Dermatology Online Journal
Herpes vegetans as a sign of HIV infection
- Author(s): Patel, Anisha B
- Rosen, Ted
- et al.
Herpes vegetans as a sign of HIV infectionDepartment of Dermatology, Baylor College of Medicine, Houston, TX. email@example.com
Anisha B Patel MD, Ted Rosen MD
Dermatology Online Journal 14 (4): 6
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.
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 . 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.
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.
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.
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 , 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  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 . 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 .
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 . 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 . 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 . This cytokine pattern increases various anti-apoptotic factors  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 .
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 . Nonetheless, acyclovir prophylaxis has been shown to have a survival benefit in HIV patients .
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 . This treatment was used successfully in both herpes vegetans and in chronic HSV ulcers by targeting the anti-viral immunodeficiency that HIV induces .
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.
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