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Chronic mucocutaneous herpes simplex virus and varicella zoster virus infections
Chronic mucocutaneous herpes simplex virus and varicella zoster virus infections Odile Wauters, MD, Eglantine Lebas, MD, and Arjen F. Nikkels, MD, PhD Lie`ge, Belgium 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)edependent 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. ( J Am Acad Dermatol 2012;66:e217-27.) Key words: acyclovir; herpes simplex; HIV; immunosuppression; resistance; thymidine kinase; varicella zoster.
INTRODUCTION Herpes simplex virus (HSV) and varicella zoster virus (VZV) belong to the a-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.1-12 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.10,11,14-19 Chronic HSV skin infections From the Department of Dermatology, University Hospital of Lie`ge. Funding sources: None. Conflicts of interest: None declared. Reprint requests: Arjen F. Nikkels, MD, PhD, Department of Dermatology, CHU of Sart Tilman, University of Lie`ge, B-4000 Lie`ge, Belgium. E-mail: [email protected]. Published online November 11, 2010. 0190-9622/$36.00 ª 2010 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2010.07.011
Abbreviations used: ACV: CHSV: CVZV: GH: HSV: HZ: IHC: ISH: PCR: VZV:
acyclovir chronic herpes simplex virus (infection) chronic varicella zoster virus (infection) genital herpes herpes simplex virus herpes zoster immunohistochemical in situ hybridization polymerase chain reaction varicella zoster virus
(CHSV)1,5,6,14,17,18,20-66 and chronic VZV skin infections (CVZV)1,3,7,8,17,36,67-88 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).
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, e217
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chronic infections, chronic genital herpes, chronic herpes labialis, chronic genital ulcerations, atypical herpes infections, verrucous herpes infections, hypertrophic herpes, thymidine kinaseedependent antiviral resistance, and herpes vegetans. A total of 125 publications were retrieved. An overwhelming majority of the clinical publications reached evidence level D (case reports or small case-series).
transplantation, hypogammaglobulinemia, chronic lymphocytic leukemia, hepatic cirrhosis resulting from chronic hepatitis C virus infection, and myeloproliferative disorders.k CHSV has been described in two patients with Wiskott-Aldrich syndrome presenting with a combined innate and acquired immune deficiency, particularly affecting the T-, B-, and NK-cell lines.25,39 CAPSULE SUMMARY Although chronic corticosteroid therapy is a recognized EPIDEMIOLOGY Chronic herpes simplex virus (CHSV) and risk factor for increased susThe prevalence of CHSV chronic varicella zoster virus (CVZV) skin ceptibility to cutaneous infecand CVZV infections is not infections are commonly associated with 103 only one report has tions, known. Most reported cases HIV infection. directly linked long-term oral have occurred in patients CHSV and CVZV infections present as steroid use to CHSV in a pawith HIV infection, supposwart-like lesions with or without tient with chronic lymphoedly as an adverse effect of ulcerations. cytic leukemia.6 immunosuppression.* Since CHSV and CVZV infecDiagnosis relies on histology, the introduction of highly actions are rare in apparently immunohistology, PCR and viral culture. tive antiretroviral therapy immunocompetent pa(HAART) in 1996, which alResistance to thymidine kinase (TK) 34,40,56,57 Genital CHSV tients. lowed restoration of immune dependent antivirals is not uncommon. may aggravate the clinical properties in HIV patients, a CHSV and CVZV infections are not a course of HIV infection.55 steady stream of publications significant risk for disseminated CVZV can occur in children on CHSVand CVZV infections cutaneous or systemic infection. following varicella1,8,77 or in has continued to add to the VZV-seropositive adult papublished literature.y In a cotients. Genital CHSV may occur after primary or hort of 1,700 HIV-infected patients, the observed 26,45 98 CHSV may develop despite prorecurrent GH. prevalence of CHSV infections was 4 cases (0.2%). 46 phylactic oral ACV therapy. There is no racial or gender predisposition. Similar to extensive HSV infection and HZ, Patients are typically adult, although cases of both 37,39 1,74,77,99 CHSV and CVZV infections are recognized indicaand CVZV, personal data have been CHSV tors of possible HIV infection.26,104 One case of reported in children. In a series of HIV-infected CVZV led to the discovery of peripheral T-cell children, 6.6% presented with ulcerative CHSV,37 lymphoma.105 and CVZV has been reported as a complication in a In short, CHSV and CVZV infections are usually newborn with congenital varicella syndrome.100 encountered in HIV-infected patients, but copresentation with other types of immunosuppresRISK FACTORS sion are not uncommon. However, there is no clear HIV-infection is a major risk factor for CHSVz and correlation with the nature and degree of CVZV.x In a retrospective study including 18 HIV immunosuppression. patients with acyclovir (ACV)-resistant CVZV, the mean CD41 cell count was 20 3 106/L, and the mean number of previous HZ episodes was 1.53.83 CLINICAL ASPECTS However, there was no direct association between By definition, CHSV and CVZV infections persist the CD4-positive count and the occurrence of CHSV for at least 1 month, but infections lasting for and CVZV. months29,96 or even years46,94 are common. One On occasion, CHSI and CVSI occur in patients case of spontaneous healing has been reported.95 who are immunocompromised due to other condiThe clinical aspects are highly polymorphic, but tions, including organ transplantation, bone marrow two features predominate: vegetating or hyperkerad
d
d
d
d
*References 1, 3, 4, 23, 24, 26, 28, 30, 33, 35, 36, 67-81, 91-94. y References 5, 6, 8, 37, 41-43, 45-52, 54-59, 61-66, 82-87, 95-97. z References 5, 6, 23, 24, 26, 28, 30, 32, 33, 35, 37, 38, 41-43, 45, 46, 48-51, 54-56, 58, 59, 61-66, 91, 93-97. x References 1, 3, 4, 8, 36, 67-71, 73-87, 101.
totic lesions61 and erosive and/or ulcerative presentations42 (Figs 1-4). Both manifestations may occur simultaneously (see Fig 1).5,46,95 Transitions between k
References 7, 17, 18, 20-22, 25, 27, 29, 39, 44, 53, 60, 88, 102.
