal (ULN) on two successive dates or bilirubin > 2 ULN on two successive dates or aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP) > 2 ULN at least once. Renal dysfunction is defined as creatinine elevated 1Æ5 times the baseline for that patient on two consecutive days. Statistical analysis Analysis was done in Excel An unpaired Student s t-test with unequal variance was used to measure significance of association between clinical and histopathological appearance and severity of liver involvement. Results Patients There were 17 female and 10 male patients; 11 were caucasian, 10 Afro-, four Asian and two black African. The mean age of patients at presentation was 40 years

3 DRESS: review of clinicopathological features, S. Walsh et al. 393 Table 1 RegiSCAR drug reaction with eosinophilia and systemic symptoms (DRESS) score Patient no. Extent > 50% Rash suggestive of DRESS Systemic involvement a (lymphadenopathy, b eosinophilia, c organ involvement d ) Relevant negative serological tests e Total f Classification Probable Probable Definite Probable Probable Probable Probable Definite Definite Probable Probable Definite Probable Definite Definite Definite Definite Probable Definite Definite Probable Probable Definite Definite Probable Probable Definite a Scored out of 4. b At two or more sites, 1 cm. c Eosinophilia: 10 19% of total white cell count = 1 point; 20% = 2 points (if total leucocytes < L )1, an eosinophil count of 0Æ7 1Æ L )1 will gain one point, an eosinophil count 1Æ L )1 will score 2 points). d Liver: transaminases > 2 upper limit of normal (ULN) on two successive dates or bilirubin 2 ULN on 2 successive days or aspartate aminotransferase, gamma-glutamyl transpeptidase and alkaline phosphatase > 2 ULN on one occasion; renal: creatinine 1Æ5 patient s baseline; cardiac: echocardiographic evidence of pericarditis. e Three or more of the following performed and negative: hepatitis A, B, C; mycoplasma chlamydia; antinuclear antibody; blood culture (performed 3 days after hospitalization). f 4 5 = probable case; > 5 = definite case. (median 41). The drugs implicated in the pathogenesis of the syndrome are detailed in Table 2. The mean latency of the reaction was 27 days (10 49 days). The clinical characteristics of the patients are summarized in Table 2. The causative drugs are summarized by group in Figure 1. Assessment of cutaneous features A predominant clinical eruption pattern was discernible in all the patients with DRESS. The most common dermatosis, seen in 13 out of 27 patients (48%), was an of urticated, monomorphic papules favouring the neck, torso and proximal limbs (Fig. 2a d). Individual lesions were deep red, urticated and sometimes purpuric; in areas, the papules were confluent resulting in an oedematous erythema. These patients were designated as having an urticated. Three of the 27 patients (11%) developed a morbilliform erythema of small pink macules (Fig. 3a c); three patients (11%) presented with an exfoliative erythroderma, in which desquamation was prominent (Fig. 4a, b). A further subgroup (eight of 27, 30%) had an eruption consisting of discrete macular purpuric lesions, reminiscent of atypical targets, with a predilection for acral skin, but also seen on the trunk and proximal limbs. Individual lesions were a dusky red, with a purpuric centre, and an atypical target appearance (Fig. 5a e). We designated these as being erythema multiforme (EM)-like. Detailed clinical examination revealed that most patients (25 27) also developed one or more secondary skin feature(s) in addition to the primary eruption. Prominent facial oedema occurred in 23 27; mild cheilitis was observed in six of 27; in four of 27, pustules were seen, both follicular and

