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Topical tacrolimus induced extensive varicella zoster infection

  • Author(s): Bovenschen, H J
  • Groeneveld-Haenen, C P M
  • et al.
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Topical tacrolimus induced extensive varicella zoster infection
H J Bovenschen MD PhD, C P M Groeneveld-Haenen MD
Dermatology Online Journal 17 (12): 5

Department of Dermatology, Maxima Medical Centre, Veldhoven, The Netherlands

Abstract

Tacrolimus ointment 0.1 percent is a well-established topical therapy for treating atopic dermatitis. Efficacy and safety have been described in several trials. Here, we present a patient with rapid onset of extensive varicella zoster infection in tacrolimus-treated skin: a side effect that has only occasionally been reported. Early recognition is important because rapid treatment for herpes zoster may lead to less frequent post-herpetic neuralgia and serious complications.



Introduction

The calcineurin inhibitor, tacrolimus ointment (Protopic®), is a well-established treatment for atopic dermatitis [1]. We encountered a patient with rapid onset of an extensive varicella zoster infection in tacrolimus-treated skin. A literature search did not readily reveal a direct association of topical tacrolimus treatment and varicella zoster infection. Therefore, we sought to explore the possible relationship between the start of this immune modulating topical treatment and the onset of varicella zoster infection in this report.


Case report


Figure 1
Figure 1. Extensive erythema with vesicles, bullae, and yellowish crusts on the lateral part of the left side of the neck, which started after treatment with tacrolimus ointment 0.1 percent for AD.

A middle-aged female at first presented at our outpatient dermatology clinic with mild atopic dermatitis (AD) on the neck and on the upper chest, which was recalcitrant to several topical corticosteroids in the past. Besides her atopic constitution, the patient was otherwise healthy and did not use any medication. She had never experienced cold sores or herpes zoster in the past. Treatment with tacrolimus ointment 0.1 percent was initiated, twice daily, on the left side of the neck and upper chest. After 2 weeks, the patient presented again with an extensively burning, erythematous vesiculobullous skin eruption with concomitant yellowish crusts. The skin eruption was clearly defined to one dermatome (Figure 1).

Based on the clinical picture suspicion was raised for a diagnosis of herpes zoster, with a differential diagnosis of eczema herpeticum, with secondary impetiginization. The patient was immediately treated with valaciclovir, 1000 mg thrice daily, in combination with topical fusidic acid two percent cream thrice daily. Retrospectively, polymerase chain reaction (PCR) investigation of the vesicular fluid was positive for varicella zoster virus, but not for herpes simplex virus. An additional bacterial culture revealed marked Staphylococcus aureus colonization.

Our patient completely recovered from this condition in two weeks, leaving slight erythema of the skin with a minimal burning sensation. The patient was followed-up for six months and there were no signs of recurrence; modest post-herpetic neuralgia was noted.


Discussion

This case illustrates the occurrence of an extensive varicella zoster virus infection, just after initiation of treatment with tacrolimus ointment for AD.

Tacrolimus ointment is a calcineurin inhibitor, which was registered for atopic dermatitis in the Netherlands in 2002. It acts by virtue of blocking calcineurin, the main intracellular enzyme that activates transcription of IL-2. By blocking IL-2 transcription, T-cell proliferation, differentiation, and activation, which are important immunologic hallmarks of AD, are inhibited [1, 2]. Theoretically, a topical immunomodulatory agent such as tacrolimus has the potential to increase the risk of cutaneous infections by altering local cutaneous immune response. On the other hand, better disease control may improve the epidermal barrier function, resulting in a decreased risk of local infection.

A literature search in Pubmed with search terms “tacrolimus ointment” or “topical tacrolimus” and “herpes zoster” or “varicella zoster” did not reveal any hits. In several studies, treatment with tacrolimus showed no increase in the risk of bacterial, fungal, or viral infections [3-7]. On the other hand, Koo et al. showed in a large cohort study that 1.3 percent of patients (76 pediatric, 24 adult) had infections classified as varicella zoster, including 62 pediatric patients and one adult patient with chicken pox, and 7 adult and 8 pediatric patients with shingles [1].

Another study showed a prevalence of 2.6 percent to 11.6 percent of chicken pox in children [8]. Next, Reitamo et al reported herpes simplex (5.7%) and skin infection not otherwise specified (4.6%) in a multi-centred trial. Varicella zoster infection was not mentioned [9]. In case reports, eczema herpeticum has been described during treatment with tacrolimus ointment [10], as well as herpes zoster in a patient on pimecrolimus for subacute cutaneous lupus erythematosus [11].

Overall, the tendency in the available reports is that the severity and frequency of such (viral) infections are consistent with expected rates in the general (atopic dermatitis patient) population. However, in our patient there is a clear association with the onset of PCR-proven varicella zoster infection in tacrolimus-treated skin, just after the start of this therapy. Therefore, it is attractive to speculate that this is a side effect of tacrolimus ointment, which may have been underreported. It is important to recognize such conditions in an early phase, because the early start of oral antiviral treatment (acyclovir or valacyclovir) may prevent a variety of sequellae. Although the results of randomized controlled trials and meta-analyses on the effects of antiviral drugs on the risk of developing post-herpetic neuralgia can be challenged, the overall findings support the use of antiviral therapy for herpes zoster to reduce the duration or incidence of prolonged pain [12].

In conclusion, varicella zoster virus infection (herpes zoster) may occur during topical tacrolimus treatment at the site of application of the ointment. It is important to recognize this complication in an early phase to prevent complications by administration of antiviral medication.

References

1. Koo JY, Fleischer AB Jr, Abramovits W Pariser DM, McCall CO, Horn TD, Gottlieb AB, Jaracz E, Rico MJ. Tacrolimus ointment is safe and effective in the treatment of atopic dermatitis: Results in 8000 patients. J Am Acad Dermatol. 2005 Aug;53(2 Suppl 2):S195-205. [PubMed]

2. Carroll CL, Fleischer AB. Tacrolimus: focusing on atopic dermatitis. Drugs Today. 2006 Jul;42(7):431-9. [PubMed]

3. Paller A, Eichenfeld LF, Leung DY, Stewart D, Appell M. A 12-week study of tacrolimus ointment for the treatment of atopic dermatitis in pediatric patients. J Am Acad Dermatol. 2001 Jan;44(1 Suppl):S47-57. [PubMed]

4. Kirsner RS, Heffernan MP, Antaya R. Safety and efficacy of tacrolimus ointment versus pimecrolimus cream in the treatment of patients with atopic dermatitis previously treated with corticosteroids. Acta Derm Venereol. 2010;90(1):58-64. [PubMed]

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11. Tatlican S, Eren C, Atacan D, Dalgic U, Canpolat F, Eskioglu F. A case of herpes zoster during pimecrolimus use for the treatment of subacute cutaneous lupus erythematosus. J Dermatolog Treat. 2010 Sep;21(5):322-3. [PubMed]

12. Mustafa MB, Arduino PG, Porter SR. Varicella zoster virus: review of its management. J Oral Pathol Med. 2009 Oct;38(9):673-88. [PubMed]

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