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Table I. The principal differences between CHSV and VZV skin infections CHSV infections
Clinical aspects Wart-like lesions Ulcerations No. of lesions Size of lesions Distribution of lesions Histologic aspects Type of infection Recurrences Immunohistochemistry First-line treatment TK antiviral resistance Risk of internal viral dissemination
CVZV infections
Rare Frequent Usually multiple lesions Small to extensive Predominantly anogenital areas; sometimes oral Hyperkeratotic (cutaneous), ulcerative (mucosal), or both Low-productive Frequent HSV late antigens in a cytoplasmic distribution Oral ACV 200 mg, 5 3/day, 1-2 weeks Very frequent Absent
Frequent Rare Usually a single lesion Small No preferential site Predominantly hyperkeratotic; rarely ulcerative Latency-mimicking VZV gene expression Unusual Predominant IE gene expression with reduced E and L gene expression Oral ACV 800 mg 5 3/day, 1-2 weeks Frequent Absent
ACV, Acyclovir; CHSV, chronic herpes simplex virus; CVZV, chronic varicella zoster virus; E, early; IE, immediate early; L, late; TK, thymidine kinase; VZV, varicella zoster virus.
the two presentations have been observed.48,59 In general, genital CHSV presents as a single lesion, but several large ulcerations are sometimes seen (see Fig 4).38 Orolabial CHSV typically presents as several small ulcerations.29 Perianal involvement (see Fig 4) usually manifests itself as multiple lesions,65 ranging from small ulcers to ulcerations of up to 50 cm2.30,38 Verrucous lesions may reach 4 to 5 cm in diameter (Figs 5 and 6). CHSV is likely to recur,34,37,58,59 whereas CVZV generally occurs as an isolated event. Wart-like CHSV is usually found on the skin,* whereas the ulcerative form nearly always involves the mucosa.y Occasionally, nodular lesions have been reported.48,51,105 Pyogenic granuloma-like lesions, prone to bleeding, may complicate genital ulcerative CHSV (Fig 3). Asymptomatic viral shedding may occur.5 Locoregional adenopathies are uncommon. CVZV predominantly presents as a localized infection, although disseminated wart-like lesions have been reported.z Ulcerative CVZV is uncommon.17,80
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 *References 14, 46, 48, 50, 51, 56-59, 61, 63, 64, 66. y References 5, 6, 14, 17, 23-25, 28-30, 32-34, 37-43, 49, 54, 59, 60, 62, 65, 86. z References 1, 3, 8, 67-71, 73, 74, 76-79, 81-88, 106.
penis,41,42,49,61,62 scrotum,48 as well as the anal and perianal areas.x 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 of CVZV is vascular rather than neural. As for HZ, dermatomal distribution of CVZV (Fig 7) has only been reported once.73
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 hyperkeratotic lesion, is the preferred method to diagnose CHSV and CVZV. Serial biopsies or sections are sometimes x
References 6, 23, 28, 33, 46, 51, 65, 66, 95, 97.
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Fig 1. Chronic hyperkeratotic and ulcerative herpes on the buttocks. 50,102
necessary. Formalin-fixed, paraffin-embedded material allows subsequent immunohistochemical (IHC), in situ hybridization (ISH), or polymerase chain reaction (PCR) methods for viral identification. For VZV, viral DNA should be searched for by ISH or PCR, and the antibody panel for IHC should ideally target immediate early (IE), early (E) and late (L) viral antigens, as viral gene expression may be incomplete in CVZV.36 For HSV, the search should combine HSV DNA detection and L protein production. HSV and VZV serology is not helpful in the diagnosis. Whenever possible, a viral culture should be obtained for identification and drug susceptibility testing.
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 ducreyi, extraintestinal Crohn’s disease, rectocolitis, and Behc¸et disease. Oral CHSV may mimic erythema multiforme107 or hyperplastic candidiasis.14,44 Pyogenic granulomaelike lesions should be differentiated from botryomycoma. Nodular indurations may suggest granulomatous reactions.
COMPLICATIONS HSV and VZV infections in immunocompromised patients may lead to serious morbidity and increased mortality rates.1-12 In contrast, neither HSV- nor VZVrelated internal dissemination nor any fatal cases have been reported in patients with CVZV and CHSV. Only two cases of cutaneous extension of CVZV
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Fig 2. Chronic herpes infection on the penile shaft, with pyogenic granulomaelike appearance.
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, and consequently some cultures may grow commensal organisms. Hyperpigmentation or hypopigmentation as well as scarring are commonly observed after healing.
