Dermatology Online Journal

Herpes vegetans as a sign of HIV infection
Anisha B Patel MD, Ted Rosen MD
Dermatology Online Journal 14 (4): 6

Department of Dermatology, Baylor College of Medicine, Houston, TX. vampireted@aol.com

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Abstract

Herpes progenitalis can present in bizarre ways when seen in conjunction with altered immune status. In the recent past, a small number of individuals have been described with herpes vegetans, an exophytic, proliferative lesion that resembles either a verrucous or malignant growth. This phenomenon can occur on the digits, genitalia or perioral skin. We present a case of a vegetating penile plaque attributed to herpesvirus in an HIV-positive patient.

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Introduction

Herpes progenitalis is among the most prevalent of sexually transmitted diseases in the United States, with some 17 percent of the population over the age of 14 being sero-positive for HSV-2 [1]. Whereas the typical manifestations of genital infection with HSV-2 in immunocompetent individuals are well known, the same disease may manifest in an unusual fashion among those who are immunocompromised or immunosuppressed. We report herein an atypical manifestation of genital herpes that led the clinician to suspect immunodeficiency, the latter being a fact deliberately not disclosed by the patient seeking medical attention. This report, therefore, emphasizes two important points: herpes progenitalis can present in bizarre ways when seen in conjunction with altered immune status and clinical clues suggestive of immune compromise should not be ignored, even in patients who provide a medical history devoid of information which would point to this situation.

Clinical Synopsis

A 45-year-old man with an unremarkable past medical history presented with a large, verrucous plaque involving the glans penis and penile corona. The lesion had developed some 8 weeks prior to consultation. This lesion of uncertain etiology had previously been evaluated by a urologist who had secured a biopsy that revealed only nonspecific findings of "tissue necrosis with mixed inflammatory infiltrate, including eosinophils." The patient's intake medical history form and verbal review of systems were entirely unremarkable. The patient specifically denied any antecedent sexually transmitted disease or systemic illness, and further asserted that he had been celibate for years.

Figure 1	Figure 2
Figure 1. Exophytic, erosive penile plaque Figure 2. Biopsy with multinucleated giant cells (white arrows; H&E x 20)

Physical examination revealed a 25 x 12 mm exophytic, partially erosive and exudative, non-tender plaque along with bilateral inguinal adenopathy (Fig. 1). A new biopsy disclosed epidermal ulceration with crust formation, along with balloon cells and multinucleated giant cells at the periphery of the ulcer, consistent with a viral vesicle (Fig. 2). Viral culture obtained at the time of the initial office visit subsequently isolated acyclovir-sensitive HSV-2. Serologic testing revealed a non-reactive RPR and positive IgG and IgM antibodies directed against HSV-2 (HerpSelect®). When the patient was contacted by phone to discuss these findings as well as the necessity for HIV screening (based on the atypical morphology and persistent nature of his herpetic infection), he then admitted to being HIV+ and to intermittent adherence to a multidrug anti-HIV regimen and a recent CD-4 count of <200 cells/ul. None of this information had been shared during the patient's first office encounter.

Figure 3

The patient had been empirically started on oral valacyclovir, at a dose of 1.0 gram twice daily, while awaiting biopsy, serology and culture results. He was considerably improved 2 months later (Fig. 3), but subsequently refused additional follow-up visits.

Discussion

Herpes simplex virus, the most common sexually transmitted disease (STD) among HIV-positive patients, has presented in a variety of ways in the immunodeficient patient [2-31]. Chronic ulcerations or erosions [3-10], hyperkeratotic lesions [11, 12], and non-traditional locations [13, 14, 15] of infection have all been reported and may be indicative of underlying immunocompromise. During the last decade, a few patients have been described with herpes vegetans, an exophytic, proliferative lesion that resembles either a verrucous or malignant growth [16-31].

In the past 40 years, chronic, persistent ulcerations or erosions from HSV have become a reliable indicator of an immunocompromised patient [3, 4, 8, 10]. It appears that herpes vegetans is also an important lesion occurring within this subset of patients as its prevalence has continued to rise. Although a depressed CD4 count has been found to correlate with chronic ulcerative HSV lesions [6], no such studies have been done yet for herpes vegetans lesions. As additional cases of herpes vegetans are recognized, perhaps such data will be forthcoming.

The differential diagnosis for a lesion such as that seen in this case includes the following: pyoderma vegetans and pyoderma gangrenosum, vegetating toxicoderma (usually secondary to iodine ingestion), pemphigus vegetans, tuberculosis verrucous cutis, secondary syphilis (condyloma lata), deep fungal infections, giant condyloma of Buschke-Lowenstein, extra-intestinal Crohn's disease and malignancy [31, 32, 33].

