Ljubka Miteva

Miroslav Kadurina

Robert A. Schwartz

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267Acta Dermatovenerol Croat 2010;18(4):267-270 CASE REPORTChildhood Acute Generalized Exanthematous Pustulosis Induced by Oral KetoconazoleLjubka Miteva1, Miroslava Kadurina2, Robert A. Schwartz31Department of Dermatology and Venereology, Medical University Sofia; 2Department of Dermatology, Military Medical Academy, Sofia, Bulgaria; 3Dermatology and Pathology, New Jersey medical School, Newark, USACorresponding author:Ljubka Miteva, MD, PhDDepartment of Dermatology and VenereologyMedical University1431 SofiaBulgaria mitev@medfac.acad.bg; roschwar@cal.berkeley,eduReceived: May 24, 2010.Accepted: October 27, 2010Summary Acute generalized exanthematous pustulo-sis is a rare disorder characterized by an acute onset of generalized, nonfollicular, pustular eruption associ-ated with fever. It is usually drug-induced and is uncom-mon in children. We report a 12-year-old girl with acute generalized exanthematous pustulosis induced by oral ketoconazole. To our knowledge, in spite of its rela-tively frequent use, acute generalized exanthematous pustulosis due to ketoconazole has not been previously reported.Key wordS: acute generalized exanthematous pus-tulosis, ketoconazole, antifungal agents, drug eruption, adverse drug reactionsIntroduCtIonThe term acute generalized exanthematous pustulosis (AGEP) was first introduced by Beylot et al. in 1980 (1) to describe a pustular eruption characterized by an acute onset after an infection and/or drug ingestion in subjects with no history of psoriasis, evolution towards spontaneous healing after a single attack, and existence of a marked dermal vasculitis in addition to nonfollicular sub-corneal sterile pustules (2,3). We report the occur-rence of AGEP as the result of ketoconazole use. To our knowledge, this is the first reported case of ketoconazole-induced AGEP.CaSe reportA 12-year-old girl with a one-year medical his-tory of dermatomyositis was evaluated for the sudden onset of high fever and a widespread ery-thematous rash of 5-days duration. Soon multiple, small pustules covered her trunk and extremities. The child had been on methylprednisolone thera-py for one year from the onset of dermatomyositis with initial dose of 40 mg daily. Methylpredniso-lone had been gradually tapered and a mainte-nance dose of 4 mg daily had been established for 15 days prior to the current presentation and was continued during and after AGEP episode. One day before the onset of fever and rash, only ketoconazole 200 mg/day was prescribed as pro-phylactic therapy for oral candidiasis.On physical examination, fever was detected (38.8 ºC). Numerous erythematous and edema-tous patches with superficial, nonfollicular pus-tules were evident over the trunk and extremities (Fig. 1). Mucous membranes and her nails were 268 ACTA DERMATOVENEROLOGICA CROATICAspared. Results of laboratory evaluation revealed white blood cell count of 21×109/L (NR 4.5-9×109/L), with neutrophil count 12.2×109/L (NR 2-6×109/L) and erythrocyte sedimentation rate (ESR) of 28 mm/h. Liver function tests, urea, creatinine, elec-trolytes, and serum calcium level were within the normal limits. Viral serology, C-reactive protein, antistreptolysin 0 titers and bacteriologic studies of pustules were negative.Histological examination of the skin revealed a large subcorneal pustule and moderate acantho-sis. The papillary dermis was edematous with a mixed perivascular inflammatory cell infiltrate of lymphocytes, neutrophils, and a few eosinophils. In some areas, leukocytoclastic vasculitis was ob-served. The endothelial cells appeared swollen; the blood vessels had decreased lumens (Fig. 2).The treatment with ketoconazole was stopped. However, methylprednisolone 4 mg daily was con-tinued as to maintain dermatomyositis during and after AGEP episode. Symptomatic treatment with topical 