HISTOLOGY Common mucocutaneous HSVand 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 into the dermis. Keratinocytes presenting cytopathic signs are only occasionally identified. The nuclei present a grayish hue, and Cowdry type A intranuclear inclusions may be observed. Swollen eosinophilic keratinocytes without signs of cytolysis are also seen. Usually, only a minor neutrophilic/lymphocytic inflammatory infiltrate underlies the lesions. Ulcerative lesions display varying degrees of epithelial ulceration. Keratinocytes with cytopathic effects are occasionally encountered at the borders of lesions. Now and then these borders assume a hyperkeratotic and hyperplastic aspect. Only IHC using specific anti-HSV-1, anti-HSV-2 and anti-VZV antibodies will allow discovery of viral antigens in keratinocytes without cytopathic effects.42,63,86,95 The IHC signal is usually nuclear and accessorily perinuclear instead of the predominantly membranous staining observed during the usual productive type of viral infection.86 The presence of HPV antigens or nucleic acids should be ruled out by IHC, ISH, or PCR.
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Fig 4. Extensive chronic ulcerative genital herpes.
TREATMENT Fig 3. Extensive chronic herpes involving gluteal region and back.
PATHOGENIC MECHANISMS The mechanism by which these viruses stimulate epithelial cell proliferation remains unclear. A genetic predisposition seems likely.98 An epidermal growth factoredependent 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 dendritic cells from providing interferon-alpha responses.96 Some authors have suggested that an immune recovery syndrome occurs during HAART, which provokes a hypersensitivity immune response.58 Altered viral gene expression patterns remain another possibility. Immediate early and late gene expression in 5 chronic verrucous VZV lesions, 4 full-blown herpes zoster vesicular lesions in HIV-infected persons, and 8 vesicular HZ lesions in immunocompetent individuals were semi-quantitatively assessed by using specific antibodies to the IE63, gE (L), and gB (L) proteins. All CVZV expressed IE63 in keratinocytes. However, gE expression was either weak or absent in keratinocytes of 3 verrucous lesions, and gB was either weak or absent in two. These results suggested that chronic VZV skin lesions are associated with diminished gE and gB expression. It was suggested that the VZV behavior in keratinocytes may vary from a latency-like state to a fully developed, productive infection.36 Another potential pathogenic pathway involves a semi-productive HSV infection, as has been suggested for chronic HSV glossitis.44
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.86,111-113 Relapses may be observed following initially successful outcomes with TK-dependent antiviral agents.27 Resistance is clearly linked to long-term ACV exposure, particularly suppressive ACV therapy for GH.110-112 Therefore, TK-dependent resistance is probably more prevalent in HSV patients than in HZ patients. Resistance has been attributed to a truncated and hence impaired or nonfunctional TK, or to the absence of TK production, rendering phosphorylization inefficacious.114 Altered viral DNA polymerase, causing decreased affinity to ACV, may be another mechanism of resistance. Initially, CHSV should be treated with oral ACV at a dose of 200 mg (5 3/d) for 1 to 2 weeks. In case of treatment resistance, the dose should be increased to 800 mg 5 times per day for 1 to 2 weeks. In patients with CVZV, the starting dose of ACV should be 800 mg 5 times per day for 1 to 2 weeks. If necessary, intravenous ACV (10 mg/kg every 8 hours for 1 to 2 weeks) can be considered for severe or extensive lesions or to overcome bioavailability issues. If no improvement is seen, the following treatment algorithm is recommended for CHSV and CVZV: another TK-dependent drug may be initiated, such as oral VCV (1000 mg, 3 3/d) or famciclovir (250-500 mg, 3 3/d) for 1 to 2 weeks. Even if these compounds are structurally similar and TK-dependent, a positive clinical response may sometimes be observed. If these options fail, one should move toward nonTK-dependent antivirals, including trifluorothymidine,114 foscarnet (a phosphonic acid derivative),38,58 *References 5, 12, 25, 28, 35, 38, 42, 45, 50, 56-59, 63, 96, 102, 110.
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Fig 5. Ulcerated, wart-like appearance of a single chronic VZV-infected lesion.
Fig 6. Chronic verrucous VZV lesions on the lip.
cidofovir (1-[(S)-3-hydroxy-2-(phosphonomethoxy) propyl] cytosine dihydrate),33,58 and vidarabine.114 These agents directly inhibit the pyrophosphate binding site of viral DNA polymerases. Topical agents include trifluorothymidine (1% ophthalmic solution, 1% cream, 3-4 3/d until healing), foscarnet (50% solution, at least 2 3/d as foscarnet has a short half-life), vidarabine114 (3% cream 5 3/d) and cidofovir (1%-3% ointment, 1%-3% cream, 0.3%-1.0% gel).33 The safety and efficacy of cidofovir 0.3% and 1.0% gel once daily for 5 days for treatment of ACV-resistant HSV infections in AIDS patients has been evaluated in a randomized, double-blind, placebo-controlled multicenter trial. Ten of 20 patients (50%) in the cidofovir group showed complete healing or a greater than 50% reduction of the lesion area, compared with none in the placebo group. Six patients (30%) in the cidofovir group healed completely. This study also revealed a median time to complete healing of 21 days. One in 4 patients experienced irritation at the application site.115 When extensive lesions are present, or if topical treatments fail, intravenous foscarnet114 (40 mg/kg, 3 3/d or 60 mg/kg, 2 3/d) can be administered. If foscarnet fails to achieve clinical healing, intravenous vidarabine (10-20 mg/kg/d, for 5-10 days)114 or
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Fig 7. Chronic hyperkeratotic VZV skin infection limited to the T5 and T6 dermatomes.