The diagnosis of herpes in the immunocompromised patient can be difficult [34] requiring multiple Tzanck smears or biopsies as well as viral cultures for confirmation. As in the case presented here, when the patient does not admit to HIV infection, the initial differential diagnosis can be obscured by an inaccurate or misleading history, thereby leading to delayed treatment. Immunohistochemistry and repeated biopsies were found to be the most successful methods of diagnosis for the cases reviewed here [2, 4, 16, 17, 34, 35].

On biopsy, features characteristic of HSV are seen mainly at the periphery [36]. Pathology reports are consistent in showing scattered keratinocytes, usually on the border of the ulceration, with multiple nuclei. The epithelium is described as hyperproliferative. Also commonly reported is a dense infiltrate of eosinophils, lymphocytes, histiocytes, and plasma cells beneath the base of the ulceration [16-31]. Abbo notes that eosinophils within the infiltrate can also be secondary to the TH2 cytokine response characteristic in advanced HIV [25].

Interestingly, herpes vegetans lesions have appeared in patients who have a long-term history of immunodeficiency and, among the patients with HIV, they are predominantly seen in patients receiving highly active anti-retroviral therapy (HAART). The pathogenesis of these hypertrophic or vegetating lesions remains unknown, although hypotheses include immune dysregulation related to concomitant HSV and HIV, with a possible contribution from immune reconstitutive effects following institution of HAART. With a normal immune system, HSV elicits a lymphocyte response that, in turn, causes an increase in plasmacytoid dendritic cells in the serum and a resulting increase in alpha interferon production [25]. Interferon is key to the body's anti-viral defense, and the deficient lymphocyte response with decreased interferon production in the HIV and HSV co-infected patient accounts for the chronic nature of HSV infections [5, 25]. The hyperproliferative nature of these lesions may be attributed to HIV's propensity to infect a second type of dendritic cell, the dermal dendritic cell. These cells are differentiated from Langerhans cells by their factor XIIIa-positive marker, their susceptibility to infection by HIV, and their proliferation during HSV infection [11]. The dermal dendritic cells respond to HIV infection by increasing production of tumor necrosis factor and interleukin-6 (IL-6) [35, 37], which causes a change in the proliferation and maturation patterns of the epidermis [12]. This cytokine pattern increases various anti-apoptotic factors [19] leading to hyperkeratotic or verrucous epidermal changes [11, 19]. However, all patients with concurrent HSV and HIV do not present with hyperproliferative lesions. Vogel therefore speculated that there is a critical but as yet undetermined host factor in herpes vegetans pathogenesis, and that HIV positive patients with these lesions likely exhibit a common pattern of immune dysregulation [19].

There remains considerable debate about whether or not to offer anti-viral prophylaxis to HSV-HIV co-infected patients and, if so, which medication to use and for how long. There does not appear to be a correlation between acyclovir prophylaxis and herpes vegetans, although a few patients have been placed on valacyclovir prophylaxis with successful suppression of recurrences. The controversy anti-viral drug overuse relates to the well-documented phenomenon of HSV-2 acyclovir-resistance linked to prolonged treatment at therapeutic doses [38]. Nonetheless, acyclovir prophylaxis has been shown to have a survival benefit in HIV patients [2].

Of the 20 cases of herpes vegetans reported in the readily available medical literature, only 6 were acyclovir susceptible. The rest of the cases failed trials of acyclovir and were eventually treated surgically or with valacyclovir. Because the infections were clinically responsive to valacyclovir, but resistant to acyclovir in-vitro, it can be inferred that there is only a partial resistance to acyclovir; perhaps the higher-bioavailability valacyclovir was sufficient for cure. Foscarnet and cidofovir have been proposed as a treatment for acyclovir-resistant strains; cidofovir can be used in conjunction with acyclovir or alone [29, 39]. Both foscarnet and cidofovir do not require activation by a viral thymidine kinase, as acyclovir and valacyclovir do. Abbo proposed imiquimod as a treatment for increasing the alpha interferon response and facilitating self-healing of the herpes infections [25]. This treatment was used successfully in both herpes vegetans and in chronic HSV ulcers by targeting the anti-viral immunodeficiency that HIV induces [25].