0.1% hydrocortisone-17-butyrate cream and levocetirizine 5 mg daily was initiated.dISCuSSIonAcute generalized exanthematous pustulosis is a rare, rapidly evolving dermatosis character-ized by numerous small, sterile nonfollicular pus-tules arising on a widespread edematous erythe-ma, accompanied by high fever (temperature >38 ºC), and neutrophilia of >7×109/L. More than 50% of patients have other cutaneous signs, including purpura, vesiculobullae, target-like lesions, and mucous membrane involvement (2). In extensive cases, a positive Nikolsky sign has been observed (2,3). Characteristic laboratory findings include an elevated total blood cell count, which is usu-ally predominantly neutrophilic (7×109/L). Eosino-philia may also be present. Hypocalcemia is less frequent, mainly related to hypoalbuminemia and renal failure (2). The main histopathologic find-ings in AGEP are spongiform superficial pustules. Papillary dermal edema, polymorphous perivas-cular infiltrates with eosinophils, leukocytoclastic vasculitis, and necrotic keratinocytes are variably present (2). Pustular eruption of necrotizing vas-culitis, Sneddon-Wilkinson disease, staphylococ-cal scalded skin syndrome, and toxic epidermal necrolysis can be distinguished more easily on the clinicopathologic basis. The pathogenetic basis of AGEP remains to be clarified, although T cells seem to play a crucial role (3).The most frequent triggers of AGEP are medi-cation, specifically ß-lactam antibiotics, macro-lides, vancomycin, doxycycline, diltiazem, nifedip-Figure 1. Close-up view of numerous superficial, non-follicular pustules arising on a widespread erythema-tous base.Figure 2. Subcorneal pustule, moderate acanthosis and edematous papillary dermis. HE x 40Miteva et al.     Acta Dermatovenerol CroatAcute generalized exanthematous pustulosis 2010;18(4):267-270269ACTA DERMATOVENEROLOGICA CROATICAine, quinidine, anti-HIV protease inhibitors, non-steroidal anti-inflammatory drugs, and corticoste-roids (2-6). Other, less common causes of AGEP are enterovirus, adenovirus, Epstein-Barr virus, cytomegalovirus, hepatitis B virus, mycoplasma pneumoniae, and hypersensitivity to mercury (2,6). Oral corticosteroids have been implicated in AGEP (6). In our case, the possibility that meth-ylprednisolone could be a mitigating or modifying factor should be excluded as the patient had been on systemic corticosteroid therapy for one year to maintain dermatomyositis under control.  AGEP is remarkable for its rapid evolution with spontaneous resolution of pustules in less than 15 days (2). It is also more common in women than men, and unusual in children (6), although it was recently described in 20 Chinese children, attributed mainly to antibiotics, sulfonamides, antipyretic analgesics and vaccines (7), and in a pregnant woman (8).AGEP has been reported with the systemic antimycotics fluconazole (9), terbinafine (10,11), itraconazole (12,13) and nystatin (14). As far as we are aware, there have been no reports of its occurrence with the use of ketoconazole. Keto-conazole itself is a highly safe agent, although it is possible that, due to its widespread use, a hyper-sensitivity reaction, especially AGEP, may appear. Ketoconazole-induced allergic reactions are in-frequent and usually consist of urticaria, rash and pruritus. In a small number of cases, ketoconazole triggered angioedema. Major allergic reactions, in-cluding anaphylaxis, have been reported (15).In our case, the diagnosis of AGEP induced by ketoconazole was established based upon the history of recent ingestion, clinical presentation, clinical course, and laboratory and histologic find-ings. We consider the occurrence of dermatomyo-sitis to be incidental, with AGEP as a drug reaction to oral ketoconazole. Patch testing may be used to diagnose drug-induced AGEP (16), but it has the potential to trigger the original generalized eruption (17,18). Therefore, patch test was not performed in our case. Recently, an in vitro γ-interferon re-lease test has been used to diagnose AGEP, but its role remains investigational (5). Although the child described herein responded well to 0.1% hydro-cortisone-17-butyrate cream and levocetirizine, in severe cases systemic steroids may be employed and the use of cyclosporine considered (19).references1.   