cidofovir (3-5 mg/kg/d, for 5-10 days, administered with probenecid) is recommended. Combination therapies are recommended if the aforementioned options fail.32 Combining topical cidofovir and foscarnet has proven efficacious.58 Imiquimod (5% cream), a topical inducer of endogenous interferon production, with or without cidofovir (1% cream) constitutes another therapeutic alternative.46,60,114 However, tolerance of imiquimod is often very poor. Surgery may be convenient for a single, small lesion that is not responding to other treatments.46,95,108,116 Cryosurgery is another solution for wart-like persistent VZV lesions.84 Treatment with oral thalidomide (100 mg, 2 3/d) was shown to be successful after only 1 week in an HIV-infected, HAART-receiving patient with VCV as well as cidofovir- and foscarnet-resistant CHSV.105 Thalidomide probably acts by immune-enhancing mechanisms, but others have reported treatment failure.108 The helicase-primase inhibitors exhibit potent antiviral properties and may constitute interesting compounds for the future for overcoming ACV resistance.117 Viral cultures are of interest for drug susceptibility testing. Unfortunately, either the test or the viral culture may not always be available, and therapeutic decisions will have to be made on clinical grounds only. As response to treatment is considerably slower than for common HSV and VZV infections, treatment failure due to antiviral resistance should not be suspected too soon.93 Furthermore, TK susceptibility is not a static process; it may vary over time and may even resolve, as has been observed in verrucous VZV lesions.86 Hence, reintroduction of antivirals that have previously failed can be considered.118 Whenever possible, episodic treatment of GH is preferable to long-term suppressive therapy to reduce the risk of developing resistance to TKdependent compounds. Table II provides a treatment algorithm for CHSV and CVZV infections.
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Table II. Treatment algorithm for CHSV and CVZV infections CHSV infections
First step Second step Third step Fourth step
Fifth step Sixth step Alternative steps
CVZV infections
Oral ACV: 200 mg, 5 3/day, 7-14 days Oral ACV: 800 mg, 5 3/day, 7-14 days Oral ACV: 800 mg, 7-14 days; intravenous Intravenous ACV: 10 mg/kg every ACV, 10 mg/kg every 8 hours, 7-14 days 8 hours, 7-14 days Oral FCV: 200-500 mg, 3 3/day, 7-14 days Oral VCV: 500-1000 mg, 7-14 days Topical foscarnet: [2 3/day; intravenous foscarnet 40 mg/kg every 8 hours; topical cidofovir: 3 to 43/day; intravenous cidofovir: 3-5 mg/kg; intravenous vidarabine: 10-20 mg/kg per day At least 1 to 2 weeks Combination therapies (topical, oral, intravenous) Reconsider earlier steps Surgical excision, cryosurgery, topical imiquimod, oral thalidomide
FCV, Famciclovir; for other abbreviations, see legend to Table I.
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, HSVleukoplakia 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 encephalitis,121 VZV-related chronic myelitis with chronic unilateral periauricular and facial pain,122 active chronic VZV infection with chronic radicular sacraldistribution pain, cervical-distribution zoster paresis, and thoracic-distribution myelopathy,123 chronic VZV ganglionitis-related postherpetic neuralgia,124 and chronic HSV-2 meningitis.125 TK-dependent antiviral resistance also frequently complicates extracutaneous HSV and VZV chronic infections.
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 anywhere on the skin. TK-dependent antivirals are recommended as first-line treatment. The common problem of TK-dependent resistance can
be overcome by using antiviral agents directly targeting viral DNA polymerase. Drug-susceptibility testing on viral cultures is helpful but rarely available. In contrast to common HSV and VZV infections in immunocompromised individuals, neither internal morbidity nor fatalities have ever been reported for CHSV and CVZV infections. The authors thank Professor Dr J. Frank and Dr M. Heitink, Maastricht University Medical Center, for Fig 7. REFERENCES 1. Jacobson MA, Berger TG, Fikrig S, Becherer P, Moohr JW, Stanat SC, et al. Acyclovir-resistant varicella zoster virus infection after chronic oral acyclovir therapy in patients with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1990;112:187-91. 2. Schubert MM. Oral manifestations of viral infections in immunocompromised patients. Curr Opin Dent 1991;1: 384-97. 3. Glesby MJ, Moore RD, Chaisson RE. Clinical spectrum of herpes zoster in adults infected with human immunodeficiency virus. Clin Infect Dis 1995;21:370-5. 4. Stewart JA, Reef SE, Pellett PE, Corey L, Whitley RJ. Herpesvirus infections in persons infected with human immunodeficiency virus. Clin Infect Dis 1995;21(Suppl. 1):S114-20. 5. Tyring SK, Carlton SS, Evans T. Herpes. Atypical clinical manifestations. Dermatol Clin 1998;16:783-8. 6. Brown TS, Callen JP. Atypical presentation of herpes simplex virus in a patient with chronic lymphocytic leukemia. Cutis 1999;64:123-5. 7. Koc Y, Miller KB, Schenkein DP, Griffith J, Akhtar M, DesJardin J, et al. Varicella zoster virus infections following allogeneic bone marrow transplantation: frequency, risk factors, and clinical outcome. Biol Blood Marrow Transplant 2000;6:44-9. 8. Zampogna JC, Flowers FP. Persistent verrucous varicella as the initial manifestation of HIV infection. J Am Acad Dermatol 2001;44:391-4. 9. Vafai A, Berger M. Zoster in patients infected with HIV: a review. Am J Med Sci 2001;321:372-80.
