Systemic Contact Dermatitis from Valacyclovir. -A Case Report and Review of the Literature. Cheng-Han Yang Chia-Yu Chu 1

Transcription

1 Valacyclovir Systemic Contact Dermatitis from Valacyclovir -A Case Report and Review of the Literature Cheng-Han Yang Chia-Yu Chu 1 Acyclovir is a widely used antiviral drug. However, allergic contact dermatitis caused by acyclovir is uncommon. We herein report a 48-year-old woman, who had been diagnosed as having adenocarcinoma of the upper lobe of the right lung, developed systemic contact dermatitis sensitized by topical acyclovir therapy first, and triggered by re-exposure of oral valacyclovir and topical acyclovir therapy. A control study of 33 healthy volunteers patch tested with acyclovir (10% aq.) showed they were all negative to this preparation. We also reviewed the literature and discussed the methods of patch testing in diagnosing drug allergy. (Dermatol Sinica 25: 24-29, 2007) Key words: Acyclovir, Allergic contact dermatitis, Patch test, Valacyclovir Acyclovir acyclovir 48 acyclovir valacyclovir acyclovir acyclovir (10% aq.) ( 25: 24-29, 2007) From the Department of Dermatology, Tao-Yuan General Hospital, Department of Health and 1 Department of Dermatology, National Taiwan University Hospital 1 Accepted for publication: September 12,2006 Reprint requests: Chia-Yu Chu, M.D., Department of Dermatology, National Taiwan University Hospital, 7, Chung-Shan South Road, Taipei 100, Taiwan. TEL: FAX: chiayu.chu@gmail.com Dermatol Sinica, Mar

2 INTRODUCTION Acyclovir is a widely used antiviral drug that inhibits the DNA polymerase of human herpes viruses. 1 Valacyclovir is one of the predrug of acyclovir. It is the L-valine ester of acyclovir and is almost completely metabolized to acyclovir after oral administration. 2 Its oral bioavailability increased 3 times to 5 times as compared to that of acyclovir. 3 Although acyclovir and valacyclovir were both widely used, allergic contact dermatitis (ACD) caused by either acyclovir or valacyclovir is uncommon. 2, 4 There are only few reports of contact allergy to acyclovir (Zovirax ) cream Systemic allergic reactions other then ACD to acyclovir or valacyclovir were also rarely reported. To the 2, 3, 13 best of our knowledge, there is no previous report of systemic ACD from valacyclovir. We herein reported a patient of systemic ACD following oral valacyclovir and topical acyclovir therapy. Case report A 48-year-old woman had been diagnosed as having adenocarcinoma of the upper lobe of the right lung. She had received lobectomy of the right upper lobe. During hospitalization, grouped vesicles on erythematous bases on the left side of the chest were noted. Herpes zoster was impressed and oral acyclovir (Zovirax 200-mg, 2 tablets every 8 hours) was given for the first 2 days followed by oral valacyclovir (Valtrex 500-mg, 2 tablets every 8 hours) for another 5 days. In addition, the patient also applied topical acyclovir cream (Zovirax, GlaxoWellcome Operations, UK) on the skin lesions at the same time. The skin lesions healed one week later. However, she noted numerous itching erythematous papules around the dressing sites of the surgical wounds on the right chest. An irritant contact dermatitis due to the adhesives (tapes) was impressed by the dermatologist. However, the patient applied acyclovir cream on the itching erythematous papules around the gauzes without contact to the draining tube insertion sites and operation wounds. She found these itching papules still Fig. 1 There were numerous tense vesicles and papules arranged in arciform or linear distribution on the peripheral areas of dressing gauzes as well as the drain-tube insertion wounds and surgical wounds. Some of them had hemorrhagic blisters and some were arranged in linear shape. Fig. 2 There were also some erythematous to brownish papules and plaques co-localized to the previously healed herpes zoster wounds on the left chest. Fig. 3 Patch testing with acyclovir (Zovirax ) cream as is (5%) revealed distinct, well demarcated infiltrated erythema with tiny vesicles, which was graded as ++ reactions according to the ICDRG criteria. 25 Dermatol Sinica, Mar 2007

