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Chronic mucocutaneous herpes simplex virus and varicella zoster virus infections

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Chronic herpes simplex virus (CHSV) and chronic varicella zoster virus (CVZV) are defined as atypical mucocutaneous wart-like and/or ulcerative HSV or VZV infections, persisting for at least 1 month. Both are commonly associated with HIV infection and may occasionally present with other types of immunosuppression. CHSV and CVZV occur despite the immune restoration effect of highly active antiretroviral therapy for HIV. The clinical polymorphism of CHSV and CVZV makes recognition difficult. Histology, immunohistology, PCR and viral culture all help to confirm the diagnosis. Treatment is frequently complicated by resistance to thymidine kinase (TK)–dependent antivirals, including acyclovir, valacyclovir and famciclovir. Viral culture remains an essential tool for antiviral drug susceptibility testing. Therapeutic alternatives include non-TK-dependent antivirals, such as foscarnet or cidofovir, which directly target viral DNA polymerase. With few exceptions, CHSV and CVZV infections do not constitute significant risk factors for disseminated cutaneous or systemic infection. This review compares the similarities of and differences between CHSV and CVZV infections.

Introduction

Herpes simplex virus (HSV) and varicella zoster virus (VZV) belong to the α-herpes virus group. HSV-I is responsible for orolabial herpes, whereas HSV-II causes genital herpes (GH). VZV causes chickenpox and herpes zoster (HZ). In immunocompromised patients, including patients undergoing allogenic bone marrow transplantation and organ transplantation, HSV and VZV mucocutaneous infections may present in their normal form, although severe or extensive infections are more common. Neither serious morbidity nor fatal cases are exceptional.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 Some preexisting skin conditions, such as pemphigus vulgaris, Darier disease, and atopic dermatitis, further increase the risk of developing severe HSV and VZV cutaneous and systemic infections.13 The spectrum of atypical HSV and VZV skin manifestations is continually expanding, particularly in the immunocompromised patient.10, 11, 14, 15, 16, 17, 18, 19 Chronic HSV skin infections (CHSV)1, 5, 6, 14, 17, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66 and chronic VZV skin infections (CVZV)1, 3, 7, 8, 17, 36, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88 are among the most common atypical manifestations; these are defined as wart-like and/or ulcerative HSV or VZV mucocutaneous infections lasting for at least 1 month and must be distinguished from longstanding lichenoid, granulomatous and pseudolymphomatous HSV and VZV reactions.16, 89, 90 Misdiagnosis is common and can delay appropriate treatment.62

The subject of this review is the epidemiology, risk factors, clinical manifestations, localization, pathogenic mechanisms, diagnostic procedures, differential diagnosis and therapeutic management of CHSV and CVZV infections (Table I).

Section snippets

Material and methods

A literature search was performed using the PubMed and OVID databases, matching the following key words: herpes simplex virus, varicella zoster virus, chronic infections, chronic genital herpes, chronic herpes labialis, chronic genital ulcerations, atypical herpes infections, verrucous herpes infections, hypertrophic herpes, thymidine kinase–dependent antiviral resistance, and herpes vegetans. A total of 125 publications were retrieved. An overwhelming majority of the clinical publications

Epidemiology

The prevalence of CHSV and CVZV infections is not known. Most reported cases have occurred in patients with HIV infection, supposedly as an adverse effect of immunosuppression. Since the introduction of highly active antiretroviral therapy (HAART) in 1996, which allowed restoration of immune properties in HIV patients, a steady stream of publications on CHSV and CVZV

Risk factors

HIV-infection is a major risk factor for CHSV and CVZV.§ In a retrospective study including 18 HIV patients with acyclovir (ACV)-resistant CVZV, the mean CD4+ cell count was 20 × 106/L, and the mean number of previous HZ

Clinical aspects

By definition, CHSV and CVZV infections persist for at least 1 month, but infections lasting for months29, 96 or even years46, 94 are common. One case of spontaneous healing has been reported.95

The clinical aspects are highly polymorphic, but two features predominate: vegetating or hyperkeratotic lesions61 and erosive and/or ulcerative presentations42 (Fig 1, Fig 2, Fig 3, Fig 4). Both manifestations may occur simultaneously (see Fig 1).5, 46, 95 Transitions between the two presentations have

Localization

CHSV is commonly facial,25, 27, 39, 45, 106 oral,14, 44 or genital, the latter involving the vulva,37, 40, 56, 57, 59, 102 penis,41, 42, 49, 61, 62 scrotum,48 as well as the anal and perianal areas.§ Occasionally, CHSV affects digits61, 65, 71 with eventual loss of a nail unit,17 toes or ears,17, 94 or may mimic inguinal ulcers.28

CVZV may be encountered anywhere on the skin with no specific distribution pattern,80 which suggests that the origin

Signs and symptoms

Unlike HSV and VZV mucocutaneous infections, CHSV and CVZV affecting the skin are typically indolent and asymptomatic. Only oral and anogenital ulcerative CHSV and CVZV are clearly painful.