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INTRODUCTION Herpes simplex virus (HSV) and varicella zoster virus (VZV) belong to the a-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.1-12 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.10,11,14-19 Chronic HSV skin infections From the Department of Dermatology, University Hospital of Lie`ge. Funding sources: None. Conflicts of interest: None declared. Reprint requests: Arjen F. Nikkels, MD, PhD, Department of Dermatology, CHU of Sart Tilman, University of Lie`ge, B-4000 Lie`ge, Belgium. E-mail: [email protected]. Published online November 11, 2010. 0190-9622/$36.00 ª 2010 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2010.07.011
Abbreviations used: ACV: CHSV: CVZV: GH: HSV: HZ: IHC: ISH: PCR: VZV:
acyclovir chronic herpes simplex virus (infection) chronic varicella zoster virus (infection) genital herpes herpes simplex virus herpes zoster immunohistochemical in situ hybridization polymerase chain reaction varicella zoster virus
(CHSV)1,5,6,14,17,18,20-66 and chronic VZV skin infections (CVZV)1,3,7,8,17,36,67-88 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).
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, e217
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chronic infections, chronic genital herpes, chronic herpes labialis, chronic genital ulcerations, atypical herpes infections, verrucous herpes infections, hypertrophic herpes, thymidine kinaseedependent antiviral resistance, and herpes vegetans. A total of 125 publications were retrieved. An overwhelming majority of the clinical publications reached evidence level D (case reports or small case-series).
transplantation, hypogammaglobulinemia, chronic lymphocytic leukemia, hepatic cirrhosis resulting from chronic hepatitis C virus infection, and myeloproliferative disorders.k CHSV has been described in two patients with Wiskott-Aldrich syndrome presenting with a combined innate and acquired immune deficiency, particularly affecting the T-, B-, and NK-cell lines.25,39 CAPSULE SUMMARY Although chronic corticosteroid therapy is a recognized EPIDEMIOLOGY Chronic herpes simplex virus (CHSV) and risk factor for increased susThe prevalence of CHSV chronic varicella zoster virus (CVZV) skin ceptibility to cutaneous infecand CVZV infections is not infections are commonly associated with 103 only one report has tions, known. Most reported cases HIV infection. directly linked long-term oral have occurred in patients CHSV and CVZV infections present as steroid use to CHSV in a pawith HIV infection, supposwart-like lesions with or without tient with chronic lymphoedly as an adverse effect of ulcerations. cytic leukemia.6 immunosuppression.* Since CHSV and CVZV infecDiagnosis relies on histology, the introduction of highly actions are rare in apparently immunohistology, PCR and viral culture. tive antiretroviral therapy immunocompetent pa(HAART) in 1996, which alResistance to thymidine kinase (TK) 34,40,56,57 Genital CHSV tients. lowed restoration of immune dependent antivirals is not uncommon. may aggravate the clinical properties in HIV patients, a CHSV and CVZV infections are not a course of HIV infection.55 steady stream of publications significant risk for disseminated CVZV can occur in children on CHSVand CVZV infections cutaneous or systemic infection. following varicella1,8,77 or in has continued to add to the VZV-seropositive adult papublished literature.y In a cotients. Genital CHSV may occur after primary or hort of 1,700 HIV-infected patients, the observed 26,45 98 CHSV may develop despite prorecurrent GH. prevalence of CHSV infections was 4 cases (0.2%). 46 phylactic oral ACV therapy. There is no racial or gender predisposition. Similar to extensive HSV infection and HZ, Patients are typically adult, although cases of both 37,39 1,74,77,99 CHSV and CVZV infections are recognized indicaand CVZV, personal data have been CHSV tors of possible HIV infection.26,104 One case of reported in children. In a series of HIV-infected CVZV led to the discovery of peripheral T-cell children, 6.6% presented with ulcerative CHSV,37 lymphoma.105 and CVZV has been reported as a complication in a In short, CHSV and CVZV infections are usually newborn with congenital varicella syndrome.100 encountered in HIV-infected patients, but copresentation with other types of immunosuppresRISK FACTORS sion are not uncommon. However, there is no clear HIV-infection is a major risk factor for CHSVz and correlation with the nature and degree of CVZV.x In a retrospective study including 18 HIV immunosuppression. patients with acyclovir (ACV)-resistant CVZV, the mean CD41 cell count was 20 3 106/L, and the mean number of previous HZ episodes was 1.53.83 CLINICAL ASPECTS However, there was no direct association between By definition, CHSV and CVZV infections persist the CD4-positive count and the occurrence of CHSV for at least 1 month, but infections lasting for and CVZV. months29,96 or even years46,94 are common. One On occasion, CHSI and CVSI occur in patients case of spontaneous healing has been reported.95 who are immunocompromised due to other condiThe clinical aspects are highly polymorphic, but tions, including organ transplantation, bone marrow two features predominate: vegetating or hyperkerad
d
d
d
d
*References 1, 3, 4, 23, 24, 26, 28, 30, 33, 35, 36, 67-81, 91-94. y References 5, 6, 8, 37, 41-43, 45-52, 54-59, 61-66, 82-87, 95-97. z References 5, 6, 23, 24, 26, 28, 30, 32, 33, 35, 37, 38, 41-43, 45, 46, 48-51, 54-56, 58, 59, 61-66, 91, 93-97. x References 1, 3, 4, 8, 36, 67-71, 73-87, 101.
totic lesions61 and erosive and/or ulcerative presentations42 (Figs 1-4). Both manifestations may occur simultaneously (see Fig 1).5,46,95 Transitions between k
References 7, 17, 18, 20-22, 25, 27, 29, 39, 44, 53, 60, 88, 102.