4 394 DRESS: review of clinicopathological features, S. Walsh et al. Table 2 Patient characteristics Patient no. Sex Age (years) Ethnicity Drug implicated Primary skin pattern Pustules Cheilitis Facial oedema Care environment Peak AST (10 50 Peak GGT (1 55 Peak alk. phos. ( Peak eosinophilia (0 0Æ L) INR Latency of rash (days) Comorbidities 1 M 54 Caucasian Tazocin (piperacillin tazobactam) EM-like N Y Y Ward Æ44 1Æ M 19 Black African Minocycline EM-like N Y Y Ward Æ51 2Æ F 28 Caucasian Sulfasalazine EM-like N Y Y LITU Æ04 2Æ28 18 SA 4 F 59 Caucasian Phenytoin EM-like N Y Y LITU Æ05 3Æ F 27 Afro- 6 F 51 Afro- 7 F 2 Asian Co-amoxiclav azithromycin Minocycline EM-like N N Y LITU Æ01 9Æ06 18 Phenytoin EM-like Y N Y Ward Æ02 1Æ36 30 DM2 HTN EM-like N N Y LITU Æ14 10Æ F 46 Black African Amoxicillin EM-like Y N Y Ward Æ12 1Æ86 30 N N Y Ward Æ18 1Æ19 29 COPD DM2 9 a F 52 Afro- 10 F 64 Afro- Carbamazepine Exfoliative erythroderma Carbamazepine Exfoliative erythroderma 11 a M 68 Caucasian Amoxicillin Exfoliative erythroderma 12 b M 55 Afro- Allopurinol Morbilliform erythema 13 F 19 Caucasian Sulfasalazine Morbilliform erythema 14 F 51 Asian Isoniazid Morbilliform erythema 15 M 59 Caucasian Allopurinol Urticated 16 F 24 Afro- 17 F 41 Afro- Sulfasalazine Urticated Carbamazepine Urticated 18 M 25 Asian Minocycline Urticated N N Y Ward Æ37 0Æ98 28 DM2 HTN N N Y Ward Æ1 0Æ95 34 N N Y Ward Æ31 1Æ19 15 DM2 HTN N N N Ward Æ38 1Æ44 43 SA N N Y LITU Æ57 4Æ67 21 N N N Ward Æ23 ND 37 HTN N N Y Ward Æ58 0Æ98 21 SA N N Y Ward Æ69 1Æ09 35 N Y Y Ward Æ28 1Æ13 45

5 DRESS: review of clinicopathological features, S. Walsh et al. 395 Table 2 Continued Patient no. Sex Age (years) Ethnicity Drug implicated Primary skin pattern Pustules Cheilitis Facial oedema Care environment Peak AST (10 50 Peak GGT (1 55 Peak alk. phos. ( Peak eosinophilia (0 0Æ L) INR Latency of rash (days) Comorbidities 19 F 28 Caucasian Trimethoprim Urticated 20 F 44 Afro- Carbamazepine Urticated 21 F 33 Caucasian Phenytoin Urticated 22 M 25 Caucasian Phenytoin Urticated 23 M 63 Caucasian Phenytoin Urticated 24 M 63 Caucasian Vancomycin Urticated 25 M 32 Afro- 26 F 29 Afro- Carbamazepine Urticated Phenytoin Urticated 27 M 9 Asian Carbamazepine Urticated N N Y Ward Æ29 ND 49 N N Y Ward Æ19 1Æ29 48 HTN N N Y Ward Æ6 1Æ16 42 N N N Ward Æ1 1Æ18 14 N N Y Ward Æ78 1Æ36 10 HTN N N Y Ward Æ72 1Æ18 23 RA Y Y Y Ward Æ87 1Æ27 19 Y N Y Ward Æ54 1Æ26 18 N N N Ward Æ47 45 AST, aspartate aminotransferase; GGT, gamma-glutamyl transpeptidase; alk. phos., alkaline phosphatase; INR, international normalized ratio; EM, erythema multiforme; LITU, liver intensive care unit; HTN, hypertension; DM2, type 2 diabetes; SA, seronegative arthritis; RA, rheumatoid arthritis; COPD, chronic obstructive pulmonary disease. a Patients 9 and 11 had renal impairment with creatinine of 192 and 210 lmol L )1, respectively. b Patient 12 had echocardiographic features of pericarditis and compatible symptoms.