3 progressed in the following 3 days after topical acyclovir treatment. Therefore, oral valacyclovir was administered again by the surgeon under the suspicion of disseminated herpes zoster. However, sudden onset of many new papules and vesicles on the drainage tube insertion sites, surgical wounds and around the dressing gauzes were noted on the following 2 days. At that time, the healed herpes zoster wounds on the left chest also showed a flare up of dermatitis. She was referred to our Contact Dermatitis Special Clinics for help. Cutaneous examinations revealed numerous tense vesicles and papules arranged in arciform or linear distribution on the peripheral areas of dressing gauzes as well as the draintube insertion wounds and surgical wounds. Some of them had hemorrhagic blisters and some were arranged in linear shape (Fig. 1). There were also many erythematous to brownish papules and plaques co-localized to the healed herpes zoster wounds on the left chest (Fig. 2). Tzanck s smear was performed at first and the result was negative. Then a skin biopsy was performed for pathological examination, which revealed epidermal spongiosis with intraepidermal vesicle formation and perivascular infiltration with markedly increased eosinophils. A hypersensitivity reaction is considered. Serial sections of the specimen failed to demonstrate keratinocytes with ground glass or ballooning nuclei, multinucleated giant cells, or any other cytological indicator of herpes simplex or herpes varicella zoster infection. Reviewing her exposure history, she had applied acyclovir cream, fluticasone (Cutivate ) cream, povidone iodine (Betadine ) ointment, chlorhexidine gluconate (Hibitane concentrate ) solution, and chloramphenicol ointment during this period. Systemic ACD to acyclovir was suspected. Therefore, patch testing was performed with the European Standard Series, Zovirax cream (as is), Cutivate cream (as is), Betadine ointment (as is), Hibitan Concentrate solution (50%), vehicle tray, and chloramphenicol ointment (as is). It showed strongly positive reactions to nickel sulfate and Zovirax cream (Fig. 3). There were no positive reactions to the vehicles of Zovirax cream. Further patch testing with different concentrations of pure acyclovir was performed (Table 1). There were positive reactions among acyclovir solution (10% aq., 15% aq., and 20% aq.) at day 3 reading, while valacyclovir tablets (10% pet. and 30% pet.) and acyclovir solution (5% aq., 1% pet., 5% pet., and 10% pet.) were all negative (Table 1). A control study of 33 healthy volunteers patch tested with acyclovir (10% aq.) showed they were all negative to this preparation, and a diagnosis of ACD in this patient has been confirmed. Because the lesions of systemic contact dermatitis were just noted on drainage tube insertion wounds, operation wounds (discharge), and the first sensitization site on the left chest, rather than the others, we think that localized form of systemic contact dermatitis was preferred. DISCUSSION Acyclovir is a widely used antiviral drug that can inhibit the DNA polymerase of human Table 1. Patch testing results of this case Substances Day 3 European Standard Series Nickel Sulfate +++ Cutivate cream (0.05%) (as is) - Betaiodine ointment (as is) - Hibitane (50%) - Vehicle trays - Chloramphenicol oint (5%) - Acyclovir (Zovirax ) cream (5%) ++ Acyclovir 5% aq. - Acyclovir 10% aq. ++ Acyclovir 15% aq. ++ Acyclovir 20% aq. +++ Acyclovir 1% pet. - Acyclovir 5% pet. - Acyclovir 10% pet. - Valacyclovir 10% pet. - Valacyclovir 30% pet. - Dermatol Sinica, Mar

4 Table 2. Review of the reported cases of systemic contact dermatitis to acyclovir Authors Gender Clinical Latent period Patch testing Reference (Publication year) /Age presentation methods and results Camarasa et al. (1988) F/66 Eczema on the buttocks A few days Acyclovir 5% aq. (++) 7 Gola et al. (1989) F/19 Eczema of the hands, urticaria 1 week Acyclovir 1%, 3% and 5% pet. (+) 11 Valsecchi et al. (1990) M/52 Eczema of the thighs 10 days Acyclovir 1%, 3% and 5% pet. (++) 12 Goday et al. (1991) F/51 Eczema of the face 3 days Acyclovir 5% aq. (+++) 6 Kim et al. (1994) M/52 Eczema A few days Acyclovir 1% aq. (+) 10 Bourezane et al. (1996) F/38 Eczema 10 days Acycloir 5% pet. (-) 4 Rodriguez-Serna et al. (1999) F/26 Vesicular edematous dermatitis 2 years Zovirax cream as is photopatch (++) 5 Bayrou et al. (2000) Case1: F/30 pruriginous maculopapular few months Zovirax cream (++) 26 rashes on the arms, Acyclovir 10% aq. (++) trunk and nner thighs Valacyclovir 10% aq. (++) Case 2: F/28 widespread eczema unknown the same as case 1 Lammintausta et al. (2001) F/44 Itchy symmetrical exanthem For 2 weeks Acyclovir as is (+) 3 on the face, trunk and Acyclovir 10% pet., 20% pet., extremities 1% aq., 10% aq. and 20% aq. (+) Acyclovir 1% pet. (-) Vernassiere et al. (2003) F/23 Urticaria & eczema on the Several Zovirax cream 50% pet. (++), trunk and extremities months Zovirax tablet as is (+) 2 Yang et al. (2006) F/48 Eczema on the trunk Several days See Table 1 The presenting case 1, 14 herpes viruses. Allergic contact dermatitis caused by acyclovir is uncommon. 1 Experimental sensitization of guinea pigs revealed a low sensitizing potential of acyclovir when compared with tromantadine. 1 Reviewing the literature, there were only 21 cases that had been documented to have contact allergy to acyclovir. 2-7 Systemic reactions secondary to oral administration of acyclovir were also rare. 2, 3, 13 The clinical features of these systemic reactions were 2, 3, 11, 14, 15 variable, including vesicular dermatitis, dermatitis of the palms and soles, 16 peripheral edema, 17, 18 erythema nodosum, 19 13, 16, exanthems, hyperphydrosis, 22 acne, 22 lichenoid eruption, 16 pruritus, 23 rash, 20 urticaria, 2, 16, 19, 24, 25 vasculitits, 19 and alopecia. 22 However, only 11 of the reported cases were considered to be systemic ACD subsequent to acyclovir contact 27 Dermatol Sinica, Mar 2007