Clearly, a diagnosis of herpes vegetans should be strongly suggestive of an underlying associated immunodeficiency, particularly HIV. Patients are not always forthcoming about HIV status, making it more difficult for physicians to diagnose and promptly treat such lesions. Although most herpes vegetans lesions have been reported resistant to acyclovir, valacyclovir is still largely effective. Other treatment options include foscarnet, cidofovir, and imiquimod. Further study is needed into the pathogenesis of herpes vegetans in the immunocompromised patient.

Disclosure: The senior author (Dr. Rosen) is on the Speaker's Bureau for GlaxoSmithKline, the manufacturers of valacyclovir. Other than this, the authors have no affiliation or financial involvement with any organization or entity with a direct financial interest in the subject matter or materials discussed in this manuscript.

References

1. Xu F, Sternberg MR, Kottiri BJ, McQuillan GM, Lee FK, et al. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA 2006; 296:964-73. PubMed

2. Severson JL, Tyring SK. Relation between herpes simplex viruses and human immunodeficiency virus infections. Arch Dermatol 1999;135:1393-1397. PubMed

3. Maier J, Bergman A, Ross M. Acquired immunodeficiency syndrome manifested by chronic primary genital herpes. Am J Obstet Gynecol 1986;155:756-758. PubMed

4. Tayal SC, Pattman RS, McLelland J, Sviland L, Snow MH. An indolent penile herpetic ulcer in a patient with previously undiagnosed human immunodeficiency virus infection. Br J Dermatol 1998;138:334-336. PubMed

5. Burgoyne M, Burke W. Atypical herpes simplex infection in patients with acute myelogenous leukemia recovering from chemotherapy. J Am Acad Dermatol 1989;20:1125-7. PubMed

6. Bagdades E, Pillay D, Squire S, O'Neil C, Johnson MA, et al. Relationship between herpes simplex virus ulceration and CD4+ cell counts in patients with HIV infection. AIDS 1992;6:1317-20. PubMed

7. Brown TS, Callen JF. Atypical presentation of herpes simplex virus in a patient with chronic lymphocytic leukaemia. Cutis 1999; 64:123-5. PubMed

8. Logan WS, Tindall JP, Elson ML. Chronic cutaneous herpes simplex. Arch Dermatol 1971;103:606-14. PubMed

9. Fox PA, Barton SE, Francis N, Youle M, Hnerson DC, et al. Chronic erosive herpes simplex virus infection of the penis, a possible immune reconstitution disease. HIV Med 1999;1:10-18. PubMed

10. Park RK, Goltz RW, Carey TB. Unusual cutaneous infection associated with immunosuppressive therapy. Arch Dermatol 1967;95:345-50. PubMed

11. Smith KJ, Skelton HG 3rd, Frissman DM, Angritt P. Verrucous lesions secondary to DNA viruses in patients infected with the human immunodeficiency virus in association with increased factor XIIIa- positive dermal dendritic cells. The Military Medical Consortium of Applied Retroviral Research, Washington, D.C. J Am Acad Dermatol 1992;27:943-50. PubMed

12. Smith KJ, Skelton HG, Yeager J, et al. Cutaneous findings in HIV1-positive patients: a 42-month prospective study. Military Medical Consortium for the Advancement of Retroviral Research. J Am Acad Dermatol 1994;31:746-54. PubMed

13. Robayna MG, Herranz P, Rubio FA, Pena P, Pena JM, et al. Destructive herpetic whitlow in AIDS: report of three cases. Br J Dermatol 1997;137:812-815. PubMed

14. Gross G, Doerr HW. Atypical herpes simplex virus type 2 manifestations on the hand. Hautarzt 2001; 52807-11. PubMed

15. Weaver G, Kostman JR. Inoculation herpes simplex virus infections in patients with AIDS: unusual appearance and location of lesions. Clin Infect Dis 1996;22:141-2. PubMed

16. Samaratunga H, Weedon D, Musgrave N, McCallum N. Atypical presentation of herpes simplex (chronic hypertrophic herpes) in a patient with HIV infection. Pathology 2001;33:532-5. PubMed

17. Nadal SR, Calore EE, Manzione CR, Horta SC, Ferreira AF, et al. Hypertrophic herpes simplex simulating anal neoplasia in AIDS patients: report of five cases. Dis Colon Rectum. 2005; 48:2289-93. PubMed

18. Gubinelli E, Cocuroccia B, Lazzarotto T, Girolomoni G. Nodular perianal herpes simplex with prominent plasma cell infiltration. Sex Transm Dis 2003;30:157-9. PubMed

19. Beasley KL, Cooley GE, Kao GF, Lowitt MH, Burnett JW, et al. Herpes simplex vegetans: atypical genital herpes infection in a patient with common variable immunodeficiency. J Am Acad Dermatol 1997;37:860-3. PubMed