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Table I. The principal differences between CHSV and VZV skin infections CHSV infections
Clinical aspects Wart-like lesions Ulcerations No. of lesions Size of lesions Distribution of lesions Histologic aspects Type of infection Recurrences Immunohistochemistry First-line treatment TK antiviral resistance Risk of internal viral dissemination
CVZV infections
Rare Frequent Usually multiple lesions Small to extensive Predominantly anogenital areas; sometimes oral Hyperkeratotic (cutaneous), ulcerative (mucosal), or both Low-productive Frequent HSV late antigens in a cytoplasmic distribution Oral ACV 200 mg, 5 3/day, 1-2 weeks Very frequent Absent
Frequent Rare Usually a single lesion Small No preferential site Predominantly hyperkeratotic; rarely ulcerative Latency-mimicking VZV gene expression Unusual Predominant IE gene expression with reduced E and L gene expression Oral ACV 800 mg 5 3/day, 1-2 weeks Frequent Absent
ACV, Acyclovir; CHSV, chronic herpes simplex virus; CVZV, chronic varicella zoster virus; E, early; IE, immediate early; L, late; TK, thymidine kinase; VZV, varicella zoster virus.
the two presentations have been observed.48,59 In general, genital CHSV presents as a single lesion, but several large ulcerations are sometimes seen (see Fig 4).38 Orolabial CHSV typically presents as several small ulcerations.29 Perianal involvement (see Fig 4) usually manifests itself as multiple lesions,65 ranging from small ulcers to ulcerations of up to 50 cm2.30,38 Verrucous lesions may reach 4 to 5 cm in diameter (Figs 5 and 6). CHSV is likely to recur,34,37,58,59 whereas CVZV generally occurs as an isolated event. Wart-like CHSV is usually found on the skin,* whereas the ulcerative form nearly always involves the mucosa.y Occasionally, nodular lesions have been reported.48,51,105 Pyogenic granuloma-like lesions, prone to bleeding, may complicate genital ulcerative CHSV (Fig 3). Asymptomatic viral shedding may occur.5 Locoregional adenopathies are uncommon. CVZV predominantly presents as a localized infection, although disseminated wart-like lesions have been reported.z Ulcerative CVZV is uncommon.17,80
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 *References 14, 46, 48, 50, 51, 56-59, 61, 63, 64, 66. y References 5, 6, 14, 17, 23-25, 28-30, 32-34, 37-43, 49, 54, 59, 60, 62, 65, 86. z References 1, 3, 8, 67-71, 73, 74, 76-79, 81-88, 106.
penis,41,42,49,61,62 scrotum,48 as well as the anal and perianal areas.x 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 of CVZV is vascular rather than neural. As for HZ, dermatomal distribution of CVZV (Fig 7) has only been reported once.73
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 hyperkeratotic lesion, is the preferred method to diagnose CHSV and CVZV. Serial biopsies or sections are sometimes x
References 6, 23, 28, 33, 46, 51, 65, 66, 95, 97.
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Fig 1. Chronic hyperkeratotic and ulcerative herpes on the buttocks. 50,102
necessary. Formalin-fixed, paraffin-embedded material allows subsequent immunohistochemical (IHC), in situ hybridization (ISH), or polymerase chain reaction (PCR) methods for viral identification. For VZV, viral DNA should be searched for by ISH or PCR, and the antibody panel for IHC should ideally target immediate early (IE), early (E) and late (L) viral antigens, as viral gene expression may be incomplete in CVZV.36 For HSV, the search should combine HSV DNA detection and L protein production. HSV and VZV serology is not helpful in the diagnosis. Whenever possible, a viral culture should be obtained for identification and drug susceptibility testing.
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 ducreyi, extraintestinal Crohn’s disease, rectocolitis, and Behc¸et disease. Oral CHSV may mimic erythema multiforme107 or hyperplastic candidiasis.14,44 Pyogenic granulomaelike lesions should be differentiated from botryomycoma. Nodular indurations may suggest granulomatous reactions.
COMPLICATIONS HSV and VZV infections in immunocompromised patients may lead to serious morbidity and increased mortality rates.1-12 In contrast, neither HSV- nor VZVrelated internal dissemination nor any fatal cases have been reported in patients with CVZV and CHSV. Only two cases of cutaneous extension of CVZV
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Fig 2. Chronic herpes infection on the penile shaft, with pyogenic granulomaelike appearance.
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, and consequently some cultures may grow commensal organisms. Hyperpigmentation or hypopigmentation as well as scarring are commonly observed after healing.