6 396 DRESS: review of clinicopathological features, S. Walsh et al nonfollicular, predominantly in a facial distribution. No involvement of the mucosae of the eyes, nose, mouth or genitalia was seen, and no patient blistered. All 27 patients mounted a fever of at least 37Æ8 C (maximum 40 C). Twenty-four of the 27 patients had lymphadenopathy in at least two sites. Eosinophilia (> 0Æ L )1 ) was seen in 25 of the 27 patients (mean peak value 3Æ L )1 ). The two patients who did not mount an eosinophilia were pancytopenic. Internal organ involvement in our patients was hepatic (27 27 patients), renal (two of 27) or cardiac (one of 27). All patients demonstrated some degree of liver function impairment, with derangement of either hepatocellular (AST) 12 Anticonvulsants Antimicrobials Anti-rheumatics Fig 1. Causative drug by category. Anticonvulsants comprised phenytoin (6) and carbamazepine (6). Antimicrobials comprised piperacillin tazobactam (1), trimethoprim (1), vancomycin (1), minocycline (3), amoxicillin (2), isoniazid (1) and coamoxiclav clarithromycin (cause uncertain, 1). Antirheumatic drugs comprised allopurinol (2) and sulfasalazine (3). or hepatobiliary (GGT, ALP) enzymes [peak AST values (: range , mean 970, median 250, interquartile range (IQR) ; peak GGT values (: range , mean 522, median 379, IQR ; peak ALP values (: range , mean 295, median 266, IQR ]. Twenty patients had significant derangement of liver function, breaching the RegiSCAR severity threshold (Table 1). Seven patients had milder hepatic dysfunction that did not meet RegiSCAR severity criteria (patients 9, 10, 11, 12, 18, 19, 21); these patients nonetheless could be classified as cases, based on the extent of other systems involved. Two patients (cases 9 and 11) developed renal impairment (creatinine > 1Æ5 ULN), and one patient (no. 12) had pericarditis demonstrated on echocardiogram that was attributed to DRESS. One patient (no. 21) had diarrhoea from which no pathogenic organism could be cultured; this was felt to be gastrointestinal involvement as a part of the DRESS syndrome; however, in the absence of an intestinal biopsy, this could not be confirmed. 14 Three patients had derangement of more than one internal organ patients 9 and 11 had liver and renal impairment; patient 12 had liver impairment and pericarditis. Three patients with severe liver involvement died (patients 4, 7 and 14); patient 4 died of sepsis of respiratory origin, patient 7 died of a pulmonary haemorrhage and patient 14 died following rejection of a liver transplant. Of the 18 patients who completed 6 month follow-up, all had experienced normalization of their liver function. (a) (b) (c) (d) Fig 2. (a d) Images demonstrating the typical appearance of the urticated in drug reaction with eosinophilia and systemic symptoms (13 27 patients), as it appears in caucasian, Asian and black skin. The raised, urticated appearance, with the deep-red colour is characteristic.

7 DRESS: review of clinicopathological features, S. Walsh et al. 397 Assessment of dermatopathological features Skin biopsies were taken from a representative area. The predominant pathological pattern seen on skin biopsy taken from patients with DRESS was a spongiotic dermatitis with a superficial perivascular lymphocytic infiltrate (16 27). The inflammatory reactions seen were somewhat heterogeneous, with primary patterns associated with secondary background changes. An inflammatory vascular reaction, as evidenced by prominent endothelial cells, was noted in 20 of 27 specimens. However, fibrin deposition was not seen in any specimen. Indirect histological evidence of increased vascular permeability (red blood cell extravasation and or dermal oedema) was identified in 24 of 27 cases. We noted that a smaller number (nine of 27) of the biopsy specimens demonstrated necrotic keratinocytes of varying frequency, accompanied by basal cell vacuolation, in a pattern reminiscent of EM. Eosinophils were variably present (10 27). Cutaneous phenotype and systemic involvement Patients with an eruption classified as EM-like, with purpura and atypical targets, were noted to have more severe hepatic involvement than the other clinical phenotypes. Mean AST in the patients with an EM-type eruption (n = 8) was 2578 IU L )1 (range ) compared with 292 IU L )1 ( ) in the patients with an urticated, exfoliative erythroderma or a morbilliform erythema (n = 19). This difference reached statistical significance (P = 0Æ01). Hepatic synthetic function was more severely affected in the EM-like eruption group [mean INR 4Æ11 (1Æ36 10Æ45) vs. 1Æ45 (0Æ95 4Æ67)]. This difference did not reach statistical significance (P = 0Æ07). No correlation could be demonstrated between clinical phenotype and degree of eosinophilia, or between severity of hepatic involvement and eosinophilia. Clinical phenotype and histopathological correlation Of the 13 patients with an urticated clinically, 11 had a superficial spongiotic dermatitis with an inflammatory vascular reaction pattern (Fig. 6a), and two had nonspecific changes on biopsy. The patients with exfoliative erythroderma or a morbilliform erythema clinically (n =6) demonstrated a superficial spongiotic dermatitis in five cases, the sixth case (a morbilliform erythema) having necrotic keratinocytes and basal cell vacuolation. The presence of an EM-like pattern clinically was frequently associated with the presence of necrotic keratinocytes and basal cell vacuolation histologically (Fig. 6b). The eight patients classified clinically as having an EM-like reaction all (a) (c) (b) Fig 3. (a c) Morbilliform erythema as seen in drug reaction with eosinophilia and systemic symptoms in a smaller number (three of 27) of patients. This eruption is macular and demonstrates less livid erythema.