Diagnosis

Atypical clinical presentations frequently delay diagnosis for as long as up to 1 year.62 Longstanding, peculiar, verrucous, and/or ulcerated lesions should raise the suspicion of CHSV and CVZV. Hyperkeratotic lesions are difficult to swab for cell culture or a Tzanck smear. Sampling of ulcerated lesions is not always successful even when repeated, resulting in negative viral cultures.31 A punch biopsy done with the patient receiving local anesthetic, including the ulcerated border or a

Differential diagnosis

Wart-like CHSV and CVZV infections may mimic a number of benign or malignant growths,61, 107 including keratoacanthoma, HPV-related verrucous lesions,93 condylomata acuminata and lata,66 basal cell carcinoma,82 verrucous carcinoma,101 and squamous cell carcinoma.56, 57 Ulcerative CHSV and CVZV may resemble other ulcerations, including genital herpes, CMV-related ulcerations, perianal longstanding herpes in bedridden patients,109 Hailey-Hailey disease, pemphigus vulgaris, syphilis, Haemophilus

Complications

HSV and VZV infections in immunocompromised patients may lead to serious morbidity and increased mortality rates.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 In contrast, neither HSV- nor VZV-related internal dissemination nor any fatal cases have been reported in patients with CVZV and CHSV. Only two cases of cutaneous extension of CVZV have been reported—a renal transplant recipient88 and a patient with HIV infection.76

CVZV and CHSV ulcers may present with bacterial or Candida species colonization,

Histology

Common mucocutaneous HSV and VZV infections exhibit cytopathic effects in infected host cells, such as multinucleated giant cells and eosinophilic intranuclear inclusions, indicating viral reproduction. In contrast, the histology of CVZV and CHSV is more heterogenous.86 The wart-like lesions are basically similar and show massive orthokeratotic hyperkeratosis with parakeratotic columns. Verrucous papillomatosis, sometimes with pseudo-epitheliomatous hyperplasia of the epidermis, extends deep

Pathogenic mechanisms

The mechanism by which these viruses stimulate epithelial cell proliferation remains unclear. A genetic predisposition seems likely.98 An epidermal growth factor–dependent pathway, similar to HPV infection, has been proposed.36 Another hypothesis involves an inadequate immune response by the immunocompromised host. The absence of membranous expression of viral glycoproteins eliciting a host immune reaction may be another explanation.36 Furthermore, HSV infection may inhibit plasmacytoid

Treatment

CHSV and CVZV infections are primarily treated with antiviral therapy, in particular, TK-dependent antivirals including ACV, VCV, penciclovir, and famciclovir. As the number of reported cases is limited, no EBM-proven data are available. Resistance to TK-dependent antiviral agents is a frequent complication of CHSV and CVZV.86, 111, 112, 113 Relapses may be observed following initially successful outcomes with

Extracutaneous chronic HSV and VZV infections

Chronic HSV and VZV infections also affect internal organs. Here, too, HIV infection is a major risk factor. These infections may present without skin lesions and pose a considerable diagnostic challenge. Both HSV and VZV display epithelial and neural tropism. Among the epithelial infections, HSV-leukoplakia of the vocal cords causing chronic hoarseness has been reported.119 Unlike skin lesions, chronic VZV keratitis is very painful.120 Neurologic disorders include longstanding active HSV

Conclusion

CHSV and CVZV remain prevalent in immunodeficient patients, in particular HIV-infected patients, including those receiving HAART. Misdiagnosis is common, which can delay treatment. Complementary diagnostic methods including histology, immunohistology, cell culture, and PCR are required to accurately diagnose CHSV and CVZV. CHSV infections are predominantly observed in the oral and genital regions and present as ulcerative lesions, whereas CVZV usually appears as wart-like lesions situated

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