HISTOLOGY Common mucocutaneous HSVand 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 into the dermis. Keratinocytes presenting cytopathic signs are only occasionally identified. The nuclei present a grayish hue, and Cowdry type A intranuclear inclusions may be observed. Swollen eosinophilic keratinocytes without signs of cytolysis are also seen. Usually, only a minor neutrophilic/lymphocytic inflammatory infiltrate underlies the lesions. Ulcerative lesions display varying degrees of epithelial ulceration. Keratinocytes with cytopathic effects are occasionally encountered at the borders of lesions. Now and then these borders assume a hyperkeratotic and hyperplastic aspect. Only IHC using specific anti-HSV-1, anti-HSV-2 and anti-VZV antibodies will allow discovery of viral antigens in keratinocytes without cytopathic effects.42,63,86,95 The IHC signal is usually nuclear and accessorily perinuclear instead of the predominantly membranous staining observed during the usual productive type of viral infection.86 The presence of HPV antigens or nucleic acids should be ruled out by IHC, ISH, or PCR.
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Fig 4. Extensive chronic ulcerative genital herpes.
TREATMENT Fig 3. Extensive chronic herpes involving gluteal region and back.
PATHOGENIC MECHANISMS The mechanism by which these viruses stimulate epithelial cell proliferation remains unclear. A genetic predisposition seems likely.98 An epidermal growth factoredependent 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 dendritic cells from providing interferon-alpha responses.96 Some authors have suggested that an immune recovery syndrome occurs during HAART, which provokes a hypersensitivity immune response.58 Altered viral gene expression patterns remain another possibility. Immediate early and late gene expression in 5 chronic verrucous VZV lesions, 4 full-blown herpes zoster vesicular lesions in HIV-infected persons, and 8 vesicular HZ lesions in immunocompetent individuals were semi-quantitatively assessed by using specific antibodies to the IE63, gE (L), and gB (L) proteins. All CVZV expressed IE63 in keratinocytes. However, gE expression was either weak or absent in keratinocytes of 3 verrucous lesions, and gB was either weak or absent in two. These results suggested that chronic VZV skin lesions are associated with diminished gE and gB expression. It was suggested that the VZV behavior in keratinocytes may vary from a latency-like state to a fully developed, productive infection.36 Another potential pathogenic pathway involves a semi-productive HSV infection, as has been suggested for chronic HSV glossitis.44
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.86,111-113 Relapses may be observed following initially successful outcomes with TK-dependent antiviral agents.27 Resistance is clearly linked to long-term ACV exposure, particularly suppressive ACV therapy for GH.110-112 Therefore, TK-dependent resistance is probably more prevalent in HSV patients than in HZ patients. Resistance has been attributed to a truncated and hence impaired or nonfunctional TK, or to the absence of TK production, rendering phosphorylization inefficacious.114 Altered viral DNA polymerase, causing decreased affinity to ACV, may be another mechanism of resistance. Initially, CHSV should be treated with oral ACV at a dose of 200 mg (5 3/d) for 1 to 2 weeks. In case of treatment resistance, the dose should be increased to 800 mg 5 times per day for 1 to 2 weeks. In patients with CVZV, the starting dose of ACV should be 800 mg 5 times per day for 1 to 2 weeks. If necessary, intravenous ACV (10 mg/kg every 8 hours for 1 to 2 weeks) can be considered for severe or extensive lesions or to overcome bioavailability issues. If no improvement is seen, the following treatment algorithm is recommended for CHSV and CVZV: another TK-dependent drug may be initiated, such as oral VCV (1000 mg, 3 3/d) or famciclovir (250-500 mg, 3 3/d) for 1 to 2 weeks. Even if these compounds are structurally similar and TK-dependent, a positive clinical response may sometimes be observed. If these options fail, one should move toward nonTK-dependent antivirals, including trifluorothymidine,114 foscarnet (a phosphonic acid derivative),38,58 *References 5, 12, 25, 28, 35, 38, 42, 45, 50, 56-59, 63, 96, 102, 110.
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Fig 5. Ulcerated, wart-like appearance of a single chronic VZV-infected lesion.
Fig 6. Chronic verrucous VZV lesions on the lip.
cidofovir (1-[(S)-3-hydroxy-2-(phosphonomethoxy) propyl] cytosine dihydrate),33,58 and vidarabine.114 These agents directly inhibit the pyrophosphate binding site of viral DNA polymerases. Topical agents include trifluorothymidine (1% ophthalmic solution, 1% cream, 3-4 3/d until healing), foscarnet (50% solution, at least 2 3/d as foscarnet has a short half-life), vidarabine114 (3% cream 5 3/d) and cidofovir (1%-3% ointment, 1%-3% cream, 0.3%-1.0% gel).33 The safety and efficacy of cidofovir 0.3% and 1.0% gel once daily for 5 days for treatment of ACV-resistant HSV infections in AIDS patients has been evaluated in a randomized, double-blind, placebo-controlled multicenter trial. Ten of 20 patients (50%) in the cidofovir group showed complete healing or a greater than 50% reduction of the lesion area, compared with none in the placebo group. Six patients (30%) in the cidofovir group healed completely. This study also revealed a median time to complete healing of 21 days. One in 4 patients experienced irritation at the application site.115 When extensive lesions are present, or if topical treatments fail, intravenous foscarnet114 (40 mg/kg, 3 3/d or 60 mg/kg, 2 3/d) can be administered. If foscarnet fails to achieve clinical healing, intravenous vidarabine (10-20 mg/kg/d, for 5-10 days)114 or
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Fig 7. Chronic hyperkeratotic VZV skin infection limited to the T5 and T6 dermatomes.