8 398 DRESS: review of clinicopathological features, S. Walsh et al. (a) (b) Fig 4. (a, b) Exfoliative erythroderma in patients with drug reaction with eosinophilia and systemic symptoms (seen in three of 27 patients). had scattered necrotic keratinocytes on histology, with six of the eight demonstrating basal cell vacuolation. A ninth patient who had scattered necrotic keratinocytes and basal cell vacuolation histologically had a morbilliform erythema clinically. There was no full-thickness keratinocyte necrosis in any specimen. Discussion The diagnosis of DRESS relies on the identification of an eruption and associated systemic symptoms which develop following exposure to a culprit medicine. Although the eruption in DRESS is extensive and symptomatic, the major morbidity arises from visceral involvement: kidneys, lung and heart, but most usually the liver, a consistent finding in our cohort. Our cohort demonstrates that there is a spectrum of severity in DRESS, ranging from relatively mild systemic upset to severe, life-threatening illness. While the systemic findings may be quantified objectively by laboratory or radiographic means, the skin findings are less clearly defined. Our series is the first in which a detailed dermatological assessment has been made of consecutive patients presenting with DRESS. Appraisal of cutaneous phenotype and degree of systemic involvement in each case has identified a potential prognostic association. The patients in this study were recruited from a hospital that is a tertiary referral centre for hepatobiliary disease. This is a potential source of bias in our study, and may have resulted in an over-representation of liver involvement in our cohort. However, in the majority of our patients (23 27), the rash was the presenting feature, not liver dysfunction. Only four of 27 were referrals from other units due to liver dysfunction. The study centre is also a regional neurosciences centre, which perhaps explains the large number of patients whose culprit drug was an anticonvulsant. In contrast to the distinct clinicopathological findings in SJS TEN, another SCAR syndrome, the heterogeneous nature of cutaneous and histopathological features in DRESS has confounded attempts to define a single phenotype. The original paper described a severe skin disease with characteristic infiltrated papules or an exfoliative dermatitis. 1 A maculo is described as being the characteristic rash. The authors go on to elaborate on the other appearances of the rash in DRESS, including a morbilliform erythema, erythroderma and the occasional presence of purpura or atypical targets. More recent authors have attempted to characterize the frequency of different rash subtypes (Table 3). Chen and colleagues noted an exfoliative dermatitis in 12%, and an eruption characterized by purpura and blistering in 10%. 6 If we correlate these latter two with our categories of rash designated exfoliative erythroderma and EM-like, respectively, we see that the proportions involved are similar to our cohort. With regard to associated features, head and neck oedema is a consistent finding in the literature describing this disease, with pustules also recognized. 1,6 Based on a detailed assessment of rash morphology in our patient cohort, we propose a classification system based on four distinct patterns of skin involvement in DRESS. The most commonly encountered dermatosis was a generalized in which the individual lesions were raised and indurated producing an eruption of urticated papules. These cutaneous signs were accompanied by histopathological findings of a lymphocytic perivascular infiltrate, spongiosis and upper dermal oedema, reflecting increased microvascular permeability. The second most common clinical pattern was an EM-like eruption consisting of atypical targets, often purpuric, evolving into confluent areas of dusky erythema. Accompanying histopathology demonstrated basal vacuolar degeneration with scattered apoptotic keratinocytes. This presentation of DRESS, with an EM-like purpuric eruption and atypical targets, can be distinguished from SJS TEN by the absence of mucosal disease in the former, and the absence of visceral involvement and eosinophilia in the latter. A morbilliform erythema and an exfoliative erythroderma were the least frequent cutaneous presentations of DRESS in our cohort.

9 DRESS: review of clinicopathological features, S. Walsh et al. 399 (a) (b) (c) (e) (d) Fig 5. (a e) Erythema multiforme-like eruption in drug reaction with eosinophilia and systemic symptoms. This consists of dusky erythema, atypical targets that may be seen both acrally and centrally, and a purpuric appearance readily distinguishable from the other subtypes of eruption. (a) (b) Fig 6. (a) Photomicrograph of a skin biopsy taken from patient 21, with an urticated. The epidermis is spongiotic, and a perivascular lymphocytic infiltrate is seen in the dermis. Eosinophils are absent. (b) Photomicrograph of a skin biopsy taken from patient 3, with an erythema multiforme-like eruption. Necrotic keratinocytes are seen at the dermoepidermal junction, with basal cell vacuolation. Fullthickness necrosis, as would be seen in Stevens Johnson syndrome toxic epidermal necrolysis, is absent. Studies of prognostic factors in DRESS are few, and have not thus far assessed the significance of specific cutaneous features as potential indicators of outcome. Chen et al. 6 (2010) identified pancytopenia as a significant predictor of mortality, while Eshki et al. 5 (2009) noted that DRESS induced by allopurinol or minocycline carried a worse prognosis. Chiou

