Herpes virus-associated erythema multiforme following valacyclovir and systemic corticosteroid treatment

ARTICLE

Auteur(s) : Kiriko Inoue, Yoko Kano, Hiroaki Kagawa, Kazuhisa Hirahara, Tetsuo Shiohara

Department of Dermatology, Kyorin University School of Medicine, 6-20-2 Shinkawa Mitaka, Tokyo, 181-8611 Japan

Recent studies by Aurelian and colleagues [1-3] have indicated that the course of herpes virus-associated erythema multiforme (HAEM) is biphasic, with early virus-specific events and late inflammatory events mediated by cytokines. If so, episodic treatment with antiviral drugs followed by a short-course of systemic corticosteroids would be expected to have a favorable response in patients with recurrent HAEM. However, the results of our patient indicate that such episodic treatments might paradoxically be associated with an increase in the recurrence and severity of HAEM.

A 16-year-old man was referred for evaluation of a 7-day history of progressive erythematous lesions on his whole body which developed 10 days after herpes labialis (HL), in October 2006. The preliminary diagnosis of HAEM or drug eruption was made. His past history revealed that he had had eight episodes of similar erythema multiforme (EM) after HL, since 2004. From May 2006, episodic treatments with valacyclovir 1000 mg daily followed by a short-course of systemic corticosteroids were started by the referring physician (figure 1A). Since then, he had had identical episodes of EM more frequently, and the eruptions worsened with every attack. Sixteen days prior to his initial presentation, he was also given oral valacyclovir followed by oral corticosteroids for EM. Despite these treatments, the EM became generalized and mucous membranes were involved.

Examination revealed general fatigue with dysphagia, high-grade fever, targetoid skin macules involving his trunk and extremities, and multiple ulcerations on his mouth and scrotum. The targetoid skin lesions were, in part, confluent to form large macules more than 10 cm in diameter (figure 1B). No pathogen was isolated from a throat swab but HSV-1 antigens were detected on his lips.

A skin biopsy specimen obtained from a typical target lesion on the arm revealed scattered necrotic keratinocytes, hydropic degeneration of the basal layer in the epidermis, and lymphohistiocytic infiltration in the upper dermis (figure 1C). Baseline blood tests were almost within normal limits. HSV IgG titer was 74.0 and anti-mycoplasma pneumoniae IgM titer was negative. The stimulation index (S.I.) value of lymphocyte transformation tests for valacyclovir examined 9 days after onset of EM were 1.8 (positive ≥ 1.8) [4, 5].

Because valacyclovir was also suspected on chronological grounds, valacyclovir was withdrawn and palliative therapy was started. His symptoms resolved gradually; he was discharged after 3 weeks’ hospitalization.

For the next 3 months, he maintained a clinical remission without any treatment. Three months however later in January 2007 the patient developed another attack of EM after HL without any drug administration; the diagnosis of HAEM was finally made. Another, the lesions were minor and did not evolve into generalized lesions. The levels of S.I. for valacyclovir decreased with time; the patch test with the drug was also negative. 3 months later he developed HL. On this occasion, he received a short-course of valacyclovir therapy (1000 mg/day, 5 days) which did not provoke any cutaneous reaction. This finding excluded its role in causation of EM and ascertained the safety of continuous therapy with valacyclovir (500 to 1000 mg per day). Prophylactic continuous therapy with valacyclovir was started and no further recurrence of HAEM with widespread target lesions was observed, although a few “minor” versions of this eruption were observed, much less frequently.

This patient with HAEM did not respond to valacyclovir followed by systemic corticosteroids, and the recurrence and severity of HAEM were increased dramatically after starting this treatment. Although various triggering factors could be involved in the development of HAEM, the episodic treatments followed by systemic corticosteroids may be added to the list.

Acknowledgments

References

2 Ono F, Sharma BK, Smith CC, et al. CD34⁺cells in the peripheral blood transport herpes simplex virus DNA fragments to the skin of patients with erythema multiforme (HAEM). J Invest Dermatol 2005; 124: 1215-24.

3 Gober MD, Laing JM, Burnett JW, Aurelian L. The herpes simplex virus gene Pol expressed in herpes-associated erythema multiforme lesions upregulates/activates SP1 and inflammatory cytokines. Dermatology 2007; 215: 97-106.

4 Pichler WJ, Tilch J. The lymphocyte transformation test in the diagnosis of drug hypersensitivity. Allergy 2004; 59: 809-20.

5 Kano Y, Takahashi R, Shiohara T, et al. Utility of lymphocyte transformation test in the diagnosis of drug sensitivity: dependence on its timing and the type of drug eruption. Allergy 2007; 62: 1439-44.