cidofovir (3-5 mg/kg/d, for 5-10 days, administered with probenecid) is recommended. Combination therapies are recommended if the aforementioned options fail.32 Combining topical cidofovir and foscarnet has proven efficacious.58 Imiquimod (5% cream), a topical inducer of endogenous interferon production, with or without cidofovir (1% cream) constitutes another therapeutic alternative.46,60,114 However, tolerance of imiquimod is often very poor. Surgery may be convenient for a single, small lesion that is not responding to other treatments.46,95,108,116 Cryosurgery is another solution for wart-like persistent VZV lesions.84 Treatment with oral thalidomide (100 mg, 2 3/d) was shown to be successful after only 1 week in an HIV-infected, HAART-receiving patient with VCV as well as cidofovir- and foscarnet-resistant CHSV.105 Thalidomide probably acts by immune-enhancing mechanisms, but others have reported treatment failure.108 The helicase-primase inhibitors exhibit potent antiviral properties and may constitute interesting compounds for the future for overcoming ACV resistance.117 Viral cultures are of interest for drug susceptibility testing. Unfortunately, either the test or the viral culture may not always be available, and therapeutic decisions will have to be made on clinical grounds only. As response to treatment is considerably slower than for common HSV and VZV infections, treatment failure due to antiviral resistance should not be suspected too soon.93 Furthermore, TK susceptibility is not a static process; it may vary over time and may even resolve, as has been observed in verrucous VZV lesions.86 Hence, reintroduction of antivirals that have previously failed can be considered.118 Whenever possible, episodic treatment of GH is preferable to long-term suppressive therapy to reduce the risk of developing resistance to TKdependent compounds. Table II provides a treatment algorithm for CHSV and CVZV infections.
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Table II. Treatment algorithm for CHSV and CVZV infections CHSV infections
First step Second step Third step Fourth step
Fifth step Sixth step Alternative steps
CVZV infections
Oral ACV: 200 mg, 5 3/day, 7-14 days Oral ACV: 800 mg, 5 3/day, 7-14 days Oral ACV: 800 mg, 7-14 days; intravenous Intravenous ACV: 10 mg/kg every ACV, 10 mg/kg every 8 hours, 7-14 days 8 hours, 7-14 days Oral FCV: 200-500 mg, 3 3/day, 7-14 days Oral VCV: 500-1000 mg, 7-14 days Topical foscarnet: [2 3/day; intravenous foscarnet 40 mg/kg every 8 hours; topical cidofovir: 3 to 43/day; intravenous cidofovir: 3-5 mg/kg; intravenous vidarabine: 10-20 mg/kg per day At least 1 to 2 weeks Combination therapies (topical, oral, intravenous) Reconsider earlier steps Surgical excision, cryosurgery, topical imiquimod, oral thalidomide
FCV, Famciclovir; for other abbreviations, see legend to Table I.
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, HSVleukoplakia 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 encephalitis,121 VZV-related chronic myelitis with chronic unilateral periauricular and facial pain,122 active chronic VZV infection with chronic radicular sacraldistribution pain, cervical-distribution zoster paresis, and thoracic-distribution myelopathy,123 chronic VZV ganglionitis-related postherpetic neuralgia,124 and chronic HSV-2 meningitis.125 TK-dependent antiviral resistance also frequently complicates extracutaneous HSV and VZV chronic infections.
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 anywhere on the skin. TK-dependent antivirals are recommended as first-line treatment. The common problem of TK-dependent resistance can
be overcome by using antiviral agents directly targeting viral DNA polymerase. Drug-susceptibility testing on viral cultures is helpful but rarely available. In contrast to common HSV and VZV infections in immunocompromised individuals, neither internal morbidity nor fatalities have ever been reported for CHSV and CVZV infections. The authors thank Professor Dr J. Frank and Dr M. Heitink, Maastricht University Medical Center, for Fig 7. REFERENCES 1. Jacobson MA, Berger TG, Fikrig S, Becherer P, Moohr JW, Stanat SC, et al. Acyclovir-resistant varicella zoster virus infection after chronic oral acyclovir therapy in patients with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1990;112:187-91. 2. Schubert MM. Oral manifestations of viral infections in immunocompromised patients. Curr Opin Dent 1991;1: 384-97. 3. Glesby MJ, Moore RD, Chaisson RE. Clinical spectrum of herpes zoster in adults infected with human immunodeficiency virus. Clin Infect Dis 1995;21:370-5. 4. Stewart JA, Reef SE, Pellett PE, Corey L, Whitley RJ. Herpesvirus infections in persons infected with human immunodeficiency virus. Clin Infect Dis 1995;21(Suppl. 1):S114-20. 5. Tyring SK, Carlton SS, Evans T. Herpes. Atypical clinical manifestations. Dermatol Clin 1998;16:783-8. 6. Brown TS, Callen JP. Atypical presentation of herpes simplex virus in a patient with chronic lymphocytic leukemia. Cutis 1999;64:123-5. 7. Koc Y, Miller KB, Schenkein DP, Griffith J, Akhtar M, DesJardin J, et al. Varicella zoster virus infections following allogeneic bone marrow transplantation: frequency, risk factors, and clinical outcome. Biol Blood Marrow Transplant 2000;6:44-9. 8. Zampogna JC, Flowers FP. Persistent verrucous varicella as the initial manifestation of HIV infection. J Am Acad Dermatol 2001;44:391-4. 9. Vafai A, Berger M. Zoster in patients infected with HIV: a review. Am J Med Sci 2001;321:372-80.
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