10 400 DRESS: review of clinicopathological features, S. Walsh et al. Table 3 Comparisons with previous series of patients with drug reaction with eosinophilia and systemic symptoms Roujeau and Stern, 2 % Chiou et al., 15 % Chen et al., 6 % Our cohort, % (n) Fever Rash Exanthematous (most common no percentage given) Exanthematous, 80; erythroderma, 3; vasculitis, 23 a Exanthematous, 100; exfoliative dermatitis, 12; purpura, 10 a Lymphadenopathy (24 27) Eosinophilia (25 27) Hepatic involvement (27 27) Renal involvement (2 27) Mortality (3 27) a Total percentages are > 100% as some patients in each study had more than one cutaneous phenotype. Urticated, 48; exfoliative erythroderma, 11; morbilliform erythema, 11; atypical targets purpura, 30 et al. 15 linked high eosinophil count with a poor outcome. Our results appear to stratify patients with DRESS into two prognostic groups: the cohort of patients with EM-type features clinically and necrotic keratinocytes histologically having significantly worse hepatic involvement than the groups manifesting other rash morphologies. This suggests a division in DRESS pathogenetic mechanisms, with one pathway resulting in more florid hepatic involvement. Interestingly, a single patient in our cohort without EM-like changes in the skin (patient 14) was found to have scattered necrotic keratinocytes and basal cell vacuolation histologically and this patient also had severe liver involvement (AST 2327, out of keeping with the other patients in that phenotypic category. Alignment of severe liver involvement with keratinocyte apoptosis in the skin invokes a pathological process which mediates damage to both organs. In drug-induced liver injury (DILI), acute hepatocellular necrosis is observed, a pathology that may mirror apoptotic epidermal changes occurring in lesional skin. 16 Studies in DRESS have identified the presence of drug-specific cytotoxic T cells at the dermoepidermal interface. 17 Drug-specific T cells have also been detected in the serum of patients with DILI. Evidence from the literature indicates that activated T cells mediate perforingranzyme B as well as Fas Fas L-dependent cell death in the liver and the skin It is possible that drug-specific T-cell clones in DRESS simultaneously induce cell death by these mechanisms in both organs. This hypothesis may explain the observed correlation between the presence of necrotic keratinocytes and more pronounced hepatotoxicity. One of the proposed pathogenetic mechanisms for DRESS is that of a complex immune response to reactivation of latent viruses of the herpesvirus family it has been suggested that in the milder forms of DRESS, there is a more attenuated antiviral immunological response, leading to a less severe clinical phenotype. 20 In conclusion, we have presented a consecutive series of patients with DRESS in which a phenotypic classification system is proposed. By delineating the clinical phenotype more clearly, we also propose that a specific clinicopathological presentation, an EM-like eruption of atypical targets, is associated with severe hepatic involvement. Further studies of a larger series of patients will be required to verify that this cutaneous phenotype may act as a prognostic indicator of severe hepatotoxicity in DRESS. What s already known about this topic? Drug reaction with eosinophilia and systemic symptoms (DRESS) has a heterogeneous clinical presentation, with a skin eruption of variable morphology. DRESS carries considerable morbidity and mortality, usually hepatic in origin, although renal, pulmonary and pericardial involvement can be seen. What does this study add? The cutaneous phenotype in DRESS can be categorized as an urticated, a morbilliform erythema, exfoliative erythroderma or erythema multiforme-like (EM-like). An EM-like eruption DRESS may be prognostic of more severe hepatic involvement. References 1 Bocquet H, Bagot M, Roujeau JC. Drug-induced pseudolymphoma and drug hypersensitivity syndrome (drug rash with eosinophilia and systemic symptoms: DRESS). Semin Cutan Med Surg 1996; 15: Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med 1994; 331: Hunter EB, Johnston PE, Tanner G et al. Bromfenac (Duract)-associated hepatic failure requiring liver transplantation. Am J Gastroenterol 1999; 94: Blazka ME, Elwell MR, Holladay SD et al. Histopathology of acetaminophen-induced liver changes: role of interleukin 1 alpha and tumor necrosis factor alpha. Toxicol Pathol 1996; 24:181 9.

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