20. Vogel P, Smith KJ, Skelton HG, Cuozzo D, Wagner KF. Verrucous lesions of herpes simplex in HIV-1+ patients. Military Medical Consortium for the Advancement of Retroviral Research. Int J Dermatol 1993;32:680-2. PubMed

21. Tong P, Mutasim DF. Herpes simplex virus infection masquerading as condyloma acuminata in a patient with HIV disease. Br J Dermatol 1996;134:797-800. PubMed

22. Husak R, Tebbe B, Goerdt S, Wolfer LU, Zeichardt H, et al. Pseudotumour of the tongue caused by herpes simplex type 2 in an HIV-1 infected immunosuppressed patient. Br J Dermatol 1998;139:118-21. PubMed

23. Tabaee A, Saltman B, Shutter J, Hibshoosh H, Markowitz A. Recurrent oral herpes simplex virus presenting as a tongue mass. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004;97:376-80. PubMed

24. Leming PD, Martin SE, Zwelling LA. Atypical herpes simplex infection in a patient with Hodgkin's disease. Cancer 1984;54:3043-3047. PubMed

25. Abbo L, Vincek V, Dickinson G, Shrestha N, Doblecki S, Haslett PA. Selective defect in plasmacyoid dendritic cell function in a patient with AIDS- associated atypical genital herpes simplex vegetans treated with imiquimod. Clin Infect Dis 2007;44:e25-7. PubMed

26. Hershko K, Hershko AY, Leibovici V, Meir K, Ingber A. Herpes simplex virus infection in a hyper-IgE patient: appearance of unusual mass lesions. Acta Derm Venereol 2002;82:204-5. PubMed

27. Carrasco DA, Trizna Z, Colome-Grimmer M, Tyring SK. Verrucous herpes of the scrotum in a human immunodeficiency virus-positive man: case report and review of the literature. J Eur Acad Dermatol Venereol 2002;16:511-5. PubMed

28. Ghislanzoni M, Cusini M, Zerboni R, Alessi E. Chronic hypertrophic acyclovir resistant genital herpes treated with topical cidofovir and with topical foscarnet at recurrence in an HIV-positive man. J Eur Acad Dermatol Venereol 2006;20:887-9. PubMed

29. Fangman WL, Rao CH, Myers SA. Hypertrophic herpes simplex virus in HIV patients. J Drugs Dermatol 2003;2:198-201. PubMed

30. Armbruster C, Drlicek M. Herpes simplex virus type II infection as an exophytic endobronchial tumor. Wien Klin Wochenschr 1995;107:344-6. PubMed

31. Meunier L, Guillot B, Lavabre-Bertrand T, Barneon G, Izam P, et al. Chronic herpes of the pyodermatitis vegetans type in chronic cutaneous lymphoid leukemia. Ann Derm Venerol 1986;113:1199-1204. PubMed

32. Civatte J. Pseudo-carcinomatous hyperplasia. J Cutan Pathol 1985;12:214-23. PubMed

33. McCallum DI, Kinmont PD. Dermatological manifestations of Crohn's disease. Br J Dermatol 1968;80: 1-8. PubMed

34. Langtry JA, Ostlere LS, Hawkins DA, Staughton RC. The difficulty in diagnosis of cutaneous herpes simplex virus infection in patients with AIDS. Clin Exp Dermatol1994;19:224-226. PubMed

35. Gilson IH, Barnet JH, Conant MA, Laskin OL, Williams J, et al. Disseminated erythematous herpes varicella-zoster virus infection inpatients with acquired immunodeficiency syndrome. J Am Acad Dermatol 1989;20: 637-42. PubMed

36. Weedon D. Skin Pathology, Chapter 22: Cutaneous infections and infestations-histological patterns. 1997: New York: Churchill-Livingstone, 2nd Ed.

37. Scala G, Ruocco MR, Ambrosino C, Mallardo M, Giordano V, et al. The expression of the interleukin 6 gene is induced by the human immunodeficiency virus 1 TAT protein. J Exp Med 1994;179:961-71. PubMed

38. Erlich K, Mills J, Chatis P, Mertz JG, Busch DF, et al. Acyclovir-resistant herpes simplex virus infections in patients with the acquired immunodeficiency syndrome. N Engl J Med 1989; 320:293-296 PubMed

39. Chilukuri S, Rosen T. Management of acyclovir-resistant herpes simplex virus. Dermatol Clin 2003;21:311-20. PubMed

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