5 allergy. 2-7, 10-12, 26 We reported here the first case of systemic ACD to valacyclovir (Table 2). A systemic ACD is defined as development of generalized eczematous dermatitis and/or aggravation of the primary sensitization sites after systemic administration (ingestion, inhalation, or intravenous injection) of a previously sensitized allergen. The patient was 27, 28 sensitized by topical acyclovir cream first and then was elicited by oral valacyclovir, which resulted in a localized form of systemic ACD presenting as eczematous dermatitis on the drainage tube insertion wounds, operation wounds (discharge), and the first sensitization site on the left chest. 27 In previous report, the concentrations and vehicles for patch testing of acyclovir were variable. No standard methods are available at present. The reported concentrations for patch testing ranged from 1% to 20%. 3 Positive patch tests were confirmed with acyclovir 5% aq. in 2 reports. 6, 7 The patch testing method for acyclovir suggested by de Groot s handbook of Patch Testing is 5% in propylene glycol or in alcohol. 8 However, other investigators had used 1%, 3%, 5%, 10% or 20% pet. or 1%, 10%, 20% aq. for patch testing (Table. 2). In our patient, patch testing to Zovirax cream (as is), acyclovir 10% aq., 15% aq. and 20% aq. were all positive, but patch testing to acyclovir 5% aq.,as well as 1% pet., 5% pet., and 10% pet. all showed negative results. The patch testing results were compatible with previous studies, 3, 26 which revealed a low bioavailability of acyclovir dispersed in petrolatum compared to dissolved in propylene glycol. Even though some reports revealed positive reactions in patch testing of Zovirax cream, some authors suggested that most of the reactions to Zovirax cream were due to its vehicle components, including sodium lauryl sulfate (SLS) and propylene glycol. 9 However, considering the low bioavailability of acyclovir dispersed in petrolatum, one should doubt the conclusions of these studies that the skin reactions were being attributed only to the vehicle components rather than acyclovir itself. 1 In the presenting case, patch testing with Zovirax cream (5%) was positive, but patch testing with acyclovir 5% aq., 1% pet., and 5% pet. were all negative. Therefore, we used higher concentrations to confirm the sensitization of acyclovir in this patient. We also patch tested with the vehicle tray including propylene glycol and SLS to exclude the possibility of contact allergy to propylene glycol and SLS. Since the patient only reacted to acyclovir without reacted to the vehicle components of acyclovir (Zovirax ) cream, sensitization to acyclovir has been confirmed. We also noticed the patch test reactions were many tiny, itching vesicles at day 3 (Fig. 3) and day 7 readings, so an allergic reaction was more likely. We performed further control study to verify the concentrations we used. In the control study, none of the 33 healthy volunteers had positive reactions at day 3 and day 7 readings, but there were five persons with irritant reaction to acyclovir at day 2 reading. All of the five persons had no previous history of acyclovir therapy. We also noted there was whitish powder coated on the tested skin surface of these persons. As stated by Koch et al., 1 acyclovir is soluble in water to a concentration of 1.3 mg/ml. If larger quantities of the pure substance are used, it would result in a solution separating out in just a few minutes. 1 Patch test using this solution will produce a deposit of powder on the skin, which leads to the irritant reaction. In conclusion, we report a rare case of oral valacyclovir-induced systemic contact dermatitis. Although (val)acyclovir is thought to have low sensitization potential, dermatologists should recognize this possible side effect and treat it as soon as possible. REFERENCES 1. Koch P: No evidence of contact sensitization to acyclovir in acute dermatitis of the lips following local application of Zovirax cream. Contact Dermatitis 33: , Vernassiere C, Barbaud A, Trechot PH, et al.: Systemic acyclovir reaction subsequent to acyclovir contact allergy: which systemic antiviral drug should then be used? Contact Dermatitis 49: Dermatol Sinica, Mar

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