Beylot C, Bioulac P, Doutre MS. Pustuloses ex-anthematiques aignes generalisess: a propos de 4 cas. Ann Dermatol Venereol 1980;107:37-48.2.   Roujeau JC, Bioulac P, Doutre MS. Acute ge-neralized exanthematous pustulosis: analysis of 63 cases. Arch Dermatol 1991;127:1333-8.3.   Sidoroff A, Dunant A, Viboud C, Halevy S, Ba-vinck JN, Naldi L, et al. Risk factors for acute generalized exanthematous pustulosis (AGEP) – results of a multinational case-control study (EuroSCAR). Br J Dermatol 2007;157:989-96.4.   Yesudian PD, Penny M, Azudria RM, King M. Ibu-profen-induced acute generalized exanthema-tous pustulosis. Int J Dermatol 2004;43:208-10.5.   Halevy S, Cohen AD, Livini E. Acute generali-zed exanthematous pustulosis associated with polysensitivity to paracetamol and bromhex-iene: the diagnostic role of in vitro interferon-γ release test. Clin Exp Dermatol 2000;25:652-4.6.   Meadows KP, Egan CA, Vanderhooft S. Acute generalized exanthematous pustulo-sis (AGEP), uncommon condition in children. Case report and review of literature. Pediatr Dermatol 2000;17:399-402.7.   Zhang JL, Chen X, Li J, Xie HF. Clinical ana-lysis of childhood acute generalized exanthe-matous pustulosis. Zhongguo Dang Dai Er Ke Za Zhi 2008;10:497-9.8.   Reich A, Szepietowski JC, Baran E. Severe acute generalized exanthematous pustulosis in a pregnant woman. Skinmed 2006;5:197-9.9.   Alsadhar A, Taher M, Krol A. Acute generali-zed exanthematous pustulosis induced by oral fluconazole. J Cut Med Surg 2002;6:122-4.10. Rodalski C, Hurlimann A, Burg G, Wuethrich B, Kempf W. Drug reaction to terbinafine si-mulating an acute generalized exanthematous pustulosis. Hautarzt 2001;52;444-8.11. Rubegni P, Mandato F, Sbano P, Fimiani M. Terbinafine-induced acute generalized exan-thematous pustulosis. G Ital Dermatol Vene-reol 2008;143:151-5.12. Park YM, Kim JW, Kim CW. Acute generalized exanthematous pustulosis induced by itraco-nazole. J Am Acad Dermatol 1997;36:794-6.13. Cançado GG, Fujiwara RT, Freitas PA, Cor-rea-Oliveira R, Bethony JM. Acute generalized exanthematous pustulosis induced by itraco-nazole: an immunological approach. Clin Exp Dermatol 2009;34:e709-11.14. Kuchler A, Hamm H, Weidenthaler–Barth B, Kampgen E, Blocker EB. Acute generalized Miteva et al.     Acta Dermatovenerol CroatAcute generalized exanthematous pustulosis 2010;18(4):267-270270 ACTA DERMATOVENEROLOGICA CROATICAexanthematous pustulosis following oral nys-tatin therapy: a report of three cases. Br J Der-matol 1977;137:808-11.15. Cauwenbergh G. Safety aspects of ketocona-zole, the most commonly used systemic anti-fungal. Mycoses 1989;32(Suppl 2):59-63.16. Writtam LR, Wakelin SH, Barker JNWN. Ge-neralized pustular psoriasis or drug-induced pustuloderma? The use of patch testing. Clin Exp Dermatol 2000;25:122-4.17. Moreau A, Dompmartin A. Drug-induced acute generalized exanthematous pustulosis with posi-tive patch tests. Int J Dermatol 1995;34:263-6.18. Nishimura T, Yoshioka K, Katoh J. Pustular reaction induced by diltiazem HCL. Skin Res 1991;31(Suppl 10):308-9.19. Di Lernia V, Grenzi L, Guareschi E, Ricci C. Rapid clearing of acute generalized exanthema-tous pustulosis after administration of cyclo-sporine. Clin Exp Dermatol 2009;34:e757-9.Miteva et al.     Acta Dermatovenerol CroatAcute generalized exanthematous pustulosis 2010;18(4):267-270Innoxa – put your skin in ‘milky’ condition; year 1929.(From the collection of Mr. Zlatko Puntijar)

Childhood Acute Generalized Exanthematous Pustulosis Induced by Oral Ketoconazole

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